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"abstract": "BACKGROUND Laryngeal sarcoidosis is a rare extrapulmonary manifestation of sarcoidosis, accounting for 0.33-2.1% of cases. A life-threatening complication of laryngeal sarcoidosis is upper airway obstruction. In this report we describe our experience in the acute and chronic care of a patient who required an emergent tracheostomy, with the aim to provide further insight into this difficult to manage disease. CASE REPORT A 37-year-old African American female with a 10-year history of stage 1 sarcoidosis presented with severe dyspnea. Laryngeal sarcoidosis was diagnosed three years previously, and she remained stable on low-dose prednisone until six months prior to admission, at which time she self-discontinued her prednisone for the homeopathic treatment Nopalea cactus juice. Her physical examination was concerning for impending respiratory failure as she presented with inspiratory stridor and hoarseness. Laryngoscopy showed a retroflexed epiglottis obstructing the glottis with edematous arytenoids and aryepiglottic folds. Otolaryngology performed an emergent tracheostomy to secure her airway and obtained epiglottic biopsies, which were consistent with sarcoidosis. She was eventually discharged home on prednisone 60 mg daily. Following months of corticosteroids, a laryngoscopy showed the epiglottis continuing to obstruct the glottis. The addition of methotrexate to a tapered dosage of prednisone 10 mg daily was unsuccessful, and she remains on prednisone 20 mg daily for disease control. CONCLUSIONS Laryngeal sarcoidosis, a rare extrapulmonary manifestation of sarcoidosis, uncommonly presents as the life-threatening complication of complete upper airway obstruction. As such, laryngeal sarcoidosis is associated with significant morbidity and mortality, requiring a high index of suspicion for timely diagnosis and treatment.",
"affiliations": "Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA.;Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA.;Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA.;Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.;Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA.",
"authors": "Ryu|Changwan|C|;Herzog|Erica L|EL|;Pan|Hongyi|H|;Homer|Robert|R|;Gulati|Mridu|M|",
"chemical_list": "D005938:Glucocorticoids; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.902231",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "18()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D000402:Airway Obstruction; D004630:Emergencies; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007818:Laryngeal Diseases; D007828:Laryngoscopy; D011241:Prednisone; D012507:Sarcoidosis; D014139:Tracheostomy; D016896:Treatment Outcome",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "157-159",
"pmc": null,
"pmid": "28190872",
"pubdate": "2017-02-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18032765;20147594;12150382;26392860;17681462;20231642;25363223;16478657;20617327",
"title": "Upper Airway Obstruction Requiring Emergent Tracheostomy Secondary to Laryngeal Sarcoidosis: A Case Report.",
"title_normalized": "upper airway obstruction requiring emergent tracheostomy secondary to laryngeal sarcoidosis a case report"
} | [
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"companynumb": "US-ACCORD-048693",
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"occurcountry": "US",
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"abstract": "We describe a 21-month-old male with relapsed clear cell sarcoma of the kidney receiving enteral nutrition who experienced recurrent, ketotic hypoglycemia. During relapse therapy, he had recurrent hypoglycemia episodes, in the setting of hematochezia and diarrhea. Evaluation revealed low carnitine levels. He received supplementation with oral levocarnitine throughout the remainder of treatment, resulting in normalization of serum carnitine levels and no further hypoglycemia. We believe adverse effects of the chemotherapy on his single kidney and gastrointestinal insult resulted in hypoglycemia and carnitine deficiency. Our case highlights that carnitine deficiency should be considered when acute onset hypoglycemia without obvious cause occurs.",
"affiliations": "Department of Pediatrics Department of Pediatrics, Division of Genetics, Walter Reed National Military Medical Center Department of Patient Services, National Institutes of Health, Bethesda, MD.",
"authors": "Vasta|Lauren M|LM|;Reynolds|Sarah M|SM|;Sami|Seppideh|S|;Schacht|John P|JP|;Emerick|Jill E|JE|;Parekh|Dina S|DS|;Vogt|Karen S|KS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000002128",
"fulltext": null,
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"issn_linking": "1077-4114",
"issue": null,
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "9505928",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33661167",
"pubdate": "2021-03-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hypoglycemia Due to Acquired Carnitine Deficiency in a Pediatric Patient Receiving Chemotherapy.",
"title_normalized": "hypoglycemia due to acquired carnitine deficiency in a pediatric patient receiving chemotherapy"
} | [
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"companynumb": "US-CADILA HEALTHCARE LIMITED-US-ZYDUS-078851",
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"abstract": "Sebaceous carcinoma is a very rare and potentially aggressive carcinoma originating from the epithelial lining of the sebaceous gland. More than 70% of all cases are in the head and neck region, especially the periorbita; therefore, they are classified into ocular and extraocular sebaceous carcinoma. The reported risk factors are advanced age, male sex, previous irradiation, and genetic predisposition for Muir-Torre syndrome. The current case is of sebaceous carcinoma found in the suprapubic area of a 67-year-old male patient who had received liver transplantation 6 years before, and had been receiving oral tacrolimus. Examination of the gastrointestinal system did not reveal any other malignancies. Although nonmelanoma skin cancers may occur as a complication after liver transplantation, there have been no previous reports of sebaceous carcinoma after liver transplantation. Furthermore, the sebaceous carcinoma in this case occurred in an uncommon location. We report this case along with a review of the literature.",
"affiliations": "Department of Plastic and Reconstructive Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Plastic and Reconstructive Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Plastic and Reconstructive Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Plastic and Reconstructive Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea.",
"authors": "Seo|Bommie F|BF|;Jung|Hyun Wook|HW|;Choi|Ik Kyun|IK|;Rhie|Jong Won|JW|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5021/ad.2014.26.3.395",
"fulltext": "\n==== Front\nAnn DermatolAnn DermatolADAnnals of Dermatology1013-90872005-3894Korean Dermatological Association; The Korean Society for Investigative Dermatology 10.5021/ad.2014.26.3.395Case ReportSebaceous Carcinoma of the Suprapubic Area in a Liver Transplant Recipient Seo Bommie F. Jung Hyun Wook Choi Ik Kyun Rhie Jong Won Department of Plastic and Reconstructive Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea.\nCorresponding author: Jong Won Rhie, Department of Plastic and Reconstructive Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Korea. Tel: 82-2-2258-2842, Fax: 82-2-594-7230, rhie@catholic.ac.kr6 2014 12 6 2014 26 3 395 398 22 6 2013 11 10 2013 16 10 2013 Copyright © 2014 The Korean Dermatological Association and The Korean Society for Investigative Dermatology2014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Sebaceous carcinoma is a very rare and potentially aggressive carcinoma originating from the epithelial lining of the sebaceous gland. More than 70% of all cases are in the head and neck region, especially the periorbita; therefore, they are classified into ocular and extraocular sebaceous carcinoma. The reported risk factors are advanced age, male sex, previous irradiation, and genetic predisposition for Muir-Torre syndrome. The current case is of sebaceous carcinoma found in the suprapubic area of a 67-year-old male patient who had received liver transplantation 6 years before, and had been receiving oral tacrolimus. Examination of the gastrointestinal system did not reveal any other malignancies. Although nonmelanoma skin cancers may occur as a complication after liver transplantation, there have been no previous reports of sebaceous carcinoma after liver transplantation. Furthermore, the sebaceous carcinoma in this case occurred in an uncommon location. We report this case along with a review of the literature.\n\nLiver transplantationPubicSebaceous carcinomaSkin neoplasms\n==== Body\nINTRODUCTION\nSebaceous carcinoma is a rare, potentially aggressive cutaneous malignancy that differentiates from the epithelial lining of the sebaceous gland1,2,3. It predominantly occurs in the periocular region, and masquerades as other benign or malignant lesions, leading to a delayed diagnosis4. More than 70% of sebaceous carcinomas occur in the head and neck region, with other areas of occurrence being the skin of the trunk, upper limb and shoulder, lower limb and hip, genitalia, and descending colon2.\n\nThe reported risk factors include advanced age, history of irradiation to the head and neck, and a genetic predisposition for Muir-Torre syndrome (MTS) or possibly familial retinoblastoma3,5. There have been several reports of sebaceous carcinoma occurring after kidney transplantation6,7. The pathogenesis of sebaceous carcinoma is thought to be related to immunosuppression, through changes either in host immunity or via independent mechanisms involving the immunosuppressant drug. Calcineurin inhibitors may enhance tumor development independent of host immunity8.\n\nHerein, we describe a unique case of a solitary sebaceous carcinoma occurring in a patient who underwent liver transplantation, with a review of the literature.\n\nCASE REPORT\nA 67-year-old male patient presented with a protruding suprapubic mass in the upper margin of his pubic hair. The lesion had started as a small nodule 1.5 years before, and the punch biopsy performed 2 weeks before his presentation led to a diagnosis of sebaceous epithelioma. He had undergone cadaveric donor liver transplantation 6 years before for hepatocellular carcinoma and liver cirrhosis owing to type C hepatitis. He was receiving oral tacrolimus as an outpatient.\n\nOn physical examination, a round, protruding sessile mass with a 3-cm diameter was observed at the cranial region of the pubic hair. The mass was pinkish with uneven purplish areas and ulcerated on its right upper surface. It was well circumscribed, rubbery, and movable, with the base easily palpable deep in the skin. The patient did not report any pain. No tenderness or signs of surrounding infection were noted (Fig. 1).\n\nComputed tomography of the pelvic area revealed an oval fat-containing skin nodule measuring 2 cm in diameter, in the left lower abdominal wall (Fig. 2). The patient refused magnetic resonance imaging because of cost issues.\n\nThe excision was performed with the patient in supine position, as an elliptical incision line with a horizontal axis distanced at the closest 5-mm margin from the mass to prevent dog-ear deformity when excising along the suprapubic area. Full-thickness skin incision and dissection of the mass from the surrounding subcutaneous tissues were performed with the patient under local anesthesia. The mass was well circumscribed and rubbery, and no particular increase in surrounding vascularity was noted (Fig. 3). Further excision was not performed because of the preoperative biopsy results of sebaceous epithelioma and the well-defined characteristics of the mass.\n\nHistopathological analysis revealed a multilobular tumor composed of basaloid cells at the periphery of lobules, with vacuolated cells presenting sebaceous differentiation in its central area. The tumor was well encapsulated and mostly well differentiated, but showed an area of regional matrix invasion. This portion showed an increase in the number of basaloid cells, nuclear atypism, and a decrease in sebocyte differentiation (Fig. 4). Histopathological findings suggested a diagnosis of sebaceous carcinoma.\n\nExaminations of the gastrointestinal tract, including endoscopy and colonoscopy, were performed to search for additional visceral tumors and rule out the possibility of MTS. Positron emission topography was also performed, and no underlying malignancies were detected in any of these evaluations. Radiation therapy with a total dose of 54 Gy was delivered in 27 fractions as an adjuvant therapy after surgery. The patient was followed-up for 6 months after the operation, with no evidence of recurrence. Short-term follow-up is still being performed.\n\nDISCUSSION\nSebaceous carcinoma is a rare, potentially aggressive cutaneous malignancy1,2. It usually occurs in the periocular region where there is an abundance of sebaceous glands, and has a diverse spectrum of clinical presentations that delay diagnosis9. The most common finding is a gradually enlarging, firm nodule10. Histopathological examination is the only definitive diagnostic method for sebaceous carcinoma. The disease is classified as either ocular or extraocular depending on the location of the primary lesion, with extraocular lesions accounting for 25% of the total cases. These 2 tumor types are known to have a similar prognosis2.\n\nReported risk factors include advanced age, history of irradiation to the head and neck, and possibly familial retinoblastoma. Furthermore, sebaceous carcinoma is commonly associated with a genetic predisposition for MTS, an autosomal dominant hereditary disease characterized by the association of a skin tumor of sebaceous lineage, with or without a keratoacanthoma associated with one or more visceral neoplasms3,5. Several cases have been reported after kidney transplantation and immunosuppression6,7.\n\nThe pathogenesis of sebaceous carcinoma occurring in other reported organ transplant recipients is thought to be through the somatic mutation of deoxyribonucleic acid (DNA) mismatch repair genes due to the effects of immunosuppressants. Some recipients may have had undetected MTS that is unmasked by the use of immunosuppressants. An association between microsatellite instability and sebaceous carcinoma in immunosuppressed patients who underwent organ transplantation and who do not have MTS has been suggested11. Kaminska et al.7 reported a case of sebaceous carcinoma mixed with sebaceous adenoma after kidney transplantation, suggesting the possibility of a sebaceous adenoma-sebaceous carcinoma neoplastic sequence. The present patient also had a specimen consisting mostly of well-differentiated sebaceous gland-forming sebocytes, with a focal region of infiltrative growth, mitotic figures, pleomorphic nuclei, and atypia, all of which may implicate a similar pathological sequence.\n\nThe patient in this report was a liver transplant recipient and had been receiving oral tacrolimus, a calcineurin inhibitor related to enhanced tumor development. Immunosuppressive drugs reduce immune surveillance and some even exert a carcinogenic effect. Cyclosporine and tacrolimus are calcineurin inhibitors, and have been hypothesized to increase tumor growth through the increase of transforming growth factor (TGF)-β, and interleukin-6, and by accelerating angiogenesis through elevated levels of vascular endothelial growth factor12. Maluccio et al.13 found that tacrolimus has a dose-dependent effect on tumor progression and TGF-β1 expression in mice. TGF-β1 is a multifunctional cytokine related to tumor invasiveness and metastatic progression.\n\nIn Western countries, the most frequently diagnosed malignancy after liver transplantation is nonmelanoma skin cancer (NMSC)14. However, Asians have a lower incidence of skin cancer in the general population, and a relatively low incidence of NMSC after organ transplantations. Stomach cancer, followed by colorectal cancer, was the most frequently observed de novo malignancy after liver transplantation in the Korean population, in a study reported by Park et al.15. De novo sebaceous carcinoma occurring in a liver transplant recipient has never been reported in the literature.\n\nThe mainstay treatment for sebaceous carcinoma consists of wide excisions with margins of 5 to 6 mm and frozen section control to confirm sufficient margins16. There have been no reports on the difference of safety margins between ocular and extraocular sebaceous lesions. Mohs micrographic surgery has been considered a useful method by some authors16. Radiation therapy is used in medically inoperable patients; however, the optimal dosage has not been established. Some reports suggest that radiotherapy is useful in controlling microscopic disease, as an adjuvant therapy17. The clinical utility of sentinel node biopsy has not been established18.\n\nThere have been several reports of sebaceous carcinoma occurring after kidney transplantation, but none in a liver transplant recipient. Sebaceous carcinoma should always be considered when a patient presents with a newly noticed skin lesion after any organ transplantation.\n\nFig. 1 A pink, well-circumscribed suprapubic mass with a diameter of 3 cm. Ulceration is seen on its right upper surface.\n\nFig. 2 Computed tomography showing a well-defined mass in the skin of the lower abdominal wall.\n\nFig. 3 The specimen after excision with 5-mm margins.\n\nFig. 4 Histopathological findings. (A) The well-differentiated areas show small lobular aggregations of sebocytes (H&E, ×40). (B) The margins consist of basaloid cells and the central portions are fully differentiated vacuolated sebocytes, as in normal sebaceous glands (H&E, ×400). (C) Poorly differentiated areas have high cellularity and invasion into the surrounding tissue (H&E, ×40). (D) Atypism (nuclear pleomorphism, prominent nucleoli, high nucleus-to-cell ratio) is seen, and mitosis is observed, with almost no differentiation into normal sebocytes (H&E, ×400).\n==== Refs\n1 Jo MS Kwon KH Shin HK Choe J Jang TJ Sebaceous carcinoma arising from the nevus sebaceous Arch Plast Surg 2012 39 431 433 22872851 \n2 Dasgupta T Wilson LD Yu JB A retrospective review of 1349 cases of sebaceous carcinoma Cancer 2009 115 158 165 18988294 \n3 Chao AN Shields CL Krema H Shields JA Outcome of patients with periocular sebaceous gland carcinoma with and without conjunctival intraepithelial invasion Ophthalmology 2001 108 1877 1883 11581065 \n4 Sakol PJ Simons KB McFadden PW Harris GJ Massaro BM Koethe S DNA flow cytometry of sebaceous cell carcinomas of the ocular adnexa: introduction to the technique in the evaluation of periocular tumors Ophthal Plast Reconstr Surg 1992 8 77 87 \n5 Kivelä T Asko-Seljavaara S Pihkala U Hovi L Heikkonen J Sebaceous carcinoma of the eyelid associated with retinoblastoma Ophthalmology 2001 108 1124 1128 11382640 \n6 Harwood CA McGregor JM Swale VJ Proby CM Leigh IM Newton R High frequency and diversity of cutaneous appendageal tumors in organ transplant recipients J Am Acad Dermatol 2003 48 401 408 12637920 \n7 Kaminska EC Iyengar V Tsoukas M Shea CR Borderline sebaceous neoplasm in a renal transplant patient without Muir-Torre syndrome J Cutan Pathol 2013 40 336 340 23174034 \n8 Euvrard S Morelon E Rostaing L Goffin E Brocard A Tromme I TUMORAPA Study Group Sirolimus and secondary skin-cancer prevention in kidney transplantation N Engl J Med 2012 367 329 339 22830463 \n9 Gaskin BJ Fernando BS Sullivan CA Whitehead K Sullivan TJ The significance of DNA mismatch repair genes in the diagnosis and management of periocular sebaceous cell carcinoma and Muir-Torre syndrome Br J Ophthalmol 2011 95 1686 1690 21979897 \n10 Nelson BR Hamlet KR Gillard M Railan D Johnson TM Sebaceous carcinoma J Am Acad Dermatol 1995 33 1 15 quiz 16-18 7601925 \n11 Harwood CA Swale VJ Bataille VA Quinn AG Ghali L Patel SV An association between sebaceous carcinoma and microsatellite instability in immunosuppressed organ transplant recipients J Invest Dermatol 2001 116 246 253 11180000 \n12 Guba M Graeb C Jauch KW Geissler EK Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation Transplantation 2004 77 1777 1782 15223891 \n13 Maluccio M Sharma V Lagman M Vyas S Yang H Li B Tacrolimus enhances transforming growth factor-beta1 expression and promotes tumor progression Transplantation 2003 76 597 602 12923450 \n14 Euvrard S Kanitakis J Claudy A Skin cancers after organ transplantation N Engl J Med 2003 348 1681 1691 12711744 \n15 Park HW Hwang S Ahn CS Kim KH Moon DB Ha TY De novo malignancies after liver transplantation: incidence comparison with the Korean cancer registry Transplant Proc 2012 44 802 805 22483500 \n16 Buitrago W Joseph AK Sebaceous carcinoma: the great masquerader: emgerging concepts in diagnosis and treatment Dermatol Ther 2008 21 459 466 19076624 \n17 Hata M Koike I Omura M Maegawa J Ogino I Inoue T Noninvasive and curative radiation therapy for sebaceous carcinoma of the eyelid Int J Radiat Oncol Biol Phys 2012 82 605 611 21300468 \n18 Sawyer AR McGoldrick RB Mackey S Powell B Pohl M Should extraocular sebaceous carcinoma be investigated using sentinel node biopsy? Dermatol Surg 2009 35 704 708 19415798\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1013-9087",
"issue": "26(3)",
"journal": "Annals of dermatology",
"keywords": "Liver transplantation; Pubic; Sebaceous carcinoma; Skin neoplasms",
"medline_ta": "Ann Dermatol",
"mesh_terms": null,
"nlm_unique_id": "8916577",
"other_id": null,
"pages": "395-8",
"pmc": null,
"pmid": "24966643",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports",
"references": "1520661;11382640;22830463;23174034;7601925;21979897;12637920;19076624;19415798;22872851;11581065;21300468;11180000;15223891;12923450;12711744;18988294;22483500",
"title": "Sebaceous carcinoma of the suprapubic area in a liver transplant recipient.",
"title_normalized": "sebaceous carcinoma of the suprapubic area in a liver transplant recipient"
} | [
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"companynumb": "KR-ACCORD-024674",
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"abstract": "Common polygenic skin disorders, such as atopic dermatitis, may rarely present in a segmental or linear distribution due to cutaneous mosaicism. Only seven cases of superimposed linear atopic dermatitis have been reported to date. Here, we present a child with severe superimposed linear atopic dermatitis and highlight the first successful use of dupilumab in its treatment.",
"affiliations": "Division of Dermatology and Dermatologic Surgery, Department of Internal Medicine, Dell Medical School at The University of Texas, Austin, TX, USA.;Division of Dermatology and Dermatologic Surgery, Department of Internal Medicine, Dell Medical School at The University of Texas, Austin, TX, USA.;Transitional Year Program, Dell Medical School at The University of Texas at Austin, Austin, TX, USA.;Division of Dermatology and Dermatologic Surgery, Department of Internal Medicine, Dell Medical School at The University of Texas, Austin, TX, USA.;Division of Dermatology and Dermatologic Surgery, Department of Internal Medicine, Dell Medical School at The University of Texas, Austin, TX, USA.",
"authors": "Leszczynska|Maria A|MA|https://orcid.org/0000-0002-4965-0050;Trainor|Megan A|MA|;Henkel|Emily|E|;Keeling|Brett H|BH|;Diaz|Lucia Z|LZ|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C582203:dupilumab",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14695",
"fulltext": null,
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"issn_linking": "0736-8046",
"issue": "38(5)",
"journal": "Pediatric dermatology",
"keywords": "atopic dermatitis; dupilumab; pruritus; therapy-systemic",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000279:Administration, Cutaneous; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D003876:Dermatitis, Atopic; D004485:Eczema; D006801:Humans; D016896:Treatment Outcome",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "1377-1378",
"pmc": null,
"pmid": "34272754",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Superimposed linear atopic dermatitis treated with dupilumab.",
"title_normalized": "superimposed linear atopic dermatitis treated with dupilumab"
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"abstract": "Atraumatic splenic rupture is a rare but potentially life-threatening event. It mostly happens when the spleen is already diseased; however, sometimes it can be drug induced in a previously normal spleen. Although anticoagulation has been attributed to spontaneous splenic rupture quite frequently, the role of dual antiplatelet therapy is underestimated. We report a case of an 80-year-old woman who developed spontaneous splenic rupture 4 weeks after starting dual antiplatelet therapy.\nAtraumatic or spontaneous splenic rupture can be life threatening.Various drugs, including granulocyte colony-stimulating factors (GCSF) and anticoagulants, can result in atraumatic splenic rupture in a previously normal spleen.Dual antiplatelet therapy can also cause splenic rupture in a previously normal spleen. It can occur as early as a few weeks after initiation of treatment.",
"affiliations": "Doncaster Royal Infirmary, Doncaster, United Kingdom.;Doncaster Royal Infirmary, Doncaster, United Kingdom.;Doncaster Royal Infirmary, Doncaster, United Kingdom.;Doncaster Royal Infirmary, Doncaster, United Kingdom.;Doncaster Royal Infirmary, Doncaster, United Kingdom.",
"authors": "Arshad|Muhammad Fahad|MF|;Javed|Nasir|N|;Karim|Syed Monawer|SM|;Ahmad|Ehtasham|E|;Abid|Noor Ul Ain|NUA|",
"chemical_list": null,
"country": "Italy",
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"doi": "10.12890/2018_000827",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2018_000827827-1-4916-1-10-20180131ArticlesAtraumatic Splenic Rupture after Myocardial Infarction Arshad Muhammad Fahad Javed Nasir Karim Syed Monawer Ahmad Ehtasham Abid Noor Ul Ain Doncaster Royal Infirmary, Doncaster, United Kingdom2018 24 4 2018 5 4 00082718 12 2017 27 12 2017 © EFIM 20182018This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseAtraumatic splenic rupture is a rare but potentially life-threatening event. It mostly happens when the spleen is already diseased; however, sometimes it can be drug induced in a previously normal spleen. Although anticoagulation has been attributed to spontaneous splenic rupture quite frequently, the role of dual antiplatelet therapy is underestimated. We report a case of an 80-year-old woman who developed spontaneous splenic rupture 4 weeks after starting dual antiplatelet therapy.\n\nLEARNING POINTS\nAtraumatic or spontaneous splenic rupture can be life threatening.\n\nVarious drugs, including granulocyte colony-stimulating factors (GCSF) and anticoagulants, can result in atraumatic splenic rupture in a previously normal spleen.\n\nDual antiplatelet therapy can also cause splenic rupture in a previously normal spleen. It can occur as early as a few weeks after initiation of treatment.\n\nAtraumatic splenic ruptureclopidogrelantiplatelet therapymyocardial infarction\n==== Body\nINTRODUCTION\nSplenic rupture happens mostly after trauma. Although atraumatic or spontaneous cases are not very common, they can be challenging to diagnose, as the absence of a classical history can result in delayed or missed diagnosis[1]. Therefore, it is very important for clinicians to consider the potential underlying risk factors that should enable them to select ‘at risk’ patients and guide further investigations. Among various medications, the role of dual antiplatelet therapy in the aetiology of atraumatic splenic rupture is underestimated. We report the following case, where the initiation of dual antiplatelet therapy resulted in splenic rupture in an elderly patient.\n\nCASE REPORT\nAn 80-year-old woman with no previous history of coronary artery disease presented to the emergency department on 28 March 2017 with central chest pain. An ECG done at the time showed anterolateral ST elevation myocardial infarction and troponin levels of 66092 ng/L (<2). She was therefore referred for immediate primary percutaneous coronary intervention. Unfortunately, she had diffuse coronary artery disease that was not amenable to successful angioplasty. She was thereafter managed with low molecular weight heparin (fondaparinux) for 5 days followed by dual antiplatelet therapy (aspirin and clopidogrel). She was discharged subsequently on 3 April 2017.\n\nShe was readmitted on 25 April 2017 with shortness of breath and left-sided pleuritic chest pain along with some left flank pain. Her ECG was no different from previous ones and there was no further increase in troponin levels. As an inpatient, she developed severe left-sided abdominal pain. On examination, she was hypotensive and had severe tenderness in her central abdomen. She and her family denied any history of trauma in the preceding weeks.\n\nHer chest X-ray showed small left-sided pleural effusion (Fig. 1) and a CT scan of her abdomen revealed splenic laceration, extensive subcapsular haematoma and free fluid in the abdomen (Fig. 2). She was urgently reviewed by the surgical team. Unfortunately, because of her recent myocardial infarction and moderate to severe left ventricular dysfunction, she was not considered fit for surgery or endovascular therapy, and was therefore managed conservatively. She did not respond to conservative management and remained hypotensive. She was reviewed by the palliative team for pain management and died 4 days later.\n\nDISCUSSION\nSplenic rupture is not uncommon after abdominal trauma. In contrast, atraumatic or spontaneous rupture of the spleen is rare, but still can be life threatening. The lack of a previous history of significant trauma can result in delayed diagnosis and poor patient outcomes. A review of the literature for atraumatic splenic rupture identified two systematic reviews consisting of 845[1] and 613[2] cases each. The first review reported mortality rates of 12.2% in this cohort of patients. It identified age of more than 40 years, splenomegaly and neoplastic disorders as risk factors associated with high mortality.\n\nRenzulli et al.[1] found that in the vast majority of cases (93%), despite the absence of compatible history, there were either one or more aetiological factors that predisposed to splenic rupture. In most cases, the underlying cause was not found until after presentation at hospital. All such causes were divided into six major groups, namely (in order of frequency): neoplastic disorders; infectious disorders; inflammatory non-infectious disorders; drug and treatment-related disorders; normal spleen; and mechanical disorders.\n\nAmong medications, although there are cases of splenic rupture reported following granulocyte colony-stimulating factors (GCSF), anticoagulants are usually the most common offenders. Several cases of spontaneous splenic rupture have been reported with unfractionated heparin, low molecular weight heparin[3], warfarin[4] and novel oral anticoagulants[5,6] in a previously described normal spleen. As expected, thrombolytic therapy, including both streptokinase and recombinant tissue plasminogen activator[7], have also been implicated. Our literature search identified only two case reports[8,9] attributing dual antiplatelet therapy (aspirin with ticagrelor and aspirin with clopidogrel) to spontaneous splenic rupture.\n\nThe data available in the literature with regard to management of atraumatic splenic rupture is very limited. Treatment options do not differ from cases of blunt abdominal trauma; however, such patients are significantly more likely to undergo splenectomy than if their rupture had been of traumatic aetiology. Renzulli et al.’s review[1] concluded that patients with non-malignant aetiology could be treated conservatively, with organ-preserving surgery or transcatheter arterial embolisation. However, they recommended surgical removal for patients with malignant aetiologies. Overall, the patient’s full clinical picture, haemodynamic stability, grade of splenic injury, and the presence or absence of peritonitis should be considered[10]. For patients who are not fit for general anaesthesia, conservative or less invasive management is the only option.\n\nOur case highlights the role of antiplatelet therapy and their association with spontaneous splenic rupture in the absence of any other risk factors described above.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 Chest X-ray, showing small left-sided pleural effusion\n\nFigure 2 CT scan of abdomen, showing splenic laceration, extensive subcapsular haematoma and free fluid in the abdomen\n==== Refs\nREFERENCES\n1 Renzulli P Hostettler A Schoepfer AM Gloor B Candinas D Systematic review of atraumatic splenic rupture Br J Surg 2009 96 1114 21 19787754 \n2 Aubrey-Bassler FK Sowers N 613 cases of splenic rupture without risk factors or previously diagnosed disease: a systematic review BMC Emerg Med 2012 12 11 22889306 \n3 Taccone FS Starc JM Sculier JP Splenic spontaneous rupture (SSR) and hemoperitoneum associated with low molecular weight heparin: a case report Support Care Cancer 2003 11 336 38 12690538 \n4 de Kubber MM de Groot B Kroft LJM Non-traumatic splenic rupture in a patient on oral anticoagulation Int J Emerg Med 2013 6 16 23694768 \n5 Lowry LE Goldner JA Spontaneous splenic rupture associated with apixaban: a case report J Med Case Rep 2016 10 217 27506776 \n6 Amin A Safaya A Ronny F Islam H Bhuta K Rajdeo H Hemorrhagic shock from spontaneous splenic rupture requiring open splenectomy in a patient taking rivaroxaban Am Surg 2016 82 e54 5 26874127 \n7 Revesz E Grimaldi JA Clark ET Podbielski FJ Spontaneous splenic rupture in a patient receiving thrombolytic therapy J Vas Bras 2009 8 274 76 \n8 Grifoni E Paniccia R Giusti B Sticchi E Padeletti L Cavallini C Non-traumatic splenic rupture on dual antiplatelet therapy with aspirin and ticagrelor after stenting for acute coronary syndrome J Cardiol Cases 2015 12 65 67 30524542 \n9 Shaileshkumar GS Shyamkumar KN Munawwar A Vijayan P Benjamin P Haemorrhagic shock due to spontaneous splenic haemorrhage complicating antiplatelet therapy: endovascular management Egypt J Intern Med 2015 27 154 56 \n10 Walker AM Foley EF Surgical management of atraumatic splenic rupture Int Surg J 2016 3 2280 88\n\n",
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"issue": "5(4)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Atraumatic splenic rupture; antiplatelet therapy; clopidogrel; myocardial infarction",
"medline_ta": "Eur J Case Rep Intern Med",
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"pages": "000827",
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"pmid": "30756025",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "12690538;19787754;22889306;23694768;26874127;27506776;30524542",
"title": "Atraumatic Splenic Rupture after Myocardial Infarction.",
"title_normalized": "atraumatic splenic rupture after myocardial infarction"
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"abstract": "Hepatitis C virus (HCV) infection negatively impacts patient and graft survival following nonhepatic solid organ transplantation. Most data, however, are in kidney transplant, where despite modest impact on outcomes, transplantation is recommended for those with mild to moderate hepatic fibrosis given overall benefit compared to remaining on dialysis. In lung transplantation (LuTx), there is little data on outcomes and international guidelines are vague on the criteria under which transplant should be considered. The University of Alberta Lung Transplant Program routinely considers patients with HCV for lung transplant based on criteria extrapolated from the kidney transplant literature. Here we describe the outcomes of 27 HCV-positive, compared to 443 HCV-negative LuTx recipients. Prior to transplant, five patients were treated for HCV and cured. At the time of transplant, 14 patients remained HCV RNA positive. The 1-, 3-, and 5-year survival were similar in HCV RNA-positive versus -negative recipients at 93%, 77%, and 77% versus 86%, 75%, and 66% (p = 0.93), respectively. Long-term follow-up in eight patients demonstrated no significant progression of fibrosis. In our cohort, HCV did not impact LuTx outcomes and in the era of interferon-free HCV therapies this should not be a barrier to LuTx.",
"affiliations": "Division of Infectious Diseases, University of Alberta, Edmonton, Alberta, Canada.;Division of Pulmonary Medicine, University of Alberta, Edmonton, Alberta, Canada.;Division of Pulmonary Medicine, University of Alberta, Edmonton, Alberta, Canada.;Division of Pulmonary Medicine, University of Alberta, Edmonton, Alberta, Canada.;Division of Pulmonary Medicine, University of Alberta, Edmonton, Alberta, Canada.",
"authors": "Doucette|K E|KE|;Halloran|K|K|;Kapasi|A|A|;Lien|D|D|;Weinkauf|J G|JG|",
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"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; fibrosis; infection and infectious agents; infectious disease; lung transplantation/pulmonology; patient survival; viral: hepatitis C",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000328:Adult; D005260:Female; D005355:Fibrosis; D005500:Follow-Up Studies; D006084:Graft Rejection; D006085:Graft Survival; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D008103:Liver Cirrhosis; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors",
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"references": null,
"title": "Outcomes of Lung Transplantation in Recipients With Hepatitis C Virus Infection.",
"title_normalized": "outcomes of lung transplantation in recipients with hepatitis c virus infection"
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"abstract": "Immune mediated necrotizing myopathy (IMNM) is part of the inflammatory myopathies group of diseases and presents with muscle weakness, myalgias and elevated serum creatine phosphokinase (CPK). Statin-induced IMNM is a rare complication. We present a patient with IMNM secondary to simvastatin use. The patient presented with proximal myopathy, dysphagia, and elevated creatinine kinase levels, and was subsequently found to have anti-3- hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies with a necrotizing process on muscle biopsy. This patient's case was further complicated by sequelae of multiple disease processes, ultimately leading to deterioration of his health.",
"affiliations": "Penn State College of Medicine.;Penn State College of Medicine.;Penn State College of Medicine.;Penn State College of Medicine.;Penn State College of Medicine.;Penn State College of Medicine.",
"authors": "Abusharar|Shady Piedra|SP|;Moku|Prashanth|P|;Banks|Sharon|S|;Khalid|Fahad M|FM|;Specht|Charles S|CS|;Polimera|Hyma V|HV|",
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"doi": "10.4081/cp.2020.1248",
"fulltext": "\n==== Front\nClin Pract\nCP\nClinics and Practice\n2039-7275 2039-7283 PAGEPress Publications, Pavia, Italy \n\n10.4081/cp.2020.1248\nCase Report\nImmune mediated necrotizing myopathy: A rare complication of statin therapy\nAbusharar Shady Piedra 1 Moku Prashanth 1 Banks Sharon 12 Khalid Fahad M. 12 Specht Charles S. 12 Polimera Hyma V. 12 1 Penn State College of Medicine\n2 Penn State Hershey Medical Center, Hershey, PA, USA\nPenn State College of Medicine and Penn State Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA. +1.484.553.7570. hpolimera@gmail.comContributions: SPA, PM, HVP, contributed equally to literature search, figures, manuscript writing, review and approval of manuscript; SB, FMK, CSS, review and approval of case report.\n\nConflict of interests: the authors declare no potential conflict of interests.\n\nEthics approval: No ethical approval is required.\n\nInformed consent: All patient's identification details are removed.\n\n\n30 6 2020 \n19 5 2020 \n10 2 124817 3 2020 22 6 2020 ©Copyright: the Author(s)2020Licensee PAGEPress, ItalyThis 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.Immune mediated necrotizing myopathy (IMNM) is part of the inflammatory myopathies group of diseases and presents with muscle weakness, myalgias and elevated serum creatine phosphokinase (CPK). Statin-induced IMNM is a rare complication. We present a patient with IMNM secondary to simvastatin use. The patient presented with proximal myopathy, dysphagia, and elevated creatinine kinase levels, and was subsequently found to have anti-3- hydroxy-3-methylglutaryl-CoA reductase (HMGCR) autoantibodies with a necrotizing process on muscle biopsy. This patient’s case was further complicated by sequelae of multiple disease processes, ultimately leading to deterioration of his health.\n\nKey words\nImmune mediated necrotizing myopathystatinsstatin-induced IMNMinflammatory myopathy\n==== Body\nIntroduction\nOver the last decade immune mediated necrotizing myopathy (IMNM) has emerged as an immune mediated process, distinct from other idiopathic inflammatory myopathies, such as dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). It has been characterized histologically by a prominent necrosis and myophagocytosis in the relative absence of lymphocytic infiltrates.1 More importantly, recent literature has shown an association of IMNM with statin use, particularly in anti-HMGCR positive myopathy.2 With a cited prevalence as rare as 1-2 cases per million, it is considered a very rare complication of statin use.3 Prompt and accurate diagnosis is crucial, as symptoms can persist and progress despite statin discontinuation. IMNM can occur within months of initiation of a statin, however in most reported cases patients have been on statin therapy for years before the onset of myopathy.3,4 This can further complicate the diagnosis, and highlights the need for high clinical suspicion. We report a case of anti-HMGCR positive IMNM secondary to simvastatin. The case was complicated by persistent dysphagia, which resulted in aspiration, respiratory failure and subsequently death.\n\nCase Report\nA 73-year-old man with a history of diabetes, hypertension, and hyperlipidemia presented with a 3-week history of progressive muscle weakness and dysphagia. He has been taking insulin detemir, metformin, lisinopril, and simvastatin for the last several years. On admission, he was found to have CPK of 12,000 U/L and elevated inflammatory markers, concerning for inflammatory myopathy and rhabdomyolysis. Thyroid function tests, ANA and creatinine were within normal limits. Given that the patient’s CPK level did not improve after administration of IV fluids, immune mediated necrotizing myopathy secondary to statin use was suspected.\n\nOther workup included Anti-Jo-1, anti- Ro-52, anti-SRP, anti-Mi-2, acetylcholine receptor antibody and muscle-specific tyrosine kinase antibody, which were all negative. Subsequent evaluation revealed positive HMG-CoA reductase antibodies, with titers greater than 200 (Normal 19), consistent with IMNM associated with statin use. Muscle biopsy revealed a necrotizing process with type 2 myofiber atrophy, consistent with immune myopathy (Figure 1). He initially received Prednisone 30 mg daily for 2 days, which was later changed to IV methylprednisolone 15 mg every 12 h secondary to confusion and agitation. He was started on methotrexate 20 mg subcutaneous once a week, which resulted in improvement in his CPK level. The patient was also treated with one course of IV immunoglobulin 2 g/kg over two days. Later, methotrexate was discontinued secondary to newly elevated LFTs (AST, ALT). He received Azathioprine for 2 days, but this was discontinued due to development of infection. The patient’s hospital course was complicated by persistent dysphagia and aspiration events leading to sepsis and hypoxic respiratory failure which ultimately led to death.\n\nDiscussion\nImmune mediated necrotizing myositis (IMNM) is part of the inflammatory myopathies group of diseases. Although it shares similarities with other idiopathic inflammatory myopathies (IIM) such as dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM), it was recognized as a distinct entity in 2003, and has been characterized by muscle cell necrosis with lack of significant lymphocytic inflammatory infiltrates.4 In 2010, novel autoantibodies with specificity to a pair of protein with weights of 200/100-kd were identified in patients with IMNM and history of statin use.5 HMGCR was subsequently identified as the 100-kd autoantigen.2 Since then, IMNM has been increasingly associated with statin use. However, it remains a very a rare complication.\n\nPatients with statin-induced IMNM often present with progressive proximal muscle weakness and significantly elevated CPK levels.6 CPK levels are usually >5 times upper limit of normal.7 It is typically a subacute process, with myopathy developing over weeks to months. The process is typically symmetric and lacks sensory involvement. Limb weakness and myalgias are the most common features, but other reported features include truncal weakness, facial weakness, dysphagia, fatigue, and weight loss.1 Symptoms and CPK elevation typically persist, despite discontinuation of statin, and usually show improvement with immunosuppressive therapy. This usually distinguishes statin-induced IMNM from myopathy secondary to direct statin toxicity, which typically improves with statin discontinuation. 8,9\n\nThe diagnosis of statin-induced IMNM can be challenging for a multitude of reasons. For one, statin-induced IMNM shares many similarities with other myopathies, which also present with elevated CPK levels and proximal muscle weakness. Furthermore, although it can present within months of statin initiation, the large majority of patients develop symptoms years after initiating statin therapy. Hence, high clinical suspicion is required for prompt diagnosis. The gold-standard for diagnosis of IMNM is generally based on muscle biopsy.10 Muscle biopsies reveal muscle fiber necrosis and inflammatory infiltrates composed of macrophages.6 However, as with other IIM, autoantibodies are now considered a hallmark in the diagnosis of IMNM.7 Not only does this allow other IIMs to be ruled out, but it also allows for subclassification. The most recent European Neuromuscular Centre (ENMC) workshop in 2016 identified three subgroups of IMNM; anti-HMGCR myopathy; anti-signal recognition particles (SRP) myopathy, and seronegative IMNM.11 Anti-HMGCR antibody is present in about half of patients with IMNM.7 It has been proposed that anti- HMGCR positive IMNM is frequently associated with statin use. This has been confirmed by subsequent literature.2 It has also been demonstrated to have high sensitivity and specificity for statin-induced IMNM, which has been reported to be as high as 94.4% and 99.3%, respectively.12 Anti-SRP positive IMNM represents 22-39% of IMNM, but unlike anti-HMGCR myopathy, has not been shown to have an association with statin use.7 With commercially available antibody testing now more readily available, biopsy is no longer required for a diagnosis of seropositive IMNM.13 However, seronegative IMNM accounts for 25-40% of IMNM, and presents with elevated CPK, muscle weakness, and a biopsy demonstrating necrotizing myopathy despite no antibody detection. Hence, muscle biopsy remains necessary for a diagnosis of seronegative IMNM, and for this reason is still often employed as part of the diagnostic work up. The association of seronegative IMNM with statins remains poorly defined in the literature.\n\nHMGCR is the rate limiting enzyme of cholesterol synthesis and statins act as competitive inhibitors of HMGCR. The ensuing reduction in hepatic intracellular LDL results in an increase in LDL receptor expression and receptor mediated endocytosis, ultimately lowering serum LDL levels.14 However, the exact pathogenesis of statin induced anti-HMGCR myopathy remains poorly understood and is an active area of investigation. It is thought that the muscle damage in statin-induced IMNM is mediated by autoantibodies against HMGCR.6 It has been demonstrated that muscle expression of HMGCR is increased with statin exposure.2,15 Although largely a subcellular protein localized to the endoplastic reticulum, studies have proposed that its expression is also increased in regenerating muscle fibers and may be present on cell surfaces. 16 Therefore, the continued muscle expression of HMGCR may sustain the immune-mediated muscle necrosis caused by anti-HMGCR autoantibodies associated with statin therapy even after its discontinuation. 17\nFigure 2 illustrates this proposed mechanism.\n\nTreatment of statin-induced IMNM requires prompt discontinuation of statin therapy and aggressive treatment with immunosuppressive agents. However, there is a lack of prospective studies and clinical trials in the literature to guide therapy. Following the recent 2016 ENMC workshop, high dose prednisone/prednisolone or pulsed IV methylprednisolone remains the recommended first-line treatment. A second agent can be added, and either azathioprine 3 mg/kg/actual body weight or methotrexate 20-25 mg per week orally or subcutaneously can be used.11 Although considered third-line therapy, the 2016 workshop also suggested rituximab as a possible alternative, and this can be combined with methotrexate in severe cases. In cases of anti-HMGCR positive myopathy, as in our case, IVIG should be considered, particularly in patients with severe disease or refractory disease at 6 months. IVIG has also been reported to be used as first-line therapy in half of reported cases.11 Little literature guides IVIG therapy in this setting, but IVIG 2g/kg/m, 3-6 times has been suggested as an induction dose.18 Cycles of every 2 weeks to 4 weeks have been reported during maintenance therapy, and can be stopped and tapered as tolerated.19\n\nFigure 1. In this cryostat section, a pale necrotic myofiber is seen in the center of the field (hematoxylin & eosin, 400x).\n\nFigure 2. Proposed mechanism of immune mediated muscle injury in statin-induced immune mediated necrotizing myopathy (IMNM). HMGCR, hydroxy-3-methylglutaryl- CoA reductase.\n\nTreatment with disease modifying agents should only be discontinued after 2-3 years of well-controlled disease and minimal corticosteroid use.1 CPK has been shown to correlate with disease activity, and hence treatment to normal range has been suggested as a target. Increases in CPK should warrant consideration of increased disease activity.\n\nThe prognosis of statin-induced IMNM is generally good. Although long term immunotherapy is usually required, symptom resolution is reported in most cases.6 The most commonly reported complication is persistent muscle weakness, which can be present even two years after onset. We report a case of anti-HMGCR positive statin-induced IMNM resulting in death secondary to associated dysphagia. Dysphagia has only been reported in 16-30% of statin-induced IMNM.16 It is not readily recognized as a characteristic symptom of the disease. However, in our case, despite down-trending CK values with immunotherapy (Figure 3), persistent dysphagia led to aspiration, and subsequent respiratory failure and death. A review of recent literature yielded only two reported cases with death as a complication of statininduced IMNM.13 Of these two cases, one described dysphagia as a presenting symptom. Interestingly, this case was also complicated by respiratory distress requiring ventilator support, and ultimately death from ventilator-acquired pneumonia.20 Furthermore, at least three of four recently published cases of statin-induced IMNM and associated dysphagia also reported the need for nutritional support with gastrostomy tube.20 Hence, although a less commonly associated symptom, dysphagia may result in increased risk of morbidity and mortality in patients with IMNM. Our case further highlights the need for prospective studies to better guide therapy in patients presenting with statin-induced IMNM. It further expands on the increasing, but still sparse literature on statin-induced IMNM, and emphasizes that complications can prove fatal.\n\nIt is also important to recognize the challenge that statin-induced IMNM can pose in patients with high cardiovascular risk. In a recently published review of 92 cases of statin-induced IMNM, atorvastatin was reported in 80% of cases, and simvastatin in 24%.13 Other statins also reported included rosuvastatin (17%) and pravastatin (3%). These are among the most commonly used statins in patients at risk for cardiovascular disease. Despite the increase in prevalence of statin-induced IMNM over the last decade, there is a lack of literature to guide management of patients with a history of statin induced IMNM who are also at high risk for cardiovascular disease. Statin rechallenge with the same or a different statin has shown to be largely unsuccessful and often results in disease flare up.19,6 A recent case series at Johns Hopkins University found that PCSK9 inhibitors were well tolerated in 7 out of 8 patients with a previous history of statin-induced IMNM.19 As a result PCSK9 may be an alternative medication for patients with high cardiovascular risk and IMNM. However, data is limited, thus highlighting an area requiring further research.\n\nConclusions\nStatins are widely used and lower the risk of death from cardiovascular causes. Statin-induced myalgias and myopathies improve with withdrawal of statin therapy and supportive care. By contrast, statininduced IMNM is a potentially fatal autoimmune disease that follows an aggressive clinical course and often presents with progressive muscle weakness, elevated CPK levels, myonecrosis, and anti-HMGCoA reductase antibodies. Treatment includes discontinuation of the statin and initiation of immunosuppressive agents. Clinicians should be aware of this devastating complication of statin use, especially in patients recently discontinued off statins with persistently elevated CPK levels, as early detection is vital and allows for prompt initiation of treatment.\n\nFigure 3. Down trending creatine phosphokinase (CPK) levels with immunotherapy.\n\nKey points\nStatin-induced immune mediated necrotizing myopathy (IMNM) is a potentially fatal autoimmune disease. Recognized cases generally follow an aggressive clinical course if not quickly recognized. This case report provides an overview of statin-induced IMNM, including its common presentations and appropriate treatment options:\n\ni) Statins are widely used agents that lower the risk of death from cardiovascular disease but their usage can present with adverse effects including myalgias and myopathies that improve with withdrawal of statin therapy and with supportive care.\n\nii) Statin-induced IMNM is an autoimmune disease with an aggressive clinical course, characterized by progressive muscle weakness, elevated CPK levels, myonecrosis on muscle biopsy, and anti-HMG-CoA reductase antibodies.\n\niii) Treatment of IMNM includes discontinuation of statin, immunosuppressive agents to prevent permanent damage, and often results in complete recovery.\n==== Refs\nReferences\n1. Day JA Limaye V. \nImmune-mediated necrotising myopathy: A critical review of current concepts\n. Semin Arthritis Rheum \n2019 [Epub ahead of print].\n2. Mammen AL Chung T Christopher-Stine L \nAutoantibodies against 3- hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy\n. Arthritis Rheum \n2011 ;63 :713 -21\n.21360500 \n3. Mohassel P Mammen AL \nStatin-associated autoimmune myopathy and anti- HMGCR autoantibodies\n. Muscle Nerve \n2013 ;48 :477 -83\n.23519993 \n4. Grable-Esposito P Katzberg HD Greenberg SA \nImmune-mediated necrotizing myopathy associated with statins\n. Muscle Nerve \n2010 ;41 :185 -90\n.19813188 \n5. Christopher-Stine L Casciola-Rosen LA Hong G \nA novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immunemediated necrotizing myopathy\n. Arthritis Rheum \n2010 ;62 :2757 -66\n.20496415 \n6. Nazir S Lohani S Tachamo N \nStatin-associated autoimmune myopathy: a systematic review of 100 cases\n. J Clin Rheumatol \n2017 ;23 :149 -54\n.28277343 \n7. Musset L Allenbach Y Benveniste O \nAnti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: A history of statins and experience from a large international multi-center study\n. Autoimmun Rev \n2016 ;15 :983 -93\n.27491568 \n8. Collins R Reith C Emberson J \nInterpretation of the evidence for the efficacy and safety of statin therapy\n. Lancet \n2016 ;388 :2532 -61\n.27616593 \n9. Dalakas MC \nInflammatory muscle diseases\n. N Engl J Med \n2015 ;372 :1734 -47\n.25923553 \n10. Hoogendijk JE Amato AA Lecky BR \n119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands\n. Neuromuscul Disord \n2004 ;14 :337 -45\n.15099594 \n11. Allenbach Y Mammen AL Benveniste O Stenzel W. \n224th ENMC International Workshop:: Clinico-seropathological classification of immunemediated necrotizing myopathies Zandvoort, The Netherlands, 14-16 October 2016\n. Neuromuscul Disord \n2018 ;28 :87 -99\n.29221629 \n12. Shovman O Gilburd B Chayat C \nAnti-HMGCR antibodies demonstrate high diagnostic value in the diagnosis of immune-mediated necrotizing myopathy following statin exposure\n. Immunol Res \n2017 ;65 :276 -81\n.27618830 \n13. Essers D Schäublin M Kullak-ublick GA Weiler S. \nStatin-associated immune-mediated necrotizing myopathy: a retrospective analysis of individual case safety reports from VigiBase\n. Eur J Clin Pharmacol \n2019 ;75 :409 -16\n.30430215 \n14. Vaughan CJ Gotto AM Basson CT \nThe evolving role of statins in the management of atherosclerosis\n. J Am Coll Cardiol \n2000 ;35 :1 -10\n.10636252 \n15. Morikawa S Murakami T Yamazaki H \nAnalysis of the global RNA expression profiles of skeletal muscle cells treated with statins\n. J Atheroscler Thromb \n2005 ;12 :121 -31\n.16020911 \n16. Mohassel P Mammen AL \nAnti- HMGCR Myopathy\n. J Neuromuscul Dis \n2018 ;5 :11 -20\n.29480216 \n17. Selva-O'callaghan A Alvarado-Cardenas M Pinal-Fernández I \nStatin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations\n. Expert Rev Clin Immunol \n2018 ;14 :215 -24\n.29473763 \n18. Pinal-Fernandez I Casal-Dominguez M Mammen AL \nImmune-mediated necrotizing myopathy\n. Curr Rheumatol Rep \n2018 ;20 :21 .29582188 \n19. Tiniakou E Rivera E Mammen AL Christopher-Stine L. \nUse of proprotein convertase subtilisin/kexin type 9 inhibitors in statin-associated immunemediated necrotizing myopathy: a case series\n. Arthritis Rheumatol \n2019 [Epub ahead of print].\n20. Ajiboye O Manesh M Asmi N Mba B. \nAtypical presentation of necrotising autoimmune myopathy\n. BMJ Case Rep \n2019 ;12 :5 .\n\n",
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"issn_linking": "2039-7275",
"issue": "10(2)",
"journal": "Clinics and practice",
"keywords": "Immune mediated necrotizing myopathy; inflammatory myopathy; statin-induced IMNM; statins",
"medline_ta": "Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "101563282",
"other_id": null,
"pages": "1248",
"pmc": null,
"pmid": "32670535",
"pubdate": "2020-05-19",
"publication_types": "D016428:Journal Article",
"references": "31058470;29221629;15099594;31142488;29473763;25923553;16020911;29480216;29582188;19813188;27618830;21360500;27491568;28277343;10636252;30430215;23519993;31109639;27616593;20496415",
"title": "Immune mediated necrotizing myopathy: A rare complication of statin therapy.",
"title_normalized": "immune mediated necrotizing myopathy a rare complication of statin therapy"
} | [
{
"companynumb": "US-HORIZON-PRE-0229-2020",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe diagnostic approach to drug hypersensitivity includes a detailed medical history, clinical examination, and skin testing and/or oral challenge with a culprit or alternative drug, depending on the type of reaction and the suspected drugs. Although skin testing is considered to be rather safe, cutaneous and systemic, including fatal, reactions have been described.\n\n\nOBJECTIVE\nTo report 3 cases with generalized delayed reactions after skin testing with clindamycin, and to review the existing literature.\n\n\nMETHODS\nThorough clinical examination, blood tests and prick, intradermal and patch tests were performed in 3 patients.\n\n\nRESULTS\nAll patients experienced generalized maculopapular exanthema after intradermal and patch testing with clindamycin and amoxicillin in the first patient, and clindamycin alone in the second and third patient. None of the patients showed immediate reactions to skin tests, while positive intradermal reactions after 24 h to amoxicillin and clindamycin were observed in the first patient, and positive intradermal reactions after 24 h to clindamycin were observed in the second and third patients.\n\n\nCONCLUSIONS\nSkin testing with clindamycin in the diagnosis of drug hypersensitivity carries some risk of adverse reactions. A stepwise and individual diagnostic work-up, considering potential risk factors, and testing in a specialized centre with emergency equipment available is highly recommended.",
"affiliations": "Department of Dermatology and Allergy, Comprehensive Allergy Centre, Hannover Medical School, 30625, Hannover, Germany.;Department of Dermatology, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg im Breisgau, Germany.;Department of Dermatology and Allergy, Comprehensive Allergy Centre, Hannover Medical School, 30625, Hannover, Germany.;Department of Dermatology and Allergy, Comprehensive Allergy Centre, Hannover Medical School, 30625, Hannover, Germany.;Department of Dermatology and Allergy, Comprehensive Allergy Centre, Hannover Medical School, 30625, Hannover, Germany.;Department of Dermatology, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg im Breisgau, Germany.;Department of Dermatology and Allergy, Comprehensive Allergy Centre, Hannover Medical School, 30625, Hannover, Germany.",
"authors": "Papakonstantinou|Eleni|E|;Müller|Sabine|S|;Röhrbein|Jan H|JH|;Wieczorek|Dorothea|D|;Kapp|Alexander|A|;Jakob|Thilo|T|;Wedi|Bettina|B|http://orcid.org/0000-0002-9868-6308",
"chemical_list": "D002981:Clindamycin",
"country": "England",
"delete": false,
"doi": "10.1111/cod.12956",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0105-1873",
"issue": "78(4)",
"journal": "Contact dermatitis",
"keywords": "drug hypersensitivity; generalized reactions; skin testing",
"medline_ta": "Contact Dermatitis",
"mesh_terms": "D000368:Aged; D002981:Clindamycin; D003875:Drug Eruptions; D004342:Drug Hypersensitivity; D005060:Europe; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010328:Patch Tests; D061214:Patient Safety; D018570:Risk Assessment",
"nlm_unique_id": "7604950",
"other_id": null,
"pages": "274-280",
"pmc": null,
"pmid": "29356000",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Generalized reactions during skin testing with clindamycin in drug hypersensitivity: a report of 3 cases and review of the literature.",
"title_normalized": "generalized reactions during skin testing with clindamycin in drug hypersensitivity a report of 3 cases and review of the literature"
} | [
{
"companynumb": "DE-TEVA-2018-DE-882314",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ELVITEGRAVIR"
},
"drugadditional": "3",
... |
{
"abstract": "The purpose of this study was to compare the occurrence of cisplatin-induced nephrotoxicity between concomitant chemoradiotherapy with high versus intermediate-dose cisplatin.\n\n\n\nOne hundred forty-four patients with locally advanced head and neck or nasopharyngeal cancer (NPC) were included; 40 patients received cisplatin 100 mg/m(2) (high dose) on days 1, 22, and 43, and 104 patients received cisplatin 40 mg/m(2) weekly (intermediate dose) during 6 weeks in combination with radiotherapy.\n\n\n\nDuring treatment with intermediate-dose cisplatin, 6.7% developed an increase of ≥50% serum creatinine versus 60.0% treated with high-dose cisplatin (p < .05). Nephrotoxicity (all grades) scored by Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0 or CTCAE version 4.03 was 53% and 100% in the high-dose group and 4.8% and 68% in the intermediate-dose group, respectively.\n\n\n\nSignificantly less nephrotoxicity occurs during chemoradiotherapy with intermediate-dose cisplatin compared with high-dose cisplatin. The CTCAE version 4.03 seems to be more appropriate in scoring nephrotoxicity than the CTCAE version 3.0. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1575-E1581, 2016.",
"affiliations": "Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.;Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.",
"authors": "Driessen|Chantal M L|CM|;Uijen|Maike J M|MJ|;van der Graaf|Winette T A|WT|;van Opstal|Claudia C M|CC|;Kaanders|Johannes H A M|JH|;Nijenhuis|Tom|T|;van Herpen|Carla M L|CM|",
"chemical_list": "D003404:Creatinine; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1002/hed.24281",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-3074",
"issue": "38 Suppl 1()",
"journal": "Head & neck",
"keywords": "chemoradiotherapy; cisplatin; head and neck cancer; nephrotoxicity; renal failure",
"medline_ta": "Head Neck",
"mesh_terms": "D000328:Adult; D059248:Chemoradiotherapy; D002945:Cisplatin; D003404:Creatinine; D005260:Female; D005919:Glomerular Filtration Rate; D006258:Head and Neck Neoplasms; D006801:Humans; D007668:Kidney; D008297:Male; D008875:Middle Aged; D009303:Nasopharyngeal Neoplasms; D012189:Retrospective Studies",
"nlm_unique_id": "8902541",
"other_id": null,
"pages": "E1575-81",
"pmc": null,
"pmid": "26614010",
"pubdate": "2016-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Degree of nephrotoxicity after intermediate- or high-dose cisplatin-based chemoradiotherapy in patients with locally advanced head and neck cancer.",
"title_normalized": "degree of nephrotoxicity after intermediate or high dose cisplatin based chemoradiotherapy in patients with locally advanced head and neck cancer"
} | [
{
"companynumb": "NL-TEVA-2018-NL-872233",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"... |
{
"abstract": "OBJECTIVE\nTo present a case where plerixafor was successfully used in combination with granulocyte colony-stimulating factor (G-CSF) for mobilization of hematopoietic stem cells in a pediatric patient.\n\n\nMETHODS\nAn 11-year-old boy with recurrent anaplastic large-cell lymphoma failed to yield an adequate number of CD34+ cells with G-CSF for mobilization. After a single subcutaneous dose of plerixafor 240 μg/kg was administered in addition to filgrastim, sufficient CD34+ cells were harvested for transplantation. A local injection site reaction was the only adverse reaction reported.\n\n\nCONCLUSIONS\nSeveral studies in adults have shown plerixafor to be effective for the mobilization of hematopoietic stem cells when used in combination with G-CSF in adults with non-Hodgkin's lymphoma and multiple myeloma who failed to mobilize sufficient CD34+ cells with G-CSF alone. There is limited information regarding the safety and efficacy of plerixafor in pediatric patients.\n\n\nCONCLUSIONS\nPlerixafor was effective in increasing the number of hematopoietic stem cells in the peripheral blood of an 11-year-old patient; studies are needed to evaluate the safety and effectiveness of plerixafor in pediatric patients.",
"affiliations": "Valeria Alejandra Bernardo PharmD, Clinical Pharmacy Resident, St. Jude Children's Research Hospital, Memphis, TN vabernardo@hotmail.com.;John Szechung Ng PharmD, Pediatric Clinical Pharmacist, Hematology, Oncology, Stem Cell Transplant, Wolfson Children's Hospital/Baptist Medical Center, Jacksonville, FL.;Michael John Joyce MD PhD, Program Director of Pediatric Blood and Marrow Transplantation, Division of Hematology, Oncology, Nemours Children's Clinic, Jacksonville.",
"authors": "Bernardo|Valeria Alejandra|VA|;Ng|John Szechung|JS|;Joyce|Michael John|MJ|",
"chemical_list": "D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D016179:Granulocyte Colony-Stimulating Factor; C088327:plerixafor",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1P564",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "45(2)",
"journal": "The Annals of pharmacotherapy",
"keywords": "AMD3100; granulocyte colony-stimulating factor; hematopoietic stem cell; plerixafor; stem cell mobilization",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D001596:Benzylamines; D002648:Child; D000080027:Cyclams; D004359:Drug Therapy, Combination; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006571:Heterocyclic Compounds; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic; D008297:Male; D012008:Recurrence",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "e12",
"pmc": null,
"pmid": "21285407",
"pubdate": "2011-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of Plerixafor with Granulocyte Colony-Stimulating Factor for Stem Cell Mobilization in a Pediatric Patient.",
"title_normalized": "use of plerixafor with granulocyte colony stimulating factor for stem cell mobilization in a pediatric patient"
} | [
{
"companynumb": "US-AMGEN-USASP2021040391",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PLERIXAFOR"
},
"drugadditional": null,
... |
{
"abstract": "Aripiprazole (APZ) has poor physicochemical properties and bitter taste. The current study aimed to prepare salts of APZ with polycarboxylic acids (citric, malic, and tartaric acids) to improve physicochemical properties and impart sour taste to the drug. The salts were prepared by solubilization-crystallization method, and characterized by electron microscopic, spectroscopic, diffractometry, and thermal methods. The salts were assessed for pH solubility, pH-stability, dissolution, and solid-state stability. Fourier transformed infrared, X-ray powder diffraction, and differential scanning calorimetry data indicated formation of new solid phases. APZ and the salts exhibited pH-dependent solubility. The pH solubility curve shape was inverted \"V,\" inverted \"W,\" and inverted \"U\" for APZ, APZ-Citrate, and APZ-Malate and APZ-Tartrate, respectively. Compared to APZ, the solubility of salts at pH 4, 5, and 6 was 3.6-7.1, 23.9-31.5, and 143.4-373.3 folds of APZ. Increase in solubility in water by citrate, malate, and tartrate salts was 5562.8, 21,284.7, and 22,846.7 folds of APZ. The salt formation also leads to an increase in rate and extent of dissolution. The dissolution extent was 3.5 ± 0.5, 71.3 ± 1.2, 80.1 ± 6.2, and 86.1 ± 1.1% for APZ, APZ-Citrate, APZ-Malate, and APZ-Tartrate, respectively. Liquid and solid-state stabilities of the salts were comparable to APZ. In conclusion, salts of APZ with polycarboxylic acids improved solubility, and dissolution, and impart sour taste, which may improve palatability of the drug.",
"affiliations": "Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M University, Reynolds Medical Building, Suite 310, College Station, Texas, 77843-1114, USA.;Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M University, Reynolds Medical Building, Suite 310, College Station, Texas, 77843-1114, USA.;Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M University, Reynolds Medical Building, Suite 310, College Station, Texas, 77843-1114, USA.;Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M University, Reynolds Medical Building, Suite 310, College Station, Texas, 77843-1114, USA.;Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M University, Kingsville, Texas, 78363, USA.;Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M University, Reynolds Medical Building, Suite 310, College Station, Texas, 77843-1114, USA.;Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M University, Reynolds Medical Building, Suite 310, College Station, Texas, 77843-1114, USA. rahman@tamu.edu.",
"authors": "Afrooz|Hamideh|H|;Mohamed|Eman M|EM|;Barakh Ali|Sogra F|SF|;Dharani|Sathish|S|;Nutan|Mohammad T H|MTH|;Khan|Mansoor A|MA|;Rahman|Ziyaur|Z|http://orcid.org/0000-0002-0402-825X",
"chemical_list": "D014150:Antipsychotic Agents; D008293:Malates; D013644:Tartrates; D019343:Citric Acid; C030298:malic acid; D000068180:Aripiprazole; C029768:tartaric acid",
"country": "United States",
"delete": false,
"doi": "10.1208/s12249-020-01875-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-9932",
"issue": "22(1)",
"journal": "AAPS PharmSciTech",
"keywords": "aripiprazole; citric acid; malic acid; salt; solubility; stability; tartaric acid",
"medline_ta": "AAPS PharmSciTech",
"mesh_terms": "D014150:Antipsychotic Agents; D000068180:Aripiprazole; D002152:Calorimetry, Differential Scanning; D019343:Citric Acid; D003460:Crystallization; D004355:Drug Stability; D008293:Malates; D008855:Microscopy, Electron, Scanning; D033362:Powder Diffraction; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013644:Tartrates",
"nlm_unique_id": "100960111",
"other_id": null,
"pages": "31",
"pmc": null,
"pmid": "33405012",
"pubdate": "2021-01-06",
"publication_types": "D016428:Journal Article",
"references": "19009597;26397209;17497799;20801200;22037447;22868234;20352537;25000481;15234801;14570313;11811758;18812020;13053435;3247326;11124216;22588676;23800704;12588738;15244079;15647467;29341912;30773201;22535520;30239203;25753376;18052022;20143257;22100517;25173870",
"title": "Salt Engineering of Aripiprazole with Polycarboxylic Acids to Improve Physicochemical Properties.",
"title_normalized": "salt engineering of aripiprazole with polycarboxylic acids to improve physicochemical properties"
} | [
{
"companynumb": "US-OTSUKA-2021_011525",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Leukemia in infants is rare but generates tremendous interest due to its aggressive clinical presentation in a uniquely vulnerable host, its poor response to current therapies, and its fascinating biology. Increasingly, these biological insights are pointing the way toward novel therapeutic approaches. Using representative clinical case presentations, we review the key clinical, pathologic, and epidemiologic features of infant leukemia, including the high frequency of KMT2A gene rearrangements. We describe the current approach to risk-stratified treatment of infant leukemia in the major international cooperative groups. We highlight recent discoveries that elucidate the molecular biology of infant leukemia and suggest novel targeted therapeutic strategies, including modulation of aberrant epigenetic programs, inhibition of signaling pathways, and immunotherapeutics. Finally, we underscore the need for increased global collaboration to translate these discoveries into improved outcomes.",
"affiliations": "Department of Oncology and.;Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands; and.;Department of Pediatrics and.",
"authors": "Brown|Patrick|P|0000-0002-8653-1069;Pieters|Rob|R|;Biondi|Andrea|A|",
"chemical_list": "D009363:Neoplasm Proteins",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2018-04-785980",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "133(3)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007167:Immunotherapy; D060828:Induction Chemotherapy; D007223:Infant; D007231:Infant, Newborn; D007938:Leukemia; D008297:Male; D058990:Molecular Targeted Therapy; D009154:Mutation; D009363:Neoplasm Proteins; D011379:Prognosis; D012074:Remission Induction",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "205-214",
"pmc": null,
"pmid": "30459160",
"pubdate": "2019-01-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "How I treat infant leukemia.",
"title_normalized": "how i treat infant leukemia"
} | [
{
"companynumb": "US-TEVA-2021-US-1904633",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSystemic chronic active Epstein-Barr virus infection is an extremely rare childhood disease. Since chronic active Epstein-Barr virus infection can trigger the onset of Epstein-Barr virus-associated lymphoproliferative disease. The clinical manifestations of the disease vary according to the site of involvement; therefore, management may be challenging. Currently, there are no standardized guidelines for treating Chronic active Epstein-Barr virus infection effectively.\n\n\nMETHODS\nWe report a case of chronic active Epstein-Barr virus infection in a 5-year-old Chinese boy with intestinal, vascular, and neurological involvement. At age of 2 years and 7 months old, he had hepatomegaly and been diagnosed with Epstein-Barr virus infection. After treatment, he showed some clinical improvement. At age of 3 years and 3 months old, he presented with recurrent fever and diarrhea. Then he received methylprednisolone for 1 year and his symptoms ameliorated. At the age of 5 years, his symptoms recurred and had gastrointestinal hemorrhage and developed polyuria, frequent convulsions and hyponatremia. He was transferred to our hospital for further management. He was unconscious on admission and was diagnosised Epstein-Barr virus-lymphoproliferative disorder, based on the results in situ hybridization of EBV-encoded miRNA in sigmoid colon. Three-dimensional CT angiography demonstrated an aneurysm in the right internal carotid artery. Abdominal CT showed dilatation of vessels in part of the intestinal wall. He was also diagnosised Epstein-Barr virus encephalitis based on the elevated Epstein-Barr virus antibody titers and presence of Epstein-Barr virus DNA in the Cerebrospinal Fluid. A repeated duodenal artery embolization and symptomatic therapy could not control the hemorrhage after admission. He subsequently received treatment with ganciclovir, glucocorticoid, thalidomide, and propranolol. Hemorrhage was controlled in 5 days; his symptoms improved. The fever did not recur and the CSF pressure was also normalized. A follow-up CT at 3 months after admission showed regression of the aneurysm in the right internal carotid artery and the vascular lesion in the duodenum.\n\n\nCONCLUSIONS\nA new treatment protocol including thalidomide and propranolol resulted in a marked improvement in his clinical symptoms, and shows promise as a novel and effective therapeutic approach for Chronic active Epstein-Barr virus infection-associated lymphoproliferative disorder.",
"affiliations": "Department of Pediatric, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2 Road, Guangzhou, 510080, People's Republic of China.;Department of Pediatric, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2 Road, Guangzhou, 510080, People's Republic of China.;Department of Pediatric, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2 Road, Guangzhou, 510080, People's Republic of China.;Department of Laboratory Medicine pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2 Road, Guangzhou, 510080, People's Republic of China.;Department of Pediatric, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2 Road, Guangzhou, 510080, People's Republic of China.;Department of Pediatric, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2 Road, Guangzhou, 510080, People's Republic of China. tangwen@mail.sysu.edu.cn.;Department of Pediatric, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2 Road, Guangzhou, 510080, People's Republic of China. kzy1969@126.com.;Department of pathology, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2 Road, Guangzhou, 510080, People's Republic of China.",
"authors": "Xu|Lingling|L|;Ba|Hongjun|H|;Lin|Hongrong|H|;Zhong|Liangying|L|;Li|Suping|S|;Tang|Wen|W|;Ke|Zhiyong|Z|;Ye|Ziyin|Z|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13052-019-0741-8",
"fulltext": "\n==== Front\nItal J PediatrItal J PediatrItalian Journal of Pediatrics1824-7288BioMed Central London 74110.1186/s13052-019-0741-8Case ReportA new therapy in Epstein-Barr virus-associated lymphoproliferative disease: a case report and a revision of the literature Xu Lingling 896931799@qq.com 1Ba Hongjun bahongjun1106@163.com 1Lin Hongrong 751228802@qq.com 1Zhong Liangying liangying2003@sina.com 2Li Suping lsping3398@163.com 1Tang Wen 0086 13688893116tangwen@mail.sysu.edu.cn 1Ke Zhiyong 0086 15011781836kzy1969@126.com 1Ye Ziyin yeziyin@mail.sysu.edu.cn 31 0000 0001 2360 039Xgrid.12981.33Department of Pediatric, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2 Road, Guangzhou, 510080 People’s Republic of China 2 0000 0001 2360 039Xgrid.12981.33Department of Laboratory Medicine pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2 Road, Guangzhou, 510080 People’s Republic of China 3 0000 0001 2360 039Xgrid.12981.33Department of pathology, The First Affiliated Hospital, Sun Yat-sen University, Zhongshan 2 Road, Guangzhou, 510080 People’s Republic of China 4 11 2019 4 11 2019 2019 45 13520 7 2019 23 10 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nSystemic chronic active Epstein-Barr virus infection is an extremely rare childhood disease. Since chronic active Epstein-Barr virus infection can trigger the onset of Epstein-Barr virus-associated lymphoproliferative disease. The clinical manifestations of the disease vary according to the site of involvement; therefore, management may be challenging. Currently, there are no standardized guidelines for treating Chronic active Epstein-Barr virus infection effectively.\n\nCase presentation\nWe report a case of chronic active Epstein-Barr virus infection in a 5-year-old Chinese boy with intestinal, vascular, and neurological involvement. At age of 2 years and 7 months old, he had hepatomegaly and been diagnosed with Epstein-Barr virus infection. After treatment, he showed some clinical improvement. At age of 3 years and 3 months old, he presented with recurrent fever and diarrhea. Then he received methylprednisolone for 1 year and his symptoms ameliorated. At the age of 5 years, his symptoms recurred and had gastrointestinal hemorrhage and developed polyuria, frequent convulsions and hyponatremia. He was transferred to our hospital for further management. He was unconscious on admission and was diagnosised Epstein-Barr virus-lymphoproliferative disorder, based on the results in situ hybridization of EBV-encoded miRNA in sigmoid colon. Three-dimensional CT angiography demonstrated an aneurysm in the right internal carotid artery. Abdominal CT showed dilatation of vessels in part of the intestinal wall. He was also diagnosised Epstein-Barr virus encephalitis based on the elevated Epstein-Barr virus antibody titers and presence of Epstein-Barr virus DNA in the Cerebrospinal Fluid.\n\nA repeated duodenal artery embolization and symptomatic therapy could not control the hemorrhage after admission. He subsequently received treatment with ganciclovir, glucocorticoid, thalidomide, and propranolol. Hemorrhage was controlled in 5 days; his symptoms improved. The fever did not recur and the CSF pressure was also normalized. A follow-up CT at 3 months after admission showed regression of the aneurysm in the right internal carotid artery and the vascular lesion in the duodenum.\n\nDiscussion and conclusions\nA new treatment protocol including thalidomide and propranolol resulted in a marked improvement in his clinical symptoms, and shows promise as a novel and effective therapeutic approach for Chronic active Epstein-Barr virus infection-associated lymphoproliferative disorder.\n\nKeywords\nChronic active Epstein-Barr virus infectionThalidomidePropranololEnteritisEncephalitisVascular lesionshttp://dx.doi.org/10.13039/501100013254National College Students Innovation and Entrepreneurship Training Program201901092201901095Xu Lingling issue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nChronic active Epstein-Barr virus infection (CAEBV) is a systemic EBV-positive lymphoproliferative disorder (EBV-LPD), which is marked by persistent infectious mononucleosis-like symptoms. CAEBV may result in life-threatening complications [1–6] such as malignant lymphomashepatic failure, interstitial pneumonia, coronary artery aneurysms, central nervous system (CNS) involvement, hemophagocytic syndromes and massive hemorrhage from the gastrointestinal tract. However, it is very rare for a patient to have several synchronous symptoms owing to EBV infection. Hematopoietic stem cell transplantation (HSCT) may be the only cure for CAEBV [7].\n\nWe report the case of a boy with CAEBV who synchronously developed an intestinal lymphoproliferative lesion, life-threatening gastrointestinal bleeding, multiple vascular lesions, and encephalitis. A new treatment strategy, which involved the combination of thalidomide, propranolol, ganciclovir, and glucocorticoids, successfully cured the symptoms.\n\nConsent\nThe guardian of the patient consented to treatment and also provided written consent for publication of the data in this case report.\n\nCase presentation\nA 5-year-old boy with no personal or family history of immunodeficiency, presented with a 29 months history of intermittent fever, recurrent diarrhea and hematochezia. At age of 2 years and 7 months old, he had hepatomegaly and been diagnosed with EBV infection when the levels of EBV deoxyribose nucleic acid (DNA) were 7.86 × 10^6 copies/mL (normal range: <1.0 × 10^3 copies/ml). After treatment with plasma exchange, high-dose intravenous immunoglobulins, ganciclovir, and methylprednisolone, he showed some clinical improvement.\n\nAt the age of 3 years and 3 months, he visited another hospital because of recurrent fever and diarrhea. Upper gastrointestinal endoscopy and enteroscopy revealed multiple ulcers in the ileum and colon (Fig. 1a). Pathological diagnosis of intestinal tract could not exclude Crohn’s disease. He was then prescribed methylprednisolone, which he continued on for 1 year with amelioration of his symptoms.\nFig. 1 Clinical materials. a Colonoscopy revealed multiple and discrete ulcers as visible in the Colon; b EBV in situ hybridization for EBER demonstrated EBV-positive in sigmoid colon (H&E stain, 40); c Three-dimensional CT angiography of the head showed the cavernous segment of the right internal carotid artery presented local dilatation (white arrow); d Abdominal CT showed dilatation of vessels (white arrow) in part of the intestinal wall; e Electroencephalography showed diffuse slowing; f The drug therapy and Epstein-Barr virus DNA levels of the patient\n\n\n\nAt the age of 5 years, he experienced recurrent fever, abdominal pain, and diarrhea, persisting for nearly 1 month. He also had gastrointestinal hemorrhage for 2 weeks. The laboratory results in the local hospital revealed coagulation dysfunction, anemia (the lowest hemoglobin was 62 g/L), low platelet counts (lowest count: 68 × 10^9/L), and raised procalcitonin levels (the highest level: 4.75 ng/ml). The highest serum ferroprotein level was 899 μg/L. Computed tomography (CT) of the abdomen revealed dilatation of blood vessels in the intestinal walls (Fig. 1d) and gastroscopy showed a duodenal ulcer with bleeding. He developed unexpected and sudden life-threatening hemorrhage from the intestinal vasculature, which led to hypovolemic shock. Routine management included treatment for shock, empirical antibiotics, blood transfusion, and hemostatic therapy. However, the hemorrhage was only controlled for 2 days using duodenal artery embolization. He also developed polyuria (3-4 L/d), frequent convulsions and hyponatremia (109 mEq/L). With treatment, his symptoms improved. However, the gastrointestinal hemorrhage and polyuria persisted, and the patient was transferred to our hospital for further management.\n\nHe was unconscious on admission, had a Glasgow Coma Scale (GCS) score of 11 and had hepatomegaly and splenomegaly. Laboratory tests demonstrated a white blood count of 6.02 × 10^9/L, hemoglobin level of 112 g/L, platelet count of 75 × 10^9/L, D-dimer level of 3.82 mg/L, prothrombin time of 13.3 s, activated partial thromboplastin time of 36.4 s, and a fibrinogen level of 1.66 g/L. The serum albumin levels were low at 26 g/L, but the liver function was within normal limits. The serum levels of triglyceride and ferroprotein were within normal range at 1.58 mmol/L (normal range: 0.45–1.7 mmol/L) and 227.5 μg/L, respectively (normal range: 20.0–200.0 μg/L). EBV DNA and cytomegalovirus DNA were both detected in the blood; the levels of viral copies were 1.17 × 10^4/mL and 2.62 × 10^3/mL, respectively. Tests for serum EBV antibodies, including immunoglobulin A (Ig A)/ VCA, immunoglobulin G (IgG) /VCA, and IgM/VCA, were negative. The numbers of natural killer cells in the blood were low, accounting for 0.6% of lymphocytes. Initially, the cerebrospinal fluid (CSF) pressure was abnormally raised (245 cm of H2O). An EBV-DNA level of 1.43 × 10^4 copies/mL was detected in the CSF by polymerase chain reaction (PCR); the CSF also tested positive for Epstein - Barr virus VCA (IgG). Three-dimensional CT angiography of the head and neck demonstrated an aneurysm in the right internal carotid artery (Fig. 1c). The echocardiography was essentially normal, without any coronary artery dilation or aneurysm. We confirmed the diagnosis of EBV-LPD, based on the results in situ hybridization of EBV-encoded miRNA (EBER) (Fig. 1b). Electroencephalo-graphy showed diffuse slowing (Fig. 1e).\n\nTreatment in our hospital and follow up\nA repeated duodenal artery embolization and symptomatic therapy could not control the hemorrhage. He subsequently received treatment with ganciclovir, glucocorticoid, thalidomide at a dose of 2 mg/kg/d in 3 divided doses, and propranolol at an initial dose of 1.5–2 mg/kg/d. Hemorrhage was controlled in 5 days; his symptoms improved and urine output was normalized. The GCS score was 14. Then, the fever did not recur and the CSF pressure was also normalized. The level of EBV DNA of CSF was 2.5 × 10^2 copies /mL (normal value: ≤500).\n\nHe had a spontaneous remission of seizures on day 19 of admission. He was discharged from hospital on day 24 of admission. After discharge, he was diagnosed with epilepsy owing to recurring seizures, which required the successive use of levetiracetam and oxcarbazepine to control. A follow-up CT at 3 months after admission showed regression of the aneurysm in the right internal carotid artery and the vascular lesion in the duodenum. The drug therapy schedule and levels of EBV DNA are shown in Fig. 1f.\n\nSimilar and contrasting cases in the literature\nA literature search revealed only 3 reports of cases with 2 or more rare EBV-associated clinical manifestations. Mashima et al. [8] reported the case of a 55-year-old woman with aplastic anemia who was diagnosed with EBV-LPD and EBV encephalitis. Another report, by Noda et al. (2011), described the case of an immunocompetent 65-year-old man who presented with complaints of general malaise and severe disturbance of consciousness. He was initially suspected to have EBV encephalitis based on the findings on MRI of the brain, elevated EBV antibody titers, and the presence of EBV DNA in the CSF. Finally, he was diagnosed with an EBV-associated B-cell LPD with CNS involvement, and found to have EBER by in situ hybridization positivity in the brain tissue on autopsy. In the third report, Raman et al. (2014) described a patient with newly diagnosed HIV infection, who also developed cerebral vasculitis and encephalitis due to EBV.\n\nA review of the literature is presented, with a summary of 8 cases of CAEBV-associated enteritis and EBV-LPD in non-immunocompromised individuals (Table 1).\nTable 1 Case reports of enteritis and/or gastrointestinal haemorrhage in immunocompetent patients with EBV- LPD\n\nSource, y\tAge at diagnosis, y/Sex\tDuration between symptom onset to hospital admission\tSymptoms;\nmisdiagnose\tDuration of haemorrhage, amount of bleeding\tDiseased region with haemorrhage\tIntestinal pathology\tPCR\nVCA-IgM\nVCA-IgG\nEA\nEBNA\nEBER\tSerum EBV DNA copies/ml\tInfected cell\tOperation\tDrug Treatment\t\nWang et al. [6], 2018\t43y/F†\t2 m\tintermittent fever, chill, abdominal pain, diarrhea, hematochezia; NA\t4d, large\tmultiple aphthous bleeding ulcers scattered from the stoma to about 40 cm away from small intestine\tMultiple colonic ulcers\tNT\n\n+\n\n+\n\n+\n\n+\n\n+\n\n\t2.55 × 10^6\tT\ttotal colectomy\tMesalazine,Glucocorticoid,antiviral medication\t\nXiao et al. [9], 2016\t14y/M†\t1.75 y\tbellyache, diarrhea, fever, hematochezia, gastrointestinal Perforations; IBD\t1 y, large\tIntestinal hemorrhea\tdiffuse heterotypic lymphoid cells infiltration, karyorrhexis and patchy necrosis\tNT\n\nNT\n\n+\n\n+\n\n+\n\n+\n\n\tNT\tT/NK\tgastrointestinal perforation repair, intestinal anastomosis\tMesalazine,Prednisone\t\nChen et al. [10], 2016*\t29/M†*\tover 1y\trecurrent diarrhea,abdominal pain, fever,intestinal perforation; CD\tNA,large\tNA\tmultiple ulcers in esophagus, stomach, terminal ileum, and the entire colon\tNT\n\n+\n\nNT\n\nNT\n\nNT\n\n+\n\n\tNT\tT\tpartial intestinal bowel resection,terminal ileum colostomy\tMethylprednisolone, mesalazine, anti-TNF, chemotherapy\t\nZheng et al. [11], 2015\t26y/M†\tOver 3 m\tintermittent fever, diarrhea, hematochezia; UC\tMore than 1 m, large\tmultiple colorectal ulcers\tMultiple colorectal ulcers\t+\n\nNT\n\n+\n\n+\n\n+\n\n+\n\n\t9 × 10^4\tT\tright hemicolectomy\tantiviral and hormonal therapy\t\nNa et al. [12], 2013\t49y/F#@\t19 m\trecurrent hematochezia, small bowel perforation; CD\t10 m, large recurrent hematochezia\tsmall bowel\tmultiple ulcer scars in the cecum and ascending colon\tNT\n\nNT\n\nNT\n\nNT\n\nNT\n\nNT\n\n\t1.75× 10^3\tT\tnear-total small bowel resection\tPrednisolone, infliximab (5 mg/kg) infusion, chemotherapy\t\nNa et al. [12], 2013\t50y/M†\t8y\tweakness, anorexia, weight loss, loose stools, fever, perforation; intestinal TB and CD\tNo\tNo\tan ulcer at the terminal ileum\n\n,multiple discrete ulcers scattered from the distal ascending colon to the rectum\n\n\tNT\n\nNT\n\nNT\n\nNT\n\nNT\n\n+\n\n\t3.45× 10^4\tT\tsmall bowel resection; jejuno-ileostomy\tanti-tuberculous,\n\nPrednisolone,\n\nMesalamine, chemotherapy\n\n\t\nAbdul-Ghafar et al. [13], 2011\t45y/M†\t45d\tdiarrhea,\n\nweight loss; UC\n\n\t3d, large\textensive ulcerations along the whole colon\tmultiple ulcerations scattered along the whole colon and ileocecal valve\t+\n\nNT\n\nNT\n\nNT\n\nNT\n\n+\n\n\tNT\tT\ttotal colectomy\toral metronidazole, intra-venous antibiotics\t\nKarlitz et al. [14],2011\t30y/M#\t2 m\tlower abdominal bloating and loose, bloody, mucoid bowel movements\tNA,small\tNA\tdiffuse erythematous and edematous mucosa located contiguously throughout the colon\t+\n\nNT\n\nNT\n\nNT\n\nNT\n\n+\n\n\tNT\tB\tND\tsupportive care alone\t\nOur case\t5y/M#\tOver 2y\trecurrent fever,diarrhea, abdominal pain, Hematochezia, polyuria;CD\t3d,large\ta duodenal ulcer and dilatation of duodenal artery\ta duodenal ulcer, and the entire colon ulcers\t+\n\n-\n\n-\n\nNT\n\nNT\n\n+\n\n\t1.17 × 10 ^ 4\tNA\tND\tPrednisolone, Ganciclovir, thalidomide, propranolol\t\nAbbreviations: EBV- LPD EBV associated lymphoproliferative disorder, PCR polymerase chain reaction, VCA-IgM Viral capsid antigen Immunoglobulin M, VCA-IgG Viral capsid antigen Immunoglobulin G, EA early antigen, EBNA Epstein-Barr virus nuclear antigen, EBER EBV-encoded early small ribonucleic acid, EBV Epstein–Barr virus, DNA Deoxyribose Nucleic Acid, F Female, IBD Inflammatory Bowel Disease, NT not tested, NA not assessed, UC ulcerative colitis, CD Crohn disease, TB tuberculosis, ND not done, + positive test, − negative, y year or years, m months, w weeks, d days, hr hours, † Died, # Recovery, * Finally,he was diagnosed with EBV-associated NK/T-cell lymphoma.@ she was diagnosed with peripheral T-cell lymphoma\n\n\n\nDiscussion and conclusions\nThe clinical manifestations of CAEBV vary according to the site of involvement, such as multiple vascular lesions, intestinal lesions, central nervous system complications and so on. A standard and effective treatment protocol for systemic EBV-LPD is lacking. HSCT is the only cure.\n\nWe report a rare case of CAEBV with intestinal, vascular, and neurological involvement. He presented a sudden life-threatening gastrointestinal hemorrhage because of enteritis and the dilatation of intestinal vasculature. It has been reported in the literature [15] that most of these conditions required surgical resection of the bowel, and if surgery was not possible, most died of massive bleeding. For our case, titanium clips and somatostatin were employed to control the hemorrhage, but it soon recurred. Interestingly, the hemorrhage was controlled within 5 days after treatment with ganciclovir, thalidomide, and propranolol. The intestinal vasculature was caused by EBV, not caused by a congenital vascular malformation, because EBER-lymphocytes were positive in the intestinal tract. A follow-up CT scan showed regression of all aneurysm. Thalidomide and propranolol are apparently effective in treating enteritis and vascular lesions secondary to EBV infection.\n\nBoth propranolol and thalidomide were known as angiogenesis inhibitor. Propranolol is the preferred treatment for accidentally diagnosed infantile hemangiomas [16, 17]. Thalidomide has proven efficacy in myeloma [18]. However, neither of these drugs have previously been used for vascular lesions associated with EBV infection.\n\nJones et al. [19] reported that thalidomide and pomalidomide may reactivate EBV-positive resting memory B cells, thereby enhancing the EBV lytic cycle and host immune suppression. However, thalidomide is less effective than pomalidomide in enhancing the EBV lytic cycle [19]. And patients with CAEBV may have deficiencies of EBV-specific cellular immunity, and nearly all resting memory B cells are activated. Therefore, only a few of these cells may be reactivated by thalidomide with minimal impact on the condition of these patients. Our case showed that thalidomide was safe for treating CAEBV.\n\nYager et al. [20] found that oral valganciclovir could inhibit EBV replication. In our patient, long-term oral ganciclovir therapy could inhibit EBV replication in the gastrointestinal tract; corticosteroids offered symptomatic relief. The improvement in the intestinal lesions in our patient confirmed this effect.\n\nWith the combination treatment, our patient’s clinical symptoms disappeared despite the persistence of EBV DNA load in peripheral blood. This proved the efficacy of this combination therapy. Our goal of treatment was not the achievement of complete remission, but long-term symptom control, regardless of the presence of the EBV genome.\n\nWe think this report and discussion may improve the understanding and management of CAEBV. This therapy may represent a safe and feasible alternative for severe CAEBV and associated LPD patients, which warrants further research.\n\nAbbreviations\nCAEBVChronic active Epstein-Barr virus infection\n\nCDCrohn disease\n\nCSFCerebro-spinal fluid\n\nCTComputed tomography\n\nDNADeoxyribose Nucleic Acid\n\nEBEREBV-encoded early small ribonucleic acid\n\nEBVEpstein–Barr virus\n\nEBV-LPDEBV associated lymphoproliferative disorder\n\nGCSGlasgow Coma Scale\n\nHSCTHematopoietic stem cell transplantation\n\nIgGImmunoglobulin G\n\nIgMImmunoglobulin M\n\nIMinfectious mononucleosis\n\nVCAViral capsid antigen\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nLingling Xu and Hongjun Ba are co-first author.\n\nAcknowledgements\nWe sincerely thank Xu Chen for helpful advice and critical reading of this manuscript and thank Editage (www.editage.com) for English language editing.\n\nAuthors’ contributions\nL-LX and H-JB were the attending physician of this patient and the director of the whole writing process. H-RL and S-PL participated in all data collection and processing. X-YJ, Z-YY were responsible for reading and interpreting the pathological images. WT and Z-YH were the major contributors in organizing records and drafting the manuscript. All authors proofread and approved the manuscript.\n\nFunding\nThis study was supported by national college students innovation and enterpreneurship training program (201901092) and national college students innovation and enterpreneurship training program (201901095).\n\nAvailability of data and materials\nAll datasets generated for this study are included in the manuscript and the supplementary files.\n\nEthics approval and consent to participate\nThe study protocols were approved by the institutional review board of The First Affiliated Hospital, Sun Yat-sen University Ethical Committee.\n\nConsent for publication\nSigned informed consent forms were obtained from the parents of this patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Cohen JI Jaffe ES Dale JK Pittaluga S Heslop HE Rooney CM Characterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States BLOOD 2011 117 5835 1482 10.1093/annonc/mdp064 21454450 \n2. Xing Y Yang J Lian G Chen S Chen L Li F Chronic active Epstein-Barr virus infection associated with hemophagocytic syndrome and extra-nodal natural killer/T-cell lymphoma in an 18-year-old girl: A case report Medicine 2017 96 e6845 10.1097/MD.0000000000006845 28489771 \n3. Rolinski J Grywalska E Pyzik A Dzik M Opoka-Winiarska V Surdacka A Interferon alpha as antiviral therapy in chronic active Epstein-Barr virus disease with interstitial pneumonia - case report BMC Infect Dis 2018 18 190 10.1186/s12879-018-3097-6 29678144 \n4. Nishimura S Ehara S Hanatani A Yoshiyama M Chronic active Epstein-Barr virus infection complicated with multiple artery aneurysms Eur Heart J Cardiovasc Imaging 2014 15 1255 10.1093/ehjci/jeu119 24939943 \n5. Kobayashi Z Tsuchiya K Takahashi M Yokota O Sasaki A Bhunchet E An autopsy case of chronic active Epstein-Barr virus infection (CAEBV): distribution of central nervous system (CNS) lesions J Neurol Sci 2008 275 170 177 10.1016/j.jns.2008.07.035 18793782 \n6. Wang Y Li Y Meng X Duan X Wang M Chen W Epstein-Barr virus-associated T-cell Lymphoproliferative disorder presenting as chronic diarrhea and intestinal bleeding: a case report Front Immunol 2018 9 2583 10.3389/fimmu.2018.02583 30519236 \n7. Matsui S Takeda Y Isshiki Y Yamazaki A Nakao S Takaishi K Chronic active Epstein-Barr virus infection with marked pericardial effusion successfully treated with allogeneic peripheral blood stem cell transplantation Rinsho Ketsueki 2016 57 624 629 10.11406/rinketsu.57.624 27263789 \n8. Mashima K Yano S Yokoyama H Saito T Machishima T Shimada T Epstein-Barr virus-associated Lymphoproliferative disorder with encephalitis following anti-thymocyte globulin for aplastic Anemia resolved with rituximab therapy: a case report and literature review Intern Med 2017 56 701 706 10.2169/internalmedicine.56.7722 28321074 \n9. Xiao HJ Li J Song HM Li ZH Dong M Zhou XG Epstein-Barr Virus-Positive T/NK-Cell Lymphoproliferative Disorders Manifested as Gastrointestinal Perforations and Skin Lesions: A Case Report Medicine 2016 95 e2676 10.1097/MD.0000000000002676 26844502 \n10. Chen H Zhang Y Jiang Z Zhou W Cao Q A Case Report of NK-Cell Lymphoproliferative Disease With a Wide Involvement of Digestive Tract Develop Into Epstein-Barr Virus Associated NK/T Cell Lymphoma in an Immunocompetent Patient Medicine 2016 95 e3176 10.1097/MD.0000000000003176 27015206 \n11. Zheng X Xie J Zhou X Epstein-Barr virus associated T-cell lymphoproliferative disease misdiagnosed as ulcerative colitis: a case report Int J Clin Exp Pathol 2015 8 8598 8602 26339440 \n12. Na HK Ye BD Yang SK Yang DH Jung KW Kim KJ EBV-associated lymphoproliferative disorders misdiagnosed as Crohn's disease J Crohns Colitis 2013 7 649 652 10.1016/j.crohns.2012.09.018 23078910 \n13. Abdul-Ghafar J Kim JW Park KH Cho MY Fulminant Epstein-Barr virus-associated T-cell lymphoproliferative disorder in an immunocompetent middle-aged man presenting with chronic diarrhea and gastrointestinal bleeding J Korean Med Sci 2011 26 1103 1107 10.3346/jkms.2011.26.8.1103 21860564 \n14. Karlitz JJ Li ST Holman RP Rice MC EBV-associated colitis mimicking IBD in an immunocompetent individual Nat Rev Gastroenterol Hepatol 2011 8 50 54 10.1038/nrgastro.2010.192 21119609 \n15. Dong XY Li J Li Y Wu D Zhang Y Cao W The clinical characteristics of immunocompetent adults with chronic active Epstein-Barr virus associated enteritis Zhonghua Nei Ke Za Zhi 2018 57 487 493 10.3760/cma.j.issn.0578-1426.2018.07.004 29996266 \n16. Hagen R Ghareeb E Jalali O Zinn Z Infantile hemangiomas: what have we learned from propranolol? Curr Opin Pediatr 2018 30 499 504 10.1097/MOP.0000000000000650 29846253 \n17. Ji Y Chen S Xu C Li L Xiang B The use of propranolol in the treatment of infantile haemangiomas: an update on potential mechanisms of action Br J Dermatol 2015 172 24 32 10.1111/bjd.13388 25196392 \n18. Weber D Rankin K Gavino M Delasalle K Alexanian R Thalidomide alone or with dexamethasone for previously untreated multiple myeloma J Clin Oncol 2003 21 16 19 10.1200/JCO.2003.03.139 12506164 \n19. Jones RJ Iempridee T Wang X Lee HC Mertz JE Kenney SC Lenalidomide, thalidomide, and Pomalidomide reactivate the Epstein-Barr virus lytic cycle through Phosphoinositide 3-kinase signaling and Ikaros expression Clin Cancer Res 2016 22 4901 4912 10.1158/1078-0432.CCR-15-2242 27297582 \n20. Yager JE Magaret AS Kuntz SR Selke S Huang ML Corey L Valganciclovir for the suppression of Epstein-Barr virus replication J Infect Dis 2017 216 198 202 10.1093/infdis/jix263 28838145\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1720-8424",
"issue": "45(1)",
"journal": "Italian journal of pediatrics",
"keywords": "Chronic active Epstein-Barr virus infection; Encephalitis; Enteritis; Propranolol; Thalidomide; Vascular lesions",
"medline_ta": "Ital J Pediatr",
"mesh_terms": "D002675:Child, Preschool; D002681:China; D003131:Combined Modality Therapy; D020031:Epstein-Barr Virus Infections; D006801:Humans; D008232:Lymphoproliferative Disorders; D008297:Male",
"nlm_unique_id": "101510759",
"other_id": null,
"pages": "135",
"pmc": null,
"pmid": "31685000",
"pubdate": "2019-11-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "12506164;27297582;26339440;25196392;24939943;28838145;27015206;29678144;21454450;28489771;21119609;23078910;26844502;30519236;29846253;29996266;28321074;21860564;18793782;27263789",
"title": "A new therapy in Epstein-Barr virus-associated lymphoproliferative disease: a case report and a revision of the literature.",
"title_normalized": "a new therapy in epstein barr virus associated lymphoproliferative disease a case report and a revision of the literature"
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"abstract": "BACKGROUND\nThe coronavirus disease of 2019, also known as COVID-19, has been declared a global pandemic. Significant controversies exist regarding treatment modalities for this novel disease, especially in immunocompromised patients. Experience with management of COVID-19 in kidney transplant recipients is scarce; effects of this virus on immunosuppressed individuals are not well understood.\n\n\nMETHODS\nWe identified 30 renal transplant recipients with confirmed COVID-19 pneumonia who were admitted to inpatient between March 2020 and April 2020. All patients received a 5-day course of hydroxychloroquine and azithromycin; half of the patients received methylprednisolone. During hospitalization, calcineurin inhibitors and antimetabolites were held; prednisone was continued.\n\n\nRESULTS\nClinical presentation of flu-like symptoms was similar to those in the general population. Hyponatremia, lymphopenia, acute kidney injury, and elevated inflammatory markers were common. Over the course of follow-up, 23 have been discharged home with a functioning allograft and in stable condition; 4 experienced acute kidney injury requiring renal replacement therapy; 7 patients were intubated, and 6 expired. The mortality rate in our cohort was 20%.\n\n\nCONCLUSIONS\nOur findings described the characteristics and outcomes of this highly fatal illness in a multi-ethnic kidney transplant cohort, with insights on immunosuppression management that could further our understanding of this unique disease in immunocompromised populations.",
"affiliations": "Department of Pharmacy, SUNY Downstate Health Sciences University Hospital, Brooklyn, New York, USA.;Department of Pharmacy, SUNY Downstate Health Sciences University Hospital, Brooklyn, New York, USA.;Department of Pharmacy, SUNY Downstate Health Sciences University Hospital, Brooklyn, New York, USA.;Department of Infectious Diseases, SUNY Downstate Health Sciences University Hospital, Brooklyn, New York, USA.;Department of Pharmacy, SUNY Downstate Health Sciences University Hospital, Brooklyn, New York, USA.;Department of Surgery, SUNY Downstate Health Sciences University Hospital, Brooklyn, New York, USA.;Department of Pharmacy, SUNY Downstate Health Sciences University Hospital, Brooklyn, New York, USA.;Department of Surgery, SUNY Downstate Health Sciences University Hospital, Brooklyn, New York, USA.",
"authors": "Chen|Tracy Yixin|TY|https://orcid.org/0000-0001-7678-5332;Farghaly|Sara|S|https://orcid.org/0000-0002-8816-9454;Cham|Samantha|S|https://orcid.org/0000-0003-2860-727X;Tatem|Luis Lantigua|LL|https://orcid.org/0000-0002-9351-4443;Sin|Jonathan H|JH|https://orcid.org/0000-0003-3155-6039;Rauda|Roberto|R|https://orcid.org/0000-0003-4924-7496;Ribisi|Maria|M|https://orcid.org/0000-0002-3693-2219;Sumrani|Nabil|N|https://orcid.org/0000-0001-7704-9847",
"chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D012367:RNA, Viral; D006886:Hydroxychloroquine; D017963:Azithromycin; D011241:Prednisone; D008775:Methylprednisolone",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13378",
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"issn_linking": "1398-2273",
"issue": "22(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "COVID-19; immunosuppression; kidney transplantation; viral pneumonia",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D017963:Azithromycin; D000086382:COVID-19; D000087123:COVID-19 Nucleic Acid Testing; D065095:Calcineurin Inhibitors; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006801:Humans; D006886:Hydroxychloroquine; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D009519:New York City; D011241:Prednisone; D012367:RNA, Viral; D017582:Renal Replacement Therapy; D012121:Respiration, Artificial; D012189:Retrospective Studies; D000086402:SARS-CoV-2; D066027:Transplant Recipients; D016896:Treatment Outcome",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13378",
"pmc": null,
"pmid": "32573882",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article",
"references": "32250388;32085846;32149036;32161940;26046523;23622590;32233057;32273593;32425950;32354634;25620767;32276031;17537853;32329975;32229705;32573882;22533718;30517367;32243698;32249845;30402328;32362390;31324482;32105090;32330343;31365162;32220278",
"title": "COVID-19 pneumonia in kidney transplant recipients: Focus on immunosuppression management.",
"title_normalized": "covid 19 pneumonia in kidney transplant recipients focus on immunosuppression management"
} | [
{
"companynumb": "US-MYLANLABS-2021M1003581",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": null... |
{
"abstract": "Children with ataxia-telangiectasia (A-T) and cancer have a poorer prognosis due in part to increased treatment-related toxicity. We piloted a curative intent approach in five children with A-T who presented with advanced stage (III, n = 2; IV, n = 3) B-NHL (diffuse large B-cell lymphoma, n = 4; Burkitt leukemia, n = 1) using a modified LMB-based protocol. Two achieved sustained CCR (one, CCR at 6 years; one, pulmonary death after 3 years in CCR). Two died from toxicity during induction and 1 failed induction with progressive disease. Novel therapeutic approaches which overcome drug resistance and are less toxic are needed for children with A-T and B-NHL.",
"affiliations": "Departments of Oncology, St. Jude Children's Research Hospital Memphis, Tennessee.",
"authors": "Sandlund|J T|JT|;Hudson|M M|MM|;Kennedy|W|W|;Onciu|M|M|;Kastan|M B|MB|",
"chemical_list": "D003561:Cytarabine; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D002955:Leucovorin; D011241:Prednisone; D006854:Hydrocortisone; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.24696",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "61(2)",
"journal": "Pediatric blood & cancer",
"keywords": "Hodgkin lymphoma; ataxia-telangiectasia; children; non-Hodgkin lymphoma",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001260:Ataxia Telangiectasia; D002648:Child; D003520:Cyclophosphamide; D003561:Cytarabine; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006854:Hydrocortisone; D002955:Leucovorin; D016393:Lymphoma, B-Cell; D008297:Male; D008727:Methotrexate; D009367:Neoplasm Staging; D010865:Pilot Projects; D011241:Prednisone; D011379:Prognosis; D011446:Prospective Studies; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "360-2",
"pmc": null,
"pmid": "23900766",
"pubdate": "2014-02",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "7414342;11745277;17634425;18394116;16123984;15289825;12542504;11208881;21923652;15789441;10707797;19142990;11807147;9835901;15069401;16772123;18403632;19418546;11902749;11369626",
"title": "Pilot study of modified LMB-based therapy for children with ataxia-telangiectasia and advanced stage high grade mature B-cell malignancies.",
"title_normalized": "pilot study of modified lmb based therapy for children with ataxia telangiectasia and advanced stage high grade mature b cell malignancies"
} | [
{
"companynumb": "US-PFIZER INC-2015020962",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "A 31-year-old male presented to our facility with complaints of shortness of breath and left-sided chest pain. On record review, it was revealed that he had been seen in 2014 for an almost identical presentation and had been found to have haemolytic anaemia with warm autoantibodies. Following his acute treatment during that hospital admission, he was lost to follow-up. During his subsequent admission, 5 years later, he was found to have a systemic autoimmune disorder with a superimposed acute bacterial infection leading to a second case of haemolytic anaemia and at this time with both cold and warm antibodies present. While his diagnosis was initially difficult to make due to both derangements in expected laboratory values and the mixed pattern of the haemolytic anaemia, he was promptly treated with intravenous immune globulin and steroids and was able to make a full recovery.",
"affiliations": "Internal Medicine, Einstein Medical Center, Philadelphia, Pennsylvania, USA Andersme@einstein.edu.;Internal Medicine, Mount Sinai Medical Center, Miami Beach, Florida, USA.;Hematology/Oncology, Einstein Medical Center, Philadelphia, Pennsylvania, USA.;Hematology/Oncology, Einstein Medical Center, Philadelphia, Pennsylvania, USA.",
"authors": "Anderson|Meghan|M|;Winter|Megan|M|;Jorge|Vinicius|V|;Dourado|Claudia|C|",
"chemical_list": "D001323:Autoantibodies; D003450:Cryoglobulins; D005938:Glucocorticoids; D016756:Immunoglobulins, Intravenous; C029443:cold agglutinins",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-232224",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(6)",
"journal": "BMJ case reports",
"keywords": "haematology (incl blood transfusion); immunology; systemic lupus erythematosus",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000744:Anemia, Hemolytic, Autoimmune; D001323:Autoantibodies; D003450:Cryoglobulins; D003937:Diagnosis, Differential; D004417:Dyspnea; D005938:Glucocorticoids; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008180:Lupus Erythematosus, Systemic; D008297:Male",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32595125",
"pubdate": "2020-06-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Development of new cold antibodies in a patient with a history of warm autoimmune haemolytic anaemia.",
"title_normalized": "development of new cold antibodies in a patient with a history of warm autoimmune haemolytic anaemia"
} | [
{
"companynumb": "US-TEVA-2020-US-1812650",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "A case of metformin encephalopathy is presented in a patient on haemodialysis for end-stage diabetic renal failure. The patient presented with frequent falls and clinical signs of Parkinsonism, on a background of recent anorexia and significant weight loss. Magnetic resonance imaging showed bilateral, symmetrical abnormalities centred on the lentiform nuclei. Metformin was withheld and signs and symptoms quickly resolved. We hypothesise that metformin may cause thiamine deficiency in patients with end-stage renal failure resulting in a specific metabolic encephalopathy.",
"affiliations": "Department of Neurology, Royal Perth Hospital, Perth, Western Australia, Australia.;Department of Neurology, Royal Perth Hospital, Perth, Western Australia, Australia.;Department of General Medicine, Royal Perth Hospital, Perth, Western Australia, Australia.;Department of Neurological Intervention and Imaging Service of WA, Royal Perth Hospital, Perth, Western Australia, Australia.",
"authors": "McGarvey|Caoimhe|C|0000-0002-5928-4912;Franconi|Catherine|C|;Prentice|David|D|;Bynevelt|Michael|M|",
"chemical_list": "D007004:Hypoglycemic Agents; D014803:Vitamin B Complex; D008687:Metformin; D013831:Thiamine",
"country": "Australia",
"delete": false,
"doi": "10.1111/imj.13693",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1444-0903",
"issue": "48(2)",
"journal": "Internal medicine journal",
"keywords": "encephalopathy; end-stage renal failure; haemodialysis; metformin; thiamine deficiency",
"medline_ta": "Intern Med J",
"mesh_terms": "D000328:Adult; D001927:Brain Diseases; D003928:Diabetic Nephropathies; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008687:Metformin; D013831:Thiamine; D014803:Vitamin B Complex",
"nlm_unique_id": "101092952",
"other_id": null,
"pages": "194-197",
"pmc": null,
"pmid": "29415360",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metformin-induced encephalopathy: the role of thiamine.",
"title_normalized": "metformin induced encephalopathy the role of thiamine"
} | [
{
"companynumb": "AU-CHARTWELL PHARMA-2042678",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Azacytidine, an antimetabolite with an original epigenetic mechanism of action, increases survival in patients diagnosed with high-risk myelodysplasic syndromes or acute myeloid leukemia with less than 30% medullar blasts. Azacytidine is a pyrimidine derivative that undergoes metabolic detoxification driven by cytidine deaminase (CDA), a liver enzyme whose gene is prone to genetic polymorphism, leading to erratic activity among patients. Clinical reports have shown that patients with the poor metabolizer (PM) phenotype are likely to experience early severe or lethal toxicities when treated with nucleosidic analogs such as gemcitabine or cytarabine. No clinical data have been available thus far on the relationships between CDA PM status and toxicities in azacytidine-treated patients. Here, we measured CDA activity in a case of severe toxicities with fatal outcome in a patient undergoing standard azacytidine treatment. Results showed that the patient was PM (i.e. residual activity reduced by 63%), thus suggesting that an impaired detoxification step could have given rise to the lethal toxicities observed. This case report calls for further prospective studies investigating the exact role that CDA status plays in the clinical outcome of patients treated with azacytidine.",
"affiliations": "aSMARTc Unit, Pharmacokinetics Laboratory, UMR_911 CRO2 AMU bPharmacy Unit cOnco-Hematology Unit dHematology Laboratory, La Conception University Hospital of Marseille eTransfer Oncology Laboratory, Nord University Hospital of Marseille, APHM, Marseille, France.",
"authors": "Fanciullino|Raphaelle|R|;Mercier|Cedric|C|;Serdjebi|Cindy|C|;Berda|Yaël|Y|;Fina|Frederic|F|;Ouafik|L'Houcine|L|;Lacarelle|Bruno|B|;Ciccolini|Joseph|J|;Costello|Regis|R|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D003841:Deoxycytidine; C056507:gemcitabine; D003564:Cytidine Deaminase; D001374:Azacitidine",
"country": "United States",
"delete": false,
"doi": "10.1097/FPC.0000000000000139",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1744-6872",
"issue": "25(6)",
"journal": "Pharmacogenetics and genomics",
"keywords": null,
"medline_ta": "Pharmacogenet Genomics",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D003561:Cytarabine; D003564:Cytidine Deaminase; D003841:Deoxycytidine; D017809:Fatal Outcome; D006801:Humans; D008658:Inactivation, Metabolic; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D020641:Polymorphism, Single Nucleotide",
"nlm_unique_id": "101231005",
"other_id": null,
"pages": "317-21",
"pmc": null,
"pmid": "25850965",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lethal toxicity after administration of azacytidine: implication of the cytidine deaminase-deficiency syndrome.",
"title_normalized": "lethal toxicity after administration of azacytidine implication of the cytidine deaminase deficiency syndrome"
} | [
{
"companynumb": "FR-MYLANLABS-2020M1085361",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "Pachyonychia congenital (PC) is a rare genetic disorder of cornification and is classified into five types on the basis of keratin gene involved. There are no established treatment options available for PC. Sirolimus in both topical and oral form has been studied in management of PC. We report a young female with a novel genetic mutation in KRT6A gene who presented with painful palmoplantar hyperkeratosis and onychogryphosis, which was cosmetically disfiguring. She was prescribed oral sirolimus after all investigations. There was significant improvement in pain within a week. Pain relief was sustained at 1 year follow-up with topical treatment only. Serial nail avulsion surgeries were also done with showed significant cosmetic improvement in the nails. Medical therapies can be combined with surgery for a better cosmetic outcome and improvement in patient quality of life.",
"affiliations": "Department of Dermatology, Venereology and Leprology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Dermatology, Venereology and Leprology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Dermatology, Venereology and Leprology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Dermatology, Venereology and Leprology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Chief Geneticist, Pachyonychia Congenita Project (PC Project), Holladay, Utah.;Department of Dermatology, Venereology and Leprology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Daroach|Manju|M|0000-0002-9439-499X;Dogra|Sunil|S|;Bhattacharjee|Rajsmita|R|0000-0002-6060-2877;Tp|Afra|A|;Smith|Frances|F|;Mahajan|Rahul|R|",
"chemical_list": "C507569:KRT6A protein, human; D053553:Keratin-6; D009539:Nicotinic Acids; C086827:tazarotene; D020156:Salicylic Acid; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.13045",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "32(5)",
"journal": "Dermatologic therapy",
"keywords": "novel mutation; pachyonychia congenita; sirolimus",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000287:Administration, Topical; D003131:Combined Modality Therapy; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053553:Keratin-6; D009154:Mutation; D009262:Nails; D009539:Nicotinic Acids; D053549:Pachyonychia Congenita; D035583:Rare Diseases; D020156:Salicylic Acid; D020123:Sirolimus; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e13045",
"pmc": null,
"pmid": "31364784",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016422:Letter; D016454:Review",
"references": null,
"title": "Pachyonychia congenita responding favorably to a combination of surgical and medical therapies.",
"title_normalized": "pachyonychia congenita responding favorably to a combination of surgical and medical therapies"
} | [
{
"companynumb": "IN-PFIZER INC-2019498809",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "A 24-year-old woman with ΔF508/Y1092X cystic fibrosis (CF) complicated by severe obstructive lung disease (FEV1 of 30% predicted) was admitted for IV antibiotics for planned sinus surgery resulting from severe chronic sinusitis causing frequent exacerbations and declining lung function. She had persistent airway infection with multidrug-resistant Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and growth of a fungus presumed to be an airway colonizer, identified as Stephanoascus ciferrii 1 year before presentation. Two days after surgery, she developed acute respiratory failure requiring mechanical ventilation. On day 4 of mechanical ventilation, venovenous-extracorporeal membrane oxygenation (VV-ECMO) was initiated for refractory respiratory failure. The following day, she was listed for bilateral lung transplant and was transplanted 4 days later. Following transplantation, she was decannulated from ECMO; however, over the next 12 hours, oxygenation deteriorated requiring reinstitution of VV-ECMO for presumed severe primary graft dysfunction. Despite treatment with broad spectrum antimicrobial coverage with piperacillin/tazobactam, ciprofloxacin, linezolid, micafungin, voriconazole, and ganciclovir, she failed to improve and developed complex bilateral pleural effusions.",
