article dict | reports listlengths 1 3.97k |
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{
"abstract": "We report a rare case of cerebellar degeneration as a paraneoplastic syndrome in an 8-year-old boy with Hodgkin lymphoma that presented during first-line treatment. Antibodies against Purkinje cells (anti-Tr antibodies) were detected in the serum of the patient. After successful treatment of the lymphoma, the cerebellar symptoms resolved partially. Childhood presentation of paraneoplastic cerebellar degeneration is extremely rare, with only a few reports in the literature. For this reason, the description of all such cases contributes to the enrichment of the medical knowledge and will improve the diagnosis and the treatment of this complication.",
"affiliations": "*Specialized Hospital for Pediatric Oncohaematology †Multispecialty Hospitals for Active Treatment in Neurology and Psychiatry \"Saint Naum\", Sofia, Bulgaria.",
"authors": "Avramova|Boryana E|BE|;Hristova|Tanya|T|;Yordanova|Maya|M|;Vlahova|Irena|I|;Muchinova|Albena|A|;Bojinova|Veneta|V|;Konstantinov|Dobrin|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000486",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "38(6)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D002526:Cerebellar Diseases; D002648:Child; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D010257:Paraneoplastic Syndromes",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "470-2",
"pmc": null,
"pmid": "26599987",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cerebellar Degeneration as a Rare Paraneoplastic Syndrome in a Child With Hodgkin Lymphoma.",
"title_normalized": "cerebellar degeneration as a rare paraneoplastic syndrome in a child with hodgkin lymphoma"
} | [
{
"companynumb": "BG-BAYER-2016-163009",
"fulfillexpeditecriteria": "1",
"occurcountry": "BG",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "A majority of kidney transplant recipients receive calcineurin inhibitor-based immunosuppression. However, some do not tolerate calcineurin inhibitors and require other immunosuppressive strategies. Until recently, alternative approaches have been associated with inferior outcomes, but recent methods have effectively utilized belatacept in calcineurin inhibitor-intolerant patients. Though promising, belatacept uptake has been limited by higher acute rejection rates, unavailability due to production shortages, and logistical challenges as a result of intravenous infusion requirements. Interestingly, its predecessor abatacept is clinically available in subcutaneous formulation to treat autoimmune disorders but has not been used in clinical transplantation. Here we report on a series of 9 calcineurin inhibitor-intolerant transplant recipients converted to abatacept early after transplant as rescue immunosuppression during periods of belatacept unavailability. Retrospective review revealed successful allograft salvage and 100% patient and graft survival (median 115 months) after conversion to abatacept. Patients received abatacept for a median duration of 82 months with stable, long-term renal allograft function, a single cellular rejection episode, and no clinically apparent protective immunity concerns. Hence our findings suggest that future clinical studies utilizing abatacept either de novo or as conversion therapy in transplant recipients should be considered.",
"affiliations": "Emory Transplant Center, Atlanta, Georgia.;Emory Transplant Center, Atlanta, Georgia.;Emory Transplant Center, Atlanta, Georgia.;Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.;Emory Transplant Center, Atlanta, Georgia.;Emory Transplant Center, Atlanta, Georgia.",
"authors": "Badell|Idelberto Raul|IR|0000-0002-6696-318X;Karadkhele|Geeta M|GM|;Vasanth|Payaswini|P|;Farris|Alton Brad|AB|;Robertson|Jennifer M|JM|;Larsen|Christian P|CP|",
"chemical_list": "D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D000069594:Abatacept",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15319",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "19(8)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; costimulation; immunosuppressant - calcineurin inhibitor: tacrolimus; immunosuppressant - fusion proteins and monoclonal antibodies: costimulation molecule specific; immunosuppression/immune modulation; immunosuppressive regimens - rescue; kidney (allograft) function/dysfunction; kidney transplantation/nephrology",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000069594:Abatacept; D000328:Adult; D065095:Calcineurin Inhibitors; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2342-2349",
"pmc": null,
"pmid": "30768841",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Abatacept as rescue immunosuppression after calcineurin inhibitor treatment failure in renal transplantation.",
"title_normalized": "abatacept as rescue immunosuppression after calcineurin inhibitor treatment failure in renal transplantation"
} | [
{
"companynumb": "US-PFIZER INC-2019139099",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "A combination of favipiravir and zanamivir successfully cleared influenza B infection in a child who had undergone bone marrow transplant for X-linked severe combined immunodeficiency, with no recovery of T lymphocytes. Deep sequencing of viral samples illuminated the within-host dynamics of infection, demonstrating the effectiveness of favipiravir in this case.",
"affiliations": "Department of Genetics, University of Cambridge, Cambridge, UK.;Department of Genetics, University of Cambridge, Cambridge, UK.;Great Ormond Street Hospital, London, UK.;Great Ormond Street Hospital, London, UK.;Division of Infection and Immunity, University College London, London, UK.;Division of Infection and Immunity, University College London, London, UK.;Great Ormond Street Hospital, London, UK.;Division of Infection and Immunity, University College London, London, UK.;Great Ormond Street Hospital, London, UK.;Department of Genetics, University of Cambridge, Cambridge, UK.;Great Ormond Street Hospital, London, UK.",
"authors": "Lumby|Casper K|CK|;Zhao|Lei|L|;Oporto|Macarena|M|;Best|Tim|T|;Tutill|Helena|H|;Shah|Divya|D|;Veys|Paul|P|;Williams|Rachel|R|;Worth|Austen|A|;Illingworth|Christopher J R|CJR|;Breuer|Judy|J|",
"chemical_list": "D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; C462182:favipiravir; D053243:Zanamivir",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciaa023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "71(7)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "favipiravir; genome sequencing; influenza; zanamivir",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000577:Amides; D000998:Antiviral Agents; D002648:Child; D006801:Humans; D007251:Influenza, Human; D011719:Pyrazines; D053243:Zanamivir",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "e191-e194",
"pmc": null,
"pmid": "32124919",
"pubdate": "2020-10-23",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Favipiravir and Zanamivir Cleared Infection with Influenza B in a Severely Immunocompromised Child.",
"title_normalized": "favipiravir and zanamivir cleared infection with influenza b in a severely immunocompromised child"
} | [
{
"companynumb": "GB-GLAXOSMITHKLINE-GB2021GSK064082",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZANAMIVIR"
},
"drugadditional": "3",... |
{
"abstract": "Adding fibrates improves liver biochemistries in patients with primary biliary cholangitis (PBC) and suboptimal response to ursodeoxycholic acid (UDCA). As there are no consistent data regarding the course and outcome, we have assessed the effects of the combined treatment with UDCA and bezafibrate on a long-term basis.\n\n\n\nA total of 48 patients (45 female) with PBC treated with UDCA and alkaline phosphatase (ALP) above 1.5 times upper normal levels (× UNL) were treated with bezafibrate (400 mg/day) plus UDCA (13-16 mg/kg/day). Changes in clinical features, liver biochemistries, and prognosis after therapy were assessed, as well as pruritus, using a visual analog scale (43 patients) and the 5-D descriptive pruritus scale.\n\n\n\nAfter a median of 38 months, 26 patients (54%) had normalized ALP. In these patients, jaundice, pruritus, and liver stiffness was lower, and age was higher than in patients who remained with elevated ALP. Biochemical improvement was less prominent in patients without ALP normalization. Five of these patients (23%) developed events of disease progression: 1 died, 3 were transplanted, and 1 developed hepatocellular carcinoma. Partial or complete itching relief was reported in all but one case with pruritus. Itching recurrence or worsening was observed after bezafibrate discontinuation.\n\n\n\nThe long-term treatment with UDCA and bezafibrate results in excellent response, and is associated with a complete or partial itching relief. Incomplete ALP normalization was observed in patients with advanced disease who remained at risk for developing severe events. The combined treatment is mainly effective in patients with lower fibrosis and severity of cholestasis.",
"affiliations": "Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.;Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.;Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.",
"authors": "Reig|Anna|A|;Sesé|Pilar|P|;Parés|Albert|A|",
"chemical_list": "D002756:Cholagogues and Choleretics; D000960:Hypolipidemic Agents; D014580:Ursodeoxycholic Acid; D000469:Alkaline Phosphatase; D001629:Bezafibrate",
"country": "United States",
"delete": false,
"doi": "10.1038/ajg.2017.287",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9270",
"issue": "113(1)",
"journal": "The American journal of gastroenterology",
"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D000469:Alkaline Phosphatase; D001629:Bezafibrate; D006528:Carcinoma, Hepatocellular; D002756:Cholagogues and Choleretics; D018450:Disease Progression; D004359:Drug Therapy, Combination; D054459:Elasticity Imaging Techniques; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents; D007565:Jaundice; D008105:Liver Cirrhosis, Biliary; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011537:Pruritus; D014580:Ursodeoxycholic Acid; D064232:Visual Analog Scale",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "49-55",
"pmc": null,
"pmid": "29016567",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19995367;15040040;11051391;18455211;19035342;2129546;27532829;14685799;26364546;24548531;15588777;12003404;19501929;25678132;12190200;10638623;15288014;11148991;18452482;11422787;28201850;26416194;22911624;8615769;26223498;22271046;26261009;23998489;12825134;19881358;8725145;27435324;16530513;26559762;25732417;21083674",
"title": "Effects of Bezafibrate on Outcome and Pruritus in Primary Biliary Cholangitis With Suboptimal Ursodeoxycholic Acid Response.",
"title_normalized": "effects of bezafibrate on outcome and pruritus in primary biliary cholangitis with suboptimal ursodeoxycholic acid response"
} | [
{
"companynumb": "ES-ALLERGAN-1759974US",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "URSODIOL"
},
"drugadditional": "3",
"dr... |
{
"abstract": "OBJECTIVE\nPulmonary embolism is a relatively common clinical presentation of venous thromboembolism, which develops in relation to acute pulmonary arterial occlusion mostly caused by thrombi of the lower limbs.\n\n\nMETHODS\n29year old female admitted to emergency department with pulmonary thromboembolism due to an ingestion of 17 Diana 35 pills (2 mg cyproterone acetate and 0.035mg ethinyl estradiol) in a suicide attempt without any previously known predisposing factors. After thrombolytic therapy, the patient was discharged with oral warfarin treatment.\n\n\nCONCLUSIONS\nWe know that exogenous estrogen increase the risk of venous thromboembolism in therapeutic use. It should be kept in mind that even single ingestion of a single high-dose exogenous estrogen intake may induce pulmonary thromboembolism.",
"affiliations": "Department of Emergency Medicine, Bağcılar Education & Research Hospital, Bağcılar, İstanbul, Turkey. Electronic address: ribescan@hotmail.com.;Department of Emergency Medicine, Bağcılar Education & Research Hospital, Bağcılar, İstanbul, Turkey.;Bağcılar Education & Research Hospital, Bağcılar, İstanbul, Turkey.",
"authors": "Çelik|Caner|C|;Carus|Murat|M|;Büyükcam|Fatih|F|",
"chemical_list": "D000925:Anticoagulants; D003278:Contraceptives, Oral, Hormonal; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2017.07.084",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "35(12)",
"journal": "The American journal of emergency medicine",
"keywords": "Drug overdose; Ethinyl estradiol; Oral contraceptives; Pulmonary embolism; Venous thromboembolism",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D003278:Contraceptives, Oral, Hormonal; D062787:Drug Overdose; D005260:Female; D006801:Humans; D011655:Pulmonary Embolism; D013406:Suicide, Attempted; D015912:Thrombolytic Therapy; D016896:Treatment Outcome; D014859:Warfarin",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "1984.e1-1984.e2",
"pmc": null,
"pmid": "29037581",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pulmonary embolism due to exogenous estrogen intoxication.",
"title_normalized": "pulmonary embolism due to exogenous estrogen intoxication"
} | [
{
"companynumb": "TR-NOVAST LABORATORIES, LTD-TR-2018NOV000002",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYPROTERONE ACETATE"
},
"d... |
{
"abstract": "Azathioprine, a purine analogue that competitively inhibits the biosynthesis of purine nucleotides, is used in a wide range of conditions. Although its side-effects are well known, cardiac side effects like paroxysmal atrial fibrillation (AF) are based on only a few case reports. We describe here the case of a 55-year-old woman with primary biliary cirrhosis who presented a first-detected, symptomatic AF 2 h after azathioprine therapy which resolved after discontinuation of the drug with no predisposing factors for supraventricular arrhythmias (systemic hypertension, diabetes or coronary artery disease). The temporal coincidence of atrial fibrillation and azathioprine intake and disappearance of the AF episode after discontinuation of therapy allows us to suggest an intrinsic pro-arrhythmic effect of azathioprine. Therefore, physicians should be aware of this problem when this drug is administered.",
"affiliations": "Departmant of Cardiology, Aksaray State Hospital, Aksaray, Turkey.;Departmant of Cardiology, Yuksek Ihtisas Education and Research Hospital, Ankara, Turkey.;Departmant of Cardiology, Aksaray State Hospital, Aksaray, Turkey.;Departmant of Cardiology, Yuksek Ihtisas Education and Research Hospital, Ankara, Turkey.;Departmant of Cardiology, Yuksek Ihtisas Education and Research Hospital, Ankara, Turkey.",
"authors": "Dogan|Pinar|P|;Grbovic|Enis|E|;Inci|Sinan|S|;Bayraktar|Fatih|F|;Cagli|Kumral|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.5582/irdr.2015.01033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2186-3644",
"issue": "4(4)",
"journal": "Intractable & rare diseases research",
"keywords": "Azathioprine; atrial fibrillation; cardiac side effects",
"medline_ta": "Intractable Rare Dis Res",
"mesh_terms": null,
"nlm_unique_id": "101586847",
"other_id": null,
"pages": "207-9",
"pmc": null,
"pmid": "26668782",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports",
"references": "8381943;2171139;9250563;17598094;3929907;15582307;16908341",
"title": "Azathioprine-induced atrial fibrillation.",
"title_normalized": "azathioprine induced atrial fibrillation"
} | [
{
"companynumb": "TR-MYLANLABS-2015M1044248",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
... |
{
"abstract": "Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency results in excess androgen production which can lead to early epiphyseal fusion and short stature. Prader-Willi syndrome (PWS) is a genetic disorder resulting from a defect on chromosome 15 due to paternal deletion, maternal uniparental disomy, or imprinting defect. Ninety percent of patients with PWS have short stature. In this article we report a patient with simple-virilizing CAH and PWS who was overtreated with glucocorticoids for CAH and not supplemented with growth hormone for PWS, resulting in a significantly short adult height.",
"affiliations": "The Warren Alpert Medical School, Brown University, Providence, RI, USA.;College of Human Ecology, Cornell University, Ithaca, NY, USA.;Alexian Brothers Women and Children's Hospital and Amita Health Medical Group, Hoffman Estates, IL, USA.;Division of Pediatric Endocrinology, Rhode Island Hospital and Hasbro Children's Hospital, The Warren Alpert Medical School, Brown University, Providence, RI, USA.;Division of Pediatric Endocrinology, Rhode Island Hospital and Hasbro Children's Hospital, The Warren Alpert Medical School, Brown University, Providence, RI, USA.",
"authors": "Wasserman|Meredith|M|;Mulvihill|Erin M|EM|;Ganan-Soto|Angela|A|;Uysal|Serife|S|;Quintos|Jose Bernardo|JB|0000-0003-1691-2293",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2017/4271978",
"fulltext": "\n==== Front\nCase Rep EndocrinolCase Rep EndocrinolCRIECase Reports in Endocrinology2090-65012090-651XHindawi 10.1155/2017/4271978Case ReportSevere Short Stature in an Adolescent Male with Prader-Willi Syndrome and Congenital Adrenal Hyperplasia: A Therapeutic Conundrum Wasserman Meredith \n1\nMulvihill Erin M. \n2\nGanan-Soto Angela \n3\nUysal Serife \n4\nhttp://orcid.org/0000-0003-1691-2293Quintos Jose Bernardo \n4\n\n*\n1The Warren Alpert Medical School, Brown University, Providence, RI, USA2College of Human Ecology, Cornell University, Ithaca, NY, USA3Alexian Brothers Women and Children's Hospital and Amita Health Medical Group, Hoffman Estates, IL, USA4Division of Pediatric Endocrinology, Rhode Island Hospital and Hasbro Children's Hospital, The Warren Alpert Medical School, Brown University, Providence, RI, USA*Jose Bernardo Quintos: jbquintos@brown.eduAcademic Editor: Wayne V. Moore\n\n2017 30 5 2017 2017 42719784 4 2017 10 5 2017 Copyright © 2017 Meredith Wasserman et al.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency results in excess androgen production which can lead to early epiphyseal fusion and short stature. Prader-Willi syndrome (PWS) is a genetic disorder resulting from a defect on chromosome 15 due to paternal deletion, maternal uniparental disomy, or imprinting defect. Ninety percent of patients with PWS have short stature. In this article we report a patient with simple-virilizing CAH and PWS who was overtreated with glucocorticoids for CAH and not supplemented with growth hormone for PWS, resulting in a significantly short adult height.\n==== Body\n1. Introduction\nCongenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders characterized by the inability to synthesize cortisol from cholesterol in the adrenal cortex. 21-hydroxylase deficiency is the most common cause of CAH and results in excess androgen production due to shunting of intermediates in the steroidogenic pathway toward androgen synthesis. Excess androgen production causes the early fusion of epiphyseal plates, which stunts growth. Treatment for patients with CAH involves the delicate balance of suppressing adrenal androgens while maintaining normal growth.\n\nShort adult stature is common in 21-hydroxylase deficiency. Final adult height in patients with CAH is 1.38 SD lower than the population norm and their corrected height (final height minus genetic height potential) is 1.03 SD lower than their genetic height potential [1]. This short stature is seen in CAH patients even in the presence of early glucocorticoid treatment to suppress excess androgen production. Excess glucocorticoids can inhibit the pituitary production of growth hormone and contribute to short stature [2]. Growth hormone therapy was found to improve final height in patients with CAH by 9.2 cm ± 6.7 cm in males and 10.5 ± 3.7 cm in females [3]. It was also found that treatment with growth hormone can counter the growth-suppressing effects of glucocorticoids [4].\n\nPrader-Willi syndrome (PWS) is a genetic disorder resulting from a defect within the Prader-Willi critical region on chromosome 15 due to paternal deletion, maternal uniparental disomy, or imprinting defect. PWS is characterized by short adult stature, morbid obesity, hypogonadism, and characteristic facial features such as narrow bifrontal diameter, almond-shaped eyes, and small mouth with downturned corners and thin upper lip [5]. Decreased growth hormone levels and serum levels of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBPG-3) are found in 40–100% of children with PWS [6, 7]. Additionally, 90% of patients with PWS have short stature [7]. In the absence of growth hormone treatment and subsequent pubertal growth spurt, average adult height in male and female patients with PWS is 155 cm and 148 cm, respectively [7]. Patients treated with growth hormone were found to attain a mean adult height SDS of −0.3 ± 1.2 [8]. In addition, growth hormone treatment has been shown to improve body composition by lowering body fat percentage and increasing lean body mass [9].\n\nTo our knowledge, no case of simultaneous PWS and CAH has been reported. Here, we report a patient with PWS and CAH who was overtreated with glucocorticoids for CAH and not supplemented with growth hormone for PWS, resulting in a significantly short adult height.\n\n2. Case Report\nWe report the case of a 20-year-old Puerto Rican male with PWS and CAH who we initially evaluated when he was 17-year-old. He was born full term with birth weight 5 pounds, birth length 21 inches, and physical exam showing bilateral cryptorchidism and hypotonia. Karyotype is 46XY. He experienced feeding difficulties in the first year of life and had delayed milestones. At 3 years of age, he developed pubic hair and his laboratory examination showed 17-hydroxyprogesterone level 8,676 ng/dL and DHEAS 29 ug/dL. He was diagnosed with CAH and prescribed hydrocortisone. He was treated with fludrocortisone for the first 1-2 years after diagnosis. At 9 years of age his dose of hydrocortisone was increased, most likely due to poor compliance to treatment and poor adrenal control. Over the years he struggled with obesity and learning and behavioral problems, including hyperactivity and short attention span. He was diagnosed with PWS at 12 years of age, showing a submicroscopic deletion of chromosome 15 (q11.2q11.2). He was not treated with growth hormone. He also had a bone age of left hand in an outside hospital when he was 12 years old and his bone age was reported as 16 years old.\n\nHe came to our clinic for the first time at age 17 years. He was taking hydrocortisone 40 mg in the morning and 20 mg in the evening (equivalent of 37.5 mg/m2/day). Usual dose of hydrocortisone is 10–20 mg/m2/day. Physical exam showed a short male with almond-shaped eyes, fair skin, narrow bifrontal diameter, upslanted palpebral fissures (Figure 1), and small hands (Figure 2). His height was 138.6 cm (<5 percentile; −5.3 height SDS), height age 10 years, weight 72.3 kg (72nd percentile; 0.6 SDS), BMI 37.48 kg/m2 (>99th percentile), and blood pressure 124/56 mmHg. He was Tanner 3 for pubic hair and genitalia and testicular volume was 5-6 cc. His mother measured 159.8 cm and his father's reported height is 167.6 cm. Based on parental heights his midparental target height is 170.2 cm.\n\nLaboratory investigation showed 17-hydroxyprogesterone 16 ng/dL, testosterone 5 ng/dL (normal for 17-year-old male is 348–1197 ng/dL), and renin 10.47 ng/mL/hr. Adrenal hormone assays were done by liquid chromatography tandem mass spectrometry at Esoterix Laboratory Services in Calabasas Hills, California, United States. Bone age of left hand was 17 years of age, consistent with his chronological age.\n\nWe decreased his hydrocortisone dosage to 20 mg twice a day (equivalent 25 mg/m2/day) with the goal of 17-hydroxyprogesterone level between 100 and 1000 ng/dL and androstenedione level normal for age and sex. His electrolytes were Na+ 135 mEq/L, Cl− 100 mEq/L, CO2 27 mEq/L, and K+ 4.3 mEq/L. Hologic DEXA scan showed bone mass density below expected range for age. Femoral neck Z-score was −3.2, total hip Z-score was −3.3, and total body Z-score was −1.7 (−1.0 to −2.5 SDS).\n\nHe returned to our clinic six months later and his laboratory work-up showed 17-hydroxyprogesterone 23 ng/dL, androstenedione < 10 ng/dL (normal 17–72 ng/dL for Tanner 3), renin 3.43 ng/mL/hr, IGFBP-3 2.8 mg/L (normal 2.5–4.8 mg/L), and IGF-1 252 ng/mL (normal 161–467 mg/mL, mean 290 mg/mL). We further decreased hydrocortisone dose to 20 mg in the morning and 10 mg in the evening (equivalent 18 mg/m2/day), which resulted in normal adrenal control (17-hydroxyprogesterone 426 ng/dL). Pituitary gonadal axis evaluation showed LH 9.6 mIU/mL, FSH 21 mIU/mL, testosterone 139 ng/dL, and androstenedione 35 ng/dL, suggesting primary gonadal dysgenesis. Patient has not had testicular ultrasound to evaluate for testicular adrenal rest tumor (TART). An ACTH stimulation test to confirm the CAH diagnosis was done after stopping hydrocortisone for 24 hours. Results were consistent with simple-virilizing CAH due to 21-hydroxylase deficiency (Table 1). Genetic testing for mutations in the 21-hydroxylase gene has not been obtained. Testosterone cypionate 50 mg IM every four weeks was started. This resulted in more aggressive behavior and violent outbursts prompting discontinuation of testosterone treatment.\n\n3. Discussion\nWe report the case of a 20-year-old male with simple-virilizing CAH and PWS, who probably had both periods of undertreatment and overtreatment of glucocorticoids and lack of growth hormone treatment for PWS, resulting in a significantly short adult height. He also displayed aggressive behavior after being treated with testosterone for hypogonadism associated with PWS. To the best of our knowledge, there has been no other reported case of a patient with both PWS and CAH.\n\nThe chance of one patient having both CAH and PWS is extremely rare. The worldwide incidence of severe classic CAH is 1 in 15,000 [10] and the incidence of PWS is estimated to be between 1 in 10,000 and 1 in 30,000 [11].\n\nThe late diagnosis of PWS and missed opportunity for growth hormone therapy contributed to his significantly short adult stature. His height is 138.6 cm, or −5.3 height SDS. The average adult height of a male with untreated PWS is 155 cm (−3 height SDS) [7]. In one study, PWS patients treated with growth hormone achieved a mean adult height of −0.3 ± 1.2 SDS, while untreated patients achieved a mean adult height of −3.1 ± 1 SDS [8]. A retrospective study evaluating the effects of hydrocortisone treatment in patients with classical CAH showed that higher doses of glucocorticoids in children with CAH may result in decreased linear growth [12]. Additionally, a study of children with classic CAH found that the average final height for males treated with an average daily hydrocortisone dose of 19.7 ± 2.9 mg/m2/day was 163.1 ± 6.6 cm [13].\n\nWe hypothesize that periods of undertreatment and overtreatment with hydrocortisone contributed to his severe short stature. Factors that cause short adult stature in patients with 21-hydroxylase deficiency are (1) elevated adrenal androgens, which cause advanced epiphyseal maturation and premature epiphyseal fusion, (2) early or precocious puberty, which also leads to premature epiphyseal fusion, and (3) overtreatment with glucocorticoids [14]. Our patient also experienced premature epiphyseal fusion, as his bone age was 16 years at a chronological age 12. This premature epiphyseal fusion could be a result of periods of glucocorticoid undertreatment for CAH. Additionally, overtreatment with glucocorticoids most likely led to growth hormone suppression leading to poor growth velocity. This case reinforces the importance of growth hormone treatment for PWS and reduced glucocorticoid treatment for CAH, especially when both disorders coexist in one patient. Additionally, our patient was born small for gestational age with a birth weight of 5 pounds. It was unclear if he had catch-up growth due to lack of growth charts from the early childhood period. This may also have contributed to his short stature.\n\nOur patient's elevated FSH and LH levels and low testosterone levels indicate that he has primary hypogonadism. Eiholzer et al. found that boys with PWS have a combination of central and primary hypogonadism involving deficiency of LH and testosterone secretion at puberty and damage of the seminiferous tubules and Sertoli cells, resulting in reduced inhibin B levels and elevated FSH levels [15]. Additionally primary hypogonadism may be due to TART. Vanzulli et al. reported a prevalence of 27% of TART in a group of 30 CAH patients with age range 9 to 32 years [16]. It is more commonly seen in patients with salt-wasting CAH; however TART also occurs in patients with simple-virilizing and nonclassical CAH.\n\nHe displayed aggressive and violent behavior after testosterone replacement therapy, prompting discontinuation of therapy. It has been suggested that, to avoid aggressive behavior, testosterone should be administered daily as gels or patches instead of monthly depot intramuscular (IM) injections [17, 18]. Depot testosterone preparations cause unpredictable peaks and troughs, which may cause mood instability. Others suggest reducing the testosterone dose for patients with PWS to one-third to one-half of the normally recommended dose [6].\n\nThis unique case highlights the importance of careful follow-up and monitoring of adrenal androgens in a patient with CAH. Glucocorticoid dosage should be adjusted to prevent premature epiphyseal fusion and to maximize growth. This case also highlights the importance of early diagnosis of PWS and initiation of growth hormone treatment. When hypotonia, feeding difficulties followed by obesity, characteristic facial features, and characteristics of hypogonadism present in an infant, PWS should be suspected [5]. This case also exemplifies the need for further research on appropriate testosterone therapy for males with PWS.\n\nConflicts of Interest\nNone of the authors have potential, perceived, or real conflicts of interest to disclose.\n\nAuthors' Contributions\nMeredith Wasserman, M.S., wrote first draft of manuscript and edited. Erin M. Mulvihill edited and revised manuscript drafts. Angela Ganan-Soto, M.D., performed data collection and edited manuscript, with direct care of patient. Serife Uysal, M.D., edited and revised manuscript drafts. Jose Bernardo Quintos, M.D., conceptualized manuscript, edited, and revised, with direct care of patient.\n\nFigure 1 Characteristic facial features of Prader-Willi syndrome.\n\nFigure 2 Small hands characteristic of Prader-Willi syndrome.\n\nTable 1 Results of high dose ACTH stimulation test with 250 mcg cosyntropin.\n\nTime (mins)\tCortisol (ug/dl)\t17-Hydroxyprogesterone (ng/dl)\tAndrostenedione (ng/dl)\tTestosterone (ng/dl)\tDHEA (ng/dl)\t\n0\t2.9\t9,410\t106\t31\t<20\t\n60\t2.7\t11,000\t77\t44\t<20\n==== Refs\n1 Muthusamy K. Elamin M. B. Smushkin G. Adult height in patients with congenital adrenal hyperplasia: a systematic review and metaanalysis Journal of Clinical Endocrinology and Metabolism 2010 95 9 4161 4172 10.1210/jc.2009-2616 2-s2.0-77956592186 20823467 \n2 Grigorescu-Sido A. Bettendorf M. Schulze E. Duncea I. Heinrich U. Growth analysis in patients with 21-hydroxylase deficiency influence of glucocorticoid dosage, age at diagnosis, phenotype and genotype on growth and height outcome Hormone Research 2003 60 2 84 90 2-s2.0-0041742310 10.1159/000071876 12876419 \n3 Lin-Su K. Harbison M. D. Lekarev O. Vogiatzi M. G. New M. I. Final adult height in children with congenital adrenal hyperplasia treated with growth hormone Journal of Clinical Endocrinology and Metabolism 2011 96 6 1710 1717 2-s2.0-79956300202 10.1210/jc.2010-2699 21450983 \n4 Allen D. B. Julius J. R. Breen T. J. Attie K. M. Treatment of glucocorticoid-induced growth suppression with growth hormone Journal of Clinical Endocrinology and Metabolism 1998 83 8 2824 2829 2-s2.0-0031726147 10.1210/jc.83.8.2824 9709954 \n5 Holm V. A. Cassidy S. B. Butler M. G. Prader-Willi syndrome: consensus diagnostic criteria Pediatrics 1993 91 2 398 402 2-s2.0-0027476242 8424017 \n6 Cataletto M. Angulo M. Hertz G. Whitman B. Prader-Willi syndrome: a primer for clinicians International Journal of Pediatric Endocrinology 2011 2011 1 12 10.1186/1687-9856-2011-12 22008714 \n7 Burman P. Ritzén E. M. Lindgren A. C. Endocrine dysfunction in Prader-Willi syndrome: a review with special reference to GH Endocrine Reviews 2001 22 6 787 799 10.1210/er.22.6.787 2-s2.0-0035719948 11739333 \n8 Angulo M. A. Castro-Magana M. Lamerson M. Arguello R. Accacha S. Khan A. Final adult height in children with Prader-Willi syndrome with and without human growth hormone treatment American Journal of Medical Genetics, Part A 2007 143 13 1456 1461 2-s2.0-34447316692 10.1002/ajmg.a.31824 \n9 Carrel A. L. Myers S. E. Whitman B. Y. Eickhoff J. Allen D. B. Long-term growth hormone therapy changes the natural history of body composition and motor function in children with prader-willi syndrome Journal of Clinical Endocrinology and Metabolism 2010 95 3 1131 1136 2-s2.0-77749270821 10.1210/jc.2009-1389 20061431 \n10 Merke D. P. Bornstein S. R. Congenital adrenal hyperplasia The Lancet 2005 365 9477 2125 2136 10.1016/S0140-6736(05)66736-0 2-s2.0-20444462824 \n11 Hurren B. J. Flack N. A. M. S. Prader-Willi Syndrome: a spectrum of anatomical and clinical features Clinical Anatomy 2016 29 5 590 605 10.1002/ca.22686 2-s2.0-84958025788 26749552 \n12 Bonfig W. Pozza S. B. Schmidt H. Pagel P. Knorr D. Schwarz H. P. Hydrocortisone dosing during puberty in patients with classical congenital adrenal hyperplasia: An evidence-based recommendation Journal of Clinical Endocrinology and Metabolism 2009 94 10 3882 3888 10.1210/jc.2009-0942 2-s2.0-70349932628 19622620 \n13 Aycan Z. Akbuga S. Cetinkaya E. Ocal G. Berberoglu M. Final height of patients with classical congenital adrenal hyperplasia The Turkish Journal of Pediatrics 2009 51 6 539 544 20196386 \n14 Quintos J. B. Q. Vogiatzi M. G. Harbison M. D. New M. I. Growth hormone therapy alone or in combination with gonadotropin-releasing hormone analog therapy to improve the height deficit in children with congenital adrenal hyperplasia Journal of Clinical Endocrinology and Metabolism 2001 86 4 1511 1517 2-s2.0-0035034620 10.1210/jc.86.4.1511 11297576 \n15 Eiholzer U. l'Allemand D. Rousson V. Hypothalamic and gonadal components of hypogonadism in boys with Prader-Labhart-Willi syndrome Journal of Clinical Endocrinology and Metabolism 2006 91 3 892 898 2-s2.0-33644822771 10.1210/jc.2005-0902 16352691 \n16 Vanzulli A. DelMaschio A. Paesano P. Testicular masses in association with adrenogenital syndrome: US findings Radiology 1992 183 2 425 429 10.1148/radiology.183.2.1561344 2-s2.0-0026631024 1561344 \n17 Cassidy S. B. Driscoll D. J. Prader-Willi syndrome European Journal of Human Genetics 2009 17 1 3 13 2-s2.0-57649228925 10.1038/ejhg.2008.165 18781185 \n18 Benarroch F. Hirsch H. J. Genstil L. Landau Y. E. Gross-Tsur V. Prader-Willi Syndrome: Medical Prevention and Behavioral Challenges Child and Adolescent Psychiatric Clinics of North America 2007 16 3 695 708 2-s2.0-34249932148 10.1016/j.chc.2007.03.007 17562587\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-651X",
"issue": "2017()",
"journal": "Case reports in endocrinology",
"keywords": null,
"medline_ta": "Case Rep Endocrinol",
"mesh_terms": null,
"nlm_unique_id": "101576457",
"other_id": null,
"pages": "4271978",
"pmc": null,
"pmid": "28638668",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "1561344;20823467;11297576;26749552;8424017;18781185;12876419;11739333;20061431;15964450;16352691;20196386;17562587;9709954;17567883;21450983;22008714;19622620",
"title": "Severe Short Stature in an Adolescent Male with Prader-Willi Syndrome and Congenital Adrenal Hyperplasia: A Therapeutic Conundrum.",
"title_normalized": "severe short stature in an adolescent male with prader willi syndrome and congenital adrenal hyperplasia a therapeutic conundrum"
} | [
{
"companynumb": "US-009507513-1707USA009731",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nAdenomyosis associated abnormal uterine bleeding (AUB-A) often remains non-responsive to medical management. Uterine sparing treatment in young patients presenting with refractory AUB-A poses a challenge.\n\n\nMETHODS\nA 28-years-old woman presenting with AUB-A with failed medical therapy did not improve with uterine artery embolization (UAE). She underwent a second session of UAE with smaller embolic particles to which she responded. The reported case is interesting as patient conceived spontaneously despite transiently diminished post-UAE ovarian reserves, indicating spontaneous recovery of ovarian function.\n\n\nCONCLUSIONS\nUAE is a promising option for young patients, though UAE for adenomyosis may require smaller embolic particles to be effective which may diminish ovarian reserves due to non-target effects, however recovery is possible in young patients..",
"affiliations": "Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: drvidushi.kul@gmail.com.;Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi 110029, India.;Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India.;Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India.;Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi 110029, India.",
"authors": "Kulshrestha|Vidushi|V|;Yadav|Ritu|R|;Malla|Sundeep|S|;Gamanagatti|Shivanand|S|;Bhatla|Neerja|N|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.jogoh.2021.102132",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2468-7847",
"issue": "50(7)",
"journal": "Journal of gynecology obstetrics and human reproduction",
"keywords": "Adenomyosis; Embolic particle size; Pregnancy outcome; Refractory; Uterine artery embolization",
"medline_ta": "J Gynecol Obstet Hum Reprod",
"mesh_terms": null,
"nlm_unique_id": "101701588",
"other_id": null,
"pages": "102132",
"pmc": null,
"pmid": "33775917",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Successful pregnancy outcome in refractory adenomyosis treated with two sessions of uterine artery embolization: A case report and brief review.",
"title_normalized": "successful pregnancy outcome in refractory adenomyosis treated with two sessions of uterine artery embolization a case report and brief review"
} | [
{
"companynumb": "IN-TOLMAR, INC.-21IN026984",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUPROLIDE ACETATE"
},
"drugadditional": "3"... |
{
"abstract": "To explore the characteristics of double seropositive myasthenia gravis (DSP-MG).\n\n\n\nA literature review of twenty-four cases of DSP-MG including 2 novel cases presented in the current study, was performed.\n\n\n\nAmong 24 reported patients, 7 were male (29.17%) and 17 were female (70.83%). Among 20 patients with known age, the mean age of onset was 37.30 ± 19.50 years, among which the average onset age of the 6 male patients was 53.17 ± 8.98 years, while the average onset age of the remaining 14 female patients was 30.50 ± 18.94 years. Three patients had simple ocular muscle-type MG (14.28%), while 18 (85.71%) had non-ocular muscle-type MG. After administration of penicillide, 1 patient developed DSP-MG. In 9 cases, patients developed DSP-MG after thymectomy, while 5 patients naturally developed DSP-MG.\n\n\n\nWomen more frequently developed DSP-MG than men and men were diagnosed at an older age. MG is typically found in the ocular muscles, bulbar and limb muscles.",
"affiliations": "The Second Affiliated Hospital of Zheng-zhou University, Department of Neurology, No. 2 of Jingba Road, Zhengzhou, CN, 450014, China.;The Second Affiliated Hospital of Zheng-zhou University, Department of Neurology, No. 2 of Jingba Road, Zhengzhou, CN, 450014, China.;The Henan Academy of Medical and Pharmacologic Sciences, Department of Neuroimmunology Research, No. 40 of Daxue Road, Zhengzhou, CN, 450052, China.;The Henan Academy of Medical and Pharmacologic Sciences, Department of Neuroimmunology Research, No. 40 of Daxue Road, Zhengzhou, CN, 450052, China.;The Henan Academy of Medical and Pharmacologic Sciences, Department of Neuroimmunology Research, No. 40 of Daxue Road, Zhengzhou, CN, 450052, China.;The Henan Academy of Medical and Pharmacologic Sciences, Department of Neuroimmunology Research, No. 40 of Daxue Road, Zhengzhou, CN, 450052, China.;The Henan Academy of Medical and Pharmacologic Sciences, Department of Neuroimmunology Research, No. 40 of Daxue Road, Zhengzhou, CN, 450052, China.;The Henan Academy of Medical and Pharmacologic Sciences, Department of Neuroimmunology Research, No. 40 of Daxue Road, Zhengzhou, CN, 450052, China.;The Second Affiliated Hospital of Zheng-Zhou University, Department of Thoracic Surgery, No. 2 of Jingba Road, Zhengzhou, CN, 450014, China.;Basic Medical College, Zhengzhou University, Department of Immunology and Microbiology, No. 100 of Science Road, Zhengzhou, CN, 450001, China.;The Second Affiliated Hospital of Zheng-Zhou University, Department of Thoracic Surgery, No. 2 of Jingba Road, Zhengzhou, CN, 450014, China.;The First Affiliated Hospital of Henan University of TCM, Department of Encephalopathy, No. 19 of People's Road, Zhengzhou, CN, 450008, China.;The First Affiliated Hospital of Henan University of TCM, Department of Encephalopathy, No. 19 of People's Road, Zhengzhou, CN, 450008, China.;The Henan Academy of Medical and Pharmacologic Sciences, Department of Neuroimmunology Research, No. 40 of Daxue Road, Zhengzhou, CN, 450052, China. Electronic address: gaoyuanshan@126.com.",
"authors": "Li|Mingqiang|M|;Ren|Lu|L|;Zhang|Yingna|Y|;Lv|Jie|J|;Fang|Hua|H|;Zhang|Jing|J|;Zhao|Xue|X|;Han|Jiaojiao|J|;Huang|Pengwei|P|;Du|Ying|Y|;Zhang|Qingyong|Q|;Yang|Junhong|J|;Zhang|Yunke|Y|;Gao|Feng|F|",
"chemical_list": "D001323:Autoantibodies; D011950:Receptors, Cholinergic; D020794:Receptor Protein-Tyrosine Kinases",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.clineuro.2018.06.041",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-8467",
"issue": "172()",
"journal": "Clinical neurology and neurosurgery",
"keywords": "Acetylcholine receptor antibody; Double-seropositive myasthenia gravis (DSP-MG); Muscle-specific tyrosine kinase antibody; Myasthenia gravis (MG)",
"medline_ta": "Clin Neurol Neurosurg",
"mesh_terms": "D001323:Autoantibodies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis; D020794:Receptor Protein-Tyrosine Kinases; D011950:Receptors, Cholinergic; D012737:Sex Factors; D013934:Thymectomy",
"nlm_unique_id": "7502039",
"other_id": null,
"pages": "69-73",
"pmc": null,
"pmid": "29986198",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Clinical characteristics of AChRAb and MuSKAb double seropositive myasthenia gravis patients.",
"title_normalized": "clinical characteristics of achrab and muskab double seropositive myasthenia gravis patients"
} | [
{
"companynumb": "CN-BAUSCH-BL-2018-022224",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "1",
... |
{
"abstract": "Coagulopathy in pediatric leukemia patients is typically associated with acute promyelocytic leukemia or after asparaginase use in acute lymphoblastic leukemia. Rarely seen in acute lymphoblastic leukemia, we report 2 patients who presented with normal coagulation markers, but subsequently developed severe hypofibrinogenemia and bleeding in induction before administration of asparaginase. In both cases, cryoprecipitate was administered as initial treatment for bleeding associated with the hypofibrinogenemia. One patient was refractory to cryoprecipitate replacement and required treatment with human fibrinogen concentrate due to the persistence of hypofibrinogenemia with significant bleeding. The hypofibrinogenemia was transient in both cases and resolved within a few weeks.",
"affiliations": "Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, GA.",
"authors": "Raikar|Sunil S|SS|;Felker|James|J|;Patel|Kavita N|KN|;Lew|Glen|G|;Sidonio|Robert F|RF|",
"chemical_list": "C026912:cryoprecipitate coagulum; D005169:Factor VIII; D005340:Fibrinogen; D001215:Asparaginase",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001114",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "40(7)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000347:Afibrinogenemia; D001215:Asparaginase; D002648:Child; D005169:Factor VIII; D005260:Female; D005340:Fibrinogen; D006470:Hemorrhage; D006801:Humans; D060828:Induction Chemotherapy; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016896:Treatment Outcome",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e470-e472",
"pmc": null,
"pmid": "29401102",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acquired Hypofibrinogenemia Before Asparaginase Exposure During Induction Therapy for Pediatric Acute Lymphoblastic Leukemia: A Report of 2 Cases and Review of the Literature.",
"title_normalized": "acquired hypofibrinogenemia before asparaginase exposure during induction therapy for pediatric acute lymphoblastic leukemia a report of 2 cases and review of the literature"
} | [
{
"companynumb": "US-PFIZER INC-2018428072",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": "3",... |
{
"abstract": "Radiation recall dermatitis (RRD) is an inflammatory reaction in an area of the skin previously irradiated for cancer treatment. The reaction usually occurs following the administration of a cytotoxic drug. Manifestations range from mild to severe, resulting in tissue necrosis. It is treated with removal of the probable causative agent, daily dressings and surgical debridement of the necrotic area.\nA 54-year-old woman had a previous diagnosis of intraductal carcinoma in situ, and had been submitted to lumpectomy and adjuvant radiotherapy and hormonal therapy. One year after surgery, sores suggestive of herpes zoster infection developed, and treatment with acyclovir was started. At the same time, there was the onset of pain and fever. In the skin area previously irradiated, there was breast hardening, skin infiltration and serosanguinolent discharge. An incisional biopsy was performed to rule out radioinduced sarcoma. The patient was treated with surgical debridement.\nThis case report describes acyclovir as a possible trigger of RRD, a rare condition that could have been mistaken for an eruption with other causes. In this case, the dermatitis reaction was confined to the previously irradiated area of the skin, which suggested radiation recall. A better understanding of the condition's mechanism and about the possible joint effects of drugs and radiotherapy on the skin is necessary.",
"affiliations": "University of Western São Paulo, Presidente Prudente, Brazil.;University of Western São Paulo, Presidente Prudente, Brazil.;University of Western São Paulo, Presidente Prudente, Brazil.;Santa Casa de São Paulo, São Paulo, Brazil.;University of Western São Paulo, Presidente Prudente, Brazil.",
"authors": "Zorzan|Marcos Tumitan|MT|;de Mello Pereira|Renata|R|;Lima|Lucas Farina|LF|;de Arruda Mattos|Tatiana Veri|TV|;Sá|Rafael|R|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5603/RPOR.a2021.0058",
"fulltext": "\n==== Front\nRep Pract Oncol Radiother\nRep Pract Oncol Radiother\nReports of Practical Oncology and Radiotherapy\n1507-1367\n2083-4640\nVia Medica\n\n10.5603/RPOR.a2021.0058\nrpor-26-3-475\nCase Report\nRadiodermatitis as a consequence of radiation recall induced by acyclovir: case report\nZorzan Marcos Tumitan 1\nde Mello Pereira Renata 1\nLima Lucas Farina 1\nde Arruda Mattos Tatiana Veri 2\nSá Rafael 13\n1 University of Western São Paulo, Presidente Prudente, Brazil\n2 Santa Casa de São Paulo, São Paulo, Brazil\n3 Federal University of São Paulo, São Paulo, Brazil\nAddress for correspondence: Marcos Tumitan Zorzan, University of Western São Paulo, Presidente Prudente, Brazil, 19.050-920, tel: 0800-7715533; e-mail: marcostzorzan@gmail.com\n2021\n09 6 2021\n26 3 475480\n06 10 2020\n24 2 2021\n© 2021 Greater Poland Cancer Centre\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially\nBackground\n\nRadiation recall dermatitis (RRD) is an inflammatory reaction in an area of the skin previously irradiated for cancer treatment. The reaction usually occurs following the administration of a cytotoxic drug. Manifestations range from mild to severe, resulting in tissue necrosis. It is treated with removal of the probable causative agent, daily dressings and surgical debridement of the necrotic area.\n\nCase presentation\n\nA 54-year-old woman had a previous diagnosis of intraductal carcinoma in situ, and had been submitted to lumpectomy and adjuvant radiotherapy and hormonal therapy. One year after surgery, sores suggestive of herpes zoster infection developed, and treatment with acyclovir was started. At the same time, there was the onset of pain and fever. In the skin area previously irradiated, there was breast hardening, skin infiltration and serosanguinolent discharge. An incisional biopsy was performed to rule out radioinduced sarcoma. The patient was treated with surgical debridement.\n\nConclusions\n\nThis case report describes acyclovir as a possible trigger of RRD, a rare condition that could have been mistaken for an eruption with other causes. In this case, the dermatitis reaction was confined to the previously irradiated area of the skin, which suggested radiation recall. A better understanding of the condition’s mechanism and about the possible joint effects of drugs and radiotherapy on the skin is necessary.\n\nradiation recall dermatitis\nradiodermatitis\nradiotherapy\nacyclovir\nintraductal carcinoma in situ\n==== Body\nIntroduction\n\nRadiation recall is defined as an inflammatory reaction on a region of the body previously irradiated by radiotherapy [1–3] usually occurring after administration of certain trigger agents, such as antineoplastic and chemotherapy drugs, antituberculosis medication, antibiotics, tamoxifen, simvastatin, and exposure to ultraviolet light [2]. The site most commonly affected by radiation recall is the skin, and in this case, it is described as radiation recall dermatitis (RRD) [3].\n\nThe manifestations of RDD vary in intensity and include maculopapular eruptions with erythema and vesicle formation, peeling of the affected skin and even severe skin necrosis, occurring days to years after the radiation, even when there was little or no residual reaction resulting from prior radiation sessions [1]. RRD is not necessarily an acute skin reaction during or at the end of the radiotherapy sessions [3].\n\nRadiotherapy uses high-energy or gamma rays directly on the tumor or on the affected site after the surgical intervention, promoting local control of the tumor and the death of cancer cells that remained after surgery [4, 5]. Radiotherapy typically causes sensitivity up to 7 days after the sessions. RRD, instead, is triggered after the use of drugs [6].\n\nRRD is a well-known but poorly understood phenomenon, mainly because of the lack of animal models. There is a myriad of hypotheses that explain the pathophysiological of RDD, like vascular damage, epithelial stem cell inadequacy, epithelial stem cell sensitivity and drug hypersensitivity reaction [7]. The theory of alteration in vascular permeability argues that previous radiotherapy changes the pharmacokinetics of the inducing drug, promoting the inflammatory reaction [6]. The epithelial stem cell inadequacy hypothesis proposes that the radiation reduces the number of stem cell and overall skin stability, yielding a cell proliferation response triggered by the drug [8, 9]. The epithelial stem cell sensitivity hypothesis relies on the fact that radiation promotes a stable long-term alteration in the epithelial cell phenotype [10], which in some cases promotes a faster rate cell cycling, increasing the number of dead cells [11]. The most acceptable hypothesis, however, is drug hypersensitivity, where the recall is caused by an idiosyncratic drug reaction activating inflammatory pathways that are not immune-dependent [7, 12].\n\nIn this report, we describe a case of RRD in a patient treated for breast cancer. The woman was operated for intraductal carcinoma one year before the onset of RRD and received prophylactic treatment with radiotherapy and tamoxifen. The RRD event reported here was triggered by oral acyclovir, an antiviral drug with viral replication inhibiting the activity of herpes simplex virus type 1 (HSV-1), 2 (HSV-2) and varicella-zoster virus (VZV) [3]. The drug has, as common adverse events, malaise, nausea, diarrhea, headache and, in rarer cases, immune thrombocytopenia [3]. However, the relationship with RRD has not yet been described.\n\nCase presentation\n\nA 54-year-old white woman sought medical attention in September 2015 in a city in the interior of the state of São Paulo with a complaint of spontaneous nipple bleeding associated with pain during physical exercise. She worked as a seamstress. The patient was married, had had four pregnancies, all cesareans, and no family history of breast cancer, but had a history of ovarian cyst surgical removal. She reported menopause at 42 years.\n\nOn physical examination, the breasts were symmetrical, with no nodules visualizations, architectural distortions or suspicion of calcifications. There was uniductal bloody papillary effusion on the left side, with the trigger point at 6 o’clock. Mammography and breast ultrasonography were performed, both coming with a BI-RADS 1 report. Despite imaging exams showing normality, the persistence of the suspicious serosanguinous secretion led the patient to be referred to the Regional Hospital’s mastology outpatient clinic at Presidente Prudente, São Paulo state, with the indication of lumpectomy/resection of the main ducts in the left breast.\n\nThe surgical procedure resected a fragment of the breast’s tissue for histopathological evaluation. The final diagnosis was intraductal carcinoma in situ of low grade, with a 3-mm single focus, of cribriform standard, with ductal ectasia, chronic mastopathy alterations, columnar cell alterations with foci of dystrophic calcification, and typical ductal hyperplasia with a 1-mm single focus and free circumferential surgical margins. The immunohistochemistry evaluation of the same material assessed the expression of C-erbB-2 (Her-2 SP3), Ki-67 (Mab SP6), estrogen receptor (SP1) and progesterone Receptor (SP2). The immunohistochemistry profile result showed positivity for estrogen receptors in about 80% of neoplastic cells, progesterone receptors in about 30%, high rate of cell proliferation measured by Ki-67 (over 14%) and negativity for overexpression of epidermal growth Her-2 factor.\n\nAfter hospital discharge, the patient was referred to radiotherapy, performed in 33 sessions, in the total dose of 5040 cGy (180 cGy/day). The patient also started the use of tamoxifen 20 mg/day as hormonal therapy.\n\nOne year after the surgery, the patient visited a dermatologist complaining of sores on the left breast, local hardening and unchecked fever for about 15 days. She reported being diagnosed as having herpes zoster by a pharmacist in a drugstore near home and that she had started to use acyclovir (200 mg, every 6 hours during 14 days). During acyclovir use, breast pain started, and the general clinical condition worsened. Because the patient self-medicated, there was no possibility to perform a microbiological analysis of pathological tissue to confirm herpes virus presence. The dermatologist noticed, on physical examination, erythema, skin hardening and infiltration throughout the left breast, and the presence of serosanguinolent discharge, without signs of herpes zoster or other skin problems. She was then referred back to the mastologist (Fig. 1A).\n\nAt the Regional Hospital, an investigation was conducted with chest and upper abdomen computed tomography, and biopsy of the dermal material from the left breast for anatomopathological examination. At the macroscopy exam, the first skin fragment taken for pathological examination was the size of 1.0 cm × 0.6 cm, with a finely grainy surface, brownish color and firm and elastic consistency; in the cuts, the surface was grayish-white. The second fragment was sized 0.6 cm × 0.4 cm, presented on the surface a 0.3 cm raised lesion, of vegetative aspect, gray-brown and firm and elastic consistency; in the cuts; the surface was grayish-brown.\n\nThe histopathological evaluation indicated acute erosive dermatitis, with vascular alterations suggestive of radiotherapy effects and absence of neoplasia (Fig. 2A and 2B). Imaging exams did not show signs of local or distant tumor recurrence. After complete anamnesis and complementary exams, the diagnostic hypothesis was radiation recall.\n\nThe patient was treated with repeated surgical debridements (Fig. 1B) associated with papain and SAF-gels (Fig. 1C) as recommended by the plastic surgery team. The patient was also referred for treatment with a hyperbaric chamber (Fig. 1D), and underwent 20 sessions. Breast reconstruction surgery with a graft has been scheduled.\n\nDiscussion and Conclusion\n\nThe patient in the RRD case reported here had a previous diagnosis of grade 2 carcinoma in situ with free margins and positive estrogen hormone receptor (ER-positive), treated with oncological surgery associated with radiotherapy and use of tamoxifen. According to Fischer et al., protocol B-17 [13], the addition of radiotherapy as an adjuvant treatment after surgery results in the reduction of local recurrence and, significantly, invasive carcinoma, playing a role as a preventive agent, since it destroys cancer cells and affects the precursors of these cells [13–15]. After 12 years of follow-up of patients submitted to the protocol B-17, the reduction in the annual incidence rate of all ipsilateral tumors, invasive or not, remained at 58% per year. The results found in the treatment of ductal carcinoma in situ by the European Organization for Research and Treatment of Cancer (EORTC), are similar to NSABP B17, in which a reduction in local recurrence rate was observed when the group submitted to the lumpectomy was treated with radiotherapy [15]. The use of tamoxifen, a selective estrogen receptor modulator [16], in patients with positive estrogen receptors provides a lower rate of ipsilateral recurrence, as well as a reduction in the occurrence of a new contralateral tumor and recurrence in the form of invasive carcinoma, according to the NSABP protocol B24 [13, 15, 17]. Therefore, both treatments were well justified for this patient at the time.\n\nOnly one report describes recall dermatitis related to the use of acyclovir, with some uncommon adverse skin reactions described with the use of acyclovir: vesicular dermatitis involving palms and soles, peripheral edema, erythema nodosum, rashes, hyperhidrosis, acne, lichenoid and skin rash, pruritus, urticaria, vasculitis and alopecia1. In that case, published in 2002, the rash appeared on the seventh day after oral acyclovir use, with small macules and erythematous papules involving the trunk and limbs symmetrically and bilaterally, along with the dermatomes previously affected by herpes varicella zoster [1]. However, the characteristics of active herpes varicella-zoster infection were not histopathologically verified by the authors, although the cutaneous eruption secondary to acyclovir was more intense in regions previously affected by the virus. Furthermore, the area of lesions had not been irradiated previously [1].\n\nRRD is widely described in the literature, occurring in patients who underwent radiotherapy with symptoms precipitated after the use of specific drugs, such as actinomycin D, adriamycin, bleomycin, docetaxel, etoposide, 5-fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, simvastatin, tamoxifen, and antituberculosis medication, such as rifampicin, isoniazid and pyrazinamide, trimetrexate and vinblastine, and also other triggering agents, such as ultraviolet radiation [6, 7]. The radiodermatitis presents in four degrees of toxicity: grade 1 (mild) with erythema, pruritus and dry flaking, grade 2 (mild-moderate) with pain, edema, urticaria or the appearance of vesicles, grade 3 (moderate) with wet desquamation and grade 4 (severe) with necrosis, ulcer or hemorrhage [7, 18].\n\nThe pathophysiology of RRD is unknown, but several hypotheses are described. One of the hypotheses is that changes in vascular permeability in the irradiated area would alter the drug’s kinetics in that region, creating a hypersensitivity reaction, leading to acute inflammation [19]. Another accepted theory is related to radiation changes in localized cellular DNA, promoting the increased expression of inflammatory cytokines, such as interleukins 1 and 6 (IL-1, IL-6) and tumor necrosis factor-alpha (TNF-alpha), in the presence of the event-inducing drug [20].\n\nThe patient here described, after acyclovir use for the treatment of unproven herpes zoster infection, presented something different from a drug eruption: the onset of breast pain, dermal lesions and fever (not measured), progressing to grade 4 radiodermatitis, with serosanguinolent secretion accompanied by erythema, hardening and infiltration in the skin of the left breast, in areas previously irradiated. There was no sign of herpes zoster and no involvement of the breast tissue. Once the probable causative agent (acyclovir) was removed, and daily dressings and surgical debridement were performed, the patient’s condition improved without complications. Imaging exams excluded the possibility of locoregional or distant tumor recurrence. The anatomopathological examination indicated acute erosive dermatitis with vascular alterations suggestive of radiotherapy effect and absence of neoplasia in the material, which suggested RRD due to the use of acyclovir as a diagnosis.\n\nFor the treatment of ductal carcinoma in situ, whenever possible, the conservative treatment is the choice, followed by radiation therapy and endocrine therapy to reduce the risk of local, contralateral recurrence and invasive carcinoma [13]. However, in some cases, total mastectomy is indicated, and immediate breast reconstruction should be considered [13]. To achieve a therapeutic success and prevent recurrence, clinical and imaging evaluation should be performed periodically, with patient informed about the risks.\n\nThe manifestation of RRD is described in different degrees of tissue involvement induced by different drug classes. However, it has not been described before in association with the use of acyclovir specifically. There are no precise descriptions of the pharmacological agents or classes of drugs that can induce RRD. Hence, for optimal diagnosis and management of patients with RRD, it is necessary to consider all the possible adverse effects of medications used after radiation, even months after radiotherapy. Also, it is advisable to use the lowest effective radiotherapy dose for the disease. This case report describes acyclovir as a possible trigger of radiation recall dermatitis, a rare condition that could have been mistaken for an eruption with other causes. In the present case, the dermatitis reaction was confined to the previously irradiated area of the skin, which suggested radiation recall dermatitis.\n\nAcknowledgements\n\nWe acknowledge our patient for providing informed consent for this case report and for her willingness to have her clinical experience published, Tatiana Veri de Arruda Mattos for the work in the Pathology Department in offering the original images and data related to this article and Rafael Sá for the clinical and surgical management of the patient.\n\nFigure 1 Clinical evolution of the patient with radiation recall dermatitis. A. Hyperemic breast with serosanguinolent secretion seen one year after breast cancer treatment. B. Aspect of the breast after surgical debridement. C. Supportive treatment with papain and SAF-gel. D. Aspect of breast healing process between hyperbaric therapy sessions.\n\nFigure 2 Histopathological evaluation of the patient with radiation recall dermatitis. A. Hematoxylin-eosin stain with 40 × magnification showing intense neutrophilic exudate throughout the epidermis and dermis. B. Hematoxylin-eosin stain with 100 × magnification showing ulcerated epidermis with foci of parakeratosis and acanthosis, liquefactive and atypical reactions of the basal layer. In the dermis, fibrosis and elastosis are noted, with intense fibrinoid exudate and vascular thickening with extravasation of red blood cells\n\nConflict of interests\n\nThe authors declare that they have no competing interests.\n\nFunding\n\nNone to declare.\n\nAuthors’ contributions\n\nM.T.Z. and R.M.P. wrote this report. R.S. and L.F.L. revised the manuscript. T.V.A.M. provided the images used in the report. M.T.Z., L.F.L., R.M.P. and R.S. saw the patient in hospital and contributed the case history notes used in this report. R.S. performed the clinical treatment and the lumpectomy. All authors read and approved the final manuscript.\n==== Refs\nReferences\n\n1 Carrasco L Pastor MA Izquierdo MJ Drug eruption secondary to aciclovir with recall phenomenon in a dermatome previously affected by herpes zoster Clin Exp Dermatol 2002 27 2 132 134 10.1046/j.1365-2230.2002.00990.x 11952706\n2 Azria D Magné N Zouhair A Radiation recall: a well recognized but neglected phenomenon Cancer Treat Rev 2005 31 7 555 570 10.1016/j.ctrv.2005.07.008 16168567\n3 Hong X Wang X Wang Z A rare case report of acyclovir-induced immune thrombocytopenia with tongue hematomas as the first sign, and a literature review BMC Pharmacol Toxicol 2017 18 1 12 10.1186/s40360-017-0120-2 28264696\n4 Simon A Robb K Cancer: Breast Cambridge Handbook of Psychology, Health and Medicine 2nd ed Cambridge University Press Cambridge 2014 577 580\n5 Sharma GN Dave R Sanadya J Various types and management of breast cancer: an overview J Adv Pharm Technol Res 2010 1 2 109 126 22247839\n6 Boström A Sjölin-Forsberg G Wilking N Radiation recall. another call with tamoxifen Acta Oncol 1999 38 7 955 959 10.1080/028418699432653 10606426\n7 Camidge R Price A Characterizing the phenomenon of radiation recall dermatitis Radiother Oncol 2001 59 3 237 245 10.1016/s0167-8140(01)00328-0 11369064\n8 Hellman S Botnick L Stem cell depletion: An explanation of the late effects of cytotoxins Int J Radiat Oncol Biol Phys 1977 2 1–2 181 184 10.1016/0360-3016(77)90028-1 849898\n9 Seymour CB Mothersill C Alper T High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation Int J Radiat Biol Relat Stud Phys Chem Med 1986 50 1 167 179 10.1080/09553008614550541 3487520\n10 Wright EG Radiation-induced genomic instability in haemopoietic cells Int J Radiat Biol 1998 74 6 681 687 10.1080/095530098140943 9881712\n11 Abadir R Liebmann J Radiation reaction recall following simvastatin therapy: a new observation Clin Oncol (R Coll Radiol) 1995 7 5 325 326 10.1016/s0936-6555(05)80545-x 8580062\n12 Wintroub B Stern R Cutaneous drug reactions: Pathogenesis and clinical classification J Am Acad Dermatol 1985 13 2 167 179 10.1016/s0190-9622(85)70156-9 2931455\n13 Fisher B Costantino J Redmond C Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer N Engl J Med 1993 328 22 1581 1586 10.1056/NEJM199306033282201 8292119\n14 Fisher B Dignam J Wolmark N Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17 J Clin Oncol 1998 16 2 441 452 10.1200/JCO.1998.16.2.441 9469327\n15 Fisher B Land S Mamounas E Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience Semin Oncol 2001 28 4 400 418 10.1016/s0093-7754(01)90133-2 11498833\n16 Patterson J Furr B Wakeling A The biology and physiology of ‘Nolvadex’ (tamoxifen) in the treatment of breast cancer Br Cancer Res Treat 1982 2 4 363 374 10.1007/bf01805878\n17 Rhee J Kim GE Lee CH Radiation recall dermatitis induced by tamoxifen during adjuvant breast cancer treatment Radiat Oncol J 2014 32 4 262 265 10.3857/roj.2014.32.4.262 25568855\n18 Mehta K Kaubisch A Tang J Radiation Recall Dermatitis in Patients Treated with Sorafenib Case Rep Oncol Med 2018 2018 2171062 10.1155/2018/2171062 29670787\n19 Phillips T Fu K Quantification of combined radiation therapy and chemotherapy effects on critical normal tissues Cancer 1976 37 S2 1186 1200 10.1002/1097-0142(197602)37:2+<1186::aidcncr2820370830>3.0.co;2-v 766958\n20 Oanţă A Irimie M Radiation Recall Dermatitis induced by Tamoxifen Med Sci 2012 5 54 113 116\n\n",
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"keywords": "acyclovir; intraductal carcinoma in situ; radiation recall dermatitis; radiodermatitis; radiotherapy",
"medline_ta": "Rep Pract Oncol Radiother",
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"title": "Radiodermatitis as a consequence of radiation recall induced by acyclovir: case report.",
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"abstract": "OBJECTIVE\nTo observe the efficacy and adverse reaction of the improvement program of cladribine combined with cytarabine (2-CdA+Ara-C) in treatment of children with refractory high-risk Langerhans cell histiocytosis (LCH).\n\n\nMETHODS\n13 patients with refractory high-risk LCH or recurrent LCH were treated by combined 2-CdA+Ara-C chemotherapy. The treatment efficacy and the disease state in the process were evaluated according to the Histiocyte Society Evaluation and Treatment Guidelines (2009). The drug toxicity was evaluated according to the Common Terminology Criteria Adverse Events Version 4.0 (CTCAE v4.0, 2009).\n\n\nRESULTS\nOf 13 patients, 10 cases achieved non active disease (NAD); 2 patients with liver cirrhosis before the improvement program with CIP-LCH-2012 gave up the treatment after 1 course of therapy; 1 patient died of infectious shock after chemotherapy with severe pulmonary infection and intestinal infection. All 13 patients had grade 3 of blood and lymphatic system toxicity; 10 patients had grade 1 of hepatobiliary and gastrointestinal side effects; 3 patients with liver cirrhosis before the improvement program had grade 2 or grade 3 of hepatobiliary system and gastrointestinal system side effects, including 1 patient of death.\n\n\nCONCLUSIONS\nThe improvement program of CIP-LCH-2012 had significant efficacy for children with refractory high-risk and relapsed LCH. The cladribine-associated toxicity was of significant myelosuppression, which may be tolerated in the most children patients. The program could be considered as a recommended salvage therapy for multi-system LCH (MS-LCH) after failure of first-line therapy, and as a first-line therapy for MS-LCH with risk organ injury. The program should be used with caution or dose-adjustment consideration for pre-treatment of severe organ damage exist, especially cirrhosis.",
"affiliations": "The Department of Hematology, The Capital Institute of Pediatrics, Beijing 100020, China.;The Department of Hematology, The Capital Institute of Pediatrics, Beijing 100020, China.;The Department of Hematology, The Capital Institute of Pediatrics, Beijing 100020, China.;The Department of Hematology, The Capital Institute of Pediatrics, Beijing 100020, China.;The Department of Hematology, The Capital Institute of Pediatrics, Beijing 100020, China.;The Department of Hematology, The Capital Institute of Pediatrics, Beijing 100020, China.;The Department of Hematology, The Capital Institute of Pediatrics, Beijing 100020, China.;The Department of Hematology, The Capital Institute of Pediatrics, Beijing 100020, China.;The Department of Hematology, The Capital Institute of Pediatrics, Beijing 100020, China.",
"authors": "Hu|Tao|T|;Liu|Rong|R|;Li|Junhui|J|;Cao|Jing|J|;Zhang|Lei|L|;Li|Juanjuan|J|;Fan|Wei|W|;Zhong|Dixiao|D|;Shi|Xiaodong|X|",
"chemical_list": "D007166:Immunosuppressive Agents; D017338:Cladribine",
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"mesh_terms": "D002648:Child; D017338:Cladribine; D006646:Histiocytosis, Langerhans-Cell; D006801:Humans; D007166:Immunosuppressive Agents; D012307:Risk Factors; D016879:Salvage Therapy",
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"abstract": "BACKGROUND\nPrognostic outcomes and safety following treatment with pembrolizumab in patients with advanced urothelial carcinoma (UC) have not been fully elucidated in clinical practice. The aim of this study was to evaluate the oncological efficacy and safety of pembrolizumab after failure of platinum-based chemotherapy in Japanese patients with advanced UC in a routine clinical setting.\n\n\nMETHODS\nThis retrospective study included 41 consecutive Japanese patients with advanced UC treated with pembrolizumab as second-line or greater therapy at Iwate Medical University Hospital from January 2018 to April 2019.\n\n\nRESULTS\nThe mean follow-up period was 6.2 months. The objective response rate, median progression-free survival, and median overall survival were 15%, 2.5 months, and 11.9 months, respectively. Univariate analysis identified poor performance status (> 1), liver metastasis, two or more metastatic organs, low hemoglobin levels, two or more prior regimens, high baseline C-reactive protein levels, higher relative C-reactive protein level change after 6 weeks, and higher relative neutrophil-to-lymphocyte ratio change after 6 weeks as significant predictors of overall survival. Among these factors, poor performance status (> 1), two or more metastatic organs, and higher relative neutrophil-to-lymphocyte ratio change after 6 weeks were identified as independent predictors of overall survival in multivariate analysis.\n\n\nCONCLUSIONS\nThe introduction of pembrolizumab can result in favorable cancer control outcomes in Japanese patients with advanced UC, and the prognosis of these patients can be stratified according to three potential parameters, including poor performance status, high number of metastatic organs, and higher relative neutrophil-to-lymphocyte ratio change.",
"affiliations": "Department of Urology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 020-3694, Japan. m08066dt@jichi.ac.jp.;Department of Urology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 020-3694, Japan.;Department of Urology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 020-3694, Japan.;Department of Urology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 020-3694, Japan.;Department of Urology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 020-3694, Japan.;Department of Urology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 020-3694, Japan.;Department of Urology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 020-3694, Japan.;Department of Urology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 020-3694, Japan.;Department of Urology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 020-3694, Japan.;Department of Urology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 020-3694, Japan.;Department of Urology, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 020-3694, Japan.",
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"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D002097:C-Reactive Protein; D005260:Female; D006801:Humans; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome; D014571:Urologic Neoplasms",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "899-905",
"pmc": null,
"pmid": "31907720",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prognostic outcomes and safety in patients treated with pembrolizumab for advanced urothelial carcinoma: experience in real-world clinical practice.",
"title_normalized": "prognostic outcomes and safety in patients treated with pembrolizumab for advanced urothelial carcinoma experience in real world clinical practice"
} | [
{
"companynumb": "JP-009507513-2001JPN005888",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nTo compare tocolysis with magnesium sulfate versus atosiban regarding the occurrence of short-term preterm labor and maternal side effects during and after open fetal myelomeningocele (MMC) repair.\n\n\nMETHODS\nA prospective nonrandomized cohort study was performed including 30 fetal MMC cases. The first 15 cases (group 1) received magnesium sulfate according to the MOMS protocol. In the following 15 cases (group 2), magnesium sulfate was substituted by atosiban. Chorioamniotic membrane separation (CMS), premature prelabor rupture of the fetal membranes (PPROM), preterm delivery <3 weeks after fetal MMC repair, and maternal complications due to the tocolytic medication were the major endpoints.\n\n\nRESULTS\nIn both groups, one CMS but no PPROM was diagnosed <3 weeks after fetal MMC repair. One patient of group 2 delivered <3 weeks after fetal MMC repair because of an intraoperative placental abruption at 25 weeks. All women of group 1 showed an electrolyte imbalance during magnesium sulfate administration. One woman of group 1 developed several episodes of a third-degree atrioventricular block within the first 3 days after fetal surgery. Lethargy was found in all women during magnesium sulfate therapy. No maternal side effects were found under atosiban.\n\n\nCONCLUSIONS\nThe use of atosiban resulted in an almost identical short-term uterine outcome without any serious maternal complications as seen when magnesium sulfate was given. Thus, the authors suggest using atosiban instead of magnesium sulfate in the context of open fetal surgery.",
"affiliations": "Zurich Center for Fetal Diagnosis and Therapy, Zurich, Switzerland.",
"authors": "Ochsenbein-Kölble|Nicole|N|;Krähenmann|Franziska|F|;Hüsler|Margret|M|;Meuli|Martin|M|;Moehrlen|Ueli|U|;Mazzone|Lucca|L|;Biro|Peter|P|;Zimmermann|Roland|R|",
"chemical_list": "D015149:Tocolytic Agents; C047046:atosiban; D008278:Magnesium Sulfate; D014668:Vasotocin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000478261",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1015-3837",
"issue": "44(1)",
"journal": "Fetal diagnosis and therapy",
"keywords": "Atosiban; Fetal myelomeningocele repair; Fetal surgery; In utero surgery; Magnesium sulfate; Tocolysis",
"medline_ta": "Fetal Diagn Ther",
"mesh_terms": "D000328:Adult; D005260:Female; D046128:Fetal Therapies; D006801:Humans; D008278:Magnesium Sulfate; D011247:Pregnancy; D011446:Prospective Studies; D015145:Tocolysis; D015149:Tocolytic Agents; D014668:Vasotocin",
"nlm_unique_id": "9107463",
"other_id": null,
"pages": "59-64",
"pmc": null,
"pmid": "28813702",
"pubdate": "2018",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Tocolysis for in utero Surgery: Atosiban Performs Distinctly Better than Magnesium Sulfate.",
"title_normalized": "tocolysis for in utero surgery atosiban performs distinctly better than magnesium sulfate"
} | [
{
"companynumb": "CH-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-183019",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MAGNESIUM SULFATE"
},
... |
{
"abstract": "The BRAFV600E mutation is the most common driver mutation in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC). This mutation is considered actionable and, for BRAFV600E-mutated ATC, a BRAF inhibitor (dabrafenib) in combination with an MEK inhibitor (trametinib) is FDA approved. BRAF inhibitors have also shown efficacy in BRAFV600E-mutated PTC. However, as with all targeted therapies, resistance to these drugs eventually develops. It is essential that we understand the mechanisms of resistance to the BRAF inhibitors in thyroid cancer to develop future strategies to effectively treat these patients and improve survival. Herein, we describe four patients with thyroid cancer treated with selective BRAF inhibitors, who developed a RAS mutation in addition to the BRAFV600E mutation at progression. Patients 1 and 3 acquired a KRASG12V mutation in the progressive tumor, patient 2 acquired a NRASQ61K mutation in a progressive lymph node, and patient 4 acquired NRASG13D mutation on liquid biopsy performed at the time of radiographic disease progression. Similar to the melanoma experience, the emergence of RAS mutations appears to act as a mechanism of resistance to BRAF inhibitors in thyroid cancers.",
"affiliations": "Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Diagnostic Radiology, and The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.",
"authors": "Cabanillas|Maria E|ME|;Dadu|Ramona|R|;Iyer|Pryianka|P|;Wanland|Kacey B|KB|;Busaidy|Naifa L|NL|;Ying|Anita|A|;Gule-Monroe|Maria|M|;Wang|Jennifer R|JR|;Zafereo|Mark|M|;Hofmann|Marie-Claude|MC|",
"chemical_list": "D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf",
"country": "United States",
"delete": false,
"doi": "10.1089/thy.2019.0514",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1050-7256",
"issue": "30(9)",
"journal": "Thyroid : official journal of the American Thyroid Association",
"keywords": "anaplastic thyroid cancer; clonal divergence; dabrafenib; differentiated thyroid cancer; drug resistance; genetic mutations; kinase inhibitors; molecular testing; mutational pathways; papillary thyroid cancer",
"medline_ta": "Thyroid",
"mesh_terms": "D003625:Data Collection; D018450:Disease Progression; D011905:Genes, ras; D006801:Humans; D007167:Immunotherapy; D000073890:Liquid Biopsy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D000072078:Positron Emission Tomography Computed Tomography; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D000077273:Thyroid Cancer, Papillary; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9104317",
"other_id": null,
"pages": "1288-1296",
"pmc": null,
"pmid": "32216548",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12670889;31085763;12068308;24265153;15195111;30036146;22448344;29156680;29631033;25417114;28058658;27127178;30353166;29969659;25907612;27416373;29962848;29742974;24798740;22180178;26636651;22170714;21107323;24628546;27460442;22281684;27791198;22471242;19147753;23138171;29431699;30094711;29141224;22113612;31666701;8334704;1322500;23365119;23066120;23524406;30265861;21107320;23060265;22247021;29595366;22205714;19915144;29072975;21156289;3510078;18070147;22395615;23569304;6092966;21705440;23969188;12460919;23288408;22194965;16462768;26608120;18682506;27312529",
"title": "Acquired Secondary RAS Mutation in BRAFV600E-Mutated Thyroid Cancer Patients Treated with BRAF Inhibitors.",
"title_normalized": "acquired secondary ras mutation in brafv600e mutated thyroid cancer patients treated with braf inhibitors"
} | [
{
"companynumb": "US-ROCHE-2717087",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VEMURAFENIB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Serotonin syndrome is a rare neuropsychiatric complication caused by serotonergic drugs. Symptoms include confusion, psychosis, tremor, palpitations, hyperthermia, and the neurological examination shows signs of central nervous system deficits. This is a case report of a 67-year-old woman, who developed serotonin syndrome in the form of delusions, tremor, cerebellar ataxia and upper neuron signs one day after administration of low-dose mirtazapine therapy. Complete symptom remission occurred one week after the discontinuation of mirtazapine.",
"affiliations": "malinisagar@gmail.com.",
"authors": "Sagar|Malini|M|;Lindelof|Mette|M|;Boesen|Magnus Spangsberg|MS|",
"chemical_list": "D008803:Mianserin; D000078785:Mirtazapine",
"country": "Denmark",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-5782",
"issue": "182(19)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D008803:Mianserin; D000078785:Mirtazapine; D020230:Serotonin Syndrome",
"nlm_unique_id": "0141730",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32400384",
"pubdate": "2020-05-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Serotonin syndrome shortly after the administration of low-dose mirtazapine.",
"title_normalized": "serotonin syndrome shortly after the administration of low dose mirtazapine"
} | [
{
"companynumb": "DK-PFIZER INC-202101016018",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Bone is a frequent site of metastases in advanced cancers including lung, breast, prostate, kidney, or myeloma. Lesions are commonly located on the spine. Neoplastic invasion of the vertebral body can result in painful vertebral fractures, leading to disability and substantial morbidity. Percutaneous vertebroplasty is a minimally invasive surgical procedure used to treat spinal fractures due to osteolytic tumors. It could result in pain reduction or resolution in 80-90% of patients with fractures, and it improves stability. Although considered safe, vertebroplasty has been associated over the years with life-threatening complications. We have reported the case of a 55-year-old patient with lung adenocarcinoma, who underwent vertebroplasty for a pathological neoplastic fracture of L2. The procedure was complicated by a leak of cement into the systemic venous circulation, characterized by an 11-cm filament in the right heart chambers and multiple pulmonary emboli. To our knowledge, only one similar case was previously reported, involving an intracardiac cement filament longer than 10 cm. The data are scant, hence the importance of collecting and reporting possible complications about what is perceived as a rather safe procedure. The case highlights the need for a robust postprocedure imaging plan to detect complications, which can impact patients' morbidity and survival.",
"affiliations": "Department of Oncology, University Hospitals of Geneva, Geneva, Switzerland.;Department of Primary Care Medicine, University Hospitals of Geneva, Geneva, Switzerland.;Department of Oncology, University Hospitals of Geneva, Geneva, Switzerland.;Department of Oncology, University Hospitals of Geneva, Geneva, Switzerland.",