"affiliations": "Walter Reed National Military Medical Center Department of Pulmonary and Critical Care, Walter Reed Military Medical Center, Bethesda, MD. Electronic address: Whittney.Warren@gmail.com.;Advanced Lung Disease and Transplant Program, Inova Heart and Vascular Institute, Inova Fairfax Hospital, Falls Church, VA.;Advanced Lung Disease and Transplant Program, Inova Heart and Vascular Institute, Inova Fairfax Hospital, Falls Church, VA.;Advanced Lung Disease and Transplant Program, Inova Heart and Vascular Institute, Inova Fairfax Hospital, Falls Church, VA.;Advanced Lung Disease and Transplant Program, Inova Heart and Vascular Institute, Inova Fairfax Hospital, Falls Church, VA.;Advanced Lung Disease and Transplant Program, Inova Heart and Vascular Institute, Inova Fairfax Hospital, Falls Church, VA; Infectious Diseases Physicians, Inc., Annandale, VA.;Department of Pathology, Inova Fairfax Hospital, Falls Church, VA.;Advanced Lung Disease and Transplant Program, Inova Heart and Vascular Institute, Inova Fairfax Hospital, Falls Church, VA.",
"authors": "Warren|Whittney A|WA|;Franco-Palacios|Domingo|D|;King|Christopher S|CS|;Shlobin|Oksana A|OA|;Nathan|Steven D|SD|;Katugaha|Shalika B|SB|;Mani|Haresh|H|;Brown|A Whitney|AW|",
"chemical_list": "D000935:Antifungal Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2017.08.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "153(3)",
"journal": "Chest",
"keywords": null,
"medline_ta": "Chest",
"mesh_terms": "D000935:Antifungal Agents; D003453:Cryptococcosis; D003454:Cryptococcus; D003550:Cystic Fibrosis; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D016040:Lung Transplantation; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome; D020775:Thoracic Surgery, Video-Assisted; D055815:Young Adult",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e53-e56",
"pmc": null,
"pmid": "29519311",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A 24-Year-Old Woman With Precipitous Respiratory Failure After Lung Transplantation.",
"title_normalized": "a 24 year old woman with precipitous respiratory failure after lung transplantation"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/18/0097764",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
... |
{
"abstract": "BACKGROUND\nAddition of erlotinib to metronomic chemotherapy (MCT) may lead to further improvement in progression-free survival (PFS) and overall survival in head and neck cancers. The aim of this study was to study the PFS with MCT + erlotinib combination in our setting.\n\n\nMETHODS\nA single-arm prospective observational study conducted at Malabar Cancer Center. Patients warranting palliative chemotherapy for head and neck cancers, having adequate organ function, not-affording cetuximab and not willing for intravenous chemotherapy were included in this study. Oral methotrexate (15 mg/m(2)/week), oral celecoxib (200 mg twice daily), and erlotinib (150 mg once daily) were administered till the progression of the disease or till intolerable side-effects. Patients underwent toxicity (CTCAE version 4.02) and response (RECIST version 1.1) assessment every 30 days. Statistical analysis was performed using SPSS version 16 (IBM, New York, USA). Descriptive statistics and Kaplan-Meier analysis have been performed.\n\n\nRESULTS\nA total of 15 patients received MCT. The median age of these patients was 65 years (range: 48-80). The Eastern Cooperative Oncology Group Performance Status was 0-1 in seven patients (46.7%), while it was 2 in eight patients (53.3%). The primary sites of tumor were predominantly oral cavity, 11 (73.4%). Prior to MCT, treatment with palliative radiation therapy was given in 11 patients and curative treatment in two patients. The best response post-MCT was complete remission in two patients, partial remission in seven patients, stable disease in four patients, and progressive disease in two patients. The median estimated PFS was 148 days (95% confidence interval 95.47-200.52 days). For a median follow-up of 181 days, there were only three deaths. Grade 3-4 toxicity was seen in six patients (40%). Dose reduction was required in four patients (26.7%).\n\n\nCONCLUSIONS\nThe addition of erlotinib to an MCT schedule of methotrexate and celecoxib resulted in a promising PFS and should be tested in future studies.",
"affiliations": "Department of Clinical Hematology and Medical Oncology, Malabar Cancer Center, Kannur, Kerala, India.;Department of Radiation Oncology, Malabar Cancer Center, Kannur, Kerala, India.;Department of Clinical Hematology and Medical Oncology, Malabar Cancer Center, Kannur, Kerala, India.;Department of Surgical Oncology, Malabar Cancer Center, Kannur, Kerala, India.;Department of Imageology, Malabar Cancer Center, Kannur, Kerala, India.;Department of Surgical Oncology, Malabar Cancer Center, Kannur, Kerala, India.;Department of Cancer Palliative Medicine, Malabar Cancer Center, Kannur, Kerala, India.;Division of Clinical Research and Biostatistics, Malabar Cancer Center, Kannur, Kerala, India.;Department of Surgical Oncology, Malabar Cancer Center, Kannur, Kerala, India.",
"authors": "Patil|Vijay M|VM|;Chakraborty|Santam|S|;Jithin|T K|TK|;Sajith Babu|T P|TP|;Babu|Satheesh|S|;Kumar|Shiva|S|;Biji|M S|MS|;Bhattacharjee|Atanu|A|;Balasubramanian|Satheesan|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/2278-330X.181624",
"fulltext": "\n==== Front\nSouth Asian J CancerSouth Asian J CancerSAJCSouth Asian Journal of Cancer2278-330X2278-4306Medknow Publications & Media Pvt Ltd India SAJC-5-4810.4103/2278-330X.181624METRONOMIC THERAPY IN HEAD AND NECK CANCERS: Original ArticleAn audit of the results of a triplet metronomic chemotherapy regimen incorporating a tyrosine kinase inhibitor in recurrent/metastatic head and neck cancers patients Patil Vijay M. Chakraborty Santam 1Jithin T. K. Sajith Babu T. P. 2Babu Satheesh 3Kumar Shiva 2Biji M. S. 4Bhattacharjee Atanu 5Balasubramanian Satheesan 2Department of Clinical Hematology and Medical Oncology, Malabar Cancer Center, Kannur, Kerala, India1 Department of Radiation Oncology, Malabar Cancer Center, Kannur, Kerala, India2 Department of Surgical Oncology, Malabar Cancer Center, Kannur, Kerala, India3 Department of Imageology, Malabar Cancer Center, Kannur, Kerala, India4 Department of Cancer Palliative Medicine, Malabar Cancer Center, Kannur, Kerala, India5 Division of Clinical Research and Biostatistics, Malabar Cancer Center, Kannur, Kerala, IndiaCorrespondence to: Dr. Vijay M. Patil, E-mail: vijaypgi@gmail.comApr-Jun 2016 5 2 48 51 Copyright: © South Asian Journal of Cancer2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background:\nAddition of erlotinib to metronomic chemotherapy (MCT) may lead to further improvement in progression-free survival (PFS) and overall survival in head and neck cancers. The aim of this study was to study the PFS with MCT + erlotinib combination in our setting.\n\nMethods:\nA single-arm prospective observational study conducted at Malabar Cancer Center. Patients warranting palliative chemotherapy for head and neck cancers, having adequate organ function, not-affording cetuximab and not willing for intravenous chemotherapy were included in this study. Oral methotrexate (15 mg/m2/week), oral celecoxib (200 mg twice daily), and erlotinib (150 mg once daily) were administered till the progression of the disease or till intolerable side-effects. Patients underwent toxicity (CTCAE version 4.02) and response (RECIST version 1.1) assessment every 30 days. Statistical analysis was performed using SPSS version 16 (IBM, New York, USA). Descriptive statistics and Kaplan–Meier analysis have been performed.\n\nResults:\nA total of 15 patients received MCT. The median age of these patients was 65 years (range: 48–80). The Eastern Cooperative Oncology Group Performance Status was 0–1 in seven patients (46.7%), while it was 2 in eight patients (53.3%). The primary sites of tumor were predominantly oral cavity, 11 (73.4%). Prior to MCT, treatment with palliative radiation therapy was given in 11 patients and curative treatment in two patients. The best response post-MCT was complete remission in two patients, partial remission in seven patients, stable disease in four patients, and progressive disease in two patients. The median estimated PFS was 148 days (95% confidence interval 95.47–200.52 days). For a median follow-up of 181 days, there were only three deaths. Grade 3–4 toxicity was seen in six patients (40%). Dose reduction was required in four patients (26.7%).\n\nConclusion:\nThe addition of erlotinib to an MCT schedule of methotrexate and celecoxib resulted in a promising PFS and should be tested in future studies.\n\nErlotinibhead and neck cancermetronomic administrationpalliative chemotherapy\n==== Body\nIntroduction\nHead and neck cancer is one of the most common cancers seen in India and it contributes to nearly one-fifth (22.1%) of the cancer-related mortality in the country.[1] The estimated mortality rates per 1000 patients in head and neck cancers are higher in a rural population (31.8 vs. 14).[1] Age-standardized cancer mortality rate is also higher in illiterate patients as opposed to inpatients educated above secondary level (24.7 vs. 9.0/100,000) in head and neck cancers.[1] This reflects that this disease is not only common in patients in a rural population and in those with the low socioeconomic condition but also is more fatal.[123] The lack of adequate treatment facilities and manpower coupled with the lack of social security may be responsible for this disparity.[4] Metronomic chemotherapy (MCT) was developed to overcome such challenges.[5] Outcomes of patients receiving oral MCT results have been published previously from Mumbai.[67] The MCT schedule used in these studies was of methotrexate (15 mg/m2/week) and daily oral celecoxib 200 mg twice daily. However, the reported progression-free survival (PFS) with this schedule in an ASCO abstract of 2014 was around 3 months.[8] A considerable proportion of these patients had subsequently received erlotinib on progression. With erlotinib, these patients had a response rate of 15.4%. In addition, high-response rates of around 29% have been reported with erlotinib in neoadjuvant chemotherapy setting.[9]\n\nThe combination of a cyclooxygenase-2 (COX-2) inhibitor and epidermal growth factor receptor (EGFR) pathway blocker has a biological rationale as a COX-2 pathway, and EGFR pathway has significant cross-talk.[101112] Resistance to EGFR tyrosine kinase inhibitor may be inhibited by COX-2 inhibitor.[11] Hence, combined inhibition upfront can target the tumor angiogenesis, apoptosis, and tumor growth suppression and decrease the metastatic potential.[11]\n\nThe mechanism of action of erlotinib and MCT are complementary and both have nonoverlapping toxicity hence we thought of combining these drugs. The aim of this study was to study the efficacy of this MCT in our setting. It was hypothesized that this MCT schedule can be considered for further studies at our center if it leads to an estimated PFS of 120 days or more.\n\nMethods\nA review of a prospective database maintained of all patients undergoing MCT in the time period of August 2013 to February 2014 was conducted. The audit protocol was the Institutional Review Board approved. Patients were considered eligible for MCT subject to their fulfilling the following criteria.\n\nInclusion criteria\n\nAge >18 years\n\nPathologically proved squamous cell carcinoma\n\nwithout uncontrolled severe comorbidity\n\nEastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2\n\nNot-affording cetuximab and unwilling for intravenous chemotherapy\n\nQTc interval below 450 ms.\n\n\n\n\nExclusion criteria\n\nPatients with HIV positivity and hepatitis B virus or hepatitis C virus-related hepatitis\n\nPatients not willing for close follow-up\n\nPrimary in nasopharynx.\n\n\n\n\nIntervention\nThese patients were discussed in the multidisciplinary clinic and option for MCT was given. The MCT schedule comprised of tablet methotrexate (2.5 mg tablet) 15 mg/m2 administered once in a week PO, capsule celecoxib 200 mg twice daily PO given daily, and tablet erlotinib 150 mg PO once daily without food.\n\nRationale for selection of doses\nPhase 1 study dose finding study of celecoxib with erlotinib (fixed dose 150 mg) and reradiation in recurrent head and neck cancers recommended a dose of 400 mg of celecoxib.[13] We selected these same doses of erlotinib and celecoxib for our study. In addition, we decided to use a dose of 15 mg/m2 of methotrexate weekly as this dose with celecoxib dose of 400 mg/day was well tolerated in the MCT published literature.[678]\n\nFollow-up schedule\nThe patients were called at regular follow-up at monthly intervals for the first 4 months and then 2 monthly intervals. Compliance was confirmed verbally. At each visit, the patients were assessed clinically for disease status and toxicity was chartered in accordance with CTCAE version 4.02. Radiological response assessment was done at 2-month intervals if the patient did not have gross clinically documented progression.\n\nData collection\nThe details of the basic demographic profile, staging details, MCT details, toxicity details (CTCAE version 4.02), response (RECIST version 1.1), date of progression, death of last follow-up, and date of death were noted from the prospective database of these patients maintained in the outpatient department.\n\nStatistical analysis\nSPSS version 16 (IBM, New York, USA) was used for analysis. The database was closed for analysis on April 14, 2014. Descriptive statistics in the form of median and interquartile range are presented for continuous variables, while frequencies for categorical variables. Kaplan–Meier survival analysis was done for estimation of PFS and overall survival (OS). PFS was defined as time duration in days from the date of start of MCT till the date of progression. Patients were censored at the date of death or last follow-up if no progression was documented. OS was defined as time duration in days from the date of start of MCT till the date of death. Patients were censored at the date of the last follow-up.\n\nResults\nBaseline characteristics\nThere were 15 patients who received MCT within the stipulated time period. The median age of these patients was 65 years (range: 48–80). There were ten males (66.6%) and five females (33.4%). The ECOG PS was 0–1 in seven patients (46.7%), whereas it was 2 in eight patients (53.3%). Details about baseline characteristics of the patient are shown in Table 1.\n\nTable 1 Baseline details of patients\n\nTumor and previous treatment details\nThe primary sites of tumor were an oral cavity in 11 (73.4%), oropharynx in 3 (20%), and hypopharynx in 1 (6.6%) patient. The indication for palliative chemotherapy was metastatic disease in 1 (6.7%) patient, while 14 (93.3%) patients had unresectable locally advanced disease or recurrent disease not amenable to local therapy. The details of previous treatment are shown in Table 2.\n\nTable 2 Previous treatment details\n\nPrior to MCT palliative treatment with palliative RT was delivered in 11 patients. In two patients treated curatively, both had undergone surgery, followed by adjuvant RT. The median time interval between initiation of MCT and primary treatment in patients treated with palliative intent was 2 months (interquartile range: 1.5–2 months).\n\nEfficacy of metronomic chemotherapy\nThe best response post-MCT was complete remission in two patients, partial remission in seven patients, stable disease in four patients, and progressive disease (PD) in two patients. Thus, the response rate was 60% (nine patients). The benefit in terms of reduction in pain grade was seen in eight patients (53.3%), while the requirement for analgesics (a decrement in WHO step of analgesic) decreased in four patients (26.7%).\n\nBy the time of analysis, MCT was stopped in nine patients. The causes of stoppage of MCT were PD in eight patients, and patients desire to discontinue treatment in one.\n\nProgression was seen in nine patients. The median estimated PFS was 148 days (95% confidence interval 95.47–200.52 days) [Figure 1]. For a median follow-up of 181 days, there were only three deaths; hence, median OS cannot be calculated.\n\nFigure 1 Kaplan–Meier estimated progression-free survival\n\nMetronomic chemotherapy toxicity\nThe details of the maximum grade of toxicity during MCT have been shown in Table 3. No Grade 5 toxic events were seen.\n\nTable 3 Toxicity details\n\nThus, Grade 3–4 toxicity was seen in six patients (40%). Indoor admission for the management of toxicity was required in 1 (6.7%) patient. This patient had a hypopharyngeal primary. He had a partial response but got admitted with aspiration pneumonia without neutropenia, with type 1 respiratory failure. The patient succumbed to this complication.\n\nDose delays were required in three patients (20%). The reasons for dose delays were toxicity in all patients. It was erlotinib-induced rash in one patient, transaminitis in one patient, and Grade 3 neutropenia in one patient. In these three patients, one patient required break once for neutropenia. The other two required breaks twice for rash and transaminitis. The maximum duration of break required for the decrement in an erlotinib-induced rash was 30 days.\n\nDose reduction was required in four patients (26.7%). Three were the above-mentioned patients with delays and breaks. The other patient required it in view of mucositis. Mortality due to toxicity was seen in no patient. Thus, 11 patients (73.3%) could receive the schedule without dose modifications or delays.\n\nDiscussion\nThe median OS even with the use of cetuximab-based EXTREME like chemotherapy in head neck cancers treated palliative is far from satisfactory. In such scenario, there is an urgent felt need for developing new regimens which may either improve survival or would provide similar survival with less toxicity. Access to care is an important issue in low- and middle-income countries, and cetuximab unfortunately is not an easily affordable drug.[5141516] In such scenario, having a cheaper chemotherapy with equivalent survival is also important.\n\nIn this study, we evaluated the efficacy of additional erlotinib with MCT. It was proposed that this combination may be considered for future testing if it showed a median PFS of 120 days or more. This figure of 120 days matches the results obtained in such a setting in the EXTREME trial.[17] In this respect, this study met its primary endpoint. This improvement in PFS is even more exciting considering the cohort of patient in which this combination was tested. The majority patients had a treatment-free interval of below 3 months. Treatment-free interval is considered to be an important prognostic factor in this setting and a lower period is associated with worse survival.[18] Most of the recently published trials did not accrue patients with treatment-free interval postchemotherapy of <6 months.[1719] Therefore, the magnitude of benefit in such patients from EXTREME like or SPECTRUM like chemotherapy schedules remains unknown. Most of these patients had also failed after receiving palliative radiotherapy. The reported OS in literature postprogression on palliative radiotherapy[202122] is in the range of 3–6 months. Finally, majority had oral cavity primaries, a site not associated with human papillomavirus[23] and having traditionally lower response rates[2425] and having poorer OS,[26] than stage-matched nonoral cavity primaries in head and neck cancers. With these selection issues in mind, it seems reasonable to say that this regimen has activity in this setting.\n\nThe results of MCT have been presented at ASCO 2014. The median PFS and OS in patients who received MCT were 101 days and 249 days, respectively, while the median PFS and OS in patients who received cisplatin chemotherapy were 66 days and 249 days, respectively.[8] Numerically, the median PFS reported in this study seems better than that reported with MCT or single-agent cisplatin. This indicates a possible synergistic effect of erlotinib with MCT in this setting.\n\nThis combination though efficacious was not without toxicity. It contradicts the traditional belief that MCT is nontoxic. A Grade 3–4 adverse event rate of 40% and dose reduction in 25% of population makes it necessary to modify this regimen. Hence, we do not recommend the use of this schedule in the present dosage for routine use outside a clinical trial.\n\nThe toxicity seen in this study was mainly of related to mucositis, transaminitis, and rash; these may be attributed mainly to erlotinib, but methotrexate is also known to cause similar side effects. Hence, in near future, we plan to conduct a Phase 2 study with two arms. In one arm dose of erlotinib would be escalated, while in another the dose of methotrexate. Postdose finding the cohorts in both arms would be expanded to compare the efficacy of both schedules for picking off the schedule for future studies.\n\nConclusion\nThe addition of erlotinib to an MCT schedule of methotrexate and celecoxib in metastatic/recurrent head and neck cancers resulted in a promising PFS and should be tested in future studies.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Dikshit R Gupta PC Ramasundarahettige C Gajalakshmi V Aleksandrowicz L Badwe R Cancer mortality in India: A nationally representative survey Lancet 2012 379 1807 16 22460346 \n2 Goss PE Strasser-Weippl K Lee-Bychkovsky BL Fan L Li J Chavarri-Guerra Y Challenges to effective cancer control in China, India, and Russia Lancet Oncol 2014 15 489 538 24731404 \n3 Jemal A Bray F Center MM Ferlay J Ward E Forman D Global cancer statistics CA Cancer J Clin 2011 61 69 90 21296855 \n4 Kwok J Langevin SM Argiris A Grandis JR Gooding WE Taioli E The impact of health insurance status on the survival of patients with head and neck cancer Cancer 2010 116 476 85 19937673 \n5 André N Banavali S Snihur Y Pasquier E Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol 2013 14 e239 48 23639324 \n6 Patil V Noronha V Krishna V Joshi A Prabhash K Oral metronomic chemotherapy in recurrent, metastatic and locally advanced head and neck cancers Clin Oncol (R Coll Radiol) 2013 25 388 23434353 \n7 Patil V Noronha V D’cruz AK Banavali SD Prabhash K Metronomic chemotherapy in advanced oral cancers J Cancer Res Ther 2012 8 Suppl 1 S106 10 22322727 \n8 Patil VM Noronha V Banavali SD Joshi A Dhumal S Arya S A phase II study comparing metronomic chemotherapy with chemotherapy (single agent cisplatin), in patients with metastatic, relapsed, or inoperable squamous cell carcinoma of head and neck J Clin Oncol 2014 Last cited on 2014 Jun 30 32 5s Suppl; abstr 601 Available from:\nhttp://http://www.meetinglibrary.asco.org/content/125716.144 \n9 Thomas F Rochaix P Benlyazid A Sarini J Rives M Lefebvre JL Pilot study of neoadjuvant treatment with erlotinib in nonmetastatic head and neck squamous cell carcinoma Clin Cancer Res 2007 13 7086 92 18056187 \n10 Altundag O Altundag K Boruban C Silay YS Cross-talk between cyclooxygenase-2 and epidermal growth factor receptor in non-small cell lung cancer Lung Cancer 2005 49 429 16102610 \n11 Chen Z Zhang X Li M Wang Z Wieand HS Grandis JR Simultaneously targeting epidermal growth factor receptor tyrosine kinase and cyclooxygenase-2, an efficient approach to inhibition of squamous cell carcinoma of the head and neck Clin Cancer Res 2004 10 5930 9 15355926 \n12 Shin DM Zhang H Saba NF Chen AY Nannapaneni S Amin AR Chemoprevention of head and neck cancer by simultaneous blocking of epidermal growth factor receptor and cyclooxygenase-2 signaling pathways: Preclinical and clinical studies Clin Cancer Res 2013 19 1244 56 23422093 \n13 Kao J Genden EM Chen CT Rivera M Tong CC Misiukiewicz K Phase 1 trial of concurrent erlotinib, celecoxib, and reirradiation for recurrent head and neck cancer Cancer 2011 117 3173 81 21246519 \n14 Molina MA Cheung MC Perez EA Byrne MM Franceschi D Moffat FL African American and poor patients have a dramatically worse prognosis for head and neck cancer: An examination of 20,915 patients Cancer 2008 113 2797 806 18839393 \n15 Collingridge D Sullivan R Affordable cancer care: Pipedream or achievable reality? Lancet Oncol 2014 15 257 8 24534291 \n16 Ignacio DN Griffin JJ Daniel MG Serlemitsos-Day MT Lombardo FA Alleyne TA An evaluation of treatment strategies for head and neck cancer in an African American population West Indian Med J 2013 62 504 9 24756735 \n17 Vermorken JB Mesia R Rivera F Remenar E Kawecki A Rottey S Platinum-based chemotherapy plus cetuximab in head and neck cancer N Engl J Med 2008 359 1116 27 18784101 \n18 Brockstein BE Management of recurrent head and neck cancer: Recent progress and future directions Drugs 2011 71 1551 9 21861540 \n19 Vermorken JB Stöhlmacher-Williams J Davidenko I Licitra L Winquist E Villanueva C Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): An open-label phase 3 randomised trial Lancet Oncol 2013 14 697 710 23746666 \n20 Mohanti BK Umapathy H Bahadur S Thakar A Pathy S Short course palliative radiotherapy of 20 Gy in 5 fractions for advanced and incurable head and neck cancer: AIIMS study Radiother Oncol 2004 71 275 80 15172142 \n21 Das S Thomas S Pal SK Isiah R John S Hypofractionated palliative radiotherapy in locally advanced inoperable head and neck cancer: CMC Vellore experience Indian J Palliat Care 2013 19 93 8 24049349 \n22 Ghoshal S Chakraborty S Moudgil N Kaur M Patel FD Quad shot: A short but effective schedule for palliative radiation for head and neck carcinoma Indian J Palliat Care 2009 15 137 40 20668593 \n23 Marur S D’souza G Westra WH Forastiere AA HPV-associated head and neck cancer: A virus-related cancer epidemic Lancet Oncol 2010 11 781 9 20451455 \n24 Shin DM Glisson BS Khuri FR Lippman SM Ginsberg L Diaz E Jr Phase II study of induction chemotherapy with paclitaxel, ifosfamide, and carboplatin (TIC) for patients with locally advanced squamous cell carcinoma of the head and neck Cancer 2002 95 322 30 12124833 \n25 Thyss A Schneider M Santini J Caldani C Vallicioni J Chauvel P Induction chemotherapy with cis-platinum and 5-fluorouracil for squamous cell carcinoma of the head and neck Br J Cancer 1986 54 755 60 3801272 \n26 Herman LC Karrison T Witt ME Muller C Stenson K Blair EA Comparison of outcomes of locoregionally advanced oropharyngeal and non-oropharyngeal SCC over two decades J Clin Oncol 2014 Last cited on 2014 Jun 30 32 5s Suppl; abstr 6048 Available from:\nhttp://www.meetinglibrary.asco.org/content/127643.144\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2278-330X",
"issue": "5(2)",
"journal": "South Asian journal of cancer",
"keywords": "Erlotinib; head and neck cancer; metronomic administration; palliative chemotherapy",
"medline_ta": "South Asian J Cancer",
"mesh_terms": null,
"nlm_unique_id": "101618774",
"other_id": null,
"pages": "48-51",
"pmc": null,
"pmid": "27275445",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
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"title": "An audit of the results of a triplet metronomic chemotherapy regimen incorporating a tyrosine kinase inhibitor in recurrent/metastatic head and neck cancers patients.",
"title_normalized": "an audit of the results of a triplet metronomic chemotherapy regimen incorporating a tyrosine kinase inhibitor in recurrent metastatic head and neck cancers patients"
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"abstract": "We present a comparative study on 124 patients with hematologic malignancies who had undergone reduced-intensity conditioning and then received a transplant from an HLA-matched related (MRD), an HLA-matched unrelated (MUD), or an HLA-haploidentical related (HAPLO) donor. The conditioning regimen, which consisted of fludarabine, melphalan or busulfan, and alemtuzumab was administered to patients with lymphoid (n = 62) or myeloid disease (n = 62). Mycophenolate mofetil was used as prophylaxis for graft-versus-host disease (GVHD), and 38, 58, and 33 patients received transplants from MRD, MUD, and HAPLO donors, respectively. Only 2 patients experienced primary graft failure (GF) after melphalan-based regimen, whereas 8 of the 17 patients who received a transplant from HAPLO donors experienced a primary GF after busulfan-based regimen. The cumulative incidence of grade III to IV acute GVHD in engrafted patients who had received transplants from MRD, MUD, or HAPLO donors was 3%, 11%, and 27%, respectively, and the 2-year overall survival (OS) rates were 51%, 22%, and 23%, respectively. According to multivariate analysis, transplantation from either MUD or HAPLO donors compared with MRD were adverse factors that affected the OS (P = .006 and P = .002, respectively). In conclusion, the reduced-intensity regimen that included fludarabine, busulfan, or melphalan and alemtuzumab using only mycophenolate mofetil as the GVHD prophylaxis conferred favorable outcomes in the MRD group but lower survival rates in the MUD and HAPLO groups. The busulfan-based regimen led to a high incidence of GF in the HAPLO group, suggesting the need for modification or intensification of immunosuppression.",
"affiliations": "Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina; Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan. Electronic address: jkandajp@gmail.com.;Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina.;Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina.;Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina.;Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina.;Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina.;Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina.;Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina.;Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.;Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina.;Adult Stem Cell Transplant Program, Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina.",
"authors": "Kanda|Junya|J|;Long|Gwynn D|GD|;Gasparetto|Cristina|C|;Horwitz|Mitchell E|ME|;Sullivan|Keith M|KM|;Chute|John P|JP|;Morris|Ashley|A|;Shafique|Michael|M|;Li|Zhiguo|Z|;Chao|Nelson J|NJ|;Rizzieri|David A|DA|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D006680:HLA Antigens; D000074323:Alemtuzumab",
"country": "United States",
"delete": false,
"doi": null,
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"issn_linking": "1083-8791",
"issue": "20(2)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Alemtuzumab; Haploidentical; Matched-related; Matched-unrelated; Reduced-intensity",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D005260:Female; D006680:HLA Antigens; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D014019:Tissue Donors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D061349:Unrelated Donors; D055815:Young Adult",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "257-63",
"pmc": null,
"pmid": "24269380",
"pubdate": "2014-02",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "20587785;19855248;21804612;21369856;10204198;7581076;17084371;1887253;23208313;18410902;23423745;18489989;11719394;17228020;21691261;21527516;22959335;21252669;19561408",
"title": "Reduced-intensity allogeneic transplantation using alemtuzumab from HLA-matched related, unrelated, or haploidentical related donors for patients with hematologic malignancies.",
"title_normalized": "reduced intensity allogeneic transplantation using alemtuzumab from hla matched related unrelated or haploidentical related donors for patients with hematologic malignancies"
} | [
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"abstract": "Behavioral and psychological symptoms of dementia are commonly treated with antipsychotic drugs (APDs), which have been associated with adverse health effects. We examine the effect of APDs on long-term care (LTC), nursing home (NH) admission, and death of dementia patients.\n\n\n\nWe used health claims data of the largest German health insurer from 2004 to 2010 and followed newly-diagnosed dementia patients aged 60 years and older into LTC, NH, and until death. Cox proportional hazards models were estimated to explore whether the risk of these outcomes differed between patients receiving haloperidol, melperone, risperidone, or quetiapine.\n\n\n\nIn a cohort of 6,930 dementia patients who were initially free of LTC dependency, APD users generally faced a twofold increased risk of LTC relative to nonusers. Quetiapine was the exception, showing a comparatively lower risk (HR = 1.64; CI = 1.35-1.98). Among 9,950 dementia patients initially living in private homes, the risk of moving into a NH was generally increased by about 50% among APD users relative to nonusers. Risk of death (N = 10,921) was significantly higher for haloperidol-, melperone-, and risperidone- but not for quetiapine users (HR = 0.91; CI = 0.78-1.08). The excess mortality associated with haloperidol and melperone was greater among patients living in private households.\n\n\n\nIn our study, APDs appeared to accelerate adverse health outcomes in German dementia patients. Differentiating between the effect of antipsychotic drug use among dementia patients residing in private households and in NHs, we found that excess mortality for haloperidol and melperone users was higher in private settings.",
"affiliations": "German Center for Neurodegenerative Diseases, Bonn, Germany.;Aging Research Center, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Sweden.;Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden.;Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden.;German Center for Neurodegenerative Diseases, Bonn, Germany.;German Center for Neurodegenerative Diseases, Bonn, Germany.",
"authors": "Nerius|Michael|M|;Johnell|Kristina|K|;Garcia-Ptacek|Sara|S|;Eriksdotter|Maria|M|;Haenisch|Britta|B|;Doblhammer|Gabriele|G|",
"chemical_list": "D014150:Antipsychotic Agents; D002090:Butyrophenones; D000069348:Quetiapine Fumarate; D006220:Haloperidol; C008522:metylperon; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.1093/gerona/glx239",
"fulltext": "\n==== Front\nJ Gerontol A Biol Sci Med SciJ. Gerontol. A Biol. Sci. Med. ScigeronaThe Journals of Gerontology Series A: Biological Sciences and Medical Sciences1079-50061758-535XOxford University Press US 10.1093/gerona/glx239glx239The Journal of Gerontology: Medical SciencesArticlesThe Impact of Antipsychotic Drugs on Long-term Care, Nursing Home Admission, and Death in Dementia Patients Nerius Michael MSc123Johnell Kristina PhD4Garcia-Ptacek Sara MD, PhD56Eriksdotter Maria MD, PhD56Haenisch Britta PhD1Doblhammer Gabriele PhD12371 German Center for Neurodegenerative Diseases, Bonn, Germany2 Institute for Sociology and Demography, University of Rostock, Germany3 Rostock Center for the Study of Demographic Change, Germany4 Aging Research Center, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Sweden5 Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden6 Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden7 Max Planck Institute for Demographic Research, Rostock, GermanyAddress correspondence to: Michael Nerius, MSc, Institute for Sociology and Demography, University of Rostock, Ulmenstraße 69, 18057 Rostock, Germany. E-mail: michael.nerius@uni-rostock.de9 2018 08 12 2017 08 12 2017 73 10 1396 1402 25 8 2017 05 12 2017 © The Author(s) 2017. Published by Oxford University Press on behalf of The Gerontological 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\nBackground\nBehavioral and psychological symptoms of dementia are commonly treated with antipsychotic drugs (APDs), which have been associated with adverse health effects. We examine the effect of APDs on long-term care (LTC), nursing home (NH) admission, and death of dementia patients.\n\nMethods\nWe used health claims data of the largest German health insurer from 2004 to 2010 and followed newly-diagnosed dementia patients aged 60 years and older into LTC, NH, and until death. Cox proportional hazards models were estimated to explore whether the risk of these outcomes differed between patients receiving haloperidol, melperone, risperidone, or quetiapine.\n\nResults\nIn a cohort of 6,930 dementia patients who were initially free of LTC dependency, APD users generally faced a twofold increased risk of LTC relative to nonusers. Quetiapine was the exception, showing a comparatively lower risk (HR = 1.64; CI = 1.35–1.98). Among 9,950 dementia patients initially living in private homes, the risk of moving into a NH was generally increased by about 50% among APD users relative to nonusers. Risk of death (N = 10,921) was significantly higher for haloperidol-, melperone-, and risperidone- but not for quetiapine users (HR = 0.91; CI = 0.78–1.08). The excess mortality associated with haloperidol and melperone was greater among patients living in private households.\n\nConclusions\nIn our study, APDs appeared to accelerate adverse health outcomes in German dementia patients. Differentiating between the effect of antipsychotic drug use among dementia patients residing in private households and in NHs, we found that excess mortality for haloperidol and melperone users was higher in private settings.\n\nCare transitionsMedicationPhysical functionEpidemiologyCohort study\n==== Body\nDementia is one of the most care-intensive diseases of old age. In addition to the cognitive symptoms, there are noncognitive features such as behavioral and psychological symptoms of dementia (BPSD). BPSD comprise apathy, agitation, psychosis, hallucinations and these affect up to 90% of all dementia patients during the course of their disease and is considered to be one of the main predictors of institutionalization (1).\n\nPharmacological treatment of BPSD is commonly based on antipsychotic drugs (APDs), which are classified either as first-generation antipsychotics (FGAs) or the newer second-generation antipsychotics (SGAs). In the past years, SGAs have increasingly replaced FGAs because of their higher efficacy and fewer extra pyramidal symptoms. However, there are concerns about the safety of both FGAs and SGAs, indicating an elevated risk of death, cerebrovascular events (2,3), and thromboembolism (4). In addition to these specific events, little is known about the impact of APDs on disability-related outcomes. Thus far, to our knowledge, there have been no studies examining the relationship between APDs and care dependency. Studies exploring activities of daily living have shown a decline of physical functioning among APD users (5,6). Regarding nursing home (NH) admission, Brodaty et al. (7) and Rongve et al. (8) suggested an increased risk of institutionalization for Norwegian (HR = 1.51) and Australian (HR = 4.32) dementia patients taking APDs, while Lopez et al. (9) did not find this association after adjusting for major confounders using U.S. data. APD use and health outcomes may differ by the type of residency but, to our knowledge, there are no studies that have compared APD doses among dementia patients living in private and NHs.\n\nIn general, the relation between specific APDs and adverse health outcomes has not yet been evaluated systematically in the German context. Thus, the aim of this study is to examine the effect of frequently prescribed FGAs (haloperidol, melperone) and SGAs (risperidone, quetiapine) in dementia patients on their risk of (i) becoming dependent on long-term care (LTC), (ii) moving into a NH, and (iii) death. In addition, we explore whether APDs have different health outcomes when administered in private households or in NHs.\n\nMethods\nData Source\nWe used routine claims data from the years 2004–2010 collected by the largest German statutory health insurance company, the “Allgemeine Ortskrankenkasse” (AOK). In Germany, about 70 million people are covered by statutory programs, one third of these are members of the AOK. The AOK covers more than 50% of the population at the highest ages (10). We drew an age-stratified random sample of 250,000 persons aged 50 years and above (2% of all AOK-members) in the first quarter of 2004 and followed these individuals through the end of 2010. In addition to many other components, these data also comprise inpatient and outpatient diagnoses by ICD-10, all treatments in the inpatient and outpatient sector relevant for billing, benefits from LTC insurance, type of residency (private household versus NH), and month of death. Information on medical treatments contains drug prescriptions filled in the outpatient sector according to the Anatomical Therapeutic Chemical Classification System (ATC). Data access was legally approved by the Scientific Institute of the AOK (WIdO). This study is based on anonymized administrative claims data that never involved patients directly. Individual patients cannot be identified and the analyses do not affect patients whose anonymized records were used.\n\nStudy Participants\nThe study population consists of incident dementia patients ages 60 years and above who received their first dementia diagnosis between the first quarter of 2006 and the last quarter of 2010, and who had not been diagnosed with dementia or exposed to APDs in 2004 and 2005. In order to examine the effect of APDs on the risk of any of the three outcomes (LTC, NH, death), three different-sized analysis samples were obtained (see section Outcome Measures and Analyses Samples and Figure 1). The time for assessing the impact of APDs on the outcomes started after the first valid dementia diagnosis.\n\nFigure 1. Study flow chart. LTC = Long-term care.\n\nDementia was defined according to the ICD-10 codes G30, G31.0, G31.82, G23.1, F00, F01, F02, F03, and F05.1. In order to avoid false-positive diagnoses, we considered only those patients with a valid dementia diagnosis based on a two-stage validation procedure. First, we included only those diagnoses internally marked as “verified” in the outpatient sector or as “discharge diagnosis” or “secondary diagnosis” in the inpatient sector. Second, a diagnosis was considered valid if a patient received a confirmative dementia diagnosis in the period 2006–2010.\n\nOutcome Measures and Analyses Samples\nLTC dependency\nLTC dependency was defined as receiving benefits or services from the German statutory LTC insurance. To receive these, individuals must file an application and pass an objective assessment, which is mainly based on impairments in ADLs and does not consider cognitive performance. Thus, LTC dependency mainly reflects physical impairments. Applicants are assigned to one of the three LTC levels if they require care for at least 90 minutes per day, of which at least 46 minutes are reserved for basic activities such as washing, eating, or mobility. LTC comprises day care, home care by nurses or nonprofessionals, as well as care in a nursing care home. The data indicate whether the patient lives in an institution, but for those patients who live at home there is no information about the care arrangement in terms of nurses or nonprofessionals.\n\nThe transition to LTC dependency was defined by the first claim of LTC dependency after an incident dementia diagnosis among patients living in private households. Because benefits or services from German’s statutory LTC insurance were only provided in case of long-term physical limitations, LTC dependency is a permanent state in which a recurrent event is extremely rare. Patients living in NHs at the time of their first dementia diagnosis were excluded and they were censored if they were institutionalized at the time of their first claim. This resulted in an analysis sample of 6,930 dementia patients (10,611 person-years) with 3,842 transitions to LTC dependency (Table 1).\n\nTable 1. Selected Characteristics of Analysis Samples (exposures given in person-years)\n\n\tLTC dependency\tNursing Home Admission\tDeath\t\nVariable\tCategory\tExposures\tCases\tExposures\tCases\tExposures\tCases\t\nSex\tMen\t4,006\t1,312\t6,628\t642\t7,911\t1,368\t\nWomen\t6,605\t2,530\t12,501\t1,740\t16,600\t2,491\t\nAge\t60–64\t407\t74\t568\t31\t665\t24\t\n65–69\t826\t131\t1,097\t68\t1,265\t94\t\n70–74\t1,744\t389\t2,491\t165\t2,888\t241\t\n75–79\t2,598\t750\t4,035\t363\t4,671\t531\t\n80–84\t2,776\t1,132\t4,953\t659\t6,202\t904\t\n85–89\t1,749\t970\t4,117\t663\t5,720\t1,124\t\n90–94\t426\t311\t1,360\t302\t2,166\t607\t\n95+\t86\t85\t507\t131\t934\t334\t\nHaloperidol\tNo\t10,519\t3,700\t18,723\t2,230\t23,720\t3,530\t\nYes\t93\t142\t405\t152\t791\t329\t\nMelperone\tNo\t10,149\t3,267\t17,278\t1,800\t21,182\t2,777\t\nYes\t462\t575\t1,850\t582\t3,329\t1,082\t\nRisperidone\tNo\t10,239\t3,409\t17,836\t1,976\t22,208\t3,181\t\nYes\t373\t433\t1,292\t406\t2,303\t678\t\nQuetiapine\tNo\t10,502\t3,714\t18,747\t2,263\t23,804\t3,696\t\nYes\t109\t128\t381\t119\t707\t163\t\nOther FGA\tNo\t10,377\t3,552\t18,244\t2,106\t22,914\t3,385\t\nYes\t235\t290\t885\t276\t1,597\t474\t\nOther SGA\tNo\t10,553\t3,810\t19,001\t2,351\t24,298\t3,817\t\nYes\t58\t32\t128\t31\t213\t42\t\nTotal\t\t10,611\t3,842\t19,128\t2,382\t24,511\t3,859\t\n\nNote: FGA = First-generation antipsychotic; LTC = Long-term care; SGA = Second-generation antipsychotic.\n\nNH admission\nThe transition to a NH was defined by the first quarter in which residency changed from a private household to an institution. Once in a NH, dementia patients remain there and did not return to the private setting. All 9,950 incident dementia patients (19,128 person-years) living in a private household at the time of their first dementia diagnosis formed the analysis sample. There were 2,382 transitions into a NH (Table 1).\n\nDeath\nThe transition to death was defined by the middle of the month of death; all 10,921 incident dementia patients (24,511 person-years), independent of LTC dependency and residency, formed the analysis sample of whom 3,859 died (Table 1).\n\nExposure to Antipsychotics\nPersons exposed to APDs before their first dementia diagnosis were excluded from this study\nThe time from the incident dementia diagnosis to the first use of APDs was considered unexposed, in order to prevent immortal time bias. A patient was assigned to a specific APD category based on having ever filled a prescription. The assignment starts from the first prescription and continues until the outcome, death, exit from the AOK insurance or the end of the study. The concurrent use of other APDs was defined in a similar way. This strategy resulted in six time-dependent dummy variables (for having ever been prescribed haloperidol, melperone, risperidone, quetiapine, another FGA, another SGA), which take the value of one starting from the first time a respective APD was prescribed and zero otherwise. The category of another FGA includes all APDs (ATC = N05A) except the APDs mentioned above and other SGA which are amisulpride, zotepine, ziprasidone, aripiprazole, sertindole, olanzapine, and clozapine.\n\nCovariates\nWe controlled for sex, age in 5-year age groups (from 60 to 95+), common morbidities in old age (diabetes mellitus, cerebrovascular diseases, hypertension, ischemic heart diseases, atrial fibrillation, hypercholesterolemia, cancer), and use of antidementia drugs (cholinesterase inhibitors or memantine) which were defined as time-dependent dummy variables. We further added a time-dependent dummy variable which takes polypharmacy into account. Patients receiving five or more drugs other than APDs or antidementia drugs during the respective quarter were assigned the value one (11).\n\nStatistical Method\nWe used Cox proportional hazards models to examine separately whether (i) LTC dependency in private households, (ii) moving into a NH, or (iii) death were associated with a type of APD use; adjusting for sex, age, major comorbidities, polypharmacy, use of antidementia drugs, and LTC dependency/residency for outcomes (ii) and (iii). Information about the dementia diagnosis and the level of LTC was given by the quarter of the year. We defined the analysis time by the number of months since the incident dementia diagnosis. For people who had experienced a transition to LTC/NH in the same quarter as the dementia diagnosis, the analysis time was set to 0.75 months. For all other cases the transitions took place in the middle of the respective quarter. People were followed until censoring or death, whichever occurred first; deaths were assigned to the middle of the month of death. For subgroup analyses, we implemented interaction terms in our model in order to test whether the mortality of APD users differed by type of residency. To compare APD dosages between persons in private households and NH residents, we calculated a dose-time index (DTI), defined as the sum of daily defined doses per package during the complete observation period divided by the number of quarters with APD exposure (12). We then compared DTI for specific APDs stratified by age and type of residency using the Kolmogorov–Smirnov test.\n\nWe conducted six sensitivity analyses to assess the robustness of our findings. First, we used a 1:1 propensity score matching to conduct an alternative approach of covariate adjustment. Second, to consider death as a competing risk, we performed competing risk models as proposed by Fine and Grey (13) for the outcomes LTC dependency and NH admission. Third, we took the duration of administration of APD use into account by dividing users into short-term (=1 quarter) and long-term users (>1 quarter). Fourth, given that information of dementia incidence and LTC dependency is only available on a quarterly basis, we excluded those patients whose first dementia diagnosis and first claims of LTC fall in the same quarter. Fifth, because APDs were also used in palliative care for cancer patients, we excluded cancer patients in order to rule out this selection bias. Sixth, we omitted patients suffering from Parkinson’s disease, for whom quetiapine is very common, in order to identify a potential indication bias.\n\nResults\nLTC Dependency Living in Private Households\nThe baseline cohort consisted of 6,930 incident dementia patients (Table 1; Supplementary Table 1 gives a complete overview). The mean age at study entry was 78.8 years (±7.4) and patients were followed for a mean time of 18.4 months (±16.2). Overall, 1,408 (20.3%) patients used at least one APD. Melperone was the most frequently prescribed drug (730 persons; 10.5%), followed by risperidone (556 persons; 8%), haloperidol (177 persons; 2.6%) and quetiapine (169 persons; 2.4%). Of these patients, 372 (5.4%) received at least one other FGA and 52 (0.8%) used at least one other SGA. These prescription frequencies are similar to those of the other outcomes presented below. During the observation period, 3,842 persons (55.4%) became LTC dependent and the mean age for this transition was 81.5 years (±7).\n\nMultivariable analyses showed that dementia patients receiving APDs had about twice the risk of becoming LTC dependent compared to those not receiving the specific drug (Table 2). The only exception was quetiapine, with a significantly lower hazard ratio (HR = 1.64; CI = 1.35–1.98) of becoming LTC dependent compared to melperone (HR = 2.34; CI = 2.13–2.58). Hazard ratios (HR) of confounding variables for all outcomes are presented in Supplementary Table 8.\n\nTable 2. HR of Becoming LTC Dependent, Moving Into a Nursing Home, and Death by Type of APD (reference group: not receiving the specific drug)\n\n\tLTC Dependencya\tNursing Home Admissionb\tDeathc\t\nHR\t\np\n\t95% CI\tHR\t\np\n\t95% CI\tHR\t\np\n\t95% CI\t\nHaloperidol\tYes\t2.12\t***\t1.78\t2.52\t1.51\t***\t1.28\t1.80\t1.56\t***\t1.38\t1.75\t\nMelperone\tYes\t2.34\t***\t2.13\t2.58\t1.74\t***\t1.58\t1.93\t1.43\t***\t1.33\t1.54\t\nRisperidone\tYes\t2.08\t***\t1.87\t2.32\t1.56\t***\t1.38\t1.75\t1.28\t***\t1.17\t1.40\t\nQuetiapine\tYes\t1.64\t***\t1.35\t1.98\t1.39\t***\t1.15\t1.69\t0.91\t\t0.78\t1.08\t\nOther FGA\tYes\t2.13\t***\t1.87\t2.42\t1.49\t***\t1.31\t1.71\t1.26\t***\t1.14\t1.39\t\nOther SGA\tYes\t0.78\t\t0.54\t1.13\t1.40\t\t0.97\t2.02\t1.09\t\t0.80\t1.49\t\n\nNote: APD = Antipsychotic drug; CI = Confidence interval; FGA = First-generation antipsychotic; HR = Hazard ratio; LTC = Long-term care; SGA = Second-generation antipsychotic.\n\n\naControlled for sex, age, comorbidities, polypharmacy, antidementia drug use; b+ LTC dependency; c+ residency.\n\n*p < .05; **p < .01; ***p < .001. There are no p-values corresponding to * or **.\n\nMoving into a NH\nA total of 9,950 incident dementia patients with a mean age of 80.1 years (±7.7) were followed over a mean period of 23.1 months (±16.9). During the observation period, 2,921 patients with dementia (29.4%) received at least one APD and 2,382 persons (23.9%) were admitted to a NH (Table 1). In the multivariable analysis, we did not find much difference in the risk of moving to a NH by single APD type (Table 2). APD users had 1.4–1.7 the risk of moving into a NH compared to nonusers.\n\nDeath\nOf the 10,921 incident dementia patients (median age: 80.4 years; ±7.8 years) who were followed for a median time of 26.9 months (±16.4), a total of 3,677 patients (33.7%) were exposed to at least one APD, and 3,859 (35.3%) died (Table 1).\n\nIn the multivariable analyses, we found that haloperidol (HR = 1.56; CI = 1.38–1.75), melperone (HR = 1.43; CI = 1.33–1.54), and risperidone (HR = 1.28; CI = 1.17–1.40) were associated with a significantly higher risk of death compared to quetiapine (HR = 0.91; CI = 0.78–1.08; Table 2).\n\nWe found that the excess mortality associated with haloperidol and melperone was significantly higher among dementia patients living in private households (haloperidol: HR = 1.96; CI = 1.67–2.30; melperone: HR = 1.70; CI = 1.53–1.88) than in NHs (haloperidol: HR = 1.24; CI = 1.04–1.48; melperone: HR = 1.19; CI = 1.07–1.33). There were no significant differences for the other APDs. This was true despite the fact that NH residents had an overall increased mortality (Figure 2).\n\nFigure 2. HR of death and 95% CI for single APDs by residency. CI = Confidence interval; FGA = First-generation antipsychotic; HR = Hazard ratio; NH = Nursing home; SGA = Second-generation antipsychotic.\n\nWe explored whether differences in APD dosages may explain mortality gaps between persons in private households and in NHs. The mean prescribed dose of haloperidol was lower for persons in private households (DTI = 23.2) than for NH residents (DTI = 27.7), but the Kolmogorov–Smirnov test indicated equal distributions (p = .111). Melperone dosages were higher for NH residents (DTI = 11.0) compared to persons in private households (DTI = 9.3) and this was confirmed by the Kolmogorov–Smirnov test (p = .001, Supplementary Figure). Thus, differences in dosage cannot explain excess the mortality of APD users in private households.\n\nSensitivity Analysis\nCox models based on propensity score matching produced results similar to the primary analysis. However, the effect sizes were somewhat smaller (Supplementary Table 2). Competing risk models revealed no remarkable changes in the risk of LTC dependency and NH admission after accounting for death (Supplementary Table 3). Mortality remained increased for haloperidol and melperone users regardless of their duration of administration, whereas the adverse effect of risperidone appeared only for long-term users. However, the duration of administration did not influence the effect of quetiapine (Supplementary Table 4). The results remained consistent when repeating the primary analysis without patients whose first dementia diagnosis and first claims of LTC fell in the same quarter (Supplementary Table 5). Furthermore, excess mortality for haloperidol and melperone users in NHs was still significantly higher than for those in private homes after excluding cancer patients (Supplementary Table 6). Finally, analyses without persons suffering from Parkinson’s disease yielded comparable results (Supplementary Table 7).\n\nDiscussion\nUsing health claims data from the largest German health insurer, we found that APDs, regardless of whether they are first or second generation, are associated with a higher need for care and an increased risk of death among dementia patients. APD users generally deteriorated more rapidly in physical health and died earlier. The only German studies to have investigated the impact of APDs on health outcomes among dementia patients focused on venous thromboembolism (4) and death (14), whereas the latter study compared single APDs with risperidone. Our study extends these results by using dependency on LTC and NH admission as outcomes which may be considered as measures of different degrees of physical limitations. We further conducted subgroup analyses for persons living in private households or NHs and found less excess mortality for APD users residing in NHs compared to those in private households.\n\nOur results indicating adverse health effects for APD users in general are in line with previous studies. Helvik et al. (5) and Dutcher et al. (6) showed a decline of physical functioning for APD users but did not differentiate among specific APDs. In our study, the relation observed between APDs and LTC dependency may also be explained by indication bias, because the occurrence of BPSD makes physical limitations and LTC dependency more likely. However, we also found differences according to specific APDs, primarily for quetiapine, which was associated with a somewhat lower risk of becoming dependent on long-term care than melperone.\n\nAs we have shown, Brodaty et al. and Rongve et al. also found an increased risk of NH admission for APD users (7,8). However, Lopez et al. (9) divided APDs into FGAs and SGAs and did not find any association between using APDs and the risk of moving into a NH. Unlike our approach, they were able to adjust for psychiatric symptoms. Excess mortality for APD users has been well documented in several studies (2,15–18). However, our findings may instead be caused by the occurrence of BPSD and the advanced stage of dementia than the APDs themselves. Additionally, our results suggest that quetiapine is not associated with a significantly increased mortality risk, and this supports the findings of Kales et al. (19), Rossom et al. (20), and Schneider et al. (21) but the mechanisms behind this mortality advantage remain unclear. In our sensitivity analyses, we show that the duration of administration does not explain quetiapine’s effect on mortality (Supplementary Table 4). Quetiapine was also not associated with an increased hazard of death after patients with Parkinson’s disease were excluded, which is why an indication bias for this relation is not likely (Supplementary Table 7). Further, dose–response analyses of Huybrechts et al. and Gerhardt et al. stated that the mortality advantage of quetiapine cannot be explained by administered doses (22,23). The advantage might be a result of another selection process. Quetiapine has more sedative than antipsychotic mechanisms of action and is frequently used “off-label” for insomnia (24). Thus, patients with early-stage dementia, less severe BPSD and consequently a lower mortality risk might be treated primarily with quetiapine.\n\nDifferentiating between the effect of APD use among dementia patients residing in private households and in NHs, we found that the negative effect of haloperidol and melperone on mortality was significantly lower among patients in NHs and comparable to that of risperidone users, which is the only APD approved for BPSD in dementia patients (1). Mortality differences of APD users in favor of NH residents have also been reported by Rochon et al. (25), who showed less pronounced excess mortality rates for Canadian NH residents receiving FGAs and SGAs, while our analysis indicates the only mortality differences by residency are in connection with the FGAs haloperidol and melperone. However, Wang et al. (16) and Schneeweis et al. (18) did not find this relation.\n\nOur results suggest that treatment with haloperidol and melperone in a NH setting is safer than in a private setting. One possible explanation is that the adverse effects of these APDs (eg, heart attack, stroke, thrombosis, falls, pneumonia) result in death less frequently for persons in NHs because these patients are monitored more closely. It may also be a result of a selection bias based on different prescription patterns. Patients in a private setting need to be sicker before they are prescribed with APDs, whereas patients in a NH would receive APDs sooner, after presenting with less severe symptoms. However, this bias is not probable because, in contrast to the outcome death, we found no higher risk of care dependency for patients in private settings compared with NH residents. Finally, reasons for entering a NH may also play a role. Persons in NHs are generally faced with an increased risk of death and the additional negative impact of APDs may be outweighed. We adjusted for a number of diseases and for LTC but this selection bias cannot be ruled out.\n\nThe strength of our study is the assessment of a large cohort of dementia patients from the largest German health insurer for a period of 7 years. The data contain information about both the private and institutionalized population, which is important due to the high prevalence of APDs among NH residents (26). Finally, because the routine documentation of diagnoses is provided by physicians, the potential problems of self-selection, nonresponse, or interviewer bias can be ruled out.\n\nOne limitation of our study is that data on medications reflect drug prescriptions that were filled, but we cannot be certain about actual intake. The restriction to incident dementia patients leads to relatively low sample sizes, in particular for haloperidol and quetiapine users, which may bias the respective results. Furthermore, time of dementia incidence (start of observation time), exposure to APDs, LTC dependency, and NH admission were only available on a quarterly basis, which might result in time related biases. Confounding by indication is also possible as dementia patients with BPSD are at a higher risk of physical limitations and death due to these disorders and the advanced stage of dementia. Methods to address indication bias can hardly be conducted using health claims data, because the respective ICD-10 codes were not used in the medical practice and the severity of dementia is also not available.\n\nConclusion\nThere are numerous studies reporting that APDs increase the subsequent risk of serious events among dementia patients. Our study confirms these findings in the German context by showing that incident APD intake predicts (i) LTC dependency, (ii) NH admission, and (iii) death. However, it should be noted that it is not clear whether the increased risk can be reduced to the APDs or the indication of these drugs. Furthermore, excess mortality with the frequently used first-generation APDs haloperidol and melperone was less pronounced for NH residents than for the dementia patients residing in private households. Based on previous studies, the present work and the suggestions from the Beers Criteria Medication List (27) and its German adaption (PRISCUS-Liste) (28), the harmful impact of APDs should be also considered in the light of physical limitations when these drugs were administered to dementia patients.\n\nConflict of Interest\nM.N., K.J., S.G-P., M.E., and B.H. have no conflict of interest to report. G.D. received honoraria for presentations at meetings of Novartis and Eli Lilly.\n\nSupplementary Material\nSupplementary data is available at The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences online.\n\nSupplementary Material\nSupplementary Figures Click here for additional data file.\n\n Supplementary Tables Click here for additional data file.\n\n Acknowledgments\nWe are grateful to Juergen-Bernhard Adler and Christian Guenster from the Scientific Research Institute of the AOK, WIdO, for providing the data. We further thank Renee Lueskow for English editing services.\n==== Refs\nReferences\n1. \nCerejeira J , Lagarto L , Mukaetova-Ladinska EB \nBehavioral and psychological symptoms of dementia . Front Neurol . 2012 ;3 :73 . doi:10.3389/fneur.2012.00073 22586419 \n2. \nSchneider LS , Dagerman K , Insel PS \nEfficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials . Am J Geriatr Psychiatry . 2006 ;14 :191 –210 . doi:10.1097/01.JGP.0000200589.01396.6d 16505124 \n3. \nRao A , Suliman A , Story G , Vuik S , Aylin P , Darzi A \nMeta-analysis of population-based studies comparing risk of cerebrovascular accident associated with first- and second-generation antipsychotic prescribing in dementia . Int J Methods Psychiatr Res . 2016 ;25 :289 –298 . doi:10.1002/mpr.1509 27121795 \n4. \nSchmedt N , Garbe E \nAntipsychotic drug use and the risk of venous thromboembolism in elderly patients with dementia . J Clin Psychopharmacol . 2013 ;33 :753 –758 . doi:10.1097/JCP.0b013e3182a412d5 24052055 \n5. \nHelvik AS , Høgseth LD , Bergh S , Šaltytė-Benth J , Kirkevold Ø , Selbæk G \nA 36-month follow-up of decline in activities of daily living in individuals receiving domiciliary care . BMC Geriatr . 2015 ;15 :47 . doi:10.1186/s12877-015-0047-7 25888187 \n6. \nDutcher SK , Rattinger GB , Langenberg P et al \nEffect of medications on physical function and cognition in nursing home residents with dementia . J Am Geriatr Soc . 2014 ;62 :1046 –1055 . doi:10.1111/jgs.12838 24823451 \n7. \nBrodaty H , Connors MH , Xu J , Woodward M , Ames D ; PRIME study group \nPredictors of institutionalization in dementia: a three year longitudinal study . J Alzheimers Dis . 2014 ;40 :221 –226 . doi:10.3233/JAD-131850 24448780 \n8. \nRongve A , Vossius C , Nore S , Testad I , Aarsland D \nTime until nursing home admission in people with mild dementia: comparison of dementia with Lewy bodies and Alzheimer’s dementia . Int J Geriatr Psychiatry . 2014 ;29 :392 –398 . doi:10.1002/gps.4015 23943275 \n9. \nLopez OL , Becker JT , Chang YF et al \nThe long-term effects of conventional and atypical antipsychotics in patients with probable Alzheimer’s disease . Am J Psychiatry . 2013 ;170 :1051 –1058 . doi:10.1176/appi.ajp.2013.12081046 23896958 \n10. \nSchulz A , Doblhammer G \nAktueller und zukünftiger Krankenbestand von Demenz in Deutschland auf Basis der Routinedaten der AOK . In: Günster C , Klose J , Schmacke N , eds. Versorgungs-Report 2012 . Stuttgart, Germany : Schattauer ; 2012 :161 –176 .\n11. \nKönig M , Spira D , Demuth I , Steinhagen-Thiessen E , Norman K \nPolypharmacy as a risk factor for clinically relevant sarcopenia: results from the Berlin Aging Study II . J Gerontol A Biol Sci Med Sci . 2017 :1–6. doi:10.1093/gerona/glx074. Advance Access publication May 6, 2017.\n12. \nGomm W , von Holt K , Thomé F et al \nRegular benzodiazepine and Z-Substance use and risk of dementia: an analysis of german claims data . J Alzheimers Dis . 2016 ;54 :801 –808 . doi:10.3233/JAD-151006 27567804 \n13. \nFine JP , Gray RJ \nA proportional hazards model for the subdistribution of a competing risk . J Am Stat Assoc . 1999 ;94 :496 –509 . doi:10.1080/01621459.1999.10474144 \n14. \nSchmedt N , Kollhorst B , Enders D et al \nComparative risk of death in older adults treated with antipsychotics: a population-based cohort study . Eur Neuropsychopharmacol . 2016 ;26 :1390 –1400 . doi:10.1016/j.euroneuro.2016.07.006 27475994 \n15. \nGill SS , Bronskill SE , Normand SL et al \nAntipsychotic drug use and mortality in older adults with dementia . Ann Intern Med . 2007 ;146 :775 –786 .17548409 \n16. \nWang PS , Schneeweiss S , Avorn J et al \nRisk of death in elderly users of conventional vs. atypical antipsychotic medications . N Engl J Med . 2005 ;353 :2335 –2341 . doi:10.1056/NEJMoa052827 16319382 \n17. \nLangballe EM , Engdahl B , Nordeng H , Ballard C , Aarsland D , Selbæk G \nShort- and long-term mortality risk associated with the use of antipsychotics among 26,940 dementia outpatients: a population-based study . Am J Geriatr Psychiatry . 2014 ;22 :321 –331 . doi:10.1016/j.jagp.2013.06.007 24016844 \n18. \nSchneeweiss S , Setoguchi S , Brookhart A , Dormuth C , Wang PS \nRisk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients . CMAJ . 2007 ;176 :627 –632 . doi:10.1503/cmaj.061250 17325327 \n19. \nKales HC , Kim HM , Zivin K et al \nRisk of mortality among individual antipsychotics in patients with dementia . Am J Psychiatry . 2012 ;169 :71 –79 . doi:10.1176/appi.ajp.2011.11030347 22193526 \n20. \nRossom RC , Rector TS , Lederle FA , Dysken MW \nAre all commonly prescribed antipsychotics associated with greater mortality in elderly male veterans with dementia ?J Am Geriatr Soc . 2010 ;58 :1027 –1034 . doi:10.1111/j.1532-5415.2010.02873.x 20487081 \n21. \nSchneider LS , Dagerman KS , Insel P \nRisk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials . JAMA . 2005 ;294 :1934 –1943 . doi:10.1001/jama.294.15.1934 16234500 \n22. \nHuybrechts KF , Gerhard T , Crystal S et al \nDifferential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: population based cohort study . BMJ . 2012 ;344 :e977 . doi:10.1136/bmj.e97722362541 \n23. \nGerhard T , Huybrechts K , Olfson M et al \nComparative mortality risks of antipsychotic medications in community-dwelling older adults . Br J Psychiatry . 2013 : doi:10.1192/bjp.bp.112.122499 \n24. \nPhilip NS , Mello K , Carpenter LL , Tyrka AR , Price LH \nPatterns of quetiapine use in psychiatric inpatients: an examination of off-label use . Ann Clin Psychiatry . 2008 ;20 :15 –20 . doi:10.1080/10401230701866870 18297582 \n25. \nRochon PA , Normand SL , Gomes T et al \nAntipsychotic therapy and short-term serious events in older adults with dementia . Arch Intern Med . 2008 ;168 :1090 –1096 . doi:10.1001/archinte.168.10.1090 18504337 \n26. \nRichter T , Mann E , Meyer G , Haastert B , Köpke S \nPrevalence of psychotropic medication use among German and Austrian nursing home residents: a comparison of 3 cohorts . J Am Med Dir Assoc . 2012 ;13 :187.e7 –187.e13 . doi:10.1016/j.jamda.2011.03.007 \n27. \nAmerican Geriatrics Society Beers Criteria Update Expert Panel . American geriatrics society 2015 updated beers criteria for potentially inappropriate medication use in older adults . J Am Geriatr Soc . 2015 ;63 :2227 –2246 . doi:10.1111/jgs.13702 26446832 \n28. \nHolt S , Schmiedl S , Thurmann P \nPRISCUS-Liste potenziell inadäquater Medikation für ältere Menschen \nhttp://priscusnet/download/PRISCUS-Liste_PRISCUS-TP3_2011pdf. 2011.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1079-5006",
"issue": "73(10)",
"journal": "The journals of gerontology. Series A, Biological sciences and medical sciences",
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"medline_ta": "J Gerontol A Biol Sci Med Sci",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D002090:Butyrophenones; D015331:Cohort Studies; D003704:Dementia; D005260:Female; D005858:Germany; D006220:Haloperidol; D006707:Homes for the Aged; D006801:Humans; D007326:Institutionalization; D008134:Long-Term Care; D008297:Male; D008875:Middle Aged; D009735:Nursing Homes; D016016:Proportional Hazards Models; D000069348:Quetiapine Fumarate; D012307:Risk Factors; D018967:Risperidone",
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"pages": "1396-1402",
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"pubdate": "2018-09-11",
"publication_types": "D016428:Journal Article",
"references": "26446832;20487081;17548409;16319382;18297582;16234500;25888187;16505124;24052055;18504337;27121795;24823451;23943275;24448780;22586419;27475994;24016844;22193526;17325327;22362541;23896958;27567804;21549645;28481965;23929443",
"title": "The Impact of Antipsychotic Drugs on Long-term Care, Nursing Home Admission, and Death in Dementia Patients.",
"title_normalized": "the impact of antipsychotic drugs on long term care nursing home admission and death in dementia patients"
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"abstract": "Infective endocarditis secondary to Mycobacterium chimaera can present with classical constitutional symptoms of infective endocarditis but can be blood culture negative and without vegetations on transthoracic or transoesophageal echocardiogram. Patients with prosthetic valves are at particularly high risk.\nWe present two patients who were diagnosed with infective endocarditis secondary to M. chimaera infection. They presented similarly with pyrexia of unknown origin and night sweats. Both patients had previously undergone aortic valve replacement; one with a tissue valve and the other with a metallic valve. New cardiac murmurs were evident on auscultation, but clinical examination showed no peripheral stigmata of endocarditis. Transoesophageal echo and transthoracic echo were both unremarkable, as were serial blood cultures. FDG PET CT scan was the key investigation, which showed increased uptake in the spleen beside other areas. Histopathology and mycobacterial cultures confirmed the diagnosis of M. chimaera infection in both cases. The first patient completed medical therapy and is now fit and well. However, the second patient unfortunately developed disseminated infection causing death.\nThe management of M. chimaera infective endocarditis is challenging, often with delayed diagnosis and poor outcomes. In the context of negative blood cultures and inconclusive echocardiograms where there remains a high index of suspicion for endocarditis, FDG PET CT scanning can be a crucial diagnostic importance and should be considered early in patients with prosthetic valves.",
"affiliations": "Department of Cardiology, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK.;Department of Cardiology, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK.;Department of Infectious Diseases, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK.;Department of Cardiothoracic Surgery, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK.;Department of Histopathology University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK.;Department of Radiology, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK.;Department of Radiology, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK.;Department of Cardiology, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK.",
"authors": "Dafaalla|Mohamed|M|0000-0003-4625-2775;Weight|Nicholas|N|0000-0001-5952-7542;Cajic|Verran|V|;Dandekar|Uday|U|;Gopalakrishnan|Kishore|K|;Adesanya|Oludolapo|O|;Low|Chen S|CS|;Banerjee|Prithwish|P|0000-0001-7793-1733",
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"doi": "10.1093/ehjcr/ytz209",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119 Oxford University Press \n\n10.1093/ehjcr/ytz209\nytz209\nCase Series\nThe utility of 18F-fluorodeoxyglucose positron emission tomography with computed tomography in Mycobacterium chimaera endocarditis: a case series\nhttp://orcid.org/0000-0003-4625-2775Dafaalla Mohamed 1 http://orcid.org/0000-0001-5952-7542Weight Nicholas 1 Cajic Verran 2 Dandekar Uday 3 Gopalakrishnan Kishore 4 Adesanya Oludolapo 5 Low Chen S 5 http://orcid.org/0000-0001-7793-1733Banerjee Prithwish 1 Tan Timothy C Handling Editor Musella Francesca Editor Vágó Hajnalka Editor Akhtar Mohammed Majid Editor Green Peregrine Editor 1 \nDepartment of Cardiology, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK\n2 \nDepartment of Infectious Diseases, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK\n3 \nDepartment of Cardiothoracic Surgery, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK\n4 \nDepartment of Histopathology University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK\n5 \nDepartment of Radiology, University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK\nCorresponding author. Tel: 44 2476965670, Email: Prithwish.Banerjee@uhcw.nhs.uk\n12 2019 \n06 12 2019 \n06 12 2019 \n3 4 1 6\n04 2 2019 18 3 2019 30 10 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.2019This 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.comAbstract\nBackground\nInfective endocarditis secondary to Mycobacterium chimaera can present with classical constitutional symptoms of infective endocarditis but can be blood culture negative and without vegetations on transthoracic or transoesophageal echocardiogram. Patients with prosthetic valves are at particularly high risk.\n\nCase summary\nWe present two patients who were diagnosed with infective endocarditis secondary to M. chimaera infection. They presented similarly with pyrexia of unknown origin and night sweats. Both patients had previously undergone aortic valve replacement; one with a tissue valve and the other with a metallic valve. New cardiac murmurs were evident on auscultation, but clinical examination showed no peripheral stigmata of endocarditis. Transoesophageal echo and transthoracic echo were both unremarkable, as were serial blood cultures. FDG PET CT scan was the key investigation, which showed increased uptake in the spleen beside other areas. Histopathology and mycobacterial cultures confirmed the diagnosis of M. chimaera infection in both cases. The first patient completed medical therapy and is now fit and well. However, the second patient unfortunately developed disseminated infection causing death.\n\nDiscussion\nThe management of M. chimaera infective endocarditis is challenging, often with delayed diagnosis and poor outcomes. In the context of negative blood cultures and inconclusive echocardiograms where there remains a high index of suspicion for endocarditis, FDG PET CT scanning can be a crucial diagnostic importance and should be considered early in patients with prosthetic valves.\n\nInfective endocarditisPET-CTMycobacteriumCase seriesEchocardiogramNational Institutes of Health10.13039/100000002\n==== Body\nFor the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast\n\n\nLearning points\n\n\nMycobacterium chimaera endocarditis can present with the usual endocarditis symptoms, i.e. fever, night sweats, swearing, and weight loss.\n\nVegetations are usually not detected on echocardiography.\n\nTypical patients are those who underwent a cardiac surgery for valve replacement several months later.\n\nThe management is of long duration and the outcome is often poor.\n\nFDG PET CT scanning may help in the diagnostic process.\n\n\n\n\n\n\n\nIntroduction\nInfective endocarditis secondary to Mycobacterium chimaera can present with classical constitutional symptoms of infective endocarditis but can be blood culture negative and without vegetations on transthoracic or transoesophageal echocardiography.1,2 Patients with prosthetic valves are at a particularly high risk of this infection and may require further surgical intervention.3\n\nTimeline\nPatient 1\t\nApril 2014\t\nA 49-year-old man underwent mechanical aortic valve replacement for a congenitally biscuspid aortic valve\n\n\n\t\nAugust 2016\t\nPresentation with pyrexia and night sweats\n\nSerial blood cultures negative with inconclusive transthoracic echocardiograms\n\nTwo negative transoesophageal echocardiograms 2 weeks apart\n\nFDG PET CT scan showing focal splenic uptake strongly suggestive of infective endocarditis\n\n\n\t\nSeptember 2016\t\nIncreasing C-reactive protein and pyrexia despite medical therapy so underwent ‘re-do’ aortic valve replacement\n\nNow clinically well under regular outpatient follow-up\n\n\n\t\nPatient 2\t\nJanuary 2011\t\nA 64-year-old man underwent a tissue aortic valve replacement for severe aortic stenosis\n\n\n\t\nMarch 2014\t\nAortic root replacement\n\n\n\t\nJune 2016\t\nPresentation with 2 weeks of pyrexia and night sweats\n\nBlood cultures negative and inconclusive transthoracic and transoesophageal echocardiogram undertaken\n\nInitially treated empirically as infective endocarditis\n\nSuggestion of gallbladder thickening on ultrasound abdomen\n\nSwitched to intravenous tazocin for presumed biliary source of infection, discharged following completion of course of antibiotics\n\n\n\t\nJuly 2016\t\nSimilar representation 2 weeks later with pyrexia and night sweats, treated empirically for infective endocarditis for full 6 weeks of intravenous antibiotics\n\nUnderwent FDG PET CT on this admission which showed focal splenic uptake suggestive of infective endocarditis\n\nCompleted course and discharged with significant improvement\n\n\n\t\nSeptember 2016\t\nRepresented to infectious diseases outpatient clinic with erythroderma and recurrent pyrexia. Multidisciplinary team opinion was that this was DRESS syndrome\n\nInitially improved with topical steroids and restarted empirical treatment for infective endocarditis, completed course and discharged home\n\n\n\t\nNovember 2016\t\nRepresentation 2 months later acutely unwell with disseminated mycobacterium infection, passed away shortly after admission\n\n\n\t\nCase presentation\nPatient 1\nThe first patient was a 47-year-old man with history of aortic regurgitation secondary to a congenitally bicuspid aortic valve. He presented with pyrexia of unknown origin and persistent night sweats for 5 weeks, 20 months after mechanical aortic valve replacement. Abdominal examination showed hepatosplenomegaly and an early diastolic murmur consistent with aortic regurgitation was noted. The thromboembolic and autoimmune manifestations of infective endocarditis were not evident on examination. There was no peripheral oedema and the jugular venous pressure was not raised.\n\nHis electrocardiogram (ECG) showed sinus rhythm and routine blood tests showed elevated C-reactive protein (CRP) (59 mg/L) (normal <5 mg/L) and normal white cell and neutrophils counts. The total protein was low (51 g/L) (60–83 g/L) and liver enzymes were high, especially the Alkaline phosphatase (859 U/L) (30–130 U/L). Hepatitis and HIV viral screens were negative. Initial transthoracic echocardiography showed severe paravalvular aortic regurgitation with no vegetations on the metallic valve; however, there was good biventricular function and no ventricular dilatation. He was started on IV flucloxacillin and gentamicin for suspected endocarditis but blood cultures were negative. Initial CRP was 59 mg/L (<5 mg/L), which remained static for 5 days, vancomycin was added on microbiology advice, resulting in a modest CRP reduction to 33 mg/L (<5 mg/L). Two subsequent transoesophageal echocardiograms carried out a few weeks apart showed no vegetations either, so despite a clinical suspicion of endocarditis this could not be confirmed. Finally, it was felt that an 18F-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET-CT) scan would be valuable to identify the source of infection. This showed mild splenomegaly and focal splenic uptake, which given the clinical context was suggestive of infective endocarditis with a splenic embolic site. Blood cultures were repeated and still showed no growth. The infectious disease team was involved at this point, who requested a liver ultrasound and liver biopsy for histopathology, mycobacterial culture, and polymerase-chain reaction (PCR). The biopsy was requested due to the combination of hepatomegaly on examination and ongoing pyrexia, as part of the pyrexia of unknown origin work-up. The histopathology (Figure 1) showed numerous scattered small epithelioid granulomas that lacked caseous necrosis. These were not specifically associated with portal tracts and were seen throughout the cores (both in the parenchyma and portal tracts).\n\n\nFigure 1 Haemotoxylin and eosin staining with 100× magnification, showing multiple scattered epithelioid granulomas.\n\nThe diagnosis was difficult and a multidisciplinary team (MDT) approach was needed. The gastroenterology, microbiology, and infectious disease teams were all involved. The case was discussed in both the infectious disease and cardiology MDT meeting. The idea of M. chimaera endocarditis first arose in the MDT meeting. Given the persistently raised inflammatory markers, normal transoesophageal echocardiogram but suspicious PET-CT findings, it was felt that this may represent an atypical organism. The similarity in presentation in this case to another in the preceding year also influenced the MDT group to consider M. chimaera as a potential underlying cause of this case of infectious endocarditis.\n\nOn infectious disease team advice, rifampicin, moxifloxacin, clarithromycin, and ethambutol were prescribed with later introduction of amikacin and withdrawal of clarithromycin due to medication intolerance. He continued medical therapy for approximately 9 months but this failed to control the infection and CRP peaked at 185 mg/L (<5 mg/L). He then underwent a ‘re-do’ mechanical aortic valve replacement in an attempt to remove the infected valve and the mechanical valve was sent to histopathology. This was decided based on the failure of infection control with IV antibiotics following a MDT meeting between the responsible cardiologist, microbiologist, and cardiothoracic surgeon who had performed the original valve surgery. He developed complete heart block post-operatively and permanent pacemaker implantation was performed. Aortic mechanical valve microscopy (of the removed valve) showed moderate numbers of acid fast bacilli and the M. chimaera species was isolated in the mycobacterium culture. Antimicrobial therapy towards mycobacteria was restarted after the operation for a 12-months course and the patient showed significant improvement without spiking temperatures. He has now been followed-up for over 3 years and has made a full recovery with his most recent annual transthoracic echo showing only mild left ventricular dilatation and preserved biventricular function.\n\nPatient 2\nThe second patient was a 64-year-old man who presented similarly, with 2 weeks of intermittent pyrexia and profuse night sweats. He had a tissue aortic valve replacement for severe aortic stenosis 5 years prior to presentation. He underwent aortic root replacement 2 years later. There were no localizing symptoms. On examination, he had an ejection systolic murmur heard throughout the precordium with a valvular click noted. Examination showed no peripheral stigmata of endocarditis.\n\nThe ECG showed sinus rhythm and chest X-ray was normal. Full blood count and renal function were normal. Liver enzymes were slightly elevated without jaundice or hypoalbuminaemia. The CRP was elevated (47 mg/L) (<5 mg/L). All blood cultures were negative and a sample for mycobacterial culture was sent. HIV and hepatitis screen were negative. Transthoracic and transoesophageal echocardiography showed no vegetations. Abdominal ultrasound showed a thickened gallbladder wall and one small gallstone. CT thorax, abdomen, and pelvis excluded the presence of malignancy or abscess as the cause of the pyrexia.\n\nAn FDG PET CT scan was performed which showed a retrosternal soft tissue density/collection involving the pericardium and linear increased uptake was noted in the ascending aorta and root (Figures 2 and 3). This mass was felt to represent an abscess. There were also metabolically active areas in the right upper lobe and focal splenic uptake. The mycobacterium blood culture isolated a Mycobacterium avium intracellular type organism which was identified later as M. chimaera infection, and diagnosis of infective endocarditis secondary to M. chimaera was established.\n\n\nFigure 2 Maximal projection FDG PET CT image from Patient 2, showing retrosternal increased signal uptake, between the sternum and ascending aorta and focal splenic uptake.\n\nFigure 3 FDG PET CT images showing retrosternal increased signal uptake between the sternum and ascending aorta with focal splenic uptake. (Top left shows computed tomography image, top right shows FDG PET CT image, and the bottom two images are fusion FDG PET CT images.)\n\nPatient 2 was initially treated as endocarditis and started on intravenous flucloxacillin, rifampicin, and gentamicin. Based on the equivocal abdominal ultrasound result, microbiologists briefly advised treating with intravenous piperacillin–tazobactam for suspected cholangitis. There was no right upper quadrant tenderness however and clinical suspicion of cholangitis was low. He continued to spike temperatures prompting the addition of doxycycline to cover for atypical bacterial infection. His temperature settled and he was discharged with infectious diseases team outpatient follow-up in 2 weeks. Over the follow-up period, he reported rigors and night sweats. The diagnosis of M. chimaera infective endocarditis was eventually established based on the results of the PET scan and the mycobacterial blood cultures.\n\nHe was commenced on rifampicin, ethambutol, and clarithromycin. His temperatures had settled and his night sweats reduced in frequency and intensity. However, his appetite remained poor and he continued to lose weight. On follow-up with the infectious disease consultant, he complained of dysphagia and ongoing weight loss. He also developed an extensive rash over his arms, legs, and back. The infectious disease team felt this was medication-related and decided to stop all antibiotics temporarily until the rash resolved.\n\nAfter stopping all medications, he continued to feel unwell and shivery with myalgia and a diffuse itchy rash. He became persistently pyrexial and developed diffuse erythroderma. The patient was admitted to hospital, received topical steroids, improved and was discharged after a week. This presentation was discussed in the multidisciplinary infectious disease meeting and diagnosed as DRESS syndrome secondary to clarithromycin. The rash completely resolved after 1 month. The patient was then admitted for reintroduction of antimicrobial therapy for M. chimaera infection and discharged without complications.\n\nAfter 2 months, the patient developed gradually worsening dysphagia. Swallowing assessment did not show structural abnormality. His barium swallow was normal, and CT scan of the chest, abdomen, and pelvis showed new diffuse parenchymal lung shadowing with new significant splenomegaly. A diagnosis of disseminated M. chimaera infection was then made. An honest and thorough discussion with the patient and family about the situation was held to discuss his poor prognosis and poor response to therapy as well as a ceiling of care. In his case repeat cardiac surgery to remove the infected valve was not feasible as he had undergone two previous cardiac operations; a third operation was felt to be too high a risk. The patient expressed the wish to die at home. After discussion with the palliative care team, a plan for care of the dying person was set up. He died almost 1 year after the initial presentation.\n\nDiscussion\nThe presenting symptoms of M. chimaera infection are usually fever, shortness of breath, fatigue, and weight loss.1,2 The non-specific symptoms, the negative results of echocardiography, deranged liver enzymes, and blood culture limitations can make the diagnosis of M. chimaera infection extremely difficult.1,2,4 For example, one of our patients discussed was initially treated as cholangitis, and in another case report a presumptive diagnosis of sarcoidosis was made and the patient discharged on oral prednisolone before the results of repeated blood culture and bone marrow culture revealed the organism.1 Misdiagnosis could cause significant harm if immunosuppressive treatment is used in patients with active infection. This was not an isolated case and there have been multiple cases of a diagnosis of sarcoidosis being made initially before the underlying M. chimaera has been found.5\n\nThe outcome of M. chimaera infection can be devastating. In a study of 10 patients with disseminated M. chimaera infection subsequent to open-heart surgery at three European Hospitals, eight patients had therapy failure and five patients died.2 In the same study, all patients who were previously considered inoperable due to presumptively high perioperative mortality had to go for immediate cardiothoracic intervention following the dissemination of the infection.2 The high mortality rate among patients with disseminated infection brings to light the impact of this infection on patient risk stratification for cardiothoracic surgery.\n\n\nMycobacterium chimaera is a Mycobacterium avium complex (MAC) species that has been thought to have relatively low virulence.3,6 Two prosthetic valve infections outbreaks of M. chimaera and associated disseminated infection were reported in the literature, after thorough epidemiologic and molecular analysis, the source of the infection was found to be the heater-cooler unit used for cardiac bypass procedures.7,8 These outbreaks were reported initially in the USA, with subsequent clusters reported elsewhere.7 Further analysis showed that the original source of contamination was the manufacturing facility of the implicated heater-cooler devices (Stockert 3T).9 These findings encouraged the Food and Drug Administration and Centers for Disease Control and Prevention in the USA to make several recommendations to decrease the risk of additional M. chimaera infections.10 As a result, any Stockert 3T heater-cooler device that has tested positive for M. chimaera or was associated with known M. chimaera infections and their accessories were removed. Despite the overall low risk of M. chimaera, providers of patients who have undergone cardiac surgery should be aware of the possibility of M. chimaera infection especially if they develop clinical features compatible with disseminated mycobacterial disease. We do now know that patients who have undergone cardiothoracic surgery are at significantly higher risk of M. chimaera compared with the general population, and that this risk can be both early post-operative or a later, more insidious presentation.7,11 There is not yet consensus regarding optimal antimicrobial therapy in the treatment of M. chimaera infective endocarditis, but it likely involves a combination of clarithromycin, ethambutol, and rifabutin, with particular susceptibility to clarithromycin.2 With increasing volume of cardiothoracic surgery in an increasingly frail and comorbid population, the decision for further cardiothoracic intervention in these patients is often a challenging decision. However, there is growing thought that early surgical discussion with view to removal of infected prosthetic material may be essential for successful treatment of the underlying infection.12\n\nHowever, there are limitations, one particular problem with the use of FDG PET CT in prosthetic valve infective endocarditis is in patients who are in the first 3 months post-operatively, where there is an inability to differentiate between infective endocarditis and normal post-operative changes.13 FDG PET CT scanning can assist in making an early diagnosis of endocarditis in this setting of negative bacterial cultures and no visible vegetations. Its growing role in the diagnosis of infective endocarditis is reflected by the inclusion in the European Society of Cardiology (ESC) modified diagnostic criteria for infective endocarditis 2015.14\n\nLead author biography\nMohamed Dafaalla is a core medical trainee (CT1) in Sheffield Teaching Hospitals NHS Foundation Trust, South Yorkshire. He completed MSc in Molecular Medicine, Institute of Endemic Diseases, Sudan and MBBS in University of Khartoum, Sudan. \n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSupplementary Material\nytz209_Supplementary_Slide_Set Click here for additional data file.\n\n Acknowledgements\nWe would like to thank the involved patients and/or their next of kin for their consent to be featured in this case series.\n\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\n\nConsent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.\n\n\nConflict of interest: none declared.\n==== Refs\nReferences\n1 \nTan N , Sampath R , Abu Saleh OM , Tweet MS , Jevremovic D , Alniemi S , Wengenack NL , Sampathkumar P , Badley AD. \nDisseminated Mycobacterium chimaera infection after cardiothoracic surgery\n. Open Forum Infect Dis 2016 ;3 :ofw131. 27703994 \n2 \nKohler P , Kuster SP , Bloemberg G , Schulthess B , Frank M , Tanner FC , Rössle M , Böni C , Falk V , Wilhelm MJ , Sommerstein R , Achermann Y , ten Oever J , Debast SB , Wolfhagen MJHM , Brandon Bravo Bruinsma GJ , Vos MC , Bogers A , Serr A , Beyersdorf F , Sax H , Böttger EC , Weber R , van Ingen J , Wagner D , Hasse B. \nHealthcare-associated prosthetic heart valve, aortic vascular graft, and disseminated Mycobacterium chimaera infections subsequent to open heart surgery\n. Eur Heart J 2015 ;36 :2745 –2753\n.26188001 \n3 \nJaworski R , Naumiuk Ł , Paczkowski K , Formella D , Pek R , Zieliński J , Haponiuk I. \n\nMycobacterium chimaera—a new threat for cardiac surgical patients?\n\nKardiochir Torakochirurgia Pol \n2017 ;14 :22 –26\n.28515744 \n4 \nAchermann Y , Rossle M , Hoffmann M , Deggim V , Kuster S , Zimmermann DR , Bloemberg G , Hombach M , Hasse B. \nProsthetic valve endocarditis and bloodstream infection due to Mycobacterium chimaera\n. J Clin Microbiol 2013 ;51 :1769 –1773\n.23536407 \n5 \nGanatra S , Sharma A , D'Agostino R , Gage T , Kinnunen P. \n\nMycobacterium chimaera mimicking sarcoidosis\n. Methodist Debakey Cardiovasc J 2018 ;14 :301 –302\n.30788017 \n6 \nTortoli E , Rindi L , Garcia MJ , Chiaradonna P , Dei R , Garzelli C , Kroppenstedt RM , Lari N , Mattei R , Mariottini A , Mazzarelli G , Murcia MI , Nanetti A , Piccoli P , Scarparo C. \nProposal to elevate the genetic variant MAC-A, included in the Mycobacterium avium complex, to species rank as Mycobacterium chimaera sp. nov\n. Int J Syst Evol Microbiol 2004 ;54 :1277 –1285\n.15280303 \n7 \nChand M , Lamagni T , Kranzer K , Hedge J , Moore G , Parks S , Collins S , del Ojo Elias C , Ahmed N , Brown T , Smith EG , Hoffman P , Kirwan P , Mason B , Smith-Palmer A , Veal P , Lalor MK , Bennett A , Walker J , Yeap A , Isidro Carrion Martin A , Dolan G , Bhatt S , Skingsley A , Charlett A , Pearce D , Russell K , Kendall S , Klein AA , Robins S , Schelenz S , Newsholme W , Thomas S , Collyns T , Davies E , McMenamin J , Doherty L , Peto TEA , Crook D , Zambon M , Phin N. \nInsidious risk of severe Mycobacterium chimaera infection in cardiac surgery patients\n. Clin Infect Dis 2017 ;64 :335 –342\n.27927870 \n8 \nWilliamson D , Howden B , Stinear T. \n\nMycobacterium chimaera spread from heating and cooling units in heart surgery\n. N Engl J Med 2017 ;376 :600 –602\n.28177865 \n9 \nPerkins KM , Lawsin A , Hasan NA , Strong M , Halpin AL , Rodger RR , Moulton-Meissner H , Crist MB , Schwartz S , Marders J , Daley CL , Salfinger M , Perz JF. \nNotes from the field: Mycobacterium chimaera contamination of heater-cooler devices used in cardiac surgery—United States\n. MMWR Morb Mortal Wkly Rep 2016 ;65 :1117 –1118\n.27740609 \n10 HAN Archive—00397 | Health Alert Network (HAN). 2018. https://emergency.cdc.gov/han/han00397.asp (17 July 2018).\n11 \nSax H , Bloemberg G , Hasse B , Sommerstein R , Kohler P , Achermann Y , Rössle M , Falk V , Kuster SP , Böttger EC , Weber R. \nProlonged outbreak of Mycobacterium chimaera infection after open-chest heart surgery\n. Clin Infect Dis 2015 ;61 :67 –75\n.25761866 \n12 \nAsadi T , Mullin K , Roselli E , Johnston D , Tan CD , Rodriguez ER , Gordon S. \nDisseminated Mycobacterium chimaera infection associated with heater-cooler units after aortic valve surgery without endocarditis\n. J Thorac Cardiovasc Surg 2018 ;155 :2369 –2374\n.29397149 \n13 \nSarrazin JF , Trottier M , Tessier M. \nAccuracy of PET/CT for detection of infective endocarditis: where are we now?\n\nJ Nucl Cardiol \n2017 ;doi:10.1007/s12350-017-1126-2.\n14 \nHabib G , Lancellotti P , Antunes MJ , Bongiorni MG , Casalta JP , Del Zotti F , Dulgheru R , El Khoury G , Erba PA , Iung B , Miro JM , Mulder BJ , Plonska-Gosciniak E , Price S , Roos-Hesselink J , Snygg-Martin U , Thuny F , Tornos Mas P , Vilacosta I , Zamorano JL ; ESC Scientific Document Group. \n2015 ESC Guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM)\n. Eur Heart J 2015 ;36 :3075 –3128\n.26320109\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "3(4)",
"journal": "European heart journal. Case reports",
"keywords": "Case series; Echocardiogram; Infective endocarditis; Mycobacterium; PET-CT",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "33043236",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports",
"references": "15280303;27703994;23536407;26188001;28515744;27740609;29397149;26320109;28177865;29143245;25761866;27927870;30788017",
"title": "The utility of 18F-fluorodeoxyglucose positron emission tomography with computed tomography in Mycobacterium chimaera endocarditis: a case series.",
"title_normalized": "the utility of 18f fluorodeoxyglucose positron emission tomography with computed tomography in mycobacterium chimaera endocarditis a case series"
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"abstract": "BACKGROUND\nIn treating refractory epilepsy, many clinicians are interested in methods used to transition patients receiving clonazepam to clobazam to maintain or increase seizure control, improve tolerability of patients' overall drug therapy regimens, and to enhance quality of life for patients and their families. However, no published guidelines assist clinicians in successfully accomplishing this change safely.\n\n\nMETHODS\nThe following three case reports provide insight into the transition from clonazepam to clobazam. First, an 8-year-old Caucasian boy with cryptogenic Lennox-Gastaut syndrome beginning at 3.5 years of age, who was experiencing multiple daily generalized tonic-clonic, absence, myoclonic, and tonic seizures at presentation. Second, a 25-year-old, left-handed, White Hispanic man with moderate mental retardation and medically refractory seizures that he began experiencing at 1 year of age, secondary to tuberous sclerosis. When first presented to an epilepsy center, he had been receiving levetiracetam, valproate, and clonazepam, but reported having ongoing and frequent seizures. Third, a 69-year-old Korean woman who had been healthy until she had a stroke in 2009 with subsequent right hemiparesis; as a result, she became less physically and socially active, and had her first convulsive seizure approximately 4 months after the stroke.\n\n\nCONCLUSIONS\nFrom these cases, we observe that a rough estimate of final clobazam dosage for each mg of clonazepam under substitution is likely to be at least 10-fold, probably closer to 15-fold for many patients, and as high as 20-fold for a few. Consideration and discussion of the pharmacokinetic, pharmacologic, and clinical properties of 1,4- and 1,5-benzodiazepine action provide a rationale on why and how these transitions were successful.",
"affiliations": "Division of Pediatric Neurology, David Geffen School of Medicine at UCLA, University of California-Los Angeles, Room 22-474 MDCC, Los Angeles, CA 90095-1752, USA. RSankar@ucla.edu.",
"authors": "Sankar|Raman|R|;Chung|Steve|S|;Perry|Michael Scott|MS|;Kuzniecky|Ruben|R|;Sinha|Saurabh|S|",
"chemical_list": "D000927:Anticonvulsants; D001569:Benzodiazepines; D000078306:Clobazam; D002998:Clonazepam",
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"doi": "10.1186/1752-1947-8-429",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 302810.1186/1752-1947-8-429Case ReportClinical considerations in transitioning patients with epilepsy from clonazepam to clobazam: a case series Sankar Raman RSankar@ucla.edu Chung Steve Steve.Chung@DignityHealth.org Perry Michael Scott Scott.Perry@cookchildrens.org Kuzniecky Ruben Ruben.Kuzniecky@nyumc.org Sinha Saurabh saurabh.sinha@duke.edu Division of Pediatric Neurology, David Geffen School of Medicine at UCLA, University of California–Los Angeles, Room 22-474 MDCC, Los Angeles, CA 90095-1752 USA Barrow Neurological Institute, 500 W. Thomas Road, Phoenix, AZ 85013 USA Jane and John Justin Neuroscience Center, Cook Children’s Medical Center, 4th Floor, 1500 Cooper Street, Fort Worth, TX 76104 USA Department of Neurology, NYU Epilepsy Center, New York University School of Medicine, 223 East 34 Street, New York, NY 10016 USA Neurology Residency Program, Epilepsy Monitoring Unit, Duke University Medical Center, DUMC 102350, Durham, NC 27710 USA 16 12 2014 2014 8 42918 8 2014 15 10 2014 © Sankar et al.; licensee BioMed Central. 2014This 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.Introduction\nIn treating refractory epilepsy, many clinicians are interested in methods used to transition patients receiving clonazepam to clobazam to maintain or increase seizure control, improve tolerability of patients’ overall drug therapy regimens, and to enhance quality of life for patients and their families. However, no published guidelines assist clinicians in successfully accomplishing this change safely.\n\nCase presentations\nThe following three case reports provide insight into the transition from clonazepam to clobazam. First, an 8-year-old Caucasian boy with cryptogenic Lennox–Gastaut syndrome beginning at 3.5 years of age, who was experiencing multiple daily generalized tonic–clonic, absence, myoclonic, and tonic seizures at presentation. Second, a 25-year-old, left-handed, White Hispanic man with moderate mental retardation and medically refractory seizures that he began experiencing at 1 year of age, secondary to tuberous sclerosis. When first presented to an epilepsy center, he had been receiving levetiracetam, valproate, and clonazepam, but reported having ongoing and frequent seizures. Third, a 69-year-old Korean woman who had been healthy until she had a stroke in 2009 with subsequent right hemiparesis; as a result, she became less physically and socially active, and had her first convulsive seizure approximately 4 months after the stroke.\n\nConclusions\nFrom these cases, we observe that a rough estimate of final clobazam dosage for each mg of clonazepam under substitution is likely to be at least 10-fold, probably closer to 15-fold for many patients, and as high as 20-fold for a few. Consideration and discussion of the pharmacokinetic, pharmacologic, and clinical properties of 1,4- and 1,5-benzodiazepine action provide a rationale on why and how these transitions were successful.\n\nKeywords\nClobazamClonazepamSwitchingTransitionissue-copyright-statement© The Author(s) 2014\n==== Body\nIntroduction\nBenzodiazepines have been used to treat seizures since 1965, when a group from Marseilles, led by Henri Gastaut, reported on the successful use of diazepam to treat non-convulsive (mainly absence) seizures [1] and its utility in the treatment of status epilepticus [2]. Prior to that, benzodiazepines such as diazepam and chlordiazepoxide had been employed primarily as anxiolytics and hypnotics. Despite the observations by Gastaut, the use of diazepam for absence epilepsy did not gain traction because the 1960s marked the emergence of succinimides such as ethosuximide, which seemed to be less sedating and better tolerated than diazepam. Subsequently, Henri Gastaut published that clonazepam was even more effective than diazepam in the treatment of status epilepticus [3].\n\nThe initial approval of clonazepam by the US Food and Drug Administration (FDA), as reviewed by Thomas Brown [4], suggested that it be used for the following types of seizures: absence (typical petit mal), infantile spasms (infantile myoclonic, massive spasms, salaam), atypical absence (atypical petit mal), akinetic (astatic, atonic, drop attack), “minor motor” attacks, and “Lennox–Gastaut syndrome,” (LGS) but not for the treatment of grand mal, partial seizures with complex symptoms (for example, psychomotor, temporal lobe), or focal seizures. The more recent version of the prescribing information is more restrictive and states that, “It is useful alone or as an adjunct in the treatment of the LGS (petit mal variant), akinetic and myoclonic seizures. In patients with absence seizures (petit mal) who have failed to respond to succinimides, clonazepam (Klonopin™) may be useful [5].” Of interest, the initial experience described in the European literature was based on the use of intravenous clonazepam, which is not available in the USA.\n\nUntil the approval of clobazam (Onfi™) in the USA in October 2011 for adjunctive treatment of seizures associated with LGS [6], benzodiazepines had been used mainly as rescue medications for status epilepticus or acute repetitive seizures. In addition to concerns about excessive sedation, long-term benzodiazepine use raises questions about maintenance of efficacy because of potential development of tolerance. The indications section of the FDA prescribing information for clonazepam indicates, “In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often within 3 months of administration. In some cases, dosage adjustment may re-establish efficacy [5].”\n\nIn addition, of the various classes of anticonvulsant medications, benzodiazepines have been especially implicated in producing cognitive and behavioral adverse effects [7, 8]. However, clobazam, a 1,5-benzodiazepine, seems to differ in its spectrum of pharmacologic activities from traditional 1,4-benzodiazepines [9, 10]. Indeed, a recent study provided sustained efficacy results for clobazam in patients with LGS over 3 years with stable dosing [11].\n\nClinicians are considerably interested in switching some patients receiving clonazepam to clobazam to maintain or improve seizure control, while also improving tolerability and quality of life for the patient. However, no published guidelines assist clinicians in successfully accomplishing this change safely. In this report, we provide three case reports on this therapy transition, and summarize in the following discussion the known pharmacokinetic, pharmacologic, and clinical aspects of benzodiazepine action to arrive at a successful therapeutic solution to this problem.\n\nCase presentations\nCase 1 (8-year-old Caucasian boy with cryptogenic LGS)\nCase 1 is an 8-year-old Caucasian boy with cryptogenic LGS beginning at 3.5 years of age. An electroencephalograph (EEG) showed diffuse slowing, with a generalized slow spike-and-wave pattern typical of LGS. His magnetic resonance imaging (MRI) was normal. At the time of presentation, he experienced multiple daily generalized tonic–clonic (GTC), absence, myoclonic, and tonic seizures. He had failed several prior antiepileptic drugs including levetiracetam (maximum dosage unknown), lamotrigine (7mg/kg/day), the ketogenic diet, and vagal nerve stimulation (VNS, output current 2.5mA, on time: 21 seconds, off time: 0.8 minutes). A physical examination revealed a thin boy, unable to walk or speak with many healing abrasions from frequent seizure-induced falls. At the time clobazam was added to his treatment regimen, he was failing zonisamide (10mg/kg/day), valproate (42mg/kg/day, concentration 103μg/mL), rufinamide (50mg/kg/day), and clonazepam 1.5mg twice daily.\n\nClobazam was initiated at 5mg daily (0.25mg/kg/day) and increased weekly by 5mg until he reached 10mg twice daily (1mg/kg/day) over 4 weeks. At this dosing, he became free of tonic and myoclonic seizures, with more than a 90% reduction of GTC and absence seizures. However, his parents reported significant somnolence, with only 6 hours of wake time each day. Clonazepam weaning was initiated by decreasing dosage by 0.5mg each week, until clonazepam was entirely discontinued by the end of 6 weeks. As clonazepam was weaned, somnolence resolved, and he continued the same good seizure control.\n\nRufinamide was subsequently discontinued without incident. Clobazam was titrated to 20mg twice daily (2mg/kg/day) 2 years after initiation and secondary to recurrent GTC seizures, which occurred in the setting of VNS dysfunction. Now, 3 years after the initiation of clobazam, he experiences rare myoclonic seizures and is able to walk independently, attend school, and communicate with his family.\n\nCase 2 (25-year-old, left-handed, White Hispanic man with moderate mental retardation and medically refractory seizures)\nCase 2 is a 25-year-old, left-handed, White Hispanic man with moderate mental retardation and medically refractory seizures that he began experiencing at age 1 year, secondary to tuberous sclerosis. His seizures commence typically with sudden body stiffening for 30 seconds with ictal cry, followed by tonic–clonic seizure, on occasion. Seizure frequency had increased over time, and he often experienced seizures three to four times per day. He had been treated previously with carbamazepine, phenytoin, phenobarbital, lamotrigine, and topiramate. Approximately 5 years ago, he underwent vagus nerve stimulator implantation, which improved his seizures only slightly.\n\nWhen he first presented to an epilepsy center, he had been receiving levetiracetam, valproate, and clonazepam, but reported having ongoing and frequent seizures. His neurologic examination showed moderate cognitive difficulty, slurred speech, and mild right-arm weakness. Further, his right hand was smaller than his left. He was able to ambulate on his own, but swayed left and right with wide-base stance. His previous EEG showed diffuse background slowing, which was focally more in the left hemisphere. Interictal epileptiform discharges were detected mainly from the left frontotemporal region, along with occasional sharp discharges from the right hemisphere. His brain MRI showed subependymal nodules bilaterally and transmantle dysplasia over the left parietal lobe. Initial scalp ictal EEG indicated diffuse bilateral seizure onset during his initial body stiffening. However, better ictal progression was observed over the left hemisphere just prior to the progression of tonic–clonic phase. A subsequent intracranial grid electrode guided study revealed diffuse seizure onset, but maximally over the left frontal and parietal lobes near the transmantle dysplasia.\n\nHe underwent surgical resection of the dysplasia, but his seizures did not improve significantly. Because of his frequent seizures, clobazam was started and gradually replaced clonazepam, as indicated in Table 1.Table 1 \nDosing transition from clonazepam to clobazam in a 25-year-old, left-handed White Hispanic man with moderate mental retardation and medically refractory seizures\n\n\nWeek 0\tClonazepam 1mg BID\t\nWeek 1\tClonazepam 0.5mg BID; Clobazam 5mg qHS\t\nWeek 2\tClonazepam 0.5mg qHS; Clobazam 5mg BID\t\nWeek 3\tClonazepam discontinued; Clobazam 5mg qAM and 10mg qPM\t\nBID, twice daily; qAM, every morning; qHS, at bedtime; qPM, every night.\n\n\n\nHis family reported that his seizure improvement was notable at Week 2, and his seizures became milder and less frequent (>80% reduction), without significant adverse effects from clobazam. During the next 6 months, his clobazam dosage was gradually increased to 15mg twice daily. His seizure frequency further improved to one to two per week. Moreover, 1 month after his clobazam dosage increase, his levetiracetam dosage was decreased by 50%. He and his family are quite happy with the improvement, and had reported that he has become more active.\n\nCase 3 (69-year-old Korean woman with convulsive seizures)\nCase 3 is a 69-year-old Korean woman who had been quite healthy until she had a stroke in 2009, with subsequent right hemiparesis. Following her stroke, she became less active physically and socially, and approximately 4 months after the stroke, she had her first convulsive seizure. Since her first seizure, she has also noted balance difficulty and worsening of right-leg weakness, requiring use of a walker and a wheelchair. She was placed on phenytoin, and later on oxcarbazepine. Because of imbalance, oxcarbazepine was changed to levetiracetam. On her subsequent visit, her friend reported significant mood changes and anger outbursts, and she was changed from levetiracetam to lamotrigine gradually. She did not have recurrent seizures with lamotrigine.\n\nHowever, because of worsening of dizziness at 100mg daily, lamotrigine was changed to valproate. Her balance issues improved, but she developed hand tremors and recurrent seizures, which often started with olfactory auras, anxiety, and confusion, typically lasting 1 to 2 minutes. On her following clinic visit, she reported another convulsive seizure, which resulted in falling to the ground. In addition, she continued to experience two to three seizures per week. Her MRI scan showed large encephalomalacia over the left frontoparietal region, and an EEG showed left-sided interictal epileptiform discharges, superimposed on background slowing over the left hemisphere. Primarily to address her anxiety, which at times could be associated with her seizures, she was started on clonazepam (1mg/day). Although her anxiety and seizures had improved, she was not able to tolerate clonazepam, often experiencing significant daytime drowsiness. Next, her clonazepam therapy was gradually replaced by clobazam over 2 weeks as described in Table 2.Table 2 \nDosing transition from clonazepam to clobazam in a 69-year-old Korean woman who had experienced a stroke in 2009 and subsequent right hemiparesis leading to convulsive seizures\n\n\nWeek 0\tClonazepam 1mg qHS\t\nWeek 1\tClonazepam 0.5mg qHS;, Clobazam 5mg qHS\t\nWeek 3\tClonazepam discontinued; Clobazam 10mg qHS\t\nqHS, at bedtime.\n\n\n\nWith clobazam 10mg/day, she felt much better cognitively and reported seizure freedom for 3 months initially. Subsequently, she reported approximately one aura every 2 months, and she decided to continue her clobazam dosage without further increase. She did not have significant adverse effects, but felt transient somnolence for the first 2 weeks of her medication transition. She has reported doing much better with balance and seizure control.\n\nDiscussion\nThe three cases represent distinct patterns of a clonazepam to clobazam transition. In the first case, the addition and titration of the clobazam dosage preceded the weaning of clonazepam. In the second and third cases, clonazepam was safely weaned as clobazam was added and titrated simultaneously. Each case highlights both improved seizure control as well as decreased adverse effects following the change from clonazepam to clobazam.\n\nA study published in 1982 compared the preclinical efficacy and the protective index (PI = toxic dose in 50% of the population/effective dose in 50% of the population) of clobazam to those of diazepam, valproate, and phenobarbital and concluded that clobazam performed superiorly in rodent models of induced seizures [12]. Similar advantages for clobazam over 10 different 1,4-benzodiazepines were documented in a study of both anxiolytic performance and antiseizure effect, as measured by electroshock convulsions in rodents compared with sedation and myorelaxant properties [13]. However, this advantage in PI was not discernible in the kindling model [14].\n\nThe advantages of clobazam over diazepam in human adaptive performance and reaction time have been studied [15, 16]. Nicholson suggested, based on these studies, that diazepam and its hydroxylated metabolites (temazepam, oxazepam, and nordiazepam) were suitable for use as hypnotics, while clobazam could be a better daytime anxiolytic [16]. In fact, the binding of clobazam and its metabolite, N-desmethylclobazam, to γ-aminobutyric acid (GABA) receptors in in vitro expression systems demonstrates that they have significantly greater binding affinities for α2- versus α1-subunit-containing GABA receptor complexes, a difference not observed for clonazepam, for which no distinction between α2 and α1 receptors was observed (Figure 1) [10]. Many lines of evidence suggest that GABA receptors containing α1 subunits mediate sedation (as is known for zolpidem), while substantial anticonvulsant activity can be achieved by activation of GABA receptors containing α2 subunits [9].Figure 1 \nDistribution of individually determined pK\ni\nvalues for (A) clobazam, (B) N-desmethylclobazam, (C) clonazepam, and (D) zolpidem across GABAA-receptor subtypes. From Jensen et al. [10]. Ki, inhibition constant.\n\n\n\nFor development of tolerance, there appears to be differences among species and models compared with humans with epilepsy. Thus, in amygdala-kindled rats, tolerance to clobazam developed more rapidly than tolerance to clonazepam [17]. In acute seizures induced by pentylenetetrazole or maximal electroshock, rats chronically treated with diazepam, clonazepam, or clobazam for 28 days and tested over the ensuing 2 weeks showed similar extents of tolerance [18].\n\nIn a prospective Canadian study of 115 children with varying types of epilepsy treated with clobazam, the 79 responders developed at least some degree of tolerance over a 24-month period [19]. The same study also reported that 25 of 37 (68%) children who had failed to respond to 1,4-benzodiazepines (that is, nitrazepam or clonazepam) had responded to the 1,5-benzodiazepine clobazam. In addition, the use of clobazam appeared to be associated with less neurotoxicity than was observed for the 1,4-benzodiazepines clonazepam and nitrazepam. Another Canadian study, involving adult patients with different types of epilepsy, observed that those who had achieved a sustained response to clobazam differed from those who had developed tolerance in duration of epilepsy and the clobazam concentrations that had been maintained [20]. Sustained responders had experienced a shorter duration of epilepsy (mean 16.5 versus 24.5 years, p=0.015) and had attained greater clobazam concentrations (0.50 versus 0.22μM, p=0.017).\n\nA human study followed patients who participated in Phase II and III LGS studies into an extended open-label phase. Of 74 patients who had achieved at least a 50% reduction in drop seizures from baseline to Month 3, 64 (86%) maintained this degree of response with stable dosages over time for up to 3 years [11]. In a subset of patients in that study for whom data were available for up to 5 years, the mean modal clobazam dosage was 0.97mg/kg/day compared with 0.90mg/kg/day in the first year. The retention rate for US patients at 2 years was nearly 80% [11]. Similar results were found in a single-center study of clobazam with children from Seoul, Korea, with LGS, which reported retention rates of 80.2% at 2 years and 76.6% at 3 years [21].\n\nThe switch from clonazepam to clobazam should be considered in light of relevant pharmacokinetic and pharmacodynamic factors of these compounds. One of the important determinants of brain uptake is relative lipophilicity, often estimated by the octanol-to-water partition ratios. Via this in vitro measure, clobazam is much less lipophilic than diazepam (ratio of 9 for clobazam versus 309 for diazepam). Similar data for clonazepam are not readily available [22, 23]. However, the retention times for diazepam, clonazepam, and clobazam in a reverse-phase, high-performance liquid chromatography (HPLC) system using a neutral mobile phase are 31.4 minutes, 14.9 minutes, and 13.1 minutes, suggesting that clonazepam and clobazam are fairly similar in this measure of lipophilicity. The retention time for N-desmethylclobazam is 12, again not far from the times for clonazepam or clobazam. Of the in vitro estimates, available data [22, 23] suggest that HPLC retention times correlated better with in vivo unbound volumes of distribution for a series of benzodiazepines. Arendt and colleagues [22] showed that despite the difference in lipophilicity, the cerebrospinal fluid-to-plasma ratio for clobazam was greater than that for diazepam, a result they attributed to the fact that clobazam is less protein-bound than diazepam (83% for clobazam versus 99% for diazepam), since it is the unbound fraction that transits the blood–brain barrier. Unfortunately, data were not provided for clonazepam in this report. The protein binding of clonazepam is reported to be 85% in a different article [24], and these values are also in agreement with those reported by Riss et al. [25]. Thus, based on a combination of lipophilicity and protein binding, the central nervous system penetration of clonazepam and clobazam should be comparable.\n\nThe binding affinities (Ki in nM) for clonazepam, clobazam, and N-desmethylclobazam to rat brain homogenates have been determined to be 0.26, 151, and 153 [10], respectively, corresponding to the greater potency of clonazepam over clobazam on a mg basis as used in patients. In the same report, Jensen et al. also showed that the pKi values for clobazam and N- desmethylclobazam for α2-subunit-containing receptors exceeded that for those containing α1 subunits, whereas these values were similar for clonazepam. Zolpidem, however, exhibited the greatest pKi values for receptors containing α1 subunits. These data would explain, at least in part, why clobazam may be much less sedating than clonazepam, as observed by Nicholson [16] nearly 35 years ago.\n\nFor drug disposition, clobazam (estimated half-life of 36 hours) undergoes hepatic metabolism to N-desmethylclobazam (estimated half-life of 80 hours). Because of the lower clearance, the latter achieves an approximately 10- to 15-fold steady concentration by approximately 4 weeks after initiation of therapy [26]. Both clobazam and N-desmethylclobazam show a bimodal response to chloride conductance when applied to cultured cerebral neurons in the presence of 10-μM GABA, peaking around 3μM clobazam or N-desmethylclobazam, and declining substantially at 10μM concentrations of either allosteric agonist [27]. Thus, under clinical conditions, N- desmethylclobazam can appear less potent. The important finding, however, is that the concentration of N-desmethylclobazam stabilizes 4 weeks after initiation of therapy. A study of drug–drug interactions found no clinically meaningful drug–drug interactions between clobazam and drugs metabolized by CYP3A4, CYP2C19, CYP1A2, or CYP2C9 [28]. The authors concluded that clobazam may be administered safely as adjunctive therapy in patients with LGS, without meaningful changes in clobazam pharmacokinetics that would require dosage adjustments.\n\nConclusions\nThe literature reviewed thus supports the transition strategies highlighted in the cases described. A rough estimate of the final dosage of clobazam for each mg of clonazepam under substitution is likely to be at least 10-fold, probably closer to 15-fold for many patients, and as high as 20- fold for a few. While there is prudent caution in delaying the weaning of clonazepam until significant clobazam is already onboard from the point of view of breakthrough seizures, patients – as well as their families and caregivers – should be counseled to expect increased sedation transiently with that approach. Given the common clinical experience with the severity of withdrawal seizures associated with removal of clonazepam, it would be wise not to begin aggressive removal of clonazepam from the patients’ regimens as soon as clobazam is initiated. These guidelines are general, because if the patient is also receiving other medications acting via GABA mechanisms, the removal of clonazepam is likely to be tolerated slightly better and breakthrough seizures are less likely or may be milder should such seizures intervene. A transition from clonazepam to clobazam, in consideration of patients’ individual seizure patterns and vulnerabilities, with careful application of the principles described in this article, and with close clinical observation, can be reasonably expected to improve seizure control and enhance quality of life for patients and their families.\n\nConsent\nWritten informed consent was obtained from both of the adult patients and the parents of the child for publication in this case series. Copies of the written consents are available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nCYP1A2Cytochrome P450 isozyme 1A2\n\nCYP2C9Cytochrome P450 isozyme 2C9\n\nCYP2C19Cytochrome P450 isozyme 2C19\n\nCYP3A4Cytochrome P450 isozyme 3A4\n\nEEGElectroencephalograph\n\nFDAFood and drug administration\n\nGABAγ-aminobutyric acid\n\nGTCGeneralized tonic–clonic\n\nHPLCHigh-performance liquid chromatography\n\nKiInhibition constant\n\nLGSLennox–Gastaut syndrome\n\nMRIMagnetic resonance imaging\n\nPIProtective index\n\nVNSVagal nerve stimulation.\n\nCompeting interests\n\nRS serves on scientific advisory boards for and has received honoraria and funding for travel from UCB Pharma, Sunovion, Upsher–Smith Laboratories, Supernus, Lundbeck LLC, and Acorda Therapeutics; and serves on speakers’ bureaus for and has received speaker honoraria from UCB, GlaxoSmithKline, Cyberonics, Supernus and Lundbeck. He receives funding from NIH NINDS NS065783 (coinvestigator), NS045911 (site PI CAE Study), P20 NS080181 (Epilepsy Research Centers without Walls), as well as from Pfizer (Lyrica pediatric partial seizures trial) and Bluebird Bio trial for gene therapy for ALD. He has received royalties for books from CRC Press and Demos Publishers. SC received funding for consulting, serving on scientific advisory boards or speakers’ bureaus, or other activities from UCB Pharma, Supernus, Eisai, Lundbeck LLC, Upsher–Smith Laboratories, SK Life Science, and Acorda. MSP has served on speakers’ bureaus for Lundbeck LLC, Quest Diagnostics, and Transgenomics, as well as advisory boards for Lundbeck LLC and Eisai. RK has served on the speakers’ bureaus for Lundbeck LLC and UCB Pharma. SS has served on advisory boards for Lundbeck LLC, Acorda, and Upsher–Smith Laboratories and on a speaker’s bureau for Cyberonics. He has received research grants from Cyberonics, Upsher–Smith Laboratories, and UCB Pharm, and is a board member for the American Board of Registration of Electroencephalographic and Evoked Potential Technologists and the American Board for Clinical Neurophysiology.\n\nAuthors’ contributions\n\nThese cases, and others, were prepared, reviewed, and discussed by the authors at a Case-Report Colloquium July 27, 2013, in Chicago, USA. The meeting was funded by Lundbeck LLC (Deerfield, IL, USA), and the authors received honoraria for preparing their research and attending the meeting. The authors received no compensation to prepare this article. RS chaired the meeting and drafted the Introduction and Discussion sections. MSP provided and drafted Case 1, and SC provided and drafted Cases 2 and 3. The first draft of this article was prepared by RS, SC, and MSP. All authors reviewed the article for important intellectual content and confirm that they meet the current International Committee of Medical Journal Editors’ four requirements for authorship. All authors read and approved the final manuscript.\n\nWriting assistance and editorial support during manuscript preparation and revision were provided by Michael A. Nissen, ELS, of Lundbeck LLC (Deerfield, IL, USA). Editorial support and article processing fees were funded by Lundbeck LLC.\n==== Refs\nReferences\n1. Gastaut H Roger J Soulayrol R Lob H Tassinari CA L‘action du diazepam (Valium) dans le traitement des formes non-convulsives de l’épilepsie généralisée Rev Neurol (Paris) 1965 112 99 118 5854459 \n2. Gastaut H Naquet R Poiré R Tassinari CA Treatment of status epilepticus with diazepam (Valium) Epilepsia 1965 6 167 182 10.1111/j.1528-1157.1965.tb03786.x 14337463 \n3. Gastaut H Courjon J Poire R Weber M Treatment of status epilepticus with a new benzodiazepine more active than diazepam Epilepsia 1971 12 197 214 10.1111/j.1528-1157.1971.tb04928.x 5004981 \n4. Brown TR Clonazepam: a review of a new anticonvulsant drug Arch Neurol 1976 33 326 332 10.1001/archneur.1976.00500050012003 817697 \n5. [prescribing information] In Klonopin (Clonazepam). South San Francisco, CA, USA: Genentech; 2010.\n6. Ng YT Conry JA Drummond R Stolle J Weinberg MA OV-1012 Study Investigators Randomized, phase III study results of clobazam in Lennox–Gastaut syndrome Neurology 2011 77 1473 1481 10.1212/WNL.0b013e318232de76 21956725 \n7. Sankar R Holmes GL Mechanisms of action for the commonly used antiepileptic drugs: relevance to antiepileptic drug-associated neurobehavioral adverse effects J Child Neurol 2004 19 Suppl 1 S6 S14 15526966 \n8. Glauser TA Effects of antiepileptic medications on psychiatric and behavioral comorbidities in children and adolescents with epilepsy Epilepsy Behav 2004 5 Suppl 3 S25 S32 10.1016/j.yebeh.2004.06.013 15351343 \n9. Sankar R GABAA receptor physiology and its relationship to the mechanism of action of the 1,5-benzodiazepine clobazam CNS Drugs 2012 26 229 244 10.2165/11599020-000000000-00000 22145708 \n10. Jensen HS Nichol K Lee D Ebert B Clobazam and its active metabolite N - desmethylclobazam display significantly greater affinities for α2- versus α1-GABA A –receptor complexes PLoS One 2014 9 e88456 10.1371/journal.pone.0088456 24533090 \n11. Conry JA Ng YT Kernitsky L Mitchell WG Veidemanis R Drummond R Isojarvi J Lee D Paolicchi JM and on behalf of the OV-1004 Study Investigators Stable dosages of clobazam for Lennox–Gastaut syndrome are associated with sustained drop-seizure and total-seizure improvements over 3 years Epilepsia 2014 55 558 567 10.1111/epi.12561 24580023 \n12. Shenoy AK Miyahara JT Swinyard EA Kupferberg HJ Comparative anticonvulsant activity and neurotoxicity of clobazam, diazepam, phenobarbital, and valproate in mice and rats Epilepsia 1982 23 399 408 10.1111/j.1528-1157.1982.tb05426.x 6807671 \n13. Stéru L Chermat R Millet B Mico JA Simon P Comparative study in mice of ten 1,4-benzodiazepines and of clobazam: anticonvulsant, anxiolytic, sedative, and myorelaxant effects Epilepsia 1986 27 Suppl 1 S14 S17 10.1111/j.1528-1157.1986.tb05728.x 2874986 \n14. Tietz EI Rosenberg HC Chiu TH A comparison of the anticonvulsant effects of 1,4- and 1,5-benzodiazepines in the amygdala-kindled rat and their effects on motor function Epilepsy Res 1989 3 31 40 10.1016/0920-1211(89)90065-X 2917546 \n15. Borland RG Nicholson AN Immediate effects on human performance of a 1,5- benzodiazepine (clobazam) compared with the 1,4-benzodiazepines, chlordiazepoxide hydrochloride and diazepam Br J Clin Pharmacol 1975 2 215 221 10.1111/j.1365-2125.1975.tb01578.x 1234503 \n16. Nicholson AN Differential effects of the 1,4- and 1,5-benzodiazepines on performance in healthy man Br J Clin Pharmacol 1979 7 Suppl 1 S83 S84 10.1111/j.1365-2125.1979.tb04670.x \n17. Rosenberg HC Tietz EI Chiu TH Tolerance to anticonvulsant effects of diazepam, clonazepam, and clobazam in amygdala-kindled rats Epilepsia 1989 30 276 285 10.1111/j.1528-1157.1989.tb05299.x 2721464 \n18. Löscher W Rundfeldt C Hönack D Ebert U Long-term studies on anticonvulsant tolerance and withdrawal characteristics of benzodiazepine receptor ligands in different seizure models in mice. I. Comparison of diazepam, clonazepam, clobazam and abecarnil J Pharmacol Exp Ther 1996 279 561 572 8930158 \n19. Munn R Farrell K Open study of clobazam in refractory epilepsy Pediatr Neurol 1993 9 465 469 10.1016/0887-8994(93)90026-9 7605555 \n20. Singh A Guberman AH Boisvert D Clobazam in long-term epilepsy treatment: sustained responders versus those developing tolerance Epilepsia 1995 36 798 803 10.1111/j.1528-1157.1995.tb01617.x 7635098 \n21. Lee EH Yum MS Choi HW Ko TS Long-term use of clobazam in Lennox–Gastaut syndrome: experience in a single tertiary epilepsy center Clin Neuropharmacol 2013 36 4 7 10.1097/WNF.0b013e3182770730 23334068 \n22. Arendt RM Greenblatt DJ de Jong RH Bonin JD Abernethy DR Ehrenberg BL Giles HG Sellers EM Shader RI In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution J Pharmacol Exp Ther 1983 227 98 106 6137558 \n23. Greenblatt DJ Arendt RM Abernethy DR Giles HG Sellers EM Shader RI In vitro quantitation of benzodiazepine lipophilicity: relation to in vivo distribution Br J Anaesth 1983 55 985 989 10.1093/bja/55.10.985 6626413 \n24. Pacifici GM Viani A Rizzo G Carrai M Rane A Plasma protein binding of clonazepam in hepatic and renal insufficiency and after hemodialysis Ther Drug Monit 1987 9 369 373 10.1097/00007691-198712000-00001 3424402 \n25. Riss J Cloyd J Gates J Collins S Benzodiazepines in epilepsy: pharmacology and pharmacokinetics Acta Neurol Scand 2008 118 69 86 10.1111/j.1600-0404.2008.01004.x 18384456 \n26. Rupp W Badian M Christ O Hajdu P Kulkarni RD Taeuber K Uihlein M Bender R Vanderbeke O Pharmacokinetics of single and multiple doses of clobazam in humans Br J Clin Pharmacol 1979 7 Suppl 1 S51 S57 10.1111/j.1365-2125.1979.tb04665.x \n27. Nakamura F Suzuki S Nishimura S Yagi K Seino M Effects of clobazam and its active metabolite on GABA-activated currents in rat cerebral neurons in culture Epilepsia 1996 37 728 735 10.1111/j.1528-1157.1996.tb00643.x 8764810 \n28. Walzer M Bekersky I Blum RA Tolbert D Pharmacokinetic drug interactions between clobazam and drugs metabolized by cytochrome P450 isoenzymes Pharmacotherapy 2012 32 340 353 10.1002/j.1875-9114.2012.01028.x 22422635\n\n",