"authors": "Chevallier|Mathieu|M|;Chevallier-Lugon|Chloé|C|;Friedlaender|Alex|A|;Addeo|Alfredo|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000513492",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575\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\n10.1159/000513492\ncro-0014-0279\nCase Report\nVertebral Metastasis Treated by Vertebroplasty, a Cause of Respiratory Failure: Case Report and Literature Review\nChevallier Mathieu a\nChevallier-Lugon Chloé b\nFriedlaender Alex a\nAddeo Alfredo a*\naDepartment of Oncology, University Hospitals of Geneva, Geneva, Switzerland\nbDepartment of Primary Care Medicine, University Hospitals of Geneva, Geneva, Switzerland\n*Alfredo Addeo, Oncology Department, University Hospital Geneva, Rue Gabrielle-Perret-Gentil 4, Geneva 1205 (Switzerland), alfredo.addeo@hcuge.ch\nJan-Apr 2021\n2 3 2021\n2 3 2021\n14 1 279283\n27 11 2020\n27 11 2020\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nThis 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.\nBone is a frequent site of metastases in advanced cancers including lung, breast, prostate, kidney, or myeloma. Lesions are commonly located on the spine. Neoplastic invasion of the vertebral body can result in painful vertebral fractures, leading to disability and substantial morbidity. Percutaneous vertebroplasty is a minimally invasive surgical procedure used to treat spinal fractures due to osteolytic tumors. It could result in pain reduction or resolution in 80–90% of patients with fractures, and it improves stability. Although considered safe, vertebroplasty has been associated over the years with life-threatening complications. We have reported the case of a 55-year-old patient with lung adenocarcinoma, who underwent vertebroplasty for a pathological neoplastic fracture of L2. The procedure was complicated by a leak of cement into the systemic venous circulation, characterized by an 11-cm filament in the right heart chambers and multiple pulmonary emboli. To our knowledge, only one similar case was previously reported, involving an intracardiac cement filament longer than 10 cm. The data are scant, hence the importance of collecting and reporting possible complications about what is perceived as a rather safe procedure. The case highlights the need for a robust postprocedure imaging plan to detect complications, which can impact patients' morbidity and survival.\n\nKeywords\n\nBone metastasis\nLung cancer\nVertebroplasty\n==== Body\nIntroduction\n\nBone is a frequent site of metastases in advanced cancers including lung, breast, prostate, kidney or myeloma. Lesions are commonly located on the spine. Neoplastic invasion of the vertebral body can result in painful vertebral fractures, leading to disability and substantial morbidity [1]. Percutaneous vertebroplasty is a minimally invasive surgical procedure used to treat vertebral hemangiomas and spinal fractures due to osteoporosis or osteolytic tumors of the spine. This method leads to pain reduction or resolution in 80–90% of patients with fractures [2], and it improves stability. Generally considered safe [3], vertebroplasty has been associated over the years with life-threatening complications (i.e., compressive myelopathy and radiculopathy due to cement leakage) [4].\n\nHere, we describe the case of a 55-year-old patient with lung adenocarcinoma, who underwent vertebroplasty for a pathological neoplastic fracture of L2. The procedure was complicated by a leak of cement into the systemic venous circulation, characterized by an 11-cm filament in the right heart chambers and multiple pulmonary emboli. As cement is a friable material, the foreign body could not be removed in a secure manner, resulting in further migration into both pulmonary arteries. To our knowledge, only one similar case was previously reported, involving an intracardiac cement filament longer than 10 cm [5]. Data in the literature are scant, hence the importance of collecting and reporting possible complications about what is perceived as a rather safe procedure.\n\nThe case highlights the need for a robust postprocedure imaging plan to detect complications, which can impact patients' morbidity and survival.\n\nCase Report\n\nA 55-year-old female patient suffering from lung adenocarcinoma with a concomitant EGFR and KRAS mutation with metastatic bone and brain lesions was referred to our Oncology Department to undergo whole-brain radiotherapy. Given the nature of the mutations, systemic therapy was less likely to be highly effective [6, 7, 8]. Her medical history was also notable for vertebral metastases requiring L2 percutaneous cement vertebroplasty 1 month prior to admission. Furthermore, she suffered from Trousseau syndrome requiring anticoagulation with rivaroxaban. Upon admission, the physical examination revealed signs of respiratory distress. The chest X-ray showed a right lung infiltrate compatible with multilobar pneumonia, and revealed a dense, thread-like structure, facing the right mediastinum.\n\nLow-dose chest computed tomography (CT) scan was then performed, confirming the presence of an 11-cm foreign body of metallic density in the right ventricle, with a 5-cm extension in the right atrium (Fig. 1). The absence of these abnormalities on the CT scan prior to the vertebroplasty led us to the conclusion of cement embolization into the right heart chambers.\n\nReviewing the vertebroplasty report revealed the occurrence of minimal cement leakage into the paravertebral veins during the procedure. During hospitalization, the patient presented with sinus tachycardia, suggesting the presence of cement in the right atrium was a trigger for arrhythmia.\n\nThereafter, we failed to perform endovascular removal of the foreign object (Fig. 2), which was further complicated by migration of cement into the left pulmonary artery. Given the grim oncological prognosis of the patient, we decided to give up further invasive procedures and leave the cement in place. The numerous cement emboli remained throughout the hospitalization despite anticoagulation with rivaroxaban. Due to a new pulmonary embolism in the left pulmonary artery, the anticoagulation was changed to subcutaneous low-molecular-weight heparin. Unfortunately, our patient died a few weeks later of respiratory failure.\n\nDiscussion\n\nPathological fractures represent a significant proportion of vertebral fractures. Moreover, 70% of women with breast cancer, 70% of men with prostate cancer, and 40% of patients with lung cancer will develop bone metastases during the course of their disease [9].\n\nPercutaneous vertebroplasty was described in 1987 by Galibert and colleagues as a minimally invasive treatment of hemangiomas. The use of vertebroplasty has since then expanded to include treatment of osteoporosis, pathological fractures related to spinal metastasis, and more rarely of traumatic fractures. Vertebroplasty for malignancy can be used as adjunctive therapy along with radiotherapy or chemotherapy. It is performed by interventional radiology specialists to stabilize vertebral fractures at risk for collapse or spinal cord compression.\n\nThis technique proved effective in the relief of pain related to metastatic fractures, and its indication for analgesic treatment of vertebral compression is widely recognized [10]. A similar approach with kyphoplasty, also corresponding to percutaneous injection of acrylic bone cement into the fracture, is possible. The difference between the two techniques is that kyphoplasty uses the inflation of a balloon in the vertebral body to create space before injecting the cement, to address curvature of the spine to restore height.\n\nStudies showed that patients with pathological vertebral fractures who were treated with vertebroplasty or kyphoplasty had a better functional outcome at 1 month follow-up than patients who received non-interventional management. They also demonstrated a marked reduction in back pain and improvement in quality of life, with fewer patients using pain medications. Improvement in functional status, quality of life, and pain persisted until 1 year after the procedure. Because of the limited improvement in patients with a conservative treatment, some investigators suggest that vertebroplasty should be considered as an early treatment option for patients with cancer who have symptomatic vertebral fractures [11]. Defining exact patient selection criteria is difficult due to a lack of consensus in the literature, but trials have shown better outcomes when vertebroplasty occurred within 6 weeks of sustaining a fracture for patients with severe pain and immobility [12].\n\nThere is an apparent increase in complication rates for vertebroplasty in cancer patients. The suggested reasons include the loss of cortical integrity and tumor angiogenesis. In the current literature, few cases are found assessing adverse outcomes related to the procedure. Most reports describe the occurrence of cement pulmonary emboli. Other complications of vertebroplasty include cement leakage in paravertebral veins, infection, and leaking in the dura. Our case is, to our knowledge, the first description of the finding of cement in the heart chambers, leading to cardiac arrhythmia which can be explained by irritation of the atrium. Furthermore, we outline that cement, when in contact with blood at 37°C, becomes filamentous and friable, making its removal challenging.\n\nConclusion\n\nVertebroplasty is a minimally invasive technique, proven to be effective to ease pain and improve quality of life in patients with vertebral metastases, with an overall low rate of complications. However, complications are possible, and some of them, such as cement embolization, can affect patients' prognosis.\n\nOur case report prompts us to consider this risk when weighing the pros and cons of the procedure. Moreover, it suggests the benefit of monitoring patients with evidence of periprocedural cement leakage as a key to avoid further complications.\n\nStatement of Ethics\n\nThe patient has provided written consent to disclose the case and the pictures.\n\nConflict of Interest Statement\n\nThe authors have no conflict of interest to disclose.\n\nFunding Sources\n\nNot funding was released or obtained for the present article.\n\nAuthor Contributions\n\nAll the authors contributed equally to the manuscript.\n\nFig. 1 Chest low-dose CT scan showing a foreign body of metallic density (arrow).\n\nFig. 2 Angioscopic view showing the fragmentation of the thread-like structure in the right ventricle, which then migrates to the left pulmonary artery.\n==== Refs\nReferences\n\n1 Friedlaender A Liu SV Passaro A Metro G Banna G Addeo A The role of performance status in small-cell lung cancer in the era of immune checkpoint inhibitors Clin Lung Cancer 2020 Nov 21 (6) e539 e543 32499210\n2 Ali Shaibani SA Bhatt H Vertebroplasty and kyphoplasty for the palliation of pain Semin Interv Radiol 2007 Stuttgart: Thieme\n3 Chew C Craig L Edwards R Moss J O'Dwyer PJ Safety and efficacy of percutaneous vertebroplasty in malignancy: a systematic review Clin Radiol 2011 66 (1) 63 72 21147301\n4 Bròdano GB Cappuccio M Gasbarrini A Bandiera S De Salvo F Cosco F et al Vertebroplasty in the treatment of vertebral metastases: clinical cases and review of the literature Eur Rev Med Pharmacol Sci 2007 11 (2) 91 17552138\n5 Makary MS Zucker IL Sturgeon JM Venous extravasation and polymethylmethacrylate pulmonary embolism following fluoroscopy-guided percutaneous vertebroplasty Acta Radiol Open 2015 4 (8) 2058460115595660 26331092\n6 Chevallier M Tsantoulis P Addeo A Friedlaender A Influence of concurrent mutations on overall survival in EGFR-mutated non-small cell lung cancer Cancer Genomics Proteomics 2020 17 (5) 597 603 32859638\n7 Friedlaender A Drilon A Weiss GJ Banna GL Addeo A KRAS as a druggable target in NSCLC: Rising like a phoenix after decades of development failures Cancer Treat Rev 2020 85 101978 32062493\n8 Torralvo J Friedlaender A Achard V Addeo A The activity of immune checkpoint inhibition in KRAS mutated non-small cell lung cancer: a single centre experience Cancer Genomics Proteomics 2019 Nov-Dec 16 (6) 577 82 31659111\n9 Macedo F Ladeira K Pinho F Saraiva N Bonito N Pinto L et al Bone metastases: an overview Oncol Rev 2017 11 (1) 321 28584570\n10 Klazen CA Lohle PN de Vries J Jansen FH Tielbeek AV Blonk MC et al Vertebroplasty versus conservative treatment in acute osteoporotic vertebral compression fractures (Vertos II): an open-label randomised trial Lancet 2010 376 (9746) 1085 92 20701962\n11 Berenson J Pflugmacher R Jarzem P Zonder J Schechtman K Tillman JB et al Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial Lancet Oncol 2011 12 (3) 225 35 21333599\n12 Montagu A Speirs A Baldock J Corbett J Gosney M A review of vertebroplasty for osteoporotic and malignant vertebral compression fractures Age Ageing 2012 41 (4) 450 5 22417981\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "14(1)",
"journal": "Case reports in oncology",
"keywords": "Bone metastasis; Lung cancer; Vertebroplasty",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "279-283",
"pmc": null,
"pmid": "33776717",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "20701962;32499210;21333599;28584570;22417981;31659111;21147301;32062493;17552138;26331092;32859638",
"title": "Vertebral Metastasis Treated by Vertebroplasty, a Cause of Respiratory Failure: Case Report and Literature Review.",
"title_normalized": "vertebral metastasis treated by vertebroplasty a cause of respiratory failure case report and literature review"
} | [
{
"companynumb": "CH-JNJFOC-20210628132",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": null,
... |
{
"abstract": "Reversible cerebral vasoconstriction syndrome(RCVS)is a clinical and radiological syndrome that is characterized by recurrent severe thunderclap headaches with or without other neurological symptoms and diffuse segmental constriction of cerebral arteries that usually resolves spontaneously within three months. Posterior reversible encephalopathy syndrome(PRES)is also a clinical and radiological syndrome characterized by headache, seizures, altered consciousness, cortical blindness, other focal neurological signs, and a diagnostic imaging picture of brain vasogenic edema. Both syndromes can occur in similar clinical contexts such as hypertension, pre-eclampsia/eclampsia, drug neurotoxicity, uremia, and some autoimmune diseases, and are frequently associated. Although the syndromes are usually fully reversible with early diagnosis and prompt treatment, some cases can develop hemorrhagic or ischemic brain lesions, often resulting in permanent disability. We need to be aware of the typical and atypical imaging manifestations of the syndromes to make an accurate diagnosis.",
"affiliations": "Department of Neurology and Neurovascular Medicine, Niigata City General Hospital.",
"authors": "Tada|Masayoshi|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.11477/mf.1436204396",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-2603",
"issue": "49(2)",
"journal": "No shinkei geka. Neurological surgery",
"keywords": null,
"medline_ta": "No Shinkei Geka",
"mesh_terms": "D002561:Cerebrovascular Disorders; D005260:Female; D006261:Headache; D051270:Headache Disorders, Primary; D006801:Humans; D054038:Posterior Leukoencephalopathy Syndrome; D011247:Pregnancy; D014661:Vasoconstriction",
"nlm_unique_id": "0377015",
"other_id": null,
"pages": "342-348",
"pmc": null,
"pmid": "33762455",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Reversible Cerebral Vasoconstriction Syndrome(RCVS)and Posterior Reversible Encephalopathy Syndrome(PRES).",
"title_normalized": "reversible cerebral vasoconstriction syndrome rcvs and posterior reversible encephalopathy syndrome pres"
} | [
{
"companynumb": "JP-BAXTER-2021BAX017650",
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{
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"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "We describe the case of a man with chromophobe renal cell carcinoma (chRCC) and numerous metastatic lesions restricted to the liver. Despite extensive courses of various systemic targeted chemotherapies, progressive disease was noted on CT and MRI and the patient suffered from persistent abdominal pain associated with his metastatic lesions. The liver lesions and associated symptoms were effectively palliated with serial transarterial chemoembolisation (TACE). While it is unclear if TACE has impacted his overall survival, this case encourages the use of TACE for palliative intent for patients with metastatic chRCC.",
"affiliations": "Department of Medicine, Virginia Mason Medical Center, Seattle, Washington, USA.;Floyd & Delores Jones Cancer Institute, Virginia Mason Medical Center, Seattle, Washington, USA.;Division of Interventional Radiology, Virginia Mason Medical Center, Seattle, Washington, USA.;Floyd & Delores Jones Cancer Institute, Virginia Mason Medical Center, Seattle, Washington, USA.",
"authors": "Whooley|Peter D|PD|;Flores|John Paul|JP|;Fotoohi|Mehran|M|;Lin|Bruce S|BS|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-229207",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(7)",
"journal": "BMJ case reports",
"keywords": "cancer intervention; interventional radiology; oncology; pain (palliative care); urological cancer",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D015746:Abdominal Pain; D000328:Adult; D002292:Carcinoma, Renal Cell; D016461:Chemoembolization, Therapeutic; D006801:Humans; D007680:Kidney Neoplasms; D008113:Liver Neoplasms; D008297:Male; D010166:Palliative Care; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31308185",
"pubdate": "2019-07-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22044519;23127803;25905562;25542065;11981011;26935559;24055389;26742998;14500854;28677067;26217079;22312487;9850836;30334003;27955832;20981218;20175033;21975434;22715810;19092099;17021903;28596261;25469271;25438288;26185343;20462447",
"title": "Palliative TACE for hepatic metastases of chromophobe renal cell carcinoma.",
"title_normalized": "palliative tace for hepatic metastases of chromophobe renal cell carcinoma"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0116371",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugaddit... |
{
"abstract": "BACKGROUND\nGuidelines for treatment of human immunodeficiency virus type 1 (HIV-1) infection consider lamivudine and emtricitabine to be interchangeable components in first-line combination antiretroviral therapy (cART). The evidence for their clinical equivalence in cART is inconsistent. The primary aim of this study was to evaluate the virological responses to lamivudine and emtricitabine in recommended cART.\n\n\nMETHODS\nThis was an observational study using data from the AIDS Therapy Evaluation in the Netherlands (ATHENA) nationwide HIV cohort. The virological responses to lamivudine and emtricitabine were compared by multivariable adjusted logistic regression and Cox proportional hazard models. Sensitivity analyses included propensity score-adjusted models.\n\n\nRESULTS\nTherapy-naive HIV-1-infected patients without baseline resistance (N = 4740) initiated lamivudine or emtricitabine with efavirenz/tenofovir or nevirapine/tenofovir. The use of lamivudine was associated with more virological failure at week 48 compared to emtricitabine with efavirenz/tenofovir (10.8% vs 3.6%; adjusted odds ratio [AOR], 1.78; 95% confidence interval [CI], 1.11-2.84) and nevirapine/tenofovir (27% vs 11%; AOR, 2.09; 95% CI, 1.25-3.52) in on-treatment analysis. Propensity score-adjusted models and intent-to-treat sensitivity analyses gave comparable results. The adjusted hazard ratio of virological failure at week 240 using lamivudine instead of emtricitabine was 2.35 (95% CI, 1.61-3.42) with efavirenz and 2.01 (95% CI, 1.36-2.98) with nevirapine. The inclusion of lamivudine or emtricitabine in cART did not influence the time to virological suppression within 48 weeks or the probability of virological rebound after successful virological suppression.\n\n\nCONCLUSIONS\nThe use of emtricitabine instead of lamivudine as part of cART was associated with better virological responses. These findings are relevant for settings with extensive use of lamivudine and for settings where generic lamivudine will be available.",
"affiliations": "Departments of Internal Medicine and Infectious Diseases.;Virology, Erasmus University Medical Center, Rotterdam.;Virology, Erasmus University Medical Center, Rotterdam.;Departments of Internal Medicine and Infectious Diseases.;Virology, Erasmus University Medical Center, Rotterdam.;Stichting HIV Monitoring, Amsterdam, The Netherlands.;Departments of Internal Medicine and Infectious Diseases.",
"authors": "Rokx|Casper|C|;Fibriani|Azzania|A|;van de Vijver|David A M C|DA|;Verbon|Annelies|A|;Schutten|Martin|M|;Gras|Luuk|L|;Rijnders|Bart J A|BJ|;|||",
"chemical_list": "D044966:Anti-Retroviral Agents",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciu763",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "60(1)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "HIV-1; antiretroviral therapy; emtricitabine; lamivudine; virological failure",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D023241:Antiretroviral Therapy, Highly Active; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D017211:Treatment Failure; D019562:Viral Load",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "143-53",
"pmc": null,
"pmid": "25273080",
"pubdate": "2015-01-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Increased virological failure in naive HIV-1-infected patients taking lamivudine compared with emtricitabine in combination with tenofovir and efavirenz or nevirapine in the Dutch nationwide ATHENA cohort.",
"title_normalized": "increased virological failure in naive hiv 1 infected patients taking lamivudine compared with emtricitabine in combination with tenofovir and efavirenz or nevirapine in the dutch nationwide athena cohort"
} | [
{
"companynumb": "NL-CIPLA LTD.-2014NL01963",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
},
"drugadditi... |
{
"abstract": "OBJECTIVE\nPneumonitis is a serious complication after radiotherapy of breast cancer. This study aimed to identify its prevalence and potential risk factors.\n\n\nMETHODS\nA total of 606 patients irradiated following breast-conserving surgery or mastectomy were retrospectively analyzed. In patients developing pneumonitis, radiation and clinical parameters were investigated to identify potential risk factors.\n\n\nRESULTS\nEleven patients (1.8%) developed a pneumonitis grade ≥2. Mean doses to the ipsilateral lung were >7 Gy in 5 patients (45%). Of the other patients, 5 had a chronic inflammatory disease. Six patients (55%) had another malignancy (4 previous contralateral breast cancers, 1 previous ovarian and thyroid cancer, 1 synchronous carcinoma-in-situ (pTis) at the contralateral breast). Five patients (45%) received chemotherapy including taxanes and 4 patients (36%) received trastuzumab.\n\n\nCONCLUSIONS\nThe prevalence of pneumonitis was 1.8%. Potential risk factors included mean radiation dose to ipsilateral lung >7 Gy, systemic treatment with taxanes or trastuzumab, chronic inflammatory disease and history of another malignancy.",
"affiliations": "Department of Radiation Oncology, University of Lübeck, Lübeck, Germany.;Department of Radiation Oncology, University of Lübeck, Lübeck, Germany.;Department of Pulmonology, University of Lübeck, Lübeck, Germany.;Department of Radiation Oncology, University of Lübeck, Lübeck, Germany dirk.rades@uksh.de.",
"authors": "Werner|Elisa M|EM|;Eggert|Marie C|MC|;Bohnet|Sabine|S|;Rades|Dirk|D|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D000074322:Antineoplastic Agents, Immunological; D011239:Prednisolone; D000068878:Trastuzumab",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.13847",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "39(11)",
"journal": "Anticancer research",
"keywords": "Breast cancer; irradiation; pneumonitis",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D000074322:Antineoplastic Agents, Immunological; D001943:Breast Neoplasms; D002278:Carcinoma in Situ; D005260:Female; D006801:Humans; D008168:Lung; D008408:Mastectomy; D015412:Mastectomy, Segmental; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary; D011239:Prednisolone; D015995:Prevalence; D017564:Radiation Pneumonitis; D012189:Retrospective Studies; D012307:Risk Factors; D000068878:Trastuzumab",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "6355-6358",
"pmc": null,
"pmid": "31704867",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prevalence and Characteristics of Pneumonitis Following Irradiation of Breast Cancer.",
"title_normalized": "prevalence and characteristics of pneumonitis following irradiation of breast cancer"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2019199460",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Blastobotrys proliferans is an ascomycetous yeast never previously reported as a human pathogen. Here we report a case of peritonitis due to Blastobotrys proliferans in a 46-year-old man undergoing peritoneal dialysis.",
"affiliations": "Service de Nephrologie, CHT de Nouvelle Caledonie, BP J5, 98849 Noumea. nquirin@mls.nc",
"authors": "Quirin|N|N|;Desnos-Ollivier|M|M|;Cantin|J F|JF|;Valery|J C|JC|;Doussy|Y|Y|;Goursaud|R|R|;Dromer|F|F|;Tivollier|J M|JM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1128/JCM.00967-07",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0095-1137",
"issue": "45(10)",
"journal": "Journal of clinical microbiology",
"keywords": null,
"medline_ta": "J Clin Microbiol",
"mesh_terms": "D001203:Ascomycota; D006801:Humans; D008297:Male; D008875:Middle Aged; D010531:Peritoneal Dialysis, Continuous Ambulatory; D010538:Peritonitis",
"nlm_unique_id": "7505564",
"other_id": null,
"pages": "3453-5",
"pmc": null,
"pmid": "17699647",
"pubdate": "2007-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12652395;15981767;14622394;14662994;4039915;8544086;9114410;9715630;16082004;16132775;16362599;16195909;16722037;16983940;17080102;17111161;17302754;17311592;10878412;10886585;10925564;11071981;11198600;11783780;11956874;12588489;10052546;15958040;12742319",
"title": "Peritonitis due to Blastobotrys proliferans in a patient undergoing continuous ambulatory peritoneal dialysis.",
"title_normalized": "peritonitis due to blastobotrys proliferans in a patient undergoing continuous ambulatory peritoneal dialysis"
} | [
{
"companynumb": "FR-PFIZER INC-202101813181",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": "3",
... |
{
"abstract": "Baloxavir marboxil (BM) is a novel drug with a cap-dependent endonuclease inhibitory action for influenza A or B; it is highly safe and requires just a single oral dose. Patients with severe heart failure use implantable ventricular assist device (iVAD) until transplantation, but they have an increased risk of thrombosis development. Their warfarin is administered based on point-of-care testing (POCT) with a strict control of prothrombin time-international normalized ratio (PT-INR).\n\n\n\nHere, we report a case of a patient with iVAD whose PT-INR was significantly increased from the target range after BM administration. The patient was a 45-year-old man and transplanted with iVAD; warfarin treatment was started when his PT-INR target range was 3.0-3.5. At home, he frequently self-measured PT-INR by POCT and precisely controlled the warfarin dose. He had a fever, was diagnosed with influenza A and was administered BM 40 mg. Thereafter, his PT-INR continued to increase, reaching 4.8 on day 12 of BM administration, exceeding his target range; warfarin was skipped for 1 day. In this case, based on the history of BM administration and clinical course, the increase in PT-INR could be due to BM. Considering the interaction between warfarin and BM, we suspected a possibility of competition for protein-binding sites. Increased PT-INR in the patient was detected early by POCT and thus severe bleeding was avoided.\n\n\n\nStrict monitoring of PT-INR when using BM in patients taking warfarin is of clinical importance.",
"affiliations": "Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Miyagi Japan.;Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Miyagi Japan.;Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Miyagi Japan.;Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Miyagi Japan.;Department of Cardiovascular Surgery, Tohoku University Hospital, Sendai, Miyagi Japan.;Organ Transplantation Center, Tohoku University Hospital, Sendai, Miyagi Japan.;Department of Cardiovascular Surgery, Tohoku University Hospital, Sendai, Miyagi Japan.;Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Miyagi Japan.",
"authors": "Kurosawa|Keiko|K|;Takasaki|Shinya|S|;Suzuki|Hisaki|H|;Sato|Yuji|Y|;Akiyama|Masatoshi|M|;Akiba|Miki|M|;Saiki|Yoshikatsu|Y|;Mano|Nariyasu|N|",
"chemical_list": "D000925:Anticoagulants; D003988:Dibenzothiepins; D009025:Morpholines; D011728:Pyridones; D014227:Triazines; C000628402:baloxavir; D014859:Warfarin",
"country": "Canada",
"delete": false,
"doi": "10.18433/jpps31375",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1482-1826",
"issue": "24()",
"journal": "Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques",
"keywords": null,
"medline_ta": "J Pharm Pharm Sci",
"mesh_terms": "D000925:Anticoagulants; D003988:Dibenzothiepins; D006333:Heart Failure; D006353:Heart-Assist Devices; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D011517:Prothrombin Time; D011728:Pyridones; D014227:Triazines; D014859:Warfarin",
"nlm_unique_id": "9807281",
"other_id": null,
"pages": "37-40",
"pmc": null,
"pmid": "33460556",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of an Increase in Prothrombin Time-International Normalized Ratio by Interaction Between Warfarin and Baloxavir Marboxil in a Patient on Implantable Ventricular Assist Device.",
"title_normalized": "a case of an increase in prothrombin time international normalized ratio by interaction between warfarin and baloxavir marboxil in a patient on implantable ventricular assist device"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1892839",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "1",
"... |
{
"abstract": "Development of pulmonary hypertension after initiation of diazoxide for the treatment of neonatal hyperinsulinemic hypoglycemia is a rare, but previously described association. Risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age and congenital heart disease. This novel case report describes an infant with noncompaction cardiomyopathy who developed pulmonary hypertension shortly after initiation of diazoxide for hyperinsulinemic hypoglycemia which resolved upon cessation of the drug. This case highlights the benefit of having pre-treatment knowledge of underlying cardiac anatomy and makes a case for routine echocardiographic screening for neonates initiating diazoxide treatment.",
"affiliations": "Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA.;Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA.;Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA.;Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI, USA.",
"authors": "Sullivan|Rachel T|RT|https://orcid.org/0000-0003-4580-9965;Tillman|Kathryn A|KA|;Kindel|Steven J|SJ|;Handler|Stephanie S|SS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2045894020987117",
"fulltext": "\n==== Front\nPulm Circ\nPulm Circ\nPUL\nsppul\nPulmonary Circulation\n2045-8932 2045-8940 SAGE Publications Sage UK: London, England \n\n10.1177/2045894020987117\n10.1177_2045894020987117\nCase Report\nDiazoxide-associated pulmonary hypertension in a patient with noncompaction cardiomyopathy\nhttps://orcid.org/0000-0003-4580-9965Sullivan Rachel T. Tillman Kathryn A. Kindel Steven J. Handler Stephanie S. Medical College of Wisconsin, Children’s Hospital of Wisconsin, Milwaukee, WI, USA\nStephanie S. Handler, MD 9000 W Wisconsin Ave, MS 217 Milwaukee, WI 53226, USA. Email: shandler@chw.org\n3 2 2021 \nJan-Mar 2021 \n11 1 204589402098711722 10 2020 18 12 2020 © The Author(s) 20212021SAGE Publications Ltd, or Pulmonary Vascular Research Institute, unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Development of pulmonary hypertension after initiation of diazoxide for the treatment of neonatal hyperinsulinemic hypoglycemia is a rare, but previously described association. Risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age and congenital heart disease. This novel case report describes an infant with noncompaction cardiomyopathy who developed pulmonary hypertension shortly after initiation of diazoxide for hyperinsulinemic hypoglycemia which resolved upon cessation of the drug. This case highlights the benefit of having pre-treatment knowledge of underlying cardiac anatomy and makes a case for routine echocardiographic screening for neonates initiating diazoxide treatment.\n\ncardiomyopathypediatric cardiovascular diseasepulmonary hypertensioncover-dateJanuary-March 2021typesetterts2\n==== Body\nCase description\nA term male infant, followed prenatally for a single umbilical artery and cerebral ventriculomegaly, presented with hypoglycemia at 8 h of age. Initially controlled on intravenous dextrose containing fluids, he ultimately maintained appropriate blood glucose levels on fortified ad lib feeds at one week of age. Postnatal workup for multiple congenital anomalies revealed mild cerebral ventriculomegaly and mild bilateral hydronephrosis. Initial echocardiogram demonstrated mild aortic isthmus hypoplasia without discrete coarctation, biventricular hypertrophy with prominent biventricular myocardial trabeculations, and an ostium secundum atrial septal defect (ASD) without signs of pulmonary hypertension.\n\nOn day of life 11, repeat echocardiogram more clearly demonstrated noncompaction cardiomyopathy with moderately diminished left ventricular function (ejection fraction 40%), mildly diminished right ventricular function, and no evidence of pulmonary hypertension. N-terminal-pro B-type natriuretic peptide (NT-pro-BNP) was elevated at 1760 pg/mL (lab normal <350 pg/mL), and enalapril was started for afterload reduction. He was hospitalized at three weeks of age for continued hypoglycemia and started on diazoxide when workup confirmed hyperinsulinism. He transiently required furosemide for pulmonary edema; however, prior to hospital discharge had clinically improved with NT-pro-BNP of 494 pg/mL and was discharged without diuretics. \n\nAt one month of age, he returned to cardiology clinic with lethargy and hypoxia with a systemic saturation of 62%. Echocardiogram demonstrated severe pulmonary hypertension with severe right atrial and ventricular dilation, interventricular septal flattening, mild right ventricular hypertrophy, mildly diminished right ventricular function, dilated main and branch pulmonary arteries, and bidirectional shunting at the ASD (Fig. 1). NT-pro-BNP was markedly elevated at 26,600 pg/mL. Saturations improved to 95% on supplemental oxygen via nasal cannula, and he was admitted. Due to concern for diazoxide-induced pulmonary hypertension given the temporal relation to drug initiation, diazoxide was discontinued. Three days after diazoxide discontinuation, echocardiogram demonstrated improvement in secondary findings of pulmonary hypertension, with improved right heart dilation and function, improved interventricular septal position, and left to right shunting across the ASD (Fig. 1). NT-pro-BNP had decreased to 1340 pg/mL. He weaned off supplemental oxygen and discharged after four days on no pulmonary vasodilator therapy with stable blood glucose off diazoxide.\n\nFig. 1. Panel (a) demonstrates Echocardiographic evidence of severe pulmonary hypertension after diazoxide initiation with severe interventricular septal flattening (a). Panel (b) shows Complete resolution of pulmonary hypertension within nine months of diazoxide discontinuation with normal interventricular septal configuration.\n\nWithin nine months following hospital discharge, he had no further evidence of pulmonary hypertension, and his left ventricular function normalized on ACE inhibitor monotherapy. Additionally, he was diagnosed with idiopathic interstitial lung disease based on chest CT demonstrating diffuse bilateral ground glass opacities with interlobular septal thickening and a new oxygen requirement well after resolution of his pulmonary hypertension. To date, no additional pulmonary laboratory or invasive testing has been pursued given mild nature of symptoms and no further evidence of pulmonary hypertension. He continues with routine pulmonary follow-up. Genetic testing revealed an unbalanced chromosomal translocation, with chromosome 1p36 deletion and 4q32 duplication. Regions involved in this translocation do not overlap with genes on commercially available gene panels for pulmonary hypertension, congenital hyperinsulinism, or left ventricular noncompaction.\n\nDiscussion\nThis case report describes a patient with noncompaction cardiomyopathy and chromosomal translocation who developed diazoxide-associated pulmonary hypertension. Immediate recognition and discontinuation of the diazoxide led to clinical improvement and resolution of pulmonary hypertension within several days.\n\nDiazoxide, a KATP channel opener, is the first-line therapy for the treatment of hyperinsulinemic hypoglycemia by inhibiting release of insulin from the pancreas. It also leads to smooth muscle cell relaxation with both systemic and pulmonary vasodilation.1 While diazoxide is well tolerated in the majority of infants receiving this therapy, there is a known association with the development of pulmonary hypertension. In 2015, the Federal Drug Agency (FDA) issued a drug safety communication citing 11 cases of diazoxide associated pulmonary hypertension.2\n\nThe first case report describing pulmonary hypertension in a patient treated with diazoxide was noted in 2004.3 Since that time, even in light of the FDA drug safety communication, less than 50 cases of diazoxide-associated pulmonary hypertension are reported in the literature. In series published from single centers or regional cohorts, the incidence of diazoxide-associated pulmonary hypertension is estimated to be 2.4–7%.4–6 Potential risk factors for development of diazoxide-associated pulmonary hypertension include lower gestational age, fluid overload, and congenital heart disease.4–6 Reported concomitant congenital heart disease diagnoses are variable in terms of hemodynamic significance and likelihood of potential contribution to pulmonary hypertension in the neonatal period, ranging from small ASD to patent ductus arteriosus to more complex lesions such as double outlet right ventricle and atrioventricular septal defect.3–8 There is one reported case associated with a restrictive cardiomyopathy.5\n\nDiazoxide’s initial clinical use was as an antihypertensive via its action as a systemic vasodilator. This prompted evaluation of diazoxide as a pulmonary vasodilator, with some report of efficacy in idiopathic pulmonary hypertension.9 The relationship between KATP channels and the development of pulmonary hypertension is complex, with differential expression of different channel subtypes depending on tissue type and physiologic state. Loss of function in one subtype can lead to heritable pulmonary hypertension.10 Gain of function in a different subtype causes a genetic disorder called Cantu syndrome, which manifests similarly to the side effects of diazoxide with edema, hypertrichosis, and pulmonary hypertension.10 One can speculate that some predisposition (e.g. a KATP channel gene mutation or overexpression) may lead to the diazoxide-associated pulmonary hypertension when stimulated by initiation of diazoxide therapy, similar to a “two-hit hypothesis” in other fields.\n\nTo the best of our knowledge, this report is the first case described in a patient with noncompaction cardiomyopathy in addition to an ASD. Noncompaction cardiomyopathy with left ventricular diastolic dysfunction may predispose to pulmonary arterial hypertension secondary to elevated post-capillary pressure; however, this is usually not a primary feature in young infants with cardiomyopathy. Importantly, our patient’s pulmonary hypertension was detected on what was intended as routine follow-up for his known cardiomyopathy, and he had not had prior echocardiographic or clinical evidence of significant diastolic dysfunction or restrictive physiology. Our center does not have routine echocardiogram protocols for initiating diazoxide treatment for neonatal hyperinsulinemic hypoglycemia. This case highlights the benefit of pre-treatment knowledge of underlying cardiac concerns and makes a case for routine post-treatment echocardiographic screening, particularly in patients with identifiable risk factors for development of pulmonary hypertension. Further, this adds to the body of literature of potential associations in this rare clinical entity.\n\nContributorship: Sullivan was a fellow at the time of data collection and patient involvement and was responsible for the primary composition of the written manuscript draft. Tillman and Kindel contributed with review of patient-specific details with regard to pulmonary hypertension and underlying cardiomyopathy, respectively. Handler contributed as senior author, with primary role in case selection and case report oversight. All authors were involved in review and final approval of this article.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: Written informed consent was obtained from the patient’s parent for patient information to be published.\n\nGuarantor: SH.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nORCID iD: Rachel T. Sullivan https://orcid.org/0000-0003-4580-9965\n==== Refs\nReferences\n1 Coetzee WA. \nMultiplicity of effectors of the cardioprotective agent, diazoxide.\n\nPharmacol Ther \n2013 ; \n140 : 167 –175\n.23792087 \n2 FDA Drug Safety Communication: FDA warns about a serious lung condition in infants and newborns treated with Proglycem (diazoxide) , www.fda.gov/drugs/drug‐safety‐and‐availabili ty/fda‐drug‐safetycommunication‐fda‐warns‐about‐serious‐lung‐\ncondition‐infants‐and‐newborns‐treated (2015, accessed 15 June 2020 ).\n3 Silvani P Camporesi A Mandelli A , et al\nA case of severe diazoxide toxicity.\n\nPediatr Anesth \n2004 ; \n14 : 607 –609\n.\n4 Chen SC Dastamani A Pintus D , et al\nDiazoxide-induced pulmonary hypertension in hyperinsulinaemic hypoglycaemia: recommendations from a multicentre study in the United Kingdom\n. Clin Endocrinol (Oxf) \n2019 ; \n91 : 770 –775\n.31520536 \n5 Herrera A Vajravelu ME Givler S , et al\nPrevalence of adverse events in children with congenital hyperinsulinism treated with diazoxide\n. J Clin Endocrinol Metab \n2018 ; \n103 : 4365 –4372\n.30247666 \n6 Thornton P Truong L Reynolds C , et al\nRate of serious adverse events associated with diazoxide treatment of patients with hyperinsulinism.\n\nHorm Res Paediatr \n2019 ; \n91 : 25 –32\n.30889588 \n7 Ziad A Antonín L Kateřina M , et al\nDevelopment of pulmonary hypertension in an infant treated with diazoxide for hyperinsulinism, a case report and literature review\n. Am J Pediatr \n2015 ; \n1 : 1 –3\n.\n8 Nebesio TD Hoover WC Caldwell RL , et al\nDevelopment of pulmonary hypertension in an infant treated with diazoxide\n. J Pediatr Endocrinol Metab \n2007 ; \n20 : 939 –944\n.17937066 \n9 Wang SW Pohl JE Rowlands DJ , et al\nDiazoxide in treatment of primary pulmonary hypertension.\n\nHeart \n1978 ; \n40 : 572 –574\n.\n10 McClenaghan C Woo KV Nichols CG. \nPulmonary hypertension and ATP-sensitive potassium channels: paradigms and paradoxes\n. Hypertension \n2019 ; \n74 : 14 –22\n.31132951\n\n",
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"medline_ta": "Pulm Circ",
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"title": "Diazoxide-associated pulmonary hypertension in a patient with noncompaction cardiomyopathy.",
"title_normalized": "diazoxide associated pulmonary hypertension in a patient with noncompaction cardiomyopathy"
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"abstract": "Bilateral internal carotid artery dissection (ICAD) is a rare but important cause of stroke in young adults. Anticoagulant and/or antiplatelet agents are usually recommended for stroke prevention;however, such treatments remain highly controversial, and there are inadequate data to compare the efficacy of anticoagulation and antiplatelet therapy. We herein report the case of 30-year-old man presenting with progressive bilateral ICAD during antiplatelet treatment. This report suggests the possibility that intramural hematomas are enlarged by antiplatelet and anticoagulant agents and draws attention to the medications associated with ICAD.",
"affiliations": "Department of Neurology, Ohme Municipal General Hospital, Japan.",
"authors": "Ohyagi|Masaki|M|;Tao|Osamu|O|;Mizutani|Tohru|T|;Takahashi|Mafuyu|M|;Mizusawa|Hidehiro|H|",
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"mesh_terms": "D000328:Adult; D020215:Carotid Artery, Internal, Dissection; D018450:Disease Progression; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors",
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"title": "Progression of bilateral internal carotid artery dissection during antiplatelet therapy.",
"title_normalized": "progression of bilateral internal carotid artery dissection during antiplatelet therapy"
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"abstract": "BACKGROUND\nSecondary hemophagocytic lymphohistiocytosis (sHLH) is a rare and fatal disease characterized by uncontrolled immune cell activation that can lead to a cytokine storm. Unfortunately, this condition can occur even during pregnancy, threatening both maternal and fetal lives.\n\n\nMETHODS\nA 23-year-old nulliparous woman at 26 weeks of gestation presented with continuous fever, coughing, and sore throat. Upon arrival at our hospital, her temperature was >38°C and laboratory findings indicated cytopenia (neutrophil count, 779/μL; hemoglobin level, 10.2 g/dL; platelet count, 29,000/μL), elevated ferritin level (1,308 ng/mL), and elevated soluble interleukin-2 receptor level (11,200 U/mL). Computed tomography showed marked splenomegaly. Bone marrow examination revealed hemophagocytosis, and blood examination showed a plasma Epstein-Barr virus (EBV) DNA level of 8.9 × 105 copies/μg. The monoclonal proliferation of EBV-infected T cells was confirmed by Southern blotting, and the patient was diagnosed with chronic active EBV-associated sHLH and T-cell lymphoproliferative disease. Immediately after admission, the patient's condition suddenly deteriorated. She developed shock and disseminated intravascular coagulation, requiring endotracheal intubation along with methylprednisolone pulse and etoposide therapy. Although the patient recovered, she delivered a stillborn baby. After delivery, she was treated with reduced-dose dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC) and steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapies. Five months after diagnosis, she received human leukocyte antigen-haploidentical allogeneic bone marrow transplantation from her sister. She remains in remission for 5 months from the time of transplantation to the present.\n\n\nCONCLUSIONS\nsHLH, which may cause maternal and fetal death, should be carefully considered in critically ill pregnant women, particularly those presenting with continuous fever and cytopenia.",
"affiliations": "Department of Obstetrics and Gynecology, Juntendo University Urayasu Hospital, Chiba, Urayasu City, Japan.;Department of Obstetrics and Gynecology, Juntendo University Urayasu Hospital, Chiba, Urayasu City, Japan. shintaro@juntendo.ac.jp.;Department of Hematology, Juntendo University Urayasu Hospital, Urayasu City, Chiba, Japan.;Department of Hematology, Juntendo University Urayasu Hospital, Urayasu City, Chiba, Japan.;Department of Obstetrics and Gynecology, Juntendo University Urayasu Hospital, Chiba, Urayasu City, Japan.",
"authors": "Takahashi|Masaya|M|;Makino|Shintaro|S|http://orcid.org/0000-0003-0258-361X;Iizuka|Hiroko|H|;Noguchi|Masaaki|M|;Yoshida|Koyo|K|",
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"doi": "10.1186/s12884-021-04150-4",
"fulltext": "\n==== Front\nBMC Pregnancy Childbirth\nBMC Pregnancy Childbirth\nBMC Pregnancy and Childbirth\n1471-2393\nBioMed Central London\n\n4150\n10.1186/s12884-021-04150-4\nCase Report\nChronic active Epstein–Barr virus-associated secondary hemophagocytic lymphohistiocytosis in pregnancy: a case report\nTakahashi Masaya 1\nhttp://orcid.org/0000-0003-0258-361X\nMakino Shintaro shintaro@juntendo.ac.jp\n\n1\nIizuka Hiroko 2\nNoguchi Masaaki 2\nYoshida Koyo 1\n1 grid.482669.7 0000 0004 0569 1541 Department of Obstetrics and Gynecology, Juntendo University Urayasu Hospital, Chiba Urayasu City, Japan\n2 grid.482669.7 0000 0004 0569 1541 Department of Hematology, Juntendo University Urayasu Hospital, Urayasu City, Chiba Japan\n7 10 2021\n7 10 2021\n2021\n21 68128 7 2021\n22 9 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nSecondary hemophagocytic lymphohistiocytosis (sHLH) is a rare and fatal disease characterized by uncontrolled immune cell activation that can lead to a cytokine storm. Unfortunately, this condition can occur even during pregnancy, threatening both maternal and fetal lives.\n\nCase presentation\n\nA 23-year-old nulliparous woman at 26 weeks of gestation presented with continuous fever, coughing, and sore throat. Upon arrival at our hospital, her temperature was >38°C and laboratory findings indicated cytopenia (neutrophil count, 779/μL; hemoglobin level, 10.2 g/dL; platelet count, 29,000/μL), elevated ferritin level (1,308 ng/mL), and elevated soluble interleukin-2 receptor level (11,200 U/mL). Computed tomography showed marked splenomegaly. Bone marrow examination revealed hemophagocytosis, and blood examination showed a plasma Epstein–Barr virus (EBV) DNA level of 8.9 × 105 copies/μg. The monoclonal proliferation of EBV-infected T cells was confirmed by Southern blotting, and the patient was diagnosed with chronic active EBV-associated sHLH and T-cell lymphoproliferative disease. Immediately after admission, the patient’s condition suddenly deteriorated. She developed shock and disseminated intravascular coagulation, requiring endotracheal intubation along with methylprednisolone pulse and etoposide therapy. Although the patient recovered, she delivered a stillborn baby. After delivery, she was treated with reduced-dose dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC) and steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapies. Five months after diagnosis, she received human leukocyte antigen-haploidentical allogeneic bone marrow transplantation from her sister. She remains in remission for 5 months from the time of transplantation to the present.\n\nConclusions\n\nsHLH, which may cause maternal and fetal death, should be carefully considered in critically ill pregnant women, particularly those presenting with continuous fever and cytopenia.\n\nKeywords\n\nSecondary hemophagocytic lymphohistiocytosis\nHemophagocytosis\nEpstein–Barr virus\nPregnancy\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nHemophagocytic lymphohistiocytosis (HLH) is an extremely rare and life-threatening disease characterized by excessive immune cell activation that may cause a cytokine storm [1–3], leading to severe tissue damage, cell death, and multiple organ failure [4]. HLH can be classified as either primary or secondary. Primary HLH is mainly observed as familial HLH, which develops in childhood in association with gene mutations, and can also present as inherited immune deficiency syndromes [5]. Secondary HLH (sHLH), also known as acquired HLH, is mainly caused by infections (50.4%), malignancies (47.7%), and autoimmune diseases (12.6%) [1, 6]. The epidemiology of HLH varies considerably depending on the population heterogeneity and variable underlying triggers [6]. In fact, sHLH is one of the most fatal diseases in adults, with a mortality rate of up to 41%, but the prognosis also depends on the underlying triggers [6]. Owing to potential malignancy, bone marrow examination (BME) should be performed to detect underlying tumors [1, 7]. Unfortunately, the fatal condition caused by sHLH can occur even during pregnancy and threaten both maternal and fetal lives via cytopenia-related complications, multiple organ failure, and aberrant cytokine storms [4, 8–10]. Considering its extremely rare occurrence during pregnancy, the exact etiology and appropriate management of sHLH during pregnancy remain unclear [8–11].\n\nAs pregnancy induces changes in clinical features and laboratory findings that appear similar to the clinical findings of sHLH, differentiating sHLH from other conditions becomes difficult [11–14]. Further, considering the likelihood of death because of delayed diagnosis and treatment, early diagnosis with immediate therapeutic intervention, including steroids, chemotherapies (such as etoposide), or hematopoietic stem cell transplantation (HSCT), is vital for treating sHLH [1, 11, 15]. The current report focuses on a novel case diagnosed with chronic active Epstein–Barr virus (CAEBV)-associated sHLH and T-cell lymphoproliferative disease during pregnancy.\n\nCase presentation\n\nA 23-year-old pregnant nulliparous woman at 26 weeks of gestation without any past medical history visited a general physician complaining of continuous fever for 3 weeks with a 2-day history of recent high fever, coughing, and sore throat. No history of recent foreign travel was noted. After excluding coronavirus disease 2019, she was transferred to our hospital owing to her critical status and admitted to maternal fetal intensive care unit. Physical examination revealed a fever (40.2°C) and tachycardia (142 beats/min) but normal blood pressure (102/56 mmHg) and respiratory rate (19/min). An initial nonstress test of the fetus showed normal baseline heart rate (140 beats/min) with moderate variability and acceleration in the absence of any deceleration. The fetal biophysical profile scoring indicated full marks. Laboratory tests showed cytopenia (neutrophil count, 779/μL; hemoglobin level, 10.2 g/dL; and platelet count, 29,000/μL), elevated C-reactive protein level (16.1 mg/dL), elevated ferritin level (1,308 ng/mL), and elevated soluble interleukin (IL)-2 receptor (sIL-2R) level (11,200 U/mL) (Table 1). No liver dysfunction was observed. Computed tomography from the thorax to the pelvis showed remarkable splenomegaly and bilateral multiple axillary lymphadenopathies (Fig. 1). Taken together, some underlying hematological etiology was suspected. Therefore, a hematologist was consulted soon after admission. BME on day 2 of hospitalization revealed hemophagocytosis (Fig. 2). Considering fever, splenomegaly, bicytopenia, hyperferritinemia, elevated sIL-2R level, and hemophagocytosis, the patient satisfied the clinical diagnostic criteria of sHLH (six out of eight). Thus, the patient was immediately started on methylprednisolone pulse (1,000 mg/day) and etoposide therapy (75 mg/m2/day) for hemophagocytosis. Broad spectrum antibiotics were also administered intravenously for treating sepsis of unknown origin. Owing to severe cytopenia and coagulation abnormality, the patient required a large amount of supporting blood products. According to the hematologist, changes in body temperature, platelet count, and serum ferritin levels indicated sHLH (Fig. 3). On day 3 of hospitalization, her serum ferritin level increased to >5,000 ng/mL. At this point, her condition suddenly deteriorated, and she developed shock and disseminated intravascular coagulation (DIC), prompting her transfer to the intensive care unit for endotracheal intubation and mechanical ventilation. Owing to high fetal mortality rates among the few studies on the prognosis of pregnancy-associated sHLH, an emergency cesarean section was considered. However, after discussions with the hematologist and emergency physician, we decided against the procedure because of the extreme critical status of the patient characterized by severe shock and DIC, preventing surgery. Our discussions also prompted us to prioritize maternal life considering her poor condition and the high mortality rate of sHLH. Throughout the disease course, obstetricians could only perform frequent assessments of fetal well-being via transabdominal ultrasound. Unfortunately, spontaneous fetal demise occurred at 27 weeks of gestation (day 4 of hospitalization).Table 1 Laboratory test on admission day\n\nLaboratory value\tValue\tNormal range or control\tUnit\t\nWBC\t19\t40–80\t102/μL\t\n Lymphocytes\t51\t25–45\t%\t\n Neutrophils\t41\t37–72\t%\t\n Neutrophil count\t779\t-\t/μL\t\nHb\t10.2\t12–16\tg/dL\t\nPlt\t2.9\t15–35\t104/μL\t\nCRP\t16.1\t0–0.3\tmg/dL\t\nBUN\t9\t8–22\tmg/dL\t\nCreatinine\t0.59\t0.47–0.79\tmg/dL\t\nTotal bilirubin\t0.6\t0.2–1.3\tmg/dL\t\nAST\t42\t13–33\tIU/L\t\nALT\t11\t8–42\tIU/L\t\nLDH\t630\t119–229\tIU/L\t\nFerritin\t1,308\t30–400\tng/mL\t\nTriglyceride\t234\t30–149\tmg/dL\t\nsIL-2R\t11,200\t157–474\tU/mL\t\nPT/INR\t0.97\t-\tINR\t\nAPTT\t37.5\t30.2\ts\t\nFibrinogen\t453\t150–400\tmg/dL\t\nEBV DNA\t8.9 × 105\t-\tcopies/mL\t\nAbbreviations: WBC white blood cell, Hb hemoglobin, Plt platelet, CRP C-reactive protein, BUN blood urea nitrogen, AST aspartate transaminase, ALT alanine transaminase, LDH lactate dehydrogenase, sIL-2R soluble interleukin-2 receptor, PT-INR prothrombin time/international normalized ratio, APTT activated partial thromboplastin time, EBV Epstein–Barr virus\n\nFig. 1 Computed tomography from the thorax to the pelvis showing remarkable splenomegaly and bilateral multiple axillary lymphadenopathy. A and B show splenomegaly. C shows bilateral multiple axillary lymphadenopathy (arrows)\n\nFig. 2 Hematoxylin and eosin staining of bone marrow aspirate showing hemophagocytosis. Scale bar, 20 μm\n\nFig. 3 Clinical course of the patient. The detailed clinical course, therapeutic interventions, and laboratory findings (EBV DNA level, ferritin level, and platelet count) are shown. Abbreviations: BT, body temperature; BME, bone marrow examination; EBV, Epstein–Barr virus; sHLH, secondary hemophagocytic lymphohistiocytosis; DIC, disseminated intravascular coagulation; CAEBV, chronic active EBV; Plt, platelet; PSL, prednisolone; mPSL, methyl PSL; ETP, etoposide; DeVIC, dexamethasone, etoposide, ifosfamide, and carboplatin; SMILE, steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide; BMT, bone marrow transplantation\n\nA critically high level of plasma EBV DNA level was observed on day 2 of hospitalization (8.9 × 105 copies/μg), suggesting EBV infection. Her peripheral blood examination showed positive immunoglobulin (Ig)G antibodies to the EBV early antigen and capsid antigen as well as negative IgM antibodies to the EBV capsid antigen, suggesting EBV infection reactivation. Southern blotting demonstrated monoclonal proliferation of EBV-infected T cells, whereas immunophenotyping was strongly positive for CD3, CD8, cytotoxic T cell-derived granzyme B, and EBV-encoded small RNA, suggesting the neoplastic proliferation of EBV-infected T cells. Based on these findings, the patient was diagnosed with CAEBV-associated T-cell lymphoproliferative disease. Patients with CAEBV often develop EBV-positive T or natural killer cell lymphomas. CAEBV is refractory to conventional chemotherapy and has a poor prognosis. At present, HSCT is the only curative therapy for CAEBV. Although steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy is the standard therapy for this condition, this could not be administered because of her poor health status. Thus, she was treated with reduced-dose dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC) chemotherapy along with prednisolone (PSL) therapy (days 6–13, PSL 80 mg/day; day 14–19, PSL 40 mg/day; after day 20, PSL 20 mg/day). Fortunately, she responded positively to these treatments. Her serum ferritin levels rapidly decreased to approximately 1,000 ng/mL soon after initiating methylprednisolone pulse and etoposide therapy. She became afebrile and no longer needed endotracheal intubation. Her platelet count gradually increased to normal levels, and her clinical condition improved on day 21 of hospitalization after reduced-dose DeVIC chemotherapy. On day 21 of hospitalization, plasma EBV DNA level decreased to 5.4 × 104 copies/μg, whereas other clinical findings suggested recovery from DIC and chemotherapy-derived bone marrow suppression. Thus, labor induction was planned as continuous pregnancy with a stillborn baby promotes DIC. Of note, the mere insertion of a stick for cervical dilation induced spontaneous labor, and she delivered an 840-g female baby who did not have any external malformations. As the patient and her family refused an autopsy of the baby, no further details could be determined. Placental and umbilical cord pathology revealed no abnormalities, such as chorioamnionitis (Fig. 4). Moreover, EBV-encoded small RNA in situ hybridization showed no EBV-infected lymphocytes in the placenta. Considering that no remarkable findings related to fetal death were noted and that the clinical features of sHLH were associated with hypercytokinemia, which leads to fetal death, we suspected that fetal demise was caused by excessive cytokine activity. To confirm this, maternal serum interferon-γ (IFN-γ) levels at admission were measured, showing marked elevation up to 380 IU/mL.Fig 4 Hematoxylin and eosin (HE) staining of the placenta. HE staining. Scale bar, 400 μm\n\nOn day 25 of hospitalization, she suddenly became febrile again and her condition deteriorated with progressive cytopenia, suggesting that reduced DeVIC chemotherapy was ineffective. Thus, we started second etoposide therapy (75 mg/m2/day) and SMILE chemotherapy. She responded to the therapies, and her platelet count returned to normal with a robust decline in plasma EBV DNA levels. For further treatment, she was transferred to another hospital that specializes in treating CAEBV. Five months after diagnosis, she received human leukocyte antigen-haploidentical allogeneic bone marrow transplantation from her sister. She remains in remission for 5 months from the time of transplantation to the present.\n\nDiscussion and conclusions\n\nThe current case report involved a novel and critical malignant case of CAEBV-associated sHLH during pregnancy with rapid deterioration, shock, and DIC. Considering the high maternal and fetal mortality rates among such cases, careful discussion regarding maternal and fetal life is needed when obtaining informed consent. In the present case, priority was given to maternal treatment because of her critical clinical status. In pregnant women diagnosed with sHLH, obstetricians are recommended to pay special attention to the fetus via frequent transabdominal ultrasounds and/or nonstress tests to assess fetal heartbeat and growth to appropriately discuss the possible next steps for the mother and baby.\n\nThis case highlights the importance of including sHLH as a differential diagnosis in critically ill pregnant women as this condition, if not detected, could be fatal for both the mother and fetus. While early diagnosis with immediate therapeutic intervention in the current case led to recovery, the patient still delivered a stillborn baby.\n\nThe pathophysiology of sHLH involves uncontrolled inflammatory responses with the excessive activation of immune cells, including IFN-γ-producing T cells [4]. Highly elevated IFN-γ promotes phagocytosis, leading to the overproduction of proinflammatory cytokines [4]. In the current case, the patient’s serum IFN-γ levels upon admission were markedly elevated, which may have caused severe tissue damage and resulted in multiple organ failure. During normal pregnancy, CD4+ helper T (Th) cells typically shift from Th1 to Th2 dominance for immune tolerance to the genetically foreign fetus; thus, humoral immunity is dominant over cell-mediated immunity [16]. However, in patients with sHLH, this homeostasis of immune cells during pregnancy collapses, leading to aberrant immune cell activities. In general, EBV, which was observed in the present case, mainly infects CD8+ T cells (also known as killer T cells) [17]. EBV-infected cytotoxic CD8+ T cells can impair their proper function, whereas activated CD8+ T cells suppress humoral immunity and drive continuous T cell hyperactivation, which is evident in sHLH [17].\n\nClinical findings are important to assess the pathology of sHLH. According to previous reports, peak serum ferritin levels >10,000 ng/mL are 90% sensitive and 96% specific for diagnosing sHLH [18]. Meanwhile, other studies have shown that serum sIL-2R levels (>2,515 U/mL) are 100% sensitive and 72.5% specific [19]. In our patient, the peak levels of serum ferritin and serum sIL-2R were 8,630 ng/mL (on day 5 of hospitalization) and 11,200 U/mL (on day 1 of hospitalization), respectively. Delayed sHLH diagnosis can result in death; however, we consulted the hematologist regarding her bicytopenia, which prompted timely diagnosis and proper therapeutic interventions (including steroids, etoposide, and other chemotherapies).\n\nOnly 44 cases of pregnancy-associated sHLH have been previously documented [8–10, 15, 20–24]. In these reports, maternal and fetal mortality were strikingly high at 20.5% (9 cases) and 27.3% (12 cases), respectively. Moreover, three cases of maternal death were caused by EBV infection. By contrast, an ex vivo study in humans by Aaltonen et al. demonstrated no evidence of transplacental transfer of several cytokines [25]. Further, some chronic inflammatory conditions, including human immunodeficiency virus 1 or hepatitis B virus infection, lead to higher cytokine levels in the umbilical cord blood that can affect fetal immune responses. In such cases, the fetus can be influenced by maternal cytokines through unknown mechanisms, possibly via the placenta [26, 27]. As our case received prompt and precise respiratory and circulatory support, we speculated that a maternal hyper-cytokine storm affected the fetus and caused fetal demise. Therefore, suppressing excessive immune response as soon as possible is crucial for preventing both maternal and fetal deaths.\n\nAlthough the exact etiology of pregnancy-induced sHLH remains unclear, a transition of fetal-derived components, including trophoblast debris and soluble RNA or DNA of fetal origins, into the maternal blood circulation might lead to abnormal immunological responses and trigger systemic inflammation, thereby causing cytokine storms [28, 29]. Previous reports showed that sHLH remission occurs after pregnancy termination via abortion or delivery [8, 28]; however, it remains unclear whether the termination itself contributes to sHLH remission. Indeed, other reports showed that deceased patients with sHLH showed progressive deterioration even after pregnancy termination [30], suggesting the difficulty of controlling cytokine storms once activated; this leads to a further hyperimmune state. Thus, preventing uncontrolled aberrant cytokine storms with rapid therapeutic interventions, such as steroids or etoposide, is imperative.\n\nBME is essential in patients suspected of sHLH, even during pregnancy, to detect hemophagocytosis and/or underlying malignancy. A recent study reported that BME did not reveal hemophagocytosis in approximately 30% of patients with sHLH and that hemophagocytosis occasionally could not be detected in the early stage of sHLH [7]. Thus, apart from repeated BME, determining whether clinical features and laboratory findings fulfill the sHLH criteria [31] and HScore, a tool used for diagnosing sHLH [32], is also required. Moreover, excluding the diagnosis of malignancy is crucial as patients with sHLH and lymphoma show poor prognosis. The overall survival rate of lymphoma-related sHLH is only 8% [33]. Most importantly, the treatment plan for sHLH differs depending on whether malignancy exists. By establishing the diagnosis of malignancy, chemotherapy or bone marrow transplantation can be initiated.\n\nRegarding lymphoma, it is important to be conscious of its transmission. Two cases of fetal transmission of maternally-derived lymphoma have been previously reported, with the infants presenting with symptoms similar to sHLH, including fever, tachycardia, hepatomegaly, and splenomegaly, within the first year of life [34, 35]. As the direct invasion of activated T cells to the placenta was not observed in the present case, we believe that no transmission to the fetus occurred. Hence, the close monitoring of newborn babies born to mothers with hematological malignancies is vital, particularly within the first year of life.\n\nThe etiology of lymphoma-related sHLH is another factor that should be considered. In the current case, sHLH symptoms appeared as a consequence of EBV reactivation that occurred during pregnancy. Haeri et al. who investigated the prevalence of EBV seropositivity in 64 healthy pregnant women [36], demonstrated that 22 (35%) women showed EBV reactivation during pregnancy, regardless of maternal age, race, parity, or insurance type [36]. Moreover, previous reports have clarified that EBV reactivation during pregnancy lead to poor obstetrical outcomes, such as fetal growth restriction [37], shorter pregnancy duration [38], and lower birth weight [38], despite not showing any symptoms. Thus, we recommend transabdominal ultrasound and/or nonstress tests to determine the presence of these complications.\n\nAs mentioned above, sHLH can occur even during pregnancy; thus, obstetricians could contribute to the early diagnosis of sHLH, provided that they have knowledge regarding its clinical features. Iron-deficiency anemia or gestational thrombocytopenia may progress with gestational age, the laboratory findings of which sometimes present simultaneously with bicytopenia, thereby satisfying the diagnostic criteria of sHLH [31]. Moreover, a progressive increase in serum triglyceride levels, one of the criteria of sHLH, has been observed during pregnancy. However, it might be confusing to discriminate between normal pregnancy status and sHLH only by these laboratory findings. Although some similarities exist between sHLH and pregnancy-related findings, the typical laboratory findings of sHLH, including neutropenia, low fibrinogen levels, and hyperferritinemia, are uncommon during pregnancy. Thus, in critically ill pregnant women with unremitting fever and bi- or pancytopenia (particularly neutropenia), sHLH should be considered. It is necessary to rapidly assess for splenomegaly and ferritin, fibrinogen, and soluble IL-2 receptor levels as well as determine whether the clinical features and laboratory findings satisfy the sHLH criteria [31] and HScore [32].\n\nHemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome should be carefully differentiated from sHLH. HELLP syndrome shares typical laboratory triads with sHLH; thus, differentiation between the two diseases can be confusing. In previous reports, four cases were misdiagnosed with HELLP syndrome instead of sHLH, and emergency cesarean section was performed. However, as their clinical condition did not improve even after delivery, the patients were rediagnosed with sHLH later [24, 33, 39, 40]. Therefore, it is important to consider sHLH when the patient shows no improvement even after pregnancy termination.\n\nSuppressing uncontrolled cytokine storm along with the intervention for underlying diseases is essential for treating sHLH [1]. Steroids, intravenous Ig, cyclosporine A, and etoposide are often used to control the hyperinflammatory state [1]. However, no established treatment guidelines are available for sHLH during pregnancy while the appropriate treatment is still being highly debated. Physicians tend to hesitate while prescribing immunosuppressants or chemotherapy considering the potential harm to the fetus. In previous reports, 16 cases were treated with etoposide for sHLH during the perinatal period, among which 7 cases (including our case) were safely treated with etoposide during pregnancy with severe sHLH [10, 15, 21, 30, 41]. As sHLH during pregnancy often occurs in the second trimester [8–10, 15, 20–24], we primarily considered fetal toxicity rather than fetal teratogenicity. Moreover, given that sHLH during pregnancy has a high mortality rate, the maternal clinical condition can be prioritized rather than harm to the fetus [10, 15, 42].\n\nWith regard to the timing of delivery, bone marrow suppression in the mother and fetus should be considered. In recent years, salvage therapies using JAK1/2 inhibitor ruxolitinib or IL-1 receptor antagonist anakinra for sHLH during pregnancy have been found to be effective [21, 22]. However, given that only a few such cases were included, the beneficial or adverse effects of these drug treatments need further investigations.\n\nThis study has a limitation that should be addressed. In particular, the follow-up period was short. The 30-day mortality of primary and secondary HLH treated with various regimens is 20%–44%, whereas the overall mortality rate is 50%–75% [4]. Hence, the patient must be continuously observed for a long time.\n\nIn conclusion, obstetricians and hematologists should consider sHLH as a differential diagnosis in critically ill pregnant women.\n\nAbbreviations\n\nHLH Hemophagocytic lymphohistiocytosis\n\nsHLH Secondary hemophagocytic lymphohistiocytosis\n\nBME Bone marrow examination\n\nHSCT Hematopoietic stem cell transplantation\n\nCAEBV Chronic active Epstein–Barr virus\n\nIL Interleukin\n\nsIL-2R Soluble IL-2 receptor\n\nDIC Disseminated intravascular coagulation\n\nEBV Epstein–Barr virus\n\nIg Immunoglobulin\n\nSMILE Steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide\n\nDeVIC Dexamethasone, etoposide, ifosfamide, and carboplatin\n\nPSL prednisolone\n\nIFN-γ Interferon-γ\n\nTh Helper T cell\n\nHELLP Hemolysis, elevated liver enzymes, and low platelets\n\nAcknowledgements\n\nWe acknowledge the whole team involved in the care of this patient. The authors would like to thank Enago (www.enago.jp) for the English language review.\n\nAuthors’ contributions\n\nMT was the principal investigator and drafted the manuscript with the help of SM, HI, MN, and KY. MT and HI contributed to data collection. MT, SM, HI, MN, and KY contributed to revising the manuscript. SM, MN, and KY supervised the study. All the authors followed up the patient. All authors have read and approved the final manuscript.\n\nFunding\n\nNo funding was received for this study.\n\nAvailability of data and materials\n\nAnonymized data are available from the corresponding author upon reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe Ethics Committee of Juntendo University Urayasu Hospital approved this research (Approval No. 3-002), and our patient provided written informed consent to participate in the study. Thus, data collection was permitted.\n\nConsent for publication\n\nOur patient provided written informed consent for publication. The documentation of the written consent will be provided to the journal upon request. All authors have read and approved the manuscript and agree with its submission to BMC Pregnancy and Childbirth.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. La Rosee P Horne A Hines M von Bahr Greenwood T Machowicz R Berliner N Recommendations for the management of hemophagocytic lymphohistiocytosis in adults Blood. 2019 133 2465 2477 10.1182/blood.2018894618 30992265\n2. Brisse E Wouters CH Matthys P Hemophagocytic lymphohistiocytosis (HLH): A heterogeneous spectrum of cytokine-driven immune disorders Cytokine Growth Factor Rev 2015 26 263 280 10.1016/j.cytogfr.2014.10.001 25466631\n3. Schulert GS Canna SW Convergent pathways of the hyperferritinemic syndromes Int Immunol 2018 30 195 203 10.1093/intimm/dxy012 29420734\n4. Schram AM Berliner N How I treat hemophagocytic lymphohistiocytosis in the adult patient Blood. 2015 125 2908 2914 10.1182/blood-2015-01-551622 25758828\n5. Janka GE Lehmberg K Hemophagocytic syndromes-an update Blood Rev 2014 28 135 142 10.1016/j.blre.2014.03.002 24792320\n6. Ramos-Casals M Brito-Zeron P Lopez-Guillermo A Khamashta MA Bosch X Adult haemophagocytic syndrome Lancet. 2014 383 1503 1516 10.1016/S0140-6736(13)61048-X 24290661\n7. Riviere S Galicier L Coppo P Marzac C Aumont C Lambotte O Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients Am J Med 2014 127 1118 1125 10.1016/j.amjmed.2014.04.034 24835040\n8. Cheng J Niu J Wang Y Wang C Zhou Q Chen Y Hemophagocytic lymphohistiocytosis in pregnancy: a case report and review of the literature J Obstet Gynaecol 2020 40 153 159 10.1080/01443615.2019.1601168 31215279\n9. Yildiz H Vandercam B Thissen X Komuta M Lanthier N Debieve F Hepatitis during pregnancy: a case of hemophagocytic lymphohistiocytosis Clin Res Hepatol Gastroenterol 2018 42 e49 e55 10.1016/j.clinre.2017.10.007 29239849\n10. Parrott J Shilling A Male HJ Holland M Clark-Ganheart CA Hemophagocytic lymphohistiocytosis in pregnancy: a case series and review of the current literature Case Rep Obstet Gynecol 2019 2019 9695367 30891322\n11. Liu L Cui Y Zhou Q Zhao H Li X Hemophagocytic lymphohistiocytosis during pregnancy: a review of the literature in epidemiology, pathogenesis, diagnosis and treatment Orphanet J Rare Dis 2021 16 281 10.1186/s13023-021-01790-9 34154616\n12. Cines DB Levine LD Thrombocytopenia in pregnancy Blood. 2017 130 2271 2277 10.1182/blood-2017-05-781971 28637667\n13. Sifakis S Pharmakides G Anemia in pregnancy Ann N Y Acad Sci 2000 900 125 136 10.1111/j.1749-6632.2000.tb06223.x 10818399\n14. Perez Botero J, Reese JA, George JN, McIntosh JJ. Severe thrombocytopenia and microangiopathic hemolytic anemia in pregnancy: a guide for the consulting hematologist. Am J Hematol. 2021. 10.1002/ajh.26328.\n15. Song Y Wang Z Hao Z Li L Lu J Kang H Requirement for etoposide in the treatment of pregnancy related hemophagocytic lymphohistiocytosis: a multicenter retrospective study Orphanet J Rare Dis 2019 14 50 10.1186/s13023-019-1033-5 30777105\n16. Whitacre CC Reingold SC O'Looney PA A gender gap in autoimmunity Science. 1999 283 1277 1278 10.1126/science.283.5406.1277 10084932\n17. Kasahara Y Yachie A Cell type specific infection of Epstein-Barr virus (EBV) in EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection Crit Rev Oncol Hematol 2002 44 283 294 10.1016/S1040-8428(02)00119-1 12467968\n18. Larroche C Hemophagocytic lymphohistiocytosis in adults: diagnosis and treatment Joint Bone Spine 2012 79 356 361 10.1016/j.jbspin.2011.10.015 22464018\n19. Hayden A Lin M Park S Pudek M Schneider M Jordan MB Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH Blood Adv 2017 1 2529 2534 10.1182/bloodadvances.2017012310 29296904\n20. Jawad S Dhariwal A Ellis L Cosgrove C Reyal Y Haemophagocytic lymphohistiocytosis in pregnancy Lancet Haematol 2020 7 e498 10.1016/S2352-3026(20)30101-0 32470441\n21. Wang S Wu J Jing X Zhang Y Tang H Wu J Etoposide combined with ruxolitinib for refractory hemophagocytic lymphohistiocytosis during pregnancy: a case report and literature review Hematology. 2019 24 751 756 10.1080/16078454.2020.1838708 33138732\n22. Yip KP Ali M Avann F Ganguly S Pregnancy-induced haemophagocytic lymphohistiocytosis J Intensive Care Soc 2020 21 87 91 10.1177/1751143718809678 32284723\n23. Neistadt B Carrubba A Zaretsky MV Natural killer/T-cell lymphoma and secondary haemophagocytic lymphohistiocytosis in pregnancy BMJ Case Rep 2018 2018 bcr2018224832 10.1136/bcr-2018-224832\n24. Kerley RN Kelly RM Cahill MR Kenny LC Haemophagocytic lymphohistiocytosis presenting as HELLP syndrome: a diagnostic and therapeutic challenge BMJ Case Rep 2017 2017 bcr2017219516 10.1136/bcr-2017-219516\n25. Aaltonen R Heikkinen T Hakala K Laine K Alanen A Transfer of proinflammatory cytokines across term placenta Obstet Gynecol 2005 106 802 807 10.1097/01.AOG.0000178750.84837.ed 16199639\n26. Bunders MJ van Hamme JL Jansen MH Boer K Kootstra NA Kuijpers TW Fetal exposure to HIV-1 alters chemokine receptor expression by CD4+T cells and increases susceptibility to HIV-1 Sci Rep 2014 4 6690 10.1038/srep06690 25341640\n27. Hong M Sandalova E Low D Gehring AJ Fieni S Amadei B Trained immunity in newborn infants of HBV-infected mothers Nat Commun 2015 6 6588 10.1038/ncomms7588 25807344\n28. Shukla A Kaur A Hira HS Pregnancy induced haemophagocytic syndrome J Obstet Gynaecol India 2013 63 203 205 10.1007/s13224-011-0073-0 24431639\n29. Moffett-King A Natural killer cells and pregnancy Nat Rev Immunol 2002 2 656 663 10.1038/nri886 12209134\n30. Giard JM Decker KA Lai JC Gill RM Logan AC Fix OK Acute liver failure secondary to hemophagocytic lymphohistiocytosis during pregnancy ACG Case Rep J 2016 3 e162 10.14309/crj.2016.135 27921061\n31. Henter JI Horne A Arico M Egeler RM Filipovich AH Imashuku S HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Pediatr Blood Cancer 2007 48 124 131 10.1002/pbc.21039 16937360\n32. Fardet L Galicier L Lambotte O Marzac C Aumont C Chahwan D Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome Arthritis Rheum 2014 66 2613 2620 10.1002/art.38690\n33. Chmait RH Meimin DL Koo CH Huffaker J Hemophagocytic syndrome in pregnancy Obstet Gynecol 2000 95 6 Pt 2 1022 1024 10808012\n34. Catlin EA Roberts JD Jr Erana R Preffer FI Ferry JA Kelliher AS Transplacental transmission of natural-killer-cell lymphoma N Engl J Med 1999 341 85 91 10.1056/NEJM199907083410204 10395632\n35. Yagasaki H Ohashi H Ito M Kobayashi S Kato M Shichino H A novel mechanism of transplacental cancer transmission: natural killer/T-cell lymphoma in the paratesticular region is of maternal origin Blood. 2011 117 6046 6047 10.1182/blood-2010-12-327627 21636718\n36. Haeri S Baker AM Boggess KA Prevalence of Epstein-Barr virus reactivation in pregnancy Am J Perinatol 2010 27 715 719 10.1055/s-0030-1253098 20387188\n37. Tomai XH Stillbirth following severe symmetric fetal growth restriction due to reactivation of Epstein-Barr virus infection in pregnancy J Obstet Gynaecol Res 2011 37 1877 1882 10.1111/j.1447-0756.2011.01662.x 21995502\n38. Eskild A Bruu AL Stray-Pedersen B Jenum P Epstein-Barr virus infection during pregnancy and the risk of adverse pregnancy outcome BJOG. 2005 112 1620 1624 10.1111/j.1471-0528.2005.00764.x 16305564\n39. Tumian NR Wong CL Pregnancy-related hemophagocytic lymphohistiocytosis associated with cytomegalovirus infection: a diagnostic and therapeutic challenge Taiwan J Obstet Gynecol 2015 54 432 437 10.1016/j.tjog.2014.11.023 26384065\n40. Sarkissian S Khan Y Farrell D Constable D Brem E Hemophagocytic lymphohistiocytosis in the setting of HELLP Syndrome Clin Case Rep 2018 6 2466 2470 10.1002/ccr3.1828 30564350\n41. Ikeda M Oba R Yoshiki Y Shingaki S Takei T Miyazaki K Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis during pregnancy Rinsho Ketsueki 2017 58 216 221 28381688\n42. Klein S Schmidt C La Rosee P Pletz M Harz S Dirsch O Fulminant gastrointestinal bleeding caused by EBV-triggered hemophagocytic lymphohistiocytosis: report of a case Z Gastroenterol 2014 52 354 359 10.1055/s-0034-1366154 24718941\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2393",
"issue": "21(1)",
"journal": "BMC pregnancy and childbirth",
"keywords": "Case report; Epstein–Barr virus; Hemophagocytosis; Pregnancy; Secondary hemophagocytic lymphohistiocytosis",
"medline_ta": "BMC Pregnancy Childbirth",
"mesh_terms": null,
"nlm_unique_id": "100967799",
"other_id": null,
"pages": "681",
"pmc": null,
"pmid": "34620104",
"pubdate": "2021-10-07",
"publication_types": "D016428:Journal Article",
"references": "30219776;21995502;12209134;21636718;16937360;29239849;24835040;24290661;32470441;10395632;27921061;24782338;28433984;30777105;28381688;10084932;20387188;12467968;25807344;29296904;22464018;25341640;16199639;28637667;24718941;10818399;30564350;25758828;34154616;24792320;24431639;34424560;26384065;30992265;25466631;16305564;29420734;30891322;10808012;32284723;33138732;31215279",
"title": "Chronic active Epstein-Barr virus-associated secondary hemophagocytic lymphohistiocytosis in pregnancy: a case report.",
"title_normalized": "chronic active epstein barr virus associated secondary hemophagocytic lymphohistiocytosis in pregnancy a case report"
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"abstract": "Adoptive immunotherapy using CD19-targeted Chimeric antigen receptor T cells (CAR-T) has revolutionized the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Data is limited on the propensity of infections and lymphohematopoietic reconstitution after Day 30 (D30) following CAR-T cell therapy. In this study, we evaluated the prevalence and nature of infectious complications in an expanded cohort of DLBCL patients treated with CD19 CAR-T therapy and its association with the dynamics of leukocyte subpopulation reconstitution post-CAR-T cell therapy.\nWe conducted a retrospective study including 19 patients who received axicabtagene ciloleucel and investigated associations between cytopenia and infectious complications after D30.\nNineteen patients were included, consisting of 42% Hispanic, 32% Caucasian, 21% African-American, and 5% Asian subjects. Post-D30 of CAR-T infusion, 47% patients (n=9) developed an infection and 53% (n=10) remained infection-free. The most common infection type observed was viral (7 patients) followed by bacterial (5 patients) and fungal (3 patients). Of 25 total infectious events, 56% were grade 1 or 2 and 44% were grade 3 with 10 being viral in etiology. To determine the kinetics of lymphohematopoietic reconstitution and its association with infection risk, we evaluated the relationship between cytopenias and rates of infection after D30. Notably, compared to non-infection group, infection group had a higher median absolute lymphocyte count (ALC) (1,000/µL vs. 600/µL, P<0.05), a lower median absolute neutrophil count (ANC)/ALC ratio (1.6 vs. 3.1, P<0.05) and a lower median AMC/ALC at D30 (0.37 vs. 1.67, P<0.05). In addition, we observed that only 22% of patients had recovered ANC >1,500/µL in the infection group as opposed to 70% in the non-infection group at D90 (P<0.05). Fifty-eight percent of the patients (11/19) with relapsed refractory DLBCL achieved a complete response with a median follow-up of 233 days (7.7 months).\nAlthough CAR-T cell therapy is highly effective, infectious complications remain an important cause of morbidity and mortality. Low ANC/ALC and AMC/ALC ratios at D30 are potential novel predictors of infection and can be considered in future prophylactic strategies.",
"affiliations": "Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Internal Medicine, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Oncology, Maimonides Medical Center, Brooklyn, NY, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Internal Medicine, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Transfusion Medicine, Montefiore Medical Center/Albert Einstein College of Medicine Bronx, NY, USA.;Department of Transfusion Medicine, Montefiore Medical Center/Albert Einstein College of Medicine Bronx, NY, USA.;Department of Transfusion Medicine, Montefiore Medical Center/Albert Einstein College of Medicine Bronx, NY, USA.;Department of Transfusion Medicine, Montefiore Medical Center/Albert Einstein College of Medicine Bronx, NY, USA.;Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine Bronx, NY, USA.;Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine Bronx, NY, USA.;Albert Einstein College of Medicine, Bronx, NY, USA.;Albert Einstein College of Medicine, Bronx, NY, USA.;Albert Einstein College of Medicine, Bronx, NY, USA.;Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Medicine, Albert Einstein College of Medicine Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Department of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Boise VA Medical Center, Boise, ID, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Infectious Diseases, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Infectious Diseases, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Infectious Diseases, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.;Division of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA.",
"authors": "Thakkar|Astha|A|;Cui|Zhu|Z|;Peeke|Stephen Zachary|SZ|;Shah|Nishi|N|;Pradhan|Kith|K|;Lombardo|Amanda|A|;Khatun|Fariha|F|;Mustafa|Jennat|J|;De Castro|Alyssa|A|;Gillick|Kailyn|K|;Joseph|Felisha|F|;Naik|Anjali|A|;Rahman|Shafia|S|;D'Aiello|Angelica|A|;Elkind|Richard|R|;Sakalian|Susan|S|;Fehn|Karen|K|;Wright|Karen|K|;Abreu|Michelly|M|;Townsend-Nugent|Latoya|L|;Chambers|Nicole|N|;Mathew|Rosmi|R|;Binakaj|Donika|D|;Nelson|Randin|R|;Palesi|Carlo|C|;Paroder|Monika|M|;Uehlinger|Joan|J|;Wang|Yanhua|Y|;Shi|Yang|Y|;Zang|Xingxing|X|;Wang|Hao|H|;Nishimura|Christopher|C|;Ren|Xiaoxin|X|;Steidl|Ulrich G|UG|;Gritsman|Kira|K|;Janakiram|Murali|M|;Kornblum|Noah|N|;Derman|Olga|O|;Mantzaris|Ioannis|I|;Shastri|Aditi|A|;Bartash|Rachel|R|;Puius|Yoram|Y|;McCort|Margaret|M|;Goldfinger|Mendel|M|;Bachier-Rodriguez|Lizamarie|L|;Verma|Amit|A|;Braunschweig|Ira|I|;Sica|R Alejandro|RA|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/sci-2021-008",
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"issn_linking": "2306-9759",
"issue": "8()",
"journal": "Stem cell investigation",
"keywords": "Chimeric antigen receptor T cell (CAR-T) CD19 cells; axicabtagene ciloleucel; infection; real-world cohort; relapsed/refractory diffuse large B-cell lymphoma (DLBCL)",
"medline_ta": "Stem Cell Investig",
"mesh_terms": null,
"nlm_unique_id": "101672113",
"other_id": null,
"pages": "18",
"pmc": null,
"pmid": "34631871",
"pubdate": "2021",
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"title": "Patterns of leukocyte recovery predict infectious complications after CD19 CAR-T cell therapy in a real-world setting.",
"title_normalized": "patterns of leukocyte recovery predict infectious complications after cd19 car t cell therapy in a real world setting"
} | [
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"companynumb": "US-GILEAD-2021-0552995",
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"activesubstancename": "AXICABTAGENE CILOLEUCEL"
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"abstract": "Olanzapine is an antipsychotic drug used in psychiatric diseases. At high doses it exhibits cardiovascular and neurological sideeffects in particular. Lipid emulsion therapy for the removal of medication from plasma in high-dose lipophilic drug use has recently become very widespread. In the light of current literature, this report discusses the successful treatment of a patient within 4 hrs of olanzapine overdose as an attempted suicide, who presented with agitation and clouded consciousness.",
"affiliations": "Haseki Training and Research Hospital, Department of Emergency Medicine, Istanbul, Turkey.;Haseki Training and Research Hospital, Department of Emergency Medicine, Istanbul, Turkey.;Haseki Training and Research Hospital, Department of Emergency Medicine, Istanbul, Turkey.;Haseki Training and Research Hospital, Department of Emergency Medicine, Istanbul, Turkey.;Haseki Training and Research Hospital, Department of Emergency Medicine, Istanbul, Turkey.;Haseki Training and Research Hospital, Department of Emergency Medicine, Istanbul, Turkey.",
"authors": "Yeniocak|S|S|;Kalkan|A|A|;Metin|D D|DD|;Demirel|A|A|;Sut|R|R|;Akkoc|I|I|",
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"mesh_terms": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D062787:Drug Overdose; D005217:Fat Emulsions, Intravenous; D006801:Humans; D000077152:Olanzapine; D013406:Suicide, Attempted",
"nlm_unique_id": "101553725",
"other_id": null,
"pages": "96-97",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful intravenous lipid emulsion therapy: Olanzapine intoxication.",
"title_normalized": "successful intravenous lipid emulsion therapy olanzapine intoxication"
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"companynumb": "TR-ORCHID HEALTHCARE-2059190",
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"activesubstancename": "OLANZAPINE"
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{
"abstract": "Hemophagocytic lymphohistiocytosis (HLH) is a disorder of immune regulation, manifested by fever, pancytopenia, hyperferritiniemia, hypertriglyceridemia, and extensive hemophagocytosis involving the bone marrow and spleen. HLH can occur in adults with an underlying hematopoietic malignancy, or with systemic infections. HLH following hematopoietic stem cell transplantation (HSCT) is unusual, and the diagnosis may be challenging particularly because the diagnostic criteria in the HLH-2004 guidelines overlap with common post-transplant complications such as engraftment syndrome, graft-vs-host disease, and infections. HLH is commonly triggered by viral, bacterial and, less commonly, parasitic infections. Following HSCT, patients with latent Toxoplasma infection may develop systemic disease secondary to reactivation, and rarely this may lead to a HLH physiology, with a very high mortality rate. Herein we describe the successful management of disseminated toxoplasmosis associated with life-threatening HLH using tocilizumab and antimicrobial therapy.",
"affiliations": "Division of Hematology and Oncology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD.;Division of Hematology and Oncology, National Institutes of Health, Bethesda, MD.;Division of Hematology and Oncology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD.;Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, MD.;Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, MD.;Department of Pathology, University of Maryland School of Medicine, Baltimore, MD.;Division of Hematology and Oncology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD.;Division of Hematology and Oncology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD.;Division of Hematology and Oncology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD.;Division of Hematology and Oncology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD.",
"authors": "Sanchez-Petitto|Gabriela|G|https://orcid.org/0000-0002-1000-1643;Holtzman|Noa G|NG|;Bukhari|Ali|A|;Brown|Matthew|M|;Morales|Megan K|MK|;Koka|Madhurima|M|;Yared|Jean A|JA|;Dahiya|Saurabh|S|;Rapoport|Aaron P|AP|;Hardy|Nancy M|NM|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D003907:Dexamethasone; C502936:tocilizumab",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13242",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "22(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "allogeneic stem cell transplantation; disseminated toxoplasmosis; haploidentical; hemophagocytic lymphohistiocytosis; tociliumab",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D003907:Dexamethasone; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D000072078:Positron Emission Tomography Computed Tomography; D014122:Toxoplasma; D014123:Toxoplasmosis; D000075442:Transplantation, Haploidentical",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13242",
"pmc": null,
"pmid": "31895492",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Toxoplasma-induced hemophagocytic lymphohistiocytosis after haploidentical allogeneic stem cell transplantation.",
"title_normalized": "toxoplasma induced hemophagocytic lymphohistiocytosis after haploidentical allogeneic stem cell transplantation"
} | [
{
"companynumb": "US-ROCHE-2595532",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Medical burden of fatal adverse drug reactions (FADRs) is significant. The epidemiological data on FADR do exist from the western world, but there is scanty from India. We hereby report a case series of FADRs recorded in a 2 years period. Point prevalence of FADRs was 0.223%. Point prevalence of all cause death in the hospital was 1.20%. The drugs causing FADRs were injection bupivacaine, amphotericin B, directly observed treatment short-course Category-1, injection streptokinase, and tablet ferrous sulfate. All these FADR were labeled as possible expect one case as probable. All FADR were labeled as type A. In three out of five the central nervous system was involved, while the hepatic system and multiorgan failure accounted for one case each. Two cases each were acute and subacute, while one was latent in nature. Reporting of FADRs shall go a long way in patient safety.",
"affiliations": "Department of Pharmacology and Therapeutics, Government Medical College Jammu, Jammu and Kashmir, India.;Department of Pharmacology and Therapeutics, Government Medical College Jammu, Jammu and Kashmir, India.;Department of General Medicine, Government Medical College Jammu, Jammu and Kashmir, India.;Department of Pharmacology and Therapeutics, Government Medical College Jammu, Jammu and Kashmir, India.;Department of Pharmacology and Therapeutics, Government Medical College Jammu, Jammu and Kashmir, India.;Department of General Medicine, Government Medical College Jammu, Jammu and Kashmir, India.",
"authors": "Tandon|Vishal R|VR|;Khajuria|Vijay|V|;Mahajan|Annil|A|;Gillani|Zahid|Z|;Mahajan|Vivek|V|;Chandail|Vijant|V|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0972-5229.132499",
"fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XMedknow Publications & Media Pvt Ltd India IJCCM-18-31510.4103/0972-5229.132499Short CommunicationFatal adverse drug reactions: Experience of adverse drug reactions in a tertiary care teaching hospital of North India - A case series Tandon Vishal R. Khajuria Vijay Mahajan Annil 1Gillani Zahid Mahajan Vivek Chandail Vijant 1From: Department of Pharmacology and Therapeutics, Government Medical College Jammu, Jammu and Kashmir, India1 Department of General Medicine, Government Medical College Jammu, Jammu and Kashmir, IndiaCorrespondence: Dr. Vishal R. Tandon, Departments of Pharmacology and Therapeutics, Government Medical College Jammu, Jammu and Kashmir, India. E-mail: dr_vishaltandon@yahoo.com5 2014 18 5 315 319 Copyright: © Indian Journal of Critical Care Medicine2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Medical burden of fatal adverse drug reactions (FADRs) is significant. The epidemiological data on FADR do exist from the western world, but there is scanty from India. We hereby report a case series of FADRs recorded in a 2 years period. Point prevalence of FADRs was 0.223%. Point prevalence of all cause death in the hospital was 1.20%. The drugs causing FADRs were injection bupivacaine, amphotericin B, directly observed treatment short-course Category-1, injection streptokinase, and tablet ferrous sulfate. All these FADR were labeled as possible expect one case as probable. All FADR were labeled as type A. In three out of five the central nervous system was involved, while the hepatic system and multiorgan failure accounted for one case each. Two cases each were acute and subacute, while one was latent in nature. Reporting of FADRs shall go a long way in patient safety.\n\nAdverse drug reactionsdrug safetyfatal ADRmortality\n==== Body\nIntroduction\nAdverse drug reaction (ADR) has been implicated as a leading cause of considerable morbidity and mortality. The overall incidence of serious ADRs has been reported 6.7% and of fatal ADRs (FADRs) to be 0.32% of hospitalized patients, which is extremely high.[1] It has been suggested that annual rates of ADR related deaths ranged from 0.08/100,000 to 0.12/100,000 and rate increase significantly over time at a rate of 0.0058/year.[2] Few other studies recorded FADR rate as high as of 6.4% and 1.66%, respectively.[34] In studies originating from India, five cases of death were recorded by Nair et al. (2005)[5] resulting from drug reaction. Similarly, 1.8% had a FADR rate in the study of Ramesh et al. (2003).[6] The epidemiological data on FADR do exist from the western world,[123478] but there is scanty data from India. Furthermore, it is important to report FADR as it can go a long way to ensure patient safety and shall help the regulators to take preventive measures to reduce the number of deaths caused by drugs. We hereby report a case series of FADRs recorded in a 2 year period.\n\nCase Reports\n\nCase 1\nA 21-year-old, 52 kg weight, male patient was admitted in the surgery department to undergo elective surgery. His preoperative biochemical and other baseline parameters were within normal limits. On the day of surgery, he was administered 2 ml of 0.5% of injection bupivacaine for spinal anesthesia. Following which he immediately went into shock. His blood pressure (BP) fell drastically to systolic 60 mg of Hg and diastolic not recordable and had thready pulse and tachypnea. His parameters PCO2-50.6 mm Hg; PO2-54.00 mm Hg; pH - 7.308; HCO3-24.5 mmol/L; hemoglobin (Hb) - 15 g/dl; serum Na + 142 mmol/L; serum K+2.7 mmol/L; blood urea 152 mg%, serum cretanine - 4.6 mg%; blood sugar - 126 mg%, serum alanine aminotransferase: 26.17 μkat/L, serum aspartate aminotransferase: 25.12 μkat/L and lipid profile were normal. Patient was given injection dopamine, mephentramine along with antibiotics and was put on ventilator support, but he succumbed within 1 day.\n\nCase 2\nA 35-year-old, HIV positive female patient suffered from difficulty in swallowing solids to start with followed by even liquids for last 2 months. She had a history of significant loss of appetite and weight loss. Endoscopic examination of upper gastrointestinal (GI) tract was carried during hospitalization to know the cause of dysphagia. She was found to be suffering from candida esophagitis with antral gastritis. Her cerebrospinal fluid examination was normal. Her blood sugar was 86 mg/dl; Hb 9 g%, total leukocyte count (TLC) - 8000/cmm, differential leukocyte count - predominant lymphocytosis, platelet count 2.4 lacs/cmm, blood urea 26 mg, serum creatinine 0.7 mg, HbA1c 6.0%, serum cholesterol 154 mg%, serum triglyceride 140 mg%, high-density lipoprotein (HDL) 35 mg%, routine urine examination, C-reactive protein + ve, erythrocyte sedimentation rate 88 mm/h, T3, T4 and thyroid stimulating hormone, LFT, serum uric acid, serum electrolyte levels were within normal limits. HIV status was positive and CD4 count - 100 (cells/μl) at the time of report. She was already on highly active antiretroviral (zidovudine + stavudine + nevirapine) therapy. She was given IV 100 μg/ml of amphotericin B in 5% dextrose for candida esophagitis. Following this she suffered from seizures that converted into status epilepticus. The nature of convulsions was generalized tonic-clonic. The BP was 86/56 mm of Hg and HR was 60 beat/min. The patient was immediately intubated. Injection diazepam - 10 mg intravenous (IV) push over 30-60 s repeated after every 10-15 min up to 30 mg was given. It was followed by loading and maintenance dose of phenytoin 600 mg in 100 ml of NS. IV midazolam loading dose was also given. Thus, patient was immediately shifted to intensive care unit for ventilator support. Patients magnetic resonance imaging done within 2 days showing marked hypoxia with cerebral edema [Figure 1], which may be due to delayed intubation following generalized tonic-clonic seizure. However, she died after 7 days.\n\nCase 3\nA 70-year-old, 80 kg postmenopausal female a known case of hypertension stage 1 as per JNC-7 with pulmonary TB Category-1 was on directly observed treatment short-course (DOTS) antitubercular therapy started 17 days before along with telmesartan presented with history of altered sensorium and loss of appetite for last 1 day. She was on isoniazid, rifampin, ethambutol, and pyrazinamide containing regimen under DOTS. In addition, she was also taking pantoprazole and calcium as and when required. A chest X-ray showed pulmonary tuberculosis (TB) with pleural effusion. Her baseline LFT, lipid profile, renal function test (RFT), complete blood count, and HIV status were normal. Gammaferon gold test for TB was positive. Electrocardiography (ECG) and ultrasonography (USG) abdomen was normal suggestive of postmenopausal status. Examination at the time of admission revealed BP 126/78 mmHg, pulse - 66/min, serum glutamic oxaloacetic transaminase 325 IU/L, serum glutamic-pyruvic transaminase - 132 IU/L, serum bilirubin 2.9 mg%. Based on these investigations, she was diagnosed as the case of antituberculosis therapy (ATT) induced hepatitis. Her ATT was stopped immediately. However, her condition deteriorated further. On 8th day of hospitalization, she went into hepatic encephalopathy followed by coma. Patient was given injection dopamine, along with antibiotics and was put on ventilator support. On day 10, she was in shock with BP 70/50 mm of Hg, pulse - 104/min, serum bilirubin 4.9 mg%, RFT - normal, blood sugar 87 mg% and she died after 20 days of admission in hospital in spite of all the medical intervention.\n\nCase 4\nA 70-year-old male a known case of hypothyroidism with stage 3-systolic hypertension as per seventh report of the Joint National Committee presented to emergency with pain chest not relieved by sublingual nitrate. ECG examination revealed acute inferior wall myocardial infarction with positive 10 h troponin-T assay. Pulse rate was 94/min, regular, normal volume, no radio-femoral delay and vessel wall not palpable. BP measured in both limbs was 190/90 mmHg. Laboratory investigations revealed Hb 13 g%, TLC 9400/cmm, platelet count 2.6 lacs/cmm, blood urea 39 mg, serum creatinine 0.9 mg, blood sugar - 100 mg%, HbA1c 6.8%, serum cholesterol 245 mg%, serum triglyceride 185 mg%, and HDL 35 mg%. Angiography was not done. Patient was treated with oxygen, morphine, beta blocker, ACE inhibitor, statins, aspirin, and clopidogrel. He was allowed to continue thyroxine 25 μg/day. Injection monocef 1 g IV and for hypertension he was given IV metoprolol. He was administered IV streptokinase after which he developed purpura and extensive ecchymosis [Figure 2]. Patient also developed epistaxis as well as macroscopic hematuria. Patient on subsequent investigations showed platelet count 350,000/cmm and Hb 6.9 g%. There were no signs of deep venous thrombosis, pulmonary embolism, gangrene or retroperitoneal bleed in the patients as suggested by USG abdomen. However, his condition continued to deteriorate further and computed tomography examination revealed major intracerebral hemorrhage [Figure 3]. Patient was started four units of platelet fraction and two units of blood transfusion. He was placed on a ventilator, but the patient died after 6 days.\n\nFigure 1 Magnetic resonance imaging of the case 2 done within 2 days showing marked hypoxia with cerebral edema with cerebral atrophy following seizure\n\nFigure 2 Extensive echymosis in case 4\n\nFigure 3 Computed tomography examination showing major intracerebral hemorrhage in case 4\n\nCase 5\nA 2½-year-old female child was admitted with history of intake of one tablets of iron which her mother was taking for pregnancy induced anemia. The child presented with drowsiness, intractable vomiting, and passage of dark colored black stools. She had major episodes of hematemesis and passage of malena. She presented with ocular hemorrhage. She went into shock. Endoscopy revealed massive GI bleed [Figure 4]. Immediately treatment for and severe anemia was instituted. Child was given desferrioxamine 150 mg/kg/h in 100 ml of normal saline at the rate of 30 ml/h. Patient developed signs of Congestive cardiac failure for which injection lasix 20 mg was given. However, patient deteriorated further and developed multi organ failure and died on the 2nd day.\n\nFigure 4 Massive gastrointestinal bleed on endoscopy in case 5\n\nDiscussion\nAll these FADR are labeled as probable expect one case as possible as per causality assessment with the Naranjo's score 6 and 4, respectively.[9] Since these ADRs were not studied for dose dependent response and were predictable as per known mechanism of action; hence, they all could not be clearly labeled as type A.[10] In three out of five cases, the central nervous system (CNS) was involved, whereas in one each case hepatic system and multiorgans were involved. Two cases each were acute subacute as well as one was latent in nature. Two patients were 70-year-old and one from pediatric age group; while other, two patients were of young age in the current case series. In the current study mild ADRs were 992 (41.8%), moderate 1300 (54.7%), severe 84 (3.5%), and fatal 5 (0.223%) out of the total 2376 ADR reported during this study period. Point prevalence of FADR reports in the current study was 0.223% (5/2242). Point prevalence of all cause death fatal reports in the hospital was 1.20% (6000/500,000). The drugs causing FADR in our case series were injection bupivacaine, IV amphotericin B, DOTS Cat-1, IV streptokinase and tablet ferrous sulfate [Table 1].\n\nTable 1 Profile of FADRs\n\nIn one of the recent study GI hemorrhages, CNS hemorrhages, cardiac disorders, drug-induced myelo suppression, and antimicrobial-related enterocolitis were the common causes of fatal disorders due to ADRs. The drugs most frequently implicated in a FADR were antithrombotic drugs, nonsteroidal antiinflammatory drugs, and corticosteroids. The only risk factors associated with FADRs in this population multiple-drug therapy and advancing age.[10]\n\nSimilarly, in another study the most common suspected FADRs were GI hemorrhages, CNS hemorrhages, cardiovascular disorders, other hemorrhages, and renal dysfunction. The drugs most commonly implicated in FADRs were antithrombotic drugs, followed by nonsteroidal antiinflammatory drugs, antidepressants, and cardiovascular drugs.[3]\n\nHowever, systemic antiinfective drugs' was associated with the highest percentage of FADRs (21.9%), followed by antineoplastic and immunomodulating agents (18.8%), and then by nervous system drugs (14.8%) in this study of Leone, et al.[4] The main distribution of suspected FADRs in another study was: Hemorrhages, blood, and bone marrow dysfunction, sudden death, and pulmonary embolism. Antithrombotic agents were the drugs most frequently implicated in the FADRs.[8]\n\nThe current small case series of FADRs impress upon a need of creating a separate national database on FADRs, which shall go a long way in enhancing patient safety.\n\nAcknowledgment\nThe author is gratefully acknowledged the Indian Pharmacopeia Commission (IPC), for all support provided under PvPI and WHO - For this important Initiative on Patient Safety.\n\nSource of Support: Indian Pharmacopeia Commission (IPC), Gaziabad, New Delhi, India and WHO.\n\nConflict of Interest: Data is confidential and only property of Indian Pharmacopeia Commission (IPC) under PvPI; reflect only suspected events and the data is generated by spontaneous reporting system as proposed by PvPI. There may be many other confounding factors which could have affected the final outcome of the event which were beyond the scope comment upon.\n==== Refs\nReferences\n1 Lazarou J Pomeranz BH Corey PN Incidence of adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies JAMA 1998 279 1200 5 9555760 \n2 Shepherd G Mohorn P Yacoub K May DW Adverse drug reaction deaths reported in United States vital statistics, 1999-2006 Ann Pharmacother 2012 46 169 75 22253191 \n3 Wester K Jönsson AK Spigset O Druid H Hägg S Incidence of fatal adverse drug reactions: A population based study Br J Clin Pharmacol 2008 65 573 9 18070216 \n4 Leone R Sottosanti L Luisa Iorio M Santuccio C Conforti A Sabatini V Drug-related deaths: An analysis of the Italian spontaneous reporting database Drug Saf 2008 31 703 13 18636789 \n5 Nair PS Moorthy PK Yogiragan K A study of mortality in dermatology Indian J Dermatol Venereol Leprol 2005 71 23 5 16394356 \n6 Ramesh M Pandit J Parthasarathi G Adverse drug reactions in a South Indian hospital - Their severity and cost involved Pharmacoepidemiol Drug Saf 2003 12 687 92 14762985 \n7 Pardo Cabello AJ González Contreras LG Manzano Gamero MV Gómez Jiménez FJ Puche Cañas E Prevalence of fatal adverse drug reactions in hospitalized patients Int J Clin Pharmacol Ther 2009 47 596 602 19825322 \n8 Wester K Jönsson A Spigset O Hägg S Spontaneously reported fatal suspected adverse drug reactions: A 10-year survey from Sweden Pharmacoepidemiol Drug Saf 2007 16 173 80 16739241 \n9 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508 \n10 Edwards IR Aronson JK Adverse drug reactions: Definitions, diagnosis, and management Lancet 2000 356 1255 9 11072960\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0972-5229",
"issue": "18(5)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Adverse drug reactions; drug safety; fatal ADR; mortality",
"medline_ta": "Indian J Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "101208863",
"other_id": null,
"pages": "315-9",
"pmc": null,
"pmid": "24914261",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports",
"references": "18070216;14762985;9555760;11072960;22253191;7249508;18636789;16739241;19825322;16394356",
"title": "Fatal adverse drug reactions: Experience of adverse drug reactions in a tertiary care teaching hospital of North India - A case series.",
"title_normalized": "fatal adverse drug reactions experience of adverse drug reactions in a tertiary care teaching hospital of north india a case series"
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{
"abstract": "The purpose of this study was to determine survival, local and distant control, toxicity, and prognostic factors in patients with stage III non-small cell lung cancer (NSCLC) treated with concurrent chemoradiation therapy (CCRT).\n\n\n\nConsecutive patients with stage IIIA and IIIB NSCLC (N = 154) staged with 18F-fluorodeoxyglucose positron emission tomography/computed tomography were retrospectively selected (2005-2015). CCRT consisted of daily low-dose cisplatin (6 mg/m2) combined with 24 fractions of 2.75 Gy to a total dose of 66 Gy.\n\n\n\nDuring a median follow-up period of 22 months (range, 1-92 months) the median overall survival was 36 months. The 1-, 2-, 3-, and 5-year survival rates were 79% (95% confidence interval [CI], 73%-86%), 61% (95% CI, 54%-70%), 52% (95% CI, 43%-60%), and 40% (95% CI, 31%-51%), respectively. The local relapse-free survival at 5 years was 55% (95% CI, 44%-69%). Metastasis-free survival at 5 years was 53% (95% CI, 44%-65%). The incidence of severe gastrointestinal disorders (grade 3-5) was 11%, among which grade 3 radiation esophagitis was 8.4%. The incidence of severe respiratory, thoracic, and mediastinal disorders (grade 3-5) was 8.4%, among which grade 3 radiation pneumonitis was 1.3%. Predictors of overall survival were lymph node gross tumor volume (GTV) (hazard ratio [HR], 1.007; 95% CI, 1.000-1.012) and sex (HR, 0.500; 95% CI, 0.320-0.870) in favor of women. Although lymph node GTV was a predictor of treatment toxicity (HR, 1.010; 95% CI, 1.000-1.013), tumor GTV was the predictor for distant metastasis during follow-up (HR, 1.002; 95% CI, 1.001-1.003).\n\n\n\nCCRT with daily low-dose cisplatin for locally advanced stage III NSCLC resulted in promising overall survival (3-year survival rate of 52% and 5-year survival rate of 40%) with low toxicity. Lymph node GTV, tumor GTV, and sex were predictors of overall survival, treatment toxicity, and distant metastasis.",
"affiliations": "Department of Radiation Oncology, Academic Medical Center, Amsterdam, Netherlands. Electronic address: e.m.dieleman@amc.nl.;Department of Radiation Oncology, Academic Medical Center, Amsterdam, Netherlands.;Department of Radiation Oncology, Academic Medical Center, Amsterdam, Netherlands.;Department of Radiation Oncology, Academic Medical Center, Amsterdam, Netherlands.;Department of Radiation Oncology, Academic Medical Center, Amsterdam, Netherlands.;Department of Pulmonary Disease, Academic Medical Center, Amsterdam, Netherlands.;Department of Radiation Oncology, Academic Medical Center, Amsterdam, Netherlands.;Department of Radiation Oncology, Academic Medical Center, Amsterdam, Netherlands.;Department of Radiology and Nuclear Medicine, Academic Medical Center, Amsterdam, Netherlands.;Department of Radiology and Nuclear Medicine, Academic Medical Center, Amsterdam, Netherlands.;Department of Pulmonary Disease, Academic Medical Center, Amsterdam, Netherlands.;Department of Radiation Oncology, Academic Medical Center, Amsterdam, Netherlands.",
"authors": "Dieleman|Edith M T|EMT|;Uitterhoeve|Apollonia L J|ALJ|;van Hoek|Meike W|MW|;van Os|Rob M|RM|;Wiersma|Jan|J|;Koolen|Mia G J|MGJ|;Kolff|Merel Willemijn|MW|;Koning|Caro C E|CCE|;Adam|Judit A|JA|;Verberne|Hein J|HJ|;Annema|Jouke T|JT|;Rasch|Coen R N|CRN|",
"chemical_list": "D019788:Fluorodeoxyglucose F18; D002945:Cisplatin",
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"doi": "10.1016/j.ijrobp.2018.07.188",
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"issn_linking": "0360-3016",
"issue": "102(3)",
"journal": "International journal of radiation oncology, biology, physics",
"keywords": null,
"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung; D059248:Chemoradiotherapy; D002945:Cisplatin; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008175:Lung Neoplasms; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000072078:Positron Emission Tomography Computed Tomography; D011379:Prognosis; D012008:Recurrence; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "7603616",
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"pages": "543-551",
"pmc": null,
"pmid": "30055239",
"pubdate": "2018-11-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Concurrent Daily Cisplatin and High-Dose Radiation Therapy in Patients With Stage III Non-Small Cell Lung Cancer.",
"title_normalized": "concurrent daily cisplatin and high dose radiation therapy in patients with stage iii non small cell lung cancer"
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"abstract": "West Nile virus (WNV) infection which is asymptomatic or mild in normal population, it may cause serious clinical conditions leading to death in eldery and immunosupressed patients. The virus is mainly transmitted by mosquito bites, however transfusion, transplantation, transplasental and nosocomial ways have also been reported to be responsible for viral transmission. It is known that WNV may cause life-threatining conditions such as central nervous system (CNS) infections especially in bone marrow and solid organ transplant recipients. In this report, the first case of WNV encephalitis in an immunosuppressed patient with renal transplant in Turkey was presented. A 25-year-old male patient admitted to our hospital with the complaints of generalized myalgia, nausea and vomiting, after the 24. day of renal transplantation from a live donor. Since he developed diffuse tonic clonic seizures during his follow up, he was diagnosed as meningoencephalitis with the results of cranial magnetic resonance imaging (MR) and cerebrospinal fluid (CSF) biochemistry. Bacterial and fungal cultures of blood and CSF yielded negative results. CMV antigenemia test and CMV IgM in blood, and nucleic acid tests for CMV, EBV, HSV-1/2, VZV, HHV-6, enterovirus and parvovirus in CSF were also negative. However, WNV RNA was detected in CSF by an in-house reverse transcriptase (RT) nested PCR method. The sequence analysis (GenBank BLAST) of the virus showed that it had 99% similarity with Lineage-1 WNV strains. To define the transmission way of the virus to the recipient, WNV-RNA was searched in the renal biopsy sample and found negative by RT nested PCR. The clinical condition of the patient was improved with supportive therapy and by the de-escalation of immunosuppressive drugs [Mycophenolate mofetil (MMF; 1 g/day), cyclosporin (1 mg/kg/day)]. However WNV meningoencephalitis recurred one month later. The patient presented with fever, myalgia, confusions, leukocytosis, anemia, and repeating WNV-RNA positivity in CSF. This time cyclosporin was stopped, MMF was given in low dose (1 g/day), and high dose parenteral acyclovir and intravenous immunoglobulin (400 mg/kg/day, 7 days) were initiated. The patient recovered completely after 10 days without any neurological abnormalities. In conclusion, especially in endemic areas, WNV should be considered in the differential diagnosis of CNS infections develop in solid organ transplant cases and patients with other immunodeficiencies who present with fever, generalized myalgia, gastrointestinal symptoms and/or neurological disorders.",
"affiliations": "Ege University Faculty of Medicine, Department of Medical Microbiology, Izmir, Turkey. aysin.zeytinoglu@ege.edu.tr.",
"authors": "Ertilav|Muhittin|M|;Ozkul|Aykut|A|;Zeytinoğlu|Ayşın|A|;Sen|Sait|S|;Sipahi|Savaş|S|;Töz|Hüseyin|H|;Kitiş|Omer|O|;Eraslan|Cenk|C|",
"chemical_list": "D012367:RNA, Viral",
"country": "Turkey",
"delete": false,
"doi": "10.5578/mb.8212",
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"fulltext_license": null,
"issn_linking": "0374-9096",
"issue": "48(4)",
"journal": "Mikrobiyoloji bulteni",
"keywords": null,
"medline_ta": "Mikrobiyol Bul",
"mesh_terms": "D000328:Adult; D003937:Diagnosis, Differential; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008297:Male; D008590:Meningoencephalitis; D012367:RNA, Viral; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D066027:Transplant Recipients; D014901:West Nile Fever; D014902:West Nile virus",
"nlm_unique_id": "7503830",
"other_id": null,
"pages": "674-82",
"pmc": null,
"pmid": "25492663",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Meningoencephalitis caused by West Nile virus in a renal transplant recipient.",
"title_normalized": "meningoencephalitis caused by west nile virus in a renal transplant recipient"
} | [
{
"companynumb": "TR-ACCORD-027806",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "To compare pharmacogenetic test predictions with self-reported treatment experience and side effect tolerability among patients with depression taking psychotherapeutic medications.\n\n\n\nSubjects completed a survey recalling medication effectiveness and side effects and then underwent pharmacogenetic testing.\n\n\n\nOur 15 gene pharmacogenetic panel predicted efficacy (p < 0.001) but did not predict side effect tolerability (p = 0.70) in a group of 352 patients. The pharmacogenetic panel and reported efficacy corresponded 60% of the time and medication tolerability agreed 71% of the time.\n\n\n\nPharmacogenetic testing may be a useful adjunct to predict efficacy of medications used to treat depression.",
"affiliations": "Pathway Genomics, San Diego, CA 92121, USA.;Pathway Genomics, San Diego, CA 92121, USA.;Pathway Genomics, San Diego, CA 92121, USA.;Patients Like Me, Cambridge, MA 02142, USA.;Department of Psychiatry, University of California, San Diego, CA 92093, USA.;Department of Psychiatry, University of California, San Diego, CA 92093, USA.",
"authors": "Tonozzi|Theresa R|TR|;Braunstein|Glenn D|GD|;Kammesheidt|Anja|A|;Curran|Chris|C|;Golshan|Shahrokh|S|;Kelsoe|John|J|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D011619:Psychotropic Drugs; D017367:Serotonin Uptake Inhibitors",
"country": "England",
"delete": false,
"doi": "10.2217/pgs-2018-0088",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-2416",
"issue": "19(15)",
"journal": "Pharmacogenomics",
"keywords": "antidepressant; antipsychotic; bipolar disorder; generalized anxiety disorder; major depressive disorder; mood stabilizer; pharmacogenetics; selective serotonin reuptake inhibitors; tricyclic antidepressants",
"medline_ta": "Pharmacogenomics",
"mesh_terms": "D000328:Adult; D000368:Aged; D000929:Antidepressive Agents, Tricyclic; D001714:Bipolar Disorder; D003430:Cross-Sectional Studies; D003865:Depressive Disorder, Major; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D000071185:Pharmacogenomic Testing; D011619:Psychotropic Drugs; D012189:Retrospective Studies; D017367:Serotonin Uptake Inhibitors; D055815:Young Adult",
"nlm_unique_id": "100897350",
"other_id": null,
"pages": "1169-1179",
"pmc": null,
"pmid": "30207201",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pharmacogenetic profile and major depressive and/or bipolar disorder treatment: a retrospective, cross-sectional study.",
"title_normalized": "pharmacogenetic profile and major depressive and or bipolar disorder treatment a retrospective cross sectional study"
} | [
{
"companynumb": "US-JNJFOC-20181208793",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "3",
... |
{
"abstract": "Some drugs are known for their fetal nephrotoxicity and should be avoided during pregnancy. We report on a pregnant woman suffering from breast cancer who received a weekly neoadjuvant trastuzumab (Herceptin(®)) therapy from 15 weeks of gestation onward, in addition to a 3-weekly carboplatin/docetaxel chemotherapy. Fetal renal insufficiency with anhydramnios and missing visualization of the fetal bladder developed at 21 weeks. After discontinuation of trastuzumab and repeated instillation of amniotic fluid, the amount of amniotic fluid remained stable after 24 weeks of gestation. After caesarean section at 34 weeks because of fetal growth restriction, the renal function of the neonate was normal postnatally. In accordance with the current literature, our case shows a reversible adverse effect of trastuzumab on the fetal renal function and confirms the current recommendation that trastuzumab in pregnancy should be avoided. In pregnancies exposed to trastuzumab, treatment should be discontinued and the fetus should be closely monitored, with particular attention to the amniotic fluid and the fetal bladder volume, as these reflect fetal renal function.",
"affiliations": "Pränatalmedizin und Gynäkologische Sonographie, Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe der Universität zu Köln, Düsseldorf, Germany.",
"authors": "Gottschalk|Ingo|I|;Berg|Christoph|C|;Harbeck|Nadia|N|;Stressig|Rüdiger|R|;Kozlowski|Peter|P|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000335202",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1661-3791",
"issue": "6(6)",
"journal": "Breast care (Basel, Switzerland)",
"keywords": null,
"medline_ta": "Breast Care (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101254060",
"other_id": null,
"pages": "475-478",
"pmc": null,
"pmid": "22419904",
"pubdate": "2011-12",
"publication_types": "D002363:Case Reports",
"references": "10502596;10577857;2179638;20164696;16595038;2198503;9562676;17498535;17666645;3798106;17921242;6946847;2678485;18985677;16821625;20824035;10968352;16800979;17399946;16894524;18349415;19398090;12650513;11779294;19624421;16823172;6234984;19745695;675555;15738038;16104005;13331791;15563850;6303698;10361108;15120665;11829371;14991918;17045211;16523825;8105555;5652604;16277887;21789157;19483741;3276379;12962283;12802024;12850341;15961766;14981994;18084047;17196514;1550143;17092404;14607056;16963391;15507181;19228622;14679135;54209;11733979;15749271;10590367;11717708;12754622;16698170;16342247;10071276;16401684",
"title": "Fetal Renal Insufficiency Following Trastuzumab Treatment for Breast Cancer in Pregnancy: Case Report und Review of the Current Literature.",
"title_normalized": "fetal renal insufficiency following trastuzumab treatment for breast cancer in pregnancy case report und review of the current literature"
} | [
{
"companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-13SUNCA08P",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugad... |
{
"abstract": "A 21-year-old man experienced unilateral vision loss associated with multiple atrophic chorioretinal lesions. He was treated for a presumptive diagnosis of acute retinal necrosis, but his vision did not improve with antiviral therapy. Over the course of several weeks, his symptoms progressed to involve both eyes. The fellow eye showed characteristic yellow-white placoid lesions, prompting treatment with oral corticosteroids for acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Despite high-dose therapy with prednisone 80 mg daily, the patient developed the acute onset of mental status changes within the next several days. Neuroimaging revealed multifocal large-vessel strokes associated with cerebral edema; these infarcts led to herniation and death. Postmortem histopathologic examination confirmed granulomatous inflammation in both ocular and cerebral vasculatures. Together with findings from multimodal imaging obtained throughout this patient's clinical course, our findings support the notion that granulomatous choroiditis is the mechanism of the ocular lesions seen in APMPPE. This granulomatous inflammation can also affect cerebral vessels, leading to strokes.",
"affiliations": "Departments of Ophthalmology and Visual Sciences (RNM, GPVS, RR, GJH) and Neurology (LS), Washington University School of Medicine in St. Louis, St. Louis, Missouri; Blue Sky Neurology (NHK), Denver, Colorado; Department of Pathology and Immunology (CJF, RES, SD, GJH), Washington University School of Medicine, St. Louis, Missouri; Department of Radiology (JT), University of Colorado Anschutz Medical Campus, Aurora, Colorado; and Department of Neurology (AD), Brigham and Women's Hospital, Boston, Massachusetts.",
"authors": "Maamari|Robi N|RN|;Stunkel|Leanne|L|;Kung|Nathan H|NH|;Ferguson|Cole J|CJ|;Tanabe|Jody|J|;Schmidt|Robert E|RE|;Dahiya|Sonika|S|;Dhand|Amar|A|;Van Stavern|Gregory P|GP|;Rajagopal|Rithwick|R|;Harocopos|George J|GJ|",
"chemical_list": "D004396:Coloring Agents; D007208:Indocyanine Green",
"country": "United States",
"delete": false,
"doi": "10.1097/WNO.0000000000000750",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1070-8022",
"issue": "39(2)",
"journal": "Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society",
"keywords": null,
"medline_ta": "J Neuroophthalmol",
"mesh_terms": "D004396:Coloring Agents; D017809:Fatal Outcome; D006801:Humans; D007208:Indocyanine Green; D008279:Magnetic Resonance Imaging; D008297:Male; D064847:Multimodal Imaging; D009887:Ophthalmoscopy; D061848:Optical Imaging; D020521:Stroke; D041623:Tomography, Optical Coherence; D014057:Tomography, X-Ray Computed; D020293:Vasculitis, Central Nervous System; D014792:Visual Acuity; D000080363:White Dot Syndromes; D055815:Young Adult",
"nlm_unique_id": "9431308",
"other_id": null,
"pages": "260-267",
"pmc": null,
"pmid": "30676416",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Posterior Multifocal Placoid Pigment Epitheliopathy Complicated by Fatal Cerebral Vasculitis.",
"title_normalized": "acute posterior multifocal placoid pigment epitheliopathy complicated by fatal cerebral vasculitis"
} | [
{
"companynumb": "PHHY2019US225182",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Drug-resistance represents a major threat in the fight against tuberculosis. Globally, isoniazid-monoresistant tuberculosis (Hr-TB) is twice as common as multidrug/rifampicin-resistant (MDR/RR)-TB. Recently updated WHO guidelines now recommend treatment of Hr-TB with rifampicin, ethambutol, pyrazinamide and levofloxacin for at least six months. Our primary objective was to define the frequency, treatment and outcomes for Hr-TB in Queensland, Australia. We also sought to determine the frequency of fluoroquinolone use and whether its inclusion improved outcomes.\n\n\n\nRetrospective case series of tuberculosis notifications in Queensland between 2000 and 2017 with at least low-level isoniazid resistance and preserved susceptibility to other first-line oral agents.\n\n\n\nHr-TB was identified in 7.2% of all notifications. Where outcomes were assessable (163/198), 76.1% were treated with first-line agents only and 11.0% received at least six months of a fluoroquinolone-containing regimen (consistent with recent WHO guidelines). Favourable outcomes were achieved in 95.7%, comparable to fully susceptible disease (94.9%). Inclusion of a fluoroquinolone did not significantly improve outcomes compared with a regimen containing first-line agents only, although these cases were more likely to have high-level resistance. Previous treatment made an unfavourable outcome more likely.\n\n\n\nHr-TB is prevalent in Queensland. Treatment outcomes in our cohort were comparable to fully susceptible disease. The current WHO-recommended regimen did not confer advantage over an appropriately constructed regimen containing first-line agents only. Our findings suggest that, in a well-resourced setting with good programmatic management, the addition of a fluoroquinolone may not substantially improve outcomes - potentially allowing these agents to be reserved for more extensively resistant disease.",
"affiliations": "Metro South Clinical Tuberculosis Service, Princess Alexandra Hospital, Queensland, Australia; The University of Queensland, School of Clinical Medicine, Princess Alexandra Hospital, Southside Clinical Unit, Australia. Electronic address: malcolm.wilson@health.qld.gov.au.;Communicable Diseases Branch, Queensland Department of Health, Queensland, Australia.;QFAB Bioinformatics, Institute for Molecular Bioscience, University of Queensland, Queensland, Australia.;Metro South Clinical Tuberculosis Service, Princess Alexandra Hospital, Queensland, Australia; The University of Queensland, School of Clinical Medicine, Princess Alexandra Hospital, Southside Clinical Unit, Australia.",
"authors": "Wilson|Malcolm|M|;O'Connor|Bridget|B|;Matigian|Nicholas|N|;Eather|Geoffrey|G|",
"chemical_list": "D000995:Antitubercular Agents; D024841:Fluoroquinolones; D011718:Pyrazinamide; D064704:Levofloxacin; D019304:Ethinyl Estradiol-Norgestrel Combination; D004977:Ethambutol; D007538:Isoniazid",
"country": "England",
"delete": false,
"doi": "10.1016/j.rmed.2020.106163",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6111",
"issue": "173()",
"journal": "Respiratory medicine",
"keywords": "Drug-resistance; Isoniazid; Tuberculosis",
"medline_ta": "Respir Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents; D001315:Australia; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D004977:Ethambutol; D019304:Ethinyl Estradiol-Norgestrel Combination; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D007538:Isoniazid; D064704:Levofloxacin; D008297:Male; D008875:Middle Aged; D011718:Pyrazinamide; D012189:Retrospective Studies; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant; D055815:Young Adult",
"nlm_unique_id": "8908438",
"other_id": null,
"pages": "106163",
"pmc": null,
"pmid": "33002798",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Management of isoniazid-monoresistant tuberculosis (Hr-TB) in Queensland, Australia: a retrospective case series.",
"title_normalized": "management of isoniazid monoresistant tuberculosis hr tb in queensland australia a retrospective case series"
} | [
{
"companynumb": "US-SA-2020SA275290",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "To identify and describe experiences of patients with colorectal cancer (CRC) who have neurotoxic side effects early in the oxaliplatin treatment period, and how neurotoxicity affects their daily lives.\n\n\n\n10 patients with stage II-III CRC were included. All were treated with adjuvant oxaliplatin postoperatively and assessed neurotoxicity via a platform-independent mobile phone-based system. Patients were recruited from two hospitals in southern Sweden from November 2013 to August 2014.\n\n\n\nQualitative interview study conducted through open-ended, face-to-face, qualitative interviews. Thematic analysis was used.\n\n\n\nA main theme was identified.\n\n\n\nNurses have an obligation to communicate the importance of early detection of neurotoxicity. Mobile phone technology seems to be a valuable tool for monitoring patient-reported neurotoxicity to improve communication and supportive care.",
"affiliations": "Linköping University.;Linköping University.;Linköping University.;Linköping University.",
"authors": "Drott|Jenny|J|;Starkhammar|Hans|H|;Kjellgren|Karin|K|;Berterö|Carina|C|",
"chemical_list": "D000077150:Oxaliplatin",
"country": "United States",
"delete": false,
"doi": "10.1188/18.ONF.690-697",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-535X",
"issue": "45(6)",
"journal": "Oncology nursing forum",
"keywords": "chemotherapy; colorectal cancer; daily life; neurotoxicity; qualitative methodology",
"medline_ta": "Oncol Nurs Forum",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020258:Neurotoxicity Syndromes; D000077150:Oxaliplatin; D036301:Qualitative Research; D011795:Surveys and Questionnaires; D013548:Sweden",
"nlm_unique_id": "7809033",
"other_id": null,
"pages": "690-697",
"pmc": null,
"pmid": "30339148",
"pubdate": "2018-11-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Neurotoxic Side Effects Early in the Oxaliplatin Treatment Period in Patients With Colorectal Cancer.",
"title_normalized": "neurotoxic side effects early in the oxaliplatin treatment period in patients with colorectal cancer"
} | [
{
"companynumb": "PHHY2019SE164154",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Many papers have reported on pregnancy and delivery after liver transplantation, but there have been no reports on pregnancy after ABO-incompatible liver transplantation. This paper reports the first successful pregnancy and delivery of a newborn after ABO-incompatible liver transplantation for fulminant hepatic failure. The patient was a 39-year-old female. She had an ABO-incompatible liver transplantation, donated from her husband, due to subacute fulminant hepatitis of unknown etiology. She was taking tacrolimus, methylprednisolone, and mizoribine orally for the maintenance of immunosuppression at the time of discharge. She was discharged uneventfully on postoperative day 38 without any rejection episodes. At 1 year and 6 mo after transplantation, she indicated a wish to become pregnant. Therefore, treatment with mycophenolate mofetil was interrupted at that time. After two miscarriages, she finally became pregnant and delivered transvaginally 3 years after the transplantation. All of the pregnancies were conceived naturally. The newborn was female with a birth weight of 3146 g; the Apgar scores were 9 and 10. Delivery was performed smoothly, and the newborn exhibited no malformations. The mother and the newborn were discharged uneventfully. We suggest that pregnancy is possible for recipients after ABO-incompatible liver transplantation.",
"affiliations": "Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.;Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.",
"authors": "Higashi|Hisanobu|H|;Obara|Hideaki|H|;Miyakoshi|Kei|K|;Shinoda|Masahiro|M|;Kitago|Minoru|M|;Shimojima|Naoki|N|;Abe|Yuta|Y|;Hibi|Taizo|T|;Yagi|Hiroshi|H|;Matsubara|Kentaro|K|;Yamada|Yohei|Y|;Itano|Osamu|O|;Hoshino|Ken|K|;Kuroda|Tatsuo|T|;Kitagawa|Yuko|Y|",
"chemical_list": "D000017:ABO Blood-Group System; D007166:Immunosuppressive Agents; D012263:Ribonucleosides; D000069283:Rituximab; C010052:mizoribine; D016559:Tacrolimus; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v23.i3.547",
"fulltext": "\n==== Front\nWorld J GastroenterolWorld J. GastroenterolWJGWorld Journal of Gastroenterology1007-93272219-2840Baishideng Publishing Group Inc jWJG.v23.i3.pg54710.3748/wjg.v23.i3.547Case ReportFirst successful perinatal management of pregnancy after ABO-incompatible liver transplantation Higashi Hisanobu Obara Hideaki Miyakoshi Kei Shinoda Masahiro Kitago Minoru Shimojima Naoki Abe Yuta Hibi Taizo Yagi Hiroshi Matsubara Kentaro Yamada Yohei Itano Osamu Hoshino Ken Kuroda Tatsuo Kitagawa Yuko Hisanobu Higashi, Hideaki Obara, Masahiro Shinoda, Minoru Kitago, Yuta Abe, Taizo Hibi, Hiroshi Yagi, Kentaro Matsubara, Osamu Itano, Yuko Kitagawa, Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, JapanKei Miyakoshi, Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo 160-8582, JapanNaoki Shimojima, Yohei Yamada, Ken Hoshino, Tatsuo Kuroda, Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, JapanAuthor contributions: Higashi H and Obara H wrote the paper; Miyakoshi K followed and treated the patient during pregnancy; all other members contributed equally to the medical treatment.\n\nCorrespondence to: Hideaki Obara, MD, PhD, FACS, Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. obara.z3@keio.jp\n\nTelephone: +81-333531211 Fax: +81-333554707\n\n21 1 2017 21 1 2017 23 3 547 550 31 8 2016 7 10 2016 12 11 2016 ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.2017This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.Many papers have reported on pregnancy and delivery after liver transplantation, but there have been no reports on pregnancy after ABO-incompatible liver transplantation. This paper reports the first successful pregnancy and delivery of a newborn after ABO-incompatible liver transplantation for fulminant hepatic failure. The patient was a 39-year-old female. She had an ABO-incompatible liver transplantation, donated from her husband, due to subacute fulminant hepatitis of unknown etiology. She was taking tacrolimus, methylprednisolone, and mizoribine orally for the maintenance of immunosuppression at the time of discharge. She was discharged uneventfully on postoperative day 38 without any rejection episodes. At 1 year and 6 mo after transplantation, she indicated a wish to become pregnant. Therefore, treatment with mycophenolate mofetil was interrupted at that time. After two miscarriages, she finally became pregnant and delivered transvaginally 3 years after the transplantation. All of the pregnancies were conceived naturally. The newborn was female with a birth weight of 3146 g; the Apgar scores were 9 and 10. Delivery was performed smoothly, and the newborn exhibited no malformations. The mother and the newborn were discharged uneventfully. We suggest that pregnancy is possible for recipients after ABO-incompatible liver transplantation.\n\nPregnancyLiver transplantationDeliveryFulminant hepatic failureABO-incompatibleLiving donor\n==== Body\nCore tip: This report is on the first successful perinatal management of pregnancy after ABO-incompatible liver transplantation. We suggest that pregnancy should be allowed for those who previously received ABO-incompatible liver transplantation.\n\nINTRODUCTION\nLiver transplantation has been established as a medical treatment for end-stage liver disease patients. In Japan, living-donor liver transplantation, including ABO-incompatible liver transplantation, is the most available procedure due to a chronic lack of deceased donor livers. We established a protocol for ABO-incompatible liver transplantation that uses immunosuppressants (e.g., cyclosporin or tacrolimus), rituximab, steroids, mizoribine, and intraportal infusion therapy[1,2]. Although there are extensive operative stresses involved and immunosuppressants are required, many papers have reported a successful pregnancy or delivery after liver transplantation[3,4]. However, only two reports described pregnancy and delivery after ABO-incompatible kidney transplantation, and there have been no reports on pregnancy after ABO-incompatible liver transplantation[5,6]. This paper reports the first successful pregnancy and delivery of a newborn after ABO-incompatible liver transplantation for fulminant hepatic failure.\n\nCASE REPORT\nA 39-year-old woman, gravida 1, para 1, received an ABO-incompatible liver transplantation, donated from her husband. The transplantation was due to subacute fulminant hepatitis that occurred two months after her first delivery; although the etiology was unknown, it was suspected to be drug-induced. She had no appreciable diseases, including hepatitis virus infections, or a past or family history of liver disease. She was allergic to crab butter but not any medicines. Her blood type was O, Rh(+), and her HLA-A, B, DR was A2/A11, B35/B55, DR9/DR12. The donor's blood type was A, Rh(+), and his HLA-A, B, DR was A2/A24, B46/B48, DR8/DR16. Her anti-A and anti-B antibodies before hepatitis were uncertain due to a plasma exchange (PE).\n\nShe gave birth to her first baby by vaginal delivery at the age of 39 years old in February 2012. After delivery, she suffered from refractory periodontitis; she took the antibiotic cephem (cefdinir) for 6 d starting in April 2012 because of the periodontitis. Subsequently, she exhibited general malaise, general itching sensations, and chills. A dermatologist prescribed levocetirizine and prednisolone unguent, but the symptoms persisted with no improvement. She also had a problem with a second premolar tooth because she had exodontia and took the antibiotic cephem (cefdinir) to prevent infection. However, after taking this antibiotic, she experienced the sudden onset of jaundice and severe hepatic dysfunction [aspartate transaminase (AST)/alanine aminotransferase (ALT) = 948/1090 IU/L, T-Bil 138 μmol/L, D/T = 0.71, prothrombin time-international normalized ratio (PT-INR) = 1.00]. She was admitted to the hospital with fulminant hepatitis of unknown etiology, and liver support therapy was performed. A liver biopsy revealed acute, drug-induced hepatitis. Her liver function continued to deteriorate (AST/ALT = 944/1114 IU/L, T-Bil 296 μmol/L, D/T = 0.76, PT-INR = 1.23), and she developed hepatic encephalopathy two weeks later, when the first symptoms appeared. On the day hepatic encephalopathy appeared, she was transferred to our hospital. We performed PE five times and started continuous hemodiafiltration. The first PE was fresh frozen plasma of blood type O, and the others were blood type AB due to the possibility of ABO-incompatible liver transplantation. Although she was registered on the waiting list for deceased donor liver transplantation in Japan, the progression of liver dysfunction did not allow for much time to be spent waiting for a deceased liver donation [the model for end-stage liver disease (MELD) score increased from 28 to 36 in a week]. In addition, pancreatitis was suspected due to the PEs because of the elevation in serum amylase. An ABO-incompatible liver transplantation was performed 10 d after the first PE was performed; the liver was donated from her 33-year-old husband. Before transplantation, her anti-A antibodies were 64 × (IgM) and 128 × (IgG), and her anti-B antibodies were 32 × (IgM) and 64 × (IgG).\n\nThe donor's left liver lobe (graft weight; 452 g, graft weight/recipient body weight = 0.93) was transplanted, and a splenectomy was also performed along with the insertion of an intraportal infusion catheter and immunosuppression, according to our protocol[1] for ABO-incompatible liver transplantation. Rituximab was infused one time just after the liver transplantation. The operation time was 10 h and 18 min, and blood loss was 538 mL.\n\nHer encephalopathy improved promptly after the transplantation. She was extubated on postoperative day (POD) 3 and discharged from the intensive care unit on POD 7. Tacrolimus, steroids, and mizoribine were given, and intraportal infusion therapy was performed to prevent rejection (Figure 1). The jaundice and liver function gradually improved, and she was discharged from the hospital on POD 38 with no bacterial infections or rejection episodes (laboratory data at the time of discharge: AST/ALT = 18/16 IU/L, T-Bil 15 μmol/L, D/T = 0.11, PT-INR = 1.08).\n\nFigure 1 Perioperative laboratory data and immunosuppressive drugs. AST: Aspartate transaminase; ALT: Alanine transaminase; T.Bil: Total bilirubin; POD: Postoperative day.\n\nWhen she was discharged, she was taking tacrolimus (1.4 mg/d), methylprednisolone (mPSL; 15 mg/d), and mizoribine (200 mg/d) orally for the maintenance of immunosuppression, and her anti-A and anti-B antibodies were not increased; anti-A antibodies: 32 × (IgM) and 256 × (IgG), anti-B antibodies: 32 × (IgM) and 64 × (IgG). Although she developed steroidal diabetes, it was well controlled with insulin (HbA1c was within the range of 5.2%-6.1% during pregnancy).\n\nHer serum tacrolimus concentration was maintained between 3 ng/mL and 8 ng/mL as an outpatient. Her general condition improved gradually, and 1 year and 6 mo after transplantation, she expressed a desire to become pregnant. Thereafter, she conceived spontaneously but miscarried twice, 2 years and 2 years plus 6 mo after the transplantation. Three years after the transplantation, when she was 42 years old, she conceived spontaneously, and the perinatal clinical course was uneventful. At the 39th week of pregnancy, a female baby weighing 3146 g was delivered vaginally with Apgar scores of 9 and 10 at 1 and 5 min, respectively. The intra- and postpartum courses were uneventful, and there was no postpartum hemorrhage. The baby exhibited no malformations and was healthy at the age of 6 mo. During the course of pregnancy, she took 4 mg/d of tacrolimus without reduction or suspension, and her levels of AST, ALT, and bilirubin remained within normal ranges. In addition, her anti-A and anti-B antibody levels were stable during the perinatal period: antenatal: anti-A antibodies: 2 × (IgM) and 16 × (IgG); anti-B antibodies: 32 × (IgM) and 64 × (IgG); postnatal: anti-A antibodies: 2 × (IgM) and 8 × (IgG), anti-B antibodies: 16 × (IgM) and 64 × (IgG). Although the blood type of the baby was uncertain, anti-A and anti-B antibodies did not increase during the pregnancy.\n\nDISCUSSION\nABO-incompatible living- related liver transplantation is a procedure that is performed to resolve the lack of deceased donors. Due to the immunosuppression protocol for ABO-incompatibility comprising rituximab[1], it has become a relatively straightforward procedure. Our protocol for ABO-incompatible liver transplantation has allowed patients to undergo transplantation with a prognosis similar to that of an ABO-compatible liver[7]. This procedure greatly increases the likelihood of a successful transplantation in acute liver dysfunction patients who could not find an ABO-compatible donor. Indeed, in this case, the only donor available within the limited time was ABO incompatible. In the past, the survival rate of ABO-incompatible liver transplantation was lower than that of ABO-compatible transplantation, but with improvements, there is currently no significant difference between ABO-compatible and ABO-incompatible transplantation in the Japanese registry[8].\n\nMany papers have reported obstetric complications during pregnancy after liver transplantation; liver dysfunction and preeclampsia are commonly reported according to systematic reviews[9,10]. The rates of cesarean section and preterm delivery are also higher after liver transplantation than in the general population; accordingly, gestational age is shorter after liver transplantation than in the general population. Fortunately, the perinatal course in our patient was uneventful. In contrast to previous reports[9,10], the patient delivered an appropriate-for-date newborn at full term.\n\nImmunosuppression is an important point in pregnancy. The interruption of mizoribine use prevented teratosis, and no liver dysfunction was observed. Because mycophenolate mofetil was used, the patient needed a six-month interval before the pregnancy because of its teratogenic effects.\n\nIn conclusion, we experienced and reported the first successful management of a case of pregnancy after ABO-incompatible liver transplantation for fulminant hepatic failure.\n\nCOMMENTS\nCase characteristics\nThe patient was a 39-year-old female. She had an ABO-incompatible liver transplantation, donated from her husband, due to subacute fulminant hepatitis of unknown etiology.\n\nClinical diagnosis\nShe was found to have jaundice, and hepatic encephalopathy was observed.\n\nDifferential diagnosis\nHer differential diagnosis included drug-induced liver failure and viral infection.\n\nLaboratory diagnosis\nThe laboratory evaluation showed significant hyperbilirubinemia, increased aspartate transaminase/alanine aminotransferase, hepatic dysfunction, and decreased prothrombin time-international normalized ratio.\n\nImaging diagnosis\nAbdominal ultrasound and computed tomography revealed the atrophic change of the liver but no evidence of biliary obstruction.\n\nPathological diagnosis\nShe was diagnosed with drug-induced fulminant hepatitis upon liver biopsy.\n\nTreatment\nThe initial treatment consisted of medical management comprising plasma exchange and continuous hemodiafiltration, followed by liver transplantation.\n\nRelated reports\nThere have been no reports on pregnancy and delivery after ABO-incompatible liver transplantation.\n\nTerm explanation\nABO-incompatible liver transplantation is a type of living-donor liver transplantation.\n\nExperiences and lessons\nThis case suggests that the possibility of pregnancy for recipients of ABO-incompatible liver transplantation is equivalent to that for recipients of ABO-compatible liver transplantation.\n\nPeer-review\nThis is a brief report of a successful pregnancy after ABO incompatible liver transplantation. The manuscript is well written and would be of interest to the readers of this journal, the references are up to date.\n\nManuscript source: Unsolicited manuscript\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry of origin: Japan\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B,B\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nInstitutional review board statement: The study was reviewed and approved by the Keio University School of Medicine Institutional Review Board.\n\nInformed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.\n\nConflict-of-interest statement: All authors declare no conflicts of interest.\n\nPeer-review started: September 1, 2016\n\nFirst decision: September 28, 2016\n\nArticle in press: November 12, 2016\n\nP- Reviewer: Kumar R, Quak SH, Ramsay MA S- Editor: Yu J L- Editor: A E- Editor: Liu WX\n==== Refs\n1 Tanabe M Shimazu M Wakabayashi G Hoshino K Kawachi S Kadomura T Seki H Morikawa Y Kitajima M Intraportal infusion therapy as a novel approach to adult ABO-incompatible liver transplantation Transplantation 2002 73 1959 1961 12131697 \n2 Mishima K Obara H Sugita K Shinoda M Kitago M Abe Y Hibi T Yagi H Matsubara K Mori T Helicobacter cinaedi bacteremia with cellulitis after ABO-incompatible living-donor liver transplantation: Case report World J Gastroenterol 2015 21 7911 7915 26167092 \n3 Nagy S Bush MC Berkowitz R Fishbein TM Gomez-Lobo V Pregnancy outcome in liver transplant recipients Obstet Gynecol 2003 102 121 128 12850617 \n4 Kainz A Harabacz I Cowlrick IS Gadgil S Hagiwara D Analysis of 100 pregnancy outcomes in women treated systemically with tacrolimus Transpl Int 2000 13 Suppl 1 S299 S300 11112018 \n5 Takahashi K Sonda K Okuda H Nakazawa H Kawaguchi H Toma H Agishi T Ota K Nakabayashi M Takeda Y The first report of a successful delivery in a woman with an ABO-incompatible kidney transplantation Transplantation 1993 56 1288 1289 8249142 \n6 Esposito L Rostaing L Kamar N Successful pregnancy after ABO-incompatible kidney transplantation Transpl Int 2016 29 506 507 26615059 \n7 Tanabe M Kawachi S Obara H Shinoda M Hibi T Kitagawa Y Wakabayashi G Shimazu M Kitajima M Current progress in ABO-incompatible liver transplantation Eur J Clin Invest 2010 40 943 949 20636381 \n8 Umeshita K Inomata Y Furukawa H Kasahara M Kawasaki S Kobayashi E Kokudo N Sakisaka S Shimada M Tanaka E Liver transplantation in Japan -Registry by the Japanese Liver Transplantation Society Hepatol Res 2016 46 1171 1186 26887781 \n9 Deshpande NA James NT Kucirka LM Boyarsky BJ Garonzik-Wang JM Cameron AM Singer AL Dagher NN Segev DL Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis Liver Transpl 2012 18 621 629 22344967 \n10 Dei Malatesta MF Rossi M Rocca B Iappelli M Giorno MP Berloco P Cortesini R Pregnancy after liver transplantation: report of 8 new cases and review of the literature Transpl Immunol 2006 15 297 302 16635752\n\n",
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"title": "First successful perinatal management of pregnancy after ABO-incompatible liver transplantation.",
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"abstract": "Primary mediastinal sarcomas are aggressive tumors with a very rare incidence. This report describes the case of a 35 year old male patient who presented with acute symptoms of dyspnoea, facial puffiness, engorged neck veins and hoarseness of voice. With the clinical picture consistent with the superior vena caval (SVC) syndrome, the patient was investigated with computed tomography of the chest. This revealed a large soft tissue density mass lesion compressing the SVC along with other critical superior mediastinal structures. Histopathological evaluation of the mass revealed features consistent with a soft tissue sarcoma and positive staining was observed for vimentin and S-100. Cytogenetic analysis by fluorescent in-situ hybridization (FISH) demonstrated the t(X: 18) translocation. Thus diagnosis was established as primary mediastinal synovial sarcoma. Patient was treated with three-cycles of neo-adjuvant (ifosfamide 2400mg/m2 on days 1-5 and doxorubicin 37.5 mg/m2 on days 1 & 2) chemotherapy, to which there was a partial response as per the RECIST criteria. Surgical excision of the mediastinal mass was performed, and further post-operative treatment with adjuvant chemo-radiotherapy was provided. Patient was under regular surveillance at our clinic and remains free of symptoms one-year after treatment completion. But after 14 months of treatment completion patient again had symptoms of progressive dyspnea, hoareness of voice and mild facial puffiness over a period of 2 months. On further investigating he was found to have right-sided centrally located mass with cystic and necrotic changes with extension and compression of trachea, SVC, right upper lobe bronchus and its branches. Histopathological examination of the biopsy from the lesion revealed adenoid cystic carcinoma of the lung. Rest of the metastatic work up was within normal. Immunohistochemistry of the specimen revealed c-Kit positivity. In view of the morbid second surgery he was put on Imatinib 400mg once a day and celecoxib 200mg twice a day. After 4 months patient had partial response and presently continuing with the same regimen. Extensive literature search didn't reveal much information on combined primary mediastinal sarcoma and adenoid cystic carcinoma of lung.",
"affiliations": "Department of Medical and Pediatric Oncology, GCRI, Ahmedabad, Gujarat, India.;Department of Medical and Pediatric Oncology, GCRI, Ahmedabad, Gujarat, India.;Department of Medical and Pediatric Oncology, GCRI, Ahmedabad, Gujarat, India.;Department of Medical and Pediatric Oncology, GCRI, Ahmedabad, Gujarat, India.;Department of Medical and Pediatric Oncology, GCRI, Ahmedabad, Gujarat, India.",
"authors": "Madabhavi|Irappa|I|;Patel|Apurva|A|;Anand|Asha|A|;Panchal|Harsha|H|;Parikh|Sonia|S|",
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"title": "Primary mediastinal synovial sarcoma with subsequent development of primary adenoid cystic carcinoma of lung presenting as superior vena cava syndrome.",
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"abstract": "We report results from a phase II study assessing the efficacy of the WEE1 inhibitor adavosertib with cisplatin in metastatic triple-negative breast cancer (mTNBC).\n\n\n\nPatients with mTNBC treated with 0-1 prior lines of chemotherapy received cisplatin 75 mg/m2 i.v. followed 21 days later by cisplatin plus adavosertib 200 mg oral twice daily for five doses every 21 days. The study had 90% power to detect the difference between null (20%) and alternative (40%) objective response rates (ORR) with a one-sided type I error of 0.1: an ORR >30% was predefined as making the regimen worthy of further study. RNA sequencing and multiplex cyclic immunofluorescence on pre- and post-adavosertib tumor biopsies, as well as targeted next-generation sequencing on archival tissue, were correlated with clinical benefit, defined as stable disease ≥6 months or complete or partial response.\n\n\n\nA total of 34 patients initiated protocol therapy; median age was 56 years, 2 patients (6%) had BRCA2 mutations, and 14 (41%) had one prior chemotherapy. ORR was 26% [95% confidence interval (CI), 13-44], and median progression-free survival was 4.9 months (95% CI, 2.3-5.7). Treatment-related grade 3-5 adverse events occurred in 53% of patients, most commonly diarrhea in 21%. One death occurred because of sepsis, possibly related to study therapy. Tumors from patients with clinical benefit demonstrated enriched immune gene expression and T-cell infiltration.\n\n\n\nAmong patients with mTNBC treated with 0-1 prior lines, adavosertib combined with cisplatin missed the prespecified ORR cutoff of >30%. The finding of immune-infiltrated tumors in patients with clinical benefit warrants validation.",
"affiliations": "Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Breast Tumor Immunology Laboratory, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Breast Tumor Immunology Laboratory, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, Massachusetts.;Breast Tumor Immunology Laboratory, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.;AstraZeneca Pharmaceuticals, Boston, Massachuetts.;Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston Massachusetts.;Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, Massachusetts.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. sara_tolaney@dfci.harvard.edu.",
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"pmid": "33257427",
"pubdate": "2021-02-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Clinical Efficacy and Molecular Response Correlates of the WEE1 Inhibitor Adavosertib Combined with Cisplatin in Patients with Metastatic Triple-Negative Breast Cancer.",
"title_normalized": "clinical efficacy and molecular response correlates of the wee1 inhibitor adavosertib combined with cisplatin in patients with metastatic triple negative breast cancer"
} | [
{
"companynumb": "US-MYLANLABS-2022M1006896",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "4",
... |
{
"abstract": "Delayed inflammatory reactions (DIRs) associated with hyaluronic acid injections are not rare and can be seen in up to 4.25% of patients. Although the exact mechanism is not clear, several triggering factors, including infections, trauma, and dental procedures, were reported in the literature. A 43-year-old female patient treated with HA fillers developed an inflammatory reaction following vaccination in all areas of injection, including temples, lips, and lower eyelids. Systemic steroid and ciprofloxacin were used as a first-line treatment without response. Colchicine 1 mg/day along with hyaluronidase in lower eyelids improved all lesions successfully.",
"affiliations": "Dermatologist, Dr. Sukran Sarigul Guduk Dermatology Clinic, Istanbul, Turkey.",
"authors": "Sarigul Guduk|Sukran|S|0000-0003-2850-6209",
"chemical_list": "D000067548:Dermal Fillers; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; D003078:Colchicine",
"country": "England",
"delete": false,
"doi": "10.1080/14764172.2021.1967997",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1476-4172",
"issue": "23(3-4)",
"journal": "Journal of cosmetic and laser therapy : official publication of the European Society for Laser Dermatology",
"keywords": "Hyaluronic acid filler; delayed inflammatory reaction; filler reaction",
"medline_ta": "J Cosmet Laser Ther",
"mesh_terms": "D000328:Adult; D003078:Colchicine; D003357:Cosmetic Techniques; D000067548:Dermal Fillers; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; D014611:Vaccination",
"nlm_unique_id": "101136419",
"other_id": null,
"pages": "52-54",
"pmc": null,
"pmid": "34407723",
"pubdate": "2021-05-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of delayed inflammatory filler reaction following vaccination with succesful response to colchicine.",
"title_normalized": "a case of delayed inflammatory filler reaction following vaccination with succesful response to colchicine"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-323207",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DESLORATADINE"
},
"d... |
{
"abstract": "Sporadic late onset nemaline myopathy (SLONM) is an extremely rare disorder which can be associated with monoclonal gammopathy of unclear significance (MGUS). Clinically SLONM appears mostly after the fourth decade of life as rapidly progressing tetraparesis, respiratory insufficiency and features, such as dropped head syndrome, facial and bulbar involvement. Diagnosis is confirmed by muscle biopsy with detection of nemaline bodies and also frequently lobulated fibres. Immunosuppressant and immunomodulating therapies have been shown to be ineffective but clinical improvement accompanied by disappearance of monoclonal gammopathy and even nemaline bodies was reported following autologous stem cell transplantation and chemotherapy with melphalan. This article presents the case of a 53-year-old man with a 4-year history of SLOMN with MGUS in which administration of intravenous immunoglobulin therapy (IVIG) was not successful in reversing gammopathy, histopathological changes or clinical symptoms.",
"affiliations": "Klinik und Poliklinik für Neurologie, Universitätsklinikum, Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle (Saale), Deutschland.",
"authors": "Hanisch|F|F|;Schneider|I|I|;Müller|T|T|;Romeike|B F|BF|;Stoltenburg|G|G|;Holzhausen|H J|HJ|;Zierz|S|S|",
"chemical_list": "D007155:Immunologic Factors; D019653:Myeloablative Agonists; D008558:Melphalan",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00115-013-3825-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2804",
"issue": "84(8)",
"journal": "Der Nervenarzt",
"keywords": null,
"medline_ta": "Nervenarzt",
"mesh_terms": "D006801:Humans; D007116:Immunization, Passive; D007155:Immunologic Factors; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D019653:Myeloablative Agonists; D017696:Myopathies, Nemaline; D033581:Stem Cell Transplantation; D016896:Treatment Outcome",
"nlm_unique_id": "0400773",
"other_id": null,
"pages": "955-61",
"pmc": null,
"pmid": "23836301",
"pubdate": "2013-08",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": "18565829;2843080;17855669;8186711;21744311;10417802;11989852;3683496;11516997;16401746;15236405;11206338;16919950;19852026;1316119;47386;9372751;19229965;19918772;18565830;21072530;21888255;18330038;6703949;11558787;19526838;10779860;16148261",
"title": "Treatability of sporadic late onset nemaline myopathy.",
"title_normalized": "treatability of sporadic late onset nemaline myopathy"
} | [
{
"companynumb": "DE-BAXTER-2014BAX040168",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": n... |
{
"abstract": "Cosmetic plastic surgery procedures continue to increase in frequency, and a greater number of them now occur outside of an acute-care hospital setting. In addition, antidepressant use is also rising, with a greater number of patients taking selective serotonin reuptake inhibitors to aid in a variety of mood and anxiety disorders. Americans spend more than $86 billion each year on antidepressants, as 34 million people in the United States are taking at least one of these medications. Many side effects of selective serotonin reuptake inhibitors are well known and not clinically relevant to practicing surgeons. Hyponatremia, however, is a well-documented side effect of these medications that has received relatively little attention in the surgical literature. Postoperative hyponatremia results because of a decrease of antidiuretic hormone suppression that occurs with selective serotonin reuptake inhibitor administration. Here, the authors first review the literature reporting hyponatremia with selective serotonin reuptake inhibitor use. The authors then present two cases of severe postoperative hyponatremia after plastic surgery operations. The authors propose that patients using selective serotonin reuptake inhibitors, especially elderly patients and those undergoing procedures with expected large fluid shifts, should be tested preoperatively and postoperatively for serum sodium levels so that a diagnosis of hyponatremia may be made early and treated before a catastrophic event.\n\n\nMETHODS\nTherapeutic, V.",
"affiliations": "New York, N.Y.;New York, N.Y.;New York, N.Y.;New York, N.Y.",
"authors": "Levine|Steven M|SM|;Sinno|Sammy|S|;Cannavo|Dominick|D|;Baker|Daniel C|DC|",
"chemical_list": "D000928:Antidepressive Agents; D017367:Serotonin Uptake Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1097/PRS.0000000000003329",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0032-1052",
"issue": "139(6)",
"journal": "Plastic and reconstructive surgery",
"keywords": null,
"medline_ta": "Plast Reconstr Surg",
"mesh_terms": "D061645:Abdominoplasty; D000368:Aged; D000556:Ambulatory Surgical Procedures; D000928:Antidepressive Agents; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007010:Hyponatremia; D008297:Male; D008875:Middle Aged; D011300:Preoperative Care; D018570:Risk Assessment; D017367:Serotonin Uptake Inhibitors; D013518:Surgery, Plastic; D016896:Treatment Outcome",
"nlm_unique_id": "1306050",
"other_id": null,
"pages": "1481-1488",
"pmc": null,
"pmid": "28207561",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Selective Serotonin Reuptake Inhibitor-Induced Hyponatremia and the Plastic Surgery Patient.",
"title_normalized": "selective serotonin reuptake inhibitor induced hyponatremia and the plastic surgery patient"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/17/0093976",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DULOXETINE"
},
"drugadditional": "3",
... |
{
"abstract": "A 57-year-old woman presented with optic neuritis with repeated clinical symptoms of focal demyelination of the cerebral white matter and brain stem for 14 years. At the end of the patient's course, the clinical signs mimicked secondary progressive multiple sclerosis, but whether it was caused by interferon administration or neuromyelitis optica spectrum disorders (NMOSD)-or a combination of both or others-was unclear. Histopathological findings indicated the etiology to be NMOSD, with no apparent plaque in spinal cord specimens. This case suggests that an accurate clinical diagnosis requires serum anti-aquaporin 4 antibody measurements as well as an autopsy examination.",
"affiliations": "Department of Neurology, Fujita Health University Bantane Hospital, Japan.;Department of Neurology, Fujita Health University Bantane Hospital, Japan.;Department of Neurology, Fujita Health University Bantane Hospital, Japan.;Aichi Medical University, Institute for Medical Science of Aging, Japan.;Department of Neurology, Yao Tokushukai General Hospital, Japan.",