"fulltext_license": "CC BY",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000927:Anticonvulsants; D001569:Benzodiazepines; D002648:Child; D000078306:Clobazam; D002998:Clonazepam; D004827:Epilepsy; D005260:Female; D006801:Humans; D008297:Male",
"nlm_unique_id": "101293382",
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"pmc": null,
"pmid": "25511520",
"pubdate": "2014-12-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "35212;35205;6137558;6626413;2874986;3424402;2917546;2721464;7605555;7635098;8764810;8930158;15526966;18384456;21956725;22145708;22422635;23334068;24533090;24580023;14337463;15351343;5854459;5004981;817697;1234503;6807671",
"title": "Clinical considerations in transitioning patients with epilepsy from clonazepam to clobazam: a case series.",
"title_normalized": "clinical considerations in transitioning patients with epilepsy from clonazepam to clobazam a case series"
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"abstract": "The uptake of fluorodeoxyglucose Positron Emission Tomography in the tumors of various cancer types demonstrates the key role of glucose in the proliferation of cancer. Dichloroacetate is a 2-carbon molecule having crucial biologic activity in altering the metabolic breakdown of glucose to lactic acid. Human cell line studies show that dichloroacetate switches alter the metabolomics of the cancer cell from one of glycolysis to oxidative phosphorylation, and in doing so restore mitochondrial functions that trigger apoptosis of the cancer cell. Reports of dichloroacetate in human subjects are rare. The authors contacted individuals from Internet forums who had reported outstanding anti-cancer responses to self-medication with dichloroacetate. With informed consent, complete medical records were requested to document response to dichloroacetate, emphasizing the context of monotherapy with dichloroacetate. Of ten patients agreeing to such an evaluation, only one met the criteria of having comprehensive clinic records as well as pathology, imaging and laboratory reports, along with single agent therapy with dichloroacetate. That individual is the focus of this report. In this case report of a man with documented relapse after state-of-the-art chemotherapy for non-Hodgkin's lymphoma, a significant response to dichloroacetate is documented with a complete remission, which remains ongoing after 4 years. Dichloroacetate appears to be a novel therapy warranting further investigation in the treatment of cancer.",
"affiliations": "International Strategic Cancer Alliance, Ashland, OR 97520, USA. sbstrum@gmail.com",
"authors": "Strum|Stephen B|SB|;Adalsteinsson|Orn|O|;Black|Richard R|RR|;Segal|Dmitri|D|;Peress|Nancy L|NL|;Waldenfels|James|J|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D003999:Dichloroacetic Acid; D011241:Prednisone",
"country": "United States",
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"issue": "45(3)",
"journal": "Journal of bioenergetics and biomembranes",
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"medline_ta": "J Bioenerg Biomembr",
"mesh_terms": "D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D003999:Dichloroacetic Acid; D004317:Doxorubicin; D006019:Glycolysis; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D010085:Oxidative Phosphorylation; D011241:Prednisone; D012074:Remission Induction; D000069283:Rituximab; D012651:Self Medication; D014750:Vincristine",
"nlm_unique_id": "7701859",
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"pmid": "23263938",
"pubdate": "2013-06",
"publication_types": "D002363:Case Reports; D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19872213;14656699;21403907;7263678;20463368;17551814;13351639;198801;10070012;15048575;17222789;16267009;3099068;18423823;18337823;11557773;11850481;20485289;17426345;9496194;19403881;9387094;20463364;18411236;19543830;18766181;16651305;16766260;16725381;18465755;18455429;12873971;13298683",
"title": "Case report: Sodium dichloroacetate (DCA) inhibition of the \"Warburg Effect\" in a human cancer patient: complete response in non-Hodgkin's lymphoma after disease progression with rituximab-CHOP.",
"title_normalized": "case report sodium dichloroacetate dca inhibition of the warburg effect in a human cancer patient complete response in non hodgkin s lymphoma after disease progression with rituximab chop"
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"companynumb": "US-ROCHE-1237615",
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"activesubstancename": "PREDNISONE"
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"abstract": "OBJECTIVE\nTo delineate and discuss a not yet described possible ocular complication of selective intra-arterial chemotherapy (SIAC) for treatment of retinoblastoma.\n\n\nMETHODS\nA 23-month-old girl with a large unilateral retinoblastoma was treated with repeated SIAC using 5 mg melphalan between July 2010 and January 2012. Clinical course of tumor and further ocular changes after therapy and histopathologic findings are described.\n\n\nRESULTS\nIn total, 5 SIAC were performed over a time period of 18 months. After the last SIAC, diffuse dense cataract prevented further funduscopy. In addition, anterior chamber seeding was obvious, leading to the decision to enucleate the eye. Histopathologically, nearly complete regression of the main tumor mass with prominent calcifications, but vital tumor seeding in the vitreous, on the lens surface, on the ciliary body, and in the anterior chamber, was observed. Peculiar vacuolation of the lens epithelial cells, liquefaction of the subepithelial lens fibers, and diffuse small vacuoles within the lens were striking.\n\n\nCONCLUSIONS\nRepeated SIAC with melphalan may induce cataract formation, possibly as a toxic effect of the chemotherapeutic to the lens, maybe combined with radiation exposure during fluoroscopy. This ocular complication should be taken into consideration as a limitation of the number of feasible repeated treatments.",
"affiliations": "1 Department of Ophthalmology, Eberhard Karls University Tübingen - Germany.",
"authors": "Suesskind|Daniela|D|;Schrader|Merle|M|;Foerster|Michael H|MH|;Ernemann|Ulrike|U|;Aisenbrey|Sabine|S|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan",
"country": "United States",
"delete": false,
"doi": "10.5301/ejo.5000393",
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"issn_linking": "1120-6721",
"issue": "24(3)",
"journal": "European journal of ophthalmology",
"keywords": null,
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D002386:Cataract; D005260:Female; D006801:Humans; D007223:Infant; D007261:Infusions, Intra-Arterial; D007908:Lens, Crystalline; D008558:Melphalan; D009887:Ophthalmoscopy; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D012189:Retrospective Studies",
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"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cataract formation: a possible complication of intra-arterial chemotherapy for retinoblastoma.",
"title_normalized": "cataract formation a possible complication of intra arterial chemotherapy for retinoblastoma"
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"companynumb": "DE-MYLANLABS-2014M1011548",
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "MELPHALAN"
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"abstract": "Antituberculosis (TB) drug exposure is associated with a mild elevation of liver enzymes that occasionally develops into severe liver injury. Herein, we identify ethambutol- and rifampicin-specific CD4+ and CD8+ T-cell clones in a patient with fatal anti TB-related liver injury. The clones were activated to proliferate and secrete IFN-γ, Il-13, and granzyme B following drug treatment. Drug-responsive T-cells may contribute to the pathogenesis of antituberculosis-related liver failure.",
"affiliations": "Department of Molecular and Clinical Pharmacology, University of Liverpool , Sherrington Building, Ashton Street, Liverpool L69 3GE, England.;Department of Respiratory Medicine, St James's Hospital , Beckett Street, Leeds LS9 7TF, England.;Department of Molecular and Clinical Pharmacology, University of Liverpool , Sherrington Building, Ashton Street, Liverpool L69 3GE, England.;Department of Respiratory Medicine, St James's Hospital , Beckett Street, Leeds LS9 7TF, England.;Department of Molecular and Clinical Pharmacology, University of Liverpool , Sherrington Building, Ashton Street, Liverpool L69 3GE, England.;Department of Molecular and Clinical Pharmacology, University of Liverpool , Sherrington Building, Ashton Street, Liverpool L69 3GE, England.;Department of Molecular and Clinical Pharmacology, University of Liverpool , Sherrington Building, Ashton Street, Liverpool L69 3GE, England.;Department of Molecular and Clinical Pharmacology, University of Liverpool , Sherrington Building, Ashton Street, Liverpool L69 3GE, England.",
"authors": "Usui|Toru|T|;Whitaker|Paul|P|;Meng|Xiaoli|X|;Watson|John|J|;Antoine|Daniel J|DJ|;French|Neil S|NS|;Park|B Kevin|BK|;Naisbitt|Dean J|DJ|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "United States",
"delete": false,
"doi": "10.1021/acs.chemrestox.6b00393",
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"issn_linking": "0893-228X",
"issue": "29(11)",
"journal": "Chemical research in toxicology",
"keywords": null,
"medline_ta": "Chem Res Toxicol",
"mesh_terms": "D000995:Antitubercular Agents; D056486:Chemical and Drug Induced Liver Injury; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "8807448",
"other_id": null,
"pages": "1793-1795",
"pmc": null,
"pmid": "27933861",
"pubdate": "2016-11-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Detection of Drug-Responsive T-Lymphocytes in a Case of Fatal Antituberculosis Drug-Related Liver Injury.",
"title_normalized": "detection of drug responsive t lymphocytes in a case of fatal antituberculosis drug related liver injury"
} | [
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"companynumb": "GB-LANNETT COMPANY, INC.-GB-2017LAN000894",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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"activesubstancename": "RIFAMPIN"
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"abstract": "BACKGROUND\nThe objective of this study was to evaluate the safety and efficacy of once-daily OROS methylphenidate (MPH) in the treatment of adults with DSM-IV attention-deficit/hyperactivity disorder (ADHD).\n\n\nMETHODS\nWe conducted a randomized, 6-week, placebo-controlled, parallel-design study of OROS MPH in 141 adult subjects with DSM-IV ADHD, using standardized instruments for diagnosis. OROS MPH or placebo was initiated at 36 mg/day and titrated to optimal response, depending on efficacy and tolerability, up to 1.3 mg/kg/day.\n\n\nRESULTS\nTreatment with OROS MPH was associated with clinically and statistically significant reductions in DSM-IV symptoms of inattention and hyperactivity/impulsivity relative to subjects treated with placebo. At endpoint, 66% of subjects (n = 44) receiving OROS MPH and 39% of subjects (n = 29) [corrected] receiving placebo attained our a priori definition of response of much or very much improved on the Clinical Global Impression-Improvement scale plus a >30% reduction in Adult ADHD Investigator System Report Scale score. OROS MPH was associated with small but statistically significant increases in systolic blood pressure (3.5 +/- 11.8 mm Hg), diastolic blood pressure (4.0 +/- 8.5 mm Hg), and heart rate (4.5 +/- 10.5 bpm).\n\n\nCONCLUSIONS\nThese results show that treatment with OROS MPH in daily doses of up to 1.3 mg/kg/day was effective in the treatment of adults with ADHD. Because of the potential for increases in blood pressure and heart rate, subjects receiving treatment with MPH should be monitored for changes in blood pressure parameters during treatment.",
"affiliations": "Clinical and Research Program in Pediatric Psychopharmacology at the Massachusetts General Hospital, Boston, Massachusetts, USA. jbiederman@partners.org",
"authors": "Biederman|Joseph|J|;Mick|Eric|E|;Surman|Craig|C|;Doyle|Robert|R|;Hammerness|Paul|P|;Harpold|Theresa|T|;Dunkel|Stephanie|S|;Dougherty|Meghan|M|;Aleardi|Megan|M|;Spencer|Thomas|T|",
"chemical_list": "D000697:Central Nervous System Stimulants; D008774:Methylphenidate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.biopsych.2005.09.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-3223",
"issue": "59(9)",
"journal": "Biological psychiatry",
"keywords": null,
"medline_ta": "Biol Psychiatry",
"mesh_terms": "D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity; D002319:Cardiovascular System; D000697:Central Nervous System Stimulants; D016009:Chi-Square Distribution; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004341:Drug Evaluation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008774:Methylphenidate; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome",
"nlm_unique_id": "0213264",
"other_id": null,
"pages": "829-35",
"pmc": null,
"pmid": "16373066",
"pubdate": "2006-05-01",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder.",
"title_normalized": "a randomized placebo controlled trial of oros methylphenidate in adults with attention deficit hyperactivity disorder"
} | [
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"companynumb": "US-JNJFOC-20131019786",
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"actiondrug": "5",
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"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
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"abstract": "Proteasome inhibitors, like bortezomib, play a key role in the treatment of multiple myeloma (MM); however, most patients eventually relapse and eventually show multiple drug resistance, and the molecular mechanisms of this resistance remain unclear. The aim of our study is to assess the expression of previously described genes that may influence the resistance to bortezomib treatment at the mRNA level (ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1) and prognosis of MM patients. mRNA expression was determined in 73 MM patients treated with bortezomib-based regimens (30 bortzomib-sensitive and 43 bortezomib-refractory patients) and 11 healthy controls. RPL5 was significantly down-regulated in multiple myeloma patients as compared with healthy controls. Moreover, POMP was significantly up-regulated in MM patients refractory to bortezomib-based treatment. In multivariate analysis, high expression of PSMB5 and CXCR and autologous stem cell transplantation were independent predictors of progression-free survival, and high expression of POMP and RPL5 was associated with shorter overall survival.",
"affiliations": "Department of Experimental Hematology, Medical University of Lodz, 93-510 Lodz, Poland.;Laboratory of Personalized Medicine, Bionanopark, 93-465 Lodz, Poland.;Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland.;Department of Clinical Genetics, Medical University of Lodz, 92-213 Lodz, Poland.;Laboratory of Personalized Medicine, Bionanopark, 93-465 Lodz, Poland.;Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland.;Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland.;Department of Experimental Hematology, Medical University of Lodz, 93-510 Lodz, Poland.;Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland.;Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland.;Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland.;Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland.",
"authors": "Robak|Pawel|P|;Jarych|Dariusz|D|0000-0003-1303-7163;Mikulski|Damian|D|0000-0002-2806-2583;Dróżdż|Izabela|I|;Węgłowska|Edyta|E|;Kotkowska|Aleksandra|A|;Misiewicz|Małgorzata|M|;Smolewski|Piotr|P|;Stawiski|Konrad|K|0000-0002-6550-3384;Fendler|Wojciech|W|;Szemraj|Janusz|J|;Robak|Tadeusz|T|0000-0002-3411-6357",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/cancers13050951",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694\nMDPI\n\n33668794\n10.3390/cancers13050951\ncancers-13-00951\nArticle\nThe Prognostic Value of Whole-Blood PSMB5, CXCR4, POMP, and RPL5 mRNA Expression in Patients with Multiple Myeloma Treated with Bortezomib\nRobak Pawel 1\nhttps://orcid.org/0000-0003-1303-7163\nJarych Dariusz 23\nhttps://orcid.org/0000-0002-2806-2583\nMikulski Damian 4\nDróżdż Izabela 5\nWęgłowska Edyta 2\nKotkowska Aleksandra 6\nMisiewicz Małgorzata 6\nSmolewski Piotr 1\nhttps://orcid.org/0000-0002-6550-3384\nStawiski Konrad 4\nFendler Wojciech 4\nSzemraj Janusz 7\nhttps://orcid.org/0000-0002-3411-6357\nRobak Tadeusz 6*\nHanda Hiroshi Academic Editor\nBacher Ulrike Academic Editor\n1 Department of Experimental Hematology, Medical University of Lodz, 93-510 Lodz, Poland; pawel.robak@umed.lodz.pl (P.R.); piotr.smolewski@umed.lodz.pl (P.S.)\n2 Laboratory of Personalized Medicine, Bionanopark, 93-465 Lodz, Poland; djarych@cbm.pan.pl (D.J.); e.weglowska@bionanopark.pl (E.W.)\n3 Laboratory of Virology, Institute of Medical Biology, Polish Academy of Sciences, 93–232 Lodz, Poland\n4 Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; damian.mikulski@stud.umed.lodz.pl (D.M.); konrad.stawiski@umed.lodz.pl (K.S.); wojciech_fendler@dfci.harvard.edu (W.F.)\n5 Department of Clinical Genetics, Medical University of Lodz, 92-213 Lodz, Poland; izabela.drozdz@umed.lodz.pl\n6 Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland; aleksandra.kotkowska@umed.lodz.pl (A.K.); malgorzata.misiewicz@umed.lodz.pl (M.M.)\n7 Department of Medical Biochemistry, Medical University of Lodz, 92-215 Lodz, Poland; janusz.szemraj@umed.lodz.pl\n* Correspondence: robaktad@csk.umed.lodz.pl; Tel.: +48-42-689-51-91; Fax: +48-42-689-51-92\n25 2 2021\n3 2021\n13 5 95123 1 2021\n16 2 2021\n© 2021 by the authors.\n2021\nLicensee 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/).\nSimple Summary\n\nThe mRNA expression of nine previously described genes that may affect resistance to multiple myeloma (MM), viz., ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1, was compared between bortezomib-refractory and bortezomib-sensitive patients. RPL5 was the only gene to be significantly down-regulated in MM patients compared with non-MM individuals, while POMP was significantly up-regulated in the bortezomib-refractory patients. Multivariate analysis found the best independent predictors of progression-free survival to be high PSMB5 and CXCR expression and autologous stem cell transplantation, and that high expression of POMP and RPL5 were associated with shorter survival.\n\nAbstract\n\nProteasome inhibitors, like bortezomib, play a key role in the treatment of multiple myeloma (MM); however, most patients eventually relapse and eventually show multiple drug resistance, and the molecular mechanisms of this resistance remain unclear. The aim of our study is to assess the expression of previously described genes that may influence the resistance to bortezomib treatment at the mRNA level (ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1) and prognosis of MM patients. mRNA expression was determined in 73 MM patients treated with bortezomib-based regimens (30 bortzomib-sensitive and 43 bortezomib-refractory patients) and 11 healthy controls. RPL5 was significantly down-regulated in multiple myeloma patients as compared with healthy controls. Moreover, POMP was significantly up-regulated in MM patients refractory to bortezomib-based treatment. In multivariate analysis, high expression of PSMB5 and CXCR and autologous stem cell transplantation were independent predictors of progression-free survival, and high expression of POMP and RPL5 was associated with shorter overall survival.\n\nbortezomib\nCXCR4\ngene expression\nmultiple myeloma\nPOMP\nPSMB5\nrefractory\nRPL5\nTXN\nXBP1\n==== Body\n1. Introduction\n\nMultiple myeloma (MM, plasma cell myeloma) is a hematological malignancy characterized by the accumulation of malignant plasma cells (PC) in the bone marrow (BM), often resulting in bone lesions, hypercalcemia, infections, anemia, and production of monoclonal immunoglobulin [1]. The disease occurs mainly in older patients and accounts for 15% of all hematologic malignancies, with an annual incidence of 4.5–6 cases per 100,000 [2], with an estimated 32,270 new cases and 12,830 deaths in the United States in 2020 [3]. Proteasome inhibitors (PI) play a key role in the treatment of MM [4,5,6]. Three PIs, bortezomib, carfilzomib, and ixazomib, are currently approved for the treatment of MM and several others are undergoing clinical trials [7].\n\nBortezomib is the first-in-class selective and reversible inhibitor of the 26S proteasome. It demonstrates antiproliferative and antitumor activity, and its use has been a breakthrough in treating MM in the past 15 years [5]. It is a boronic acid-based compound, which inhibits β5 chymotrypsin-like (CT-L) and to a lesser extent, β1 caspase-like (C-L) of the proteasome; it has been approved for treatment both in front-line and in relapsed/refractory patients [7]. However, the development of resistance and side effects can limit its use in MM [8]. Most patients show resistance to bortezomib after several courses of treatment and most of them demonstrate multiple drug resistance. In addition, approximately 20% of patients exhibit primary resistance, which determines lack of response to treatment [8,9].\n\nAlthough resistance to PIs appears to be acquired through a number of different mechanisms, genetic abnormalities play a key role for most anti-myeloma drugs [8,10,11,12]. Single-point mutations and modification of gene expression in neoplastic cells refractory to PI have been reported in previous studies [11,13,14,15,16]. Several genes associated with bortezomib resistance have been identified in MM cells, including POMP, XBP1, PSMB5, MARCKS, ABCB1, CXCR4, MAF, TXN, TJP1, RPL5, CDK5, and CYP1A1 [16,17,18,19,20,21,22,23]; however, these genes have been examined individually, and usually only using commercially available MM cell lines. The aim of our study was to evaluate the prognostic value of nine previously described genes that may affect the prognosis in patients with a clinically detected loss of response to bortezomib treatment: ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1. A better understanding of the genetic disorders involved in MM drug resistance can improve the prognosis and prognostication, and assist the development of new therapeutic options to improve the treatment of this disease.\n\n2. Results\n\nThe demographic, clinical, and laboratory characteristics of the MM patients enrolled for the study are presented in Table 1. Overall, 30 of the 73 patients were bortezomib sensitive, while the other 43 were refractory. No statistically significant differences were observed between bortezomib-sensitive and bortezomib-refractory MM patients with regard to bone involvement at diagnosis (p = 0.96), calcium > 2.75 mmol/L at diagnosis (p = 0.89), creatinine > 2 mg/dL at diagnosis (p = 0.31) or Hb < 10 g/dL at diagnosis (p = 0.73) and ISS (p = 0.86). The only statistically significant difference was observed in predominant paraprotein level (p = 0.02). In addition, light chain disease (LCD) was more common (36.7%) among the sensitive group than the refractory group (9.3%).\n\nTwelve patients had received at least one prior therapy before bortezomib-based regimen initiation and 11 of them had become refractory to bortezomib. It was found that 41 patients displayed IgG paraprotein, 17 demonstrated IgA, and 15 had LCD. Most of the patients (79.5%) had received a bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen, six (8.2%) VMP (bortezomib, melphalan, and prednisone), four (5.5%) VTD (bortezomib, thalidomide, and dexamethasone), another four VD (bortezomib and dexamethasone), and one received IsaVRd (isatuximab, lenalidomide, bortezomib, and dexamethasone). Cytogenetics data were available for 41 patients (56.1%). Amp (1q) was the most common abnormality (53.7%), followed by IGH rearrangements (46.3%), t(4;14) (22.0%), and del(13q) (19.5%).\n\nA flowchart depicting the number of patients in all stages of the study, and giving reasons for exclusion, is presented in Figure 1. The expression of nine mRNAs (ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1) was determined in all 73 MM patients treated with bortezomib-based regimens and the 11 non-MM controls. Differential expression analysis indicated that RPL5 was significantly down-regulated in MM patients compared with controls (Table 2, Figure 2A). Moreover, POMP was significantly up-regulated in bortezomib-refractory MM patients (Table 3, Figure 2B). No statistically significant differences were found between the groups with regard to the expression of selected mRNAs and the quality of response to treatment (Tables S1 and S2).\n\nTo provide a unified assessment of the prognostic impact of selected mRNA expression level at diagnosis, twelve patients who had received prior treatment before the bortezomib-based regimen were excluded from the outcome analysis. In the course of multiple myeloma, the duration of response decreases consistently with each successive regimen [24]. In this way, previous treatment itself is a factor that severely impacts PFS. Data on PFS was available in 11/12 previously treated patients, and the impact of this factor is presented in Figure S1. In contrast, in the previously treated group, no statistically significant differences were observed in mRNA expression (Table S3); however, in order to increase the statistical power of the analysis, this group was not excluded from differential expression analyses.\n\nOverall, data on progression free survival (PFS) were available for 49 patients and data on overall survival (OS) for 56 patients. The median PFS was 14.4 months and the median OS was 29.0 months. Univariate Cox proportional hazards regression analysis was conducted to determine the prognostic value of the quantified mRNA expression; the results indicated that in MM patients, higher expression of CXCR4, MARCKS, POMP, PSMB5, TXN, and XBP1 was significantly correlated with shorter PFS (Table 4, Figure 3). Univariate analysis found higher expression of POMP and RPL5 to be associated with shorter OS in MM patients (Figure 4). In addition, the only clinical variable that was related to PFS and OS was the use of autologous stem cell transplantation (ASCT) during the treatment schedule (Figure 5).\n\nThe PFS analyses included 12 cases of missing data. Therefore, to check its robustness, we repeated the univariate Cox regressions, including seven of the missing cases for which OS time was known. The analysis yielded similar hazard ratios and p-values as before, and the previously significant mRNAs maintained their significance (Table S4).\n\nTo further investigate the prognostic factors, multivariate analyses were carried out using Cox’s proportional hazards regression model with a stepwise selection procedure. As ASCT was the only significant clinical variable in our univariate analyses with proven prognostic significance, it was entered as covariate in the multivariable model. The results found high expression of PSMB5 and CXCR and the presence of ASCT to be the best independent predictors of PFS (Table 5). Multivariate analysis of OS found high expression of POMP and RPL5 to be associated with shorter survival.\n\nWe repeated our analyses with mRNA expression as a continuous variable (Table S5). In the univariate analyses, PSMB5 and CXCR4 lost their significance. In the next step, multivariate proportional hazard regression was performed with a stepwise selection procedure (Model 2, Table S6). An approach based on dichotomized variables yielded a model with a better fit to the data and with a lower AIC value.\n\n3. Discussion\n\nThe study comprehensively determined the mRNA expression of nine genes that may affect resistance in 73 MM patients treated with bortezomib-based regimens and 11 healthy volunteers: ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1. The genes were selected on the basis of previous laboratory and clinical studies investigating the bortezomib resistance in MM patients [17,18,19,20,21,25]. For the present study, it was decided to evaluate the gene expression using whole-blood samples, as this is an easier procedure to perform in clinical practice than preliminary PC isolation. However, standardization of mRNA expression profiling after cytometric isolation of specific population of cells may be technically challenging because of the variability of material quality, cell number, and other factors important at this experimental scale (cell cycle, mutation profile, clonicity etc.). Moreover, designing a model based only on a selected population of cells could downplay the interactions between the cells and the immune system, as well as other unforeseeable effects. Restricting the analysis to a cell subset would therefore potentially result in a potentially, very accurate test if cells are isolated correctly, but not sufficiently robust to use in different settings, with different technical tools and in varying clinical scenarios. Although a functional analysis of how these genes change their activity within cells during different phases of treatment would be an exciting study to perform, it would likely require a different experimental model, cell cultures, and in-depth mechanistic evaluations far exceeding the scope of this survival-oriented analysis. A similar method but based only on leukocytes in peripheral blood, not whole blood, was recently used by Watanabe et al. in evaluating the novel biomarkers to predict bortezomib response in MM patients [26].\n\nAccording to the differential expression analysis, RPL5 gene was the only gene that was significantly down-regulated in MM patients compared to the normal individuals; however, higher RPL5 expression correlated with shorter survival in MM patients. RPL5 has also been found to be deleted in 20–40% of MM patients, and it is the only recurrently mutated ribosomal protein gene in MM [27,28].\n\nIn addition, RPL5 mRNA expression level was proposed as a clinical biomarker for response to bortezomib in MM patients; Hofman et al. [28] reported significantly lower RPL5 mRNA expression in patients with MM who initially responded to bortezomib and then relapsed, and both newly diagnosed and relapsed patients with low RPL5 expression had better PFS when bortezomib was used in their treatment. In addition, they reported an association between low RPL5 mRNA levels and initial response to bortezomib in relapsed MM patients. RPL5 expression has also been associated with shorter survival in newly diagnosed patients [28].\n\nIn our study, POMP gene was significantly up-regulated in MM patients refractory to bortezomib-based treatment in comparison with bortezomib-sensitive patients. Higher expression of POMP was found to be associated with shorter survival: POMP protein expression is essential for the biogenesis of proteasome de novo and its increased expression facilitates acquired resistance to PI [16]. An increase in POMP protein expression has also been noted in V10R, RPMI 8226, OPM-2, ANBL-6, and KAS-6/1 MM cells resistant to bortezomib [16,29]. Similarly to the present study, POMP protein suppression via shRNAs restored cell sensitivity, while over-expression favored resistance.\n\nA protein-binding site for a suppressive factor, NRF2, has also been identified in the promoter region of the POMP protein. Although its increased expression should increase sensitivity to bortezomib, expression of POMP has been found to be increased in resistant cells, together with increased levels of POMP protein. The activation of both proteins varies according to cell line, and POMP appeared to have a greater effect on bortezomib sensitivity in the KAS-6/1 than OPM-2 line [30].\n\nIn the MM patients in the present study, univariate Cox proportional hazards regression analysis found the expression of six of the nine studies genes, viz. PSMB5, CXCR4, MARCKS, POMP, TXN, and XBP1, to significantly correlate with PFS. In addition, the multivariate analysis found high expression of PSMB5, CXCR, and ASCT to be the best independent predictors of PFS. Proteasome subunit β type 5 (PSMB5) is the target for bortezomib and other PI inhibitors that harbor chymotrypsin-like proteolytic activity [31]. Bortezomib occupies the PSMB5 substrate-binding pocket, interfering with the catalytic N-terminal threonine residue. Apart from β5 point mutations, the most frequent change observed in the bortezomib-resistant cell lines was overexpression of the β5 subunit [21,32,33,34]. A recent study by Barrio et al. identified somatic PSMB5 substitutions in an MM patient treated with bortezomib, suggesting that resistance acquired through PSMB5 point mutations is clinically relevant [21]. Recently, in KMS-18 and KMS-27 MM cells, the PSMB5 gene was found to harbor novel bortezomib resistance alleles which determine response to second-generation proteasome inhibitors in MM [35]. In addition, PSMB5 deletion resensitized drug-resistant, PSMB5-mutated cell lines to bortezomib, suggesting that PSMB5 mutation plays a role in drug resistance [36].\n\nOur findings indicated that higher CXCR4 expression correlated with shorter PFS. CXCR4 is a pleiotropic chemokine receptor which acts through its ligand (CXCL12) and influences proliferation, invasion, dissemination, and drug resistance in MM [37,38]. The current therapeutic focus is on disrupting the interaction of MM cells with their protective tumor microenvironment, in which the CXCR4 axis plays an essential role [39]. In contrast to our present study, reduced expression of CXCR4, a single biomarker in the Bcl-XL/Myc model system, has indicated poorer outcomes in MM patients treated with bortezomib [40]. In addition, low CXCR4 expression was associated with a worse outcome than high CXCR4 expression, and correlated with increased MM severity and aggressiveness in patients treated with bortezomib, either alone or in combination with other agents [18,40].\n\nThe univariate Cox proportional hazards regression analysis found that the higher expression of MARCKS, TXN, and XBP1 significantly correlated with shorter PFS in MM patients. Another marker of PI resistance is MARCKS. This protein is important in cell adhesion and metastatic spread [41] and is involved in resistance to apoptosis in prostate cancer cells [16]. Its expression is significantly elevated in many types of cancer [42]. Micallef et al. reported overexpression of MARCKS in nine of 18 (50%) studied MM cell lines [43]; in addition, in line with our present findings, Yang et al. reported increased MARCKS expression in bortezomib-refractory MM patients, as well as increased bortezomib sensitivity in bortezomib-resistant MM cells following inhibition of MARCKS phosphorylation [44]. Similar effects were achieved in an MM xenograft model [45].\n\nA key role in bortezomib resistance is played by the increased expression of proteasomes and proteins involved in providing protection from oxidative stress, such as thioredoxin (TXN) [46]. Our findings indicate that higher expression of TXN correlates with shorter PFS. Previous studies have also found TXN to be overexpressed in primary myeloma cells isolated from bortezomib-resistant MM patients, and that overexpression of TXN correlated with poor overall survival in patients with MM [46]. In bortezomib-resistant myeloma cell lines, TXN inhibition overcomes adaptive bortezomib resistance [47]. In addition, higher TXN1 expression levels were found to correlate with myeloma cell survival and growth, and to protect MM cells against increased intrinsic oxidative stress [48]. Moreover, inhibition of TXN1 leads to apoptosis in drug-resistant MM.\n\nAnother gene whose high expression significantly correlated with shorter PFS in MM patients is XBP1, coding for X-box-binding protein 1. The XBP1 protein is an important transcription factor necessary for differentiation of B cells into plasma cells, being responsible for the final maturation of plasmablasts to plasmocytes and the induction of immunoglobulin secretion [49]. XBP1 is also a particularly important regulator in the UPR mechanism. It is spliced into two isoforms. One isoform, XBPs1s, activates the genes necessary to reduce ER stress and UPR activation after penetration into the cell nucleus. XBP1 may have a significant impact on resistance to bortezomib in MM cells. Low expression of XBPS1 has been associated with a lack of sensitivity to PI treatment [50]. Two point mutations in the XBP1 gene have been identified to date [49,51]: the first, XBP1-L167I, is located within the splice site of the XBP1 gene, and has been shown to prevent the XBP1 mRNA splicing process needed to form the active XBP1s protein, while the second, XBP1s-P326R, is located within the transactivation domain of the XBP1s molecule and has no effect on the splicing process. Cells displaying one of the described mutations lose their sensitivity to bortezomib, inducing disease resistance [52].\n\nIn conclusion, our results suggest that high expression of PSMB5 and CXCR may serve as predictors of PFS in MM patients treated with bortezomib-based regimens. In addition, high expression of POMP and RPL5 can be useful to predict shorter survival of these patients. However, further studies are needed to determine the role of these factors in effective strategy for improving anti-myeloma therapy.\n\n4. Materials and Methods\n\n4.1. Patients\n\nThe patients were recruited prospectively in our institution (Department of Hematology, Copernicus Memorial Hospital, Lodz, Poland) as a part of a planned marker study. The main exclusion criterion was using bortezomib-based therapy prior to the study. The main inclusion criteria were diagnosis of multiple myeloma according to International Myeloma Working Group (IMWG) criteria and planned treatment with a bortezomib-based regimen [53]. A total of 73 MM patients (43 men and 30 women) treated were included. The mean age of the group was 61.9 ± 10.8 years (range: 38.2 to 83.7 years). Their demographic, clinical, and laboratory details are shown in Table 1. All of the patients received bortezomib treatment as first-line treatment or in progression after previous therapy. The participants were classified as either bortezomib-sensitive or bortezomib-refractory, as previously reported, according to their response to bortezomib-based therapy [12,54]. Response to treatment and relapse/progression events were classified according to the IMWG [55,56].\n\nThe bortezomib-sensitive patients demonstrated CR, VGPR, or PR lasting longer than six months following discontinuation of bortezomib-based therapies [56,57,58]. In total, 30 patients were bortezomib refractory and 43 were bortezomib sensitive with no progression for at least six months of treatment discontinuation. The control group consisted of 11 healthy volunteers (six women and five men; mean age 61.9 ± 10.8 years; range: 38.2–83.7 years). The study was conducted according to good clinical and laboratory practice. The experimental protocol was conducted in accordance with the Declaration of Helsinki. All procedures were approved by the local ethical committee (The Ethical Committee of the Medical University of Lodz, No RNN/103/16/KE). Informed consent was obtained from all subjects involved in the study.\n\n4.2. Blood Collection\n\nPeripheral blood was collected in PAXgene Blood RNA Tubes (Qiagen, Germantown, MD, USA) from 73 multiple myeloma patients and 11 healthy volunteers and stored frozen at −80 °C. Venous blood samples were collected from MM patients, before treatment with bortezomib-based regimens, most commonly on the first day of the bortezomib administration. In previously treated MM patients, blood was collected at the time of progression, during the qualification process for commencement of a new therapy line.\n\n4.3. The Analysis of Gene Expression Using Real-Time PCR\n\n4.3.1. Isolation of Total RNA\n\nFrozen blood samples were thawed on ice and total RNA was isolated from 1.5 mL of blood using the QIAamp RNA Blood Mini Kit (Qiagen) according to the manufacturer’s protocol. The final elution of total RNA was performed using 50 µL of RNase-free water. Total RNA quality was determined using the High Sensitivity RNA Screen Tape on a 2200 TapeStation bioanalyzer (Agilent, Santa Clara, CA, USA). The degradation rate of RNA was determined using RNA integrity number (RIN). Only the samples with RIN > 7 were further analyzed. The quantity of RNA was measured using NanoVue Plus Spectrophotometer (GE Healthcare, Wauwatosa, USA. Directly after isolation, RNA was used for the reverse transcription process.\n\n4.3.2. Reverse Transcription Reaction\n\nThe reverse transcription was performed using the high-capacity cDNA reverse transcription kit (Applied Biosystems, ThermoFisher Scientific, Waltham, MA, USA,) according to the manufacturer’s protocol. The total volume of reverse transcription mix was 20 µL per reaction, containing 2 µL RT buffer (10X), 0.8 µL dNTP mixture (100 mM of each dNTP), 2 µL random primers (10X), 1 µL RNase inhibitor (20 U/µL), 1 µL MultiScribe Reverse Transcriptase (50 U/µL), and 10 µL RNA template, whereby the reagent mix was prepared on ice. The thermal profile of the reverse transcription program consisted of 10 min incubation at 25 °C, 120 min at 37 °C, 5 min reverse transcriptase inactivation at 85 °C, and cooling down to 4 °C. Total amount of 100 ng of RNA was used as a sample input per 20 µL of reverse transcription reaction. All reactions were performed in a 96-well SureCycler 8800 thermal cycler (Agilent, Santa Clara, CA, USA). The resulting cDNA was stored at −20 °C.\n\n4.3.3. Selection of Reference Genes\n\nA reference gene provides the internal control of the reaction and allows to determine the absolute and reliable value of the studied gene expression using real-time PCR. In order to normalize the variations in sample input for relative quantitation of gene expression, the selection of endogenous control genes was performed using the TaqMan™ Array Human Endogenous Control (Thermo Fisher Scientific, Waltham, MA, USA).\n\nThe analysis was performed for six total RNA samples isolated from whole blood of MM patients, according to the manufacturer’s protocol.\n\nThe stability of mRNAs was measured by NormiRazor [59]. This is an integrative tool which implements existing normalization algorithms (geNorm, NormFinder and BestKeeper) in a parallel manner. Three reference genes were selected by NormiRazor and TaqMan™ probes ((Thermo Fisher Scientific, Waltham, MA, USA) ACTB (Assay ID: Hs99999903_m1), RPLP0 (Assay ID: Hs99999902_m1), MT-ATP6 (Assay ID: Hs02596862_g1) and their average expression was used as reference.\n\n4.3.4. Real-Time PCR\n\nThe expression of nine genes was analyzed in all samples: ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1. The analysis was performed using commercially available ready-to-use TaqMan® Assays (Applied Biosystems- Thermo Fisher Scientific, Waltham, MA, USA). These were preloaded with a probe labeled with 6-FAM™ dye (emission spectra at ~517 nm) and forward and reverse primers for the amplification of the following genes: ABCB1 (Assay ID: Hs00184500_m1), CXCR4 (Assay ID: Hs00976734_m1), MAF (Assay ID: Hs00193519_m1), MARCKS (Assay ID: Hs00158993_m1), POMP (Assay ID: Hs01106088_m1), PSMB5 (Assay ID: Hs00605652_m1, RPL5 (Assay ID: Hs00851991_u1), TXN (Hs00828652_m1), XBP1 (Assay ID: Hs00231936_m1).\n\nThe PCR mixture consisted of 10 µL of 2X TaqMan™ Genotyping Master Mix (Aplaied Biosystems-Thermo Fisher Scientific, Waltham, MA, USA), 1 µL of appropriate 20X TaqMan® Assay, and 1 µL of cDNA template. The mixture was filled up with a distilled, DNase- and RNase-free water (Gibco, Gaithersburg, MD, USA) to a final volume of 20 µL. The analysis was carried out using the TOptical thermal cycler (Analytik, Jena, Germany). The reactions were performed under the following conditions: an initial denaturation step at 95 °C for 10 min, followed by 40 amplification cycles of denaturation (95 °C, 15 s), a single annealing and extension step (60 °C for 1 min). Fluorescence signal detection was performed after each cycle. Gene expression analysis was performed for each sample in duplicates. Absolute quantification analysis was performed using qPCR Soft 3.1.15.0 (Analytik, Jena, Germany).\n\n4.4. Statistical Analysis\n\n4.4.1. Data Preparation\n\nData were normalized based on the mean expression of three mRNAs in a given sample (ACTB, RPLP0, MT-ATP6); this has proved to be the most stable normalization factor (according to NormiRazor). The normalized Ct values were calculated as:\n\nNormalized ΔCt = Ct mRNA − (mean Ct of ACTB, RPLP0 and MT-ATP6)\n\nNormalized ΔCt values for all samples and with class assignments were provided as Table S7.\n\n4.4.2. Analysis\n\nNominal variables were expressed as percentages and analyzed using the Chi-square test with appropriate corrections if needed: the Yates correction for continuity or Fisher’s exact test.\n\nFor continuous variables, normally distributed data were tested using a two-sided independent Student’s t-test. Continuous variables were presented as mean ± standard deviation (SD) or medians with 25% to 75% values according to the data distribution. Survival analysis was conducted using a Kaplan–Meier estimate with univariate and multivariate Cox’s proportional hazards models, as well as the log-rank test. Cutoff Finder was used to determine the optimal cutpoint for gene expression dichotomization based on the log-rank test minimum p-value approach [60]. A procedure based on stratification of a continuous biomarker variable into two groups seems appropriate for use in clinics where most of the decisions are binary. Although such cutoffs are usually based on the mean or median value of the diagnostic factor, they can also be set based on the distribution of the variable or by optimizing the correlation with response to a treatment or outcome. A common problem in biomarker research is overestimating the actual effect when multiple cutoff points are investigated with no correction for multiple testing. The advantage of Cutoff Finder is that it determines the robustness of particular cutoff points and estimates the effect size with confidence intervals [60].\n\nAll statistical analyses were conducted using Statistica Version 13.1 (TIBCO, Palo Alto, CA, USA) and R programming language (version 4.0.2). p values lower than 0.05 were considered statistically significant. To control the family-wise error rate (FWER), the significant genes were chosen at 5% using Holm’s step-down method. FWER was used to insure a low probability of any false positives among the differentially expressed mRNA.\n\n5. Conclusions\n\nThe present study examined the mRNA expression of nine genes with a possible influence on bortezomib sensitivity and refractoriness in MM, viz., ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1. Of these, RPL5 was down-regulated in MM patients as compared with the normal individuals. POMP was significantly up-regulated in MM patients refractory to bortezomib-based treatment. Multivariate analysis found that high expression of PSMB5 and CXCR and autologous stem cell transplantation were the best independent predictors of PFS, and that high expression of POMP and RPL5 were associated with shorter survival. The clinical and biological importance of these findings need further investigation.\n\nAcknowledgments\n\nWe thank Edward Lowczowski from the Medical University of Lodz for editorial assistance and Andrzej Berut from Bionanopark, Lodz for administrative support.\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/2072-6694/13/5/951/s1. Supplementary Table S1: ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1 mRNA expression in MM patients with complete remission (CR) to bortezomib-based chemotherapy and those without. Supplementary Table S2: ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1 mRNA expression in MM patients with at least very good partial response (VGPR), partial response, stable disease, or disease progression (<VGPR) after bortezomib-based treatment. No difference was found between the two groups. Supplementary Table S3: mRNA expression in treatment-naive and previously treated MM patients. A higher ΔCt value represents lower expression of the gene at the mRNA level. Supplementary Table S4: Univariate Cox regression analyses for progression-free survival with missing data (n = 7) replaced by overall survival. Supplementary Table S5: Univariate Cox regression analyses for progression-free survival and overall survival- mRNAs expression as continuous variables. Supplementary Table S6: Comparison of final Cox regression of multivariate models based on dichotomized variables (model 1) and continuous variables (model 2). Supplementary Table S7: Normalized ΔCt of mRNA expression for all samples and with class assignments. Supplementary Figure S1: Kaplan–Meier plots for previous treatment and treatment-naïve groups in the univariate analysis for PFS.\n\nClick here for additional data file.\n\nAuthor Contributions\n\nConceptualization, P.R., I.D., J.S. and T.R.; methodology, P.R., I.D., D.J., D.M., A.K., M.M., K.S., W.F., J.S., P.S. and T.R.; software, P.R., D.J., D.M., A.K., W.F., J.S., P.S.; validation P.R., D.M. and T.R.; formal analysis, P.R., D.M., K.S.; W.F. D.J. and T.R.; investigation P.R., D.J., M.M.; E.W.; A.K. and I.D.; resources, T.R.; P.R. and J.S; data curation, P.R., I.D., D.M.; writing— P.R., I.D., D.J., D.M. and T.R.; writing—review and editing, P.R., I.D., D.J., D.M. P.S., J.S. E.W. and T.R.; visualization, P.R., D.J., D.M. and T.R.; supervision, T.R.; project administration, T.R.; P.R. and I.D.; funding investigation, T.R.; P.R. and I.D.; resources, P.R.; I.D. and T.R. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis work was supported by a grant from the NCN (2016/23/B/NZ5/02529).\n\nInstitutional Review Board Statement\n\nThe experimental protocol was conducted in accordance with the Declaration of Helsinki. All procedures were approved by the local ethical committee (The Ethical Committee of the Medical University of Lodz, No RNN/103/16/KE).\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nData is contained within the article or supplementary material are available according to “MDPI Research Data Policies” at https://www.mdpi.com/journal/cancers/ instructions#suppmaterials. Normalized ΔCt of mRNA expression for all samples with class assignments are provided in Supplementary Table S7.\n\nConflicts of Interest\n\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\nAbbreviations\n\nABCB1\tAdenosine-triphosphate-binding cassette sub-family B member 1\t\nACTB\tbeta-actin gene\t\nASCT\tautologous stem cell transplantation\t\nBM\tbone marrow\t\nCXCR-4\tC-X-C chemokine receptor type 4\t\nDLBCL\tdiffuse large B-cell lymphoma\t\nECM\textracellular matrix\t\nFWER\tfamily-wise error rate\t\nIPO8\tImportin 8 gene\t\nIsaRVD\tisatuximab, lenalidomide, bortezomib, dexamethasone\t\nMAF\tmusculoaponeurotic fibrosarcoma\t\nMARCKS\tmyristoylated alanine-rich C-kinase substrate\t\nMM\tmultiple myeloma\t\nMT-ATP6\tmitochondrially Encoded ATP Synthase Membrane Subunit 6 gene\t\nNRF2\tnuclear factor erythroid 2-related factor 2\t\nNF-κB\tnuclear factor kappa B\t\nOS\toverall survival\t\nPC\tplasma cells\t\nPOMP\tproteasome maturation protein\t\nPFS\tprogression free survival\t\nPI\tproteasome inhibitor\t\nPSMB5\tproteasome subunit β type 5\t\nRPLP0\tRibosomal Protein Lateral Stalk Subunit P0 gene\t\nRPL5\tribosomal protein L5\t\nUPR\tunfolded protein response\t\nTXN\tthioredoxin\t\nVCD\tbortezomib, cyclophosphamide, dexamethasone\t\nVD\tbortezomib and dexamethasone\t\nVMP\tbortezomib, melphalan and prednisone.\t\nVTD\tbortezomib, thalidomide, dexamethasone\t\nTXN\tthioredoxin\t\nXBP1\tX-box binding protein 1\t\n\nFigure 1 Flowchart of study protocol and main analyses. Abbreviations: CR—complete response; MM—multiple myeloma; OS—overall survival; PFS—progression-free survival.\n\nFigure 2 Dot plot representation of the ΔCt values of differentially expressed mRNA. The box plots depict the mean and SD. A higher ΔCt value represents the lower expression of the gene at the mRNA level: (A) ΔCt of RPL5 in multiple myeloma patients healthy donors (p = 0.0033) and (B) ΔCt of POMP in sensitive and refractory to bortezomib MM patients (0.0062).\n\nFigure 3 Kaplan–Meier plots for each of the significant mRNAs in the univariate analyses for PFS: (A) CXCR4, (B) MARCKS, (C) POMP, (D) PSMB5, (E) TXN, (F) XBP1.\n\nFigure 4 Kaplan–Meier plots for each of the significant mRNAs in the univariate analyses for OS: (A) POMP, (B) RPL5.\n\nFigure 5 Kaplan–Meier plots for ASCT in the univariate analyses for (A) PFS and (B) OS.\n\ncancers-13-00951-t001_Table 1 Table 1 The characteristics of the MM patients treated with bortezomib-based therapy and healthy donors. Data are presented as frequency, percentage (%) unless otherwise specified.\n\nVariable\tMM Total\tRefractory\tSensitive\tHealthy Donors\tp\t\nNumber of patients\t73\t43\t30\t11\t-\t\nGender (%)\nN (%)\tM: 43 (58.9)\nF: 30 (41.1)\tM: 25 (58.1)\nF: 18 (41.9)\tM: 18(60.0)\nF: 12(40.0)\tM: 5 (45.5)\nF: 6 (54.5)\t0.69\t\nAge + SD (range)\t61.9 ± 10.8\n(38.2–83.7)\t62.2 ± 11.5\n(38.2–83.7)\t61.3 ± 9.7\n(39.8–81.6)\t63.0 ± 6.2\n(52.6–74.4)\t0.73\t\nBortezomib regimen:\t-\t-\t-\t-\t0.18\t\nVCD\t58 (79.5)\t32 (74.4)\t26 (86.7)\t-\t\nVMP\t6 (8.2)\t5 (11.6)\t1 (3.3)\t-\t\nVTD\t4 (5.5)\t2 (4.7)\t2 (6.7)\t-\t\nVD\t4 (5.5)\t4 (9.3)\t0\t-\t\nIsaVRD\t1 (1.4)\t0\t1 (6.7)\t-\t\nParaprotein–N (%)\t-\t-\t-\t-\t0.02\t\nIgG\t41 (56.2)\t28 (65.1)\t13 (43.3)\t\t\nIgA\t17 (23.3)\t11 (25.6)\t6 (20.0)\t-\t\nLCD\t15 (20.5)\t4 (9.3)\t11 (36.7)\t-\t\nPrior treatment\t12 (16.4)\t11 (25.6)\t1 (3.3)\t-\t0.01\t\nBone involvement at diagnosis\t40 (54.8)\t23 (53.5)\t17 (56.6)\t-\t0.96\t\nCalcium > 2.75 mmol/L at diagnosis\t12 (16.4)\t7 (16.3)\t5 (16.7)\t-\t0.89\t\nHB < 10g/dL at diagnosis\t26 (35.6)\t14 (32.6)\t12 (40.0)\t-\t0.73\t\nCreatinine > 2 mg/dL at diagnosis\t10 (13.7)\t4 (9.3)\t6 (20.0)\t-\t0.31\t\nInternational Staging System (ISS) at diagnosis\tI: 22 (30.1)\nII: 17 (23.3)\nIII:32(43.8)\tI: 14 (32.6)\nII: 10 (23.3)\nIII: 18(41.9)\tI: 8 (26.7)\nII: 7 (23.3)\nIII: 14(46.7)\t-\t0.86\t\nCRP > 5 mg/L\t33 (45.2)\t16 (37.2)\t17 (56.7)\t-\t0.06\t\nBeta2-microglobuline increased (>3mg/L)\t51 (69.9)\t31 (72.1)\t20 (66.7)\t-\t0.36\t\nLDH > 240U/L\t9 (12.3)\t5 (11.6)\t4 (13.3)\t-\t0.85\t\nCytogenetics (%)\tN = 41\tN = 24\tN = 17\t-\t\t\nt(4;14)\t9 (22.0)\t7 (29.2)\t2 (11.8)\t0.26\t\nt(14;16)\t0\t0\t0\t-\t\nt(14;20)\t0\t0\t0\t-\t\ndel(17p)\t6 (14.6)\t4 (16.7)\t2 (11.8)\t1.00\t\namp(1q)\t22 (53.7)\t12 (50.0)\t10 (58.8)\t0.75\t\ndel(13q)\t8 (19.5)\t2 (8.3)\t6 (35.3)\t0.61\t\nt(11; 14)\t1 (2.4)\t1 (4.2)\t0\t\t\t\ndel(1p)\t2 (4.9)\t1 (4.2)\t1 (5.9)\t\t1.00\t\nIGH rearrangements\t19 (46.3)\t12 (50.0)\t7 (41.2)\t\t0.71\t\nAbbreviations: CRP—c-reactive protein; IGH—immunoglobulin heavy chain; LCD—light chain disease; IsaVRD—isatuximab, lenalidomide, bortezomib, dexamethasone; LDH—lactate dehydrogenase; MM—multiple myeloma; VCD—bortezomib, cyclophosphamide, dexamethasone; VD—bortezomib and dexamethasone: VMP—bortezomib, melphalan and prednisone; VTD—bortezomib, thalidomide, dexamethasone.\n\ncancers-13-00951-t002_Table 2 Table 2 mRNA expression in multiple myeloma patients and healthy donors. The higher ΔCt value represents the lower expression of gene at mRNA level.\n\nmRNA\tΔCt MM\n(N = 73)\nmean ± SD\tΔ Ct Healthy Donors (N = 11)\nMean ±SD\tFC\tp-Value\tFWER\t\nABCB1\t7.55 ± 0.99\t7.12 ± 0.74\t0.74\t0.1075\t0.6451\t\nCXCR4\t3.83 ± 0.82\t3.56 ± 0.21\t0.82\t0.0209\t0.1669\t\nMAF\t7.75 ± 1.08\t7.20 ± 0.85\t0.68\t0.0737\t0.5159\t\nMARCKS\t5.99 ± 0.83\t5.63 ± 0.90\t0.78\t0.2346\t1.0000\t\nPOMP\t5.17 ± 0.67\t5.12 ± 0.39\t0.97\t0.7541\t1.0000\t\nPSMB5\t6.96 ± 0.78\t6.80 ± 0.59\t0.90\t0.4341\t1.0000\t\nRPL5\t2.73 ± 0.81\t2.02 ± 0.46\t0.61\t0.0004\t0.0033\t\nTXN\t3.43 ± 0.74\t3.69 ± 0.66\t1.20\t0.2508\t1.0000\t\nXBP1\t3.26 ± 0.92\t3.21 ± 0.66\t0.96\t0.8036\t1.0000\t\nAbbreviations: MM—multiple myeloma; FC—fold change; FWER—family-wise error rate.\n\ncancers-13-00951-t003_Table 3 Table 3 mRNA expression in MM patients sensitive and refractory to bortezomib-based chemotherapy. The higher ΔCt value represents the lower expression of gene at mRNA level.\n\nmRNA\tΔCt Refractory (N = 43)\nMean ± SD\tΔCt Sensitive (N = 30)\nMean ± SD\tFC\tp-Value\tFWER\t\nABCB1\t7.58 ± 1.02\t7.50 ± 0.98\t0.95\t0.7384\t1.0000\t\nCXCR4\t3.75 ± 0.70\t3.95 ± 0.96\t1.15\t0.3438\t1.0000\t\nMAF\t7.70 ± 1.12\t7.82 ± 1.03\t1.09\t0.6516\t1.0000\t\nMARCKS\t5.79 ± 0.70\t6.27 ± 0.92\t1.40\t0.0190\t0.1522\t\nPOMP\t4.94 ± 0.57\t5.48 ± 0.67\t1.45\t0.0007\t0.0062\t\nPSMB5\t6.84 ± 0.70\t7.12 ± 0.87\t1.22\t0.1421\t0.8523\t\nRPL5\t2.69 ± 0.87\t2.78 ± 0.75\t1.06\t0.6622\t1.0000\t\nTXN\t3.35 ± 0.72\t3.55 ± 0.77\t1.15\t0.2676\t1.0000\t\nXBP1\t3.08 ± 0.84\t3.51 ± 0.97\t1.35\t0.0537\t0.3759\t\nAbbreviations: MM—multiple myeloma; FC – fold change; FWER—family-wise error rate.\n\ncancers-13-00951-t004_Table 4 Table 4 Univariate Cox regression analyses for progression-free survival and overall survival.\n\nVariables\tPFS\tOS\t\nCoefficient\tp-Value\tHR\t95% CI\tCoefficient\tp-Value\tHR\t95% CI\t\nLower\tUpper\tLower\tUpper\t\nABCB1 expression (high vs. low)\t−0.248\t0.2716\t0.609\t0.252\t1.474\t−0.226\t0.2950\t0.637\t0.273\t1.482\t\nCXCR4 expression (high vs. low)\t0.571\t0.0327\t3.134\t1.099\t8.940\t0.272\t0.2865\t1.722\t0.634\t4.679\t\nMAF expression (high vs. low)\t0.261\t0.1348\t1.685\t0.850\t3.336\t0.390\t0.2968\t2.183\t0.504\t9.464\t\nMARCKS expression (high vs. low)\t0.594\t0.0018\t3.281\t1.559\t6.907\t−0.343\t0.1115\t0.504\t0.217\t1.172\t\nPOMP expression (high vs. low)\t0.409\t0.0236\t2.266\t1.116\t4.601\t0.573\t0.0108\t3.144\t1.303\t7.585\t\nPSMB5 expression (high vs. low)\t0.476\t0.0088\t2.591\t1.271\t5.280\t0.348\t0.1497\t2.004\t0.778\t5.158\t\nRPL5 expression (high vs. low)\t−0.137\t0.4206\t0.760\t0.389\t1.483\t0.641\t0.0035\t3.607\t1.526\t8.524\t\nTXN expression (high vs. low)\t0.394\t0.0290\t2.198\t1.084\t4.456\t0.298\t0.1683\t1.813\t0.778\t4.228\t\nXBP1 expression (high vs. low)\t0.479\t0.0099\t2.605\t1.259\t5.389\t0.270\t0.2091\t1.715\t0.739\t3.981\t\nAge\t0.006\t0.7070\t1.006\t0.975\t1.038\t0.037\t0.1281\t1.038\t0.989\t1.089\t\nASCT\t\t\t\t\t\t\t\t\t\t\t\nNo\tReference\t\t\t\t\tReference\t\t\t\t\t\nYes\t−0.487\t0.0089\t0.378\t0.182\t0.783\t−0.624\t0.0157\t0.287\t0.104\t0.790\t\nBone involvement at diagnosis\t\t\t\t\t\t\t\t\t\t\t\nNo\tReference\t\t\t\t\tReference\t\t\t\t\t\nYes\t0.303\t0.1043\t1.832\t0.882\t3.805\t0.309\t0.1932\t1.856\t0.731\t4.709\t\nCalcium > 2.75 mmol/L at diagnosis\t\t\t\t\t\t\t\t\t\t\t\nNo\tReference\t\t\t\t\tReference\t\t\t\t\t\nYes\t0.374\t0.0929\t2.112\t0.883\t5.052\t−0.089\t0.7501\t0.837\t0.281\t2.495\t\nCRP >5 mg/L\t\t\t\t\t\t\t\t\t\t\t\nNo\tReference\t\t\t\t\tReference\t\t\t\t\t\nYes\t0.101\t0.6100\t1.224\t0.563\t2.663\t−0.461\t0.0637\t0.398\t0.150\t1.054\t\nHB < 10 g/dL at diagnosis\t\t\t\t\t\t\t\t\t\t\t\nNo\tReference\t\t\t\t\tReference\t\t\t\t\t\nYes\t0.092\t0.6243\t1.202\t0.576\t2.505\t0.009\t0.9698\t1.018\t0.409\t2.530\t\nISS I\tReference\t\t\t\t\tReference\t\t\t\t\t\nISS II\t−0.682\t0.0590\t0.375\t0.124\t1.134\t0.030\t0.9389\t1.828\t0.460\t7.267\t\nISS III\t0.383\t0.1594\t1.089\t0.509\t2.326\t0.544\t0.0684\t3.056\t1.035\t9.021\t\nCreatinine > 2 mg/dL at diagnosis\t\t\t\t\t\t\t\t\t\t\t\nNo\tReference\t\t\t\t\tReference\t\t\t\t\t\nYes\t−0.396\t0.1952\t0.453\t0.136\t1.502\t−0.253\t0.4984\t0.603\t0.140\t2.606\t\nLDH >240U/L\t\t\t\t\t\t\t\t\t\t\t\nNo\tReference\t\t\t\t\tReference\t\t\t\t\t\nYes\t0.188\t0.4221\t1.457\t0.581\t3.651\t0.411\t0.1526\t2.277\t0.737\t7.032\t\nGender\t\t\t\t\t\t\t\t\t\t\t\nF\tReference\t0.1008\t0.564\t0.284\t1.118\tReference\t\t\t\t\t\nM\t−0.287\t\t\t\t\t0.352\t0.1583\t2.022\t0.760\t5.376\t\nAbbreviations: ASCT—autologous stem cell transplantation; CRP- c-reactive protein; CXCR-4—C-X-C chemokine receptor type 4; FWER—family-wise error rate: HB—hemoglobin; ISS—International scoring system; LDH—lactate dehydrogenase; MM—multiple myeloma; OS—overall survival; PFS—progression free survival.\n\ncancers-13-00951-t005_Table 5 Table 5 Final multivariate Cox regression analyses for PFS and OS of MM patients.\n\nVariables\tPFS\t\nCoefficient\tp-Value\tHR\t95% CI\t\nLower\tUpper\t\nPSMB5 expression (high vs. low)\t0.386\t0.0451\t2.164\t1.017\t4.603\t\nCXCR expression (high vs. low)\t0.748\t0.0073\t4.465\t1.496\t13.320\t\nASCT\t\t\t\t\t\t\nNo\tReference\t\t\t\t\t\nYes\t−0.612\t0.0024\t0.294\t0.133\t0.649\t\nVariables\tOS\t\nPOMP expression (high vs. low)\t0.523\t0.0258\t2.849\t1.135\t7.148\t\nRPL5 expression (high vs. low)\t0.664\t0.0026\t3.777\t1.591\t8.963\t\nAbbreviations: ASCT—autologous stem cell transplantation; HR—hazard ratio; MM—multiple myeloma; OS—overall survival; PFS—progression free survival.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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Inactivating PSMB5 mutations and P-glycoprotein (multidrug resistance-associated protein/ATP-binding cassette B1) mediate resistance to proteasome inhibitors: Ex vivo efficacy of (immuno)proteasome inhibitors in mononuclear blood cells from patients with rheumatoid arthritis J. Pharmacol. Exp. Ther. 2012 341 174 182 22235146\n35. Allmeroth K. Horn M. Kroef V. Miethe S. Müller R.U. Denzel M.S. Bortezomib resistance mutations in PSMB5 determine response to second-generation proteasome inhibitors in multiple myeloma Leukemia 2020 10.1038/s41375-020-0989-4 32690882\n36. Shi C.X. Zhu Y.X. Bruins L.A. Bonolo de Campos C. Stewart W. Braggio E. Stewart A.K. Proteasome subunits differentially control myeloma cell viability and proteasome inhibitor sensitivity Mol. Cancer Res. 2020 18 1453 1464 10.1158/1541-7786.MCR-19-1026 32561655\n37. Ullah T.R. The role of CXCR4 in multiple myeloma: Cells’ journey from bone marrow to beyond J. 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MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells Biochem. Biophys. Res. Commun. 2009 383 280 285 10.1016/j.bbrc.2009.03.077 19302977\n42. Niewerth D. Jansen G. Riethoff L.F. Van Meerloo J. Kale A.J. Moore B.S. Assaraf Y.G. Anderl J.L. Zweegman S. Kaspers G.J. Antileukemic activity and mechanism of drug resistance to the marine Salinispora tropica proteasome inhibitor salinosporamide (Marizomib) Mol. Pharmacol. 2014 86 12 19 10.1124/mol.114.092114 24737138\n43. Micallef J. Taccone M. Mukherjee J. Croul S. Busby J. Moran M.F. Guha A. Epidermal growth factor receptor variant III-induced glioma invasion is mediated through myristoylated alanine-rich protein kinase C substrate over-expression Cancer Res. 2009 69 7548 7556 10.1158/0008-5472.CAN-08-4783 19773446\n44. Wang J. Hendrix A. Hernot S. Lemaire M. De Bruyne E. Van Valckenborgh E. Lahoutte T. De Wever O. Vanderkerken K. Menu E. Bone marrow stromal cell-derived exosomes as communicators in drug resistance in multiple myeloma cells Blood 2014 124 555 566 10.1182/blood-2014-03-562439 24928860\n45. Yang Y. Chen Y. Saha M.N. Chen J. Evans K. Qiu L. Reece D. Chen G.A. Chang H. Targeting phospho-MARCKS overcomes drug resistance and induces antitumor activity in preclinical models of multiple myeloma Leukemia 2015 29 715 726 10.1038/leu.2014.255 25179733\n46. Dytfeld D. Luczak M. Wrobel T. Usnarska-Zubkiewicz L. Brzezniakiewicz K. Jamroziak K. Giannopoulos K. Przybylowicz-Chalecka A. Ratajczak B. Czerwinska-Rybak J. Comparative proteomic profiling of refractory/relapsed multiple myeloma reveals biomarkers involved in resistance to bortezomib-based therapy Oncotarget 2016 7 56726 56736 10.18632/oncotarget.11059 27527861\n47. Zheng Z. Fan S. Zheng J. Huang W. Gasparetto C. Chao N.J. Hu J. Kang Y. Inhibition of thioredoxin activates mitophagy and overcomes adaptive bortezomib resistance in multiple myeloma J. Hematol. Oncol. 2018 11 1 15 10.1186/s13045-018-0575-7 29298689\n48. Raninga P.V. Di Trapani G. Vuckovic S. Bhatia M. Tonissen K.F. Inhibition of thioredoxin 1 leads to apoptosis in drug-resistant multiple myeloma Oncotarget 2015 6 15410 15424 10.18632/oncotarget.3795 25945832\n49. Leung-Hagesteijn C. Erdmann N. Cheung G. Keats J.J. Stewart A.K. Reece D.E. Chung K.C. Tiedemann R.E. Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma Cancer Cell 2013 24 289 304 10.1016/j.ccr.2013.08.009 24029229\n50. Liu N. Liu C. Li X. Liao S. Song W. Yang C. Zhao C. Huang H. Guan L. Zhang P. A novel proteasome inhibitor suppresses tumor growth via targeting both 19S proteasome deubiquitinases and 20S proteolytic peptidases Sci. Rep. 2014 4 5240 10.1038/srep05240 24912524\n51. Hong S.Y. Hagen T. Multiple myeloma Leu167Ile (c.499C>A) mutation prevents XBP1 mRNA splicing Br. J. Haematol. 2013 161 898 901 10.1111/bjh.12310 23560553\n52. Nikesitch N. Silvia C. Ling W. Molecular mechanisms in multiple myeloma drug resistance J. Clin. Pathol. 2016 69 97 101 10.1136/jclinpath-2015-203414 26598624\n53. Rajkumar S.V. Dimopoulos M.A. Palumbo A. Blade J. Merlini G. Mateos M.V. Kumar S. Hillengass J. Kastritis E. Richardson P. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma Lancet Oncol. 2014 15 e538 e548 10.1016/S1470-2045(14)70442-5 25439696\n54. Robak P. Węgłowska E. Dróżdż I. Mikulski D. Jarych D. Ferlińska M. Wawrzyniak E. Misiewicz M. Smolewski P. Fendler W. Cytokine and chemokine profile in patients with multiple myeloma treated with bortezomib Mediat. Inflamm. 2020 2020 1835836 10.1155/2020/1835836 32587468\n55. Durie B.G. Harousseau J.L. Miguel J.S. Bladé J. Barlogie B. Anderson K. Gertz M. Dimopoulos M. Westin J. Sonneveld P. International uniform response criteria for multiple myeloma Leukemia 2006 20 1467 1473 10.1038/sj.leu.2404284 16855634\n56. Kyle R.A. Rajkumar S.V. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma Leukemia 2009 23 3 9 10.1038/leu.2008.291 18971951\n57. Anderson K.C. Kyle R.A. Rajkumar S.V. Stewart A.K. Weber D. Richardson P. ASH/FDA Panel on Clinical Endpoints in Multiple Myeloma. Clinically relevant end points and new drug approvals for myeloma Leukemia 2008 22 231 239 10.1038/sj.leu.2405016 17972944\n58. Laubach J.P. Mitsiades C.S. Mahindra A. Luskin M.R. Rosenblatt J. Ghobrial I.M. Schlossman R.L. Avigan D. Raje N. Munshi N.C. Management of relapsed and relapsed/refractory multiple myeloma J. Natl. Compr. Cancer Netw. 2011 9 1209 1216 10.6004/jnccn.2011.0098\n59. Grabia S. Smyczynska U. Pagacz K. Fendler W. NormiRazor: Tool applying GPU-accelerated computing for determination of internal references in microRNA transcription studies BMC Bioinform. 2020 21 425 10.1186/s12859-020-03743-8\n60. Budczies J. Klauschen F. Sinn B.V. Győrffy B. Schmitt W.D. Darb-Esfahani S. Denkert C. Cutoff Finder: A comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization PLoS ONE 2012 7 e51862 10.1371/journal.pone.0051862 23251644\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2072-6694",
"issue": "13(5)",
"journal": "Cancers",
"keywords": "CXCR4; POMP; PSMB5; RPL5; TXN; XBP1; bortezomib; gene expression; multiple myeloma; refractory",
"medline_ta": "Cancers (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101526829",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33668794",
"pubdate": "2021-02-25",
"publication_types": "D016428:Journal Article",
"references": "25179733;31103265;19924305;26115406;24928860;16855634;21978467;29482577;17972944;22235146;33166494;26491355;12015144;30245231;28428269;29196868;32561655;30954557;30993606;23475625;26483548;18971951;18753647;25109961;27527861;24029229;25439696;24737138;15244382;32690882;18502982;12780789;31912902;23251644;24912524;23560553;28676669;25945832;19302977;21628408;32587468;19773446;25670156;23111325;32236619;24434212;32993488;32916955;26598624;21975917;30026573;22932796;30102324;31372333;19426847;21410373;17185464;23728080;18565852",
"title": "The Prognostic Value of Whole-Blood PSMB5, CXCR4, POMP, and RPL5 mRNA Expression in Patients with Multiple Myeloma Treated with Bortezomib.",
"title_normalized": "the prognostic value of whole blood psmb5 cxcr4 pomp and rpl5 mrna expression in patients with multiple myeloma treated with bortezomib"
} | [
{
"companynumb": "PL-TAKEDA-2021TUS025086",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
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{
"abstract": "We present the case of a 77-year-old woman who had an accidental fall in her garden, resulting in a fracture of her left ankle. After manipulation of the fracture, she developed sudden onset shortness of breath. An echo led to the diagnosis of Takotsubo cardiomyopathy. Shortly after this she developed sudden onset receptive and expressive dysphasia. Magnetic resonance imaging (MRI) of the head confirmed a left parietal infarct thought to be secondary to left ventricular thrombus formation. She was started on dabigatran. A few days later, she developed abdominal pain, and was subsequently diagnosed with a spontaneous splenic rupture. This case was interesting due to the unusual chain of events following a simple fall, and also a rare complication of anticoagulant therapy.",
"affiliations": "Royal Berkshire Hospital, Reading, UK racheljcarey@outlook.com.;Royal Berkshire Hospital, Reading, UK.",
"authors": "Carey|Rachel|R|;Nelatur|Varun|V|",
"chemical_list": "D000925:Anticoagulants; D014336:Troponin; D000069604:Dabigatran",
"country": "England",
"delete": false,
"doi": "10.7861/clinmedicine.18-5-406",
"fulltext": null,
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"issn_linking": "1470-2118",
"issue": "18(5)",
"journal": "Clinical medicine (London, England)",
"keywords": "Anticoagulation; Takotsubo; side effect; splenic rupture; thrombus",
"medline_ta": "Clin Med (Lond)",
"mesh_terms": "D000058:Accidental Falls; D000208:Acute Disease; D000368:Aged; D064386:Ankle Fractures; D000925:Anticoagulants; D000069604:Dabigatran; D005260:Female; D006257:Head; D006801:Humans; D008279:Magnetic Resonance Imaging; D011654:Pulmonary Edema; D011860:Radiography, Abdominal; D013161:Splenic Rupture; D054549:Takotsubo Cardiomyopathy; D014336:Troponin",
"nlm_unique_id": "101092853",
"other_id": null,
"pages": "406-408",
"pmc": null,
"pmid": "30287437",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29404350;27506776;23694768;19787754;29203578",
"title": "Spontaneous splenic rupture secondary to dabigatran: the last in a series of unfortunate events.",
"title_normalized": "spontaneous splenic rupture secondary to dabigatran the last in a series of unfortunate events"
} | [
{
"companynumb": "GB-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-031875",
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"actiondrug": "5",
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"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
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{
"abstract": "Activating germline mutations of the MET gene are associated with hereditary papillary renal cancer. This a very rare autosomal dominant condition, which is usually considered not to display a phenotype of multiple types of malignancy. However, this report describes the case of a man who has been affected with testicular teratoma, diffuse large B-cell lymphoma and multiple hepatic cysts, as well as multiple papillary renal cancers. There is good supporting evidence for roles of over-expression/activity of the HGF/MET ligand-receptor in development of these tumours, raising the possibility of other increased cancer risks associated with activating germline MET gene mutations.",
"affiliations": "Yorkshire Regional Genetics Service, Chapel Allerton Hospital, LS7 4SA, Leeds, United Kingdom. j.adlard@nhs.net.",
"authors": "Adlard|Julian|J|0000-0002-1693-0435",
"chemical_list": "C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10689-020-00196-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1389-9600",
"issue": "20(1)",
"journal": "Familial cancer",
"keywords": "Cancer; Germline; Lymphoma; MET; Multiple; Teratoma",
"medline_ta": "Fam Cancer",
"mesh_terms": "D000328:Adult; D002291:Carcinoma, Papillary; D003560:Cysts; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms; D008107:Liver Diseases; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary; D019859:Proto-Oncogene Proteins c-met; D013724:Teratoma; D013736:Testicular Neoplasms",
"nlm_unique_id": "100898211",
"other_id": null,
"pages": "81-83",
"pmc": null,
"pmid": "32686009",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple primary cancers (renal papillary, lymphoma and teratoma) and hepatic cysts in association with a pathogenic germline mutation in the MET gene.",
"title_normalized": "multiple primary cancers renal papillary lymphoma and teratoma and hepatic cysts in association with a pathogenic germline mutation in the met gene"
} | [
{
"companynumb": "GB-TEVA-2021-GB-1900015",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
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"actiondrug": "6",
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"activesubstancename": "CISPLATIN"
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... |
{
"abstract": "The increased use of immune-checkpoint inhibitors to treat various types of cancer has increased the incidence of immune-related adverse events (irAEs). Hepatic irAEs are frequent and can lead to serious conditions. Among the various types of hepatic irAEs reported to date, bile duct injury has been shown refractory to steroid treatment. This study describes 2 patients with hepatic irAEs manifesting as intrahepatic bile duct injury. Immunostaining with antibodies to both CD8 and cytokeratin-7 was useful for the diagnosis, and both patients were refractory to steroid treatment. Prompt diagnosis and active immunosuppressive therapies are required in such cases.",
"affiliations": "The Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.;The Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.;Department of Gastroenterology, Takaoka Municipal Hospital, Takaoka, Japan.;Department of Gastroenterology, Takaoka Municipal Hospital, Takaoka, Japan.;The Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.;The Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.;The Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.;The First Department of Pathology, Faculty of Medicine, University of Toyama, Toyama, Japan.;The Second Department of Pathology, Faculty of Medicine, University of Toyama, Toyama, Japan.;The Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.",
"authors": "Murayama|Aiko|A|;Tajiri|Kazuto|K|;Nakaya|Atsuko|A|;Ito|Hiroyuki|H|;Hayashi|Yuka|Y|;Entani|Toshiki|T|;Nagata|Kohei|K|;Tanaka|Shinichi|S|;Hamashima|Takeru|T|;Yasuda|Ichiro|I|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000516199",
"fulltext": "\n==== Front\nCase Rep Gastroenterol\nCase Rep Gastroenterol\nCRG\nCase Reports in Gastroenterology\n1662-0631\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\n10.1159/000516199\ncrg-0015-0645\nCase and Review\nIntrahepatic Bile Duct Injury as a Hepatic Immune-Related Adverse Event after Immune-Checkpoint Inhibitor Treatment\nMurayama Aiko a b\nTajiri Kazuto a *\nNakaya Atsuko b\nIto Hiroyuki b\nHayashi Yuka a\nEntani Toshiki a\nNagata Kohei a\nTanaka Shinichi c\nHamashima Takeru d\nYasuda Ichiro a\naThe Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan\nbDepartment of Gastroenterology, Takaoka Municipal Hospital, Takaoka, Japan\ncThe First Department of Pathology, Faculty of Medicine, University of Toyama, Toyama, Japan\ndThe Second Department of Pathology, Faculty of Medicine, University of Toyama, Toyama, Japan\n*Kazuto Tajiri, tajikazu@med.u-toyama.ac.jp\nMay-Aug 2021\n13 7 2021\n13 7 2021\n15 2 645651\n12 3 2021\n19 3 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.\nThe increased use of immune-checkpoint inhibitors to treat various types of cancer has increased the incidence of immune-related adverse events (irAEs). Hepatic irAEs are frequent and can lead to serious conditions. Among the various types of hepatic irAEs reported to date, bile duct injury has been shown refractory to steroid treatment. This study describes 2 patients with hepatic irAEs manifesting as intrahepatic bile duct injury. Immunostaining with antibodies to both CD8 and cytokeratin-7 was useful for the diagnosis, and both patients were refractory to steroid treatment. Prompt diagnosis and active immunosuppressive therapies are required in such cases.\n\nKeywords\n\nImmune-checkpoint inhibitors\nImmune-related adverse events\nCholangitis\nCytokeratin-7\nMycophenolate mofetil\n==== Body\npmcIntroduction\n\nImmune-checkpoint inhibitors (ICIs) have been approved for the treatment of various malignant tumors [1]. Although ICIs inhibit tumor growth by blocking the transmission of immunosuppressive signals, such as the binding of program death-1 (PD-1) and program death-ligand 1 (PD-L1) or the binding of cytotoxic T-lymphocyte antigen-4 (CTLA-4) with CD28-ligands (CD28L), these agents induce various immune-related adverse events (irAEs) in various organs [2]. For example, hepatic irAEs have been reported in 1–16% of patients administered ICIs and can lead to serious conditions [3, 4]. Depending on the degree of liver damage, hepatic irAEs can be treated with immunosuppressive agents such as prednisolone (PSL) and other immunosuppressive [5]. The present study describes 2 patients who experienced severe cholestatic liver injury after treatment with ICIs. Both patients showed injury to intrahepatic small bile ducts, with these injuries being refractory to steroid administration. One patient recovered after treatment with mycophenolate mofetil (MMF). The literature of patients who experienced hepatic irAE manifesting as bile duct damage is discussed.\n\nCase Reports\n\nPatient 1\n\nThe patient was an 83-year-old man who had undergone laparoscopic left nephrectomy for advanced left renal cell carcinoma. He was found to have pleural metastasis 1 month after the operation and was treated with 4 cycles of the anti-PD-1 antibody nivolumab and the anti-CTLA-4 antibody ipilimumab for 12 weeks. Disease progression was observed, and the patient was started on second-line treatment with pazopanib. Blood tests 4 weeks later showed a marked elevation of liver enzymes, including an aspartate aminotransferase (AST) concentration of 980 IU/L (normal range 12–31 IU/L), an alanine transaminase (ALT) concentration of 714 IU/L (normal range 8–40 IU/L), an alkaline-phosphatase (ALP) concentration of 2004 IU/L (normal range 100–310 IU/L), and a total bilirubin concentration of 4.02 mg/dL. He was treated with ursodeoxycholic acid (300 mg/day) and PSL (1.0 mg/kg/day), but his liver function and jaundice did not improve. One week later, he was referred to our hospital. At admission, he showed prolonged severe cholestatic liver injury, including AST 903 IU/L, ALT 1045 IU/L, ALP 3083 IU/L, total bilirubin 20.0 mg/dL, and direct bilirubin 15.6 mg/dL and elongation of prothrombin time (PT) (PT-%, 45%, PT-INR 1.60). Serological examination showed no evidence of hepatitis A, B, C, or E virus infection and no evidence of infection with other viruses, such as Epstein-Barr virus and cytomegalovirus (CMV). His serum immunoglobulin G concentration was within the normal range, and he was negative for antinuclear and anti-mitochondrial antibodies. Computed tomography and ultrasonography showed no evidence of abnormalities in his biliary tracts. He was started on steroid-pulse therapy with methylprednisolone (1,000 mg/day for 3 days) and vitamin K supplementation. Although his PT activity improved to 100%, his cholestatic liver injury showed no improvements, with AST 358 IU/L, ALT 646 IU/L, ALP 2187 IU/L, total bilirubin 23.7 mg/dL, and direct bilirubin 18.0 mg/dL. A percutaneous liver biopsy was performed to evaluate his liver injury.\n\nLiver biopsy showed infiltration of inflammatory cells, mainly lymphocytes, into the portal area, as well as interface hepatitis. Advanced fibrosis was not observed (shown in Fig. 1a). Cytokeratin (CK)-7 staining showed partial destruction of the intrahepatic bile duct and cholestasis around such destroyed bile duct, mimicking chronic nonsuppurative destructive cholangitis (shown in Fig. 1b). Immunostaining showed that most of the infiltrating lymphocytes were positive for CD8, with few positive for CD4 (shown in Fig. 1c, d). These findings suggested that an autoimmune mechanism induced by ICIs caused intrahepatic bile duct injury, leading to severe cholestasis. Although pazopanib-induced liver injury could not be completely ruled out, those histological findings and the timing of liver injury support a diagnosis of hepatic irAE. Because he was considered steroid refractory, a decision was made to treat him with MMF, and approval from the institutional review board of the Ethics Committee of our center was obtained. However, he developed CMV pneumonia, requiring treatment with ganciclovir for 2 weeks to control the CMV infection. After the control of CMV, he was started on MMF (500 mg/bid). However, his general condition already worsened markedly and his organ function deteriorated. Two days after starting MMF treatment, the patient died of multiple organ failures.\n\nPatient 2\n\nThe patient was a 77-year-old man who had undergone resection of a malignant melanoma on his left foot 3 years earlier but had developed multiple lymph node recurrences. He was, therefore, treated with the anti-PD-L1 antibody pembrolizumab, which had shown good antitumor activity. Eleven months after pembrolizumab treatment, a blood examination revealed liver injury with jaundice, including AST 147 IU/L, ALT 263 IU/L, ALP 739 IU/L, and total bilirubin 3.8 mg/dL. He was serologically negative for viral hepatitis including hepatitis A, B, C, and E viruses and for other viruses such as Epstein-Barr virus and CMV. Administration of new drugs was not recognized during these several months. He was also negative for antinuclear and anti-mitochondrial antibodies. Abdominal ultrasonography showed no evidence of biliary obstructive changes. He was thereafter referred to our hospital and was tentatively diagnosed with hepatic irAE, for which he was treated with high-dose PSL (1.5 mg/kg/day). Five days after the steroid therapy, he showed prolonged liver injury, including AST 188 IU/L, ALT 483 IU/L, ALP 1265 IU/L, and total bilirubin 3.0 mg/dL. A US-guided percutaneous liver biopsy was performed to evaluate his liver injury, and after approval by the institutional review board of the Ethics Committee of our institution, he was started on MMF (500 mg/bid).\n\nLiver biopsy showed the infiltration of inflammatory cells, mainly lymphocytes, into the portal area, along with interface hepatitis, but advanced fibrosis was not observed (shown in Fig. 2a). CK-7 staining showed that inflammation occurred mainly in the portal areas, and partial destruction of intrahepatic bile duct was also observed (shown in Fig. 2b). Immunostaining showed that most of the lymphocytes accumulating around the intrahepatic bile ducts were CD8-positive, not CD4-positive (shown in Fig. 2c, d). These findings suggested that an autoimmune mechanism induced by ICI caused intrahepatic bile ductal damage, leading to cholestatic liver injury. Two weeks after starting MMF, his liver injury had improved, with AST 33 IU/L, ALT 124 IU/L, ALP 456 IU/L, and total bilirubin 0.9 mg/dL. He was subsequently discharged, and PSL was gradually reduced. Eight weeks after MMF administration, his liver injury had normalized and MMF followed PSL were discontinued. His condition remained good, with no evidence of recurrence of liver injury.\n\nDiscussion\n\nICIs that suppress interactions between PD-1 and PD-L1 or between CTLA-4 and CD28L have become widely used to treat cancer, increasing the incidence of irAEs associated with ICIs [1]. Hepatic irAE have been reported to occur 4–12 weeks after ICIs administration [4]. Rates of liver dysfunction with a single ICI were found to be 6.4% for nivolumab and 7.1% for ipilimumab. However, the incidence of all grade liver dysfunction in patients treated with a combination of nivolumab and ipilimumab combination therapy was 30% and rates of severe liver injury (Grade 3 or higher) was as high as 18.8% [2, 3], indicating that stronger immunosuppression could lead to more and more severe irAEs.\n\nThe patterns of liver damage from hepatic irAEs vary from hepatocellular type to cholangitis type, with ICIs recently reported to induce various types of cholangitis. A review of patients with hepatic irAEs, including cholangitis, showed the occurrence of cholangitis at various levels of the bile ducts, from the extrahepatic to the intrahepatic bile ducts (Table 1) [6, 7, 8, 9, 10, 11]. Histopathological findings include the infiltration of mostly CD8-positive T cells around Glisson's capsule [7, 10, 11]. Liver biopsy from both of our patients showed interface hepatitis with intrahepatic bile duct injury and infiltration predominantly by CD8 positive cells. Although the intrahepatic bile duct could not be clearly found in Patient 1 by hematoxylin-eosin staining, however, CK-7 staining showed damage to the intrahepatic bile duct. CK-7 staining was shown effective in evaluating intrahepatic bile ductal damage in patients with severe damage, such as patients with vanishing bile duct syndrome [9]. Both CD8 and CK-7 staining should be considered in evaluating patients with hepatic irAEs showing cholestatic liver injury.\n\nGuidelines regarding treatment for hepatic irAEs have suggested that patients with Grade 4 liver dysfunction be treated with a high-dose steroid such as PSL 2 mg/kg. Patients who do not improve after 3 days of high-dose PSL should be switched to treatment with MMF [12]. ICI-induced cholangitis is a serious adverse event with an inadequate response to steroid treatment [6, 9]. Moreover, liver injury with cholangitis due to ICIs is regarded as a hepatic irAE [12], suggesting that hepatic irAEs with cholestasis be managed more cautiously. Imaging methods are required to evaluate extrahepatic bile ductal changes and liver biopsy should also be considered.\n\nSteroid treatment is not recommended for patients with chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis due to adverse events. In contrast, budesonide, a steroid almost completely metabolized during its first pass in the liver, may be effective in patients with cholestatic liver disease [13, 14]. Furthermore, immunosuppressants such as MMF, cyclosporine, and azathioprine are not recommended for patients with PBC or primary sclerosing cholangitis [13]. Budesonide has been shown effective in patients with early stage PBC but not in cirrhotic patients [14]. Nonspecific immunosuppressive treatment may be effective only in patients with early stage cholestatic liver diseases but may be harmful in patients with later stage diseases due to adverse events. Previous studies and the present report suggest that patients with severe damage to the bile ducts who develop organic changes such as vanishing bile duct are refractory to immunosuppressive treatment and that this condition could be fatal. Earlier MMF administration may have improved the clinical outcome in Patient 1 of the present study. Early diagnosis and positive interventions are important for improving the prognosis of patients with hepatic irAE and cholangitis, preventing organic damage to the bile ducts.\n\nIn conclusion, this study described 2 patients with hepatic irAE with cholestasis. Immunostaining with antibodies to both CD8 and CK-7 may be useful for the diagnosis of this condition. Prompt and active immunosuppressive treatment should be considered for these patients.\n\nStatement of Ethics\n\nWritten informed consent for publication was obtained from the patient's wife and son in Patient 1 and from the patient in Patient 2. Our work was approved by our institutional clinical Ethics Committee (Clinical Ethics Committee of Toyama University Hospital, Approved number: MKTY2019001).\n\nConflict of Interest Statement\n\nThe authors declare that they have no conflicts of interest.\n\nFunding Sources\n\nThere were no funding sources.\n\nAuthor Contributions\n\nM.A. and T.K. wrote this paper, and all the authors contributed to the patient's medical treatment.\n\nFig. 1 Liver biopsy findings in Patient 1. a Hematoxylin-eosin staining, portal area. ×200. b CK-7 staining. ×200. c Azan staining. ×40. c CD4 staining, nonspecific staining was found. ×200. d CD8 staining. ×200. CK, cytokeratin.\n\nFig. 2 Liver biopsy findings in Patient 2. a Hematoxylin-eosin staining. ×100. b CK-7 staining. ×100. c CD4 staining, nonspecific staining was found. ×100. d, e CD8 staining. ×100. CK, cytokeratin.\n\nTable 1 Treatment and the response in reported cases with hepatic irAE showing cholangitis\n\nCase\tAge\tSex\tPattern of cholangitis\tSteroid (/day), mg/kg\tAdditional treatment\tBiliary drainage\tImprovement\tRef\t\n1\t81\tF\tEHD, IHD\tmPSL 2\tMMF 1 g/day\tNone\tYes\t[6]\t\n2\t75\tM\tNE\tmPSL 2\tNone\tYes\tNo\t[6]\t\n3\t55\tM\tEHD, IHD\tmPSL 2\tMMF 1 g/day\tYes (EST)\tYes\t[6]\t\n4\t82\tF\tEHD, IHD\tmPSL 2\tNone\tNone\tYes\t[6]\t\n5\t64\tM\tEHD\tPSL 0.5\tNone\tNone\tYes\t[7]\t\n6\t73\tF\tEHD\tPSL 0.5\tNone\tYes\tYes\t[7]\t\n7\t82\tF\tEHD\tNone\tNone\tYes\tYes\t[7]\t\n8\t63\tM\tEHD\tPSL 2\tNone\tYes\tYes\t[8]\t\n9\t49\tF\tIHD (VBDS)\tPSL 1\tMMF 1 g/day\tNone\tNo\t[9]\t\n10\t59\tF\tIHD\tPSL 1\tNone\tNone\tYes\t[9]\t\n11\t76\tM\tIHD (partial VBDS)\tPSL 1\tMMF 500 mg\tNone\tPartially improved\t[9]\t\n12\t79\tM\tIHD\tmPSL 1\tNone\tNone\tYes\t[10]\t\n13\t76\tM\tEHD, IHD\tPSL 0.5\tNone\tNone\tYes\t[11]\t\n14\t83\tM\tIHD\tmPSL 20\tMMF 1 g/day\tNone\tNo\tOur case\t\n15\t77\tM\tIHD\tPSL 1.5\tMMF 1 g/day\tNone\tYes\tOur case\t\nirAE, immune-related adverse event; F, female; M, male; MMF, mycophenolate mofetil; F, female; M, male; EHD, extrahepatic duct; IHD, intrahepatic duct; NE, not evaluated; VBDS, vanishing bile duct syndrome; mPSL, methyl prednisolone; BD, biliary drainage; EST, endoscopic sphinctectomy; PSL, prednisolone.\n==== Refs\nReferences\n\n1 Martin-Liberal J Ochoa de Olza M Hierro C Gros A Rondon J Tabernero J The expanding role of immunotherapy Cancer Treat Rev 2017 54 74 86 28231560\n2 Postow MA Chesney J Pavlick AC Robert C Grossmann K McDermott D Nivolumab and ipilimumab versus ipilimumab in untreated melanoma N Engl J Med 2015 372 2006 17 25891304\n3 Larkin J Hodi FS Wolchok JD Combined nivolumab and ipilimumab or monotherapy in untreated melanoma N Engl J Med 2015 373 (13) 1270 1\n4 Peeraphatdit TB Wang J Odenwald MA Hu S Hart J Charlto MR Hepatotoxicity from immune checkpoint inhibitors: a systematic review and management recommendation Hepatology 2020 72 315 29 32167613\n5 Haanen J Carbonnel F Robert C Kerr KM Peters S Larkin J Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2017 28 iv119 42 28881921\n6 Izumi H Kodani M Kurai J Takeda K Okazaki R Yamane K Nivolumab-induced cholangitis in patients with non-small cell lung cancer: case series and a review of literature Mol Clin Oncol 2019 11 439 46 31616560\n7 Kawakami H Tanizaki J Tanaka K Haratani K Hayashi H Takeda M Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer Invest New Drugs 2017 35 529 36 28317087\n8 Kashima J Okuma Y Shimizuguchi R Chiba K Bile duct obstruction in a patient treated with nivolumab as second-line chemotherapy for advanced non-small-cell lung cancer: a case report Cancer Immunol Immunother 2018 67 61 5 28913619\n9 Doherty GJ Duckworth AM Davies SE Mells GF Brais R Harden SV Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury ESMO Open 2017 2 e000268 29081991\n10 Gelsomino F Vitale G D'Errico A Bertuzzi C Andreone P Ardizzoni A Nivolumab-induced cholangitic liver disease: a novel form of serious liver injury Ann Oncol 2017 28 671 2 27993797\n11 Sawada K Shonaka T Nishikawa Y Hasegawa K Hayahi H Hasebe T Successful treatment of nivolumab-related cholangitis with prednisolone: a case report and review of the literature Intern Med 2019 58 1747 52 30799364\n12 Brahmer JR Lacchetti C Schneider BJ Atkins MB Brassil KJ Caterino JM Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline J Clin Oncol 2018 36 1714 68 29442540\n13 Goldstein J Levy C Novel and emerging therapies for cholestatic liver diseases Liver Int 2018 38 1520 35 29758112\n14 de Vries E Beuers U Management of cholestatic disease in 2017 Liver Int 2017 37 (Suppl 1) 123 9 28052628\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "15(2)",
"journal": "Case reports in gastroenterology",
"keywords": "Cholangitis; Cytokeratin-7; Immune-checkpoint inhibitors; Immune-related adverse events; Mycophenolate mofetil",
"medline_ta": "Case Rep Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101474819",
"other_id": null,
"pages": "645-651",
"pmc": null,
"pmid": "34616270",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "29758112;28317087;28231560;29442540;27993797;30799364;31616560;28881921;28913619;29081991;28052628;25891304;26398076;32167613",
"title": "Intrahepatic Bile Duct Injury as a Hepatic Immune-Related Adverse Event after Immune-Checkpoint Inhibitor Treatment.",
"title_normalized": "intrahepatic bile duct injury as a hepatic immune related adverse event after immune checkpoint inhibitor treatment"
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"abstract": "Enasidenib is an FDA-approved isocitrate dehydrogenase 2 (IDH2) inhibitor, which is used in the treatment of acute myeloid leukemia (AML). We present a case of AML with an IDH2 mutation treated with a regimen of enasidenib and 5-azacitidine, where thyroiditis was noted to be a part of differentiation syndrome. The patient is a 77-year-old woman with IDH2-mutated AML who had initially been started on 100 mg of enasidenib and then presented with dyspnea and was diagnosed with pleural effusion - a common presentation with enasidenib - but was also noted to have thyroiditis. She was started on steroids, but due to continued hyperbilirubinemia and thyroiditis, her dose of enasidenib was reduced to half, which resulted in clinical improvement. This case demonstrates thyroiditis as one of the rare manifestations in the treatment of AML with enasidenib-induced differentiation syndrome.",
"affiliations": "Johnston Memorial Hospital, Ballad Health System, Abingdon, Virginia, USA.;Medical Center of Central Georgia, Mercer University, Macon, Georgia, USA.;Johnston Memorial Hospital, Ballad Health System, Abingdon, Virginia, USA.;Johnston Memorial Hospital, Ballad Health System, Abingdon, Virginia, USA.;Division of Hematology/Oncology, Georgia Cancer Center, Augusta University, Augusta, Georgia, USA.;Division of Hematology/Oncology, Georgia Cancer Center, Augusta University, Augusta, Georgia, USA.",
"authors": "Annamaraju|Pavan|P|;Gopishetty|Swathi|S|;Goparaju|Naga|N|;Beasey|Matthew|M|;Kota|Vamsi|V|;Guddati|Achuta K|AK|",
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"doi": "10.1159/000507613",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 S. 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\n32547385\n10.1159/000507613\ncro-0013-0583\nCase Report\nThyroiditis: A Rare Manifestation of Enasidenib-Induced Differentiation Syndrome\nAnnamaraju Pavan a* Gopishetty Swathi b Goparaju Naga a Beasey Matthew a Kota Vamsi c Guddati Achuta K. c aJohnston Memorial Hospital, Ballad Health System, Abingdon, Virginia, USA\nbMedical Center of Central Georgia, Mercer University, Macon, Georgia, USA\ncDivision of Hematology/Oncology, Georgia Cancer Center, Augusta University, Augusta, Georgia, USA\n*Pavan Annamaraju, 16000 Johnston Memorial Hospital, Suite 312, Medical Plaza, Abingdon, VA 24211 (USA), pavan.fivestar@gmail.com\nMay-Aug 2020 \n27 5 2020 \n27 5 2020 \n13 2 583 587\n30 3 2020 30 3 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This 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.Enasidenib is an FDA-approved isocitrate dehydrogenase 2 (IDH2) inhibitor, which is used in the treatment of acute myeloid leukemia (AML). We present a case of AML with an IDH2 mutation treated with a regimen of enasidenib and 5-azacitidine, where thyroiditis was noted to be a part of differentiation syndrome. The patient is a 77-year-old woman with IDH2-mutated AML who had initially been started on 100 mg of enasidenib and then presented with dyspnea and was diagnosed with pleural effusion – a common presentation with enasidenib – but was also noted to have thyroiditis. She was started on steroids, but due to continued hyperbilirubinemia and thyroiditis, her dose of enasidenib was reduced to half, which resulted in clinical improvement. This case demonstrates thyroiditis as one of the rare manifestations in the treatment of AML with enasidenib-induced differentiation syndrome.\n\nKeywords\nAcute myeloid leukemiaChemotherapyDrug therapyEnasidenib\n==== Body\nIntroduction\nAcute myeloid leukemia (AML) in younger adults has a guarded prognosis, whereas it is significantly worse for older adults and those with secondary AML, which has evolved from antecedent myeloid neoplasms [1]. In patients with relapsed or refractory disease, the 5-year survival rate is only 5–10% [2]. Enasidenib mesylate is a selective mutant inhibitor of isocitrate dehydrogenase 2 (IDH2) protein, which promotes the differentiation of leukemic myoblasts. It was recently approved by the US Food and Drug Administration (FDA) in relapsed/refractory mutant IDH2 AML in 2017 for adults. It is a first-in-class, oral, selective inhibitor of the mutant IDH2 enzyme. Approximately 8–19% of patients with AML have IDH2 mutations [3]. It has been shown that reductions in IDH2 variant allele frequency and molecular clearance with enasidenib were associated with complete remission, and it also induces responses in approximately 40% of patients with mutant IDH2 relapsed/refractory AML regardless of prior treatment [3].\n\nAs this is a recently FDA-approved treatment regimen, not many clinical effects of differentiation syndrome have been documented, and, as such, medical literature documenting these effects is crucial to clinicians who treat AML.\n\nCase Presentation\nA 77-year-old Caucasian woman initially presented with pancytopenia, referred from the primary care physician to the hematology/oncology clinic for further evaluation in April 2019. Her past medical history was notable for paroxysmal atrial fibrillation, hyperlipidemia, and recurrent allergic sinusitis. She was on metoprolol, apixaban, and ezetimibe. On presentation, she was afebrile with a blood pressure of 126/80 mm Hg, a heart rate of 72 beats/min (regular), and a respiratory rate of 16 breaths/min. A comprehensive physical examination was unremarkable.\n\nThe laboratory data revealed pancytopenia with a platelet count of 116 × 1,000/mm3, a white blood cell count of 1.7 × 1,000/mm3 with 25% neutrophils, and a hemoglobin level of 9.5 g/dL with a mean corpuscular volume of 80.9 fL/cell and a red blood cell distribution width of 22.9. Flow cytometry was unremarkable. All other laboratory investigations, including a liver function test, creatinine, thyroid function tests, and a hepatitis panel, were also within normal limits. Her iron studies and hemoglobin electrophoresis results were also normal.\n\nShe was initially suspected of having α-thalassemia, but a bone marrow biopsy in May 2019 demonstrated findings consistent with AML positive for IDH2 mutation with 16% marrow blasts/promonocytes without circulating blasts. Due to the diagnosis of AML with IDH2 mutation, she was advised against bone marrow transplantation given her age. She was started on a regimen of 5-azacitidine and enasidenib. Prophylactic antiviral, antifungal, and antibiotic medications were also initiated.\n\nAfter 2 weeks, she was scheduled for the second cycle of chemotherapy. However, it was held off as she reported having subjective fevers associated with headache, frontal sinus pressure, and loss of appetite. Computed tomography of the sinuses showed evidence of inflammatory disease. She was treated with amoxicillin/clavulanic acid (Augmentin) for a presumed diagnosis of bacterial sinusitis. A few days later, her second dose of chemotherapy was administered. During a follow-up visit, her laboratory data revealed hyperbilirubinemia of 3.8 mg/dL, which raised a concern for differentiation syndrome. Therefore, she was started on dexamethasone 8 mg twice a day.\n\nOn her next follow-up visit, she complained of dyspnea. Her physical examination was notable for diminished breath sounds at the lung bases and bilateral pitting edema. The chest radiograph confirmed bilateral pleural effusions. A 2D echocardiogram showed a preserved left ventricular ejection fraction. She was treated with oral furosemide along with steroids and pantoprazole. Apixaban was held due to pancytopenia. During this time, she was hospitalized for dehydration in the setting of furosemide use and reduced oral intake. An EKG showed rapid atrial fibrillation. Her laboratory data showed a worsening hyperbilirubinemia up to 5.5 mg/dL, and new-onset hyperthyroidism with TSH less than 0.02 ng/dL and elevated free T4 of 2.1 ng/dL. An I-123 thyroid scan showed slightly increased uptake in the upper portion of the right thyroid lobe with no suppression in the remainder of the gland, consistent with thyroiditis. Rate control of atrial fibrillation was achieved with uptitration of β-blocker; methimazole was avoided due to concerns for bone marrow suppression.\n\nDue to persistent hyperbilirubinemia despite being on steroids, the dosage of enasidenib was reduced to half. After the dose reduction, repeat total bilirubin started trending down to 4.4 mg/dL. A few weeks later, during a follow-up visit, she was feeling better and was switched to a steroid taper. Her free T4 levels also trended down to 1.5 ng/dL. Subsequently, she started her third cycle of chemotherapy with a reduced dose of enasidenib (50 mg). During a follow-up visit, her dyspnea and fatigue were noted to have improved and her thyroid panel and bilirubin levels had normalized.\n\nShe was able to complete cycles 4/5 and 5/5 of azacytidine with enasidenib uneventfully. Her antifungal and antibiotics were discontinued due to normalization of her absolute neutrophil count.\n\nDiscussion\nDifferentiation syndrome is an autoimmune response and is associated with fatal complications as it leads to a high mortality rate. AML patients receiving targeted therapy have been shown to have neutrophil recovery in the setting of clinical differentiation syndrome [4]. The differentiation of leukemic blasts and promyelocytes can lead to the release of a systemic inflammatory response leading to cellular migration, endothelial activation, and the release of interleukins (IL-1, IL-6, IL-8, TNF-α, and CCL2) and vascular factors which are responsible for tissue damage [5]. Septal edema, intra-alveolar hemorrhage, and capillaritis are seen in the lungs during differentiation syndrome. The symptoms of differentiation syndrome include unexplained fever, weight gain, dyspnea, hypotension, acute respiratory distress with interstitial pulmonary infiltrates, vascular capillary leak syndrome leading to acute renal failure, and hyperbilirubinemia [6]. An elevated white blood cell count is frequently present in differentiation syndrome, but the syndrome can also present with a low white blood cell count, anemia, thrombocytopenia, and coagulopathy. Chest imaging findings are mostly based on the severity of the differentiation syndrome and can present with an increased cardiothoracic ratio, pleural effusion, ground-glass opacity, and pulmonary hemorrhage [7].\n\nMutant IDH2 proteins neomorphically catalyze the oncometabolite (R)-2-hydroxyglutarate (R-2HG), and high R-2HG concentrations promote hypermethylation, altered gene expression, and blocked differentiation of hematopoietic cells [8, 9]. Cancer-associated IDH mutations block the normal cellular differentiation via the production of R-2HG. Enasidenib suppresses R-2HG and induces cellular differentiation of mutated IDH2 leukemic cells. Treated cells were noted to have fully functioning neutrophils retaining IDH2 mutation [10]. Pleural effusion is common with enasidenib. This could occur months after initiation of enasidenib treatment and could mimic symptoms of disease progression, and prompt intervention with steroids can be an effective management approach [10]. If not responsive to steroids, an alternative diagnosis should be suspected based on the clinical presentation.\n\nAmong patients with relapsed or refractory AML, the overall response rate was 40.3%, with a median response duration of 5.8 months. Median overall survival among relapsed/refractory patients was 9.3 months, and 19.3% of patients attained complete remission with an overall survival of 19.7 months [11]. Grade 3–4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH inhibitor-associated differentiation syndrome (7%) during clinical testing of enasidenib. It appears that instead of cytotoxicity, inducing differentiation is the key mechanism of enasidenib [12].\n\nThere have been no reports of thyroid dysfunction in previous clinical studies involving enasidenib. In our patient, differentiation syndrome was suspected, as she presented with dyspnea with pleural effusion and hyperbilirubinemia, and she was started on steroids. She was also noted to have thyroiditis; her symptoms did not respond to the steroid therapy, but later responded to a decreased dose of enasidenib. This report underlines the importance of considering thyroiditis as a possible manifestation of differentiation syndrome in AML patients being treated with enasidenib.\n\nStatement of Ethics\nThe patient had consented for her clinical history and case details to be published.\n\nDisclosure Statement\nNo conflicts of interest exist for any of the authors.\n\nFunding Sources\nThe authors declare that there was no funding for this study.\n\nAuthor Contributions\nP. Annamaraju, S. Gopishetty, N. Goparaju, V. Kota, and A.K. Guddati: literature review, and writing and revision of the manuscript; M. Beasey: literature review and revision of the manuscript.\n==== Refs\nReferences\n1 Walter RB Estey EH Management of older or unfit patients with acute myeloid leukemia Leukemia 2015 29 (4) 770 5 25005246 \n2 Oran B Weisdorf DJ Survival for older patients with acute myeloid leukemia: a population-based study Haematologica 2012 97 (12) 1916 24 22773600 \n3 Stein EM DiNardo CD Fathi AT Pollyea DA Stone RM Altman JK Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib Blood 2019 133 (7) 676 87 30510081 \n4 Birendra KC DiNardo CD Evidence for clinical differentiation and differentiation syndrome in patients with acute myeloid leukemia and IDH1 mutations treated with the targeted mutant IDH1 inhibitor, AG-120 Clin Lymphoma Myeloma Leuk 2016 16 (8) 460 5 27245312 \n5 Luesink M Jansen JH Advances in understanding the pulmonary infiltration in acute promyelocytic leukaemia Br J Haematol 2010 151 (3) 209 20 20735400 \n6 Montesinos P Sanz MA The differentiation syndrome in patients with acute promyelocytic leukemia: experience of the PETHEMA group and review of the literature Mediterr J Hematol Infect Dis 2011 3 (1) e2011059 22220256 \n7 Jung JI Choi JE Hahn ST Min CK Kim CC Park SH Radiologic features of all-trans-retinoic acid syndrome AJR Am J Roentgenol 2002 178 (2) 475 80 11804921 \n8 Losman JA Kaelin WG Jr What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer Genes Dev 2013 27 (8) 836 52 23630074 \n9 Figueroa ME Abdel-Wahab O Lu C Ward PS Patel J Shih A Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation Cancer Cell 2010 18 (6) 553 67 21130701 \n10 Fathi AT DiNardo CD Kline I Kenvin L Gupta I Attar EC Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: analysis of a phase 1/2 study JAMA Oncol 2018 4 (8) 1106 10 29346478 \n11 Stein EM DiNardo CD Pollyea DA Fathi AT Roboz GJ Altman JK Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia Blood 2017 130 (6) 722 31 28588020 \n12 Stein EM Enasidenib, a targeted inhibitor of mutant IDH2 proteins for treatment of relapsed or refractory acute myeloid leukemia Future Oncol 2018 14 (1) 23 40\n\n",
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"issn_linking": "1662-6575",
"issue": "13(2)",
"journal": "Case reports in oncology",
"keywords": "Acute myeloid leukemia; Chemotherapy; Drug therapy; Enasidenib",
"medline_ta": "Case Rep Oncol",
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"nlm_unique_id": "101517601",
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"pages": "583-587",
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"title": "Thyroiditis: A Rare Manifestation of Enasidenib-Induced Differentiation Syndrome.",
"title_normalized": "thyroiditis a rare manifestation of enasidenib induced differentiation syndrome"
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"abstract": "A summary analysis of three descriptive studies of significant adverse drug events (ADEs) was conducted. Case reports of ADEs published in Clin-Alert during 1976-97 were the source of information on ADEs, including drug-induced deaths, disabilities, and threats to life. The results of the three studies were compared, and recommendations were made. During the 21-year period, 1520 significant ADEs were reported (29% resulting in death, 15% in permanent disability, and 56% in life threats). Event types were distributed as adverse drug reactions (52%), allergic drug reactions (25%), medication errors (15%), and drug interactions (8%). Only 12% of the drug interactions were classified as having highest significance by one drug information reference, while 32% of the drug interactions were unclassified. Typically, patients were 40-69 years old and relatively healthy or only moderately ill and had received usual dosages. However, 29% of the patients with a drug-induced permanent disability were less than 10 years old. Only 17% of the drugs that could have been monitored by blood level tests were so monitored. The drug categories most commonly involved in ADEs were central-nervous-system agents, antimicrobials, antineoplastics, and cardiovascular agents. The nervous, hematopoietic, cardiovascular, and respiratory systems were affected the most. Faulty prescribing was the most common reason for medication error, and wrong dosage was the most common type of error. A lawsuit was reported in 13% of the cases. Overall, 52% of the cases were judged to have been preventable; of these, 50% could have been prevented by a pharmacist. Litigation was reported for 13% of the cases; settlements and judgments averaged $3.1 million. A summary analysis of more than 1500 published case reports of ADEs for 1976-97 yielded information on possible risk factors for drug-related deaths, disabilities, and life threats and on which events may have been preventable.",
"affiliations": "Department of Pharmacy Administration, Southern School of Pharmacy, Mercer University, 3001 Mercer University Drive, Atlanta, GA, USA. kelly_wn@mercer.edu",
"authors": "Kelly|W N|WN|",
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"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D000707:Anaphylaxis; D015984:Causality; D006233:Disabled Persons; D004347:Drug Interactions; D016903:Drug Monitoring; D004358:Drug Therapy; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D016365:Liability, Legal; D008508:Medication Errors; D004364:Pharmaceutical Preparations; D012720:Severity of Illness Index",
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"abstract": "BACKGROUND\nPatients with refractory status epilepticus (RSE) have high morbidity and mortality rates, are hospitalised for longer periods of time, suffer greater neurological damage and progress to symptomatic epilepsy. Continuous electroencephalogram (cEEG) monitoring is a valuable aid in the early detection of RSE, especially in the case of non-convulsive status epilepticus (NCSE). In this study we describe the clinical characteristics, treatment and use of cEEG in paediatric patients with RSE.\n\n\nMETHODS\nA retrospective study was conducted at the Hospital Clinico de la Pontificia Universidad Catolica de Chile between November 2005 and March 2011 in patients aged between 1 month and 15 years diagnosed with RSE and cEEG. Demographic characteristics, baseline and final conditions, and therapy were recorded.\n\n\nRESULTS\nA total of 15 patients, 12 of whom were males, with a mean age of 4 years (1.5 months-13 years) were identified. Eight patients had a history of epilepsy. The most frequent aetiologies were progressive symptomatic and acute symptomatic. Convulsive epileptic status (CSE) was present in 11 patients and NCSE in the other four. During the cEEG, six of the 11 patients with CSE later progressed to NCSE. The mean amount of time with RSE was 10.2 days. Of the 15 patients, 13 responded to anticonvulsive drugs and the main secondary complications were respiratory depression and hypotension. Patients with CSE tended to evolve in a more torpid manner than patients with NCSE. On discharge from hospital, 13 patients (86.6%) presented new neurological deficit or difficult-to-manage epilepsy, one still had RSE and one died (6%).\n\n\nCONCLUSIONS\nThe aggregate neurological morbidity and mortality rates of RSE were high. The use of cEEG monitoring should be considered for use in the management of such cases of status epilepticus.",
"affiliations": "División de Pediatría; Unidad de Neurología.",
"authors": "Cardoso|Ingrid|I|;Acevedo|Keryma|K|;Hernández|Marta|M|;Santin|Julia|J|;Moya|Pedro|P|;Godoy|Jaime|J|;Castillo|Andrés|A|;Soto|Pilar|P|;Mesa|Tomás|T|",
"chemical_list": "D000927:Anticonvulsants",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0210-0010",
"issue": "56(8)",
"journal": "Revista de neurologia",
"keywords": null,
"medline_ta": "Rev Neurol",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D001925:Brain Damage, Chronic; D002648:Child; D002675:Child, Preschool; D003128:Coma; D000013:Congenital Abnormalities; D002658:Developmental Disabilities; D004351:Drug Resistance; D004569:Electroencephalography; D004660:Encephalitis; D005260:Female; D006801:Humans; D007022:Hypotension; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008581:Meningitis; D012120:Respiration Disorders; D012189:Retrospective Studies; D013226:Status Epilepticus",
"nlm_unique_id": "7706841",
"other_id": null,
"pages": "401-8",
"pmc": null,
"pmid": "23568682",
"pubdate": "2013-04-16",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Refractory status epilepticus in children: characterisation of epilepsies, continuous electroencephalographic monitoring and response to treatment.",
"title_normalized": "refractory status epilepticus in children characterisation of epilepsies continuous electroencephalographic monitoring and response to treatment"
} | [
{
"companynumb": "PHHY2015CL042688",
"fulfillexpeditecriteria": "1",
"occurcountry": "CL",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