"authors": "Azuma|Fumika|F|;Nokura|Kazuya|K|;Kako|Tetsuharu|T|;Yoshida|Mari|M|;Tatsumi|Shinsui|S|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.7635-21",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n34645756\n10.2169/internalmedicine.7635-21\nCase Report\nAn Autopsy Confirmed Neuromyelitis Optica Spectrum Disorder with Extensive Brain White Matter Lesion and Optic Neuritis but Intact Spinal Cord, Clinically Mimicking a Secondary Progressive Multiple Sclerosis-like Course\nAzuma Fumika 1\nNokura Kazuya 1\nKako Tetsuharu 1\nYoshida Mari 2\nTatsumi Shinsui 3\n1 Department of Neurology, Fujita Health University Bantane Hospital, Japan\n2 Aichi Medical University, Institute for Medical Science of Aging, Japan\n3 Department of Neurology, Yao Tokushukai General Hospital, Japan\nCorrespondence to Dr. Fumika Azuma, fazuma@fujita-hu.ac.jp\n\n12 10 2021\n1 5 2022\n61 9 14151422\n28 3 2021\n19 8 2021\nCopyright © 2022 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 57-year-old woman presented with optic neuritis with repeated clinical symptoms of focal demyelination of the cerebral white matter and brain stem for 14 years. At the end of the patient's course, the clinical signs mimicked secondary progressive multiple sclerosis, but whether it was caused by interferon administration or neuromyelitis optica spectrum disorders (NMOSD) - or a combination of both or others - was unclear. Histopathological findings indicated the etiology to be NMOSD, with no apparent plaque in spinal cord specimens. This case suggests that an accurate clinical diagnosis requires serum anti-aquaporin 4 antibody measurements as well as an autopsy examination.\n\nneuromyelitis optica (NMO)\nNMO spectrum disorder (NMOSD)\nmultiple sclerosis (MS)\nanti-aquaporin 4 antibody (NMO-IgG)\noptic-brain/brainstem type\nautopsy examination\n==== Body\npmcIntroduction\n\nNeuromyelitis optica (NMO), also known as Devic's disease, is an inflammatory disease of the central nervous system characterized by severe optic neuritis and transverse myelitis (1,2). NMO and optic-spinal multiple sclerosis are NMO spectrum disorders (NMOSD) and can be distinguished from multiple sclerosis (MS) by the serum autoantibody marker NMO-IgG/anti-aquaporin 4 antibody (AQP4-IgG) (3). The recognition of variable distributions of NMO lesions outside the spinal cord and optic nerves has promoted the concept of NMOSD (4,5). Recently, the specificity of AQP4-IgG for making an NMO diagnosis has facilitated observations that further broadened the clinical and neuroimaging spectrum of NMO. The International Panel for NMO Diagnosis released an updated set of guidelines for diagnosing NMO and NMOSD in 2015. These disorders are now known as NMOSD (6).\n\nInitially, NMOSD had been considered mild or with low numbers of cerebral lesions. NMOSD is relatively frequent in Asia (7,8). Characteristic images are described regularly, but progressive and extensive lesions of the brain are not well described in NMOSD. However, there have been some recent reports of progressive white-matter lesions in NMOSD (9-11).\n\nThe present patient showed optic neuritis as the initial symptom after 50 years old. Nine years after the initial symptom, the patient showed exacerbation of clinical symptoms without remission, with lesions mainly in the cerebral white matter and brain stem during the total course of 14 years. There was no evidence of spinal cord symptoms. Thus, we suspected that the patient had secondary progressive MS and did not measure AQP4-IgG. Nevertheless, this case was pathologically diagnosed as NMOSD after an autopsy. In NMOSD, the secondary progressive type is thought to be extremely rare. Therefore, this case is an extremely valuable case diagnosed as NMOSD by a histopathological examination, although this diagnosis was unable to be deduced from the clinical course.\n\nCase Report\n\nA 57-year-old woman with no specific medical history or a family history of neurological illness visited the Department of Ophthalmology because of decreased visual acuity in her left eye. An ophthalmologist diagnosed her with optic neuritis. She received intravenous methylprednisolone (1,000 mg/day for 2 days) and a retrobulbar injection of dexamethasone (80 mg/day for 5 days). A month after starting the treatment, her symptoms subsided.\n\nAt 60 years of age (X+3 years), she presented with symptoms of left hemiparesis, including the face, when she visited the Department of Neurology. Computed tomography of the head showed a low-density area at the right internal capsule. She was treated as a patient with ischemic stroke. After this episode, the patient again experienced visual deterioration in her left eye, and she was hospitalized in the ophthalmology department. She was prescribed oral steroids for two months and completely recovered.\n\nAt 63 years old (X+6 years), she presented with hemiparalysis on the right side and facial paralysis on the left side. Magnetic resonance imaging (MRI) of the head revealed multiple lesions in her right superior cerebellar peduncle and middle cerebellar peduncle. A diagnosis of MS was made, and we administered steroid pulse therapy, upon which she almost completely recovered. Data on oligoclonal bands and myelin basic protein in the cerebrospinal fluid were not available, but her serum was positive for both anti-SS-A antibody 70.4 (<20) and anti-SS-B antibody 26.8 (<20) without sicca syndrome. Mizoribine was administered for 6 months. However, she had to discontinue treatment due to hepatic dysfunction.\n\nAt 67 years of age (X+10 years), she presented with gait disturbance, nystagmus, and left-sided ataxia. At this time, we found a lesion in the cerebellar peduncle. After steroid pulse therapy, β-interferon therapy was initiated. However, even after starting the treatment, her symptoms remained, and she showed gradual deterioration in her activities of daily living (ADL).\n\nAt 68 years old (X+11 years), she became susceptible to falling and presented with symptoms of incontinence and cognitive impairment. MRI of the head showed new lesions, including in the right parietal subcortical region and lateral geniculate body. Although steroid pulse therapy was performed, walking difficulties remained, and cognitive impairment progressed.\n\nAt 69 years old (X+12 years), she again showed signs of decreasing left visual acuity and received steroid pulse therapy. However, she failed to regain visual acuity and was declared completely blind. During that time, she had another fall and suffered a right femoral and thoracolumbar vertebral fracture. During the course, she had been administered an average steroid dose of 2.5-20 mg/day, but her osteoporosis required reducing these doses. We started to administer tacrolimus hydrate 3 mg/day, to no effect.\n\nAt this time, head magnetic resonance T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging revealed small multiple irregular plaques in her pons and periventricular white matter in which plaques tended to fuse. The new lesion found in the diffusion-weighted image presented with a vague high intensity with an irregular margin (Fig. 1a). The lesions were not enhanced with gadolinium.\n\nFigure 1. MRI of the head. (a) At 69 years old. Small multiple irregular plaques were found in the pons and periventricular area (T2 and DWI) (yellow arrow). A new lesion was also found on DWI (red arrow). (b) At 70 years old. Progressed white matter lesions accompanied by cerebral atrophy and ventricular dilatation were shown (T2 and FLAIR) (yellow arrow).\n\nAt 70 years old (X+13 years), the patient became bedridden and underwent endoscopic gastrostomy because of dysphagia. While β-interferon was considered ineffective, instead exacerbating the symptoms, it had been continued for over three years. MRI of the head showed progression of cerebral atrophy and ventricular dilatation (Fig. 1b). The corpus callosum showed a high intensity and thinning.\n\nAt 71 years old (X+14 years), a chest roentgenogram revealed right pleural effusion. A cytological test revealed adenocarcinoma from the effusion. After one month, she died at 71 years old, 14 years after the onset of the disease.\n\nShe had experienced no episodes of spinal cord symptoms for 14 years. MRI of the whole spinal cord revealed no abnormal findings at 69 years old. She also did not have Sjögren's syndrome (SjS). Unfortunately, AQP4-IgG had not been measured. The clinical course is shown in Fig. 2. After X+9 years, there was no remission period, and she showed a gradual decline in her ADL and spontaneity, progressive cognitive symptoms, and dysphagia.\n\nFigure 2. Clinical course.\n\nAn autopsy was performed three hours after the patient's death with the family's informed consent. General pathology revealed pancreatic adenocarcinoma and its metastasis to the thorax.\n\nThe central nervous system obtained at the autopsy was fixed with 10% formalin, embedded in paraffin blocks, and sectioned at a thickness of 4-6 μm. Spinal cord specimens were cut in every spinal cord segment. The specimens were stained using hematoxylin and eosin (HE), Klüver-Barrera (KB), and Bodian methods. Immunohistochemical staining was performed on formalin-fixed and paraffin-embedded sections. The primary antibodies used in this study are listed in Table.\n\nTable. List of the Antibodies Used for Immunohistochemistry.\n\nAntibody\t\tSource\t\tCategory\t\tDilution\t\nGFAP (glial fibrillary acidic protein)\t\tDako\t\tMouse monoclonal\t\t400\t\nMBP (myelin basic protein)\t\tDako\t\tRabbit polyclonal\t\t1,000\t\nAQP (aquaporin)\t\tSigma Aldrich\t\tMouse monoclona\t\t800\t\n\nAfter formalin fixation, the brain weighed 1,020 g. Macroscopically, the corpus callosum was atrophied, and diffuse white-matter lesions were present around the lateral ventricle (Fig. 3a, b). No lesions were found in the cerebral cortex. The optic nerve showed severe atrophy (Fig. 3c), and the pons showed signs of moderate atrophy. Cavitated lesions were noted on the cut surface of the pons (Fig. 3d). There were no lesions in the spinal cord segments (Fig. 3e).\n\nFigure 3. Macroscopic findings. (a, b) The corpus callosum was atrophied, and diffuse white matter lesions were present around the lateral ventricle (arrow). (c) The optic nerve displayed severe atrophy. (d) The pons showed moderate atrophy and cavitated lesions. (e) The spinal cord findings were unremarkable.\n\nMicroscopically, multifocal irregular-shaped lesions were found in the cerebral white matter, corpus callosum, and brain stem using KB staining. However, no lesions were found in the cerebral cortex or surround the third and fourth ventricles (Fig. 4a-f). KB staining and myelin basic protein immunostaining labeled the lesions only weakly, but neurofilament immunostaining labeled the lesions strongly. No obvious lesions were observed in any spinal cord section (Fig. 4g-i). AQP4 immunoreactivity was severely decreased in the cystic lesion (Fig. 5). There were severe cystic destructive lesions in the optic nerve (Fig. 6). Many of the demyelinated lesions were obsolete plaques with necrosis or porosity. In these lesions, no AQP4 labeling was found in the perivascular spaces. Multiple irregular cystic plaques in the corpus callosum and periventricular white matter and irregular demyelinating lesions on the same slice were identified by myelin staining. Immunohistochemistry studies revealed no AQP4 labeling in the lesion.\n\nFigure 4. Microscopic findings (KB). Multifocal irregularly shaped lesions were found in the cerebral white matter, corpus callosum, and brainstem (arrow). (a, b) Corpus callosum and the area around the lateral ventricle. (c) Splenium of the corpus callosum. (d-f) Irregular cystic destructive lesions in the brainstem. (g-i) No obvious lesions were observed in any spinal cord specimens.\n\nFigure 5. Immunohistochemistry using anti-AQP4, anti-MBP, and anti-NF antibodies in plaques at occipital white matter lesions. Staining for AQP4 was negative in the lesions.\n\nFigure 6. Optic nerve (HE, KB, NF). Lesions along the blood vessel with hyaline degeneration (arrow).\n\nDiscussion\n\nThe main characteristics of this case were as follows: first, we found extensive white matter lesions and severe optic neuritis but no spinal cord lesion; second, the patient's serum was positive for anti-Sjögren's syndrome antibodies; third, the use of β-interferon was not effective but instead harmful; and fourth, clinically, a secondary progressive MS was diagnosed after X+9 years.\n\nAt the initial stage, we diagnosed the patient with relapsing and remitting-type conventional MS (12). However, at nine years after her initial symptoms manifested, there had been no remission period, and the gradual decline in her ADL and spontaneity, progressive cognitive symptoms, and dysphagia due to pseudobulbar palsy seemed to instead mimic secondary progressive MS (13,14). This was mainly because she had repeated optic neuritis and clinical symptoms of demyelination of the cerebral white matter and had never presented with spinal cord symptoms. The red flags for MS (15) applicable in this case included “no spinal cord lesions” and “onset of the disease after 50 years old”. The patient's serum was positive for anti-SS-A/B, but she did not have sicca syndrome. The MRI findings indicated indistinct lesion margins, which was also a red flag for MS (16).\n\nRecently, AQP4-IgG positive cases without optic nerve lesions or distinctive spinal cord lesions have been reported. Tanaka et al. reported that about 10% of patients with NMOSD initially developed a cerebral or brain stem lesion (17). Another study on 106 NMO-IgG-positive cases in England and Japan reported that after phenotype analyses, the brain and optic neuritis type accounted for 8% in England and 13% in Japan (18). Of 14 consecutive autopsy cases diagnosed with NMOSD at Aichi Medical University from 1980 to 2013, there was only 1 case (the present case) without lesions in the spinal cord. Similarly, among the nine patients diagnosed with MS, there was one case where there was no spinal cord lesion (19). Therefore, the presentation in our case is thought to be part of a range of NMOSD presentations.\n\nOn analyzing the MRI scans of 60 patients with NMO, 36 (60%) showed evidence of brain abnormalities. Six of these patients had MS-like lesions. Diencephalic, brain stem, or cerebral hemispheric lesions were observed in 5 of these patients (8%), mostly in children, which is distinctly atypical for MS (20). Another study suggested that 8 out of 120 patients had recurring and distinctive MRI abnormalities in the hypothalamic and periventricular areas (21). Li et al. reported that, in an MRI analysis of Chinese patients with NMO, 66.7% presented with well-defined brain parenchymal lesions, 18.2% with macroscopic symmetrical diffuse hyperintensities in deep white matter, and 15.1% with no brain lesion at all (7). These lesions, apparent on MRI, predominantly involve the hypothalamus and occasionally extend to the brain stem areas that surround the third and fourth ventricles. The corpus callosum is also sometimes affected. The distribution of the characteristics of NMO brain lesions mirrors the periventricular and hypothalamic localization of AQP4 (22). Therefore, it might be helpful to differentiate the diagnosis from MS based on the imaging findings of the brain using MRI. Interestingly, the case reported here did not show the typical distribution of NMOSD lesions, such as in the hypothalamus or tegmentum of the brain stem.\n\nThere is a case report of SjS showing only brain lesions without optic neuritis or myelitis with positive NMO-IgG findings (23). In addition, there is a report of 49 patients with coexisting SjS and NMOSD. Thirty-two out of 37 patients in whom NMO-IgG was measured were positive, 4 were negative, and 1 patient was borderline (24). In another report in China, serum AQP4-antibodies were detected in 89.3% of patients who were diagnosed with primary SjS with NMOSD (25). The reason for the high positive rate of antibody against SjS in NMOSD patients should be elucidated in future studies. Nevertheless, the presence of anti-SjS antibodies might help diagnose NMOSD. NMOSD should be considered in the early stage of the disease, when anti-SjS antibodies are detected.\n\nIFN-β treatment may not be effective in NMO. Previous studies reported that both patients with NMO and MS with long spinal cord lesion (LSCL) had a poor response to IFN-β treatment. Furthermore, patients with NMO had a worse response to IFN-β treatment than patients with MS with LSCL (26). The patient described in the present case had no spinal cord lesion despite having been administered INF-β for over three years. However, we hypothesize that the cerebral lesions were exacerbated by INF-β. Since the administration of INF-β and progression of the clinical course, similar to that for secondary progressive type, occurred at the same time, whether or not INF-β actually affected the progression of symptoms remains unclear.\n\nHistopathologically, the lesions showed multiple irregularly shaped areas of softening in NMOSD. This is substantially different from the sharp margin associated with MS plaques. As a pathological characteristic, severe cystic destructive lesions are found in NMOSD, but MS lesions tend to be milder and fewer in number (19). The AQP4 and glial fibrillary acidic protein (GFAP) expression is decreased in NMOSD lesions. The characteristic pathological change in our case was that the lesions had an irregular margin, showed strong necrosis and softening, occurred along the blood vessel with hyaline degeneration of the vessels, and had negative AQP4 immunostaining. These findings are consistent with the histopathological findings of AQP4-positive NMOSD (27). The plaques were all obsolete lesions, so we did not further examine the deposition of immunoglobulins and complements in this case. Thus, a comparative analysis of the acute pathologic patterns of NMOSD is important. Our case was compatible with NMOSD pathology, but there were several unusual aspects. The absence of lesions in the spinal cord was demonstrated histologically for all spinal segments. Based on his, our case was considered optic-brain-brainstem-type NMOSD.\n\nIn another report, only 2 (2%) of 96 patients with definite NMO converted to a secondary progressive course (myelopathy) during a median follow-up of 6.1 years, contrary to the estimate of 21 converted cases based on MS data (28). Yanagawa et al. found no secondary progressive type in 17 definite and limited form cases of NMO. In their report, they concluded that NMO displays homogeneous pathogenic effector immune mechanisms through terminal stages, whereas MS should be recognized as a heterogeneous two-stage disease that can switch from an inflammatory to a degenerative phase (29). In fact, progressive neurologic deterioration (over months to years) unrelated to attacks is a clinical “red flag” in the newly proposed diagnostic criteria for NMOSD. In general, elderly patients with progressive MS have a very low probability of relapse (30,31); however, the patient in this case, over 60 years old, had several incidents of relapse. MS plaques commonly have distinct margins (16), and relapse is usually rare in elderly patients with progressive MS. Hence, the incidents of relapses in the present case implied a greater possibility of NMOSD rather than MS.\n\nNMOSD patients show progression exclusively at the time of each clinical attack and do not deteriorate without attacks. In contrast, MS patients show spontaneous improvement or deterioration, independent of relapses. The progressive patterns of neurological disability in MS and NMOSD are suggested to differ markedly (11). However, several studies have reported a progressive course in NMOSD (9-11). In our case, it was not possible to distinguish between the two based on the clinical course. The patient's clinical signs mimicked secondary progressive MS, and it was unclear whether it was caused by IFN administration or NMOSD itself (or a combination of both or others). Since this case was observed for a relatively long period compared to the previous report, it became apparent that the patient was progressive after nine years, indicating the importance of long-term follow-up studies.\n\nRecently, Gelfand reported a case with NMOSD wherein an underlying disease process involving the innate immune system was suspected to have caused massive monocytic infiltration and tissue destruction. They proposed that their case illustrated that progressive worsening of NMO could occur in the absence of clinical relapses or contrast-enhanced lesion activity on MRI as a consequence of tissue injury associated with monocytic infiltration (10). The disease process described above might have been similar to that in our own case.\n\nGiven the abovementioned findings, it is difficult to distinguish between MS and NMOSD. Even in cases without spinal cord lesions, NMO-IgG should be measured, regardless of whether or not the patients exhibit a typical clinical course or MRI findings.\n\nOur case is extremely rare for secondary progressive-type NMOSD with an optico-brain-brainstem distribution of lesions, and further studies are necessary to elucidate the pathophysiology of NMOSD.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Okinaka S , Tsubaki T , Kuroiwa Y , Toyokura Y , Imamura Y . Multiple sclerosis and allied diseases in Japan; clinical characteristics. Neurology 8 : 756-763, 1958.13590382\n2. Wingerchuk DM , Hogancamp WF , O'Brien PC , Weinshenker BG . The clinical course of neuromyelitis optica (Devic's syndrome). Neurology 53 : 1107-1114, 1999.10496275\n3. Lennon VA , Wingerchuk DM , Kryzer TJ , et al . A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet (London, England) 364 : 2106-2112, 2004.\n4. Wingerchuk DM , Lennon VA , Pittock SJ , Lucchinetti CF , Weinshenker BG . Revised diagnostic criteria for neuromyelitis optica. Neurology 66 : 1485-1489, 2006.16717206\n5. Wingerchuk DM , Pittock SJ , Lucchinetti CF , Lennon VA , Weinshenker BG . A secondary progressive clinical course is uncommon in neuromyelitis optica. Neurology 68 : 603-605, 2007.17310032\n6. Wingerchuk DM , Banwell B , Bennett JL , et al . International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85 : 177-189, 2015.26092914\n7. Li Y , Xie P , Lv F , et al . Brain magnetic resonance imaging abnormalities in neuromyelitis optica. Acta Neurol Scand 118 : 218-225, 2008.18384459\n8. Nagaishi A , Takagi M , Umemura A , et al . Clinical features of neuromyelitis optica in a large Japanese cohort: comparison between phenotypes. J Neurol Neurosurg Psychiatry 82 : 1360-1364, 2011.21665917\n9. Fujihara K , Nakashima I . Secondary progression and innate immunity in NMO: a possible link to alemtuzumab therapy? Neurol Neuroimmunol Neuroinflamm 1 : e38, 2014.25340089\n10. Gelfand JM , Cotter J , Klingman J , Huang EJ , Cree BA . Massive CNS monocytic infiltration at autopsy in an alemtuzumab-treated patient with NMO. Neurol Neuroimmunol Neuroinflamm 1 : e34, 2014.25340086\n11. Akaishi T , Takahashi T , Misu T , et al . Progressive patterns of neurological disability in multiple sclerosis and neuromyelitis optica spectrum disorders. Sci Rep 10 : 13890, 2020.32807848\n12. Thompson AJ , Banwell BL , Barkhof F , et al . Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 17 : 162-173, 2018.29275977\n13. Lublin FD , Reingold SC . Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46 : 907-911, 1996.8780061\n14. Lublin FD , Coetzee T , Cohen JA , Marrie RA , Thompson AJ . The 2013 clinical course descriptors for multiple sclerosis: a clarification. Neurology 94 : 1088-1092, 2020.32471886\n15. Miller DH , Weinshenker BG , Filippi M , et al . Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler 14 : 1157-1174, 2008.18805839\n16. Geraldes R , Ciccarelli O , Barkhof F , et al . The current role of MRI in differentiating multiple sclerosis from its imaging mimics. Nat Rev Neurol 14 : 199-213, 2018.29521337\n17. Tanaka K . [MS (multiple sclerosis) and NMO (neuromyelitis optica)] clinical symptoms, MRI and laboratory findings of NMO: significance of anti-aquaporin-4 antibody. Brain Med 22 : 331-336, 2010(in Japanese).\n18. Kitley J , Leite MI , Nakashima I , et al . Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain J Neurol 135 : 1834-1849, 2012.\n19. Yoshida M . Neuropathology of demyelinating diseases in Japan. J Neurol Disord Stroke 2 : 1086, 2014.\n20. Pittock SJ , Lennon VA , Krecke K , Wingerchuk DM , Lucchinetti CF , Weinshenker BG . Brain abnormalities in neuromyelitis optica. Arch Neurol 63 : 390-396, 2006.16533966\n21. Pittock SJ , Weinshenker BG , Lucchinetti CF , Wingerchuk DM , Corboy JR , Lennon VA . Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol 63 : 964-968, 2006.16831965\n22. Nakashima I , Fujihara K , Miyazawa I , Watanabe S , Itoyama Y . Clinical and radiological features of multiplesclerosis patients positive for NMO-lgG. Shinkeinaika 65 : 377-381, 2006(in Japanese).\n23. Furukawa T , Matsui N , Tanaka K , Izumi Y , Kaji R . A case of neuromyelitis optica spectrum disorder (NMOSD) with Sjögren's syndrome manifested only brain involvement by preceding parotitis. Rinsho Shinkeigaku Clin Neurol 57 : 77-81, 2017(in Japanese).\n24. Carvalho DC , Tironi TS , Freitas DS , Kleinpaul R , Talim NC , Lana-Peixoto MA . Sjögren syndrome and neuromyelitis optica spectrum disorder co-exist in a common autoimmune milieu. Arq Neuropsiquiatr 72 : 619-624, 2014.25098478\n25. Qiao L , Wang Q , Fei Y , et al . The clinical characteristics of primary Sjögren's syndrome with neuromyelitis optica spectrum disorder in China: a STROBE-compliant article. Medicine 94 : e1145, 2015.26181553\n26. Wang KC , Lin KH , Lee TC , et al . Poor responses to interferon-beta treatment in patients with neuromyelitis optica and multiple sclerosis with long spinal cord lesions. PloS One 9 : e98192, 2014.24887452\n27. Misu T , Fujihara K , Kakita A , et al . Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis. Brain J Neurol 130 : 1224-1234, 2007.\n28. Wingerchuk DM , Lennon VA , Lucchinetti CF , Pittock SJ , Weinshenker BG . The spectrum of neuromyelitis optica. Lancet Neurol 6 : 805-815, 2007.17706564\n29. Yanagawa K , Kawachi I , Toyoshima Y , et al . Pathologic and immunologic profiles of a limited form of neuromyelitis optica with myelitis. Neurology 73 : 1628-1637, 2009.19917985\n30. Paz Soldán MM , Novotna M , Abou Zeid N , et al . Relapses and disability accumulation in progressive multiple sclerosis. Neurology 84 : 81-88, 2015.25398229\n31. Vaughn CB , Jakimovski D , Kavak KS , et al . Epidemiology and treatment of multiple sclerosis in elderly populations. Nat Rev Neurol 15 : 329-342, 2019.31000816\n\n",
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"issue": null,
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Anti-aquaporin 4 antibody (NMO-IgG); Multiple sclerosis (MS); NMO spectrum disorder (NMOSD); Neuromyelitis optica (NMO); autopsy examination; optic-brain/brainstem type",
"medline_ta": "Intern Med",
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"pmid": "34645756",
"pubdate": "2021-10-12",
"publication_types": "D016428:Journal Article",
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"title": "An Autopsy Confirmed Neuromyelitis Optica Spectrum Disorder with Extensive Brain White Matter Lesion and Optic Neuritis but Intact Spinal Cord, Clinically Mimicking a Secondary Progressive Multiple Sclerosis-like Course.",
"title_normalized": "an autopsy confirmed neuromyelitis optica spectrum disorder with extensive brain white matter lesion and optic neuritis but intact spinal cord clinically mimicking a secondary progressive multiple sclerosis like course"
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"abstract": "Background: The ongoing corona virus disease 2019 (COVID-19) pandemic is having a worldwide impact. Valuable information on the clinical characteristics of COVID-19 in pregnant patients with an autoimmune disease, such as systemic lupus erythematosus (SLE), is currently lacking. Methods: Herein, we describe the clinical presentation of 2 pregnant patients with SLE and mild symptomatic COVID-19 infection. Results: In both pregnant SLE patients, a watchful-waiting approach without initiation of treatment for COVID-19 was taken. No adverse outcomes were reported and both pregnancies resulted in healthy neonates born at term. In one patient we observed a flare in SLE disease activity, most likely attributed to discontinuing SLE treatment. Conclusion: Our report highlights the importance of multidisciplinary collaboration between health care professionals as well as individualized treatment decisions during unprecedented periods such as the current COVID-19 pandemic. Discontinuation of immunosuppressive drugs during the acute phase of a COVID-19 infection should be considered on a case-by-case basis. Maternal treatment decisions should be in line with current recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection and in line with treatment of COVID- 19 during pregnancy.",
"affiliations": "Department of Rheumatology, Erasmus University Medical Center, Rotterdam, The Netherlands.;Department of Rheumatology, Erasmus University Medical Center, Rotterdam, The Netherlands.;Department of Rheumatology, Erasmus University Medical Center, Rotterdam, The Netherlands.;Department of Gynaecology and Obstetrics, Erasmus University Medical Center, Rotterdam, The Netherlands.;Department of Gynaecology and Obstetrics, Erasmus University Medical Center, Rotterdam, The Netherlands.;Department of Rheumatology, Erasmus University Medical Center, Rotterdam, The Netherlands.",
"authors": "Smeele|Hieronymus Tw|HT|https://orcid.org/0000-0001-7724-7712;Perez-Garcia|Luis F|LF|;Grimminck|Koen|K|;Schoenmakers|Sam|S|;Mulders|Annemarie Gmgj|AG|;Dolhain|Radboud Jem|RJ|",
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"fulltext": "\n==== Front\nLupus\nLupus\nLUP\nsplup\nLupus\n0961-2033\n1477-0962\nSAGE Publications Sage UK: London, England\n\n33715506\n10.1177/09612033211002270\n10.1177_09612033211002270\nCase Reports\nSystemic lupus erythematosus and COVID-19 during pregnancy\nhttps://orcid.org/0000-0001-7724-7712\nSmeele Hieronymus TW 1\nPerez-Garcia Luis F 1\nGrimminck Koen 12\nSchoenmakers Sam 3\nMulders Annemarie GMGJ 3\nDolhain Radboud JEM 1\n1 Department of Rheumatology, Erasmus University Medical Center, Rotterdam, The Netherlands\n2 Department of Gynaecology and Obstetrics, Reiner de Graaf Gasthuis, Delft, The Netherlands\n3 Department of Gynaecology and Obstetrics, Erasmus University Medical Center, Rotterdam, The Netherlands\nHieronymus TW Smeele, Erasmus MC, room Na523, PO Box 2040, 3000 CA, Rotterdam, The Netherlands. Email: h.smeele@erasmusmc.nl\n14 3 2021\n6 2021\n30 7 11881191\n11 12 2020\n22 2 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nBackground: The ongoing corona virus disease 2019 (COVID-19) pandemic is having a worldwide impact. Valuable information on the clinical characteristics of COVID-19 in pregnant patients with an autoimmune disease, such as systemic lupus erythematosus (SLE), is currently lacking. Methods: Herein, we describe the clinical presentation of 2 pregnant patients with SLE and mild symptomatic COVID-19 infection. Results: In both pregnant SLE patients, a watchful-waiting approach without initiation of treatment for COVID-19 was taken. No adverse outcomes were reported and both pregnancies resulted in healthy neonates born at term. In one patient we observed a flare in SLE disease activity, most likely attributed to discontinuing SLE treatment. Conclusion: Our report highlights the importance of multidisciplinary collaboration between health care professionals as well as individualized treatment decisions during unprecedented periods such as the current COVID-19 pandemic. Discontinuation of immunosuppressive drugs during the acute phase of a COVID-19 infection should be considered on a case-by-case basis. Maternal treatment decisions should be in line with current recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection and in line with treatment of COVID- 19 during pregnancy.\n\nSystemic lupus erythematosus\npregnancy\nCOVID-19\nReumaNederland https://doi.org/10.13039/501100006315 LLP-26 typesetterts2\n==== Body\nThe corona virus disease 2019 (COVID-19) pandemic has spread across the world. Infection with the novel corona virus can result in hypoxemic respiratory failure in a small percentage of patients.1 Compared to the SARS-CoV-1 (SARS) pandemic in 2008, which is associated with spontaneous miscarriage, preterm delivery, and intrauterine growth restriction, COVID-19 seems to have less impact on pregnancy.2 To date, evidence suggest that there is no increased risk of severe disease in pregnant women, with low risks of vertical transmission or fetal distress.3–5\n\nSystemic lupus erythematosus (SLE) is characterized by an abnormal activation of the immune system and subsequent generation of autoantibodies resulting in a wide spectrum of systemic clinical manifestations.6 The clinical and therapeutic management of SLE during pregnancy is considered a clinical challenge due to the teratogenicity of effective drugs and because SLE flares are associated with a higher risk of pregnancy complications and serious adverse pregnancy outcomes.6,7\n\nCurrently, practical clinical information is lacking on the characteristics of COVID-19 in pregnant patients with an autoimmune disease. During the beginning of the current pandemic, we encountered 2 pregnant patients with SLE and symptomatic COVID-19. To the best of our knowledge, no reports on the presentation and outcome of pregnant SLE patients suffering from COVID-19 have been published. An overview of the cases is described in Table 1.\n\nTable 1. Clinical and demographic features of the described SLE patients with COVID-19 during pregnancy and their offspring.\n\n\tCase 1\tCase 2\t\nMaternal age (years)\t31\t39\t\nDisease duration (years)\t16\t20\t\nDisease characteristics (SLICC/ACR score)Damage Index, organ involvement\t1 (arthritis)\t2 (arthritis, renal)\t\nSLEDAI score, (description)\t2 (low complement)\t4 (arthritis)\t\nMedication use\tAzathioprine\tAzathioprine\t\nHydroxychloroquine\tEtanercept\t\nPrednisone\t\nGravidity, parity (n)\tG1P0\tG2P1\t\nMode of delivery\tInduced labor\tCaesarean section\t\nSex of the newborn\tFemale\tMale\t\nGestational age (weeks, days)\t38, 1\t38, 5\t\nBirthweight (grams)\t2880\t4205\t\nAPGAR score (after 5 minutes)\t9\t9\t\nCongenital malformations\t–\t–\t\nSLICC/ACR damage index indicates Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index, SLEDAI indicates Systemic Lupus Erythematosus Disease Activity Index score.\n\nCase 1: 31 year old, gravida 1, para 0, gestational age of 38 weeks, diagnosed with SLE at age 15 and preexisting hypertension. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI)8 was 1. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive. At the time she was being treated with azathioprine (25 mg/day), hydroxychloroquine (200 mg/day), prednisone (5 mg/day). Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed, this was agreed after multidisciplinary consultation. During pregnancy, SLE disease activity was mild. Based on her risk profile, she was admitted at 38 + 1 weeks of gestation to induce labor. At admission, she reported mild respiratory symptoms and tested positive for COVID-19 the next day. Her SLE treatment (azathioprine, hydroxychloroquine and prednisone) was not stopped nor reduced in dosage. She was induced on the same day as the positive test and protective measures were taken to prevent viral spreading during labor. A healthy girl with an Apgar score of 9/10, birthweight of 2880 grams, without congenital malformations was born. Vertical transmission of SARS-CoV-2 was ruled out by a negative PCR. Pathological examination of the placenta was not performed. Mother and daughter spent the night in isolation in the hospital and were discharged the next morning. The patient did not breastfeed and made a full recovery without residual symptoms.\n\nCase 2: 39 year old patient diagnosed with SLE at age 19, SDI score 2 (lupus nephritis class 4, anti-phospholipid antibodies negative), gravida 2 para 1, 19 weeks of gestation and an obstetric history of preeclampsia. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive while being treated with hydroxychloroquine, azathioprine and etanercept. She was treated with etanercept because of disabling and therapy resistant arthritis. Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed. At 19 + 0 weeks of gestation she presented herself at the emergency room with complaints of dyspnea and coughing. The diagnosis of COVID-19 was confirmed by a positive PCR test. No signs of severe disease were detected (O2 = 99%). Treatment with azathioprine and etanercept was discontinued. She was sent home to recover in quarantine. 9 days after the positive test, the patient reported arthralgia after which azathioprine was restarted. At day 15 after testing, she did not report any further symptoms related to COVID-19 and treatment with etanercept was restarted. Following current treatment recommendations etanercept was stopped at 30 weeks of gestation.9 Henceforth, oligoarthritis was confirmed by her rheumatologist (CMC1, MCP2, right knee and ankle). For this reason, she received local injections with glucocorticoids (triamcinolone acetonide). The patient was admitted to the hospital for a repeat caesarean section. A healthy son was born, Apgar score of 9/10 and a birthweight of 4205 gram. The delivery was complicated by a placenta accrete resulting in a massive hemorrhage which was treated with intravenous sulpostron, tranexamic acid, calcium en fibrinogen as well as two packed cells. Postpartum hemoglobin was 7.57 g/dl. Pathological examination of the placenta (weight: 460 gram, P33) showed no abnormalities related to a COVID-19 infection4: no local inflammation or fibrin depositions. Three days after delivery, the patient and her newborn were discharged from the hospital in good health.\n\nHerein, we present two cases of pregnant patients with SLE with confirmed COVID-19 disease and mild symptoms during pregnancy. In both cases a watchful-waiting approach, in line with (inter)national guidelines, was taken without initiation of treatment for COVID-19. In both cases healthy newborns were born. One patient showed a flare in SLE disease activity, most likely induced by discontinuation of treatment and unrelated to the COVID-19 infection. Our cases highlight the importance of individualizing treatment decisions that present during unprecedented times like the current COVID-19 pandemic. Currently there is no information on how to manage COVID-19 during pregnancy in patients diagnosed with rheumatic diseases. Therefore, close collaboration between rheumatologists and gynaecologists is encouraged. The decisions whether to continue or discontinue immunosuppressive drugs should be taken using a multidisciplinary approach and should be dynamic in line with possible rapidly changing, new insights. Patients should also be informed and involved in this shared decision making process. If needed, consultation with expertise centers is advised. In mild cases, like the ones presented here, discontinuation of immunosuppressive drugs in the acute phase of COVID-19 infection should be considered on a case-by-case basis. Our approach was in line with the current European League Against Rheumatism (EULAR) recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection outside pregnancy [9]. Current information on the safety of breastfeeding of COVID-19 patients is reassuring and seems to be safe.10 Case reports on neonatal COVID-19 are scarce and show mild disease in newborns.10 In the coming months, the discussion on this topic should expand and cover the safety and need of the future COVID-19 vaccine in pregnant patients with auto-immune diseases.\n\nKey message\n\nAn individualized and multidisciplinary therapeutic approach in pregnant SLE patients diagnosed with COVID-19 is recommended.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dutch Arthritis Foundation (ReumaNederland) (project number: LLP-26), a non-profit organization.\n\nEthical approval: Informed consent was obtained.\n\nContributorship: All authors met the authorship criteria. They had a substantial contribution to the conception and design of the work and the acquisition and interpretation of the data used for the work. They were involved in revising a draft of this work, gave final approval of this version to be published, and are accountable for all aspects of the work in ensuring accuracy and integrity.\n\nORCID iD: Hieronymus TW Smeele https://orcid.org/0000-0001-7724-7712\n==== Refs\nReferences\n\n1 Li H Liu L Zhang D , et al . SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet 2020; 395 : 1517–1520.32311318\n2 Wong SF Chow KM Leung TN , et al . Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome. Am J Obstet Gynecol 2004; 191 : 292–297.15295381\n3 Chen L Li Q Zheng D , et al . Clinical characteristics of pregnant women with covid-19 in Wuhan, China. N Engl J Med 2020; 382 : e100.32302077\n4 Schoenmakers S, Snijder P, Verdijk RM, et al. Severe Acute Respiratory Syndrome Coronavirus 2 Placental Infection and Inflammation Leading to Fetal Distress and Neonatal Multi-Organ Failure in an Asymptomatic Woman. J Pediatric Infect Dis Soc. 2020; doi: 10.1093/jpids/piaa153. Epub ahead of print. PMID: 33367801; PMCID: PMC7798999.\n5 Fenizia C Biasin M Cetin I , et al . Analysis of SARS-CoV-2 vertical transmission during pregnancy. Nat Commun 2020; 11 : 5128.33046695\n6 Kiriakidou M Ching CL. Systemic lupus erythematosus. Ann Intern Med 2020; 172 : ITC81–ITC96.32479157\n7 Peart E Clowse MEB. Systemic lupus erythematosus and pregnancy outcomes: an update and review of the literature. Curr Opin Rheumatol 2014; 26 : 118–123.24419751\n8 Gladman DD Goldsmith CH Urowitz MB , et al . The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index for systemic lupus erythematosus international comparison. J Rheumatol 2000; 27 : 373–376.10685799\n9 Gotestam Skorpen C Hoeltzenbein M Tincani A , et al . The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis 2016; 75 : 795–810.26888948\n10 Raschetti R Vivanti AJ Vauloup-Fellous C Loi B Benachi A De Luca D. Synthesis and systematic review of reported neonatal SARS-CoV-2 infections. Nat Commun 2020; 11 : 5164.33060565\n\n",
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"issn_linking": "0961-2033",
"issue": "30(7)",
"journal": "Lupus",
"keywords": "COVID-19; Systemic lupus erythematosus; pregnancy",
"medline_ta": "Lupus",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious",
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"title": "Systemic lupus erythematosus and COVID-19 during pregnancy.",
"title_normalized": "systemic lupus erythematosus and covid 19 during pregnancy"
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"abstract": "BACKGROUND\nThe development of symptomatic ascites from a ventriculoperitoneal shunt is rare in children without prior intra-abdominal pathology. Here we report a case of symptomatic ascites in a young child with a ventriculoperitoneal shunt and metastatic atypical teratoid rhabdoid tumor.\n\n\nMETHODS\nThis 15-month-old boy developed symptomatic ascites while undergoing chemotherapy for his malignant brain tumor. Diagnostic work up to identify the etiology of this ascites yielded a non-malignant, sterile transudate, refractory to repeated paracentesis. The ascites finally resolved with the conversion of the ventriculoperitoneal shunt to a ventriculoatrial shunt.\n\n\nCONCLUSIONS\nThis case report highlights the need to be suspicious of non-malignant cerebrospinal fluid ascites as a cause of peritoneal fluid accumulation even in children with malignant primary brain tumor. In this setting, conversion of the shunt from peritoneal to atrial drainage can rapidly alleviate the morbidity associated with this condition.",
"affiliations": null,
"authors": "Upadhyaya|Santhosh A|SA|;Klimo|Paul|P|;Robinson|Giles W|GW|",
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"country": "Netherlands",
"delete": false,
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"issue": "40(4)",
"journal": "Oncology research and treatment",
"keywords": null,
"medline_ta": "Oncol Res Treat",
"mesh_terms": "D001201:Ascites; D001932:Brain Neoplasms; D020878:Device Removal; D003937:Diagnosis, Differential; D006801:Humans; D006849:Hydrocephalus; D008297:Male; D018335:Rhabdoid Tumor; D013724:Teratoma; D016896:Treatment Outcome; D017287:Ventriculoperitoneal Shunt",
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"title": "Non-Malignant Cerebrospinal Fluid Ascites in a Patient with Atypical Teratoid Rhabdoid Tumor.",
"title_normalized": "non malignant cerebrospinal fluid ascites in a patient with atypical teratoid rhabdoid tumor"
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"abstract": "BACKGROUND\nPulmonary tumor thrombotic microangiopathy (PTTM) is rare, cancer-related pulmonary complication leading to hypoxia, pulmonary hypertension, and heart failure. The standard treatment for PTTM is not established. However, imatinib, a tyrosine kinase inhibitor of the PDGF receptor, may cause regression of pulmonary hypertension and pulmonary artery remodeling in PTTM.\n\n\nMETHODS\nWe report two cases of PTTM who received an anti-PDGF agent of imatinib for PTTM developed during chemotherapy for metastatic breast cancer. Case 1: 61-year-old woman who underwent resection of the left breast and axillary lymph node dissection and received adjuvant chemotherapy (CAF followed by docetaxel), then endocrine therapy for 5 years. Twelve years after surgery, multiple bone and mediastinal lymph node metastases occurred. She was under treatment with eribulin for one year but admitted because of rapid progressing dyspnea. Case 2: 45-year-old woman with metastatic breast cancer in multiple bones was under treatment for 5 years. Receiving capecitabine, she suffered from dyspnea for 2 months, she was admitted to our hospital with diagnosis of severe hypoxia. In both cases, the wedged pulmonary arterial blood cell sampling revealed cytologically malignant cells which confirmed the diagnosis of PTTM. They were treated with imatinib, which alleviated pulmonary hypertension. However, they died due to progression of metastatic breast cancer.\n\n\nRESULTS\nSingle use of imatinib did not showed sufficient efficacy. It is necessary to conduct a well-designed clinical trial using chemotherapies combined with imatinib for PTTM.\n\n\nCONCLUSIONS\nImatinib, which alleviated pulmonary hypertension, could be a new strategy for pulmonary tumor thrombotic microangiopathy in patient with metastatic breast cancer.",
"affiliations": "Breast Medical Oncology, Breast Oncology Center, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550 Japan.;Breast Medical Oncology, Breast Oncology Center, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550 Japan.;Breast Medical Oncology, Breast Oncology Center, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550 Japan.;Breast Medical Oncology, Breast Oncology Center, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550 Japan.;Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, Japan.;Medical Oncology, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.;Breast Surgical Oncology, Breast Oncology Center, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.;Breast Oncology Center, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.;Breast Medical Oncology, Breast Oncology Center, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550 Japan.",
"authors": "Fukada|Ippei|I|;Araki|Kazuhiro|K|;Kobayashi|Kokoro|K|;Shibayama|Tomoko|T|;Hatano|Masaru|M|;Takahashi|Shunji|S|;Iwase|Takuji|T|;Ohno|Shinji|S|;Ito|Yoshinori|Y|",
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"fulltext": "\n==== Front\nSpringerplusSpringerplusSpringerPlus2193-1801Springer International Publishing Cham 328010.1186/s40064-016-3280-4Case StudyImatinib could be a new strategy for pulmonary hypertension caused by pulmonary tumor thrombotic microangiopathy in metastatic breast cancer Fukada Ippei 03-3520-0111ippei.fukada@jfcr.or.jp 1Araki Kazuhiro kazuhiro.araki@jfcr.or.jp 1Kobayashi Kokoro kokoro.kobayashi@jfcr.or.jp 1Shibayama Tomoko tomoko.shibayama@jfcr.or.jp 1Hatano Masaru hatanoma@pg8.so-net.ne.jp 2Takahashi Shunji s.takahashi-chemotherapy@jfcr.or.jp 3Iwase Takuji takuji.iwase@jfcr.or.jp 4Ohno Shinji shinji.ohno@jfcr.or.jp 5Ito Yoshinori yito@jfcr.or.jp 11 Breast Medical Oncology, Breast Oncology Center, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550 Japan 2 Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, Japan 3 Medical Oncology, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan 4 Breast Surgical Oncology, Breast Oncology Center, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan 5 Breast Oncology Center, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan 15 9 2016 15 9 2016 2016 5 1 158222 3 2016 9 9 2016 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Introduction\nPulmonary tumor thrombotic microangiopathy (PTTM) is rare, cancer-related pulmonary complication leading to hypoxia, pulmonary hypertension, and heart failure. The standard treatment for PTTM is not established. However, imatinib, a tyrosine kinase inhibitor of the PDGF receptor, may cause regression of pulmonary hypertension and pulmonary artery remodeling in PTTM.\n\nCase descriptions\nWe report two cases of PTTM who received an anti-PDGF agent of imatinib for PTTM developed during chemotherapy for metastatic breast cancer. Case 1: 61-year-old woman who underwent resection of the left breast and axillary lymph node dissection and received adjuvant chemotherapy (CAF followed by docetaxel), then endocrine therapy for 5 years. Twelve years after surgery, multiple bone and mediastinal lymph node metastases occurred. She was under treatment with eribulin for one year but admitted because of rapid progressing dyspnea. Case 2: 45-year-old woman with metastatic breast cancer in multiple bones was under treatment for 5 years. Receiving capecitabine, she suffered from dyspnea for 2 months, she was admitted to our hospital with diagnosis of severe hypoxia. In both cases, the wedged pulmonary arterial blood cell sampling revealed cytologically malignant cells which confirmed the diagnosis of PTTM. They were treated with imatinib, which alleviated pulmonary hypertension. However, they died due to progression of metastatic breast cancer.\n\nDiscussion and Evaluation\nSingle use of imatinib did not showed sufficient efficacy. It is necessary to conduct a well-designed clinical trial using chemotherapies combined with imatinib for PTTM.\n\nConclusions\nImatinib, which alleviated pulmonary hypertension, could be a new strategy for pulmonary tumor thrombotic microangiopathy in patient with metastatic breast cancer.\n\nKeywords\nPulmonary tumor thrombotic microangiopathyImatinibMetastatic breast cancerPulmonary hypertensionissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nPulmonary tumor thrombotic microangiopathy (PTTM) is very rare cancer-related complication that causes pulmonary hypertension, heart failure and hypoxia. Although the standard treatment for PTTM is not established, imatinib, a tyrosine kinase inhibitor of the PDGF receptor, may cause regression of pulmonary hypertension and pulmonary artery remodeling in PTTM. We report two cases of PTTM in patients with metastatic breast cancer who receiving imatinib for pulmonary hypertension caused by PTTM.\n\nCase presentation\nCase1\nThe patient was a 61-year-old woman who had undergone resection of the left breast and axillary lymph node dissection. She received adjuvant chemotherapy (CAF; cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2, fluoropyrimidine 500 mg/m2 followed by docetaxel, then tamoxifen followed by anastrozole for a total of 5 years. Twelve years after surgery, multiple bone and mediastinal lymph node metastases were detected. She was under treatment with eribulin for 1 year but admitted because of rapid progressing dyspnea. Although the enhanced computed tomography showed no pulmonary embolism, ventilation-perfusion scintigraphy demonstrated multiple small peripheral perfusion defects in both lungs. A transthoracic echocardiogram showed severe pulmonary hypertension with estimated right ventricular systolic pressure of 76 mmHg. She was transferred to the Department of Cardiovascular Medicine, the wedged pulmonary arterial blood cell sampling showed clusters of malignant cells with high nuclear/cytoplasm ratio, focal glandular structures which confirmed the diagnosis of PTTM (Fig. 1a). Pulmonary arterial pressure (PAP) was measured at 93/39(60) mmHg, the cardiac index (CI) was 1.63 L/min/m2 and pulmonary vascular resistance elevated to 1947 dyne·s/cm5. Nine days after administering the imatinib (200 mg/day), the PAP was reduced to 87/30(50) mmHg, and the CI was improved to 2.83 L/min/m2. We increased the dose of imatinib to 400 mg, then the CI was improved to 2.97 L/min/m2 though the PAP was slightly elevated to 95/44(56) mmHg (Table 1). The patient died due to progression of breast cancer itself 54 days after her initial admission. In autopsy, an embolus of tumor cells was noted in the pulmonary artery and the lumen of the pulmonary artery was severely narrowed. Tumor cells were immunohistochemically positive for PDGF-B.Fig. 1 Cytology from pulmonary artery (a case 1, b case 2). The cytology of the blood in the pulmonary artery revealed adenocarcinoma cells (Papanicolaou stain)\n\nTable 1 The result of catheterization study in case1 and case2\n\n\tCase 1\tCase 2\t\nDay 1\tDay 7\tDay 22\tDay 1\tDay 7\t\nMedication\tNone\tImatinib 200 mg\tImatinib 400 mg\tNone\tImatinib 200 mg\t\nPAP (mmHg)\t93/39 (60)\t87/30 (50)\t95/40 (56)\t47/18 (29)\t45/22 (30)\t\nCI (L/min/m2)\t1.63\t2.83\t2.97\t2.98\t3.65\t\nPVR (dyne·s/cm2)\t1947\t914\t1037\t490\t410\t\n\n\nCase2\nA 45-year-old woman with metastatic breast cancer in multiple bones. The core needle biopsy from primary breast tumor revealed that invasive ductal carcinoma with nuclear grade1, ER+ , PgR+ , HER2:0. She was under treatment for 5 years (Tamoxifen, FAC therapy; Cyclophosphomide 500 mg/m2, Doxorubicin 50 mg/m2, Fluorouracil 500 mg/m2 for 7 months, triweekly docetaxel for 11 months, anastrozole and leuprorelin for 21 months, and capecitabine for 8 months with zoledronic acid. After she suffered from dyspnea for 2 months, she was admitted to our hospital with diagnosis of severe hypoxia. Although the enhanced computed tomography did not show pulmonary embolism, the scintigraphy demonstrated patchy flow reduction in both lungs. The test of blood coagulation suggested the micro-thromboembolism. Hypoxia rapidly progressed even after anticoagulation therapy. On the 21st day after admission, she was transferred to the Department of Cardiovascular Medicine for a more precise diagnosis and intensive treatment. Wedged pulmonary arterial blood cell sampling revealed cytologically malignant cells which confirmed the diagnosis of PTTM (Fig. 1b). The serum of the patient exhibited a high level of platelet-derived growth factor (PDGF), which produced by tumor cells, would promote vascular remodeling. Pulmonary arterial pressure (PAP) was measured at 47/18(27) mmHg, and the cardiac index (CI) was 2.98 L/min/m2. Pulmonary vascular resistance elevated to 490 dyne·s/cm5. Imatinib (200 mg/day) was administered as a clinical trial immediately. Seven days administering imatinib, the PAP was still 45/22(30) mmHg, but the CI was improved to 3.65 L/min/m2 and pulmonary vascular resistance reduced to 400 dyne·s/cm5 (Table 1). Although we increased the dose of imatinib to 400 mg, she died of respiratory insufficiency in 24 days from her initial admission.\n\nDiscussion\nWe demonstrated that imatinib could alleviated pulmonary hypertension in two patient with PTTM. PTTM is one of the very rare cancer-related pulmonary complications, leading to pulmonary hypertension, heart failure and hypoxia. Von Herbay et al. reported 21 cases of PTTM in 630 carcinoma autopsies, the incidence of PTTM was 3.3 % (von Herbay et al. 1990). In their report, all 21 cases had carcinoma with distant metastases and 19 cases had adenocarcinomas of various organs. Although the stomach cancer was the most common, there was two cases of breast cancer. The other previous reports by Okubo et al. showed six cases of PTTM in 37 gastric carcinoma autopsies (Okubo et al. 2011). The mechanism of PTTM is still unclear. However, the morphometric and immunohistochemical analyses have been developed recently. There are two hypotheses for the development of pulmonary hypertension and right-heart failure, the dysregulation of signaling pathways which respond to the presence of an embolic cell or other intravascular insult, causes vascular remodeling and the other hypothesis proposes that tumor emboli occlude the pulmonary arterial bed and increase pulmonary vascular resistance (Roberts et al. 2003). Von Herbay et al. revealed that tumor cells invaded the pulmonary vascular system and occluded the small arteries and arterioles that activate coagulation systems, releasing inflammatory mediators and growth factors, which induced both local activation of coagulation and fibrocellular intimal proliferation (von Herbay et al. 1990; Sakashita et al. 2007). Okubo et al. also reported the morphometric analysis of pulmonary arteries and suggested that pulmonary arterial remodeling induced by carcinoma cell adhesion onto the endothelium affected the status of pulmonary hypertension. Some previous studies revealed that cancer cells produced the molecules that cause PTTM, which contains the tissue factor (Okubo et al. 2011), the vascular endothelial growth factor (Sakashita et al. 2007; Chinen et al. 2010; Takahashi et al. 2009; Yokomine et al. 2010) and osteopontin (Takahashi et al. 2009; Denhardt et al. 2001). The platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR) is also important molecular agents in development of pulmonary hypertension in patients with PTTM (Abe et al. 2013). von Herbay et al. (1990) reported that attachment of tumor cell emboli might damage endothelial cells, releasing PDGF (von Herbay et al. 1990). Yokomine et al. reported an autopsied case of PTTM with gastric carcinoma that expressed the PDGF and PDGFR in cancer cells. They also revealed that the overexpression of PDGF was detected in alveolar macrophages and PDGFR in intimal mesenchymal cells in the pulmonary arterial wall, which suggested the contribution of the activated alveolar macrophages to the onset of PTTM (Yokomine et al. 2010). The standard treatment for PTTM has not been established. However, imatinib, a tyrosine kinase inhibitor of the PDGF receptor, may cause regression of pulmonary hypertension and pulmonary artery remodeling in PTTM (Ogawa et al. 2013). In our cases, imatinib was administered as a clinical trial, approved by the Institutional Review Board of the University of Tokyo Hospital. Although imatinib alleviated pulmonary hypertension and the cardiac index temporarily improved after administration of imatinib in both cases, they died due to progression of metastatic breast cancer. Single use of imatinib did not showed sufficient efficacy to suppress the disease progression of breast cancer itself. Therefore, it is necessary to establish a new strategy for PTTM in metastatic breast cancer, using the combination of imatinib and the other chemotherapies. However, there are some important problems to establish this new strategy.\n\nThe first is that the combination of imatinib and the other chemotherapies for the treatment of metastatic breast cancer have not been established and their safety and efficacy are unclear. Treatment with a combination of imatinib and cytotoxic chemotherapies have been reported in the previous several articles. Kumar et al. also reported two cases of patients with synchronous gastrointestinal stromal tumor (GIST) and colorectal adenocarcinoma (Kumar et al. 2011). They received FOLFOX chemotherapy for colon cancer while administering imatinib (400 mg/day) and did not experience unexpected toxictity from either the imatinib or chemotherapy. Uemura et al. reported secondary chronic myelogenous leukemia following postoperative S-1 (80 mg/day) therapy for advanced gastric cancer (Uemura et al. 2010). Although skin eruption, palpebral edema and appetite loss were appeared after weeks starting imatinib therapy, these symptoms were alleviated when he stopped taking imatinib. Furthermore, the results of PhaseI and II trial of combination of imatinib and chemotherapy have been reported recently. Lin et al. showed a phaseI trial of docetaxel/estramustine/imatinib in patients with hormone-refractory prostate cancer (Lin et al. 2007). Thirteen patients with hormone-refractory metastatic prostate cancer were treated every 21 days with fixed doses of estramustine (280 mg orally 3 times a day on days 1–5), imatinib (400 mg orally daily on days 1–21) and docetaxel, in which cohorts of 3–6 patients were enrolled to receive escalating doses of docetaxel on day 2 from 50 to 60 to 70 mg/m2. On dose level 3 (docetaxel 70 mg/m2 and imatinib 400 mg daily), grade 3 elevations of prothrombin time in two patients. Although the protocol was amended to include an intermediate dose level (docetaxel 60 mg/m2 and imatinib 300 mg daily), there were five unacceptable toxicities (2 cerebrovascular accidents, one myocardial infarction, one mesenteric ischemia, and 1 deep venous thrombosis) in 13 patients, and two of those toxicities resulted in death. Another phaseIdose-escalation study of imatinib mesylate plus capecitabine in advanced solid tumor was reported (Dugan et al. 2010). In their study, 24 patients with advanced solid tumors were treated with capecitabine twice daily on days 1–14 and imatinib mesylate once daily on a 21-day cycle. Six patients who were treated with capecitabine at 1000 mg/m2 and imatinib mesylate 300 mg, had unacceptable toxicity due to grade 2 intolerable hand–foot syndrome and/or grade 2 and grade 3 diarrhea. These full doses of capecitabine and imatinib mesylate were not tolerable. Although Doses were subsequently reduced to capecitabine at 750 mg/m2 and imatinib mesylate at 300 mg, adverse events greater than or equal to grade 3 included anemia, diarrhea, dysuria, hypophosphatemia and vertigo. There is a result of multi-institutional phase 2 study of imatinib mesylate and gemcitabine for first-line treatment of advanced pancreatic cancer (Moss et al. 2012). Gemcitabine was given at 1200 mg/m2 on days 3 and 10. Imatinib (400 mg) was taken orally on days 1 to 5 and 8 to 12 of a 21-day cycle. Forty-four patients were enrolled and the median number of cycles completed was three. Common adverse effects included neutropenia, nausea, anemia, and fatigue. 50 % of patients had grade 3 or higher neutropenia and 17 % had grade 3 or higher thrombocytopenia. The significant nonhematologic toxicity related to treatment were grade 3 or higher dehydration in 9 %, grade 3 or higher rash in 9 %, grade 3 or higher fatigue in 6 %, grade 3 or higher nausea in 6 %, and grade 3 or higher renal failure in 2 %. Clinically significant grade 1 and 2 toxicities included edema in 4 % and rash in 6 %. Overall, half of the patients required dose reduction.\n\nThe other problem is that the patient with PTTM generally have not been able to tolerate chemotherapy at symptom onset because of poor physical condition. Therefore, the combination therapy of imatinib and chemotherapy might not be tolerable for the patients with PTTM. It is necessary to conduct a well-designed clinical trial to evaluate the use of chemotherapies combined with imatinib for PTTM.\n\nConclusion\nImatinib, which alleviated pulmonary hypertension, could be a new strategy for pulmonary tumor thrombotic microangiopathy in patient with metastatic breast cancer.\n\n\nAbbreviations\nPTTMpulmonary tumor thrombotic microangiopathy\n\nPDGFplatelet-derived growth factor\n\nPDGFRplatelet-derived growth factor receptor\n\nGISTgastrointestinal stromal tumor\n\nAuthors’ contributions\nIF performed literature review, drafted the manuscript and supervised the writing. YI were responsible for the management of the patient. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent\nWritten informed consent was obtained from the patient for publication of these cases report and any accompanying images.\n==== Refs\nReferences\nAbe H Hino R Fukayama M Platelet-derived growth factor-A and vascular endothelial growth factor-C contribute to the development of pulmonary tumor thrombotic microangiopathy in gastric cancer Virchows Arch 2013 462 523 531 10.1007/s00428-013-1403-7 23536282 \nChinen K Tokuda Y Fujiwara M Fujioka Y Pulmonary tumor thrombotic microangiopathy in patients with gastric carcinoma: an analysis of 6 autopsy cases and review of the literature Pathol Res Pract 2010 206 682 689 10.1016/j.prp.2010.05.002 20554399 \nDenhardt DT Noda M O’Regan AW Pavlin D Berman JS Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival J Clin Invest 2001 107 1055 1061 10.1172/JCI12980 11342566 \nDugan E Truax R Meadows KL Nixon AB Petros WP Favaro J A phase I dose-escalation study of imatinib mesylate (Gleevec/STI571) plus capecitabine (Xeloda) in advanced solid tumors Anticancer Res 2010 30 4 1251 1256 20530436 \nKumar K Rowsell C Law C Ko YJ Coexistence of gastrointestinal stromal tumour and colorectal adenocarcinoma: two case reports J Gastrointest Oncol 2011 2 1 50 54 22811828 \nLin AM Rini BI Derynck MK Weinberg V Park M Ryan CJ A phase I trial of docetaxel/estramustine/imatinib in patients with hormone-refractory prostate cancer Clin Genitourin Cancer 2007 5 5 323 328 10.3816/CGC.2007.n.011 17645829 \nMoss RA Moore D Mulcahy MF Nahum K Saraiya B Eddy S A multi-institutional phase 2 study of imatinib mesylate and gemcitabine for first-line treatment of advanced pancreatic cancer Gastrointest Cancer Res 2012 5 3 77 83 22888387 \nOgawa A Yamadori I Matsubara O Matsubara H Pulmonary tumor thrombotic microangiopathy with circulatory failure treated with imatinib Intern Med 2013 52 1927 1930 10.2169/internalmedicine.52.0718 23994985 \nOkubo Y Wakayama M Kitahara K Nemoto T Yokose T Abe F Pulmonary tumor thrombotic microangiopathy induced by gastric carcinoma: morphometric and immunohistochemical analysis of six autopsy cases Diagn Pathol 2011 6 27 10.1186/1746-1596-6-27 21450103 \nRoberts KE Hamele-Bena D Saqi A Stein CA Cole RP Pulmonary tumor embolism: a review of the literature Am J Med 2003 115 228 232 10.1016/S0002-9343(03)00305-X 12935829 \nSakashita N Yokose C Fujii K Matsumoto M Ohnishi K Takeya M Pulmonary tumor thrombotic microangiopathy resulting from metastatic signet ring cell carcinoma of the stomach Pathol Int 2007 57 383 387 10.1111/j.1440-1827.2007.02111.x 17539970 \nTakahashi F Kumasaka T Nagaoka T Wakiya M Fujii H Shimizu K Osteopontin expression in pulmonary tumor thrombotic microangiopathy caused by gastric carcinoma Pathol Int 2009 59 752 756 10.1111/j.1440-1827.2009.02439.x 19788622 \nUemura Y Imai T Machida T Shima Y Secondary chronic myelogenous leukemia following postoperative TS-1 therapy for advanced gastric cancer Rinsho Ketsueki 2010 51 7 559 563 20693777 \nvon Herbay A Illes A Waldherr R Otto HF Pulmonary tumor thrombotic microangiopathy with pulmonary hypertension Cancer 1990 66 587 592 10.1002/1097-0142(19900801)66:3<587::AID-CNCR2820660330>3.0.CO;2-J 2163747 \nYokomine T Hirakawa H Ozawa E Shibata K Nakayama T Pulmonary thrombotic microangiopathy caused by gastric carcinoma J Clin Pathol 2010 63 376 379 10.1136/jcp.2010.075739 20354216\n\n",
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"title": "Imatinib could be a new strategy for pulmonary hypertension caused by pulmonary tumor thrombotic microangiopathy in metastatic breast cancer.",
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"abstract": "The authors report an Indian adult female patient with a history of generalized tonic clonic seizures who developed severe features of phenytoin (DPH) toxicity on therapeutic dosage of this antiepileptic drug. Administration of 300 mg/day of DPH in this patient resulted in toxic symptoms associated with an excessive serum DPH concentration of 33 microg/ml. The PCR-RFLP analysis revealed a homozygosity involving CYP2C9*3*3. This mutation results in a marked decrease in the enzymatic activity (CYP2C9) and leads to a decreased clearance of the drug which can lead to severe acute and chronic toxicity. On switching the antiepileptic therapy from DPH to sodium valproate, there was reversal of both.",
"affiliations": "Department of Pharmacology, Jawaharlal Institute of Medical Education and Research, Dhanvanthari Nagar, Pondicherry-6, India.",
"authors": "Ramasamy|Kesavan|K|;Narayan|Sunil K|SK|;Chanolean|Shashindran|S|;Chandrasekaran|Adithan|A|",
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"title": "Severe phenytoin toxicity in a CYP2C9*3*3 homozygous mutant from India.",
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"abstract": "BACKGROUND Acute pancreatitis is rare following solid organ transplantation but is associated with high mortality. It has been most commonly reported following renal transplant but can occur with other solid organ transplantations. CASE REPORT A 46-year-old male who had an orthotopic heart transplant 6 months ago presented with a 3-week history of abdominal pain. The patient described it as intermittent, sharp, and stabbing, originating in the periumbilical area and radiating to the back. His lipase was elevated at 232 U/L. Given that the patient's symptoms and lipase were elevated to greater than three times the upper limit of normal, he patient was diagnosed with acute pancreatitis. The patient also mentioned a diffuse itchy rash that started a few days prior to admission. Dermatology was consulted, and given the man's clinical presentation, there was concern for atypical reactivation of varicella zoster virus (VZV). VZV polymerase chain reaction of the vesicles returned positive. The patient was started on acyclovir and his symptoms improved. CONCLUSIONS This is the first reported case of VZV-associated pancreatitis in a heart transplant patient. Our patient presented with acute pancreatitis and was treated supportively. However, he did not receive antiviral treatment until his rash was discovered. Timely treatment of VZV resulted in resolution of both the rash and pancreatitis. Timely diagnosis of pancreatitis and VZV is important to prevent development of multiorgan failure and death.",
"affiliations": "Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA, USA.;Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA, USA.;Division of Cardiology, Thomas Jefferson University, Philadelphia, PA, USA.;Department of Transplantation, Thomas Jefferson University, Philadelphia, PA, USA.;Division of Cardiology, Thomas Jefferson University, Philadelphia, PA, USA.;Division of Cardiology, Thomas Jefferson University, Philadelphia, PA, USA.;Department of Cardiothoracic Surgery, Thomas Jefferson University, Philadelphia, PA, USA.;Division of Cardiology, Thomas Jefferson University, Philadelphia, PA, USA.",
"authors": "Shieh|Christine|C|;Barnes|Ashley|A|;Johnson|Drew M|DM|;Danelich|Ilya M|IM|;Pirlamarla|Preethi|P|;Alvarez|Rene|R|;Massey|Howard|H|;Shah|Mahek|M|",
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"doi": "10.12659/AJCR.923969",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32785212\n10.12659/AJCR.923969\n923969\nArticles\nAtypical Reactivation of Varicella Zoster Virus Associated with Pancreatitis in a Heart Transplant Patient\nShieh Christine BCDEF1 Barnes Ashley BD1 Johnson Drew M. B2 Danelich Ilya M. BE3 Pirlamarla Preethi B2 Alvarez Rene B2 Massey Howard B4 Shah Mahek ABCDE2 \n1 Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA, U.S.A.\n\n2 Division of Cardiology, Thomas Jefferson University, Philadelphia, PA, U.S.A.\n\n3 Department of Transplantation, Thomas Jefferson University, Philadelphia, PA, U.S.A.\n\n4 Department of Cardiothoracic Surgery, Thomas Jefferson University, Philadelphia, PA, U.S.A.\nCorresponding Author: Christine Shieh, e-mail: christine.shieh@jefferson.eduAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n12 8 2020 \n21 e923969-1 e923969-4\n02 3 2020 22 5 2020 26 6 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 46-year-old\n\nFinal Diagnosis: Varicella zoster virus infection\n\nSymptoms: Abdominal and/or epigastric pain\n\nMedication:—\n\nClinical Procedure: Biopsy\n\nSpecialty: Cardiology • Gastroenterology and Hepatology • Infectious Diseases • Transplantology\n\nObjective:\nRare disease\n\nBackground:\nAcute pancreatitis is rare following solid organ transplantation but is associated with high mortality. It has been most commonly reported following renal transplant but can occur with other solid organ transplantations.\n\nCase Report:\nA 46-year-old male who had an orthotopic heart transplant 6 months ago presented with a 3-week history of abdominal pain. The patient described it as intermittent, sharp, and stabbing, originating in the periumbilical area and radiating to the back. His lipase was elevated at 232 U/L. Given that the patient’s symptoms and lipase were elevated to greater than three times the upper limit of normal, he patient was diagnosed with acute pancreatitis. The patient also mentioned a diffuse itchy rash that started a few days prior to admission. Dermatology was consulted, and given the man’s clinical presentation, there was concern for atypical reactivation of varicella zoster virus (VZV). VZV polymerase chain reaction of the vesicles returned positive. The patient was started on acyclovir and his symptoms improved.\n\nConclusions:\nThis is the first reported case of VZV-associated pancreatitis in a heart transplant patient. Our patient presented with acute pancreatitis and was treated supportively. However, he did not receive antiviral treatment until his rash was discovered. Timely treatment of VZV resulted in resolution of both the rash and pancreatitis. Timely diagnosis of pancreatitis and VZV is important to prevent development of multiorgan failure and death.\n\nMeSH Keywords:\nAbdominal PainHeart TransplantationHerpesvirus 3, HumanImmunosuppressionPancreatitis\n==== Body\nBackground\nAcute pancreatitis is rare following solid organ transplantation but is associated with high mortality [1]. It has most commonly been reported following renal transplant, with an incidence ranging from 2% to 7% and a 50% to 100% mortality rate [2]. Acute pancreatitis is known to occur after heart transplantation, especially in the early postoperative period [3]. Given the high morbidity and mortality associated with such cases, early recognition and identification of a reversible etiology remains key. Common etiologies of pancreatitis in immunocompetent patients include gallstones, alcohol use, and medications. Among solid organ transplant recipients who are immunosuppressed, specific etiologies such as steroid use, azathioprine, and cytomegalovirus (CMV) reactivation have also been reported [1]. While only a few cases of pancreatitis in renal transplant patients have been attributed to VZV, some patients became critically ill and died from disseminated disease [4]. Here, we present the first reported case of acute pancreatitis associated with atypical reactivation of VZV presenting as a varicella-like rash in a heart transplant recipient.\n\nCase Report\nA 46-year-old male with a history of non-ischemic dilated cardiomyopathy who had an orthotopic heart transplant 6 months prior presented with a 3- week history of abdominal pain. The patient thought the pain was from lifting, but it had gotten progressively worse over the last few days. Other medical history included chronic obstructive pulmonary disorder, pulmonary sarcoidosis, hypertension, and diabetes. At the time of presentation, the patient was on triple immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone.\n\nThe patient described his abdominal pain as intermittent, sharp, and stabbing, originating in the periumbilical area and radiating to the back. Associated symptoms included decreased oral intake, nausea, and vomiting. Work-up in the emergency department 3 days prior for mild abdominal pain included a computed tomography scan of the abdomen, which revealed no evidence of pancreatitis, cholecystitis, colitis, hydronephrosis, or gallstones. During the patient’s current hospitalization, his blood alcohol and triglyceride levels were within normal limits. His blood lipase was elevated at 232 U/L, uptrending from 130 U/L 3 days previously. Given the patient’s symptoms and lipase being elevated to greater than three times the upper limit of normal, he was diagnosed with acute pancreatitis.\n\nThe patient was admitted to the inpatient service and was in mild-moderate distress from the abdominal pain. He was started on supportive care for acute pancreatitis with intravenous fluids and opioids for pain control. An abdominal ultra-sound showed no evidence of gall stones, or gallbladder wall thickening. The etiology of the pancreatitis remained unclear. The patient’s steroid dose was halved and atorvastatin was discontinued in case it was contributory.\n\nThe patient mentioned an itchy rash over his body that started a few days prior to admission and had progressed since. The rash was noted to be vesicular, erythematous, diffuse on his neck, back, and groin, and present on both sides of the midline (Figure 1A). He denied sick contacts and reported a remote history of chicken pox. A review of previous records demonstrated presence of pre-transplant immunoglobulin G (IgG) varicella zoster virus (VZV) antibodies. Dermatology was consulted and described the lesions as vesicles on an erythematous base with no dermatomal distribution (Figure 1B). Given that the lesions were in multiple stages of development, there was concern for atypical reactivation of VZV that appeared more like varicella than herpes zoster in the setting of immunosuppression. The vesicles were swabbed for VZV polymerase chain reaction (PCR testing), which returned positive. A Tzanck smear showed giant multinucleated keratinocytes, confirming the PCR findings. VZV PCR and both VZV immunoglobulin M (IgM) and IgG antibodies tested positive in blood. CMV and herpes simplex virus PCR were negative.\n\nThe patient was started on acyclovir 10 mg/kg q8h for 7 to 10 days and placed on airborne precaution within hours of suspicion for disseminated VZV. His symptoms improved with continued supportive care for pancreatitis. After the lesions crusted over, the patient was transitioned to oral valacyclovir to complete a 10-day course. He was discharged and followed up in transplant clinic, where the symptoms had completely resolved and lipase levels were back within normal limits (31 U/L). He continues to have an uneventful post-transplant course.\n\nDiscussion\nTo our knowledge, this is the first reported case of VZV-associated pancreatitis in a heart transplant patient. Our patient presented with a subtle rash that appeared more like VCV than HZV despite the prior history of chickenpox. Incidence of pancreatitis among heart transplant recipients can range from 2% to 18%, significantly higher than for other cardiac procedures [5]. However, the diagnosis may be delayed due to subtler clinical presentations and the potentially large differential diagnoses for abdominal pain post solid organ transplant. While gallstones and alcohol intake are the most common causes, other etiologies in immunocompromised patients, such as drugs or opportunistic infections, must be entertained.\n\nOur patient met the Atlanta criteria for pancreatitis based on his lipase level and clinical presentation although his imaging was negative. Nearly all common etiologies of pancreatitis were ruled out in this patient; however, his symptoms did not begin to resolve until he initiated antiviral treatment for VZV. Although VZV may not be an irrefutable cause of his pancreatitis, the association between VZV and visceral organ involvement in immunosuppressed patients has been documented in the literature and should not be overlooked. In nearly all cases, the presentation of visceral involvement preceded the VZV rash, and a delayed diagnosis of VZV resulted in organ failure and death [6]. A study by Locksley et al. on VZV infection in bone marrow transplant recipients found that 21% had visceral symptoms before skin manifestations [7].\n\nCases of VZV-induced pancreatitis have been described in immunocompetent patients as well [8].\n\nThis case and other similar cases presented previously in renal transplant patients (Table 1) reinforce the importance of preventing VZV infection in immunocompromised patients [10–13]. Our patient had prior immunity to varicella, as evidenced by a reactive VZV IgG antibody, but interestingly, presented with what appears to be VZV despite no recent sick contacts with positive IgM and IgG serology. IgM serology can provide evidence for a recent active VZV infection, but does not discriminate between a primary infection and reinfection or reactivation of latent infection due to transient increase in specific IgM antibodies on such re-exposure to VZV. Thus, we hypothesize that our patient likely represents a case of VZV reactivation from previous latency. In general, all potential transplant patients should undergo serologic testing and seronegative patients should be vaccinated prior to the surgery [9]. Those who are not vaccinated and are exposed post-transplant should receive VZV immunoglobulin or acyclovir [9]. Therapy with acyclovir or alternative equivalent antiviral therapies should be initiated within 24 to 72 hours of symptom onset to maximize efficacy.\n\nConclusions\nIn summary, timely diagnosis of pancreatitis in the setting of disseminated VZV is important in immunocompromised patients to prevent development of multiorgan failure and death. Identification of the appropriate etiology for pancreatitis in post-transplant patients requires maintaining a high suspicion for alternative diagnosis beyond conventional known risk factors.\n\nThe authors thank Dr. Matthew Scott Keller and Dr. Christina Ring from Dermatology for their assistance in confirming VZV diagnosis from vesicle smears and Dr. Nana Aburjurnia from Transplant Infectious Disease for assistance with treatment.\n\nFigure 1. Non-dermatomal distribution of rash over back in various stages of healing (A). Close-up of vesicular lesions on erythematous base (B).\n\nTable 1. A review of disseminated VZV cases predominantly reported in renal transplant patients in the past.\n\nStudy\tPatients\tOutcomes\tConclusions\t\nMetanalysis 1985–2011\nRommelaere et al. [10]\t56 adult renal transplant patients with disseminated VZV\tMortality rate: 47% before 1995 and 17% after 1995\nComplications: 2/3 with disseminated intravascular coagulation\tDisseminated VZV is life threatening but the mortality rate has decreased since 1995\nSeropositive VZV patients with disseminated infection can still have fatal outcome\t\nSingle center retrospective study\nMustapic et al. [11]\t40 renal transplant patients, 5 of which had disseminated VZV\tNo deaths\nComplications: 7 with cutaneous scarring, 2 with post-herpetic neuralgia, and 5 relapsed.\nImmunosuppression was decreased for the relapsed patients\tFrequency and intensity of VZV infections is associated with degree of immunosuppression, particularly MMF\nHigh-dose acyclovir and reduction of immunosuppression is important for treatment\t\nRetrospective study 2003–2013\nChitasombat et al. [12]\t22 renal transplant patients with disseminated VZV\tNo deaths\nAll were treated with systemic acyclovir for 3–31 days.\nImmunosuppression reduced for 59% of patients\tIncidence of disseminated VZV post kidney transplant is low\nTreatment with IV acyclovir and reduction of immunosuppression provides a favorable outcome in resource limited environments\t\nSingle center case report series Fehr et al. [13]\t4 renal transplant patients with disseminated VZV\tNo deaths\nComplications: hepatitis, pneumonitis, disseminated intravascular coagulation\tFurther literature search reveals a high mortality rate of 34% but this has decreased in the recent years\nHigh-dose acyclovir is the drug of choice\t\nVZV – varicella zoster virus.\n==== Refs\nReferences:\n1. Sinha S Ratan J Lakhtakia S Narayan G Acute pancreatitis following kidney transplantation – role of viral infections J Clin Translat Res 2003 17 1 32 36 \n2. Tabakovic M Salkic NN Bosnjic J Alibegovic E Acute pancreatitis after kidney transplantation Case Rep Transplant 2012 2012 768193 23259142 \n3. Herline AJ Pinson CW Wright JK Acute pancreatitis after cardiac transplantation and other cardiac procedures: Case control analysis in 24,631 patients Am Surg 1999 65 9 819 25 10484083 \n4. Chhabra P Ranjan P Bhasin DK Simultaneous occurrence of varicella zoster virus induced pancreatitis and hepatitis in a renal transplant recipient: A case report and review of the literature Perm J 2017 21 16 083 \n5. Lin TW Tsai MT Roan JN Obscured hemorrhagic pancreatitis after orthotopic heart transplantation complicated with acute right heart failure and hepatic dysfunction: a case report J Cardiothorac Surg 2016 11 1 166 27908284 \n6. Bookhout C Molylan V Thorne LB Two fatal herpesvirus cases: Treatable but easily missed diagnoses ID Cases 2016 6 65 67 27747159 \n7. Locksley RM Flournoy N Sullivan KM Meyers JD Infection with varicella-zoster virus after marrow transplantation J Infect Dis 1985 152 6 1172 81 3905982 \n8. Wang Z Ye J Han YH Acute pancreatitis associated with herpes zoster: Case report and literature review World J Gastroenterol 2014 20 47 18053 56 25548507 \n9. Pergam SA Limaye AP AST Infectious Diseases Community of Practice: Varicella zoster virus (VZV) in solid organ transplant recipients Am J Transplant 2009 9 S4 S108 15 20070670 \n10. Rommelaere M Marechal C Yombi JC Disseminated varicella zoster virus infection in adult renal transplant recipients: Outcome and risk factors Transplant Proc 2012 44 9 2814 17 23146530 \n11. Mustapic Z Basic-Jukic N Kes P Varicella zoster infection in renal transplant recipients: Prevalence, complications and outcome Kidney Blood Press Res 2011 34 382 86 21654179 \n12. Chitasombat MN Watcharananan SP Prevalence and outcome of disseminated varicella zoster infection post kidney transplantation J Med Assoc Thai 2016 99 4 381 85 27396221 \n13. Fehr T Bossart W Wahl C Binswanger U Disseminated varicella infection in adult renal allograft recipients: Four cases and a review of the literature Transplant 2002 73 4 608 11\n\n",
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"mesh_terms": "D016027:Heart Transplantation; D006801:Humans; D000085343:Latent Infection; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis; D066027:Transplant Recipients; D000073618:Varicella Zoster Virus Infection; D014775:Virus Activation",
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"title": "Atypical Reactivation of Varicella Zoster Virus Associated with Pancreatitis in a Heart Transplant Patient.",
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"abstract": "Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), is a mild-to-life-threatening process that has been described after exposure to many antiepileptic drugs. The increased use of antiepileptic drugs for treatment of bipolar disorder and neurologic disorders has extended the risk of exfoliative disorder to this population of patients, and these patients and their health care providers may not be familiar with the risks involved with these drugs. We describe the cases of a 28-year-old woman with bipolar 1 disorder initially treated with lamotrigine, and two adolescent girls with bipolar 2 disorder treated with lamotrigine after poor responses to other drug regimens. In all three patients, rashes progressed to toxic epidermal necrolysis in spite of treatment with corticosteroids at their local hospitals; thus, they were transferred to our burn treatment center. Response to early corticosteroid treatment in suppressing progression of exfoliation was variable in these patients. Ultimately, two of the three required ventilatory support; their conditions improved within 8-32 days of treatment, and they were discharged from the hospital. Case reports of lamotrigine-induced exfoliative disorder in patients with bipolar disorder have been published. However, these three patients were admitted to our burn treatment center within a 12-month period. Our institution admits approximately 10-12 patients with TEN/year, and the increased use of lamotrigine for treatment of bipolar disorder is likely to result in more patients with TEN. Therefore, health care professionals need to be aware of the early signs and symptoms of exfoliative dermatotoxicity when treating patients with lamotrigine.",
"affiliations": "Department of Pharmacy Services, Thomas Jefferson Medical Center, Philadelphia, Pennsylvania, USA.",
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"title": "Lamotrigine-induced toxic epidermal necrolysis in three patients treated for bipolar disorder.",
"title_normalized": "lamotrigine induced toxic epidermal necrolysis in three patients treated for bipolar disorder"
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"abstract": "An adolescent female with a past medical history significant for Crohn's disease presented with fevers, tonsillitis without exudate, and tender posterior cervical lymphadenopathy. Laboratory results showed transaminitis, leukocytosis with a left shift, and atypical lymphocytes on a blood smear. The patient did not respond to supportive care or dexamethasone, necessitating a tonsillectomy and adenoidectomy. Although her presentation was consistent with infectious mononucleosis, diagnosis was not confirmed until Epstein-Barr virus (EBV) polymerase chain reaction (PCR) from tonsillar tissue was positive. False-negative results on the heterophile antibody test are common in pediatric populations and the detection of EBV antibodies is further complicated in immunocompromised patients. Studies indicate PCR is a more sensitive test, although there is no consensus regarding ideal material to use or quantitative levels necessitating intervention.",
"affiliations": null,
"authors": "Garg|Richa|R|;Rusciolelli|Colleen|C|;Gerber|Mark E|ME|",
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"title": "An adolescent girl with Crohn's disease, fever, and sore throat.",
"title_normalized": "an adolescent girl with crohn s disease fever and sore throat"
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"abstract": "The aim of the study is to assess the rate of any potential adverse effects on women who became pregnant under cabergoline (CAB) treatment and to evaluate any effects on the embryo-fetal development and on children who were born from mothers exposed to CAB in early weeks of gestation. Observational, retrospective and multicenter study on 103 pregnancies in 90 women with hyperprolactinemia. All patients were under CAB at conception. Serum prolactin at baseline was between 30 and 1921 ng/ml. Duration of therapy before pregnancy ranged from 1 to 120 months and doses ranged from 0.125 to 5 mg/week. Fetal exposure ranged from 3 to 25 weeks, 96.9% of patients received CAB during the first trimester of pregnancy and the rest until the second one. No significant complications during pregnancy were found. Seven women (7.2%) had spontaneous abortions. Preterm deliveries were recorded in eight (8.8%), only one with low weight for gestational age. Neonatal abnormalities were observed in 3 (3.6%): 1 major (Down syndrome) and 2 minor malformations (umbilical and inguinal hernia). We were able to asses the children's development in 61. Two had epilepsy and two had Pervasive Developmental Disorder (PDD). No significantly higher frequency of complications was found in pregnancies and/or offspring exposed to CAB than in the normal population. We registered 2 abnormalities in the development of the children: epilepsy and PDD. Larger series of patients are needed to assess the safety of this drug during pregnancy.",
"affiliations": "Departamento de Neuroendocrinología, Sociedad Argentina de Endocrinología y Metabolismo, Diaz Velez 3889, 1200 Buenos Aires, Argentina, graciela.stalldecker@gmail.com",
"authors": "Stalldecker|Graciela|G|;Mallea-Gil|María Susana|MS|;Guitelman|Mirtha|M|;Alfieri|Analía|A|;Ballarino|María Carolina|MC|;Boero|Laura|L|;Chervin|Alberto|A|;Danilowicz|Karina|K|;Diez|Sabrina|S|;Fainstein-Day|Patricia|P|;García-Basavilbaso|Natalia|N|;Glerean|Mariela|M|;Gollan|Viviana|V|;Katz|Débora|D|;Loto|Mónica Graciela|MG|;Manavela|Marcos|M|;Rogozinski|Amelia Susana|AS|;Servidio|Marisa|M|;Vitale|Nicolás Marcelo|NM|",
"chemical_list": "D018491:Dopamine Agonists; D004873:Ergolines; D011388:Prolactin; D000077465:Cabergoline",
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"issue": "13(4)",
"journal": "Pituitary",
"keywords": null,
"medline_ta": "Pituitary",
"mesh_terms": "D000328:Adult; D000077465:Cabergoline; D003430:Cross-Sectional Studies; D018491:Dopamine Agonists; D004873:Ergolines; D005260:Female; D005865:Gestational Age; D006801:Humans; D006966:Hyperprolactinemia; D008875:Middle Aged; D011247:Pregnancy; D011248:Pregnancy Complications; D047928:Premature Birth; D011388:Prolactin; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "9814578",
"other_id": null,
"pages": "345-50",
"pmc": null,
"pmid": "20676778",
"pubdate": "2010-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "16705142;9413809;12138991;12675507;9709946;19539908;19152064;10207689;17760883;10401709;18803677;12536359;12401507;2570790;10649822;20357175;8829257;17921134;20141661;15947492;17602689;7062462;19079957;16456489;7915824;15511894;20455894;10864550;7911037;10404830;17164564;2656736;17287716",
"title": "Effects of cabergoline on pregnancy and embryo-fetal development: retrospective study on 103 pregnancies and a review of the literature.",
"title_normalized": "effects of cabergoline on pregnancy and embryo fetal development retrospective study on 103 pregnancies and a review of the literature"
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"abstract": "OBJECTIVE\nThe World Health Organization (WHO) prospective surveys of acquired HIV drug resistance (HIVDR) evaluate HIVDR emerging after the first year of antiretroviral therapy (ART) and associated factors.\n\n\nMETHODS\nConsecutive ART starters in 2009 were enrolled at 3 sentinel sites in Namibia. Genotyping was performed at start and after 12 months in patients with HIV viral load (VL) >1000 copies per mL. HIVDR outcomes were: HIVDR prevention (VL ≤1000 copies/mL), possible HIVDR (VL >1000 copies/mL without detectable HIVDR or loss to follow-up or ART stop), and HIVDR (VL >1000 copies/mL with detectable HIVDR). Adherence was assessed using medication possession ratio (MPR).\n\n\nRESULTS\nOf 394 starters, at 12 months, 80% were on first-line ART, 1% died, 4% transferred out, 1% stopped ART, <1% switched to second-line, and 15% were lost to follow-up. Among patients on first-line, 77% had VL testing, and 94% achieved VL ≤1000 copies per mL. At baseline, 7% had HIVDR. After 12 months, among patients with VL testing, 5% had HIVDR. A majority of patients failing therapy had high-level resistance to nonnucleoside reverse transcriptase inhibitors but none to protease inhibitors. All sites achieved the WHO target of ≥70% HIVDR prevention. Factors associated with not achieving HIVDR prevention were: baseline resistance to nonnucleoside reverse transcriptase inhibitors [odds ratio (OR) 3.0, P = 0.023], WHO stage 3 or 4 at baseline (OR 2.0, P = 0.012), and MPR <75% (OR 4.9, P = 0.021).\n\n\nCONCLUSIONS\nEarlier ART initiation and removal of barriers to on-time drug pickups may help to prevent HIVDR. These data inform decisions at national and global levels on the effectiveness of first- and second-line regimens.",
"affiliations": "*Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA; †Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA; ‡Republic of Namibia Ministry of Health and Social Services, Windhoek, Namibia; §Molecular Diagnosis Unit, Namibia Institute of Pathology, Windhoek, Namibia; ‖World Health Organization, Klein Windhoek, Windhoek, Namibia; and ¶Centre for HIV & STIs: HIV Virology Section, National Institute for Communicable Diseases, Johannesburg, South Africa.",
"authors": "Hong|Steven Y|SY|;Jonas|Anna|A|;DeKlerk|Michael|M|;Shiningavamwe|Andreas|A|;Desta|Tiruneh|T|;Badi|Alfons|A|;Morris|Lynn|L|;Hunt|Gillian M|GM|;Ledwaba|Johanna|J|;Sheehan|Heidi B|HB|;Lau|Kiger|K|;Trotter|Andrew|A|;Tang|Alice M|AM|;Wanke|Christine|C|;Jordan|Michael R|MR|",
"chemical_list": "D044966:Anti-Retroviral Agents",
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"journal": "Journal of acquired immune deficiency syndromes (1999)",
"keywords": null,
"medline_ta": "J Acquir Immune Defic Syndr",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D023241:Antiretroviral Therapy, Highly Active; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques; D006678:HIV; D015658:HIV Infections; D006801:Humans; D008297:Male; D009276:Namibia; D011446:Prospective Studies; D018571:Sentinel Surveillance",
"nlm_unique_id": "100892005",
"other_id": null,
"pages": "463-71",
"pmc": null,
"pmid": "25564107",
"pubdate": "2015-04-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "11376051;14999613;15127346;15608522;15695685;16652319;16890837;16912954;17457090;18578063;18575188;18575198;19266092;20102272;20838224;21245156;23509605;23762406;24602844;24988387",
"title": "Population-based surveillance of HIV drug resistance emerging on treatment and associated factors at sentinel antiretroviral therapy sites in Namibia.",
"title_normalized": "population based surveillance of hiv drug resistance emerging on treatment and associated factors at sentinel antiretroviral therapy sites in namibia"
} | [
{
"companynumb": "US-JNJFOC-20150319381",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETRAVIRINE"
},
"drugadditional": null,
... |
{
"abstract": "Mucormycosis and aspergillosis are two opportunistic fungal infections, which can evolve into life-threatening complications. They generally affect patients with relevant risk factors such as immunocompromisation or long-term use of antibiotics or corticosteroids. Treatment usually combines medical and surgical approaches, often including extended necrosectomies, although the prognosis of generalized fungal infections is very poor. In this paper, we present the case of a 17-year-old girl affected by combined aspergillosis and mucormycosis, following treatment of a recurrent glioma. The patient was hospitalized for a suspected cellulitis of the right hemi-face, involving frontal maxillary area and the upper airways and was immediately put on intravenous antibiotic therapies; after performing nasal septum and maxillary biopsies, concomitant mucormycosis and aspergillosis were diagnosed and antimycotic therapy with liposomal B-amphotericin was administered. After evaluation by the oral surgeon and otolaryngologist, surgical cranio-facial necrosectomy was suggested, but refused by the parents of the patient. The girl died only few days later, due to a respiratory arrest. Awareness of this pathology with prompt diagnosis and early treatment may improve the outcome of these infections and reduce the mortality.",
"affiliations": "Division of Oral Medicine, Dental Science Department, University of Trieste, Piazza dell'Ospitale 2, 34125, Trieste, Italy.;Division of Oral Medicine, Dental Science Department, University of Trieste, Piazza dell'Ospitale 2, 34125, Trieste, Italy.;Division of Oral Medicine, Dental Science Department, University of Trieste, Piazza dell'Ospitale 2, 34125, Trieste, Italy.;Division of Oral Medicine, Dental Science Department, University of Trieste, Piazza dell'Ospitale 2, 34125, Trieste, Italy.;Department of Otorhinolaryngology, Head and Neck Surgery, Cattinara Hospital, Strada di Fiume 447, 34149, Trieste, Italy.;UCO Pathological Anatomy and Histopathology Unit, Cattinara Hospital, Strada di Fiume 447, 34149, Trieste, Italy.;Infectious Diseases Unit, University Hospital, Trieste, Italy.;Division of Oral Medicine, Dental Science Department, University of Trieste, Piazza dell'Ospitale 2, 34125, Trieste, Italy.;Division of Oral Medicine, Dental Science Department, University of Trieste, Piazza dell'Ospitale 2, 34125, Trieste, Italy. m.biasotto@fmc.units.it.",
"authors": "Chermetz|Maddalena|M|;Gobbo|Margherita|M|;Rupel|Katia|K|;Ottaviani|Giulia|G|;Tirelli|Giancarlo|G|;Bussani|Rossana|R|;Luzzati|Roberto|R|;Di Lenarda|Roberto|R|;Biasotto|Matteo|M|",
"chemical_list": "D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11046-016-0021-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-486X",
"issue": "181(9-10)",
"journal": "Mycopathologia",
"keywords": "Aspergillosis; Early diagnosis; Invasive fungal infection; Mucormycosis",
"medline_ta": "Mycopathologia",
"mesh_terms": "D000293:Adolescent; D000666:Amphotericin B; D000935:Antifungal Agents; D001228:Aspergillosis; D001921:Brain; D060085:Coinfection; D005148:Facial Dermatoses; D017809:Fatal Outcome; D005260:Female; D005910:Glioma; D006651:Histocytochemistry; D006801:Humans; D008279:Magnetic Resonance Imaging; D008437:Maxilla; D008853:Microscopy; D009091:Mucormycosis; D012008:Recurrence; D013280:Stomatitis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "7505689",
"other_id": null,
"pages": "723-33",
"pmc": null,
"pmid": "27350324",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "24225291;19082205;22149972;6693115;14748801;22004440;15599783;7907626;26026174;15370266;290047;15335427;24378282;16770203;25210515;22190810;25103141;17315828;24471053;10841105;23964036;20484814;1607403;18416972;10524965;2802948;18194369;23817660;24150958;20205795;23444832;19074669;12689933;23381980;16634536;24085614;24396630;9200041;15048146;15755275;24279587;17591380;24278780;15480762;20514893;16416267;24476149;19545701;3281109;22247443;21729455;23874118;24479848;16545708;7938799;24105873;23381986;23866727;25840851;23267784;24450842;24445340;17890370;12661747;24299522;23687575;18589192;18805647;25295745;19624514;26168914;20002357;17370565;11317646;16080086;11014632;22684277;2497008;25086667;25187314;18621437;20946236;22994038;22852999;18753183;17959418;23172021",
"title": "Combined Orofacial Aspergillosis and Mucormycosis: Fatal Complication of a Recurrent Paediatric Glioma-Case Report and Review of Literature.",
"title_normalized": "combined orofacial aspergillosis and mucormycosis fatal complication of a recurrent paediatric glioma case report and review of literature"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1032964",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "We studied the tolerance of humans to rifabutin, a rifamycin with antimycobacterial and in vitro anti-HIV activity. Sixteen subjects with AIDS-related complex were treated for 4-66 weeks with stepwise increasing oral doses of rifabutin from 300 to 2400 mg/day. The highest dose attained was twice that previously reported for humans. Serum and cerebrospinal fluid levels of drug were detected by high-pressure liquid chromatography. A reversible syndrome of arthritis/arthralgia, not previously described, was seen in most (nine out of 10) of those given doses exceeding 1050 mg/day. Uveitis and aphthous stomatitis developed at doses of approximately 1800 mg in two of those with joint manifestations. Typical manifestations of Reiter's syndrome were not seen in any patient. An orange-tan skin pigmentation was almost universal. Other toxicities resembled those previously associated with rifampin. Serum levels did not approach those found to inhibit HIV significantly in vitro. No consistent antiviral or immunological effects were observed; even at the highest doses, rifabutin did not appear to inhibit cellular immunity. Rifabutin was well tolerated at daily doses blow 1 g.",
"affiliations": "Department of Medicine, Long Island Jewish Medical Center, New Hyde Park 11042.",
"authors": "Siegal|F P|FP|;Eilbott|D|D|;Burger|H|H|;Gehan|K|K|;Davidson|B|B|;Kaell|A T|AT|;Weiser|B|B|",
"chemical_list": "D015704:CD4 Antigens; D012294:Rifamycins; D017828:Rifabutin",
"country": "England",
"delete": false,
"doi": "10.1097/00002030-199005000-00009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-9370",
"issue": "4(5)",
"journal": "AIDS (London, England)",
"keywords": null,
"medline_ta": "AIDS",
"mesh_terms": "D000386:AIDS-Related Complex; D000328:Adult; D001168:Arthritis; D015704:CD4 Antigens; D004305:Dose-Response Relationship, Drug; D015497:HIV-1; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010859:Pigmentation Disorders; D017828:Rifabutin; D012294:Rifamycins; D014605:Uveitis",
"nlm_unique_id": "8710219",
"other_id": null,
"pages": "433-41",
"pmc": null,
"pmid": "2164820",
"pubdate": "1990-05",
"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": "Dose-limiting toxicity of rifabutin in AIDS-related complex: syndrome of arthralgia/arthritis.",
"title_normalized": "dose limiting toxicity of rifabutin in aids related complex syndrome of arthralgia arthritis"
} | [
{
"companynumb": "US-PFIZER INC-2020267708",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIFABUTIN"
},
"drugadditional": "1",
... |
{
"abstract": "Selective serotonin reuptake inhibitors (SSRIs) are associated with an increased risk of bleeding, and the inhibition of serotonin transporters by SSRIs is thought to be responsible for this side effect. Here, we report that the platelet count returned to normal after discontinuation of paroxetine in a patient with idiopathic thrombocytopenic purpura.",
"affiliations": "Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.",
"authors": "Ono|Shin|S|;Suzuki|Yutaro|Y|;Someya|Toshiyuki|T|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D017374:Paroxetine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-8343",
"issue": "35(2)",
"journal": "General hospital psychiatry",
"keywords": null,
"medline_ta": "Gen Hosp Psychiatry",
"mesh_terms": "D006801:Humans; D008297:Male; D008875:Middle Aged; D017374:Paroxetine; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic; D017367:Serotonin Uptake Inhibitors; D016896:Treatment Outcome",
"nlm_unique_id": "7905527",
"other_id": null,
"pages": "213.e13-5",
"pmc": null,
"pmid": "22832136",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prolongation of idiopathic thrombocytopenic purpura associated with paroxetine administration.",
"title_normalized": "prolongation of idiopathic thrombocytopenic purpura associated with paroxetine administration"
} | [
{
"companynumb": "PHHY2013JP047635",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PAROXETINE\\PAROXETINE HYDROCHLORIDE"
},
"drugaddition... |
{
"abstract": "Anticonvulsant hypersensitivity syndrome (AHS) is a rare, potentially life-threatening drug reaction which usually occurs after exposure to aromatic antiepileptics. AHS secondary to non-aromatic antiepileptics is even more rare and there are only few case reports of AHS presenting as aseptic meningitis. We present the case of a 48-year-old patient who presented with meningism within 3 weeks of adding lamotrigine for control of her juvenile myoclonic epilepsy. When lamotrigine was restarted 2 weeks later she developed similar but more severe symptoms which resolved on stopping lamotrigine. Our patient was subsequently rendered seizure free on levetiracetam which has not so far been linked with this syndrome. It is important to be aware of this life-threatening complication associated with the use of antiepileptics.",
"affiliations": null,
"authors": "Maniyar|Farooq|F|;Rooney|Chris|C|;Lily|Oliver|O|;Bazaz|Rohit|R|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D013256:Steroids; D014227:Triazines; D000077287:Levetiracetam; D000077213:Lamotrigine; D010889:Piracetam",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00415-009-5089-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-5354",
"issue": "256(7)",
"journal": "Journal of neurology",
"keywords": null,
"medline_ta": "J Neurol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005334:Fever; D006261:Headache; D006801:Humans; D000077213:Lamotrigine; D000077287:Levetiracetam; D008578:Meninges; D008582:Meningitis, Aseptic; D008875:Middle Aged; D020190:Myoclonic Epilepsy, Juvenile; D009325:Nausea; D010889:Piracetam; D013256:Steroids; D014227:Triazines",
"nlm_unique_id": "0423161",
"other_id": null,
"pages": "1190-1",
"pmc": null,
"pmid": "19330481",
"pubdate": "2009-07",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": "15934861;8067500;18028184;15679516;14992991;3198757;18986457",
"title": "Anticonvulsant hypersensitivity syndrome presenting as aseptic meningitis.",
"title_normalized": "anticonvulsant hypersensitivity syndrome presenting as aseptic meningitis"
} | [
{
"companynumb": "GB-GLAXOSMITHKLINE-GB2017189295",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": nul... |
{
"abstract": "Olmesartan use has been associated with chronic diarrhoea and weight loss due to severe sprue-like enteropathy, yet this is still not well known among clinicians. We present the unique case of an 84-year-old Filipino woman diagnosed with olmesartan-induced sprue-like enteropathy after an extensive work up for chronic diarrhoea, and without improvement despite multiple empiric treatments for nearly 15 months. Withdrawal of olmesartan resulted in clinical and histological improvement. This case provides further evidence for olmesartan-induced sprue-like enteropathy, and emphasises the importance of its awareness and recognition among gastroenterologists and primary care physicians alike.",
"affiliations": "Department of Internal Medicine, University of Florida, Gainesville, Florida, USA.;Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA.;Department of Pathology, University of Florida, Gainesville, Florida, USA.;Division of Gastroenterology, Hepatology, and Nutrition, University of Florida College of Medicine, Gainesville, Florida, USA.;Division of Gastroenterology, Hepatology, and Nutrition, University of Florida College of Medicine, Gainesville, Florida, USA.",
"authors": "Naik|Dhaval K|DK|;Martelli|Matthew G|MG|;Gonzalo|David Hernandez|DH|;Sharma|Anil K|AK|;Pannu|Davinderbir|D|",
"chemical_list": "D007093:Imidazoles; D013777:Tetrazoles; D000068557:Olmesartan Medoxomil; C437965:olmesartan",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D001284:Atrophy; D002446:Celiac Disease; D003967:Diarrhea; D005260:Female; D006801:Humans; D007093:Imidazoles; D007410:Intestinal Diseases; D007422:Intestines; D000068557:Olmesartan Medoxomil; D013777:Tetrazoles",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26370634",
"pubdate": "2015-09-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22728033;23644957;24805127;25199794",
"title": "An atypical case of chronic diarrhoea: olmesartan-induced sprue-like enteropathy.",
"title_normalized": "an atypical case of chronic diarrhoea olmesartan induced sprue like enteropathy"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-08113",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLMESARTAN"
},
"druga... |
{
"abstract": "BACKGROUND\nThough scientifically undisputed, cutaneous syncarcinogenesis is not reflected in German occupational disease (OD) regulations, which tend to be guided by the tenet of monocausality. Recognition of nonmelanoma skin cancer (NMSC) and its precursor lesions as OD requires individual assessment as to whether the requirements pursuant to either OD 5103 (occupational exposure to natural UV radiation) or OD 5102 (occupational exposure to polycyclic aromatic hydrocarbons) are fulfilled.\n\n\nMETHODS\nRetrospective analysis of 28 patients (median age 72.5 years) with NMSC and respective precursor lesions who had been occupationally exposed to natural UV radiation and polycyclic aromatic hydrocarbons. All cases had undergone expert medical assessment between September 2012 and September 2015.\n\n\nRESULTS\nAccording to our assessments, all 28 cases met the occupational requirements pursuant to OD 5103 and 5102. In 26 cases (93 %), we recommended recognition of skin cancer as occupational disease pursuant to both OD 5103 and OD 5102. The competent occupational insurance association (BG) followed our recommendation in four cases. In eight cases, recognition was solely based on OD 5103; in ten cases, only on OD 5102. Four cases were denied recognition.\n\n\nCONCLUSIONS\nFollowing adequate cumulative occupational exposure to natural UV light as well as occupational exposure to polycyclic aromatic hydrocarbons, NMSC or its precursor lesions arising in UV-exposed areas should be reported to the competent occupational insurance association as \"OD 5103 and 5102 in terms of syncarcinogenesis\". Apart from the fact that the ensuing recognition proceedings will be able to more adequately reflect real-life workplace conditions, filing a report pursuant to both ODs also allows for recognition of basal cell carcinoma as occupational disease. According to current regulations, this would not be possible, if the assessment were solely based on OD 5103.",
"affiliations": "Department of Dermatology, Venereology, and Allergology, St. Josef's Hospital, Medical Center of the Ruhr University Bochum, Bochum, Germany.;IAEBK, Cologne, Germany.;Dermatology Practice Peter Wenzel, MD, Hattingen, Germany.;Institute of Medical Biometry and Informatics (IMBI), University Hospital Heidelberg, Heidelberg, Germany.;Department of Dermatology, Venereology, and Allergology, St. Josef's Hospital, Medical Center of the Ruhr University Bochum, Bochum, Germany.;Department of Dermatology, Venereology, and Allergology, St. Josef's Hospital, Medical Center of the Ruhr University Bochum, Bochum, Germany.",
"authors": "Dickel|Heinrich|H|;Blome|Otto|O|;Dickel|Beate|B|;Bruckner|Thomas|T|;Stockfleth|Eggert|E|;Soemantri|Silas Paras|SP|",
"chemical_list": "D002274:Carcinogens, Environmental; D011084:Polycyclic Aromatic Hydrocarbons",
"country": "Germany",
"delete": false,
"doi": "10.1111/ddg.13003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1610-0379",
"issue": "14(12)",
"journal": "Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG",
"keywords": "OD no. 5103 and 5102; Skin cancer; natural UV radiation; occupational disease; polycyclic aromatic hydrocarbons; syncarcinogenesis",
"medline_ta": "J Dtsch Dermatol Ges",
"mesh_terms": "D000368:Aged; D002274:Carcinogens, Environmental; D009783:Dermatitis, Occupational; D005260:Female; D005858:Germany; D006801:Humans; D008297:Male; D016273:Occupational Exposure; D011084:Polycyclic Aromatic Hydrocarbons; D011230:Precancerous Conditions; D012878:Skin Neoplasms; D013472:Sunlight",
"nlm_unique_id": "101164708",
"other_id": null,
"pages": "1284-1296",
"pmc": null,
"pmid": "27892658",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Occupational syncarcinogenesis in the skin - combined effects of two carcinogens from the German occupational disease list.",
"title_normalized": "occupational syncarcinogenesis in the skin combined effects of two carcinogens from the german occupational disease list"
} | [
{
"companynumb": "DE-MYLANLABS-2017M1025999",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRBESARTAN"
},
"drugadditional": "3",
... |
{
"abstract": "Hand-foot syndrome (HFS) is the main side effect of capecitabine and affects the compression zones of the body such as the palms and soles, causing numbness, paresthesias, skin swelling or erythema, scaling, chapping, hard nodule-like blisters, and severe pain. Loss of fingerprints is also observed in some cases. Severe cases of HFS are common in the review of clinical reports. However, loss of fingerprints has not received significant attention. Two reported cases of loss of fingerprints in The New England Journal of Medicine and The BMJ have drawn attention to this side effect of capecitabine. Loss of fingerprints has a serious impact on patients' daily life, especially on personal identification. This report describes a patient who lost her fingerprints during the early stage of chemotherapy. Our aim is to draw the medical profession's attention to this problem.",
"affiliations": "Department of Oncology, The First Affiliated Hospital of Dalian Medical UniversityDalianP.R. China.;Department of Oncology, The Fifth People's Hospital of DalianDalianP.R. China.;Department of Oncology, The First Affiliated Hospital of Dalian Medical UniversityDalianP.R. China.;Department of Oncology, The First Affiliated Hospital of Dalian Medical UniversityDalianP.R. China.;Department of Oncology, The First Affiliated Hospital of Dalian Medical UniversityDalianP.R. China.;Department of Oncology, The First Affiliated Hospital of Dalian Medical UniversityDalianP.R. China.",
"authors": "Zhao|Jian|J|;Zhang|Xia|X|;Cui|Xiaonan|X|;Wang|Di|D|;Zhang|Bin|B|;Ban|Liying|L|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000077143:Docetaxel; D000069287:Capecitabine",
"country": "United States",
"delete": false,
"doi": "10.3727/096504019X15605078731913",
"fulltext": "\n==== Front\nOncol Res\nOncol Res\nOR\nOncology Research\n0965-0407 1555-3906 Cognizant Communication Corporation Elmsford, NY \n\n31558182\nOR1390\n10.3727/096504019X15605078731913\nCase Report/Review\nLoss of Fingerprints as a Side Effect of Capecitabine Therapy: Case Report and Literature Review\nLOSS OF FINGERPRINTS: CASE REPORT/LITERATURE REVIEWZHAO ET AL.Zhao Jian *\n1\n Zhang Xia †\n1\n Cui Xiaonan * Wang Di * Zhang Bin *‡ Ban Liying * *Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, P.R. China\n\n†Department of Oncology, The Fifth People’s Hospital of Dalian, Dalian, P.R. China\n\n‡Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, P.R. China\n\n\n1These authors provided equal contribution to this work.\n\nAddress correspondence to Liying Ban, Department of Oncology, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Liaoning, Dalian 116000, P.R. China. Tel: +86 411 8363 5963; Fax: +86 411 8363 5963; E-mail: bly7011@163.comor Bin Zhang, Department of Oncology, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Liaoning, Dalian, 116000, P.R. China. Tel: +86 411 8363 5963; Fax: +86 411 8363 5963; E-mail: zhangbin_dlmu@163.com\n2020 \n07 2 2020 \n28 1 103 106\nCopyright © 2020 Cognizant, LLC.2020This article is licensed under a Creative Commons Attribution-NonCommercial NoDerivatives 4.0 International License.Hand–foot syndrome (HFS) is the main side effect of capecitabine and affects the compression zones of the body such as the palms and soles, causing numbness, paresthesias, skin swelling or erythema, scaling, chapping, hard nodule-like blisters, and severe pain. Loss of fingerprints is also observed in some cases. Severe cases of HFS are common in the review of clinical reports. However, loss of fingerprints has not received significant attention. Two reported cases of loss of fingerprints in The New England Journal of Medicine and The BMJ have drawn attention to this side effect of capecitabine. Loss of fingerprints has a serious impact on patients’ daily life, especially on personal identification. This report describes a patient who lost her fingerprints during the early stage of chemotherapy. Our aim is to draw the medical profession’s attention to this problem.\n\nKey words\nHand–foot syndrome (HFS)CapecitabineLoss of fingerprintsBreast cancer\n==== Body\nCASE REPORT\nConsent from the patient’s family and approval by the ethics committee of our hospital have been obtained. A 73-year-old female patient visited our hospital on November 1990 due to “a mass found in the left breast half a year ago.” The patient underwent radical left mastectomy with axillary lymph node dissection at another hospital after definitive diagnosis. Postoperative pathology indicated simple carcinoma. The size of the mass was 2.0 cm × 2.0 cm, and no metastatic lesion was found in the axillary lymph nodes (0/3). The postoperative diagnosis was stage IIA breast cancer (pT2N0M0). The patient underwent one cycle of postoperative CMF chemotherapy and then refused to continue chemotherapy. She subsequently underwent treatment with tamoxifen for 1 month as pathology demonstrated ER (+) and PR (+) tumor cells. The patient stopped taking tamoxifen without consultation with her doctor due to asthenia.\n\nOn June 2013, a mass was found in the left chest wall, and a biopsy was performed. Pathology showed metastatic carcinoma, which was considered to have originated from the breast, with ER (+), PR (+), HER-2 (1+), Ki-67 < 3% pathology. On August 2013, the patient received six cycles of TP chemotherapy with intravenous infusions of docetaxel 120 mg on day 1 and cisplatin 60 mg on days 1 and 2, every 21 days. The efficacy evaluation indicated stable disease. After chemotherapy, the patient received endocrine therapy with oral letrozole 2.5 mg daily until March 2015. Due to ulcerated cancerous nodules in the chest, the endocrine therapy regimen was changed to oral exemestane 25 mg daily.\n\nOn January 2017, the ulcer in the chest wall enlarged. On April 2017, a lung CT showed 1) multiple nodules in the right lung, with several newly found nodules and some enlarged nodules compared with the CT results of October 11, 2016, highly suspicious for metastasis; and 2) irregular soft tissue shadow in the left anterior chest wall found after the left mammectomy, with an enlarged area compared with the previous study, swelling of the right axillary fossa with enlarged lymph nodes, highly suspicious for malignant tumor. The disease had clearly progressed. The patient started to take combination chemotherapy with docetaxel and capecitabine (21-day cycles with intravenous infusion of docetaxel 120 mg on day 1 and oral capecitabine 1500 mg twice daily on days 1–14) in April 2017. On the 10th day of treatment, the skin of the hands and feet was found to be thinner. After the second cycle of medication, the patient experienced slight pain in the hands and feet, with thinner texture of the fingertips. The patient had difficulty opening the fingerprint lock of her front door when returning home. The skin of her interphalangeal joints became red and swollen.\n\nAt the end of the third cycle of medication, the patient’s hand–foot syndrome (HFS) had worsened, with thinning and peeling of the skin of the fingers, toes, and interphalangeal joints, as well as a gradual loss of the texture of the palm and loss of fingerprints, resulting in inability to open her fingerprint lock. During the fourth cycle of medication, the peeling of the skin of the hands and feet gradually worsened, resulting in chapping and bleeding (Figs. 1 and 2). The patient was diagnosed with grade IV HFS, and Vaseline was applied to the affected area. The fifth cycle of chemotherapy was postponed for 2 weeks, and the HFS improved slightly. During the fifth and sixth cycles of chemotherapy, the dosage of capecitabine was reduced to 1,000 mg twice daily. The last dose of chemotherapy was administered on August 10, 2017. Due to severe HFS, the patient refused to continue chemotherapy and chose to be observed with follow-up. No disease progression had been observed at 17 months.\n\nFigure 1 Severe hand–foot syndrome in the patient after the fourth cycle of chemotherapy, with loss of fingerprints, peeling of skin, blisters, chapping, and scabbing in some areas.\n\nFigure 2 Location of lost fingerprints indicated by the arrows.\n\nDISCUSSION\nChinese researchers have proposed a “full-course management strategy” for advanced breast cancer. Combination chemotherapy with capecitabine followed by maintenance capecitabine monotherapy is particularly suitable for the full-course management of advanced breast cancer1. As the clinical uses of capecitabine have expanded, its side effects have received more attention. More than 50% of patients who are treated with capecitabine develop HFS2.\n\nCapecitabine-related loss of fingerprints was initially reported by Chavarri-Guerra and Soto-Perez-de-Celis3. The patient in that report experienced loss of fingerprints after oral treatment with Xeloda, which made it impossible for the patient to conduct routine banking activities through fingerprint identification. She had grade 1 PPE when she was treated with capecitabine in combination with bevacizumab in the first cycle, and this improved after topical treatment. In the third cycle of chemotherapy, the patient developed limited use of her hands and feet. The dosage of capecitabine was subsequently reduced. No acute toxicity occurred, but the patient’s fingerprints disappeared. The authors believed that the loss of fingerprints in this patient was closely related to the HFS caused by Xeloda.\n\nAl-Ahwal reported that a patient who received capecitabine chemotherapy had a grade 1 HFS after the second and third cycles of chemotherapy, and a grade 3 HFS and disappearance of fingerprints after the fifth and sixth cycles of chemotherapy4. The patient delayed chemotherapy and reduced capecitabine while receiving paracetamol, tramadol, and a local moisturizer. He lost the ability to process required government documents because of his fingerprint loss. This unbearable phenomenon seriously affected the quality of life. When the patient began second-line Bev-Xeliri 18 weeks after completing the first-line treatment, he developed a grade 3 HFS, although the capecitabine dose was not high in the second-line regimen4.\n\nLightowlers and Soomal also reported a case of fingerprint loss after chemotherapy5. The patient was unable to turn on his cell phone using the fingerprint recognition technology, as he had previously done, after he experienced skin dryness and palmar erythema during chemotherapy with oxaliplatin and capecitabine. His cell phone could not recognize his fingerprints due to his skin peeling and loss of the surface texture. The authors also believed that the loss of fingerprints was related to HFS.\n\nHowever, a prospective study by the Erasmus Medical Center Cancer Institute offers a different perspective. Mathijssen and colleagues suggested that the loss of fingerprints induced by capecitabine might not be associated with the severe skin reactions caused by HFS6. Their study collected fingerprint information from 66 patients who were treated with capecitabine. After 8 weeks of treatment, 9 patients had loss of fingerprints, while 46 patients had severe HFS. Although some patients were afflicted with severe HFS, they did not experience loss of fingerprints, and vice versa. This finding suggested that there is no definite correlation between the severity of HFS and loss of fingerprints. Most of the damaged fingerprints improved within 2 to 4 weeks after the treatment was stopped. No study to date has offered a plausible explanation for the mechanism underlying loss of fingerprints secondary to HFS.\n\nThe patient in our report experienced gradually worsening HFS immediately after the first cycle of treatment, with thinning and partial peeling of the skin of both hands, as well as fading of fingerprints on the fingertips. After the fourth cycle, the skin of the entire palm of both hands started to peel off, and she also experienced chapping, loss of fingerprints, and gradual fading of palm texture. Hard nodule-like blisters were observed in some areas of the fingers, along with nail discoloration. She also experienced swollen joints and restricted flexion of the fingers, which caused her significant discomfort. The patient was unable to open the door to her home due to loss of fingerprints. The patient reported that “she could not return to her home,” which caused her psychological harm. The reported median time to onset of HFS is 79 days (ranging from 11 to 360 days)7. Most of the symptoms are grade 1. The patient in our report developed HFS on the 10th day after the start of treatment, and her fingerprints disappeared during the fourth cycle of treatment, possibly because the patient was overly sensitive to the drug.\n\nBecause capecitabine-induced HFS may be related to the overexpression of the COX-2 enzyme in the hands and feet, metabolism of capecitabine in small sweat glands, or mechanical compression8–10, it can be speculated that COX-2 inhibitors can treat or prevent capecitabine-induced HFS, such as celecoxib. Most experts suggest that reducing capecitabine doses and delaying chemotherapy can be a key way to relieve symptoms in the absence of evidence11. The therapeutic methods of HFS include oral celecoxib, cod liver oil, vitamin B6, etc., as well as topical antiperspirants, urea ointment, antioxidants, or regional cooling12,13. There are also many traditional Chinese medicine decoction used for the treatment of HFS14. These studies suggest that oral celecoxib has a preventive effect on ≥2 grade HFS, while regional use of urea ointment and antiperspirant has no preventive effect on HFS12,13. Oral cod liver oil, oral vitamin B6, and local cooling or use of local antioxidants may be effective, but they are not as effective as celecoxib. However, these treatments cannot completely prevent or cure the effects of HFS, especially loss of fingerprints10,15–17. Loss of fingerprints is a low-risk adverse reaction. However, as a type of unique personal information, fingerprints are increasingly used for personal identification for electronic devices such as smart phones, laptops, and door locks. Loss of fingerprints brings great inconvenience to patients. Clinicians should inform the patient of the loss of fingerprints as a common adverse reaction and should encourage patients to save relevant fingerprint information before chemotherapy so that they can provide such information when needed. We hope that this case report calls clinicians’ attention to this adverse reaction.\n\nACKNOWLEDGMENTS\n\nThis work was supported by basic research projects of the Liaoning province higher education institutions, P.R. China (No. LQ2017024).\n\n\nThe authors declare no conflicts of interest.\n==== Refs\nREFERENCES\n1 \nBraghiroli CS , Ieiri R , Ocanha JP , Paschoalini RB , Miot HA . Do you know this syndrome? Hand–foot syndrome\n. An Bras Dermatol. \n2017 ;92 (1 ):131 –3\n.28225974 \n2 \nGressett SM , Stanford BL , Hardwicke F . Management of hand–foot syndrome induced by capecitabine\n. J Oncol Pharm Pract. \n2006 ;12 (3 ):131 –41\n.17022868 \n3 \nChavarri-Guerra Y , Soto-Perez-de-Celis E . Images in clinical medicine. Loss of fingerprints\n. N Engl J Med. \n2015 ;372 (16 ):e22 .25875278 \n4 \nAl-Ahwal MS . Chemotherapy and fingerprint loss: Beyond cosmetic\n. Oncologist \n2012 ;17 (2 ):291 –3\n.22298801 \n5 \nLightowlers S , Soomal R . Loss of fingerprints secondary to palmoplantar erythrodysesthesia in a patient on capecitabine chemotherapy\n. BMJ \n2015 ;351 .\n6 \nvan Doorn L , Veelenturf S , Binkhorst L , Bins S , Mathijssen R . Capecitabine and the risk of fingerprint loss\n. JAMA Oncol. \n2017 ;3 (1 ):122 –3\n.27560202 \n7 \nGao Y . The adverse effect cause by capecitabine chemotherapy and its nursing measures\n. Chin J Trauma Disbil Med. \n2011 ;19 (3 ):36 –7\n.\n8 \nLin EH , Curley SA , Crane CC , Feig B , Skibber J , Delcos M , Vadhan SR , Morris J , Ayers GD , Ross A , Brown T , Rodriguez-Bigas MA , Janjan N . Retrospective study of capecitabine and celecoxib in metastatic colorectal cancer: Potential benefits and COX-2 as the common mediator in pain toxicities and survival?\n\nAm J Clin Oncol. \n2006 ;29 (3 ):232 –9\n.16755175 \n9 \nMrozek-Orlowski ME , Frye DK , Sanborn HM . Capecitabine: Nursing implications of a new oral chemotherapeutic agent\n. Oncol Nurs Forum \n1999 ;26 (4 ):753 –62\n.10337653 \n10 \nNarasimhan P , Narasimhan S , Hitti IF , Rachita M . Serious hand-and-foot syndrome in black patients treated with capecitabine: Report of 3 cases and review of the literature\n. Cutis \n2004 ;73 (2 ):101 –6\n.15027515 \n11 \nvon Moos R , Thuerlimann BJK , Aapro M , Rayson D , Harrold K , Sehouli J , Scotte F , Lorusso D , Dummer R , Lacouture ME , Lademann J , Hauschild A . Pegylated liposomal doxorubicin-associated hand–foot syndrome: Recommendations of an international panel of experts\n. Eur J Cancer \n2008 ;44 (6 ):781 –90\n.18331788 \n12 \nHuang XZ , Chen Y , Chen WJ , Zhang X , Wu CC , Wang ZN , Wu J . Clinical evidence of prevention strategies for capecitabine-induced hand–foot syndrome\n. Int J Cancer \n2018 ;142 (12 ):2567 –77\n.29355976 \n13 \nMacedo LT , Lima JP , dos Santos LV , Sasse AD . Prevention strategies for chemotherapy-induced hand–foot syndrome: A systematic review and meta-analysis of prospective randomised trials\n. Support Care Cancer \n2014 ;22 (6 ):1585 –93\n.24463616 \n14 \nLi Y , Bai Y . Observation on curative effect and nursing experience of wet compress of traditional Chinese medicine in patients with hand and foot syndrome caused by chemotherapy\n. World Latest Med Inform. \n2016 ;16 (55 ):369 .\n15 \nCorrie PG , Bulusu R , Wilson CB , Armstrong G , Bond S , Hardy R , Lao-Sirieix S , Parashar D , Ahmad A , Daniel F , Hill M , Wilson G , Blesing C , Moody AM , McAdam K , Osborne M . A randomised study evaluating the use of pyridoxine to avoid capecitabine dose modifications\n. Br J Cancer \n2012 ;107 (4 ):585 –7\n.22814578 \n16 \nJo SJ , Shin H , Kwon O , Myung SK . Prophylactic and therapeutic efficacy of pyridoxine supplements in the management of hand–foot syndrome during chemotherapy: A meta-analysis\n. Clin Exp Dermarol. \n2015 ;40 (3 ):260 –70\n.\n17 \nOta M , Tatsumi K , Suwa H , Watanabe J , Watanabe K , Osada S , Tanaka K , Shoichi F , Ichikawa Y , Kunisaki C , Endo I . The effect of pyridoxine for prevention of hand–foot syndrome in colorectal cancer patients with adjuvant chemotherapy using capecitabine: A randomized study\n. Hepato-gastroenterology \n2014 ;61 (132 ):1008 –13\n.26158157\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0965-0407",
"issue": "28(1)",
"journal": "Oncology research",
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"medline_ta": "Oncol Res",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000069287:Capecitabine; D003878:Dermatoglyphics; D000077143:Docetaxel; D005260:Female; D060831:Hand-Foot Syndrome; D006801:Humans",
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"pages": "103-106",
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"pmid": "31558182",
"pubdate": "2020-02-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "25875278;15027515;18331788;28225974;22814578;10337653;25557587;17022868;24463616;22298801;16755175;29355976;27560202;26158157",
"title": "Loss of Fingerprints as a Side Effect of Capecitabine Therapy: Case Report and Literature Review.",
"title_normalized": "loss of fingerprints as a side effect of capecitabine therapy case report and literature review"
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"abstract": "Several psychoactive medications are known to cause QTc prolongation. Patient factors also increase the risk for QTc prolongation, including bradycardia, female sex, older age, metabolic abnormalities, and polypharmacy. Donepezil, a cholinesterase inhibitor, prolongs the QTc interval through a multimodal mechanism.\nA 26-year-old African American female was admitted to the inpatient psychiatric hospital following a suicide attempt that was not an overdose. Past medical history was significant for major depression, traumatic brain injury, seizures, hemiplegia, gastroesophageal reflux disease, and tachycardia. Two baseline electrocardiograms (EKGs) were obtained showing normal QTc intervals. After several weeks, donepezil (5 mg by mouth once daily) was initiated for cognitive rehabilitation and titrated over 3 weeks to a dose of 20 mg. An EKG performed after the last dose change showed a prolonged QTc of 463 ms. Another follow-up EKG performed 9 days later showed further prolongation to 528 ms. Laboratory values were within normal limits during her hospital stay. Donepezil was discontinued completely, leading to normalization of the QTc interval.\nQTc prolongation and torsades de pointes have been identified in postmarketing case reports of donepezil. Instances of QTc prolongation have predominantly been documented in the geriatric population, primarily in those with additional risk factors. Additionally, current literature does not support the use of donepezil for neurocognitive rehabilitation in daily doses exceeding 10 mg. A temporal and causal relationship was observed between the initiation and titration of donepezil and development of QTc prolongation.",
"affiliations": null,
"authors": "Vogel|Samantha M|SM|https://orcid.org/0000-0002-6281-7038;Mican|Lisa M|LM|https://orcid.org/0000-0002-2852-6632;Smith|Tawny L|TL|https://orcid.org/0000-0002-7512-4919",
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"doi": "10.9740/mhc.2019.05.128",
"fulltext": "\n==== Front\nMent Health ClinMent Health ClinmhclMent Health ClinThe Mental Health Clinician2168-9709College of Psychiatric & Neurologic Pharmacists 10.9740/mhc.2019.05.128mhcl-09-03-02Case ReportsDonepezil-induced QTc prolongation: A case report Vogel Samantha M. https://orcid.org/0000-0002-6281-7038PharmDMican Lisa M. https://orcid.org/0000-0002-2852-6632PharmD, BCPP2Smith Tawny L. https://orcid.org/0000-0002-7512-4919PharmD, BCPP31 Clinical Assistant Professor, The University of Texas at Austin College of Pharmacy, Austin, Texas; Behavioral Health Pharmacist, UT Health Austin, Dell Medical School, Austin, Texas, svogel@austin.utexas.edu. Previously: Pharmacist, Seton Healthcare Family, Austin State Hospital, Health and Human Services Commission, Austin, Texas\n2 Assistant Director of Pharmacy, Clinical Coordinator, Austin State Hospital, Health and Human Services Commission, Austin, Texas\n\n3 Associate Professor of Psychiatry, Dell Medical School, The University of Texas at Austin, Austin, Texas\n\nDisclosures: None.\n\n5 2019 10 5 2019 9 3 128 132 © 2019 CPNP. The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists.2019This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nSeveral psychoactive medications are known to cause QTc prolongation. Patient factors also increase the risk for QTc prolongation, including bradycardia, female sex, older age, metabolic abnormalities, and polypharmacy. Donepezil, a cholinesterase inhibitor, prolongs the QTc interval through a multimodal mechanism.\n\nPatient History\nA 26-year-old African American female was admitted to the inpatient psychiatric hospital following a suicide attempt that was not an overdose. Past medical history was significant for major depression, traumatic brain injury, seizures, hemiplegia, gastroesophageal reflux disease, and tachycardia. Two baseline electrocardiograms (EKGs) were obtained showing normal QTc intervals. After several weeks, donepezil (5 mg by mouth once daily) was initiated for cognitive rehabilitation and titrated over 3 weeks to a dose of 20 mg. An EKG performed after the last dose change showed a prolonged QTc of 463 ms. Another follow-up EKG performed 9 days later showed further prolongation to 528 ms. Laboratory values were within normal limits during her hospital stay. Donepezil was discontinued completely, leading to normalization of the QTc interval.\n\nDiscussion\nQTc prolongation and torsades de pointes have been identified in postmarketing case reports of donepezil. Instances of QTc prolongation have predominantly been documented in the geriatric population, primarily in those with additional risk factors. Additionally, current literature does not support the use of donepezil for neurocognitive rehabilitation in daily doses exceeding 10 mg. A temporal and causal relationship was observed between the initiation and titration of donepezil and development of QTc prolongation.\n\ndonepezilQTc prolongationelectrocardiogramneurocognitive rehabilitationCitationHow to cite: Vogel SM, Mican LM, Smith TL. Donepezil-induced QTc prolongation: A case report. Ment Health Clin [Internet].\n==== Body\nBackground\nQTc prolongation can increase the risk of torsades de pointes (TdP), which may lead to the development of ventricular fibrillation, cardiac arrest, and sudden death. A prolonged QTc interval is defined as >480 ms in women and >460 ms in men although this definition varies by source.1 Risk of developing TdP increases significantly with QTc intervals >500 ms.1 Patient risk factors for QTc prolongation include bradycardia, structural heart disease, female sex, older age (>65 years), metabolic abnormalities, traumatic brain injury (TBI), and concomitant QTc-prolonging agents.1\n\nDrug-induced QTc prolongation is the most common cause of QTc prolongation.2 Medications that increase the QTc interval are thought to do so through their ability to inhibit or interfere with delayed rectifier potassium channels.3 Several psychoactive medications are known to cause QTc prolongation, including antidepressants, antipsychotics, and cholinesterase inhibitors.3,4\n\nSince its approval in 1996 for use in Alzheimer disease (AD), there have been postmarketing reports of QTc prolongation and development of TdP with donepezil use.5 However, most published cases6-11 have been in older adults with additional risk factors, including structural heart disease and concomitant QTc-prolonging drugs. We report a case of suspected donepezil-induced QTc prolongation in a 26-year-old female patient with a history of TBI. Currently available case reports6-11 are limited to individuals over the age of 65. Additionally, use of donepezil for cognitive rehabilitation following TBI is considered off label. To our knowledge, no case reports of QTc prolongation with donepezil use have been documented in the TBI population or those of younger age.\n\nCase Report\nThe patient was a 26-year-old African American female admitted to the inpatient psychiatric hospital after a suicide attempt by means that were not an overdose. Past medical history was significant for major depressive disorder, TBI, seizures, asthma, dysarthria, hemiplegia, gastroesophageal reflux disease, constipation, and tachycardia. Her social history was noncontributory. She was initially continued on her previous outpatient medications, including quetiapine 100 mg in the morning, 200 mg at noon, and 300 mg at bedtime for mood stabilization; divalproex sodium extended-release 500 mg twice daily for mood stabilization and history of seizures; metoprolol extended-release 25 mg daily for tachycardia; montelukast 10 mg daily for asthma; polyethylene glycol-3350 17 g daily for constipation; calcium with vitamin D supplement daily for nutritional deficiency; pantoprazole 40 mg daily for gastroesophageal reflux disease; and cephalexin 500 mg 4 times daily for cellulitis. Two baseline electrocardiograms (EKGs) were obtained on admission. The first showed a QTc of 425 ms with T-abnormality in the inferior lead. The second showed a QTc of 438 ms. She was noted to be in sinus tachycardia with a heart rate of 112 beats/min (bpm) during both reads.\n\nDuring the few weeks following admission, several medication changes were made, including a significant dose reduction of quetiapine to 50 mg 3 times daily due to daytime sedation and a 7-day trial of sertraline 50 mg, which was discontinued due to increased agitation. On hospital day (HD) 35, donepezil 5 mg daily was initiated for cognitive rehabilitation due to TBI. An EKG performed 5 days after donepezil initiation (HD 40) showed sinus rhythm, a normal QTc of 423 ms and a heart rate of 97 bpm. Relevant scheduled medications at this time included quetiapine 50 mg 3 times daily, donepezil 5 mg at bedtime, and pantoprazole 40 mg in the morning. Approximately 7 days after donepezil initiation (HD 42), donepezil was increased to 5 mg twice daily. Five days later (HD 47), the bedtime dose was titrated to 10 mg for a total of 15 mg daily. The donepezil dose was further titrated to 10 mg twice daily 8 days later (HD 56). There was no documentation of gastrointestinal side effects during this time. A repeat EKG performed on HD 68 showed sinus rhythm, an increased QTc of 463 ms, and heart rate of 70 bpm. At the time of this EKG, she was taking donepezil 10 mg twice daily, pantoprazole 40 mg in the morning, and quetiapine 50 mg twice daily. Notable as needed (PRN) medications during the week prior to this EKG included quetiapine 25 mg (4 doses total with 2 doses given on HD 66), which was administered for agitation and aggression.\n\nA follow-up EKG on HD 77 revealed a prolonged QTc of 528 ms with a heart rate of 81 bpm and sinus rhythm noted. Her quetiapine dose was increased back to 50 mg 3 times daily the day prior. Donepezil 10 mg twice daily and pantoprazole 40 mg in the morning had been continued at the same doses. Notable PRN medications during the week prior to this EKG included quetiapine 25 mg (5 doses total with 2 given on HD 76) and 1 PRN dose of both quetiapine 100 mg and olanzapine 10 mg. At this point, donepezil was reduced to 10 mg in the morning, and she continued to take scheduled quetiapine 50 mg 3 times daily.\n\nOn HD 81 an EKG showed the patient was in sinus rhythm; however, QTc remained prolonged at 496 ms, heart rate 95 bpm. At this time, an adverse drug reaction was reported to the pharmacy. Notable PRN medications in the days preceding this EKG included a single dose of oral quetiapine 25 mg and intramuscular diphenhydramine 50 mg for acute agitation. Donepezil was discontinued completely. She continued to take quetiapine and pantoprazole during this time. Due to the half-life of donepezil, a follow-up EKG was performed 15 days later with a normal QTc of 416 ms. From available labs, there was no evidence of electrolyte abnormalities during her hospital admission. Potassium levels remained within normal limits; however, there were no magnesium concentrations on record. A hospital course summary is outlined in the Figure.\n\nFIGURE Hospital course and timeline of donepezil-induced QTc prolongation (bpm = beats/min; EKG = electrocardiogram; ER = extended release; HR = heart rate; PRN = as needed)\n\nDiscussion\nA literature search was conducted to identify current reports of QTc prolongation associated with donepezil use. A PubMED search was conducted using the keywords donepezil, QTc prolongation, cardiac, torsades de pointes, and arrhythmia. Approval by the facility privacy officer was obtained.\n\nDonepezil, pantoprazole, and quetiapine are known to potentially contribute to QTc prolongation. QTc prolongation and TdP have been identified in postmarketing reports of donepezil.5,12-14 Donepezil is on the CredibleMeds list of medications12 with known risk of TdP, and pantoprazole and quetiapine are listed as a conditional risk, meaning that there is no convincing evidence that these medications cause TdP or pathological QTc prolongation unless certain clinical conditions are present. Furthermore, diphenhydramine and olanzapine are also listed as medications with a conditional risk for TdP.12 Quetiapine has a moderate-to-high risk of QTc prolongation compared with most antipsychotics with the exception of thioridazine, iloperidone, and ziprasidone.13 Studies and case series have demonstrated that risk of QTc prolongation with quetiapine is minimal when used within recommended therapeutic doses.14 However, this minimal risk has only been demonstrated in patients without other risk factors for QTc prolongation.14 There is limited evidence regarding effects on the QTc interval with intermittent doses of quetiapine, olanzapine, or diphenhydramine.\n\nDonepezil is a cholinesterase inhibitor prescribed for the treatment of AD.5 The donepezil package insert5 recommends that patients tolerate the 5 mg dose daily for 4 to 6 weeks before titrating to 10 mg daily due to the incidence of adverse gastrointestinal events. It is not known if the rate at which donepezil is titrated correlates with cardiovascular side effects. Furthermore, the package insert5 recommends patients tolerate donepezil 10 mg daily for 3 months before increasing the dose further (up to 23 mg). Donepezil is currently only approved for the treatment of AD.1 Because acetylcholine pathways play an important role in neurological recovery following injury, donepezil has also been studied for neurocognitive rehabilitation following TBI.15 Per our literature review, the results are variable for the available studies. Donepezil has only been studied up to 10 mg daily for this use, and dosing regimens were diverse between case reports and studies.15\n\nThere is limited information regarding the cardiovascular adverse effects of donepezil; however, donepezil is known to cause bradycardia through its cholinergic effect on vagal tone at the sinoatrial and atrioventricular nodes. Donepezil has also demonstrated inhibition of the rapid delayed rectifier potassium channel in addition to its ability to interfere with potassium channel trafficking.3,4 Case reports on donepezil use in the elderly population have demonstrated significant prolongations of the QTc interval even at recommended doses. Three cases of elderly female patients documented prolonged QTc interval with use of donepezil 5 mg daily with 2 of the 3 cases progressing to TdP.8,10 Two additional case reports7,9 of QTc prolongation occurred in an elderly male and female after donepezil was increased from 5 mg to 10 mg daily with TdP and atrioventricular block occurring in each case, respectively. The Table summarizes published reports on QTc prolongation with donepezil use.6-11\n\nTABLE Available evidence for EKG changes with donepezil\n\nStudy\tStudy Characteristics\tDonepezil Dose Intervention\tEKG Findings\t\nStudy Design\tPatient Population\tPotential Patient Risk Factors\t\nPourmad et al17 (2017)\tCase report\t84-year-old male\tOld age, possible structural heart disease\t35 mg (accidental ingestion)\tQTc = 502 ms\t\nKitt et al7 (2015)\tCase report\t80-year-old female\tOld age, female, atrial fibrillation, polypharmacy\t5 mg increased to 10 mg for 2 wk\tQTc = 490 ms TdP occurred despite dose reduction\t\nIgeta et all11 (2014)\tProspective cohort\tN = 18 (80% male) Mean age = 74 years old\tOld age\t5-10 mg daily for an average of 4 mo\tProlonged PR interval; no change in QTc interval\t\nShinozaki8 (2012)\tCase report\t80-year-old female\tOld age, female, polypharmacy\t5 mg daily\tQTc = 470 ms\t\nTanaka et al10 (2009)\tCase report\t90-year-old male\tOld age\t5 mg increased to 10 mg for 3 d\tQTc = 514 ms Atrioventricular block\t\nTakaya et al9 (2009)\tCase report\t87-year-old female\tOld age, female, possible structural heart disease, atrial fibrillation, bradycardia, polypharmacy\t5 mg daily\tQTc #1 = 461 ms QTc #2 (1 mo later) = 594 ms TdP occurred\t\nCase report\t83-year-old female\tOld age, female, structural heart disease, atrial fibrillation, electrolyte abnormality\t5 mg daily\tQTc = 645 ms TdP occurred\t\nEKG = electrocardiogram; PR = P-R interval on an EKG; TdP = torsades de pointes.\n\nThe patient in this case had a QTc within normal range on admission while taking quetiapine 600 mg. Her quetiapine dose was reduced prior to initiation of donepezil. After initiation of donepezil at 5 mg in the morning, her QTc was within normal range. Following rapid titration of donepezil to a total daily dose of 20 mg (without documented gastrointestinal side effects), QTc prolongation was found on EKG. Her QTc improved following a dose reduction of donepezil to 10 mg daily, and her QTc eventually normalized following discontinuation of donepezil. The patient's QTc remained within normal range while taking quetiapine and pantoprazole.\n\nThe Naranjo Adverse Drug Reactions Probability Scale provides a score of 5, indicating this event is a probable adverse event resulting from donepezil use.16 Per the review of the data and this patient's history, it is possible that use of higher doses of donepezil in association with other patient risk factors for QTc prolongation (female sex, concomitant QTc-prolonging drugs, TBI, and use of medications that may cause bradycardia) contributed to this adverse event. Although there is no current data supporting that EKG changes are related to the rate of titration, it cannot be ruled out that a slower titration of donepezil may have helped prevent QTc prolongation despite concomitant use of quetiapine and pantoprazole. Although her heart rate at the time of the EKG finding was normal, it was significantly lower following donepezil titration compared with initial EKG readings on admission (a difference of 42 bpm). Furthermore, current data do not support donepezil doses greater than 10 mg for cognitive enhancement due to TBI.\n\nConclusion\nAlthough there are potential confounding factors, including polypharmacy and inherent patient risk factors, such as TBI and female sex, we were able to identify a temporal and causal relationship between the initiation and titration of donepezil and the development of QTc prolongation. Reduction of donepezil dose resulted in shortening of the QTc interval and normalization with discontinuation. Clinicians should be aware that donepezil has the potential to cause life-threatening cardiac effects even at recommended doses. Providers and pharmacists should be cautious when initiating donepezil in individuals with risk factors for QTc prolongation, including patients with TBI. Additionally, practitioners should adhere to the recommended titration schedule when increasing beyond initial starting doses. Cardiac monitoring should be considered at baseline and following initiation or dose increases of donepezil in all patients but especially patients with multiple risk factors for QTc prolongation.\n==== Refs\nReferences\n1 Drew BJ Ackerman MJ Funk M Gibler WB Kligfield P Menon V Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation Circulation 2010 121 8 1047 60 DOI: 10.1161/CIRCULATIONAHA.109.192704 PubMed PMID: 20142454 PubMed Central PMCID: PMC3056123 20142454 \n2 Pickham D Helfenbein E Shinn JA Chan G Funk M Weinacker A High prevalence of corrected QT interval prolongation in acutely ill patients is associated with mortality Crit Care Med 2012 40 2 394 9 DOI: 10.1097/CCM.0b013e318232db4a PubMed PMID: 22001585 22001585 \n3 Vieweg WVR New generation antipsychotic drugs and QTc interval prolongation Prim Care Companion J Clin Psychiatry 2003 5 5 205 15 DOI: 10.4088/PCC.v05n0504 PubMed PMID: 15213787 15213787 \n4 Cubeddu L Drug-induced inhibition and trafficking disruption of ion channels: pathogenesis of QT abnormalities and drug-induced fatal arrhythmias Curr Cardiol Rev 2016 12 2 141 54 DOI: 10.2174/1573403x12666160301120217 PubMed PMID: 26926294 26926294 \n5 Jublient Cadista Pharmaceuticals Inc DONEPEZIL HYDROCHLORIDE (donepezil hydrochloride) tablet, film coated. 1996 [rev. 2016 Feb; cited 2018 Jun 19] DailyMed [Internet] Bethesda (MD) National Library of Medicine (US) Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0baef0fd-e6c0-4ee8-bb7e-1d2e89d6e0ec \n6 Pourmand A Shay C Redha W Aalam A Mazer-Amirshahi M Cholinergic symptoms and QTc prolongation following donepezil overdose Am J Emerg Med 2017 35 9 1386.e1 1386.e3 DOI: 10.1016/j.ajem.2017.06.044 PubMed PMID: 28668178 \n7 Kitt J Irons R Al-Obaidi M Missouris C A case of donepezil-related torsades de pointes BMJ Case Rep 2015:bcr2015211900 DOI: 10.1136/bcr-2015-211900 PubMed PMID: 26438681 PubMed Central PMCID: PMC4600768 \n8 Shinozaki K Shortening of donepezil-induced QTc prolongation with a change in the interacting drug, after electrocardiograph monitoring by community pharmacists: a case report Yakugaku Zasshi 2012 132 2 237 41 10.1248/yakushi.132.237 22293706 \n9 Takaya T Okamoto M Yodoi K Hata K Kijima Y Nakajima H Torsades de pointes with QT prolongation related to donepezil use J Cardiol 2009 54 3 507 11 DOI: 10.1016/j.jjcc.2009.03.011 PubMed PMID: 19944332 19944332 \n10 Tanaka A Koga S Hiramatsu Y Donepezil-induced adverse side effects of cardiac rhythm: 2 cases report of atrioventricular block and torsade de pointes Intern Med 2009 48 14 1219 23 DOI: 10.2169/internalmedicine.48.2181 PubMed PMID: 19602789 19602789 \n11 Igeta H Suzuki Y Tajiri M Someya T Cardiovascular pharmacodynamics of donepezil hydrochloride on the PR and QT intervals in patients with dementia Hum Psychopharmacol Clin Exp 2014 29 3 292 4 DOI: 10.1002/hup.2398 PubMed PMID: 24615803 \n12 Woosley RL Romero KA CredibleMeds: risk categories for drugs that prolong QT & induce torsades de pointes (TdP) [Internet] Oro Valley (AZ) AZCERT 2013 [updated 2018 May 20; cited 2018 Jun 19]. Available from: https://www.crediblemeds.org/new-drug-list/ \n13 Wenzel-Seifert K Wittmann M Haen E QTc prolongation by psychotropic drugs and the risk of torsade de pointes Dtsch Arztebl Int 2011 108 41 687 93 DOI: 10.3238/arztebl.2011.0687 PubMed PMID: 22114630 PubMed Central PMCID: PMC3221427 22114630 \n14 Hasnain M Vieweg WVR Howland RH Kogut C Breden Crouse EL Koneru JN Quetiapine, QTc interval prolongation, and torsade de pointes: a review of case reports Ther Adv Psychopharmacol 2014 4 3 130 8 DOI: 10.1177/2045125313510194 PubMed PMID: 25057346 PubMed Central PMCID: PMC4107702 25057346 \n15 Ballesteros J Güemes I Ibarra N Quemada JI The effectiveness of donepezil for cognitive rehabilitation after traumatic brain injury: a systematic review J Head Trauma Rehabil 2008 23 3 171 80 DOI: 10.1097/01.HTR.0000319935.99837.96 PubMed PMID: 18520431 18520431 \n16 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 45 10.1038/clpt.1981.154 7249508\n\n",
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"medline_ta": "Ment Health Clin",
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"title": "Donepezil-induced QTc prolongation: A case report.",
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"abstract": "Benign intracranial hypertension due to tetracycline is described in an adolescent female. Complete resolution of the condition occurred when the drug was withdrawn.",
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"authors": "Ohlrich|G D|GD|;Ohlrich|J G|JG|",
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"abstract": "Genital warts in immunocompromised patients can be extensive and recalcitrant to treatment. We report a case of recalcitrant genital warts in a female patient with systemic lupus erythematosus (SLE), who achieved complete remission with a combination approach of surgical debulking and oral isotretinoin at an initial dose of 20 mg/day with a gradual taper of dose over 8 months. She had previously been treated with a combination of topical imiquimod cream and regular fortnightly liquid nitrogen. Although there was partial response, there was no complete clearance. Her condition worsened after topical imiquimod cream was stopped because of her pregnancy. She underwent a combination approach of surgical debulking and oral isotretinoin after her delivery and achieved full clearance for more than 2 years duration. Oral isotretinoin, especially in the treatment of recalcitrant genital warts, is a valuable and feasible option when other more conventional treatment methods have failed or are not possible. It can be used alone or in combination with other local or physical treatment methods.",
"affiliations": "National Skin Centre, Singapore, Singapore.",
"authors": "Yew|Yik Weng|YW|;Pan|Jiun Yit|JY|",
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"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D003131:Combined Modality Therapy; D003218:Condylomata Acuminata; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D015474:Isotretinoin; D008180:Lupus Erythematosus, Systemic; D011247:Pregnancy; D012074:Remission Induction; D013997:Time Factors; D016896:Treatment Outcome",
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"title": "Complete remission of recalcitrant genital warts with a combination approach of surgical debulking and oral isotretinoin in a patient with systemic lupus erythematosus.",
"title_normalized": "complete remission of recalcitrant genital warts with a combination approach of surgical debulking and oral isotretinoin in a patient with systemic lupus erythematosus"
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"abstract": "Stevens-Johnson syndrome (SJS) is serious conditions that happen as a result of infection, side effects to medications, or unknown etiology. Carbamazepine is one of the common medications that can cause SJS. Good history taking is crucial if treatment with carbamazepine is clinically indicated. We would like to alert all physicians that carbamazepine should be avoided in any patient with a previous history of drug reaction such as mast cell activation syndrome.",
"affiliations": "Critical Care Unit Ahmadi Hospital Kuwait Oil Company Ahmadi Kuwait.;Critical Care Unit Ahmadi Hospital Kuwait Oil Company Ahmadi Kuwait.;Critical Care Unit Ahmadi Hospital Kuwait Oil Company Ahmadi Kuwait.;Critical Care Unit Ahmadi Hospital Kuwait Oil Company Ahmadi Kuwait.",
"authors": "Zaalouk|Tamer Mohamed|TM|https://orcid.org/0000-0003-1556-5795;Bitar|Zouheir Ibrahim|ZI|https://orcid.org/0000-0001-8426-8685;Maadarani|Ossama Sajeh|OS|;Elhabibi|Mohamed Elsayed|ME|",
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"doi": "10.1002/ccr3.3509",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3509\nCCR33509\nCase Report\nCase Reports\nCarbamazepine‐induced Stevens‐Johnson syndrome in a patient with history of methotrexate‐induced mast cell activation syndrome\nZAALOUK et al.Zaalouk Tamer Mohamed https://orcid.org/0000-0003-1556-5795\n1\ntzaalouk@hkockw.comforevertn@hotmail.com Bitar Zouheir Ibrahim https://orcid.org/0000-0001-8426-8685\n1\n Maadarani Ossama Sajeh \n1\n Elhabibi Mohamed Elsayed \n1\n \n1 \nCritical Care Unit\nAhmadi Hospital\nKuwait Oil Company\nAhmadi\nKuwait\n\n* Correspondence\n\nTamer Mohamed Zaalouk, Critical Care Unit, Ahamdi Hospital, Kuwait Oil Company, P.O.Box 46468, Postal code 64015, Ahmadi, Kuwait.\n\nEmails: tzaalouk@hkockw.com; forevertn@hotmail.com\n\n11 11 2020 \n1 2021 \n9 1 10.1002/ccr3.v9.1256 259\n06 8 2020 20 10 2020 23 10 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons LtdThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nStevens‐Johnson syndrome (SJS) is serious conditions that happen as a result of infection, side effects to medications, or unknown etiology. Carbamazepine is one of the common medications that can cause SJS. Good history taking is crucial if treatment with carbamazepine is clinically indicated. We would like to alert all physicians that carbamazepine should be avoided in any patient with a previous history of drug reaction such as mast cell activation syndrome.\n\nStevens‐Johnson syndrome (SJS) is serious conditions that happen as a result of infection, side effects to medications, or unknown etiology. Carbamazepine is one of the common medications that can cause SJS. Good history taking is crucial if treatment with carbamazepine is clinically indicated. We would like to alert all physicians that carbamazepine should be avoided in any patient with a previous history of drug reaction such as mast cell activation syndrome.\n\n\n\ncarbamazepinemast cell activation syndromemethotrexateStevens‐Johnson syndrome source-schema-version-number2.0cover-dateJanuary 2021details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:18.01.2021\n\n\nZaalouk \nTM \n, \nBitar \nZI \n, \nMaadarani \nOS \n, \nElhabibi \nME \n. Carbamazepine‐induced Stevens‐Johnson syndrome in a patient with history of methotrexate‐induced mast cell activation syndrome\n. Clin Case Rep .2021 ;9 :256 –259\n. 10.1002/ccr3.3509 \n\n\n\n\nFunding informationThe authors received no financial support for the research, authorship, and/or publication of this article. This research was performed as part of the authors duties in Kuwait Oil Company, Kuwait.\n==== Body\n1 CASE REPORT\nA 42‐year‐old woman was presented to the hospital with history of methotrexate‐induced pruritus and severe skin reaction. She had ectopic pregnancy 2 years ago and was treated with methotrexate after which she developed severe stomatitis, leucopenia, and severe inflammation of urinary bladder, diagnosed as mast cell activation syndrome at that time. Recently, she was admitted to the critical care unit as a case of SJS with fever, generalized macular rash, buccal ulceration, and burning sensation in her eyes. Further history revealed that she started treatment with carbamazepine 2 weeks before admission treating trigeminal neuralgia. The medical history was otherwise unremarkable. On physical examination, there are several flaccid and ruptured bullae on the Rt hand, back, and legs, and generalized maculopapular rash with target lesions all over the body in centrifugal distribution (Figures 1 and 2). Total area of skin involvement was <10%. Nikolsky's sign was positive (Figure 3). There are erythema and painful erosions on both lips (Figure 4). Patient complain of odynophagia but able to swallow some liquids with involvement of genital mucosa.\n\nFIGURE 1 Generalised maculopapular rash on both hands\n\nFIGURE 2 Generalised maculopapular rash with target lesions on lower limbs\n\nFIGURE 3 Nikolsky's sign\n\nFIGURE 4 Erythema and erosion on both lips\n\nLaboratory investigations showed mild leukopenia, no eosinophilia, and thrombocytopenia with mildly elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), and C‐reactive protein (CRP). No symptoms or signs of infection were found with negative blood, urine, and sputum cultures. No skin biopsy was taken.\n\nPatient was admitted to the critical care unit, and carbamazepine was discontinued immediately; patient received intravenous fluid maintaining positive balance, nutritional support, eye care, and wound care.\n\nSteroid treatment was given for 5 days in the form of 40 milligram methyl prednisolone daily. On the 10th day, patient was discharged.\n\n\nLaboratory results\n\n\n\nBlood test results\t\nWBCs (white blood counts) = 3600\t\nHB (hemoglobin) = 13.4 g\t\nPlatelets = 103 000\t\nUrea = 15 mg/dL\t\nCreatinine = 1 mg/dL\t\nALT = 61.9 U/L\t\nAST = 55.1 U/L\t\nGGT = 109 U/L\t\nCRP = 47.3 mg/L\t\n\n\n\n2 DISCUSSION\nStevens‐Johnson syndrome (SJS) is a severe mucocutaneous reaction, most commonly triggered by medications and infection, and in 1 of 3 cases, no cause was identified. There are extensive necrosis and detachment of the epidermis.\n1\n\n\n\nMucous membranes are usually affected in more than 90% of cases. Both SJS and TEN are distinguished chiefly by severity, based upon the percentage of blisters and erosions.\n2\n, \n3\n\n\n\nMedications are main trigger of SJS, especially allopurinol and antiepileptic medications.\n4\n, \n5\n\n\n\nThe pathology of Stevens‐Johnson syndrome is incompletely understood. Studies suggested a cell‐mediated reaction against keratinocytes leading to necrosis.\n6\n\n\n\nDrugs can stimulate the immune system by binding to the major histocompatibility complex (MHC) class I and the T‐cell receptor. The hallmark of SJS is the keratinocyte necrosis, ranging from partial‐ to full‐thickness necrosis of the epidermis.\n7\n, \n8\n\n\n\nFor patients with suspected drug‐induced SJS, withdrawal of the offending agent may improve the prognosis. In one observational study of 113 patients with SJS, early drug withdrawal reduced the risk of death by 30 percent for each day before the development of blisters and erosions.\n9\n\n\n\nThe main lines of management include fluid and electrolyte management, wound care, nutritional support, pain control, temperature management, and treatment of infections.\n10\n, \n11\n\n\n\nThere are no definitive therapies for SJS.\n12\n, \n13\n Several immunosuppressive or immunomodulating therapies have been used in clinical practice, including systemic corticosteroids, intravenous immune globulin (IVIG), cyclosporine, plasmapheresis, and antitumor necrosis factor (TNF) monoclonal antibodies.\n\nNone of these therapies have been adequately studied in randomized trials except thalidomide, which was found to be harmful.\n14\n\n\n\nThe use of systemic corticosteroids in patients with SJS has not been evaluated in clinical trials and remains controversial.\n15\n\n\n\nAnother immunologically medicated disorders is mast cell activation syndrome (MCAS), which is one of mast cell disorders present with signs and symptoms that are caused either by activation of mast cells or by mast cells infiltrating organs.\n16\n\n\n\nMast cell activation syndrome (MCAS) was first proposed as a distinct idiopathic disorder in 2010.\n17\n Subsequently, the definition of MCAS expanded to also include primary and secondary categories, making \"mast cell activation syndrome\" essentially an umbrella term that describes a clinical presentation, rather than a specific diagnosis.\n18\n\n\n\nIn our case, the patient was diagnosed earlier with mast cell activation syndrome with pruritus and severe skin reaction; 2 years later, the patient was prescribed carbamazepine treating trigeminal neuralgia; the history of drug‐induced immunologically mediated mast cell activation with skin pruritus was missed; and patient developed severe form of SJS Good history taking is crucial if treatment with carbamazepine is clinically indicated. We would like to alert all physicians that carbamazepine should be avoided in any patient with a previous history of drug reaction such as mast cell activation syndrome.\n\n3 CONCLUSION\nStevens‐Johnson syndrome (SJS) is very serious skin condition. Carbamazepine is one of the common medications that can cause (SJS). Good history taking is crucial if treatment with carbamazepine is clinically indicated. Physicians should be alert to avoid carbamazepine in any patient with a previous history of drug reaction such as mast cell activation syndrome.\n\nCONFLICT OF INTEREST\nThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nAUTHOR CONTRIBUTIONS\nTZ: wrote the article. ZIB and OSM: shared in the discussion. MA: collected data and revised the manuscript. All authors reviewed the final draft of the manuscript and approved its submission.\n\nCONSENT\nInformed consent was obtained from the patient for the publication of this clinical image.\n==== Refs\nREFERENCES\n1 \n\nStern \nRS \n, \nDivito \nSJ \n. Stevens‐Johnson syndrome and toxic epidermal necrolysis: associations, outcomes, and pathobiology‐thirty years of progress but still much to be done\n. J Invest Dermatol . 2017 ;137 :1004 .28411832 \n2 \n\nBastuji‐Garin \nS \n, \nRzany \nB \n, \nStern \nRS \n, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens‐Johnson syndrome, and erythema multiforme\n. Arch Dermatol . 1993 ;129 :92 .8420497 \n3 \n\nRoujeau \nJC \n. Stevens‐Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme\n. J Dermatol . 1997 ;24 :726 .9433029 \n4 \n\nWetter \nDA \n, \nCamilleri \nMJ \n. Clinical, etiologic, and histopathologic features of Stevens‐Johnson syndrome during an 8‐year period at Mayo Clinic\n. Mayo Clin Proc . 2010 ;85 :131 .20118388 \n5 \n\nKhalaf \nD \n, \nToema \nB \n, \nDabbour \nN \n, \nJehani \nF \n. Toxic epidermal necrolysis associated with severe cytomegalovirus infection in a patient on regular hemodialysis\n. Mediterr J Hematol Infect Dis . 2011 ;3 :e2011004.21625308 \n6 \n\nCorreia \nO \n, \nDelgado \nL \n, \nRamos \nJP \n, et al. Cutaneous T‐cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement\n. Arch Dermatol . 1993 ;129 (4 ):466 .8466217 \n7 \n\nKo \nTM \n, \nChung \nWH \n, \nWei \nCY \n, et al. Shared and restricted T‐cell receptor use is crucial for carbamazepine‐induced Stevens‐Johnson syndrome\n. J Allergy Clin Immunol . 2011 ;128 :1266 .21924464 \n8 \n\nRzany \nB \n, \nHering \nO \n, \nMockenhaupt \nM \n, et al. Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, Stevens‐Johnson syndrome and toxic epidermal necrolysis\n. Br J Dermatol . 1996 ;135 :6 .\n9 \n\nNaegele \nD \n, \nSekula \nP \n, \nPaulmann \nM \n, \nMockenhaupt \nM \n. Incidence of Stevens‐Johnson syndrome/toxic epidermal necrolysis: results of 10 years from the German Registry\n. Pharmacoepidemiol Drug Saf . 2017 ;26 (Supp 2 ):3 .28547787 \n10 \n\nSekula \nP \n, \nDunant \nA \n, \nMockenhaupt \nM \n, et al. Comprehensive survival analysis of a cohort of patients with Stevens‐Johnson syndrome and toxic epidermal necrolysis\n. J Invest Dermatol . 2013 ;133 :1197 .23389396 \n11 \n\nMittmann \nN \n, \nKnowles \nSR \n, \nKoo \nM \n, et al. Incidence of toxic epidermal necrolysis and Stevens‐Johnson Syndrome in an HIV cohort: an observational, retrospective case series study\n. Am J Clin Dermatol . 2012 ;13 :49 .22145749 \n12 \n\nValeyrie‐Allanore \nL \n, \nPoulalhon \nN \n, \nFagot \nJP \n, et al. Stevens‐Johnson syndrome and toxic epidermal necrolysis induced by amifostine during head and neck radiotherapy\n. Radiother Oncol . 2008 ;87 :300 .18328585 \n13 \n\nWolkenstein \nP \n, \nCarrière \nV \n, \nCharue \nD \n, et al. A slow acetylator genotype is a risk factor for sulphonamide‐induced toxic epidermal necrolysis and Stevens‐Johnson syndrome\n. Pharmacogenetics . 1995 ;5 :255 .8528274 \n14 \n\nSlatore \nCG \n, \nTilles \nSA \n. Sulfonamide hypersensitivity\n. Immunol Allergy Clin North Am . 2004 ;24 :477 .15242722 \n15 \n\nRotunda \nA \n, \nHirsch \nRJ \n, \nScheinfeld \nN \n, \nWeinberg \nJM \n. Severe cutaneous reactions associated with the use of human immunodeficiency virus medications\n. Acta Derm Venereol . 2003 ;83 :1 .12636014 \n16 \n\nTheoharides \nTC \n, \nValent \nP \n, \nAkin \nC \n. Mast cells, mastocytosis, and related disorders\n. N Engl J Med . 2015 ;373 :163 .26154789 \n17 \n\nAkin \nC \n, \nValent \nP \n, \nMetcalfe \nDD \n. Mast cell activation syndrome: Proposed diagnostic criteria\n. J Allergy Clin Immunol . 2010 ;126 :1099 .21035176 \n18 \n\nValent \nP \n, \nAkin \nC \n, \nArock \nM \n, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal\n. Int Arch Allergy Immunol . 2012 ;157 :215 .22041891\n\n",
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"issue": "9(1)",
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"keywords": "Stevens‐Johnson syndrome; carbamazepine; mast cell activation syndrome; methotrexate",
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"title": "Carbamazepine-induced Stevens-Johnson syndrome in a patient with history of methotrexate-induced mast cell activation syndrome.",
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"abstract": "Optimum dose, route and duration of use of prophylactic magnesium sulphate in women with severe pre-eclampsia is still controversial. We compared the efficacy and safety of 'low-dose Dhaka' regime with 'Loading dose only' regime for seizure prophylaxis in severe preeclampsia using a randomised controlled trial in 402 women. The incidence of eclampsia in the 'low-dose Dhaka' regime group was 1.49% and that in the 'Loading dose only regime' was 2.98% (p = .321). In the low-dose Dhaka regime, injection site abscess and respiratory depression occurred in one woman each. Neonatal outcomes such as Apgar score at 5 minutes (5.0% vs. 8.05% p = .251) and perinatal mortality (20.4% vs. 21.9%, p = .724) were similar in both groups. Loading dose only regime may be considered an effective alternative regime for the prevention of eclampsia in women with severe preeclampsia. Impact statement What is already known on this subject: Efficacy of therapeutic short regime magnesium sulphate in eclampsia has already been reported. Data regarding prophylactic short regime in women with preeclampsia is sparse. What the results of this study add: We have shown that short regime of magnesium sulphate using only the loading dose in the prevention of seizure in preeclampsia is an effective alternative to the low-dose Dhaka regime. What the implications are of these findings for clinical practice and/or further research: The short regime is less resource-intensive. Further larger studies are needed to confirm the efficacy of this short regime and to establish its cost-effectiveness.",
"affiliations": "a Department of Obstetrics and Gynecology , Jawaharlal Institute of Post-graduate Medical Education and Research , Puducherry , India.;a Department of Obstetrics and Gynecology , Jawaharlal Institute of Post-graduate Medical Education and Research , Puducherry , India.;a Department of Obstetrics and Gynecology , Jawaharlal Institute of Post-graduate Medical Education and Research , Puducherry , India.;a Department of Obstetrics and Gynecology , Jawaharlal Institute of Post-graduate Medical Education and Research , Puducherry , India.;a Department of Obstetrics and Gynecology , Jawaharlal Institute of Post-graduate Medical Education and Research , Puducherry , India.;a Department of Obstetrics and Gynecology , Jawaharlal Institute of Post-graduate Medical Education and Research , Puducherry , India.",
"authors": "Keepanasseril|Anish|A|;Maurya|Dilip Kumar|DK|;Manikandan|K|K|;Suriya J|Yavana|Y|;Habeebullah|Syed|S|;Raghavan|S Soundara|SS|",
"chemical_list": "D008278:Magnesium Sulfate",
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"keywords": "Dhaka regime; loading dose only regime; magnesium sulphate; maternal medicine; severe preeclampsia",
"medline_ta": "J Obstet Gynaecol",
"mesh_terms": "D000328:Adult; D001034:Apgar Score; D001724:Birth Weight; D004305:Dose-Response Relationship, Drug; D004461:Eclampsia; D005260:Female; D006801:Humans; D007194:India; D007231:Infant, Newborn; D007751:Labor, Induced; D008278:Magnesium Sulfate; D066087:Perinatal Death; D011225:Pre-Eclampsia; D011247:Pregnancy; D011256:Pregnancy Outcome; D050497:Stillbirth",
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"pages": "305-309",
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"references": null,
"title": "Prophylactic magnesium sulphate in prevention of eclampsia in women with severe preeclampsia: randomised controlled trial (PIPES trial).",
"title_normalized": "prophylactic magnesium sulphate in prevention of eclampsia in women with severe preeclampsia randomised controlled trial pipes trial"
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"abstract": "Acquired hemophilia A (AHA) is a rare hemorrhagic disorder caused by the production of autoantibodies against coagulation factor VIII (FVIII). AHA is associated with significant morbidity and mortality primarily as a result of bleeding. Although many disorders are associated with the development of these inhibitors, up to 50% of cases remain idiopathic. The approach to therapy involves an initial strategy often to control acute bleeding episodes followed by definitive treatment to eradicate the inhibitor with immunosuppressive agents. We present the case of a 63-year-old Caucasian male hospitalized for severe Covid-19 who developed bleeding due to an acquired FVIII inhibitor that had never been treated definitively. Our case presentation focuses on in-hospital management of this patient's acute bleeding episodes with by-passing agents and recombinant porcine factor VIII.",
"affiliations": "Internal Medicine Residency Program, Baton Rouge General, Baton Rouge, USA.;Internal Medicine, Baton Rouge General, Baton Rouge, USA.;Internal Medicine Residency Program, Baton Rouge General, Baton Rouge, USA.",
"authors": "Miatech|Jennifer L|JL|;Kantamani|Deepti|D|;Stagg|M Patrick|MP|",