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"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nPosterior reversible leukoencephalopathy syndrome (PRES) was first described by Hinchey in 1996. The syndrome is characterized by altered level of consciousness, headache, visual changes, and seizures associated with a vasogenic edema of the white matter that occurs predominantly in the occipital and parietal lobes. Imaging tests such as computed tomography (CT) and especially magnetic resonance imaging (MRI) support the diagnosis.\n\n\nMETHODS\nWe report a case of a 48-year-old female patient who underwent a deceased donor kidney transplant and received tacrolimus as a part of the immunosuppressive regimen. Five weeks after transplantation she was admitted to the emergency due to sudden onset of confusion, disorientation, visual disturbances, and major headache. PRES was suspected and the diagnosis confirmed by brain MRI. Tacrolimus was withdrawn and rapid improvement of the neurological signs occurred leading to the conclusion that this drug triggered the syndrome.\n\n\nCONCLUSIONS\nPRES is an unusual complication after organ transplantation and should be considered in the appropriate clinical setting. Physicians must be aware of this condition in order to provide early detection and appropriate treatment since delay in removing the cause may lead to permanent sequelae.",
"affiliations": "Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil.;Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil.;Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil.;Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil.;Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil.;Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil.;Universidade Federal do Rio Grande do Sul, Faculdade de Medicina, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil.",
"authors": "Davi|Carla Beatriz|CB|;Moraes|Bruna Pinheiro de|BP|;Lichtenfels|Bruno Fontes|BF|;Castro Filho|João Batista Saldanha de|JBS|;Portal|Marcelle Maria|MM|;Montenegro|Rosangela Munhoz|RM|;Manfro|Roberto Ceratti|RC|",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": "10.1590/1678-4685-JBN-3825",
"fulltext": "\n==== Front\nJ Bras NefrolJ Bras NefroljbnJornal Brasileiro de Nefrologia0101-28002175-8239Sociedade Brasileira de Nefrologia 2979658510.1590/1678-4685-JBN-3825Case ReportPosterior reversible leukoencephalopathy syndrome (PRES) after kidney\ntransplantation: a case report Síndrome da leucoencefalopatia posterior reversível (PRES) após\ntransplante renal: um relato de caso Davi Carla Beatriz de Moraes Bruna Pinheiro 1Lichtenfels Bruno Fontes 1de Castro João Batista Saldanha Filho1Portal Marcelle Maria 1Montenegro Rosangela Munhoz 1Manfro Roberto Ceratti 1\n1 Universidade Federal do Rio Grande do Sul, Faculdade de Medicina,\nHospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil.Correspondence to: Roberto C. Manfro. E-mail:\nrmanfro@hcpa.edu.br19 4 2018 Jan-Mar 2018 40 1 91 94 09 6 2017 06 8 2017 This is an Open Access article distributed under the terms of the\nCreative Commons Attribution License, which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original work is\nproperly cited.ABSTRACT\nIntroduction:\nPosterior reversible leukoencephalopathy syndrome (PRES) was first described\nby Hinchey in 1996. The syndrome is characterized by altered level of\nconsciousness, headache, visual changes, and seizures associated with a\nvasogenic edema of the white matter that occurs predominantly in the\noccipital and parietal lobes. Imaging tests such as computed tomography (CT)\nand especially magnetic resonance imaging (MRI) support the diagnosis.\n\nCase Report:\nWe report a case of a 48-year-old female patient who underwent a deceased\ndonor kidney transplant and received tacrolimus as a part of the\nimmunosuppressive regimen. Five weeks after transplantation she was admitted\nto the emergency due to sudden onset of confusion, disorientation, visual\ndisturbances, and major headache. PRES was suspected and the diagnosis\nconfirmed by brain MRI. Tacrolimus was withdrawn and rapid improvement of\nthe neurological signs occurred leading to the conclusion that this drug\ntriggered the syndrome.\n\nConclusion:\nPRES is an unusual complication after organ transplantation and should be\nconsidered in the appropriate clinical setting. Physicians must be aware of\nthis condition in order to provide early detection and appropriate treatment\nsince delay in removing the cause may lead to permanent sequelae.\n\nRESUMO\nIntrodução:\nA síndrome da leucoencefalopatia posterior reversível (PRES) foi descrita\npela primeira vez por Hinchey, em 1996. A síndrome é caracterizada por nível\nalterado de consciência, cefaleia, alterações visuais e convulsões\nassociadas a edema vasogênico da substância branca, oriundo\npredominantemente nos lobos occipital e parietal. Exames de imagem como\ntomografia computadorizada (TC) e em particular a ressonância magnética\n(MRI) corroboram o diagnóstico.\n\nRelato de caso:\nrelatamos o caso de uma paciente do sexo feminino de 48 anos submetida a\ntransplante renal com doador falecido em regime imunossupressor com\ntacrolimus. Cinco semanas após o transplante, a paciente deu entrada no\npronto-socorro por conta de aparecimento súbito de confusão, desorientação,\ndistúrbios visuais e cefaleia intensa. As suspeitas diagnósticas recaíram\nsobre PRES, e a confirmação foi feita por imagens de ressonância magnética\ndo cérebro. Tacrolimus foi suspenso e os sinais neurológicos da paciente\nmelhoraram rapidamente, indicando que o medicamento desencadeou a\nsíndrome.\n\nConclusão:\nPRES é uma complicação incomum após o transplante de órgãos e deve ser\nconsiderada em ambiente clínico adequado. O corpo clínico deve estar ciente\ndessa patologia, de modo a detectá- -la precocemente e dar início ao\ntratamento, uma vez que atrasos na eliminação da causa podem levar a\nsequelas permanentes.\n\nKeywords:\nPosterior Leukoencephalopathy SyndromeKidney TransplantationTacrolimusPalavras-chave:\nSíndrome da Leucoencefalopatia Posterior ReversívelTransplante de RimTacrolimus\n==== Body\nINTRODUCTION\nPosterior reversible leukoencephalopathy syndrome (PRES) was first described by\nHinchey in 1996.1 The syndrome is\ncharacterized by the occurrence of encephalopathy that may present with a variety of\nsigns and symptoms including headache, altered vision, decreased visual acuity,\ncortical blindness, confusion, stupor, seizures, and hallucinations.1\n,\n2 It is associated with vasogenic edema of the\nwhite matter, predominantly in the occipital and parietal lobes,5\n,\n6 however, its pathophysiology is not yet\nfully understood. It is believed that endothelial dysfunction and alterations of\ncerebral autoregulation are involved.1 PRES is\nusually associated with hypertensive encephalopathy, eclampsia, and use of\nimmunosuppressive drugs, particularly calcineurin inhibitors; the majority of the\npatients present with marked elevation of blood pressure.1\n\n\nHere, we present a case of PRES in a kidney transplant recipient receiving tacrolimus\nin the immunosuppressive regimen, and emphasize the importance of early diagnosis\nand therapeutic measures.\n\nCASE REPORT\nA 48-year-old white female with end-stage renal disease due to adult polycystic\nkidney disease was admitted for deceased donor kidney transplantation in April 2015.\nShe had started renal replacement therapy with hemodialysis 7 years before and was\nin good general health with no significant co-morbidities. The donor was a\n2-year-old female who suffered anoxic encephalopathy. At organ retrieval, donor\nserum creatinine was 0.58 mg/dL. Donor and recipient presented 4 HLA (ABDR)\nmismatches, cross matching was negative and no anti-donor specific HLA antibodies\nwere found in the recipient’s serum. The kidneys were implanted “en bloc” and the\ntransplant was performed after 18 hours of cold ischemia in static preservation on\nEuro-Collins solution. Immunosuppressive regimen consisted of Basiliximab®\ninduction, tacrolimus, sodium mycophenolate, and steroids. The graft presented\nimmediate function and the patient was discharged at post-operative day 36 (POD).\nDuring hospitalization, she presented a urinary tract infection and was submitted to\nantibiotic treatment for 10 days. The blood tacrolimus level three weeks before\ndischarge was 15 µg/mL (receiving tacrolimus 7 mg twice daily orally). The dosage\nwas immediately reduced to 5 mg twice daily, and three days after dose adjustment\nthe blood level was 11.4 µg/mL; a new dose adjustment to 4 mg twice daily was done.\nAt discharge, serum creatinine was stable at 1.6 mg/dL and blood tacrolimus level\naround 10 µg/mL. On the 19th POD, sodium mycophenolate was replaced by azathioprine\ndue to severe diarrhea not responsive to dose fractioning and reduction.\n\nThree days after discharge she was admitted to the emergency room complaining of\nsevere headache, visual blurring, and confusion. Blood pressure was 180/100 mmHg,\naxillary temperature 38°C, and the general physical examination revealed no\nabnormalities. On neurological examination, she was confused, hallucinating, and\ndisoriented. She presented transient visual alterations and left hemianopia without\nsigns of meningeal irritation. Laboratory work up revealed stable graft function\n(serum creatinine 1.53 mg/dL), anemia (hemoglobin 7.7 g/dL) with normal white blood\ncell counts, slightly increased C reactive protein (10 mg/dL) and 10.3 ng/mL\ntacrolimus blood level. She received iv esmolol for blood pressure control and\nempiric iv antibiotics until cultures results. A brain CT scan disclosed extensive\nhypo-density at the sub cortical white and gray matter of the parietal and occipital\nlobes. Erasure of the cortical sulci, most evident on the cerebral hemispheres\nrecesses, was also present, and PRES was considered in the differential diagnosis\n(Figure 1A). The magnetic resonance imaging\n(MRI) showed hyperintensity on T2/FLAIR of the temporo-occipital and fronto-parietal\nregions in the upper convexity, without diffusion or bleeding signals (Figure 1B).\n\n\nFigure 1 A. Brain CT scan disclosing extensive hypo-density at the sub\ncortical white and gray matter of the parietal and occipital lobes.\nErasure of the cortical sulci, most evident on the cerebral hemispheres\nrecesses. B. Magnetic resonance imaging disclosing hyperintensity on\nT2/FLAIR of the temporo-occipital and fronto-parietal regions in the\nupper convexity, without diffusion or bleeding signals.\n\n\n\nTacrolimus was discontinued from immunosuppressive therapy. In the next two days, the\npatient had complete reversal of neurological symptoms. Cyclosporine was started at\n100 mg twice a day reaching a blood level of 146 ng/mL. The graft function remained\nstable and at two years after transplantation, the patient is enjoying good general\ncondition and good graft function (serum creatinine 1.2 mg/dL), protein-creatinine\nratio on random urine sample of 0.35 mg/mg, without new episodes of altered mental\nstatus or other neurologic signs.\n\nDISCUSSION\nPRES is associated with a variety of conditions including hypertensive\nencephalopathy, eclampsia, porphyria, hypomagnesemia, sepsis, chronic kidney\ndisease, and use of immunosuppressive drugs, especially calcineurin inhibitors\n(CNI).1\n,\n2 The syndrome has been reported in solid\norgan and bone marrow transplant recipients.3\n,\n4\n,\n5\n,\n6\n,\n7 Its incidence after solid organ\ntransplantation has been estimated to be around 0.5%.1\n,\n6\n,\n8 Most of the PRES reports involved patients\nreceiving immunosuppressive therapy with CNIs (cyclosporine or tacrolimus), although\nmTOR inhibitors (sirolimus or everolimus) have also been implicated.9\n,\n10\n,\n11 Tacrolimus was predominantly used in the\ncases described; no apparent relationship with blood levels has been reported and\ndiscontinuation of offending drugs usually led to clinical improvement.7\n,\n9\n,\n11\n\n\nPRES diagnosis requires a high level of suspicion. In a clinical setting, patient\ncomplaints and careful physical and especially neurologic examination are crucial in\nthe diagnostic work up. Imaging tests, usually CT and especially MRI, support the\ndiagnosis as they reveal the presence of edema of the gray and white matter, mainly\nin the occipital and parietal lobes and to a lesser extent in the frontal and\ntemporal lobes, pons, cerebellum, and other locations.1 In the post-transplant setting, the differential diagnosis includes\ninfections or autoimmune encephalitis, vasculitis, and malignant diseases of the\nnervous system.12 “Top of basilar” embolism\ncausing simultaneous bilateral posterior cerebral artery territory infarction is\nanother important differential diagnosis and MRI establishes the diagnosis.13 MRI findings provide the dominant\npathophysiological aspect of the syndrome, which is endothelial dysfunction leading\nto cerebral edema.1\n,\n14\n,\n16\n\n\nIn the case reported here, PRES seemed to be associated with tacrolimus use since a\nrapid clinical improvement occurred upon its discontinuation. Our patient was never\nexposed to toxic levels of tacrolimus, which prevented us from trying a lower dosage\nregimen of such drug. Instead, we opted for the use of cyclosporine starting with\nlow doses and controlling blood levels up to the lowest therapeutic level. Our\noption for cyclosporine was based on the lower incidence of neurotoxicity in\npatients receiving cyclosporin as compared to tacrolimus.7\n,\n8\n,\n9 However we must recognize that recurrence\ncould have occurred with cyclosporine therapy.\n\nTwo main approaches have been described for the handling of the syndrome in solid\norgan transplant recipients: discontinuation of the putative offending drug and dose\nreduction.7\n,\n8\n,\n9 In the first approach, the drug is usually\nreplaced by another immunosuppressive agent, as was the case in our report; in the\nsecond possibility, the lowest effective drug level should be targeted.\n\nPRES pathophysiology remains not fully elucidated. Two main hypotheses have been\nproposed both related to changes in cerebral blood flow.8\n,\n12\n,\n13\n,\n17 In short, it is currently accepted that\nhypertension and transient failure in self-regulation of cerebral blood flow causes\nvasogenic edema. Both neurogenic and myogenic responses lead to cerebral vessel\nvasodilation, and subsequent fluid leakage into the brain parenchyma.1\n,\n11\n,\n15 However, some patients have normal blood\npressure, and an alternate explanation would be related to endothelial damage and\ndysfunction, followed by vasoconstriction leading to cerebral hypoperfusion.6\n,\n12\n,\n17 Likewise, the pathophysiology of PRES\nassociated with immunosuppressive and cytotoxic drugs remains uncertain. It is\nthought to occur due to a direct toxic effect that damages the vascular endothelium,\nleading to endothelial dysfunction. This results in vasospasm, reduced tissue\nperfusion, activation of the coagulation cascade, and fluid leakage.1\n,\n12\n,\n17 It was initially suggested that an acute\ntoxic insult of undetermined origin produced by these pharmacological agents results\nin axonal swelling and increased water content in the white matter.6\n,\n15\n,\n16 Alternatively, it has been proposed that\nvascular spasm, secondary to raised endothelin concentrations, might produce\nreversible ischemia. 12\n,\n17\n,\n18\n\n\nPrevious studies have indicated that polymorphisms in drug metabolizing genes could\nexplain the propensity towards neurotoxicity. Tacrolimus is a substrate for the\nP-glycoprotein efflux pump encoded by the multidrug resistance gene-1. Although\ntacrolimus is lipophilic, it does not cross the blood-brain barrier by the action of\nthe P-glycoprotein efflux pump. However, polymorphisms that impair the proper\nfunction of the efflux pumps may allow tacrolimus to enter the blood-brain barrier\nand therefore cause toxicity.7\n,\n19\n\n\nPersistent neurological damage is reported in 10-20% of the patients and, even though\nPRES is not a frequent complication after transplantation, its early recognition and\nwithdrawal of the offending immunosuppressive agent is crucial since delays in these\nmeasures may lead to significant morbidity and mortality while timely recognition\nand intervention usually leads to full recovery.6\n,\n7\n,\n8\n\n\nIn conclusion, our patient presented tacrolimus-related PRES, which was diagnosed\nearly showing full recovery upon tacrolimus discontinuation. PRES should be\nconsidered in the differential diagnosis of solid organ transplant recipients with\nneurological symptoms in order to identify the syndrome and provide appropriate\nsupport and treatment.\n==== Refs\nREFERENCES\n1 Hinchey J Chaves C Appignani B Breen J Pao L Wang A A reversible posterior leukoencephalopathy\nsyndrome N Engl J Med 1996 334 494 500 8559202 \n2 Lee VH Wijdicks EF Manno EM Rabinstein AA Clinical spectrum of reversible posterior leukoencephalopathy\nsyndrome Arch Neurol 2008 65 205 210 18268188 \n3 Song T Rao Z Tan Q Qiu Y Liu J Huang Z Calcineurin Inhibitors Associated Posterior Reversible\nEncephalopathy Syndrome in Solid Organ Transplantation Report of 2 Cases and\nLiterature Review Medicine (Baltimore) 2016 95 e3173 27057842 \n4 Haughey D Narsipus S Posterior reversible encephalopathy syndrome after renal\ntransplant a simple solution for a complicated patient Case Rep Nephrol Dial 2015 5 20 25 25849670 \n5 Staykov D Schwab S Posterior reversible encephalopathy syndrome J Intensive Care Med 2012 21 11 24 \n6 Bartynski WS Tan HP Boardman JF Shapiro R Marsh JW Posteriorreversible encephalopathy syndrome after solid organ\ntransplantation Am J Neuroradiol 2008 29 924 930 18272559 \n7 Hammerstrom AE Howell J Gulbis A Rondon G Champlin RE Popat U Tacrolimus-associated posterior reversible encephalopathy\nsyndrome in hematopoietic allogeneic stem cell\ntransplantation Am J Hematol 2013 88 301 305 23460378 \n8 Wu Q Marescaux C Wolff V Jeung MY Kessler R Lauer V Tacrolimus-associated posterior reversible encephalopathy\nsyndrome after solid organ transplantation Eur Neurol 2010 64 169 177 20699617 \n9 Barbas AS Rege AS Castleberry AW Gommer J Ellis MJ Brennan TV Posterior reversible encephalopathy syndrome independently\nassociated with tacrolimus and sirolimus after multivisceral\ntransplantation Am J Transplant 2013 13 808 810 23331705 \n10 Touhami S Arzouk N Darugar A Heron E Clarençon F Bodaghi B Everolimus-induced posterior reversible syndrome and bilateral\npotic neuropathy after kidney transplantation Transplantation 2014 98 e102 e104 25955341 \n11 Apuri S Carlin K Bass E Nguyen PT Greene JN Tacrolimus associated posterior reversible encephalopathy\nsyndrome - a case series and review Mediterr J Hematol Infect Dis 2014 6 e2014014 24678391 \n12 Fugate JE Rabinstein AA Posterior reversible encephalopathy syndrome clinical and\nradiological manifestations, pathophysiology, and outstanding\nquestions Lancet Neurol 2015 14 914 925 26184985 \n13 Garg R Posterior leukoenceophalopathy syndrome Postgrad Med J 2001 77 24 28 11123390 \n14 Ay H Buonanno FS Schaefer PW Le DA Wang B Gonzalez RG Posterior leukoencephalopathy without severe hypertension utility\nof diffusion weighted MRI Neurology 1998 51 1369 1376 9818862 \n15 Besenski N Rumboldt Z Emovon O Nicholas J Kini S Milutinovic J Brain MR imaging abnormalities in kidney transplant\nrecipients AJNR Am J Neuroradiol 2005 26 2282 2289 16219834 \n16 Bartynski WS Posterior reversible encephalopathy syndrome, part 1 fundamental\nimaging and clinical features AJNR Am J Neuroradiol 2008 29 1036 1042 18356474 \n17 Bartynski WS Posterior reversible enceolopathy syndrome, part 2 controversies\nsurrounding pathophysiology of vasogenic edema AJNR Am J Neuroradiol 2008 29 1043 1049 18403560 \n18 Stott VL Hurrell MA Anderson TJ Reversible posterior leukoencephalopathy syndrome a misnomer\nreviewed Internal Med J 2005 35 83 90 15705136 \n19 Yamauchi A Ieiri I Kataoka Y Tanabe M Nishizaki T Oishi R Neurotoxicity induced by tacrolimus after liver transplantation\nrelation to genetic polymorphisms of the ABCB1(MDR1) gene Transplantation 2002 74 571 572 12352921\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0101-2800",
"issue": "40(1)",
"journal": "Jornal brasileiro de nefrologia : 'orgao oficial de Sociedades Brasileira e Latino-Americana de Nefrologia",
"keywords": null,
"medline_ta": "J Bras Nefrol",
"mesh_terms": "D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008875:Middle Aged; D054038:Posterior Leukoencephalopathy Syndrome; D011183:Postoperative Complications",
"nlm_unique_id": "9426946",
"other_id": null,
"pages": "91-94",
"pmc": null,
"pmid": "29796585",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11123390;12352921;15705136;16219834;18268188;18272559;18356474;18403560;20699617;21257628;23331705;23460378;24678391;25849670;25955341;26184985;27057842;8559202;9818862",
"title": "Posterior reversible leukoencephalopathy syndrome (PRES) after kidney transplantation: a case report.",
"title_normalized": "posterior reversible leukoencephalopathy syndrome pres after kidney transplantation a case report"
} | [
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"companynumb": "BR-ACCORD-067386",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
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"actiondrug": "1",
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"activesubstancename": "MYCOPHENOLIC ACID"
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"drugadditional": "1",
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{
"abstract": "OBJECTIVE\nFatal adverse drug reactions (ADRs) are important causes of death, but data from resource-limited settings are scarce. We determined the proportion of deaths in South African medical inpatients attributable to ADRs, and their preventability, stratified by human immunodeficiency virus (HIV) status.\n\n\nMETHODS\nWe reviewed the folders of all patients who died over a 30 day period in the medical wards of four hospitals. We identified ADR-related deaths (deaths where an ADR was 'possible', 'probable' or 'certain' using WHO-UMC criteria and where the ADR contributed to death). We determined preventability according to previously published criteria.\n\n\nRESULTS\nADRs contributed to the death of 2.9% of medical admissions and 56 of 357 deaths (16%) were ADR-related. Tenofovir, rifampicin and co-trimoxazole were the most commonly implicated drugs. 43% of ADRs were considered preventable. The following factors were independently associated with ADR-related death: HIV-infected patients on antiretroviral therapy (adjusted odds ratio (aOR) 4.4, 95% confidence interval (CI) 1.6, 12), exposure to more than seven drugs (aOR 2.5, 95% CI 1.3, 4.8) and increasing comorbidity score (aOR 1.3, 95% CI 1.1, 1.7).\n\n\nCONCLUSIONS\nIn our setting, where HIV and tuberculosis are highly prevalent, fatal in-hospital ADRs were more common than reported in high income settings. Most deaths were attributed to drugs used in managing HIV and tuberculosis. A large proportion of the ADRs were preventable, highlighting the need to strengthen systems for health care worker training and support.",
"affiliations": "Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town.;Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town.;Department of Medicine, Cecilia Makiwane Hospital and Walter Sisulu University, East London.;Department of Medicine, Edendale Hospital, Pietermaritzburg, South Africa.;Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town.;Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town.;Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town.;Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town.;Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town.;Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town.",
"authors": "Mouton|Johannes P|JP|;Mehta|Ushma|U|;Parrish|Andy G|AG|;Wilson|Douglas P K|DP|;Stewart|Annemie|A|;Njuguna|Christine W|CW|;Kramer|Nicole|N|;Maartens|Gary|G|;Blockman|Marc|M|;Cohen|Karen|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bcp.12567",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "80(4)",
"journal": "British journal of clinical pharmacology",
"keywords": "South Africa; adverse drug reaction; anti-tuberculosis therapy; antiretroviral therapy; in-hospital death; preventability",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D003430:Cross-Sectional Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006761:Hospitals; D006801:Humans; D007297:Inpatients; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013019:South Africa; D055815:Young Adult",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "818-26",
"pmc": null,
"pmid": "25475751",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "19209224;17439421;16180936;21390458;20673002;10118597;17689801;11576320;16224307;24533894;12389071;11009053;23298396;18070216;18070223;15231615;21701642;9555760;12792009;11606147",
"title": "Mortality from adverse drug reactions in adult medical inpatients at four hospitals in South Africa: a cross-sectional survey.",
"title_normalized": "mortality from adverse drug reactions in adult medical inpatients at four hospitals in south africa a cross sectional survey"
} | [
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"companynumb": "ZA-MYLANLABS-2017M1032557",
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"abstract": "Pneumocystis jirovecii pneumonia (PJP) was reported among immunosuppressed patients with deficits in cell-mediated immunity and in patients treated with immunomodulatory drugs. The aim of this study was to identify risk-factors for PJP in noninfected HIV patients.\n\n\n\nThis retrospective, test negative, case-control study was conducted in six hospitals in Israel, 2006-2016. Cases were hospitalized HIV-negative patients with pneumonia diagnosed as PJP by bronchoalveolar lavage. Controls were similar patients negative for PJP.\n\n\n\nSeventy-six cases and 159 controls were identified. Median age was 63.7 years, 65% males, 34% had hematological malignancies, 11% inflammatory diseases, 47% used steroids and 9% received antilymphocyte monoclonal antibodies. PJP was independently associated with antilymphocyte monoclonal antibodies (OR 11.47, CI 1.50-87.74), high-dose steroid treatment (OR 4.39, CI 1.52-12.63), lymphopenia (OR 8.13, CI 2.48-26.60), low albumin (OR 0.15, CI 0.40-0.54) and low BMI (OR 0.80, CI 0.68-0.93).\n\n\n\nIn conclusion, rituximab, which is prescribed for a wide variety of malignant and inflammatory disorders, was found to be significant risk-factor for PJP. Increased awareness of possible PJP infection in this patient population is warranted.",
"affiliations": "Department of Internal Medicine A, Meir Medical Center, Kfar Saba, Israel.;Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;Department of Internal Medicine A, Meir Medical Center, Kfar Saba, Israel.;Infectious Disease Unit, Hadassah Medical Center, Jerusalem, Israel.;Infectious Disease Unit, Hadassah Medical Center, Jerusalem, Israel.;Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"authors": "Zalmanovich|Anat|A|;Ben-Ami|Ronen|R|;Rahav|Galia|G|;Alon|Danny|D|;Moses|Allon|A|;Olshtain-Pops|Karen|K|;Weinberger|Miriam|M|;Shitrit|Pnina|P|;Katzir|Michal|M|;Gottesman|Bat-Sheva|BS|;Chowers|Michal|M|0000-0001-6148-254X",
"chemical_list": "D000961:Antilymphocyte Serum; D000074322:Antineoplastic Agents, Immunological; D007155:Immunologic Factors; D013256:Steroids; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0239042",
"fulltext": "\n==== Front\nPLoS One\nPLoS ONE\nplos\nplosone\nPLoS ONE\n1932-6203 Public Library of Science San Francisco, CA USA \n\n10.1371/journal.pone.0239042\nPONE-D-20-00026\nResearch Article\nMedicine and Health Sciences\nEpidemiology\nMedical Risk Factors\nCancer Risk Factors\nMedicine and Health Sciences\nOncology\nCancer Risk Factors\nMedicine and Health Sciences\nOncology\nCancers and Neoplasms\nHematologic Cancers and Related Disorders\nMedicine and Health Sciences\nHematology\nHematologic Cancers and Related Disorders\nMedicine and Health Sciences\nOncology\nCancer Treatment\nPhysical Sciences\nChemistry\nChemical Compounds\nOrganic Compounds\nSteroids\nPhysical Sciences\nChemistry\nOrganic Chemistry\nOrganic Compounds\nSteroids\nMedicine and Health Sciences\nClinical Medicine\nSigns and Symptoms\nLymphopenia\nMedicine and Health Sciences\nPharmaceutics\nDrug Therapy\nMedicine and Health Sciences\nMedical Conditions\nInflammatory Diseases\nMedicine and Health Sciences\nOncology\nCancer Treatment\nAntibody Therapy\nMedicine and Health Sciences\nClinical Medicine\nClinical Immunology\nAntibody Therapy\nBiology and Life Sciences\nImmunology\nClinical Immunology\nAntibody Therapy\nMedicine and Health Sciences\nImmunology\nClinical Immunology\nAntibody Therapy\nRituximab identified as an independent risk factor for severe PJP: A case-control study\nPJP in HIV-negative adultsZalmanovich Anat ConceptualizationData curationInvestigationProject administrationWriting – original draft1 Ben-Ami Ronen InvestigationWriting – review & editing23 Rahav Galia InvestigationWriting – review & editing24 Alon Danny InvestigationWriting – review & editing12 Moses Allon InvestigationWriting – review & editing56 Olshtain-Pops Karen InvestigationWriting – review & editing56 Weinberger Miriam InvestigationWriting – review & editing27 Shitrit Pnina ConceptualizationInvestigationWriting – review & editing28 Katzir Michal ConceptualizationInvestigationWriting – review & editing28 Gottesman Bat-Sheva MethodologyWriting – review & editing28 http://orcid.org/0000-0001-6148-254XChowers Michal ConceptualizationFormal analysisWriting – review & editing28* 1 \nDepartment of Internal Medicine A, Meir Medical Center, Kfar Saba, Israel\n2 \nSackler School of Medicine, Tel Aviv University, Tel Aviv, Israel\n3 \nInfectious Disease Unit, Tel Aviv Medical Center, Tel Aviv, Israel\n4 \nInfectious Disease Unit, Sheba Medical Center, Ramat Gan, Israel\n5 \nInfectious Disease Unit, Hadassah Medical Center, Jerusalem, Israel\n6 \nHebrew University of Jerusalem, Jerusalem, Israel\n7 \nInfectious Disease Unit, Assaf Harofeh Medical Center, Be’er Yaakov, Israel\n8 \nInfectious Diseases Unit, Meir Medical Center, Kfar Saba, Israel\nWu Minghua Editor University of Texas McGowan Medical School at Houston, UNITED STATES\nCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: chowersm@post.tau.ac.il\n11 9 2020 \n2020 \n15 9 e02390421 1 2020 28 8 2020 © 2020 Zalmanovich et al2020Zalmanovich et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Objective\nPneumocystis jirovecii pneumonia (PJP) was reported among immunosuppressed patients with deficits in cell-mediated immunity and in patients treated with immunomodulatory drugs. The aim of this study was to identify risk-factors for PJP in noninfected HIV patients.\n\nMethods\nThis retrospective, test negative, case-control study was conducted in six hospitals in Israel, 2006–2016. Cases were hospitalized HIV-negative patients with pneumonia diagnosed as PJP by bronchoalveolar lavage. Controls were similar patients negative for PJP.\n\nResults\nSeventy-six cases and 159 controls were identified. Median age was 63.7 years, 65% males, 34% had hematological malignancies, 11% inflammatory diseases, 47% used steroids and 9% received antilymphocyte monoclonal antibodies. PJP was independently associated with antilymphocyte monoclonal antibodies (OR 11.47, CI 1.50–87.74), high-dose steroid treatment (OR 4.39, CI 1.52–12.63), lymphopenia (OR 8.13, CI 2.48–26.60), low albumin (OR 0.15, CI 0.40–0.54) and low BMI (OR 0.80, CI 0.68–0.93).\n\nConclusion\nIn conclusion, rituximab, which is prescribed for a wide variety of malignant and inflammatory disorders, was found to be significant risk-factor for PJP. Increased awareness of possible PJP infection in this patient population is warranted.\n\nThe author(s) received no specific funding for this work. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nPneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal infection that mostly afflicts immunosuppressed patients with deficits in cell-mediated immunity [1]. PJP was first described in malnourished infants in Europe following World War II [2]. In the 1960s and 1970s, it was diagnosed primarily among patients with hematologic malignancies [3]. From the 1980s until the present, PJP is most often found in patients with advanced AIDS. Other known risk-factors include corticosteroid treatment for various indications [4], solid tumors [1, 5], inflammatory diseases [6], and immunosuppressive drug use following bone marrow and solid organ transplantation [7]. The introduction of active antiretroviral therapy and the use of cotrimoxazole prophylaxis resulted in a dramatic drop in the incidence of PJP among patients with HIV infection. Several studies have reported increased rates of PJP among patients treated with new immunomodulatory drugs (monoclonal antibodies, anti-TNF therapy, tyrosine kinase inhibitors and proteosome inhibitors) [8–12]. Patients in most of these studies were treated with combinations of immunosuppressive drugs; thus, it was impossible to separate the role of each one.\n\nThe prognosis of PJP among patients without HIV is typically worse than in those with HIV, with high rates of in-hospital mortality (50% to 86%, according to some reports [4, 13]), respiratory failure and ICU admission [14]. Due to a tendency for rapid and severe progression, early diagnosis and treatment of PJP is vital. Furthermore, since the diagnosis of PJP is usually established by bronchoalveolar lavage (BAL), a high level of suspicion is needed for early detection and initiation of appropriate treatment.\n\nThe aim of this study was to assess risk-factors for PJP among non-HIV patients.\n\nMethods\nStudy design: This retrospective, test-negative, case-control study was performed at 6 tertiary-level medical centers in Israel. All participating hospitals had a dedicated haemato-oncology department, 5 had stem cell transplantation units, and 5 had solid organ transplantation services. The 6 general hospitals had a total of 5,516 beds, among 15,871 in the entire country (35%). The study was conducted from January 2006 through December 2016.\n\nCase definition: A case was defined as a hospitalized patient with clinical and radiological evidence of pneumonia and a positive direct microscopic examination for PJP (May-Grunwald-Giemsa stain, Gomori-Grocott staining or immunofluorescence) from BAL fluid. All PJP diagnosed by pathology were available, and electronic medical records were reviewed for evidence of pneumonia and HIV status. All cases diagnosed during the study period were followed until discharge.\n\nControls were defined as hospitalized patients with clinical and radiological evidence of pneumonia, for which PJP was excluded by BAL. Controls were matched 2:1 by age and sex to PJP cases. Exclusion criteria were younger than 18 years-of-age and HIV-positive status. HIV negativity was determined based on documentation in the medical records. To minimize false positive results representing PJP colonization, we did not include patients with PJP detected by PCR alone [15, 16].\n\nData extracted from the electronic medical records of cases and controls included demographics, past medical history, presence of an immunosuppressive condition considered a risk-factor for PJP (including hematological malignancies, solid tumors, solid organ transplant, bone marrow transplant and inflammatory disorders), use of immunosuppressant drugs (including corticosteroids with a dosage equivalent to ≥20 mg prednisone for ≥2 weeks, cytotoxic chemotherapy and immunomodulatory drugs) and use of trimethoprim/sulfamethoxazole as prophylactic agents. Laboratory results and clinical outcomes were collected, as well. Due to the large variety of risk-factors in the medical history and the large number of immunosuppressive drugs in use, we grouped drugs and diseases by mechanisms. The complete list is presented in S1 and S2 Tables.\n\nMeir MC review board approved the study approval number 268–16. Tel-Aviv MC review board approved the study, Sheba MC review board approved the study, Hadassah MC review board approved the study, Assaf Harofeh MC review board approved the study, Rabin MC review board approved the study.\n\nNo consent was required, data were analyzed anonymously.\n\nStatistical analyses\nNominal parameters are presented as numbers and percentages. For nominal variables, the study and control groups were compared using Chi-square or Fisher’s exact test, as appropriate. For continuous variables, differences between the groups were determined using Student’s t-test or the Mann-Whitney non-parametric test, according to the distribution of the values. Multivariate logistic regression analysis was conducted including variables significantly associated with PJP on univariate analysis (p<0.1), selecting risk variables among correlated data. All data were analyzed using SPSS-25 software.\n\nResults\nSeventy-six patients met the case definition for non-HIV related PJP and were compared to 159 matched control patients. The average age of both groups was 63 years. Most patients were men, 64% and 67% in the case and control groups, respectively. Demographic, clinical, laboratory and hospitalization outcome data for both groups are presented in Table 1.\n\n10.1371/journal.pone.0239042.t001Table 1 Demographics, medical history, drug, clinical, laboratory, imaging and hospitalization outcomes for case and control groups.\nVariable\tPJP Cases (N = 76)\tNon-PJP Controls (N = 159)\tP-value\t\nMale sex, n (%)\t49 (64.5)\t109 (67.3)\t0.661\t\nMedian (IQR) age (years)\t66 (57–73)\t64 (58–72)\t0.713\t\nBody mass index, kg/m2, median (IQR)\t21 (19–23) (n = 47)\t25 (22–27) (n = 114)\t<0.001\t\nMedical history, n (%)\tHematologic malignancies\t34 (44.7)\t46 (28.9)\t0.017\t\nInflammatory disease\t14 (18.4)\t11 (6.9)\t0.007\t\nSolid tumor\t14 (18.4)\t18 (11.3)\t0.138\t\nOrgan transplant\t7 (9.2)\t33 (20.8)\t0.028\t\nDrugs, n (%)\tCorticosteroidsa\t47 (61.8)\t36 (22.6)\t<0.001\t\nChemotherapy\t28 (36.8\t31 (19.5)\t0.006\t\nRituximab\t12 (15.8)\t8 (5.0)\t0.008\t\nAntimetabolites\t8 (10.5)\t6 (3.8)\t0.072\t\nImmunomodulatory\t2 (2.6)\t5 (3.1)\t0.594\t\nImmunosuppressive\t10 (13.2)\t33 (20.8)\t0.207\t\nKinase inhibitors\t2 (2.6)\t6 (3.8)\t0.727\t\nPreventive therapy for PJP, n (%)\tSulfamethoxazole and trimethoprim\t5 (6.6)\t26 (16.4)\t0.038\t\nSymptoms, n (%)\tCough\t38 (50)\t108 (67.9)\t0.008\t\nFever\t56 (72.4)\t115 (73.0)\t0.925\t\nDyspnea\t58 (76.3)\t110 (67.7)\t0.257\t\nLaboratory results\tWhite blood cells, 106/L\t10.8 ± 20.7\t15.8 ± 24.3\t0.02\t\nHemoglobin, g/L\t10.7 ± 1.74\t11 ± 1.96\t0.187\t\nLymphopenia, <1000/mcl, n (%)\t61 (80.3)\t74 (46.5)\t<0.001\t\nAlbumin, g/dL\t2.7 ± 0.56\t3.2 ± 0.53\t<0.001\t\nC-reactive protein, mg/dL\t13.9 ±8.9\t15.4 ± 10.1\t0.339\t\nLactate dehydrogenase, U/L\t912 ± 907\t713 ± 1682\t0.383\t\nCreatinine, mg/dL\t1.19 ± 0.75\t1.3 ± 0.86\t0.315\t\nImaging, n (%)\tGround glass opacities\t38 (50)\t31 (19.6)\t<0.001\t\nLobar infiltration\t2 (2.6)\t58 (36.7)\t<0.001\t\nOutcomes, n (%)\tVentilation\t46 (63.1)\t70 (44.3)\t0.015\t\nIntensive care unit\t30 (39.5)\t43 (27)\t0.054\t\nMortality\t34 (47.2)\t59 (37)\t0.146\t\nIQR- Interquartile range\n\naCorticosteroids- >20 mg prednisone per day for 2 weeks or more\n\nUnivariate analysis (Table 1), demonstrated that, compared to controls, patients with PJP had a higher incidence of hematologic malignancies (44.7% vs. 28.9%, p = 0.017), and inflammatory diseases (18.4% vs. 6.9%, p = 0.007), and a lower frequency of organ transplantation (9.2% vs. 20.8%, p = 0.028). They were treated more frequently with corticosteroids, (61.8% vs. 22.6%, p < 0.001) chemotherapy (36.8% vs. 19.5%, p = 0.006) and antilymphocyte monoclonal antibodies, mainly rituximab (15.8% vs. 5%, p = 0.008). Fewer were treated with sulfamethoxazole and trimethoprim prophylaxis (6.6% vs. 16.4%, p = 0.038). Patients with PJP had lower body mass index (21 vs. 25, p < 0.001), lower albumin levels (2.7 g/dL vs. 3.2 g/dL, p < 0.001), and greater incidence of lymphopenia (<1000/mcl) (80.3% vs. 46.5%, p < 0.001).\n\nThe in-hospital mortality rate (47.2% vs. 37%, respectively, p = 0.15) was similar in both groups. However, the rate of invasive ventilator support was higher among the PJP cohort (61.3% vs. 44.3%, p = 0.015).\n\nIn multivariate logistic regression analysis for risk factors (Table 2), PJP was independently associated with Rituximab use (OR 11.47 (95%CI 1.5–87.7), p = 0.019), high-dose steroid treatment (OR 4.39 (95%CI 1.52–12.66), p = 0.006), lymphopenia (OR 8.13 (95%CI 2.48–26.61), p = 0.001), low albumin (OR 0.15 (95%CI 0.04–0.54), p = 0.004) and low BMI (OR 0.80 (95%CI 0.68–0.93), p = 0.018).\n\n10.1371/journal.pone.0239042.t002Table 2 Risk factors for PJP based on multivariate logistic regression analysisa.\nRisk factor\tOR\tCI (95%)\tP-value\t\nRituximab\t11.47\t1.5–87.7\t0.019\t\nHigh dose steroidsb\t4.39\t1.52–12.66\t0.006\t\nLymphopenia (<1000/mcl)\t8.13\t2.48–26.61\t0.001\t\nAlbumin (per 1-gram increase)\t0.15\t0.04–0.54\t0.004\t\nBMI\t0.80\t0.68–0.93\t0.018\t\naVariables included: age, sex, BMI, medical history, drugs (steroids, chemotherapy, rituximab, antimetabolites), preventive therapy, lymphopenia, albumin);\n\nbEquivalent to ≥20 mg of prednisone\n\nFollowing the identification of rituximab as a major risk factor for PJP, we present the demographic and clinical data of this cohort of patients, including the time frame from last rituximab treatment to PJP onset (Table 3).\n\n10.1371/journal.pone.0239042.t003Table 3 Demographic and clinical data of PJP patients treated with rituximab.\nSex\tAge\tDiagnosis\tTreatment\tPrevention\tDeath\tDays since treatment\t\nF\t71\tDLBCL\tCHOP\tNo\tNo\t90\t\nM\t70\tDLBCL\tCHOP\tNo\tNo\t36\t\nM\t69\tDLBCL\tCHOP\tNo\tYes\t20\t\nM\t42\tDLBCL\tCHOP\tYes\tNo\t7\t\nM\t68\tDLBCL\tCHOP\tNo\tNo\t7\t\nM\t83\tCLL\tSteroids\tNo\tNo\t27\t\nM\t60\tCLL\tSteroids\tYes\tYes\t13\t\nF\t56\tCLL\tBendamustine\tNo\tYes\t50\t\nM\t74\tAML, ITP\tSteroids\tNo\tNo\t4\t\nM\t52\tALL\tCyclophosphamide\tNo\tNo\t20\t\nF\t68\tANCA vasculitis\tSteroids\tNo\tYes\t30\t\nF\t68\tCNS lymphoma\tSteroids\tNo\tNo\t14\t\nDLBCL-Diffuse large B-cell lymphoma; CHOP-Cyclophosphamide, Doxorubicin, Vincristine, Prednisone; CLL-Chronic lymphocytic leukemia; AML-Acute myelocytic leukemia; ITP-Immune thrombocytopenic purpura; ALL-Acute lymphocytic leukemia; ANCA-Antineutrophil cytoplasmic antibodies; CNS-Central nervous system\n\nDiscussion\nIn this multicenter study of risk factors for PJP in non-HIV patients, antilymphocyte antibodies, mainly rituximab, were found to be the leading risk factor for PJP, with an OR >11. Rituximab, an anti-CD20 antibody was approved in 1997 for B-cell hematological malignancies and autoimmune disorders. In 2007, a black box warning regarding excessive risk for progressive multifocal leukoencephalopathy was issued. Several publications implied a role of rituximab in causing CD4 lymphopenia, although most patients treated with rituximab did not have serial CD4 measurements [17]. Another study on the immunity required for PJP clearance identified a critical role for B cells. In addition to production of PJP-specific antibodies, B-cells are required to prime CD-4 cells for normal expansion and memory generation [18]. The link between rituximab and PJP was reported previously [19]; although, most patients received it as part of combination therapy. Martin-Garrido et al. followed patients treated with rituximab: 30 subsequently developed PJP, but only 3 had been treated with rituximab alone, while the others had received it in combination with either steroids or chemotherapy [19]. In a group of 7,554 rituximab-treated patients in Taiwan, the prevalence of PJP was found to be 2.95%, as compared to 1.3% in controls [20].\n\nIn our cohort of 12 PJP patients treated with rituximab, all developed the disease within 90 days of last treatment. This is in accordance with a short report by Alexandre et al. of 11 similar patients who developed PJP within 11 weeks [21]. Although the numbers are small, this might suggest that long term preventive therapy might not be required.\n\nSteroid use (OR 4.98) is a well-known risk-actor for PJP and an indication for preventive therapy [4]. Of note, the odds for developing PJP were twice as high in patients treated with antilymphocyte antibodies than in those treated with steroids. Low BMI and low albumin are proxies for inadequate nutrition, and thus, are expected risk-factors [2].\n\nMansharamani et al. showed that CD4 <300 denoted a higher risk for PJP infection among immunocompromised patients and recommended they receive prophylaxis [22]. We identified lymphopenia (<1000/mcl) as a risk-factor (OR 7.96), but we did not have CD4 lymphocyte counts for our non-HIV patients.\n\nThis study had several limitations. It included patients whose PJP was diagnosed by microscopy only. Although this diagnostic method decreased the number of false positive results and instances of colonization in the case group, it might have increased the incidence of false negative results in the control group. Due to the retrospective nature of the study, data on BMI were incomplete, and HIV status was not ascertained in the HIV-negative individuals. However, information regarding drug therapy, the primary focus of the study, was retrieved from pharmacy records and thus, was complete.\n\nIn conclusion, rituximab, which is prescribed for a wide variety of malignant and inflammatory disorders, was found to be significant risk-factor for PJP. Increased awareness of possible PJP infection in this patient population is warranted.\n\nSupporting information\nS1 Table Diseases in cases and controls grouped by mechanism.\n(DOCX)\n\nClick here for additional data file.\n\n S2 Table Drugs used in the case group, grouped by mechanism.\n(DOCX)\n\nClick here for additional data file.\n\n Faye Schreiber, MS edited the manuscript. She is an employee of Meir Medical Center.\n==== Refs\nReferences\n1 Sepkowitz KA . Opportunistic infections in patients with and patients without Acquired Immunodeficiency Syndrome\n. Clin Infect Dis . 2002 ;34 (8 ):1098 –107\n. Epub 2002/03/27. 10.1086/339548 .11914999 \n2 Vanek J , Jirovec O . [Parasitic pneumonia. 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Polymerase chain reaction for diagnosing pneumocystis pneumonia in non-HIV immunocompromised patients with pulmonary infiltrates\n. Chest . 2009 ;135 (3 ):655 –61\n. Epub 2009/03/07. 10.1378/chest.08-1309 .19265086 \n16 Wilson JW , Limper AH , Grys TE , Karre T , Wengenack NL , Binnicker MJ . Pneumocystis jirovecii testing by real-time polymerase chain reaction and direct examination among immunocompetent and immunosuppressed patient groups and correlation to disease specificity\n. Diagn Microbiol Infect Dis . 2011 ;69 (2 ):145 –52\n. Epub 2011/01/22. 10.1016/j.diagmicrobio.2010.10.021 .21251557 \n17 Focosi D , Tuccori M , Maggi F . Progressive multifocal leukoencephalopathy and anti-CD20 monoclonal antibodies: What do we know after 20 years of rituximab\n. Rev Med Virol . 2019 :e2077 Epub 2019/08/02. 10.1002/rmv.2077 .31369199 \n18 Opata MM , Hollifield ML , Lund FE , Randall TD , Dunn R , Garvy BA , et al\nB Lymphocytes Are Required during the Early Priming of CD4+ T Cells for Clearance of Pneumocystis Infection in Mice\n. J Immunol . 2015 ;195 (2 ):611 –20\n. Epub 2015/06/05. 10.4049/jimmunol.1500112 \n26041535 \n19 Martin-Garrido I , Carmona EM , Specks U , Limper AH . Pneumocystis pneumonia in patients treated with rituximab\n. Chest . 2013 ;144 (1 ):258 –65\n. Epub 2012/12/22. 10.1378/chest.12-0477 \n23258406 \n20 Wei KC , Sy C , Wu SY , Chuang TJ , Huang WC , Lai PC . Pneumocystis jirovecii pneumonia in HIV-uninfected, rituximab treated non-Hodgkin lymphoma patients\n. Sci Rep . 2018 ;8 (1 ):8321 Epub 2018/05/31. 10.1038/s41598-018-26743-4 \n29844519 \n21 Alexandre K , Ingen-Housz-Oro S , Versini M , Sailler L , Benhamou Y . Pneumocystis jirovecii pneumonia in patients treated with rituximab for systemic diseases: Report of 11 cases and review of the literature\n. Eur J Intern Med . 2018 ;50 :e23 –e4\n. Epub 2017/12/05. 10.1016/j.ejim.2017.11.014 .29198498 \n22 Mansharamani NG , Balachandran D , Vernovsky I , Garland R , Koziel H . Peripheral blood CD4 + T-lymphocyte counts during Pneumocystis carinii pneumonia in immunocompromised patients without HIV infection\n. Chest . 2000 ;118 (3 ):712 –20\n. Epub 2000/09/16. .10988193\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "15(9)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000961:Antilymphocyte Serum; D000074322:Antineoplastic Agents, Immunological; D016022:Case-Control Studies; D005260:Female; D018023:HIV Seronegativity; D019337:Hematologic Neoplasms; D006801:Humans; D007155:Immunologic Factors; D007557:Israel; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D012189:Retrospective Studies; D012307:Risk Factors; D000069283:Rituximab; D013256:Steroids",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0239042",
"pmc": null,
"pmid": "32915907",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "15489347;20583109;29092853;23258406;20367135;10988193;14959297;17934116;22273250;8538233;25148074;11914999;29198498;4589515;26041535;21325762;21251557;31369199;19265086;24440053;29844519;19058233",
"title": "Rituximab identified as an independent risk factor for severe PJP: A case-control study.",
"title_normalized": "rituximab identified as an independent risk factor for severe pjp a case control study"
} | [
{
"companynumb": "IL-TEVA-2020-IL-1861517",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Background: Pemphigus vulgaris is an autoimmune blistering disease affecting the skin and mucous membranes. Current treatments for pemphigus vulgaris include anti-inflammatory and immunosuppressive agents. Rituximab, an anti-CD20 monoclonal antibody, has been shown to be effective for the treatment of pemphigus vulgaris. However, the optimal dosage of rituximab for the treatment of this autoimmune bullous disease has not been clearly defined.The aim of this study was to investigate the clinical efficacy and adverse effects of an ultra-low dosage regimen of rituximab for pemphigus vulgaris.Methods: We performed a prospective non-randomized open case series including eight patients affected by pemphigus vulgaris. Patients were treated with an ultra-low dosage of rituximab (a single infusion of 200 mg).Results: All patients had a positive response after infusion. At the end of the follow-up period, 5 patients achieved a complete remission and 3 a partial remission. Except for one case of sepsis due to Citrobacer freundii and a pneumonia due to Haemophilus influenzae, no adverse events were documented in our patients.Conclusions: Data from our study suggest that an ultra-low dosage of rituximab could be an effective treatment for pemphigus vulgaris. Consequently, there is a need for a larger, confirmatory, randomized, multicenter trial.",
"affiliations": "Unit of Dermatology, University of Padua, Padua, Italy.;Unit of Dermatology, University of Padua, Padua, Italy.;Unit of Dermatology, University of Padua, Padua, Italy.;Unit of Dermatology, University of Padua, Padua, Italy.",
"authors": "Russo|Irene|I|;Miotto|Serena|S|;Saponeri|Andrea|A|;Alaibac|Mauro|M|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000074322:Antineoplastic Agents, Immunological; D001323:Autoantibodies; D051183:Desmoglein 1; D051184:Desmoglein 3; D000069283:Rituximab; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1080/14712598.2020.1727440",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1471-2598",
"issue": "20(6)",
"journal": "Expert opinion on biological therapy",
"keywords": "Pemphigus; autoimmunity; bullous disorders; rituximab; skin",
"medline_ta": "Expert Opin Biol Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents; D000074322:Antineoplastic Agents, Immunological; D001323:Autoantibodies; D051183:Desmoglein 1; D051184:Desmoglein 3; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010392:Pemphigus; D010865:Pilot Projects; D011241:Prednisone; D011446:Prospective Studies; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "101125414",
"other_id": null,
"pages": "673-678",
"pmc": null,
"pmid": "32027810",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ultra-low dose rituximab for refractory pemghigus vulgaris: a pilot study.",
"title_normalized": "ultra low dose rituximab for refractory pemghigus vulgaris a pilot study"
} | [
{
"companynumb": "IT-PFIZER INC-2020076920",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE HYCLATE"
},
"drugadditional": "3",... |
{
"abstract": "BACKGROUND\nAzacitidine is a therapeutic alternative to low-dose cytarabine in patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy.\n\n\nMETHODS\nWe retrospectively analyzed all AML patients treated with azacitidine at the University Hospital Zurich and the Kantonsspital Munsterlingen between January 2005 and December 2011. The primary end point was overall survival (OS).\n\n\nRESULTS\nThirty-eight patients were included in the analysis. Twenty-one (55%) patients had newly diagnosed AML, 14 (37%) had relapsed AML, and 3 (8%) underwent bridging therapy before allogeneic stem-cell transplantation. Age at diagnosis was 72 years in the newly diagnosed cohort and 58 years in the relapsed cohort, 19 (50%) patients were female, 20 (53%) patients were transfusion dependent, and bone marrow blast count was 43% (interquartile range, 26-80). Most patients (58%) had poor or very poor risk AML. Patients received a median (range) of 7 (3-13) therapy cycles. The median (range) OS in the newly diagnosed and previously treated patient groups were 308 (175-580) days and 346 (293-628) days, respectively (P = .94). Median OS in the 3 patients treated before allogeneic stem-cell transplantation has not been reached. Sixty-day mortality was 7.9%, with no difference between the 2 groups. Ongoing or increasing transfusion dependency was associated with adverse outcome (hazard ratio, 3.09; 95% confidence interval, 1.29-7.37, P = .011).\n\n\nCONCLUSIONS\nTreatment with azacitidine led to a median OS of 10 months in both a previously untreated and a previously treated frail AML patient cohort. A positive effect in transfusion dependency was observed in 29% of these patients and was associated with better survival.",
"affiliations": "Division of Hematology, University Hospital and University of Zurich, Zurich, Switzerland.;Department of Internal Medicine, Kantonsspital Munsterlingen, Munsterlingen, Switzerland.;Institute of Primary Care, University Hospital and University of Zurich, Zurich, Switzerland.;Division of Hematology, University Hospital and University of Zurich, Zurich, Switzerland.;Division of Hematology, University Hospital and University of Zurich, Zurich, Switzerland.;Division of Hematology, University Hospital and University of Zurich, Zurich, Switzerland. Electronic address: bernhard.gerber@usz.ch.",
"authors": "Gemuenden|Cornelia|C|;Benz|Rudolf|R|;Senn|Oliver|O|;Goede|Jeroen S|JS|;Manz|Markus G|MG|;Gerber|Bernhard|B|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "15(12)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Acute myeloid leukemia; Azacitidine; Hospitalization; Overall survival; Transfusion",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012189:Retrospective Studies; D033581:Stem Cell Transplantation; D016896:Treatment Outcome",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "811-5",
"pmc": null,
"pmid": "26437871",
"pubdate": "2015-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Efficacy of Azacitidine in De Novo and Relapsed Acute Myeloid Leukemia: A Retrospective Comparative Study.",
"title_normalized": "efficacy of azacitidine in de novo and relapsed acute myeloid leukemia a retrospective comparative study"
} | [
{
"companynumb": "CH-CELGENE-CHE-2015102024",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "Leukocyte adhesion deficiency type III (LADIII) is an autosomal recessive disorder that presents with a severe leukocyte adhesion defect and a Glanzmann-type thrombocytopathy. Hematopoietic stem cell transplantation (HSCT)--the only definitive treatment for LADIII--appears to have a high rate of complications. In this study, we describe a new group of patients with LADIII, highlighting further clinical and immunologic aspects of this disease, and reevaluating the effectiveness of HSCT for its treatment. The patients had clinical and laboratory findings consistent with LADIII. Molecular analysis confirmed the presence of a mutation in the kindlin-3 gene. HSCT was carried out in 3 patients and was successful in 2. The diagnosis of LADIII should be considered in all patients who present with recurrent infections and a bleeding diathesis, regardless of the leukocyte count. LADIII is a primary immune deficiency, which can be successfully corrected by bone marrow transplantation if applied early in the course of the disease using appropriate conditioning.",
"affiliations": "Departments of *Pediatric Hematology-Oncology and Bone Marrow Transplantation ‡Pediatrics §Orthopedic Surgery ∥Medical Imaging, Hadassah - Hebrew University Medical Center, Jerusalem †Laboratory for Leukocyte Functions & The Pediatric Immuno-Hematology Clinic, Meir Medical Center, Kfar Saba and The Sackler School of Medicine, Tel Aviv University, Tel Aviv ¶Meyer Children's Hospital, Rambam Campus, Rappaport Faculty of Medicine, Technion, Haifa, Israel.",
"authors": "Stepensky|Polina Y|PY|;Wolach|Baruch|B|;Gavrieli|Ronit|R|;Rousso|Sharon|S|;Ben Ami|Tal|T|;Goldman|Vladimir|V|;Rozovsky|Katya|K|;Hanna|Suhair|S|;Etzioni|Amos|A|;Weintraub|Michael|M|",
"chemical_list": "C477322:FERMT3 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000228",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "37(4)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D018370:Leukocyte-Adhesion Deficiency Syndrome; D008297:Male; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009504:Neutrophils; D011859:Radiography",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "264-8",
"pmc": null,
"pmid": "25072369",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Leukocyte adhesion deficiency type III: clinical features and treatment with stem cell transplantation.",
"title_normalized": "leukocyte adhesion deficiency type iii clinical features and treatment with stem cell transplantation"
} | [
{
"companynumb": "IL-SA-2016SA041824",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but these conditions are associated with high mortality. There have been few reports of SJS and TEN in children. The aim of this study was to evaluate the clinical features and outcomes of SJS and TEN in a group of Japanese children.\n\n\nMETHODS\nWe retrospectively reviewed pediatric cases of SJS and TEN, from 2000 to 2015.\n\n\nRESULTS\nWe identified 12 pediatric cases of SJS and three of TEN. Six (all SJS) were caused by infection, and eight of the cases (SJS, n = 5; TEN, n = 3) were drug induced. Respiratory complications were the most common in terms of organ involvement, followed by hepatitis and gastrointestinal symptoms. Thirteen patients were treated with systemic corticosteroids, and two patients were treated with supportive therapy only. Concomitant with corticosteroid, four patients were given i.v. immunoglobulin. One patient with severe TEN was treated with systemic corticosteroids combined with plasmapheresis and cyclosporine. None of the present patients died. One patient with TEN had severe sequelae, with bronchiolitis obliterans and ocular involvement.\n\n\nCONCLUSIONS\nSJS/TEN are rare, but are associated with severe complications. General pediatricians need to have up-to-date information regarding these conditions. The present study provides insights into the confirmation of the risk of SJS/TEN as well as the treatment of these diseases.",
"affiliations": "Division of Infectious Diseases and Immunology, Saitama Children's Medical Center, Saitama, Japan.;Division of Ophthalmology, Saitama Children's Medical Center, Saitama, Japan.;Division of Dermatology, Saitama Children's Medical Center, Saitama, Japan.;Division of Infectious Diseases and Immunology, Saitama Children's Medical Center, Saitama, Japan.;Division of Infectious Diseases and Immunology, Saitama Children's Medical Center, Saitama, Japan.;Division of Infectious Diseases and Immunology, Saitama Children's Medical Center, Saitama, Japan.;Division of Infectious Diseases and Immunology, Saitama Children's Medical Center, Saitama, Japan.;Division of Infectious Diseases and Immunology, Saitama Children's Medical Center, Saitama, Japan.",
"authors": "Sato|Satoshi|S|http://orcid.org/0000-0003-0459-4128;Kanbe|Tomoka|T|;Tamaki|Zenshiro|Z|;Furuichi|Mihoko|M|;Uejima|Yoji|Y|;Suganuma|Eisuke|E|;Takano|Tadamasa|T|;Kawano|Yutaka|Y|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents",
"country": "Australia",
"delete": false,
"doi": "10.1111/ped.13613",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1328-8067",
"issue": "60(8)",
"journal": "Pediatrics international : official journal of the Japan Pediatric Society",
"keywords": "Stevens-Johnson syndrome; cyclosporine; i.v. immunoglobulin; toxic epidermal necrolysis",
"medline_ta": "Pediatr Int",
"mesh_terms": "D000293:Adolescent; D000893:Anti-Inflammatory Agents; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007564:Japan; D008297:Male; D012189:Retrospective Studies; D013262:Stevens-Johnson Syndrome; D016896:Treatment Outcome",
"nlm_unique_id": "100886002",
"other_id": null,
"pages": "697-702",
"pmc": null,
"pmid": "29888432",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical features of Stevens-Johnson syndrome and toxic epidermal necrolysis.",
"title_normalized": "clinical features of stevens johnson syndrome and toxic epidermal necrolysis"
} | [
{
"companynumb": "JP-JNJFOC-20180925766",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Although treatments for adult T-cell leukemia/lymphoma in the past two decades have advanced, the current standard treatment for aggressive adult T-cell leukemia/lymphoma, particularly in patients who are not eligible for stem cell transplantation, remains inadequate; therefore, treatments to prolong the duration of remission and provide relevant benefits in terms of survival and quality of life are needed. Adult T-cell leukemia/lymphoma tumor cells express CD30 in some cases and the increased expression of CD30 is considered to be one of the causes of constitutive NF-κB activation in adult T-cell leukemia/lymphoma cells. Brentuximab vedotin represents a major breakthrough in the treatment of CD30-positive lymphomas. Elderly patients treated with chemotherapy generally have higher rates of grade 3 or 4 adverse events; however a retrospective analysis demonstrated the safety and efficacy of brentuximab vedotin in adults ≥60 years with relapsed and refractory CD30-positive lymphomas. We herein report the clinical effects of brentuximab vedotin and the significance of CD30 expression in an elderly refractory/relapse adult T-cell leukemia/lymphoma patient. CD30 expression is associated with disease progression in adult T-cell leukemia/lymphoma patients and brentuximab vedotin may be a new and promising treatment option for these patients. Further investigations on the use of brentuximab vedotin for adult T-cell leukemia/lymphoma are needed.",
"affiliations": "Division of Hematology, Japanese Red Cross Society Wakayama Medical Center, Wakayama.;Division of Pathology, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan.;Division of Hematology, Japanese Red Cross Society Wakayama Medical Center, Wakayama.",
"authors": "Oka|Satoko|S|;Ono|Kazuo|K|;Nohgawa|Masaharu|M|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000079963:Brentuximab Vedotin",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000895",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "31(5)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D000079963:Brentuximab Vedotin; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D016879:Salvage Therapy",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "536-539",
"pmc": null,
"pmid": "31934889",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment with brentuximab vedotin for relapsed and refractory adult T cell leukemia.",
"title_normalized": "successful treatment with brentuximab vedotin for relapsed and refractory adult t cell leukemia"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-297195",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
... |
{
"abstract": "Eight patients with secondary leukemia and specific cytogenetic abnormalities involving inversion of chromosome 16, or translocations between chromosomes 15 and 17, or 8 and 21, are presented. Seven of them (87%) achieved complete remission with chemotherapy. The occurrence of these karyotypes, which is unusual in secondary leukemia, and the favorable response to chemotherapy are discussed in relation to the pathogenesis of the disease.",
"affiliations": null,
"authors": "Kantarjian|H M|HM|;Keating|M J|MJ|;Walters|R S|RS|;Beran|M|M|;McLaughlin|P|P|;McCredie|K B|KB|;Freireich|E J|EJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/1097-0142(19860815)58:4<924::aid-cncr2820580420>3.0.co;2-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "58(4)",
"journal": "Cancer",
"keywords": null,
"medline_ta": "Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001853:Bone Marrow; D002869:Chromosome Aberrations; D007446:Chromosome Inversion; D005260:Female; D006801:Humans; D007938:Leukemia; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011379:Prognosis; D014178:Translocation, Genetic",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "924-7",
"pmc": null,
"pmid": "3719557",
"pubdate": "1986-08-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "The association of specific \"favorable\" cytogenetic abnormalities with secondary leukemia.",
"title_normalized": "the association of specific favorable cytogenetic abnormalities with secondary leukemia"
} | [
{
"companynumb": "US-PFIZER INC-2018152567",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
... |
{
"abstract": "The higher incidence of immunosuppressive status is increasing in the last years the diagnosis of tumours of unusual location and behaviour. We present the case of a HIV-seropositive 41 years-old woman, bearing of high dysphagia and pharyngolalic voice. The exploration showed a tumour emerging in lingual tonsil and spreading out to hypopharynx and larynx. No lymph nodes were observed. Its resistance to chemotherapy made necessary its surgical removal.",
"affiliations": "Servicio de ORL, Departamento de Cirugía, Hospital Clínico Universitario, Valencia.",
"authors": "García Callejo|F J|FJ|;Morant Ventura|A|A|;Tormos|M M|MM|;Marco Algarra|J|J|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.1016/s0001-6519(03)78392-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-6519",
"issue": "54(2)",
"journal": "Acta otorrinolaringologica espanola",
"keywords": null,
"medline_ta": "Acta Otorrinolaringol Esp",
"mesh_terms": "D000328:Adult; D002051:Burkitt Lymphoma; D003680:Deglutition Disorders; D019008:Drug Resistance, Neoplasm; D005260:Female; D006679:HIV Seropositivity; D006801:Humans; D014066:Palatine Tonsil",
"nlm_unique_id": "14540260R",
"other_id": null,
"pages": "109-12",
"pmc": null,
"pmid": "12802986",
"pubdate": "2003-02",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Upper dysphagia due to a chemotherapy resistant Burkitt's lymphoma in a lingual tonsil.",
"title_normalized": "upper dysphagia due to a chemotherapy resistant burkitt s lymphoma in a lingual tonsil"
} | [
{
"companynumb": "ES-CHEPLA-C20213038",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Biliary sludge and/or biliary pseudolithiasis occur in patients treated with ceftriaxone with prevalence of 3-57%. Biliary obstruction can be the cause of the acute gallbladder enlargement. It is a minor complication, that usually does not give clinical symptoms and resolves once the drug is discontinued. The authors present a case of a 5-month old boy treated for the acute pyelonephritis. Routine ultrasound, performed on the 5th day of treatment with ceftriaxone, showed gallbladder enlargement. In the consecutive studies small gallblader sludge was visible. Patient had no symptoms related to the gallbladder enlargement. Ultrasound performed 6 weeks from the drug discontinuation was completely normal.\n\n\nCONCLUSIONS\nPatients treated with ceftroiaxone should be monitored for biliary sludge and pseudolithiasis.",
"affiliations": "Department of Pediatrics and Nephrology, The Medical University of Warsaw, Poland.;Department of Pediatrics and Cardiology, The Medical University of Warsaw, Poland.;Department of Pediatrics and Nephrology, The Medical University of Warsaw, Poland.;Department of Pediatrics Radiology, The Medical University of Warsaw, Poland.;Department of Pediatrics and Nephrology, The Medical University of Warsaw, Poland.;Department of Pediatrics and Cardiology, The Medical University of Warsaw, Poland.;Department of Pediatrics Radiology, The Medical University of Warsaw, Poland.",
"authors": "Krzemień|Grażyna|G|;Książczyk|Tomasz|T|;Szmigielska|Agnieszka|A|;Bombiński|Przemysław|P|;Roszkowska-Blaim|Maria|M|;Werner|Bożena|B|;Brzewski|Michał|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1428-345X",
"issue": "19(2)",
"journal": "Developmental period medicine",
"keywords": null,
"medline_ta": "Dev Period Med",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001646:Bile; D002443:Ceftriaxone; D005705:Gallbladder Diseases; D006801:Humans; D007223:Infant; D008297:Male; D011704:Pyelonephritis; D014463:Ultrasonography; D014552:Urinary Tract Infections",
"nlm_unique_id": "101636421",
"other_id": null,
"pages": "182-5",
"pmc": null,
"pmid": "26384120",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ceftriaxone-associated acute gallbladder enlargement - an unexpected diagnosis in the child with urinary tract infection.",
"title_normalized": "ceftriaxone associated acute gallbladder enlargement an unexpected diagnosis in the child with urinary tract infection"
} | [
{
"companynumb": "PL-LUPIN PHARMACEUTICALS INC.-2015-03945",
"fulfillexpeditecriteria": "2",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditiona... |
{
"abstract": "We report the case of an 82-year-old female diagnosed with HER2-negative, hormone receptor (HR)-positive metastatic breast cancer. Upon biochemical disease progression of the initially HR-receptor positive disease under anti-hormonal treatment with tamoxifen and letrozole, she received combination chemotherapy with paclitaxel/gemcitabine. Due to her suffering from severe toxicity, therapy was switched to nab-paclitaxel/gemcitabine. From April 22, 2013, to July 15, 2013, the patient received 5 cycles of nab-paclitaxel/gemcitabine as a 30-min infusion every 3 weeks, with excellent biochemical responses to treatment. Tumor marker levels as well as bilirubin were reduced to baseline levels. Chemotherapy with nab-paclitaxel/gemcitabine was well tolerated. At a follow-up visit immediately after the end of chemotherapy, the patient reported well-being and presented with a Karnofsky performance status (KPS) of 100%. At the last follow-up in October 2013, she was alive with multiple metastatic sites in the liver and bone metastases in the spine without risk of fracture and a KPS of 90%. She has received palliative single agent chemotherapy with capecitabine (14/7 regimen, 1,500 mg b.i.d.) since August 2013 and continued to show a good biochemical treatment response at the last follow-up in October 2013. Since August 2013, the patient has also received denosumab (120 mg sc, q4w) for her metastatic bone disease. As of July 2014, treatment has not been changed and the patient reports her well-being.",
"affiliations": "MVZ MOP Elisenhof, Munich, Germany.",
"authors": "Völkl|Siegfried J|SJ|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000367782",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000367782cro-0007-0638Published online: September, 2014Excellent Biochemical Response to Polychemotherapy with Nab-Paclitaxel/Gemcitabine in an 82-Year-Old Female with Metastatic Breast Cancer Völkl Siegfried J. *MVZ MOP Elisenhof, Munich, Germany*Dr. med. Siegfried Völkl, Innere Medizin Hämatologie und Internistische Onkologie, Prielmayerstr. 1, DE-80335 München (Germany) E-Mail voelklsi@gmail.comSep-Dec 2014 17 9 2014 17 9 2014 7 3 638 642 Copyright © 2014 by S. Karger AG, Basel2014This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.We report the case of an 82-year-old female diagnosed with HER2-negative, hormone receptor (HR)-positive metastatic breast cancer. Upon biochemical disease progression of the initially HR-receptor positive disease under anti-hormonal treatment with tamoxifen and letrozole, she received combination chemotherapy with paclitaxel/gemcitabine. Due to her suffering from severe toxicity, therapy was switched to nab-paclitaxel/gemcitabine. From April 22, 2013, to July 15, 2013, the patient received 5 cycles of nab-paclitaxel/gemcitabine as a 30-min infusion every 3 weeks, with excellent biochemical responses to treatment. Tumor marker levels as well as bilirubin were reduced to baseline levels. Chemotherapy with nab-paclitaxel/gemcitabine was well tolerated. At a follow-up visit immediately after the end of chemotherapy, the patient reported well-being and presented with a Karnofsky performance status (KPS) of 100%. At the last follow-up in October 2013, she was alive with multiple metastatic sites in the liver and bone metastases in the spine without risk of fracture and a KPS of 90%. She has received palliative single agent chemotherapy with capecitabine (14/7 regimen, 1,500 mg b.i.d.) since August 2013 and continued to show a good biochemical treatment response at the last follow-up in October 2013. Since August 2013, the patient has also received denosumab (120 mg sc, q4w) for her metastatic bone disease. As of July 2014, treatment has not been changed and the patient reports her well-being.\n\nKey Words\nMetastatic breast cancerLiver metastasesBone metastasesChemotherapyElevated bilirubin levelsNab-paclitaxel\n==== Body\nIntroduction\nStage IV breast cancer (metastatic breast cancer, MBC) is still an uncurable disease with a median 5-year overall survival rate of 25% [1]. However, this figure does not reflect the broad range of different courses of MBC with patients surviving only a few months, and others having a chronic disease for many years. The most important treatment issues in patients with MBC are to control the disease and its symptoms and to maintain the patients’ quality of life as long as possible. There are many treatment options for patients in the metastatic setting. To select the appropriate therapy, the individual patient and the special situation of her illness as well as her personal wishes must be respected. In elderly patients, comorbidities and performance status influence the available and feasible treatment possibilities.\n\nEndocrine therapy alone is the first therapy of choice for patients with hormone receptor-positive, HER2-negative MBC. After the failure of anti-hormonal agents (anti-estrogens, aromatase inhibitors) and/or rapid progression of existing metastases or new metastastic sites, either single-agent or combination chemotherapy is recommended. The choice of treatment depends on the aggressiveness of the disease, metastatic sites and individual factors such as age, comorbidities and performance status of the patient. In this palliative setting, chemotherapy remains the mainstay of treatment.\n\nApart from disease control, one crucial treatment goal in this non-curative setting must be maintaining the patient's quality of life. Anthracyclines and/or taxanes are recommended agents for first-line treatment. A new treatment option is nab-paclitaxel (nanoparticle albumin-bound paclitaxel). Although it is currently approved for second-line treatment after the failure of anthracycline-based chemotherapy [2], nab-paclitaxel can also be a possible therapeutic approach in first-line treatment, especially in a weekly schedule [3].\n\nAlbumin-bound paclitaxel with a mean particle size of 130 nm has significant practical advantages compared to solvent-based taxanes. It can be administered without antiallergic premedication and shows favorable linear pharmacokinetic characteristics. With albumin as the transport protein for the cytotoxic agent, albumin-specific pathways and mechanisms are used for nab-paclitaxel to gain access to the tumor interstitium [4, 5, 6].\n\nCase Report\nAn 82-year-old woman was diagnosed with an invasive ductal adenocarcinoma of the left breast in November 2012. TNM classification was cT4 cN1 M1 (hep). The tumor was well differentiated (G2), hormone receptor positive (OR 95%, PR 30%) and HER2 negative. The patient received antihormonal treatment with the antiestrogen tamoxifen 20 mg (once/day) from November 21, 2012, until February 5, 2013. While bilirubin levels remained low during that period (1.0 mg/dl at baseline, 0.8 mg/dl on February 5, 2013), tumor marker levels of CA 15–3 and CEA increased from 1,068 U/ml (CA 15–3) and 13.9 ng/ml (CEA) to 2,779 U/ml and 43.5 ng/ml, respectively. Due to this biochemical disease, progression therapy was switched to the nonsteroidal aromatase-inhibitor letrozole on February 5, 2013, upon which tumor marker levels continued to rise and bilirubin levels doubled, indicating a resistance to the antihormonal treatment and active growing process in the liver. Therefore, letrozole was discontinued and a taxane-based combination chemotherapy was started.\n\nThe first course of chemotherapy consisting of gemcitabine 1,000 mg/m2 and paclitaxel 200 mg/m2 was administered on March 18, 2013. No response was observed, but progressive disease with a remarkable surge in tumor marker and bilirubin levels with a peak of 6,982 U/ml in CA 15–3 levels, 127.6 ng/ml in CEA levels and 13.1 mg/dl in bilirubin levels on April 3, 2013. The patient developed a severe mucositis from March 28 until April 11. The oral symptoms made swallowing and, as a consequence, eating and drinking extremely painful, and her quality of life was dramatically reduced. Due to the progression of the disease and the painful mucositis, we stopped the treatment with paclitaxel/gemcitabine.\n\nOn April 22, 2013, after the severe mucositis had disappeared and symptoms had receded, we started a new therapy with nab-paclitaxel 200 mg/m2 and gemcitabine 1,000 mg/m2 every 3 weeks. On April 11, tumor marker and bilirubin levels had gone to 4,232 U/ml (CA 15–3), 74. 3 ng/ml (CEA) and 3.8 mg/dl (bilirubin) and continued to decline during the 5 further cycles of nab-paclitaxel/gemcitabine. Treatment with nab-paclitaxel/gemcitabine was tolerated well, with no severe toxicity, and especially no neurotoxicity was observed. On June 24, 2013, the CA 15–3 level was reduced to 947 U/ml, the CEA level to 12.7 ng/ml, and the bilirubin level was at 0.7 mg/dl. All biochemical parameters were below baseline. Due to the patient‘s excellent tolerance of the applied dose of 200 mg/m2 nab-paclitaxel in combination with gemcitabine, the nab-paclitaxel dosage was escalated to 300 mg/m2 on June 24, 2013, for the 4th cycle of chemotherapy. By July 15, 2013, bilirubin levels had been reduced even further to 0.5 mg/dl, CA 15–3 level was at 770 U/ml, and CEA level was 14.3 ng/ml (see table 1). On July 15, the patient received the last cycle of nab-paclitaxel/gemcitabine, and treatment was still tolerated well, without any neurotoxicity. On a follow-up visit on July 19, 2013, the patient reported her well-being and presented with a Karnofsky performance status (KPS) of 100%. She had no edema and no palpable enlarged lymph nodes.\n\nRestaging examinations at the end of July showed a stable disease of the known primary tumor, and the liver metastases revealed multiple small ossary metastases in the spine as well as in the os sacrum and os ilium. A restaging CT performed on July 22, 2013, showed multiple liver metastases with partly irregular borders (multiple metastatic sites in the liver) in all segments and multiple small bone metastases in the spine without discernible fracture risk. A restaging mammography performed on July 22, 2013, showed the tumor in the left breast (BI-RADS assessment category 5) without infiltrations in the chest wall and axilla. A bone scan performed on July 29, 2013, revealed 3 vertebrae in need of further assessment upon which an MRI scan was done on August 5, 2013. It showed the same metastatic sites in the thoracic and lower spine without any risk of fracture or further damaging the existing fractures. Therapy with nab-paclitaxel had stabilized tumor and metastases, and disease symptoms were well controlled. On August 27, 2013, the patient was started on single-agent chemotherapy with capecitabine (14/7 regimen, 1,500 mg b.i.d.) and denosumab 120 mg s.c. every 4 weeks as well as calcium and vitamin D for the metastatic bone disease.\n\nRestaging with various imaging modalities on October 22, 2013, showed stable disease of the tumor in the breast as well as of all metastatic sites: an upper abdominal ultrasound scan showed no enlarged lymph nodes and no relevant changes compared to the abdominal scan performed in July. Her breast ultrasound confirmed the known tumor in the left breast without enlarged or pathologic lymph nodes in the left axilla. Chest and abdominal CT scans showed no pulmonary metastases and confirmed stable disease of the liver metastases. No involvement of the left axilla was observed. Ossary metastases were reported to be stable without fractures or larger osteolysis.\n\nBiochemical response to treatment was good with bilirubin levels remaining at 0.7 mg/dl. Tumor marker levels of CA 15–3 were reduced to 280 U/ml. At a follow-up visit, the patient presented with a KPS of 90% and reported a subjective well-being.\n\nAs of July 2014, the patient still receives capecitabine and denosumab and continues to show stable disease.\n\nDiscussion\nIn Germany, nab-paclitaxel is currently approved for the treatment of MBC after failure of first-line chemotherapy and for whom anthracycline-containing chemotherapy is not indicated [7]. Relevant to everyday clinical practice is the more favorable safety profile of nab-palitaxel compared to the solvent-based, conventional paclitaxel [8]. Maintaining the patient‘s quality of life is crucial in the metastatic, non-curative setting. Since our patient developed severe mucositis and wanted to discontinue chemotherapy, good tolerability was one of the main aspects in the choice of the subsequent chemotherapy. Roy et al. [9] reported significant antitumor activity and a favorable toxicity profile of weekly nab-paclitaxel/gemcitabine in 50 previously untreated patients with MBC. Although our patient was pretreated with conventional paclitaxel with considerable mucosal toxicity, we observed an excellent tolerability of nab-paclitaxel/gemcitabine as well as a considerable efficacy in our patient. Excellent biochemical response was achieved with all parameters reverting to levels below base line. Remarkably, the 82-year-old patient presented with a KPS of 100% after the end of all 5 cycles of nab-paclitaxel/gemcitabine.\n\nDespite metastatic disease in the liver and elevated bilirubin levels, treatment with nab-paclitaxel/gemcitabine was very well tolerated and no neuropathy or recurrent mucositis was observed. Our findings suggest that patients with elevated bilirubin up to 10 mg/ml can be safely treated with nab-paclitaxel/gemcitabine with the initially reduced nab-paclitaxel dosage being escalated in the course of the treatment.\n\nTable 1 Bilirubin- and tumor marker levels during anti-hormonal treatment and chemotherapy\n\n\tCA 15-3 (U/ml)\tCEA (ng/ml)\tBilirubin (mg/dl)\t\nTamoxifen\t\n November 29, 2012\t1,068\t013.9\t01.0\t\n January 22, 2013\t2,102\t031.4\t00.7\t\nLetrozole\t\n March 6, 2013\t4,121\t082.5\t02.0\t\nPaclitaxel/gemcitabine\t\n April 3, 2013\t6,982\t127.6\t13.1\t\nNab-paclitaxel/gemcitabine\t\n April 22, 2013\t3,694\t048.3\t01.6\t\n May 13, 2013\t1,651\t023.8\t00.9\t\n June 3, 2013\t1,259\t015.8\t00.9\t\n July 15, 2013\t0.770\t014.3\t00.5\n==== Refs\nReferences\n1 Howlader N Noone AM Krapcho M Garshell J Neyman N Altekruse SF Kosary CL Yu M Ruhl J Tatalovich Z Cho H Mariotto A Lewis DR Chen HS Feuer EJ Cronin KA SEER Cancer Statistics Review 1975–2011 2014 Bethesda National Cancer Institute http://seer.cancer.gov/csr/1975_2011/ \n2 Gradishar WJ Tjulandin S Davidson N Phase III trial of nanoparticle albumin bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer J Clin Oncol 2005 23 7794 7803 16172456 \n3 Gradishar WJ Krasnojon D Cheporov S Phase II trial of nab -paclitaxel compared with docetaxel as first-line chemotherapy in patients with metastatic breast cancer: final analysis of overall survival Clin Breast Cancer 2012 12 313 321 22728026 \n4 Kiessling F Nab -paclitaxel has demonstrated greater efficacy and an improved safety profile compared to conventional solvent based paclitaxel Invest Radiol 2002 37 193 198 11923641 \n5 Desai NP Trieu V Hwang LY Improved effectiveness of nanoparticle albumin-bound (nab ) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status Anticancer Drugs 2008 19 899 909 18766004 \n6 Gradishar WJ Tjulandin S Davidson N Phase III trial of nanoparticle albumin bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer J Clin Oncol 2005 23 7794 7803 16172456 \n7 Product Information Abraxane 5 mg/ml for suspension for infusion Uxbridge Celgene Europe Limited http://www.celgene.co.uk/ \n8 Gradishar WJ Tjulandin S Davidson N Phase III trial of nanoparticle albumin bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer J Clin Oncol 2005 23 7794 7803 16172456 \n9 Roy V Laplant BE Gross GG Phase II trials of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane® ) in combination with gemcitabine in patients with metastatic breast cancer (N0531) Ann Oncol 2009 20 449 453 19087987\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "7(3)",
"journal": "Case reports in oncology",
"keywords": "Bone metastases; Chemotherapy; Elevated bilirubin levels; Liver metastases; Metastatic breast cancer; Nab-paclitaxel",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "638-42",
"pmc": null,
"pmid": "25408657",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports",
"references": "16172456;18766004;19087987;22728026",
"title": "Excellent biochemical response to polychemotherapy with nab-paclitaxel/gemcitabine in an 82-year-old female with metastatic breast cancer.",
"title_normalized": "excellent biochemical response to polychemotherapy with nab paclitaxel gemcitabine in an 82 year old female with metastatic breast cancer"
} | [
{
"companynumb": "DE-DRREDDYS-GER/GER/18/0106163",
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"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,... |
{
"abstract": "Fatal pulmonary hypertension developed in an infant during the 7-month period in which he received, via a central venous catheter, combination chemotherapy for stage IV neuroblastoma as well as intermittent parenteral feeding. In a lung biopsy and at autopsy, small pulmonary arteries showed diffuse medial hypertrophy and peripheral muscularization, very extensive concentric intimal fibrosis, and focal eccentric fibrosis evolving from organizing thrombi. Pulmonary veins were normal. Hypothetically, chemotherapeutic drug therapy (possibly potentiated either by the parenteral nutrition or simply by the vehicular fluids causing volume loading of the pulmonary circulation) could cause occlusive pulmonary arterial disease by several mechanisms, but the association has not been described previously, although use of such drugs has been reported with pulmonary veno-occlusive disease.",
"affiliations": "Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.",
"authors": "Bentur|L|L|;Cullinane|C|C|;Wilson|P|P|;Greenberg|M|M|;O'Brodovich|H|H|;Silver|M M|MM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/0046-8177(91)90116-7",
"fulltext": null,
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"issn_linking": "0046-8177",
"issue": "22(12)",
"journal": "Human pathology",
"keywords": null,
"medline_ta": "Hum Pathol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001157:Arterial Occlusive Diseases; D006801:Humans; D006976:Hypertension, Pulmonary; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D010288:Parenteral Nutrition; D011651:Pulmonary Artery",
"nlm_unique_id": "9421547",
"other_id": null,
"pages": "1295-8",
"pmc": null,
"pmid": "1748437",
"pubdate": "1991-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal pulmonary arterial occlusive vascular disease following chemotherapy in a 9-month-old infant.",
"title_normalized": "fatal pulmonary arterial occlusive vascular disease following chemotherapy in a 9 month old infant"
} | [
{
"companynumb": "CA-PFIZER INC-2015275828",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Human C1q deficiency is frequently associated with systemic lupus erythematosus (SLE), which requires long-term systemic corticosteroid administration. We report the case of a 12-year-old female patient with C1q deficiency presenting with intractable SLE who successfully underwent bone marrow transplantation from a human leukocyte antigen (HLA)-mismatched unrelated donor with an immunosuppressive conditioning regimen based on fludarabine, melphalan, and anti-thymocyte globulin. She developed Grade I graft-versus-host disease, but did not have any transplantation-related morbidity. Complete donor chimerism has been maintained for 2 years after transplantation, leading to the restoration of C1q levels and the resolution of SLE symptoms. Normal C1q mRNA expression was observed in CD14 + cells. Hematopoietic stem cell transplantation from an HLA-mismatched donor is a feasible treatment for patients with C1q deficiency with refractory SLE that is dependent on systemic corticosteroid treatment who do not have an HLA-matched donor.",
"affiliations": "Department of Pediatrics, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. rmats@hiroshima-u.ac.jp.;Department of Pediatrics, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Pediatrics, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Pediatrics, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Pediatrics, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Pediatrics, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.;Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Pediatrics, Tsuyama Central Hospital, Tsuyama, Okayama, Japan.;Department of Pediatrics, National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Pediatric Hematology and Oncology, Okayama University Hospital, Okayama, Japan.;Department of Pediatrics, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.",
"authors": "Matsumura|Risa|R|http://orcid.org/0000-0002-4871-928X;Mochizuki|Shinji|S|;Maruyama|Natsuki|N|;Morishita|Yusuke|Y|;Kawaguchi|Hiroshi|H|;Okada|Satoshi|S|;Tsumura|Miyuki|M|;Kaji|Shunsaku|S|;Shimizu|Junya|J|;Shimada|Akira|A|;Kobayashi|Masao|M|",
"chemical_list": "D006680:HLA Antigens; D015922:Complement C1q",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-020-03004-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "113(2)",
"journal": "International journal of hematology",
"keywords": "C1q deficiency; Hematopoietic stem cell transplantation; Systemic lupus erythematosus",
"medline_ta": "Int J Hematol",
"mesh_terms": "D016026:Bone Marrow Transplantation; D002648:Child; D015922:Complement C1q; D019468:Disease Management; D004198:Disease Susceptibility; D005260:Female; D006086:Graft vs Host Disease; D006680:HLA Antigens; D006650:Histocompatibility Testing; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D061349:Unrelated Donors",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "302-307",
"pmc": null,
"pmid": "33000368",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7499868",
"title": "Bone marrow transplantation from a human leukocyte antigen-mismatched unrelated donor in a case with C1q deficiency associated with refractory systemic lupus erythematosus.",
"title_normalized": "bone marrow transplantation from a human leukocyte antigen mismatched unrelated donor in a case with c1q deficiency associated with refractory systemic lupus erythematosus"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-290583",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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{
"abstract": "Myeloid neoplasms and eosinophilia with rearrangements of PDGFRB are uncommon Philadelphia-negative myeloproliferative neoplasms. Patients are typically male, with morphologic features of a Philadelphia-negative chronic myeloproliferative syndrome or chronic myelomonocytic leukemia with eosinophilia. Reciprocal translocations involving PDGFRB result in fusion genes with constitutively activated receptor tyrosine kinase sensitive to inhibition with imatinib. We present an updated and expanded analysis of a cohort of 26 such patients treated with imatinib. After a median follow-up of 10.2 years (range, 1.8-17 years), the 10-year overall survival rate was 90% (95% confidence interval, 64%-97%); after median imatinib duration of 6.6 years (range, 0.1-12 years), the 6-year progression-free survival rate was 88% (95% confidence interval, 65%-96%). Of the patients, 96% responded; no patients who achieved a complete cytogenetic (n = 13) or molecular (n = 8) remission lost their response or progressed to blast crisis. Imatinib is well-tolerated and achieves excellent long-term responses in patients with PDGFRB rearrangements.",
"affiliations": "Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; University of Melbourne, Parkville, VIC, Australia;;Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; University of Melbourne, Parkville, VIC, Australia;;Department of Haematology, Faculty of Medicine, Imperial College London, London, United Kingdom;;Department of Haematology, Centre Hospitalier Universitaire, Toulouse, France;;Oncologia Medica e Trapianto di Midollo Osseo, Messina, Italy;;Department of Haematology, Centre Hospitalier Universitaire, Angers, France;;Haematology, South Australia Pathology, Adelaide, SA, Australia; School of Medicine, University of Adelaide, Adelaide, SA, Australia; School of Medicine, Flinders University, Adelaide, SA, Australia;;British Columbia Cancer Agency, Vancouver, BC, Canada;;Department of Haematology, Hôpital Victor Dupouy, Argenteuil, France;;Department of Haematology, Hôpital de Versailles and Université de Versailles Saint-Quentin, Le Chesnay, France;;Department of Haematology, Auckland City Hospital, Auckland, New Zealand;;Department of Haematology, St. James's University Hospital, Leeds, United Kingdom;;Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD;;Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD;;Department of Medicine, University of Texas Health Science Center, San Antonio, TX; Audie Murphy Veterans Affairs Hospital, San Antonio, TX;;Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL;;Northshore University Health Systems, Chicago, IL;;Faculty of Medicine, University of Southampton, Southampton, United Kingdom.;Department of Haematology, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; University of Melbourne, Parkville, VIC, Australia;",
"authors": "Cheah|Chan Y|CY|;Burbury|Kate|K|;Apperley|Jane F|JF|;Huguet|Francoise|F|;Pitini|Vincenzo|V|;Gardembas|Martine|M|;Ross|David M|DM|;Forrest|Donna|D|;Genet|Philippe|P|;Rousselot|Philippe|P|;Patton|Nigel|N|;Smith|Graeme|G|;Dunbar|Cynthia E|CE|;Ito|Sawa|S|;Aguiar|Ricardo C T|RC|;Odenike|Olatoyosi|O|;Gimelfarb|Alla|A|;Cross|Nicholas C P|NC|;Seymour|John F|JF|",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2014-02-555607",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "123(23)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D001549:Benzamides; D002648:Child; D002675:Child, Preschool; D004802:Eosinophilia; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007223:Infant; D007951:Leukemia, Myeloid; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D020797:Receptor, Platelet-Derived Growth Factor beta; D012074:Remission Induction; D014178:Translocation, Genetic; D055815:Young Adult",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "3574-7",
"pmc": null,
"pmid": "24687085",
"pubdate": "2014-06-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "18307562;17666373;12745287;8168137;11919393;22587685;22705991;23704092;17508004;12907457;15087377;15956284;17122866;16960151;12660384;23976869;24186319;19006078;12181402;15496975;20965785;15477214;14504072;12130532;18262053",
"title": "Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib.",
"title_normalized": "patients with myeloid malignancies bearing pdgfrb fusion genes achieve durable long term remissions with imatinib"
} | [
{
"companynumb": "PHHY2014AU080121",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadditional": null,
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{
"abstract": "BACKGROUND\nIntrapartum single-dose (SD) nevirapine (NVP) reduces perinatal transmission of human immunodeficiency virus (HIV) infection but selects for NVP-resistant virus, which compromises subsequent NVP-based therapy. A 1-week \"tail\" of lamivudine and zidovudine after SD-NVP decreases the risk of resistance. We hypothesized that increasing the duration or potency of the tail would further reduce this risk to <10%, using a sensitive assay to measure resistance.\n\n\nMETHODS\nHIV-infected pregnant Thai women with a CD4 cell count >250 cells/μL, most receiving zidovudine, were randomized at 28-38 weeks gestation to receive 1 of 3 intrapartum and postpartum regimens: (A) zidovudine plus enteric-coated didanosine plus lopinavir and ritonavir for 7 days, (B) zidovudine plus enteric-coated didanosine for 30 days, or (C) regimen 1 for 30 days. The incidence of NVP resistance mutations at day 10 or week 6 post partum in each arm was compared with that of a historical comparison group who received prenatal zidovudine and SD-NVP. NVP resistance was identified by consensus sequencing and a sensitive oligonucleotide ligation assay (OLA).\n\n\nRESULTS\nAt entry, the 169 participants had a median CD4 cell count of 456 cells/μL and an HIV load of 3.49 log(10) copies/mL. The incidence of mutations in each of the 3 P1032 arms was 0% by sequencing and 1.8%, 7.1%, and 5.3% by OLA in arms A, B, and C, respectively, compared with 13.4% by sequencing and 29.4% by OLA in the comparison group (P < .001 for each study arm vs comparison group). Grade 4 anemia developed in 1 woman.\n\n\nCONCLUSIONS\nA 7-day tail of highly active combination therapy or 1 month of dual therapy after SD-NVP prevents most NVP resistance to minimal toxicity.\n\n\nBACKGROUND\nThe IMPAACT P1032 Clinical Trial is NCT00109590, and the PHPT-2 Clinical Trial is NCT00398684.",
"affiliations": "Department of Pediatrics, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. vandyke@tulane.edu",
"authors": "Van Dyke|Russell B|RB|;Ngo-Giang-Huong|Nicole|N|;Shapiro|David E|DE|;Frenkel|Lisa|L|;Britto|Paula|P|;Roongpisuthipong|Anuvat|A|;Beck|Ingrid A|IA|;Yuthavisuthi|Praparb|P|;Prommas|Sinart|S|;Puthanakit|Thanyawee|T|;Achalapong|Jullapong|J|;Chotivanich|Nantasak|N|;Rasri|Wirawan|W|;Cressey|Tim R|TR|;Maupin|Robert|R|;Mirochnick|Mark|M|;Jourdain|Gonzague|G|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D015215:Zidovudine; D019829:Nevirapine",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/cir798",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "54(2)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": null,
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D005260:Female; D006678:HIV; D015658:HIV Infections; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D008875:Middle Aged; D009154:Mutation; D019829:Nevirapine; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D016896:Treatment Outcome; D019562:Viral Load; D015215:Zidovudine",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "285-93",
"pmc": null,
"pmid": "22144539",
"pubdate": "2012-01-15",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "16419112;19886836;16603851;15942891;18614915;15247339;20181911;19133804;11311097;15247338;19307941;15735445;12516578;9722213;16425126;15297515;14722443;20377434;20169113;19237646;10364600;17178792;17457089;20377404;11600822;18197758;20397941;20158398;20827166;19859531;11923366;18549313;17215531;16641095;20942666;17997151",
"title": "A comparison of 3 regimens to prevent nevirapine resistance mutations in HIV-infected pregnant women receiving a single intrapartum dose of nevirapine.",
"title_normalized": "a comparison of 3 regimens to prevent nevirapine resistance mutations in hiv infected pregnant women receiving a single intrapartum dose of nevirapine"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP019722",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"drugadditional... |
{
"abstract": "We report two unique cases of patients with Darier disease and hidradenitis suppurativa. Although it is unknown whether there is a connection between the two diseases, it is possible that an interaction between sarcoendoplasmic reticulum calcium transport ATPase and Notch homolog 1, translocation-associated (Drosophila) caused both diseases in these individuals.",
"affiliations": "School of Medicine, University of California, Davis, Sacramento, California.;Department of Dermatology, University of California, Davis, Sacramento, California.;Department of Dermatology, University of California, Davis, Sacramento, California.",
"authors": "Ornelas|Jennifer|J|;Sivamani|Raja|R|;Awasthi|Smita|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005938:Glucocorticoids; D015474:Isotretinoin",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.12891",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "33(4)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D007644:Darier Disease; D005260:Female; D005938:Glucocorticoids; D017497:Hidradenitis Suppurativa; D006801:Humans; D015474:Isotretinoin; D055815:Young Adult",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e265-6",
"pmc": null,
"pmid": "27282829",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Report of Two Patients with Darier Disease and Hidradenitis Suppurativa.",
"title_normalized": "a report of two patients with darier disease and hidradenitis suppurativa"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0082544",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLINDAMYCIN\\CLINDAMYCIN PHOSPHATE"
},
... |
{
"abstract": "We report an unusual case of hypocalcemia and respiratory distress related to acid-suppressive therapy. The patient was a 50-year-old woman with bilateral laryngeal paralysis and hypoparythyroidism resulting from a thyroidectomy performed more than 30 years previously. She required large doses of calcium supplementation to maintain a normal calcium level. Her airway had been marginally adequate. A few weeks prior to presentation, she began to experience increasing dyspnea. Examination was suggestive of laryngopharyngeal reflux, and she was started on a therapeutic trial of esomeprazole 40 mg twice daily. Three days later, she presented to the emergency room with airway distress. Laboratory studies indicated that the patient had hypocalcemia. The esomeprazole was discontinued, and she was treated with intravenous calcium; her symptoms resolved. We attribute the airway distress to tetany in synkinetically reinnervated laryngeal adductor muscles. We recommend that acid-suppressive therapy should be used with caution in patients with hypoparathyroidism or hypocalcemia.",
"affiliations": "Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL 62794-9662, USA.",
"authors": "Zaya|Ninef E|NE|;Woodson|Gayle|G|",
"chemical_list": "D054328:Proton Pump Inhibitors; D002117:Calcitriol; D002118:Calcium",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-5613",
"issue": "89(2)",
"journal": "Ear, nose, & throat journal",
"keywords": null,
"medline_ta": "Ear Nose Throat J",
"mesh_terms": "D002117:Calcitriol; D002118:Calcium; D005260:Female; D006801:Humans; D006996:Hypocalcemia; D008875:Middle Aged; D054328:Proton Pump Inhibitors; D012131:Respiratory Insufficiency; D012720:Severity of Illness Index; D014826:Vocal Cord Paralysis",
"nlm_unique_id": "7701817",
"other_id": null,
"pages": "78-80",
"pmc": null,
"pmid": "20155676",
"pubdate": "2010-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Proton pump inhibitor suppression of calcium absorption presenting as respiratory distress in a patient with bilateral laryngeal paralysis and hypocalcemia.",
"title_normalized": "proton pump inhibitor suppression of calcium absorption presenting as respiratory distress in a patient with bilateral laryngeal paralysis and hypocalcemia"
} | [
{
"companynumb": "US-HETERO-HET2020US00932",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ESOMEPRAZOLE MAGNESIUM"
},
"drugadditional": "... |
{
"abstract": "Literature on the association of methylphenidate and obsessive-compulsive symptoms (OCS) is sparse. This report discusses a case of a 14-year-old boy, who developed OCS (in the form of need for symmetry, obsessive doubts; compulsive symptoms included the need to order/arrange articles and repeated checking behavior), within 10 days of starting methylphenidate at the dose of 15 mg/day. Stoppage of methylphenidate led to amelioration of OCS over 2 weeks. The case description suggests that whenever a child on stimulants presents with new-onset OCS, association of OCS with stimulants must be suspected before considering an independent diagnosis of comorbid OCS/obsessive-compulsive disorder.",
"affiliations": "Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.;Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Jhanda|Soumya|S|;Singla|Neha|N|;Grover|Sandeep|S|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/1817-1745.199461",
"fulltext": "\n==== Front\nJ Pediatr NeurosciJ Pediatr NeurosciJPNJournal of Pediatric Neurosciences1817-17451998-3948Medknow Publications & Media Pvt Ltd India JPN-11-31610.4103/1817-1745.199461Case ReportMethylphenidate-induced obsessive-compulsive symptoms: A case report and review of literature Jhanda Soumya Singla Neha Grover Sandeep Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh, IndiaAddress for correspondence: Dr. Sandeep Grover, Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012, India. E-mail: drsandeepg2002@yahoo.comOct-Dec 2016 11 4 316 318 Copyright: © 2017 Journal of Pediatric Neurosciences2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Literature on the association of methylphenidate and obsessive-compulsive symptoms (OCS) is sparse. This report discusses a case of a 14-year-old boy, who developed OCS (in the form of need for symmetry, obsessive doubts; compulsive symptoms included the need to order/arrange articles and repeated checking behavior), within 10 days of starting methylphenidate at the dose of 15 mg/day. Stoppage of methylphenidate led to amelioration of OCS over 2 weeks. The case description suggests that whenever a child on stimulants presents with new-onset OCS, association of OCS with stimulants must be suspected before considering an independent diagnosis of comorbid OCS/obsessive-compulsive disorder.\n\nKey words\nCompulsionsmethylphenidateobsessionspsychiatric disorder\n==== Body\nIntroduction\nStimulant medications such as methylphenidate have been used extensively for the management of attention deficit hyperkinetic disorder (ADHD). The efficacy and safety of methylphenidate have been examined in numerous clinical trials, systematic reviews, and meta-analyses.[1] Available evidence suggests that stimulants are more effective than placebo, with effect sizes varying from 0.8 to 1.1 and a positive early response in approximately 70% of cases.[1] The most common side effects associated with methylphenidate are insomnia, headache, irritability, agitation, loss of appetite, nausea, and weight loss.[1]\n\nObsessive-compulsive symptoms (OCS) as a side effect of methylphenidate have rarely been reported. There are occasional case reports describing these in children and adolescents.[2345678] In this report, we present a case of an adolescent boy diagnosed with ADHD and mixed disorder of scholastic skills, who developed OCS after starting methylphenidate, which resolved completely after stoppage of the medication, and review the literature on the association of OCS with methylphenidate.\n\nCase Report\nA 14-year-old boy presented to the hospital with a history of behavioral problems since early childhood. Since 3 years of age, he was found to be fidgety, would frequently run about/leave his place in situations where he was expected to be seated, would not be able to engage in play activities calmly with friends, would not be able to wait for his turn, and would frequently interrupt others during their conversation. He would frequently forget his belongings in school and would easily get distracted with the slightest of noise. He would have difficulty in sustaining attention on tasks including studies, play activities, and would leave the same unfinished.\n\nIn addition, since 6 years of age, he had difficulty in reading, i.e., would read words incorrectly and slowly; had difficulties in written expression, i.e., would make multiple grammatical errors, write mirror images of alphabets, had lack of clarity in his writings, had difficulties with number sense, calculations, and problem-solving.\n\nOver the years, his symptoms kept on worsening, and he continued to have poor grades in the school. He was diagnosed to have ADHD along with mixed disorder of scholastic skills (after detailed assessment for learning disability) at 14 years of age. In view of ADHD, he was started on methylphenidate and the dose was gradually increased to 15 mg/day.\n\nWithin 10 days of starting methylphenidate, he started to have OCS in the form of need for symmetry or exactness about furniture/paper/books being properly aligned, worry about words not being said in a “perfect” way, and obsessive doubts. Compulsive symptoms included the need to order/arrange articles, checking locks and appliances repeatedly, and the need to repeat routine activities such as turning appliances on and off, and going in and out of doorway unless he felt he did it the right number of times (not associated with magical thinking). During this period, there was no associated history of fever, sore throat, arthralgia, skin lesions, tics, depressive, manic, and psychotic symptoms. Past history and family history did not reveal any evidence of obsessive-compulsive disorder (OCD).\n\nIn view of the temporal correlation of onset of OCS with methylphenidate, an association of two was suspected and methylphenidate was stopped. Over the period of the next 2 weeks, the OCS subsided completely. In view of the disappearance of symptoms with stoppage of methylphenidate, a diagnosis of methylphenidate-associated OCS was made. Later, he was managed with nonpharmacological measures for his ADHD as family refused to administer any medication.\n\nDiscussion\nOCSs are rarely described in patients treated with psychostimulants. A search of PubMed revealed only seven case reports of patients who developed OCS with stimulant medications[2345678] and only one study reported on the prevalence of OCS with stimulants.[9] As is evident from Table 1, in eight out of the nine cases, stimulants were used for ADHD and in one case stimulant was used for the management of treatment-resistant depression in an 82-year-old man. All the children and adolescents were aged 8–14 years and there was slight preponderance for boys.[248] All cases of OCS were seen with the use of methylphenidate,[245678] with the exception of one case description in which OCS was noted with the use of d-amphetamine.[2] The dose range of methylphenidate, at which OCSs were noted, varied from 10 to 90 mg/day, and in few cases, OCSs were accompanied by tics.[58] In the majority of cases, OCSs emerged during the initial phase of treatment with methylphenidate; however, in few cases, OCSs were detected after 10 months[5] to 2 years.[7] In majority of the cases, stoppage of methylphenidate led to amelioration of OCSs or significant improvement in OCSs in 1–2-month time. However, in few cases, selective serotonin reuptake inhibitors were used for the management of OCS.[345] The type of OCSs varied across the case reports, with some authors reporting typical OCSs such as repeated hand washing,[348] wiping the furniture and walls with shirt sleeves,[2] checking rituals,[3] and reassurance seeking[34]. In other case reports, OCSs included compulsive stealing and hoarding,[7] thoughts of stabbing and killing people, thoughts of mother doing dirty things; compulsions in the form of drumming, crowing,[2] smelling people, food, and cloths, ordering and symmetry,[3] locking and unlocking and writing excessively about mechanics of locking and unlocking, and tying and untying shoelaces repeatedly.[6] There is the only one study that evaluated abnormal movements or perserverative/compulsive behaviors with the use of stimulants and reported that 34 (76%) out of 45 hyperactive boys had such symptoms. However, these adverse effects were transient and in only one case, severe OCS led to discontinuation of stimulant. The authors noted that compulsive behavior, resembling typical OCD, was more common with dextroamphetamine when compared with methylphenidate. Further, it was observed that compulsive behaviors associated with tics were seen only with methylphenidate.[9]\n\nTable 1 Case reports of obsessive-compulsive symptoms seen with stimulants\n\nThese reports suggest that though rare, OCSs can present as adverse effects of methylphenidate. Hence, whenever a child who is on stimulants presents with new-onset OCS, the association of OCS with stimulants must be suspected before considering an independent diagnosis of comorbid OCS/OCD. In such situations, stoppage of methylphenidate must be considered as a first step in the management of OCS; however, if the symptoms of OCS persist, then the addition of anti-obsessional agents such as selective serotonin reuptake inhibitors may be considered.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Storebø OJ Krogh HB Ramstad E Moreira-Maia CR Holmskov M Skoog M Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials BMJ 2015 351 h5203 26608309 \n2 Koizumi HM Obsessive-compulsive symptoms following stimulants Biol Psychiatry 1985 20 1332 3 4063424 \n3 Coskun M Methylphenidate induced obsessive-compulsive symptoms treated with sertraline Bull Clin Psychopharmacol 2011 21 274 \n4 Woolley JB Heyman I Dexamphetamine for obsessive-compulsive disorder Am J Psychiatry 2003 160 183 \n5 Guegant G Crochette A Methylphenidate, tics and compulsions Encephale 2000 26 45 7 \n6 Serby M Methylphenidate-induced obsessive-compulsive symptoms in an elderly man CNS Spectr 2003 8 612 3 12907924 \n7 Kotsopoulos S Spivak M Obsessive-compulsive symptoms secondary to methylphenidate treatment Can J Psychiatry 2001 46 89 \n8 Kouris S Methylphenidate-induced obsessive-compulsiveness J Am Acad Child Adolesc Psychiatry 1998 37 135 \n9 Borcherding BG Keysor CS Rapoport JL Elia J Amass J Motor/vocal tics and compulsive behaviors on stimulant drugs: Is there a common vulnerability? Psychiatry Res 1990 33 83 94 2217661\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1817-1745",
"issue": "11(4)",
"journal": "Journal of pediatric neurosciences",
"keywords": "Compulsions; methylphenidate; obsessions; psychiatric disorder",
"medline_ta": "J Pediatr Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101273794",
"other_id": null,
"pages": "316-318",
"pmc": null,
"pmid": "28217153",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "10858915;12505824;9473905;12907924;26608309;2217661;11221499;4063424",
"title": "Methylphenidate-induced obsessive-compulsive symptoms: A case report and review of literature.",
"title_normalized": "methylphenidate induced obsessive compulsive symptoms a case report and review of literature"
} | [
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"companynumb": "IN-ALVOGEN-2017-ALVOGEN-091652",
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"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE"
},
"drugadditional": "1... |
{
"abstract": "BACKGROUND\nInfections are the leading cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Invasive fungal infections (IFI) comprise a group of diseases caused by Cryptococcus, Histoplasma, Aspergillus and Candida. Few studies of IFI have been published in patients with SLE and associated factors have not been completely defined.\n\n\nOBJECTIVE\nThe objectives of this paper are to estimate the frequency of IFI in admitted patients with SLE in our hospital, to determine the risk factors associated with IFI in our patients with SLE, and to compare IFI group with a control group (SLE without IFI).\n\n\nMETHODS\nThe medical charts of patients with IFI (EORTC/MSG, 2008) and SLE (ACR, 1997) admitted to our hospital from June 2001 until June 2012 were reviewed. To identify factors associated with IFI, we developed a case-control study (SLE + IFI vs SLE alone) in a one to three ratio adjusted for sex and age and hospitalization for other reasons. Comparison was made of demographic characteristics, duration of disease and disease activity previous to IFI diagnosis, especially three months before fungal infection. We defined severe activity as SLEDAI ≥ 8. Infection by fungi of the genus Candida was considered only in its disseminated form.\n\n\nRESULTS\nTen cases of IFI were identified in 208 patients with SLE admitted between June 2001 and June 2012. We included 40 patients with SLE (10 with IFI and 30 controls). Of the SLE-IFI patients, eight were women and the average age was 27.5 years (range, 19-42 years). Fungal isolation: eight Cryptococcus neoformans, one Histoplasma capsulatum and one Candida albicans. Sites affected: five in peripheral blood, five in central nervous system (CNS), four in skin/soft tissue and one in pleura. Mortality was 40% (p = 0.002), with Cryptococcus neoformans being the most common fungus. The SLE disease activity was severe in 70% of infected patients and no significant difference with the control group was found (p = 0.195). We also found no association with leukopenia, lymphopenia, hypocomplementemia, hypogammaglobulinemia or anti-DNA positivity; neither with meprednisone doses >20 mg/day or intravenous methylprednisolone pulse therapy before fungal infection. The use of immunosuppressive therapy with azathioprine showed a significant association (p = 0.017). Cyclophosphamide (p = 0.100) or mycophenolate mofetil (p = 0.256) did not show similar results.\n\n\nCONCLUSIONS\nThe frequency of IFI in hospitalized SLE patients in our hospital was 4.8%. Cryptococcus neoformans was the most common etiologic agent and was primarily responsible for the deaths in this cohort. These data are consistent with publications in East Asia rather than North America where Candida spp. is more common. Unlike other publications, previous immunosuppression with azathioprine was the only risk factor associated with the development of the infection. Invasive fungal infection should be suspected in hospitalized patients with SLE and immunosuppression with CNS or atypical cutaneous manifestation of SLE in order to start appropriate treatment early and obtain better outcome.",
"affiliations": "División Reumatología, Hospital de Clínicas, Universidad de Buenos Aires, Avenida Córdoba 2351, Buenos Aires, Argentina. jpvinicki@hotmail.com",
"authors": "Vinicki|J P|JP|;Catalan Pellet|S|S|;Pappalardo|C|C|;Cruzat|V C|VC|;Spinetto|M A|MA|;Dubinsky|D|D|;Tiraboschi|I N|IN|;Laborde|H A|HA|;Nasswetter|G|G|",
"chemical_list": "D007166:Immunosuppressive Agents; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1177/0961203313496342",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "22(9)",
"journal": "Lupus",
"keywords": "Systemic lupus erythematosus; anti-DNA antibodies; nephritis",
"medline_ta": "Lupus",
"mesh_terms": "D000328:Adult; D001118:Argentina; D001379:Azathioprine; D016022:Case-Control Studies; D005260:Female; D006760:Hospitalization; D006801:Humans; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D008297:Male; D009181:Mycoses; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D055815:Young Adult",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "892-8",
"pmc": null,
"pmid": "23861029",
"pubdate": "2013-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Invasive fungal infections in Argentine patients with systemic lupus erythematosus.",
"title_normalized": "invasive fungal infections in argentine patients with systemic lupus erythematosus"
} | [
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"activesubstancename": "METHYLPREDNISOLONE"
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"abstract": "Immune checkpoint inhibitors (ICPIs) are novel therapeutic agents targeting a variety of cancers by enhanced T cell activation. Immune-related adverse events (irAEs) commonly occur with ICPI use and can affect multiple organ systems including the gastrointestinal tract. Due to irAEs, the use of ICPIs is limited in autoimmune diseases. We present a case of microscopic colitis diagnosed after the initiation of nivolumab and a case of ipilimumab colitis and Clostridium difficile in the setting of Crohn's colitis.",
"affiliations": "Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, Arizona, USA.;Department of General Internal Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.;Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, Arizona, USA.;Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, Arizona, USA.;Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, Arizona, USA.;Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, USA.;Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, Arizona, USA.",
"authors": "Kuo|Jean R|JR|;Davis|Amy D|AD|;Rodriguez|Eduardo A|EA|;Vela|Marcelo F|MF|;Heigh|Russell I|RI|;Salomao|Marcela A|MA|;Gurudu|Suryakanth R|SR|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000493183",
"fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000493183crg-0012-0704Case SeriesSevere Diarrhea in the Setting of Immune Checkpoint Inhibitors Kuo Jean R. a*Davis Amy D. bRodriguez Eduardo A. aVela Marcelo F. aHeigh Russell I. aSalomao Marcela A. cGurudu Suryakanth R. aaDivision of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, Arizona, USAbDepartment of General Internal Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USAcDepartment of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, USA*Jean R. Kuo, MD, Mayo Clinic Arizona, 13400 East Shea Boulevard, Phoenix, AZ 85259 (USA), E-Mail kuo.jean@mayo.eduSep-Dec 2018 28 11 2018 28 11 2018 12 3 704 708 15 5 2018 23 8 2018 Copyright © 2018 by S. Karger AG, Basel2018This 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.Immune checkpoint inhibitors (ICPIs) are novel therapeutic agents targeting a variety of cancers by enhanced T cell activation. Immune-related adverse events (irAEs) commonly occur with ICPI use and can affect multiple organ systems including the gastrointestinal tract. Due to irAEs, the use of ICPIs is limited in autoimmune diseases. We present a case of microscopic colitis diagnosed after the initiation of nivolumab and a case of ipilimumab colitis and Clostridium difficile in the setting of Crohn's colitis.\n\nKeywords\nDiarrheaImmune checkpoint inhibitorsMicroscopic colitisIpilimumab colitisCrohn's diseaseClostridium difficile\n==== Body\nIntroduction\nImmune checkpoint inhibitors (ICPIs) are novel immunotherapy agents that are used to treat an increasingly wider array of cancers. ICPIs were initially used in metastatic melanoma and are now used in multiple malignancies [1, 2]. There are two categories of ICPIs that are currently used in clinical practice: anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) antibodies and anti-programmed cell death-protein 1 (anti-PD-1) antibodies. Anti-CTLA-4 antibodies include ipilimumab (Yervoy). Anti-PD-1 antibodies include nivolumab (Opdivo) and pembrolizumab (Keytruda). ICPIs increase T cell activation which can then lead to immune related adverse events, including those of the gastrointestinal tract [2]. We present 2 cases of severe diarrhea in the setting of ICPIs and autoimmune disease.\n\nCase Reports\nCase 1\nA 74-year-old male with a history of metastatic pulmonary squamous cell carcinoma was admitted with 2 weeks of severe diarrhea. He had been started on second-line nivolumab 9 months prior to admission. He was only able to complete 10 cycles as he developed diarrhea that initially responded to steroids. On admission, he reported 10–15 episodes of large-volume watery stools per day without mucus, blood or significant abdominal pain. Stool studies for bacteria, viruses, and parasites were negative, and a fecal lactoferrin was positive. Computed tomography (CT) of the abdomen/pelvis with contrast showed mild mural thickening of the inferior cecum and terminal ileum. A colonoscopy was notable for a few 3- to 5-mm ulcerations scattered through entire colon and a 5-mm flat polypoid lesion in the transverse colon. Random biopsies including those of the polyp and ulcers were obtained. Pathology demonstrated preserved crypt architecture, marked propria lymphoplasmacytic inflammation, diffuse intraepithelial lymphocytosis, and marked increase in subepithelial collagen deposition (Fig. 1a). These features were consistent with collagenous colitis. The patient required two budesonide tapers starting at 9 mg daily for his diarrhea, and nivolumab was not restarted. Although the patient was started on docetaxel, he unfortunately had progression of his disease and ultimately died in hospice.\n\nCase 2\nA 68-year-old female with a history of stage III melanoma presented to her oncologist with diarrhea of 1 month's duration. An abdomen/pelvis CT revealed mucosal thickening of the terminal ileum. A colonoscopy noted mild inflammation from the transverse colon to cecum, sigmoid colon to descending colon, and moderate inflammation in the rectum. Biopsies of her terminal ileum and colon were consistent with Crohn's disease. She was referred to Gastroenterology and was started on mesalamine 2.4 g twice daily. She was then initiated on first-line pembrolizumab. A month after starting pembrolizumab, the patient was hospitalized for acute on chronic diarrhea. Her CT abdomen/pelvis and flexible sigmoidoscopy demonstrated nonspecific active chronic colitis. She improved with intravenous methylprednisolone 20 mg three times daily, transitioned to prednisone 40 mg daily, and eventually to a budesonide taper. Six months later, the patient was started on ipilimumab and nivolumab due to progression of her melanoma. The patient developed bloody diarrhea 3 days after initiating the new combination therapy. Repeat flexible sigmoidoscopy demonstrated severe inflammation from the rectum to the splenic flexure concerning for worsened colitis. Her pathology was notable for marked inflammation, cryptitis, and crypt cell apoptosis which was consistent with ipilimumab colitis (Fig. 1b). Her diarrhea improved with two doses of infliximab 200 mg and intravenous methylprednisolone 20 mg three times daily transitioned to a prednisone taper. One month later, she received another dose of the combination immunotherapy and experienced similar symptoms of diarrhea the following day. She also tested positive for Clostridium difficile. She was treated with oral vancomycin 250 mg every 6 h, intravenous hydrocortisone 20 mg three times daily, and another slow prednisone taper. Unfortunately, she continued to decline and ultimately died in hospice.\n\nDiscussion\nICPIs work primarily by inhibiting T-cell inhibitory signals and lead to increased T cell activation which then leads to increased anti-tumor T-cell response [2]. Due to increased T cell activation, autoimmune-like adverse events can occur. These autoimmune-like adverse events have been labelled immune-related adverse events (irAEs) [2]. irAEs most commonly affect the skin and gastrointestinal organ systems. Gastrointestinal irAEs include diarrhea, colitis, hepatotoxicity, pancreatitis, esophagitis, and inflammatory enteric neuropathy with constipation [3, 4]. Life-threatening consequences such as perforation have also been described [2].\n\nGastroenterologists are typically consulted when patients develop significant diarrhea. CT abdomen/pelvis can demonstrate evidence of colitis with bowel wall thickening and mesenteric engorgement [2]. After ruling out infectious etiologies of diarrhea such as C. difficile, colonoscopy is typically pursued. On colonoscopy, the findings are nonspecific and can range from normal mucosa to ulceration of the colon and ileum [5, 6]. Typically, lesions are predominately in the descending colon [2, 3]. On biopsy, neutrophilic and lymphocytic infiltrates as well as cryptitis and crypt abscesses have been described [5, 7, 8, 9].\n\nAfter diagnosing immune-related enterocolitis, patients should be started on high-dose steroid therapy. If the patient remains refractory to high-dose steroids, infliximab can be considered. If the patient continues to have significant diarrhea refractory to steroids and infliximab, tacrolimus or mycophenolate mofetil are also utilized. In severe cases, colectomy may be required [2].\n\nDue to the autoimmune-like process of ICPIs, aggravation of known inflammatory conditions or discovery of occult inflammatory conditions has also been described. There have been 2 case reports of microscopic colitis diagnosed after the initiation of pembrolizumab and ipilimumab [10, 11]. In addition, there have been 3 case reports of ICPI use in Crohn's disease. In one patient, there was a possible flare of Crohn's disease after a patient was started on pembrolizumab for metastatic colon cancer [12]. In another patient, ipilimumab-induced colitis was diagnosed in a patient with Crohn's disease on ipilimumab for metastatic melanoma [13]. Finally, in a separate patient, an intra-abdominal abscess concerning for Crohn's disease flare was diagnosed in a patient with Crohn's disease on pembrolizumab [14].\n\nWe describe the first case of microscopic colitis after the initiation of nivolumab. In addition, we describe a case of ipilimumab colitis and C. difficile in the setting of Crohn's disease. Our cases highlight the importance of investigating a broad differential when managing patients with diarrhea on ICPIs.\n\nStatement of Ethics\nBoth patients described were deceased by the time of abstract submission. Consent was obtained from the first patient's wife. The emergency contact for the second patient was unable to be reached.\n\nDisclosure Statement\nSuryakanth R. Gurudu receives grant support from Gilead Sciences, but there are no other conflicts of interest.\n\nFig. 1 a Colonic biopsy demonstrating marked thickening of subepithelial collagen layer, consistent with collagenous colitis. b Colonic biopsy demonstrating marked inflammation, cryptitis, and crypt cell apoptosis. Inset demonstrates increase in crypt cell apoptosis. Hematoxylin and eosin-stained biopsy specimens at ×100 magnification, inset at ×400 magnification.\n==== Refs\nReferences\n1 Gonzalez RS Salaria SN Bohannon CD Huber AR Feely MM Shi C PD-1 inhibitor gastroenterocolitis: case series and appraisal of ‘immunomodulatory gastroenterocolitis’ Histopathology 2017 3 70 (4) 558 67 28000302 \n2 Spain L Diem S Larkin J Management of toxicities of immune checkpoint inhibitors Cancer Treat Rev 2016 3 44 51 60 26874776 \n3 Pernot S Ramtohul T Taieb J Checkpoint inhibitors and gastrointestinal immune-related adverse events Curr Opin Oncol 2016 7 28 (4) 264 8 27138569 \n4 Villadolid J Amin A Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities Transl Lung Cancer Res 2015 10 4 (5) 560 75 26629425 \n5 Oble DA Mino-Kenudson M Goldsmith J Hodi FS Seliem RM Dranoff G Alpha-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis Am J Surg Pathol 2008 8 32 (8) 1130 7 18545145 \n6 Berman D Parker SM Siegel J Chasalow SD Weber J Galbraith S Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma Cancer Immun 2010 11 10 11 21090563 \n7 Bertrand A Kostine M Barnetche T Truchetet ME Schaeverbeke T Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis BMC Med 2015 9 13 (1) 211 26337719 \n8 Chen JH Pezhouh MK Lauwers GY Masia R Histopathologic Features of Colitis Due to Immunotherapy With Anti-PD-1 Antibodies Am J Surg Pathol 2017 5 41 (5) 643 54 28296676 \n9 Marthey L Mateus C Mussini C Nachury M Nancey S Grange F Cancer Immunotherapy with Anti-CTLA-4 Monoclonal Antibodies Induces an Inflammatory Bowel Disease J Crohn's Colitis 2016 4 10 (4) 395 401 26783344 \n10 Baroudjian B Lourenco N Pagès C Chami I Maillet M Bertheau P Anti-PD1-induced collagenous colitis in a melanoma patient Melanoma Res 2016 6 26 (3) 308 11 26990271 \n11 García-Varona A Odze RD Makrauer F Lymphocytic colitis secondary to ipilimumab treatment Inflamm Bowel Dis 2013 2 19 (2) E15 6 22114048 \n12 Esfahani K Miller WH Jr Reversal of Autoimmune Toxicity and Loss of Tumor Response by Interleukin-17 Blockade N Engl J Med 2017 5 376 (20) 1989 91 28514612 \n13 Gielisse EA de Boer NK Ipilimumab in a patient with known Crohn's disease: to give or not to give? J Crohn's Colitis 2014 12 8 (12) 1742 25154682 \n14 Uemura M Trinh VA Haymaker C Jackson N Kim DW Allison JP Selective inhibition of autoimmune exacerbation while preserving the anti-tumor clinical benefit using IL-6 blockade in a patient with advanced melanoma and Crohn's disease: a case report J Hematol Oncol 2016 9 9 (1) 81 27595932\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "12(3)",
"journal": "Case reports in gastroenterology",
"keywords": "Clostridium difficile; Crohn's disease; Diarrhea; Immune checkpoint inhibitors; Ipilimumab colitis; Microscopic colitis",
"medline_ta": "Case Rep Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101474819",
"other_id": null,
"pages": "704-708",
"pmc": null,
"pmid": "30631256",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "18545145;21090563;22114048;25154682;26337719;26629425;26783344;26874776;26990271;27138569;27595932;28000302;28296676;28514612",
"title": "Severe Diarrhea in the Setting of Immune Checkpoint Inhibitors.",
"title_normalized": "severe diarrhea in the setting of immune checkpoint inhibitors"
} | [
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"companynumb": "PHHY2019US027029",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"abstract": "BACKGROUND\nDiagnosing progressive disseminated histoplasmosis (PDH) in patients with systemic lupus erythematosus (SLE) is diagnostically challenging. Since PDH is lethal when untreated, awareness of this infection in patients with SLE is of utmost importance. To the best of our knowledge, this is the first description of a case of PDH in a patient with SLE in Europe.\n\n\nMETHODS\nA 56-year-old woman of Surinamese descent with a history of SLE, presented with fever and polyarthritis. Although a flare of SLE was suspected initially, cultures of bone marrow and broncho-alveolar lavage fluid grew Histoplasma capsulatum.\n\n\nCONCLUSIONS\nThis case report highlights that physicians should be aware of progressive disseminated histoplasmosis in patients with SLE treated with immunosuppressive agents. The signs and symptoms can easily mimic a SLE flare, which would then be treated with more aggressive immunosuppression. Failure to recognize the infection will therefore invariably lead to death of the patient. Progressive disseminated histoplasmosis is usually not recognized by doctors in non-endemic areas such as Europe. However, globalisation and more frequent intercontinental traffic of immunocompromised patients currently increases the incidence of histoplasmosis in these areas. It is therefore of life-saving importance that doctors are aware of the features of the infection in areas where H. capsulatum is not endemic.",
"affiliations": "Department of Medical Microbiology and Infection Control, VU University Medical Center , Amsterdam , the Netherlands.;Department of Internal Medicine, VU University Medical Center , Amsterdam , the Netherlands.;Department of Rheumatology, VU University Medical Center , Amsterdam , the Netherlands.;Intensive Care Unit, VU University Medical Center , Amsterdam , the Netherlands.;Department of Medical Microbiology and Infection Control, VU University Medical Center , Amsterdam , the Netherlands.",
"authors": "van Doorn-Schepens|M L M|ML|;Peters|E J|EJ|;van Vugt|R M|RM|;van der Spoel|J I|JI|;van Dijk|K|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1099/jmmcr.0.005035",
"fulltext": "\n==== Front\nJMM Case RepJMM Case RepJMMCRJMM Case Reports2053-3721Microbiology Society jmmcr00503510.1099/jmmcr.0.005035Case ReportRespiratoryClinical MycologyHuman Pathogenic FungiOpportunistic InfectionsTropical DiseasesProgressive disseminated histoplasmosis mimicking a flare of systemic lupus erythematosus: a European case report http://jmmcr.microbiologyresearch.orgProgressive disseminated histoplasmosis mimicking a flare of systemic lupus erythematosusM. L. M. van Doorn-Schepens and othersvan Doorn-Schepens M. L. M. 1Peters E. J. 2van Vugt R. M. 3van der Spoel J. I. 4van Dijk K. 11 Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, the Netherlands2 Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands3 Department of Rheumatology, VU University Medical Center, Amsterdam, the Netherlands4 Intensive Care Unit, VU University Medical Center, Amsterdam, the NetherlandsCorrespondence M. L. M. van Doorn-Schepens m.schepens@vumc.nl8 2016 30 8 2016 3 4 e00503501 3 2016 04 4 2016 © 2016 The Authors2016This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.Introduction:\n Diagnosing progressive disseminated histoplasmosis (PDH) in patients with systemic lupus erythematosus (SLE) is diagnostically challenging. Since PDH is lethal when untreated, awareness of this infection in patients with SLE is of utmost importance. To the best of our knowledge, this is the first description of a case of PDH in a patient with SLE in Europe.\n\nCase presentation:\n A 56-year-old woman of Surinamese descent with a history of SLE, presented with fever and polyarthritis. Although a flare of SLE was suspected initially, cultures of bone marrow and broncho-alveolar lavage fluid grew Histoplasma capsulatum.\n\nConclusion:\n This case report highlights that physicians should be aware of progressive disseminated histoplasmosis in patients with SLE treated with immunosuppressive agents. The signs and symptoms can easily mimic a SLE flare, which would then be treated with more aggressive immunosuppression. Failure to recognize the infection will therefore invariably lead to death of the patient. Progressive disseminated histoplasmosis is usually not recognized by doctors in non-endemic areas such as Europe. However, globalisation and more frequent intercontinental traffic of immunocompromised patients currently increases the incidence of histoplasmosis in these areas. It is therefore of life-saving importance that doctors are aware of the features of the infection in areas where H. capsulatum is not endemic.\n\nhistoplasmosisdisseminatedamphotericin BOpenAccessEmbargo0Abbreviations:\nSLEsystemic lupus erythematosus\n\nCTcomputed tomography\n\nBALbroncho-alveolar lavage\n\nEBVEpstein-Barr virus\n\nPDHprogressive disseminated histoplasmosis\n\nPCRpolymerase chain reaction\n\nPOper os\n==== Body\nIntroduction\nHistoplasma capsulatum is a soil-based fungus which is mostly associated with river valleys (e.g. Ohio and Mississippi river valleys), and places where bats live and birds roost, predominantly in (sub) tropical regions. After inhalation of spores, this microorganism can cause a broad range of clinical manifestations. The vast majority of infections (>90 %) are asymptomatic, but symptoms ranging from an influenza-like illness to death are also described (Goodwin et al., 1981). Contributing factors to the extent of the disease are higher inoculum size, increasing age and underlying disease. The use of immunosuppressive drugs is a risk factor for disseminated or fatal disease (Wheat et al., 1982). Adequate cell-mediated immunity is necessary to control a Histoplasma\ncapsulatum infection after exposure (Porta & Maresca, 2000). Patients with systemic lupus erythematosus (SLE) have defects in their humoral and cellular immune systems (Tsokos, 1994). The combination of intrinsic immune system defects with chronic immunosuppressive therapy makes patients with SLE prone to develop progressive disseminated histoplasmosis (PDH) when infected. Although the reported incidence of invasive fungal infections in patients with SLE is low, 0.64–1.04 % (Weng et al., 2010), timely recognition of PDH is important because of the high mortality if untreated. Diagnosis is frequently delayed because symptoms are often attributed to SLE (Lim et al., 2013). Here we describe the first reported case of disseminated histoplasmosis in a patient with SLE in Europe.\n\nCase report\nA 56-year-old woman of Surinamese descent with a history of SLE and splenectomy was admitted to the Department of Rheumatology at the VU University Medical Center in Amsterdam because she had collapsed and had a fever. Her last visit to Suriname was in 2008. She had been treated with mycophenolate mofetil 1250 mg orally (PO) twice daily and prednisone 20 mg PO once daily. The dosage of both these drugs was recently increased because of exacerbation of her SLE-nephritis with a nephrotic syndrome. On admission, her temperature was 39.1 °C. She had polyarthritis with swelling and calor of her left knee and interphalangeal joints of her right hand. The white blood cell count was 7.9 × 109 l−1 (segmented neutrophils 7.50 × 109 l−1, lymphocytes 0.24 × 109 l−1), haemoglobin 7.5 mmol l−1, platelet count 419 × 109 l−1, and C-reactive protein 210 mg l−1. Nitrite in urine was positive. Antibiotic treatment was started with intravenous ceftriaxone, 2 g once a day, because a complicated urinary tract infection was suspected. Within one week of admission, the patient was admitted to the ICU because of respiratory insufficiency, and mechanical ventilation was started. Computed tomography (CT) of the lungs showed segmental pulmonary embolism, diffuse ground glass opacities and bilateral consolidations in the upper pulmonary lobes (Fig. 1). She also had progressive liver failure; bilirubin was 35 µmol l−1, alkaline phosphatase 950 U l−1, gamma-glutamyl transferase 6335 U l−1, aspartate aminotransferase 116 U l−1, and alanine transaminase 273 U l−1. A CT-scan of the abdomen revealed no explanation for the liver failure. The culture of the broncho-alveolar lavage (BAL) fluid was negativein the first days. PCRs for Legionella pneumophila, Mycobacterium tuberculosis, M. genus, Chlamydia pneumoniae, Chlamydia psittaci, Pneumocystis jiroveci, cytomegalovirus, Epstein-Barr virus and respiratory viruses were negative. With these negative microbiological test results, clinical deterioration of the patient was attributed to an exacerbation of SLE, and subsequently intravenous methylprednisolone pulse therapy was started in a daily dose of 1000 mg for three days. At first, her clinical condition improved and she was extubated. However within three days she was increasingly somnolent, in respiratory failure and she was intubated again. CT-scans of the lungs showed profound progression of the ground glass opacities. Histoplasmosis was considered in the differential diagnosis. However, at that moment fungal culture was negative, and with a low likelihood of H. capsulatum, no (toxic) pre-emptive therapy was initiated. A course of methylprednisolone pulse therapy was started again, but to no avail. Nine days after performing the BAL, culture of the BAL fluid grew a fungus, which was determined as H. capsulatum by the dimorphic character of the fungus, with a mycelial phase at 37 °C and a yeast phase at 30 °C. PCR performed on a bone marrow biopsy and culture of this biopsy were both positive for H. capsulatum. Antifungal therapy with liposomal amphotericin B (3.0 mg kg−1 daily) was started to treat this PDH, and immunosuppressive therapy was reduced to 20 mg prednisone per day. Two weeks after starting antifungal therapy the patient developed a lesion resembling pyogenic granuloma in her oral cavity from which she bled profoundly. A periodic acid-Schiff stain (PAS stain) of a needle biopsy of the gingiva showed encapsulated yeast cells and a haematoxylin-eosin stain of this biopsy showed 2–4 µm yeast buds and septated hyphae (Fig. 2). The patient could slowly be weaned from mechanical ventilation, and after one month on the ICU, she was extubated. After four weeks, liposomal amphotericin B was switched to itraconazole PO, 200 mg three times daily for three months, and then 200 mg once daily as lifelong suppressive therapy. Three months after she was diagnosed with PDH and treatment was started, the patient could be discharged from the hospital. Two months after her discharge her liver and kidney function tests had fully recovered.\n\nFig. 1. Thoracic computed tomography (CT) of the lungs showing diffuse ground glass opacities and bilateral consolidations in the upper pulmonary lobe.\n\nFig. 2. Histopathology of the gingival biopsy showing yeast buds and septate hyphae (haematoxylin-eosin stain). The inlet is a periodic acid-Schiff stain of the gingival biopsy showing encapsulated yeast cells.\n\nDiscussion\nSymptoms of disseminated histoplasmosis mimic SLE-related symptoms, with focal lesions in the same organs affected by SLE. As a consequence, disseminated histoplasmosis is a diagnostic challenge for physicians. A complicating factor is that culturing H. capsulatum can take seven days to three weeks. H. capsulatum antigen testing on urine or serum can lead to a faster diagnosis with a reported sensitivity of 95–100 % (Connolly et al., 2007; Hage et al., 2010, 2011). As a consequence, diagnosing PDH solely by fungal culture can lead to a significant delay in initiating adequate antifungal therapy. In case the treating physician does not consider disseminated histoplasmosis, the dose of corticosteroids will likely be increased to treat a suspected flare of SLE. When symptoms temporarily improve by the increase in dosage of steroids, clinicians are put on the wrong track even more; the response to steroids affirms the initial diagnosis of SLE exacerbation. Even though the diagnosis of PDH was already considered in this patient three weeks after admission, a slight increase of SLE activity could not be excluded and symptoms were initially attributed to SLE. A case-based review on PDH in patients with SLE suggested that there is significant delay from onset of symptoms to time of diagnosis with a median time of 6.5 months (range 0.75–31 months) (Lim et al., 2013). Most of the patients in that review were using chronic immunosuppression, most commonly steroids with 56.3 % of the patients taking a dose of 20 mg prednisone or higher per day. In four out of the five fatal cases, the patients were using additional immunosuppressant drugs, like mycophenolate mofetil. Since the spleen plays an important role in our immune response it would be plausible that (functional) asplenia makes a patient prone to infection with H. capsulatum. However, splenectomy or asplenia does not seem to be a risk factor for an infection with H. capsulatum. Only sporadic cases have been reported of H. capsulatum infection in asplenic patients (Naina et al., 2010; Rose et al., 1982; Stone et al., 1990). Most case reports of disseminated histoplasmosis in patients with SLE are described in high-endemic areas (Table 1) (Lim et al., 2013). The patient in this case report is of Surinam descent, where H. capsulatum is also high-endemic (Colombo et al., 2011). In such high-endemic areas, physicians are more aware of PDH in patients with SLE than physicians in non-endemic areas. This case report describes the first reported case of disseminated histoplasmosis in a patient with SLE in Europe. The difficult diagnosis of PDH and the low awareness of European clinicians might well have resulted in under-reporting of PDH in European medical literature. Furthermore, the diagnosis was (partially) based on a positive fungal culture of BAL-fluid. The classical histopathological findings of the gingival biopsy showing yeast buds and septate hyphae and encapsulated yeast cells is a rarity. These findings make it a unique case.\n\nTable 1. Cases of progressive disseminated histoplasmosis in systemic lupus erythematosus patients\n\nClinical data of 17 cases described in the literature, plus the data of the current case report. PDH, Progressive disseminated histoplasmosis; SLE, systemic lupus erythematosus; M, male; F, female; u/a, unavailable; D, death; S, survived; bx, biopsy; hpe, histopathologic examination; cx, culture.\n\nAge (years)/ gender\tSymptom\tSLE flare\tAntifungal treatment\tOutcome\tInitial presentation to diagnosis (time)\tInitial method of diagnosis\tDose of steroid per day at onset of symptoms\tOther immunosuppressants \nat onset\n of symptoms\t\n49/F\tDyspnea, productive cough, pleurisy, night sweats, weight loss\tYes\tAmphotericin B\tD\t4–5 months\tAutopsy\tPrednisone >20 mg\t\t\n22/F\tFever, vision change\tu/a\tAmphotericin B\tD\tu/a\tAutopsy\tSteroids, dose not specified\tAzathioprine\t\n23/F\tFever, night sweats, lethargy, pleurisy\tNo\tAmphotericin B\tS\t7 months\tHistoplasmosis fixation antibody titer 1:128\tPrednisone 40–60 mg\t\t\n65/M\tFever, fatigue, dyspnea\tu/a\tAmphotericin B\tD\tu/a\tBone marrow bx\tPrednisone 20–60 mg\t6-Mercaptopurine\t\n23/F\tFever, malaise, weight loss\tu/a\tAmphotericin B\tS\tu/a\tLiver bx\tPrednisone 20–60 mg\t\t\n35/M\tFever, malaise, dyspnea\tu/a\tNo treatment\tD\tu/a\tAutopsy\tPrednisone 20–60 mg\t6-Mercaptopurine\t\n56/F\tFever, rash, headache, myalgia\tYes\tAmphotericin B, fluorocytosin\tS\t3 weeks\thpe (skin bx)\tNo steroids\t\t\n53/F\tFever, confusion, fatigue, weakness, jaundice, papulonodular skin lesion\tYes\tAmphotericin B, itraconazole\tS\t6–7 months\tcx (bone marrow bx)\tPrednisone 30–80 mg\t\t\n39/F\tHeadache, confusion\tNo\tAmphotericin B, itraconazole\tS\t6.5 months\thpe (cerebrospinal fluid)\tPrednisone 20 mg\t\t\n32/F\tFever, night sweats, lethargy, weight loss, irregular menses (ovarian dysfunction)\tNo\tKetoconazole\tS\t2 years 7 months\thpe (ovary-surgical specimen)\tPrednisone 10 mg\t\t\n49/F\tNasal ulceration, cutaneous ulcer\tu/a\tAmphotericin B, itraconazole, voriconazole\tS\t2 years\thpe (cutaneous ulcer, nasal ulceration bx)\tPrednisone 5 mg\t\t\n47/F\tNasal ulceration\tNo\tKetoconazole\tS\tu/a\tcx (nasal septum bx)\tSteroids, dose not specified\t\t\n35/F\tHoarseness\tu/a\tAmphotericin B, itraconazole\tS\t7 months\tcx (nasal crusts)\tPrednisone 10 mg\t\t\n48/F\tFever, malaise, fatigue and arthralgias, swelling and stiffness of left hand, swelling of left ankle\tYes\tAmphotericin B, miconazole\tD\t6 months\thpe (palmar mass surgical specimen)\tMethylprednisolone 16 mg\tAzathioprine\t\n42/F\tSwelling and stiffness of index finger of left hand\tNo\tItraconazole\tS\t3 months\tcx (synovium bx)\tNo steroids\t\t\n32/F\tSwelling, erythema in right forearm\tNo\tItraconazole\tS\t2 months\tcx (synovium bx)\tPrednisone 30 mg\tMycophenolate mofetil\t\n56/F\tFever and polyarthritis\tYes\tLiposomal Amphotericin B, itraconazole\tS\t3 weeks\tPCR (bone marrow bx), cx (BAL), hpe (gingival bx)\tPrednisone 20 mg\tMycophenolate mofetil\t\nIn conclusion, this case report highlights that physicians should be aware of progressive disseminated histoplasmosis in patients with SLE, treated with immunosuppressive agents. The signs and symptoms can easily mimic a SLE flare, which would then be treated with more aggressive immunosuppression. Failure to recognize the infection will therefore invariably lead to death of the patient. Progressive disseminated histoplasmosis is usually not recognized by doctors in non-endemic areas such as Europe. However, globalisation and more frequent intercontinental traffic of immunocompromised patients currently increases the incidence in these areas. It is therefore of life-saving importance that doctors in areas where H. capsulatum is not endemic are aware of the features of the infection, especially in patients from endemic areas. By creating awareness of this infection, faster diagnostic tests can be used to diagnose PDH. In this particular case, specific fungal staining, such as methenamine silver or periodic acid-Schiff stains (PAS), could have been performed on the BAL fluid or a bone marrow aspirate. Furthermore H. capsulatum antigen testing could have been performed on urine or serum for faster diagnosis (Connolly et al., 2007; Hage et al., 2010, 2011).\n\nAcknowledgements\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 at the Editor-in-Chief of this journal.\n==== Refs\nReferences\nColombo A. L. Tobón A. Restrepo A. Queiroz-Telles F. Nucci M. \n(2011 ). Epidemiology of endemic systemic fungal infections in Latin America . Med Mycol 49 785 –798 .10.3109/13693786.2011.577821 21539506 \nConnolly P. A. Durkin M. M. Lemonte A. M. Hackett E. J. Wheat L. J. \n(2007 ). Detection of Histoplasma antigen by a quantitative enzyme immunoassay . Clin Vaccine Immunol 14 1587 –1591 .10.1128/CVI.00071-07 17913863 \nGoodwin R. A. Loyd J. E. Des Prez R. M. \n(1981 ). Histoplasmosis in normal hosts . Medicine 60 231 –266 .10.1097/00005792-198107000-00001 7017339 \nHage C. A. Bowyer S. Tarvin S. E. Helper D. Kleiman M. B. Wheat L. J. \n(2010 ). Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy . Clin Infect Dis 50 85 –92 . \n10.1086/648724 19951231 \nHage C. A. Ribes J. A. Wengenack N. L. Baddour L. M. Assi M. McKinsey D. S. Hammoud K. Alapat D. Babady N. E. other authors \n(2011 ). A multicenter evaluation of tests for diagnosis of histoplasmosis . Clin Infect Dis 53 448 –454 . \n10.1093/cid/cir435 21810734 \nLim S. Y. Kijsirichareanchai K. Winn R. \n(2013 ). Progressive disseminated histoplasmosis in systemic lupus erythematosus-an unusual presentation of acute tenosynovitis and a literature review . Clin Rheumatol 32 135 –139 . \n10.1007/s10067-012-2102-5 23065146 \nNaina H. V. Thomas C. F., Jr. Harris S. \n(2010 ). Histoplasmosis and asplenia . Thorax 65 372 . \n10.1136/thx.2008.100214 20388769 \nPorta A. Maresca B. \n(2000 ). Host response and Histoplasma capsulatum/macrophage molecular interactions . Med Mycol 38 399 –406 .10.1080/mmy.38.6.399.406 11204877 \nRose F. B. Camp C. J. Chisdak M. \n(1982 ). Disseminated histoplasmosis and asplenia . Ann Intern Med 96 790 .10.7326/0003-4819-96-6-790_1 7091948 \nStone M. M. Frenkel L. M. Howard D. H. \n(1990 ). Histoplasmosis after multiple trauma . Pediatr Infect Dis J 9 747 –749 .2235151 \nTsokos G. C. \n(1994 ). Lymphocytes, cytokines, inflammation, and immune trafficking . Curr Opin Rheumatol 6 461 –467 .10.1097/00002281-199409000-00002 7993702 \nWeng C. T. Lee N. Y. Liu M. F. Weng M. Y. Wu A. B. Chang T. W. Lin T. S. Wang J. Y. Chang H. Y. Wang C. R. \n(2010 ). A retrospective study of catastrophic invasive fungal infections in patients with systemic lupus erythematosus from southern Taiwan . Lupus 19 1204 –1209 .10.1177/0961203310368969 20515999 \nWheat L. J. Slama T. G. Norton J. A. Kohler R. B. Eitzen H. E. French M. L. Sathapatayavongs B. \n(1982 ). Risk factors for disseminated or fatal histoplasmosis. Analysis of a large urban outbreak . Ann Intern Med 96 159 –163 .10.7326/0003-4819-96-2-159 7059062\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2053-3721",
"issue": "3(4)",
"journal": "JMM case reports",
"keywords": "amphotericin B; disseminated; histoplasmosis",
"medline_ta": "JMM Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101639133",
"other_id": null,
"pages": "e005035",
"pmc": null,
"pmid": "28348765",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports",
"references": "2235151;19951231;17913863;23065146;7017339;21810734;21539506;7993702;7091948;7059062;11204877;20515999;20388769",
"title": "Progressive disseminated histoplasmosis mimicking a flare of systemic lupus erythematosus: a European case report.",
"title_normalized": "progressive disseminated histoplasmosis mimicking a flare of systemic lupus erythematosus a european case report"
} | [
{
"companynumb": "NL-TEVA-700912ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo describe and discuss the use of maintenance electroconvulsive therapy (ECT) in a young woman with Down syndrome and depression with catatonia.\n\n\nMETHODS\nClinical case report.\n\n\nRESULTS\nA 23-year-old woman with Down syndrome (mosaic type) and a 4-year history of depressed mood triggered by adverse life events presented with mutism, psychomotor retardation, and compromised oral intake. Multiple trials of antidepressant medications were either ineffective or complicated by adverse reactions. She improved rapidly with a course of bilateral ECT but required maintenance ECT to sustain recovery. A series of premorbid, morbid, and post-treatment drawings by the young woman highlight the efficacy of treatment.\n\n\nCONCLUSIONS\nElectroconvulsive therapy was found to be a safe and effective treatment for life-threatening mental illness in a young woman with Down syndrome who had failed multiple trials of antidepressant medications. This case highlights the importance of considering catatonia as a diagnosis in persons with Down syndrome and the effectiveness of electroconvulsive treatment.",
"affiliations": "From the *Centre for Developmental Disability Health Victoria, Monash University and †Mental Health Intensive Care Unit, Prince of Wales Hospital, Randwick, NSW, Australia.",
"authors": "Torr|Jennifer|J|;D'Abrera|Juan Carlos|JC|",
"chemical_list": "D000928:Antidepressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/YCT.0000000000000116",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1095-0680",
"issue": "30(4)",
"journal": "The journal of ECT",
"keywords": null,
"medline_ta": "J ECT",
"mesh_terms": "D000928:Antidepressive Agents; D002389:Catatonia; D003866:Depressive Disorder; D004314:Down Syndrome; D004565:Electroconvulsive Therapy; D005260:Female; D006801:Humans; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9808943",
"other_id": null,
"pages": "332-6",
"pmc": null,
"pmid": "24755717",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Maintenance electroconvulsive therapy for depression with catatonia in a young woman with Down syndrome.",
"title_normalized": "maintenance electroconvulsive therapy for depression with catatonia in a young woman with down syndrome"
} | [
{
"companynumb": "AU-DRREDDYS-USA/AUS/15/0054865",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditio... |
{
"abstract": "The Solitaire (Medtronic Inc, Mansfield, Massachusetts, USA) is a stentriever device for endovascular treatment of acute ischemic stroke. Temporary endovascular bypass and mechanical thrombectomy are well-described applications of this device. However, few reports of permanent stent placement have been published. We present a series of five cases in which the Solitaire stent was implanted to restore distal flow after failure of conventional mechanical thrombectomy. All patients presented with large vessel occlusions with thrombi that were resistant to retrieval or suction-aspiration. Immediately after implantation the patients were given a loading dose of abciximab and then transitioned to dual antiplatelet therapy within 24 hours. Our series suggests that permanent deployment of the Solitaire may be considered as a bailout technique in the treatment of cerebral large vessel occlusion. Long-term antiplatelet therapy is required after deployment.",
"affiliations": "Division of Neurosurgery and Department of Medical Imaging, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.;Division of Neurosurgery and Department of Medical Imaging, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.;Division of Neurosurgery and Department of Medical Imaging, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.;Division of Neurosurgery and Department of Medical Imaging, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.;Division of Neurosurgery and Department of Medical Imaging, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.;Division of Neurosurgery and Department of Medical Imaging, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.",
"authors": "Ahmed|Syed Uzair|SU|;Mann|Jenna|J|;Houde|Jeremie|J|;Barber|Evan|E|;Kelly|Michael E|ME|;Peeling|Lissa|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/neurintsurg-2017-013418",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1759-8478",
"issue": "11(2)",
"journal": "Journal of neurointerventional surgery",
"keywords": "stent; stroke; technique; thrombectomy",
"medline_ta": "J Neurointerv Surg",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001807:Blood Vessel Prosthesis; D002545:Brain Ischemia; D002561:Cerebrovascular Disorders; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000069322:Self Expandable Metallic Stents; D020521:Stroke; D017131:Thrombectomy; D016896:Treatment Outcome",
"nlm_unique_id": "101517079",
"other_id": null,
"pages": "133-136",
"pmc": null,
"pmid": "30154250",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Permanent implantation of the Solitaire device as a bailout technique for large vessel intracranial occlusions.",
"title_normalized": "permanent implantation of the solitaire device as a bailout technique for large vessel intracranial occlusions"
} | [
{
"companynumb": "CA-ROCHE-2268265",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "The induction of CYP2C9 by dabrafenib using S-warfarin as a probe and the effects of a CYP3A inhibitor (ketoconazole) and a CYP2C8 inhibitor (gemfibrozil) on dabrafenib pharmacokinetics were evaluated in patients with BRAF V600 mutation-positive tumors. Dabrafenib single- and repeat-dose pharmacokinetics were also evaluated. S-warfarin AUC(0- ∞) decreased 37% and Cmax increased 18% with dabrafenib. Dabrafenib AUC(0- τ) and C(max) increased 71% and 33%, respectively, with ketoconazole. Hydroxy- and desmethyl-dabrafenib AUC(0-τ) increased 82% and 68%, respectively, and AUC for carboxy-dabrafenib decreased 16%. Dabrafenib AUC(0-τ) increased 47%, with no change in C(max), after gemfibrozil co-administration. Gemfibrozil did not affect systemic exposure to dabrafenib metabolites. Single- and repeat-dose dabrafenib pharmacokinetics were consistent with previous reports. All cohorts used the commercial capsules. More-frequent monitoring of international normalized ratios is recommended in patients receiving warfarin during initiation or discontinuation of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A or CYP2C8 is recommended during treatment with dabrafenib.",
"affiliations": "GlaxoSmithKline, Research Triangle Park, NC, USA.",
"authors": "Suttle|A Benjamin|AB|;Grossmann|Kenneth F|KF|;Ouellet|Daniele|D|;Richards-Peterson|Lauren E|LE|;Aktan|Gursel|G|;Gordon|Michael S|MS|;LoRusso|Patricia M|PM|;Infante|Jeffrey R|JR|;Sharma|Sunil|S|;Kendra|Kari|K|;Patel|Manish|M|;Pant|Shubham|S|;Arkenau|Hendrik-Tobias|HT|;Middleton|Mark R|MR|;Blackman|Samuel C|SC|;Botbyl|Jeff|J|;Carson|Stanley W|SW|",
"chemical_list": "D000925:Anticoagulants; D065687:Cytochrome P-450 CYP2C8 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D014859:Warfarin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D015248:Gemfibrozil; C561627:dabrafenib; D007654:Ketoconazole",
"country": "England",
"delete": false,
"doi": "10.1002/jcph.437",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-2700",
"issue": "55(4)",
"journal": "Journal of clinical pharmacology",
"keywords": "CYP2C8; CYP2C9; CYP3A; dabrafenib; drug interaction",
"medline_ta": "J Clin Pharmacol",
"mesh_terms": "D000925:Anticoagulants; D065687:Cytochrome P-450 CYP2C8 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D005260:Female; D015248:Gemfibrozil; D006801:Humans; D007093:Imidazoles; D007654:Ketoconazole; D008297:Male; D008875:Middle Aged; D010091:Oximes; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D014859:Warfarin",
"nlm_unique_id": "0366372",
"other_id": null,
"pages": "392-400",
"pmc": null,
"pmid": "25449654",
"pubdate": "2015-04",
"publication_types": "D018848:Controlled Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib.",
"title_normalized": "assessment of the drug interaction potential and single and repeat dose pharmacokinetics of the braf inhibitor dabrafenib"
} | [
{
"companynumb": "US-JNJFOC-20150321651",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "KETOCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSerotonin syndrome is a rare but potentially fatal complication of drugs that have effects on central nervous system serotonin. It is characterized by sudden onset of altered mental status, increased neuromuscular activity, and autonomic instability.\n\n\nMETHODS\nThe authors reported a case of serotonin syndrome associated with combined therapy of monoamine oxidase-B inhibitors and selective serotonin reuptake inhibitor A 77-year-old Thai man had been taking escitalopram for depression for three years. He presented with high-grade fever and confusion two days after taking rasagiline for Parkinson's disease. He also had agitation, hallucination, and behavioral change. Escitalopram and rasagiline were discontinued but his renal function worsened, turning to acute kidney injury. He was diagnosed as serotonin syndrome.\n\n\nCONCLUSIONS\nThis is the first case report of serotonin syndrome due to combination of escitalopram and rasagiline used.",
"affiliations": null,
"authors": "Suphanklang|Juthathip|J|;Santimaleeworagun|Wichai|W|;Supasyndh|Ouppatham|O|",
"chemical_list": "D007189:Indans; D017367:Serotonin Uptake Inhibitors; C031967:rasagiline; D015283:Citalopram",
"country": "Thailand",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0125-2208",
"issue": "98(12)",
"journal": "Journal of the Medical Association of Thailand = Chotmaihet thangphaet",
"keywords": null,
"medline_ta": "J Med Assoc Thai",
"mesh_terms": "D000368:Aged; D015283:Citalopram; D003863:Depression; D006801:Humans; D007189:Indans; D008297:Male; D010300:Parkinson Disease; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors; D016896:Treatment Outcome; D028761:Withholding Treatment",
"nlm_unique_id": "7507216",
"other_id": null,
"pages": "1254-7",
"pmc": null,
"pmid": "27004312",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Combination of Escitalopram and Rasagiline Induced Serotonin Syndrome: A Case Report and Review Literature.",
"title_normalized": "combination of escitalopram and rasagiline induced serotonin syndrome a case report and review literature"
} | [
{
"companynumb": "TH-LUPIN PHARMACEUTICALS INC.-2016-01613",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RASAGILINE"
},
"drugadditional... |
{
"abstract": "Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for some inherited disorders, including selected primary immunodeficiencies (PIDs). In the absence of a well-matched donor, HSCT from a haploidentical family donor (HIFD) may be considered. In adult recipients high-dose post-transplant cyclophosphamide (PTCY) is increasingly used to mitigate the risks of graft failure and graft-versus-host disease (GVHD). However, data on the use of PTCY in children (and especially those with inherited disorders) are scarce. We reviewed the outcomes of 27 children transplanted with an HIFD and PTCY for a PID (n = 22) or osteopetrosis (n = 5) in a single center. The median age was 1.5 years (range, .2 to 17). HSCT with PTCY was a primary procedure (n = 21) or a rescue procedure after graft failure (n = 6). The conditioning regimen was myeloablative in most primary HSCTs and nonmyeloablative in rescue procedures. After a median follow-up of 25.6 months, 24 of 27 patients had engrafted. Twenty-one patients are alive and have been cured of the underlying disease. The 2-year overall survival rate was 77.7%. The cumulative incidences of acute GVHD grade ≥ II, chronic GVHD, and autoimmune disease were 45.8%, 24.2%, and 29.6%, respectively. There were 2 cases of grade III acute GVHD and no extensive cGVHD. The cumulative incidences of blood viral replication and life-threatening viral events were 58% and 15.6%, respectively. There was evidence of early T cell immune reconstitution. In the absence of an HLA-identical donor, HIFD HSCT with PTCY is a viable option for patients with life-threatening inherited disorders.",
"affiliations": "Pediatric Hematology-Immunology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM U1163 and Institut Imagine, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France. Electronic address: benedicte.neven@aphp.fr.;Pediatric Hematology-Immunology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France; Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.;Pediatric Hematology-Immunology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.;INSERM U1163 and Institut Imagine, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France; Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.;INSERM U1163 and Institut Imagine, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France; Study Center for Primary Immunodeficiencies, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.;INSERM U1163 and Institut Imagine, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France; Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.;Immunology Laboratory, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.;Pediatric Hematology-Immunology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM U1163 and Institut Imagine, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France.;Pediatric Hematology-Immunology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France.;Pediatric Hematology-Immunology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France.;Pediatric Hematology-Immunology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France.;Pediatric Hematology-Immunology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France.;INSERM U1163 and Institut Imagine, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France.;INSERM U1163 and Institut Imagine, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France; Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.;Functional explorations Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.;Immunology Laboratory, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.;Pediatric Hematology-Immunology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM U1163 and Institut Imagine, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France; Study Center for Primary Immunodeficiencies, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.;Pediatric Hematology-Immunology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM U1163 and Institut Imagine, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France; College de France, Paris, France.;Pediatric Hematology-Immunology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM U1163 and Institut Imagine, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France.;Pediatric Hematology-Immunology and Rheumatology Unit, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris-Descartes University, Sorbonne Paris Cité, Paris, France.",
"authors": "Neven|Bénédicte|B|;Diana|Jean-Sébastien|JS|;Castelle|Martin|M|;Magnani|Alessandra|A|;Rosain|Jérémie|J|;Touzot|Fabien|F|;Moreira|Baptiste|B|;Fremond|Marie-Louise|ML|;Briand|Coralie|C|;Bendavid|Matthieu|M|;Levy|Romain|R|;Morelle|Guillaume|G|;Vincent|Marc|M|;Magrin|Elsa|E|;Bourget|Philippe|P|;Chatenoud|Lucienne|L|;Picard|Capucine|C|;Fischer|Alain|A|;Moshous|Despina|D|;Blanche|Stéphane|S|",
"chemical_list": "D003520:Cyclophosphamide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2019.03.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "25(7)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Haploidentical hematopoietic stem cell transplantation; Immune reconstitution; Inherited disorder; Post-transplant cyclophosphamide; Primary immunodeficiency",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D001327:Autoimmune Diseases; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide; D005260:Female; D030342:Genetic Diseases, Inborn; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D000081207:Primary Immunodeficiency Diseases; D014019:Tissue Donors; D019172:Transplantation Conditioning",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1363-1373",
"pmc": null,
"pmid": "30876929",
"pubdate": "2019-07",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide for Primary Immunodeficiencies and Inherited Disorders in Children.",
"title_normalized": "haploidentical hematopoietic stem cell transplantation with post transplant cyclophosphamide for primary immunodeficiencies and inherited disorders in children"
} | [
{
"companynumb": "FR-ASPEN-GLO2019FR008005",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": n... |
{
"abstract": "OBJECTIVE\nDespite living-donor liver transplant being a life-saving therapy for patients with hepatitis B virus with or without hepatocellular carcinoma, outcomes for patients with these diseases are worse. Hepatitis B virus recurrence or relapse of hepatocellular carcinoma can result in subsequent graft loss or patient death. In this study, we discuss the postoperative outcomes of patients with hepatitis B virus infection after living-donor liver transplant.\n\n\nMETHODS\nWe retrospectively analyzed 125 patients with hepatitis B virus-related end-stage liver disease, comparing results with 1228 control patients who had other pathologies, including hepatitis C virus, combined hepatitis B virus and hepatitis C virus, and neither virus.\n\n\nRESULTS\nSurvival rates of patients with hepatitis B virus did not differ from the control groups (P > .05). Patients with concurrent hepatitis B virus and hepatocellular carcinoma were significantly older (P < .0001), had critical status (P < .0001), had chronic underlying pathology (P = .001), lower graft-to-recipient body weight ratio (P = .047), needed more intraoperative plasma transfusion, and experienced more rejection episodes than those without hepatocellular carcinoma. Of interest, in 5 patients who had hepatitis B virus recurrence after living-donor liver transplant, Model for End-Stage Liver Disease score was significantly higher than those who did not have recurrence (P = .015). In addition, 2 patients had hepatocellular carcinoma recurrence in the form of peritoneal metastasis, with both patients having high preoperative alpha-fetoprotein levels.\n\n\nCONCLUSIONS\nOur study provides details on long-term outcomes of patients with hepatitis B virus infection who had undergone living-donor liver transplant. Based on our results, we suggest that prolonged antiviral prophylactic therapy in the form of hepatitis B immunoglobulin with either lamivudine or entecavir be considered for patients who associated with risk factors to prevent postoperative recurrence.",
"affiliations": "From the Department of Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt; and the Department of Hematology and Immunology, Faculty of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia.",
"authors": "Nafady-Hego|Hanaa|H|;Elgendy|Hamed|H|;Nafady|Asmaa|A|;Uemoto|Shinji|S|",
"chemical_list": "D000998:Antiviral Agents",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2015.0206",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "14(2)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D006528:Carcinoma, Hepatocellular; D002648:Child; D002675:Child, Preschool; D058625:End Stage Liver Disease; D005260:Female; D019694:Hepatitis B, Chronic; D006801:Humans; D007223:Infant; D007564:Japan; D008113:Liver Neoplasms; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014775:Virus Activation; D055815:Young Adult",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "207-14",
"pmc": null,
"pmid": "26867537",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcome of Hepatitis B Virus Infection After Living-Donor Liver Transplant: A Single-center Experience Over 20 Years.",
"title_normalized": "outcome of hepatitis b virus infection after living donor liver transplant a single center experience over 20 years"
} | [
{
"companynumb": "JP-CIPLA LTD.-2016JP01547",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ENTECAVIR"
},
"drugadditional": null,
... |
{
"abstract": "Complications in the accessory pathway in Wolff-Parkinson-White (WPW) syndrome could cause different clinical conditions by inducing different arrhythmias. Atrial fibrillation (AF) is one of these arrhythmias and is important as it causes life-threatening arrhythmias. It is known that some drugs, underlying cardiac diseases, and the number of accessory pathways, cause a predisposition to this condition. In the current report, we presented a patient with WPW who was admitted to the emergency department with AF, wide QRS and a rapid ventricular response that progressed to ventricular fibrillation.",
"affiliations": "Departmant of Cardiology, Aksaray State Hospital, Aksaray, Turkey;;Departmant of Cardiology, Aksaray State Hospital, Aksaray, Turkey;;Departmant of Cardiology, Aksaray State Hospital, Aksaray, Turkey;;Departmant of Cardiology, Aksaray State Hospital, Aksaray, Turkey;;Departmant of Cardiology, Medical Faculty, Erciyes University, Kayseri, Turkey.",
"authors": "Inci|Sinan|S|;Izgu|Ibrahim|I|;Aktas|Halil|H|;Dogan|Pinar|P|;Dogan|Ali|A|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.5582/irdr.2015.01030",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2186-3644",
"issue": "4(3)",
"journal": "Intractable & rare diseases research",
"keywords": "Atrial fibrillation; Wolff-Parkinson-White syndrome; sildenaphil",
"medline_ta": "Intractable Rare Dis Res",
"mesh_terms": null,
"nlm_unique_id": "101586847",
"other_id": null,
"pages": "159-61",
"pmc": null,
"pmid": "26361569",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports",
"references": "10737566;18308751;10910376;16883306;10073864;11321851;64320;9729136",
"title": "Ventricular fibrillation development following atrial fibrillation after the ingestion of sildenaphil in a patient with Wolff-Parkinson-White syndrome.",
"title_normalized": "ventricular fibrillation development following atrial fibrillation after the ingestion of sildenaphil in a patient with wolff parkinson white syndrome"
} | [
{
"companynumb": "TR-PFIZER INC-2015303812",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SILDENAFIL CITRATE"
},
"drugadditional": null,... |
{
"abstract": "Neuroleptic malignant syndrome is a neurological emergency caused by dysregulation of dopaminergic neurotransmission. While it is typically characterized by muscle rigidity, fever and altered mental status, it may have a heterogeneous and non-specific presentation, leading to delays in diagnosis and treatment. Treatment involves cessation of dopamine-receptor antagonists and supportive measures, but in more severe cases, bromocriptine, dantrolene, benzodiazepines and/or electroconvulsive therapy should be considered. We present the case of a 66-year-old man with severe neuroleptic malignant syndrome, diagnosed due to need for continuous invasive ventilation in an Intensive Care Unit, after successful treatment for respiratory sepsis. The patient recovered after electroconvulsive therapy and administration of bromocriptine. This unusually severe case illustrates the need for a high level of suspicion for neuroleptic malignant syndrome in critically ill patients with malignant catatonic syndromes, allowing for an early diagnosis and potentially lifesavingtreatment.",
"affiliations": "Departament of Psychiatry and Mental Health. Hospital Egas Moniz. Centro Hospitalar de Lisboa Ocidental. Lisboa. NOVA Medical School | Faculdade de Ciências Médicas. Universidade NOVA de Lisboa. Lisboa. Champalimaud Research and Clinical Centre. Champalimaud Centre for the Unknown. Lisboa. b. NOVA Medical School | Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal c. Champalimaud Research and Clinical Centre, Champalimaud Centre for the Unkown, Lisboa, Portugal.;Departament of Psychiatry and Mental Health. Hospital Egas Moniz. Centro Hospitalar de Lisboa Ocidental. Lisboa. NOVA Medical School | Faculdade de Ciências Médicas. Universidade NOVA de Lisboa. Lisboa. Champalimaud Research and Clinical Centre. Champalimaud Centre for the Unknown. Lisboa. b. NOVA Medical School | Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal c. Champalimaud Research and Clinical Centre, Champalimaud Centre for the Unkown, Lisboa, Portugal.;Departament of Psychiatry and Mental Health. Hospital Egas Moniz. Centro Hospitalar de Lisboa Ocidental. Lisboa. NOVA Medical School | Faculdade de Ciências Médicas. Universidade NOVA de Lisboa. Lisboa. Champalimaud Research and Clinical Centre. Champalimaud Centre for the Unknown. Lisboa. b. NOVA Medical School | Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal c. Champalimaud Research and Clinical Centre, Champalimaud Centre for the Unkown, Lisboa, Portugal.;Departament of Psychiatry and Mental Health. Hospital Egas Moniz. Centro Hospitalar de Lisboa Ocidental. Lisboa. NOVA Medical School, Faculdade de Ciências Médicas. Universidade NOVA de Lisboa. Lisboa. Champalimaud Research and Clinical Centre. Champalimaud Centre for the Unknown. Lisboa. b. NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal c. Champalimaud Research and Clinical Centre, Champalimaud Centre for the Unkown, Lisboa, Portugal.",
"authors": "Maia|Ana|A|;Cotovio|Gonçalo|G|;Barahona-Corrêa|Bernardo|B|;Oliveira-Maia|Albino J|AJ|",
"chemical_list": "D001569:Benzodiazepines; D003620:Dantrolene",
"country": "Portugal",
"delete": false,
"doi": "10.20344/amp.13019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0870-399X",
"issue": "34(6)",
"journal": "Acta medica portuguesa",
"keywords": "Intensive Care Units; Neuroleptic Malignant Syndrome/diagnosis; Neuroleptic Malignant Syndrome/therapy",
"medline_ta": "Acta Med Port",
"mesh_terms": "D000368:Aged; D001569:Benzodiazepines; D003620:Dantrolene; D005334:Fever; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D009459:Neuroleptic Malignant Syndrome",
"nlm_unique_id": "7906803",
"other_id": null,
"pages": "464-467",
"pmc": null,
"pmid": "32997617",
"pubdate": "2021-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diagnosis and Treatment of Neuroleptic Malignant Syndrome in the Intensive Care Unit: A Case Report.",
"title_normalized": "diagnosis and treatment of neuroleptic malignant syndrome in the intensive care unit a case report"
} | [
{
"companynumb": "PT-TEVA-2020-PT-1846113",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": "1",
... |
{
"abstract": "Serotonin (5-hydroxytryptamine) is a potent vasoconstrictor amine. The authors report three patients who developed thunderclap headache, reversible cerebral arterial vasoconstriction, and ischemic strokes (i.e., the Call-Fleming syndrome). The only cause for vasoconstriction was recent exposure to serotonergic drugs in all patients, and to pseudoephedrine in one patient. These cases, and the literature, suggest that the use of serotonin-enhancing drugs can precipitate a cerebrovascular syndrome due to reversible, multifocal arterial narrowing.",
"affiliations": "Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA. asinghal@partners.org",
"authors": "Singhal|A B|AB|;Caviness|V S|VS|;Begleiter|A F|AF|;Mark|E J|EJ|;Rordorf|G|G|;Koroshetz|W J|WJ|",
"chemical_list": "D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; D004809:Ephedrine",
"country": "United States",
"delete": false,
"doi": "10.1212/wnl.58.1.130",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "58(1)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000328:Adult; D002545:Brain Ischemia; D002536:Cerebral Arteries; D004809:Ephedrine; D005260:Female; D006261:Headache; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017366:Serotonin Receptor Agonists; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "130-3",
"pmc": null,
"pmid": "11781419",
"pubdate": "2002-01-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cerebral vasoconstriction and stroke after use of serotonergic drugs.",
"title_normalized": "cerebral vasoconstriction and stroke after use of serotonergic drugs"
} | [
{
"companynumb": "US-PFIZER INC-2017337993",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXTROMETHORPHAN HYDROBROMIDE"
},
"drugadditio... |
{
"abstract": "To improve prognosis of post-transplant lymphoproliferative disease (PTLD), a sequential therapeutic strategy that rituximab-based treatments followed by donor lymphocyte infusion (DLI) or autologous EBV-specific cytotoxic T lymphocytes (EBV-CTL) for biopsy-proven EBV-associated PTLD in recipients of allogeneic hematopoietic stem cell transplantation was designed. 84 patients with EBV-PTLD were enrolled in this prospective study. After two cycles of the rituximab-based treatments, 68 of 84 patients (81% [95% CI 71-88]) responded and 52 (62% [51-72]) had CRs. This increased to 73 of 77 patients (95% [87-98]) with completion of sequential cell infusions, and 70 of 77 (91% [82-96]) achieved CRs after DLI or autologous EBV-CTL infusion. 22 patients experienced acute GVHD (aGVHD) (grade I in 5 and grade II in 13, grade III in 4) and 13 chronic GVHD (limited cGVHD in 7 and extensive cGVHD in 6) in 62 patients undergoing a median of three doses of DLI. The incidences of GVHD were similar between DLI and EBV-CTL group (aGVHD 35% vs. 33%, p = 0.876; cGVHD 21% vs. 13%; p = 0.503). EBV-CTL activity after the rituximab-based treatments did not change, while increased after cell infusions and reached its maximum in the 3rd or 6th month after EBV-CTL or DLI treatment, respectively. The 5-y cumulative incidence of PTLD relapse was 4.5% ± 3.3%. The 5-y overall survival (OS) and progression-free survival (PFS) after PTLD were 70.7% ± 5.2% and 68.9% ± 5.3%, respectively. Rituximab-based treatments combined with adoptive cellular immunotherapy might elevate CR rates and reduce relapse of PTLD after allo-HSCT.",
"affiliations": "Institution of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou, China.;Institution of Hematology, People's Hospital, Peking University , Beijing, China.;Institution of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou, China.;Institution of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou, China.;Institution of Hematology, People's Hospital, Peking University , Beijing, China.;Institution of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou, China.;Institution of Hematology, Zhujiang Hospital, Southern Medical University , Guangzhou, China.;The First People's Hospital of Chenzhou , Chenzhou, China.;Institution of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou, China.;Institution of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou, China.;Institution of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou, China.;Institution of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou, China.;Institution of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou, China.;Institution of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou, China.;Institution of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou, China.;Institution of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou, China.;Institution of Hematology, People's Hospital, Peking University , Beijing, China.;Institution of Hematology, Nanfang Hospital, Southern Medical University , Guangzhou, China.",
"authors": "Jiang|Xinmiao|X|;Xu|Lanping|L|;Zhang|Yu|Y|;Huang|Fen|F|;Liu|Daihong|D|;Sun|Jin|J|;Song|Chaoyang|C|;Liang|Xinquan|X|;Fan|Zhiping|Z|;Zhou|Hongsheng|H|;Dai|Min|M|;Liu|Can|C|;Jiang|Qianli|Q|;Xu|Na|N|;Xuan|Li|L|;Wu|Meiqing|M|;Huang|Xiaojun|X|;Liu|Qifa|Q|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/2162402X.2016.1139274",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2162-4011",
"issue": "5(5)",
"journal": "Oncoimmunology",
"keywords": "Adoptive cellular immunotherapy; EBV; EBV-CTL; PTLD; donor lymphocyte infusion; hematopoietic stem cell transplantation; relapse; rituximab",
"medline_ta": "Oncoimmunology",
"mesh_terms": null,
"nlm_unique_id": "101570526",
"other_id": null,
"pages": "e1139274",
"pmc": null,
"pmid": "27467959",
"pubdate": "2016-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15707412;16331281;17242396;17522862;8616714;23394705;9207483;22138512;20947485;25246295;21703987;26170206;26337639;24472371;26462561;10961887;22173060;23564232;23085828;23266740;19558376;25185261;8093146;20576725;18836488;15678918;7581076;16149091;20085936;7004534;19822293;11722420;23871780;22337715;19043458;22289799;21792960;20642490;11222357;21440066;18790456;19880495;16254143;21584931;22909192",
"title": "Rituximab-based treatments followed by adoptive cellular immunotherapy for biopsy-proven EBV-associated post-transplant lymphoproliferative disease in recipients of allogeneic hematopoietic stem cell transplantation.",
"title_normalized": "rituximab based treatments followed by adoptive cellular immunotherapy for biopsy proven ebv associated post transplant lymphoproliferative disease in recipients of allogeneic hematopoietic stem cell transplantation"
} | [
{
"companynumb": "CN-ROCHE-1797203",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nSmall cell carcinoma of the esophagus (SCCE) is an uncommon but lethal disease characterized by dismal prognosis. Only 10% of advanced SCCE patients survive longer than 1 year. Resection is a choice for limited-stage cases, whereas the optimal treatment regimen for primary SCCE is yet to be elucidated. To the best of our knowledge, the efficacy of S-1 plus apatinib for irinotecan-refractory SCCE has not been reported before.\nA 61-year old, previously healthy male was admitted for dysphagia and fatigue. Endoscopic biopsy revealed a tumor in the middle third of the esophagus. Further exams including abdomen computed tomography excluded distant metastasis.\nPrimary SCCE (pT1bN1M0, IIB) was established after salvage operation.\n\n\nMETHODS\nThe tumor was enlarged after 1 cycle of first-line chemotherapy using irinotecan plus cisplatin, which indicated drug resistance. Second-line oral apatinib (425 mg daily) plus S-1 (60 mg, twice daily for 4 weeks with a 2-week drug-free interval) for a month showed efficacy, as shown by decreased serum neuron-specific enolase and stable of the esophageal lesion. Thereafter, salvage minimally invasive Ivor-Lewis esophagectomy and 2-field lymph node dissection was performed, followed by oral apatinib plus S-1 at the prior dosage for 6 months. In addition, maintenance therapy using low-dose apatinib (250 mg daily) plus S-1 (40 mg, twice daily for 4 weeks with a 2-week interval) were administered for another 6 months. Then the patient was followed up irregularly at the outpatient clinic.\n\n\nRESULTS\nThe adverse events including hand-foot syndrome, hypertension, vomiting, leukopenia, impaired hepatic function, and fatigue were mainly tolerable. Forty months after the operation, he was readmitted for back pain and disseminated bone metastases appeared in magnetic resonance images. His progression-free survival could not be obtained precisely, and his overall survival was longer than 40 months up to September 2019.\n\n\nCONCLUSIONS\nS-1 plus apatinib followed by a timely esophagectomy with curative intent might be an alternative option for chemotherapy-refractory SCCE in selected patients. Better evidence is warranted.",
"affiliations": "Department of Thoracic Surgery, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing.;Department of Thoracic Surgery, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing.;Department of Surgery, Xuzhou Central Hospital Affiliated to Southeast University, Xuzhou, China.;Department of Surgery, Xuzhou Central Hospital Affiliated to Southeast University, Xuzhou, China.;Department of Surgery, Xuzhou Central Hospital Affiliated to Southeast University, Xuzhou, China.",
"authors": "Zhang|Chu|C|;Yu|Guang-Mao|GM|;Zhang|Miao|M|;Wu|Wenbin|W|;Gong|Long-Bo|LB|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; C553458:apatinib; D010094:Oxonic Acid; D000077146:Irinotecan",
"country": "United States",
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"doi": "10.1097/MD.0000000000018892",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\n32011517\nMD-D-19-05959\n10.1097/MD.0000000000018892\n18892\n5700\nResearch Article\nClinical Case Report\nS-1 plus apatinib followed by salvage esophagectomy for irinotecan-refractory small cell carcinoma of the esophagus\nA case report and review of the literatureZhang Chu MDa Yu Guang-Mao MDa Zhang Miao MDb Wu Wenbin PhDb Gong Long-Bo PhDb∗ NA. a Department of Thoracic Surgery, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing\nb Department of Surgery, Xuzhou Central Hospital Affiliated to Southeast University, Xuzhou, China.\n∗ Correspondence: Long-Bo Gong, Department of Surgery, Xuzhou Central Hospital Affiliated to Southeast University, 199 Jiefang South Road, Xuzhou 221009, China (e-mail: gonglb0804@hotmail.com).\n17 1 2020 \n1 2020 \n99 3 e1889229 7 2019 21 11 2019 23 12 2019 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nSmall cell carcinoma of the esophagus (SCCE) is an uncommon but lethal disease characterized by dismal prognosis. Only 10% of advanced SCCE patients survive longer than 1 year. Resection is a choice for limited-stage cases, whereas the optimal treatment regimen for primary SCCE is yet to be elucidated. To the best of our knowledge, the efficacy of S-1 plus apatinib for irinotecan-refractory SCCE has not been reported before.\n\nPatient concerns:\nA 61-year old, previously healthy male was admitted for dysphagia and fatigue. Endoscopic biopsy revealed a tumor in the middle third of the esophagus. Further exams including abdomen computed tomography excluded distant metastasis.\n\nDiagnoses:\nPrimary SCCE (pT1bN1M0, IIB) was established after salvage operation.\n\nInterventions:\nThe tumor was enlarged after 1 cycle of first-line chemotherapy using irinotecan plus cisplatin, which indicated drug resistance. Second-line oral apatinib (425 mg daily) plus S-1 (60 mg, twice daily for 4 weeks with a 2-week drug-free interval) for a month showed efficacy, as shown by decreased serum neuron-specific enolase and stable of the esophageal lesion. Thereafter, salvage minimally invasive Ivor-Lewis esophagectomy and 2-field lymph node dissection was performed, followed by oral apatinib plus S-1 at the prior dosage for 6 months. In addition, maintenance therapy using low-dose apatinib (250 mg daily) plus S-1 (40 mg, twice daily for 4 weeks with a 2-week interval) were administered for another 6 months. Then the patient was followed up irregularly at the outpatient clinic.\n\nOutcomes:\nThe adverse events including hand-foot syndrome, hypertension, vomiting, leukopenia, impaired hepatic function, and fatigue were mainly tolerable. Forty months after the operation, he was readmitted for back pain and disseminated bone metastases appeared in magnetic resonance images. His progression-free survival could not be obtained precisely, and his overall survival was longer than 40 months up to September 2019.\n\nLessons:\nS-1 plus apatinib followed by a timely esophagectomy with curative intent might be an alternative option for chemotherapy-refractory SCCE in selected patients. Better evidence is warranted.\n\nKeywords\napatinibesophagectomyS-1salvageserratus anterior plane blockOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nPrimary SCCE arises from pluripotent stem cells, accounting for 0.4% to 2.8% of the esophageal malignancies.[1] No treatment consensus in SCCE has been established. The therapeutic options include surgical resection, radiotherapy and chemotherapy, alone or in combination, but their prognosis remains dismal, underlining a need of new therapeutic strategies.\n\nApatinib is a small-molecule agent targeting vascular endothelial growth factor receptor-2 (VEGFR-2). The evidence regarding apatinib and S-1 for chemotherapy-resistance SCCE has not been reported before. Herein we present an irinotecan-refractory primary SCCE patient using S-1 plus apatinib followed by salvage radical esophagectomy, and he obtained an overall survival for more than 40 months. In addition, the literature regarding SCCE was reviewed briefly.\n\n2 Case presentation\nA 61-year-old male without smoking or drinking history was admitted on January 21th, 2016 for gradually aggravated dysphagia and fatigue, with an Eastern Cooperative Oncology Group (ECOG) score of 1. His previous history was unremarkable. Thorough physical examination failed to identify any superficial lesions, thus, laboratory, endoscopic, and radiological tests were conducted. His blood cell counts, hematocrit, hepatic and renal function, cytokeratin-19 fragment, carcinoembryonic antigen, squamous cell carcinoma, and carbohydrate antigen 125 were all in normal range, except significantly elevated serum neuron-specific enolase (NSE) of 133.0 ng/ml (normal range, 0–16.3 ng/ml). Further contrast-enhanced thoracic and abdomen computed tomography (CT) images revealed the significantly thickened middle-third esophageal wall (Fig. 1A). Esophagogastroscopy showed an irregular ulcerated lesion measuring approximately 6.0 cm × 3.0 cm, which was confirmed as primary SCCE by histopathology. Positron emission tomography was not carried out as it was not covered by his insurance. Further cranial magnetic resonance image (MRI) and bone emission computed tomography (ECT) did not indicate obviously enlarged supraclavicular lymph nodes.\n\nFigure 1 CT images of the preoperative tumor and postoperative gastric conduit (indicated by arrows). A. The middle-third esophageal wall was thickened on admission (January 21th, 2016). B. The esophageal lesion was slightly enlarged after 1 cycle of irinotecan and cisplatin. C. The tumor was stable after 1 cycle of second-line S-1 plus apatinib (1 day before surgery). D. Local recurrence was not indicated in gastric conduit about 40 months after Ivor-Lewis esophagectomy.\n\nThe patient was afraid of surgery initially, therefore, first-line chemotherapy using irinotecan hydrochloride injection (Pfizer [Perth] Pty Limited, Australia; 65 mg/m2 of body surface area) combined with cisplatin (Qilu Pharmaceutical Co., Ltd., China; 80 mg/m2 of body surface area) was administered empirically. The efficacy was evaluated by CT images according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). However, the esophageal lesion was slightly thickened (stable disease) after 1 cycle of chemotherapy (Fig. 1B), meanwhile, the serum NSE was significantly elevated to be 217.5 ng/ml. The adverse events (AEs) included grade 2 thrombocytopenia, leukocytopenia, and grade 3 diarrhea according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. In addition, impaired hepatic function was indicated by elevated serum aspartate aminotransferase (AST) (250.7 U/L, normal range 1–40 U/L), and alanine aminotransferase (ALT) (189.6 U/L, normal range 1–40 U/L).\n\nBased on these results, the patient was considered to be chemotherapy-refractory. Then he received second-line oral apatinib (425 mg, once daily) plus S-1 (60 mg, twice daily for 4 weeks with a 2-week drug-free interval, in accordance with his body surface area of 1.7 m2). Encouragingly, efficacy was demonstrated 1 month later, as indicated by decreased serum NSE (70.9 ng/ml) and shrinkage of the esophageal tumor (Fig. 1C).\n\nAccording to the multi-disciplinary consultation and a preoperative workup, the patient was assigned to hybrid minimally invasive Ivor-Lewis esophagectomy and extended two-field lymphadenectomy on March 9th, 2016. A gastric conduit was reconstructed using end-to-side anastomosis in the upper chest.[2] The operation time was 190 minutes, without obvious intraoperative blood loss. Pyloric drainage and jejunostomy for enteral nutrition were not used, except the insertion of a nasogastric tube for gastric decompression. Ultrasound-guided serratus anterior block was performed at the level of the fifth rib,[3] using 0.2% bupivacaine (Marcaine, AstraZeneca, UK) at a dosage of 0.3 ml per kilogram of body weight through a 21-guage needle. Oral feeding was introduced on postoperative day (POD) 5, because no anastomotic leakage was suspected. The postoperative recovery was uneventful, and the patient was discharged on POD 9. R0 resection was achieved. The tumor in the specimen was 3.5 cm × 3 cm × 0.5 cm in size. Postoperative pathological staining revealed positive human epidermal growth factor receptor 2, VEGF, synaptophysin, chromogranin A, neuronal cell adhesion molecules (CD56), and thyroid transcriptional factor-1. The final diagnosis was G3-neuroendocrine carcinoma (small cell carcinoma) of the esophagus (pT1bN1M0, IIB) according to the 8th edition of TNM staging system for esophageal cancer.[4]\n\nThe patient refused postoperative mediastinal radiotherapy for personal reasons. Subsequently, oral S-1 (60 mg, twice daily of the same schedule) combined with apatinib (425 mg, once daily) was continued as adjuvant therapy for 6 months, followed by low-dose apatinib (250 mg, once daily) plus S-1 (40 mg, twice daily of the same schedule) were administered as maintenance therapy for another 6 months. Grade 2/3 AEs including hypertension, vomiting, leukopenia, impaired hepatic function (elevated serum AST and ALT), and hand-foot syndrome were controlled effectively, without grade 4 toxicity. During the adjuvant treatment, the serum NSE was maintained at 11.7 to 15.2 ng/ml (Fig. 3).\n\nThe patient was readmitted to our hospital on July 18th, 2019 for gradually aggravated low back pain and loss of body weight in the previous 1 month, with compromised performance status as the ECOG score was 2. Although the CT showed normal gastric conduit, the MRI revealed disseminated osteolytic lesions in the spine and pelvis (Fig. 2), and distal metastases of SCCE was suspected. However, the patient was reluctant to be involved in a trial of anti-programmed cell death-1 (PD-1) agent, and the oral apatinib and S-1 were discontinued. Best supportive care and zoledronic acid for injection (CHIATAI TIANQING Pharmaceutical Group Co., Ltd; 4 mg every 4 weeks) was administered. The progression-free survival (PFS) of this patient could not be obtained whereas he demonstrated an overall survival (OS) for more than 40 months up to September 2019.\n\nFigure 2 Distant metastasis was shown on his readmission at July 18th, 2019. A. The MRI images showed osteolytic lesions in the ilium. B. Another metastatic lesion was noticeable in lumbar vertebra (indicated by arrows).\n\nFigure 3 The serum NSE of this patient during the therapy.\n\n3 Discussion\nPrimary SCCE is the most common extrapulmonary small cell carcinoma, and most SCCE patients die within 2 years of diagnosis with a median survival of 8 to 13 months.[5] A systemic review of 1176 SCCE cases in China shows that, 89.7% of the tumors are located in middle and lower thoracic esophagus, with an average length of 5.4 cm (0.5–17 cm), and the median OS is 11.1 months.[6] Therefore, investigation regarding the optimal therapy is urgently needed. To the best of our knowledge, this is the first report of apatinib plus S-1 followed by salvage esophagectomy in SCCE.\n\nApatinib monotherapy is preferred in third-line setting of advanced esophageal cancer.[7] The addition of apatinib (500 mg/d) to chemotherapy could further improve the PFS of metastatic gastroesophageal junction adenocarcinoma refractory to 1 or more lines of prior chemotherapy.[8] Although S-1 plus cisplatin has a high rate of AEs,[9] a meta-analysis indicates that this regimen shows a favorable efficacy in gastric cancer,[10] however, the findings of this review should be interpreted cautiously because of the low-quality of the included studies. The major limitations of anti-angiogenic strategy include but not limited to inevitable resistance, lacking individualized efficacy-specific biomarkers.[11]\n\nThe consensus of optimal treatment for SCCE is lacking to date. Stage I/IIA SCCE may be treated by surgical operation alone, especially patients with negative regional lymph nodes, and stage IIB/III disease would not benefit from operation.[12] Systemic therapy could benefit the patients with advanced disease (Stage II-IV).[13] A review of indicates that both esophagectomy and chemoradiation might improve the OS of the patients with limited-stage SCCE.[14] Postoperative chemoradiotherapy does not improve survival in limited stage I (1–2N0M0) cases, however, chemoradiotherapy does not further improve the prognosis in completely resected limited-stage II SCCE patients as compared to chemotherapy alone.[15–17] In detail, esophagectomy is the primary treatment for stage I/IIA SCCE, and neoadjuvant chemotherapy followed by esophagectomy is effective for stage ≥ IIB SCCE.[16,18] Chemotherapy is associated with better survival than surgery alone or radiotherapy alone.[19] Another study indicates that chemoradiotherapy is more effective than surgery and radiotherapy in limited-stage SCCE patients.[20] A Surveillance, Epidemiology, and End Results (SEER) database analysis indicates that induction radiotherapy and surgery are associated with improved survival, suggesting that all SCCE patients should be considered for preoperative radiotherapy and surgery.[21] On the other hand, brain metastases are uncommon in SCCE patients, and the prophylactic cranial irradiation might be unnecessary.[22]\n\nA case report shows that neoadjuvant irinotecan and cisplatin (IP) followed by surgery could achieve long-term survival,[23] while another case series also show that the IP regimen appears to be effective in SCCE.[24] However, the presented case is refractory to irinotecan plus cisplatin but is responsive to S-1 combined with apatinib.\n\nFurthermore, higher lymph node stage, length of tumor >3 cm,[16] the depth of invasion, and chemotherapy are independent prognostic factors of SCCE,[25] which recurs frequently at distant sites within 1 year after curative treatment such as definitive chemoradiotherapy.[26] In addition, the recurrence time of N0/ N1 patients is significantly longer than that of the N2 patients.[27] A review of 313 cases of SCCE shows that, only age (<50 years vs >50 years) and disease stage (limited stage vs extensive stage) are independent prognostic factors, and the median survival for patients with limited-stage is 17.8 months as compared to 4.9 months in those with extensive-stage disease.[28] The OS of the SCCE patients with high NSE levels is worse than those with low NSE, which may be a reliable biomarker of efficacy during definitive chemoradiotherapy.[29]\n\nBased on these findings, although whether surgery can prolong the survival of SCCE patients remains controversial, it seems feasible at least in part for patients with stage I/IIA SCCE. Further large studies are needed for precise selection of patients for whom surgery is indicated. Meanwhile, chemotherapy should always be part of multimodality treatment.\n\nAdditionally, SCCE has a different biological background than small cell carcinomas originating from pulmonary cells.[5] Neuroendocrine neoplasm G3 of the gastrointestinal tract is defined by a proliferation index Ki67 above 20%. Definitive chemoradiotherapy with cisplatin/carboplatin and etoposide is feasible for resectable small cell neuroendocrine carcinoma of the esophagus.[30] Cisplatin plus etoposide is the standard treatment regimen for advanced gastrointestinal neuroendocrine neoplasm, whereas carboplatin in combination with irinotecan could be considered as alternative first-line therapy, however, there is no standard second-line treatment.[31]\n\nLastly, next-generation sequencing enables genome-wide molecular profiling of esophageal malignancies regarding specific oncogenic pathways of tumorigenesis and progression.[32] Immunotherapy treatment response is often durable, therefore, future research should focus on the combination of immunotherapy with other therapeutic modalities to increase response rate.[33] A phase II interventional trial (NCT03811379) of anti-PD-1 Toripalimab (JS001) as monotherapy (240 mg, every 3 weeks until disease progress or intolerable toxicity) for SCCE patients who failed chemotherapy is ongoing, and its estimated completion date is December 30, 2021.\n\nIn summary, oral S-1 plus apatinib followed by salvage esophagectomy might be a reasonable option for selected SCCE patients. However, well-designed trials for better evidence are required to verify our findings.\n\nAuthor contributions\nConceptualization: Long-Bo Gong.\n\nData curation: Chu Zhang.\n\nFormal analysis: Miao Zhang, Wenbin Wu.\n\nFunding acquisition: Guang-Mao Yu, Long-Bo Gong.\n\nMethodology: Chu Zhang.\n\nResources: Guang-Mao Yu.\n\nSupervision: Miao Zhang.\n\nWriting – original draft: Chu Zhang, Long-Bo Gong.\n\nWriting – review & editing: Guang-Mao Yu, Wenbin Wu, Long-Bo Gong.\n\nLong-Bo Gong orcid: 0000-0003-0644-8730.\n\nAbbreviations: CT = computed tomography, ECT = emission computed tomography, MRI = magnetic resonance imaging, ECOG = Eastern Cooperative Oncology Group, AEs = adverse events, PFS = progression-free survival, OS = overall survival, SD = stable disease, VEGF = vascular endothelial growth factor, RECIST 1.0 = response evaluation criteria in solid tumors version 1.0, NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events, NSE = neuron-specific enolase, AST = aspartate aminotransferase, ALT = alanine aminotransferase, ALP = alkaline phosphatase.\n\nHow to cite this article: Zhang C, Yu GM, Zhang M, Wu W, Gong LB. S-1 plus apatinib followed by salvage esophagectomy for irinotecan-refractory small cell carcinoma of the esophagus: A case report and review of the literature. Medicine. 2020;99:3(e18892).\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. The clinical data was treated anonymously for privacy concern.\n\nThis study is supported by Zhejiang Medical and Health Research Fund Project (No.2018KY171).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Nayal B Vasudevan G Rao AC \nPrimary small cell carcinoma of the esophagus - an eight year retrospective study\n. J Clin Diagn Res \n2015 ;9 :EC04 –6\n.\n[2] Mariette C Markar SR Dabakuyo-Yonli TS \nHybrid minimally invasive esophagectomy for esophageal cancer\n. N Engl J Med \n2019 ;380 :152 –62\n.30625052 \n[3] Rahimzadeh P Imani F Faiz SHR \nImpact of the ultrasound-guided serratus anterior plane block on post-mastectomy pain: a randomised clinical study\n. Turk J Anaesthesiol Reanim \n2018 ;46 :388 –92\n.30263863 \n[4] D’journo XB \nClinical implication of the innovations of the 8(th) edition of the TNM classification for esophageal and esophago-gastric cancer\n. J Thorac Dis \n2018 ;10 :S2671 –81\n.30345104 \n[5] Wang F Liu DB Zhao Q \nThe genomic landscape of small cell carcinoma of the esophagus\n. Cell Res \n2018 ;28 :771 –4\n.29728688 \n[6] Lu XJ Luo JD Ling Y \nManagement of small cell carcinoma of esophagus in China\n. J Gastrointest Surg \n2013 ;17 :1181 –7\n.23609140 \n[7] Ter Veer E Haj Mohammad N Van Valkenhoef G \nSecond- and third-line systemic therapy in patients with advanced esophagogastric cancer: a systematic review of the literature\n. Cancer Metastasis Rev \n2016 ;35 :439 –56\n.27417221 \n[8] Guo Y Tang J Huang XE \nEfficacy and toxicity of apatinib combined with or without chemotherapy for patients with advanced or metastatic chemotherapy-refractory gastric adenocarcinoma: A prospective clinical study\n. Medicine (Baltimore) \n2019 ;98 :e13908 .30732125 \n[9] Yang L Wang X Wang B \nThe clinical outcomes of S-1 plus cisplatin for patients with advanced gastric cancer: A meta-analysis and systematic review\n. Medicine (Baltimore) \n2018 ;97 :e12789 .30544367 \n[10] Liu Y Zhou C Zhang K \nThe combination of apatinib and S-1 for the treatment of advanced gastric cancer in China: A meta-analysis of randomized controlled trials\n. Medicine (Baltimore) \n2018 ;97 :e13259 .30461630 \n[11] Procaccio L Damuzzo V Di Sarra F \nSafety and tolerability of anti-angiogenic protein kinase inhibitors and vascular-disrupting agents in cancer: focus on gastrointestinal malignancies\n. Drug Saf \n2019 ;42 :159 –79\n.30649744 \n[12] Purwar P Jiwnani S Karimundackal G \nManagement of esophageal small cell carcinoma\n. Ann Thorac Surg \n2015 ;99 :1488 .\n[13] Ishida H Kasajima A Onodera Y \nA comparative analysis of clinicopathological factors between esophageal small cell and basaloid squamous cell carcinoma\n. Medicine (Baltimore) \n2019 ;98 :e14363 .30813135 \n[14] Wong AT Shao M Rineer J \nTreatment and survival outcomes of small cell carcinoma of the esophagus: an analysis of the National Cancer Data Base\n. Dis Esophagus \n2017 ;30 :1 –5\n.\n[15] Zou B Li T Zhou Q \nAdjuvant therapeutic modalities in primary small cell carcinoma of esophagus patients: a retrospective cohort study of multicenter clinical outcomes\n. Medicine (Baltimore) \n2016 ;95 :e3507 .27124057 \n[16] Xu L Li Y Liu X \nTreatment strategies and prognostic factors of limited-stage primary small cell carcinoma of the esophagus\n. J Thorac Oncol \n2017 ;12 :1834 –44\n.29024756 \n[17] Xie MR Xu SB Sun XH \nRole of surgery in the management and prognosis of limited-stage small cell carcinoma of the esophagus\n. Dis Esophagus \n2015 ;28 :476 –82\n.24787553 \n[18] Chen WW Wang F Chen S \nDetailed analysis of prognostic factors in primary esophageal small cell carcinoma\n. Ann Thorac Surg \n2014 ;97 :1975 –81\n.24726599 \n[19] Raja S Rice TW Rajeswaran J \nEsophageal small-cell cancer: study of a rare disease\n. Dis Esophagus \n2013 ;26 :690 –5\n.23317158 \n[20] Meng MB Zaorsky NG Jiang C \nRadiotherapy and chemotherapy are associated with improved outcomes over surgery and chemotherapy in the management of limited-stage small cell esophageal carcinoma\n. Radiother Oncol \n2013 ;106 :317 –22\n.23498325 \n[21] Kukar M Groman A Malhotra U \nSmall cell carcinoma of the esophagus: a SEER database analysis\n. 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Saudi Med J \n2015 ;36 :297 –303\n.25737171 \n[26] Jeene PM Geijsen ED Muijs CT \nSmall cell carcinoma of the esophagus: a nationwide analysis of treatment and outcome at patient level in locoregional disease\n. Am J Clin Oncol \n2019 ;42 :534 –8\n.31021827 \n[27] Xu X Yang Y Cao L \nLymph node metastasis and recurrence in primary small cell carcinoma of the esophagus: A retrospective study of 125 cases\n. Cancer Biother Radiopharm \n2019 ;doi: 10.1089/cbr.2019.2800. [Epub ahead of print] .\n[28] Al Mansoor S Ziske C Schmidt-Wolf IG \nPrimary small cell carcinoma of the esophagus: patient data metaanalysis and review of the literature\n. Ger Med Sci \n2013 ;11 :Doc12 .23983673 \n[29] Yan H Wang R Jiang S \nNSE can predict the sensitivity to definitive chemoradiotherapy of small cell carcinoma of esophagus\n. Med Oncol \n2014 ;31 :796 .24307347 \n[30] Katada C Komori S Yoshida T \nA retrospective study of definitive chemoradiotherapy in patients with resectable small cell neuroendocrine carcinoma of the esophagus\n. Esophagus \n2019 ;doi: 10.1007/s10388-019-00686-9. [Epub ahead of print] .\n[31] Rinke A Gress TM \nNeuroendocrine cancer, therapeutic strategies in G3 cancers\n. Digestion \n2017 ;95 :109 –14\n.28161703 \n[32] Rubinstein JC Nicolson NG Ahuja N \nNext-generation sequencing in the management of gastric and esophageal cancers\n. Surg Clin North Am \n2019 ;99 :511 –27\n.31047039 \n[33] Lee S Cohen DJ \nPharmacotherapy for metastatic esophageal cancer: where do we need to improve?\n\nExpert Opin Pharmacother \n2019 ;20 :357 –66\n.30526127\n\n",
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"title": "S-1 plus apatinib followed by salvage esophagectomy for irinotecan-refractory small cell carcinoma of the esophagus: A case report and review of the literature.",
"title_normalized": "s 1 plus apatinib followed by salvage esophagectomy for irinotecan refractory small cell carcinoma of the esophagus a case report and review of the literature"
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"abstract": "The authors report a case of spontaneous bilateral diaphyseal femoral fractures believed to be caused by oversuppression of bone remodeling as a result of long-term, high-dose treatment with bisphosphonate. The patient reported pain in both thighs before the fractures. Typical pathologic changes appeared on both femoral radiograph and bone scan before the fractures. Several hours after admission to the emergency department of the authors' institution, the patient underwent closed reduction and internal fixation with intramedullary nails for the bilateral femoral diaphyseal fractures. Treatment with zoledronic acid was immediately discontinued. In recent years, low-energy femoral diaphyseal fractures in patients undergoing long-term bisphosphonate treatment have been reported. It is believed that the prolonged treatment causes long-term suppression of bone remodeling and accumulation of microdamage. It is important to observe patients who are undergoing bisphosphonate treatment carefully. In this case study, the authors report the patient's unique medical history.",
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"authors": "Brin|Yaron S|YS|;Palmanovich|Ezequiel|E|;Heler|Ziv|Z|;Kish|Benyamin Josef|BJ|;Nyska|Meir|M|;Bismuth|Henry|H|;Coughlin|Ryan|R|;Zehavi|Tanya|T|;Rotman|Pnina|P|",
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"abstract": "We retrospectively investigated whether perampanel (PER) could serve as an alternative for treating drug-resistant seizures in lissencephaly. We investigated the following data: age at onset of epilepsy, age at start of PER, etiology, brain MRI findings, seizure type, seizure frequency, adverse effects, and concomitant anti-epileptic drugs. There were 5 patients with lissencephaly, including 2 with Miller-Dieker syndrome. Four out of five patients exhibited ≥ 50% seizure reduction. Myoclonic seizures disappeared in 1 patient. PER was an effective adjunctive anti-seizure drug in our series of patients with lissencephaly.",
"affiliations": "Division of Neurology, Saitama Children's Medical Center, 2-1 Shin-toshin, Chuou-ku, Saitama-city, Saitama 330-8777, Japan.;Division of Neurology, Saitama Children's Medical Center, 2-1 Shin-toshin, Chuou-ku, Saitama-city, Saitama 330-8777, Japan.;Division of Neurology, Saitama Children's Medical Center, 2-1 Shin-toshin, Chuou-ku, Saitama-city, Saitama 330-8777, Japan.;Division of Neurology, Saitama Children's Medical Center, 2-1 Shin-toshin, Chuou-ku, Saitama-city, Saitama 330-8777, Japan.;Department for Child Health and Human Development, Saitama Children's Medical Center, 2-1 Shin-toshin, Chuou-ku, Saitama-city, Saitama 330-8777, Japan.",
"authors": "Ikemoto|Satoru|S|;Hamano|Shin-Ichiro|SI|;Hirata|Yuko|Y|;Matsuura|Ryuki|R|;Koichihara|Reiko|R|",
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"fulltext": "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-3232Elsevier S2213-3232(18)30144-010.1016/j.ebcr.2019.01.001ArticlePerampanel in lissencephaly-associated epilepsy Ikemoto Satoru ike-satoru@hotmail.co.jpab⁎Hamano Shin-ichiro acHirata Yuko abMatsuura Ryuki aKoichihara Reiko ca Division of Neurology, Saitama Children's Medical Center, 2-1 Shin-toshin, Chuou-ku, Saitama-city, Saitama 330-8777, Japanb Department of Pediatrics, The Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo 105-8471, Japanc Department for Child Health and Human Development, Saitama Children's Medical Center, 2-1 Shin-toshin, Chuou-ku, Saitama-city, Saitama 330-8777, Japan⁎ Corresponding author at: Division of Neurology, Saitama Children's Medical Center, 2-1 Shin-toshin, Chuou-ku, Saitama-city, Saitama 330-8777, Japan. ike-satoru@hotmail.co.jp11 1 2019 2019 11 1 2019 11 67 69 7 10 2018 3 1 2019 4 1 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We retrospectively investigated whether perampanel (PER) could serve as an alternative for treating drug-resistant seizures in lissencephaly. We investigated the following data: age at onset of epilepsy, age at start of PER, etiology, brain MRI findings, seizure type, seizure frequency, adverse effects, and concomitant anti-epileptic drugs. There were 5 patients with lissencephaly, including 2 with Miller–Dieker syndrome. Four out of five patients exhibited ≥ 50% seizure reduction. Myoclonic seizures disappeared in 1 patient. PER was an effective adjunctive anti-seizure drug in our series of patients with lissencephaly.\n\nHighlights\n• PER could treat drug-resistant seizures of patients with lissencephaly.\n\n• PER could be effective against epileptic myoclonus in lissencephaly.\n\n• AMPA receptor phenotype in neuronal migration disorder may explain effects of PER.\n\n\n\nAbbreviations\nAMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acidDRPLA, dentatorubral–pallidoluysian atrophyGTCS, generalized tonic–clonic seizuresNMDA, N-methyl-d-aspartatePER, perampanelKeywords\nPerampanelNeuronal migration disorderLissencephaly\n==== Body\n1 Introduction\nAlpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors have long been suggested to play an important role in ictogenesis and epileptogenesis [1]. Perampanel (PER) is a selective noncompetitive AMPA receptor antagonist that was developed for the treatment of epilepsy. PER does not inhibit N-methyl-d-aspartate (NMDA) receptors, a different class of ionotropic glutamate receptors. Recently, it has been reported effective for the treatment of various epileptic disorders, including Lennox–Gastaut syndrome; it has been effective for treatment of myoclonic seizures, such as progressive myoclonus epilepsy; Lafora disease [2], dentatorubral–pallidoluysian atrophy (DRPLA) [3] and Unverricht–Lundborg disease [4].\n\nNeuronal migration disorders include lissencephaly, pachygyria, subcortical band heterotopia (SBH), and periventricular nodular heterotopias, which are rare brain malformations caused by defective neuronal migration during embryonic development. Complete cortical disorganization results in lissencephaly, which typically manifests with drug-resistant epilepsy. Seizures occur in > 90% of children; most children have multiple seizure types including persisting spasms, focal seizures, tonic seizures, and atonic seizures [5]. Most cases of daily seizures are a burden to both patients and caregivers; they commonly fail to exhibit seizure control, despite the use of many anti-seizure drugs for the resolution of seizures [6].\n\nWe retrospectively investigated whether PER could serve as an alternative for treating drug-resistant seizures in lissencephaly.\n\n2 Case report\nWe retrospectively surveyed patients with lissencephaly who were treated with PER at the Saitama Children's Medical Center from 2016 to 2018. A total of 5 patients (4 boys, 1 girls) were included in this study. We retrospectively collected the following clinical data: age at the onset of epilepsy, age at the start of PER, etiology, brain magnetic resonance imaging (MRI) findings, seizure types, seizure frequency before and after PER administration, adverse effects, and concomitant anti-seizure drugs used at the start of PER. PER was administered at 0.04 mg/kg/day, and was increased at 2–4-week intervals. In this study, drug efficacy was defined as ≥ 50% seizure reduction rate at 3 months from the start of PER. Seizure frequency was observed by caregivers in daily life and finally assessed by a pediatric epileptologist.\n\nSince 2016, PER has been approved for use in Japan in patients with epilepsy who are > 12 years of age; it can be used for the adjunctive treatment of primary generalized tonic–clonic seizures (GTCS) and partial-onset seizures. Therefore, informed consent was obtained from the parents or guardians of each patient. For patients < 12 years of age, we explained the nature of the study and obtained age-appropriate assent. This study was approved by the Saitama Children's Medical Center Institutional Review Board [2018-03-05].\n\nClinical data of 5 patients with lissencephaly are shown in Table 1. The median age at onset of epilepsy was 2 months (range: 1 month–6 months). Median age at the start of PER was 7 years, 4 months (range: 2 years, 6 months–16 years, 1 month). Five patients with lissencephaly included 2 with Miller–Dieker syndrome. Gene analysis was performed in 2 patients, 1 with LIS-1 deletion associated with lissencephaly, and 1 in whom the short arm of chromosome 17 was monosomic; FISH analysis confirmed G-banding indicative of Miller–Dieker syndrome. All patients, except patient no. 3, exhibited ≥ 50% seizure reduction (4/5). Notably, myoclonic seizures were effectively managed in patient no. 5. Adverse effects included respiratory failure in 1 patient and mild sedation in 1 patient. Brain MRI was performed in all patients and is shown in Fig. 1.Table 1 Clinical profiles of patients.\n\nTable 1Patient no./sex\tEtiology\tAge at epilepsy onset\tAge at the start of PER\tSeizure type\tSeizure frequency\tConcomitant medication\tAdverse effect\t\nBefore PER\tAfter PER\t\n1/F\tMDS\t6 m\t7 y 4 m\tGT\t20/d\t10/d\tVPA, PB\tRespiratory failure\t\n2/M\tMDS\t1 m\t7 y 10 m\tGT\t10/d\t2/d\tVPA, LEV, TPM, KBr\tSedative effect\t\n3/M\tLIS-1\t2 m\t2 y 6 m\tGT\t10/d\t10/d\tVPA, PHT, ZNS\t\t\n4/M\tUnknown\t2 m\t4 y 0 m\tGT\t5/d\t1/d\tPB, CZP\t\t\n5/M\tUnknown\t4 m\t16 y 1 m\tGT\nMyoclonic sz\t5/d\n3/m\t2/d\n0/m\tVPA, TPM, CZP\t\t\nPerampanel, PER; CZP, clonazepam; d, day; GT, generalized tonic seizure; KBr, potassium bromide; LEV, levetiracetam; m, month; MDS, Miller–Dieker syndrome; PB, phenobarbital; PHT, phenytoin; sz, seizure; TPM, topiramate; VPA, valproic acid; w, week; ZNS, zonisamide.\n\nFig. 1 Representative brain magnetic resonance imaging (MRI) findings in T2-weighted images. Each number indicates patient number in Table 1.\n\nFig. 1\n\n3 Discussion\nIn this retrospective cohort study, PER was effective in the treatment of patients with lissencephaly. A 50% responder rate (50% RR; i.e., at least 50% seizure reduction upon administration of PER) of PER was observed in 4 of 5 patients (80.0%) in our study. A prior adult study reported that the efficacy (50% responder rate) of PER in patients with primary GTCS was 64.2% [7]. Patients with lissencephaly typically exhibit drug-resistant daily seizures. Drug-resistant seizures are a burden to both patients and their caregivers. Most patients with lissencephaly commonly fail to exhibit seizure control, despite the use of many anti-seizure drugs for the resolution of seizures [6]. This case series demonstrated a response to PER in patients with lissencephaly. Interestingly, 1 patient (patient 5) exhibited improvement of daily activities and motor development, including rolling over, and spontaneously began to vocalize. A case report of patients with DRPLA revealed seizure improvement and recovery of activities of daily living [2]. PER might have effects on activities of daily living other than seizure reduction, including for treatment of myoclonic seizure [2], [3], [4]. One patient exhibited epileptic myoclonus in our study and was effectively treated with PER.\n\nIt is important to consider the mechanism by which PER is effective for the treatment of neuronal migrational disorders. Many reports have surveyed neuronal migration, which is affected by a variety of factors [8]. Glutamate plays an essential role in neuronal migration. Glutamate receptors consist of ionotropic receptors: NMDA, AMPA, kainic, and metabolic receptors. AMPA receptors, but not NMDA receptors, are involved in neuronal migration. AMPA receptors play a key role in neuronal migration [9]. Functional AMPA receptors are reportedly expressed by tangentially migrating interneurons in the developing brain, while metabotropic glutamate receptor primarily appears in radial glial cells [10]. Neurons involved in lissencephaly are thought to be immature migrating cells. PER has recently been shown to act on the AMPA receptor. In this context, PER could selectively affect AMPA receptors in immature migrating interneurons, whereas other anti-seizure drugs with other functional mechanisms, including those that use NMDA receptor blockage, may not be effective for patients with lissencephaly. Moreover, a report of the rat kindling model showed that the anti-ictogenic effect of PER is stronger in immature brain [11]. The authors speculated that low expression of the GluA2 subunit of the AMPA receptor in immature neurons may contribute to this effect. AMPA receptors may exhibit a specific phenotype in neuronal migration disorder, which may explain why PER, an AMPA receptor antagonist, may be effective for treatment of lissencephaly.\n\nAdverse effects of PER are largely mild or moderate in severity [12]. Two of 5 patients (40.0%) exhibited adverse effects: sedative effects in 1 patient and respiratory failure in 1 patient. Neuronal migration disorder and complications, concomitant drug treatment, sedative effects and respiratory failure, in the context of the underlying disease, may readily occur in a variety of situations. We regard the PER sedative effect as mild. Indeed, sedative effects and respiratory failure in those patients resolved soon after discontinuation of PER.\n\nA principal limitation of this study is the small number of patients. However, neuronal migrational disorders are relatively rare. In addition, evaluation of anti-seizure drugs was limited to the subjective assessments of seizure frequency dependent on observations by caregivers. Moreover, the mechanism underlying the effectiveness of PER for lissencephaly-associated epilepsy is unknown. Therefore, our study findings are preliminary, and we speculate that PER may be effective.\n\nIn conclusion, PER was an effective adjunctive anti-seizure drug in our series of patients with lissencephaly.\n\nAcknowledgments\nThis research was supported by a grant-in-aid for the Kawano Masanori Memorial Foundation for Promotion of Pediatrics and Research on Measures for Intractable Diseases, No. H29-Nanchi-Ippan-10, from the Ministry of Health, Labour and Welfare, Japan.\n\nDeclarations of interest\nNone.\n\nEthical statement\nWe confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.\n==== Refs\nReferences\n1 Rogawski M.A. Revisiting AMPA receptors as an antiepileptic drug target Epilepsy Curr 11 2011 56 63 21686307 \n2 Goldsmith D. Minassian B.A. Efficacy and tolerability of perampanel in ten patients with Lafora disease Epilepsy Behav 62 2016 132 135 27459034 \n3 Shiraishi H. Efficacy of perampanel for controlling seizures and improving neurological dysfunction in a patient with dentatorubral–pallidoluysian atrophy (DRPLA) Epilepsy Behav Case Rep 8 2017 44 46 28856097 \n4 Crespel A. Gelisse P. Tang N.P. Genton P. Perampanel in 12 patients with Unverricht–Lundborg disease Epilepsia 58 2017 543 547 28166365 \n5 Fogli A. Guerrini R. Moro F. Fernandez-Alvarez E. Livet M.O. Renieri A. Intracellular levels of the LIS1 protein correlate with clinical and neuroradiological findings in patients with classical lissencephaly Ann Neurol 45 1999 154 161 9989616 \n6 Herbt S. LIS-1 associated classic lissencephaly: a retrospective, multicenter survey of the epileptic phenotype and response to antiepileptic drugs Brain Dev 38 2016 399 406 26494205 \n7 French J. Krauss G. Wechsler R. Wang X. DiVentura B. Brandt C. Adjunctive perampanel (PER) for treatment of drug-resistant primary generalized tonic–clonic (PGTC) seizures in patients (PTS) with idiopathic generalized epilepsy (IGE): a double-blind, randomized, placebo-controlled phase III trial Epilepsy Curr 15 2015 367 \n8 Jansson L.C. Louhivuori L. Wigren H.K. Nordström T. Louhivuori V. Castrén M.L. Effect of glutamate receptor antagonists on migrating neural progenitor cells Eur J Neurosci 37 2013 1369 1382 23383979 \n9 Manent J.B. Glutamate acting on AMPA but not NMDA receptors modulates the migration of hippocampal interneurons J Neurosci 31 2006 5901 5909 \n10 Yozu M. Tabata H. König N. Nakajima K. Migratory behaviour of presumptive interneurons is affected by AMPA receptor activation in slice cultures of embryonic neocortex Dev Neurosci 30 2008 105 116 18075259 \n11 Dupuis N. Enderlin J. Desnous B. Desnous B. Dournaud P. Allorge D. Anti-ictogenic and antiepileptogenic properties of perampanel in mature and immature rats Epilepsia 58 2017 1985 1992 28850671 \n12 Plosker G.L. Perampanel: as adjunctive therapy in patients with partial-onset seizures CNS Drugs 26 2012 1085 1096 23179642\n\n",
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"affiliations": "Department of Haemato-Oncology, University College London Hospitals, London, United Kingdom.;Department of Paediatric Haematology and.;Department of Paediatric Immunology, Great Ormond Street Hospital for Children, London, United Kingdom; and.;Department of Paediatric Haematology and.;Department of Paediatric-Haematology, The Newcastle-upon-Tyne Hospital NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom.;Department of Paediatric-Haematology, The Newcastle-upon-Tyne Hospital NHS Foundation Trust, Newcastle-upon-Tyne, United Kingdom.;Department of Paediatric Haematology and.",
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"abstract": "Dravet Syndrome (DS) is burdened by high epilepsy-related premature mortality due to status epilepticus (SE). We surveyed centres within Europe through the Dravet Italia Onlus and EpiCARE network (European Reference Network for Rare and Complex Epilepsies). We collated responses on seven DS SCN1A+ patients who died following refractory SE (mean age 6.9 year, range 1.3-23.4 year); six were on valproate, clobazam, and stiripentol. All patients had previous SE. Fatal SE was always triggered by fever: either respiratory infection or one case of hexavalent vaccination. SE lasted between 80 min and 9 h and all patients received IV benzodiazepines. Four patients died during or within hours of SE; in three patients, SE was followed by coma with death occurring after 13-60 days. Our survey supports the hypothesis that unresponsive fever is a core characteristic feature of acute encephalopathy. We highlight the need for management protocols for prolonged seizures and SE in DS.",
"affiliations": "Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, 00165 Rome, Italy.;Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, 00165 Rome, Italy.;Paediatric Neurology Unit, V. Buzzi Hospital, A.O. ICP, 20019 Milan, Italy.;Department of Child Neurology and Psychiatry, Policlinico Universitario Gemelli Foundation, Catholic University of Rome, 00153 Rome, Italy.;Department of Neurology, Paediatric Neurology, Psychiatry, Neurosurgery, \"Carol Davila\" University of Medicine of Bucharest, Full Member of European Reference Network EpiCARE, 050474 Bucharest, Romania.;Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, 00165 Rome, Italy.;Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, 00165 Rome, Italy.;Centre for Rare Epilepsies, Department of Paediatric Neurology, Necker-Enfants Malades Hospital, Imagine Institute, INSERMU1163, Paris Descartes University, Full Member of European Reference Network EpiCARE, 75006 Paris, France.;Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, 00165 Rome, Italy.",
"authors": "De Liso|Paola|P|;Pironi|Virginia|V|;Mastrangelo|Massimo|M|;Battaglia|Domenica|D|;Craiu|Dana|D|;Trivisano|Marina|M|;Specchio|Nicola|N|0000-0002-8120-0287;Nabbout|Rima|R|;Vigevano|Federico|F|",
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"fulltext": "\n==== Front\nBrain Sci\nBrain Sci\nbrainsci\nBrain Sciences\n2076-3425 MDPI \n\n33238377\n10.3390/brainsci10110889\nbrainsci-10-00889\nArticle\nFatal Status Epilepticus in Dravet Syndrome\nDe Liso Paola 1† Pironi Virginia 12† Mastrangelo Massimo 3 Battaglia Domenica 4 Craiu Dana 5 Trivisano Marina 1 https://orcid.org/0000-0002-8120-0287Specchio Nicola 1 Nabbout Rima 6 Vigevano Federico 1* 1 Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, Full Member of European Reference Network EpiCARE, 00165 Rome, Italy; paola.deliso@opbg.net (P.D.L.); virginia.pironi@gmail.com (V.P.); marina.trivisano@opbg.net (M.T.); nicola.specchio@opbg.net (N.S.)\n2 Center for Rare Diseases and Birth Defects, Department of Woman and Child Health, Institute of Pediatrics, Policlinico Universitario Gemelli Foundation, Catholic University of Rome, 00168 Rome, Italy\n3 Paediatric Neurology Unit, V. Buzzi Hospital, A.O. ICP, 20019 Milan, Italy; massimo.mastrangelo@asst-fbf-sacco.it\n4 Department of Child Neurology and Psychiatry, Policlinico Universitario Gemelli Foundation, Catholic University of Rome, 00153 Rome, Italy; domenicaimmacolata.battaglia@policlinicogemelli.it\n5 Department of Neurology, Paediatric Neurology, Psychiatry, Neurosurgery, “Carol Davila” University of Medicine of Bucharest, Full Member of European Reference Network EpiCARE, 050474 Bucharest, Romania; dcraiu@yahoo.com\n6 Centre for Rare Epilepsies, Department of Paediatric Neurology, Necker-Enfants Malades Hospital, Imagine Institute, INSERMU1163, Paris Descartes University, Full Member of European Reference Network EpiCARE, 75006 Paris, France; rimanabbout@yahoo.com\n* Correspondence: federico.vigevano@opbg.net† Both authors contributed equally to this work.\n\n\n23 11 2020 \n11 2020 \n10 11 88921 10 2020 17 11 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/).Dravet Syndrome (DS) is burdened by high epilepsy-related premature mortality due to status epilepticus (SE). We surveyed centres within Europe through the Dravet Italia Onlus and EpiCARE network (European Reference Network for Rare and Complex Epilepsies). We collated responses on seven DS SCN1A+ patients who died following refractory SE (mean age 6.9 year, range 1.3–23.4 year); six were on valproate, clobazam, and stiripentol. All patients had previous SE. Fatal SE was always triggered by fever: either respiratory infection or one case of hexavalent vaccination. SE lasted between 80 min and 9 h and all patients received IV benzodiazepines. Four patients died during or within hours of SE; in three patients, SE was followed by coma with death occurring after 13–60 days. Our survey supports the hypothesis that unresponsive fever is a core characteristic feature of acute encephalopathy. We highlight the need for management protocols for prolonged seizures and SE in DS.\n\nDravet syndromestatus epilepticusacute encephalopathySCN1Acause of death\n==== Body\n1. Introduction\nDravet syndrome (DS) is a severe developmental and epileptic encephalopathy (DEE) that is usually due to SCN1A genetic variants for the voltage-gated sodium channel Nav1.1. DS is characterized by onset of hemiclonic or generalised fever-triggered seizures within the first year of birth followed by afebrile multiple seizure types. The majority of patients have repeated episodes of status epilepticus (SE), often triggered by fever [1].\n\nMortality is high with DS (range 5.75–10%) [1,2,3], with sudden unexpected death in epilepsy (SUDEP) seemingly more frequent than intractable SE (49% versus 32%) [3]. However, death due to intractable SE is frequent among patients younger than 10 years old (86%), with a peak around 6 years old [2]. SE-related mortality risk might be due to an acute encephalopathy (AE), a potentially fatal complication in children with DS. SE has been reported as the initial manifestation of AE in children with DS, followed by prolonged consciousness disturbance, severe neurological sequalae, or death [4].\n\nDeaths and long-term sequelae due to SE and AE have been increasingly reported over the past decade [4,5,6,7]. Incidence of AE was estimated as between 5.6% and 7.6% from several DS case series [4,7]. Fatal SE and AE usually occur in patients who have already experienced SE without sequelae [4,6,7]. Brain magnetic resonance imaging (MRI) studies performed in closed temporal proximity to the SE are rare but revealed diffuse cerebral oedema [4,6,7].\n\nPossible predictive factors for SE with AE include early age at epilepsy onset (<6 m), epilepsy severity and recurrent SE, age under five years [7,8], and truncating SCN1A mutation [6]. Several hypotheses explain mechanisms leading to death: hemodynamic failure due to duration of SE, cardiac rhythm abnormalities due to SCN1A channelopathy, and effect of drugs for SE on cerebral blood flow [5]. Most authors agreed that highly intractable fever was a constant feature in AE [4,6,7]. Chronic use of benzodiazepines has been considered responsible for SE refractoriness; however, its role was not confirmed [7].\n\nFollowing the death of two of our patients during a febrile refractory SE, we designed a survey with the aim of identifying causative and predisposing factors to fatal SE in DS.\n\n2. Materials and Methods\nWe launched an international request through the Dravet Italia Onlus patients association and the 28 centres affiliated to the European Reference Network on Rare and Complex Epilepsies (EpiCARE) to identify patients with DS who died following generalized convulsive status epilepticus (GCSE). In June 2018, an electronic form was sent to all centres that reported at least one case to collect clinical features, history of epilepsy, and data about the SE leading to death. Patients who died from SUDEP or causes other than SE, or had insufficient clinical data were excluded from our analysis. Patients’ data were collected anonymously (Table 1). The study was approved by the local Ethics Committees.\n\n3. Results\nFour Dravet Italia Onlus centres and six EpiCARE centres responded to our request. Survey forms were returned for ten patients. Seven patients (4 females) fulfilled the inclusion criteria. Four patients came from Italy (3 centres), two from France (1 centre), and one from Romania.\n\nThe median age at death was 2.5 years (range 1.3–23.4 year, mean 6.9, SD 8.1 year). All patients had a SCN1A genetic variant: three truncating, three missense, and one frameshift (Table 1). Mean age at epilepsy-onset (n = 4) was five months (range 4–7 m). During the six months before the fatal SE, two patients were seizure-free, two had rare tonic-clonic seizures, and three had monthly seizures. All patients received polytherapy: six had valproate (VPA) combined with clobazam (CLB) and stiripentol (STP); one had VPA and Topiramate (TPM). All patients had a seizure action-plan for out-of-hospital management; caregivers were instructed on early initiation of paracetamol in case of fever and home rescue-medication with benzodiazepines in case of prolonged or clustering seizures. All patients previously experienced SE, with four having experienced multiple SE events. Previous SE were treated successfully with benzodiazepines for all patients, with three having also received phenytoin or propofol.\n\nIn all cases, SE was triggered by fever and body temperature increased progressively during the SE. Mean (SD) temperature was 40 (1.8) °C (range 38–42 °C). In six patients, fever was associated with respiratory symptoms. In one patient, temperature increased 10 h after vaccination (single dose of DTPa-HBV-IPV/Hib vaccine). Duration of the GCSE ranged from 80 min to 9 h (n = 4). Four patients died within hours of convulsive SE (Table 1). With three patients (#3, #4, #6), SE was followed by a deep coma-state and death after several days (13, 60, and 25 d, respectively). All patients died in hospital.\n\nFollowing the onset of seizures that led to SE, all patients but one received benzodiazepines within 3 to 5 min, and all patients received intravenous anti-seizure medications within 30 min. Four patients received rectal or oromucosal benzodiazepines in an out-of-hospital setting, and all patients had IV benzodiazepines in hospital (Table 1). Phenytoin and propofol were each given to three patients. Patient #6 died 25 days after receiving ketogenic diet as adjunctive treatment. Compared with previous episodes for each patient, no remarkable differences were evident in triggers of SE, type of treatment, or time interval to treatment.\n\nThree patients (#4, #6, #7) underwent a neuroimaging study soon after SE onset (2 had brain MRI and #7 had computerised tomography), which each showed diffuse cerebral oedema (Figure 1). Patient #6 also had brain MRI 20 days after SE onset, which showed cortical and subcortical atrophy. Although requested on the survey form, no data from autopsy were available.\n\n4. Discussion\nWe describe seven patients with DS who died following SE. Death followed two distinct developments: four patients died during or within a few hours of SE beginning; the SE of three patients evolved into a coma-like state until death several days later. The latter progression to death has been described more frequently in the literature (Table 2).\n\nCerebral oedema, persistent seizure activity, and hypoxia might explain the ultimate cause of death in patients with DS and fatal SE. According to reported data, a massive brain oedema is evident during the early phase of AE, quickly leading to death or severe brain damage. Neuroradiologic findings from the three of our patients who received a brain MRI in the early phase did indeed have evidence of brain oedema.\n\nSeveral hypotheses for development of cerebral oedema in patients with DS have been proposed, though a complex of these mechanisms could underlie the pathogenesis. Ultimately, cerebral oedema in patients with epilepsy might be due to the excessive influx of sodium and calcium ions into neurons [9]. That hyperthermia induces epileptic seizures in DS is well known, and these might lead to post-ictal respiratory failure and cardiac arrest, and subsequently to neuronal sodium-ion influx. The latter could also be directly due to the mutations in SCN1A.\n\nSE is known to be the second most common cause of death in DS, though deaths from SE occur more frequently in patients younger than 10 years old. Several patients have been reported to have died from SE in previous case series [2,4,6,7,10,11,12,13,14,15,16], but few cases had their clinical features described (Table 2) [4,6,7].\n\nDemographic data of our patients are consistent with those previously reported and support that children under the age of six years have a higher risk of SE with AE [7,8]. However, one of our patients (#1) was a young adult, which we believe is only the second patient reported in literature to have died from SE in adulthood, the other being reported by Genton et al. in less detail [11]. Similarly, a 17 year-old from the UK was reported to have died from SE, but clinical data are unavailable for comparison [12].\n\nAll our patients were treated with anti-seizure medications (ASMs) recommended for DS. None of the patients was on known potentially aggravating ASMs. Propofol was used for the treatment of SE in only three out of seven patients, so—if a putative contributor to cerebral oedema—this was not a risk factor common to all patients. Moreover, some data from animals exposed to propofol have been reported to support attenuation of cerebral oedema after transient cerebral ischaemia [17].\n\nAt the time of the SE leading to death, patients had variable control of seizures; moreover, two patients were seizure-free in the preceding 6 months. These data support that death can occur unpredictably, including in patients with seemingly good seizure-control. Six of our patients were taking an ASM regimen that included STP; in contrast, only one patient was on STP in previously reported series [6]. Even if STP was demonstrated to decrease significantly prolonged seizures and motor SE frequency [18], it seems that it does not prevent the occurrence of fatal SE. All patients had previously received appropriate treatment based on the current recommendations; however, we acknowledge that none was treated with newly approved drugs for DS, such as cannabidiol and fenfluramine. Based on our observation, we suggest an early use of new compounds that might be effective in reducing the recurrence of SE and potentially protect patients with DS from fatal evolution of SE.\n\nHigh body temperature was reported as a key factor in the development of AE [4,6]. Presumed viral infections are frequently reported and these as a possible triggering factor is consistent with the AE pathogenesis reported by Mizuguchi and colleagues [19]. With Patient #5, fever was triggered by a second dose of hexavalent vaccine. Vaccination has been previously reported to be a trigger for febrile seizures with SCN1A genetic variants [20]. McIntosh et al. reported that 45% of DS patients who presented a first seizure in proximity of vaccination might experience a SE [21]. Tsuij et al. described a patient with DS with a SE associated with AE after influenza vaccination; fortunately, without a fatal outcome [22]. Recently, Deng et al. reported a fatal SE following vaccination in a 12 month-old boy with SCN1A genetic variant [23]; clinical phenotype of this patient was suggestive of ‘generalized epilepsy with febrile seizures plus’ (GEFS+) rather than DS. Notably, this patient had a febrile illness before vaccination, so other aetiological agents could plausibly have been involved in this catastrophic outcome. Therefore, we suggest particular attention is required during vaccination of patients with DS and, in our opinion, tailored recommendations are needed.\n\nThe role of fever and immune mechanisms should be further investigated to clarify if AE can be considered as a DS-specific complication or as the extreme spectrum of an immune-mediated disorder [19]. However, such a high mortality with SE or AE has not been described for other DEE that share with DS a sensitivity to fever, such as PCDH19-Girl Clustering Epilepsy [24]. Nevertheless, cases of death from SE and SUDEP are also reported with GEFS+, highlighting that death may also occur in patients with a less severe epileptic phenotype than DS [23,25].\n\nThe presence of sodium-channel variants may have further increased the SUDEP risk. Noteworthy is that SCN1B genetic variants have also been associated with cardiac arrhythmias, including Brugada and long QT-interval syndromes [26]. These data suggest that sodium-channel mutations might play a crucial role in causing AE and SUDEP [27].\n\nWith respect to emergency care, most patients died in local hospitals and time was minimal for transfer to the reference centre for rare epilepsies of their regional hospital; SE developed and progressed rapidly and did not allow time for referral. Hence, a SE-management protocol for DS should be available for patients and carers. Rapid access to specific recommendations for management of fever and prolonged or repetitive seizures in this syndrome should be available to emergency room physicians unfamiliar with this syndrome and some psychiatric intensive care-unit physicians away from the reference centres.\n\n5. Conclusions\nThis retrospective analysis of patients who died during a SE supports—albeit weakly—the hypothesis that unresponsive fever is a core characteristic feature of AE. Treatment of fever should be part of the management plan for prolonged seizures in DS and families should be instructed on its management. Vaccination requires close monitoring [28].\n\nConsidering chronic treatment, current recommendations for the treatment of DS should be implemented with inclusion of newer compounds, since any protection of existing drugs against fatal events remains undiscovered. Since fatal SE is a rare, unpredictable event, increased effort to collect the few data available and request for post-mortem examination might enhance the understanding of the mechanisms of this acute event.\n\nAcknowledgments\nThe authors thank Isabella Brambilla and Italia Dravet Onlus, and all physicians in the EpiCARE network for their kind cooperation; they also thank Charlotte Dravet for her helpful advice and suggestions.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor Contributions\nConceptualization, P.D.L. and F.V.; methodology, P.D.L., F.V., N.S., R.N., V.P.; formal analysis P.D.L., V.P., M.T., D.C., M.M., D.B.; data curation, P.D.L., V.P., M.T., D.C., M.M., D.B.; writing—original draft preparation, P.D.L., V.P.; review and editing, F.V., N.S., R.N.; supervision, F.V. 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\nAbbreviations\nAE\tacute encephalopathy\t\nASMs\tanti-seizure medications\t\nDEE\tdevelopmental and epileptic encephalopathy\t\nDS\tDravet syndrome\t\nEpiCARE\tEuropean Reference Network on Rare and Complex Epilepsies\t\nGEFS+\tgeneralized epilepsy with febrile seizures plus\t\nGCSE\tgeneralized convulsive status epileptic\t\nMRI\tmagnetic resonance imaging\t\nSE\tstatus epilepticus\t\nSUDEP\tsudden unexpected death in epilepsy\t\nFigure 1 Brain MR of patient #6. (A). Axial T2 weighted MR at 6 months of age with no abnormalities. (B). Axial T1 weighted MR after 20 h from SE onset, showing diffuse brain edema.\n\nbrainsci-10-00889-t001_Table 1Table 1 Clinical features, epilepsy history, and fatal status epilepticus.\n\nPt\tSex\tAge at Epilepsy Onset (m)\tAge at Death (y)\tSCN1A Variant\tSeizures during the 6 Months before Death\tOngoing ASMs\tPrevious SE\tTreatment of Previous SE\tTrigger of SE\tSE Duration (min)\tBody Temperature (°C)\tNeuroimaging after SE Onset\tSE Treatment\t\n1\tM\tNA\t23.4\tc.5414-5415delTT (p.Phe1805Stop)\tNo seizures\tVPA, CLB, STP, TPM, PER\tYes\tDZP\tFlu\t120\t42\tnp\tRectal DZP (at home), IV MDZ\t\n2\tM\t4\t2.5\tc.17_18dupTT (p.Val7Leufsx86)\tfocal, 1/m, <10 min\tVPA, TPM\tYes\tDZP\tNSFI\t80\t38\tnp\tVPA, TPM\t\n3\tM\tNA\t4.8\tc.664T>C (p.Arg222*)\tGTC, 1-3/m, 8–30 min; focal, 2–3/m, 10–20 min\tVPA, CLB, STP\tYes\tDZP, MDZ\tNSFI\tNA\tNA\tnp\tPHT, DZP, MDZ, propofol\t\n4\tF\tNA\t11.9\tc.2503T>A (p.Leu835Met)\tGTC, rare, <10 min\tVPA, CLB, STP\tYes\tDZP, MDZ, PHT\tFever, respiratory distress, ab ingestis pneumoniae\tNA\t40\tnp\tRectal DZP (at home), IV MDZ, IV LEV, IV PHT\t\n5\tF\t4\t2.5\tc.4934G>A (p.Arg1645Gln)\tno seizures\tVPA, CLB, STP\tYes\tMDZ, Propofol\tFever, vaccination (DTPa-HBV-IPV-Hib)\t150\t38\tnp\tRectal DZP, IV MDZ, propofol\t\n6\tF\t5\t2.3\tc.1837C>T (p.Arg613*)\tGTC, monthly, long lasting; focal, rare, brief\tVPA, CLB, STP, CLZ\tYes\tMDZ, DZP, CLZ PHT\tRSV infection\t(25 days)\t42\tMRI: significant cytotoxic oedema in the grey matter and cortex\tOromucosal MDZ, CZP; PHT; MDZ; propofol; LEV; KD\t\n7\tF\t7\t1.3\tc.4427A>G (p.Asn1476Ser)\tGTC rare brief\tVPA, CLB, STP, LEV\tYes\tDZP, MDZ, CLZ\tNSFI\t540\t40\tCT scan: diffuse cerebral oedema\tMDZ\t\nASMs, anti-seizure medications; CLB, clobazam; CLZ, clonazepam; CT, computerised tomography; DZP, diazepam; F, female; Flu, influenza-like symptoms; GTC, generalized tonic-clonic; KD, ketogenic diet; LEV, levetiracetam; M, male; MDZ, midazolam; MRI, magnetic resonance imaging; NA, not available; np, not performed; NSFI, nonspecific febrile illness; PER, perampanel; PHT, phenytoin; Pt, patient; RSV, respiratory syncytial virus; SE, status epilepticus; STP, stiripentol; TPM, topiramate; VPA, valproic acid.\n\nbrainsci-10-00889-t002_Table 2Table 2 Published cases of death of patients with Dravet syndrome presenting acute encephalopathy during status epilepticus.\n\nAuthor\tSex\tAge at Epilepsy Onset (m)\tAge at Death (y)\tSCN1A Variant\tHistory of SE\tSeizures Frequency\tOngoing ASMs at Death\tFatal SE Trigger\tDuration of SE (h)\tTemp (°C)\tFatal SE Treatment\t\nOkumura, 2012 [4]\tM\t3\t4.4\tR568X\t3\tmonthly *\tVPA, CZP, KBr\tFlu\t4\tNA\tDZP, PHT, TL MDZ\t\nOkumura, 2012 [4]\tF\t3\t1.1\tR701X\t0\tnone *\tVPA, CZP, PB\tNSFI\t3\tNA\tDZP, MDZ, PHT, PTB, TP\t\nOkumura, 2012 [4]\tM\t5\t15.3\tnp\t1\tmonthly *\tVPA, ZNS, NZP\tURI\t1\tNA\tDZP, MDZ\t\nOkumura, 2012 [4]\tM\t4\t3.6\tnp\t7\tmonthly *\tVPA, ZNS, CLB\tNSFI\t5\tNA\tDZP, MDZ, PB, TP\t\nMyers, 2017 [6]\tNA\tNA\t5\tc.5347G>A, p. Ala1783thr\tseveral\tseizure free **\tVPA, TPM\tURI, Flu (A+)\t1.25\t40\tMDZ, PHT, TP\t\nMyers, 2017 [6]\tNA\tNA\t8\tc.5741_5742delAA, p.Gln1914fs*1943\t3\t1–2/year\tVPA, TPM\tabdominal pain, diarrhoea\t1.5\t43.7\tMDZ, PHT\t\nMyers, 2017 [6]\tNA\tNA\t11\tc. 4633A>G\tseveral\tseizure free ^\tVPA, TPM, STP\tsore throat\t2\t41\tMDZ, PB\t\nMyers, 2017 [6]\tNA\tNA\t5\tc.4970G>A, p. Arg1657His\t12\t2 seizures ^^\tLTG, VPA\tviral URI\t4\t40\tMDZ, DZP, PHT, TP, PB\t\nMyers, 2017 [6]\tNA\tNA\t0.8\tc.3136delG, p.Asp1046Metfs*1055\t0\t1–2/m, long lasting\tTPM, LEV\tviral URI\t1.5\t40\tCZP, MDZ, PHT\t\nTian, 2018 [7]\tF\t5\t3\tR101W\t2–3/year\tmonthly\tVPA, LEV\tNA\t2\t39.3\tNA\t\nTian, 2018 [7]\tM\t2.5\t4\tV422A\t3–4/year\tmonthly\tVPA, LEV\tNA\t2\t40.5\tNA\t\nTian, 2018 [7]\tM\t5.5\t5\tL556fsX\t4–5/year\tmonthly\tVPA, TPM\tNA\t4\t40.4\tNA\t\nTian, 2018 [7]\tF\t5\t10\tR612X\t1–2/year\tmonthly\tVPA, LEV, CZP\tNA\t2\t39.5\tNA\t\nTian, 2018 [7]\tF\t4\t3\tW1286X\t4–5/year\tmonthly\tVPA, LEV\tNA\t2\t39.3\tNA\t\nTian, 2018 [7]\tF\t5\t5\tA1783T\t2–3/year\tyearly\tVPA, TPM\tNA\t3\t40.6\tNA\t\nTian, 2018 [7]\tM\t2\t4.2\tc659-1G>A\t1–2/year\tmonthly\tVPA, TPM, CZP\tNA\t3\t39.5\tNA\t\nTian, 2018 [7]\tF\t4\t5.2\tR1892X\t2–3/year\tmonthly\tVPA, TPM\tNA\t2\tnormal\tNA\t\nTian, 2018 [7]\tM\t5\t3.4\tF1699S\t2–3/year\tmonthly\tVPA, LEV\tNA\t5\t39.5\tNA\t\nTian, 2018 [7]\tM\t5\t1.3\tQ1904X\t2–3/year\tyearly\tVPA, TPM\tNA\t5\t40.2\tNA\t\nTian, 2018 [7]\tF\t3\t2.7\tS243Y\t1–2/year\tmonthly\tCZP, LEV, ZNS\tNA\t12\t40.3\tNA\t\nTian, 2018 [7]\tF\t4.5\t3.3\tI1810N\t1–2/year\tmonthly\tVPA, LEV\tNA\t2\t39.5\tNA\t\n* Seizure frequency refers to the last 3 months before the acute encephalopathy (AE); ** Seizure frequency refers to the last 5 months before the AE; ^ Seizure frequency refers to the last 18 months before the AE; ^^ Seizure frequency refers to the last 9 months before the AE. AE, acute encephalopathy; ASMs, anti-seizure medications; CLB, clobazam; CZP, clonazepam; DZP, diazepam; F, female; Flu, influenza-like symptoms; KBr, potassium bromide; LEV, levetiracetam; LTG, lamotrigine; M, male; MDZ, midazolam; NA, not available; np, not performed; NSFI, nonspecific febrile illness; PB, phenobarbital; PER, perampanel; PHT, phenytoin; SE, status epilepticus; STP, stiripentol; TL, thiamylal; TP, thiopental; TPM, topiramate; URI, upper respiratory tract infection; VPA, valproic acid; ZNS, zonisamide.\n==== Refs\nReferences\n1. Dravet C. Oguni H. Cokar O. Guerrini R. Dravet Syndrome (Previously Severe Myoclonic Epilepsy in Infancy) Epileptic Syndromes in Infancy, Childhood and Adolescence John Libbey Eurotext Ltd. Montrouge, France 2019 139 172 \n2. Sakauchi M. Oguni H. Kato I. Osawa M. Hirose S. Kaneko S. Takahashi Y. Takayama R. Fujiwara T. 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Severe myoclonic epilepsy in infants--a review based on the Tokyo Women’s Medical University series of 84 cases Brain Dev. 2001 23 736 748 10.1016/S0387-7604(01)00276-5 11701288 \n15. Akiyama M. Kobayashi K. Yoshinaga H. Ohtsuka Y. A long-term follow-up study of Dravet syndrome up to adulthood Epilepsia 2010 51 1043 1052 10.1111/j.1528-1167.2009.02466.x 20041943 \n16. Dravet C. Bureau M. Guerrini R. Giraud N. Roger J. Severe Myoclonic Epilepsy in Infancy Epileptic Syndromes in Infancy, Childhood and Adolescence John Libbey Eurotext Ltd. Montrouge, France 1992 75 88 \n17. Lee J.H. Cui H.S. Shin S.K. Kim J.M. Kim S.Y. Lee J.E. Koo B.-N. Effect of propofol post-treatment on blood-brain barrier integrity and cerebral edema after transient cerebral ischemia in rats Neurochem. Res. 2013 38 2276 2286 10.1007/s11064-013-1136-7 23990224 \n18. De Liso P. Chemaly N. Laschet J. Barnerias C. Hully M. Leunen D. Desguerre I. Chiron C. Dulac O. Nabbout R. Patients with dravet syndrome in the era of stiripentol: A French cohort cross-sectional study Epilepsy Res. 2016 125 42 46 10.1016/j.eplepsyres.2016.05.012 27389706 \n19. Mizuguchi M. Yamanouchi H. Ichiyama T. Shiomi M. Acute encephalopathy associated with influenza and other viral infections Acta Neurol. Scand. Suppl. 2007 186 45 56 10.1111/j.1600-0404.2007.00809.x 17784537 \n20. Berkovic S.F. Harkin L. McMahon J.M. Pelekanos J.T. Zuberi S.M. Wirrell E.C. Gill D.S. Iona X. Mulley J.C. Scheffer I.E. De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: A retrospective study Lancet Neurol. 2006 5 488 492 10.1016/S1474-4422(06)70446-X 16713920 \n21. McIntosh A.M. McMahon J. Dibbens L.M. Iona X. Mulley J.C. Scheffer I.E. Berkovic S.F. Effects of vaccination on onset and outcome of Dravet syndrome: A retrospective study Lancet Neurol. 2010 9 592 598 10.1016/S1474-4422(10)70107-1 20447868 \n22. Tsuji M. Mazaki E. Ogiwara I. Wada T. Iai M. Okumura A. Yamashita S. Yamakawa K. Osaka H. Acute encephalopathy in a patient with Dravet syndrome Neuropediatrics 2011 42 78 81 10.1055/s-0031-1279725 21647847 \n23. Deng L. Ma A. Wood N. Ardern-Holmes S. Vaccination management in an asymptomatic child with a novel SCN1A variant and family history of status epilepticus following vaccination: A case report on a potential new direction in personalised medicine Seizure 2020 78 49 52 10.1016/j.seizure.2020.03.005 32193085 \n24. Trivisano M. Specchio N. The role of PCDH19 in refractory status epilepticus Epilepsy Behav. 2019 101 106539 10.1016/j.yebeh.2019.106539 31678000 \n25. Myers K.A. Shevell M.I. Sébire G. Sudden unexpected death in GEFS+ families with sodium channel pathogenic variants Epilepsy Res. 2019 150 66 69 10.1016/j.eplepsyres.2019.01.009 30660056 \n26. Riuró H. Campuzano O. Arbelo E. Iglesias A. Batlle M. Pérez-Villa F. Brugada J. Pérez G.J. Scornik F.S. Brugada R. A missense mutation in the sodium channel β1b subunit reveals SCN1B as a susceptibility gene underlying long QT syndrome Heart Rhythm 2014 11 1202 1209 10.1016/j.hrthm.2014.03.044 24662403 \n27. Myers K.A. Bello-Espinosa L.E. Symonds J.D. Zuberi S.M. Clegg R. Sadleir L.G. Buchhalter J. Scheffer I.E. Heart rate variability in epilepsy: A potential biomarker of sudden unexpected death in epilepsy risk Epilepsia 2018 59 1372 1380 10.1111/epi.14438 29873813 \n28. Wirrell E.C. Laux L. Donner E. Jette N. Knupp K. Meskis M.A. Miller I. Sullivan J. Welborn M. Berg A.T. Optimizing the Diagnosis and Management of Dravet Syndrome: Recommendations From a North American Consensus Panel Pediatr. Neurol. 2017 68 18 34 10.1016/j.pediatrneurol.2017.01.025 28284397\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2076-3425",