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"doi": "10.7759/cureus.19145",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.19145\nInternal Medicine\nHematology\nManagement of Acquired Factor VIII Inhibitors With NovoSeven and Obizur\nMuacevic Alexander\nAdler John R\nMiatech Jennifer L 1\nKantamani Deepti 2\nStagg M. Patrick 1\n1 Internal Medicine Residency Program, Baton Rouge General, Baton Rouge, USA\n2 Internal Medicine, Baton Rouge General, Baton Rouge, USA\nJennifer L. Miatech jennifer.miatech@brgeneral.org\n30 10 2021\n10 2021\n13 10 e1914529 10 2021\nCopyright © 2021, Miatech et al.\n2021\nMiatech 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/74179-management-of-acquired-factor-viii-inhibitors-with-novoseven-and-obizur\nAcquired hemophilia A (AHA) is a rare hemorrhagic disorder caused by the production of autoantibodies against coagulation factor VIII (FVIII). AHA is associated with significant morbidity and mortality primarily as a result of bleeding. Although many disorders are associated with the development of these inhibitors, up to 50% of cases remain idiopathic. The approach to therapy involves an initial strategy often to control acute bleeding episodes followed by definitive treatment to eradicate the inhibitor with immunosuppressive agents. We present the case of a 63-year-old Caucasian male hospitalized for severe Covid-19 who developed bleeding due to an acquired FVIII inhibitor that had never been treated definitively. Our case presentation focuses on in-hospital management of this patient's acute bleeding episodes with by-passing agents and recombinant porcine factor VIII.\n\ncoagulation inhibitor\nsurgical management of obstetrical hemorrhage\nfactor viii\nfactor viii inhibitor bypassing agents (feiba)\nacquired hemophilia a (aha)\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\npmcIntroduction\n\nAcquired factor VIII (FVIII) inhibitors are antibodies of different IgG subclasses directed against epitopes on coagulation factor VIII molecules. The disorder, also known as acquired hemophilia A (AHA), causes significant morbidity and mortality, with severe bleeding in up to 90% of cases. Alloantibodies to FVIII develop in approximately 20-40% of hemophilia patients who receive frequent FVIII replacement. In the non-hemophiliac population, this disorder is rare with an estimated incidence of 1 to 4 per million/year [1]. FVIII autoantibodies may be associated with the postpartum period, autoimmune diseases, malignancies, infections, or medications, such as penicillin and sulfa antibiotics. Although it may be associated with several underlying pathologies, up to 50% of reported cases remain idiopathic [1, 2].\n\nAHA-associated bleeding can range from mild ecchymosis to life-threatening bleeding. By-passing agents and recombinant porcine FVIII are established treatment modalities to achieve hemostasis. Currently, no randomized studies are available comparing the efficacy between these agents, and decision-making is often dependent upon clinical judgment and product availability. We present the case of a 63-year-old male hospitalized for severe Covid-19 who developed bleeding because of an acquired FVIII inhibitor that had never been treated definitively. The patient achieved hemostatic control with recombinant porcine factor VIII (susoctocog alfa [e.g. Obizur]) after initial management with recombinant factor VIIa (e.g. NovoSeven) did not completely control his bleeding. This case highlights clinical management of AHA-related bleeding outside of an institution with the robust resources of a hemophilia center.\n\nCase presentation\n\nA 63-year-old Caucasian male with a medical history of type 2 diabetes, temporary tracheostomy placement after West Nile infection in 2012, provoked deep vein thrombosis after debility from West Nile infection, and an idiopathic factor VIII inhibitor was admitted for severe Covid-19 viral pneumonia in January 2021. He was initially diagnosed with an acquired FVIII inhibitor in July 2016 after bruising and extremity swelling following minor arm trauma. Laboratory studies at that time revealed a white blood count of 12 K/uL with a normal differential, hemoglobin of 11.3 g/dL, and platelets of 333 K/uL. Coagulation studies revealed a prothrombin time (PT) of 13.9 sec, a partial thromboplastin time (PTT) of 62 sec, an international normalized ratio (INR) of 1.07, and a thrombin time of 15.4 seconds. A mixing study revealed the presence of inhibitors. Factor VIII activity level was <1%, with an inhibitor level of 200 Bethesda units. Lupus anticoagulant was negative. Factor IX, XI, XII, XIII, and von Willebrand factor activities were normal. Rheumatologic serologic testing was negative, as were Hepatitis B and C. The patient was first treated with steroids, but declined a plan to initiate eradication therapy with cyclophosphamide or rituximab due to cost.\n\nHis next presentation was in May 2018 with excessive bleeding and significant edema of the posterior compartment of his calf after a ground level fall. He received two units of packed red blood cells for a hemoglobin of 7.5 g/dL. His PTT was prolonged at 50 sec. His bleeding resolved with factor VIII inhibitor by-passing activity (FEIBA) 50 units/kg. Unfortunately, he never followed up to pursue eradication therapy.\n\nDuring this admission in January 2021 for Covid-19, he developed worsening hypoxemia requiring mechanical ventilation and central venous catheter placement. His admission hemoglobin was 12.5 g/dL, platelets were 313 K/uL, and PTT was 81 sec with an INR of 1.1. Routine prophylactic anticoagulation was held on admission due to a prolonged PTT. His oxygenation continued to worsen, prompting concern for possible pulmonary embolism. Further evaluation with computed tomography angiography was deemed unsafe as the patient was clinically unstable for transfer to the radiology department. Therapeutic enoxaparin was provided empirically. Following administration of empiric anticoagulation, he developed excessive oozing from his central venous access site with subsequent hematoma formation. The hematology service was consulted and abruptly discontinued enoxaparin. He achieved adequate hemostasis without further intervention.\n\nThe patient then required a repeat central venous catheter placement two weeks later, for which he received a one-time dose of prophylactic and post-procedure recombinant human factor VIIa (NovoSeven) at 90 mcg/kg. FEIBA was not available at our institution. Seven days later, the patient required a tracheostomy and percutaneous endoscopic gastrostomy tube placement. He received two doses of NovoSeven at 90 mcg/kg perioperatively along with one unit of packed red blood cells with only minor bleeding. Post-operatively he developed continuous oozing from his tracheostomy site raising concerns for possible airway compromise, for which he received Novoseven every 2 hours. Recombinant porcine factor VIII (susoctocog alfa [e.g. Obizur]) administration was considered, unfortunately, was not available at our institution, and delivery was delayed due to severe weather conditions. He continued to have oozing despite NovoSeven. Obizur became available two days later and he received a dose of 9,000 units (100 units/kg) with rapid resolution of his bleeding. Ten days later his oozing from the tracheostomy site recurred, and two additional doses of 9000 units of Obizur were given 48 hours apart with successful cessation of bleeding. He did not have any further bleeding episodes and was transferred to a long-term acute care facility for mechanical ventilation weaning.\n\nDiscussion\n\nThe development of acquired FVIII inhibitors, otherwise known as acquired hemophilia A, is rare. The most common clinical scenario for their development is in hemophilia patients who receive frequent FVIII replacement. The estimated incidence is 1 to 4 million/year in the non-hemophilic population. These autoantibodies produce significant morbidity in the form of bleeding in up to 90% of cases and a mortality rate of 8% to 22% [1,2]. FVIII autoantibodies are associated with the postpartum period, autoimmune disease, malignancy, infection, and medications, although 50% of cases are idiopathic. Autoantibody detection is typically biphasic with a small peak between 20-30 years due to postpartum inhibitors, with the more prominent peak in patients between 60-80 years [2]. The clinical presentation of patients with acquired hemophilia differs from those with hereditary hemophilia A as hemorrhage into the skin, soft tissues, muscle, or mucous membranes (such as gastrointestinal and urological) frequently occurs, whereas hemarthrosis is uncommon.\n\nThe diagnosis of AHA is often based on the initial detection of an isolated prolongation of activated partial thromboplastin time, which cannot be corrected by normal plasma (mixing study), and subsequent identification of a reduced FVIII level with evidence of FVIII inhibitor activity (titrated using the Bethesda assay or its Nijmegen modification). The treatment priorities are first to arrest any acute bleeding then eradicate the factor VIII autoantibody with immunosuppressive agents. Spontaneous resolution of inhibitors has been reported in up to a third of cases, however, this is more commonly observed in pregnancy or drug-related AHA. Prednisolone at 1 mg/kg/day results in inhibitor eradication in approximately 30% of patients, with the addition of cyclophosphamide increasing the response rate to 60-70% [1]. Other agents can be used to achieve eradication including azathioprine, vincristine, mycophenolate mofetil, and rituximab. Immune tolerance induction protocols, similar to the ones used for the treatment of alloantibodies in congenital hemophilia, have also been proposed for the eradication of FVIII autoantibodies. These protocols demonstrated inhibitor eradication in 90% of patients [3]. The choice of the most appropriate therapeutic strategy will depend on the size and severity of the bleeding and the inhibitor titer. Treatment options for bleeding include desmopressin (DDAVP), factor VIII concentrates, by-passing agents such as recombinant human factor VIIa (rFVIIa; e.g., NovoSeven) and activated prothrombin complex concentrates (aPCC; e.g., factor eight inhibitor by-passing activity [FEIBA]), and recombinant porcine sequence factor VIII concentrate (e.g., susoctocog alfa [Obizur]).\n\nNon-life-threatening bleeding and low inhibitor titers (e.g. <5 Bethesda units) can occasionally be managed with DDAVP. Replacement with factor VIII concentrates is often unable to overcome the inhibitor burden completely. In patients with life-threatening bleeding or high-titers, two strategies are available to achieve hemostatic control of acute bleeding, including the use of by-passing agents or therapies to raise the level of circulating FVIII. In current clinical practice, by-passing agents are the most utilized first-line treatment with activated prothrombin complex concentrates or rFVIIa. FEIBA, currently the only approved aPCC in the United States for AHA, is a plasma-derived concentrate consisting of activated factor VII and non-activated factors II, IX, and X. RFVIIa contains only recombinant activated factor VII. Both agents are considered safe with similar efficacy of >80%, rFVIIa is often preferred among clinicians due to its viral safety [4-6]. FEIBA is a vapour-heated plasma-derived coagulation factor concentrate with the potential for viral transmission, although no cases of human immunodeficiency virus or hepatitis transmission have been reported in the literature. Concerns surrounding the possibility of trace amounts of FVIII in FEIBA producing an anamnestic response have not been definitively answered [7]. FEIBA and rFVIIa control bleeding by promoting thrombin generation in all plasmas except those deficient in Factor V [8]. These by-passing agents have been associated with thromboembolic complications, although rare and mostly seen after large and repeated doses exceeding the recommended doses [9]. The FENOC study, a randomized comparison of FEIBA and NovoSeven, found similar hemostatic efficacy between the products. It is important to note that patients who received both, approximately a third of patients demonstrated better efficacy with one product over the other [4]. Therefore, it is essential to individualize by-pass therapy for clinical management.\n\nThe limitations of by-passing agents are the lack of routine clinical monitoring and the risk of thrombotic complications, which has led to the development of alternative factor VIII concentrates. Porcine factor VIII (pFVIII) was studied and thought to be less inactivated by FVIII inhibitors. A porcine plasma-derived pFVIII (Hayate:C) was removed from the market in 2004 due to viral safety and hypersensitivity reaction concerns [10]. A safe recombinant porcine factor VIII product known as Obizur was designed to lack the B domain subsequently, decreasing FVIII antibody formation. Obizur achieves hemostasis through the binding of human von Willebrand factor and becomes activated by thrombin to achieve hemostasis. Unlike by-passing agents, Obizur replaces the missing coagulation protein and enables measurement of FVIII activity using available standard FVIII assays, thereby, guiding dosing and enhancing treatment efficacy and safety.\n\nClinical trial data evaluating the efficacy of Obizur reported 86% success of achieving hemostatic control [11]. The authors also found a higher rate of treatment success among subjects receiving Obizur as ‘first-line’ therapy compared to subjects treated with another hemostatic agent prior to treatment. No serious adverse events with Obizur were reported in this trial. A limitation to the study was the highly variable dosing. Fosbury et al. reported that the response to treatment is unique to each patient and may be influenced by the presence and development of anti-pFVIII antibodies.\n\nTreatment delays can result in potential harm if clinically significant bleeding is not managed urgently. Current efficacy and safety data do not appear to favor by-passing agents or recombinant porcine FVIII. In clinical practice, front-line management is often determined by product availability and institutional laboratory testing. Monitoring of FVIII activity and quantifying rpVIII antibodies is possible with Obizur, although often not feasible at all institutions during acute management. We managed this patient clinically as laboratory measurements were not readily available and he did not demonstrate life-threatening bleeding. The patient developed minor bleeding episodes during his hospitalization that was initially managed successfully with rVIIa, and when bleeding continued he received Obizur without further bleeding or complications.\n\nConclusions\n\nThis case highlights the management of AHA-related bleeding clinically at an institution without the robust resources of a hemophilia center. Individual institutional approaches will vary based upon product availability and laboratory capabilities. Treatment should be started with an agent that is immediately available. A clear consensus on the management of this disorder has not yet been established. Contacting a hemophilia center can be beneficial for successful management. It is possible to successfully manage acute AHA bleeding clinically. Further studies are needed to address the assessment and management of these patients.\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 Acquired factor VIII inhibitors: pathophysiology and treatment Hematology Am Soc Hematol Educ Program Ma AD Carrizosa D 432 437 2006 2006\n2 Acquired hemophilia A: a concise review Am J Hematol Franchini M Gandini G Di Paolantonio T Mariani G 55 63 80 2005 16138334\n3 Acquired hemophilia A: a review of recent data and new therapeutic options Hematology Franchini M Vaglio S Marano G Mengoli C Gentili S Pupella S Liumbruno GM 514 520 22 2017 28441921\n4 A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study Blood Astermark J Donfield SM DiMichele DM Gringeri A Gilbert SA Waters J Berntorp E 546 551 109 2007 16990605\n5 Factor eight inhibitor bypass activity (FEIBA) in the management of bleeds in hemophilia patients with high-titer inhibitors Vasc Health Risk Manag Tjønnfjord GE Holme PA 527 531 2007 2007 https://www.dovepress.com/articles.php?article_id=1498\n6 Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry Blood Baudo F Collins P Huth-Kühne A 39 46 120 2012 22618709\n7 Long-term FEIBA prophylaxis does not prevent progression of existing joint disease Haemophilia Hilgartner MW Makipernaa A Dimichele DM 261 268 9 2003 12694515\n8 FEIBA: mode of action Haemophilia Turecek PL Váradi K Gritsch H Schwarz HP 3 9 10 2004 15385040\n9 Safety of factor VIII inhibitor bypass activity (FEIBA): 10-year compilation of thrombotic adverse events Haemophilia Ehrlich HJ Henzl MJ Gomperts ED 83 90 8 2002 11952842\n10 Review of recombinant anti-haemophilic porcine sequence factor VIII in adults with acquired haemophilia A Ther Adv Hematol Fosbury E Drebes A Riddell A Chowdary P 263 272 8 2017 29051804\n11 Efficacy and safety of OBI-1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A Haemophilia Kruse-Jarres R St-Louis J Greist A 162 170 21 2015 25623166\n\n",
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"issue": "13(10)",
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"title": "Management of Acquired Factor VIII Inhibitors With NovoSeven and Obizur.",
"title_normalized": "management of acquired factor viii inhibitors with novoseven and obizur"
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{
"abstract": "Disease relapse is the most common cause of treatment failure after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes, yet treatment options for such patients remain extremely limited. Azacitidine is an important new therapy in high-risk myelodysplastic syndromes and acute myeloid leukemia but its role in patients who relapse post allograft has not been defined. We studied the tolerability and activity of azacitidine in 181 patients who relapsed after an allograft for acute myeloid leukemia (n=116) or myelodysplastic syndromes (n=65). Sixty-nine patients received additional donor lymphocyte infusions. Forty-six of 157 (25%) assessable patients responded to azacitidine therapy: 24 (15%) achieved a complete remission and 22 a partial remission. Response rates were higher in patients transplanted in complete remission (P=0.04) and those transplanted for myelodysplastic syndromes (P=0.023). In patients who achieved a complete remission, the 2-year overall survival was 48% versus 12% for the whole population. Overall survival was determined by time to relapse post transplant more than six months (P=0.001) and percentage of blasts in the bone marrow at time of relapse (P=0.01). The concurrent administration of donor lymphocyte infusion did not improve either response rates or overall survival in patients treated with azacitidine. An azacitidine relapse prognostic score was developed which predicted 2-year overall survival ranging from 3%-37% (P=0.00001). We conclude that azacitidine represents an important new therapy in selected patients with acute myeloid leukemia/myelodysplastic syndromes who relapse after allogeneic stem cell transplantation. Prospective studies to confirm optimal treatment options in this challenging patient population are required.",
"affiliations": "Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, UK charles.craddock@uhb.nhs.uk.;Faculté de Médecine Saint Antoine Hospital, Paris, France.;Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, France.;Freiburg University Medical Centre, Germany.;Centre Hospitalier et Universitaire, Nantes, France.;Institut de Cancerologie Gustave Roussy, Villejuif, France.;Division of Hematology, Institut Gustav Roussy, Villejuif, France.;Department of Hematology, National University Hospital, Rigshospitalet, Copenhagen, Denmark.;Hematology Department, Paoli Calmettes Institute, Marseille, France.;Department Medicine V, University of Heidelberg, Germany.;Department I of University Medicine, University of Cologne, Germany.;Department of Bone Marrow Transplantation, University Hospital of Hamburg-Eppendorf, Hamburg, Germany.;Chaim Sheba, Medical Centre, Tel Hasomer, Israel.;Faculté de Médecine Saint Antoine Hospital, Paris, France.",
"authors": "Craddock|Charles|C|;Labopin|Myriam|M|;Robin|Marie|M|;Finke|Juergen|J|;Chevallier|Patrice|P|;Yakoub-Agha|Ibrahim|I|;Bourhis|Jean Henri|JH|;Sengelov|Henrik|H|;Blaise|Didier|D|;Luft|Thomas|T|;Hallek|Michael|M|;Kröger|Nicolaus|N|;Nagler|Arnon|A|;Mohty|Mohamad|M|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.2015.140996",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6078",
"issue": "101(7)",
"journal": "Haematologica",
"keywords": null,
"medline_ta": "Haematologica",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009190:Myelodysplastic Syndromes; D011379:Prognosis; D012008:Recurrence; D016879:Salvage Therapy; D016019:Survival Analysis; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "0417435",
"other_id": null,
"pages": "879-83",
"pmc": null,
"pmid": "27081178",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22234690;22493216;23918951;21886171;19230772;17962510;24488048;25540937;22952334;20385793;19959106;23292243;12933558;20530795;25085359;23314834;22167752;19951968;20026804;19896087;14673054;23223186;23519388;17909197",
"title": "Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia.",
"title_normalized": "clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia"
} | [
{
"companynumb": "GB-CELGENEUS-GBR-2014114975",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "Hypophosphatemia is a relatively frequent and a potentially serious adverse drug effect. Clinically it is characterized by bone pain and muscle weakness. There are several mechanisms by which a drug can induce hypophosphatemia and they can be classified according to whether or not they are mediated by an excess of Fibroblast Growth Factor 23 (FGF23). We report two patients with the condition: (i) A 49-year-old woman with Chronic Myeloid Leukemia (CML) and gastric sleeve surgery at 46 years of age. After receiving intravenous carboxymaltose iron in one occasion due to refractory anemia, she developed symptomatic hypophosphatemia. Urinary phosphate losses associated with high FGF23 levels were confirmed. Plasma phosphate returned to normal values 90 days after the iron administration. (ii) A 40-year-old man with a history of CML in whom imatinib was started. He developed symptomatic hypophosphatemia due to non FGF23-mediated hyperphosphaturia. As treatment with imatinib could not be interrupted, hypophosphatemia and its symptoms resolved with oral phosphate intake. These cases illustrate the importance of recognizing and treating drug-induced hypophosphatemia in a timely manner, and thus avoid the morbidity associated with this entity.",
"affiliations": "Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.;Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.;Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.;Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.;Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.;Sección de Nefrología, Hospital Clínico Universidad de Chile, Santiago, Chile.;Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.;Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.",
"authors": "Ivanovic-Zuvic|Danisa|D|;Fischman|Alexandra|A|;Jiménez|Macarena|M|;Martínez|Alejandra|A|;Ernst|Daniel|D|;Toro|Luis|L|;Guarda|Francisco J|FJ|;Florenzano|Pablo|P|",
"chemical_list": "C000717427:FGF23 protein, human; D010710:Phosphates; D000089703:Fibroblast Growth Factor-23; D000068877:Imatinib Mesylate; D007501:Iron",
"country": "Chile",
"delete": false,
"doi": "10.4067/S0034-98872020000300404",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0034-9887",
"issue": "148(3)",
"journal": "Revista medica de Chile",
"keywords": null,
"medline_ta": "Rev Med Chil",
"mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D005260:Female; D000089703:Fibroblast Growth Factor-23; D006801:Humans; D017674:Hypophosphatemia; D000068877:Imatinib Mesylate; D007501:Iron; D008297:Male; D008875:Middle Aged; D010710:Phosphates",
"nlm_unique_id": "0404312",
"other_id": null,
"pages": "404-408",
"pmc": null,
"pmid": "32730387",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypophosphatemia induced by carboxymaltose iron and imatinib. Report of two cases.",
"title_normalized": "hypophosphatemia induced by carboxymaltose iron and imatinib report of two cases"
} | [
{
"companynumb": "CL-DRREDDYS-USA/CHI/20/0128785",
"fulfillexpeditecriteria": "1",
"occurcountry": "CL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": ... |
{
"abstract": "Imatinib mesylate is an inhibitor of the tyrosine kinase Bcr-Abl and a first-line treatment for Philadelphia chromosome-positive chronic myeloid leukaemia (CML). Dermatological side effects include superficial oedema, pustular eruption, lichenoid reactions, erythroderma, and skin rash. Depigmentation of the skin and/or mucosa is uncommon, and hyperpigmentation is rare.\nWe present the case of a 63-year-old Caucasian male with widespread hyperpigmentation of the hard palate associated with a 9-year history of imatinib therapy to treat CML. He did not complain of any symptoms. Clinical examination did not reveal any abnormal pigmentation of the skin or other region of the oral mucosa. He did not smoke cigarettes or drink alcohol. His medication regimen was a proton pump inhibitor, a beta-blocker, cardioaspirin, atorvastatin, and imatinib 400 mg/day. Histopathologically, melanin and haemosiderin deposits were evident in the lamina propria. The lesion persisted, with no clinical change, through several follow-ups. We reviewed the literature to explore the possible relationship between oral hyperpigmentation and long-term imatinib mesylate treatment.\nWe diagnosed oral pigmentation associated with imatinib intake based on the medical history and clinical features of the pigmented macules. Oral pigmentation may have a variety of causes, and differential diagnosis requires nodal analysis. Clinicians should be aware of possible oral mucosal hyperpigmentation in patients taking imatinib mesylate. Such pigmentation is benign and no treatment is needed, but surveillance is advisable.",
"affiliations": "Maxillo-Facial and Dental Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, University of Milan, Via Commenda 10, 20122 Milan, Italy.;Maxillo-Facial and Dental Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, University of Milan, Via Commenda 10, 20122 Milan, Italy.;Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.;Maxillo-Facial and Dental Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, University of Milan, Via Commenda 10, 20122 Milan, Italy.;Maxillo-Facial and Dental Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, University of Milan, Via Commenda 10, 20122 Milan, Italy.;Maxillo-Facial and Dental Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, University of Milan, Via Commenda 10, 20122 Milan, Italy.;Maxillo-Facial and Dental Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, University of Milan, Via Commenda 10, 20122 Milan, Italy.",
"authors": "Bombeccari|Gian Paolo|GP|;Garagiola|Umberto|U|;Pallotti|Francesco|F|;Rossi|Margherita|M|;Porrini|Massimo|M|;Giannì|Aldo Bruno|AB|;Spadari|Francesco|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40902-017-0136-y",
"fulltext": "\n==== Front\nMaxillofac Plast Reconstr SurgMaxillofac Plast Reconstr SurgMaxillofacial Plastic and Reconstructive Surgery2288-81012288-8586Springer Berlin Heidelberg Berlin/Heidelberg 13610.1186/s40902-017-0136-yCase ReportHyperpigmentation of the hard palate mucosa in a patient with chronic myeloid leukaemia taking imatinib Bombeccari Gian Paolo gpbombeccari@libero.it 12Garagiola Umberto 02 97286732umberto.garagiola@unimi.it 12Pallotti Francesco francesco.pallotti@policlinico.mi.it 23Rossi Margherita margherita.rossi@unimi.it 1Porrini Massimo massimo.porrini@unimi.it 1Giannì Aldo Bruno aldo.gianni@unimi.it 12Spadari Francesco francesco.spadari@unimi.it 121 0000 0004 1757 2822grid.4708.bMaxillo-Facial and Dental Unit, Fondazione Ca’ Granda IRCCS Ospedale Maggiore Policlinico, University of Milan, Via Commenda 10, 20122 Milan, Italy 2 0000 0004 1757 2822grid.4708.bDepartment of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy 3 0000 0004 1757 2822grid.4708.bUnit of Anatomical Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Via Commenda 10, 20122 Milan, Italy 5 12 2017 5 12 2017 12 2017 39 1 3725 10 2017 31 10 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nImatinib mesylate is an inhibitor of the tyrosine kinase Bcr–Abl and a first-line treatment for Philadelphia chromosome-positive chronic myeloid leukaemia (CML). Dermatological side effects include superficial oedema, pustular eruption, lichenoid reactions, erythroderma, and skin rash. Depigmentation of the skin and/or mucosa is uncommon, and hyperpigmentation is rare.\n\nCase presentation\nWe present the case of a 63-year-old Caucasian male with widespread hyperpigmentation of the hard palate associated with a 9-year history of imatinib therapy to treat CML. He did not complain of any symptoms. Clinical examination did not reveal any abnormal pigmentation of the skin or other region of the oral mucosa. He did not smoke cigarettes or drink alcohol. His medication regimen was a proton pump inhibitor, a beta-blocker, cardioaspirin, atorvastatin, and imatinib 400 mg/day. Histopathologically, melanin and haemosiderin deposits were evident in the lamina propria. The lesion persisted, with no clinical change, through several follow-ups. We reviewed the literature to explore the possible relationship between oral hyperpigmentation and long-term imatinib mesylate treatment.\n\nConclusions\nWe diagnosed oral pigmentation associated with imatinib intake based on the medical history and clinical features of the pigmented macules. Oral pigmentation may have a variety of causes, and differential diagnosis requires nodal analysis. Clinicians should be aware of possible oral mucosal hyperpigmentation in patients taking imatinib mesylate. Such pigmentation is benign and no treatment is needed, but surveillance is advisable.\n\nKeywords\nChronic myeloid leukaemiaOral melanosisDrug-induced oral reactionsOral pigmentationMucosal pigmentationissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nPigmentation of the oral mucosa associated with overproduction of melanin is relatively common and may involve any region of the oral cavity. The prevalence varies by geographical region and ethnicity. A cross-sectional study of 1275 Jordanian subjects found that 30.2% exhibited oral pigmentation [1]. In Sweden, such lesions are found in about 10% of the population [2]. The differential diagnosis includes physiological and environmental causes, as well as manifestations of systemic disease [3]. Drug-induced pigmentation constitutes 10–20% of all cases of acquired hyperpigmentation and should be considered during diagnosis, especially in elderly patients on multidrug therapy [4]. The aetiology of drug-induced pigmentation varies with the causative drug. One or more of three potential pathways may be involved: these are deposition of the drug per se or a metabolite thereof, stimulation of melanin production, and bacterial metabolism of the drug, alone or in combination [5]. The colour ranges from brown (associated with the use of oral contraceptives) to blue–black (often associated with hydroxychloroquine treatment) [5, 6].\n\nImatinib mesylate (Gleevec®; Novartis, Basel, Switzerland), a tyrosine kinase inhibitor targeting the Bcr–Abl protein, is a first-line treatment for Philadelphia chromosome-positive CML [7]. The dermatological side effects include superficial oedema and skin rash (the most frequent side effects), pustular and/or lichenoid eruptions, erythroderma, graft-versus-host-like disease, and small-vessel vasculitis [8–10]. Hypopigmentation of the skin and/or mucosa is an uncommon side effect [11]. Intraoral side effects are unusual and, in a few cases, have included lichenoid reactions [12–14] and dental pigmentation [15–17]. Rarely, hyperpigmentation of the hard palate has been observed, presumably related to drug intake [3, 18–23]. Here, we describe a case of widespread hyperpigmentation of the hard palate mucosa associated with long-term imatinib treatment of a CML patient.\n\nCase presentation\nIn January 2016, a 63-year-old Caucasian male was referred to us for evaluation of painless grey–blue hyperpigmentation of the hard palate, noted by his dentist during a routine dental examination (Fig. 1). His medical history included hypertension, hyperlipidaemia, and CML diagnosed about 10 years prior. His medication regimen was a proton pump inhibitor (20 mg/day), a beta-blocker (50 mg/day), cardioaspirin (100 mg/day), atorvastatin (20 mg/day), and imatinib (400 mg/day). He had been taking imatinib for about 9 years. He had never taken hydroxyurea, minocycline, or any anti-malarial agent. Clinical examination revealed no abnormal pigmentation of the skin or other region of the oral mucosa. He denied smoking and alcohol consumption. We scheduled a complete blood count test and screening for Addison’s disease. No serological abnormalities were evident. Under local anaesthesia, we performed a 3-mm incisional punch biopsy. The histopathological report and medical history were consistent with drug-induced palatal hyperpigmentation. We diagnosed mucosal pigmentation associated with imatinib therapy, thus excluding other environmental, physiological, and pathological causes (Table 1).Fig. 1 An extensive blue–grey pigmented lesion of the hard palate mucosa evident on clinical examination\n\n\nTable 1 Conditions associated with mucosal pigmentation that should be considered during the differential diagnosis of oral melanosis [1, 6, 25–27]\n\nEnvironmental causes\t\t\n Smoking-associated melanosis\t\t\n Heavy metal pigmentation due to metallic deposit\t\t\n Dental amalgam tattoos\t\t\n Drug-induced pigmentation\t\t\nPhysiological causes\t\t\n Physiological ethnic and/or racial pigmentation\t\t\n Labial melanotic macule\t\t\n Oral melanocytic nevi\t\t\nPathological causes\t\t\n Post-inflammatory deposits of melanin\t\t\n Peutz–Jeghers syndrome\t\t\n AIDS\t\t\n Hemochromatosis\t\t\n Addison’s disease\t\t\n Laugier–Hunziker disease\t\t\n Oral melanoacanthoma\t\t\n Pseudo-ochronosis\t\t\n Bandler’s syndrome\t\t\n McCune–Albright syndrome\t\t\n Cowden syndrome\t\t\n Neurofibromatosis\t\t\n Riehl’s melanosis\t\t\n LAMB syndrome (Carney complex)\t\t\n Polyostotic fibrous dysplasia syndrome\t\t\n LEOPARD syndrome\t\t\n Hyperthyroidism\t\t\n Nelson’s syndrome\t\t\n Melanosis associated with melanoma\t\t\n\n\n\nHistopathological findings\nHistopathological examination revealed a non-inflamed palatal mucosa with pigment-containing histiocytes in the mucous membrane (Fig. 2). Immunohistochemically, both haemosiderin (Perl’s Prussian blue staining) and melanin (Fontana–Masson staining) were detected (Figs. 3 and 4).Fig. 2 The lamina propria of the oral mucosa contained brown pigment scattered between collagen fibres and in the cytoplasm of macrophages (H&E ×10)\n\n\nFig. 3 The lamina propria of the oral mucosa contained blue-staining spherical particles that included iron (Perl’s stain, ×40)\n\n\nFig. 4 The lamina propria of the oral mucosa contained brown-staining spherical particles that included melanin (Fontana–Masson staining, ×40)\n\n\n\n\nOutcome and follow-ups\nAt the 6-month follow-up, neck ultrasonography did not reveal any swollen lymph node. We took close-up colour photographs of the lesion to confirm the absence of any morphological change. In May 2017, palatal hyperpigmentation was still evident, and the clinical appearance was unchanged, but he reported no symptoms.\n\nDiscussion\nDiagnostic considerations when encountering oral melanosis should include physiological, pathological, and environmental variables. Physiological oral melanosis is usually localised to the gingival and buccal mucosa and is bilateral and symmetrical, brownish in colour, and clinically more common among dark-skinned populations [1]. Oral melanotic macules present as well-circumscribed brown-to-black flat lesions, mainly on the lower vermilion. The pathogenesis of physiological melanotic macules remains controversial; both reactive and genetic factors may be involved [6]. Oral nevi typically appear as solitary brown-to-black mucosal macules, mainly on the palate and buccal mucosa. Although the pathogenesis of nevi remains unknown, it has been suggested that the lesions are benign neoplasms. No malignant transformation of oral nevi has yet been reported, and no evidence points to an increased risk of oral melanoma in affected subjects [24]. Notably, palatal melanosis must be differentiated from an oral melanoma, which may present as an asymptomatic brown-to-grey-black macula with irregular borders. Further, an oral melanoma grows rapidly and exhibits ulcerative evolution with bleeding and pain [25]. Several systemic diseases, including Addison’s disease, Peutz–Jeghers syndrome, McCune–Albright syndrome, Cowden syndrome, neurofibromatosis, acquired immunodeficiency syndrome, haemochromatosis, and hyperthyroidism, as well as uncommon conditions such as Nelson’s syndrome, polyostotic fibrous dysplasia syndrome, Laugier–Hunziker syndrome, and the Carney complex, may feature oral melanotic macules [1, 26, 27]. Melanosis associated with these conditions is due to increased levels of melanin within the basal cell layer, attributable to incontinent melanophages in the lamina propria, in the absence of iron deposits and bleeding [3, 28]. Oral pigmentation induced by smoking (smoker’s melanosis) may be associated with the effects of components of tobacco on oral melanocytes [29]. It has been hypothesised that stimulation of melanin production may be a protective reaction of the oral mucosa, associated with detoxification of polycyclic amines and benzopyrenes, thus being a side effect of tobacco use [30]. Post-inflammatory melanin deposits scattered throughout the oral connective tissue are frequently observed in patients with chronic inflammatory diseases such as oral lichen planus, pemphigoid, and pemphigus [31]. Hyperpigmentation following inflammation may be caused by an increase in melanogenesis triggered by cytokines and reactive oxygen species, which induce melanocyte activity and the proliferation of dendritic cells, and increase tyrosinase activity [31, 32].\n\nA history of occupational or environmental exposure to heavy metals and clinical signs of metal toxicity help to identify pigmentations of the oral mucosa. Heavy metals such as bismuth, lead, copper, arsenic, gold, copper, cobalt, chromium, silver, mercury, and magnesium can induce the development of a bluish-black line, the so-called Burton’s line, along the gingival margin, the thickness of which is proportional to the extent of gingival inflammation [31]. In some cases, however, the hard palate mucosa adjacent to amalgam dental fillings develops blue–grey macules, termed the “amalgam tattoo.” Histologically, the amalgam tattoo presents as discrete dark granules or fragments, usually surrounding collagen bundles and blood vessels, associated with low-level infiltrations of inflammatory cells [33]. The aetiology of medication-associated oral pigmentation may be related to the use of drugs that induce melanin formation. These include clofazimine used to treat leprosy, anti-malarials such as quinine, and immunomodulatory agents. In patients on hormonal therapy, conjugated oestrogens can lower the serum cortisol concentration by stimulating adrenocorticotropic hormone (ACTH) production. Notably, oral hyperpigmentation induced by anti-malarials, minocycline, and imatinib often involves the mucosa of the hard palate [18]. Histopathologically, imatinib-induced oral pigmentation usually presents as spherical pigmented melanin bundles in the lamina propria, with no sign of inflammation or haemorrhage [3, 18–20, 23].\n\nOf the 15 cases published in the English language literature, eight reported the histopathological features, i.e. deposits of melanin and/or haemosiderin in the lamina propria. Of these, four described co-existing melanin and haemosiderin deposits. Our findings are consistent with those of the cited reports; both Fontana–Masson staining for melanin and Perl’s Prussian blue staining for haemosiderin were positive (Table 2).Table 2 Summary of previous case reports on oral mucosal pigmentation associated with imatinib therapy\n\nAuthor(s), year\tDuration of treatment with imatinib\tDosage (mg/dose)\tAge and sex of patient\tSite(s) affected\tHistological findings\tCondition treated\t\nSingh and Bakhshi 2007 [15]\t4 years\t300\t13 F\tGingivae, teeth\tClinical diagnosis only\tCML\t\nLewis, 2009 [18]\tUnknown\t800\t70 M\tPalate\tMelanin and haemosiderin deposits in lamina propria\tCML\t\nMcpherson et al. 2009 [38]\t6 years\tUnknown\t59 F\tGingivae, toes, fingernails\tClinical diagnosis only\tCML\t\nWong et al. 2011 [19]\t3 months\tUnknown\t43 F\tPalate\tMelanin deposits in lamina propria\tCML\t\nMattsson et al. 2011 [20]\t5 years\n5 years\n5 years\t400\n400\n400\t66 F\n66 F\n64 F\tPalate\nPalate\nPalate\tMelanin deposits in lamina propria\nClinical diagnosis only\tMetastatic gastrointestinal stromal tumour\nCML\nCML\t\nLi et al. 2012 [3]\t4 years\n10 years\n5 years\t400\n400\n400\t64 M\n53 M\n29 F\tPalate\nPalate\nPalate\tMelanin and haemosiderin deposits in lamina proria\tCML\nCML\nPelvic fibromatosis\t\nResende et al. 2012 [21]\t5 years\t600\t38 M\tPalate, nose, earlobes\tClinical diagnosis only\tPost-haematopoietic stem\nCells transplant\t\nRoeker and Wolanskyj 2014 [22]\t6 years\tUnknown\t65 F\tPalate\tClinical diagnosis only\tCML\t\nSong and Kang 2014 [23]\tUnknown\tUnknown\t58 M\tPalate, nose\tClinical diagnosis only\tCML\t\nLyne et al. 2015 [24]\t13 years\t400–600\t58 F\tPalate\tHaemosiderin deposits in lamina propria\tCML\t\nRomeo et al. 2015 [39]\t11 years\t400\t72 F\tPalate\tBrown spherical bodies located within the lamina propria\tCML\t\n\nCML chronic myeloid leukaemia\n\n\n\n\nThe pathophysiological mechanism of mucocutaneous pigmentation induced by imatinib remains unclear. Imatinib targets the ATP-binding site of the Bcr–Abl tyrosine kinase and also inhibits the actions of other tyrosine kinases, including platelet-derived growth factor receptor-b, C-kit, and C-ABL [17]. C-kit is a transmembrane growth factor expressed in basal skin cells, melanocytes, epithelial cells of the breast, and mast cells, stimulation of which leads to activation (followed by the rapid degradation) of microphthalmia transcription factor (MITF); in turn, this transactivates the promoter of the tyrosinase pigmentation gene of melanocytes [9]. It has been suggested that imatinib inhibits ligand binding to specific receptors on the surfaces of human melanocytes, reducing cellular activity and thus commonly triggering hypopigmentation [10]. However, imatinib may rarely cause hyperpigmentation of the skin and/or mucosae; a metabolite of the drug may chelate iron and melanin, as do minocycline and anti-malarial drugs [3]. Currently, it is not known why the mucosa of the hard palate is the tissue invariably affected by hyperpigmentation. However, the palate contains a large number of mucosal melanocytes [34] in which imatinib metabolites accumulate. Also, C-kit signalling may play a role in oral hyperpigmentation, and indeed, C-kit is widely expressed in mesenchymal cells of the human oral cavity, including dental pulp cells and gingival fibroblasts [35]. In addition, the cases of oral hyperpigmentation reported to date do not appear to be drug dose-dependent (Table 2). Only a few oral mucosal hyperpigmentation cases caused by administration of imatinib mesylate to treat haematological malignancies have been reported. Hence, it remains speculative to suggest that imatinib mesylate may directly influence melanocyte C-kit signalling in the oral mucosa, activating melanogenesis. It is possible that genetic and/or other factors are also involved in the development of oral melanotic maculae. Finally, the time of onset of CML may be relevant; sometimes, patients are treated initially with hydroxyurea, which may also cause mucocutaneous hyperpigmentation and melanonychia [36–39].\n\nConclusions\nThe diagnosis of imatinib-associated oral pigmentation requires a thorough history-taking and clinical examination of the melanotic maculae. Medical and dental practitioners should be aware of possible oral mucosal hyperpigmentation in patients taking imatinib mesylate. The hyperpigmented lesions are benign; no treatment is required. However, annual follow-up is advisable to monitor changes in morphology or colour over time.\n\nAbbreviation\nACTHAdrenocorticotropic hormone\n\nCMLChronic myeloid leukaemia\n\nMITFMicrophthalmia transcription factor\n\nAcknowledgements\nNone.\n\nFunding\nNone.\n\nAvailability of data and materials\nThe dataset supporting the conclusions of this article is included within the article (and its additional file).\n\nAuthors’ contributions\nBGP conceived and drafted the manuscript. GU revised the manuscript and made English editing and checked grammar. RM, GU, PM, SF, and ABG participated in the design and co-ordination of the study. PF performed the histopathological analysis. All authors have read and approved of the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent has been obtained from the patient for the publication of this case report and the accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Hassona Y Sawair F Al-Karadsheh O Scully C Prevalence and clinical features of pigmented oral lesions Int J Dermatol 2016 55 1005 1013 10.1111/ijd.13133 26711197 \n2. Axell T A prevalence study of oral mucosal lesions in an adult Swedish population Odontol Rev 1976 36 1 103 \n3. Li CC Malik SM Blaeser BF Dehni WJ Mucosal pigmentation caused by imatinib: report of three cases Head Neck Pathol 2012 6 290 295 10.1007/s12105-011-0325-4 22209988 \n4. Dereure O Drug-induced skin pigmentation. Epidemiology, diagnosis and treatment Am J Clin Dermatol 2001 2 253 262 10.2165/00128071-200102040-00006 11705252 \n5. Ciҫek Y Ertaş U The normal and pathological pigmentation of oral mucous membrane: a review J Contemp Dent Pract 2003 4 76 86 \n6. Meleti M Vescovi P Mooi WJ Pigmented lesions of the oral mucosa and perioral tissues: a flow-chart for the diagnosis and some recommendations for the management Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008 105 606 616 10.1016/j.tripleo.2007.07.047 18206403 \n7. National Institute for Health and Care Excellence Guidance on the use of imatinib for chronic myeloid leukaemia, TA70 2012 London NICE \n8. Scheinfeld N Imatinib mesylate and dermatology part 2: a review of the cutaneous side effects of imatinib mesylate J Drugs Dermatol 2006 5 228 231 16573254 \n9. Arora B Kumar L Sharma A Wadhwa J Kochupillai V Pigmentary changes in chronic myeloid leukemia patients treated with imatinib mesylate Ann Oncol 2004 15 358 359 10.1093/annonc/mdh068 14760137 \n10. Robert C Soria JC Spatz A le Cesne A Malka D Pautier P Cutaneous side-effects of kinase inhibitors and blocking antibodies Lancet Oncol 2005 6 491 500 10.1016/S1470-2045(05)70243-6 15992698 \n11. Tsao AS Kantarjian H Cortes J O'Brien S Talpaz M Imatinib mesylate causes hypopigmentation in the skin Cancer 2003 98 2483 2487 10.1002/cncr.11812 14635084 \n12. Ena P Chiarolini F Siddi GM Cossu A Oral lichenoid eruption secondary to imatinib (Glivec) J Dermatolog Treat 2004 15 253 255 10.1080/09546630410015556 15764042 \n13. Lim DS Muir J Oral lichenoid reaction to imatinib (STI 571, Gleevec) Dermatology 2002 205 169 171 10.1159/000063899 12218235 \n14. Pascual JC Matarredona J Miralles J Conesa V Borras-Blasco J Oral and cutaneous lichenoid reaction secondary to imatinib: report of two cases Int J Dermatol 2006 45 1471 1473 10.1111/j.1365-4632.2006.03171.x 17184272 \n15. Singh N Bakhshi S Imatinib-induced dental hyperpigmentation in childhood chronic myeloid leukemia J Pediatr Hematol Oncol 2007 29 208 209 10.1097/MPH.0b013e318033a76c 17356407 \n16. Singh O Agrawal P Agarwal A Yadav S Imatinib induced dental hyperpigmentation chronic myeloid leukemia in adult female J Assoc Physicians India 2016 64 138 27728560 \n17. Agrawal P Singh O Nigam AK Upadhyay S Imatinib induced dental hyperpigmentation in chronic myeloid leukemia in an adult female Indian J Pharmacol 2015 47 685 686 10.4103/0253-7613.169576 26729966 \n18. Lewis DM Diffuse pigmentation of the palate J Okla Dent Assoc 2009 100 24 25 19998620 \n19. Wong M Sade S Gilbert M Klieb HB Oral melanosis after tyrosine kinase inhibition with imatinib for chronic myelogenous leukemia: report of a case and review of the literature Dermatol Online J 2011 17 4 21635826 \n20. Mattsson U Halbritter S Mörner Serikoff E Oral pigmentation in the hard palate associated with imatinib mesylate therapy: a report of three cases Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011 111 e12 e16 10.1016/j.tripleo.2010.11.006 21330162 \n21. Resende RG Teixeira RG Vasconcelos Fde O Imatinib associated hyperpigmentation of the palate in post-HSCT patient J Cranio-Maxillo-Facial Surgery 2012 40 e140 e143 10.1016/j.jcms.2011.07.010 \n22. Roeker LE Wolanskyj AP Imatinib-associated melanosis of the palate Am J Hematol 2014 89 564 10.1002/ajh.23589 24030927 \n23. Song HS Kang HY Imatinib mesylate-induced hyperpigmentation of the nose and palate Ann Dermatol 2014 26 532 533 10.5021/ad.2014.26.4.532 25143691 \n24. Lyne A Creedon A Bailey BM Mucosal pigmentation of the hard palate in a patient taking imatinib BMJ Case Rep 2015 16 2015 \n25. Meleti M Mooi WJ Casparie MK Melanocytic nevi of the oral mucosa—no evidence of increased risk for oral malignant melanoma: an analysis of 119 cases Oral Oncol 2007 43 976 981 10.1016/j.oraloncology.2006.11.013 17258496 \n26. Reddy GJ Kanth MR Kumar DR Oral malignant melanoma J Clin Diagn Res 2015 9 ZL03 25738107 \n27. De Schepper S Boucneau J Lambert J Messiaen L Naeyaert JM Pigment cell-related manifestations in neurofibromatosis type 1: an overview Pigment Cell Res 2005 18 13 24 10.1111/j.1600-0749.2004.00206.x 15649148 \n28. Kim IS Kim ER Nam HJ Chin MO Moon YH MR O Activating mutation of GS alpha in McCune-Albright syndrome causes skin pigmentation by tyrosinase gene activation on affected melanocytes Horm Res 1999 52 235 240 10844413 \n29. Cinotti E Couzan C Perrot JL Habougit C Labeille B In vivo confocal microscopic substrate of grey colour in melanosis J Eur Acad Dermatol Venereol 2015 29 2458 2462 10.1111/jdv.13394 26403597 \n30. Alawi F Pigmented lesions of the oral cavity: an update Dent Clin N Am 2013 57 699 710 10.1016/j.cden.2013.07.006 24034073 \n31. Hedin CA Pindborg JJ Axell T Disappearance of smoker’s melanosis after reducing smoking J Oral Pathol Med 1993 22 228 230 10.1111/j.1600-0714.1993.tb01061.x 8315602 \n32. Kauzman A Pavone M Blanas N Pigmented lesions of the oral cavity: review, differential diagnosis, and case presentations J Can Dent Assoc 2004 70 682 683 15530266 \n33. Callender VD St Surin-Lord S Davis EC Maclin M Postinflammatory hyperpigmentation: etiologic and therapeutic considerations Am J Clin Dermatol 2011 12 87 99 10.2165/11536930-000000000-00000 21348540 \n34. Vera-Sirera B Risueńo-Mata P Ricart-Vaya JM Clinicopathological and immunohistochemical study of oral amalgam pigmentation Acta Otorrinolaringol Esp 2012 63 376 381 10.1016/j.otorri.2012.02.004 22502738 \n35. Barrett AW Scully C Human oral mucosal melanocytes: a review J Oral Pathol Med 1994 23 97 103 10.1111/j.1600-0714.1994.tb01095.x 8021847 \n36. Gagari E Rand MK Tayari L Vastardis H Sharma P Expression of stem cell factor and its receptor, C-kit, in human oral mesenchymal cells Eur J Oral Sci 2006 114 409 415 10.1111/j.1600-0722.2006.00388.x 17026507 \n37. Kumar B Saraswat A Kaur I Mucocutaneous adverse effects of hydroxyurea: a prospective study of 30 psoriasis patients Clin Exp Dermatol 2002 27 8 13 10.1046/j.0307-6938.2001.00947.x 11952660 \n38. McPherson T Sherman V Turner R Imatinib-associated hyperpigmentation, a side effect that should be recognized J Eur Acad Dermatol Venereol 2009 23 82 83 10.1111/j.1468-3083.2008.02706.x 18384557 \n39. Romeo U, Palaia G, Fantozzi PJ, Tenore G, Bosco D (2015) A rare case of melanosis of the hard palate mucosa in a patient with chronic myeloid leukemia. Case Rep Dent 2015;9:817094\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2288-8101",
"issue": "39(1)",
"journal": "Maxillofacial plastic and reconstructive surgery",
"keywords": "Chronic myeloid leukaemia; Drug-induced oral reactions; Mucosal pigmentation; Oral melanosis; Oral pigmentation",
"medline_ta": "Maxillofac Plast Reconstr Surg",
"mesh_terms": null,
"nlm_unique_id": "101633100",
"other_id": null,
"pages": "37",
"pmc": null,
"pmid": "29230387",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports",
"references": "15649148;21635826;15992698;16573254;15530266;26711197;8021847;21348540;21862339;186740;24030927;12218235;17184272;18384557;25883257;26451262;17026507;11952660;14635084;12937598;25143691;21330162;14760137;26729966;25738107;15764042;8315602;17258496;17356407;22209988;18206403;26403597;11705252;19998620;22502738;24034073;10844413",
"title": "Hyperpigmentation of the hard palate mucosa in a patient with chronic myeloid leukaemia taking imatinib.",
"title_normalized": "hyperpigmentation of the hard palate mucosa in a patient with chronic myeloid leukaemia taking imatinib"
} | [
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"companynumb": "IT-DRREDDYS-GER/ITL/18/0096004",
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"activesubstancename": "ASPIRIN"
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{
"abstract": "OBJECTIVE\nTo evaluate chemotherapy (CT) compliance in patients treated with chemoradiotherapy (CRT) for high-risk Merkel cell cancer (MCC).\n\n\nMETHODS\nData from three prospective clinical trials in high-risk MCC performed by the Trans-Tasman Radiation Oncology Group were included in this analysis. Patients were treated with one of two carboplatin-based CT schedules and standardised radiotherapy (RT) to the primary site and nodes to a dose of 50-60 Gy in 25-30 fractions. Patients' baseline characteristics were analysed using χ2 tests to determine compliance factors for completing CT. A Cox univariate analysis was performed to assess the impact of CT compliance on time to locoregional failure, time-to-distant failure, time-to-recurrence and time-to-death.\n\n\nRESULTS\nA total of 88 patients were identified, with a median follow up of 38.5 months. Of these, 75 (85%) completed CT (median age 64.2 years, range 62.0-66.4), while 13 did not (median age 72 years, range 68.1-75.9), P = 0.006. Women comprised 18/75 patients who completed CT and 7/13 patients who did not complete it (P = 0.03). Performance status, site, stage, surgical margins, RT dose and toxicity did not impact on their CT compliance. At 5 years, 26% of patients had locoregional relapse, 26% had distant failure and 34% had died.\n\n\nCONCLUSIONS\nIn this small cohort of patients treated with CRT for high-risk MCC, older age and female sex were associated with failure to complete CT. Severe acute skin and haematological toxicity did not correlate with failure to complete CT.",
"affiliations": "Radiation Oncology Centres, St Andrew's Toowoomba Hospital, Toowoomba, Australia.;Cancer Care Services, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.;Division of Cancer Services, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia.",
"authors": "Gorayski|Peter|P|;Tripcony|Lee|L|;Poulsen|Michael|M|",
"chemical_list": "D016190:Carboplatin",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajd.12419",
"fulltext": null,
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"issn_linking": "0004-8380",
"issue": "58(1)",
"journal": "The Australasian journal of dermatology",
"keywords": "Merkel cell carcinoma; chemoradiotherapy; compliance; skin",
"medline_ta": "Australas J Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D015266:Carcinoma, Merkel Cell; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012878:Skin Neoplasms; D015996:Survival Rate",
"nlm_unique_id": "0135232",
"other_id": null,
"pages": "35-41",
"pmc": null,
"pmid": "26627052",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Chemotherapy compliance in high-risk Merkel cell carcinoma treated with chemoradiotherapy.",
"title_normalized": "chemotherapy compliance in high risk merkel cell carcinoma treated with chemoradiotherapy"
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"companynumb": "AU-CIPLA LTD.-2015AU09959",
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"activesubstance": {
"activesubstancename": "CARBOPLATIN"
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... |
{
"abstract": "In early stages, Parkinson disease typically begins with asymmetric or unilateral motor symptoms due to combinations of mild bradykinesia, rigidity, and tremor. In most cases, with progression, signs of more generalized bradykinesia appear, which include facial masking, reduced voice volume, and slowing of activities of daily living. In more advanced Parkinson disease, other disabling manifestations may follow, such as impaired balance, gait freezing, falls, speech disturbance, and cognitive impairment. Levodopa is the most effective medical treatment for Parkinson disease. However, motor complications uniquely related to levodopa treatment may emerge that may be difficult to manage. These include fluctuating levodopa responses and involuntary movements and postures known as dyskinesia and dystonia. Medication adjustments are usually effective, but in some cases surgical intervention with deep brain stimulation becomes necessary to alleviate motor complications. The case of Mr L, a man with an 11-year history of Parkinson disease, illustrates these emerging motor complications and the manner in which they may be managed both medically and surgically.",
"affiliations": "Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. dtarsy@bidmc.harvard.edu",
"authors": "Tarsy|Daniel|D|",
"chemical_list": "D000977:Antiparasitic Agents; D002396:Catechols; D009570:Nitriles; D007980:Levodopa; C071192:entacapone; D000547:Amantadine; D002230:Carbidopa",
"country": "United States",
"delete": false,
"doi": "10.1001/jama.2012.4829",
"fulltext": null,
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"issn_linking": "0098-7484",
"issue": "307(21)",
"journal": "JAMA",
"keywords": null,
"medline_ta": "JAMA",
"mesh_terms": "D000547:Amantadine; D000977:Antiparasitic Agents; D002230:Carbidopa; D002396:Catechols; D003657:Decision Making; D046690:Deep Brain Stimulation; D018450:Disease Progression; D004409:Dyskinesia, Drug-Induced; D020233:Gait Disorders, Neurologic; D005917:Globus Pallidus; D006801:Humans; D007980:Levodopa; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D010300:Parkinson Disease; D011788:Quality of Life; D020530:Subthalamus",
"nlm_unique_id": "7501160",
"other_id": null,
"pages": "2305-14",
"pmc": null,
"pmid": "22706836",
"pubdate": "2012-06-06",
"publication_types": "D002363:Case Reports; D016429:Clinical Conference; D016428:Journal Article",
"references": null,
"title": "Treatment of Parkinson disease: a 64-year-old man with motor complications of advanced Parkinson disease.",
"title_normalized": "treatment of parkinson disease a 64 year old man with motor complications of advanced parkinson disease"
} | [
{
"companynumb": "US-009507513-1610USA016656",
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"occurcountry": "US",
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"activesubstancename": "CARBIDOPA\\ENTACAPONE\\LEVODOPA"
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{
"abstract": "OBJECTIVE\nMost patients with asymptomatic intracranial aneurysms treated with endovascular methods are closely observed overnight in an intensive care unit setting for complications, including ischemic and hemorrhagic stroke, cardiac dysfunction, and groin access complications. The purpose of this study was to analyze the timing, nature, and rate of in-house postoperative events.\n\n\nMETHODS\nPatients who underwent endovascular treatment or retreatment of unruptured cerebral aneurysms from March 2002 to June 2012 were identified from a prospective case log and their medical records were reviewed. The presentation, patient characteristics, aneurysm size and location, and method of endovascular treatment of each cerebral aneurysm were recorded. Patients with adverse intraprocedural events including perforation and thromboembolism were excluded from this analysis. Overnight postprocedural monitoring was performed in a neurological intensive care unit or postanesthesia care unit for all patients, with discharge planned for postoperative Day 1. Postprocedural events occurring during hospitalization were categorized as intracranial hemorrhage, ischemic stroke, groin hematoma resulting in additional treatment or prolonged hospital stay, retroperitoneal hematoma, and cardiac events. The time from the completion of the procedure to event discovery was recorded.\n\n\nRESULTS\nA total of 687 endovascular treatments of unruptured cerebral aneurysms were performed. Nine treatments were excluded from our analysis due to intraprocedural events. Endovascular procedures included coiling alone, stent-assisted coiling, balloon-assisted coiling, balloon-assisted embolization with a liquid embolic agent, and placement of a flow diversion device with or without coiling. Twenty-seven treatments (4.0%) resulted in postprocedural complications: 3 intracranial hemorrhages, 6 ischemic strokes, 4 cardiac events, 5 retroperitoneal hematomas, and 9 groin hematomas. The majority (20 [74.0%]) of these 27 complications were detected within 4 hours from the procedure. These included 1 hemorrhage, 4 ischemic strokes, 4 cardiac events, 2 retroperitoneal hematomas, and 9 groin hematomas. All cardiac events and groin hematomas were detected within 4 hours. Four (14%) of the 27 complications were detected between 4 and 12 hours, 1 (3.7%) between 12 and 24 hours, and 2 (7.4%) more than 24 hours after the procedure. The complications detected more than 4 hours from the conclusion of the procedure included 2 minor intracranial hemorrhages causing headache and resulting in no permanent deficits, 2 mild ischemic strokes, and 3 asymptomatic retroperitoneal hematomas identified by falling hematocrit levels that required no further intervention or treatment.\n\n\nCONCLUSIONS\nThe large majority of significant postprocedural events after uncomplicated endovascular aneurysm intervention occur within the first 4 hours; these events become less frequent with increasing time. Transfer to a floor bed after 4-12 hours for further observation is reasonable to consider in some patients.",
"affiliations": "Department of Neurological Surgery.",
"authors": "Arias|Eric J|EJ|;Patel|Bhuvic|B|;Cross|DeWitte T|DT|;Moran|Christopher J|CJ|;Dacey|Ralph G|RG|;Zipfel|Gregory J|GJ|;Derdeyn|Colin P|CP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3171/2014.7.JNS132676",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3085",
"issue": "121(5)",
"journal": "Journal of neurosurgery",
"keywords": "DAPT = dual antiplatelet therapy; ICA = internal carotid artery; MCA = middle cerebral artery; POD = postoperative day; aneurysm; endovascular; hematoma; postoperative complications; stroke; vascular disorders",
"medline_ta": "J Neurosurg",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic; D011183:Postoperative Complications; D012008:Recurrence; D012737:Sex Factors; D013997:Time Factors",
"nlm_unique_id": "0253357",
"other_id": null,
"pages": "1063-70",
"pmc": null,
"pmid": "25170666",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Timing and nature of in-house postoperative events following uncomplicated elective endovascular aneurysm treatment.",
"title_normalized": "timing and nature of in house postoperative events following uncomplicated elective endovascular aneurysm treatment"
} | [
{
"companynumb": "US-BAYER-2016-178657",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": null,... |
{
"abstract": "Respiratory syncytial virus (RSV) represents a significant public health burden and the leading cause of lower respiratory tract infections globally, and it is the major cause of hospitalization during the winter. We aimed to evaluate the effectiveness of palivizumab prophylaxis to reduce the hospitalization in children at high risk of RSV infection.\n\n\n\nWe performed a retrospective observational single-arm hospital-based study including five RSV seasons (September to March) from 2012 to 2017. We retrospectively included premature infants born at less than 35 weeks of gestation with chronic lungs disease or hemodynamic significant congenital heart disease for palivizumab prophylaxis against RSV infection according to the criteria presented.\n\n\n\nA total of 925 children were enrolled in the study over the five RSV seasons. Of them, 410 (44.3%) infants born at <32 weeks of gestation and 515 (55.6%) infants born at 32-35 weeks of gestation with mean (±SD) birth weight of 1104.8 ± 402.85 and 1842.5 ± 377.5, respectively. The compliance with the course of palivizumab was reported in 841 (90.9%) children. Of them, about 75 (8.9%) hospitalized children were reported, and 17 (2.02%) RSV positive children were detected. Hospitalization due to RSV infection was decreased from 9.23% in the 2012-2013 season to 0.67% in the 2016-2017 season.\n\n\n\nThis study demonstrated that palivizumab prophylaxis in children at high risk of developing RSV infection was effective in reducing the risk of hospitalization with a high compliance rate over the five RSV seasons.",
"affiliations": "Neonatal Intensive Care Unit, Latifa Women & Children Hospital, Dubai Health Authority, Dubai, UAE.;Neonatal Intensive Care Unit, Latifa Women & Children Hospital, Dubai Health Authority, Dubai, UAE.;Neonatal Intensive Care Unit, Latifa Women & Children Hospital, Dubai Health Authority, Dubai, UAE.;Neonatal Intensive Care Unit, Latifa Women & Children Hospital, Dubai Health Authority, Dubai, UAE.;Neonatal Intensive Care Unit, Latifa Women & Children Hospital, Dubai Health Authority, Dubai, UAE.;Neonatal Intensive Care Unit, Latifa Women & Children Hospital, Dubai Health Authority, Dubai, UAE.;Neonatal Intensive Care Unit, Latifa Women & Children Hospital, Dubai Health Authority, Dubai, UAE.;Neonatal Intensive Care Unit, Latifa Women & Children Hospital, Dubai Health Authority, Dubai, UAE.;Neonatal Intensive Care Unit, Latifa Women & Children Hospital, Dubai Health Authority, Dubai, UAE.;Neonatal Intensive Care Unit, Latifa Women & Children Hospital, Dubai Health Authority, Dubai, UAE.",
"authors": "Elhalik|M|M|0000-0002-9679-9886;El-Atawi|K|K|;Dash|S K|SK|;Faquih|A|A|;Satyan|A D|AD|;Gourshettiwar|N|N|;Khan|A|A|;Varughese|S|S|;Ramesh|A|A|;Khamis|E|E|",
"chemical_list": "D000998:Antiviral Agents; D000069455:Palivizumab",
"country": "Egypt",
"delete": false,
"doi": "10.1155/2019/2986286",
"fulltext": "\n==== Front\nCan Respir JCan. Respir. JCRJCanadian Respiratory Journal1198-22411916-7245Hindawi 10.1155/2019/2986286Research ArticlePalivizumab Prophylaxis among Infants at Increased Risk of Hospitalization due to Respiratory Syncytial Virus Infection in UAE: A Hospital-Based Study https://orcid.org/0000-0002-9679-9886Elhalik M. hussien.ahmed@ray-cro.comEl-Atawi K. Dash S. K. Faquih A. Satyan A. D. Gourshettiwar N. Khan A. Varughese S. Ramesh A. Khamis E. Neonatal Intensive Care Unit, Latifa Women & Children Hospital, Dubai Health Authority, Dubai, UAEAcademic Editor: Theodoros I. Vassilakopoulos\n\n2019 1 12 2019 2019 29862862 5 2019 16 7 2019 28 10 2019 Copyright © 2019 M. Elhalik et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\n Respiratory syncytial virus (RSV) represents a significant public health burden and the leading cause of lower respiratory tract infections globally, and it is the major cause of hospitalization during the winter. We aimed to evaluate the effectiveness of palivizumab prophylaxis to reduce the hospitalization in children at high risk of RSV infection. \n\nMethods\n We performed a retrospective observational single-arm hospital-based study including five RSV seasons (September to March) from 2012 to 2017. We retrospectively included premature infants born at less than 35 weeks of gestation with chronic lungs disease or hemodynamic significant congenital heart disease for palivizumab prophylaxis against RSV infection according to the criteria presented. \n\nResults\n A total of 925 children were enrolled in the study over the five RSV seasons. Of them, 410 (44.3%) infants born at <32 weeks of gestation and 515 (55.6%) infants born at 32–35 weeks of gestation with mean (±SD) birth weight of 1104.8 ± 402.85 and 1842.5 ± 377.5, respectively. The compliance with the course of palivizumab was reported in 841 (90.9%) children. Of them, about 75 (8.9%) hospitalized children were reported, and 17 (2.02%) RSV positive children were detected. Hospitalization due to RSV infection was decreased from 9.23% in the 2012-2013 season to 0.67% in the 2016-2017 season. \n\nConclusion\n This study demonstrated that palivizumab prophylaxis in children at high risk of developing RSV infection was effective in reducing the risk of hospitalization with a high compliance rate over the five RSV seasons.\n==== Body\n1. Introduction\nRespiratory syncytial virus (RSV) is a single-stranded, negative-sense ribonucleic acid (RNA) virus and belongs to the genus Orthopneumovirus, family Pneumoviridae, and order Mononegavirales [1]. RSV was divided into two antigenic subgroups, A and B, based on the gene sequence variability of the second hypervariable region located on the distal third region of the G gene [2].\n\nPeak RSV timing is highly focused on winter months in temperate locations of the Northern Hemisphere, with a mode in February [3]. RSV epidemics start in the South moving to the North. Results from a global seasonality of RSV study showed that RSV waves in Southern Hemisphere countries start between March and June while, in the Northern Hemisphere, between September and December [4].\n\nAcute lower respiratory tract infection (LRTI) remains one of the leading causes of morbidity and mortality in children less than five years of age globally. The most common viral pathogen identified in children with LRTI is the human respiratory syncytial virus (RSV) [5]. RSV hospitalization rates were highest among premature infants less than one year (63.9 per 1000) [6].\n\nIn 2015, there was about 33.1 million episodes of RSV in children with LRTI globally, which lead to 3.2 million (2.7–3.8) hospital admissions and 59600 (48000–74500) in-hospital deaths in children younger than five years. It also reported that the overall mortality due to RSV in children with LRTI could be more than 118200 (94,600–149,400) [7]. About 45% of the hospitalization (1.4 million) and death (27,300) occurred in young infants <6 months of age.\n\nIn the Middle East, the number of children admitted with RSV diseases from developing countries in 2005 was more than double than that estimated in 1986, and the incidence of RSV induced acute LRTI was twice than that of developed countries [8]. A review of RSV infections in the Middle East shows that RSV infections occurred in the winter season peaking around January as in other parts of the world. In Saudi Arabia, RSV hospitalizations showed that the majority of cases were due to bronchopneumonia, prematurity, and lung/heart disorders [9]. While in Kuwait, RSV was the commonest viral infections identified in 52% cases of bronchiolitis, 29% of pneumonia, and 51% of croup [10]. Prevalence of RSV in LRTI equals 28.6% among children less six years in the United Arab Emirates (UAE) [11].\n\nImmunoprophylactic drugs for RSV were developed after the epidemiologic studies, suggesting that infants with high RSV titers of maternally acquired RSV-neutralizing antibody develop less severe RSV disease [12]. Preclinical studies demonstrated that higher immunoglobulin G antibodies against the RSV F glycoprotein correlated with a decreased incidence of severe RSV infection and reinfection [13].\n\nPalivizumab was licensed in June 1998 by the Food and Drug Administration for the reduction of serious lower respiratory tract infection caused by RSV in children at increased risk of severe disease [14]. Palivizumab prophylaxis resulted in significant reductions in the number of RSV-related hospitalizations including the number of RSV-related hospital days with a moderate to severe lower respiratory tract illness, the number of RSV-related hospital days with increased supplemental oxygen, and the incidence of admission to intensive care units [15, 16].\n\nThe IMpact-RSV Study in 1996-1997 was the first to investigate the effect of Palivizumab to reduce the hospitalization from respiratory syncytial virus infection in high-risk infants. It revealed an overall reduction in RSV hospitalization rate from 10.6% among placebo recipients to 4.8% among children who received palivizumab prophylaxis, which is 55% reduction [17]. In a descriptive single-centered study performed in Qatar across three RSV seasons (2009 to 2012), the compliance rate of palivizumab immunoprophylaxis was 85.7%, and the cumulative RSV hospitalization rate was 1.9%. They also observed that increase in the compliance rate is directly proportional to a corresponding decrease in RSV-LRTI-related hospitalization, from 3.7% to 1.7% [18].\n\nData about RSV-related LRTI and palivizumab immunoprophylaxis are scarce in the United Arab Emirates (UAE). This study is performed to determine the effect of RSV immunoprophylaxis on the incidence of RSV-LRTI, over a 5-year period in the UAE.\n\n2. Materials and Methods\n2.1. Study Design and Procedures\nThis is a retrospective observational study and is conducted at the department of pediatrics of Latifa Women and Children Hospital (LWCH), Dubai, UAE. We retrieved all clinical information of the patients from their documented charts and medical records. The study population involved all at-risk infants discharged from the neonatal intensive care unit (NICU) and are eligible for RSV immunoprophylaxis. Study duration was five consecutive RSV season, between September 2012 and March 2017. We followed the enrolled children up to two years of age.\n\nAs per the prevailing pattern in the middle east, RSV season begins during winter months, from September or October up to March of every year. Majority of admission related to RSV occurred during the earlier epidemic months.\n\nThe beginning of the RSV season was determined if more than two consecutive patients with positive RSV infections were admitted to the hospital, while the end of the season was determined if less than one patient with positive RSV infection per week for two consecutive weeks was admitted to the hospital.\n\nNasopharyngeal secretions from at-risk hospitalized infants were collected. RSV infection was confirmed by the Multiplex real-time polymerase chain reaction assay (RT-PCR) using fast tract diagnostics. Samples were collected from nasopharyngeal aspirates from each hospitalized infant.\n\nThe dose of palivizumab used was 15 mg/kg/dose intramuscular injection every month for a total of 3–5 doses over the RSV season, according to the starting month of the first dose and eligibility criteria. Baseline data on demographics, the subject's neonatal course, and details of palivizumab administration were collected, respectively, from the patient's record.\n\nThis study was approved by Dubai scientific research ethics committee (DSREC), Dubai Health Authority (DSREC-11/2018_3), and informed consent from the parent for each participant was obtained.\n\n2.2. Study Population\nWe included premature infants who were <35 weeks of gestational age at birth and fulfilled the inclusion criteria listed in Table 1. In case of a high-risk infant of a multiple birthset approved for the season, the siblings in the same set are also eligible for same prophylaxis. We followed the American Academy of Pediatrics recommendation for palivizumab immunoprophylaxis (Modified recommendation 2009) [19, 20].\n\nWe excluded infants having congenital heart disease (CHD) who were not hemodynamically significant, surgically corrected CHD, and not requiring medication for congestive cardiac failure. Also, infants having life-threating congenital or genetic anomalies were excluded.\n\n2.3. Study Objectives and Data Collection\nThe primary outcome measure of this study was to determine the effectiveness of RSV immunoprophylaxis on the rate of severe RSV-LRTI and related hospitalization. However, the secondary outcome measures were to determine the compliance (received prophylaxis as per guideline), the incidence of RSV positivity, age at the first dose of palivizumab, the need for pediatric intensive care unit admission, and the length of hospital stay.\n\nBaseline demographic characteristics, medical history (e.g., gestational age, age at the 1st dose of prophylaxis, birth weight, multiple birth status, and presence of risk factors like CHD and CLD), and social history (e.g., mother's age, sibling histories, tobacco smoke exposure, and childcare center exposure) were obtained from the medical records of the hospitals using a standardized questionnaires. The parents were queried in Arabic/English, and the information was recorded. Retrospectively, medical records were searched, and required demographic, epidemiologic, and clinical data were collected systematically.\n\n2.4. Statistical Analysis\nThe data were analyzed using SPSS version 25 software. All categorical variables were presented in frequency and percentage, whereas the numerical variables were presented with descriptive statistics (median and IQR). To compare the baseline data and the outcome variables on a continuous scale, 2 sample t-tests or Mann–Whitney test were used as appropriate. To compare the baseline and outcome variables on the nominal type of data, the Fisher exact test or chi-square was used as appropriate. Effect of independent variables, i.e., gestational age, birth weight, CHD, CLD, and smoke exposure (2 or more smokers in the household), on the primary outcome was evaluated in a logistic regression model. The odds ratio (OR) and 95% confidence interval (95% CI) were reported. A value of p < 0.05 was considered statistically significant.\n\n3. Results\nA total of 925 eligible children were enrolled in the study across five RSV seasons (September to March) from 2012 to 2017. Most of the admission related to RSV occurred during the earlier epidemic months and within one to two doses of RSV immunoprophylaxis. In the 2012-2013 season, about 66.70% (4 out of 6) of the admission occurred during November and December. The subsequent seasons also demonstrated a similar pattern, where more than half of the RSV infection-related hospitalization occurred during November and December.\n\nDemographics, medical history, and family history are presented in Table 2. Out of the 925 enrolled infants, 44.30% (n = 410) were born at <32 weeks of gestation with median (IQR) gestational age of 30.28 (4.1) weeks, while 55.6% (n = 515) infants were born at 32–35 weeks of gestation with a median (IQR) gestational age of 33.04 (4.2) weeks at birth. The median (IQR) birth weight of the included babies was 1100.8 (383.8) grams and 1820.5 (397) grams for babies born at <32 weeks and 32–35 weeks, respectively.\n\nFor all enrolled babies, 54% (n = 501) of them were female. The included boys were younger and had lower birth weight at birth compared to girls. Chronic lung disease was diagnosed in 19.4% (n = 180) of the included infants who had CLD, which were more in babies with gestational age <32 weeks compared to babies with gestational age between 32 and 35 weeks. Hemodynamically significant CHD was seen in 4% (n = 37) of infants, which was significantly more in children with gestational age <32 weeks.\n\nMajority of the children 75.40% (n = 698) had one or more siblings; of them, 8.40% (n = 78) had a history of asthma. One-third, 33.10% (n = 307), of the children enrolled lived in a smoking environment. Among siblings, 42% (n = 389) were in school, and 7% (n = 65) had exposure to childcare centers. Multiple births were present in 16.5% (n = 153) infants. Most of the babies (81%) (n = 757) were enrolled before six months of age. Among them, 63.60% (n = 589) and 18.10% (n = 168) were less than 3 months and 3–6 months of age, respectively. Only 10.50% (n = 98) and 7.50% (n = 70) infants were enrolled at age between 7 and 12 months and more than 1 year, respectively.\n\nIn comparison to subgroup with a gestational age of 32–35 weeks, children with a gestational age <32 weeks at birth had more incidence of BPD, CHD, family history of asthma, and more siblings with childcare center exposure.\n\nThe overall compliance to the protocol with the course of prophylactic treatment with palivizumab was 90.90% (n = 841), as shown in Figure 1 and Table 3.\n\nThere was no statistically significant difference in the compliance rate between the infants born at <32 weeks and 32–35 weeks of gestation (90.80% and 91%, p value 0.84), and only 9% of the children had an interruption in their dosing schedule.\n\nFrom the enrolled babies, 9.40% (n = 87) were hospitalized for acute LRTI. Rate of hospitalization was significantly more in babies with a gestational age <32 weeks compared to the babies with gestational age between 32 and 35 weeks (12.43%, n = 51/410, versus 6.99%, n = 36/515, p value = 0.03).\n\nBabies from the noncompliant group (n = 13/84) had 1.7 times more hospitalization rate compared to compliant subjects (n = 75/841) and the unadjusted OR = 1.87 (95% CI: 0.98–3.53, p value 0.05). The adjusted odds ratio for gestational age, birth weight, CHD, CLD, and smoke exposure in multivariate regression analysis revealed a high rate of hospitalization in the noncompliant group (OR = 2.32, 95% CI: [1.08–4.12], p value 0.04). There is an observed negative correlation between the compliance to palivizumab immunoprophylaxis, gestational age and birth weight, and the rate of hospitalization of at-risk babies. In the group who were compliant to immunoprophylaxis, more babies from <32 weeks group were hospitalized compared to the group with gestational age between 32 and 32 weeks (12.09%, n = 45/372, vs 6.39%, n = 30/469, p value 0.04) (Figure 2 and Table 3).\n\nBabies with hemodynamically significant CHD, CLD, and exposure to smoking environment had a positive correlation on the hospitalization rate.\n\nFor children hospitalized due to RSV, the median (IQR) age at the time of first palivizumab dose was 2.1 (1.3) months. Infants with gestational age <32 weeks at birth received immunoprophylaxis later at the median (IQR) age of 2.8 (1.5) months compared to at 1.5 (1.0) months for babies who were 32–35 weeks at birth, but there was wide variation in the age of receiving the first dose (Table 3).\n\nOverall age at hospital admission was 2.35 (1.35) months, and duration of hospital stay was 7.9 (4.6) days. Infants with <32 weeks were older at the time of admission, 3.1 (1.6) months versus 1.6 (1.1) months, and had a longer duration of hospital stay 10.8 (6.0) days versus 5 (3.2) days, when compared to infants with a gestational age of 32–35 weeks, respectively.\n\nPediatric intensive care unit (PICU) admission rate was 23.5% (n = 4/17). Rate of PICU admission in babies who are <32 weeks was about three times higher than babies who were 32–35 weeks at birth (33.33%, n = 3/9, versus 12.50%, n = 1/8, respectively).\n\nOf the 925 enrolled at-risk cases, 2.27% (n = 21) were confirmed RSV positive as detected by RT-PCR. The incidence of positive RSV in the group of <32 weeks of gestation (2.68%, n = 11/410) was higher than the 32–35 weeks of the gestation group (1.94%, n = 10/515).\n\nPositive RSV infections were lower (2.02%, 17/841) in compliance babies compared to noncompliant subgroups (4.76%, n = 4/84), which is about 58% reduction (OR = 2.42, 95% CI: [0.79–7.37], p value 0.04).\n\nOn the other hand, it was observed that RSV RT-PCR was positive in about 22.66% (n = 17/75) in the compliant hospitalized children as compared to 33.33% (n = 4/12) in subgroups who were noncompliant to palivizumab (OR = 1.5, 95% CI: [0.41–5.54]).\n\nThere was a gradual but significant reduction in incidence hospitalization due to RSV-LRTI from 9.23% in the 2012-2013 season to 0.67% in the 2016-2017 season. The reduction in the hospitalization rate could be explained by the increase in the rate of compliance from 64.60% in the 2012-2013 season to 95.3% in the 2016-2017 season, as shown in Figure 3.\n\n4. Discussion\nThe present observational hospital-based study discusses a survey of hospitalizations due to RSV-LRTI infection in children who were eligible for palivizumab prophylaxis. The study covers five RSV seasons (September to March) from 2012 to 2017 at Latifa Women and Children Hospital in UAE. This study is the first of its kind in Dubai, UAE.\n\nThis observation gives comprehensive insight on the practice of RSV immunoprophylaxis (palivizumab), compliance with the protocol, and effectiveness in reducing the RSV-LRTI-related hospitalization rate in this part of the Middle East.\n\nThe scheduling of palivizumab immunoprophylaxis and infant characteristics included in our study was in accordance with the guideline formulated by the American Academy of Pediatrics and adopted at our institution [19, 21].\n\nWe reported a compliance rate to palivizumab prophylaxis of 90.90%, which is significantly higher than that observed in the other published literatures, 85.70% by Abushahin et al. [18], and 81.70% by Borecka and Lauterbach [22] We also registered an increase in compliance across 5 seasons which is comparable to the study quoted above [18]. This can be linked directly to increase awareness campaign and focused approach of care givers, which also observed in other studies [23].\n\nThe cumulative RSV infection-related hospitalization accounted for 2.20% of all at-risk babies, which is significantly lower than that observed in the IMpact study group result of 4.80% [17], and the result of a systematic review was conducted in 2016 by Mauskopf et al., where the incidence rates range from 2.30% to 10% [24]. Our data are comparable to other data from the middle east and other countries [7, 18, 25].\n\nThe hospitalization rate is significantly higher in the noncompliant group, 15.47% compared to 8.91% in children who were compliant to palivizumab prophylaxis, which corresponded to a significant reduction in incidence of RSV infection (62.40%) in the palivizumab prophylaxis group. Rate of hospitalization was significantly more in babies <32 weeks compared to the other subgroups (32–35 weeks). RSV positivity was lower in compliance babies compared to noncompliant subgroups, which is about 58% reduction in the incidence of RSV infection.\n\nOur result was better than 55% reduction seen in the IMpact study [17]. A 2013 Cochrane meta-analysis of three randomized trials comparing palivizumab with placebo in high-risk infants showed a 50% reduction in RSV-LRTI hospitalizations (from 101 to 50 per 1000) and intensive care unit admissions (from 34 to 17 per 1000) [26]. These results clearly show the protective effect of RSV palivizumab on RSV-LRTI-related hospitalization. In our study, the rate of RSV hospitalization reduced from 9.23% in the year 2012-13 to 0.67% in the year 2016-17. This decrease in hospitalization correlated directly with the increase in compliance to palivizumab (64.60% in 2012-2013 RSV season to 95.30% in 2016-2017 RSV season), which is comparable to the trend observed in other studies [18, 22].\n\nWe observed an average length of hospital stay of 7.7 ± 3.67 days, in babies admitted for RSV-related respiratory illness, which is very similar to the available literature [24, 27]. Pediatric intensive care admission rate was 23.50% of our RSV-LRTI hospitalized children, which is slightly higher than 6.50% reported by Viguria et al. [27] but is consistent with the results shown in a systematic review conducted by Mauskopf et al., and these incidences were more in babies of lower gestational age, which is quite similar to our result [24]. There was no death observed in our study.\n\nThe Japanese survey of pediatric ward hospitalization due to RSV infection after the introduction of palivizumab to high-risk infants showed that 8163 children were admitted to participating hospitals. Of that, 811 (9.93%) children had confirmed RSV-LRTI, with a mean gestational age of those at birth was 38 weeks. This study found that the appropriate use of palivizumab could reduce the hospitalization rate by 72% in infants and young children with a gestational age of 33–35 weeks [28].\n\nIn our study, we observed good tolerance to palivizumab injection, and no adverse effects were observed to the therapy. Our observation is consistent with other reports on palivizumab safety profiles [29].\n\nOur study is the first of its kind in Dubai, United Arab Emirates. The data collection process is robust. This research gave us baseline data regarding RSV infection and the effect of RSV immunoprophylaxis in the region.\n\nThe main limitation of this study is that it is a retrospective analysis. Retrospective observational studies limit the generalizability of the results. So, a randomized trial is needed to determine the efficacy of RSV prophylaxis in specific high-risk infants. We were not able to include at-risk children who were admitted to other hospitals or migrated out of UAE and have RSV-LRTI.\n\n5. Conclusion\nOur study demonstrated that RSV immunoprophylaxis with palivizumab in high-risk children leads to decrease in the incidence of RSV-related respiratory infection and related hospitalization. With increased awareness and effective implementation, high compliance to RSV immunoprophylaxis could be achieved.\n\nAcknowledgments\nEditorial support was provided by Hussien Ahmed, MD, of RAY Contract Research Organization. All the patients were acknowledged for their participation in the study.\n\nData Availability\nThe data used to support the findings of this study are available from the corresponding author upon request.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Flow diagram of the study participants and outcomes (gestational age subgroups). RSV, respiratory syncytial virus.\n\nFigure 2 Flow diagram of the study participants and outcomes (compliance subgroups). RSV, respiratory syncytial virus.\n\nFigure 3 Rates of hospitalization due to RSV infection and compliance to palivizumab across (2012-2013, 2013-2014, 2014-2015, 2015-2016, and 2016-2017) seasons. RSV, respiratory syncytial virus; LRTI, lower respiratory tract infection.\n\nTable 1 Inclusion criteria for RSV immunoprophylaxis (palivizumab).\n\nInclusion criteria\tAge at the start of RSV season\t\nGestational age ≤28 weeks\t≤12 months\t\nGestational age ≥29 to <32 weeks\t≤6 months\t\nGestational age ≥32 to <35 weeks\t≤6 months and RSV high-risk score of ≥49\t\nHemodynamically significant CHD, CCF, pulmonary hypertension, etc.\t≤6 months\t\nCLD who required medical therapy or required medical treatment within preceding 6 months before starting RSV season\t≤24 months\t\nCongenital anomaly of airways or neuromuscular diseases that compromise handling of respiratory secretions\t≤24 months\t\nCystic fibrosis, immunocompromised\t≤24 months (case by case basis)\t\nRSV, respiratory syncytial virus; CHD, congenital heart disease; CCF; congestive cardiac failure.\n\nTable 2 Babies' characteristics during a total of 5 seasons.\n\nVariables\tTotal babies (N = 925)\t<32 weeks (N = 410)\t32–35 weeks (N = 515)\t\np value\t\nGender, N (%)\t \t \t \t \t\n Female\t501 (54.10%)\t245 (59.80%)\t256 (49.70%)\t0.38\t\n Male\t424 (46.60%)\t165 (40.20%)\t259 (50.2%)\t \t\nGestational age in weeks, median (IQR)\t30.28 (4.1)\t27.52 (4.3)\t33.04 (4.2)\t0.35\t\n Female\t30.60 (3.8)\t27.90 (4.1)\t33.3 (3.95)\t \t\n Male\t29.96 (4.4)\t27.12 (4.5)\t32.8 (4.45)\t \t\nBirth weight, g median (IQR)\t1460.6 (410.2)\t1100.8 (383.8)\t1820.5 (397)\t0.42\t\n Female\t1482.5 (398.1)\t1116.5 (365.1)\t1848.5 (431)\t \t\n Male\t1438.7 (422.3)\t1084 (402.5)\t1792 (442)\t \t\nAge at enrollment, N (%)\t \t \t390 (75.70%)\t0.42\t\n ≤3 months\t589 (63.60%)\t199 (48.50%)\t50 (9.70%)\t \t\n 4–6 months\t168 (18.10%)\t118 (22.90%)\t29 (5.60%)\t \t\n 7–12 months\t98 (10.50%)\t69 (16.80%)\t7 (1.30%)\t \t\n >12 months\t70 (7.50%)\t63 (15.30%)\t \t \t\nMultiple birth, N (%)\t153 (16.50%)\t105 (25.60%)\t48 (9.30%)\t0.15\t\nChronic lungs disease, N (%)\t180 (19.40%)\t122 (29.70%)\t58 (11.20%)\t0.09\t\nCongenital heart disease, N (%)\t37 (4%)\t30 (7.30%)\t7 (1.30%)\t0.04\t\nPresence of siblings, N (%)\t698 (75.40%)\t333 (81.20%)\t365 (70.80%)\t0.71\t\nSiblings in school, N (%)\t389 (42%)\t140 (34.10%)\t249 (48.30%)\t0.23\t\nParental asthma, N (%)\t135 (14.50%)\t76 (18.50%)\t59 (11.40%)\t0.85\t\nSibling history of asthma, N (%)\t78 (8.43%)\t44 (10.73%)\t34 (6.60%)\t0.62\t\nMother's age, years median (IQR)\t30.5 (9)\t31.6 (9.4)\t29.4 (8.6)\t0.36\t\nChildcare center exposure, N (%)\t65 (7%)\t49 (11.90%)\t16 (3.10%)\t0.18\t\nSmoke exposure, N (%)\t307 (33.10%)\t157 (38.20%)\t150 (29.10%)\t0.29\t\nRSV, respiratory syncytial virus; IQR, interquartile range.\n\nTable 3 RSV-related respiratory disease characteristics of hospitalized infants during a total of 5 seasons.\n\nVariables\tTotal babies (N = 925)\t<32 weeks (N = 410)\t32–35 weeks (N = 515)\t\np value\t\nCompliance (received prophylaxis as per guidelines), N (%)\t841 (90.90%)\t372 (90.80%)\t469 (91%)\t0.84\t\nBabies hospitalized (from compliance babies), N (%)\t75/841 (8.91%)\t45/372 (12.01%)\t30/469 (6.39%)\t0.04\t\nRSV positive among compliance babies, N (%)\t17/841 (2.02%)\t9/372 (2.41%)\t8/469 (1.70%)\t0.46\t\nRSV positive among hospitalized babies (compliance babies), N (%)\t17/75 (22.66%)\t9/45 (20%)\t8/30 (26.66%)\t0.50\t\nTotal hospitalized baby (from at-risk population), N (%)\t87/925 (9.40%)\t51/410 (12.43%)\t36/515 (6.99%)\t0.03\t\nRSV positive in all at risk babies, N (%)\t21/925 (2.27%)\t11/410 (2.68%)\t10/515 (1.94%)\t0.45\t\nRSV positive among at risk hospitalized babies, N (%)\t21/87 (24.13%)\t11/51 (21.56%)\t10/36 (27.77%)\t0.50\t\nBabies hospitalized (noncompliance babies), N (%)\t12/84 (14.28%)\t6/38 (15.78%)\t6/46 (13.04%)\t0.50\t\nRSV positivity in babies not received palivizumab, N (%)\t4/84 (4.76%)\t2/38 (5.26%)\t2/46 (4.3%)\t0.80\t\nRSV-related length of stay, days median (IQR)\t7.9 (4.6)\t10.8 (6.0)\t5 (3.2)\t0.15\t\nRSV-related PICU admission, N (%)\t4/17 (23.50%)\t3/9 (33.30%)\t1/8 (12.50%)\t0.32\t\nAge at the 1st dose of palivizumab for RSV hospitalized babies, months median (IQR)\t2.1 (1.3)\t2.8 (1.5)\t1.5 (1.0)\t0.26\t\nAge at hospital admission, months median (IQR)\t2.35 (1.35)\t3.1 (1.6)\t1.6 (1.1)\t0.30\t\nRSV, respiratory syncytial virus; IQR, interquartile range; PICU, pediatric intensive care unit.\n==== Refs\n1 Griffiths C. 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Controlled trial to evaluate protection of high-risk infants against respiratory syncytial virus disease by using standard intravenous immune globulin Antimicrobial Agents and Chemotherapy 1993 37 8 1655 1658 10.1128/aac.37.8.1655 2-s2.0-0027255190 8215279 \n13 Kasel J. A. Walsh E. E. Frank A. L. Baxter B. D. Taber L. H. Glezen W. P. Relation of serum antibody to glycoproteins of respiratory syncytial virus with immunity to infection in children Viral Immunology 1987 1 3 199 205 10.1089/vim.1987.1.199 2-s2.0-0023465658 3509676 \n14 Committee on Infectious Diseases and Bronchiolitis Guidelines Committee Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection Pediatrics 2014 134 2 e620 e638 10.1542/peds.2014-1666 2-s2.0-84905228480 25070304 \n15 Feltes T. F. Cabalka A. K. Meissner H. C. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease The Journal of Pediatrics 2003 143 4 532 540 10.1067/s0022-3476(03)00454-2 2-s2.0-0242298724 14571236 \n16 Subramanian K. N. Weisman L. E. Rhodes T. Safety, tolerance and pharmacokinetics of a humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. MEDI-493 study group Pediatric Infectious Disease Journal 1998 17 2 110 115 9493805 \n17 The IMpact-RSV Study Group Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants Pediatrics 1998 102 3 531 537 10.1542/peds.102.3.531 2-s2.0-0031683919 \n18 Abushahin A. Janahi I. Tuffaha A. Effectiveness of palivizumab immunoprophylaxis in preterm infants against respiratory syncytial virus disease in Qatar International Journal of General Medicine 2018 11 41 46 10.2147/ijgm.s156078 2-s2.0-85042708146 29430194 \n19 Committee on Infectious Diseases Modified recommendations for use of palivizumab for prevention of respiratory syncytial virus infections Pediatrics 2009 124 6 1694 1701 10.1542/peds.2009-2345 2-s2.0-71949099031 19736258 \n20 Paes B. Steele S. Janes M. Pinelli J. Risk-scoring Tool for respiratory syncytial virus prophylaxis in premature infants born at 33–35 completed weeks’ gestational age in Canada Current Medical Research and Opinion 2009 25 7 1585 1591 10.1185/03007990902929112 2-s2.0-67650489089 19469698 \n21 Committee on Infectious Diseases and Bronchiolitis Guidelines Committee Updated guidance for palivizumab prophylaxis Among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection Pediatrics 2014 134 2 415 420 10.1542/peds.2014-1665 2-s2.0-84905278885 25070315 \n22 Borecka R. Lauterbach R. Compliance with the RSV immunoprophylaxis dosing schedule in the polish registry for palivizumab (2008–2014) Developmental Period Medicine 2018 22 4 308 314 30636227 \n23 Bernard L. Lecomte B. Pereira B. Proux A. Boyer A. Sautou V. Optimisation de la prévention de la bronchiolite à VRS chez les nouveaux-nés à risque et les prématurés: mesure de l’impact d’une intervention éducative ciblée Archives de Pédiatrie 2015 22 2 146 153 10.1016/j.arcped.2014.11.015 2-s2.0-84921550318 25534557 \n24 Mauskopf J. Margulis A. V. Samuel M. Lohr K. N. Respiratory syncytial virus hospitalizations in healthy preterm infants The Pediatric Infectious Disease Journal 2016 35 7 e229 e238 10.1097/inf.0000000000001163 2-s2.0-84964402644 27093166 \n25 Paes B. Mitchell I. Li A. Harimoto T. Lanctôt K. L. Respiratory-related hospitalizations following prophylaxis in the Canadian registry for palivizumab (20052012) compared to other international registries Clinical and Developmental Immunology 2013 2013 15 917068 10.1155/2013/917068 2-s2.0-84880152109 \n26 Andabaka T. Nickerson J. W. Rojas-Reyes M. X. Rueda J. D. Bacic Vrca V. Barsic B. Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children Cochrane Database of Systematic Reviews 2013 4 CD006602 10.1002/14651858.CD006602.pub4 2-s2.0-84881346119 \n27 Viguria N. Martínez-Baz I. Moreno-Galarraga L. Sierrasesúmaga L. Salcedo B. Castilla J. Respiratory syncytial virus hospitalization in children in northern Spain PLoS One 2018 13 11 e0206474 10.1371/journal.pone.0206474 2-s2.0-85056548884 \n28 Kusuda S. Takahashi N. Saitoh T. Survey of pediatric ward hospitalization due to respiratory syncytial virus infection after the introduction of palivizumab to high-risk infants in Japan Pediatrics International 2011 53 3 368 373 10.1111/j.1442-200x.2010.03249.x 2-s2.0-79959748044 20854284 \n29 Romero J. R. Palivizumab prophylaxis of respiratory syncytial virus disease from 1998 to 2002: results from four years of palivizumab usage The Pediatric Infectious Disease Journal 2003 22 S46 S54 10.1097/01.inf.0000053885.34703.84 12671452\n\n",