"issue": "10(11)",
"journal": "Brain sciences",
"keywords": "Dravet syndrome; SCN1A; acute encephalopathy; cause of death; status epilepticus",
"medline_ta": "Brain Sci",
"mesh_terms": null,
"nlm_unique_id": "101598646",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33238377",
"pubdate": "2020-11-23",
"publication_types": "D016428:Journal Article",
"references": "28330972;21463280;29692967;29873813;22092154;30660056;29573403;24662403;23990224;16713920;21647847;21719429;31678000;28284397;32193085;27389706;21463290;17784537;20447868;27810515;27732919;11701288;20041943;20172746;21463279",
"title": "Fatal Status Epilepticus in Dravet Syndrome.",
"title_normalized": "fatal status epilepticus in dravet syndrome"
} | [
{
"companynumb": "IT-ACI HEALTHCARE LIMITED-2104154",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": n... |
{
"abstract": "Voriconazole is the recommended agent of choice for treatment of invasive aspergillosis; however, achieving therapeutic serum concentrations while avoiding toxicity, both with intravenous and oral formulations, is challenging in infants. We report the case of an infant with confirmed invasive aspergillosis who developed renal toxicity possibly associated with IV voriconazole. Renal function improved upon withdrawal of the IV agent and switch to the oral formulation. The infant subsequently required large oral weight-based dosing to achieve therapeutic voriconazole serum concentrations. This case illustrates a rare side effect associated with voriconazole as well as the issues surrounding the pharmacokinetic profile of voriconazole in a pediatric patient.",
"affiliations": null,
"authors": "Walldorf|Jenny A|JA|;Kishk|Omayma A|OA|;Campbell|James D|JD|;Lardieri|Allison B|AB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5863/1551-6776-23.1.54",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-6776",
"issue": "23(1)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "adverse effect; aspergillosis; drug-related side effects; infant; therapeutic drug monitoring; voriconazole",
"medline_ta": "J Pediatr Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101089851",
"other_id": null,
"pages": "54-58",
"pmc": null,
"pmid": "29491753",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "24510446;27009030;22450974;21768513;22430956;23114771;18171251;19845698;25859166;22761409;20660687;22751544;14616409;19951112;7249508;23320795;22190607;19075073;19340528",
"title": "Voriconazole: Poor Oral Bioavailability and Possible Renal Toxicity in an Infant With Invasive Aspergillosis.",
"title_normalized": "voriconazole poor oral bioavailability and possible renal toxicity in an infant with invasive aspergillosis"
} | [
{
"companynumb": "US-PFIZER INC-2018100780",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": ": Opioid use disorder and its associated mortality have become national epidemic problems. Different measures and regulations have been implemented to curb this trend, including stricter opioid prescribing practice. With the decreased access to prescription opioids, individuals with opioid use disorder have explored alternatives including loperamide, a peripheral opioid mu-receptor agonist. There are reports of increased loperamide misuse, dependence, and mortality rate in the past few years from poison control centers, medical examiners' offices, and clinical settings. Here, we report a case of loperamide use disorder, which led to the death of the patient. Associated clinical features and treatment of loperamide use disorder, including management of intoxication and withdrawal, and long-term maintenance therapy are discussed along with potential prescribing and sale regulations to manage this newly emerging substance use disorder.",
"affiliations": "Department of Psychiatry, Sanford Medical School, University of South Dakota (AO); Sioux Falls Veterans Health Care System, Sioux Falls, SD (AO, XL).",
"authors": "Okusanya|Ayodeji|A|;Li|Xiaofan|X|",
"chemical_list": "D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D008139:Loperamide",
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000440",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1932-0620",
"issue": "12(6)",
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D062787:Drug Overdose; D017809:Fatal Outcome; D006801:Humans; D008139:Loperamide; D008297:Male; D009293:Opioid-Related Disorders; D017450:Receptors, Opioid, mu",
"nlm_unique_id": "101306759",
"other_id": null,
"pages": "496-498",
"pmc": null,
"pmid": "30067552",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Loperamide Abuse and Dependence: Clinical Features and Treatment Considerations.",
"title_normalized": "loperamide abuse and dependence clinical features and treatment considerations"
} | [
{
"companynumb": "US-BION-007360",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LOPERAMIDE HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "The authors present a man with Huntington disease who was treated with levetiracetam (Keppra) in an effort to reduce chorea. Chorea was markedly reduced, but the patient developed parkinsonism and lethargy after 6 weeks of treatment. Symptoms consisted of resting tremor, rigidity, increased dystonia, and gait difficulty. Side effects from levetiracetam resolved completely within 7 days of levetiracetam discontinuation, and chorea returned to baseline.",
"affiliations": "Parkinson's Disease and Movement Disorders Center, NPF Centers of Experience, Department of Neurology, University of South Florida Tampa, Florida 33612, USA. tzesiewi@hsc.usf.edu",
"authors": "Zesiewicz|Theresa A|TA|;Sanchez-Ramos|Juan|J|;Sullivan|Kelly L|KL|;Hauser|Robert A|RA|",
"chemical_list": "D014150:Antipsychotic Agents; D018697:Nootropic Agents; D000077287:Levetiracetam; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1097/01.wnf.0000169732.00690.32",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "28(4)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D014150:Antipsychotic Agents; D003704:Dementia; D020233:Gait Disorders, Neurologic; D006801:Humans; D006816:Huntington Disease; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D009127:Muscle Rigidity; D009483:Neuropsychological Tests; D018697:Nootropic Agents; D010302:Parkinson Disease, Secondary; D010889:Piracetam; D014202:Tremor",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "188-90",
"pmc": null,
"pmid": "16062099",
"pubdate": "2005",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Levetiracetam-induced parkinsonism in a Huntington disease patient.",
"title_normalized": "levetiracetam induced parkinsonism in a huntington disease patient"
} | [
{
"companynumb": "US-PFIZER INC-2014324923",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PAROXETINE\\PAROXETINE HYDROCHLORIDE"
},
"drug... |
{
"abstract": "BACKGROUND\nDissecting cellulitis of the scalp (DCS), also known as Hoffmann disease or perifolliculitis capitis abscedens et suffodiens, is a rare disease characterized by chronic inflammation of the scalp. Treatment is difficult and often disappointing.\n\n\nOBJECTIVE\nTo report our experience of TNF inhibitors in a series of patients with DCS.\n\n\nMETHODS\nWe conducted a monocentric retrospective study of nine patients with DCS treated with TNF blocker after failure of other conventional treatments.\n\n\nRESULTS\nAfter a mean duration of treatment by TNF inhibitors of 17 ± 16 months, four patients (44% versus 0%) had a Physician's Global Assessment score of 0 or 1. We observed a 67% reduction in the number of inflammatory nodules, an 88% reduction in purulent drainage and a 45% improvement in Dermatology Life Quality Index. The mean treatment satisfaction index was 6.6 ± 1.6 out of 10.\n\n\nCONCLUSIONS\nOur study suggests that TNF inhibitors are effective against disease activity and may improve quality of life in the management of DCS refractory to conventional treatments.",
"affiliations": "Dpt of Dermatology and Inserm Unit 1098 RIGHT, University of Franche Comté and University Hospital, Besançon, France.;Dpt of Dermatology and Inserm Unit 1098 RIGHT, University of Franche Comté and University Hospital, Besançon, France.;Dpt of Dermatology and Inserm Unit 1098 RIGHT, University of Franche Comté and University Hospital, Besançon, France.;Dpt of Dermatology and Inserm Unit 1098 RIGHT, University of Franche Comté and University Hospital, Besançon, France.;Dpt of Dermatology and Inserm Unit 1098 RIGHT, University of Franche Comté and University Hospital, Besançon, France.;Dpt of Dermatology and Inserm Unit 1098 RIGHT, University of Franche Comté and University Hospital, Besançon, France.;Dpt of Dermatology and Inserm Unit 1098 RIGHT, University of Franche Comté and University Hospital, Besançon, France.;Dpt of Dermatology and Inserm Unit 1098 RIGHT, University of Franche Comté and University Hospital, Besançon, France.",
"authors": "Frechet|Laure|L|;Puzenat|Eve|E|;Charollais|Romain|R|;Dresco|Flora|F|;Carlet|Clémentine|C|;Gallais-Serezal|Irène|I|;Nardin|Charlée|C|;Aubin|François|F|",
"chemical_list": "D000079424:Tumor Necrosis Factor Inhibitors",
"country": "France",
"delete": false,
"doi": "10.1684/ejd.2021.3969",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1167-1122",
"issue": "31(1)",
"journal": "European journal of dermatology : EJD",
"keywords": "adalimumab; infliximab; issecting cellulitis of the scalp",
"medline_ta": "Eur J Dermatol",
"mesh_terms": "D000328:Adult; D002481:Cellulitis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012536:Scalp Dermatoses; D012873:Skin Diseases, Genetic; D000079424:Tumor Necrosis Factor Inhibitors; D055815:Young Adult",
"nlm_unique_id": "9206420",
"other_id": null,
"pages": "81-85",
"pmc": null,
"pmid": "33648906",
"pubdate": "2021-02-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Dissecting cellulitis of the scalp treated by tumour necrosis factor inhibitors: a case series.",
"title_normalized": "dissecting cellulitis of the scalp treated by tumour necrosis factor inhibitors a case series"
} | [
{
"companynumb": "FR-CELLTRION INC.-2021FR014762",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "The rapidly expanding cases of the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have exposed vulnerable populations, including pregnant women to an unprecedented public health crisis. Recent data show that pregnancy in COVID-19 patients is associated with increased hospitalization, admission of the intensive care unit, and intubation. However, very few resources exist to guide the multidisciplinary team in managing critically ill pregnant women with COVID-19. We report our experience with managing a morbidly obese pregnant woman at 36 weeks' gestation with history of asthma and malignancy who presented with persistent respiratory symptoms at an outside hospital after being tested positive for SARS-CoV-2 polymerase chain reaction (PCR). Early in the course of the hospitalization, patient received remdesivir, convalescent plasma, bronchodilator, systemic steroids, and IV heparin for COVID-19 and concomitant asthma exacerbation and pulmonary embolism. Due to increasing oxygen requirements, she was eventually intubated and transferred to our institution for higher level of care. Respiratory acidosis, severe hypoxemia, and vent asynchrony were managed with vent setting adjustment and paralytics. After 12 hours from spontaneous rupture of her membranes and with stabilization of maternal status, patient underwent a term cesarean delivery for nonreassuring fetal heart tracing. The neonate was discharged on the 2nd day of life, while the patient was extubated on the 6th postpartum day and was discharged to acute inpatient rehabilitation facility on the 19th hospital day. This report highlights the disease progression of COVID-19 in a pregnant woman, the clinical challenges in the critical care aspect of patient management, and the proposed multidisciplinary strategies utilizing an algorithmic approach to optimize maternal and neonatal outcomes.",
"affiliations": "Department of Medicine, Einstein Medical Center Philadelphia, Philadelphia, PA, USA.;Department of Obstetrics and Gynecology, Einstein Medical Center Philadelphia, Philadelphia, PA, USA.;Department of Medicine, Einstein Medical Center Philadelphia, Philadelphia, PA, USA.;Department of Medicine, Einstein Medical Center Philadelphia, Philadelphia, PA, USA.;Division of Maternal Fetal Medicine, Einstein Medical Center Philadelphia, Philadelphia, PA, USA.;Department of Obstetrics and Gynecology, Einstein Medical Center Philadelphia, Philadelphia, PA, USA.;Department of Medicine, Einstein Medical Center Philadelphia, Philadelphia, PA, USA.",
"authors": "Pelayo|Jerald|J|https://orcid.org/0000-0002-5603-7078;Pugliese|Gabriella|G|;Salacup|Grace|G|;Quintero|Eduardo|E|;Khalifeh|Adeeb|A|;Jaspan|David|D|;Sharma|Bhavna|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/8889487",
"fulltext": "\n==== Front\nCase Rep Crit Care\nCase Rep Crit Care\nCRICC\nCase Reports in Critical Care\n2090-6420 2090-6439 Hindawi \n\n33083063\n10.1155/2020/8889487\nCase Report\nSevere COVID-19 in Third Trimester Pregnancy: Multidisciplinary Approach\nhttps://orcid.org/0000-0002-5603-7078Pelayo Jerald pelayoje@einstein.edu\n1\n Pugliese Gabriella \n2\n Salacup Grace \n1\n Quintero Eduardo \n1\n Khalifeh Adeeb \n3\n Jaspan David \n2\n Sharma Bhavna \n1\n\n4\n\n5\n \n1Department of Medicine, Einstein Medical Center Philadelphia, Philadelphia, PA, USA\n\n2Department of Obstetrics and Gynecology, Einstein Medical Center Philadelphia, Philadelphia, PA, USA\n\n3Division of Maternal Fetal Medicine, Einstein Medical Center Philadelphia, Philadelphia, PA, USA\n\n4Division of Pulmonary and Critical Care and Sleep Medicine, Einstein Medical Center Philadelphia, Philadelphia, PA, USA\n\n5Sidney Kimmel College of Thomas Jefferson University, Philadelphia, PA, USA\nAcademic Editor: Mehmet Doganay\n\n\n2020 \n14 10 2020 \n2020 888948723 7 2020 13 9 2020 27 9 2020 Copyright © 2020 Jerald Pelayo et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The rapidly expanding cases of the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have exposed vulnerable populations, including pregnant women to an unprecedented public health crisis. Recent data show that pregnancy in COVID-19 patients is associated with increased hospitalization, admission of the intensive care unit, and intubation. However, very few resources exist to guide the multidisciplinary team in managing critically ill pregnant women with COVID-19. We report our experience with managing a morbidly obese pregnant woman at 36 weeks' gestation with history of asthma and malignancy who presented with persistent respiratory symptoms at an outside hospital after being tested positive for SARS-CoV-2 polymerase chain reaction (PCR). Early in the course of the hospitalization, patient received remdesivir, convalescent plasma, bronchodilator, systemic steroids, and IV heparin for COVID-19 and concomitant asthma exacerbation and pulmonary embolism. Due to increasing oxygen requirements, she was eventually intubated and transferred to our institution for higher level of care. Respiratory acidosis, severe hypoxemia, and vent asynchrony were managed with vent setting adjustment and paralytics. After 12 hours from spontaneous rupture of her membranes and with stabilization of maternal status, patient underwent a term cesarean delivery for nonreassuring fetal heart tracing. The neonate was discharged on the 2nd day of life, while the patient was extubated on the 6th postpartum day and was discharged to acute inpatient rehabilitation facility on the 19th hospital day. This report highlights the disease progression of COVID-19 in a pregnant woman, the clinical challenges in the critical care aspect of patient management, and the proposed multidisciplinary strategies utilizing an algorithmic approach to optimize maternal and neonatal outcomes.\n==== Body\n1. Introduction\nDeemed as one of the most profound public health threats over the past decades, COVID-19 has now been reported from all continents except for Antartica, affecting 7,124,043 individuals in 118 countries with the recorded mortality rate of 5.7% as of June 8, 2010 [1]. It has exposed vulnerable populations, including the pregnant patients, to an unparalleled global health crisis.\n\nOutcomes from multiple studies demonstrated a significant risk of morbidity and mortality among pregnant women infected by influenza, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS) compared to nonpregnant women [2–4]. Based on the previous limited data, this particular patient population is not at higher risk for developing severe disease due to COVID-19 compared to the general population [1, 5, 6]. However, the most recent data from the Centers for Disease Control and Prevention (CDC) showed the pregnant women with COVID-19 are more likely to be hospitalized, admitted to the intensive care unit, and intubated [7].\n\nData on the effect of COVID-19 in pregnancy in large retrospective study of 119 pregnant women and systematic review of 109 pregnancies showed a 2.7% to 6.9% incidence rate of severe infection requiring ICU admission with no maternal deaths [8, 9]. However, there has been no one-size-fits-all approach in managing critically ill pregnant women with COVID-19 given unique physiologic maternal adaptations and important management and ethical considerations. Furthermore, few contemporary resources are available to guide the multidisciplinary team through decisions regarding intensive care strategies, optimal maternal-fetal surveillance, and route as well as timing of delivery.\n\nWe present a case of a woman at 36 weeks' gestation who had a rapid clinical deterioration from COVID-19-related ARDS to highlight clinical challenges and potential strategies through multidisciplinary team approach to optimize maternal and neonatal outcomes.\n\n2. Case Presentation\nPatient is a 35-year-old G4P1-1-1-2 with a past medical history notable for mild intermittent asthma, hepatitis C, gastric carcinoid tumor, ileal malignant carcinoma S/P hemicolectomy, morbid obesity (body mass index of 51 kg/m2), abdominal hernia s/p mesh repair, bipolar, and anxiety disorder, with a confirmed SARS-CoV2 PCR after a recent known exposure to a positive household contact. She was admitted to a tertiary care hospital after failing self-quarantine measures at home, with persistent nonproductive cough, hemoptysis and worsening shortness of breath without significant response to frequent albuterol nebulization at home. At the time of admission, age of gestation by the last menstrual period (LMP) was 36 2/7 weeks. At presentation, she was normotensive, tachycardic, and tachypneic but not hypoxic on room air. She had diffuse wheezing and rhonchi on lung auscultation. Significant laboratory findings include thrombocytopenia (98,000/uL), normocytic anemia with normal haptoglobin level (145 mg/ml), elevated LDH of 264 IU/L with mild transaminitis (AST 53 IU/L, ALT 53 IU/L) without schistocytes on peripheral blood smear and normal bilirubin levels, elevated ferritin (140 ng/mL), and D-dimer (2810 ng/mL). The nonstress test was reactive with reassuring fetal heart tracing. Chest radiograph (Figure 1) showed worsening bilateral pulmonary opacities compared to the previous (Figure 2). CT pulmonary angiography demonstrated extensive bilateral ground-glass opacities with peripheral distribution, small bilateral pleural effusion, and multiple bilateral intraluminal filling defects of the pulmonary arteries suggestive of pulmonary embolism (Figures 3 and 4).\n\nThe patient was admitted to the general medical floor where she received convalescent plasma transfusion, in addition to bronchodilators and intravenous methylprednisolone. She was started on a 10-day course of remdesivir treatment. Over the next four days, she had increasing oxygen requirement from 4 L to 12 L via nasal cannula to keep her oxygen saturation above 92%. On the 5th day of admission, patient was noted to be agitated and hypoxic to 88% on 40 L of oxygen via a combination of nasal cannula with nonrebreather mask on it. During this time, fetal heart tracing was reassuring. Tocogram showed contractions every 4 to 6 minutes. She was then transferred to the medical intensive care unit (MICU) to attempt high flow nasal cannula (HFNC). After persistent hypoxia on HFNC, the decision was made to intubate the patient. Mechanical ventilation with assist control/volume control settings includes tidal volume (TV) of 500 ml (7 ml/kg), respiratory rate (RR) of 25, positive end expiratory pressure (PEEP) of 14, and fraction of inspired oxygen (FiO2) of 100%. Heparin, cis-atracurium, fentanyl, and propofol drips were initiated and continued. She was then transferred to our institution via air ambulance for higher level of care.\n\nMaternal-fetal medicine (MFM), obstetric, neonatal, and medical intensive care teams were alerted prior to arrival. Patient arrived to our MICU sedated and intubated. She was initially requiring vecuronium pushes to achieve vent synchrony and oxygen saturation above 92%. Chest radiograph did show worsening of lower lobe predominant diffuse reticular and alveolar airspace opacifications (Figure 5). Mechanical ventilation settings were modified to TV of 460 ml (6 ml/kg), RR of 24, PEEP of 12, and 100% FiO2. Arterial blood gas (ABG) on this setting includes a pH of 7.19, PaCO2 of 63 mmHg, and PaO2 of 80 mmHg. The computed PaO2 : FiO2 ratio was 80 indicative of severe acute respiratory distress syndrome (ARDS). The respiratory rate was increased to 28/minute. On exam, her membranes had spontaneously ruptured, and her cervix was dilated to 4 cm and 50% effaced. Bedside ultrasound showed decreased amniotic fluid index and cephalic presentation. The fetal heart rate was 135 beats per minutes (bpm) with overall minimal variability and positive acceleration response on scalp stimulation. Induction of labor with IV oxytocin was started with initial plan to attempt vaginal delivery with the assisted second stage. However, plans for emergency cesarean delivery were in place in the event it was indicated. IV heparin was continued. This plan was reviewed in the multidisciplinary approach including the medical and neonatal intensive care, obstetric, MFM, and anesthesiology teams.\n\nEight hours after admission, patient was saturating in the high 88-91% range on a PEEP of 12 and 100% FiO2. ABG on this setting showed a pH of 7.21, PaCO2 of 55 mmHg, and PaO2 of 82 mmHg. Plateau pressure was high, ranging between 38 and 40 cm H20.This was partially due to patient's body habitus, morbid obesity, and a gravid uterus. The severe hypoxemia was deemed potentially harmful to the fetus, and various options were considered to improve patient's oxygenation.\n\nGiven her gravid uterus, active labor, and BMI >50 kg/m2, prone ventilation was not an option. As a rescue measure, PEEP was then increased to 16 despite the high plateau pressure and RR to 32/minute. She received additional doses of paralytics to maintain vent synchrony. IV heparin was held in preparation for imminent delivery. Given the mother's severe hypoxia and potential for deterioration due to fluid shifts during delivery, extracorporeal membrane oxygenation (ECMO) was also discussed. An emergent discussion was held with another tertiary care hospital within the city with ECMO expertise. The patient was accepted there, in case she required ECMO, and our cardiothoracic surgeon was on board to establish femoral and jugular access in anticipation of emergent ECMO needs in the operating room, with improvement of oxygen status and respiratory acidosis, respectively, as evidenced by pH of 7.31, PaCO2 43 mmHg, and PaO2 377 mmHg on repeat ABG. FiO2 was then decreased to 90%.\n\nCervical dilatation remained relatively unchanged over the next hour or so, with three contractions palpated to be occurring within 10 minutes. Fetal heart monitoring showed minimal variability with no acceleration response on scalp stimulation. In view of this nonreassuring fetal heart tracing, the decision was made to proceed with cesarean delivery in the operating room. The medical intensive care, obstetric, MFM, neonatal intensive care, anesthesiology, cardiothoracic surgery teams were in coordination to ensure the stability of the patient and to address anticipated fetomaternal complications. Patient remained stable throughout the cesarean section and did not require ECMO.\n\nShe gave birth to an early term male infant with APGAR scores of 1 at 1st minute, 2 at 5th minute, and 4 at 10th until the 20th minute. As anticipated prior to delivery, the neonate required invasive mechanical ventilation, due to prolonged exposure to sedatives and paralytics from the mother. He needed bag mask ventilation with 100% FiO2 without return of spontaneous breathing. The heart rate was less than 60 beats per minute (bpm) requiring 30-second chest compression. After 5 minutes, the heart rate was 120 bpm; however, he was hypoxic to 85% while on 100% FiO2 necessitating mechanical ventilation. Neonate was then admitted to neonatal ICU which was tested for SARS-CoV2 which turned out negative twice. The following day, patient's baby was extubated to room air and was subsequently released on his 3rd day of life to his aunt for primary care as his father was still positive for SARS-COV2.\n\nIn the interim, patient received a five-day course vancomycin and ceftriaxone for sputum culture growing Haemophilus influenzae and methicillin-resistant Staphyloccus aureus. There was a very low suspicion for bacterial superinfection given transient fever, mild leukocytosis with lymphocytic predominance, and absence of consolidation on chest radiograph. Most of the treatment were geared towards supportive management for COVID-19 and acute respiratory distress syndrome.\n\nOn the other hand, patient remained intubated, with decreasing oxygen requirements in the postpartum period. Her hypoxia improved significantly after delivery, despite a newly diagnosed cardiomyopathy as evidenced with 45% ejection fraction on echocardiography. IV heparin was resumed 6 hours postpartum. She was eventually extubated to bilevel positive airway pressure (BiPAP) on the 6th day of intubation. She developed postextubation stridor necessitating administration of racemic epinephrine and solumedrol. She finished the 10-day course of remdesivir and 5-day course of IV methylprednisolone. IV heparin was also transitioned to subcutaneous enoxaparin. Patient was discharged to acute inpatient rehabilitation facility after 19 days of hospitalization.\n\n3. Discussion\nThis case highlights the clinical course of the COVID-19 infection in a pregnant woman with multiple comorbidities, the importance of taking into consideration physiologic maternal adaptations, and the intricate critical care aspects in managing the patient with anticipated fetomaternal complications from COVID-19-related ARDS and as well as the multidisciplinary approach to optimize maternal and neonatal outcomes (Figure 6).\n\nPatient's current pregnancy with her comorbidities including malignancy, asthma ,and morbid obesity further complicated by pulmonary embolism during her hospitalization may have largely contributed to the development of severe acute respiratory distress syndrome (ARDS) in the setting of COVID-19 pneumonia [7–11].\n\nMany potential challenges confronted the medical and neonatal intensive care, obstetric, and maternal fetal medicine teams in managing patient's severe hypoxemia with severe ARDS. It is of paramount importance to take into consideration maternal physiologic adaptations to pregnancy. Apart from leaving the woman more vulnerable to cell-mediated viral infection such as COVID-19, pregnant women are more susceptible to rapid cardio-pulmonary decompensation due to reduced cardiac and pulmonary reserves [12]. Particularly in the third trimester, the gravid uterus decreases functional residual capacity and expiratory reserve volume, which can potentially increase the risk of severe hypoxemia especially those who are critically ill [13]. Moreover, the physiologic adaptations to labor, delivery, and the immediate postpartum should also be considered as these could exacerbate the dysregulated inflammatory cascade in the setting of an underlying severe systemic infection. These physiologic changes include significant fluid shifts between the interstitial, intracellular, and intravascular compartments, maximization of the maternal cardiac output, autotransfusion of up to 500 mL of blood back into the intravascular compartment, catecholamine surge, and release of inflammatory mediators within the endothelium [11]. These in the setting of COVID-19 infection could place the patient at a higher risk for developing endothelial dysfunction, pulmonary edema, myocardial edema, and cardiac dysfunction [14]. Such considerations were at the forefront, in the minds of the entire medical and surgical team in optimizing patient's oxygenation while she was mechanically ventilated before, during and after the delivery.\n\nWhile patient's labor was induced with IV oxytocin, options to improve patient's oxygenation prior to the contemplated delivery were maximized. First, ventilatory goals include consideration for the diminished functional residual capacity, higher PEEP requirement, greater physiologic tidal volume, and less lung compliance from higher innate plateau pressures due to diaphragmatic compression by the gravid uterus and rotund abdomen and chest wall compression from enlarged breast tissue [12, 15]. These presented a challenge to the “lung protective” strategy for mechanical ventilation in pregnant patients. It was then reasonable to increase the PEEP and FiO2 of this patient to meet oxygenation target. Second is the use of neuromuscular blocking agents with sedation in the early phase of ARDS. It was found to have added clinical benefit by minimizing the manifestations of ventilator-induced lung injury by reducing pulmonary and systemic production of inflammatory mediators [14]. Patient did receive cis-atracurium drip in another hospital before transfer and intermittent vecuronium pushes while admitted to our ICU. Patient ended up with cesarean delivery at term for nonreassuring fetal heart status with stable maternal status after correcting respiratory acidosis and achieving oxygenation goals. This is congruous with the result of a systematic review and meta-analysis showing increased cesarean delivery rate among pregnant women with COVID-19 [16].\n\nAlthough the safety and efficacy of prone ventilation in pregnancy has been documented [17, 18], patient's weight, size and active labor precluded the performance of this maneuver. Pregnancy is also a contraindication for prone ventilation per our institutional policy. Thus, venovenous ECMO was considered as a life-saving salvage therapy in the event of worsening oxygenation and hemodynamic compromise during and after the delivery [19]. Cardiothoracic surgeon placed central venous access in the internal jugular and femoral veins prior to the cesarean delivery, in anticipation of ECMO. In the interim, patient was already accepted in another tertiary hospital for ECMO should the need arise.\n\nAs most of the trials for treatment of COVID-19 exclude pregnant women, few agents although available remain investigational in terms of their clinical utility. These include remdesivir, systemic steroids, and convalescent plasma which are offered in different hospitals under compassionate-use protocol [20–22]. After a lengthy discussion, patient and her husband provided consent for the administration of the remdesivir and convalescent plasma early in the course of patient's hospitalization. Timely initiation of bronchodilator and steroid therapy, as well as IV heparin for asthma exacerbation and pulmonary embolism, respectively, might have afforded additional benefit leading to patient's excellent overall clinical outcomes.\n\nAs to the neonatal outcome, patient's baby improved clinically after resuscitation and mechanical ventilation for 24 hours. Cardiorespiratory depression was likely secondary to prolonged maternal exposure to sedation and paralytics. The SARS-CoV-2 PCR test of the baby turned out negative which is consistent with recent findings documenting no evidence of vertical transmission in women with COVID-19 pneumonia [6, 23].\n\nA proposed algorithmic approach to the management of a parturient with severe COVID-19 is included in this report (Figure 7). This entailed valuable input from multiple disciplines involving the medical and neonatal intensive care, obstetric, MFM, anesthesiology, and cardiothoracic surgery teams. A framework utilizing direct open communication that optimized team dynamics was established, along with active involvement of patient's husband in the decision-making vis-à-vis available therapeutic options. Maternal and neonatal outcomes were excellent as a result of highly coordinated care through a multidisciplinary approach.\n\nData Availability\nThe data used to support the findings of this study are included within the article.\n\nConflicts of Interest\nNone of the authors have any conflicts of interest to disclose.\n\nFigure 1 Chest radiograph on admission at the outside hospital showing interval worsening of hazy airspace opacities in the bilateral mid to lower lung fields.\n\nFigure 2 Chest radiograph on prior ED visit showing haziness overlying the right mid and lower lung fields.\n\nFigure 3 CT Pulmonary angiography (coronal section) showing extensive bilateral ground-glass and consolidative opacities with peripheral distribution and small bilateral pleural effusion.\n\nFigure 4 CT Pulmonary angiography (axial section) showing extensive bilateral ground-glass and consolidative opacities with peripheral distribution, small bilateral pleural effusion, and multiple bilateral intraluminal filling defects.\n\nFigure 5 Chest radiograph shows interval worsening of bilateral lower lobe predominant diffuse reticular and alveolar airspace opacifications with trace bilateral pleural effusions.\n\nFigure 6 Summary of multidisciplinary management and outcomes of our COVID-19 pregnant patient.\n\nFigure 7 Proposed algorithm for multidisciplinary management of a parturient with severe COVID-19.\n==== Refs\n1 World health organization COVID19 situation reports 2020 https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports \n2 Rasmussen S. A. Jamieson D. J. Uyeki T. M. Effects of influenza on pregnant women and infants. Am J 405 Obstetrics and Gynecology 2012 207 Supplement 3 S3 S8 10.1016/j.ajog.2012.06 \n3 Silasi M. Cardenas I. Racicot K. Kwon J.-Y. Aldo P. Mor G. Viral infections during pregnancy American Journal of Reproductive Immunology 2015 73 3 199 213 10.1111/aji.12355 2-s2.0-84922778684 25582523 \n4 Schwartz D. A. An analysis of 38 pregnant women with COVID-19, their newborn infants, and maternal-fetal transmission of SARS-CoV-2: maternal coronavirus infections and pregnancy outcomes Archives of Pathology & Laboratory Medicine 2020 17 \n5 Centers for disease control and prevention COVID19. People who need to take extra precautions https://www.cdc.gov/coronavirus/2019-ncov \n6 Chen H. Guo J. Wang C. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records The Lancet 2020 395 10226 809 815 10.1016/S0140-6736(20)30360-3 32151335 \n7 Ellington S. Strid P. Tong V. T. Characteristics of women of reproductive age with laboratory-confirmed SARS-COV-2 infection by pregnancy status – united States, January 22–June 7, 2020 MMWR. Morbidity and Mortality Weekly Report 2020 69 25 769 775 10.15585/mmwr.mm6925a1 32584795 \n8 Yan J. Guo J. Fan C. Coronavirus disease 2019 in pregnant women: a report based on 116 cases American Journal of Obstetrics and Gynecology 2020 223 1 111.e1 111.e14 10.1016/j.ajog.2020.04.014 32335053 \n9 Zaigham M. Andersson O. Maternal and perinatal outcomes with COVID-19: a systematic review of 108 pregnancies Acta Obstetricia et Gynecologica Scandinavica 2020 99 7 823 829 10.1111/aogs.13867 32259279 \n10 Centers for disease control and prevention COVID 19. People with certain medical conditions https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html#cancer \n11 Xu L. Yaqian M. Chen G. Risk factors for severe corona virus disease 2019 (COVID-19) patients : a systematic review and meta analysis 2020 10.1101/2020.03.30.20047415 \n12 Schettler W. Al Ahwel Y. Suhag A. Severe ARDS in COVID-19-infected pregnancy: obstetric and intensive care considerations American Journal of Obstetrics & Gynecology MFM 2020 2 10.1016/j.ajogmf.2020.100120 \n13 Oxford C. M. Ludmir J. Trauma in pregnancy Clinical Obstetrics and Gynecology 2009 52 4 611 629 10.1097/GRF.0b013e3181c11edf 2-s2.0-70449469763 20393413 \n14 Juusela A. Nazir M. Gimovsky M. Two Cases of COVID-19 Related Cardiomyopathy in Pregnancy American Journal of Obstetrics & Gynecology MFM 2020 2 \n15 Eisner M. D. Thompson T. Hudson L. D. Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome American Journal of Respiratory and Critical Care Medicine 2001 164 2 231 236 10.1164/ajrccm.164.2.2011093 2-s2.0-0035880166 11463593 \n16 Bourenne J. Hraiech S. Roch A. Gainnier M. Papazian L. Forel J. M. Sedation and neuromuscular blocking agents in acute respiratory distress syndrome Annals of Translational Medicine 2017 5 14 p. 291 10.21037/atm.2017.07.19 2-s2.0-85026403795 28828366 \n17 Dennis A. T. Hardy L. Leeton L. The prone position in healthy pregnant women and in women with preeclampsia – a pilot study BMC Pregancy Childbirth 2018 18 1 p. 445 10.1186/s12884-018-2073-x 2-s2.0-85056737068 30445912 \n18 Akatsuka M. Tatsumi H. Yama N. Masuda Y. Therapeutic evaluation of computed tomography findings for efficacy of prone ventilation in acute respiratory distress syndrome patients with abdominal surgery The Journal of Critical Care Medicine 2020 6 1 32 40 10.2478/jccm-2020-0003 32104729 \n19 Webster C. M. Smith K. A. Manuck T. A. Extracorporeal membrane oxygenation in pregnant and postpartum women: a ten-year case series American Journal of Obstetrics & Gynecology MFM 2020 2 2 p. 100108 10.1016/j.ajogmf.2020.100108 32835205 \n20 Wang M. Cao R. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro Cell Research 2020 30 3 269 271 10.1038/s41422-020-0282-0 32020029 \n21 Li H. Wang Y. M. Xy J. Y. Cao B. Potential antiviral therapeutics for 2019 coronavirus Zhonghua Ji He He Hu Xi Za Zhi 2020 43 3 170 172 \n22 Bhergella V. Coronavirus disease 2019 (COVID-19): pregnancy issues https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-pregnancy-issues \n23 Di Mascio D. Khalil A. Saccone G. Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis American Journal Of Obstetrics & Gynecology MFM 2020 2 2 p. 100107 10.1016/j.ajogmf.2020.100107 32292902\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6420",
"issue": "2020()",
"journal": "Case reports in critical care",
"keywords": null,
"medline_ta": "Case Rep Crit Care",
"mesh_terms": null,
"nlm_unique_id": "101598416",
"other_id": null,
"pages": "8889487",
"pmc": null,
"pmid": "33083063",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "30445912;32335053;32104729;20393413;32292902;32259279;25582523;32020029;32164080;32151335;32835205;11463593;32180426;32584795;32363336;28828366;22920056;32363337",
"title": "Severe COVID-19 in Third Trimester Pregnancy: Multidisciplinary Approach.",
"title_normalized": "severe covid 19 in third trimester pregnancy multidisciplinary approach"
} | [
{
"companynumb": "US-DRREDDYS-LIT/USA/21/0138315",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISATRACURIUM"
},
"drugadditional": "3",... |
{
"abstract": "We report 5 cases of cutaneous CD30+ lymphomatoid drug reactions that occurred shortly after the onset of drug exposure and resolved promptly upon withdrawal of the offending agents. The cases showed protean dermatologic manifestations ranging from diffuse erythema with desquamation to macules, papules, and annular plaques. The suspect drugs were amlodipine (a calcium channel blocker) for 2 cases, sertraline (a selective serotonin reuptake inhibitor) for 1 case, gabapentin for 1 case, and levofloxacin (a fluoroquinolone) versus cefepime (a fourth generation cephalosporin), and metoprolol (a beta blocker), in the fifth case. The histopathologic findings included varying combinations of spongiotic dermatitis, lichenoid infiltrates, and interface dermatitis with a dermal infiltrate of large atypical lymphocytes. Three of the 5 cases contained as much as 30% CD30+ staining of all lymphocytes, whereas the remaining 2 showed 5%-15% positivity. Three patients had a history of allergy or immune dysregulation. Increased knowledge of CD30 positivity in lymphomatoid drug reactions may be relevant in an era of targeted drug therapies. Recognition of these findings may help clinicians to tailor appropriate clinical evaluation and treatment including a review of medications and the removal of possible offending agents.",
"affiliations": "Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.",
"authors": "Pulitzer|Melissa P|MP|;Nolan|Katherine A|KA|;Oshman|Robin G|RG|;Phelps|Robert G|RG|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D000588:Amines; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D015415:Biomarkers; D002121:Calcium Channel Blockers; D003509:Cyclohexanecarboxylic Acids; D017730:Ki-1 Antigen; D017367:Serotonin Uptake Inhibitors; D017311:Amlodipine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D064704:Levofloxacin; D015242:Ofloxacin; D008790:Metoprolol; D020280:Sertraline",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0b013e31826bc1e5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "35(3)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D000368:Aged; D000369:Aged, 80 and over; D000588:Amines; D017311:Amlodipine; D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D015415:Biomarkers; D001706:Biopsy; D002121:Calcium Channel Blockers; D003509:Cyclohexanecarboxylic Acids; D003875:Drug Eruptions; D004890:Erythema; D005260:Female; D000077206:Gabapentin; D006801:Humans; D007150:Immunohistochemistry; D017730:Ki-1 Antigen; D064704:Levofloxacin; D008214:Lymphocytes; D008232:Lymphoproliferative Disorders; D008297:Male; D008790:Metoprolol; D008875:Middle Aged; D015242:Ofloxacin; D011237:Predictive Value of Tests; D019310:Pseudolymphoma; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline; D012867:Skin; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "343-50",
"pmc": null,
"pmid": "23328787",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "CD30+ lymphomatoid drug reactions.",
"title_normalized": "cd30 lymphomatoid drug reactions"
} | [
{
"companynumb": "US-JNJFOC-20130414419",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nPreoperative chemotherapy and radiation for localized esophageal cancer produces cure rates near 30% when combined with surgical resection. Vandetanib, a small molecule receptor tyrosine kinase inhibitor of VEGFR-2, VEGFR-3, RET, and EGFR, demonstrated synergy with radiation and chemotherapy in preclinical models. We conducted a phase I study to assess the safety and tolerability of vandetanib when combined with preoperative chemoradiation in patients with localized esophageal carcinoma who were surgical candidates.\n\n\nMETHODS\nPatients with stage II-III esophageal and gastroesophageal junction carcinoma without prior therapy were enrolled in a 3+3 phase I design. Patients received once-daily vandetanib (planned dosing levels of 100, 200, and 300 mg) with concomitant daily radiotherapy (1.8 Gy/d, 45 Gy total) and chemotherapy, consisting of infusional 5-FU (225 mg/m/d over 96 h, weekly), paclitaxel (50 mg/m, days 1, 8, 15, 22, 29) and carboplatin (AUC of 5, days 1, 29).\n\n\nRESULTS\nA total 9 patients were enrolled with 8 having either distal esophageal or gastroesophageal junction carcinomas. All patients completed the planned preoperative chemoradiation and underwent esophagectomy. Nausea (44%) and anorexia (44%) were the most common acute toxicities of any grade. One grade 4 nonhematologic toxicity was observed (gastrobronchial fistula). One additional patient suffered a late complication, a fatal aortoenteric hemorrhage, not definitively related to the investigational regimen. Five (56%) patients achieved a pathologic complete response. Three (33%) additional patients had only microscopic residual disease. Five (56%) patients remain alive and disease free with a median follow-up of 3.7 years and median overall survival of 3.2 years. The maximum tolerated dose was vandetanib 100 mg/d.\n\n\nCONCLUSIONS\nVandetanib at 100 mg daily is tolerable in combination with preoperative chemotherapy (5-FU, paclitaxel, carboplatin) and radiation therapy with encouraging efficacy worthy of future study.",
"affiliations": "*Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY Departments of †Radiation Oncology §Medical Oncology ∥Pathology ††Surgical Oncology ¶Protocol Management Office, Fox Chase Cancer Center ‡Department of Surgery, Thomas Jefferson University Hospital, Philadelphia, PA #Department of Surgical Oncology, Brigham and Women's Hospital, Boston, MA **Department of Medical Oncology, Yale University School of Medicine, New Haven, CT ‡‡Department of Biochemistry, Kazan Federal University, Kazan, Russia.",
"authors": "Boland|Patrick M|PM|;Meyer|Joshua E|JE|;Berger|Adam C|AC|;Cohen|Steven J|SJ|;Neuman|Tzahi|T|;Cooper|Harry S|HS|;Olszanski|Anthony J|AJ|;Davey|Monica|M|;Cheng|Jonathan D|JD|;Lebenthal|Abraham|A|;Burtness|Barbara A|BA|;Scott|Walter J|WJ|;Astsaturov|Igor A|IA|",
"chemical_list": "D010880:Piperidines; D011799:Quinazolines; D016190:Carboplatin; D017239:Paclitaxel; D005472:Fluorouracil; C452423:N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine",
"country": "United States",
"delete": false,
"doi": "10.1097/COC.0000000000000171",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "40(4)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms; D016629:Esophagectomy; D004943:Esophagogastric Junction; D005472:Fluorouracil; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D017239:Paclitaxel; D010880:Piperidines; D011799:Quinazolines; D016896:Treatment Outcome",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "393-398",
"pmc": null,
"pmid": "26986978",
"pubdate": "2017-08",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": "21764243;19901100;22101387;8672151;18309943;12781882;23165781;17409986;17211865;8194005;22564870;23180560;15781882;16377413;22237781;15986037;18936474;22450065;14695149;21684205;15905307;15719440;19931663;16865594;12967135;15923432;17197919;17457164;22646630;18379357",
"title": "Induction Therapy for Locally Advanced, Resectable Esophagogastric Cancer: A Phase I Trial of Vandetanib (ZD6474), Paclitaxel, Carboplatin, 5-Fluorouracil, and Radiotherapy Followed by Resection.",
"title_normalized": "induction therapy for locally advanced resectable esophagogastric cancer a phase i trial of vandetanib zd6474 paclitaxel carboplatin 5 fluorouracil and radiotherapy followed by resection"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US03504",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANDETANIB"
},
"drugadditional": null,
... |
{
"abstract": "METHODS\nA 75-year-old man who underwent nivolumab as the third-line chemotherapy for advanced gastric cancer had chylous ascites (CA) after the primary tumor shrank remarkably. Total parenteral nutrition and subcutaneous octreotide were initiated, and CA disappeared. Nivolumab was continued for a total of 23 courses. Computed tomography showed lymph node swelling; however, staging laparoscopy showed that peritoneal metastasis had disappeared. Therefore, conversion surgery and distal gastrectomy with D1+ dissection were performed.\n\n\nRESULTS\nThe pathological diagnosis was type IV, poorly differentiated adenocarcinoma (por2) with signet ring cells, ypT2 (muscularis propria), without lymphatic or venous invasion, and no involvement of the proximal and distal margins. After the operation, no recurrence was observed over 7 months with no adjuvant chemotherapy.\n\n\nCONCLUSIONS\nNivolumab has the potential to lead to R0 resection for patients with peritoneal carcinomatosis gastric cancer. To our knowledge, this is the first report of successful conversion surgery after nivolumab-related chylous ascites.",
"affiliations": "Department of Surgery, Nakatsu Municipal Hospital, Nakatsu, Japan sa-toyoda@nakatsu-hosp.jp.;Department of Surgery, Nakatsu Municipal Hospital, Nakatsu, Japan.;Department of Surgery, Nakatsu Municipal Hospital, Nakatsu, Japan.;Department of Surgery, Nakatsu Municipal Hospital, Nakatsu, Japan.;Department of Surgery, Nakatsu Municipal Hospital, Nakatsu, Japan.;Department of Surgery, Nakatsu Municipal Hospital, Nakatsu, Japan.;Department of Surgery, Nakatsu Municipal Hospital, Nakatsu, Japan.;Department of Surgery, Nakatsu Municipal Hospital, Nakatsu, Japan.;Department of Surgery, Nakatsu Municipal Hospital, Nakatsu, Japan.;Department of Surgery, Nakatsu Municipal Hospital, Nakatsu, Japan.;Department of Surgery, Nakatsu Municipal Hospital, Nakatsu, Japan.;Department of Surgery, Nakatsu Municipal Hospital, Nakatsu, Japan.;Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.",
"authors": "Toyota|Satoshi|S|;Orita|Hiroyuki|H|;Fukuyama|Yasuro|Y|;Motoyoshi|Saki|S|;Kawanami|Shogo|S|;Maeda|Shohei|S|;Kuramitsu|Erina|E|;Ichimanda|Michihiro|M|;Nagamatsu|Satoko|S|;Nagata|Shigeyuki|S|;Kai|Seiichiro|S|;Korenaga|Daisuke|D|;Mori|Masaki|M|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab",
"country": "Greece",
"delete": false,
"doi": "10.21873/invivo.11810",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0258-851X",
"issue": "34(2)",
"journal": "In vivo (Athens, Greece)",
"keywords": "Gastric cancer; chylous ascites; conversion surgery; nivolumab; peritoneal metastasis; pseudo progression",
"medline_ta": "In Vivo",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D002915:Chylous Ascites; D003131:Combined Modality Therapy; D005743:Gastrectomy; D005773:Gastroscopy; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D000077594:Nivolumab; D011860:Radiography, Abdominal; D013274:Stomach Neoplasms; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "8806809",
"other_id": null,
"pages": "583-585",
"pmc": null,
"pmid": "32111756",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21573743;4166570;28459940;31396474;19934295;15197201;19777180;28993052;27284475;30487951",
"title": "Successful Conversion Surgery Following Chylous Ascites After Nivolumab for Advanced Gastric Cancer.",
"title_normalized": "successful conversion surgery following chylous ascites after nivolumab for advanced gastric cancer"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-243188",
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"activesubstancename": "OXALIPLATIN"
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"abstract": "Thyroid storm is a rare, life-threatening endocrine emergency with a high mortality rate of up to 30%. We present a unique management challenge of a critically ill patient who developed thyroid storm in the setting of a duodenal perforation from amphetamine-associated non-occlusive mesenteric ischaemia. The diagnosis of 'thyroid storm' was made based on clinical criteria and a Burch-Wartofsky score of 100. During emergent exploratory laparotomy, a 1 cm duodenal perforation with surrounding friable tissue was found and repaired. Intraoperatively, a nasogastric tube was guided distal to the area of perforation to allow for enteric administration of medications, which was critical in the setting of thyroid storm. Therapeutic plasma exchange achieved biochemical control of our patient's thyroid storm but ultimately did not prevent in-hospital mortality.",
"affiliations": "Internal Medicine, University of California Davis, Sacramento, California, USA jinsol.meded@gmail.com aazeki@ucdavis.edu.;Surgery, University of California Davis, Sacramento, California, USA.;Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of California Davis, Sacramento, California, USA.;Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of California Davis, Sacramento, California, USA jinsol.meded@gmail.com aazeki@ucdavis.edu.",
"authors": "Lee|Jin Sol Gene|JSG|;Brown|Ian Elliott|IE|;Semrad|Alison M|AM|;Zeki|Amir A|AA|",
"chemical_list": "D000661:Amphetamine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-238889",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "14(8)",
"journal": "BMJ case reports",
"keywords": "adult intensive care; general surgery; hyperthyroidism; thyroid disease; thyrotoxicosis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000661:Amphetamine; D004381:Duodenal Ulcer; D006801:Humans; D007511:Ischemia; D010439:Peptic Ulcer Perforation; D013958:Thyroid Crisis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34413029",
"pubdate": "2021-08-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Getting around the gut: a unique management challenge of thyroid storm precipitated by amphetamine-associated duodenal ischaemia leading to compromised enteric absorption.",
"title_normalized": "getting around the gut a unique management challenge of thyroid storm precipitated by amphetamine associated duodenal ischaemia leading to compromised enteric absorption"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-317863",
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{
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"activesubstancename": "AMPHETAMINE"
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"abstract": "Subacute cutaneous lupus erythematosus (SCLE) is a rare cutaneous lupus erythematosus (CLE) subtype manifesting in middle-aged Caucasians with photo-distributed papulosquamous or annular lesions. Drug-induced SCLE (DI-SCLE) forms present in a similar manner but direct oral anticoagulants are rarely implicated. We report an unusual case of SCLE in a 37-year-old African American patient with a history of unprovoked deep vein thromboses (DVT) who presented with new-onset photoprotected polymorphic lesions two months after the initiation of apixaban anticoagulation therapy. Our case demonstrates the heterogeneous nature of SCLE presentation and highlights the possibility of apixaban as a potential causative agent of DI-SCLE in immunogenetically susceptible individuals. Moreover, we hypothesize on the etiopathogenesis of our patient's atypical presentation.",
"affiliations": "Dermatology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, USA.;Department of Dermatology, John H. Stroger, Jr. Hospital of Cook County, Chicago, USA.;Dermatology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, USA.;Department of Dermatology, John H. Stroger, Jr. Hospital of Cook County, Chicago, USA.;Department of Dermatology, John H. Stroger, Jr. Hospital of Cook County, Chicago, USA.",
"authors": "Rakita|Uros|U|;Grushchak|Solomiya|S|;Guo|Lily|L|;Braniecki|Marylee|M|;Mehta|Shilpa|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.16571",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.16571\nDermatology\nAtypical Subacute Cutaneous Lupus in a Patient on Apixaban Anticoagulation Therapy: A Case Report and Review of the Literature\nMuacevic Alexander\nAdler John R\nRakita Uros 1\nGrushchak Solomiya 2\nGuo Lily 1\nBraniecki Marylee 2\nMehta Shilpa 2\n1 Dermatology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, USA\n2 Department of Dermatology, John H. Stroger, Jr. Hospital of Cook County, Chicago, USA\nUros Rakita uros.rakita@my.rfums.org\n22 7 2021\n7 2021\n13 7 e165715 7 2021\nCopyright © 2021, Rakita et al.\n2021\nRakita 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/55614-atypical-subacute-cutaneous-lupus-in-a-patient-on-apixaban-anticoagulation-therapy-a-case-report-and-review-of-the-literature\nSubacute cutaneous lupus erythematosus (SCLE) is a rare cutaneous lupus erythematosus (CLE) subtype manifesting in middle-aged Caucasians with photo-distributed papulosquamous or annular lesions. Drug-induced SCLE (DI-SCLE) forms present in a similar manner but direct oral anticoagulants are rarely implicated. We report an unusual case of SCLE in a 37-year-old African American patient with a history of unprovoked deep vein thromboses (DVT) who presented with new-onset photoprotected polymorphic lesions two months after the initiation of apixaban anticoagulation therapy. Our case demonstrates the heterogeneous nature of SCLE presentation and highlights the possibility of apixaban as a potential causative agent of DI-SCLE in immunogenetically susceptible individuals. Moreover, we hypothesize on the etiopathogenesis of our patient’s atypical presentation.\n\ncutaneous lupus erythematosus\nsubacute cutaneous lupus erythematosus\napixaban\nskin of color\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\nSubacute cutaneous lupus erythematosus (SCLE) is a rare cutaneous lupus erythematosus (CLE) subtype, and it usually manifests in middle-aged Caucasian individuals [1]. SCLE presents with photo-distributed papulosquamous or annular lesions and often fulfills systemic lupus erythematosus (SLE) diagnostic criteria, with limited systemic involvement [2]. We describe an unusual case of SCLE presenting in an African American female patient with photoprotected polymorphic lesions with onset two months after the initiation of apixaban anticoagulation therapy. Additionally, we review the related literature and hypothesize on the etiology and predisposing factors of her atypical presentation.\n\nCase presentation\n\nA 37-year-old African American female with a history of two unprovoked deep venous thromboses (DVT) treated with apixaban was evaluated for a pruritic rash of two weeks' duration. She had started apixaban two months prior to the rash onset; there were otherwise no changes in her medication regimen. The exam showed hyperpigmented brown scaly plaques with central atrophic patches on the conchal bowl of the ears (Figure 1a), violaceous nodules, and indurated plaques with scattered flaccid vesicles on the medial thighs, knees, and antecubital fossae (Figures 1b, 1c), and eroded plaques with dry, serosanguinous crust on the elbows. Vesicles were not appreciated on non-lesional skin and there was no mucosal involvement. She endorsed hematuria and weight loss but denied lesion photosensitivity. Laboratory analysis was significant for leukopenia (WBC of 3.4 thousands/μL), anemia (hemoglobin of 5.6 g/dL), and proteinuria. Serology was positive for antinuclear antibodies (ANA) (>1:160), anti-double-stranded DNA (anti-dsDNA), anti-Smith, anti-Ro/SSA, cardiolipin antibody, beta2 glycoprotein antibody, and low C3 and C4 complement.\n\nFigure 1 Clinical photographs\n\n(a) Hyperpigmented brown scaly plaques with central atrophic patches on bilateral conchal bowls. (b-c) Representative lesion of those found on the medial thigh, medial knee, and antecubital fossa. Red to violaceous nodules and plaques with scattered flaccid vesicles on (b) left and (c) right medial knees and thighs\n\nA 4-mm punch biopsy of a representative lesion from the medial knee was performed. Histopathologic findings suggested early SCLE and consisted of basilar vacuolar degeneration with scant dermal perivascular lymphocytic infiltrate (Figure 2a). Colloidal iron staining highlighted mucin deposition throughout the superficial and deep dermis (Figure 2b). Apixaban was discontinued and warfarin initiated. Triamcinolone 0.01% was used as needed for her skin. She remains in remission at her three-month follow-up, treated with hydroxychloroquine (200 mg BID), mycophenolate mofetil (1 gm BID), and prednisone (40 mg daily) for her SLE and lupus nephritis, respectively.\n\nFigure 2 Skin histopathology\n\n(a) Early vacuolar degeneration of basal epidermal layer and scant dermal perivascular lymphocytic infiltrate (hematoxylin and eosin stain, original magnification x40). (b) Mucin deposition in superficial and deep dermal layers (colloidal iron stain, original magnification x10)\n\nDiscussion\n\nCLE comprises three subtypes for which no standardized classification criteria exist [2]. The SCLE subtype occurs most commonly in middle-aged Caucasian females, and those presenting with SCLE roughly represent 10-15% of lupus patients in a given locale [1]. Typical lesions are papulosquamous or scaly, annular photodistributed plaques that paradoxically spare the midface while involving the lateral face, trunk, and extensor aspects of the upper extremities [1,3]. Rare, vesiculobullous SCLE variants primarily present with erosions and crusting with occasional vesicles at the active periphery or central plaque areas [4]. Compared to lesions of the more common discoid lupus erythematosus (DLE), SCLE lesions are more photosensitive [1]. Also, unlike DLE lesions, SCLE ones are nonscarring and nonindurated, representing a more superficial pathology with a relatively sparse inflammatory infiltrate [1,2]. Of note, patients can concurrently present with multiple CLE subtypes. Roughly 20% of SCLE patients develop DLE lesions during their disease course [1]. Moreover, up to half of SCLE patients also meet the criteria for SLE; however, serious systemic involvement is infrequent [2].\n\nThere is significant histologic overlap between CLE phenotypes, and their differentiation on the basis of histology alone is unreliable. Common CLE findings include interface dermatitis with mononuclear cell infiltrate at the dermoepidermal junction, basal cell degeneration, perivascular and periadnexal inflammation, dermal mucin deposition, and hyperkeratosis [3]. A superficial infiltrate with a milder histological presentation of the above features is suggestive of SCLE [2]. Serologic associations add diagnostic clarity since, unlike other CLE variants, SCLE is highly associated with anti-Ro/SSA antibodies with 70% of patients testing positive [2]. On the other hand, the SLE-specific antibodies (anti-dsDNA and anti-Smith) are relatively rare in SCLE patients [1,2].\n\nAs SCLE is rare in African Americans [1], our patient’s ethnicity, the indurated and vesicular presentation of her rash, as well as the presence of lesions in photoprotected areas were reasons this case was atypical and diagnostically challenging. Interestingly, anti-Ro/SSA antibodies may serve a photoprotective role in patients with skin of color (SOC) [5]; however, this may only be limited to specific ethnicities in SOC patients [6]. This suggests that certain ethnic groups with SCLE may have an atypical presentation. Areas of vesiculation perhaps represented accentuations of interface dermatitis [4]. Vesicular lupus lesions lack uniform classification [4]; however, given our patient’s histologic and serologic findings, the etiology is likely related to the underlying lupus pathology. Although not histologically examined, the co-occurrence of characteristic DLE lesions in the conchal bowl raised our suspicion for lupus erythematosus. Antibody profiles had features specific for both SCLE and SLE. This in conjunction with renal, hematologic, and immunologic involvement indicate that our patient belongs to the minority of SCLE patients meeting SLE diagnostic criteria with notable systemic disease.\n\nMoreover, it is possible that her new-onset SCLE was related to the recently initiated apixaban therapy. Drug-induced SCLE (DI-SCLE) is clinically as well as serologically indistinguishable from the idiopathic form and can occur days or years after drug initiation [7]. Unlike drug-induced SLE, DI-SCLE is not typically associated with anti-histone antibodies [8].\n\nA wide range of drugs have been associated with DI-SCLE; however, direct oral anticoagulants are rarely implicated. McCarthy et al. have published a case of rivaroxaban-induced SCLE, which presented with typical clinicopathologic features three weeks after the drug administration and resolved within four months of drug discontinuation and concurrent topical corticosteroid therapy [9]. Recently, apixaban was implicated in anti-histone antibody-positive drug-induced SLE with cutaneous manifestation consistent with leukocytoclastic vasculitis [10]. Rash appearance in the aforementioned case occurred 15 days after the drug initiation. Considering the temporal association between SCLE appearance and apixaban administration along with improvement upon apixaban discontinuation, we believe apixaban therapy was possibly associated with SCLE precipitation in our patient. Given our patient’s DVT history, we hypothesize that apixaban may have exacerbated her baseline immunogenetic susceptibility to SCLE.\n\nConclusions\n\nWe presented a patient with SCLE with newly diagnosed SLE. Our patient displayed features spanning the lupus erythematous spectrum, which along with atypical findings makes this case unique and equally informative. It is important to emphasize that the hypothesized relationship between our patient’s ethnicity and photoprotected SCLE distribution, as well as the possible association between apixaban and DI-SCLE, are both merely speculative and require further investigation.\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 Subacute cutaneous lupus erythematosus: 25-year evolution of a prototypic subset (subphenotype) of lupus erythematosus defined by characteristic cutaneous, pathological, immunological, and genetic findings Autoimmun Rev Sontheimer RD 253 263 4 2005 15990071\n2 A comprehensive review of immune-mediated dermatopathology in systemic lupus erythematosus J Autoimmun Li Q Wu H Liao W 1 15 93 2018 30017673\n3 Cutaneous lupus erythematosus: issues in diagnosis and treatment Am J Clin Dermatol Walling HW Sontheimer RD 365 381 10 2009 19824738\n4 Vesiculobullous diseases in relation to lupus erythematosus Clin Cosmet Investig Dermatol Rutnin S Chanprapaph K 653 667 12 2019\n5 Photosensitivity and anti-Ro (SS-A) antibodies in black patients with systemic lupus erythematosus (SLE) Br J Rheumatol Sutej PG Gear AJ Morrison RC Tikly M de Beer M Dos Santos L Sher R 321 324 28 1989 2787184\n6 Photosensitivity and antinuclear antibodies in black patients with systemic lupus erythematosus J Assoc Acad Minor Phys Smikle MF Barton EN Morgan OS Deceulaer K 53 55 7 1996 https://pubmed.ncbi.nlm.nih.gov/8998392/ 8998392\n7 Subacute cutaneous lupus erythematosus with positive anti-Ro antibodies following palbociclib and letrozole treatment: a case report and literature review J Cutan Pathol Russell-Goldman E Nazarian RM 654 658 47 2020 32119141\n8 Drug-induced subacute cutaneous lupus erythematosus Lupus Callen JP 1107 1111 19 2010 20693204\n9 A case of rivaroxaban-induced subacute lupus erythematosus J Eur Acad Dermatol Venereol McCarthy S Foley CC Dvorakova V Heffron CC Murphy M 0 9 31 2017\n10 Drug-induced lupus with leukocytoclastic vasculitis associated with apixaban Case Rep Rheumatol Yang J Lena S Tarditi D Banker G 8866761 2021 2021 33628568\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(7)",
"journal": "Cureus",
"keywords": "apixaban; cutaneous lupus erythematosus; skin of color; subacute cutaneous lupus erythematosus",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e16571",
"pmc": null,
"pmid": "34434672",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "31564947;15990071;20693204;8998392;30017673;33628568;19824738;2787184;27228969;32119141",
"title": "Atypical Subacute Cutaneous Lupus in a Patient on Apixaban Anticoagulation Therapy: A Case Report and Review of the Literature.",
"title_normalized": "atypical subacute cutaneous lupus in a patient on apixaban anticoagulation therapy a case report and review of the literature"
} | [
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"companynumb": "US-BION-010025",
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"activesubstance": {
"activesubstancename": "APIXABAN"
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"drugadmin... |
{
"abstract": "OBJECTIVE\nRheumatoid arthritis (RA) patients with moderate disease activity show progression of joint damage and have impaired quality of life, physical function, work and daily activities. Little is known about management of patients with moderate RA. The aim of the study was to assess the 1-year response to anti-TNF in biologic-naïve RA patients with moderate (3.2 <DAS28 ≤5.1) disease activity despite DMARD treatment, in the Italian clinical practice.\n\n\nMETHODS\nThe MODERATE study is a multicentre prospective, cohort non-interventional study, conducted in 19 Italian rheumatology sites. Patients with moderate RA, diagnosed according to the 2010 American College of Rheumatology (ACR)/EULAR criteria, were enrolled if they also were aged ≥18 years, had disease onset after 16 years old, moderate disease at baseline (DAS28 score >3.2 and ≤5.1), and were naïve to anti-TNF treatment.\n\n\nRESULTS\nAmong 157 RA patients, 93 (59%) underwent etanercept, 43 (22%) adalimumab, 26 (17%) certolizumab, 10 golimumab and 2 infliximab; 80% of patients were still in treatment after 12-month observation. One-year clinical remission was achieved by 27 RA patients (21%), reduction of DAS28 score greater than 1.2 was observed in 75 (58%) patients. Moderate and good response according to EULAR criteria was observed in 59 (46%) and 45 (35%) patients, respectively.\n\n\nCONCLUSIONS\nResults confirm the efficacy of anti-TNF alpha also in moderate RA patients, who may achieve a substantial decrease of disease activity, and improve their quality of life. The low rate of patients achieving remission may suggest that therapeutic strategies should be more timely and aggressive.",
"affiliations": "Dipartimento di Medicina Interna e Specialità Mediche, La Sapienza Università di Roma, Italy.;U.O.S. Reumatologia, Medicina Interna, Ospedale S.Pietro Fatebenefratelli, Rome, Italy.;Dipartimento di Medicina Interna e Specialità Mediche, La Sapienza Università di Roma, Italy.;S.S.O. Reumatologia, Ospedale Civile Maggiore Borgo Trento, Verona, Italy.;Chair and Clinical Unit of Rheumatology, Department of Biotechnological and Applied Clinical Science, School of Medicine, 'San Salvatore' University Hospital, University of L'Aquila, Italy.;Reumatologia, Medicina Clinica e Sperimentale, A.O.U. Seconda Università di Napoli, Italy.;Medicina III, S.S. Reumatologia A.O.R.N. A. Cardarelli, Napoli, Italy.;II Divisione Medicina Interna, ARNAS Civico Di Cristina Benfratelli, Palermo,Italy.;Chair and Clinical Unit of Rheumatology, Department of Biotechnological and Applied Clinical Science, School of Medicine, 'San Salvatore' University Hospital, University of L'Aquila, Italy.;Struttura Complessa Reumatologia, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Italy.;Ambulatorio Immuno-Reumatologico, Ospedale Maggiore della Carità, Novara, Italy.;U.O. di Medicina Interna, Ambulatorio di Reumatologia Ospedale Ninetto Melli, San Pietro V.co, Brindisi, Italy.;MediData srl, Modena, Italy.;Pfizer srl, Rome, Italy.;U.O.S. Reumatologia, Medicina Interna, Ospedale S.Pietro Fatebenefratelli, Rome, Italy.;Dipartimento di Medicina Interna e Specialità Mediche, La Sapienza Università di Roma, Italy. guido.valesini@uniroma1.it.",
"authors": "Ceccarelli|Fulvia|F|;Massafra|Umberto|U|;Perricone|Carlo|C|;Idolazzi|Luca|L|;Giacomelli|Roberto|R|;Tirri|Rosella|R|;Russo|Romualdo|R|;Pistone|Giovanni|G|;Ruscitti|Piero|P|;Parisi|Simone|S|;Sainaghi|Pier Paolo|PP|;Cacciapaglia|Fabio|F|;Zullo|Alessandro|A|;Marino|Valentina|V|;Migliore|Alberto|A|;Valesini|Guido|G|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001688:Biological Products; D014409:Tumor Necrosis Factor-alpha; C529000:golimumab; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept; D000068582:Certolizumab Pegol",
"country": "Italy",
"delete": false,
"doi": null,
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"issn_linking": "0392-856X",
"issue": "35(1)",
"journal": "Clinical and experimental rheumatology",
"keywords": null,
"medline_ta": "Clin Exp Rheumatol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001688:Biological Products; D000068582:Certolizumab Pegol; D018450:Disease Progression; D000068800:Etanercept; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011788:Quality of Life; D012074:Remission Induction; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8308521",
"other_id": null,
"pages": "24-32",
"pmc": null,
"pmid": "27974105",
"pubdate": "2017",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Anti-TNF treatment response in rheumatoid arthritis patients with moderate disease activity: a prospective observational multicentre study (MODERATE).",
"title_normalized": "anti tnf treatment response in rheumatoid arthritis patients with moderate disease activity a prospective observational multicentre study moderate"
} | [
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"companynumb": "IT-UCBSA-2017000130",
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"occurcountry": "IT",
"patient": {
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"activesubstancename": "CERTOLIZUMAB PEGOL"
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... |
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"abstract": "Diagnosis and management of status epilepticus (SE), including non-convulsive status epilepticus (NCSE), is challenging, with a reported 30%-50% of epilepticus patients not responding to available antiseizure medications (ASMs). Injectable benzodiazepines, fosphenytoin, valproate, levetiracetam, lacosamide and phenobarbital are commonly used for treating SE. Brivaracetam, a new ASM, with higher affinity and greater selectivity for the synaptic vesicle glycoprotein 2A than levetiracetam, has been approved as monotherapy or adjunct for treatment of focal onset seizures. Brivaracetam may have a role in the management of SE. However, limited data exist on brivaracetam's efficacy in SE. We describe a patient case with focal NCSE refractory to levetiracetam, fosphenytoin, lacosamide and valproate who demonstrated clinical and electrographic improvement on continuous electroencephalography monitoring after brivaracetam administration.",
"affiliations": "Department of Pharmacy, Yale New Haven Health System, New Haven, Connecticut, USA abdalla.ammar@ynhh.org.;Department of Pharmacy, Yale New Haven Health System, New Haven, Connecticut, USA.;Department of Pharmacy, Yale New Haven Health System, New Haven, Connecticut, USA.;Department of Neurology, Division of Neurocritical Care and Emergency Neurology, Division of Epilepsy, Yale New Haven Health System, New Haven, Connecticut, USA.",
"authors": "Ammar|Abdalla A|AA|http://orcid.org/0000-0002-1427-1173;Ammar|Mahmoud A|MA|http://orcid.org/0000-0002-3401-9960;Owusu|Kent|K|;Gilmore|Emily J|EJ|",
"chemical_list": "D000927:Anticonvulsants; D011760:Pyrrolidinones; C482793:brivaracetam",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-234955",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(11)",
"journal": "BMJ case reports",
"keywords": "epilepsy and seizures; neurology (drugs and medicines); pharmacology and therapeutics",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D000927:Anticonvulsants; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008991:Monitoring, Physiologic; D011760:Pyrrolidinones; D013226:Status Epilepticus",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33229472",
"pubdate": "2020-11-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intravenous brivaracetam for the management of refractory focal non-convulsive status epilepticus.",
"title_normalized": "intravenous brivaracetam for the management of refractory focal non convulsive status epilepticus"
} | [
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"companynumb": "US-MYLANLABS-2020M1055191",
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{
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"activesubstance": {
"activesubstancename": "CLOBAZAM"
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... |
{
"abstract": "Little observational data exist regarding the use of cisplatin, etoposide, and bleomycin (BEP) chemotherapy regimen in patients with gestational trophoblastic neoplasia (GTN).\nThis is a retrospective study of 95 patients with GTN in our center from June/2010 to June/2018. All patients received at least 2 cycles of BEP chemotherapy. The primary outcomes were the rate of complete remission (CR) and overall survival (OS). The secondary outcomes were disease-free survival (DFS), pregnancy rates after BEP exposure, drug resistance rate, and other adverse events.\nOf the 95 patients included, 66 (69.5%) patients received BEP as primary treatment and 29 (30.5%) were Salvage chemotherapy. The median age at diagnosis was 37 years (range 29.75-46) and 34 years (range 27-40) in two groups, respectively. The median WHO prognostic scores were 6 (range 3.5-8), and 77.32% of patients were FIGO stage III-IV in the primary treatment group. The median WHO prognostic scores were 5 (range 3-9), and 66.55% of patients were FIGO stage III-IV in the salvage treatment group. Median cycles of BEP treatment were 4 (3, 5) and 3 (2, 4) in two groups, respectively. In the primary chemotherapy group, 18.2% received additional hysterectomy, 4.5% received UAE for vaginal bleeding, and 1.52% received whole-brain radiotherapy. In the salvage chemotherapy group, 20.7% received hysterectomy, 6.9% received lobectomy, 3.4% received hysteroscopic lesion resection, and 3.4% received whole-brain radiotherapy. CR rates to initial chemotherapy were 86.4%, including 87.9% in the primary chemotherapy group and 82.8% in the salvage chemotherapy group. No predictive factor of chemotherapy resistance was identified. The rate of 5 year-DFS was 96.52% (95% CI 86.78-99.12) in the primary chemotherapy group and 92.44% (95% CI 73.02-98.06) in the salvage chemotherapy group. The rate of 5 year-OS was 98.31% (95% CI 88.57-99.76) and 95.65% (95% CI 79.93-99.38) in the two groups, respectively. During the treatment, neutropenia, thrombocytopenia, anemia, and liver dysfunction occurred in 80.3%, 6.1%, 25.8%, and 50% primary chemotherapy patients and 82.8%, 31%, 10.3%, and 86.2% salvage chemotherapy patients. In patients with fertility requirements, live birth rates were 100% (10/10) in primary chemotherapy patients and 80% (4/5) in salvage chemotherapy patients.\nBEP regimen was effective in the treatment of GTINs. The treatment was well tolerated, with no safety concerns on patients' fertility.",
"affiliations": "Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.;Department of Gynecologic and Obsterics, Shenzhen Sixth People's Hospital, Huazhong University of Science and Technology, Shenzhen, China.;Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.;Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.;Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.;Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.;Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.;Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.",
"authors": "Wang|Ming|M|;Shen|Lianna|L|;Xu|Xiaohong|X|;Duan|Wei|W|;Miao|Jinwei|J|;Kong|Weimin|W|;Su|Li|L|;Wu|Yumei|Y|https://orcid.org/0000-0002-2242-9348",
"chemical_list": "D000970:Antineoplastic Agents; D001761:Bleomycin; D005047:Etoposide; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1155/2021/6661698",
"fulltext": "\n==== Front\nBiomed Res Int\nBiomed Res Int\nBMRI\nBioMed Research International\n2314-6133\n2314-6141\nHindawi\n\n10.1155/2021/6661698\nResearch Article\nReal-World Study of Cisplatin, Etoposide, and Bleomycin Chemotherapy Regimen in Gestational Trophoblastic Neoplasia\nWang Ming 1\nShen Lianna 2\nXu Xiaohong 1\nDuan Wei 1\nMiao Jinwei 1\nKong Weimin 1\nSu Li 1\nhttps://orcid.org/0000-0002-2242-9348\nWu Yumei wym597118@163.com\n1\n1Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China\n2Department of Gynecologic and Obsterics, Shenzhen Sixth People's Hospital, Huazhong University of Science and Technology, Shenzhen, China\nAcademic Editor: A.Seval Ozgu-Erdinc\n\n2021\n24 6 2021\n2021 666169829 10 2020\n12 5 2021\n15 6 2021\nCopyright © 2021 Ming Wang et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nObjective\n\nLittle observational data exist regarding the use of cisplatin, etoposide, and bleomycin (BEP) chemotherapy regimen in patients with gestational trophoblastic neoplasia (GTN).\n\nMethods\n\nThis is a retrospective study of 95 patients with GTN in our center from June/2010 to June/2018. All patients received at least 2 cycles of BEP chemotherapy. The primary outcomes were the rate of complete remission (CR) and overall survival (OS). The secondary outcomes were disease-free survival (DFS), pregnancy rates after BEP exposure, drug resistance rate, and other adverse events.\n\nResults\n\nOf the 95 patients included, 66 (69.5%) patients received BEP as primary treatment and 29 (30.5%) were Salvage chemotherapy. The median age at diagnosis was 37 years (range 29.75-46) and 34 years (range 27-40) in two groups, respectively. The median WHO prognostic scores were 6 (range 3.5-8), and 77.32% of patients were FIGO stage III-IV in the primary treatment group. The median WHO prognostic scores were 5 (range 3-9), and 66.55% of patients were FIGO stage III-IV in the salvage treatment group. Median cycles of BEP treatment were 4 (3, 5) and 3 (2, 4) in two groups, respectively. In the primary chemotherapy group, 18.2% received additional hysterectomy, 4.5% received UAE for vaginal bleeding, and 1.52% received whole-brain radiotherapy. In the salvage chemotherapy group, 20.7% received hysterectomy, 6.9% received lobectomy, 3.4% received hysteroscopic lesion resection, and 3.4% received whole-brain radiotherapy. CR rates to initial chemotherapy were 86.4%, including 87.9% in the primary chemotherapy group and 82.8% in the salvage chemotherapy group. No predictive factor of chemotherapy resistance was identified. The rate of 5 year-DFS was 96.52% (95% CI 86.78–99.12) in the primary chemotherapy group and 92.44% (95% CI 73.02-98.06) in the salvage chemotherapy group. The rate of 5 year-OS was 98.31% (95% CI 88.57–99.76) and 95.65% (95% CI 79.93-99.38) in the two groups, respectively. During the treatment, neutropenia, thrombocytopenia, anemia, and liver dysfunction occurred in 80.3%, 6.1%, 25.8%, and 50% primary chemotherapy patients and 82.8%, 31%, 10.3%, and 86.2% salvage chemotherapy patients. In patients with fertility requirements, live birth rates were 100% (10/10) in primary chemotherapy patients and 80% (4/5) in salvage chemotherapy patients.\n\nConclusions\n\nBEP regimen was effective in the treatment of GTINs. The treatment was well tolerated, with no safety concerns on patients' fertility.\n\nBeijing Hospital AuthorityQMS20191701\n==== Body\n1. Introduction\n\nThe gestational trophoblastic disease is a spectrum of tumors that arise from placental tissue. Gestational trophoblastic neoplasia (GTN) refers to the invasive and malignant forms of gestational trophoblastic disease that include invasive mole, choriocarcinoma, placental-site trophoblastic tumor, and epithelioid trophoblastic tumor [1]. The incidence of GTN is ≤1/1000 deliveries, and the etiology of GTN is not well understood. The therapeutic decision is based on the International Federation of Gynecology and Obstetrics (FIGO) anatomic staging and prognostic scoring index [2]. Combination chemotherapy was recommended for primary treatment of high-risk (FIGO Stage III/IV or WHO score z7), salvage chemotherapy, resistant, or recurrent gestational trophoblastic neoplasms [3–5]. Combination chemotherapy with or without adjuvant radiotherapy or surgery could achieve a cure rate of 80%–90%.\n\nEMA/CO is the most commonly used first-line therapy, with platinum-etoposide combinations, particularly EMA/EP (etoposide, methotrexate, dactinomycin/etoposide, and cisplatin). Alternatives, including TP/TE (paclitaxel, cisplatin/paclitaxel, and etoposide), BEP (bleomycin, etoposide, and cisplatin), FAEV (floxuridine, dactinomycin, etoposide, and vincristine), and FA (5-fluorouracil (5-FU) and dactinomycin), may be as effective as EMA/EP and associated with fewer side effects [3].\n\nBEP regimen is recommended for treating high-risk, recurrent, or persisting GTN; however, high-quality evidence in support of this is still lacking. More studies about BEP chemotherapy in GTN are needed to enhance the body of therapeutic knowledge and capture the uncommon adverse events (AEs). Therefore, we conducted a prospective one-arm study of 95 patients to verify the safety and efficacy of the BEP regimen for GTN based on the patient-physician decision in a real-world setting.\n\n2. Methods\n\n2.1. Patient Selection\n\nThis is a retrospective single-arm study in which patients were recruited from a tertiary care hospital, the Beijing Obstetrics and Gynecology Hospital in China between July 2010 and July 2018. Subjects who were diagnosed with GTN and received BEP regimen chemotherapy were included in this study. The subjects were categorized as high risk according to the modified World Health Organization (WHO) scoring system, with extrauterine metastasis, or failed with other regimens. The trial was approved by the institutional ethics review committee (approval no: 2021-KY-052-01). The patients were stratified into two subgroups: primary chemotherapy group and salvage chemotherapy group based on having the previous chemotherapy or not.\n\n2.2. Study Procedures\n\nThe electronic medical record system and hospital paper charts, pertinent data from the clinic, and inpatient services in the Department of Gynecological Oncology in Beijing Obstetrics and Gynecology Hospital were retrospectively reviewed.\n\nPatients fulfilling the inclusion and exclusion criteria were included in the study. The chemotherapy protocol was chosen depending on the experience of the surgeons and patients' preference. Cisplatin 20 mg/m2 (30 mg) IV and etoposide 70 mg/m2 (100 mg) IV on days 1–5, as well as bleomycin 10 mg/m2 (15 mg) im on days 1-3 (see Supplementary Table 1). The regimens were repeated every 21-28 days. Pulmonary function testing was performed before initiation of therapy and every fourth dose thereafter.\n\nTo decrease the incidence of severe neutropenia, which occurs almost universally with these protocols, and avoid treatment delays, polyethylene glycol recombinant human granulocyte colony-stimulating factor (rhG-CSF) 3 mg/60Kg was administered in patients with previous III-IV neutropenia on days 3–14 of each treatment cycle, and a complete blood count was obtained at 3-4 days interval. No treatment course began unless the white blood cell count was ≥3,000/mL, and the platelet count was ≥100,000/mL. Anemia was treated with blood transfusion if the hemoglobin concentration was lower than 80 g/L. Serotonin 5-HT3 receptor antagonists were used to prevent nausea and vomiting. During chemotherapy, patients were monitored every 3 weeks for response and toxicity by physical examination, hematologic and chemistry profiles, and β-hCG levels.\n\n2.3. Other Adjuvant Treatment\n\nSurgery was considered to either excise sites of bulky and/or resistant tumors or less frequently to treat complications such as tumor hemorrhage or infection. Selective arterial embolization was used to control deep bleeding from the uterovaginal or other tumor sites. In cases with the isolated disease in the uterus or lungs, surgical resection was used in selected patients, for example, hysterectomy in patients who did not want to preserve fertility.\n\n2.4. Radiotherapy\n\nFor patients with resistant or metastatic lesions in the brain, the chemotherapy regimen was adjusted and radiotherapy was given when necessary.\n\n2.5. Follow-Up\n\nDuring the therapies, history, and physical examination, complete blood counts, chemistry profiles, and β-hCG were done at the first day of each course of the treatment. Patients were considered to be responding by the decrease in β-hCG levels. After the β-hCG levels were normal, continue systemic therapy regimen for 2 cycles.\n\nAfter the complete remission, follow-up β-hCG levels were measured monthly for 12 months, every 3 months during the second year and at 6-month intervals indefinitely thereafter. Patients were advised not to become pregnant for 1 year with the use of oral or barrier contraception to prevent pregnancy.\n\n2.6. Outcome Measurements and Endpoints\n\nThe primary outcome was the rate of complete remission and overall survival through the end of June 2020. Complete remission was defined as three consecutive weekly B-hCG levels less than 10 mIU/mL. Besides, all tests showed (including physical examination and imaging studies) that the lesions had disappeared, clinical symptoms disappeared. Overall survival was defined as the time interval from the initiation of BEP chemotherapy to the date of death for any reason. Data of patients who were lost to follow-up were still included in the analysis.\n\nThe secondary outcomes were the rates of disease-free survival (DFS), pregnancy after BEP exposure, drug resistance, and other adverse events. Disease-free survival was defined as the length of time that the women remained disease-free. In this study, we will judge the disease-free survival time from the initiation of BEP chemotherapy. Drug resistance [5] was defined in patients whose serum β-hCG level was not decreased logarithmically or showed a platform-like level after two cycles of chemotherapy; metastases grow or does not shrink, or even the emerging new metastatic lesions. Recurrence was defined when the β-hCG level rose (except for pre-pregnancy) or other examination revealed new lesions. Adverse events evaluations were conducted by performing a CBC, urinalysis, renal and liver function tests, chest PA, and pulmonary function test (PFT). PFT was performed before initiation of therapy and in patients who complained of respiratory symptoms such as dyspnea and more than 4 cycles of BEP regimen. AEs were graded according to the Common Terminology Criteria for Adverse Events (version 5.0).\n\n2.7. Statistical Analysis\n\nDemographics, baseline characteristics, and safety results were summarized descriptively. Adverse events except fertility rates were evaluated using the full analysis set, defined as all patients included who received at least ≥1 cycle of BEP regimen, as well as the efficacy-evaluable analysis set, which included patients who received at least ≥1 cycle and who had at least 1 evaluable postbaseline tumor assessment. Fertility rates were evaluated using the fertility requirement analysis set, defined as patients included who did not receive hysterectomy and had the willingness to conceive.\n\nBased on the previous study on BEP, we estimated 88.89% [6] patients achieved complete remission after the BEP chemotherapy, and the number of patients needed to verify the primary outcome was calculated to be 81 with a significance level of 0.05 and detection power of 0.80. Considering a 10% dropout rate in the retrospective study, a sample size of the patient included more than 89 was a reasonable estimation for the current study. For endpoint measurements, we performed the intention to treat (ITT) analysis, which was defined as analysis that included all included patients, including those with protocol deviations. Baseline characteristics and laboratory results were summarized for the three groups using descriptive statistics, including percentage, means ± standard deviation (SD), and 95% CI. For the quantitative variable, the t-test was used to compare group differences. For categorical variables, the chi-square test was used for group comparisons. The significance level was set at P < 0.05; all data were analyzed by SPSS 17.0 (SPSS, Inc., Chicago, IL).\n\n3. Results\n\n3.1. Study Population\n\nAmong the 115 patients reviewed, 95 patients were included in the study. 66 patients with gestational trophoblastic neoplasia and received BEP as the primary treatment and 29 patients who had failed primary treatment of other chemotherapy regimens for persistent or relapsed from remission selected BEP as the salvage therapy in the records of our center from June/2010 to June/2018 (Figure 1).\n\nPatients ranged in age from 29.75 to 46 years (median = 37) in primary treatment patients and from 27 to 40 years (median = 34) in salvage chemotherapy patients. Human chorionic gonadotropin (hCG) levels before BEP treatment ranged from 4.08∗103 to 1.28∗105 mIU/mL (median = 1.53∗104 mIU/mL) in primary treatment patients and from 417.65 to 6.50∗104 mIU/mL (median = 3.87∗103 mIU/mL) in salvage chemotherapy patients. 30.3% in the primary group and 24.1% in the salvage group had nonmolar antecedent pregnancies.\n\nMetastatic sites were vagina 1.52% (1/66), cervix 3.03% (2/66), adnexa 4.55% (3/66), lung 75.8% (50/66), humerus 1.52% (1/66), in primary group and lung 62.1% (18/29), and brain 3.45% (1/29) in salvage group. 15.2% (10/66) in the primary treatment group and 34.5% (10/29) patients in the salvage group with the refractory disease in the uterus had no evidence of metastasis. FIGO stage in the primary treatment group was as follows: 15.2% had stage I disease, 7.6% had stage II, 75.8% had stage III, and 1.52% had stage IV disease. FIGO stages in the salvage treatment group were as follows: 34.5% had stage I disease, 0% had stage II, 62.1% had stage III, and 3.45% had stage IV disease. World Health Organization (WHO) prognostic scores ranged from 3.5 to 8 (median = 6) in patients who received BEP as primary treatment, and 3 to 9 (median = 5) in patients who received BEP as salvage treatment (Table 1).\n\n3.1.1. Response to BEP Chemotherapy\n\nThe median (IQR) duration of chemotherapy cycles was 4 (3, 5) in patients who received BEP as primary chemotherapy. Of 66 primary chemotherapy patients, 18.2% underwent additional hysterectomy, 4.5% underwent UAE for vaginal bleeding, and 1.52% underwent whole-brain radiotherapy. 87.9% (58/66) had a complete response and 98.5% (65/66) survived. 25.8% (17/66) patients received another regimen during the treatment including 12.1% (8/66) patients who did not have CR, 4.5% (3/66) who did not tolerate the adverse events of BEP, and 9.1% (6/66) for the absence of bleomycin. 87.5% (7/8) patients who failed primary treatment with BEP had a complete clinical response to secondary chemotherapy with EMA-CO, EMA-EP, or 5-FU + Act-D (Table 2).\n\n29 patients with persistent/relapsed gestational trophoblastic neoplasia received BEP salvage chemotherapy. The BEP regimen yielded complete responses in 82.8% (24/29) patients, including 34.5% (10/29) patients who had failed 5-Fu based combined regimen, 27.6% (8/29) patients who had failed methotrexate/actinomycin D/5-Fu single-drug regimen, and 37.9% (11/29) patients who had failed other combined regimens. Of 29 salvage chemotherapy patients, 20.7% received additional hysterectomies, 6.9% underwent the resection of resistant pulmonary nodules, 3.4% received transcervical resection of focus, and 3.4% underwent whole-brain radiotherapy. 27.6% (8/29) patients received other regimens during the treatment including 17.2% (5/29) patients who did not have CR and 10.3% (3/29) who did not tolerate the adverse events of BEP. 80% (4/5) patients who failed primary treatment with BEP had a complete clinical response to other regimens (Table 2).\n\nNo predictive factor of chemotherapy resistance was identified in two subgroups.\n\n3.1.2. Overall and Disease-Free Survival\n\nThe median duration of follow-up was 68.70 months (range, 47.23-80.96 months) in the primary treatment group and 68.86 months (range, 49.55-91.97months) in the salvage chemotherapy group. During the follow-up, 7 patients were lost to follow-up. 2 patients died of the disease. In all treated patients, the overall survival rate at 5 years was 98.31% (95% CI 88.57–99.76) in the primary chemotherapy group and 95.65% (95% CI 79.93-99.38) in the salvage chemotherapy group, respectively (Figure 2(a)). Only 1 patient died of multiple metastasis 19 months in the primary chemotherapy group after the initial treatment. The remaining patients were placed into lasting remission (Table 3). 1 patient in the salvage chemotherapy group died 40 months after the BEP treatment. The rate of disease-free survival at 5 years was 96.52% (95% CI 86.78–99.12) in the primary chemotherapy group and 92.44% (95% CI 73.02-98.06) in the salvage chemotherapy group (Figure 2(b)). 5 patients had a recurrence, including 2 in the primary chemotherapy group and 3 in the salvage chemotherapy group. Patients who had a recurrence in the primary chemotherapy group were 1 simple β-HCG elevating and 1 multiple metastasis. Patients having a recurrence in the salvage chemotherapy group were 1 in lung, 1 in brain, and 1 in pelvic cavity. The patients with recurrence in lung were further returned to the general hospital with thoracic surgery. As expected, the patients achieved complete remission after the residual disease resected. 1 patient developed brain and lung metastasis 5 years after 6 courses of salvage BEP, and she received brain radiation, lobectomy, and other regimen chemotherapy. She is now in persisting remission but has epilepsy as the sequelae of brain metastasis and treated with Keppra. The patients with pelvic relapsed achieved complete remission after chemotherapy of EMA/CO regimen. She is now in the additional chemotherapy of EMA/CO.\n\n3.2. BEP Chemotherapy Side Effects\n\nThere were 10 itemized AEs recorded based on the patients' complaints, physical findings, and laboratory abnormalities, which included neutropenia, thrombocytopenia, anemia, liver dysfunction, renal toxicity, epilepsy, leukemia, femur head necrosis, pulmonary toxicity, and POF (as shown in Table 2). The study did not show a severe allergic reaction and obvious heart, liver, lung, and kidney dysfunction in patients. In patients with fertility requirements, live birth rates were 100% (10/10) in primary chemotherapy patients and 80% (4/5) in salvage chemotherapy patients. 1 patient underwent recurrent IVF failure for POI after the chemotherapy.\n\nThe most common treatment-related adverse events of were bone marrow suppression, including 80.3% (53/66) neutropenia, 50% (33/66) ALT elevation, 25.8% (17/66) anemia, 6.1% (4/66) thrombocytopenia, 1.5% (1/66) leukemia, 1.5% (1/66) in primary chemotherapy patients, 86.2% (25/29) ALT elevation, 82.8% (24/29) neutropenia, 31% (9/29) thrombocytopenia, 10.3% (3/29) anemia, and 3.4% (1/29) epilepsy in salvage chemotherapy patients, respectively. No treatment-related patient deaths or cases of BEP or acute allergic reaction occurred. However, most AEs on bone marrow suppression reported were grade I-II and were observed in this study, including 55.8% (43/77) neutropenia, 70% (14/20) anemia, and 84.6% (11/13) thrombocytopenia. Except for 1 case in which severe bone marrow suppression occurred leading to the cessation of chemotherapy, the other patients were not influenced by the side effects in the course of chemotherapy. The 57 cases with ALT elevation observed during chemotherapy were 59.2 (IQR: 48.1-84.9) IU/L (grade I-II AE). 1 patient who received 6 courses of BEP regimen and 2 additional courses of EMA-CO for drug resistance had leukemia 11 months after primary BEP chemotherapy and received bone transplantation. She is now being well (Table 3).\n\n4. Discussion\n\nIn this study, we report data on BEP therapy on the treatment of GTN in high-risk, relapsed, or uncontrolled patients in a real-world setting. To our knowledge, this is the largest real-life study with 96 subjects included to evaluate the effects and safety of BEP chemotherapy in patients with GTN. Our results indicated that the BEP regimen was effective and well-tolerated concerns on patients' fertility. In combination with additional treatment, the use of the BEP regimen yielded a 97.7% successful rate of treating MTCT in the on-protocol analysis in our real-life setting. Currently, the treatment principle of high-risk GTN is combinational chemotherapy as the first choice, and on this basis, radiotherapy and (or) other treatments such as surgery are given when appropriate [1]. EMA/CO is currently the most widely used first-line combination chemotherapy for high-risk GTN, although this regimen has not been rigorously compared to other combinations such as EMA/EP, BEP, TP/TE, or 5-FU based regimen.\n\nIn previous studies, EMA/EP salvage treatment following EMA/CO treatment failure, cure rates ranged from 66.6% to 84.9% [7–9]. However, EMA/EP was associated with significant myelosuppression and hepatotoxicity, leading to treatment delays and dose reductions. The taxane-containing regimen, TP/TE, was found to be associated with comparable cure rates to EMA/EP (70% of 10 patients) but with relatively reduced toxicity and no dose delays or reductions [10]. In a study of 222 patients, FA (5-FU and dactinomycin) was found to be effective as primary treatment for low- and high-risk GTN (with remission rates of 99% and 84%, respectively), except in patients with extensive metastases [11]. BEP regimen is recognized as the preferred choice in the treatment of malignant ovarian germ cell tumors (including primary ovarian choriocarcinoma). The regimen has been reported in the literature for its good effect in early, advanced, and recurrent malignant ovarian germ cell tumors. Song et al. examined the safety and efficacy outcomes on high-risk gestational trophoblastic tumors who were treated with BEP (n = 45 for endpoint analysis). The total complete remission rate of the BEP regimen was 88.89% (40/45). Five patients developed drug resistance after an average of 4.8 courses of BEP, and the regimen converted EMA/CO. Ultimately, four cases achieved CR and one case died of cancer. One of 45 patients who developed grade IV bone marrow suppression and worsened pulmonary fibrosis after chemotherapy. None of the survival patients developed a secondary tumor during the follow-up [6]. BEP is favored as salvage therapy in FA-resistant GTN, citing greater convenience compared with EMA/CO, and reporting a remission rate of 80% (10 out of 12) in high-risk cases. We observed 87.9% CR in primary chemotherapy GTNs and 82.8% in salvage chemotherapy GTNs. One patient died early of massive metastasis half a year after diagnosis, 1 died of disease relapse 40 months after treatment initiation, and 86 were alive until now except 7 patients who were lost to follow-up. Our data, together with the previous study, further support the use of BEP chemotherapy had a similar response to other combination regimens.\n\nThe adverse reactions of BEP are relatively mild, and the cure rate of malignant ovarian germ cell tumors could reach over 90%. Following these strategies, most patients will be cured, and the vast majority will still be able to give birth [12, 13]. In terms of safety data, salvage BEP-treated patients experienced a less cycle but higher adverse events (besides anemia) than primary BEP-treated patients, such as neutropenia, thrombocytopenia, and liver injury. The myelosuppression may be related to previous other regimens and BEP chemotherapy together. These observations yielded similar safety profiles with those data published in the aforementioned studies. However, our study showed 1 leukemia and 1 femur head necrosis after BEP chemotherapy. After bone marrow transplantation, the patients with leukemia were CR until now. No evidence of decreased fertility after chemotherapy for trophoblastic neoplasia was observed. Only one patient underwent POI after chemotherapy and failed for several IVF-ET. No congenital abnormalities were observed in our study.\n\nIn the traditional BEP regimen, bleomycin was used weekly for 12 weeks [14]. In our center, the dosage and interval of bleomycin were changed for the concerns of developing pulmonary fibrosis. The bleomycin was used in three weeks intervals, and the dosage was 45 mg per cycle in our study. Then, the accumulating dosage of bleomycin of 4 cycle chemotherapy was 180 mg not 360 mg in the traditional regimen, which was lower than the restriction dosage of pulmonary fibrosis. And, no pulmonary fibrosis was found.\n\nHowever, no control group was obtained in our study for patient characteristics in our study varying widely about the type and number of previous regimens administered, risk scores, and other factors. Then, direct comparisons of BEP with other regimens in a larger sample are needed for patients with GTN.\n\nIn conclusion, our results indicated that the BEP regimen was effective in the treatment of GTINs. The treatment was well tolerated, with no safety concerns on patients' fertility.\n\nAcknowledgments\n\nThis study was supported by Beijing Hospital Authority Talent Training Plan (grant number: QMS20191701).\n\nAbbreviations\n\nBEP: Cisplatin, etoposide, and bleomycin\n\nGTN: Gestational trophoblastic neoplasia\n\nCR: Complete remission\n\nFIGO: International Federation of Gynecology and Obstetrics\n\nAEs: Adverse events\n\nOS: Overall survival\n\nDFS: Disease-free survival\n\nITT: Intention to treat analysis.\n\nData Availability\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthical Approval\n\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The institutional ethics review committee of Beijing Obstetrics and Gynecology Hospital, Capital Medical University approved the trial, and the need for informed consent was waived.\n\nConflicts of Interest\n\nThe authors declare that they have no conflict of interest.\n\nAuthors' Contributions\n\nDrs. Yumei Wu and Ming Wang proposed the concept and designed the study. Drs. Ming Wang and Lianna Shen contributed to the acquisition of data. Dr. Wu supervised the data collection. Dr. Wang performed the statistics, interpreted the data, and wrote the manuscript with assistance from Dr. Wu. All authors provided inputs for the manuscript. Dr. Wu performed critical revisions of the manuscript and addressed the comments from the journal.\n\nSupplementary Materials\n\nSupplementary Materials Supplementary Table 1 showed the BEP treatment regimen applied in this study.\n\nClick here for additional data file.\n\nFigure 1 Patients' selections and study design.\n\nFigure 2 Kaplan–Meier estimates of overall survival and disease-free survival. (a) shows the Kaplan–Meier plot for overall survival, measured from the date of initiation of chemotherapy to the date of death or the date that the patient was last known to be alive. (b) shows the cumulative incidence curves for disease-free survival, measured from the date of surgery to the date of death or the date that the patient was last known without recurrence. A Cox proportional-hazards model was used to determine the hazard ratio and 95% confidence interval. Tick marks indicate censored data.\n\nTable 1 Baseline Values of GTN patients who received BEP chemotherapy (n = 95).\n\nN (percentile) Mothers\tPrimary treatment group (n = 66)\tSalvage treatment group (n = 29)\t\nMedian age (range)\t37 (29.75, 46)\t34 (27, 40)\t\n<40 years\t36 (54.5)\t21 (72.4)\t\n≥40 years\t30 (45.5)\t8 (27.6)\t\nAntecedent pregnancy\t\nHydatidiform mole\t46 (69.7)\t22 (75.9)\t\nAbortion\t14 (21.2)\t3 (10.3)\t\nTerm pregnancy\t6 (9.1)\t4 (13.8)\t\nInterval\t\n<4 months\t43 (65.2)\t18 (62.1)\t\n4–6 months\t10 (15.2)\t6 (20.7)\t\n7–12 months\t2 (3.0)\t2 (6.9)\t\n>12 months\t11 (16.7)\t3 (10.3)\t\nPretreatment β-hCG level\t\n<1,000\t5 (7.6)\t10 (34.5)\t\n1,000–<10,000\t22 (33.3)\t5 (17.2)\t\n10,000–<100,000\t21 (31.8)\t10 (34.5)\t\n>100,000\t18 (27.3)\t4 (13.8)\t\nPrevious chemotherapy\t\nYes\t0\t29\t\nNo\t66\t0\t\nTumor size (in cm)\t\n<3\t34 (51.5)\t21 (72.4)\t\n3-5\t18 (27.2)\t4 (13.8)\t\n≥5\t14 (21.2)\t4 (13.8)\t\nSite of metastasis\t\nVagina\t1 (1.52)\t0 (0)\t\nCervix\t2 (3.03)\t0 (0)\t\nAdnexa\t3 (4.55)\t0 (0)\t\nLung\t50 (75.8)\t18 (62.1)\t\nBrain\t0 (0)\t1 (3.45)\t\nHumerus\t1 (1.52)\t0 (0)\t\nFIGO stage\t\nI\t10 (15.2)\t10 (34.5)\t\nII\t5 (7.6)\t0\t\nIII\t50 (75.8)\t18 (62.1)\t\nIV\t1 (1.52)\t1 (3.45)\t\nPrognostic score\t6 (3.5,8)\t5 (3,9)\t\nLow-risk\t35 (53)\t18 (62.1)\t\nHigh-risk\t31 (47)\t11 (37.9)\t\n∗Note: BEP: cisplatin, etoposide, and bleomycin; GTN: gestational trophoblastic neoplasia; FIGO: International Federation of Gynecology and Obstetrics.\n\nTable 2 Efficacy of BEP chemotherapy in GTN patients (n = 95).\n\nN (percentile)\tPrimary treatment group (n = 66)\tSalvage treatment group (n = 29)\t\nCourse of BEP\t4 (3, 5)\t3 (2, 4)\t\nAdditional treatment\t15 (22.7)\t10 (34.5)\t\n Hysterectomy\t12 (18.2)\t6 (20.7)\t\n UAE\t3 (4.5)\t0 (0)\t\n Radiation\t1 (1.52)\t1 (3.4)\t\n Lobectomy\t0 (0)\t2 (6.9)\t\n Hysteroscopic lesion resection\t0 (0)\t1 (3.4)\t\nResponse\t\t\t\n CR\t58 (87.9)\t24 (82.8)\t\n PR\t8 (12.1)\t5 (17.2)\t\nReasons to change BEP regimen\t17 (25.8)\t8 (27.6)\t\n Resistance\t8 (12.1)\t5 (17.2)\t\n Nontolerable\t3 (4.5)\t3 (10.3)\t\n Strengthen for no bleomycin or restriction\t6 (9.1)\t0 (0)\t\n∗Note: BEP: cisplatin, etoposide, and bleomycin; GTN: gestational trophoblastic neoplasia; UAE: uterine artery embolism; CR: complete remission; PR: partial remission.\n\nTable 3 Adverse events reported in the study (n = 95).\n\nAdverse events N (%)\tPrimary treatment group (n = 66)\tSalvage treatment group (n = 29)\t\nNeutropenia\t53 (80.3)\t24 (82.8)\t\nGrade 1/2\t31 (50)\t12 (41.4)\t\nGrade 3/4\t22 (33.3)\t12 (41.4)\t\nThrombocytopenia\t4 (6.1)\t9 (31)\t\nGrade 1/2\t4 (6.1)\t7 (24.1)\t\nGrade 3/4\t0 (0)\t2 (6.9)\t\nAnemia\t17 (25.8)\t3 (10.3)\t\nGrade 1/2\t13 (19.7)\t1 (3.4)\t\nGrade 3/4\t4 (6.1)\t2 (6.9)\t\nLiver dysfunction\t33 (50)\t25 (86.2)\t\nGrade I/II (1-2.5, 2.5-5)\t33 (50)\t25 (86.2)\t\nGrade III/IV (5-20, >20)\t0 (0)\t0 (0)\t\nRenal toxicity\t0 (0)\t0 (0)\t\nEpilepsy\t0 (0)\t1 (3.4)\t\nLeukemia\t1 (1.5)\t0 (0)\t\nFemur head necrosis\t1 (1.5)\t0 (0)\t\nPulmonary toxicity\t0 (0)\t0 (0)\t\nPOF\t0 (0)\t2 (6.90)\t\nPregnancy rates\t10/10 (100)\t4/5 (80)\t\n∗Note: AEs: adverse events; POF: premature ovarian failure.\n==== Refs\n1 Lurain J. R. Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia American Journal of Obstetrics and Gynecology 2011 204 1 11 18 10.1016/j.ajog.2010.06.072 2-s2.0-78650707087 20739008\n2 Ngan H. Y. Bender H. Benedet J. L. Gestational trophoblastic neoplasia, FIGO 2000 staging and classification International Journal of Gynaecology and Obstetrics 2003 83 175 177 10.1016/S0020-7292(03)90120-2 2-s2.0-10644245919 14763174\n3 Deng L. Zhang J. Wu T. Lawrie T. A. Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group Combination chemotherapy for primary treatment of high-risk gestational trophoblastic tumour Cochrane Database of Systematic Reviews 2013 31 10.1002/14651858.CD005196.pub4 2-s2.0-84874984511\n4 Lurain J. R. Nejad B. Secondary chemotherapy for high-risk gestational trophoblastic neoplasia Gynecologic Oncology 2005 97 2 618 623 10.1016/j.ygyno.2005.02.004 2-s2.0-18144416191 15863169\n5 Alazzam M. Tidy J. Osborne R. Chemotherapy for resistant or recurrent gestational trophoblastic neoplasia Cochrane Database of Systematic Reviews 2016 13 10.1002/14651858.CD008891.pub3 2-s2.0-84966283990\n6 Song S. Q. Wang C. Zhang G. N. BEP for high-risk gestational trophoblastic tumor: results from a cohort of 45 patients European Journal of Gynaecological Oncology 2015 36 6 726 729 26775361\n7 Newlands E. S. Mulholland P. J. Holden L. Seckl M. J. Rustin G. J. Etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EMA) chemotherapy for patients with high-risk gestational trophoblastic tumors refractory to EMA/cyclophosphamide and vincristine chemotherapy and patients presenting with metastatic placental site trophoblastic tumors Journal of Clinical Oncology 2000 18 4 854 859 10.1200/JCO.2000.18.4.854 10673528\n8 Mao Y. Wan X. Lv W. Xie X. Relapsed or refractory gestational trophoblastic neoplasia treated with the etoposide and cisplatin/etoposide, methotrexate, and actinomycin D (EP-EMA) regimen International Journal of Gynaecology and Obstetrics 2007 98 1 44 47 10.1016/j.ijgo.2007.03.037 2-s2.0-34250197923 17481633\n9 Lu W. G. Ye F. Shen Y. M. EMA-CO chemotherapy for high-risk gestational trophoblastic neoplasia: a clinical analysis of 54 patients International Journal of Gynecologic Cancer 2008 18 2 357 362 10.1111/j.1525-1438.2007.00999.x 2-s2.0-40549083394\n10 Wang J. Short D. Sebire N. J. Salvage chemotherapy of relapsed or high-risk gestational trophoblastic neoplasia (GTN) with paclitaxel/cisplatin alternating with paclitaxel/etoposide (TP/TE) Annals of Oncology 2008 19 9 1578 1583 10.1093/annonc/mdn181 2-s2.0-50849111051 18453518\n11 Zhao Y. Zhang W. Duan W. Management of gestational trophoblastic neoplasia with 5-fluorouracil and actinomycin D in northern China Journal of Reproductive Medicine 2009 54 88 94 19301571\n12 Tangir J. Zelterman D. Ma W. Schwartz P. E. Reproductive function after conservative surgery and chemotherapy for malignant germ celltumors of the ovary Obstetrics and Gynecology 2003 101 2 251 257 10.1016/s0029-7844(02)02508-5 2-s2.0-0037308684 12576247\n13 de La Motte Rouge T. Pautier P. Duvillard P. Survival and reproductive function of 52 women treated with surgery and bleomycin, etoposide, cisplatin (BEP) chemotherapy for ovarian yolk sac tumor Annals of Oncology 2008 19 1435 1441 10.1093/annonc/mdn162 2-s2.0-48749126166 18408223\n14 Saxman S. B. Finch D. Gonin R. Einhorn L. H. Long-term follow-up of a phase III study of three versus four cycles of bleomycin, etoposide, and cisplatin in favorable-prognosis germ-cell tumors: the Indian University experience Journal of Clinical Oncology 1998 16 2 702 706 10.1200/JCO.1998.16.2.702 2-s2.0-0031894195 9469360\n\n",
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"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D001761:Bleomycin; D002945:Cisplatin; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005047:Etoposide; D005260:Female; D005500:Follow-Up Studies; D031901:Gestational Trophoblastic Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011247:Pregnancy; D011248:Pregnancy Complications; D011379:Prognosis; D011446:Prospective Studies; D011878:Radiotherapy; D012074:Remission Induction; D012189:Retrospective Studies; D016879:Salvage Therapy; D016896:Treatment Outcome",
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"title": "Real-World Study of Cisplatin, Etoposide, and Bleomycin Chemotherapy Regimen in Gestational Trophoblastic Neoplasia.",
"title_normalized": "real world study of cisplatin etoposide and bleomycin chemotherapy regimen in gestational trophoblastic neoplasia"