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"issue": "2019()",
"journal": "Canadian respiratory journal",
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"medline_ta": "Can Respir J",
"mesh_terms": "D000998:Antiviral Agents; D018890:Chemoprevention; D002675:Child, Preschool; D003550:Cystic Fibrosis; D005260:Female; D006330:Heart Defects, Congenital; D006760:Hospitalization; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D008171:Lung Diseases; D008297:Male; D009468:Neuromuscular Diseases; D000069455:Palivizumab; D018357:Respiratory Syncytial Virus Infections; D015619:Respiratory System Abnormalities; D012189:Retrospective Studies; D012306:Risk; D014479:United Arab Emirates",
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"title": "Palivizumab Prophylaxis among Infants at Increased Risk of Hospitalization due to Respiratory Syncytial Virus Infection in UAE: A Hospital-Based Study.",
"title_normalized": "palivizumab prophylaxis among infants at increased risk of hospitalization due to respiratory syncytial virus infection in uae a hospital based study"
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"abstract": "Background and objective: To describe the clinical characteristics including the bronchoalveolar lavage fluid (BALF) characteristics of patients with antisynthetase syndrome (AS) associated interstitial lung disease (ILD) in a tertiary ILD outpatient clinic, their medical therapy and outcome. Methods: Retrospective cohort study of patients with AS-ILD. All available data of clinical characteristics, pulmonary function tests, laboratory parameters, BALF analysis, histology, high-resolution computed tomography (HRCT) and treatment were collected from the patient files. Results and conclusions: Twelve patients with AS-ILD were identified. Mean age at diagnosis was 55 years (range 45-69), 67% were female. Mean follow-up time was 7 years. The anti-aminoacyl tRNA-synthetase antibodies presented were anti-Jo1 (n = 6), anti-PL7 (n = 3), anti-PL12 (n = 2) and anti-EJ (n = 1). HRCT patterns were mainly non-specific interstitial pneumonia (75%). Four patients had BALF-eosinophilia (two of four anti-Jo1 patients) and two anti-PL12 positive patients had BALF-neutrophilia. Two AS-ILD patients improved on rituximab (RTX) as induction treatment and three out of four patients were stabilised on RTX as maintenance treatment. Two patient obtained remission by cyclophosphamide. Four patients were stabilised on azathioprine alone or in combination with oral corticosteroids. Our cohort of AS-ILD patients showed clinical characteristics in accordance with previous reports at baseline and was comparable to other cohorts. Most patients can be stabilised with immunosuppressive treatment.",
"affiliations": "Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark.;Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark.;Department of Respiratory Diseases, Vejle Hospital, Vejle, Denmark.;Diagnostic Center, Silkeborg Regional Hospital, Silkeborg, Denmark.;Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark.;Department of Respiratory Diseases, Sydvestjydsk Regional Hospital, Esbjerg, Denmark.",
"authors": "Jensen|Mads Lynge|ML|;Løkke|Anders|A|0000-0002-6905-4141;Hilberg|Ole|O|0000-0002-3075-3463;Hyldgaard|Charlotte|C|;Bendstrup|Elisabeth|E|0000-0002-4238-6963;Tran|Dan|D|",
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"country": "United States",
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"doi": "10.1080/20018525.2019.1583516",
"fulltext": "\n==== Front\nEur Clin Respir JEur Clin Respir JZECRzecr20European Clinical Respiratory Journal2001-8525Taylor & Francis 158351610.1080/20018525.2019.1583516Research ArticleClinical characteristics and outcome in patients with antisynthetase syndrome associated interstitial lung disease: a retrospective cohort study M. L. JENSEN ET AL.EUROPEAN CLINICAL RESPIRATORY JOURNALJensen Mads Lynge ahttp://orcid.org/0000-0002-6905-4141Løkke Anders ahttp://orcid.org/0000-0002-3075-3463Hilberg Ole bHyldgaard Charlotte chttp://orcid.org/0000-0002-4238-6963Bendstrup Elisabeth aTran Dan da Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmarkb Department of Respiratory Diseases, Vejle Hospital, Vejle, Denmarkc Diagnostic Center, Silkeborg Regional Hospital, Silkeborg, Denmarkd Department of Respiratory Diseases, Sydvestjydsk Regional Hospital, Esbjerg, DenmarkCONTACT Mads Lynge Jensen madjesen@rm.dkDepartment of Respiratory Diseases and Allergy, Aarhus University Hospital, Nørrebrogade 44, 8000Aarhus, DenmarkSUMMARY AT A GLANCE:\n\nAntisynthetase syndrome is a rare entity, which is often associated to interstitial lung disease and polymyositis. Early diagnosis is essential for disease control. This study describes the outcomes of different treatment regimes with focus on diagnostic approaches and pulmonary outcomes, including bronchoalveolar lavage differential count, which have not been described in previous reports of this condition.\n\n2019 27 2 2019 6 1 158351603 11 2018 07 2 2019 © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.2019The Author(s)This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 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.ABSTRACT\nBackground and objective: To describe the clinical characteristics including the bronchoalveolar lavage fluid (BALF) characteristics of patients with antisynthetase syndrome (AS) associated interstitial lung disease (ILD) in a tertiary ILD outpatient clinic, their medical therapy and outcome.\n\nMethods: Retrospective cohort study of patients with AS-ILD. All available data of clinical characteristics, pulmonary function tests, laboratory parameters, BALF analysis, histology, high-resolution computed tomography (HRCT) and treatment were collected from the patient files.\n\nResults and conclusions: Twelve patients with AS-ILD were identified. Mean age at diagnosis was 55 years (range 45–69), 67% were female. Mean follow-up time was 7 years. The anti-aminoacyl tRNA-synthetase antibodies presented were anti-Jo1 (n = 6), anti-PL7 (n = 3), anti-PL12 (n = 2) and anti-EJ (n = 1). HRCT patterns were mainly non-specific interstitial pneumonia (75%). Four patients had BALF-eosinophilia (two of four anti-Jo1 patients) and two anti-PL12 positive patients had BALF-neutrophilia. Two AS-ILD patients improved on rituximab (RTX) as induction treatment and three out of four patients were stabilised on RTX as maintenance treatment. Two patient obtained remission by cyclophosphamide. Four patients were stabilised on azathioprine alone or in combination with oral corticosteroids.\n\nOur cohort of AS-ILD patients showed clinical characteristics in accordance with previous reports at baseline and was comparable to other cohorts. Most patients can be stabilised with immunosuppressive treatment.\n\nKEYWORDS\nAntisynthetase syndromebronchoalveolar lavage fluidinterstitial lung diseasespolymyositistreatments\n==== Body\nIntroduction\nAntisynthetase syndrome (AS) is defined by the occurrence of IgG anti-aminoacyl RNA-synthetase (anti-ARS) antibodies and associated types of autoimmune manifestations, mainly myositis. The autoimmunity accounts for important clinical manifestations, such as interstitial lung disease (ILD), arthritis, fever, Raynaud´s phenomenon and mechanic’s hand, which can be present at disease onset or appear later as the disease progresses [1]. At present, eight anti-aminoacyl tRNA-synthetase antibodies (anti-ARS) have been identified: anti-Jo1 (histidyl), anti-PL7 (threonyl), anti-PL12 (alanyl), anti-EJ (glycyl), anti-OJ (isoleucyl), anti-KS (asparaginyl), anti-ZO (phenylalanyl) and anti-YRS/HA (tyrosyl). The most commonly encountered antibody is anti-Jo1 that accounts for up to 60–80% [2–4]. ARS are cytoplasmic enzymes that play a vital role in protein synthesis. Defect of these enzymes can theoretically cause adverse events from every organ. AS is a rare, but probably underdiagnosed disease with a reported prevalence for Caucasians of 87/100,000 in a Norwegian study [5]. The reported incidence was 6–10 per million inhabitants per year diagnosed by presence of anti-ARS and polymyositis/dermatomyositis (PM/DM). Approximately, 25–30% of PM/DM patients had anti-ARS [5]. In a US population, the incidence of AS is considered as low as one in 3–4 million with a diagnostic delay of more than 2 years [6].\n\nThe typical triad of ILD, myositis and arthritis accounts for up to 90% of AS [1]. However, more recent studies report increased number of cases with mono-organ involvement at the time of diagnosis, most likely due to earlier diagnosis caused by increasing awareness [7]. In rare cases, cardiac and renal involvement have been reported [8,9].\n\nILD is a major contributor to morbidity and mortality [3,10], and recent data suggest that different AS-phenotypes, especially anti-PL7 and 12, could be related to incidence and severity of ILD. The pulmonary damage may be irreversible, which is consistent with early scarring of the interstitium [7]. The most common radiological and histopathological pattern is non-specific interstitial pneumonia (NSIP)[11].\n\nThe optimal treatment regimen has yet to be established. Due to a high relapse rate in patients treated with corticosteroid alone, a combination of corticosteroid and other immunosuppressants, such as methotrexate, azathioprine (AZA), cyclophosphamide and mycophenolate is now frequently used. In severe or rapidly progressive ILD, rituximab (RTX) has been used with some success [12].\n\nThe aim of the present study was to describe the clinical characteristics, therapy and outcome of a cohort of patients with AS associated ILD (AS-ILD).\n\nMethods\nICD-10 codes, J84 and M33, in the hospital registries were used to identify all patients with an AS-ILD diagnosis in our tertiary ILD referral centre in Aarhus between October 2006 and August 2017. The centre serves 1.9 million citizens from the central and north Denmark regions. All available data regarding clinical characteristics, pulmonary function (PF) tests, laboratory parameters, bronchoalveolar lavage fluid (BALF), high-resolution computed tomography (HRCT), treatment and disease course were collected from the patient files.\n\nThe diagnosis of AS was made by the presence of anti-ARS accompanied by key clinical features, including ILD and/or PM/DM and evaluated by an expert panel of rheumatologist, respiratory physicians and radiologist. Raynaud’s phenomenon, arthritis, fever and mechanic’s hands supported the diagnosis, but their presence was not mandatory. The presence of ILD was evaluated at a multidisciplinary team discussion with the presence of an expert ILD radiologist and expert ILD respiratory physicians.\n\nPatients underwent clinical evaluation every 3–6 months. Follow-up included PF tests and laboratory parameters. A change in FVC of more than 10% points (absolute) and/or a change in DLCO of more than 15% points were considered significant whereas smaller changes in FVC and DLCO were regarded as stable disease.\n\nPatient data were retrieved from the Danish National Registry for Interstitial Lung Diseases. The registry is approved by the Danish Health Authority. Patient confidentiality was maintained.\n\nResults\nTwelve patients with AS-ILD were identified between 2005 and 2017. Three patients were diagnosed with AS at our clinic whereas the remaining nine patients were referred from rheumatology outpatient clinics. The prevalence of AS-ILD was 6.3/1.000.000 population.\n\nMedian age at symptom onset was 55 years (range 44–68 years) and median age at the time of diagnosis was 57 years (range 45–69 years). Median diagnostic delay was 24 months (range 3–38 months) from the first visit at the rheumatology or respiratory outpatient clinic. Eight patients (66%) were female (Table 1). All were Caucasians except one who was African-American. Median follow-up time was 7 years (range 1–11 years).10.1080/20018525.2019.1583516-T0001Table 1. Demographics and clinical features of AS associated ILD.\n\nCase\tSerology\tSex/age at onset\tTobacco\n- Status\n- PYa\tPulmonary symptoms\tOthers symptoms\tMax. CKb\tPM/DM\nScleroderma\tArthritis\t\n1\tJo1\nRO5\tF/44\tFormer\n2PY\tAcute onset dyspnoea\nCough\tFever\nRaynaud\nMechanic’s hands\t5940\tPM\tYes\t\n2\tJo1\nRO5\tF/47\tNever\tAsymptomatic\tRaynaud\nGottron’s sign Mechanic’s hands\nSicca symptoms\t574\tDM\nScleroderma\tYes\t\n3\tJo1\nANA\nRO5\tF/53\tNever\tDyspnoea\tMyalgia\nGottron’s sign\nMechanic’s hands\t111\tScleroderma\tNo\t\n4\tJo1\nANA\nRO5\tF/61\tFormer\n10PY\tDyspnoea\tGottron’s sign\t76\tPM\tYes\t\n5\tJo1\nANCA\nc\tF/67\tFormer\n30PY\tAcute onset dyspnoea\nCough\tFever\nRaynaud,\nGottron’s sign\t189\tDM\nScleroderma\tYes\t\n6\tJo1\nANA\nRO5\tM/51\tNever\tDyspnoea\nCough\tNone\t825\tDM\tYes\t\n7\tPL7\nANA\nRO5\tF/55\tActive\n80PY\tDyspnoea\nCough\tFever\nMechanic’s hands\t305\tPM\tNo\t\n8\tPL7\nRO5\tM/58\tNever\tDyspnoea\nCough\tFever\nRaynaud\nMechanic’s hands\t40\tNo\tYes\t\n9\tPL7\nRO5\tM/68\tActive\n20PY\tDyspnoea\nCough\tRaynaud\nGottron’s sign\t3583\tDM\tNo\t\n10\tPL12\nRO5\tF/52\tFormer\n35PY\tDyspnoea\tFever\nMyalgia,\nRaynaud\t107\tNo\tYes\t\n11\tPL12\nANA\nRO5\tM/48\tFormer\n40PY\tAcute onset dyspnoea\nCough\tFever\t481\tNo\tYes\t\n12\tEJ\nRO5\tF/55\tFormer\n2PY\tDyspnoea\tMechanic’s hands\t48\tNo\tYes\t\nF: Female, M: Male, aPack years, bMaximum creatine kinase. Reference range: 50–150 units per litre. cNot tested for RO5\n\n\n\nCough and/or dyspnoea were reported in 11 of 12 patients. Acute onset of dyspnoea was reported in three patients, gradual onset of dyspnoea in eight patients and one patient had no respiratory symptoms. The most common extrapulmonary symptoms were joint involvement (9/12), fever (6/12), mechanic’s hands (6/12), Raynaud’s phenomenon (5/12), Gottron’s sign (5/12) and sicca symptoms (2/12).\n\nFive of six anti-Jo1 positive patients had PM/DM. Two anti-PL12-positive patients were amyopathic.\n\nAntibody distribution, demographics and clinical features are shown in Table 2. Coexistence of anti-SSA/Ro5 was found in all 11 patients tested, and positive ANA in five patients. One patient with anti-SSA/Ro5 had sicca symptoms. Three patients were diagnosed with an overlap syndrome of systemic scleroderma and AS. Creatinine kinase was elevated in seven patients (Table 1).10.1080/20018525.2019.1583516-T0002Table 2. Demographics and clinical features according to serology.\n\nSerology\tPatient (n)\tMean agea\tFemale %\tPM/DM %\tArthritis %\tInitial HRCT pattern\nNSIP/UIP/non-specific (n)\tOthers signs\t\nJo1\t6\t56\t83\t87\t87\t4/1/1\tRaynaud:\t50%\t\nMH:\t50%\t\nGT:\t67%\t\nFever:\t33%\t\nPL7\t3\t61\t33\t66\t33\t3/0/0\tRaynaud:\t66%\t\nMH:\t66%\t\nGT:\t33%\t\nFever:\t66%\t\nPL12\t2\t52\t50\t0\t100\t1/1/0\tRaynaud:\t50%\t\nMH:\t0%\t\nGT:\t0%\t\nFever\t100%\t\nEJ\t1\t55\t100\t0\t100\t1/0/0\tRaynaud:\t0%\t\nMH:\t100%\t\nGT:\t0%\t\nFever:\t0%\t\nMH = Mechanic’s hands, GT = Gottron’s sign. aAt symptom onset\n\n\n\nBronchoscopy data were available in nine patients. All cultures were negative, including culture for mycobacteria. BAL neutrophilia was seen in the two anti-PL12-positive patients, BAL lymphocytosis was seen in three patients and eosinophilia in four patients, two of those were anti-Jo1 positive, one anti-PL7 and one anti-EJ positive (Table 3). All four patients were non-smokers. There was no correlation between BAL differential count and HRCT pattern or disease progression.10.1080/20018525.2019.1583516-T0003Table 3. Bronchoalveolar lavage leukocyte differential count.\n\nCase\tSerology\t% Macrophages\t% Granulocytes\t% Lymphocytes\t% Eosinophils\t\n1\tJo1\t82\t10\t4\t4\t\n2\tJo1\t–\t–\t22\t–\t\n4\tJo1\t72\t6\t4\t18\t\n6\tJo1\t49\t6\t23\t22\t\n7\tPL7\t36\t7\t22\t35\t\n8\tPL7\t67\t15\t17\t1\t\n10\tPL12\t70\t25\t3\t2\t\n11\tPL12\t48\t50\t0\t2\t\n12\tEJ\t76\t12\t3\t9\t\n\n\nHRCT at onset revealed a NSIP-pattern in nine patients, a non-specific ILD-pattern in one patient and a usual interstitial pneumonia (UIP) pattern in two patients (Table 4).10.1080/20018525.2019.1583516-T0004Table 4. Treatment and outcome.\n\n \tTreatment\tPulmonary function\t \t \t\nCase\tInitial\tMaintenance\tPrimary\tInitial Maintenance\tILD\tFollow-up (years)\t\n1\tRTX\nAZA\nOral steroid\tRTX\nAZA\nOral steroid\tFVC: 75% \nDLCO: 53%\t88%\n49%\t106%\n68%\tNon-specific\nProgression to NSIP\t9\t\n2\tOral steroid\tAZA\tFVC: 84% \nDLCO: 64%\t90%\n49%\t90%\n52%\tNSIP\nProgression to UIP\t11\t\n3\tOral steroid\tNone\tFVC: 86%\nDLCO: 77%\t94%\n70%\t99%\n72%\tNSIP\nUnchanged\t4\t\n4\tSteroid pulse\nCyclophosphamide\tNone\tFVC: 120%\nDLCO: 64%\t105%\n64%\t103%\n55%\tUIP\nProgression\t5 † colorectal cancer\t\n5\tSteroid pulse\nCyclophosphamide\tAZA\nOral steroid\tFVC: 29%\nDLCO: 19%\t38%\n30%\t37%\n20%\tNSIP\nUnchanged\t10 †\nsepsis\t\n6\tSteroid pulse\nCyclophosphamide\tAZA\tFVC: 85%\nDLCO: 40%\t92%\n54%\t87%\n61%\tNSIP\nProgression to UIP\t10\t\n7\tSteroid pulse\nMTX\tRTX\nMycophenolate\nOral steroid\tFVC: 51%\nDLCO: 34%\t51%\n37%\t55%\n39%\tNSIP\nProgression\t2\t\n8\tRTX\nOral steroid\tRTX\nMTX\nOral steroid\tFVC: 51%\nDLCO: 47%\t90%\n67%\t83%\n60%\tNSIP\nImprovement\t7\t\n9\tSteroid pulse\nCyclophosphamide\tAZA\nOral steroid\tFVC: 83%\nDLCO: 38%\t133%\n66%\t73%\n33%\tNSIP\nProgression\n(mild)\t7\t\n10\tSteroid pulse\nCyclophosphamide\tNone\tFVC: 58%\nDLCO: 45%\t65%\n38%\tDeceased\tNSIP\nProgression\t4 †\nmulti-organ failure\t\n11\tSteroid pulse\nCyclophosphamide\tRTX\nMTX\nOral steroid\tFVC: 51%\nDLCO: 30%\t57%\n33%\t33%\n32%\tUIP\nProgression\t9 †\nsepsis\t\n12\tSteroid pulse Cyclophosphamide\tAZA\nOral steroid\tFVC: 49%\nDLCO: 43%\t73%\n54%\t73%\n58%\tNSIP\nImprovement\t7\t\n†: Died during follow-up\n\nSteroid pulse protocol: 500 mg methyl prednisone daily for 3 days, repeated every second week for 3 months, then each months for a total of 12 months.\n\nRituximab protocol: Two infusions of 1,000 mg rituximab, at days 0 and 14, repeated every 6 months.\n\nCyclophosphamide pulse therapy protocol: infusion of 600 mg per m2 every 4 weeks\n\n\n\nSeven patients presented with a restrictive PF pattern and two with an obstructive PF, one former smoker and one never smoker. The median FVC was 69% predicted (29–120%) and median DLCO 42% predicted (19–70%). One patient developed a restrictive pattern during follow-up.\n\nFour different treatment regimens were used as initial therapy (Table 4). Each patient could receive more than one treatment regimen depending on treatment response. Seven patients were initially treated with steroid pulses and cyclophosphamide, which resulted in improved PF in two patients, unchanged in four and deterioration in one. Two patients were initially started on RTX with either AZA plus oral steroids (OS) or OS alone. Both patients had significant improvement of their PF. Two patients had OS as initial therapy and remained stable.\n\nMaintenance therapy with AZA ± OS was given to five patients and stabilised four of them. Four patients received RTX in combination with other immunosuppressants, which resulted in improvement of one patient, stabilisation of two and one with deterioration. Only one patient (case 3) had no maintenance therapy due to mild symptoms and stable PF and HRCT, cases 4 and 10 were deemed terminally ill and it was decided to refrain from maintenance therapy. All other patients were on continuous maintenance therapy.\n\nAll three anti-PL7-positive patients had an initial low PF, but two patients improved on initial therapy. Two patients were stabilised on maintenance therapy.\n\nOne of the two anti-PL12-positive patients had a low PF and was stabilised with initial therapy but deteriorated on maintenance therapy (case 11). The other patient deteriorated in spite of treatment (case 10).\n\nChanges in HRCT after treatment are presented in Table 4. Of the seven patients receiving steroid pulse courses and cyclophosphamide as initial therapy, three had HRCT improvement and three progressed despite treatment. Two patients received RTX, and one improved. During maintenance therapy, one patient was stabilised on RTX, one improved and one regressed from unspecific mild ILD to a NSIP pattern. Two patients were stabilised on AZA ± OS and three progressed in spite of treatment (Figures 1 and 2). Two patients (cases 2 and 6) progressed to a UIP pattern.10.1080/20018525.2019.1583516-F0001Figure 1. HRCT at debut. A NSIP pattern with consolidations, sub-pleural sparing and ground glass opacities in a perilobular localisation are seen in the basal lung zones.\n\n10.1080/20018525.2019.1583516-F0002Figure 2. HRCT 3 years later. Distributions of the interstitial features are unchanged but the pattern has turned more fibrotic with the development of traction bronchiectasis and increased reticulation.\n\n\n\nFour patients (cases 3, 5, 10 and 11) developed pulmonary hypertension diagnosed by echocardiography (verified by right heart catheterisation in two patients).\n\nFour patients died during follow-up. Causes of death were colorectal cancer (case 4), pneumonia/sepsis (cases 5 and 11) and prolonged multi-organ failure (case 10).\n\nDiscussion\nThe present study reports the characteristics of a cohort of 12 patients with AS-ILD. The clinical characteristics are in accordance with previous reports with respect to gender and age distribution and the majority being anti-Jo1 positive. NSIP was the most common radiological pattern. We initially observed two definite UIP patterns, and two patients progressed to a UIP pattern during treatment. A large previous study did not report the presence of UIP in AS-ILD [11].\n\nThe clinical characteristics at the time of diagnosis are consistent with the classic triad of arthritis, myositis and ILD. However, the presence of the triad at diagnosis could be caused by diagnostic delay and cumulative, progressive symptoms [7,13]. Pinal-Fernandez et al. [7] found that >60% of AS patients experienced pulmonary and muscle involvement but not necessarily simultaneously. This was also reported by Cavagna et al. [1,13] who recommend an earlier screening for anti-ARS in patients presenting with arthritis alone and even in those fulfilling the criteria for rheumatoid arthritis given the similarities of the diseases. Screening for anti-ARS in patients with mono-symptomatic arthritis would be costly and with a low positive hit rate and even risk of false positive or negative results. ILD may also be the only initial presenting manifestation of the disease, typically for anti-PL7 and anti-PL12, although we did not find this correlation in our cohort [14]. Pinal-Fernandez et al. [7] speculated that the pulmonary lesions in AS-ILD – especially for anti-PL12 patients – were irreversible, which is supported by our findings. Diagnostic delay is not uncommon in rare diseases, however early diagnosis and initiation of therapy is essential in order to slow down or hopefully prevent irreversible lung damage in AS-ILD [15]. We therefore suggest to screen for anti-ARS in patients with clinical suspicion of connective tissue disease, females, middle age, symptoms or clinical signs of connective tissue disease and a HRCT pattern of NSIP. Especially a thorough investigation for skin manifestations, such as the red, scaly, elevated Gottron’s papules on the metacarpophalangeal and interphalangeal finger joints or mechanic’s hands with hyperkeratotic, scaly and fissured papules on the first web space (Figure 3) could lead to an earlier diagnosis.\n10.1080/20018525.2019.1583516-F0003Figure 3. Left: Gottron’s papules; right: mechanic’s hands.\n\n\n\nThe definition of ILS is non-coherent when different studies of AS-ILD are compared. We defined ILS by criteria for both PF and HRCT patterns, while other studies only used HRCT patterns. This compromises the comparability of the few published studies as the definition of AS varies among studies. In our study, an expert panel of radiologists, respiratory physicians and rheumatologists assessed every patient, but the diagnosis still rely on the expert opinions of the panel rather than on well-defined internationally accepted criteria and is opt to vary depending on, e.g. the level of experience and culture. The need for diagnostic criteria for AS is obvious.\n\nOur study is the first to report BAL findings in AS-ILD. No specific pattern or relationship with HRCT patterns was found. All BALF was collected at diagnosis when AS was active. Passadore I et al. [16] analysed BALF of four AS patients for protein content but did not present differential counts. Interestingly, both our patients with anti-PL12 had BALF neutrophilia revealing a possible trend. Four patients had eosinophilia. None were smokers in the months up to and at the time of the bronchoscopy. Thus, BALF differential count may have a role as a possible step towards a personalised treatment in AS-ILD in the future, but larger studies are needed.\n\nCase 4 died of malignancy (colorectal cancer). It has previously been suggested that AS patients have increased risk of cancer. However, in recent studies, the incidence of malignancy seemed similar to the general population [7].\n\nTreatment of AS is challenging and based upon small case series rather than randomised, clinical trials. It is generally agreed that corticosteroids are the first line therapy with the addition of other immunosuppressants, such as mycophenolate, methotrexate, AZA or cyclophosphamide, but there is no consensus on which immunosuppressive agents to prefer. The choice depends primarily on the severity of the disease [3,17]. Treatment in our cohort followed these recommendations. Seven of our patients (case 4–6, 9–12) received high doses of corticosteroid and cyclophosphamide pulse courses as induction therapy. This resulted in improvement in PF of only two patients, but stabilised four. Schnabel et al. [18] reported a favourable response to intravenous pulse cyclophosphamide in 10 patients with progressive ILD. We found disease progression in spite of cyclophosphamide therapy in three of seven patients, however, two of these patients were anti-PL12 positive, which correlates to other studies also finding a high risk of treatment failure in patients with anti-PL12 antibodies[7].\n\nIn recent years, treatment regimes with RTX as initial therapy to AS-ILD have emerged. Sem M et al. [19] reported some success with RTX in nine AS-ILD patients. However, their follow-up period was limited to 6 months after treatment initiation. Two of our patients received RTX as initial therapy with favourable response. They both continued on RTX as maintenance therapy with one still being stabilised after a follow-up period of 7 years and another with a mild progression to a NSIP pattern during the 9-year follow-up. Two other patients were started on RTX as maintenance therapy and one of them stabilised. The two patients with UIP pattern on HRCT (case 4 and 11) showed no response to treatment. This is in line with lacking treatment responses seen in other patients with connective tissue disease and UIP pattern, especially rheumatoid arthritis associated UIP [20]. It could be speculated that a subgroup of AS patients with non-UIP pattern could be treated successfully with RTX as the first choice of treatment, however more studies are needed.\n\nThere are obvious limitations to our study due to the small patient number. Not all AS-ILD patients may have been included because we did not include arthritis codes in our inclusion criteria. Cases with ILD and arthritis, who had not presented with myositis yet, may have been missed. The strength of our study is the multidisciplinary diagnosis and the well-characterised cohort with long follow-up\n\nIn summary, our cohort of AS-ILD patients showed clinical characteristics in accordance with previous reports. The clinical course and the response to treatments were variable. Complete remission in AS-ILD is rare and long-term immunosuppressive therapy is usually required. The optimal treatment regime is not yet defined and well-designed prospective, multicentre studies are warranted. However, promising studies for the treatment of ILD-associated connective tissue diseases are ongoing [21]. Our cohort is limited by the small sample size, but contributes to the general knowledge of AS. Hopefully, improved sub-classification of AS-ILD by specific anti-ARS, ILD patterns and symptomatology will lay the foundation for more specific and personalised treatment strategies.\n\nMads Lynge Jensen, MD, is a specialist registrar at The Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Denmark. He is a 5th year registrar in pulmonary diseases.\n\nAnders Løkke, MD, is a consultant at The Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Denmark. He is a specialist in pulmonary diseases, and his main research focus is COPD.\n\nOle Hilberg, MD, DMSc, is a consultant at The Department of Respiratory Diseases, Vejle Hospital, Vejle, Denmark. He is a specialist in pulmonary diseases with several research areas.\n\nCharlotte Hyldgaard, MD, PhD, is a speciality registrar at The Diagnostic Center, Silkeborg Hospital, Silkeborg, Denmark. She is a specialist in pulmonary medicine, and her main research focus is interstitial lung diseases.\n\nElisabeth Bendstrup, MD, PhD, is a consultant at The Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Denmark. She is a specialist in pulmonary diseases, and her main research focus is interstitial lung diseases.\n\nDan Tran, MD, is a consultant at The Department of Respiratory Diseases, Sydvestjydsk Regional Hospital, Esbjerg, Denmark. He is a specialist in pulmonary diseases.\n\nDisclosure statement\nNo potential conflict of interest was reported by the authors.\n==== Refs\nReferences\n[1] Cavagna L , Nuño L , Scirè CA , et al \nAENEAS (American and European Network of Antisynthetase Syndrome) collaborative group. Serum Jo-1 autoantibody and isolated arthritis in the antisynthetase syndrome: review of the literature and report of the experience of AENEAS collaborative group . Clin Rev Allerg Immunol . 2017 ;52 :71 –7 .\n[2] Satoh M , Tanaka S , Ceribelli A , et al \nA comprehensive overview on myositis-specific antibodies: new and old biomarkers in idiopathic inflammatory myopathy . Clin Rev Allerg Immunol . 2017 2 ;52 (1 ):1 –19 .\n[3] Marie I , Josse S , Hatron PY , et al \nInterstitial lung Disease in anti-Jo-1 patients with antisynthetase syndrome . Arthritis Res Ther . 2013 5 ;65 (5 ):800 –808 .\n[4] Marie I , Josse S , Decaux O , et al \nComparison of long-term outcome between anti-Jo-1 and anti-PL7/PL12 positive patients with antisynthetase syndrome . Autoimmun Rev . 2012 ;11 :739 –745 .22326685 \n[5] Dobloug C , Garen T , Bitter H , et al \nPrevalence and clinical characteristics of adult polymyositis and dermatomyositis; data from a large and unselected Norwegian cohort . Ann Rheum Dis . 2015 ;74 :1551 –1556 .24695011 \n[6] Smoyer-Tomic KE , Amato AA , Fernandes AW. Incidence and prevalence of idiopathic inflammatory myopathies among commercially insured, Medicare supplemental insured, and Medicaid enrolled populations: an administrative claims analysis . BMC Musculosketal Disord . 2012 6 ;15 (13 ):103 .\n[7] Pinal-Fernandez I , Casal-Dominguez M , Huapaya JA , et al \nA longitudinal cohort study of the anti-synthetase syndrome: increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies . Rheumatology (Oxford) . 2017 6 1 ;56 (6 ):999 –1007 .28339994 \n[8] Poveda Gomez F , Merino JL , Maté I , et al \nPolymyositis associated with anti-Jo1 antibodies: severe cardiac involvement as initial manifestation . Am J Med . 1993 ;94 :110 –111 .8420288 \n[9] Frost NA , Morand EF , Hall CL , et al \nIdiopathic polymyositis complicated by arthritis and mesangial proliferative glomerulonephritis: case report and review of the literature . Br J Rheumatol . 1993 ;32 :929 –931 .8402004 \n[10] Marguerie C , Bunn CC , Beynon HL , et al \nPolymyositis, pulmonary fibrosis and autoantibodies to aminoacyl-tRNA synthetase enzymes . Q J med . 1990 ;77 :1019 –1038 .2267280 \n[11] Zamora AC , Hoskote SS , Abascal-Bolade B , et al \nClinical features and outcomes of interstitial lung disease in anti-Jo-1 positive antisynthetase syndrome . Respir Med . 2016 9 ;118 :39 –45 .27578469 \n[12] Bauhammer J , Blank N , Max R , et al \nRituximab in the treatment of Jo1 antibody-associated antisynthetase syndrome: anti-Ro52 positivity as a marker for severity and treatment response . J Rheumatol . 2016 8 ;43 (8 ):1566 –1574 .27252419 \n[13] Cavagna L , Nuño L , Scirè CA , et al \nAENEAS (American, European Network of Antisynthetase Syndrome) collaborative group. Clinical spectrum time course in anti-Jo-1 positive antisynthetase syndrome. Results from an international retrospective multicenter study . Med August . 2015 ;94 (32 ):1 –7 .\n[14] Mileti LM , Strek ME , Niewold TB , et al \nClinical characteristics of patients with anti–jo-1 antibodies: a single center experience . J Clin Rheumotolol . 2009 ;15 (5 ):254 –255 .\n[15] Hyldgaard C , Hilberg O , Muller A , et al \nA cohort study of interstitial lung diseases in central Denmark . Respir Med . 2014 ;May:108 (5 ):793 –799 .\n[16] Passadore I , Ladarola P , Di Poto C , et al \n2-DE and LC-MS/MS for a comparative proteomic analysis of BALf from subjects with different subsets of inflammatory myopathies . J Proteome Res . 2009 5 ;8 (5 ):2331 –2340 .19301896 \n[17] Cavagna L , Carapoli R , Abdi-Ali L , et al \nCyclosporine in anti-Jo1- positive patients with corticosteroid-refractory interstitial lung disease . J Rheumatol . 2013 ;49 (4 ):483 –492 .\n[18] Schnabel A , Reuter M , Biederer J , et al \nInterstitial lung disease in polymyositis and dermatomyositis: clinical course and response to treatment . Semin Arthritis Rheum . 2003 ;32 (5 ):273 –284 .12701038 \n[19] Sem M , Molberg O , Lund MB , et al \nRituximab treatment of the anti synthetase syndrome – a retrospective case series . Rheumatology . 2009 ;48 :968 –971 .19531628 \n[20] Kim EJ , Collard HR , King TE Jr \nRheumatoid arthritis-associated interstitial lung disease. The relevance of histopathologic and radiographic pattern . Chest Nov . 2009 ;136 (5 ):1397 –1405 .\n[21] Saunders P , Tsipouri V , Keir GJ , et al \nRituximab versus cyclophosphamide for the treatment of connective tissue disease-associated interstitial lung disease (RECITAL): study protocol for a randomised controlled trial . Trials . 2017 6 15 ;18 (1 ):275 .28619061\n\n",
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"title": "Clinical characteristics and outcome in patients with antisynthetase syndrome associated interstitial lung disease: a retrospective cohort study.",
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"abstract": "Addition of carboplatin (Cb) to anthracycline chemotherapy improves pathologic complete response (pCR), and carboplatin plus taxane regimens also yield encouraging pCR rates in triple-negative breast cancer (TNBC). Aim of the NeoSTOP multisite randomized phase II trial was to assess efficacy of anthracycline-free and anthracycline-containing neoadjuvant carboplatin regimens.\n\n\n\nPatients aged ≥18 years with stage I-III TNBC were randomized (1:1) to receive either paclitaxel (P) weekly × 12 plus carboplatin AUC6 every 21 days × 4 followed by doxorubicin/cyclophosphamide (AC) every 14 days × 4 (CbP → AC, arm A), or carboplatin AUC6 + docetaxel (D) every 21 days × 6 (CbD, arm B). Stromal tumor-infiltrating lymphocytes (sTIL) were assessed. Primary endpoint was pCR in breast and axilla. Other endpoints included residual cancer burden (RCB), toxicity, cost, and event-free (EFS) and overall survival (OS).\n\n\n\nOne hundred patients were randomized; arm A (n = 48) or arm B (n = 52). pCR was 54% [95% confidence interval (CI), 40%-69%] in arm A and 54% (95% CI, 40%-68%) in arm B. RCB 0+I rate was 67% in both arms. Median sTIL density was numerically higher in those with pCR compared with those with residual disease (20% vs. 5%; P = 0.25). At median follow-up of 38 months, EFS and OS were similar in the two arms. Grade 3/4 adverse events were more common in arm A compared with arm B, with the most notable differences in neutropenia (60% vs. 8%; P < 0.001) and febrile neutropenia (19% vs. 0%; P < 0.001). There was one treatment-related death (arm A) due to acute leukemia. Mean treatment cost was lower for arm B compared with arm A (P = 0.02).\n\n\n\nThe two-drug CbD regimen yielded pCR, RCB 0+I, and survival rates similar to the four-drug regimen of CbP → AC, but with a more favorable toxicity profile and lower treatment-associated cost.",
"affiliations": "Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas. psharma2@kumc.edu.;Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, Kansas.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;University of Kansas Cancer Center, Kansas City, Kansas.;University of Kansas Cancer Center, Kansas City, Kansas.;University of Kansas Cancer Center, Kansas City, Kansas.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas.;Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas.;Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas.;Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;Department of Internal Medicine, University of Missouri-Kansas City, Kansas City, Missouri.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;Department of Hematology, Hays Medical Center, Hays, Kansas.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;Richard & Annette Bloch Cancer Center, Truman Medical Center, Kansas City, Missouri.;Tammy Walker Cancer Center, Salina Regional Health Center, Salina, Kansas.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;Olathe Cancer Care, Olathe Medical Center, Olathe, Kansas.;University of Kansas Cancer Center, Kansas City, Kansas.;University of Kansas Cancer Center, Kansas City, Kansas.;University of Kansas Cancer Center, Kansas City, Kansas.;Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas.;Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas.;University of Kansas Cancer Center, Kansas City, Kansas.;University of Kansas Cancer Center, Kansas City, Kansas.;Division of Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.;Department of Internal Medicine, University of Kansas Medical Center, Westwood, Kansas.",
"authors": "Sharma|Priyanka|P|;Kimler|Bruce F|BF|0000-0001-7021-6964;O'Dea|Anne|A|;Nye|Lauren|L|;Wang|Yen Y|YY|;Yoder|Rachel|R|;Staley|Joshua M|JM|0000-0001-9273-0286;Prochaska|Lindsey|L|;Wagner|Jamie|J|;Amin|Amanda L|AL|0000-0002-9784-6226;Larson|Kelsey|K|0000-0003-1977-9459;Balanoff|Christa|C|0000-0002-4320-122X;Elia|Manana|M|;Crane|Gregory|G|;Madhusudhana|Sheshadri|S|;Hoffmann|Marc|M|;Sheehan|Maureen|M|;Rodriguez|Roberto|R|;Finke|Karissa|K|;Shah|Rajvi|R|;Satelli|Deepti|D|;Shrestha|Anuj|A|;Beck|Larry|L|;McKittrick|Richard|R|;Pluenneke|Robert|R|;Raja|Vinay|V|;Beeki|Venkatadri|V|;Corum|Larry|L|;Heldstab|Jaimie|J|;LaFaver|Stephanie|S|;Prager|Micki|M|;Phadnis|Milind|M|;Mudaranthakam|Dinesh Pal|DP|0000-0001-9767-1158;Jensen|Roy A|RA|0000-0003-4430-2281;Godwin|Andrew K|AK|0000-0002-3987-9580;Salgado|Roberto|R|;Mehta|Kathan|K|;Khan|Qamar|Q|",
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"country": "United States",
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"doi": "10.1158/1078-0432.CCR-20-3646",
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"issue": "27(4)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
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"medline_ta": "Clin Cancer Res",
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"nlm_unique_id": "9502500",
"other_id": null,
"pages": "975-982",
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"pmid": "33208340",
"pubdate": "2021-02-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D052061:Research Support, N.I.H., Extramural",
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"title": "Randomized Phase II Trial of Anthracycline-free and Anthracycline-containing Neoadjuvant Carboplatin Chemotherapy Regimens in Stage I-III Triple-negative Breast Cancer (NeoSTOP).",
"title_normalized": "randomized phase ii trial of anthracycline free and anthracycline containing neoadjuvant carboplatin chemotherapy regimens in stage i iii triple negative breast cancer neostop"
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"abstract": "Imatinib mesylate is the drug of choice for patients with chronic myeloid leukemia (CML). Imatinib pharmacokinetics is affected by a number of transport proteins and enzymes.\nIn the present study we evaluated the association of eight polymorphisms in the seven genes CYP3A5*3 (rs776746), CYP3A4*1 (rs2740574), CYP2C9*3 (rs1057910), SLC22A1 (rs683369), ABCB1 (rs1045642, rs1128503), ABCG2 (rs2231142) and ABCC2 (rs717620) with imatinib plasma level and achieving an optimal clinical response in 112 CML patients (53 men and 59 women).\nNo association was found between the examined polymorphisms in rs776746, rs2740574, rs1057910, rs683369, rs1045642, rs1128503, rs2231142, rs717620 and the achieved imatinib plasma level. The influence of rs776746 (CYP3A5*3) on the achievement of a complete cytogenetic response (CCyR) at 6 months was borderline non-significant (p = 0.06). Furthermore, no association was demonstrated between rs776746 polymorphisms and the achievement of a major molecular response (MMR) at 12 or 18 months. Polymorphisms rs776746, rs2740574, rs1057910, rs683369, rs1045642, rs1128503, rs2231142, rs717620 showed no impact on the optimal therapeutic response.\nDespite the results of some other studies, no other polymorphism we analyzed was associated with imatinib plasma level or clinical response. The treatment outcomes cannot be predicted using the candidate gene approach and treatment decisions cannot be made according to the polymorphisms investigated in this study.",
"affiliations": "4 Department of Internal Medicine - Hematology, Charles University Hospital, Hradec Kralove, Czech Republic.;4 Department of Internal Medicine and Hematology, Charles University, Faculty Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic.;4 Department of Internal Medicine and Hematology, Charles University, Faculty Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic.;Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic.;Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic.;Department of Clinical Biochemistry, Charles University, Faculty Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic.;Department of Clinical Biochemistry, Charles University, Faculty Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic.;Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic.;4 Department of Internal Medicine and Hematology, Charles University, Faculty Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic.",
"authors": "Belohlavkova|Petra|P|;Vrbacky|Filip|F|;Voglova|Jaroslava|J|;Racil|Zdenek|Z|;Zackova|Daniela|D|;Hrochova|Katerina|K|;Malakova|Jana|J|;Mayer|Jiri|J|;Zak|Pavel|P|",
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"fulltext": "\n==== Front\nArch Med SciArch Med SciAMSArchives of Medical Science : AMS1734-19221896-9151Termedia Publishing House 3183010.5114/aoms.2018.73538Clinical ResearchThe significance of enzyme and transporter polymorphisms for imatinib plasma levels and achieving an optimal response in chronic myeloid leukemia patients Belohlavkova Petra 1Vrbacky Filip 2Voglova Jaroslava 2Racil Zdenek 3Zackova Daniela 3Hrochova Katerina 4Malakova Jana 4Mayer Jiri 3Zak Pavel 2\n1 4th Department of Internal Medicine – Hematology, Charles University Hospital, Hradec Kralove, Czech Republic\n2 4th Department of Internal Medicine and Hematology, Charles University, Faculty Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic\n3 Department of Internal Medicine, Hematology and Oncology, Masaryk University and University Hospital Brno, Brno, Czech Republic\n4 Department of Clinical Biochemistry, Charles University, Faculty Hospital and Faculty of Medicine, Hradec Kralove, Czech RepublicCorresponding author: Petra Belohlavkova MD, PhD, 4th Department of Internal Medicine – Hematology, Charles University Hospital, 501 Sokolska St, 50005 Hradec Kralove, Czech Republic. Phone: +42 0606213400. E-mail: belohlavkova@fnhk.cz15 2 2018 10 2018 14 6 1416 1423 01 9 2017 16 11 2017 Copyright: © 2018 Termedia & Banach2018This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.Introduction\nImatinib mesylate is the drug of choice for patients with chronic myeloid leukemia (CML). Imatinib pharmacokinetics is affected by a number of transport proteins and enzymes.\n\nMaterial and methods\nIn the present study we evaluated the association of eight polymorphisms in the seven genes CYP3A5*3 (rs776746), CYP3A4*1 (rs2740574), CYP2C9*3 (rs1057910), SLC22A1 (rs683369), ABCB1 (rs1045642, rs1128503), ABCG2 (rs2231142) and ABCC2 (rs717620) with imatinib plasma level and achieving an optimal clinical response in 112 CML patients (53 men and 59 women).\n\nResults\nNo association was found between the examined polymorphisms in rs776746, rs2740574, rs1057910, rs683369, rs1045642, rs1128503, rs2231142, rs717620 and the achieved imatinib plasma level. The influence of rs776746 (CYP3A5*3) on the achievement of a complete cytogenetic response (CCyR) at 6 months was borderline non-significant (p = 0.06). Furthermore, no association was demonstrated between rs776746 polymorphisms and the achievement of a major molecular response (MMR) at 12 or 18 months. Polymorphisms rs776746, rs2740574, rs1057910, rs683369, rs1045642, rs1128503, rs2231142, rs717620 showed no impact on the optimal therapeutic response.\n\nConclusions\nDespite the results of some other studies, no other polymorphism we analyzed was associated with imatinib plasma level or clinical response. The treatment outcomes cannot be predicted using the candidate gene approach and treatment decisions cannot be made according to the polymorphisms investigated in this study.\n\nclinical responseimatinibchronic myeloid leukemiagenetic polymorphisms\n==== Body\nIntroduction\nThe discovery of imatinib mesylate substantially changed the results of the treatment and survival of patients with chronic myeloid leukemia (CML) [1, 2]. The final clinical response in CML patients is affected by many factors which may be divided into three basic groups. The first group involves age-related factors (the patient’s age, overall health, associated diseases and cooperation). The second group includes disease-related factors (CML phase, prognostic risk score, cytogenetic finding, transcript type, presence of tyrosine kinase mutations, and pharmacokinetics of imatinib). The last group involves the treatment of CML and comprises the choice of an appropriate tyrosine kinase inhibitor (TKI) and dealing with adverse effects. Despite the remarkable progress in the treatment of CML, approximately 20–30% of patients still remain resistant to imatinib therapy. The known causes of imatinib resistance include BCR-ABL inhibition, development of kinase domain mutations, BCR-ABL1 gene amplification and overexpression or clonal evolution [3–7].\n\nHowever, many cases of resistance development are unclear.\n\nRecently, increased attention has been paid to the pharmacokinetics of imatinib mesylate because it could clarify some cases of therapeutic failures. Imatinib mesylate is predominantly metabolized in the liver to an active metabolite via cytochrome CYP3A4 and CYP3A5. Other cytochromes are of very little importance in the metabolism of imatinib (CYP1A2, CYP2D6, CYP2C9, CYP2C19) [8–10]. Various ethnic groups show significantly different representation of CYP3A5 and CYP3A4 allele variants, which explains the variable pharmacokinetics of TKI in patients. The TKI transport mechanisms can be divided into a group of proteins which ensure transport into the cell and those which ensure transport out of the cell. Human organic cation transporter 1 (hOCT1), a membrane transporter of imatinib into the cell that is encoded by the SLC22A gene, plays an important role in BCR-ABL kinase inhibition. Conversely, the proteins ABCB1 (MDR-1) and ABCG2 (BCRP) rank among important transporters which remove imatinib from the cell [8–10].\n\nOur study investigated whether the diverse pharmacokinetics of imatinib mesylate caused by polymorphisms in the CYP3A5*3, CYP3A4*1, and CYP2C9*3 enzymes or by polymorphisms in the transporter proteins SLC22A1, ABCB1, ABCG2 and ABCC2 affects plasma levels of imatinib and achievement of an optimal clinical response. It is likely that pharmacogenetics, genetic variability in the metabolism of therapeutic agents, plays a role in the prediction of survival in other cancers too [11–13].\n\nMaterial and methods\nCohort of patients\nIn this study we performed a retrospective evaluation of 112 patients with CML – chronic phase (97%) and accelerated phase (3%) – receiving treatment in two hospitals in the Czech Republic. The cohort included 53 Caucasian men (47%) and 59 Caucasian women (53%) with a median age at diagnosis of 56 years (range: 19–84). The CML was diagnosed in these hospitals between 5/1997 and 12/2012 and the median of patient monitoring was 104 months (M) (range: 29–236). The information of current medical condition and survival of the patients was completed in 6/2016. The patients gave informed consent to the analysis of genetic polymorphisms. The characteristics of the patients under evaluation are described in Table I. Patients who had received imatinib 400 mg/day for at least 18 months were eligible for inclusion in our study. Patients whose imatinib dose was reduced (< 400 mg/day for > 2 weeks) were not included in the evaluation. Furthermore, we did not assess patients with imatinib resistance caused by a mutation in the kinase domain.\n\nTable I Patients’ and disease characteristics of study cohort (n = 112)\n\nParameter\tValue\t\nAge at diagnosis, median (range) [years]\t56 (range: 19–84)\t\nDisease stage, n (%):\t\n Chronic phase\t109 (97)\t\n Accelerated phase\t3 (3)\t\n Blastic phase\t0\t\nGender, n (%):\t\n Male\t53 (47)\t\n Female\t59 (53)\t\nSokal risk group, n (%):\t\n Low\t34 (30)\t\n Intermediate\t60 (54)\t\n High\t11 (10)\t\n Not applicable\t7 (6)\t\nHasford risk group, n (%):\t\n Low\t43 (39)\t\n Intermediate\t44 (40)\t\n High\t18 (15)\t\n Not applicable\t7 (6)\t\nCytogenetics, n (%):\t\n t (9;22) only\t109 (97)\t\n Additional abnormalities\t3 (3)\t\nPreview treatment to imatinib, n (%):\t\n Interferon\t11 (10)\t\n Hydroxyurea > 1 months\t3 (3)\t\nResponse to imatinib, n (%):\t\n CHR at 3 months\t108 (96)\t\n CCyR at 6 months\t63 (56)\t\n MMR at 12 months\t61 (54)\t\nCurrent status, n (%):\t\n Alive\t107 (95.5)\t\n Dead\t5 (4.5)\t\nBoth hospitals evaluated optimal clinical responses in accordance with the recommendations of the European LeukemiaNet (ELN) from 2013 [6, 7]. At 3 months of treatment, a complete hematologic response (CHR) was assessed. CHR was defined as the number of thrombocytes < 450 × 109/l, the number of leukocytes < 10 × 109/l, the absence of young forms of leukocytes and the number of basophils < 5% in a complete blood count and a peripheral smear. Simultaneously, the spleen could not be palpable during the physical examination of the patients. A cytogenetic response was assessed according to the number of the mitoses detected by standard cytogenetic methods in Ph+ cells in the bone marrow. Complete cytogenetic response (CCyR) is defined as the absence of Ph+ mitoses in the bone marrow. Molecular response and its depth are assessed according to the BCR-ABL1 transcript level, which was determined by means of a quantitative polymerase chain reaction method using a reverse transcriptase (RT-PCR). The result was expressed as a ratio of BCR-ABL1 to ABL (or to another control gene) × 100% and was converted to the International Scale (IS). Major molecular response (MMR) is defined as BCR-ABL1/control gene ≤ 0.1%.\n\nImatinib plasma level determination\nThe imatinib plasma level was determined by high-performance liquid chromatography and the analysis was validated for a detection limit of 10 ng/ml. Peripheral blood of the patients was taken 24 ±2 h prior to another imatinib dose. The imatinib plasma level was determined at least 12 months after imatinib therapy commencement. Because our study is retrospective, the taking of the imatinib plasma levels in all patients was not performed at exactly the same time from the beginning of the imatinib therapy.\n\nGenotyping\nDNA was obtained from peripheral blood and the sample was then frozen at –80°C until the completion of the analysis. Single-nucleotide polymorphisms (SNP) were detected by means of real-time allele-discriminating PCR using TaqMan dual labeled hydrolysis probes. Commercial genotyping assays and a commercial master mix were used for detection. The PCR reaction comprises three steps: activation of DNA polymerase, denaturation and primer annealing. The obtained amplification curves of the genotypes of the selected polymorphisms in genes were evaluated by means of the Rotor Gene 6000 Series software, which is part of the Rotor Gene 6000 thermal cycler manufactured by Qiagen. The analysis of the data was performed in the controlling and analytical software of the cycler under an ‘allelic discrimination’ mode. The limit distinguishing the positive and negative signal of the individual alleles was set by comparison with a known genotype.\n\nIn the present study we evaluated eight polymorphisms in seven genes: rs776746 CYP3A5*3 (6986A>G), rs2740574 CYP3A4*1 (–392A>G), rs1057910 CYP2C9*3 (1075A>C), rs683369 SLC22A1 (480C>G), rs1045642 ABCB1 (3435C>T), rs1128503 ABCB1 (1236 C>T), rs2231142 ABCG2 (421C>A), and rs717620 ABCC2 (–24C>T).\n\nStatistical analysis\nA χ2 test was used to evaluate the statistically significant dependences of qualitative variables. Quantitative variables were compared using the Mann-Whitney test and some analyses were completed by means of ANOVA tests. The significance level applied (p-value) was 0.05. Power of all significant and borderline non-significant results was verified and it was higher than 0.8 in all cases.\n\nResults\nClinical response in the cohort\nThe following responses were achieved in the evaluated cohort: CHR was achieved in 108 (96%) patients at 3 months, CCyR was achieved in 63 (56%) patients at 6 months, CCyR was achieved in 101 (90%) patients at 12 months, MMR was achieved in 61 (54%) patients at 12 months, and MMR was achieved in 79 (70%) patients at 18 months of imatinib therapy. Hematologic toxicities of all grades occurred in 35.5% of subjects during treatment with imatinib (anemia – all degrees, 3.5%; neutropenia – all degrees, 18%; thrombocytopenia, 14%). Non-hematologic toxicities observed during therapy most often included peripheral edemas (24%), bone and muscle pain (20.5%), nausea or vomiting (19%), diarrhea (11%), rash (7%), and hypophosphatemia (7%). Five (5%) patients died. Two of these deaths were associated with CML (blast crisis), 1 patient suffered from progressing CML and concurrent heart failure, and 2 female patients died of breast carcinoma.\n\nImpact of polymorphisms on final imatinib plasma level\nIt was our aim to prove whether the polymorphisms in the genes affecting the metabolism of imatinib mesylate affect the final imatinib plasma level. The median imatinib plasma levels identified for the individual polymorphism genotypes are presented in Table II. No association between the polymorphism genotypes in rs776746 (CYP3A5*3), rs2740574 (CYP3A4*1), rs1057910 (CYP2C9*3), rs683369 (SLC22A1), rs1045642 and rs1128503 (ABCB1), rs2231142 (ABCG2), rs717620 (ABCC2) and the achieved imatinib plasma level was established. Also, our study did not prove any association between the CC genotypes as compared with the other genotypes of CYP3A5, any association between the GG and CC genotypes as compared with the other genotypes of SLC22A1, any association between the GG or AA genotype as compared with the other genotypes of ABCB1 (3435C>T) and ABCB1 (1236C>T), any association between the GG or TT genotype as compared with the other genotypes of ABCG2, or any association between the TT or CC genotype as compared with the other genotypes of ABCG2.\n\nTable II Correlation between candidate genotypes and imatinib plasma levels\n\nGenotypes\tN\n\t%\tMedian imatinib plasma levels [ng/ml]\tRange of imatinib plasma levels [ng/ml]\tP-value\t\nCYP 3A5*3 (rs776746):\t\n C – C\t98\t87\t841\t173–2173\t0.72\t\n T – C\t13\t12\t621\t423–1472\t\t\n T – T\t1\t1\t975*\t\t0.39\t\n CC vs. TC + TT\t\nCYP3A4*1 (rs2740574):\t\t\t\t\t0.99\t\n T – T\t104\t93\t881\t173–2173\t\t\n T – C\t8\t7\t605\t423–1094\t\t\nCYP2C9*3 (rs1057910):\t\n A – A\t95\t85\t823\t210–2173\t0.99\t\n A – C\t17\t15\t1045\t223–1502\t\t\nSLC22A1 (rs683369):\t\n C – C\t78\t70\t838\t173–2173\t0.20\t\n C – G\t27\t24\t727\t374–1724\t\t\n G – G\t7\t6\t925\t627–1163\t\t\n GG vs. CG + CC\t0.17\t\n CC vs. CG + GG\t\t\t\t\t0.50\t\nABCB1 (rs1045642):\t\n A – G\t58\t51\t881\t223–2173\t0. 84\t\n A – A\t32\t29\t793\t319–1724\t\t\n G – G\t22\t20\t825\t173–1477\t0.76\t\n GG vs. AA + AG\t\t\t\t\t0.79\t\n AA vs. AG + GG\t\nABCB1 (rs1128503):\t\n A – A\t18\t16\t1039\t173–1304\t0.80\t\n A – G\t62\t55\t838\t210–2173\t\t\n G – G\t32\t29\t727\t392–1477\t\t\n GG vs. AA + AG\t\t\t\t\t0.65\t\n AA vs. AG + GG\t\t\t\t\t0.74\t\nABCG2 (rs2231142):\t\n G – G\t87\t80\t804\t439–2173\t0.47\t\n T – G\t23\t19\t910\t173–1710\t\t\n T – T\t2\t1\t647*\t\t\t\n GG vs. TG + TT\t\t\t\t\t0.27\t\n TT vs. GT + GG\t\t\t\t\t0.79\t\nABCC2 (rs717620):\t\t\t\t\t\t\n C – C\t70\t63\t889\t210–2173\t0.70\t\n C – T\t37\t33\t910\t319–1519\t\t\n T – T\t5\t4\t763\t661–1484\t\t\n TT vs. CC + CT\t\t\t\t\t0.85\t\n CC vs. TT + CT\t\t\t\t\t0.46\t\n* Not evaluated, minor frequency.\n\nWith regard to the number of individual polymorphism genotypes it was possible to evaluate three genes for the quantitative measure of the expression of the polymorphism of rs683369 SLC22A1, rs1045642 and rs1128503 in the ABCB1 gene using an ANOVA test. Even this evaluation did not confirm a statistically significant association of these polymorphisms with the achieved imatinib plasma level.\n\nImpact of polymorphisms on achieving an optimal clinical response\nOur study showed that none of the polymorphisms under examination was associated with the achievement of a CHR at 3 months. At 6th month of imatinib treatment the influence of rs776746 (CYP3A5*3) on the achievement of CCyR was borderline non-significant (p = 0.06). There was a significant difference between CC genotype and other genotypes (p = 0.05). We did not evaluate the association of rs776746 and the achievement of CCyR at 12 months due to low incidence of heterozygotes and homozygotes in nonresponder patients. Furthermore, no association was demonstrated between the other polymorphisms and the achievement of CCyR at 6 and 12 months (Table III).\n\nTable III Correlation between candidate genotypes and clinical response (CCyR, MMR)\n\nReferent genotype\tN\tCCyR at 6M Yes\tCCyR at 6M No\tP-value\tCCyR at 12M Yes\tCCyR at 12M No\tP-value\t\nCYP3A5*3 (rs776746):\t\n C – C\t98\t59\t39\t0.06\t89\t9\t±\t\n T – C\t13\t4\t9\t\t12\t1\t\t\n T – T\t1\t0\t1\t0.05\t0\t1\t0.90\t\n CC vs. TC + TT\t\t\t\t\t\t\t\t\nReferent genotype\tN\tMMR at 12M Yes\tMMR at 12M No\tP-value\tMMR at 18M Yes\tMMR at 18M No\tP-value\t\nCYP3A5*3 (rs776746):\t\n C – C\t98\t54\t44\t0.54\t70\t28\t0.31\t\n T – C\t13\t7\t6\t\t9\t4\t\t\n T – T\t1\t0\t1\t\t0\t1\t\t\n CC vs. TC + TT\t\t\t\t0.94\t\t\t0.87\t\nABCG2 (rs2231142):\t\n G – G\t87\t52\t35\t0.06\t64\t23\t0.23\t\n T – G\t23\t9\t14\t\t14\t9\t\t\n T – T\t2\t0\t2\t\t1\t1\t\t\n GG vs. TG + TT\t\t\t\t0.06\t\t\t0.15\t\n TT vs. GT + GG\t\t\t\t0.39\t\t\t1\t\nCCyR – complete hematologic response, MMR – major molecular response ± not evaluated (minor frequency nonresponders).\n\nThe assessment of MMR at 12 months has shown a possible influence of the polymorphism rs2231142 in the gene ABCG2 but without statistical significance (p = 0.06). The same implication resulted from the evaluation of the association between the GG genotype and the other (TG and TT) genotypes (p = 0.06). The other polymorphisms did not show any influence on the achievement of MMR at 12 months. Moreover, none of the polymorphisms under investigation showed any association with the achievement of MMR at 18 months (Table III). We did not prove any differences between homozygotes and heterozygotes, when we evaluated the cumulative achievement of a stable response (CCyR) or MMR in rs776746 (CYP3A5*3) and rs2231142 (ABCG2) (Figures 1, 2).\n\nFigure 1 \nA – Cumulative incidence of achievement of stable CCyR in CYP3A5*3 (rs776746) (p = 0.85). B – Cumulative incidence of achievement of stable MMR in CYP3A5*3 (rs776746) (p = 0.38)\n\nFigure 2 \nA – Cumulative incidence of achievement of stable CCyR in ABCG2 (rs2231142) (p = 0.26). B – Cumulative incidence of achievement of stable MMR in ABCG2 (rs2231142) (p = 0.33)\n\nDiscussion\nThe first study to investigate the significance of genetic polymorphisms for the imatinib plasma level was published by Takahashi et al. in 2010 [14]. In this study, the polymorphisms of CYP3A5*3 (6986A>G), SLC22A1 (156T>C, 480G>C, 1022C>T and 1222A>G), ABCB1 (1236T>C, 2677G>T, 3435T>C), ABCC2 (–24C>T) and ABCG2 (421C>A) were analyzed in 67 patients. Only one correlation between the imatinib plasma level and polymorphism was confirmed, namely with ABCG2 polymorphism. The detected imatinib plasma level was statistically higher than the level of non-CC alleles in ABCG2 polymorphism (p = 0.015). Another study dealing with the evaluation of certain polymorphisms and their impact on the imatinib plasma level was presented by Seong et al. in 2012 and assessed 10 genotypes [15]. However, none of the examined polymorphisms showed a correlation between a certain genotype and an imatinib plasma level and this observation corresponds to our findings.\n\nSeveral studies have reported that certain variants of polymorphisms may predict a clinical response. The first of these studies was published by Kim et al. in 2009 and described the investigation of 16 SNPs in the five candidate genes CYP3A5*3, SLC22A1, ABCB1, ABCC2, and AGP in 229 patients [16]. The analysis established that the GG genotype of ABCG2 (rs2231142) had a negative impact on achieving CCyR (p = 0.03), whereas the AC or CC genotype had a positive influence on achieving MMR. Seong’s study suggests that the individual ABCG2 genotypes did not affect the achievement of a cytogenetic response, while molecular responses achieved by individual genotypes (p = 0.02) showed significant differences, with the AC or CC genotype once again accounting for a lower number of patients with MMR [15]. In 2013 Au et al. published an analysis of 215 patients which proved the significance of the individual ABCG2 genotype variants on the achievement of MMR (p = 0.004) [17]. This observation is similar to results of this study showing borderline non-significant tendency of the ABCG2 polymorphism to influence the achievement of MMR at 12 months (p = 0.06), even though our findings are not as conclusive as those presented in the above-mentioned studies.\n\nIn their studies Kim et al., Takahashi et al. and Seong et al. also examined the polymorphisms in the gene ABCB1 without proving the impact of this polymorphism on a clinical response. This finding is in agreement with our observations. On the other hand, other studies by Au et al. and Salimizand et al. confirmed an association between the CC genotype of the ABCB1 3435C allele and a worse response to imatinib [17, 18]. In 2015 Wang et al. published a meta-analysis of 10 studies which involved 987 patients with CML and evaluated the significance of the polymorphisms rs1045642, rs1128503 and rs2032582 in ABCB1 (MDR1). The meta-analysis did not demonstrate an association between achieving optimal response and the genotypes of a certain polymorphism [19].\n\nThe available published results on the significance of the polymorphism of the hepatic enzymes CYP3A5 and CYP3A4 are not unambiguous. Kim’s study suggests that the AA genotype in CYP3A5 (rs776746) is associated with a lower probability of achieving MMR (p = 0.01). This observation corresponds with our findings which demonstrated the implied significance of CYP3A5*3 polymorphism for achieving CCyR at 6 months of treatment (p = 0.06). The recent, less extensive analysis by Bedewy et al. were published in 2013. It evaluated 78 CML patients and confirmed the impact of polymorphisms in the CYP3A5 gene on achieving an optimal response [20]. On the other hand, Seong’s analysis examined six different polymorphisms in the CYP3A4*18, CYP3A5*3, CYP2C9*3, CYP2C19*2, CYP2C19*3 and CYP2D6*10B genes and did not establish any impact of those polymorphisms.\n\nAngelini’s study from 2012 included 189 patients and evaluated 20 polymorphisms. Of hepatic enzymes, only the polymorphism in the gene CYP3A4 was assessed. It was not confirmed to affect the achievement of an optimal response [21]. The evaluation of the whole cohort presented in the study implied the impact of the polymorphism in ABCB1 (MDR1; rs60023214) on achieved MMR (p = 0.06). The statistically significant impact on the achievement of MMR (p = 0.005) was confirmed, when this analysis was performed only on a cohort of Caucasians who had different patterns of allele frequencies. However, our analysis did not prove the association of the rs1045642 and rs1128503 polymorphisms in ABCB1 with the achievement of an optimal response.\n\nIn conclusion, our results support the theory that there is an association between CYP3A5 genotype (allele *3) and clinical response to imatinib mesylate. Surprisingly, no association between imatinib plasma level and genotype was found. Despite the results of some other studies, no other polymorphism we analyzed was associated with clinical response or imatinib plasma level and further analyses in a larger patient cohort seem fully warranted. Based on our results and inconsistency among different studies, we believe that it is not possible to predict therapeutic outcome and make treatment decisions according to polymorphisms involved in this study, and other risk factors (i.e., Sokal or Euro score) are more important.\n\nAcknowledgments\nThis work was supported by the program PROGRES Q40/08.\n\nConflict of interest\nThe authors declare no conflict of interest.\n==== Refs\nReferences\n1 de Lavallade H Apperley J Khorashad J Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis J Clin Oncol 2008 26 3358 63 18519952 \n2 Hughes T Hochhaus A Branford S IRIS investigators Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS) Blood 2010 116 3758 65 20679528 \n3 Marin D Bazeos A Mahon F Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib J Clin Oncol 2010 28 2381 8 20385986 \n4 Apperley J Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia Lancet Oncol 2007 8 1018 29 17976612 \n5 Apperley J Part II: management of resistance to imatinib in chronic myeloid leukaemia Lancet Oncol 2007 8 1116 28 18054881 \n6 Baccarani M Cortes J Pane F European Leukemia Net. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet J Clin Oncol 2009 27 6041 51 19884523 \n7 Baccarani M Deininger M Rosti G European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013 Blood 2013 122 872 84 23803709 \n8 Peng B Lloyd P Schran H Clinical pharmacokinetics of imatinib Clin Pharmacokinet 2005 44 879 94 16122278 \n9 Cortes JE Egorin MJ Guilhot F Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia Leukemia 2009 23 1537 44 19404318 \n10 Bruhn O Cascorbi I Polymorphisms of the drug transporters ABCB1, ABCG2, ABCC2 and ABCC3 and their impact on drug bioavailability and clinical relevance Expert Opinion 2014 10 1337 54 \n11 Zhai X Wang H Zhu X Gene polymorphisms of ABC transporters are associated with clinical outcomes in children with acute lymphoblastic leukemia Arch Med Sci 2012 8 659 671 23056078 \n12 Hosseini M Houshmand M Ebrahimi A MTHFR polymorphisms and breast cancer risk Arch Med Sci 2011 7 134 7 22291746 \n13 Mrozikiewicz-Rakowska B Malinowski M Nehring P The MDR1/ABCB1 gene rs1045642 polymorphism in colorectal cancer Arch Med Sci 10.5114/aoms.2017.70329 \n14 Takahashi N Miura M Scott SA Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia J Hum Gene 2010 55 731 7 \n15 Seong S Lim M Sohn S Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients Ann Oncol 2013 24 756 60 23117072 \n16 Kim D Sriharsha L Xu W Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia Clin Cancer Res 2009 15 4750 8 19584153 \n17 Au A Aziz Baba A Goh A Association of genotypes and haplotypes of multi-drug transporter genes ABCB1 and ABCG2 with clinical response to imatinib mesylate in chronic myeloid leukemia patients Biomed Pharmacother 2014 68 343 9 24581936 \n18 Salimizand H Amini S Abdi M Concurrent effects of ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp genetic polymorphisms with risk of cancer, clinical output, and response to treatment with imatinib mesylate in patients with chronic myeloid leukemia Tumour Biol 2016 1 791 8 \n19 Wang J Liu H Li F Multidrug resistance gene (MDR1) polymorphisms may not be directly associated with response to imatinib in chronic myeloid leukemia Genet Mol Res 2015 14 14967 78 26634458 \n20 Bedewy A El-Maghraby S Do SLCO1B3 (T334G) and CYP3A5*3 polymorphisms affect response in Egyptian chronic myeloid leukemia patients receiving imatinib therapy? Hematology 2013 18 211 6 23394475 \n21 Angelini S Soverini S Ravegnini G Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy Haematologica 2013 98 193 200 22875622\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1734-1922",
"issue": "14(6)",
"journal": "Archives of medical science : AMS",
"keywords": "chronic myeloid leukemia; clinical response; genetic polymorphisms; imatinib",
"medline_ta": "Arch Med Sci",
"mesh_terms": null,
"nlm_unique_id": "101258257",
"other_id": null,
"pages": "1416-1423",
"pmc": null,
"pmid": "30393497",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": "22875622;26634458;19884523;19404318;25162314;23056078;18054881;23117072;26250462;23394475;23803709;17976612;16122278;20679528;20385986;22291746;18519952;20720558;24581936;19584153",
"title": "The significance of enzyme and transporter polymorphisms for imatinib plasma levels and achieving an optimal response in chronic myeloid leukemia patients.",
"title_normalized": "the significance of enzyme and transporter polymorphisms for imatinib plasma levels and achieving an optimal response in chronic myeloid leukemia patients"
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"abstract": "BACKGROUND\nPneumocystis jirovecii, formerly named Pneumocystis carinii, is one of the most common opportunistic infections in human immunodeficiency virus (HIV)-infected patients.\n\n\nMETHODS\nWe encountered two cases of spontaneous pneumomediastinum with subcutaneous emphysema in HIV-infected patients being treated for Pneumocystis jirovecii pneumonia with trimethoprim/sulfamethoxazole.\n\n\nCONCLUSIONS\nClinicians should be aware that cystic lesions and bronchiectasis can develop in spite of trimethoprim/sulfamethoxazole treatment for P. jirovecii pneumonia. The newly formed bronchiectasis and cyst formation that were noted in follow up high resolution computed tomography (HRCT) but were not visible on HRCT at admission could be risk factors for the development of pneumothorax or pneumomediastinum with subcutaneous emphysema in HIV-patients.",
"affiliations": "Department of Internal Medicine, Chosun University, College of Medicine, Republic of Korea. bconfident@hanmail.net",
"authors": "Cho|Ju-Yeon|JY|;Kim|Dong-Min|DM|;Kwon|Yong Eun|YE|;Yoon|Sung Ho|SH|;Lee|Seung Il|SI|",