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"abstract": "Suicide by self-poisoning is rather common around the world. This paper presents an exceptional complex suicide in which nicotine was applied in the form of self-made patches soaked with an extraction from fine-cut tobacco. In addition, the 51-year-old suicide victim took a lethal dose of diphenhydramine. Toxicological analysis also revealed the presence of tetrazepam in subtherapeutic concentrations. The scene of death suggested an autoerotic accident at first, as the body was tied with tapes, cables and handcuffs. As a result of the entire investigations, the fatality had to be classified as a suicidal intoxication by nicotine and diphenhydramine.",
"affiliations": "Institute of Forensic Medicine, Freiburg University Medical Center, Albertstraße 9, 79104 Freiburg im Breisgau, Germany; University Center of Legal Medicine, Geneva University Hospitals (HUG), Rue Michel-Servet 1, 1211 Geneva 4, Switzerland. Electronic address: christelle.lardi@uniklinik-freiburg.de.;Institute of Forensic Medicine, Freiburg University Medical Center, Albertstraße 9, 79104 Freiburg im Breisgau, Germany.;Institute of Forensic Medicine, Freiburg University Medical Center, Albertstraße 9, 79104 Freiburg im Breisgau, Germany.;Institute of Forensic Medicine, Freiburg University Medical Center, Albertstraße 9, 79104 Freiburg im Breisgau, Germany.",
"authors": "Lardi|C|C|;Vogt|S|S|;Pollak|S|S|;Thierauf|A|A|",
"chemical_list": "D005731:Ganglionic Stimulants; D006993:Hypnotics and Sedatives; D009538:Nicotine; D004155:Diphenhydramine",
"country": "Ireland",
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"issn_linking": "0379-0738",
"issue": "236()",
"journal": "Forensic science international",
"keywords": "Complex suicide; Diphenhydramine; Nicotine; Self-tying; Transdermal application",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D002853:Chromatography, Liquid; D004155:Diphenhydramine; D053593:Forensic Toxicology; D005731:Ganglionic Stimulants; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D008875:Middle Aged; D009538:Nicotine; D013405:Suicide; D061485:Tobacco Use Cessation Devices",
"nlm_unique_id": "7902034",
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"pages": "e14-8",
"pmc": null,
"pmid": "24439154",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Complex suicide with homemade nicotine patches.",
"title_normalized": "complex suicide with homemade nicotine patches"
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"abstract": "Immune checkpoint inhibitors are known to cause a variety of immune-related adverse events, including pneumonitis. When symptomatic, treatment typically consists of temporary or permanent cessation of the checkpoint inhibitor and several weeks of corticosteroid therapy. However, a subset of patients may suffer from severe pneumonitis, and the optimal treatment for this group is not known. Here we describe the case of a patient receiving pembrolizumab for non-small cell lung cancer who developed severe checkpoint inhibitor pneumonitis. After treatment with high-dose corticosteroids failed to produce a response, a course of intravenous immunoglobulin catalyzed rapid and durable improvement. In this review, we discuss the current evidence regarding the incidence and outcomes of severe checkpoint inhibitor pneumonitis and propose a role for intravenous immunoglobulin as a possible treatment strategy.",
"affiliations": "Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.;Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.;Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.;Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.;Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.",
"authors": "Petri|Camille R|CR|;Patell|Rushad|R|;Batalini|Felipe|F|;Rangachari|Deepa|D|;Hallowell|Robert W|RW|",
"chemical_list": null,
"country": "England",
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"doi": "10.1016/j.rmcr.2019.100834",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(19)30021-810.1016/j.rmcr.2019.100834100834ArticleSevere pulmonary toxicity from immune checkpoint inhibitor treated successfully with intravenous immunoglobulin: Case report and review of the literature Petri Camille R. cpetri@bidmc.harvard.edua∗Patell Rushad rpatell@bidmc.harvard.edubBatalini Felipe fbatalin@bidmc.harvard.edubRangachari Deepa drangach@bidmc.harvard.edubHallowell Robert W. rhallowe@bidmc.harvard.eduaa Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USAb Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA∗ Corresponding author. Beth Israel Deaconess Medical Center, 330 Brookline Avenue, KS-B23, Boston, MA 02215, USA. cpetri@bidmc.harvard.edu06 4 2019 2019 06 4 2019 27 10083415 1 2019 3 4 2019 © 2019 Published by Elsevier Ltd.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Immune checkpoint inhibitors are known to cause a variety of immune-related adverse events, including pneumonitis. When symptomatic, treatment typically consists of temporary or permanent cessation of the checkpoint inhibitor and several weeks of corticosteroid therapy. However, a subset of patients may suffer from severe pneumonitis, and the optimal treatment for this group is not known. Here we describe the case of a patient receiving pembrolizumab for non-small cell lung cancer who developed severe checkpoint inhibitor pneumonitis. After treatment with high-dose corticosteroids failed to produce a response, a course of intravenous immunoglobulin catalyzed rapid and durable improvement. In this review, we discuss the current evidence regarding the incidence and outcomes of severe checkpoint inhibitor pneumonitis and propose a role for intravenous immunoglobulin as a possible treatment strategy.\n\nKeywords\nImmune checkpoint inhibitorPneumonitisPulmonary toxicityIntravenous immunoglobulinAbbreviations\nImmune checkpoint inhibitor, ICIIntravenous immunoglobulin, IVIgProgrammed cell-death 1, PD-1Programmed cell-death ligand, PD-L1Cytotoxic T-lymphocyte antigen-4, CTLA-4\n==== Body\n1 Case presentation\nA 76-year-old woman with metastatic lung adenocarcinoma receiving palliative chemoimmunotherapy presented with acute onset fevers, dyspnea, and cough.\n\nThe patient had a past medical history remarkable for invasive ductal carcinoma of the right breast treated with lumpectomy followed by an aromatase inhibitor, which was diagnosed eight months prior to the lung cancer. She had a prior 20 pack-year tobacco use history, but had ceased smoking 35 years ago. She had recently traveled to the Southwest United States. She had no known occupational or environmental exposures. Notably, there was no history of chest radiation.\n\nLung cancer had been diagnosed three months prior to the current presentation, when she presented with hypoxemia on exertion and computed tomography (CT) showed a right upper lobe mass with evidence of lung and liver metastases. Biopsy of the lung and liver revealed metastatic adenocarcinoma consistent with lung origin and no actionable mutations on standard tumor molecular profiling. Palliative systemic therapy with carboplatin, pemetrexed, and pembrolizumab administered intravenously every 21 days was commenced as per the evidence-based standard of care. Imaging following the first two cycles of therapy showed stable disease.\n\nMidway through the fourth cycle of therapy, the patient developed fevers, dyspnea on exertion, and cough. CT angiogram of the chest showed no pulmonary embolism, but revealed confluent regions of consolidation in the lungs bilaterally – significantly worse on the left – and a small left pleural effusion on a background of known bilateral cavitary lung lesions (Fig. 1).Fig. 1 Representative axial image from CT chest obtained on presentation showing bilateral consolidations bilaterally, significantly worse on the left, and a small left pleural effusion.\n\nFig. 1\n\nShe was admitted to the intensive care unit with severe hypoxemic respiratory failure and PaO2/FiO2 ratio of 87. She was treated with broad-spectrum antibiotics due to concern for a primary infectious process, but experienced worsening hypoxemia on day three necessitating endotracheal intubation and mechanical ventilation. Positive end-expiratory pressure was titrated, and lung protective ventilation utilizing a low tidal volume strategy was employed.\n\nBronchoscopy on day three revealed thin secretions in the left lower lobe, but was otherwise unremarkable. Bronchoalveolar lavage studies showed slight neutrophilic predominance (70% and 54% polymorphonuclear cells in two separate samples). Negative microbiology studies included gram stain and bacterial, viral, legionella, fungal, nocardia, and acid-fast bacteria cultures. Aspergillus galactomannan antigen from the bronchoalveolar lavage fluid was negative, as were blood and urine markers of infection. A transthoracic echocardiogram showed mild symmetric left ventricular hypertrophy with normal right ventricular size and systolic function without significant valvular disease, signs of increased filling pressures, or atrial septal defect. Additional invasive diagnostic procedures (i.e. lung biopsy) were deferred due to clinical instability.\n\nImmune checkpoint inhibitor (ICI) pneumonitis was suspected, and she was initiated on intravenous methylprednisolone at a dose of 2 mg/kg/day on day three. On day nine, the patient continued to have significant desaturations despite an FiO2 of 0.8, positive end-expiratory pressure of 10 cmH2O, and negative total body fluid balance.\n\nDue to concern for steroid-refractory pembrolizumab-induced pneumonitis, intravenous immunoglobulin (IVIg) dosed at 2g/kg was administered on days 9–13 for a five-day course. This therapy was chosen due to its relatively mild toxicity profile in comparison to other more aggressive immunosuppressive agents, i.e. infliximab, cyclophosphamide, and mycophenolate mofetil. The patient experienced rapid and significant clinical and radiographic improvement allowing for successful extubation on day 12. Repeat chest CT imaging on day 12 demonstrated a marked improvement in the severe interstitial abnormality felt to represent an organizing phase of acute lung injury, consistent with a clinical response to immunomodulatory therapy (Fig. 2).Fig. 2 Representative axial image from CT chest obtained after three days of IVIg therapy showing marked improvement in severe interstitial abnormality.\n\nFig. 2\n\nAfter two weeks of high-dose methylprednisolone, she was transitioned to prednisone 1 mg/kg/day. Her supplemental oxygen requirement decreased, she was weaned to an oxymizer device and ultimately discharged on day 23. At a follow-up visit three weeks later, oxygen needs had decreased to 1.5 L per minute via nasal cannula, and her exercise tolerance had improved substantially. Her prednisone was decreased to 0.5mg/kg/day with plans for a continued slow taper completed over the course of 2 months. Re-staging CT of the torso performed six weeks after her admission to reassess malignant tumor burden demonstrated continued improvement of the predominantly left-sided infiltrate, but a remaining bilateral subpleural interstitial fibrotic abnormality; the malignant disease burden was noted to be stable (Fig. 3).Fig. 3 Representative axial image from CT chest performed six weeks after admission showing near resolution of infiltrates with residual bilateral subpleural interstitial fibrosis.\n\nFig. 3\n\n2 Discussion\nICI pneumonitis is a rare, but potentially fatal complication of programmed cell-death 1 (PD-1), programmed cell-death ligand (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) blockade, occurring in 3–5% of patients – though some studies have reported a frequency of up to 11.8% [[1], [2], [3], [4], [5], [6]]. Fortunately, the majority of these patients experience only mild or moderate pneumonitis and will improve with withdrawal of the immunotherapy and/or a course of corticosteroids [6,7].\n\nHowever, a subset of patients will develop severe pneumonitis, classified as grade 3 or higher by the Common Terminology Criteria for Adverse Events (version 5.0), defined by: requiring hospitalization, involving >50% of lung parenchyma, limiting activities of daily living, or requiring supplemental oxygen. In general, severe pneumonitis accounts for approximately 30% of ICI pneumonitis cases. Severe manifestations of this toxicity have been associated with tumor histology (i.e. non-small cell lung cancer (NSCLC), renal cell carcinoma (RCCA) – both of which are the most common current indications for ICI use) and underlying lung disease, though larger datasets are needed to establish these risk factors more definitively [5,6,8,9]. Overall, severe pneumonitis represents a distinct category of patients, for which the prognosis is more variable and for which the management may differ.\n\nCurrent understanding of the incidence, natural history, and treatment of severe pneumonitis is limited to several small retrospective series, summarized in Table 1.Table 1 Summary of studies of ICI pneumonitis and treatments included in this review.\n\nTable 1Source\tICI used\tTumor type\tIncidence of pneumonitis (%)\tIncidence of severe pneumonitis (%)\tTreatment\t\nDelaunay et al.\tCTLA-4, PD-1, PD-L1 inhibitors\tNSCLC, melanoma, others\t64/1826 (3.5%)\t29/64 (45%)\tCorticosteroids\t\nNaidoo et al.\tPD-1, PD-L1 inhibitors ± CTLA-4 inhibitor\tNSCLC, melanoma, others\t43/915 (4.7%)\t12/43 (27%)\tCorticosteroids; infliximab ± cyclophosphamide\t\nKhunger et al.\tPD-1, PD-L1 inhibitors\tNSCLC\t140/5038 (2.8%)\t49/140 (33%)\tNot discussed\t\nNishino et al.\tPD-1 inhibitor\tNSCLC, melanoma, RCCA\t154/4496 (3.4%)\t44/154 (29%)\tNot discussed\t\nSuresh et al.\tPD-1, PD-L1 inhibitors\tAdvanced NSCLC\t39/205 (19%)\t25/39 (64%)\tCorticosteroids; mycophenolate mofetil or infliximab\t\n\n\nIn a study of 64 ICI-induced pneumonitis cases, Delaunay and colleagues reported that 45% (29/64) were classified as severe, including six fatalities [7]. Of note, deaths occurred only in NSCLC patients treated with PD-1/PD-L1 inhibitors. No patient in this cohort was treated with immunosuppression beyond corticosteroids, and in the 43 patients who improved or were stable, 41.9% (18/43 patients) had had grade 3 or 4 pneumonitis.\n\nNaidoo and colleagues studied 43 patients treated with ICIs [6]. In this cohort, 12 patients (27%) experienced grade 3 or higher pneumonitis, including one fatal case. Pneumonitis improved or resolved in seven of these 12 patients with severe pneumonitis. The remaining five patients were treated with additional immunosuppression, including infliximab with and without cyclophosphamide. Ultimately, all five patients died, most often from infectious complications. One death was attributed to pneumonitis alone.\n\nKhunger and colleagues performed a systematic review and meta-analysis of nineteen clinical trials of PD-1 and PD-L1 inhibitors that included 5,038 NSCLC patients accounting for 140 cases of pneumonitis, and 49 cases grade 3 or higher [8]. Patients treated with PD-1 inhibitors had a higher incidence of pneumonitis of any grade (3.6% vs. 1.3%) and severe pneumonitis (1.1% vs 0.4%) when compared to those treated with PD-L1 inhibitors. Roughly 30% of all pneumonitis cases associated with PD-1 or PD-L1 inhibitors were considered severe. Additionally, patients who had had no prior cancer therapy had a higher rate of pneumonitis (4.2% vs. 2.8%), though treatment status did not confer a higher rate of severe pneumonitis. This report did not examine treatment strategies.\n\nNishino and colleagues performed a systematic review and meta-analysis of clinical trial data to evaluate the incidence of pneumonitis related to PD-1 inhibitors specifically across NSCLC, melanoma, and RCCA trials [5]. Here, they reported an incidence of severe pneumonitis (grade 3 or higher) of 0.8% with immune monotherapy (30% of pneumonitis cases), and 1.5% with combination immunotherapy (23% of pneumonitis cases). This report also did not examine treatment strategies.\n\nFinally, Suresh and colleagues recently published a retrospective study of 205 patients with advanced NSCLC who received PD-1 or PD-L1 inhibitors through clinical trials or standard of care [10]. Here, they reported a much higher rate of ICI pneumonitis compared to prior studies: ICI pneumonitis ≥ grade 2 severity occurred in 39 of 205 (19%) patients, including 25 cases (64%) ≥ grade 3 and five deaths. Of ICI pneumonitis cases, fourteen were steroid-refractory or steroid-unresponsive despite 72 hours of high dose steroids. Four patients went on to receive additional immunosuppressive therapy with mycophenolate mofetil or infliximab. Three of these four patients improved with additional therapy. In this study, the occurrence of ICI pneumonitis negatively impacted patients’ overall survival.\n\nA challenge to the practitioner in making treatment decisions is the unknown biological mechanisms that lead to ICI pneumonitis. Current understanding includes contributions from increased immune surveillance and decreased self-tolerance with resultant autoimmunity via T-cell recognition of antigens. This leads to cytokine production, increased humoral immunity, and the production of autoantibodies whose activity results in the activation of tissue degrading enzymes that finally lead to tissue injury [11]. The impact of common environmental and therapeutic factors (i.e. tobacco, radiation, and prior chemotherapeutic exposure) remains uncertain. Additional studies are needed to further elucidate this proposed pathophysiology and to better establish risk factors and models for predicting toxicity, as increasing use of ICIs across the spectrum of oncologic care is a growing reality.\n\nRecommendations for the treatment of ICI pneumonitis are drawn from consensus opinion, as there have been no prospective trials establishing the preferred regimen. According to American Society of Clinical Oncology guidelines, pneumonitis of grade 3 or higher should prompt treatment with intravenous corticosteroids and permanent withdrawal of the ICI [9]. Clinical improvement is expected within the first 48 hours of treatment, otherwise the pneumonitis is considered steroid-refractory. Clinicians may then consider additional immunosuppression, usually with infliximab, mycophenolate mofetil, or cyclophosphamide. We advocate that IVIg should be included amongst these agents.\n\nTo our knowledge, there are no published reports of utilizing IVIg for the treatment of ICI pneumonitis. However, IVIg has been used successfully in other ICI-related toxicities, such as myasthenia gravis [12], thrombocytopenia, and other neurological syndromes [13,14]. Additionally, IVIg has an evolving role in the treatment of interstitial lung disease (ILD), including ILD-associated with connective tissue disease and idiopathic pulmonary fibrosis [[15], [16], [17]]. As detailed recently by Hallowell and colleagues, IVIg is felt to exert its immunomodulatory effect via three mechanisms: (1) regulating the function of immune cells causing inflammation, (2) binding and neutralizing autoantibodies and (3) downregulating expression of various chemokines, cytokines, chemo-receptors and adhesion molecules [18]. Other benefits to the use of IVIg include a relatively modest toxicity profile, (i.e. headache, myalgias, nausea and fever), though more serious events such as venous thromboembolism, aseptic meningitis, and anaphylaxis may occur [19]. Finally, IVIg has been postulated to have more immunomodulatory rather than immunosuppressive effects. Therefore, in light of multiple reports of infectious complications related to additional immunosuppression used for steroid-refractory pneumonitis [6], clinicians should consider IVIg as a potentially effective agent with a more favorable therapeutic index.\n\n3 Conclusion\nOur case demonstrates the safety and efficacy of the addition of IVIg to high-dose corticosteroid therapy as a treatment for steroid-refractory ICI pneumonitis. We acknowledge the difficulty in ascertaining how much of the patient's improvement can be attributed to the corticosteroids versus IVIg; however, the lack of improvement despite one week of high-dose intravenous corticosteroids and subsequent rapid improvement within 72 hours of IVIg administration suggests a meaningful impact from this adjunctive therapy. We believe that IVIg represents an attractive treatment option for steroid-refractory pneumonitis, with a favorable toxicity/benefit profile as compared to other traditional immunosuppressive agents. Rigorous prospective evaluation of IVIg and other immunosuppressive agents in the treatment of severe ICI pneumonitis is needed to establish best practice in this evolving field.\n\nDeclarations of interest\nCP, RP, FB and RH have no conflicts of interest. DR has received research funding from Bristol-Myers Squibb unrelated to this work.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgments\nNone.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2019.100834.\n==== Refs\nReferences\n1 Reck M. Rodríguez-Abreu D. Robinson A.G. Hui R. Csőszi T. Fülöp A. Gottfried M. Peled N. Tafreshi A. Cuffe S. O'Brien M. Rao S. Hotta K. Leiby M.A. Lubiniecki G.M. Shentu Y. Rangwala R. Brahmer J.R. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer N. Engl. J. Med. 375 2016 1823 1833 27718847 \n2 Herbst R.S. Baas P. Kim D.W. Felip E. Pérez-Gracia J.L. Han J.Y. Molina J. Kim J.H. Arvis C.D. Ahn M.J. Majem M. Fidler M.J. De Castro G. Garrido M. Lubiniecki G.M. Shentu Y. Im E. Dolled-Filhart M. Garon E.B. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial Lancet 387 2016 1540 1550 26712084 \n3 Rosenberg J.E. Hoffman-Censits J. Powles T. Van Der Heijden M.S. Balar A.V. Necchi A. Dawson N. O'Donnell P.H. Balmanoukian A. Loriot Y. Srinivas S. Retz M.M. Grivas P. Joseph R.W. Galsky M.D. Fleming M.T. Petrylak D.P. Perez-Gracia J.L. Burris H.A. Castellano D. Canil C. Bellmunt J. Bajorin D. Nickles D. Bourgon R. Frampton G.M. Cui N. Mariathasan S. Abidoye O. Fine G.D. Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial Lancet 387 2016 1909 1920 26952546 \n4 Fehrenbacher L. Spira A. Ballinger M. Kowanetz M. Vansteenkiste J. Mazieres J. Park K. Smith D. Artal-Cortes A. Lewanski C. Braiteh F. Waterkamp D. He P. Zou W. Chen D.S. Yi J. Sandler A. Rittmeyer A. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial Lancet 387 2016 1837 1846 26970723 \n5 Nishino M. Giobbie-Hurder A. Hatabu H. Ramaiya N.H. Hodi F.S. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer a systematic review and meta-analysis JAMA Oncol. 2 2016 1607 1616 27540850 \n6 Naidoo J. Wang X. Woo K.M. Iyriboz T. Halpenny D. Cunningham J. Chaft J.E. Segal N.H. Callahan M.K. Lesokhin A.M. Rosenberg J. Voss M.H. Rudin C.M. Rizvi H. Hou X. Rodriguez K. Albano M. Gordon R.A. Leduc C. Rekhtman N. Harris B. Menzies A.M. Guminski A.D. Carlino M.S. Kong B.Y. Wolchok J.D. Postow M.A. Long G.V. Hellmann M.D. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy J. Clin. Oncol. 35 2017 709 717 27646942 \n7 Delaunay M. Cadranel J. Lusque A. Meyer N. Gounaut V. Moro-Sibilot D. Michot J.M. Raimbourg J. Girard N. Guisier F. Planchard D. Metivier A.C. Tomasini P. Dansin E. Pérol M. Campana M. Gautschi O. Früh M. Fumet J.D. Audigier-Valette C. Couraud S. Dalle S. Leccia M.T. Jaffro M. Collot S. Prévot G. Milia J. Mazieres J. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients Eur. Respir. J. 50 2017 \n8 Khunger M. Rakshit S. Pasupuleti V. Hernandez A.V. Mazzone P. Stevenson J. Pennell N.A. Velcheti V. 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Lin C.T. Psoter K.J. Danoff S.K. Naidoo J. Pneumonitis in non–small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors J. Thorac. Oncol. 13 2018 1930 1939 30267842 \n11 Postow M.A. Sidlow R. Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade N. Engl. J. Med. 378 2018 158 168 29320654 \n12 Makarious D. Horwood K. Coward J.I.G. Myasthenia gravis: an emerging toxicity of immune checkpoint inhibitors Eur. J. Cancer 82 2017 128 136 28666240 \n13 Wilson R. Menassa D.A. Davies A.J. Michael S. Hester J. Kuker W. Collins G.P. Cossins J. Beeson D. Steven N. Maddison P. Rinaldi S. Jacob S. Irani S.R. Seronegative antibody-mediated neurology after immune checkpoint inhibitors Ann. Clin. Transl. Neurol. 5 2018 640 645 29761126 \n14 Tchapyjnikov D. Borst A.J. Immune-related neurological symptoms in an adolescent patient receiving the checkpoint inhibitor nivolumab J. Immunother. 40 2017 286 288 28604555 \n15 Suzuki Y. Hayakawa H. Miwa S. Shirai M. Fujii M. Gemma H. Suda T. Chida K. Intravenous immunoglobulin therapy for refractory interstitial lung disease associated with polymyositis/dermatomyositis Lung 187 2009 201 206 19387736 \n16 Bakewell C.J. Raghu G. Polymyositis associated with severe interstitial lung disease: remission after three doses of IV immunoglobulin Chest 139 2011 441 443 21285059 \n17 Donahoe M. Valentine V.G. Chien N. Gibson K.F. Raval J.S. Saul M. Xue J. Zhang Y. Duncan S.R. Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis PLoS One 10 2015 1 17 \n18 Hallowell R.W. Amariei D. Danoff S.K. Intravenous immunoglobulin as potential adjunct therapy for interstitial lung disease Ann. Am. Thorac. Soc. 13 2016 1682 1688 27482830 \n19 Wittstock M. Benecke R. Zettl U.K. Therapy with intravenous immunoglobulins: complications and side-effects Eur. Neurol. 50 2003 172 175 14530624\n\n",
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"keywords": "Cytotoxic T-lymphocyte antigen-4, CTLA-4; Immune checkpoint inhibitor; Immune checkpoint inhibitor, ICI; Intravenous immunoglobulin; Intravenous immunoglobulin, IVIg; Pneumonitis; Programmed cell-death 1, PD-1; Programmed cell-death ligand, PD-L1; Pulmonary toxicity",
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"title": "Severe pulmonary toxicity from immune checkpoint inhibitor treated successfully with intravenous immunoglobulin: Case report and review of the literature.",
"title_normalized": "severe pulmonary toxicity from immune checkpoint inhibitor treated successfully with intravenous immunoglobulin case report and review of the literature"
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"abstract": "Deaths-related to medications errors are common in Pakistan but these are not accurately reported. Recently, the death of a 9 months old baby due to abrupt administration of 15% potassium chloride injection sparked the issue of high alert medications (HAMs) related errors in the country. Since drug administration is the prime responsibility of the nurses, it is pivotal that they possess good knowledge of HAMs. Since there is no published data regarding the knowledge of HAMs among Pakistani nurses, we aimed to assess knowledge of HAMs among registered nurses of Pakistan.\nA cross-sectional study was conducted among registered nurses, recruited using a convenient sampling technique, from 29 hospitals all over the Punjab Province. Data were collected using a validated self-administered instrument. All data were entered and analyzed using SPSS version 22.\nThe study sample was comprised of 2,363 registered nurses (staff nurses = 94.8%, head nurses = 5.2%). Around 63% were working in tertiary hospitals whereas almost 25 and 12% were from district headquarter hospitals and tehsil headquarter hospitals, respectively. Around 84% of the study participants achieved scores <70%, indicating majority of Pakistani nurses having poor knowledge of HAMs administration as well as regulation. There was no significant difference of overall knowledge among age, hospitals, departments, training, designations, qualification, and experience categories. Major obstacles encountered during HAMs administration were \"getting uncertain answers from colleagues\" (72.9%), \"unavailability of suitable person to consult\" (61.1%) and \"receiving verbal orders\" (55.6%).\nOur study revealed the serious inadequacies in HAMs knowledge among Pakistani nurses which may lead to adverse patient outcomes. Nurses should receive comprehensive pharmacology knowledge not only during in-school nursing education but also as hospital-based continuing education. Moreover, it is of immense importance to bridge the gaps between physicians, clinical pharmacists, and nurses through effective communication as this will help reduce medication errors and improve patient care.",
"affiliations": "Department of Pharmacy Practice, Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan.;Department of Pharmacy, District Headquarter Hospital, Pakpattan, Pakistan.;Punjab University College of Pharmacy, University of the Punjab, Lahore, Pakistan.;Department of Pharmacy, Punjab Institute of Cardiology, Lahore, Pakistan.;Punjab University College of Pharmacy, University of the Punjab, Lahore, Pakistan.;Punjab University College of Pharmacy, University of the Punjab, Lahore, Pakistan.;Punjab University College of Pharmacy, University of the Punjab, Lahore, Pakistan.;Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan.;Department of Pharmacology, Faculty of Pharmacy, The University of Lahore, Islamabad, Pakistan.",
"authors": "Salman|Muhammad|M|;Mustafa|Zia Ul|ZU|;Rao|Alina Zeeshan|AZ|;Khan|Qurat-Ul-Ain|QU|;Asif|Noman|N|;Hussain|Khalid|K|;Shehzadi|Naureen|N|;Khan|Muhammad Farhan Ali|MFA|;Rashid|Amir|A|",
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"doi": "10.3389/fphar.2020.01026",
"fulltext": "\n==== Front\nFront Pharmacol\nFront Pharmacol\nFront. Pharmacol.\nFrontiers in Pharmacology\n1663-9812 Frontiers Media S.A. \n\n10.3389/fphar.2020.01026\nPharmacology\nOriginal Research\nSerious Inadequacies in High Alert Medication-Related Knowledge Among Pakistani Nurses: Findings of a Large, Multicenter, Cross-sectional Survey\nSalman Muhammad \n1\n\n*\n Mustafa Zia Ul \n2\n Rao Alina Zeeshan \n3\n Khan Qurat-ul-Ain \n4\n Asif Noman \n3\n Hussain Khalid \n3\n Shehzadi Naureen \n3\n Khan Muhammad Farhan Ali \n5\n Rashid Amir \n6\n \n1\nDepartment of Pharmacy Practice, Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan\n\n\n2\nDepartment of Pharmacy, District Headquarter Hospital, Pakpattan, Pakistan\n\n\n3\nPunjab University College of Pharmacy, University of the Punjab, Lahore, Pakistan\n\n\n4\nDepartment of Pharmacy, Punjab Institute of Cardiology, Lahore, Pakistan\n\n\n5\nDepartment of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan\n\n\n6\nDepartment of Pharmacology, Faculty of Pharmacy, The University of Lahore, Islamabad, Pakistan\n\nEdited by: Joseph O. Fadare, Ekiti State University, Nigeria\n\nReviewed by: Tanveer Ahmed Khan, National Institute of Health, Pakistan; Brian Godman, Karolinska Institutet (KI), Sweden\n\n*Correspondence: Muhammad Salman, muhammad.salman@pharm.uol.edu.pk; msk5012@gmail.com\nThis article was submitted to Pharmaceutical Medicine and Outcomes Research, a section of the journal Frontiers in Pharmacology\n\n\n14 7 2020 \n2020 \n11 102612 12 2019 24 6 2020 Copyright © 2020 Salman, Mustafa, Rao, Khan, Asif, Hussain, Shehzadi, Khan and Rashid2020Salman, Mustafa, Rao, Khan, Asif, Hussain, Shehzadi, Khan and RashidThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Introduction\nDeaths-related to medications errors are common in Pakistan but these are not accurately reported. Recently, the death of a 9 months old baby due to abrupt administration of 15% potassium chloride injection sparked the issue of high alert medications (HAMs) related errors in the country. Since drug administration is the prime responsibility of the nurses, it is pivotal that they possess good knowledge of HAMs. Since there is no published data regarding the knowledge of HAMs among Pakistani nurses, we aimed to assess knowledge of HAMs among registered nurses of Pakistan.\n\nMethods\nA cross-sectional study was conducted among registered nurses, recruited using a convenient sampling technique, from 29 hospitals all over the Punjab Province. Data were collected using a validated self-administered instrument. All data were entered and analyzed using SPSS version 22.\n\nResults\nThe study sample was comprised of 2,363 registered nurses (staff nurses = 94.8%, head nurses = 5.2%). Around 63% were working in tertiary hospitals whereas almost 25 and 12% were from district headquarter hospitals and tehsil headquarter hospitals, respectively. Around 84% of the study participants achieved scores <70%, indicating majority of Pakistani nurses having poor knowledge of HAMs administration as well as regulation. There was no significant difference of overall knowledge among age, hospitals, departments, training, designations, qualification, and experience categories. Major obstacles encountered during HAMs administration were “getting uncertain answers from colleagues” (72.9%), “unavailability of suitable person to consult” (61.1%) and “receiving verbal orders” (55.6%).\n\nConclusion\nOur study revealed the serious inadequacies in HAMs knowledge among Pakistani nurses which may lead to adverse patient outcomes. Nurses should receive comprehensive pharmacology knowledge not only during in-school nursing education but also as hospital-based continuing education. Moreover, it is of immense importance to bridge the gaps between physicians, clinical pharmacists, and nurses through effective communication as this will help reduce medication errors and improve patient care.\n\nbarriershigh alert medicationsknowledgenursesPakistan\n==== Body\nIntroduction\nMedication error is defined as “any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health professional, patient, or consumer. Such events may be related to professional practice, health care products, procedures, and systems, including prescribing, order communication, product labeling, packaging, and nomenclature, compounding, dispensing, distribution, administration, education, monitoring, and use” (NCCMERP, 2015). There are several ways to classify these errors. One way is to classify these errors in the sequence of medication use process: prescribing, transcribing, dispensing, administration, or monitoring (WHO, 2016). Another approach is to classify them according to whether they occur from mistakes in planning actions (knowledge-based or rule-based errors) or errors in carrying out an action (action-based errors, also called “slips,” or memory-based errors, also called “lapses”) (Ferner and Aronson, 2006; Aronson, 2009). A further approach is to classify medication errors as wrong patient, medication, dose, frequency, duration, and route of administration (WHO, 2016). Medication errors pose life threatening risk to the patient and a high economic loss (Perrone et al., 2014; Tshiamo et al., 2015; Akhideno et al., 2018; Formica et al., 2018). Medication error is the prime patient safety and quality care concern nowadays. Globally, 2–5% hospital admissions are due to medication errors and most of them are preventable (Roughead et al., 2013; Perrone et al., 2014; AHRQ, 2015; Latimer et al., 2017; Iftikhar et al., 2018). According to the statistics of Centers for Disease Control and Prevention, medications errors are the third leading cause of mortality in United States with 98,000 deaths per annum (Pham et al., 2012; Makary and Daniel, 2016).\n\nHigh alert medications (HAMs) cause serious health injuries or even death to the patient if use improperly. As compared to ordinary drugs, HAMs carry greater risks of adverse events (Labib et al., 2018; Shen et al., 2018). The American Pharmaceutical Association categorizes HAMs into following classes, chemotherapeutic agents, cardiovascular medications, anticoagulants, opioids and their derivatives, neuromuscular blocking agents, benzodiazepines, and some electrolytes like potassium chloride (15%) (Zyoud et al., 2019). Majorly, these medications are used in acute and emergency rooms. Others places of HAMs usage are intensive care unit, coronary care unit, hemodialysis unit, pediatrics ward, medical ward, as well in labor room and surgical ward.\n\nNurses are the nucleus of health care system. Being a vital member of health care provision team, they are actively involved in patient care. Administration of drug to the particular patient according to the prescriber’s order is one of the most crucial tasks performed by nursing staff. Unlike the other health care team members, nurses are always in close contact with the patient throughout the course of their treatment. Therefore, they are well aware about the actual condition of patient before and after drug administration and can actively report adverse drug reactions. The most common nursing-associated medication errors are related to administrations of drugs (Choi et al., 2016). Published data showed that the major reasons of medication administration errors by nurses are related to medication packaging e.g. similarities in packaging, appearance and names (Mrayyan et al., 2007; Dumo, 2012; Mrayyan, 2012; Hammoudi et al., 2018), and poor communication between physicians and nurses (Kim et al., 2011; Dumo, 2012; Topcu et al., 2017; Hammoudi et al., 2017). With regards to the barriers of medication errors reporting, important factors are the administrator’s responses to medication errors, fear, reporting efforts, disagreements on the definitions of errors (Chiang et al., 2010; Petrova et al., 2010; Kim et al., 2011; Aboshaiqah, 2013; Shamim et al., 2016; Hammoudi et al., 2018). Pakistan is a resource-limited country where disease burden is very high. The current status of country’s health care system is worrying. Deaths due to medications errors are common but these are not reported due to the lack of required mechanism and fear of patient relatives’ reaction or adverse career-related repercussions (DAWN News, 2017). Recently, the death of a 9 months old baby in a private sector hospital of Karachi (Capital city of Sindh, Pakistan) due to abrupt administration of 15% potassium chloride (KCl) injection had highlighted the issue of high alert related medication errors in the country (Jafferi, 2019; Geo News, 2019; 92 News, 2019). According to the Pakistan economic survey 2017–2018, 108,474 registered nurses were performing duties across the country (FDGOP, 2019). Their awareness about the high alert medication is of vital importance as these drugs possess greater potential to cause serious consequences, if administered inappropriately. To the best of our knowledge and literature survey, there is no published data regarding the knowledge of HAMs among registered Pakistani nurses. Therefore, current study was carried out to estimate the knowledge about administration and regulation of HAMs among registered nurses of Pakistan. Moreover, the possible barriers faced in the administration of HAMs were also evaluated.\n\nMethods\nStudy Design and Setting\nThis cross-sectional study was conducted among the registered nurses from four metropolitan divisions of province Punjab namely Sahiwal, Multan, Faisalabad, and Lahore. The data were obtained from 29 health care settings (Secondary and tertiary care hospitals), including 11 tertiary/teaching hospitals, 9 District Head Quarter (DHQ) hospitals, and 9 Tehsil Head Quarter (THQ) hospitals during a period of 6 months (Feb–July 2019). A convenient sampling technique was employed and trained investigators approached the nursing staff in the above-mentioned hospitals and briefed them about the intent of this study. Those who were willing to be enrolled were administered the study questionnaire.\n\nEthical Approval\nProtocol of the current study was reviewed and approved by the Research Ethics Committee of the Department of Pharmacy Practice, Faculty of Pharmacy, The University of Lahore (REC/DPP/FOP/10A). Additionally, written requests, along with documents, were submitted and approvals were obtained from relevant authorities at study sites. The research was conducted in accordance with ethical principles laid down in the 1964 Declaration of Helsinki and its later amendments. As the committee waived the need for written consent, a verbal informed consent was obtained from every nurse before the enrollment and all the participants were ensured about the confidentiality of their responses.\n\nInclusion and Exclusion Criteria\nThe nursing staff registered under the Pakistan nursing council, currently providing services in the emergency room, intensive care unit, dialysis unit, cardiac ward, pediatrics ward, medical ward, obstetrics and gynecology ward, surgical ward, operation theatre, and labor room of the afore-mentioned public sector hospitals were included in the current study. These wards were selected as they carry high risk of errors. Nursing students or nurses working in private sector as well as in the departments other than those mentioned above were excluded from this study.\n\nStudy Instrument\nIn the present study, a self-administered questionnaire developed by Hsaio et al. (2010) was used to determine HAM-related knowledge of nurses (\nAppendix\n). This instrument was in English as all the nursing curriculum in Pakistan are taught in English so there was no need for translation into Urdu language. The study instrument had four sections. Sections 1 had 10-items to gather demographics details. Sections 2 and 3 had 10-items each to assess knowledge of HAM administration and regulation, respectively. Each correct response was given 1 score while incorrect or don’t know response were scored 0. Therefore, total knowledge score of HAM administration and regulation was 10 each. To calculate overall HAM-related knowledge score, each correct answer in sections 2 and 3 (total of 20 questions) was given five points, with a total score of 100; incorrect or don’t know answers were scored zero. Knowledge scores were classified as good knowledge ≥70%, or poor knowledge <70%.\n\nA pilot study was conducted in twenty nurses to check the clarity and understandability of all the questions in the study instrument. All participants responded that questions were clear and they were able to understand them all.\n\nStatistical Analysis\nCategorical data were presented as number with percentages. Results of Shapiro-Wilk test revealed the non-normal distribution of continuous variables. Therefore, continuous variables were presented as medians and 25th and 75th percentiles. Continuous data were compared between two groups using the Mann-Whitney U test, and between more than two groups using the Kruskal-Wallis H test. Categorical data were compared using the chi-square test. All statistical analyses were performed using SPSS version 22 for Windows. A p value of less than 0.05 was considered statistically significant.\n\nResults\nA total of 2,500 registered nurses were approached by the investigators and received completely filled study instrument from 2,363 with a response rate of 94.5%.\n\nDemographic Characteristics\nDemographic data of the study participants are shown in \nTable 1\n. Our study sample was comprised of only females (staff nurses = 94.8%, head nurses = 5.2%), with majority of nurses between 26 and 30 years (36.1%) of age followed by 31–35 years (29.2%). Around 63% were working in teaching hospitals whereas almost 25 and 12% from DHQ and THQ hospitals, respectively. Majority of nurses (37%) were providing services in the Acute & Emergency departments followed by cardiology (16.4%) and gynecology (11.4%).\n\nTable 1 Demographic details of the study participants.\n\nVariables\tN\t%\t\n\nAge (years)\n\t\t\t\n≤25\t494\t20.9\t\n>25–30\t852\t36.1\t\n>30–35\t689\t29.2\t\n>35\t328\t13.9\t\n\nHospital type\n\t\t\t\nTHQ hospital\t292\t12.4\t\nDHQ hospital\t588\t24.9\t\nTeaching hospital\t1,483\t62.8\t\n\nWorking department\n\t\t\t\nCardiac\t387\t16.4\t\nDialysis\t148\t6.3\t\nEmergency\t875\t37.0\t\nObstetrics and gynecology\t277\t11.7\t\nLabor room\t87\t3.7\t\nMedical\t238\t10.1\t\nOperation theater\t195\t8.2\t\nPediatric\t140\t5.9\t\nSurgery\t16\t0.7\t\n\nTraining\n\t\t\t\nBasic life support\t164\t6.9\t\nEmergency room training\t414\t17.5\t\nInfection control\t477\t20.2\t\nMidwifery\t167\t7.1\t\nOperation theater\t77\t3.3\t\nPersonal protective equipment\t169\t7.1\t\nNursery (Neonatal ICU)\t83\t3.5\t\nNo training\t812\t34.3\t\n\nQualification\n\t\t\t\nBachelor\t2,276\t96.3\t\nMaster\t87\t3.7\t\n\nDesignation\n\t\t\t\nStaff nurse\t2,240\t94.8\t\nHead nurse\t123\t5.2\t\n\nExperience (years)\n\t\t\t\n≤2\t465\t19.7\t\n>2–4\t755\t32.0\t\n>4–6\t228\t9.6\t\n>6–8\t206\t8.7\t\n>8–10\t152\t6.4\t\n>10\t557\t23.6\t\nDHQ, District Headquarter; THQ, Tertiary Headquarter.\n\nNurses’ Knowledge of High Alert Medication Administration\nResponses to the questions related to HAMs administration are presented in \nTable 2\n. The median (25th and 75th percentile) knowledge score of HAMs administration was 6 (5 and 7). There was no significant difference (P > 0.05) of knowledge scores related to HAMs administration among categories of age, hospitals, departments, training, designations, qualification, and experience.\n\nTable 2 Knowledge of High Alert Medications administration.\n\nNo.\tQuestions\tAnswers\tCorrect\tIncorrect\t\nN (%)\tN (%)\t\n1\tFast intravenous push of 1:1000 epinephrine 1 ampule for patient who has mild allergic reaction\tFalse\t1,578 (66.8)\t728 (33.2)\t\n2\tWhen an emergency happens, administer 10% calcium chloride (CaCl2) 10 ml as a fast intravenous push (in 1–2 minutes)\tFalse\t1,726 (66.6)\t638 (27.0)\t\n3\t10% calcium gluconate and 10% CaCl2 are the same drug and are interchangeable\tFalse\t1,491 (63.1)\t873 (36.9)\t\n4\tDosage expression for insulin injection is “cc” or “ml”\tFalse\t1,381 (58.4)\t983 (41.6)\t\n5\tAccurate chemotherapy dose calculation for adults is based on body weight whereas chemotherapy for children is based on body surface area\tFalse\t1,446 (61.2)\t917 (38.8)\t\n6\tWhen an emergency such as ventricular fibrillation happens, push fast 15% potassium chloride (KCl) 10 ml intravenously\tFalse\t1,502 (63.5)\t862 (36.5)\t\n7\t15% KCl is better be added to Ringer’s solution for rapid infusion\tFalse\t1,485 (62.8)\t878 (37.2)\t\n8\tInsulin syringe can be replaced by 1 ml syringe\tFalse\t942 (39.8)\t1,421 (60.1)\t\n9\tGive fast IV infusion of 3% NaCl 500 ml for patient who has low sodium level\tFalse\t1,298 (54.9)\t1,065 (45.1)\t\n10\tPort-A route can be used for blood withdrawal and drug injection generally\tFalse\t1,431 (60.6)\t932 (39.4)\t\nNurses’ Knowledge of High Alert Medication Regulation\nParticipants’ responses to the items regarding the regulation of high risk medications are presented in \nTable 3\n. The median (25th and 75th percentile) knowledge score of HAMs regulation was 5 (4 and 6). No significant difference of knowledge scores related to HAM regulation was seen among age, departments, training, designations, qualification, and experience categories. However, a statistically significant difference was found among hospital categories. In post hoc analysis using Bonferroni correction, only the nurses from DHQ hospitals were found to have significantly less knowledge of HAMs regulation than those working in teaching hospitals (p = 0.003).\n\nTable 3 Nurses’ knowledge of high alert medications regulation.\n\nNo.\tQuestions\tAnswers\tCorrect\tIncorrect\t\nN (%)\tN (%)\t\n1\tIt is better to use “Amp” or “Vial” for dose expression instead of “mg” or “gm”\tFalse\t1,645 (69.6)\t718 (30.4)\t\n2\tDistinctive labeling should be used on look-alike drugs\tTrue\t1,564 (66.2)\t799 (33.8)\t\n3\tIt is right to use “U” instead of unit for dose expression\tFalse\t1,834 (77.6)\t529 (22.4)\t\n4\tFor convenience, heparin and insulin should be stored together in the refrigerator\tFalse\t1,842 (77.9)\t522 (22.1)\t\n5\tEach drug better have multiple concentrations for nurse to choose\tFalse\t1,432 (60.6)\t931 (39.4)\t\n6\tIf a patient can tolerate, potassium can be administered orally instead of IV route\tTrue\t395 (16.7)\t1,968 (83.8)\t\n7\t15% KCl is frequently used, so it should be easily and freely accessed by nurses\tFalse\t1,292 (54.7)\t1,071 (45.3)\t\n8\tFor pediatric dose, use teaspoon for dose expression\tFalse\t450 (19.0)\t1,913 (81.0)\t\n9\tFentanyl skin patch is a controlled medicine.\tTrue\t644 (27.3)\t1,719 (72.7)\t\n10\tIf a ward stores Atracurium for tracheal intubation, the drug should be stored with other drugs and easily accessed by nurses\tFalse\t1,753 (74.2)\t610 (25.8)\t\nOverall Knowledge Related to High Alert Medications\nAround 84% of the study participants achieved scores <70%, indicating majority of Pakistani nurses having poor knowledge of HAMs administration as well as regulation. Chi-square tests revealed that there was no significant difference of knowledge among different demographic variables (age, hospitals, departments, training, designations, qualification, and experience).\n\nBarriers Encountered During High Alert Medications Administration\nObstacles that nurses encounter during HAMs administration are shown in \nTable 4\n. Major barriers related to HAMs administration were “getting uncertain answers from colleagues” (72.9%), “unavailability of suitable person to consult” (61.1%), and “receiving verbal orders” (55.6%).\n\nTable 4 Comparisons of high alert medications administration and high alert medications regulation scores among different demographic variables.\n\nVariables\tHAM administration score (mean rank)\tp-value\tHAM regulation score (mean rank)\tp-value\t\n\nAge (years)\n\t\t0.797\t\t0.867\t\n≤25\t1,184.45\t\t1,194.81\t\t\n>25–30\t1,185.95\t\t1,169.03\t\t\n>30–35\t1,191.47\t\t1,180.65\t\t\n>35\t1,148.13\t\t1,199.26\t\t\n\nHospital type\n\t\t0.435\t\t0.010\t\nTHQ hospital\t1,204.50\t\t1,199.15\t\t\nDHQ hospital\t1,205.30\t\t1,109.89\t\t\nTeaching hospital\t1,168.33\t\t1,207.21\t\t\n\nWorking department\n\t\t0.172\t\t0.524\t\nCardiac\t1,250.51\t\t1,197.48\t\t\nDialysis\t1,143.54\t\t1,241.20\t\t\nEmergency\t1,145.29\t\t1,174.59\t\t\nGynea\t1,196.02\t\t1,159.08\t\t\nLabor room\t1,209.24\t\t1,034.19\t\t\nMedical\t1,137.37\t\t1,216.43\t\t\nOperation theatre\t1,199.17\t\t1,187.39\t\t\nPaeds\t1,276.45\t\t1,203.34\t\t\nSurgery\t1,125.84\t\t1,101.00\t\t\n\nTraining\n\t\t0.991\t\t0.919\t\nBasic life support\t1,205.57\t\t1,242.53\t\t\nEmergency room training\t1,195.53\t\t1,185.75\t\t\nInfection control\t1,169.99\t\t1,159.38\t\t\nMidwifery\t1,209.46\t\t1,177.07\t\t\nOperation theatre\t1,197.45\t\t1,147.25\t\t\nPersonal protective equipment\t1,158.82\t\t1,169.46\t\t\nNursery (Neonatal ICU)\t1,156.17\t\t1,146.07\t\t\nNo training\t1,177.75\t\t1,191.74\t\t\n\nDesignation\n\t\t0.332\t\t0.841\t\nStaff nurse\t1,178.88\t\t1,182.64\t\t\nHead nurse\t1,238.91\t\t1,170.28\t\t\n\nQualification\n\t\t0.910\t\t0.402\t\nBachelor\t1,181.70\t\t1,179.76\t\t\nMaster\t1,189.94\t\t1,240.72\t\t\n\nExperience (years)\n\t\t0.885\t\t0.118\t\n≤2\t1,187.09\t\t1,239.79\t\t\n>2–4\t1,203.40\t\t1,162.24\t\t\n>4–6\t1,174.41\t\t1,129.91\t\t\n>6–8\t1,182.24\t\t1,136.30\t\t\n>8–10\t1,156.35\t\t1,127.50\t\t\n>10\t1,158.75\t\t1,213.64\t\t\nDHQ, District Headquarter; HAM, High alert medication; ICU, Intensive care unit; THQ, Tertiary Headquarter.\n\nDiscussion\nThis is the first ever study that provided insight not only about the knowledge of HAMs administration and regulation among Pakistani nurses but also the barriers encountered during administration of these medications. Our findings revealed that majority of nurses were found to have inadequate knowledge of HAMs which was comparable to the findings from Taiwan (Hsaio et al., 2010) and Palestine (Zyoud et al., 2019). Adrenaline should preferably administered via intramuscular route and IV route to be reserved only for extreme emergency in the presence of trained physician. Around one third of the nursing staff did not choose the right answer of adrenaline administration which was comparable to the findings of Hsaio et al. (2010) and Zyoud et al. (2019). Concentrated electrolyte solutions like KCl (15%), calcium chloride (CaCl2), and hypertonic saline should not be administer via IV push due to greater risk of complications. Incorrect IV administration of KCl (15%) causes adverse events like arrhythmias and cardiac arrest leading to patient’s death as documented in the previous studies (Reeve et al., 2005; Bonvin et al., 2009). Similarly, inappropriate administration of hypertonic saline cause phlebitis, extravasation injuries, and hypernatremia resulting in hypertensive emergencies especially in cardiac patients (Dillon et al., 2018). Administration of calcium salts via fast IV push is also associated with significant adverse events (Anger et al., 2014). The current study revealed that one third of the study population did not give correct response regarding 15% KCl and 10% CaCl2 administration, which was similar to the findings of a study conducted in Palestinian Nurses (Zyoud et al., 2019). Shockingly, around 39% of the study participants gave incorrect response about the dose calculation in children and cancerous patients. Likewise, Lan et al. also reported that knowledge of Taiwanese nurses about the dose calculation in aforementioned diseased population was poor (Lan et al., 2014).\n\nWhile writing medication order for a particular patient, the clarity of written medication order is the key factor that can contribute to majority of mediations errors. Extreme caution should be taken while prescribing HAMs and defined units must be written in each medication instead of writing ampule or vial. Around 30% of the study participants were unaware of this regulation which was slightly better than the findings (correct response = 59.7%) of Hsaio and colleagues (2010). Zyoud et al. (2019) reported that around 20% of Palestinian nurses gave incorrect answer to question regarding the use of ampule or vial for dose expression instead of milligram or grams. Regarding the storage, HAMs must carry distinct labeling in order to differentiate them from rest of the medicines. Moreover, “heparin” and “insulin” should not be stored together in a single refrigerator due to chances of their mix up (Belknap, 2001). Around 22% of our nurses gave incorrect response to the aforementioned drugs which was similar to the findings of earlier studies (Hsaio et al., 2010; Lo et al., 2013; Zyoud et al., 2019). Similarly, atracurium can cause severe respiratory depression. Therefore, it must be separated from rest of the ward medicines in refrigerator, in separate box with clear labeling. Since spoons vary in sizes, they cannot be used to measure the accurate amount of medications. However, higher proportion (81%) of the study sample were unaware about the inappropriateness of spoon for pediatric dose measurement which was significantly higher than the findings of previous studies (Hsaio et al., 2010; Zyoud et al., 2019). Inadequacies in the knowledge of HAMs regulation and administration can be attributed to not obtaining extensive HAMs training. None of the study participants reported receiving extensive HAMs trainings in the present study which can be attributable to the severe shortage of clinical pharmacists in Pakistani health settings. Studies from Taiwan (mean 64.6 vs 54.6, p < 0.01) and Palestine (median 65 vs 50, p = 0.002) reported that HAMs trainings were associated with better knowledge (Hsaio et al., 2010; Zyoud et al., 2019). We strongly endorse the recommendation of Lo et al. (2013) regarding the inclusion of classes on the HAMs subject as a part of formal, in-school nursing education, as well as of hospital-based continuing education. Moreover, there is a dire need to bridge the gaps between physicians, clinical pharmacists, and nurses (\nTable 5\n) through effective communication. This will help reduce medication errors and improve patient care. Additionally, as there is a very high deficit of qualified and skilled healthcare workers, particularly nurses and midwives (FDGOP, 2019), Govt. should take measures necessary to improve the strength of nurses, doctors, and pharmacists in Pakistani hospitals.\n\nTable 5 Barriers encountered during administration of high alert medication.\n\nNo.\tObstacles\tN (%)\t\n1\tInsufficient knowledge\t807 (34.1)\t\n2\tHave to accept oral order\t1,314 (55.6)\t\n3\tConfused prescription\t1,029 (43.5)\t\n4\tInconsistent opinions between nurses\t828 (35.0)\t\n5\tInconsistent opinions between doctor and nurse\t1,206 (51.0)\t\n6\tNo reference for drug use\t766 (32.4)\t\n7\tReceive uncertain answers from colleagues\t1,724 (72.9)\t\n8\tUnclear dose calculation\t910 (38.5)\t\n9\tNo established standard operating procedures for high alert medications\t867 (36.7)\t\n10\tNo rigorous regulations for high alert medication\t1,005 (42.5)\t\n11\tMix high alert medications with other drugs\t835 (35.3)\t\n12\tEasy access to high alert medications\t898 (38.0)\t\n13\tNo suitable person to consult\t1,444 (61.1)\t\nConclusions\nThe current study revealed the serious inadequacies in HAMs knowledge among Pakistani nurses which can cause medication errors leading to adverse patient outcomes. Major obstacles faced by nurses during HAMs administration were “getting uncertain answers from colleagues,” “unavailability of suitable person to consult,” and “receiving verbal orders.” Nursing students should receive comprehensive HAMs related education and training during graduation. Moreover, the training of the nursing staff should also be conducted on periodic basis. Each health facility in Pakistan must recruit sufficient number of medication experts (clinical pharmacists and pharmacovigilance officers) in order to ensure consultancy and availability of standard operation procedure for high alert medication safe storage, dispensing, and administration.\n\nData Availability Statement\nThe datasets generated during and/or analyzed during the present study are available from the corresponding author (muhammad.salman@pharm.uol.edu.pk, msk5012@gmail.com) on reasonable request.\n\nEthics Statement\nThis study was approved by the Research Ethics Committee of the Department of Pharmacy Practice, Faculty of Pharmacy, The University of Lahore. As the committee waived the need for written consent, a verbal informed consent was taken from every nurse before the enrollment.\n\nAuthor Contributions\nAll the authors contributed equally to this study.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAcknowledgments\nAuthors are grateful to all the study participants for sparing time to fill-out questionnaires.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2020.01026/full#supplementary-material\n\n\nClick here for additional data file.\n==== Refs\nReferences\n\n92 News (2019 ). 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Literature review: medication safety in Australia (Sydney : Australian Commission on Safety and Quality in Health Care ).\n\nShamim S. Sharib S. M. Malhi S. M. Muntaha S. U. Raza H. Ata S. (2016 ). Adverse drug reactions (ADRS) reporting: awareness and reasons of under-reporting among health care professionals, a challenge for pharmacists\n. SpringerPlus \n5 (1 ), 1778 . 10.1186/s40064-016-3337-4 \n27795920 \n\nShen L. Yan J. Xin X. Sun Z. (2018 ). Cognition of high-alert medication knowledge of clinical nurses and improvement measures to eradicate medication errors\n. Biomed. Res \nS370 –73\n. 10.4066/biomedicalresearch.29-17-1491 \n\n\nTopcu I. Türkmen A. S. Sahiner N. C. Savaser S. Sen H. (2017 ). Physicians’ and nurses’ medical errors associated with communication failures\n. J. Pakistan Med. Assoc. \n67 (4 ), 600 –604\n.\n\nTshiamo W. B. Kgositau M. Ntsayagae E. Sabone M. B. (2015 ). The role of nursing education in preventing medication errors in Botswana\n. Int. J. Afr. Nurs. Sci. \n3 , 18 –23\n. 10.1016/j.ijans.2015.06.001 \n\n\nWorld Health Organization (2016 ). Medication Errors: Technical Series on Safer Primary Care\n. Licence: CC BY-NC-SA 3.0 IGO. Available at: https://apps.who.int/iris/bitstream/handle/10665/252274/9789241511643-eng.pdf;jsessionid=FDB1BE2683396D2DA592F947714EBF5E?sequence=1.\n\nZyoud H. S. Khaled S. M. Kawasmi B. M. Habeba A. M. Hamadneh A. T. Anabosi H. H. (2019 ). Knowledge about the administration and regulation of high alert medications among nurses in Palestine: a cross-sectional study\n. BMC Nurs. \n18 (1 ), 11 . 10.1186/s12912-019-0336-0 \n30936779\n\n",
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"journal": "Frontiers in pharmacology",
"keywords": "Pakistan; barriers; high alert medications; knowledge; nurses",
"medline_ta": "Front Pharmacol",
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"title": "Serious Inadequacies in High Alert Medication-Related Knowledge Among Pakistani Nurses: Findings of a Large, Multicenter, Cross-sectional Survey.",
"title_normalized": "serious inadequacies in high alert medication related knowledge among pakistani nurses findings of a large multicenter cross sectional survey"
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"abstract": "Charcot spinal arthropathy (CSA) is a rare spinal disorder presenting neuropathic osteoarthropathy of facet joints leading to progressive destruction. After L4-5 PLIF, a 63-year-old woman with Parkinson's disease (PD) underwent L3-4 and L5-S1 PLIF for primary adjacent segment disease caused by degenerative change, which was found as facet joint osteophytes and a vacuum disc phenomenon with endplate sclerosis. However, her postural disorder from PD deteriorated, and strong opioid analgesics were administered for severe recurring low back pain. Anterior subluxation at L2-3 occurred because of destructive secondary adjacent segment disease, which was found as destruction of the endplate and the facet without degenerative change, and formation of paravertebral osteophytes and fluid collection in the intervertebral space. The appearance on imaging met that for neuroarthropathic change, which was previously reported as CSA. L2-3 PLIF following extension of posterior fusion to T10 was additionally performed, and the postoperative course was uneventful with symptomatic improvement. In this case, the important finding was in the different appearance of the disease between adjacent segments on imaging. It is possible that deterioration of PD and administration of the analgesics inhibited deep pain sensation, and concentration of mechanical stress in the proximal adjacent segment by the long lever arm because of extension of the fusion level resulted in neuroarthropathic change of the facets in the secondary adjacent segments. The pathophysiology of association of CSA and PD remains unknown. However, we recommend vigilance for destructive neuroarthropathic facet change as CSA after spinal surgery in patients with severe PD.",
"affiliations": "Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan; Department of Rehabilitation Medicine, Faculty of Medicine, University of Tsukuba Hospital, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: kmiura@tsukuba-seikei.jp.;Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Orthopaedic Surgery and Sports Medicine, Tsukuba University Hospital Mito Clinical Education and Training Center, 3-2-7 Miya-Machi, Mito, Ibaraki 310-0015, Japan.;Department of Orthopaedic Surgery, Moriya Daiichi General Hospital, 1-17 Matsumaedai, Moriya, Ibaraki 302-0102, Japan.;Department of Orthopaedic Surgery and Sports Medicine, Tsukuba University Hospital Mito Clinical Education and Training Center, 3-2-7 Miya-Machi, Mito, Ibaraki 310-0015, Japan.;Department of Orthopaedic Surgery and Sports Medicine, Tsukuba University Hospital Mito Clinical Education and Training Center, 3-2-7 Miya-Machi, Mito, Ibaraki 310-0015, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.;Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.",
"authors": "Miura|Kousei|K|;Koda|Masao|M|;Tatsumura|Masaki|M|;Shiina|Itsuo|I|;Mammoto|Takeo|T|;Hirano|Atsushi|A|;Abe|Tetsuya|T|;Funayama|Toru|T|;Noguchi|Hiroshi|H|;Yamazaki|Masashi|M|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "Scotland",
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"doi": "10.1016/j.jocn.2018.11.013",
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"issue": "61()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Adjacent segment disease; Charcot spinal arthropathy; Neuroarthropathic change; Parkinson’s disease",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000701:Analgesics, Opioid; D005260:Female; D006801:Humans; D008159:Lumbar Vertebrae; D008875:Middle Aged; D054850:Osteophyte; D010300:Parkinson Disease; D011183:Postoperative Complications; D013122:Spinal Diseases; D013123:Spinal Fusion; D013314:Stress, Mechanical; D021801:Zygapophyseal Joint",
"nlm_unique_id": "9433352",
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"pages": "281-284",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Charcot spinal arthropathy presenting as adjacent segment disease after lumbar spinal fusion surgery in Parkinson's disease: A case report.",
"title_normalized": "charcot spinal arthropathy presenting as adjacent segment disease after lumbar spinal fusion surgery in parkinson s disease a case report"
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"abstract": "The term 'antibiomania' refers to manic episodes that occur after a patient starts taking antibiotics. We report the case of a 49-year-old male who developed acute psychosis secondary to initiation of triple therapy for Helicobacter pylori eradication. Unlike with proton pump inhibitors, there have been several reported cases of central nervous system side effects and psychiatric consequences due to amoxicillin, however evidence points to clarithromycin as the likely culprit. On average onset of symptoms occurred within 1-5 days of initiating therapy. In all cases, symptoms resolved upon cessation of clarithromycin, mostly within 1-3 days. Unfortunately, the mechanism through which clarithromycin causes neurotoxicity remains unclear. Clinicians should be cognizant of psychiatric side effects secondary to clarithromycin, and discontinuation should be prompt for rapid recovery of mental status.",
"affiliations": "Department of Internal Medicine, Nassau University Medical Center, East Meadow, N.Y., USA.",
"authors": "Shah|Mitanshu|M|;Subhani|Miral|M|;Rizvon|Kaleem|K|;Mustacchia|Paul|P|",
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"doi": "10.1159/000339713",
"fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 2285565610.1159/000339713crg-0006-0381Published online: June, 2012Transient Psychotic Episode Induced by Helicobacter pylori Triple Therapy Treatment Shah Mitanshu a*Subhani Miral aRizvon Kaleem bMustacchia Paul baDepartment of Internal Medicine, Nassau University Medical Center, East Meadow, N.Y., USAbDepartment of Gastroenterology, Nassau University Medical Center, East Meadow, N.Y., USA*Mitanshu Shah, MD, 2201 Hempstead Turnpike, East Meadow, N.Y. 11554 (USA), Tel. +1 516 572 6501, E-Mail mshah1@numc.eduMay-Aug 2012 19 6 2012 19 6 2012 6 2 381 386 Copyright © 2012 by S. Karger AG, Basel2012This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial-No-Derivative-Works License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.The term ‘antibiomania’ refers to manic episodes that occur after a patient starts taking antibiotics. We report the case of a 49-year-old male who developed acute psychosis secondary to initiation of triple therapy for Helicobacter pylori eradication. Unlike with proton pump inhibitors, there have been several reported cases of central nervous system side effects and psychiatric consequences due to amoxicillin, however evidence points to clarithromycin as the likely culprit. On average onset of symptoms occurred within 1–5 days of initiating therapy. In all cases, symptoms resolved upon cessation of clarithromycin, mostly within 1–3 days. Unfortunately, the mechanism through which clarithromycin causes neurotoxicity remains unclear. Clinicians should be cognizant of psychiatric side effects secondary to clarithromycin, and discontinuation should be prompt for rapid recovery of mental status.\n\nKey Words\nTransient psychotic episodeHelicobacter pylori triple therapy treatment\n==== Body\nIntroduction\nAntibiomania, a term used to describe antibiotic-induced manic episodes, is a rare but genuine side effect of some antimicrobials. Clarithromycin is among those more commonly associated with psychosis, with few reported cases involving amoxicillin. Onset of these symptoms typically occurs within 7 days of medication initiation and resolution of symptoms occurs 24–48 h after medication cessation. We report the case of a 49-year-old male without any previous psychiatric history who developed acute psychosis after starting triple therapy for Helicobacter pylori with return of mental status to baseline after discontinuation of the regimen. The widely popular triple therapy that includes a proton pump inhibitor (PPI), amoxicillin and clarithromycin is most commonly prescribed for patients infected with H. pylori. After an extensive review of the literature it was found that acute psychotic episodes in patients undergoing this treatment regimen have been reported, with clarithromycin as the probable culprit.\n\nCase Report\nA 49-year-old male with a history of gastroesophageal reflux disease and recently diagnosed H. pylori gastritis was brought to the emergency by his wife who had noted strange behavior in the patient 4 h prior at home. The wife initially had found the patient on the toilet non-verbal and unresponsive with a blank stare. The patient abruptly stated he felt as if he was ‘leaving the planet’, followed by cat-like screeching and movements. In the emergency room, the patient was noted to have bilateral upper extremity jerky movements, which resolved after 10 s without any medical intervention. No lip or tongue bites, bowel or urinary incontinence, foaming from the mouth or post-ictal confusion was witnessed. Upon further inquiry, the patient's wife of 8 years denied any psychiatric or substance abuse history. The patient did not have any history of previous seizures, stroke or transient ischemic attack. He was an emergency room attending physician maintaining his usual daily activities several hours prior to admission. There was no recent head trauma, subjective fevers, drug allergies, headaches, nausea or vomiting. Family history was negative for epilepsy or psychiatric disorders. The wife denied any recent travel. The patient's only medication was omeprazole 40 mg of 6 years duration daily for gastroesophageal reflux disease, and he had recently started on triple therapy for H. pylori gastritis, which included lansoprazole 30 mg twice daily, amoxicillin 1 g twice daily and clarithromycin 500 mg twice daily 5 days prior to presentation.\n\nThe patient was a well-appearing, slender, middle-aged male. He was lethargic and at times exhibiting involuntary movement of his upper extremities. Vital signs at presentation were remarkable for a pulse rate of 108 bpm. On physical examination, he was disoriented to place and time. Nuchal rigidity was absent and there was no evidence of trauma. Reflexes were normal with no focal neurologic signs. Cardiopulmonary and abdominal exams were within normal limits. Initial investigations included a finger stick glucose of 100 mg/dl along with a complete blood count, comprehensive metabolic panel, urinalysis, urine toxicology screen, and thyroid-stimulating hormone that were within normal limits. A chest X-ray and CT scan of the head were unremarkable. An electrocardiogram was significant for sinus tachycardia at 106 bpm, however acute coronary syndrome was ruled out with two consecutive negative sets of cardiac enzymes.\n\nThe patient was admitted to the medical intensive care unit for further exploration of his acute psychosis and altered mentation. All of his medications were discontinued while he was being observed. He underwent extensive testing to find an organic cause of this psychotic episode, including magnetic resonance imaging of the brain, magnetic resonance angiogram of the cranial vessels and a 24-hour electroencephalogram (EEG), which failed to show any pathologies or irregularities.\n\nDuring inpatient hospitalization, symptoms began to subside within 24 h with complete resolution within 36 h. The patient became oriented and returned to his baseline mental status with no administration of antipsychotics. With no evidence of metabolic disturbances, neurologic illness, infection or organ failure, the patient's symptoms were attributed to a medication side effect. Onset of symptoms days after initiation of treatment with rapid resolution of psychosis after discontinuation of medications verified amoxicillin, clarithromycin, lansoprazole or a combination of these drugs to be the likely trigger.\n\nDiscussion\nThe term ‘antibiomania’ refers to manic episodes that occur after a patient starts taking antibiotics. According to the World Health Organization, the Food and Drug Administration and the published literature, it was found that clarithromycin and ciprofloxacin are those most commonly linked to antibiomania [1]. Our report describes a patient who was being treated for H. pylori with triple therapy, which included the antimicrobials amoxicillin and clarithromycin, in addition to a PPI (lansoprazole). H. pylori is a Gram-negative bacterium that is found in the stomach of humans and which may lead to complications such as chronic gastritis, peptic ulcer disease and, more severely, gastric carcinoma. Identification of the organism warrants treatment, initially with triple therapy. Treatment duration lasts between 7 and 14 days with re-testing for H. pylori to verify eradication. Although the incidence of antibiomania as a side effect of antimicrobials is low, it should still be recognized as a risk for patients undergoing treatment.\n\nThe side effect profile of triple therapy is extensive with more common reactions relating to the gastrointestinal tract. Commonly reported adverse reactions to PPIs include nausea, vomiting, diarrhea, abdominal pain, dizziness and fatigue [2]. Adverse effects of penicillins, specifically amoxicillin, are typically related to allergic reactions as well as gastrointestinal symptoms including severe colitis. Clarithromycin may also cause similar gastrointestinal symptoms as amoxicillin including headache and irritability. Unlike with PPIs, there have been several reported cases of central nervous system (CNS) side effects and psychiatric consequences due to amoxicillin and clarithromycin.\n\nBased on our review of the literature, acute psychosis from acid suppression therapy has not been well documented. A case of acute mania in a 60-year-old woman has been described secondary to use of ranitidine (a histamine H2-receptor antagonist) with resolution of symptoms after discontinuation of the offending medication [3]. Despite this report, our research lacked support of acute psychotic episodes secondary to acid suppression therapy via proton pump inhibition. In our patient, a history of long-term PPI use disqualified this element of triple therapy from being the likely trigger of acute psychosis.\n\nA review of the literature linking acute psychosis to amoxicillin yielded a few reported cases. Beal et al. [4] reported a patient with mania and psychosis 10 days after initiation of amoxicillin for a urinary tract infection with complete resolution of these symptoms 12 days after discontinuation of the antibiotic. Similarly, a patient prescribed amoxicillin-clavulanate for suspected pneumonia developed agitation and bizarre behavior with visual hallucinations and delusions within 2 h of administering antibiotics [5]. Another two reports described visual and auditory hallucinations within 1–2 days of starting amoxicillin in patients with no underlying psychiatric disorders [6, 7]. All of these cases showed complete resolution of acute psychiatric symptoms upon cessation of amoxicillin.\n\nClarithromycin is classified as a macrolide antibiotic derived from its parent compound, erythromycin [8]. Uses of this antibiotic include treatment of respiratory tract infections, infections due to Mycobacterium avium complex (M. avium or M. intracellulare) and H. pylori. In addition to gastrointestinal complaints, clarithromycin may also produce symptoms of confusion, insomnia, dizziness, and lightheadedness. CNS side effects including psychosis and depersonalization have also been reported, more so than with amoxicillin.\n\nA number of these cases presume drug interactions as the trigger for psychosis when a patient is receiving two or more medications. Clarithromycin is metabolized via the CYP3A pathway, specifically via cytochrome P450 isoenzyme by oxidation and demethylation [9, 10]. Many occurrences of clarithromycin-induced psychosis can be explained in patients receiving other drugs also metabolized through this same mechanism. Clarithromycin occupies and inhibits the P450 enzyme during metabolism, resulting in accumulation of the co-administered drug(s), leading to toxic levels. Pollak et al. [11] reported fluoxetine toxicity in a patient who had been on fluoxetine for 16 months and experienced psychosis within 1 day of starting clarithromycin. There are also reports of patients with HIV on highly active antiretroviral therapy in whom neuropsychiatric reactions are described upon initiation of clarithromycin [12]. Corticosteroids are a known trigger for psychotic episodes, and there have been studies revealing a correlation between dose of the steroid and prevalence of psychosis [13, 14]. Finkenbine and Frye [15] report psychosis in a patient on prednisone and clarithromycin, likely due to decreased clearance of prednisolone. Transient carbamazepine overdose as a result of delayed metabolism [16, 17] and serotonin syndrome with psychosis caused by intake of both clarithromycin and paroxetine have also been described [18]. In the aforementioned cases, onset of symptoms on average occurred within 1–5 days of initiating therapy. In all cases, symptoms resolved upon cessation of clarithromycin, mostly within 1–3 days.\n\nThe mechanism by which clarithromycin produces psychosis alone remains unclear. Gomez-Gil et al. [19] described two middle-aged females without any past psychiatric history who presented with bizarre behavior and an inability to comprehend after initiation of clarithromycin therapy for H. pylori infection. The onset of symptoms occurred within 7 days in each patient, similar to our patient; however amoxicillin was not included in their regimen. Symptoms subsided within 24 h after discontinuation of clarithromycin. Similarly, a 65-year-old female undergoing treatment with clarithromycin and omeprazole developed a manic episode 3 days after initiation of this antimicrobial with resolution of symptoms occurring 2 days after medication was stopped [20]. Clarithromycin has been known to cause acute psychiatric episodes in the treatment for various infections in addition to H. pylori. Vicente de Vera et al. [21] described a patient with no previous psychiatric history who developed agitation and delirium 3 days after starting clarithromycin treatment for a community-acquired pneumonia with complete resolution of symptoms after removing treatment. Clarithromycin used for treatment of M. avium complex triggered reversible mania in two patients with AIDS not on highly active antiretroviral therapy. Acute psychotic symptoms resolved after clarithromycin was discontinued and recurred when it was resumed. A trial of azithromycin, another macrolide antibiotic, did not induce psychotic episodes in these patients [22]. A group of elderly patients (n = 13, mean age 70 years) with chronic mycobacterial lung disease without HIV were monitored after receiving clarithromycin monotherapy. Common side effects included bitter taste and nausea, with 7 of the 13 patients experiencing confusion and insomnia. Symptoms resolved following discontinuation of treatment [23]. A 52-year-old female being treated for acute bronchitis with clarithromycin twice daily developed acute psychosis with symptoms of disorganized behavior, paranoid ideation, anxiety, confusion and depersonalization 24 h after initiation of therapy. She returned to baseline 3 days after terminating treatment [24]. There are several other reports in the literature describing mania after starting clarithromycin monotherapy with extinction of symptoms within several days (average 3–5 days) of discontinuing this drug [25, 26, 27, 28, 29].\n\nNeurotoxicity of clarithromycin leading to non-convulsive status epilepticus (NCSE) has also been associated with this antibiotic. NCSE can manifest as changes in consciousness without evidence of clinical seizures. The diagnosis is made by ‘continuous epileptiform activity’ on EEG. Bandettini di Poggio et al. [8] reported the first case of clarithromycin-induced delirium due to NCSE in a 74-year-old woman being treated for bronchitis with clarithromycin. Among previously reported cases of clarithromycin-induced neurotoxicity, only 6 patients were evaluated with an EEG, with 5 showing no evidence of epileptic activity. An EEG was performed in our patient excluding the possibility of epileptiform activity induced by clarithromycin. EEG is an important tool in working up a patient presenting with acute psychosis suspected to be secondary to an antimicrobial because with NCSE there is response to treatment with benzodiazepines in addition to drug cessation.\n\nThe cause of CNS toxicity as a result of clarithromycin use remains uncertain. A commonly accepted theory with polypharmacy includes the suppression of cytochrome p450 by clarithromycin with a resultant accumulation of clarithromycin and/or the associated drug(s). Clarithromycin alone may be directly toxic to the CNS via its lipid-soluble active metabolite 14-hydroxyclarithromycin [25]. Clarithromycin and its metabolite have also been known to alter cortisol and prostaglandin metabolism, and interact with glutaminergic and γ-aminobutyric acid pathways possibly leading to CNS side effects [1, 12]. Though these are all plausible explanations, how clarithromycin causes neurotoxicity remains a matter of debate requiring further research.\n\nConclusion\nAcute psychosis in patients without previous psychiatric illness entails a wide differential requiring extensive investigation. Initial workup should focus on causes secondary to infectious processes, along with both toxic and metabolic etiologies, however medications must be thoroughly reviewed. Antibiomania is an infrequent but valid consequence of antimicrobials and must be included in the differential as a trigger for acute psychosis. In our patient, amoxicillin and clarithromycin had been started several days prior to the onset of psychosis for eradication of H. pylori. After ruling out other possible causes of psychosis, it was concluded that either amoxicillin or clarithromycin were the likely triggers. Based off an extensive literature review, clarithromycin was the likely agent responsible for symptoms. Unfortunately, the mechanism through which clarithromycin causes neurotoxicity remains unclear. Clinicians should be cognizant of the psychiatric side effects secondary to clarithromycin and discontinuation should be prompt for rapid recovery of mental status.\n==== Refs\nReferences\n1 Abouesh A Stone C Hobbs WR Antimicrobial-induced mania (antibiomania): a review of spontaneous reports J Clin Psychopharmacol 2002 22 71 81 11799346 \n2 Sachs G Shin JM Howden CW Review article: the clinical pharmacology of proton pump inhibitors Aliment Pharmacol Ther 2006 23 (suppl 2) 2 8 16700898 \n3 Delerue O Muller JP Destee A Warot P Mania-like episodes associated with ranitidine Am J Psychiatry 1988 145 271 3341479 \n4 Beal DM Hudson B Zaiac M Amoxycillin-induced psychosis? Am J Psychiatry 1986 143 255 256 3946666 \n5 Bell CL Watson B Waring WS Acute psychosis caused by co-amoxiclav BMJ 2008 337 a2117 18945734 \n6 Stell IM Ojo OA Amoxycillin-induced hallucinations – a variant of Hoigne's syndrome? Br J Clin Pract 1996 50 279 8794605 \n7 Oliver DJ Hallucinations associated with amoxycillin? A case report Practitioner 1984 228 884 6483751 \n8 Bandettini di Poggio M Anfosso S Audenino D Primaver A Clarithromycin-induced neurotoxicity in adults J Clin Neurosci 2011 18 313 318 21269833 \n9 Peter DH Clissold SP Clarithromycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential Drugs 1992 44 117 164 1379907 \n10 Sturgill MG Rapp RP Clarithromycin: review of a new macrolide antibiotic with improved microbiological spectrum and favorable pharmacokinetic and adverse effect profiles Ann Pharmacother 1992 26 1099 1108 1421677 \n11 Pollak PT Sketris IS MacKenzie SL Hewlett TJ Delirium probably induced by clarithromycin in a patient receiving fluoxetine Ann Pharmacother 1995 29 486 488 7655131 \n12 Prime K French P Neuropsychiatric reaction induced by clarithromycin in a patient on highly active antiretroviral therapy (HAART) Sex Transm Infect 2001 77 297 298 11463936 \n13 Lewis DA Smith RE Steroid-induced psychiatric syndromes: a report of 14 cases and a review of the literature J Affect Disord 1983 5 319 332 6319464 \n14 The Boston Collaborative Drug Surveillance Program Acute adverse reactions to prednisone in relation to dosage Clin Pharmacol Ther 1972 13 694 698 5053810 \n15 Finkenbine RD Frye MD Case of psychosis due to prednisone-clarithromycin interaction Gen Hosp Psychiatry 1998 20 325 326 9788033 \n16 Yasui N Otani K Kaneko S Carbamazepine toxicity induced by clarithromycin co-administration in psychiatric patients Int Clin Psychopharmacol 1997 12 225 229 9347384 \n17 Gelisse P Hillare-Buys D Halaili E Carbamazepine and clarithromycin: a clinically relevant drug interaction Rev Neurol 2007 162 1096 1099 18033049 \n18 Jaber BI Lobon LF Madias NE The serotonin syndrome complicating co-prescription of paroxetine and clarithromycin Am J Med 2006 119 e3 16564762 \n19 Gomez-Gil E Garcia F Pintor L Clarithromycin-induced acute psychoses in peptic ulcer disease Eur J Clin Microbiol Infect Dis 1999 18 70 71 10192720 \n20 Ortiz-Dominguez A Berlanga C Gutierrez-Mora D A case of clarithromycin-induced manic episode (antibiomania) Int J Neuropsychopharmacol 2004 7 99 100 14731313 \n21 Vicente de Vera C Garcia M Pifarre Teixido R Barbe F Delirium induced by clarithromycin in a patient with community-acquired pneumonia Eur Respir J 2006 28 671 672 16946100 \n22 Nightingale SD Koster FT Mertz GJ Clarithromycin induced mania in two patients with AIDS Clin Infect Dis 1995 20 1563 1564 7548513 \n23 Wallace RJ Brown BA Griffith DE Drug intolerance to high-dose clarithromycin among elderly patients Diagn Microbiol Infect Dis 1993 16 215 221 8477575 \n24 Warner A Clarithromycin – a precipitant for acute psychotic stress Psychosomatics 2000 41 539 11110120 \n25 Ozsoylar G Sayn A Bolay H Clarithromycin monotherapy-induced delirium J Antimicrob Chemother 2007 59 331 17208955 \n26 Mermelstein HT Clarithromycin induced delirium in a general hospital Psychosomatics 1998 39 540 542 9819955 \n27 Cone LA Sneider RA Nazemi R Mania due to clarithromycin therapy in a patient who was not infected with human immunodeficiency virus Clin Infect Dis 1996 22 595 596 8853002 \n28 Jiménez-Pulido I Navarro-Ruiz A Sendra P Hallucinations with therapeutic doses of clarithromycin Int J Clin Pharmacol Ther 2002 40 20 22 11837378 \n29 Brooks JO Hoblyn JC Secondary mania in older adults Am J Psychiatry 2005 162 2033 2038 16263839\n\n",
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"abstract": "BACKGROUND\nHerpesvirus infections often complicate the clinical course of patients with inflammatory bowel disease; however, invasive disease due to herpes simplex virus is distinctly uncommon.\n\n\nMETHODS\nWe present a case of herpes simplex virus colitis and hepatitis, review all the previously published cases of herpes simplex virus colitis, and discuss common clinical features and outcomes. We also discuss the epidemiology, clinical manifestations, diagnosis, and management of herpes simplex virus infections, focusing specifically on patients with inflammatory bowel disease.\n\n\nRESULTS\nA 43-year-old man with ulcerative colitis, previously controlled with an oral 5-aminosalicylic agent, developed symptoms of a colitis flare that did not respond to treatment with systemic corticosteroid therapy. One week later he developed orolabial ulcers and progressive hepatic dysfunction, with markedly elevated transaminases and coagulopathy. He underwent emergent total colectomy when imaging suggested bowel micro-perforation. Pathology from both the colon and liver was consistent with herpes simplex virus infection, and a viral culture of his orolabial lesions and a serum polymerase chain reaction assay also identified herpes simplex virus. He was treated with systemic antiviral therapy and made a complete recovery.\n\n\nCONCLUSIONS\nDisseminated herpes simplex virus infection with concomitant involvement of the colon and liver has been reported only 3 times in the published literature, and to our knowledge this is the first such case in a patient with inflammatory bowel disease. The risk of invasive herpes simplex virus infections increases with some, but not all immunomodulatory therapies. Optimal management of herpes simplex virus in patients with inflammatory bowel disease includes targeted prophylactic therapy for patients with evidence of latent infection, and timely initiation of antiviral therapy for those patients suspected to have invasive disease.",
"affiliations": "Division of Infectious Diseases, Emory University School of Medicine Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Emory University Hospital Division of Digestive Diseases, Emory University School of Medicine Emory Transplant Center, Atlanta, GA.",
"authors": "Phadke|Varun K|VK|;Friedman-Moraco|Rachel J|RJ|;Quigley|Brian C|BC|;Farris|Alton B|AB|;Norvell|J P|JP|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2775963610.1097/MD.0000000000005082050824900Research ArticleClinical Case ReportConcomitant herpes simplex virus colitis and hepatitis in a man with ulcerative colitis Case report and review of the literaturePhadke Varun K. MDa∗Friedman-Moraco Rachel J. MDaQuigley Brian C. MDbFarris Alton B. MDbNorvell J. P. MDcdLu. Min a Division of Infectious Diseases, Emory University School of Medicineb Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Emory University Hospitalc Division of Digestive Diseases, Emory University School of Medicined Emory Transplant Center, Atlanta, GA.∗ Correspondence: Varun K. Phadke, 49 Jesse Hill Jr. Drive, Atlanta 30303, GA (e-mail: vphadke@emory.edu).10 2016 21 10 2016 95 42 e50822 6 2016 2 7 2016 15 9 2016 Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.2016This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nBackground:\nHerpesvirus infections often complicate the clinical course of patients with inflammatory bowel disease; however, invasive disease due to herpes simplex virus is distinctly uncommon.\n\nMethods:\nWe present a case of herpes simplex virus colitis and hepatitis, review all the previously published cases of herpes simplex virus colitis, and discuss common clinical features and outcomes. We also discuss the epidemiology, clinical manifestations, diagnosis, and management of herpes simplex virus infections, focusing specifically on patients with inflammatory bowel disease.\n\nResults:\nA 43-year-old man with ulcerative colitis, previously controlled with an oral 5-aminosalicylic agent, developed symptoms of a colitis flare that did not respond to treatment with systemic corticosteroid therapy. One week later he developed orolabial ulcers and progressive hepatic dysfunction, with markedly elevated transaminases and coagulopathy. He underwent emergent total colectomy when imaging suggested bowel micro-perforation. Pathology from both the colon and liver was consistent with herpes simplex virus infection, and a viral culture of his orolabial lesions and a serum polymerase chain reaction assay also identified herpes simplex virus. He was treated with systemic antiviral therapy and made a complete recovery.\n\nConclusions:\nDisseminated herpes simplex virus infection with concomitant involvement of the colon and liver has been reported only 3 times in the published literature, and to our knowledge this is the first such case in a patient with inflammatory bowel disease. The risk of invasive herpes simplex virus infections increases with some, but not all immunomodulatory therapies. Optimal management of herpes simplex virus in patients with inflammatory bowel disease includes targeted prophylactic therapy for patients with evidence of latent infection, and timely initiation of antiviral therapy for those patients suspected to have invasive disease.\n\nKeywords\ncase reportCrohn's diseaseherpes simplex virusimmunomodulatory therapyinflammatory bowel diseaseulcerative colitisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nHerpesvirus infections frequently complicate the clinical course of patients with inflammatory bowel disease (IBD).[1,2] Immunosuppressive therapy increases the risk of herpesvirus reactivation and predisposes to more severe infections.[2] Whereas cytomegalovirus (CMV) is a well-recognized cause of tissue-invasive disease in this population,[1] herpes simplex virus (HSV) has only rarely been implicated.[3–7] When HSV infections do occur they are usually limited to sites of local reactivation, for example, mucosal surfaces (such as the oropharynx, anogenital area, and eyes) and skin sites. Here we report the first case, to our knowledge, of a patient with IBD who developed disseminated HSV infection with concomitant colonic and hepatic involvement. We also review all of the previously reported cases of HSV colitis and hepatitis, as well as the published literature of HSV infections, in patients with IBD.\n\nThe patient provided informed consent for the use of clinical information and images for this case report.\n\n2 Case report\nA 43-year-old man with ulcerative colitis (UC) was transferred to our hospital for evaluation and management of refractory colitis symptoms and abnormal liver function tests. One year earlier he had been diagnosed with UC and started on maintenance therapy with oral balsalazide. He continued to have intermittent flares of his colitis which were well-controlled with short courses of systemic corticosteroids. After his last flare 6 months earlier, he was prescribed a trial of azathioprine, which he discontinued after a few weeks due to intolerance, followed by mesalamine suppositories. One month prior to admission he was asymptomatic.\n\nApproximately 3 weeks prior to transfer he developed fatigue, decreased oral intake, diffuse crampy abdominal discomfort, and loose bloody stools, consistent with his prior UC flares. He was prescribed prednisone 40 mg daily, but his symptoms did not improve after 1 week of this therapy. He was admitted to his local hospital. Laboratory testing was unremarkable (Table 1) and stool evaluation for bacterial and parasitic pathogens was unrevealing. A flexible sigmoidoscopy demonstrated “severe ulcerative colitis” without pseudomembranes; biopsies were not performed. He was treated with intravenous methylprednisolone and discharged with prednisone 60 mg daily and a course of metronidazole—however, he was readmitted 1 week later for persistent symptoms. Laboratory testing on readmission was notable for: aspartate aminotransferase (AST), 98 U/L; alanine aminotransferase (ALT), 136 U/L; total bilirubin 1.6 mg/dL, and a prothrombin time of 15.7 seconds (international normalized ratio, INR, of 1.25). Computed tomography (CT) of the abdomen and pelvis demonstrated pan-colitis. He was started on intravenous corticosteroids and empiric broad-spectrum antibiotics. For persistent colitis symptoms, he also received a dose of golimumab 48 hours after admission.\n\nTable 1 Progression of laboratory values of case patient.\n\nOver the next 96 hours, his serum aminotransferase levels and prothrombin time continued to increase (Table 1). A serologic evaluation for viral causes of acute hepatitis was notable for a positive CMV IgG and HSV-1 IgM; tests for hepatitis A and B and HSV-2 were negative. He subsequently underwent percutaneous liver biopsy, and then was transferred to our hospital for further management.\n\nOn arrival to our hospital, he was febrile to 39.6°C and in distributive shock. On physical examination, he had multiple small shallow ulcerations of the hard palate as well as diffuse abdominal tenderness to palpation. Laboratory testing was notable for pancytopenia and markedly elevated serum transaminases, with AST, 3072 U/L, and ALT, 3392 U/L (other results in Table 1). Blood cultures were obtained, swabs of his oral ulcers were sent for viral culture, and serum polymerase chain reaction (PCR) assays for CMV and HSV were performed. A repeat CT of the abdomen and pelvis revealed diffuse colonic wall thickening and a micro-perforation in the distal sigmoid colon.\n\nThe patient received intravenous fluid boluses, transfusions of packed red cells, and empiric antimicrobial therapy with vancomycin, piperacillin/tazobactam, and intravenous ganciclovir. He underwent emergent total abdominal colectomy with end ileostomy as well as intraoperative liver biopsy. Blood cultures obtained on admission grew Escherichia coli and Citrobacter amalonaticus—his anti-bacterial therapy was changed to intravenous ertapenem. Viral culture of his oral ulcers grew herpes simplex virus (Fig. 1). A serum PCR assay was positive for HSV (cycle threshold value of 18.5, cutoff for positivity <39), but negative for CMV. Pathology slides sent from the referring hospital and intraoperative specimens from our hospital were reviewed. The colon had “chronic active colitis with ulceration” (Fig. 2A) and the liver had “patchy foci of nonzonal hepatocellular necrosis” (Fig. 2B). Histopathology and immunohistochemistry (IHC) of both the liver and colon were consistent with HSV infection (Fig. 2A–D); IHC stains for CMV and adenovirus were negative.\n\nFigure 1 Representative positive herpes simplex viral culture using the Enzyme Linked Virus Inducible System (ELVIS). A swab of the case patient's oral ulcers grew herpes simplex virus (Photo courtesy of Dr. Lori Racsa (Department of Pathology, Emory University)).\n\nFigure 2 (A) Herpes simplex colitis, colectomy specimen. Deep ulceration in the colon (left) with adjacent nonulcerated mucosa (right). Hematoxylin and eosin stain, 20× overall magnification. (B) Herpes simplex virus hepatitis, intraoperative liver biopsy 1 day after initiation of antiviral therapy. Patches of nonzonal hepatocyte necrosis with minimal inflammation. Hematoxylin and eosin stain, 20× overall magnification. (C) Herpes simplex virus colitis. An immunohistochemical stain for herpes simplex virus (types 1 and 2, combined stain) darkly stains these inclusion-like structures (some denoted with arrows). Despite the apparently high background staining, note absence of staining within macrophage nuclei. No staining whatsoever was observed in the nonulcerated colonic mucosa. Immunohistochemical stain for herpes simplex virus, 1000× overall magnification. (D) Herpes simplex virus hepatitis. The patches of hepatocyte necrosis are highlighted strongly with an immunohistochemical stain for herpes simplex virus (types 1 and 2, combined stain). 20× overall magnification. Photo courtesy of Dr. Brian Quigley (Department of Pathology and Laboratory Medicine, Emory University).\n\nHis antiviral therapy was changed to intravenous acyclovir for disseminated HSV infection. His steroids were tapered over a period of 1 month. At the time of discharge, 10 days after admission, his serum AST and ALT levels had decreased to 173 U/L and 55 U/L, respectively. He was discharged with oral valacyclovir 1000 mg 3 times daily to take for an additional 4 weeks, to be followed by indefinite suppressive therapy. Four months after discharge his serum transaminase levels had returned to normal. In the 1 year following discharge, he has remained clinically well with no evidence of relapse.\n\n3 Discussion\n3.1 Epidemiology of HSV infections in IBD\nHerpes simplex virus 1 and 2 infections are common, with an estimated seroprevalence of 50% and 15% respectively in the general US population.[8] Importantly, rates of infection vary between certain age, race, and socioeconomic groups[8]—since no seroepidemiologic studies of latent HSV infection have been conducted specifically in patients with IBD, the prevalence in this particular population is unknown. Nevertheless, data from single center analyses and meta-analyses of multicenter trials indicate that HSV infections are fairly common among patients with IBD,[9–12] mirroring trends in the general population. In fact, the actual incidence is likely to be underestimated by these studies due to underreporting and inadequate duration of follow-up.\n\nUse of immunomodulatory agents, particularly systemic corticosteroids and antimetabolites (e.g., azathioprine, 6-mercaptourine, and methotrexate), has been associated with an elevated risk of localized mucocutaneous HSV reactivation,[9,10] similar to herpes zoster.[2] Invasive HSV infections have also been reported in patients taking azathioprine[5–7,13] and methotrexate[14] for IBD. Post-marketing surveillance studies of IBD patients receiving newer immunomodulatory therapies (e.g., biologic therapies) less frequently evaluate the specific risk of HSV infections, as compared to herpes zoster, mycobacterial, and fungal infections.[11,15] As a result, the effect of biologic agents, such as tumor necrosis factor (TNF)-alpha antagonists, anti-integrin antibodies, or interleukin (IL)-12/23 receptor antagonists, on the incidence of HSV infections—both localized and invasive—among IBD patients is less clear. However, given the paucity of reported cases, the risk is likely lower than with antimetabolite therapy (Table 4).[11,15] Indeed, although there have been small case series of tissue-invasive HSV infections in patients receiving TNF-alpha antagonists and anti-integrin antibodies,[16,17] none have included patients with IBD.\n\nTable 4 Immunomodulatory therapies for inflammatory bowel disease (IBD) and risk for infections, including invasive herpes simplex virus (HSV) disease.\n\nPatient-specific immunologic factors can also influence the course of infections due to herpes simplex viruses. These may include individual-level variations in pathogen recognition receptors, major histocompatibility complex proteins, naturally occurring anti-viral peptides, and effector cell function.[18–21] Although IBD has been associated with a variety of genetic polymorphisms linked to a dysregulated immune response to enteric microbes, none of these genetic factors have been investigated specifically for their role in immunity to herpes simplex viruses.\n\n3.2 Clinical manifestations of HSV infections in IBD\nThe most common clinical manifestations of HSV in IBD are similar to those in otherwise healthy individuals. Overall, mucocutaneous (i.e., oropharynx and anogenital areas) disease predominates and is generally benign; however, progression to more invasive disease or widespread cutaneous dissemination has occasionally been described.[13,22,23] Importantly, oropharyngeal and anogenital lesions due to HSV can mimic those seen with Crohn's disease[24]; thus, it is important to exclude active HSV infection before initiating or escalating immunomodulatory therapy.[25] Herpes simplex viruses can also occasionally cause disseminated disease with end-organ involvement; however, there have been only a few reports of visceral HSV disease among patients with IBD. The gastrointestinal tract is a frequent site of HSV involvement in immunocompromised patients,[26] with the esophagus and rectum being the most frequently affected organs, followed by isolated reports of stomach and small bowel disease. Interestingly, the vast majority of these cases have been in patients with HIV/AIDS or among solid organ and bone marrow transplant recipients, and not those with IBD—we found only 1 report of HSV duodenitis in a patient with Crohn's disease.[27] Involvement of other organs in IBD patients is even less common—to date only 2 cases of HSV meningoencephalitis[6,7] and a single case of HSV pneumonia/pneumonitis[5] have been reported, all in the setting of corticosteroid or anti-metabolite therapy.\n\nColitis due to HSV was first described in 1982[28] and since then only 16 cases have been reported in the literature.[4,28–42] Almost all of the cases occurred in immunocompromised hosts, nearly a third (n = 5) of whom were receiving corticosteroid therapy for IBD (Table 2).[4,33,39,41,42] In contrast, CMV is routinely implicated as an intestinal pathogen in patients with IBD. Indeed, among patients with IBD presenting with acute colitis, reported prevalence rates of CMV infection have ranged from 21% to 34%, and in those with steroid-refractory disease it can be as high 36%.[1] As is the case for CMV, HSV colitis in this population often mimics the underlying disease, presenting as fever, abdominal pain and diarrhea, rectal bleeding,[4,39,42] or even paralytic ileus,[41] generally in the absence of suggestive mucocutaneous involvement. Endoscopic findings may be nonspecific and can include edema, erythema sometimes with petechiae, and well-demarcated ulcers of variable size and depth with or without purulent exudate, often separated by normal-appearing mucosa.[41,42]\n\nTable 2 Published cases of herpes simplex virus (HSV) colitis in the English-language literature. Patients with inflammatory bowel disease (n = 4) in bold.\n\nThe relative paucity of cases of HSV colitis as compared to CMV colitis (not only in the context of IBD) suggests a fundamental difference in the pathophysiology of end-organ involvement due to these viruses. Differences in the site of viral latency (e.g. neural ganglion cells for HSV vs leukocytes and endothelial cells for CMV) may account for the relative infrequency of colonic involvement due to HSV as compared to CMV. Alternatively, these viruses may differ in their tropism for colonic tissue. In studies that have exploited the oncolytic properties of herpes simplex viruses, investigators have shown diminished binding of HSV-1 to normal colonic tissue as compared to cancerous lesions.[43] Similarly, although HSV-1 has been used successfully in an ex vivo colonic explant model of virally induced immune activation in Crohn's disease,[44] it is rarely detected in the large intestines of patients with IBD.[45]\n\nHepatitis due to HSV is also uncommon and almost exclusively occurs in the context of impaired cell-mediated immunity.[46] We found only 8 previous cases of HSV hepatitis in patients with IBD, all of whom were receiving systemic corticosteroids with or without anti-metabolite therapy (Table 3).[3,47–53] Similar to other patient populations, HSV hepatitis in patients with IBD tends to progress rapidly and is associated with a high case fatality rate, particularly if the diagnosis is not considered early enough in the disease course to allow for timely initiation of appropriate antiviral therapy.[51]\n\nTable 3 Published cases of herpes simplex virus (HSV) hepatitis in patients with inflammatory bowel disease (IBD) in the English-language literature.\n\nWe identified only 3 prior reports[31,37,38] describing simultaneous colonic and hepatic involvement of disseminated herpes simplex virus infection (one of which did not report pathologic confirmation of hepatic involvement),[37] none of which involved a patient with IBD (Table 2). One of the cases was a neonate presumably with perinatal acquisition of HSV,[37] the second case was a patient who had received re-induction chemotherapy for acute lymphoblastic leukemia and developed reactivation HSV infection (prior history of herpes labialis) with multiorgan involvement,[38] and the third case was a liver transplant recipient who developed disseminated HSV with liver, colon, lung, and laryngeal involvement.[31]\n\n3.3 Diagnosis of HSV infections in IBD\nThe gold-standard diagnostic test for tissue-invasive HSV disease, including colitis and hepatitis, is histopathologic evidence of herpes simplex virus infection, which can include characteristic eosinophilic intracytoplasmic inclusions (Fig. 2A and B) as well as positive immunohistochemical staining using labeled HSV-1- and HSV-2-specific monoclonal antibodies (Fig. 2C and D). In practice, particularly given the challenges of obtaining pathologic specimens from critically ill patients, a combination of noninvasive diagnostic tests is often used to support a clinical diagnosis of HSV end-organ disease and the decision to begin antiviral therapy.\n\nA variety of noninvasive tests are available to aid in the diagnosis of tissue-invasive HSV infections.[54] Typically the most readily available is HSV type-specific serology; however, given high background seroprevalence rates, a positive result is typically not useful for the diagnosis of suspected active disease,[55] and a negative result does not exclude the possibility of a primary infection. As in our case, assays that detect IgM antibodies may suggest the diagnosis of early primary infection, especially if IgG antibodies are absent. Unfortunately, the sensitivity and specificity of these assays are limited by the fact that HSV IgM antibodies are not always detected, they can persist for months after primary infection, and they often reappear in the setting of reactivation.[54]\n\nDirect detection of HSV in non-invasively obtained specimens (e.g., scrapings of mucocutaneous lesions, respiratory or gastrointestinal tract secretions, etc.) using culture, direct immunofluorescence, or PCR-based assays can also support the diagnosis of end-organ involvement in the appropriate clinical setting. For instance, the appearance of characteristic herpetic mucocutaneous lesions in the context of mildly abnormal serum liver enzyme levels—transaminases and lactate dehydrogenase in particular—may herald impending fulminant HSV hepatitis and should prompt the initiation of timely antiviral therapy.[50] However, concomitant skin findings are present in fewer than one-third of patients with HSV hepatitis,[46,51,53] including those with IBD. Similarly, less than half (n = 6) of all the previously reported cases of HSV colitis had suggestive mucocutaneous lesions at the time of presentation. More importantly, recovery of virus in the absence of lesions should be interpreted with caution since HSV reactivation and shedding is not uncommon in the context of critical illness and may or may not be indicative of active tissue-invasive HSV disease.[56]\n\nAs illustrated by our case, visceral or disseminated HSV infections (particularly those with hepatic involvement) are frequently accompanied by some degree of HSV viremia,[52,57] which can be detected using PCR assays of whole blood using HSV specific primers. Notably, in the United States none of these assays is currently approved by the Food and Drug Administration (FDA) for this application.[54,58] Concomitant viremia was described in only one of the previously reported cases of HSV hepatitis in patients with IBD,[53] and none of the cases of HSV colitis; however, HSV viremia has been used to predict hepatic involvement in other patient populations.[52,57–60] Importantly, even the presence of HSV viremia is generally not sufficient to make a definitive diagnosis of visceral HSV disease because it too can be frequently detected in patients with non-HSV-related critical illness.[56,61] Although quantification of viremia may be useful for differentiating between inconsequential reactivation and end-organ disease in this setting,[57] this has not been studied in a prospective fashion.\n\n3.4 Treatment and prevention of invasive HSV infections in IBD\nThere have been no prospective comparative studies of antiviral therapy for visceral or disseminated HSV infection. Acyclovir is the drug of choice for HSV infections and earlier treatment has been associated with improved outcomes for both HSV hepatitis and encephalitis.[51,62,63] Primary mucocutaneous infections (i.e., occurring in a patient known to be HSV seronegative) in patients on immunomodulatory therapy for IBD should be treated promptly with antiviral therapy as this may prevent secondary complications.[25] For tissue-invasive HSV infections (e.g., colitis, hepatitis, meningoencephalitis, pneumonia, etc.), most experts would recommend a minimum of 2 to 3 weeks of parenteral antiviral therapy. In the case of HSV hepatitis, a highly morbid disease with a high case fatality rate and no well-validated marker of disease activity, the duration may be significantly longer depending on the patient's clinical course. After completion of a course of systemic antiviral therapy some experts advocate indefinite suppressive therapy with prophylactic doses of oral antiviral agents, particularly if further immunosuppressive therapy is anticipated in the future (i.e., post-transplantation), although this may lead to the subsequent emergence of acyclovir resistance.[64] Our patient received a total of 6 weeks of antiviral therapy (intravenous acyclovir followed by oral valacyclovir) with a plan to continue lifelong suppressive therapy to prevent potential recurrence. Interestingly, four of the previously reported cases of HSV colitis were cured without specific antiviral therapy, though most of those patients did not have significant immunologic defects and ultimately required surgical resection of the diseased tissue before achieving symptom resolution.\n\nIn addition to initiating antiviral therapy, most experts as well as consensus guidelines from the European Crohn's and Colitis Organization (ECCO) also recommend interruption of immunomodulatory therapy for IBD in the context of severe HSV infections.[25,65] For more typical mucocutaneous infections immunomodulatory therapy may be continued, though there is a small risk for widespread dissemination and invasive disease.[13,22,23] Patients with suspected hepatic involvement—particularly those with high-risk features, such as age >40 years, immunocompromised status, or evidence of fulminant hepatic failure (encephalopathy, coagulopathy, or thrombocytopenia)—should also be referred promptly for consideration for liver transplantation, as this may be life-saving.[51]\n\nCurrent guidelines make no formal recommendations regarding baseline serologic testing of patients with IBD for HSV or for routine antiviral prophylaxis, even when initiating immunomodulatory therapy.[25,66] Given the observed increased rates of reactivation HSV disease—albeit mild—in patients receiving certain classes of immunomodulatory drugs, it has been suggested that patients with a previous history of frequent HSV outbreaks who are being prescribed immunomodulatory medications also receive suppressive antiviral therapy,[65,67,68] though there are limited clinical data to support that recommendation. The likelihood of developing disseminated infection due to specific immunomodulatory agents has not been prospectively evaluated; however, based on post-licensure studies in other populations commonly prescribed similar therapies, the risk is likely to be greater with certain drug classes (Table 4). Consequently, it may be reasonable to offer secondary prophylaxis to HSV seropositive individuals or those with a history of recurrent localized mucocutaneous HSV infections who are going to receive prolonged courses of systemic corticosteroids, anti-metabolite therapy, or a calcineurin inhibitor. Patients with a previous history of disseminated or tissue-invasive HSV disease may be offered lifelong suppressive therapy/secondary prophylaxis, similar to the case patient, especially if any underlying or iatrogenic immunologic defect(s) cannot be reversed. However, the true risk of recurrence for tissue-invasive HSV disease has not been well established, secondary antiviral prophylaxis has variable efficacy depending on the site of disease, and ongoing antiviral therapy may lead to the development of drug resistance in immunocompromised patients.[69]\n\n4 Conclusion\nHerpes simplex virus infections are common in patients with inflammatory bowel disease, but systemic dissemination and end-organ involvement have been infrequently reported. Patients with IBD are often at a higher risk for reactivation of HSV and tissue-invasive disease due to immunomodulatory therapy. Colitis and hepatitis due to HSV are particularly rare in this population, but HSV colitis should be considered in the differential diagnosis of refractory colitis symptoms, particularly if CMV disease has already been excluded. Treatment of suspected disseminated HSV infections should include prompt initiation of systemic antiviral therapy, with routine involvement of organ-specific and infectious disease specialists. Strategies for prevention of these infections include symptom-based and serologic screening of patients that are going to receive immunomodulatory therapy, especially with systemic corticosteroids or antimetabolites, with consideration of prophylactic antiviral therapy in those with a history of recurrent or complicated HSV infections.\n\nAbbreviations: ALT = alanine transaminase, AST = aspartate transaminase, CMV = cytomegalovirus, CT = computed tomography, ECCO = European Crohn's and Colitis Organisation, FDA = Food and Drug Administration, HIV/AIDS = human immunodeficiency virus/acquired immunodeficiency syndrome, HSV = herpes simplex virus, IBD = inflammatory bowel disease, IHC = immunohistochemistry, IL = interleukin, PCR = polymerase chain reaction, TNF = tumor necrosis factor, UC = ulcerative colitis.\n\nDeclaration: The content of this review is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.\n\nFunding: Varun K. Phadke is supported by the Emory Vaccinology Training Program under award number T32AI074492 from the National Institute of Allergy and Infectious Diseases.\n\nAuthorship: VKP wrote the initial draft and performed the review of the literature. VKP and RJF were the infectious diseases clinicians caring for this patient. BCQ and ABF provided images of the biopsy and operative specimens and were also the attending pathologists for this case. JPN was the attending hepatology clinician caring for this patient. All authors reviewed and edited the manuscript for important intellectual content.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1 Kandiel A Lashner B \nCytomegalovirus colitis complicating inflammatory bowel disease . Am J Gastroenterol \n2006 ; 101 :2857 –2865 .17026558 \n2 Long MD Martin C Sandler RS \nIncreased risk of herpes zoster among 108 604 patients with inflammatory bowel disease . 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J Immunol \n2012 ; 188 :4412 –4420 .22490439 \n20 Griffiths SJ Koegl M Boutell C \nA systematic analysis of host factors reveals a Med23-interferon-lambda regulatory axis against herpes simplex virus type 1 replication . PLoS Pathog \n2013 ; 9 :e1003514 .23950709 \n21 Moraru M Black LE Muntasell A \nNK cell and Ig interplay in defense against herpes simplex virus type 1: epistatic interaction of CD16A and IgG1 allotypes of variable affinities modulates antibody-dependent cellular cytotoxicity and susceptibility to clinical reactivation . J Immunol \n2015 ; 195 :1676 –1684 .26179905 \n22 Sykora J Varvarovska J Stozicky F \nAdolescent herpes simplex viral infection related Ludwig's angina in ulcerative colitis . J Pediat Gastroenterol Nutr \n2004 ; 38 :221 –223 .\n23 Sciaudone G Pellino G Guadagni I \nEducation and imaging: gastrointestinal: herpes simplex virus-associated erythema multiforme (HAEM) during infliximab treatment for ulcerative colitis . J Gastroenterol Hepatol \n2011 ; 26 :610 .21332558 \n24 Hoentjen F Rubin DT \nInfectious proctitis: when to suspect it is not inflammatory bowel disease . Dig Dis Sci \n2012 ; 57 :269 –273 .21994137 \n25 Rahier JF Magro F Abreu C \nSecond European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease . J Crohn's Colitis \n2014 ; 8 :443 –468 .24613021 \n26 Buss DH Scharyj M \nHerpesvirus infection of the esophagus and other visceral organs in adults. Incidence and clinical significance . Am J Med \n1979 ; 66 :457 –462 .433952 \n27 Lee BH Um WH Jeon SR \nHerpes simplex virus duodenitis accompanying Crohn's disease . Kor J Gastroenterol \n2013 ; 62 :292 –295 .\n28 Boulton AJ Slater DN Hancock BW \nHerpesvirus colitis: a new cause of diarrhoea in a patient with Hodgkin's disease . Gut \n1982 ; 23 :247 –249 .7068049 \n29 Guttman D Raymond A Gelb A \nVirus-associated colitis in homosexual men: two case reports . Am J Gastroenterol \n1983 ; 78 :167 –169 .6299098 \n30 Adler M Goldman M Liesnard C \nDiffuse herpes simplex virus colitis in a kidney transplant recipient successfully treated with acyclovir . Transplantation \n1987 ; 43 :919 –921 .3296363 \n31 Singh N Dummer JS Kusne S \nImpact of OKT3 therapy on cytomegalovirus and herpes simplex virus infections after liver transplantation . Transplant Proc \n1988 ; 20 \n(1 suppl 1) :661 –663 .\n32 Colemont LJ Pen JH Pelckmans PA \nHerpes simplex virus type 1 colitis: an unusual cause of diarrhea . Am J Gastroenterol \n1990 ; 85 :1182 –1185 .2167608 \n33 Ruther U Nunnensiek C Muller HA \nHerpes simplex-associated exacerbation of Crohn's disease. Successful treatment with acyclovir . Deutsche Medizinische Wochenschrift \n1992 ; 117 :46 –50 .1309692 \n34 Rathgaber SW Rex DK \nColonoscopy and endoscopic therapy of hemorrhage from viral colitis . Gastrointest Endosc \n1993 ; 39 :737 –738 .8224715 \n35 Naik HR Chandrasekar PH \nHerpes simplex virus (HSV) colitis in a bone marrow transplant recipient . Bone marrow Transplant \n1996 ; 17 :285 –286 .8640181 \n36 Delis S Kato T Ruiz P \nHerpes simplex colitis in a child with combined liver and small bowel transplant . Pediatr Transplant \n2001 ; 5 :374 –377 .11560759 \n37 Daley AJ Craven P Holland AJ \nHerpes simplex virus colitis in a neonate . Pediatr Infect Dis J \n2002 ; 21 :887 –888 .12380594 \n38 Herget GW Riede UN Schmitt-Graff A \nGeneralized herpes simplex virus infection in an immunocompromised patient--report of a case and review of the literature . Pathol Res Pract \n2005 ; 201 :123 –129 .15901133 \n39 Blaszyk H Hyman NH Cooper K \nHerpes simplex virus colitis in ulcerative colitis, simulating malignancy . Histopathology \n2006 ; 49 :316 –318 .16918983 \n40 Dray X Treton X Mazeron MC \nHerpes simplex virus type 1 colitis in a patient with common variable immunodeficiency syndrome . Eur J Gastroenterol Hepatol \n2006 ; 18 :541 –544 .16607152 \n41 Schunter MO Walles T Fritz P \nHerpes simplex virus colitis complicating ulcerative colitis: a case report and brief review on superinfections . J Crohn's Colitis \n2007 ; 1 :41 –46 .21172183 \n42 Smith JO Sterling RK Mills AS \nHerpes simplex virus colitis in a patient with Crohn's disease and hepatitis B and D cirrhosis . Gastroenterol Hepatol \n2010 ; 6 :120 –122 .\n43 Kolodkin-Gal D Zamir G Edden Y \nHerpes simplex virus type 1 preferentially targets human colon carcinoma: role of extracellular matrix . J Virol \n2008 ; 82 :999 –1010 .17977977 \n44 Silva MA Menezes J Dionne S \nHerpes simplex virus-1 infection of colonic explants as a model of viral-induced activation of Crohn's disease . J Crohns Colitis \n2012 ; 6 :454 –463 .22398063 \n45 Wakefield AJ Fox JD Sawyerr AM \nDetection of herpesvirus DNA in the large intestine of patients with ulcerative colitis and Crohn's disease using the nested polymerase chain reaction . J Med Virol \n1992 ; 38 :183 –190 .1287131 \n46 Kaufman B Gandhi SA Louie E \nHerpes simplex virus hepatitis: case report and review . Clin Infect Dis \n1997 ; 24 :334 –338 .9114181 \n47 Wolfsen HC Bolen JW Bowen JL \nFulminant herpes hepatitis mimicking hepatic abscesses . J Clin Gastroenterol \n1993 ; 16 :61 –64 .8421151 \n48 Seksik P Gozlan J Guitton C \nFatal herpetic hepatitis in adult following short corticotherapy: a case report . Intensive Care Med \n1999 ; 25 :415 –417 .10342519 \n49 Rigau V Comperat E Bouillot JL \nFulminant herpes hepatitis in a young adult with hemorrhagic colitis . Gastroenterologie Clinique et Biologique \n2003 ; 27 :350 –351 .12700529 \n50 Bissig KD Zimmermann A Bernasch D \nHerpes simplex virus hepatitis 4 years after liver transplantation . J Gastroenterol \n2003 ; 38 :1005 –1008 .14614611 \n51 Norvell JP Blei AT Jovanovic BD \nHerpes simplex virus hepatitis: an analysis of the published literature and institutional cases . Liver Transpl \n2007 ; 13 :1428 –1434 .17902129 \n52 Levitsky J Duddempudi AT Lakeman FD \nDetection and diagnosis of herpes simplex virus infection in adults with acute liver failure . Liver Transpl \n2008 ; 14 :1498 –1504 .18825709 \n53 Haag LM Hofmann J Kredel LI \nHerpes simplex virus sepsis in a young woman with Crohn's disease . J Crohn's Colitis \n2015 ; 9 :1169 –1173 .26351382 \n54 Anderson NW Buchan BW Ledeboer NA \nLight microscopy, culture, molecular, and serologic methods for detection of herpes simplex virus . J Clin Microbiol \n2014 ; 52 :2 –8 .24131689 \n55 Pinna AD Rakela J Demetris AJ \nFive cases of fulminant hepatitis due to herpes simplex virus in adults . Dig Dis Sci \n2002 ; 47 :750 –754 .11991604 \n56 Lepiller Q Sueur C Solis M \nClinical relevance of herpes simplex virus viremia in Intensive Care Unit patients . J Infect \n2015 ; 71 :93 –100 .25749257 \n57 Beersma MF Verjans GM Metselaar HJ \nQuantification of viral DNA and liver enzymes in plasma improves early diagnosis and management of herpes simplex virus hepatitis . J Viral Hepat \n2011 ; 18 :e160 –166 .20704650 \n58 Berrington WR Jerome KR Cook L \nClinical correlates of herpes simplex virus viremia among hospitalized adults . Clin Infect Dis \n2009 ; 49 :1295 –1301 .19807272 \n59 Nienaber JH McNamara DR Banerjee R \nFulminant gestational hepatitis due to primary herpes simplex type 2 infection: use of serum HSV polymerase chain reaction for noninvasive diagnosis . Diagn Microbiol Infect Dis \n2012 ; 72 :181 –184 .22104186 \n60 Ambrosioni J Kaiser L Giostra E \nHerpes simplex virus load to monitor antiviral treatment after liver transplantation for acute herpetic hepatitis . Antiviral Ther \n2012 ; 17 :401 –404 .\n61 Walton AH Muenzer JT Rasche D \nReactivation of multiple viruses in patients with sepsis . PloS One \n2014 ; 9 :e98819 .24919177 \n62 Whitley RJ Alford CA Hirsch MS \nVidarabine versus acyclovir therapy in herpes simplex encephalitis . N Engl J Med \n1986 ; 314 :144 –149 .3001520 \n63 Raschilas F Wolff M Delatour F \nOutcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study . Clin Infect Dis \n2002 ; 35 :254 –260 .12115090 \n64 Longerich T Eisenbach C Penzel R \nRecurrent herpes simplex virus hepatitis after liver retransplantation despite acyclovir therapy . Liver Transpl \n2005 ; 11 :1289 –1294 .16184558 \n65 Viget N Vernier-Massouille G Salmon-Ceron D \nOpportunistic infections in patients with inflammatory bowel disease: prevention and diagnosis . Gut \n2008 ; 57 :549 –558 .18178610 \n66 D’Haens GR Panaccione R Higgins PD \nThe London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? \nAm J Gastroenterol \n2011 ; 106 :199 –212 .quiz 213 .21045814 \n67 Checchin D Buda A Sgarabotto D \nRDI . Successful prophylaxis with valaciclovir for relapsing HSV-1 in a girl treated with infliximab for moderate Crohn's disease . Eur J Gastroenterol Hepatol \n2009 ; 21 :1095 –1096 .19430300 \n68 Kittai A Ali MA Borum M \nHerpes simplex virus blepharitis in a patient with Crohn's colitis . Am J Med \n2014 ; 127 :e1 –2 .\n69 Englund JA Zimmerman ME Swierkosz EM \nHerpes simplex virus resistant to acyclovir. A study in a tertiary care center . Ann Int Med \n1990 ; 112 :416 –422 .2155570\n\n",
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"mesh_terms": "D000328:Adult; D003092:Colitis; D003093:Colitis, Ulcerative; D003113:Colonoscopy; D004279:DNA, Viral; D006525:Hepatitis, Viral, Human; D006561:Herpes Simplex; D006801:Humans; D008297:Male; D018139:Simplexvirus; D014057:Tomography, X-Ray Computed",
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"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
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"title": "Concomitant herpes simplex virus colitis and hepatitis in a man with ulcerative colitis: Case report and review of the literature.",
"title_normalized": "concomitant herpes simplex virus colitis and hepatitis in a man with ulcerative colitis case report and review of the literature"
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"abstract": "Clinicopathologic and cytogenetic findings of an unusual EBV+ve, HHV8-ve germinotropic lymphoma, with a nongerminal center immunophenotype occurring in an immunocompetent individual, are presented. A comprehensive literature search revealed a single report of three similar cases. These may represent a unique subset of EBV-positive large B-cell lymphomas in immunocompetent individuals.",
"affiliations": "Department of Pathology Beth Israel Deaconess Medical Center Boston Massachusetts.;Department of Laboratory Medicine University of California San Francisco California.;Department of Cytogenetics Beth Israel Deaconess Medical Center Boston Massachusetts.",
"authors": "Asakrah|Saja K|SK|0000-0002-0037-2707;Bhargava|Parul|P|;Bryke|Christine R|CR|",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1713CCR31713Case ReportCase Reports\nEBV‐positive, HHV8‐negative large B‐cell lymphoma with an unusual germinotropic growth pattern in an immunocompetent patient ASAKRAH et al.Asakrah Saja K. http://orcid.org/0000-0002-0037-2707sasakrah@bidmc.harvard.edu \n1\nBhargava Parul \n2\nBryke Christine R. \n3\n\n1 \nDepartment of Pathology\nBeth Israel Deaconess Medical Center\nBoston\nMassachusetts\n\n2 \nDepartment of Laboratory Medicine\nUniversity of California\nSan Francisco\nCalifornia\n\n3 \nDepartment of Cytogenetics\nBeth Israel Deaconess Medical Center\nBoston\nMassachusetts\n* Correspondence: Saja K. Asakrah, Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215 (sasakrah@bidmc.harvard.edu).29 7 2018 9 2018 6 9 10.1002/ccr3.2018.6.issue-91818 1824 21 3 2018 19 6 2018 © 2018 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Key Clinical Message\nClinicopathologic and cytogenetic findings of an unusual EBV+ve, HHV8−ve germinotropic lymphoma, with a nongerminal center immunophenotype occurring in an immunocompetent individual, are presented. A comprehensive literature search revealed a single report of three similar cases. These may represent a unique subset of EBV‐positive large B‐cell lymphomas in immunocompetent individuals.\n\nEpstein‐Barr virusgerminotropicHHV8immunocompetentkaryotypelymphomanongerminal center source-schema-version-number2.0component-idccr31713cover-dateSeptember 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.7.1 mode:remove_FC converted:11.09.2018\n\n\nAsakrah \nSK \n, \nBhargava \nP \n, \nBryke \nCR \n. EBV‐positive, HHV8‐negative large B‐cell lymphoma with an unusual germinotropic growth pattern in an immunocompetent patient . Clin Case Rep . 2018 ;6 :1818 –1824 . 10.1002/ccr3.1713\n==== Body\n1 INTRODUCTION\nSeveral Epstein‐Barr virus (EBV)‐associated non‐Hodgkin B‐cell lymphomas have been described in the 2008 World Health Organization (WHO)1 classification of lymphoid disorders, and some have been further refined in the 2017 WHO update.2 These include entities that are EBV‐positive by definition, for example, EBV‐positive diffuse large B‐cell lymphoma, EBV‐positive mucocutaneous ulcer (provisional entity), lymphomatoid granulomatosis, and others where a significant proportion of cases have EBV expression such as Burkitt lymphoma, plasmablastic lymphoma, primary effusion lymphoma, and diffuse large B‐cell lymphoma associated with chronic inflammation. A majority of these occur in the context of primary or secondary immunodeficiency disorders and present with distinct clinicopathologic features.\n\nOf note, EBV‐positive diffuse large B‐cell lymphoma (NOS), previously known as EBV‐positive DLBCL of the elderly, can occur in young and immunocompetent patients with no history of any immunosuppressive disorders.3, 4, 5 Extranodal involvement and poor clinical outcome are common. Histologically, the lymphoma can present as either a monomorphic infiltrate of large atypical cells or a polymorphic infiltrate composed of atypical cell within a reactive background. The atypical cells are, by definition, EBV‐positive. They more frequently have a nongerminal center (GC) immunophenotypic profile, lacking CD10, and expressing IRF4/MUM1. CD30 expression has been reported and is associated with a worse outcome.6\n\n\nEBV‐positive large B‐cell lymphoma with an exclusive intrafollicular growth pattern has not been described in any of the above‐mentioned WHO entities. This pattern of growth is classically seen in HHV8‐positive, EBV‐positive, B‐cell lymphoma known as germinotropic lymphoproliferative disorder (GLPD). This lymphoproliferative disorder is seen in HIV‐negative individuals, usually presents as a lower stage disease and has an indolent clinical course. The large atypical infiltrating germinal centers have plasmablastic features, are negative for CD20, CD10, BCL6, CD138, show light chain restriction, but are polyclonal.7, 8\n\n\nAlthough our case has a germinotropic growth pattern and expresses EBV, unlike GLPD, the tumor cells lack HHV8 and have retained their B‐cell signature, expressing B‐cell markers‐like CD20. The lymphoma cells show a non‐GC immunophenotype and high‐proliferation index. Cases with similar features have been reported in a recent study,9 and we believe these represent a unique entity in the spectrum of EBV‐positive B‐cell lymphoma in immunocompetent individuals.\n\n2 CASE REPORT\nThe patient is an 84‐year‐old woman with a long‐standing history of mild leukopenia attributed to possible myelodysplastic syndrome, who presented with marked right leg swelling and hypercalcemia. Positron emission tomography (PET) scan showed FDG‐avid extensive axillary, left hilar, pelvic and inguinal lymphadenopathy. She was admitted and a lymph node biopsy from the left inguinal region was performed.\n\n3 MATERIALS AND METHODS\nThe lymph node biopsy was received fresh in pathology and processed according to the standard lymphoma protocol at our institution. A representative portion was submitted in RPMI media and sent for flow cytometry, and a separate fresh portion sent for cytogenetic analysis. The remainder was fixed in buffered formalin and embedded in paraffin. Hematoxylin and eosin stains were performed on 5‐Mm tissue sections.\n\n3.1 Immunohistochemical staining\nParaffin immunoperoxidase stains were performed on a DAKO autostainer (DAKO Agilent technologies, Santa Clara, CA, USA). The antibodies used in this study are the following: CD20, PAX5, CD30, CD10, BCL6, MUM1, CD21, CD23, CD2, CD7, CD4, CD8, MIB1 (ready to use antibodies, DAKO), CD15 (1/25 dilution, DAKO), CD3 (1/200 dilution, DAKO), CD5 (1/40 dilution, Nonvocastra Leica Biosystems Inc. 1700 Leider LaneBuffalo Grove, IL 60089 United States), HHV8 (ready to use antibody, Cell Marque, Rocklin, CA, USA), CXCL13, and PD1 performed at Neogenomics Laboratories (Fort Myers, FL, USA). In situ hybridization was performed using the DAKO probes against Epstein‐Barr virus (EBV) RNA.\n\n3.2 Flow cytometry\nTen‐color flow cytometric analysis was performed on a Navios© flow cytometer (Beckman Coulter, Indianapolis, IN, USA). The following antibodies were tested: Kappa, Lambda, ckappa, clambda, and CD antigens 2, 3, 4, 5, 7, 8, 10, 11c, 19, 20, 23, 34, 38, 45, and 56. The technical processing was performed at Neogenomics Laboratories (Fort Myers, FL, USA), where the test was developed and its performance characteristics determined. The professional interpretation of this test was completed at Beth Israel Deaconess Medical Center, Boston, MA, USA.\n\n3.3 Cytogenetic studies\nUnstimulated and 3‐day DSP30/IL2‐stimulated (B‐cell mitogen) cultures were set up for Giemsa‐banded metaphase chromosome analysis. A total of 20 mitotic cells were examined in detail. Fluorescence in situ hybridization was performed on uncultured cells, and a total of 200 nuclei were scored for each probe set used. These included dual color break apart probe sets for BCL6 and MYC, an IGH‐BCL2 dual color dual fusion translocation probe set, and a ATM and TP53 dual color probe set from Abbott Molecular (Abbott Park, IL, USA) and a IRF4 (MUM1) dual color break apart probe set and an IGH‐CCND3 dual color dual fusion translocation probe set from Leica Biosystems (Nussloch, Germany).\n\n4 RESULTS\n4.1 Pathologic findings\nThe lymph node (see Figure 1) architecture was effaced by vaguely nodular large cell aggregates composed mainly of large atypical centroblast‐like cells. Occasional polylobulated cells and cells with prominent cherry‐red nucleoli (Reed‐Sternberg‐like cells) were seen. Variably abundant background small lymphocytes with irregular nuclear outlines were present. Occasional mitoses and apoptotic cells were seen.\n\nFigure 1 \nEBV‐positive large B‐cell lymphoma with intrafollicular growth pattern. Hematoxylin and eosin stains show complete effacement of the lymph node architecture by large lymphoma cells, with a vague nodular growth pattern, ×20 (A) composed of atypical centroblasts (thin arrows), centrocytes (thick arrow), ×100 (B), and Hodgkin‐like cells (thin arrow) (C). By immunohistochemical stains, pan B‐cell marker CD20 highlights the nodular arrangement of neoplastic B cells (D) and CD23 (E) highlights prominent follicular dendritic meshwork throughout, ×20. The neoplastic cells are negative for CD10, ×20 (F), partially positive BCL6, ×50 (G), and MUM1, ×50 (H). Ki‐67 proliferation index is high, ×50 (I). A subset of the atypical B‐cells express CD30 in a Golgi‐like pattern, ×100 (J). In situ hybridization for Epstein‐Barr virus encoded RNA (EBER) shows positivity in large lymphoma cells, ×20 (K)\n\nBy immunohistochemical staining, the clusters of large cells were diffusely immunoreactive for pan B‐cell markers (CD20, PAX5). These B cells coexpress CD30, but were nonimmunoreactive for CD15 and ALK. They were CD10(−), with a subset expressing BCL6 and MUM1, in keeping with a nongerminal center immunophenotype (by Hans classifiers). The B‐cell‐rich nodular areas had background intact CD21 and CD23 immunoreactive follicular dendritic meshwork as well as admixed background small lymphocytes that were CXCL13 and PD1‐positive, in keeping with overrun germinal centers. The atypical large B cells were HHV8‐negative, but expressed EBV‐encoded RNA (ie, EBER+). No immunoreactivity was seen by in situ hybridization studies for kappa or lambda. A majority of the background small lymphocytes were T cells (CD2+, CD3+, CD5+, CD7+), predominantly CD4+, with fewer CD8+ T cells. By Ki‐67 staining, the proliferation index within the large B cells was approximately 80%.\n\n4.2 Flow cytometry\nThe concurrent flow cytometry did not detect clonal B cells by either light chain surface expression or cytoplasmic expression.\n\n4.3 Cytogenetics\nNine of the 20 metaphase lymph node cells analyzed had complex abnormal karyotypes. A composite karyotype of the cells is: 46‐47,XX,trp(1)(q21q25),t(3;5)(q27;q22),add(6)(q13),t(6;12;14) (p21.2;p13;q32),+12,add(13)(p11.2),del(13)(q12q14),add(14)(q32),hsr(14)(q32),add(15)(p11.2), add(19)(q13.3),del(20)(q13.1)[cp9]. Among the many aberrations were 6q−, trisomy 12, 13q−, and a variant of the t (6;14)(p21;q32) translocation also involving chromosome 12 that FISH demonstrated resulted in the IGH‐CCND3 gene rearrangement. Figure 2 shows a representative G‐banded metaphase cell and FISH with an IGH‐CCND3 dual color dual fusion probe set (Leica Biosystems) performed on the same cell. An IGH‐CCND3 fusion signal due to a t (6;12;14)(p21;p13;q32) is present on the short arm of the derivative chromosome 6.\n\nFigure 2 Cytogenetic findings of EBV‐positive large B‐cell lymphoma with intrafollicular growth pattern. A, Representative abnormal metaphase cell with 6q−, trisomy 12, 13q−, a variant of the t(6;14)(p21;q32) translocation also involving chromosome 12, and other chromosome aberrations. B, FISH with an IGH‐CCND3 dual color dual fusion probe set (Leica Biosystems) performed on the same metaphase cell. An IGH‐CCND3 fusion signal due to a t (6;12;14)(p21;p13;q32) is present on the short arm of the derivative chromosome 6 (yellow arrow). A normal red CCND3 signal is on the chromosome 6 with a deletion of the long arm. Green IGH signals are on the derivative chromosome 14 and the normal chromosome 14\n\nApproximately 15% of the uncultured interphase lymph node cells examined by FISH had an extra intact BCL6 signal, trisomy 12, deletion 13q14, and an IGH‐CCND3 fusion signal. There was no evidence of the IGH‐BCL2 gene rearrangement or rearrangements of the BCL6, MYC, and IRF4 (MUM1) genes. There was also no evidence of deletion of the ATM and TP53 genes.\n\n5 CLINICAL FOLLOW‐UP\nThe patient was treated with rituximab initially while awaiting final pathology report. Once lymphoma was confirmed, she received six cycles of rituximab combined with low‐dose of doxorubicin, cyclophosphamide, vincristine, and prednisone (R‐mini‐CHOP). Her chemotherapy course was complicated by pneumonia and respiratory failure after cycle 1. This was managed by antibiotics and resulted in a delay in cycle 2. She also had a delay in cycle 5 due to influenza B requiring admission.\n\nPositron emission tomography scans following cycle 6 showed significantly improved pelvic adenopathy, and resolution of splenomegaly. However, increased uptake in the right axillary nodes was noted, for which she received local radiotherapy. The patient was last seen at a follow‐up visit 1 month after the completion of radiation treatment. She was stable and in clinical remission.\n\n6 DISCUSSION\nWe describe a rare presentation of an EBV (+) HHV8(−)germinotropic large B‐cell lymphoma. A comprehensive work‐up including immunohistochemistry, flow cytometry, and cytogenetic analysis was performed. Our patient is HIV(−) with a clinical suspicion of low‐grade myelodysplasia and no other comorbidities. The lymphoma has a nongerminal center immunophenotype (by Hans classifiers). Cytogenetic analysis showed a complex abnormal karyotype including a variant of the t(6;14)(p21.2;q32) translocation which resulted in an IGH‐CCND3 gene rearrangement.\n\nWe conducted a comprehensive literature search to look for similar cases. Mackrides et al10 tested EBV expression in 382 cases of follicular lymphoma and identified 10 EBV‐positive follicular lymphomas (prevalence 2.6%). About 80% of these patients were immunocompetent and presented with lymphadenopathy and initial clinical stage between IIA and IVA. A diagnosis of follicular lymphoma was rendered based on the immunophenotype and follicular distribution. All the EBV‐positive cases were CD10‐positive and coexpressed BCL2. Most of these cases also expressed BCL6. CD30 expression was found in four of the 10 cases and demonstrated a strong intrafollicular expression with a distribution similar to the EBER expression. No Hodgkin‐Reed‐Sternberg‐like cells were reported. FISH studies for t(14;18) were available for only two cases which was positive in one case and negative in the other. Interestingly, 70% (7/10) of the EBV‐positive follicular lymphoma in this study showed high‐grade features (3A/3B) and the remainder 30% initially composed low‐grade histological criteria (grade 1‐2) then progressed to either high‐grade follicular lymphoma (3A) or diffuse large B‐cell lymphoma. Our case shares some histological and immunophenotypic features with some of the cases reported in the above study, including restricted intrafollicular growth pattern with increased atypical centroblasts, EBER, and CD30 expression. However, unlike the above cases, the morphologic findings are not that of a follicular lymphoma. The malignant intrafollicular B cells in our case are CD10 negative and have a nongerminal center immunophenotype with partial expression of MUM1 and BCL6. No BCL2 rearrangement was seen on cytogenetic analysis. Therefore, a diagnosis of EBV‐positive follicular lymphoma is unlikely in our case.\n\nIn another recent study, Lorenzi et al9 reported three cases of EBV‐positive intrafollicular lymphoma with nongerminal center immunophenotype and considered them as a variant of germinotropic lymphoproliferative disorder. Similar to our case, all three patients reported by Lorenzi were immunocompetent and presented with an advanced clinical stage (IIIsB‐IVB). The lymph node architecture in all three cases was completely or partially effaced by a nodular lymphoid infiltrate. No normal follicles were identified. The atypical follicles were composed of large cells including immunoblasts, centroblasts, and Hodgkin‐Reed‐Sternberg‐like cells. All follicles had follicular dendritic meshwork that variably expressed CD21, CD23, CXCL13, Clusterin, Claudin 4, and EGFR. The atypical cells were strongly positive for B‐cell marker CD20 with coexpression of CD30, MUM1, and CXCR5. CD10 was mostly negative and showed <25% positivity in one of the cases. BCL6 staining was variable among the cases. EBV was expressed mainly within the atypical follicles. Ki‐67 proliferation index was high within the follicles and approached 70%. FISH analysis reported for BCL2, MYC, BCL6, and PAX5 genes did not show any chromosomal rearrangements or other aberration. By immunohistochemistry, atypical large B cells showed increased c‐MYC and STAT3 expression. Similar to the cases reported by Lorenzi et al, the B‐cell lymphoma in our case shows a germinotropic growth pattern, has a nongerminal center immunophenotype by Hans algorithm and a high‐proliferation index by Ki‐67 (80%). We have summarized the clinicopathologic features of all these four reported cases in Table 1. The present case additionally had fresh tissue submitted for metaphase chromosome analysis which showed a complex abnormal karyotype with a rearrangement of chromosome 3 resulting in gain of BCL6, trisomy 12, deletion 13q, a translocation involving chromosomes 6, 12, and 14 resulting in the IGH‐CCND3 gene rearrangement, and several other chromosome aberrations (see Figure 2).\n\nTable 1 Summary of clinicopathologic findings of reported patients with germinotropic, EBV (+), HHV8 (−) lymphomas\n\nReference\tAge/Sex\tClinical\tEBV\tHHV8\tB‐cell markers\tImmunoglobulin light chains\tCOO\tHIV\tTreatment\tFollow‐up\t\nVirchows Arch (2016) 468:441‐450\t66/M\tMediastinal, retroperitoneal, axillary, inguinal LAD, splenomegaly\t+\t−\tCD20, PAX5,\tPolyclonal\tNon‐GC\t−\tR‐CHOP\tDOD, 18 m\t\nVirchows Arch (2016) 468:441‐450\t77/F\tCervical & abdominal LAD, splenomegaly, bone\t+\t−\tCD20, PAX5,\tKappa restricted\tNon‐GC\t−\tR\tAWD, 12 m\t\nVirchows Arch (2016) 468:441‐450\t63/F\tSupra‐diaphragmatic & mesenteric LAD, bone\t+\t−\tCD20, PAX5,\tPolyclonal\tNon‐GC\t−\tR‐CHOP\tNED, 28 m\t\nOur case\t84/F\tAxillary, left hilar, pelvic and inguinal lymphadenopathy\t+\t−\tCD20+, PAX5+\tNo surface or cytoplasmic immunoglobulin\tNon‐GC\t−\tR‐CHOP & local radiation\tNED, 1 m\t\nAWD, alive and well with disease; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; COO, cell of origin; DOD, dead of disease; NED, no evidence of disease; GC, germinal center; HIV, human immunodeficiency virus; R, rituximab.\n\nJohn Wiley & Sons, LtdIn conclusion, we report a rare case of a high‐grade B‐cell lymphoma with an exclusive intrafollicular growth pattern that is EBV‐positive, HHV8‐negative, in an immunocompetent patient. A comprehensive work‐up including karyotypic analysis is presented. The recent WHO 2016 update does not describe such cases and no specific categorization for such cases exists. Together with the three cases reported by Lorenzi et al, such cases may represent a unique subtype of EBV‐positive, HHV8‐negative diffuse large B‐cell lymphoma.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHORSHIP\nPB (primary hematopathologist): evaluated the histopathology of the lymph node, conducted immunophenotypic work‐up, and formulated the pathologic diagnosis. She helped in writing and editing the case report. SA (pathologist): gathered all the clinicopathologic information regarding the case and took photomicrographs. She wrote the primary draft of the manuscript. CB (primary cytogeneticist): evaluated the karyotypic findings and conducted further FISH work‐up on tissue from this case. She provided the cytogenetic findings on the case including the corresponding karyotype and FISH images.\n==== Refs\nREFERENCES\n1 \n\nSwerdlow \nS \n, \nCampo \nE \n, \nHarris \nNL \n, et al. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues . Lyon, France : International agency for research on Cancer ; 2008 .\n2 \n\nSwerdlow \nS \n, \nCampo \nE \n, \nHarris \nNL \n, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues . Lyon, France : International agency for research on cancer ; 2017 .\n3 \n\nBeltran \nBE \n, \nMorales \nD \n, \nQuiñones \nP \n, \nMedeiros \nLJ \n, \nMiranda \nRN \n, \nCastillo \nJJ \n. EBV‐positive diffuse large B‐cell lymphoma in young immunocompetent individuals . Clin Lymphoma Myeloma Leuk . 2011 ;11 :512 ‐516 .21889434 \n4 \n\nEditor \nC \n, \nTefferi \nA \n, \nCastilllo \nJJ \n, et al. CME Information: EBV‐positive diffuse large B‐cell lymphoma of the elderly: 2016 update on diagnosis, risk‐stratification and management . Instructions on Receiving Credit. 10.1002/ajh.09105 \n\n5 \n\nOk \nCY \n, \nLi \nL \n, \nXu‐Monette \nZY \n, et al. Prevalence and clinical implications of Epstein‐Barr virus infection in de Novo diffuse large B‐cell lymphoma in western countries . Clin Cancer Res . 2014 ;20 :2338 ‐2349 .24583797 \n6 \n\nLu \nT‐X \n, \nLiang \nJ‐H \n, \nMiao \nY \n, et al. Epstein‐Barr virus positive diffuse large B‐cell lymphoma predict poor outcome, regardless of the age . Sci Rep . 2015 ;5 :12168 .26202875 \n7 \n\nBhavsar \nT \n, \nLee \nJC \n, \nPerner \nY \n, et al. KSHV‐associated and EBV‐associated germinotropic lymphoproliferative disorder new findings and review of the literature . Am J Surg Pathol . 2017 ;41 :795 ‐800 .28248818 \n8 \n\nDu \nMQ \n, \nDiss \nTC \n, \nLiu \nH \n, et al. KSHV‐ and EBV‐associated germinotropic lymphoproliferative disorder . Blood . 2002 ;100 :3415 ‐3418 .12384445 \n9 \n\nLorenzi \nL \n, \nLonardi \nS \n, \nEssatari \nMHM \n, et al. Intrafollicular Epstein‐Barr virus‐positive large B cell lymphoma. A variant of “germinotropic” lymphoproliferative disorder . Virchows Arch . 2016 ;468 :441 ‐450 .26762526 \n10 \n\nMackrides \nN \n, \nCampuzano‐Zuluaga \nG \n, \nMaque‐Acosta \nY \n, et al. Epstein‐Barr virus‐positive follicular lymphoma . Mod Pathol . 2017 ;30 :519 ‐529 .27982024\n\n",
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"title": "EBV-positive, HHV8-negative large B-cell lymphoma with an unusual germinotropic growth pattern in an immunocompetent patient.",
"title_normalized": "ebv positive hhv8 negative large b cell lymphoma with an unusual germinotropic growth pattern in an immunocompetent patient"
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"abstract": "This report details prominent neuropsychiatric features in one family with an ADCY5 gene mutation. ADCY5 mutations cause a variable motor phenotype, though most cases have some core involuntary movement features. The psychiatric aspects of the disorder have not been emphasised in previous publications. We discuss possible pathogenesis.",
"affiliations": "Department of Neurology, Royal Free, London, UK. Electronic address: nirosenv@gmail.com.;Department of Neurology, Leeds General Infirmary, Leeds, UK.;Department of Neuroscience, Monash Medical Centre, Australia. Electronic address: peter.kempster@monashhealth.org.",
"authors": "Vijiaratnam|Nirosen|N|;Newby|Rachel|R|;Kempster|Peter A|PA|",
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"mesh_terms": "D000262:Adenylyl Cyclases; D000328:Adult; D003863:Depression; D020820:Dyskinesias; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D011618:Psychotic Disorders",
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"title": "Depression and psychosis in ADCY5-related dyskinesia-part of the phenotypic spectrum?",
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"abstract": "COVID-19 is a relatively new and rapidly emerging disease. Given current knowledge of the disease process, it is of the utmost importance to gain further insight into its different clinical manifestations. In this report we describe three cases involving Hispanic males with COVID-19 all of whom developed pneumomediastinum during their hospital course. We want to emphasize the importance of this adverse event despite their non-smoking history and the exclusion of positive pressure ventilation. Frequent chest radiographs help with early recognition of this disease process. Early detection of pneumomediastinum is important as this could lead to worse morbidity if left unrecognized despite its usually benign nature.",
"affiliations": "Fellow pulmonary/critical care, Nassau University Medical Center 2201 Hempstead turnpike East Meadow, NY 11554 USA. Electronic address: alexdiazdo@gmail.com.;Fellow pulmonary/critical care, Nassau University Medical Center 2201 Hempstead turnpike East Meadow, NY 11554 USA.;Fellow pulmonary/critical care, Nassau University Medical Center 2201 Hempstead turnpike East Meadow, NY 11554 USA.;Director of medical intensive care unit, Associate program director of pulmonary and critical care fellowship program, Assistant professor of medicine at Hofstra/Northwell, Nassau University Medical Center 2201 Hempstead turnpike East Meadow, NY 11554 USA.",
"authors": "Diaz|Alex|A|;Patel|Dolly|D|;Sayedy|Najia|N|;Anjum|Fatima|F|",
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"mesh_terms": "D000086382:COVID-19; D006801:Humans; D007385:Intermittent Positive-Pressure Ventilation; D008297:Male; D008478:Mediastinal Emphysema; D000086402:SARS-CoV-2; D013352:Subcutaneous Emphysema",
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"title": "COVID-19 and Spontaneous Pneumomediastinum: A case series.",
"title_normalized": "covid 19 and spontaneous pneumomediastinum a case series"
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"abstract": "BACKGROUND\nThe incidence of periprosthetic fractures after total knee arthroplasty (TKA) is rising due to the increasing number of TKAs performed annually and the growing elderly population. A periprosthetic fracture of the proximal tibia following TKA is a rare injury that may be a challenging clinical scenario.\n\n\nMETHODS\nThe case of an 84-year-old woman who sustained a periprosthetic tibial fracture 10 years after a TKA is presented. This patient had multiple risk factors. The fracture was not deemed amenable to conventional treatment because the bone fragment was too small. This patient underwent fixation of her tibial fracture above the TKA using a five-ring Ilizarov external fixator. This allowed immediate full weight-bearing. The fixator was removed at 12 weeks, at which time the fracture was solidly healed. At the most recent follow-up, 2 years from injury, she was fully weight-bearing without walking aids and had a knee range of motion (ROM) of 0-110°.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this is the first report in which Ilizarov external fixation has been used for a periprosthetic tibial fracture after TKA.",
"affiliations": "Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan. kk-nozaka@mue.biglobe.ne.jp.;Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.;Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.;Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.",
"authors": "Nozaka|Koji|K|http://orcid.org/0000-0003-0238-8929;Miyakoshi|Naohisa|N|;Sato|Takeshi|T|;Shimada|Yoichi|Y|",
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"doi": "10.1186/s12891-020-3176-x",
"fulltext": "\n==== Front\nBMC Musculoskelet Disord\nBMC Musculoskelet Disord\nBMC Musculoskeletal Disorders\n1471-2474 BioMed Central London \n\n3176\n10.1186/s12891-020-3176-x\nCase Report\nIlizarov external fixation for a periprosthetic tibial fracture in severe osteoporosis: a case report\nhttp://orcid.org/0000-0003-0238-8929Nozaka Koji kk-nozaka@mue.biglobe.ne.jp Miyakoshi Naohisa miyakosh@doc.med.akita-u.ac.jp Sato Takeshi nozakak@med.akita-u.ac.jp Shimada Yoichi koji4591114213@gmail.com 0000 0001 0725 8504grid.251924.9Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543 Japan \n4 3 2020 \n4 3 2020 \n2020 \n21 14531 12 2019 27 2 2020 © The Author(s). 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons 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\nThe incidence of periprosthetic fractures after total knee arthroplasty (TKA) is rising due to the increasing number of TKAs performed annually and the growing elderly population. A periprosthetic fracture of the proximal tibia following TKA is a rare injury that may be a challenging clinical scenario.\n\nCase presentation\nThe case of an 84-year-old woman who sustained a periprosthetic tibial fracture 10 years after a TKA is presented. This patient had multiple risk factors. The fracture was not deemed amenable to conventional treatment because the bone fragment was too small. This patient underwent fixation of her tibial fracture above the TKA using a five-ring Ilizarov external fixator. This allowed immediate full weight-bearing. The fixator was removed at 12 weeks, at which time the fracture was solidly healed. At the most recent follow-up, 2 years from injury, she was fully weight-bearing without walking aids and had a knee range of motion (ROM) of 0–110°.\n\nConclusion\nTo the best of our knowledge, this is the first report in which Ilizarov external fixation has been used for a periprosthetic tibial fracture after TKA.\n\nKeywords\nPeriprosthetic tibial fractureTotal knee arthroplastyIlizarov external fixatorissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nThe incidence of periprosthetic fractures after total knee arthroplasty (TKA) is rising due to the increasing number of TKAs performed annually and the growing elderly population. Periprosthetic fractures after TKA are an increasing problem and challenging to treat. Periprosthetic fractures of the tibia, or fractures below TKAs, are less common than periprosthetic fractures of the distal femur. However, the literature on the outcomes of periprosthetic tibial fractures treated with modern techniques is limited.\n\nCase report\nThe case of an 84-year-old woman who sustained a periprosthetic tibial fracture as a result of a fall from standing height (Felix classification type IIA [1]) 10 years after a left TKA is presented (Fig. 1). A posterior-stabilized total knee prosthesis (NexGen LPS-Flex system) was used. The patient was unable to walk due to severe knee pain after the injury. She had severe rheumatoid arthritis (Steinbrocker class III), hypertension, diabetes mellitus, and glucocorticoid-induced osteoporosis. Her medications included methotrexate 8 mg/week, prednisolone 10 mg/day, and intravenous alendronate once monthly. A baseline dual-energy X-ray absorptiometry scan showed that her femoral neck bone mineral density was 0.31 g/cm2. The patient was also at high risk for general anesthesia due to severe heart failure and renal failure. She was neurovascularly intact distally. Thus, the decision was made to apply a circular thin-wire external fixator with only an epidural block.\nFig. 1 a Preoperative antero-posterior X-ray. b Preoperative lateral angle X-ray\n\n\n\nA five-ring Ilizarov external fixator was applied, using thin wires (1.8 mm) under fluoroscopic guidance. The frame was placed to span the knee joint. Postoperative radiographs showed satisfactory reduction of the fracture fragments (Fig. 2). The total operating time was 90 min. The patient began full weight-bearing immediately, and knee range of motion (ROM) exercises were started at postoperative 2 weeks after femoral ring removal. Radiographs at 8 weeks showed good callus formation. The fixator was removed at 12 weeks. Though the bone defect vacancy had sunk after reduction, and the posterior tilt was increased, there were no particular clinical symptoms due to the increased posterior tilt (Fig. 3). This patient was allowed to walk with full weight-bearing immediately after surgery. A knee joint-spanning external fixator was used, the femoral ring was removed 2 weeks after surgery, and ROM exercises were started. At follow-up, 14 months after injury, she was mobilizing independently, with a knee range of movement of 0–110°. During the 12 weeks in the fixator, there was only one superficial pin-tract infection, which was treated with empirical oral antibiotics and daily pin-tract dressings.\nFig. 2 a Postoperative antero-posterior X-ray. b Postoperative lateral angle X-ray\n\n\nFig. 3 a After ring removal, antero-posterior X-ray. b After ring removal, lateral angle X-ray\n\n\n\nSurgical technique\nThere was fracture site instability and a medial spike. Therefore, the skin on the medial side of the fracture site was in poor condition. Reduction by manual manipulation alone was impossible. First, two straight wires were inserted into the proximal tibia and attached to the proximal 5/8 ring. The surgeon used the lateral fluoroscopic view to identify a safe starting point and inserted the wire from the front and back of the tibial TKA component without touching the stem (Fig. 4). Two straight wires were then inserted into the distal tibia and attached to the full ring. The middle two full rings were left free near the distal ring so that they did not interfere when checking reduction of the fracture area. An assistant held the proximal ring, and the surgeon moved the distal tibia ring anchored to the proximal tibia in distraction, flexion, extension, valgus, and varus. This maneuver was gently and carefully repeated over time. By relieving the “jamming” of the fracture area by longitudinal traction with a large force with the tibial ring, most of the dislocation could be reduced by closed manipulation with accurate alignment. By using ligamentotaxis, reduction was possible from the outside of the body.\nFig. 4 a, b The surgeon uses the lateral fluoroscopic view to identify a safe starting point and inserts the wire from the front and back of the tibial TKA component (arrow) without touching the stem\n\n\n\nAfter reduction, the two full rings, which were left free between the proximal ring and the most distal ring, were moved near the fracture site and fixed with straight wires. In addition, three straight wires were added to the proximal ring in the tibia for increased fixation.\n\nFinally, the parts of the rods for ligament traction that protruded distally were cut so that they did not interfere with rehabilitation.\n\nDiscussion and conclusions\nPeriprosthetic fractures of the tibia, or fractures below TKAs, are less common than periprosthetic fractures of the distal femur, with a prevalence of between 0.4 and 1.7% [1–3]. Many authors have reported several fixation options to treat these difficult fractures [4–7]. However, no consensus exists regarding the optimal fixation for periprosthetic tibial fractures.\n\nThis case did not require a skin incision for reduction, and the osteosynthesis could be completed by closed reduction with an extracorporeal operation using the ligament traction method with an Ilizarov external fixator. The frame was constructed to span the knee joint, with the joint held in extension. After 2 weeks, the patient started knee ROM exercises after femoral frame removal.\n\nAn Ilizarov external fixator is an adequate treatment option that a surgeon should have in mind for the management of very elderly and debilitated patients with periprosthetic tibial fractures.\n\nThere have been some reports of Ilizarov external fixation for the treatment of periprosthetic fractures of the distal femur [7, 8]. Robin et al. reported that an Ilizarov external fixator is indicated in an elderly patient with periprosthetic fractures of the distal femur with extremely osteopenic bone [8].\n\nSome studies have reported that a major advantage of Ilizarov external fixation is the ability to achieve rigid fixation for osteoporotic bones, which can be obtained through the insertion of multiple thin, straight wires [7–9]. Beris et al. reported that Ilizarov external fixation is a feasible and effective treatment option, because it provides stable fixation, prompt postoperative mobilization, and has no major complications, especially in elderly patients treated for periprosthetic fractures [7]. Furthermore, gentle closed reduction and fixation are beneficial for effective bone union in terms of biological characteristics and vascularization of the fracture area [10]. Since long-term non-weight-bearing leads to reduced walking ability in older patients, walking with an Ilizarov external fixator with strong fixation immediately after surgery may greatly benefit them, and mechanical stimulation by weight-bearing may have additional effects [11].\n\nThere is a risk of pin-tract infections with this approach. When treating periprosthetic fractures around the knee with an Ilizarov external fixator, meticulous pin care and immediate treatment with antibiotics are necessary at any sign of infection [8]. In addition, walking with an Ilizarov external fixator is difficult. However, this method is very promising because it is minimally invasive with low intraoperative blood loss and minimal patient discomfort.\n\nSchreiner et al. reported that periprosthetic tibial fractures predominantly affect elderly patients with reduced bone quality and have a high complication rate [12]. Osteoporosis makes the use of internal fixation devices for periprosthetic tibial fractures more challenging in elderly patients [9, 12].\n\nIlizarov external fixation provides stable fixation, prompt postoperative mobilization, and has no major complications. It provides the postoperative capability for malalignment correction, and in the hands of an expert, Ilizarov external fixation is not time-consuming [8, 13].\n\nIn the present case, the fracture occurred in a patient with severe rheumatoid arthritis, osteoporosis, and heart failure. Kim et al. reported that osteoporosis, such as that which occurs with old age, rheumatoid arthritis, and use of corticosteroids, is a risk factor for periprosthetic tibial fractures [4].\n\nTreatment options for periprosthetic tibial fractures include using a knee immobilizer, traction, casting, open reduction and internal fixation with a plate-and-screw construct, revision arthroplasty, and amputation [14–18]. In the present case, the decision to place an Ilizarov external thin-wire fixator as minimally invasive surgery was made due to the patient’s severe heart failure and renal failure. With periprosthetic tibial fractures in cases of severe osteoporosis, there is the option of revision arthroplasty with a long stem, but this was not deemed suitable in the present case due to the high risk of general anesthesia. Open reduction and internal fixation were considered, but poor bone quality and the relatively small distal fragment, which would not allow adequate screw fixation, resulted in the Ilizarov external fixator being used. The decision was made to place the device to allow immediate full weight-bearing.\n\nAbbreviations\nROMRange of motion\n\nTKATotal knee arthroplasty\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nKN performed the surgery. MN helped with surgery and helped to draft the manuscript. TS and YS helped draft the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThe author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThe patient received prior information before providing her written, informed consent in accordance with the Declaration of Helsinki. The article was approved by the ethics committee of Akita University Hospital (registration number 1970).\n\nConsent for publication\nWritten, informed consent was obtained from the patient for publication of this article and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Felix NA Stuart MJ Hanssen AD Periprosthetic fractures of the tibia associated with total knee arthroplasty Clin Orthop Relat Res 1997 345 113 124 10.1097/00003086-199712000-00016 \n2. Jeong GK Pettrone SK Liporace FA Meere PA “Floating total knee”: ipsilateral periprosthetic fractures of the distal femur and proximal tibia after total knee arthroplasty J Arthroplast 2006 21 1 138 140 10.1016/j.arth.2004.10.017 \n3. Chmell MJ Moran MC Scott RD Periarticular fractures after total knee arrthroplasty: principles of management J Am Acad Orthop Surg 1996 4 2 109 116 10.5435/00124635-199603000-00006 10795045 \n4. Kim HJ Park KC Kim JW Oh CW Kyung HS Oh JK Park KH Yoon SD Successful outcome with minimally invasive plate osteosynthesis for periprosthetic tibial fracture after total knee arthroplasty Orthop Traumatol Surg Res 2017 103 2 263 268 10.1016/j.otsr.2016.10.007 27890690 \n5. Platzer P Schuster R Aldrian S Prosquill S Krumboeck A Zehetgruber I Kovar F Schwameis K Vécsei V Management and outcome of periprosthetic fractures after total knee arthroplasty J Trauma 2010 68 6 1464 1470 10.1097/TA.0b013e3181d53f81 20539190 \n6. Nagwadia H Joshi P Outcome of osteosynthesis for periprosthetic fractures after total knee arthroplasty: a retrospective study Eur J Orthop Surg Traumatol 2018 28 4 683 690 10.1007/s00590-017-2121-7 29299767 \n7. Beris AE Lykissas MG Sioros V Mavrodontidis AN Korompilias AV Femoral periprosthetic fracture in osteoporotic bone after a total knee replacement:treatment with Ilizarov external fixation J Arthroplasty 2010 25 7 1168.e9 1168.12 10.1016/j.arth.2009.10.009 \n8. Robin G Simon DO Brinker M Use of Ilizarov external fixation for a periprosthetic supracondylar femur fracture J Arthroplast 1999 14 1 118 121 10.1016/S0883-5403(99)90214-0 \n9. Iliopoulos E Morrissey N Cho S Khaleel A Outcomes of the Ilizarov frame use in elderly patients J Orthop Sci 2017 22 4 783 786 10.1016/j.jos.2017.03.002 28365167 \n10. Brunner UH Cordey J Schweiberer L Perren SM Force required for bone segment transport in the treatment of large bone defects using medullary nail fixation Clin Orthop Relat Res 1994 301 147 155 \n11. Nozaka K Miyakoshi N Kashiwagura T Kasukawa Y Saito H Kijima H Chida S Tsuchie H Shimada Y Effectiveness of distal tibial osteotomy with distraction arthroplasty in varus ankle osteoarthritis BMC Musculoskelet Disord 2020 21 1 31 10.1186/s12891-020-3061-7 31937287 \n12. Schreiner AJ Schmidutz F Ateschrang A Ihle C Stöckle U Ochs BG Gonser C Periprosthetic tibial fractures in total knee arthroplasty - an outcome analysis of a challenging and underreported surgical issue BMC Musculoskelet Disord 2018 19 1 323 10.1186/s12891-018-2250-0 30200931 \n13. Morwood MP Gebhart SS Zamith N Mir HR Outcomes of fixation for periprosthetic tibia fractures around and below total knee arthroplasty Injury 2019 50 4 978 982 10.1016/j.injury.2019.03.014 30929804 \n14. Kuzyk PRT Watts E Backstein D Revision total knee arthroplasty for the management of periprosthetic fractures J Am Acad Orthop Surg 2017 25 9 624 633 10.5435/JAAOS-D-15-00680 28837455 \n15. Yoo JD Kim NK Periprosthetic fractures following total knee arthroplasty Knee Surg Relat Res 2015 27 1 1 9 10.5792/ksrr.2015.27.1.1 25750888 \n16. Agarwal S Sharma RK Jain JK Periprosthetic fractures after total knee arthroplasty J Orthop Surg (Hong Kong) 2014 22 1 24 29 10.1177/230949901402200108 24781608 \n17. Born CT Gil JA Johnson JP Periprosthetic tibial fractures J Am Acad Orthop Surg 2018 26 e167 e172 10.5435/JAAOS-D-16-00387 29528870 \n18. Borade A Sanchez D Kempegowda H Maniar H Pesantez RF Suk M Horwitz DS Minimally invasive plate Osteosynthesis for Periprosthetic and Interprosthetic fractures associated with knee Arthroplasty: surgical technique and review of current literature J Knee Surg 2019 32 5 392 402 10.1055/s-0039-1683443 30921821\n\n",
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"issn_linking": "1471-2474",
"issue": "21(1)",
"journal": "BMC musculoskeletal disorders",
"keywords": "Ilizarov external fixator; Periprosthetic tibial fracture; Total knee arthroplasty",
"medline_ta": "BMC Musculoskelet Disord",
"mesh_terms": "D000369:Aged, 80 and over; D019645:Arthroplasty, Replacement, Knee; D016267:External Fixators; D005260:Female; D006801:Humans; D010024:Osteoporosis; D058866:Osteoporotic Fractures; D057068:Periprosthetic Fractures; D012720:Severity of Illness Index; D013978:Tibial Fractures",
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"pubdate": "2020-03-04",
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"title": "Ilizarov external fixation for a periprosthetic tibial fracture in severe osteoporosis: a case report.",
"title_normalized": "ilizarov external fixation for a periprosthetic tibial fracture in severe osteoporosis a case report"
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"abstract": "SQUIRE demonstrated addition of necitumumab to gemcitabine and cisplatin significantly improved survival in patients with stage IV sq-NSCLC. Here, we report additional outcomes for the subpopulation of patients with tumor epidermal growth factor receptor (EGFR) protein expression.\n\n\n\nPatients with pathologically confirmed stage IV sq-NSCLC were randomized 1:1 to receive a maximum of six 3-week cycles of gemcitabine (1250 mg/m(2) i.v., days 1 and 8) and cisplatin (75 mg/m(2) i.v., day 1) chemotherapy with or without necitumumab (800 mg i.v., days 1 and 8). Patients in the chemotherapy plus necitumumab group with no progression continued on necitumumab alone until disease progression or intolerable toxicity. SQUIRE included mandatory tissue collection. EGFR protein expression was detected by immunohistochemistry (IHC) in a central laboratory. Exploratory analyses were pre-specified for patients with EGFR protein expressing (EGFR > 0) and non-expressing (EGFR = 0) tumors.\n\n\n\nA total of 982 patients [90% of intention-to-treat (ITT)] had evaluable IHC results. The large majority of these patients (95%) had tumor samples expressing EGFR protein; only 5% had tumors without detectable EGFR protein. Overall survival (OS) for EGFR > 0 patients was significantly longer in the necitumumab plus gemcitabine-cisplatin group than in the gemcitabine-cisplatin group {stratified hazard ratio (HR) 0.79 [95% confidence interval (CI) 0.69, 0.92; P = 0.002]; median 11.7 months (95% CI 10.7, 12.9) versus 10.0 months (8.9, 11.4)}. Additionally, an OS benefit was seen in all pre-specified subgroups in EGFR > 0 patients. However, OS HR for EGFR = 0 was 1.52. Adverse events of interest with the largest difference between treatment groups in EGFR > 0 patients (Grade ≥3) were hypomagnesemia (10% versus <1%) and skin rash (6% versus <1%).\n\n\n\nIn line with SQUIRE ITT, addition of necitumumab to gemcitabine-cisplatin significantly prolonged OS and was generally well tolerated in the subpopulation of patients with EGFR-expressing advanced sq-NSCLC. The benefit from addition of necitumumab to chemotherapy was not apparent in this analysis for the small subgroup of patients with non-EGFR-expressing tumors.\n\n\n\nNCT00981058.",
"affiliations": "Department of Medical Oncology, Hospital Universitario Doce de Octubre & CNIO, Madrid, Spain lpazaresr@seom.org.;Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, USA.;Oncology Clinical Development, Eli Lilly and Company, Bridgewater, USA.;Oncology Patient Tailoring, Eli Lilly and Company, Indianapolis, USA.;Global Statistical Science, Oncology, Eli Lilly and Company, Bad Homburg, Germany.;Oncology Clinical Development, Eli Lilly and Company, Bad Homburg, Germany.;Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, USA.;Department of Medical Oncology, The Christie Hospital, Manchester, UK.;Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, USA.",
"authors": "Paz-Ares|L|L|;Socinski|M A|MA|;Shahidi|J|J|;Hozak|R R|RR|;Soldatenkova|V|V|;Kurek|R|R|;Varella-Garcia|M|M|;Thatcher|N|N|;Hirsch|F R|FR|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; D003841:Deoxycytidine; C527969:necitumumab; C056507:gemcitabine; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin",
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"fulltext": "\n==== Front\nAnn OncolAnn. OncolannoncannoncAnnals of Oncology0923-75341569-8041Oxford University Press 10.1093/annonc/mdw214mdw214Original ArticlesThoracic TumorsEditor's choiceCorrelation of EGFR-expression with safety and efficacy outcomes in SQUIRE: a randomized, multicenter, open-label, phase III study of gemcitabine–cisplatin plus necitumumab versus gemcitabine–cisplatin alone in the first-line treatment of patients with stage IV squamous non-small-cell lung cancer Paz-Ares L. 1*Socinski M. A. 2Shahidi J. 3Hozak R. R. 4Soldatenkova V. 5Kurek R. 6Varella-Garcia M. 7Thatcher N. 8Hirsch F. R. 71 Department of Medical Oncology, Hospital Universitario Doce de Octubre & CNIO, Madrid, Spain2 Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, USA3 Oncology Clinical Development, Eli Lilly and Company, Bridgewater, USA4 Oncology Patient Tailoring, Eli Lilly and Company, Indianapolis, USA5 Global Statistical Science, Oncology, Eli Lilly and Company, Bad Homburg, Germany6 Oncology Clinical Development, Eli Lilly and Company, Bad Homburg, Germany7 Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, USA8 Department of Medical Oncology, The Christie Hospital, Manchester, UK* Correspondence to: Dr Luis Paz-Ares, Department of Medical Oncology, University Hospital 12 De Octubre, Madrid, Spain. Tel: +34-913908349; Fax: +34-914603310; E-mail: lpazaresr@seom.org8 2016 20 5 2016 20 5 2016 27 8 1573 1579 19 2 2016 5 5 2016 13 5 2016 © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.2016This 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.comSQUIRE was a phase III study of gemcitabine and cisplatin with or without necitumumab in patients with metastatic squamous NSCLC. The majority of SQUIRE patients had EGFR protein expressing tumors. Similar to SQUIRE ITT, patients with EGFR protein expressing tumors benefitted from addition of necitumumab to chemotherapy with a safety profile consistent with that of the overall SQUIRE population.\n\nBackground\nSQUIRE demonstrated addition of necitumumab to gemcitabine and cisplatin significantly improved survival in patients with stage IV sq-NSCLC. Here, we report additional outcomes for the subpopulation of patients with tumor epidermal growth factor receptor (EGFR) protein expression.\n\nPatients and methods\nPatients with pathologically confirmed stage IV sq-NSCLC were randomized 1:1 to receive a maximum of six 3-week cycles of gemcitabine (1250 mg/m2 i.v., days 1 and 8) and cisplatin (75 mg/m2 i.v., day 1) chemotherapy with or without necitumumab (800 mg i.v., days 1 and 8). Patients in the chemotherapy plus necitumumab group with no progression continued on necitumumab alone until disease progression or intolerable toxicity. SQUIRE included mandatory tissue collection. EGFR protein expression was detected by immunohistochemistry (IHC) in a central laboratory. Exploratory analyses were pre-specified for patients with EGFR protein expressing (EGFR > 0) and non-expressing (EGFR = 0) tumors.\n\nResults\nA total of 982 patients [90% of intention-to-treat (ITT)] had evaluable IHC results. The large majority of these patients (95%) had tumor samples expressing EGFR protein; only 5% had tumors without detectable EGFR protein. Overall survival (OS) for EGFR > 0 patients was significantly longer in the necitumumab plus gemcitabine–cisplatin group than in the gemcitabine–cisplatin group {stratified hazard ratio (HR) 0.79 [95% confidence interval (CI) 0.69, 0.92; P = 0.002]; median 11.7 months (95% CI 10.7, 12.9) versus 10.0 months (8.9, 11.4)}. Additionally, an OS benefit was seen in all pre-specified subgroups in EGFR > 0 patients. However, OS HR for EGFR = 0 was 1.52. Adverse events of interest with the largest difference between treatment groups in EGFR > 0 patients (Grade ≥3) were hypomagnesemia (10% versus <1%) and skin rash (6% versus <1%).\n\nConclusions\nIn line with SQUIRE ITT, addition of necitumumab to gemcitabine–cisplatin significantly prolonged OS and was generally well tolerated in the subpopulation of patients with EGFR-expressing advanced sq-NSCLC. The benefit from addition of necitumumab to chemotherapy was not apparent in this analysis for the small subgroup of patients with non-EGFR-expressing tumors.\n\nClinical Trial\nNCT00981058.\n\nEGFR expressingnecitumumabsquamous NSCLCSQUIREEli Lilly and Company\n==== Body\nintroduction\nAdvanced squamous non-small-cell lung cancer (NSCLC) imposes a heavy worldwide burden [1]. Prognosis is typically poor and the majority of patients are diagnosed with locally advanced or metastatic disease [2]. Squamous NSCLC is a distinct disease and is differentiated from other types of lung cancer not only by the difference in histology, but also its genetic profile [3].\n\nIn contrast to adenocarcinoma, genetic alterations such as ALK-translocation and epidermal growth factor receptor (EGFR) mutations are rare in squamous disease, making these patients unsuitable for ALK-inhibitors or EGFR TKIs [4, 5]. In addition, pemetrexed and bevacizumab are only indicated for non-squamous NSCLC. Therefore, platinum-based chemotherapy has remained the standard of care for the first-line treatment of squamous NSCLC for many years. Recently, new molecules have been approved in the United States and the EU for the treatment of advanced squamous NSCLC in the second-line setting including the immunotherapy agents nivolumab and pembrolizumab, and the anti-VEGFR2 monoclonal antibody (mAb) ramucirumab. Recently, the US Food and Drug Administration granted approval to necitumumab—an anti-EGFR mAb—for first-line treatment of patients with metastatic squamous NSCLC in combination with gemcitabine and cisplatin chemotherapy [6]. Also, the European Medicines Agency approved necitumumab for first-line treatment of patients with locally advanced or metastatic EGFR-expressing squamous NSCLC [7]. These marked the first approvals of a targeted therapy in squamous NSCLC in the first-line setting, despite numerous attempts over the past two decades.\n\nThe EGFR is implicated in a variety of cancers, including NSCLC of squamous histology [8, 9]. Activated EGFR enhances processes responsible for tumor growth and progression including angiogenesis, invasion/metastasis, the promotion of proliferation, and inhibition of apoptosis [8, 10]. EGFR protein is detectable in the majority of tumor specimens of patients with NSCLC (especially squamous carcinomas) [11–13]. Previously, the phase III FLEX trial reported a significant improvement in overall survival (OS) with the addition of the anti-EGFR antibody cetuximab to chemotherapy in patients with NSCLC tumors having EGFR protein expression. On subgroup analysis, patients with squamous histology compared with non-squamous had a more pronounced survival effect [14].\n\nNecitumumab is a second-generation, recombinant, human immunoglobulin IgG1 EGFR antibody that binds to EGFR with high specificity and affinity, competing with natural ligands and preventing receptor activation and downstream signaling [15]. Necitumumab inhibits EGFR-dependent tumor-cell proliferation and can exert cytotoxic effects in tumor cells through ADCC [16]. In contrast to the phase III study INSPIRE that did not show a benefit for the addition of necitumumab to pemetrexed and cisplatin in patients with advanced non-squamous NSCLC [17], the pivotal randomized phase III trial SQUIRE showed that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improved OS compared with chemotherapy alone {hazard ratio (HR) = 0.84 [95% confidence interval (CI) 0.74, 0.96; P = 0.01]}, was well tolerated, and did not negatively affect health-related quality-of-life in patients with advanced squamous NSCLC [18].\n\nIn SQUIRE, tissue collection for study participants was mandatory. Approximately 90% of study population in SQUIRE had tissue available for an analysis of EGFR protein expression by immunohistochemistry (IHC) [18]. Noting the relevance of the EGFR pathway in the etiology of squamous NSCLC [19–21], here we report the efficacy and safety results of the subpopulation of SQUIRE patients with EGFR-expressing tumors.\n\npatients and methods\nstudy design\nThe SQUIRE study design, treatments, and eligibility criteria have been previously reported [18]. Briefly, patients with stage IV squamous NSCLC were randomized 1:1 to necitumumab (800 mg absolute dose i.v. days 1, 8) plus gemcitabine–cisplatin (G = 1250 mg/m2 i.v. days 1, 8; C = 75 mg/m2 i.v. day 1), or gemcitabine–cisplatin alone every 21 days for up to 6 cycles. Patients in the experimental arm with no disease progression continued on necitumumab monotherapy until disease progression. The primary objective of SQUIRE was OS. Secondary end points included progression-free survival (PFS), objective response rate (ORR), time to treatment failure (TtTF), safety, and quality of life.\n\nThe study was conducted in compliance with the Declaration of Helsinki, International Conference on Harmonisation Guidelines for Good Clinical Practice, and applicable local regulations. The protocol was approved by the ethics committees of all participating centers, and all patients provided written informed consent before study entry.\n\nprocedures related to EGFR IHC\nArchived tumor tissue (pretreatment) derived from either the primary tumor or metastatic sites were collected and stored at a secure central laboratory. A tissue block or minimum of four tissue slides (paraffin embedded) was required for analyses. Tumor EGFR protein expression was assayed at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory by IHC with the EGFR PharmDx Kit (Dako, Glostrup, Denmark) and evaluated independently by two trained pathologists to derive percent positive. Discordant results were jointly resolved by the two pathologists.\n\nstatistical analysis\nIn a preplanned exploratory analysis, patients were categorized into detectable (EGFR > 0) where at least one positive cell was identified by EGFR IHC or non-detectable (EGFR = 0) EGFR expression groups. Efficacy was assessed in all randomized patients with evaluable IHC assay results [intention-to-treat (ITT) EGFR subpopulations; EGFR > 0 and EGFR = 0]. OS, PFS, and TtTF were compared between treatment groups using a stratified log-rank test, and survival curves estimated using the Kaplan–Meier method. HRs and 95% CIs were estimated from stratified Cox proportional hazards models. Stratification factors were ECOG performance status (0–1 versus 2) and geographic region (North America, Europe, Australia versus South America, South Africa, India versus eastern Asia). ORR was summarized by treatment group, and compared using a Cochran–Mantel–Haenszel test. A series of efficacy analyses including a STEPP analysis assessed the efficacy outcomes across the range of EGFR expression based on percent positive cells. A sensitivity analysis for OS was carried out among EGFR > 0 patients using censoring for post-study docetaxel.\n\nSafety was assessed in the specified subpopulations in all patients who received at least one dose of study medication and was analyzed according to actual treatment received (safety EGFR subpopulations). Adverse events were coded according to the Medical Dictionary for Regulatory Activities, version 16.0 and graded with the NCI-CTCAE version 3.0.\n\nIn a separate exploratory post hoc analysis, the correlation of EGFR copy number gain by FISH with efficacy outcomes was assessed. For this analysis, tumor samples from 557 patients (51% of ITT) were available. Tumors were categorized as FISH positive or negative based on Colorado Classification [22].\n\nresults\nArchived tissue was collected from 1060 patients (97% of ITT). Tumor EGFR protein expression data based on IHC were available for 982 of 1093 (90%) patients from the SQUIRE study ITT population out of whom, 935 (95%) had tumor samples expressing EGFR protein (EGFR > 0). In both treatment groups, most tumor tissue samples expressing detectable EGFR protein had a high percentage of cells staining positive (supplementary Figure S1, available at Annals of Oncology online). Baseline characteristics were well balanced between treatment groups in the EGFR > 0 subpopulation (Table 1). Only 47 of 982 (5%) patients had tumor tissue samples without detectable EGFR protein (EGFR = 0). Supplementary Table S1, available at Annals of Oncology online, presents baseline characteristics for EGFR = 0 subpopulation.\nTable 1. Baseline characteristics of patients (intention-to-treat epidermal growth factor receptor > 0 subpopulation)\n\n\tNecitumumab plus gemcitabine–cisplatin (n = 462)\tGemcitabine–cisplatin (n = 473)\t\nAge: years, median (range)\t62 (35–84)\t62 (32–86)\t\nAge group (years)\t\n <65\t285 (62%)\t296 (63%)\t\n ≥65\t177 (38%)\t177 (37%)\t\n <70\t380 (82%)\t396 (84%)\t\n ≥70\t82 (18%)\t77 (16%)\t\nSex\t\n Male\t381 (82%)\t400 (85%)\t\n Female\t81 (18%)\t73 (15%)\t\nECOG performance status\t\n 0–1\t418 (90%)\t436 (92%)\t\n 2\t44 (10%)\t37 (8%)\t\nEthnicity\t\n Caucasian\t388 (84%)\t396 (84%)\t\n Asian\t36 (8%)\t38 (8%)\t\n All others\t38 (8%)\t39 (8%)\t\nSmoking\t\n Smoker\t424 (92%)\t430 (91%)\t\n Non-smoker or ex-light smoker\t37 (8%)\t43 (9%)\t\nGeographic region\t\n North America, Europe, Australia\t400 (87%)\t407 (86%)\t\n South America, South Africa, India\t47 (10%)\t50 (11%)\t\n Eastern Asia\t15 (3%)\t16 (3%)\t\nNumber of metastatic organ systems\t\n 1\t42 (9%)\t45 (10%)\t\n 2\t164 (35%)\t175 (37%)\t\n >2\t256 (55%)\t253 (53%)\t\nSites of metastatic disease\t\n Bone\t103 (22%)\t108 (23%)\t\n Brain\t20 (4%)\t24 (5%)\t\n Liver\t89 (19%)\t96 (20%)\t\nData are n (%).\n\n\n\nExposure to chemotherapy was similar in both treatment groups in the EGFR > 0 subpopulation (supplementary Table S2, available at Annals of Oncology online). Of the 456 patients who received necitumumab plus gemcitabine–cisplatin, 242 (52%) continued on necitumumab continuation monotherapy. The maximum number of cycles reached on necitumumab by the cutoff date was 45.\n\nSupplementary Table S3, available at Annals of Oncology online, summarizes the efficacy results for the EGFR > 0 subpopulation. Patients in the necitumumab plus gemcitabine–cisplatin group had significantly prolonged OS compared with those in the gemcitabine–cisplatin group [stratified HR 0.79 (95% CI 0.69, 0.92), P = 0.002]. The Kaplan–Meier curve for OS in the EGFR > 0 subpopulation showed an early separation in favor of the necitumumab plus gemcitabine and cisplatin group (Figure 1A). PFS of the EGFR > 0 subpopulation was also significantly prolonged in the experimental arm compared with control [stratified HR 0.84 (95% CI 0.72, 0.97), P = 0.018] (Figure 1B). TtTF also showed significant prolongation (P = 0.006); ORR and disease control rate were numerically higher in favor of the experimental arm without statistical significance (supplementary Table S3, available at Annals of Oncology online). In subgroup analyses for OS and PFS in the EGFR > 0 subpopulation, necitumumab treatment benefit was reported across most subgroups including PS2 (OS HR = 0.74, PFS HR = 0.84) (Figure 2). Supplementary Table S4, available at Annals of Oncology online, summarizes the number of patients in the EGFR > 0 subpopulation who received post-study systemic anticancer therapy. Overall, post-study therapy was balanced between treatment arms. Based on a sensitivity analysis of OS censoring at the start of post-study docetaxel, it is unlikely that the imbalance in docetaxel therapy (32% necitumumab plus gemcitabine and cisplatin group; 24% gemcitabine and cisplatin group) was a driver for the observed OS benefit (supplementary Figure S2, available at Annals of Oncology online).\nFigure 1. Kaplan–Meier estimates of (A) overall survival and progression-free survival (B) (intention-to-treat epidermal growth factor receptor > 0 subpopulation).\n\n\nFigure 2. Subgroup analyses. Forest plots of overall survival and progression-free survival (intention-to-treat epidermal growth factor receptor > 0 subpopulation) in subgroups defined by baseline characteristics. HR, hazard ratio; NA, North America; EU, Europe; SA, South America; S Africa, South Africa.\n\n\n\nThe STEPP analysis across the ranges of EGFR protein expression for OS and PFS did not lead to the identification of a cutpoint to differentiate those who benefit from the addition of necitumumab versus those who do not (supplementary Figure S3, available at Annals of Oncology online). The survival benefit for patients with EGFR > 0 seemed to extend across the range of EGFR IHC values including low-expressing subgroups (supplementary Table S5, available at Annals of Oncology online). However, patients in the EGFR = 0 subpopulation did not appear to benefit from the addition of necitumumab to gemcitabine and cisplatin (OS HR = 1.52; PFS HR = 1.33). In interaction analyses modeling, the EGFR = 0 and EGFR > 0 patients together using a stratified model, the P values for the interaction of treatment with EGFR subgroup for OS and PFS were 0.015 and 0.252, respectively.\n\nIn the EGFR > 0 subpopulation, 323 (71%) of 456 patients in the necitumumab plus gemcitabine and cisplatin group and 281 (60%) of 468 in the gemcitabine and cisplatin group had one or more grade 3 or worse treatment-emergent adverse events. Grade 3 or worse adverse events that were more common (>2%) in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin group included hypomagnesemia (9% versus <1%) and rash (3% versus <1%) (supplementary Table S6, available at Annals of Oncology online).\n\nAdverse events in the EGFR > 0 subpopulation leading to discontinuation of at least one study drug were reported by 139 (30%) patients in the necitumumab plus gemcitabine and cisplatin group and by 118 (25%) in the gemcitabine and cisplatin group (data not shown). Neutropenia and thrombocytopenia were the most common reasons for treatment discontinuation of any therapy. In the experimental arm, 1.1% of patients discontinued treatment because of rash (versus 0% in the control arm). Including events related to disease progression in the EGFR > 0 subpopulation, adverse events with an outcome of death were reported for 50 (11%) patients in the necitumumab plus gemcitabine and cisplatin group and 46 (10%) patients in the gemcitabine and cisplatin group.\n\nIn addition to the analysis of treatment-emergent adverse events, selected composite event categories based on the known safety profiles of other EGFR antibodies and the previous clinical experience of necitumumab were analyzed as adverse events of interest. Based on these categories, grade 3 or more adverse events that were more common (≥2%) in necitumumab plus gemcitabine and cisplatin arm versus gemcitabine and cisplatin arm in the EGFR > 0 population included: hypomagnesemia (10% versus <1%), rash (6% versus <1%), venous thromboembolic events (5% versus 3%), and arterial thromboembolic events (4% versus 2%) (Table 2). Adverse events of interest for the EGFR = 0 population are summarized in supplementary Table S7, available at Annals of Oncology online.\nTable 2. Adverse events of interest (safety epidermal growth factor receptor > 0 subpopulation)\n\n\tNecitumumab plus gemcitabine–cisplatin (n = 456)\tGemcitabine–cisplatin (n = 468)\t\nAny grade\tGrade ≥3\tAny grade\tGrade ≥3\t\nNeutropenia\t199 (44%)\t112 (25%)\t206 (44%)\t126 (27%)\t\nFebrile neutropenia\t5 (1%)\t4 (<1%)\t8 (2%)\t7 (1%)\t\nAnemia\t186 (41%)\t46 (10%)\t212 (45%)\t50 (11%)\t\nThrombocytopenia\t101 (22%)\t48 (11%)\t120 (26%)\t51 (11%)\t\nDiarrhea\t72 (16%)\t9 (2%)\t53 (11%)\t7 (1%)\t\nFatigue\t191 (42%)\t36 (8%)\t195 (42%)\t33 (7%)\t\nHypomagnesemia\t145 (32%)\t44 (10%)\t72 (15%)\t4 (<1%)\t\nHypomagnesemia (laboratory data)\t327 (83%)\t81 (21%)\t282 (71%)\t24 (6%)\t\nSkin reactions\t\n Rash\t351 (77%)\t29 (6%)\t48 (10%)\t2 (<1%)\t\nHypersensitivity/infusion-related reaction\t8 (2%)\t2 (<1%)\t10 (2%)\t0\t\nConjunctivitis\t37 (8%)\t1 (<1%)\t12 (3%)\t0\t\nInterstitial lung disease\t4 (<1%)\t2 (<1%)a\t4 (<1%)\t3 (<1%)\t\nArterial thromboembolic events\t26 (6%)\t18 (4%)b\t18 (4%)\t9 (2%)b\t\nVenous thromboembolic events\t46 (10%)\t25 (5%)c\t25 (5%)\t12 (3%)c\t\nThis table shows adverse events of interest according to either composite categories or preferred terms (febrile neutropenia and diarrhea only). Data are n (%).\n\naIncludes one fatal event (0.2%).\n\nbFatal arterial thromboembolic events, n (%): Neci + Gem–Cis 3 (0.7%), Gem–Cis 1 (0.2%).\n\ncFatal venous thromboembolic events, n (%): Neci + Gem–Cis 1 (0.2%), Gem–Cis 1 (0.2%).\n\n\n\nThe efficacy results of exploratory post hoc analysis of EGFR copy number gain are presented in supplementary Table S8, available at Annals of Oncology online. The OS HR for EGFR FISH positive and negative subgroups were 0.70 and 1.02, respectively, with a statistically non-significant treatment-by-marker interaction P value (0.066).\n\ndiscussion\nThe SQUIRE trial showed that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improved survival in patients with advanced squamous NSCLC, leading to the approval of necitumumab as a new treatment option in this patient population. In line with the SQUIRE ITT, the addition of necitumumab to chemotherapy was associated with a statistically significant improvement in OS and PFS in the subpopulation of patients with EGFR-expressing tumors. In addition, subgroup analyses of OS and PFS based on age, gender, smoking status, ethnicity, and performance status for patients with advanced EGFR-expressing squamous NSCLC showed consistent benefit across most subgroups. The safety profile of necitumumab plus gemcitabine and cisplatin was acceptable in this subpopulation of patients as well. In general, the findings for the advanced EGFR-expressing squamous NSCLC subpopulation paralleled the results of the SQUIRE ITT with a slightly more pronounced efficacy and a similar safety profile.\n\nSQUIRE confirmed the hypothesis generated by a subgroup analysis from the FLEX trial of cetuximab: the addition of an anti-EGFR mAb to first-line chemotherapy can be of particular use in patients with metastatic squamous NSCLC, indicating the relevance of EGFR pathway in this patient population [14, 23]. While FLEX only recruited patients with EGFR-expressing tumors, SQUIRE also included patients without detectable EGFR protein, which allowed for an exploratory analysis of efficacy outcomes in this group of patients. SQUIRE results suggest that the small group of patients with no detectable EGFR protein may not benefit from the addition of necitumumab to chemotherapy. A biologically plausible rationale can be hypothesized for the apparent lack of efficacy of an anti-EGFR mAb in patients whose tumor cells do not express the target. The value of a biomarker-oriented approach to guide the prescription of a targeted therapy is well understood in the era of precision medicine; however, the SQUIRE results (given the small subpopulation of patients with EGFR = 0, together with the complexity of EGFR pathway in NSCLC) are not conclusive regarding the lack of benefit in patients with EGFR = 0. Importantly, no specific safety concern was identified in this group that could explain the observed lack of effect.\n\nAs previously reported [18], the level of EGFR protein expression (high expression versus low expression based on H-score cutoff of 200) was not of predictive value in SQUIRE. While patients with high expression (EGFR H-score ≥200) had a more favorable HR for OS, the same trend was not observed for PFS, and the treatment-by-marker interaction test P values were not significant [18]. Further analyses of SQUIRE results across the range of EGFR IHC presented here also suggest that patients whose tumors have detectable EGFR protein benefit from the addition of necitumumab to chemotherapy, regardless of the level of EGFR protein expression.\n\nSQUIRE was a large randomized trial specifically conducted in patients with advanced squamous NSCLC and incorporated a mandatory tissue collection. One major strength of the presented results is the high percentage of available tissue for EGFR IHC analysis in SQUIRE. In addition, the exploratory analysis of main efficacy outcomes in EGFR > 0 subpopulation was pre-specified. Nevertheless, these data should be interpreted in the context of the SQUIRE ITT results and caution should be exercised, especially when it comes to the outcomes of smaller subgroups.\n\nThe results of EGFR copy number gain by FISH in SQUIRE showed a trend for a more favorable survival HR in the EGFR FISH positive subpopulation but without statistically significant treatment-by-marker interaction tests. Half of the SQUIRE population had tumor tissue available for this analysis and this exploratory analysis was not pre-specified. Further analyses of the data are needed in order to better understand the potential predictive role of EGFR copy number gain in this setting.\n\nIn conclusion, the outcomes of SQUIRE patients with advanced EGFR-expressing squamous NSCLC treated with necitumumab in combination with gemcitabine and cisplatin are consistent with that of the ITT population; this suggests a positive benefit/risk profile and further corroborates the mechanism of action of necitumumab. This work supports the existing evidence regarding the importance of EGFR in squamous NSCLC, and highlights the need for continued efforts to increase our understanding of the complex biology of the EGFR pathway in this disease.\n\nfunding\nThis work was supported by Eli Lilly and Company and there is no grant number.\n\ndisclosure\nLP-A has received honorarium from Eli Lilly and Company. MAS has received advisory honorarium from Eli Lilly and Company. JS, RRH, VS, and RK are employees of Eli Lilly and Company and hold equity in the company. MV-G declares no conflict of interest. NT has received speaker and advisory board honoraria from Eli Lilly and Company. FRH has received research funding to his laboratory (through University of Colorado) for biomarker studies related to the SQUIRE study and has received advisory board honoraria from Eli Lilly and Company.\n\nSupplementary Material\nSupplementary Data\n acknowledgements\nWe thank the patients, their families, and the study personnel across all sites for participating in this study. We wish to acknowledge Gu Mi for additional statistical support. We acknowledge Jill Kolodsick and Anastasia Perkowski from Eli Lilly and Company, who provided medical writing and editorial assistance, respectively.\n==== Refs\nreferences\n1 Ferlay J , Soerjomataram I , Ervik M , Dikshit R et al \nGLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 . Lyon, France : IARC Press \n2013 .\n2 Siegel R , Ma J , Zou Z , Jemal A \nCancer statistics, 2014 . CA Cancer J Clin \n2014 ; 64 : 364 .\n3 Gandara DR , Hammerman PS , Sos ML et al \nSquamous cell lung cancer: from tumor genomics to cancer therapeutics . Clin Cancer Res \n2015 ; 21 : 2236 –2243 .25979930 \n4 Besse B , Adjei A , Baas P et al \n2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease . Ann Oncol \n2014 ; 25 : 1475 –1484 .24669016 \n5 NCCN Clinical Practice Guidelines in Oncology—Non-Small Cell Lung Cancer . NCCN 2014 \nhttp://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site (10 February 2016, date last accessed ).\n6 Portrazza™ (necitumumab). US Prescribing Information . Eli Lilly and Company \n2015 .\n7 Portrazza™ (necitumumab). EU Prescribing Information . Eli Lilly and Company \n2016 .\n8 Mendelsohn J \nTargeting the epidermal growth factor receptor for cancer therapy . J Clin Oncol \n2002 ; 20 : 1s –13s .12235219 \n9 Baselga J \nWhy the epidermal growth factor receptor? The rationale for cancer therapy . Oncologist \n2002 ; 7 (Suppl 4) : 2 –8 .12202782 \n10 Salomon DS , Brandt R , Ciardiello F , Normanno N \nEpidermal growth factor-related peptides and their receptors in human malignancies . Crit Rev Oncol Hematol \n1995 ; 19 : 183 –232 .7612182 \n11 Veale D , Ashcroft T , Marsh C et al \nEpidermal growth factor receptors in non-small cell lung cancer . Br J Cancer \n1987 ; 55 : 513 .3038157 \n12 Fontanini G , Vignati S , Bigini D et al \nEpidermal growth factor receptor (EGFr) expression in non-small cell lung carcinomas correlates with metastatic involvement of hilar and mediastinal lymph nodes in the squamous subtype . Eur J Cancer \n1995 ; 31 : 178 –183 .7718322 \n13 Veale D , Kerr N , Gibson G et al \nThe relationship of quantitative epidermal growth factor receptor expression in non-small cell lung cancer to long term survival . Br J Cancer \n1993 ; 68 : 162 .8391303 \n14 Pirker R , Pereira JR , Szczesna A et al \nCetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial . Lancet \n2009 ; 373 : 1525 –1531 .19410716 \n15 Li S , Kussie P , Ferguson KM \nStructural basis for EGF receptor inhibition by the therapeutic antibody IMC-11F8 . Structure \n2008 ; 16 : 216 –227 .18275813 \n16 Liu M , Zhang H , Jimenez X et al \nIdentification and characterization of a fully human antibody directed against epidermal growth factor receptor for cancer therapy . Cancer Res \n2004 ; 64 : 163 .\n17 Paz-Ares L , Mezger J , Ciuleanu TE et al \nNecitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 trial . Lancet Oncol \n2015 ; 16 : 328 –337 .25701171 \n18 Thatcher N , Hirsch FR , Luft AV et al \nNecitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial . Lancet Oncol \n2015 ; 16 : 763 –774 .26045340 \n19 Meert AP , Martin B , Delmotte P et al \nThe role of EGF-R expression on patient survival in lung cancer: a systematic review with meta-analysis . Eur Respir J \n2002 ; 20 : 975 –981 .12412692 \n20 Sheng J , Yang YP , Zhao YY et al \nThe efficacy of combining EGFR monoclonal antibody with chemotherapy for patients with advanced nonsmall cell lung cancer: a meta-analysis from 9 randomized controlled trials . Medicine (Baltimore) \n2015 ; 94 : e1400 .26313787 \n21 Dacic S , Flanagan M , Cieply K et al \nSignificance of EGFR protein expression and gene amplification in non-small cell lung carcinoma . Am J Clin Pathol \n2006 ; 125 : 860 –865 .16690485 \n22 Hirsch FR , Herbst RS , Olsen C et al \nIncreased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy . J Clin Oncol \n2008 ; 26 : 3351 –3357 .18612151 \n23 Pirker R , Pereira JR , von Pawel J et al \nEGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study . Lancet Oncol \n2012 ; 13 : 33 –42 .22056021\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0923-7534",
"issue": "27(8)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "EGFR expressing; SQUIRE; necitumumab; squamous NSCLC",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D003841:Deoxycytidine; D018572:Disease-Free Survival; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors; D016896:Treatment Outcome",
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"pages": "1573-9",
"pmc": null,
"pmid": "27207107",
"pubdate": "2016-08",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "16690485;25979930;25701171;8391303;19410716;26313787;3038157;18275813;18612151;12412692;12202782;22056021;12235219;24399786;7718322;26045340;7612182;24669016",
"title": "Correlation of EGFR-expression with safety and efficacy outcomes in SQUIRE: a randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin plus necitumumab versus gemcitabine-cisplatin alone in the first-line treatment of patients with stage IV squamous non-small-cell lung cancer.",
"title_normalized": "correlation of egfr expression with safety and efficacy outcomes in squire a randomized multicenter open label phase iii study of gemcitabine cisplatin plus necitumumab versus gemcitabine cisplatin alone in the first line treatment of patients with stage iv squamous non small cell lung cancer"
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"abstract": "A 55-year-old woman with asthma presented with adrenal insufficiency of unknown origin. She was referred to our Division of Reproductive Endocrinology to further evaluate an undetectable morning cortisol level discovered during the evaluation of a low serum DHEA-S level. She was asymptomatic other than having mild fatigue and weight gain. Her medication list included 220 μg of inhaled fluticasone propionate twice daily for asthma, which she was taking as prescribed. On presentation, the undetectable morning cortisol level was confirmed. A urinary measurement of fluticasone propionate 17β-carboxylic acid was markedly elevated. Fluticasone therapy was discontinued and salmeterol therapy initiated with supplemental hydrocortisone. Hydrocortisone therapy was discontinued after 2 months. A repeat urinary fluticasone measurement 4 months after the discontinuation of fluticasone therapy was undetectably low and morning cortisol level was normal at 18.0 μg/dl. Inhaled fluticasone is generally considered to be minimally systemically absorbed. This patient's only clinical evidence suggesting adrenal insufficiency was fatigue accompanying a low serum DHEA-S level. This case demonstrates that adrenal insufficiency can be caused by a routine dose of inhaled fluticasone. Missing this diagnosis could potentially result in adrenal crisis upon discontinuation of fluticasone therapy.\n\n\nCONCLUSIONS\nStandard-dose inhaled fluticasone can cause adrenal insufficiency.Adrenal insufficiency should be considered in patients taking, or who have recently discontinued, inhaled fluticasone therapy and present with new onset of nonspecific symptoms such as fatigue, weakness, depression, myalgia, arthralgia, unexplained weight loss, and nausea that are suggestive of adrenal insufficiency.Adrenal insufficiency should be considered in postoperative patients who exhibit signs of hypoadrenalism after fluticasone therapy has been withheld in the perioperative setting.Routine screening for hypoadrenalism in patients without clinical signs or symptoms of adrenal insufficiency after the discontinuation of inhaled fluticasone therapy is not indicated due to the apparently low incidence of adrenal insufficiency caused by fluticasone.",
"affiliations": "Department of Obstetrics and Gynecology Maine Medical Center 22 Bramhall Street, Portland, Maine, 04102 USA.;Division of Reproductive Endocrinology and Infertility Maine Medical Center 22 Bramhall Street, Portland, Maine, 04102 USA.",
"authors": "Hay|Casey M|CM|;Spratt|Daniel I|DI|",
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"doi": "10.1530/EDM-13-0080",
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepedmEDM Case ReportsEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol EDM13008010.1530/EDM-13-0080Unusual Effects of Medical TreatmentAdrenal insufficiency in a woman secondary to standard-dose inhaled fluticasone propionate therapy Adrenal insufficiency during fluticasone therapyHay Casey M 1Spratt Daniel I 21 Department of Obstetrics and GynecologyMaine Medical Center22 Bramhall Street, Portland, Maine, 04102USA2 Division of Reproductive Endocrinology and InfertilityMaine Medical Center22 Bramhall Street, Portland, Maine, 04102USACorrespondence should be addressed to D I Spratt Email: spratd@mmc.org01 2 2014 2014 2014 13008018 12 2013 8 1 2014 © 2014 The authors2014This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Summary\nA 55-year-old woman with asthma presented with adrenal insufficiency of unknown origin. She was referred to our Division of Reproductive Endocrinology to further evaluate an undetectable morning cortisol level discovered during the evaluation of a low serum DHEA-S level. She was asymptomatic other than having mild fatigue and weight gain. Her medication list included 220 μg of inhaled fluticasone propionate twice daily for asthma, which she was taking as prescribed. On presentation, the undetectable morning cortisol level was confirmed. A urinary measurement of fluticasone propionate 17β-carboxylic acid was markedly elevated. Fluticasone therapy was discontinued and salmeterol therapy initiated with supplemental hydrocortisone. Hydrocortisone therapy was discontinued after 2 months. A repeat urinary fluticasone measurement 4 months after the discontinuation of fluticasone therapy was undetectably low and morning cortisol level was normal at 18.0 μg/dl. Inhaled fluticasone is generally considered to be minimally systemically absorbed. This patient's only clinical evidence suggesting adrenal insufficiency was fatigue accompanying a low serum DHEA-S level. This case demonstrates that adrenal insufficiency can be caused by a routine dose of inhaled fluticasone. Missing this diagnosis could potentially result in adrenal crisis upon discontinuation of fluticasone therapy.\n\nLearning points\n\nStandard-dose inhaled fluticasone can cause adrenal insufficiency.\n\nAdrenal insufficiency should be considered in patients taking, or who have recently discontinued, inhaled fluticasone therapy and present with new onset of nonspecific symptoms such as fatigue, weakness, depression, myalgia, arthralgia, unexplained weight loss, and nausea that are suggestive of adrenal insufficiency.\n\nAdrenal insufficiency should be considered in postoperative patients who exhibit signs of hypoadrenalism after fluticasone therapy has been withheld in the perioperative setting.\n\nRoutine screening for hypoadrenalism in patients without clinical signs or symptoms of adrenal insufficiency after the discontinuation of inhaled fluticasone therapy is not indicated due to the apparently low incidence of adrenal insufficiency caused by fluticasone.\n==== Body\nBackground\nAdrenal suppression is a well-known consequence of chronic administration of pharmacologic doses of glucocorticoids. Routine doses of inhaled corticosteroids (ICS) are generally felt to have a minimal impact on the adrenal axis, except in certain subsets of the population such as children and patients on specific medications such as ritonavir (1, 2). It has been suggested that inhaled fluticasone propionate has an improved risk:benefit ratio compared with other ICS, probably due to a very high first-pass metabolism (3). The safety of inhaled fluticasone with respect to adrenal axis suppression has been supported by one study of 500 severe asthmatics, which showed that high-dose inhaled fluticasone (1–2 mg daily) did not decrease morning cortisol levels outside of the normal range (4). However, a large meta-analysis showed that inhaled fluticasone exhibited a greater dose-related systemic bioactivity compared with other available ICS, particularly at doses above 0.8 mg/day (5).\n\nHerein, we report on a 55-year-old woman with profound adrenal axis suppression caused by routine doses of inhaled fluticasone. Given the prevalence of fluticasone prescriptions, it is likely that other cases of adrenal suppression with inhaled fluticasone occur. According to a 2011 review of the use of medications in the USA, published by the IMS Institute for Healthcare Informatics, medications containing fluticasone are the 16th most prescribed medications in the country. In 2011, there were 38.4 million prescriptions dispensed containing fluticasone. If even a small proportion of patients using fluticasone have resulting undiagnosed adrenal insufficiency, there could be significant health consequences.\n\nCase presentation\nA 55-year-old woman was referred to our Reproductive Endocrinology Clinic to further evaluate an undetectable morning serum cortisol level. Initial concern for adrenal insufficiency had been raised 5 years earlier during evaluation for low bone density when a serum DHEA-S level was measured and found to be ‘low’ by the patient's history. Earlier this year, the patient's primary gynecologist observed ‘worsening’ osteopenia and referred her to an endocrinologist. Metabolic bone evaluation was normal. However, the patient mentioned her history of low DHEA-S level, prompting an evaluation of morning cortisol level, which was found to be undetectably low. She subsequently underwent two cosyntropin stimulation tests and both tests revealed baseline morning serum cortisol and adrenocorticotropic hormone (ACTH) levels below the assay detection limits (1.5 μg/dl for cortisol and 5 pg/ml for ACTH) consistent with central hypoadrenalism. Cortisol levels remained undetectably low after cosyntropin stimulation. Serum thyroxine (6.1 μg/dl), thyroid-stimulating hormone (TSH; 2.03 μU/ml), and insulin-like growth factor 1 (101 ng/ml) measurements were normal as was a chemistry panel including tests for renal and hepatic functions and fasting glucose (79 mg/dl). Follicle-stimulating hormone (FSH) levels were in the menopausal range (66.9 IU/l). Dual energy X-ray absorptiometry (DEXA) bone density measurements demonstrated T-scores of the spine, femoral neck, and total hip of −2.4, −1.9, and −2.1. Spinal Z-score was −1.3. Spinal BMD was stable between 2009 and 2012 (0.794 and 0.785 g/cm2). She was placed on hydrocortisone supplementation, but she did not tolerate it due to malaise. At this time, she presented to our clinic for further evaluation. She reported only mild fatigue with mild weight gain and denied having nausea, increased skin pigmentation, or postural symptoms. Symptoms of hypoadrenalism were notably absent, despite the very low cortisol levels. She also reported no symptoms of Cushing's syndrome other than mild weight gain and fatigue and had no symptoms suggestive of cortisol excess on physical examination. Past medical history was relevant for asthma controlled with 220 μg of inhaled fluticasone twice daily (a dose of 110 twice daily initiated in May 2001 and increased to 220 μg in February 2009), ipratropium bromide, and levalbuterol. She denied having any other health problems or using steroids with no history of autoimmune or pituitary disease, hepatic or renal disease, or pulmonary disease other than asthma.\n\nInvestigation\nOur initial evaluation included the confirmation of persistent suppression of ACTH and cortisol levels, evaluation of other pituitary functions with measurements of FSH and TSH levels, a complete metabolic panel, measurement of serum aldosterone levels, screening of serum and urine for exogenous glucocorticoids, and magnetic resonance imaging of the pituitary and hypothalamus. Undetectably low morning serum cortisol and ACTH levels were confirmed. All other results were within normal limits, except for the urinary measurement of fluticasone propionate 17β-carboxylic acid, which was markedly elevated at 7060 pg/ml. While there is no standard reference range for this laboratory, 10 pg/ml is considered average. Repeat testing confirmed the elevated urinary fluticasone metabolite measurement with a value of 2500 pg/ml. The patient confirmed that she was taking only the prescribed dose of inhaled fluticasone at the prescribed frequency.\n\nTreatment\nFluticasone therapy was discontinued, and the patient was started on salmeterol therapy for asthma control. Hydrocortisone was administered at a dose of 10 mg in the morning and 5 mg in the afternoon.\n\nOutcome and follow-up\nRepeat morning cortisol measurements 2 weeks and 2 months after the discontinuation of fluticasone therapy were 4.0 and 4.2 μg/dl with the afternoon hydrocortisone dose being held on the day before testing. The patient discontinued hydrocortisone treatment at that time, and 3 weeks later, the morning cortisol level had risen to 8.1 μg/dl. A repeat urinary fluticasone propionate 17β-carboxylic acid measurement was undetectably low. The final morning cortisol level 4 months later was 18.0 μg/dl.\n\nDiscussion\nThere have been some case reports of ICS causing adrenal suppression and crisis in adult patients receiving high-dose therapy without ritonavir (for fluticasone doses ≥1 g daily) (5)\n(6)\n(7)\n(8)\n(9)\n(10). Our patient is notable because she presented with complete adrenal axis suppression in the setting of standard-dose inhaled fluticasone therapy in the absence of ritonavir therapy or any other predisposing factors. She was asymptomatic other than having fatigue and underwent an extensive evaluation before establishing the correct diagnosis, indicating that this occurrence may currently be difficult to recognize and therefore underdiagnosed.\n\nThe mechanism of increased fluticasone absorption in our patient is unclear. She had no evidence of pulmonary or vascular disease. She was taking no other medications that would enhance absorption. The mechanism of adrenal axis suppression by ritonavir is the impairment of the cytochrome p450 system, leading to the accumulation of fluticasone in the blood. However, in our patient, fluticasone propionate 17β-carboxylic acid, which is the inactive metabolite of fluticasone propionate, was present at high levels consistent with intact cytochrome p450. Thus, no specific mechanism that would enable the identification of a subpopulation of patients receiving fluticasone who are more likely to have adrenal axis suppression could be identified in our patient.\n\nThis case report illustrates the potential for significant adrenal insufficiency due to standard doses of inhaled fluticasone and emphasizes the need to consider this diagnosis in patients taking ICS, particularly when glucocorticoid therapy is being discontinued. The lack of clinical symptoms of hypoadrenalism in the patient despite the consistently undetectable morning cortisol levels was most probably due to the glucocorticoid effects of the absorbed fluticasone. Recognition of the possibility of adrenal axis suppression by standard-dose inhaled fluticasone is important in two contexts. First, in patients similar to our patient whose adrenal status is being evaluated for reasons not related to their fluticasone use (e.g. fatigue, weight loss or gain, and low DHEA-S levels), the possibility of adrenal axis suppression should be considered. The reportedly low DHEA-S level in our patient while taking 110 μg of fluticasone twice daily appropriately prompted an evaluation of her adrenal axis, although the DHEA-S finding may have been incidental. Although our patient did not exhibit hyperglycemia, low Z-scores on DEXA, or suppression of TSH or FSH secretion, these factors should also prompt an investigation of adrenal status in patients receiving fluticasone therapy. If central adrenal insufficiency is evident, inhaled fluticasone should promptly be considered as an etiology to avoid a potentially expensive and confusing evaluation. Second and more importantly, adrenal insufficiency should be suspected in any patient who is discontinuing inhaled fluticasone therapy and developing clinical symptoms of hypoadrenalism such as unusual fatigue. Recognition of adrenal insufficiency may be difficult because symptoms are nonspecific and may include weakness, myalgia, arthralgia, nausea, weight loss, and psychiatric symptoms in addition to fatigue. Furthermore, the lack of symptoms of adrenal insufficiency in our patient despite consistently undetectable morning cortisol levels suggests that excess circulating fluticasone may induce glucocorticoid effects that prevent the symptoms of glucocorticoid deficiency. Testing for adrenal insufficiency should also be conducted when fluticasone therapy is withheld in the perioperative setting if a patient's hemodynamics or other factors suggest hypoadrenalism. Routine screening for adrenal insufficiency in patients without symptoms suggestive of hypoadrenalism after the discontinuation of inhaled fluticasone therapy is not warranted because the incidence of adrenal suppression due to inhaled fluticasone therapy appears to be low.\n\nPatient consent\nWritten informed consent was obtained from the patient for publication of this article.\n\nAuthor contribution statement\nDr D I Spratt is the patient's primary endocrinologist and contributed to the writing of this case report. Dr C M Hay is an obstetrics and gynecology resident who also directly cared for the patient and contributed to the writing of this case report.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n==== Refs\nReferences\n1 \nFoisy \nMM \n, \nYakiwchuk \nEM \n, \nChiu \nI \n & \nSingh \nAE \n. 2008 Adrenal suppression and Cushing's syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature . HIV Medicine . 9 : 389 –396 \n10.1111/j.1468-1293.2008.00579.x 18459946 \n2 \nSchwartz \nRH \n, \nNeacsu \nO \n, \nAscher \nDP \n & \nAlpan \nO \n. 2012 Moderate dose inhaled corticosteroid-induced symptomatic adrenal suppression: case report and review of the literature . Clinical Pediatrics . 51 : 1184 –1190 \n10.1177/0009922812462235 23043135 \n3 \nFuller \nR \n, \nJohnson \nM \n & \nBye \nA \n. 1995 Fluticasone propionate – an update on preclinical and clinical experience . Respiratory Medicine . 89 : 3 –18 \n10.1016/0954-6111(95)90259-7 7569173 \n4 \nAyres \nJG \n, \nBateman \nED \n, \nLundback \nB \n & \nHarris \nTA \n. 1995 High dose fluticasone propionate, 1 mg daily, versus fluticasone propionate, 2 mg daily, or budesonide, 1.6 mg daily, in patients with chronic severe asthma. International Study Group . European Respiratory Journal . 8 : 579 –586 \n10.1183/09031936.95.08040579 7664857 \n5 \nLipworth \nBJ \n. 1999 Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis . Archives of Internal Medicine . 159 : 941 –955 \n10.1001/archinte.159.9.941 10326936 \n6 \nDuplantier \nJE \n, \nNelson \nRP \nJr\n, \nMorelli \nAR \n, \nGood \nRA \n & \nKornfeld \nSJ \n. 1998 Hypothalamic–pituitary–adrenal axis suppression associated with the use of inhaled fluticasone propionate . Journal of Allergy and Clinical Immunology . 102 : 699 –700 \n10.1016/S0091-6749(98)70292-1 9802384 \n7 \nMolimard \nM \n, \nGirodet \nPO \n, \nPollet \nC \n, \nFourrier-Réglat \nA \n, \nDaveluy \nA \n, \nHaramburu \nF \n, \nFayon \nM \n & \nTabarin \nA \n. 2008 Inhaled corticosteroids and adrenal insufficiency: prevalence and clinical presentation . Drug Safety . 31 : 769 –774 \n10.2165/00002018-200831090-00005 18707191 \n8 \nTodd \nGR \n. 2003 Adrenal crisis due to inhaled steroids is underestimated . Archives of Disease in Childhood . 88 : 554 –555 \n10.1136/adc.88.6.554 12765935 \n9 \nTodd \nGR \n, \nAcerini \nCL \n, \nRoss-Russell \nR \n, \nZahra \nS \n, \nWarner \nJT \n & \nMcCance \nD \n. 2002 Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom . Archives of Disease in Childhood . 87 : 457 –461 \n10.1136/adc.87.6.457 12456538 \n10 \nWong \nJ \n & \nBlack \nP \n. 1992 Acute adrenal insufficiency associated with high dose inhaled steroids . BMJ . 304 : 1415 10.1136/bmj.304.6839.1415-a 1628017\n\n",
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"abstract": "Pruritus can be a distressing symptom seen in various cholestatic disorders. It is treated with medications like bile acid sequestrants. Drug-induced cholestasis usually resolves with withdrawal of the causative medication. We describe a case of refractory pruritus due to drug-induced cholestasis, not improved with withdrawal of the drug, managed effectively with multiple sessions of plasmapheresis.",
"affiliations": "Department of Pulmonary, Critical Care and Sleep, Baylor College of Medicine, Houston, TX, USA.;Department of Abdominal Transplantation, Baylor College of Medicine, Houston, TX, USA.;Department of Abdominal Transplantation, Baylor College of Medicine, Houston, TX, USA.;Department of Pulmonary, Critical Care and Sleep, Baylor College of Medicine, Houston, TX, USA.",
"authors": "Al-Azzawi|Hasan|H|;Patel|Ruchi|R|;Sood|Gagan|G|;Kapoor|Sumit|S|",
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"fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000454674crg-0010-0814Single CasePlasmapheresis for Refractory Pruritus due to Drug-Induced Cholestasis Al-Azzawi Hasan aPatel Ruchi bSood Gagan bKapoor Sumit a*aDepartment of Pulmonary, Critical Care and Sleep, Baylor College of Medicine, Houston, TX, USAbDepartment of Abdominal Transplantation, Baylor College of Medicine, Houston, TX, USA*Sumit Kapoor, MD, Department of Pulmonary, Critical Care and Sleep, Baylor College of Medicine, One Baylor Plaza, Mail Stop BCM-621, Houston, TX 77030 (USA), E-Mail sumit.kapoor@bcm.eduSep-Dec 2016 6 1 2017 6 1 2017 10 3 814 818 28 9 2016 21 11 2016 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Pruritus can be a distressing symptom seen in various cholestatic disorders. It is treated with medications like bile acid sequestrants. Drug-induced cholestasis usually resolves with withdrawal of the causative medication. We describe a case of refractory pruritus due to drug-induced cholestasis, not improved with withdrawal of the drug, managed effectively with multiple sessions of plasmapheresis.\n\nKeywords\nRefractoryPlasmapheresisCholestasisPruritusDrug-induced cholestasis\n==== Body\nIntroduction\nPruritus is a common and disabling symptom seen in various cholestatic liver disorders like primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), intrahepatic cholestasis of pregnancy (ICP), and drug-induced cholestasis, the incidence ranging from 20 to 80% [1]. Bile salts, endogenous opioids, serotonin, and lysophosphatidic acid have been implicated in the pathogenesis of pruritus [2, 3]. Plasmapheresis has been described in the literature as a safe and rapidly effective treatment for intractable pruritus due to cholestasis of PBC, PSC, and ICP [4, 5, 6, 7, 8, 9, 10]. We report a case of refractory pruritus due to drug-induced cholestasis, not improved with withdrawal of the offending drug, managed effectively by plasmapheresis.\n\nCase Description\nA 77-year-old male with a past medical history of obstructive sleep apnea using CPAP (continuous positive airway pressure) device at home, hypertension, hyperlipidemia, and atrial fibrillation was referred to our hospital for a higher level of care. He complained of intense itching all over the body for 10 days, which was gradually worsening and yellowish discoloration of the skin for 4 days. He was a past smoker, quit smoking 35 years ago, and had occasional alcohol intake. He denied any history of abdominal pain, fever, fatty stools, anorexia, fatigue, body piercing, or blood transfusions. There was no family history of any liver disorders. Before coming to our hospital, his pruritus was treated with diphenhydramine 25 mg 3 times a day, prednisone 40 mg daily for 5 days and fexofenadine 180 mg daily for 5 days with minimal relief. Of note, he took amiodarone 200 mg daily for 2 years for atrial fibrillation and was taken off the medication 2 months prior to the presentation. He was also taking over-the-counter herbal medication at the time of admission. His pertinent physical exam findings were scleral icterus and jaundice all over the body and evidence of scratch marks and excoriations from itching but no abdominal distention and tenderness. His admission laboratory results were significant for AST of 349 U/L, ALT of 592 U/L, ALP of 825 U/L, total bilirubin of 20 mg/dL, direct bilirubin of 12.5 mg/dL, creatinine of 1.59 mg/dL, hemoglobin of 11.5 gm/dL, INR of 1.9, PT 22.2 s, and PTT 36.3 s. His lab workup for liver failure was essentially negative including hepatitis panel, antimitochondrial antibody, α1-antitrypsin and α-fetoprotein levels. The abdomen MRI upon admission showed no cirrhosis and no intra- and extrahepatic biliary dilatation. He underwent transjugular liver biopsy which showed mixed cholestatic and hepatocellular injury pattern with acute hepatitis, hepatocyte necrosis, extensive intrahepatic and intracanalicular cholestasis, and micro- and macrovesicular steatosis, probably related to drug-induced liver disease (DILD) due to the use of amiodarone and over-the-counter herbal supplements (Fig 1, 2). His intractable pruritus was refractory to management with antihistamines and cholestyramine, and was impacting his care leading to sleep deprivation and agitation. We do not have resources for extracorporeal liver dialysis at our hospital. He was transferred to medical ICU for the initiation of plasmapheresis. He showed quick, significant, and long-lasting improvement in pruritus after 3 daily sessions (4 h each) of plasmapheresis in medical ICU. His mean total bilirubin levels improved from 21 to 14 mg/dL after 3 sessions of plasmapheresis.\n\nDiscussion\nPBC, PSC, ICP, drug-induced cholestasis, and benign recurrent intrahepatic cholestasis are the common intrahepatic cholestatic disorders associated with pruritus [1]. Pruritus or itching can manifest as simple intermittent itching to severe disability interfering with patient's quality of life, leading to sleep deprivation, emotional disturbances, and even suicidal ideations. Severe refractory pruritus has been accepted as an indication for liver transplantation to improve patient's quality of life [11]. Pruritus is usually worse at night, can be generalized or localized to palms, soles, extensor surfaces of extremities or upper trunk, and is exacerbated by stress. Multiple mechanisms have been proposed for the pathogenesis of itching in liver disease [2, 3]. The most common theory relates to the bile salt deposition on nerve endings on the skin or direct effect of bile salts on hepatocytes. Endogenous opioids like met-enkephalins and leu-enkephalins, serotonin, and lysophosphatidic acid have also been implicated in the pathogenesis of itching. There is no single pruritogenic factor, and the treatment of pruritus is considered empiric and none of the options are consistently effective.\n\nIn the US, the prevalence of drug-induced cholestasis is reported to be around 20% in the elderly population [12]. Cholestatic and mixed cholestatic and hepatocellular injury are the 2 most severe manifestations of DILD. Drug-induced cholestasis usually resolves with withdrawal of the offending drug [13]. The conventional management of pruritus includes bile acid sequestrants like cholestyramine and colestipol which bind bile acids in the intestine, thereby preventing their enterohepatic circulation and excreting them in stool [1]. Rifampicin, phenobarbital, opioid antagonists like naltrexone and naloxone, serotonin antagonists like ondansetron and sertraline, and antihistamines have also been studied and used clinically with inconsistent results [1].\n\nMore invasive measures like plasmapheresis and extracorporeal liver dialysis with molecular adsorbent recirculating system (MARS) have been used effectively in cases of severe refractory pruritus not amenable to conventional management [4, 5, 6, 7, 8, 9, 10, 14, 15]. There have been only 2 reports in the literature of intractable pruritus due to drug-induced cholestasis managed by extracorporeal albumin dialysis using MARS but none with plasmapheresis [14, 15]. We believe that one limitation of extracorporeal liver dialysis is that it is not readily available at all centers compared to plasmapheresis. Plasmapheresis removes all peripherally and centrally acting pruritogens from plasma and tissues of patients with cholestasis and pruritus. It is a relatively safe procedure, well tolerated, even in pregnant patients [4, 10]. Some rare complications of plasmapheresis include bleeding, infection, coagulation abnormalities, and electrolyte disturbances [5].\n\nWe report a case of refractory pruritus due to drug induced cholestasis (secondary to amiodarone and herbal supplement use) where patient symptoms did not get better with withdrawal of the offending drug and the patient underwent plasmapheresis without any complications, leading to long-lasting improvement of his symptoms.\n\nConclusion\nPlasmapheresis is a safe and effective treatment for management of refractory pruritus in cholestatic liver diseases. We describe a case of refractory pruritus due to DILD where plasmapheresis led to a quick and long-lasting relief of patient's symptoms. Plasmapheresis should be strongly considered for refractory pruritus due to drug-induced cholestasis if symptoms are not improved with stopping the offending drug and if resources for extracorporeal liver support are limited.\n\nStatement of Ethics\nWritten informed consent was obtained for the publication of this case report. The research was performed at Baylor St. Luke's Medical Center, Houston, TX. Our research is independent and impartial, and we ensure quality and integrity of the case report.\n\nDisclosure Statement\nThe authors have no conflict of interest to disclose.\n\nFig. 1 Focal areas of periportal confluent necrosis with focal disruption of the limiting plate by inflammation, ductular reaction, and fibrosis. Magnification ×20.\n\nFig. 2 The hepatocytes showed predominant microvesicular steatosis with many pale pink Mallory-Denk bodies (red arrowheads). There is also marked intrahepatic and intracanalicular cholestasis (black arrowheads). Magnification ×200.\n==== Refs\nReferences\n1 Bunchorntavakul C Reddy KR Pruritus in chronic cholestatic liver disease Clin Liver Dis 2012 16 331 346 22541702 \n2 Khandelwal M Malet PF Pruritus associated with cholestasis A review of pathogenesis and management. Dig Dis Sci 1994 39 1 8 8281842 \n3 Garden JM Ostrow JD Roenigk HH Jr Pruritus in hepatic cholestasis Pathogenesis and therapy. Arch Dermatol 1985 121 1415 1420 3901929 \n4 Alallam A Barth D Heathcote EJ Role of plasmapheresis in the treatment of severe pruritus in pregnant patients with primary biliary cirrhosis: case reports Can J Gastroenterol 2008 22 505 507 18478137 \n5 Ambinder EP Cohen LB Wolke AM Field SP Adelsberg B Schaffner F Zaroulis CG The clinical effectiveness and safety of chronic plasmapheresis in patients with primary biliary cirrhosis J Clin Apher 1985 2 219 223 4030709 \n6 Fuhrmann V Drolz A Trauner M Extracorporeal artificial liver support systems in the management of intractable cholestatic pruritus Liver Int 2011 31 suppl 3 31 33 21824282 \n7 Geerdink P Snel P van Berge Henegouwen GP Huybregts A Tangerman A Kunst VA van Tongeren JH Treatment of intractable pruritus in patients with cholestatic jaundice by plasma exchange and plasma perfusion Netherlands J Med 1978 21 239 244 \n8 Omokawa S Yamashita M Malchesky PS Koo AP Matsushita M Nose Y Therapeutic plasmapheresis for cholestatic liver diseases: study of 9 cases Prog Clin Biol Res 1990 337 233 236 2352983 \n9 Pusl T Denk GU Parhofer KG Beuers U Plasma separation and anion adsorption transiently relieve intractable pruritus in primary biliary cirrhosis J Hepatol 2006 45 887 891 17046095 \n10 Warren JE Blaylock RC Silver RM Plasmapheresis for the treatment of intrahepatic cholestasis of pregnancy refractory to medical treatment Am J Obstet Gynecol 2005 192 2088 2089 15970907 \n11 Murray KF Carithers RL Jr AASLD practice guidelines: evaluation of the patient for liver transplantation Hematology 2005 41 1407 1432 \n12 Lewis JH Drug-induced liver disease Med Clin North Am 2000 84 1275 1311 11026929 \n13 Padda MS Sanchez M Akhtar AJ Boyer JL Drug induced cholestasis Hepatology 2011 53 1377 1387 21480339 \n14 Bellmann R Feistritzer C Zoller H Graziadei IW Schwaighofer H Propst A Wiedermann CJ Joannidis M Treatment of intractable pruritus in drug induced cholestasis with albumin dialysis: a report of two cases ASAIO J 2004 50 387 391 15307554 \n15 Anand JS Chodorowski Z Hajduk A Waldman W Cholestasis induced by parabolan successfully treated with the molecular adsorbent recirculating system ASAIO J 2006 52 117 118 16436902\n\n",
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"keywords": "Cholestasis; Drug-induced cholestasis; Plasmapheresis; Pruritus; Refractory",
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"title": "Plasmapheresis for Refractory Pruritus due to Drug-Induced Cholestasis.",
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"abstract": "Blastomycosis is a rare fungal infection that frequently involves the skin. Atypical presentations are important to identify, especially in pregnant patients, to initiate appropriate therapy and prevent complications. Uniquely, we describe a case of atypical blastomycosis that presented with painful cutaneous abscesses in a pregnant patient, with dissemination to the central nervous system. The case was successfully treated with liposomal amphotericin B transitioned to voriconazole after delivery without complications for the patient or fetus.",
"affiliations": "University of Vermont College of Medicine.;University of Vermont College of Medicine.;University of Vermont College of Medicine.;University of Vermont College of Medicine.",
"authors": "DeWitt|Corey M|CM|;Shea|Katelyn|K|;Greene|Laura A|LA|;Pierson|Joseph C|JC|",
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"fulltext": "\n==== Front\nInt J Womens DermatolInt J Womens DermatolInternational Journal of Women's Dermatology2352-6475Elsevier S2352-6475(18)30068-610.1016/j.ijwd.2018.11.002ArticleAtypical blastomycosis in a pregnant woman☆☆☆ DeWitt Corey M. MDcorey.dewitt@uvmhealth.org⁎Shea Katelyn MDGreene Laura A. MDPierson Joseph C. MDUniversity of Vermont College of Medicine⁎ Corresponding Author. corey.dewitt@uvmhealth.org29 12 2018 6 2019 29 12 2018 5 2 131 133 29 5 2018 17 10 2018 2 11 2018 © 2018 Published by Elsevier Inc. on behalf of Women's Dermatologic Society.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Blastomycosis is a rare fungal infection that frequently involves the skin. Atypical presentations are important to identify, especially in pregnant patients, to initiate appropriate therapy and prevent complications. Uniquely, we describe a case of atypical blastomycosis that presented with painful cutaneous abscesses in a pregnant patient, with dissemination to the central nervous system. The case was successfully treated with liposomal amphotericin B transitioned to voriconazole after delivery without complications for the patient or fetus.\n\nKeywords\nBlastomycosispregnancy, amphotericin B\n==== Body\nIntroduction\nBlastomycosis is a rare fungal infection that typically involves the lungs, with frequent dissemination to the skin (Saccente and Woods, 2010). Cutaneous lesions are most commonly painless ulcers and verrucous plaques, with pustules observed in the minority of cases. Pregnancy predisposes patients to a partial immunosuppression state, but central nervous system (CNS) involvement is exceptionally rare in pregnant patients with blastomycosis.\n\nIn this case report, we present an atypical presentation of blastomycosis during pregnancy with exquisitely tender abscesses and dissemination to the CNS.\n\nCase\nA 25-year-old woman who was 26 weeks pregnant was admitted with multiple skin abscesses. She first noticed a small erythematous papule on her right thigh 3 weeks prior to admission, which progressed with worsening tenderness and pain with weight bearing. Similar lesions began to develop on her left thigh and upper back. She was placed empirically on oral clindamycin with no improvement. The patient was evaluated at our dermatology clinic 2 weeks after the development of the first lesion, at which point three of the four abscesses were incised and drained. Bacterial cultures at that time tested negative.\n\nA few days later, the patient was admitted for worsening pain and failure to respond to outpatient therapies. She was started on intravenous vancomycin without significant improvement. At the time of our evaluation in the hospital, the patient was found to have four 2- to 3-cm, erythematous, firm, tender nodules on her left and right thighs and upper back (Fig. 1, Fig. 2). A punch biopsy specimen of one of the lesions was obtained and sent for histopathologic evaluation and culture (Fig. 3). Within the dermis, diffuse abscess with associated fungal organisms was noted. Staining with Grocott methenamine-silver and periodic acid Schiff with diastase digestion highlighted the thickened capsule and broad-based budding, consistent with Blastomyces species. Fungal cultures obtained at the time of the biopsy tested positive for budding yeast forms suggestive of Blastomyces.Fig. 1 Left thigh showing 2 to 3 cm erythematous, firm, exquisitely tender nodule.\n\nFig. 1Fig. 2 Hematoxylin and eosin staining that shows diffuse dermal abscess formation with fungal organisms and a thickened capsule, with evidence of broad-based budding.\n\nFig. 2Fig. 3 Grocott methenamine-silver staining that highlights broad-based bud fungal organisms.\n\nFig. 3\n\nDuring her admission, the patient was found to have coughing, headache, dysarthria, and left-sided weakness. Magnetic resonance imaging was performed and demonstrated multifocal abnormally increased T2 and T2 flair signal throughout the brain that was most confluent within the pons and medulla (Fig. 4), suggestive of dissemination. In addition, a chest x-ray was performed, and showed a patchy opacity in the right upper lobe, suggestive of pulmonary involvement.Fig. 4 Head magnetic resonance imaging showing multifocal abnormally increased T2 and T2 flair signal throughout the brain, but most confluent within the pons and medulla.\n\nFig. 4\n\nThe patient was initiated on liposomal amphotericin B, which resulted in prompt improvement of her cutaneous lesions, cough, and neurologic symptoms. Treatment was continued for 60 days until preterm vaginal delivery at 35 weeks, at which time the patient was switched to voriconazole to complete a 12-month course. While on amphotericin B, the patient’s creatinine, potassium, and magnesium levels were monitored on Mondays, Wednesdays, and Fridays, and a complete blood cell count was obtained weekly throughout therapy. The patient was maintained on magnesium and potassium supplementation during this portion of her treatment. Once switched to voriconazole, monitoring included weekly liver function tests and voriconazole troughs for 1 month, followed by monthly monitoring.\n\nThe patient has shown complete resolution of her symptoms at 9-month follow-up, and the child is healthy without complications.\n\nDiscussion\nFirst described in 1894, blastomycosis is a rare fungal infection that typically involves the skin and lungs (Saccente and Woods, 2010). Blastomycosis is most common in the Ohio and Mississippi River Valleys, with cases also reported in the Northeast. Although most commonly a pulmonary infection, blastomycosis can disseminate to involve the skin and CNS as observed in our patient. In addition, in rare cases, primary cutaneous blastomycosis can be seen secondary to direct inoculation (Saccente and Woods, 2010).\n\nApproximately 60% of patients with blastomycosis have skin involvement, with most resulting from dissemination. Typically, lesions are painless and are most frequently seen on the head, neck, and extremities (Saccente and Woods, 2010). Our patient’s presentation was atypical, because the skin lesions were exquisitely tender and painful. In addition, though papular, nodular, and pustular skin lesions can be seen, typical presentation is ulcers and verrucous plaques (Saccente and Woods, 2010).\n\nPregnancy itself predisposes mothers to partial immunosuppression, likely increasing the likelihood of initial infection and subsequent dissemination. In cases of blastomycosis during pregnancy, multisystem organ involvement is seen in 48% of cases, including 61% with skin involvement (Baker et al., 2017). CNS involvement occurs in < 5% of immunocompetent patients and appears to be more rare during pregnancy, with no cases in a recent case series of 23 patients (Baker et al., 2017).\n\nWhen the disseminated infection involves the CNS, the Infectious Diseases Society of America considers this to be a severe disseminated infection. The Infectious Diseases Society of America published guidelines on the treatment of severe disseminated blastomycosis recommending initial treatment with liposomal amphotericin B for a minimum of 4 to 6 weeks and then switching to an azole agent for 12 months (Chapman et al., 2008). In the case of a pregnant patient, therapy with liposomal amphotericin B should be continued until delivery, following which the transition can be made to an azole agent.\n\nAlthough standard amphotericin B has been implicated in renal failure, liposomal amphotericin (as used in our patient) has not been shown to pose such a risk and has better CNS penetration (Chapman et al., 2008, Wortmann et al., 2010). Additionally, amphotericin B is relatively safe to use during pregnancy and is the therapy of choice in neonates who show signs of infection (Chapman et al., 2008).\n\nIn contrast, the teratogenic risk of azole agents is too great to be used in a pregnant patient. The resulting phenotype has been compared with that seen in patients with Antley-Bixler Syndrome, which is caused by a mutation in FGFR2 and leads to abnormal sterol metabolism or in CYP P-450. Because fluconazole is a selective inhibitor of CYP P-450, embryonic exposure can lead to similar birth defects that most frequently include craniosynostosis, dysmorphic facial features, and other skeletal anomalies (Lopez-Rangel and Van Allen, 2005). When severe disseminated blastomycosis in a pregnant patient is identified and treated appropriately, the patient and fetus can have a good outcome.\n\nConclusions\nWe report on an atypical presentation of disseminated blastomycosis during pregnancy. This case demonstrates exquisitely painful abscess formation and dissemination to the CNS, which are both rare presentations of a relatively uncommon infectious process. We highlight the importance of identifying this atypical presentation of blastomycosis to guide proper treatment, and prevent complications for both patient and fetus.\n\n☆ Sources of support: This work had no specific funding.\n\n☆☆ Conflicts of interest: The authors have no conflicts of interest to disclose.\n==== Refs\nReferences\nBaker T. Patel A. Halteh P. Toussi S.S. DeLaMora P. Lipner S. Blastomycosis during pregnancy: A case report and review of the literature Diagn Microbiol Infect Dis 88 2017 145 151 28291633 \nChapman S.W. Dismukes W.E. Proia L.A. Bradsher R.W. Pappas P.G. Threlkeld M.G. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America Clin Infect Dis 46 2008 1801 1812 18462107 \nLopez-Rangel E. Van Allen M.I. Prenatal exposure to fluconazole: An identifiable dysmorphic phenotype Birth Defects Res A Clin Mol Teratol 73 2005 919 923 16265639 \nSaccente M. Woods G.L. Clinical and laboratory update on blastomycosis Clin Microbiol Rev 23 2010 367 381 20375357 \nWortmann G. Zapor M. Ressner R. Fraser S. Hartzell J. Pierson J. Lipsosomal amphotericin B for treatment of cutaneous leishmaniasis Am J Trop Med Hyg 83 2010 1028 1033 21036832\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-6475",
"issue": "5(2)",
"journal": "International journal of women's dermatology",
"keywords": "Blastomycosis; pregnancy, amphotericin B",
"medline_ta": "Int J Womens Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101654170",
"other_id": null,
"pages": "131-133",
"pmc": null,
"pmid": "30997389",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "16265639;18462107;20375357;21036832;28291633",
"title": "Atypical blastomycosis in a pregnant woman.",
"title_normalized": "atypical blastomycosis in a pregnant woman"
} | [
{
"companynumb": "PHHY2019US104107",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": null,
"... |
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