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"fulltext": "\n==== Front\nBMC Infect DisBMC Infectious Diseases1471-2334BioMed Central 1471-2334-9-1711983563510.1186/1471-2334-9-171Case ReportNewly formed cystic lesions for the development of pneumomediastinum in Pneumocystis jirovecii pneumonia Cho Ju-Yeon 1bconfident@hanmail.netKim Dong-Min 1drongkim@chosun.ac.krKwon Yong Eun 1allergist@chosun.ac.krYoon Sung Ho 1drdbs@chosun.ac.krLee Seung Il 1silee@chosun.ac.kr1 Department of Internal Medicine1, Chosun University, College of Medicine, Republic of Korea2009 18 10 2009 9 171 171 29 1 2009 18 10 2009 Copyright ©2009 Cho et al; licensee BioMed Central Ltd.2009Cho et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nPneumocystis jirovecii, formerly named Pneumocystis carinii, is one of the most common opportunistic infections in human immunodeficiency virus (HIV)-infected patients.\n\nCase presentations\nWe encountered two cases of spontaneous pneumomediastinum with subcutaneous emphysema in HIV-infected patients being treated for Pneumocystis jirovecii pneumonia with trimethoprim/sulfamethoxazole.\n\nConclusion\nClinicians should be aware that cystic lesions and bronchiectasis can develop in spite of trimethoprim/sulfamethoxazole treatment for P. jirovecii pneumonia. The newly formed bronchiectasis and cyst formation that were noted in follow up high resolution computed tomography (HRCT) but were not visible on HRCT at admission could be risk factors for the development of pneumothorax or pneumomediastinum with subcutaneous emphysema in HIV-patients.\n==== Body\nBackground\nPneumocystis jirovecii, formerly named Pneumocystis carinii, is one of the most common opportunistic infections in human immunodeficiency virus (HIV)-infected patients [1,2]. Spontaneous pneumothorax has been recognized as a frequent complication in patients with P. jirovecii pneumonia (PCP) since it was first described in 1984 [3], and pneumomediastinum is an uncommon complication associated with pneumothorax in the aforementioned population. We report two cases of spontaneous pneumomediastinum with subcutaneous emphysema in HIV-infected patients being treated for P. jirovecii pneumonia with trimethoprim/sulfamethoxazole.\n\nCase presentation\nCase 1\nA 33-year-old man presented with fever, dyspnea, and odynophagia. Five months prior to admission, the patient had been treated for dental caries at a local hospital, and at that time examination revealed seropositivity for human immunodeficiency virus. On admission, temperature was 39.0'C, pulse 92 beats per minute, respiratory rate 20 breaths per minute and blood pressure 130/80 mmHg. Physical examination revealed oral thrush, consistent with findings of extensive esophageal candidiasis in endoscopic gastroduodenscopy performed five days before admission. Laboratory data on admission revealed a WBC count of 1,760/uL, Hb 10.9 g/dL, and platelet count of 297,000/uL. Arterial blood gas analysis while breathing room air revealed PaO2 of 48.0 mmHg, PaCO2 of 32.7 mmHg, and saturation of 88.5%, and the calculated (A-a)DO2 was 53.7. CD4 count and HIV viral load were 4/uL and 130,000 IU/mL, respectively. Diffuse bilateral infiltrates of both lung fields were noted, and no cystic lesions were observed on the chest X-ray and high resolution computed tomography (HRCT) taken on admission. Bronchoscopic alveolar lavage for diagnosis of P. jirovecii was carried out, and microscopic examination of the bronchoalveolar lavage fluid obtained showed P. jirovecii; no other microorganisms were detected by culture. Treatment with trimethoprim/sulfamethoxazole, fluconazole and corticosteroids at standard dosages was started. The patient had never been on HAART therapy prior to admission. HAART therapy was added to the treatment on the 8th hospital day. During the treatment with trimethoprim/sulfamethoxazole, pancytopenia worsened. Bone marrow biopsy revealed inflamed marrow and partial necrosis. Granulocyte colony stimulating factor was used without avail. On the 22nd hospital day, the chest X-ray obtained as the patient's hypoxemia worsened revealed pneumomediastinum. HRCT showed newly formed cystic lesions in both lung fields. Pneumomediastinum was treated conservatively with high oxygen supply. CD4 cell count and HIV levels were not followed during treatment. However, as the general condition of the patient deteriorated, the patient was started on intravenous pentamidine on the 23rd hospital day. On the 25th hospital day, his oxygen requirement increased. Without intubation, as the patient and guardian refused the patient being put on a ventilator due to multiple economical and sociological reasons, the patient died on the 26th hospital day.\n\nCase 2\nA 48-year-old man presented with insidious dyspnea that had developed over a period of 2 months. The patient had been seropositive for human immunodeficiency virus in 2005 in a routine physical examination for a job position as a sailor. He was on zidovudine and didanosine for 8 months but stopped taking these antiretroviral agents at another hospital for economic reasons. On admission, temperature was 38.2'C, pulse 96 beats per minute, respiratory rate 22 breaths per minute, and blood pressure 100/60 mmHg. Physical examination was normal except for decreased breathing sound in both lung fields. Laboratory data showed a WBC count of 11,010/uL, Hb 13.6 g/dL, a platelet count of 425,000/uL, and LDH of 1,095 U/L. Arterial blood gas analysis in room air demonstrated PaO2 of 54.1 mmHg, PaCO2 of 34.4 mmHg, and saturation of 89.9%, and the calculated (A-a)DO2 was 45.5. CD4 count and HIV viral load were 21/uL and 260,000 IU/mL, respectively. Chest X-ray on admission revealed diffuse ground glass opacity in both lung fields. HRCT showed interlobular septal thickening of the bronchus and bronchioles without any cyst formation (Figure 1). Microscopic examination of bronchoalveolar lavage revealed P. jiroveci, and Staphylococcus aureus was detected by culture. The patient met the criteria of respiratory failure [PaO2 less than 70 mmHg or (A-a)DO2 more than 35 mmHg] and corticosteroids were co-administered with trimethoprim/sulfamethoxazole. On hospital day 4 the patient developed sudden chest pain radiating to the shoulder and neck. Chest X-ray, electrocardiography, and arterial blood gas analysis were performed. The chest X-ray revealed air lining the cardiac border, indicating development of pneumomediastinum. HRCT revealed newly developed cystic changes, bronchiectatic change, and parenchymal tear (Figure 1). The pneumomediastinum was treated conservatively with administration of high oxygen supply without the need for invasive procedures. On hospital day 10, HAART was started with lopinavir/ritonavir, lamivudine, and zidovudine. On hospital day 13, follow up HRCT revealed more aggravated pneumomediastinum, bronchiectasis and parenchymal tear in the lingular division of the left upper lobe. Trimethoprim/sulfamethoxazole was changed to intravenous pentamidine. The patient experienced nausea, vomiting, and hypoglycemia on pentamidine, leading to a further change of antibiotics to primaquine and clindamycin. The patient's dyspnea improved and no particular complications were observed. The patient was discharged on the 42nd hospital day and is being followed up in the outpatient clinic.\n\nFigure 1 Radiological findings of an 48-year-old man with Pneumocystis jirovecii pneumonia on admission and at follow up. A. Computed tomography on admission reveals diffuse bilateral infiltrates. B. Diffuse ground glass opacities are noted on both lung fields on admission. C. High resolution computed tomography reveals newly developed bronchiectatic changes (white arrow) and parenchymal tears (black arrow) at follow up. D. Pneumomediastinum (black arrow) and cystic changes (white arrow) are seen at follow up.\n\nDiscussion\nThe overall incidence of P. jirovecii pneumonia has decreased with the use of highly active antiretroviral therapy [4]. However, approximately 85% of patients with advanced HIV infections continue to experience P. jirovecii pneumonia in the course of their disease when management is inadequate [5]. The most common radiographic finding in P. jirovecii pneumonia is the presence of diffuse, bilateral perihilar interstitial infiltrates (ground-glass opacity) in both lungs [6]. Atypical radiographic manifestations of PCP include cystic spaces and bullae, adenopathy, pleural effusions and pneumothorax [7-10]. The exact mechanism behind the development of the pulmonary cysts and P. jirovecii is not yet known. However, various mechanisms have been proposed including direct lung destruction by P. jirovecii, over-distension of the lungs caused by obstructive bronchiolitis acting as a ball-valve (inflammatory exudates in the small bronchioles), interstitial emphysema and abnormal remodeling of pulmonary architecture due to interstitial fibrosis, and release of elastase and other proteolytic enzymes [5,10-12]. A review of the literature indicates that the development of spontaneous pneumomediastinum with subcutaneous emphysema in HIV patients is rare. The pathophysiology of pneumomediastinum depends on a pressure gradient between the alveoli and the lung interstitium; this leads to alveolar rupture, and consequently air in the interstitial space flows towards the mediastinum along a pressure gradient between the lung periphery and the mediastinum [13]. Other mechanisms leading to this outcome have been attributed to gas-producing microorganisms present in the pneumomediastinum, and rupture of the mucosal barrier of the esophagus or tracheobronchial tree [14]. However, how the presence of P. jirovecii contributes to the development of pneumomediastinum is unknown.\n\nSpontaneous pneumothorax occurs in as many as 35% of patients with active cystic P. jirovecii pneumonia [8]. Even though it is not known exactly how the disease progresses to pneumothorax or pneumomediastinum, it is important to identify associated factors and be able to predict their occurrence. A history of cigarette smoking, pentamidine aerosol treatment, and detection of pneumatoceles by chest radiography, are reported risk factors associated with spontaneous pneumothorax [15,16].\n\nIn relation to the aforementioned risk factors, a 22 pack-year history of smoking was noted in one of our two patients. Pneumatoceles or cysts were not seen on the chest X-rays or HRCT scans taken on admission in either patient. However, cystic lesions and bronchiectasis developed de novo in spite of the standard trimethoprim/sulfamethoxazole treatment, and they are presumed to have developed into pneumomediastinum with subcutaneous emphysema [17]. Staphylococcus aureus that was cultured in the second case may have attributed to the development of pneumomediastinum [18]. However, the use of trimethoprim/sulfamethoxazole was adequate for treating Staphylococcus aureus without the need for an additional antibiotic [19]. Treatment of spontaneous pneumomediastinum is generally limited to observation without the need for invasive measures [20]. However, in the above patients, P. jirovecii pneumonia may have been an underlying cause to the development of pneumomediastinum. Therefore, the standard trimethorpim/sulfamethoxazole was analyzed as a treatment failure warranting a change of antibiotics to pentamidine.\n\nThere is no guideline regarding the treatment of the acute phase of P. jirovecii pneumonia in HIV-infected patients with HAART. However, administration of HAART therapy early in the acute phase of P. jirovecii pneumonia was done in both patients as improved survival rates in HIV-infected patients with severe P. jirovecii pneumonia was associated with HAART therapy [21,22]. Although the developement of pneumothorax was not anticipated in our patients when HAART therapy was initiated, Morris et al reported decreased rates of pneumothorax development in P. jirovecii infected HIV-patients receiving HAART therapy[21]. The possible contribution of antiretroviral therapy to the clinical worsening of the patients was considered. Wislez et al reported of acute respiratory failure following HAART in P. jirovecii pneumonia due to immune reconstitution inflammatory syndrome [23]. HRCT of both patients in this study did not reveal any findings relevant to the development of acute respiratory failure.\n\nThe occurrence of newly formed cystic lesions or bronchiectasis despite treatment may be risk factors for the development of pneumothorax or pneumomediastinum with subcutaneous emphysema in HIV-patients. Therefore close follow up with HRCT in HIV-patients with P. jirovecii pneumonia might assist in predicting the development of pneumothorax or pneumomediastinum. Our findings suggest that clinicians should be aware of the clinical importance of newly formed cystic lesions and bronchiectasis for the development of pneumomediastinum and pneumothorax in P. jirovecii pneumonia.\n\nConclusion\nIn conclusion, clinicians should be aware that cystic lesions and bronchiectasis can develop in spite of trimethoprim/sulfamethoxazole treatment for P. jirovecii pneumonia. Newly formed bronchiectasis and cyst formation may be risk factors for the development of pneumomediastinum with subcutaneous emphysema.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nJu-Yeon Cho took care of the patient in the ICU and drew\n\nup the first draft of the report, Yong Eun Kwon, Sung Ho Yoon, and Seung Il Lee, consultant pulmonologists, made a substantial contribution to draft the manuscript\n\nand revised the draft all over the course of submission, Dong-Min Kim conceived\n\nof the study, participated in its design and coordination and drafted the manuscript. All authors read and approved the final manuscript.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\nhttp://www.biomedcentral.com/1471-2334/9/171/prepub\n\nAcknowledgements\nWritten consent was obtained from the patient or their relative for publication of study.\n==== Refs\nHIV/AIDS surveillance supplemental report Centers for Disease Control and Prevention 2003 1 20 \nStringer JR Beard CB Miller RF Wakefield AE A new name (Pneumocystis jiroveci) for Pneumocystis from humans Emerg infect Dis 2002 8 891 6 12194762 \nWollschlager CM Khna FA Chitkara RK Shivaram U Pulmonary manifestations of the acquired immunodeficiency syndrome (AIDS) Chest 1984 85 197 202 10.1378/chest.85.2.197 6607153 \nPalella FJ JrDelaney KM Moorman AC Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection N Engl J Med 1998 338 853 60 10.1056/NEJM199803263381301 9516219 \nKonishi M Amimotom M Yoshiomoto E AIDS-related Pneumocystis carinii pneumonia with disappearance of cystic lesions after treatment Intern Med 2002 41 896 8 10.2169/internalmedicine.41.896 12413019 \nGoodman PC Gamsu G Radiographic findings in the acquired immunodeficiency syndrome Postgrad Radiol 1987 7 3 15 \nKuhlman JE Kavuru M Fishman EK Siegelman SS Pneumocystis carinii pneumonia: spectrum of parenchymal CT findings Radiology 1990 175 711 4 2343118 \nChow C Templeton PA White CS Lung cysts associated with Pneumocystis carinii pneumonia: radiographic characteristics, natural history, and complications Am J Roentgenol 1993 161 527 31 \nPastores SM Garay SM Naidich DP Rom WN Review: pneumothorax in patients with AIDS-related Pneumocystis carinii pneumonia Am J Med Sci 1996 312 229 34 10.1097/00000441-199611000-00008 8900387 \nSandhu JS Goodman PC Pulmonary cysts associated with Pneumocystis carinii pneumonia in patients with AIDS Radiology 1989 173 33 5 2789413 \nFeurestein IM Archer A Pluda JM Thin-walled cavities, cysts, and pneumothorax in Pneumocystis carinii pneumonia: further observations with histopathologic correlation Radiology 1990 174 697 702 2305052 \nEng RHK Binshburg E Smith SM Evidence for destruction of lung tissues during Pneumocystis carinii infection Arch Intern Med 1987 147 746 9 10.1001/archinte.147.4.746 3493747 \nMacklin MT Macklin CC Malignant intersititial emphysema of the lungs and mediastinum as an important occult complication in many respiratory diseases and other conditions: interpretation of the clinical literature in the light of laboratory experiment Medicine 1944 23 281 358 10.1097/00005792-194412000-00001 \nMacia I Moya J Ramos R Spontaneous pneumomediastinum: 41 cases European journal of Cardio-thoracic surgery 2007 31 1110 4 10.1016/j.ejcts.2007.03.008 17420139 \nMetersky ML Colt HG Olson LK Shanks TG AIDS-related spontaneous pneumothorax: risk factors and treatment Chest 1995 108 946 51 10.1378/chest.108.4.946 7555166 \nGruden JF Huang L Turner J HRCT in the evaluation of clinically suspected Pneumocystis carinii pneumonia in AIDS patients with normal, equivocal, or nonspecific radiographic findings Am J Roentgenol 1997 167 967 75 \nThe National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), and the HIV Medicine Association of the Infectious Disease Society of America (HIVMA/IDSA) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-infected Adults and Adolescents. MMWR 2009 http://aidsinfo.nih.gov/contentfiles/Adult_OI.pdf\nMacfarlane J Rose D Radiographic features of staphylococcal pneumonia in adults and children Thorax 1996 51 539 40 10.1592/phco.25.2.253.56956 8711686 \nGrim SA Rapp RP Martin CA Trimethoprim-sulfamethoxazole as a viable treatment option for infections caused by methicillin-resistant Staphylococcus aureus Pharmacotherapy 2005 25 253 64 10.1016/j.athoracsur.2008.04.067 15767239 \nCaceres M Ali SZ Braud R Spontaneous pneumomediastinum: A comparative study and review of the literature Ann Thorac Surg 2008 86 962 6 10.1097/00002030-200301030-00010 18721592 \nMorris A Wachter RM Luce J Improved survival with highly active antiretroviral therapy in HIV-infected patients with severe Pneumocystis carinii pneumonia AIDS 2003 17 73 80 10.1097/00002030-200301030-00010 12478071 \nZolopa A Andersen J Komarow L Immediate vs deferred ART in the setting of acute AIDS-related opportunistic infection: Final results of a randomized strategy trial, ACTG A5164 15th Conference on Retroviruses Opportunistic Infection. 2008 Feb 3-6. Boston. Oral abstract 142 \nWislez M Bergot E Antoine M Acute respiratory failure following HAART introduction in patients treated for Pneumocystis carinii pneumonia Am J Respir Crit Care Med 2001 164 847 51 11549544\n\n",
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"title": "Newly formed cystic lesions for the development of pneumomediastinum in Pneumocystis jirovecii pneumonia.",
"title_normalized": "newly formed cystic lesions for the development of pneumomediastinum in pneumocystis jirovecii pneumonia"
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"abstract": "Transplant teams face increasing challenges to manage diabetes following kidney transplantation. There is an increasing number of diabetics undergoing transplantation and there is an increased incidence of posttransplant diabetes mellitus (PTDM) due to a higher prevalence of obesity, increased use of steroids and calcineurin inhibitors, and the acceptance of older patients as potential candidates. The options for treating diabetes in the general population are expanding. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors is one of the new modalities of treatment. We report the cases of 8 patients who underwent kidney transplantation and were treated with the SGLT-2 inhibitor empagliflozin for their pre-existing diabetes or for the development of PTDM. They were followed for an average of 12 months. The average age of the patients was 42.5 years. All 8 patients were taking tacrolimus, mycophenolate, and prednisolone. Although creatinine increased slightly (from 88.5 mmol/L to 99.5 mmol/L) in the month after starting empagliflozin, it stabilized after that. Hemoglobin A1c decreased on average 0.85 g/dL. Urine protein decreased by 0.6 g per day and weight decreased on average 2.4 kg throughout the year. One patient discontinued the medication due to recurrent urinary tract infections.",
"affiliations": "Department of Nephrology, Medical Subspecialties Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates. Electronic address: attalln@clevelandclinicabudhabi.ae.;Imperial College of London Diabetes Center, Abu Dhabi, United Arab Emirates.",
"authors": "Attallah|Nizar|N|;Yassine|Lina|L|",
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"title": "Use of Empagliflozin in Recipients of Kidney Transplant: A Report of 8 Cases.",
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"abstract": "Sickle cell disease can present with neurological manifestations. One such presentation is with posterior reversible leukoencephalopathy also known as reversible posterior leukoencephalopathy. The condition is classically described as reversible over time; it commonly presents with oedematous changes involving the white matter of the occipital and parietal regions. Only a few patients with the association between sickle cell disease and posterior reversible leukoencephalopathy have been described in the adult literature. We present two patients from our institutions to emphasise the association between the two conditions and summarise the published cases in the literature.",
"affiliations": "Department of Neurology, Royal North Shore Hospital, Reserve Road, St Leonards, Sydney, NSW 2065, Australia; Western Clinical School, University of Sydney, Sydney, NSW, Australia. Electronic address: ngeevasi@med.usyd.edu.au.;School of Paediatrics and Child Health, University of Western Australia, Crawley, WA, Australia; Departments of Paediatric and Adolescent Haematology and Oncology, Princess Margaret Hospital for Children, Perth, WA, Australia.;Department of Neurology, Royal North Shore Hospital, Reserve Road, St Leonards, Sydney, NSW 2065, Australia; Northern Clinical School, University of Sydney, Sydney, NSW, Australia.;Department of Radiology, Royal North Shore Hospital, Sydney, NSW, Australia; Brain and Mind Research Institute, Camperdown, NSW, Australia.;Department of Neurology, Royal North Shore Hospital, Reserve Road, St Leonards, Sydney, NSW 2065, Australia.;Department of Neurology, Royal North Shore Hospital, Reserve Road, St Leonards, Sydney, NSW 2065, Australia; Northern Clinical School, University of Sydney, Sydney, NSW, Australia.",
"authors": "Geevasinga|Nimeshan|N|;Cole|Catherine|C|;Herkes|Geoffrey K|GK|;Barnett|Yael|Y|;Lin|Jamie|J|;Needham|Merrilee|M|",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell; D001921:Brain; D038524:Diffusion Magnetic Resonance Imaging; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D054038:Posterior Leukoencephalopathy Syndrome",
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"abstract": "SummaryForensic psychiatric services care for patients who present with a mental disorder as well as a risk to themselves or others, and have usually been convicted of an offence. Their needs are complex and the length of stay (LoS) in forensic settings is long. LoS is affected by patient factors as well as legal and policy issues. Owing to the considerable economic and ethical issues surrounding lengthy stays in highly restrictive settings, it is crucial that a strategy is developed for how to deal with this patient group.Declaration of interestNone.",
"affiliations": "University of Rostock.",
"authors": "Völlm|Birgit|B|",
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"country": "England",
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"doi": "10.1192/bjb.2019.24",
"fulltext": "\n==== Front\nBJPsych BullBJPsych BullBJBBJPsych Bulletin2056-46942056-4708Cambridge University Press Cambridge, UK 3128284810.1192/bjb.2019.24S205646941900024X00024EditorialHow long is (too) long? VöllmHow long is (too) long?Völlm Birgit 11 University of RostockCorrespondence to Prof Birgit Völlm (birgit.voellm@med.uni-rostock.de)8 2019 43 4 151 153 15 2 2019 21 2 2019 © The Author 20192019The AuthorThis is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.Summary\nForensic psychiatric services care for patients who present with a mental disorder as well as a risk to themselves or others, and have usually been convicted of an offence. Their needs are complex and the length of stay (LoS) in forensic settings is long. LoS is affected by patient factors as well as legal and policy issues. Owing to the considerable economic and ethical issues surrounding lengthy stays in highly restrictive settings, it is crucial that a strategy is developed for how to deal with this patient group.\n\nDeclaration of interest\nNone.\n==== Body\nEarnshaw et al, in this issue, describe a study looking at the length of admissions in a medium secure unit in England over a period of nearly 30 years. They show a significant increase in length of stay (LoS) in the most recent cohort, as well as far more discharges to other psychiatric settings and fewer to independent living, with the diagnostic composition of the cohorts remaining largely unchanged. The paper is a welcome addition to the literature on LoS in forensic settings. Evidence on LoS is scarce, despite its obvious ethical and economic relevance. This editorial summarises the research on LoS to date and considers ideas to improve service organisation for this group of patients.\n\nMethodological issues\nThere are a number of ways to investigate LoS:1 (a) admission samples (i.e. considering all patients admitted during a particular period with LoS calculated from admission to discharge); (b) cross-sectional samples (the sample consisting of all patients resident in the particular unit of interest on a particular date with LoS calculated from date of admission to this time point); and (c) discharge samples (all patients discharged during a particular period with LoS calculated from date of admission to this date). Which method is the best depends on the questions to be answered. Earnshaw et al use admission samples, which has the advantage that the political and service provision context is likely to be the same for all patients in the sample at point of admission. What this method cannot capture is those patients who have not been discharged at the time of data collection, as their length of admission cannot be known at this point, thereby underestimating LoS. Another, and more significant, limitation of most research to date, regardless of which of the three approaches is used, is that it only considers a relatively short period in the patient's care trajectory, the admission to a single unit. In reality, patients' pathways are complex and an individual may be admitted to a number of secure units consecutively, adding to their overall LoS in secure care.\n\nWhat we know about LoS in forensic settings\nConcerns that some patients stay for too long in too high a level of security were first raised following studies in high secure settings in the 1990s involving assessments by the patients' own teams as well as independent multi-disciplinary reviews. These suggested that between one-third and two-thirds of patients did not require that level of security.2–5 Inadequate provision of beds in less secure settings and inefficiencies in the system of transfer and discharge were thought to be significant factors in the delayed transfer to a more appropriate level of security. These findings led to the ‘accelerated discharge programme’,6 aimed at reducing patient numbers in high secure care while bed numbers in medium and low secure settings increased. At the beginning of the 1990s, there were 1700 high and 600 medium secure beds,7 while in 2015 there were just under 800 high and about 3200 medium secure beds.8 Although the reduction of high secure beds is a welcome development, the increase in the overall number of patients detained in secure settings is worrying. In addition, while I am not aware of any published research in this area, anecdotally, restrictions have increased in medium secure settings, e.g. with regards to leave and handcuffing during leave.\n\nMaybe somewhat surprisingly, there is no agreement or guidance as to how long patients should stay in high secure settings in the UK. For medium secure care, the original guidance from government, based on the recommendations in the Glancy and Butler reports,9 suggested an upper limit of 2 years; however, a number of studies have demonstrated that this LoS is far exceeded in a large proportion of cases.10 In a multicentre study in the UK, including all three high secure hospitals and 23 medium secure services, both within the National Health Service and the independent sector,11 we found that 23.5% of high secure and 18.1% of medium secure patients fulfilled our criteria for ‘long-stay’. We defined ‘long-stay’ as having been in a high secure setting for more than 10 years, in a medium secure setting for more than 5 years or in a combination of both for more than 15 years. These figures were based on pilot work showing that these thresholds would identify a population large enough in size to provide meaningful conclusions for service developments, but not so large that a substantial proportion of the total patient population would be captured. Whether there has been an actual increase in LoS, however, remains unclear – the paper in this issue of the Bulletin is the first to investigate this question.\n\nResearch identifying factors associated with long stay is limited. In the UK, one early study at one of the three high secure hospitals12 identified severity of index offence as the most important factor for personality disordered patients, while for those with mental illness psychopathology was a more relevant predictor of LoS. Studies in medium secure settings have identified severity of psychopathology, psychiatric history, seriousness of offending, patients being on ‘restriction orders’ (requiring Ministry of Justice permission for transfer), non-engagement in interventions, dependency needs and lack of step-down facilities as factors associated with long stay. A review of the international literature1 similarly found that the factors most frequently associated with longer stay were seriousness of index offence, longer previous prison sentence, psychotic illness, symptom severity and having no close relationship.\n\nPatient perspective has thus far been largely neglected in research on long stay in forensic settings. A qualitative study which formed part of the multicentre study described above12 and included 40 patient interviews investigated patients' perspective on reasons for long stay, their current situation and the prospect of moving on. Based on the emerging themes – attribution, outlook, approach and readiness for change – four overall ‘stances’ could be identified. Patients in the ‘dynamic acceptance’ group attributed their long-stay to themselves; they felt overall positive about therapy and being in secure care but felt they were ready to move on. Patients in the group we labelled ‘static acceptance’ attributed the reason for long stay internally and externally, were somewhat less positive about therapies and did not believe they were ready to move on. Those in the ‘dynamic resistance’ and ‘static resistance’ categories attributed their long-stay to external factors and were largely negative about their placement and interventions. Whereas the former group still believed they would move on eventually, the latter had largely given up on the prospect of moving on, despite their belief that they did not need to be in secure care.\n\nService provision\nService provision in secure care is complex, entailing different levels of security with vague entry and even vaguer exit criteria. For example, those admitted to high secure care should present a ‘grave and immediate’ danger, obviously words that leave a lot of room for interpretation. Maybe somewhat surprisingly there is no agreement that those having entered high secure care presenting such a danger should then move on or be discharged if they no longer do so. In addition, how does one measure progress, e.g. of a patient having committed sexual offences against children? Such a patient might be very well adapted in any setting not giving access to children, but what should be the criteria to decide which level of security is the right one and when to move on after years of settled behaviour? The debate around the poor to moderate accuracy of risk assessment instruments for long-term predictions is also pertinent here.13 Unfortunately, in the UK there seems to be little appetite to tackle these complex questions nationally. Instead, each responsible clinician makes their own judgement, and in many cases has to fight individual battles with the next unit, trying to ‘sell’ their patient.\n\nLittle is known about the complex pathways forensic patients take. In theory, they move from higher to lower levels of security in accordance with the lowering of their risk and progress in therapy. In practice, such ideal pathways are rarely achieved. For instance, we showed in our study11 that less than one-third of the sample of long-stayers had stayed in their current secure unit only, while about 40% had stayed in three or more settings. More than 50% of long-stay medium secure patients had been admitted from another medium secure unit. This may be good practice in order to try a different approach in individuals with limited treatment gains. Nevertheless, it is clear that rather than moving on, a large number of patients seem to be moving around. It is difficult to see how this unfortunate state of affairs could be changed without taking a longitudinal view and without the development of national policy for this patient group.\n\nConsidering their pathways, the group of long-stay patients probably consists of three subgroups: (a) those who are still on a trajectory of positive, albeit slow, progress; (b) those who are ‘stuck’ currently but might move to less secure conditions under certain circumstances; and (c) those who require secure care for life. The first group is of least concern. The second might benefit from improvements in service organisation and advancements in psychotherapeutic and pharmacological therapies. The third group is most controversial. In our own study, consultants predicted that more than 40% of long-stay patients currently resident in high secure care would still be there in 5 years' time. Even for long-stay patients in medium secure care at the time of the study, only a minority of patients were expected to achieve independent living in the next 5 years.\n\nNevertheless, interviews with professionals in the UK demonstrated that staff working in secure units still conceptualise the process of care along the lines of ‘admission, treatment, rehabilitation, cure’, in denial of the actual situation of most patients.14 Staff felt uncomfortable with the idea of dedicated ‘long-stay units’, which they saw as warehousing. Many did not consider long periods of detention to be problematic as long as treatment was still offered, despite the fact that such treatment did not seem to make a difference to the patient's chances of moving on. Although these sentiments are understandable, not openly recognising long stay as a problem is likely to act as a barrier to considering service improvements for this patient group.\n\nInternational perspective\nA number of countries have started to recognise the problem of long stay in forensic psychiatric hospitals, resulting in a range of legal and service provision developments.15 Croatia, Italy and Portugal now have legal provisions such that detention in hospital can no longer exceed the length of a prison sentence the individual would have been given had they been convicted as a non-mentally disordered offender. While not going that far, in Germany the constitutional court ruled that the length of detention has to be proportionate to the index offence and that the longer detention lasts, the more the individual's right to freedom weighs in relation to the protection of the public. While this principle has long been established in the case law of the German constitutional court, the new Criminal Code additionally specifies that after 6 years of detention in a forensic psychiatric hospital, detention has to be terminated unless there is a risk that further offences will be committed that will cause ‘serious’ physical or psychological harm to a victim; after 10 years such risk has to be ‘grave’.16\n\nOther countries have developed policies and services specifically for long-stay forensic populations. One example of particular interest is service provision in The Netherlands. There patients can be given ‘long-stay status’ by a court on the application of their treating team. Criteria for this status are:\n• having been an in-patient in a forensic institution for at least 6 years;\n\n• having been a patient in two separate forensic hospitals;\n\n• having completed relevant treatment programmes but with little discernible progress (or consistently refusing to participate in such programmes);\n\n• no reduction in risk in the foreseeable future expected.\n\n\n\nIndividuals with long-stay status are diverted to specific long-stay units, where the emphasis is on quality of life rather than risk-reducing interventions. Crucially, an open discussion is held with the patient about this process and they are fully aware of their new status. Importantly, from a human rights point of view, this status is not a dead end; rather, patients can move back into mainstream provision if it is clinically indicated.\n\nRecommendations\nGiven the significant ethical and economic consequences of long stay in forensic care, it is essential that a national strategy is developed to deal with this complex patient group. Issues to consider in such a strategy are:\n• taking a whole pathway approach;\n\n• clear entry and exit criteria for services;\n\n• cut-off points for the definition of ‘long stay’ in the different levels of security;\n\n• independent reviews of long-stay patients;\n\n• exploration of interventions designed to reduce LoS;\n\n• improvement of the efficiency of pathways for this group;\n\n• incentives to move patients on (e.g. through the Commissioning for Quality and Innovation framework, as is already happening in some trusts);\n\n• flexibility in moving between services with prolonged transition periods;\n\n• introduction and evaluation of pilot services for long-stay patients.\n\n\n\nTo develop such a strategy, wide consultation including patients and carers is required to capture relevant perspectives and concerns.\n\nAbout the author\nBirgit Völlm is Professor of Forensic Psychiatry at the University of Rostock and Medical Director at the Hospital for Forensic Psychiatry, Rostock, Mecklenburg-Vorpommern, Germany.\n==== Refs\nReferences\n1 Huband N , Furtado V , Schel S , Eckert M , Cheung N , Bulten E , \nCharacteristics and needs of long-stay forensic psychiatric inpatients: a rapid review of the literature . Int J Forensic Ment Health \n2018 ; 17 : 45 –60 .\n2 Maden A , Rutter S , McClintock C , Friendship C , Gunn J. \nOutcome of admission to a medium secure psychiatric unit . Br J Psychiatry \n1999 ; 175 : 313 –6.10789295 \n3 Reed J. \nThe need for longer term psychiatric care in medium or low security . Crim Behav Ment Health \n1997 ; 7 : 201 –12.\n4 Pierzchniak P , Farnham F , de Taranto N , Bull D , Gill H , Bester P , \nAssessing the needs of patients in secure settings: a multi-disciplinary approach . J Forensic Psychiatry \n1999 ; 10 : 343 –54.\n5 Thomas S , Leese M , Dolan M , Harty M , Shaw J , Middleton H , \nThe individual needs of patients in high secure psychiatric hospitals in England . J Forensic Psychiatry Psychol \n2004 ; 15 : 222 –43.\n6 Department of Health . Report of the Review of Security at the High Security Hospitals . TSO (The Stationery Office) , 2000 .\n7 Craissati J , Taylor P. \nForensic mental health services in the United Kingdom and Ireland In Gunn J , Johnson C , Taylor P (eds): Forensic Psychiatry: Clinical, Legal and Ethical Issues (eds. Gunn J , Taylor P ): 589 –619 . Taylor and Francis , 2014 .\n8 NHS England . 2014/15 NHS Standard Contract for High Secure Mental Health Services (Adults) . NHS Commissioning Board , 2013 .\n9 Butler . Report of the Committee on Mentally Abnormal Offenders (Chairman Lord Butler) . Cmnd 6244 \nHMSO , 1975 .\n10 Shah A , Waldron G , Boast N , Coid JW , Ullrich S. \nFactors associated with length of admission at a medium secure forensic psychiatric unit . J Forensic Psychiatry Psychol \n2011 ; 2 : 496 –512 .\n11 Völlm B , Edworthy R , Holley J , Talbot E , Majid S , Duggan C , \nA mixed-methods study exploring the characteristics and needs of long-stay patients in high and medium secure settings in England: implications for service organisation . Health Serv Deliv Res \n2017 ; 5 : 11 .\n12 Dell S , Robertson G , Parker E. \nDetention in Broadmoor. Factors in length of stay . Br J Psychiatry \n1987 ; 150 : 824 –7.3651737 \n13 Ramnesh T , Igoumenou A , Vazquez Montes M , Fazel S. \nUse of risk assessment instruments to predict violence in forensic psychiatric hospitals: a systematic review and meta-analysis . Eur Psychiatry \n2018 ; 52 : 47 –53 .29626758 \n14 McDonald R , Furtado V , Völlm B. \nMedicine, madness and murderers: the context of English forensic psychiatric hospitals . J Health Organ Manag \n2017 ; 31 : 598 –611 .28933678 \n15 Edworthy R , Sampson S , Völlm BA. \nInpatient forensic-psychiatric care: legal frameworks and service provision in three European countries . Int J Law Psychiatry \n2016 ; 29 : 18 –27 .\n16 Pfister W. \nNeues (und nicht so Neues) im Recht der Unterbringung nach §63 StGB . Forensische Psychiatrie Psychol Kriminol \n2017 ; 11 : 31 –38 .\n\n",
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"abstract": "BACKGROUND\nAtypical femoral fracture (AFF) occurs with minor trauma in patients receiving antiresorptive drugs such as bisphosphonate and denosumab. We hypothesized that patients with bone metastasis who receive higher doses of antiresorptive drugs tend to experience AFF more frequently. This study aimed to investigate the prevalence rate of AFF in patients receiving antiresorptive drugs for bone metastasis of breast cancer.\n\n\nMETHODS\nBased on the database from our hospital, patients with breast cancer between March and September 2014 were investigated. Thirty-two patients with bone metastasis who received higher doses of antiresorptive drugs were included for analysis and defined as the metastasis (M) group. For the control (C) group, 32 patients in the same period with breast cancer without bone metastasis who did not undergo antiresorptive drug therapy were included. We evaluated the localized periosteal thickening of the lateral cortex (beaking) and femoral neck-shaft angle in CT scout view, the periods from induction of antiresorptive drugs to the appearance of beaking, and the occurrence rate of complete fracture. The 2 groups were compared.\n\n\nRESULTS\nOf the 64 limbs in 32 patients of the M group, 8 limbs in 6 patients showed beaking at the subtrochanteric area (12.5%). After the occurrence of beaking, 5 limbs in 3 patients eventually had a complete fracture with minor trauma (7.8%). On the other hand, no beaking was observed in the C group.\n\n\nCONCLUSIONS\nThe frequency of AFF in patients with breast cancer receiving bisphosphonate and/or denosumab for bone metastasis was high. More attention should be paid to the occurrence of AFF in these patients than osteoporotic patients.",
"affiliations": "Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Aomori, Japan. otaseiya012@gmail.com.;Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Aomori, Japan.;Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Aomori, Japan.;Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Aomori, Japan.;Department of Surgery, Aomori Prefectural Central Hospital, Aomori, Japan.;Department of Orthopaedic Surgery, Aomori Prefectural Central Hospital, Aomori, Japan.;Department of Orthopaedic Surgery, Aomori Prefectural Central Hospital, Aomori, Japan.;Department of Orthopaedic Surgery, Aomori Prefectural Central Hospital, Aomori, Japan.;Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Aomori, Japan.",
"authors": "Ota|Seiya|S|;Inoue|Ryo|R|;Shiozaki|Takashi|T|;Yamamoto|Yuji|Y|;Hashimoto|Naoki|N|;Takeda|On|O|;Yoshikawa|Kei|K|;Ito|Junji|J|;Ishibashi|Yasuyuki|Y|",
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"fulltext": "\n==== Front\nBreast CancerBreast CancerBreast Cancer (Tokyo, Japan)1340-68681880-4233Springer Japan Tokyo 2794316374610.1007/s12282-016-0746-8Original ArticleAtypical femoral fracture after receiving antiresorptive drugs in breast cancer patients with bone metastasis Ota Seiya +81-172-39-5083otaseiya012@gmail.com 1Inoue Ryo 1Shiozaki Takashi 1Yamamoto Yuji 1Hashimoto Naoki 2Takeda On 3Yoshikawa Kei 3Ito Junji 3Ishibashi Yasuyuki 11 0000 0001 0673 6172grid.257016.7Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562 Aomori Japan 2 0000 0004 0378 7152grid.413825.9Department of Surgery, Aomori Prefectural Central Hospital, Aomori, Japan 3 0000 0004 0378 7152grid.413825.9Department of Orthopaedic Surgery, Aomori Prefectural Central Hospital, Aomori, Japan 10 12 2016 10 12 2016 2017 24 4 601 607 22 6 2016 28 11 2016 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nAtypical femoral fracture (AFF) occurs with minor trauma in patients receiving antiresorptive drugs such as bisphosphonate and denosumab. We hypothesized that patients with bone metastasis who receive higher doses of antiresorptive drugs tend to experience AFF more frequently. This study aimed to investigate the prevalence rate of AFF in patients receiving antiresorptive drugs for bone metastasis of breast cancer.\n\nMethods\nBased on the database from our hospital, patients with breast cancer between March and September 2014 were investigated. Thirty-two patients with bone metastasis who received higher doses of antiresorptive drugs were included for analysis and defined as the metastasis (M) group. For the control (C) group, 32 patients in the same period with breast cancer without bone metastasis who did not undergo antiresorptive drug therapy were included. We evaluated the localized periosteal thickening of the lateral cortex (beaking) and femoral neck-shaft angle in CT scout view, the periods from induction of antiresorptive drugs to the appearance of beaking, and the occurrence rate of complete fracture. The 2 groups were compared.\n\nResults\nOf the 64 limbs in 32 patients of the M group, 8 limbs in 6 patients showed beaking at the subtrochanteric area (12.5%). After the occurrence of beaking, 5 limbs in 3 patients eventually had a complete fracture with minor trauma (7.8%). On the other hand, no beaking was observed in the C group.\n\nConclusions\nThe frequency of AFF in patients with breast cancer receiving bisphosphonate and/or denosumab for bone metastasis was high. More attention should be paid to the occurrence of AFF in these patients than osteoporotic patients.\n\nKeywords\nAtypical femoral fractureBisphosphonateDenosumabBreast cancerBeakingissue-copyright-statement© The Japanese Breast Cancer Society 2017\n==== Body\nIntroduction\nAtypical femoral fracture (AFF) occurs with minor trauma from the lesser trochanter to the supracondylar. This fracture configuration is transverse or short oblique, non-comminuted or minimally comminuted, and has focal or diffuse cortical thickening in the lateral cortex of the subtrochanteric or femoral shaft region. This localized periosteal or endosteal thickening of the lateral cortex is called “beaking” and is one of the major features of this fracture. Minor features are a generalized increase in cortical thickness of the femoral diaphysis, prodromal symptoms such as dull or aching pain in the groin or thigh, and delayed fracture healing [1].\n\nAFFs have been reported as a potential complication of long-term bisphosphonate therapy for the treatment of osteoporosis [2]. There are many studies and case reports indicating that AFF could be more frequent in osteoporotic patients receiving antiresorptive drugs such as bisphosphonate and denosumab [3, 4]. Antiresorptive drugs reduce not only bone loss and risk of fractures in patients with osteoporosis [5], but also the frequency of skeletal-related events such as pathologic bone fracture, spinal cord compression, and hypercalcemia due to cancer with bone metastasis [6–8]. The doses of bisphosphonates used for bone metastasis are up to 10 times greater than those for osteoporosis [9]. Similarly, the doses of denosumab used for metastasis are greater than those for osteoporosis. If antiresorptive drugs cause AFF, patients with bone metastasis who receive a much higher dose of those drugs than patients with osteoporosis might be at higher risk for AFF. However, there have been few reports that investigated the association between AFF and antiresorptive drugs in patients with bone metastasis.\n\nRecently, we experienced several cases of AFF caused by minor trauma in patients with breast cancer undergoing antiresorptive drug treatment. In our hospital, computed tomography (CT) is performed in breast cancer patients to follow up for distant metastasis at the department of breast surgery. CT allows sequential image evaluation and early diagnosis of AFF in patients with breast cancer. We hypothesized that patients with bone metastasis who receive higher doses of antiresorptive drugs would tend to incur AFF at earlier phases and higher rates compared to those who do not receive antiresorptive drugs. The purpose of this study was to investigate the prevalence rate of AFF in patients receiving antiresorptive drugs for bone metastasis of breast cancer.\n\nMaterials and methods\nPatients\nBased on the database from the department of breast surgery in our hospital, patients with breast cancer between March and September 2014 were investigated. Of these, 53 female patients who were treated as bone metastasis were identified. An average age of these patients was 61.3 years (range 38–86 years). Detailed review of all medical records and imaging studies was performed retrospectively, and the height, weight, body mass index (BMI), past history, hormonal therapy, serum calcium and follow-up periods after induction of antiresorptive therapy from 2006 to 2015 were identified. The inclusion criteria were as follows: (1) use of intravenous pamidronic acid and/or zoledronic acid and/or subcutaneous denosumab as treatment for bone metastasis, and (2) clinical follow-up for at least 2 years after induction of high-dose antiresorptive drugs, and (3) CT scan taken from the neck level to proximal thigh level every 6 months for at least 2 years. Patients who had a history of osteoporosis or incomplete medical records were excluded. The remaining 32 patients were included for analysis. These patients were defined as the Metastasis (M) group. For the control group, 32 patients who had breast cancer without bone metastasis, and did not undergo antiresorptive therapy in the same period were extracted. These patients were matched to the M group by sex, BMI, follow-up period and hormonal therapy, and defined as the control (C) group. The institutional review board of the Hirosaki University Graduate School of Medicine approved the protocol, and all patients and their families were informed that the data concerning their case would be submitted for publication. We obtained their consent.\n\nImaging\nTo determine the presence of AFF, all patients’ CT images during the follow-up periods were evaluated by one investigator (S.O.) who knew the incidence of fractures. The checkpoint was the presence of localized periosteal or endosteal thickening of the lateral cortex at the subtrochanteric region (beaking) in CT scout view (Fig. 1). Beaking was defined as the presence of cortex extrusion. When it was difficult to judge beaking on the CT scout view, a senior orthopedic surgeon (R.I.) was consulted and a consensus was reached. After detection of beaking on CT, the periods from induction of antiresorptive agents to the appearance of beaking, the occurrence rate of complete fracture, and the period from appearance of beaking to the occurrence of complete fracture were investigated. The femoral neck-shaft angle was measured in CT scout view. The femoral neck-shaft angle was defined as the angle formed by the intersection of a line down the centre of the femoral neck and a line through the centre of the femoral shaft. Bony union was defined as bridging of 3 of the 4 cortices on AP and lateral radiographs [10].Fig. 1 Beaking of lateral cortex in scout view of CT. The presence of localized periosteal or endosteal thickening of the lateral cortex at the subtrochanteric region (beaking) in CT scout view\n\n\n\n\nStatistical analysis\nData input and calculation were performed with the SPSS ver.12.0 J (SPSS Inc., Chicago, IL, USA). The comparison of age, height, body weight, BMI, follow-up period, and neck-shaft angle between the M group and C group was performed using the Student’s t test for parametric data and Mann–Whitney U test for nonparametric data. Correlations of treatment duration of antiresorptive drugs and beaking or AFF were investigated with Spearman’s correlation. In all analyses, P values <0.05 were considered significant.\n\nResults\nCharacteristics of the M and C groups are shown in Table 1. The average age of the M group was 59.2 ± 11.6 years, height was 152.8 ± 6.7 cm, weight was 54.2 ± 8.8 kg, BMI was 23.2 ± 3.6 kg/m2, and follow-up period was 56.6 ± 25.7 months. On the other hand, the average age of the C group was 61.9 ± 13.4 years, height was 154.4 ± 5.8 cm, weight was 56.5 ± 9.4 kg, BMI was 23.7 ± 3.6 kg/m2, and follow-up period was 53.5 ± 27.4 months. There were no significant differences in age (p = 0.444), height (p = 0.485), body weight (p = 0.452), BMI (p = 0.677), and follow-up period (p = 0.528) between the 2 groups. One patient of the M group underwent pamidronic acid and zoledronic acid therapy, 12 underwent zoledronic acid only, 18 underwent zoledronic acid and denosumab, and 1 underwent denosumab only (Table 2). These antiresorptive drugs were not used concomitantly. Patients typically received 4 mg zoledronic acid or 120 mg denosumab every 3–4 weeks. The average of administration period of zoledronic acid was 43.5 ± 28.0 months. That of denosumab was 27.6 ± 9.7 months. There were many variations of past history in both groups, such as hypertension, diabetes, hyperlipidaemia, angina, cerebral haemorrhage and infarction, tuberculosis, cholecystitis, asthma, systemic lupus erythematosus, rheumatoid arthritis, Hashimoto’s thyroiditis, Sjogren’s syndrome, uterine myoma, endometriosis, ovarian cyst, cervical cancer, gastric cancer, thyroid cancer, and malignant lymphoma. Two patients of the M group took oral prednisolone during the follow-up period. The sites for metastasis of M group were brain (3 patients), lung (15 patients), liver (15 patients), and stomach (1 patient). Those of C group were brain (1 patient) and liver (2 patients). The other 29 patients of C group did not have metastasis (Table 3).Table 1 Characteristics, follow-up period, hormonal therapy, and femoral neck-shaft angle of patients\n\n\tM group (n = 32)\tC group (n = 32)\t\np value\t\nAge (years)\t59.2 ± 11.6\t61.9 ± 13.4\t0.444\t\nHeight (cm)\t152.8 ± 6.7\t154.4 ± 5.8\t0.485\t\nWeight (kg)\t54.2 ± 8.8\t56.5 ± 9.4\t0.452\t\nBMI (kg/m2)\t23.2 ± 3.6\t23.7 ± 3.6\t0.677\t\nFollow-up period (months)\t56.6 ± 25.7\t53.5 ± 27.4\t0.528\t\nLuminal type\t25 (78.1%)\t26 (75.0%)\t0.756\t\nHER2-positive type\t3 (9.4%)\t3 (9.4%)\t1.000\t\nTriple-negative type\t0\t3 (9.4%)\t0.119\t\nUnknown\t4 (12.5%)\t0\t0.057\t\nChemotherapy\t20 (62.5%)\t9 (28.1%)\t0.006\t\nEndocrine therapy\t28 (87.5%)\t28 (87.5%)\t1.000\t\nNeck-shaft angle (right)\t140.7 ± 6.4\t143.0 ± 5.8\t0.056\t\nNeck-shaft angle (left)\t140.0 ± 6.7\t140.7 ± 6.6\t0.453\t\nThe values of age, height, weight, BMI, follow-up period, and femoral neck-shaft angle are in mean ± SD\n\n\nP values below 0.05* indicate significant level of difference between the M group and C group, using the Student’s t test for parametric data and Mann–Whitney U test for nonparametric data\n\n\nTable 2 Types of antiresorptive drugs in the M group\n\nType of antiresorptive drug\tThe number of patients\t\nPamidronic acid, zoledronic acid\t1\t\nZoledronic acid only\t12\t\nZoledronic acid, denosumab\t18\t\nDenosumab only\t1\t\nTotal\t32\t\nOne patient of the M group underwent pamidronic acid and zoledronic acid therapy, 12 underwent zoledronic acid only, 18 underwent zoledronic acid and denosumab, and 1 underwent denosumab only\n\n\nTable 3 The site for distant metastasis in subjects\n\n\tM group (n = 32)\tC group (n = 32)\t\nBrain\t3 (9.4%)\t1 (3.1%)\t\nLung\t15 (46.9%)\t0\t\nLiver\t15 (46.9%)\t2 (6.3%)\t\nStomach\t1 (3.1%)\t0\t\nBone\t32 (100%)\t0\t\nNo metastasis\t0\t29 (90.6%)\t\nThe numbers of brain, lung, liver, stomach, bone and no metastasis are shown\n\n\n\n\nOf the 64 limbs in 32 patients of the M group, 8 limbs in 6 patients showed beaking at the subtrochanteric area (12.5%). On the other hand, in the C group, no beaking was observed. All 6 patients with beaking underwent bone scintigraphy to exclude bone metastasis. Five of six patients had no uptake of 99mTc and one patient showed uptake in the subtrochanteric area. However, there were no findings of bone sclerosis and osteolysis suggestive of the metastasis on CT scan in this one patient. The period from induction of antiresorptive drugs to the occurrence of beaking was, on an average, 48.4 months (range 22–75 months). After the occurrence of beaking, 5 limbs in 3 patients eventually had a complete fracture with minor trauma (7.8%) (Table 4). There were no patients with rheumatoid arthritis or received steroid treatment. Only 1 limb showed a complete fracture in the distal femoral shaft, and the site of this fracture was out of range of CT evaluation. All of these patients underwent surgery. The period from the presence of beaking to complete fracture was on, an average, 23.0 months (range 17–31 months). Only 1 patient with AFF (16.7%) experienced hypocalcemia during the follow-up period, and 6 (23.1%) patients without AFF experienced hypocalcemia in M group. The mean right femoral neck-shaft angles were 140.7° ± 6.4° in the M group and 143.0° ± 5.8° in the C group, and left were 140.0° ± 6.7° in the M group and 140.7° ± 6.6° in the C group (Table 1). There were no significant differences in right (p = 0.056) and left (p = 0.453) between the 2 groups. Treatment duration significantly correlated with the presence of beaking (r = 0.486, p = 0.005); on the other hand, it did not correlate with the occurrence of complete fracture (r = 0.285, p = 0.114).Table 4 Characteristics of patients with AFF\n\nPatient\tAge (years)\tSide\tMetastasis (excluding bone)\tDrugs\tDuration (months)\tResponse to therapy\tBeaking (months)\tFracture (months)\t\nA\t50\tRight\tLiver\tZ\t74\tSD\t42\t–\t\nB\t53\tRight\tLiver\tZ, D\t78\tPD\t62\t–\t\nB\t53\tLeft\tLiver\tZ, D\t78\tPD\t64\t–\t\nC\t58\tRight\t–\tP, Z\t89\tSD\t41\t68\t\nC\t58\tLeft\t–\tP, Z\t89\tSD\t46\t77\t\nD\t64\tRight\t–\tZ\t100\tPD\t35\t52\t\nE\t68\tRight\t–\tZ, D\t101\tPD\t75\t–\t\nF\t73\tRight\t–\tZ, D\t54\tSD\t22\t39\t\nF\t73\tLeft\t–\tZ, D\t54\tSD\tUNK\t45\t\nThe period to beaking and complete fracture from induction of antiresorptive drug therapy is shown. Eight limbs in 6 patients showed beaking at the subtrochanteric area (12.5%). The period from induction of antiresorptive drugs to the occurrence of beaking was, on average, 48.4 months. After the occurrence of beaking, 5 limbs in 3 patients eventually had a complete fracture from minor trauma (7.8%). The period from the presence of beaking to a complete fracture was, on an average, 23.0 months. Patient F underwent AFF on the supracondylar of the left side, and this area was out of CT evaluation. Therefore, the occurrence time of beaking in the left femur was unknown. Bone metastasis’s response to therapy was measured as progressive disease (enlargement of metastatic lesion on CT scan) or stable disease (no enlargement of metastatic lesion on CT scan)\n\n\nD denosumab, P pamidronic acid, Z zoledronic acid, PD progressive disease, SD stable disease, UNK unknown\n\n\n\n\nDiscussion\nThis study showed that the occurrence rate of AFF in patients with breast cancer receiving antiresorptive therapy for bone metastasis was higher than that of those who did not receive antiresorptive drugs. Of those who received antiresorptive therapy, 8 limbs in 6 patients (12.5%) showed beaking in the subtrochanteric area and 5 limbs in 3 patients (7.8%) had a complete fracture. There are several studies on the frequency of AFF in patients using bisphosphonate for osteoporosis. Schilcher J et al. investigated 12,777 Swedish women using bisphosphonate for osteoporosis and reported 59 patients with AFF [11]. Black DM et al. reviewed 3 clinical trials and reported 12 of 14,195 patients with AFF [12]. As mentioned above, most previous reports about AFF were intended for the patients receiving lower doses of bisphosphonate typically used to treat osteoporosis. Two case series reported the frequency in patients with cancer. Puhaindran et al. investigated 327 patients with skeletal malignant involvement who received a minimum of 24 doses of intravenous bisphosphonates and reported 4 cases of AFF [13]. Chang et al. who investigated 62 patients with breast cancer or multiple myeloma with a femur fracture and prior intravenous bisphosphonate treatment for bone malignancy, reported 6 cases of AFF [14]. The frequency of AFF may have been higher (12.5%) in our study because only breast cancer patients were subjects of investigation and all patients underwent CT scans to diagnose AFF.\n\nThe beaking appeared, on an average, at 48.4 months after antiresorptive therapy induction in patients with breast cancer and bone metastasis. On the other hand, no beaking was observed in those who did not undergo antiresorptive drugs in this study. There have been several reports on the period of fracture after bisphosphonate induction. Park-Wyllie et al. explored the association between bisphosphonate and fractures in a cohort of elderly women using bisphosphonate. They mentioned that among these elderly women, treatment with a bisphosphonate for more than 5 years was associated with an increased risk of subtrochanteric or femoral shaft fractures [15]. Also, there have been a few case reports for denosumab [16]. The mechanism of AFF and its association with antiresorptive drugs remains unknown. One hypothesis is that the chronic suppression of bone turnover by bisphosphonates may lead to an accumulation of microdamage in the bone, weakening and eventually leading to a fracture [3]. Therefore, there is an interval of several years from induction of antiresorptive therapy to the occurrence of AFF.\n\nIn this study, there was no significant association between the femoral neck-shaft angle and the occurrence of AFF. The cause of AFF is unknown and likely multifactorial. The biomechanical factor is one of the reasons for AFF. Hagen et al. mentioned that patients who presented with AFF had more varus proximal femoral geometry than those who did not sustain a fracture [17]. Oh et al. reported that of the 12 cases of low-energy femoral shaft fractures associated with bowing deformity, 6 cases were not treated with bisphosphonate at all [18]. They said that stress fractures associated with a femoral shaft bowing deformity should be recognized as another cause of AFF. In this study, there was no difference in the femoral neck-shaft angle between patients with AFF and without AFF in the M group. However, it is possible that our measurements overestimated or underestimated the actual varus in our patients because of limb rotation.\n\nIn regard to the complete fracture after beaking occurrence, this study showed that 3 of 5 patients with beaking definitely resulted in complete fracture (Fig. 2). There have been few reports about the prevalence rate of complete fracture after beaking occurrence due to AFF. However, in general, all incomplete AFF may progress to a complete fracture. Ha et al. mentioned that femoral insufficiency fractures after prolonged bisphosphonate therapy seldom healed spontaneously and most patients underwent surgery for fracture displacement or persistent pain [19]. Shane et al. reported that if there is no symptomatic and radiographic improvement after 2–3 months of conservative therapy, preventive nail fixation should be strongly considered as these patients may progress to a complete fracture [1].Fig. 2 Complete fracture of the bilateral femur by AFF. a Complete fracture of the right femur and beaking on the contralateral side. b Post open reduction and internal fixation of right femur. c Complete fracture of the left femur by AFF. d Post open reduction and internal fixation of the left femur\n\n\n\n\nAlthough the number of reports about the surgical treatment of AFF is increasing, it is unclear if a preventive surgery is needed or useful in incomplete fractures [20]. Several reports recommended conservative therapy that involves replacing bisphosphonate with teriparatide and limiting weight-bearing through the use of crutches or a walker. However, these conservative therapies have a significant negative impact on quality of life in these patients, and in a cancer patient, teriparatide is a contraindication. If a complete fracture occurs, the patient may require surgery and rehabilitation [21, 22]; therefore, the prevention of complete fracture is important. Routine X-rays should be undertaken to investigate any signs and symptoms associated with AFF. Preventive surgery may be effective to avoid complete fracture. Chang et al. retrospectively investigated 20 incomplete, non-displaced AFF with intramedullary nailing. They concluded that preventive fixation of AFF is recommended [14]. In this study, complete fracture after the appearance of beaking was seen in 5 of 9 limbs. Only 1 patient (1 limb) underwent preventive intramedullary nailing before the occurrence of complete fracture because transverse cortical fracture line inside beaking was detected, which was a possible precursor lesion of complete fracture. Of the complete fractures, 2 patients (4 limbs) received intramedullary nailing and 1 patient (1 limb) received hemiarthroplasty. Bony union was observed 6–12 months after the operation. It is possible that preventive intramedullary nailing in patients with beaking is necessary.\n\nThis study had several limitations. First, as bone biopsy was not performed, histopathological examination was not studied. Second, bone mineral density measurements were not taken for the patients, which would have helped us to determine whether these patients had decreased bone density, which is a major risk factor for fragility fracture. Third, the range of CT was from the neck level to proximal thigh level; thus, not all of the femoral shaft was investigated.\n\nIn spite of above limitations, this study showed that the frequency of AFF in patients with breast cancer receiving bisphosphonate and/or denosumab for bone metastasis was higher than those who did not undergo antiresorptive drugs. Also, the rate of complete fracture after the appearance of beaking was high. Therefore, more attention should be paid to the occurrence of AFF in these patients than osteoporotic patients, and it is possible that preventive surgery for AFF before a complete fracture is necessary.\n\nCompliance with ethical standards\nConflict of interest\nAll authors have no conflicts of interest.\n==== Refs\nReferences\n1. Shane E Burr D Abrahamsen B Adler RA Brown TD Cheung AM Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American society for bone and mineral research J Bone Miner Res 2014 29 1 23 10.1002/jbmr.1998 23712442 \n2. Shane E Burr D Ebeling PR Abrahamsen B Adler RA Brown TD Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research J Bone Miner Res 2010 25 2267 2294 10.1002/jbmr.253 20842676 \n3. Odvina CV Zerwekh JE Rao DS Maalouf N Gottschalk FA Pak CY Severely suppressed bone turnover: a potential complication of alendronate therapy J Clin Endocrinol Metab 2005 90 1294 1301 10.1210/jc.2004-0952 15598694 \n4. Drampalos E Skarpas G Barbounakis N Michos I Atypical femoral fractures bilaterally in a patient receiving denosumab Acta Orthop 2014 85 3 5 10.3109/17453674.2013.854668 24171686 \n5. Matsumoto T Hagino H Shiraki M Fukunaga M Nakano T Takaoka K Effect of daily oral minodronate on vertebral fractures in Japanese postmenopausal women with established osteoporosis: a randomized placebo-controlled double-blind study Osteoporos Int 2009 20 1429 1437 10.1007/s00198-008-0816-7 19101754 \n6. Rosen LS Gordon D Kaminski M Howell A Belch A Mackey J Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial Cancer 2003 98 1735 1744 10.1002/cncr.11701 14534891 \n7. Rosen LS Gordon D Tchekmedyian S Yanagihara R Hirsh V Krzakowski M Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial—the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group J Clin Oncol 2003 21 3150 3157 10.1200/JCO.2003.04.105 12915606 \n8. Kohno N Aogi K Minami H Nakamura S Asaga T Iino Y Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial J Clin Oncol 2005 23 3314 3321 10.1200/JCO.2005.05.116 15738536 \n9. Coleman RE McCloskey EV Bisphosphonates in oncology Bone 2011 49 71 76 10.1016/j.bone.2011.02.003 21320652 \n10. Frölke JP Patka P Definition and classification of fracture non-unions Injury 2007 38S S19 S22 10.1016/S0020-1383(07)80005-2 \n11. Schilcher J Michaëlsson K Aspenberg P Bisphosphonate use and atypical fractures of the femoral shaft N Engl J Med 2011 364 1728 1737 10.1056/NEJMoa1010650 21542743 \n12. Black DM Kelly MP Genant HK Palermo L Eastell R Bucci-Rechtweg C Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur N Engl J Med 2010 362 1761 1771 10.1056/NEJMoa1001086 20335571 \n13. Puhaindran ME Farooki A Steensma MR Hameed M Healey JH Boland PJ Atypical subtrochanteric femoral fractures in patients with skeletal malignant involvement treated with intravenous bisphosphonates J Bone Joint Surg Am 2011 93 1235 1242 10.2106/JBJS.J.01199 21776577 \n14. Chang ST Tenforde AS Grimsrud CD O’Ryan FS Gonzalez JR Baer DM Atypical femur fractures among breast cancer and multiple myeloma patients receiving intravenous bisphosphonate therapy Bone 2012 51 524 527 10.1016/j.bone.2012.05.010 22634175 \n15. Park-Wyllie LY Mamdani MM Juurlink DN Hawker GA Gunraj N Austin PC Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women JAMA 2011 305 783 789 10.1001/jama.2011.190 21343577 \n16. Khow KS Yong TY Atypical femoral fracture in a patient treated with denosumab J Bone Miner Metab 2015 33 355 358 10.1007/s00774-014-0606-6 24996528 \n17. Hagen JE Miller AN Ott SM Gardner M Morshed S Jeray K Association of atypical femoral fractures with bisphosphonate use by patients with varus hip geometry J Bone Joint Surg Am 2014 96 1905 1909 10.2106/JBJS.N.00075 25410509 \n18. Oh Y Wakabayashi Y Kurosa Y Ishizuki M Okawa A Stress fracture of the bowed femoral shaft is another cause of atypical femoral fracture in elderly Japanese: a case series J Orthop Sci 2014 19 579 586 10.1007/s00776-014-0572-9 24789301 \n19. Ha YC Cho MR Park KH Kim SY Koo KH Is surgery necessary for femoral insufficiency fractures after long-term bisphosphonate therapy? Clin Orthop Relat Res 2010 468 3393 3398 10.1007/s11999-010-1583-2 20865463 \n20. Oh CW, Oh JK, Park KC, Kim JW, Yoon YC. Prophylactic nailing of incomplete atypical femoral fractures. Sci World J. 2013.\n21. Egol KA Park JH Rosenberg ZS Peck V Tejwani NC Healing delayed but generally reliable after bisphosphonate-associated complete femur fractures treated with IM nails Clin Orthop Relat Res 2014 472 2728 2734 10.1007/s11999-013-2963-1 23604648 \n22. Grady MK Watson JT Cannada LK Treatment of femoral fracture nonunion after long-term bisphosphonate use Orthopedics 2012 35 991 995 10.3928/01477447-20120525-51\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1340-6868",
"issue": "24(4)",
"journal": "Breast cancer (Tokyo, Japan)",
"keywords": "Atypical femoral fracture; Beaking; Bisphosphonate; Breast cancer; Denosumab",
"medline_ta": "Breast Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D001943:Breast Neoplasms; D000069448:Denosumab; D005260:Female; D005264:Femoral Fractures; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D011379:Prognosis; D012307:Risk Factors",
"nlm_unique_id": "100888201",
"other_id": null,
"pages": "601-607",
"pmc": null,
"pmid": "27943163",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": "21542743;25410509;20865463;24789301;24171686;12915606;23712442;17920413;21776577;21320652;14534891;22634175;20842676;22691683;15738536;23604648;15598694;19101754;24996528;20335571;21343577;23365544",
"title": "Atypical femoral fracture after receiving antiresorptive drugs in breast cancer patients with bone metastasis.",
"title_normalized": "atypical femoral fracture after receiving antiresorptive drugs in breast cancer patients with bone metastasis"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1050004",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": "5",
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"activesubstancename": "DENOSUMAB"
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{
"abstract": "Invasive fungal infections are one of the main infectious complications in allogeneic stem cell transplantation (SCT). Triazoles (voriconazole, posaconazole) are the main prophylactic and therapeutic options for the treatment of invasive aspergillosis. However, pharmacological interactions and hepatotoxicity limit its use. Isavuconazole (ISV) is a recently approved azole with a promising interaction and safety profile. We present a case with invasive aspergillosis in the post-allogeneic SCT setting in a critically ill patient with severe multiorgan failure due to veno-occlusive disease. The patient was treated with ISV and B amphotericin during severe kidney and liver failure and multiple immunosuppressants, without significant drug-related toxicity and with favorable outcome. The interaction and safety profile of ISV is discussed along the reported experience. ISV can be an effective salvage therapy even in complex clinical situations with multiple potential interactions.",
"affiliations": "Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, Spain, gillen.oarbeascoa@salud.madrid.org.;Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, Spain.;Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, Spain.;Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, Spain.;Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, Spain.;Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, Spain.;Instituto de Investigación Sanitaria Gregorio Marañon, Madrid, Spain.;Instituto de Investigación Sanitaria Gregorio Marañon, Madrid, Spain.;Instituto de Investigación Sanitaria Gregorio Marañon, Madrid, Spain.;Instituto de Investigación Sanitaria Gregorio Marañon, Madrid, Spain.;Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, Spain.;Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, Spain.;Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, Spain.;Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, Spain.",
"authors": "Oarbeascoa|Gillen|G|;Dorado|Nieves|N|;Bailén|Rebeca|R|;Serrano|David|D|;Balsalobre|Pascual|P|;Pradillo|Virginia|V|;Guinea|Jesus|J|;Padilla|Belen|B|;Sancho|Milagros|M|;Machado|Marina|M|;Buño|Ismael|I|;Anguita|Javier|J|;Diez-Martin|Jose Luis|JL|;Kwon|Mi|M|",
"chemical_list": "D000935:Antifungal Agents; D004271:DNA, Fungal; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000502279",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-3157",
"issue": "64(2)",
"journal": "Chemotherapy",
"keywords": "Antifungal agents; Antifungals; Aspergillosis; Interaction; Isavuconazole; Stem cell transplantation",
"medline_ta": "Chemotherapy",
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"title": "Successful Treatment of Severe Aspergillosis with Isavuconazole Therapy after Allogeneic Stem Cell Transplantation.",
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"abstract": "Lithium is widely used in the treatment of bipolar disorder. Here we describe the syndrome of irreversible lithium-effectuated neurotoxicity in a patient within therapeutic doses and levels, which persisted after discontinuation of Lithium. A 50-year-old gentleman with Bipolar disorder presented with symptoms of Mania following drug default. Lithium was initiated as a mood stabilizer. On day 4, the patient developed abdominal pain, itching, and sore throat. On day 5, lithium levels were 0.9 mEq/L. Subsequently, the patient was noted to have slurring of speech, dysarthria, past pointing, and dysdiadochokinesis. Lithium was withdrawn on day 7. When lithium was re-introduced at a lower dose, the neurological symptoms re-appeared after 2 days and lithium was discontinued. Mild degree of slurring of speech persisted at 2-month follow-up. The patient had no history of side effects with antipsychotics in the past or current episode. In the absence of predisposing factors, Lithium has resulted in neurotoxicity at therapeutic doses and levels. Slurring of speech persisted despite adequate dose of anticholinergics. In addition to presumed neuroprotective effects of lithium, it can produce neurotoxic symptoms at therapeutic doses and levels.",
"affiliations": "Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bangalore, Karnataka, India.",
"authors": "Jha|Aishwariya|A|;Pai|Naveen Manohar|NM|;Ganjekar|Sundarnag|S|;Desai|Geetha|G|;Chaturvedi|Santosh K|SK|",
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"abstract": "Eruptive actinic keratosis (AK) consequent to systemic chemotherapy can be confused with drug allergies. We present the first case of inflamed AKs in one patient after receiving combination therapy with pemetrexed and carboplatin.A 68-year-old woman with non-small cell lung adenocarcinoma (NSCLC) presented with numerous pruritic ill-defined, gritty, erythematous papules consistent with AKs on her upper chest, upper back, and arms two weeks after completing the first cycle of combination therapy with carboplatin and pemetrexed. The care team managed her with topical steroids and the lesions resolved within one month. The patient resumed the second cycle of chemotherapy and reported the occurrence of a similar but milder eruption.This case illustrates that eruptive AKs should be considered in the differential diagnosis of drug-related rashes, especially if the physical exam is suggestive. The mainstay of treatment should be directed at symptomatic improvement, and chemotherapy may be continued.",
"affiliations": "Boston University School of Medicine, Boston, Massachusetts.",
"authors": "Lam|Jimmy|J|;Ellis|Samantha R|SR|;Sivamani|Raja K|RK|",
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"title": "Inflamed actinic keratoses associated with pemetrexed and carboplatin therapy.",
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"abstract": "Functional tricuspid regurgitation (TR) is a serious pathology to be noted for severe right heart failure (HF) and poor prognosis; however, the conventional assessment of TR has some limitations and the optimal timing of surgical intervention remains unclear. A 79-year-old Japanese female was admitted to our hospital to undergo cardiac surgery, because edema gradually got worse despite the increase in diuretics. She had a history of atrial fibrillation (AF) and chronic HF due to severe TR and had been treated with a furosemide for leg edema 4 years ago. A transthoracic echocardiogram (TTE), transesophageal echocardiogram, cardiac magnetic resonance imaging, and cardiac pool scintigraphy demonstrated severe functional TR with tricuspid annular dilation, insufficient tricuspid valve coaptation, and reduced right ventricular ejection fraction (EF) but preserved left ventricular EF. In addition, Swan-Ganz catheter study showed normal pulmonary arterial wedge pressure and mean pulmonary arterial pressure. Tricuspid ring annuloplasty was performed with MC3 ring. Postoperative TTE showed trivial TR, and she had no edema with normal sinus rhythm two months later. Annuloplasty to severe functional TR caused by tricuspid annular dilation due to AF dramatically improved right HF. Cardiologist should pay strict attention to the optimal timing of surgical intervention for TR.",
"affiliations": "Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.",
"authors": "Nakanishi|Nobuhiro|N|;Ishii|Masanobu|M|;Kaikita|Koichi|K|0000-0003-2962-8056;Okamoto|Ken|K|;Izumiya|Yasuhiro|Y|0000-0003-2332-9151;Yamamoto|Eiichiro|E|;Takashio|Seiji|S|;Hokimoto|Seiji|S|;Fukui|Toshihiro|T|;Tsujita|Kenichi|K|",
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"doi": "10.1155/2017/9232658",
"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi 10.1155/2017/9232658Case ReportWhen Is the Optimal Timing of Surgical Intervention for Severe Functional Tricuspid Regurgitation? Nakanishi Nobuhiro \n1\nIshii Masanobu \n1\nhttp://orcid.org/0000-0003-2962-8056Kaikita Koichi \n1\n\n*\nOkamoto Ken \n2\nhttp://orcid.org/0000-0003-2332-9151Izumiya Yasuhiro \n1\nYamamoto Eiichiro \n1\nTakashio Seiji \n1\nHokimoto Seiji \n1\nFukui Toshihiro \n2\nTsujita Kenichi \n1\n1Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan2Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan*Koichi Kaikita: kaikitak@kumamoto-u.ac.jpAcademic Editor: Hiroaki Kitaoka\n\n2017 19 6 2017 2017 923265818 4 2017 25 5 2017 Copyright © 2017 Nobuhiro Nakanishi et al.2017This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Functional tricuspid regurgitation (TR) is a serious pathology to be noted for severe right heart failure (HF) and poor prognosis; however, the conventional assessment of TR has some limitations and the optimal timing of surgical intervention remains unclear. A 79-year-old Japanese female was admitted to our hospital to undergo cardiac surgery, because edema gradually got worse despite the increase in diuretics. She had a history of atrial fibrillation (AF) and chronic HF due to severe TR and had been treated with a furosemide for leg edema 4 years ago. A transthoracic echocardiogram (TTE), transesophageal echocardiogram, cardiac magnetic resonance imaging, and cardiac pool scintigraphy demonstrated severe functional TR with tricuspid annular dilation, insufficient tricuspid valve coaptation, and reduced right ventricular ejection fraction (EF) but preserved left ventricular EF. In addition, Swan-Ganz catheter study showed normal pulmonary arterial wedge pressure and mean pulmonary arterial pressure. Tricuspid ring annuloplasty was performed with MC3 ring. Postoperative TTE showed trivial TR, and she had no edema with normal sinus rhythm two months later. Annuloplasty to severe functional TR caused by tricuspid annular dilation due to AF dramatically improved right HF. Cardiologist should pay strict attention to the optimal timing of surgical intervention for TR.\n==== Body\n1. Background\nMorbidity of atrial fibrillation (AF) increases annually over the world [1]. In the management of AF, although thromboembolism is a critical problem in clinical practice, functional tricuspid regurgitation (TR) which is caused by tricuspid annular dilation due to AF is also a serious complication leading to severe right heart failure (HF) because previous study showed that increasing TR severity was associated with poor prognosis, independent of biventricular systolic function and pulmonary artery pressure [2]. Surgical intervention which current guidelines recommended may improve the prognosis of patients with severe TR and right HF; however, the conventional assessment of the etiology and severity of TR has some limitations and the appropriate timing of surgery for functional TR without left-sided surgery remains unclear. Recently, transcatheter therapies for treating TR have been developed and could provide better treatment option for isolated severe TR [3–5]. Therefore the optimal timing of surgical intervention including transcatheter therapy needs to be determined urgently.\n\n2. Case Presentation\nA 79-year-old Japanese female with a history of AF, hypertension, chronic kidney disease [estimated glomerular filtration rate (eGFR), 53.0 mL/min/1.73 m2], and deep venous thrombosis suffering from leg edema, previously diagnosed as right HF due to severe TR free of left-sided heart disease and treated with a diuretic agent furosemide 20 mg/day since 4 years ago, was referred to our institution to undergo cardiac surgery, because her renal function had gradually worsened (eGFR, 30.7 mL/min/1.73 m2) with increasing diuretics up to furosemide 40 mg/day for leg edema. On admission, jugular venous distention, extreme pretibial edema, and systolic regurgitant murmur in the third intercostal space at the left sternal border were observed during physical examination. Cardiac biomarkers were elevated [brain natriuretic peptide (BNP), 129.1 pg/mL; high sensitivity troponin T, 0.0206 ng/mL] without liver function abnormality (alanine aminotransferase, 8 U/L; aspartate aminotransferase, 23 U/L; total bilirubin, 0.8 mg/dL) and anemia in the laboratory test. Table 1 shows other preoperative laboratory data. Electrocardiogram showed AF rhythm (Figure 1(a)). Two-dimensional transthoracic echocardiogram (TTE) showed a tricuspid annular dilation (41 mm), insufficient tricuspid valve coaptation, reduced tricuspid annular plane systolic excursion (16 mm), dilated right atrium, dilated right ventricle, and cardiac output 2.4 L/min (cardiac index, 1.61 L/min/m2) with preserved left ventricular ejection fraction (EF) and severe TR was detected without left-sided heart disease by Doppler echocardiography (Figure 1(b)). Three-dimensional transesophageal echocardiography revealed tricuspid annular dilation (40.6 mm) and cusp separation without apparent leaflet tethering (Figure 1(c)). In addition, right ventricular EF was established by cardiac magnetic resonance imaging and cardiac pool scintigraphy (39% and 57%, resp.) (Figure 2). However, there were no abnormalities in the structure of subvalvular and leaflets. Swan-Ganz catheter study revealed that pulmonary arterial wedge pressure was 5 mmHg, mean pulmonary arterial pressure was 8 mmHg, mean right atrial pressure was 4 mmHg, pulmonary vascular resistance index was 155 dynes ∗ sec/cm5/m2, and cardiac index was 1.46 L/min/m2 measured by Fick method. EuroSCORE II was calculated as 2.76%, indicating low-to-moderate perioperative risk. On the basis of these findings and current guideline, tricuspid ring annuloplasty was planned. As the right atrium and ventricle were dilated, the tricuspid valve annulus was also dilated; however, tricuspid valve leaflets were intact. Tricuspid ring annuloplasty with MC3 ring (28 mm) was performed successfully. After the annuloplasty, her edema gradually disappeared with normal sinus rhythm (Figure 1(d)), and postoperative TTE showed trivial TR (Figure 1(e)) and increased cardiac output, 2.8 L/min (cardiac index, 1.88 L/min/m2). The plasma BNP was significantly decreased to 41.0 pg/mL at 9 months after surgery. Other postoperative laboratory data are listed in Table 1.\n\n3. Discussion\nTricuspid valve disorders had traditionally tended to be ignored compared to left-sided valvular heart disease in spite of the association between increasing TR severity and long-term poor prognosis [2]. The major causes of TR (more than 80%) are functional (secondary) TR with right ventricular and tricuspid annular dilation due to pressure or volume overload, left-sided heart disease, or trauma, whereas primary TR is rare [6]. As in the present case, one of the causes of functional TR is AF, which often develops adverse right ventricular remodeling by altering right ventricular compliance, resulting tricuspid annular dilation, and leaflet coaptation defect [7]. In addition, previous study showed that AF caused more dilation of the tricuspid annulus than the mitral because the annular fibrous skeleton was less developed in the tricuspid than the mitral [8].\n\nPharmacological therapy using diuretics is effective for systemic congestion in the early phases of the disease; however, such therapy does not affect prognosis. For the improvement of survival, surgical intervention should be performed with the optimal timing. It has been shown that right ventricular dysfunction is important for decision-making in surgery because perioperative adverse right ventricular function was a risk factor for poor prognosis. Kim et al. reported that right ventricular end-systolic area emerged as an independent determinant of clinical outcome after surgery in patients with isolated TR [9]. However, most patients with isolated TR in the previous study [9] had a history of left-sided valve surgery, and no study reported the prognostic impact of perioperative right ventricular function in patients with TR free of left-sided heart disease. In addition, because of complex geometry of right ventricle, right ventricular function cannot be evaluated reliably and reproducibly. In fact, the two imaging modalities (cardiac magnetic resonance imaging and cardiac pool scintigraphy) used in the present case showed quite different right ventricular EF. Therefore, further studies are warranted to clarify the prognostic impact of perioperative right ventricular function using multiple imaging modalities in patients with TR free of left-sided heart disease. Besides right ventricular function, hemoglobin level, TR jet area, and pulmonary artery systolic pressure were also predictors of mortality after surgery in the previous studies [9, 10]. The evaluation of these preoperative risk factors could be needed for improvement of clinical outcome after TR surgery.\n\nCurrent guideline regarding the indication for TR surgery indicated that TR surgery was recommended for patients with severe functional TR at the time of left-sided valve surgery [11]. However, the optimal timing of TR surgery for patients with isolated functional TR free of left-sided valve heart disease has not been established, as described above. In addition, if patients with severe functional TR were treated with diuretics, TR often would become mild. This transient improvement of TR grade might mislead the optimal timing for TR surgery. Although the timing when diuretics become unresponsive may be the appropriate timing when the TR surgery should be performed, more accurate indicators are needed to determine the optimal timing of surgical intervention for severe TR. In this regard, Dreyfus et al. proposed a new method for assessing functional TR using 3 parameters: TR severity, annular dilation, and mode of leaflet coaptation (extent of tethering) [7]. Based on this staging system, the present case, presenting severe TR, a tricuspid annular dilation (41 mm), and tricuspid leaflet cusp separation without tethering, was staged as category 3, indicating that the appropriate timing of surgery could improve her prognosis and quality of life free of heart failure despite the fact that conventional assessment showed right ventricular dysfunction without pulmonary artery hypertension and other organ failures except for renal dysfunction.\n\n4. Conclusions\nAnnuloplasty to severe functional TR caused by tricuspid annular dilation due to AF dramatically improved right HF. Recently, transcatheter therapies for tricuspid valve disorders are available. Cardiologists should revise their recognition for the assessment and optimal timing of surgical intervention for TR and need to stay aware of the indication of TR surgery even if TR is mild.\n\nAbbreviations\nTR:Tricuspid valve regurgitation\n\nHF:Heart failure\n\nAF:Atrial fibrillation\n\neGFR:Estimated glomerular filtration rate\n\nTTE:Transthoracic echocardiogram\n\nEF:Ejection fraction\n\nBNP:Brain natriuretic peptide.\n\nEthical Approval\nThis report was based on the approval for publication of the case report and any accompanying data by the Human Ethics Review Committee of Kumamoto University Graduate School of Medicine.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying data.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nAuthors' Contributions\nNobuhiro Nakanishi and Masanobu Ishii contributed equally to this work. Nobuhiro Nakanishi, Masanobu Ishii, Koichi Kaikita, and Kenichi Tsujita contributed to conception and design, analysis and interpretation of data, and writing of the manuscript. Nobuhiro Nakanishi, Kenichi Tsujita, attending physician, Masanobu Ishii, Koichi Kaikita, Ken Okamoto, Yasuhiro Izumiya, Eiichiro Yamamoto, Seiji Takashio, Seiji Hokimoto, Toshihiro Fukui, and Kenichi Tsujita contributed to acquisition and analysis of data and its interpretation and revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript.\n\nFigure 1 Twelve-lead electrocardiogram (ECG) demonstrating AF rhythm on admission (a) but demonstrating normal sinus rhythm two months after annuloplasty (d). Doppler echocardiography showing severe TR due to insufficient leaflet coaptation on admission (b) but showing the improvement of TR after annuloplasty (e) in the apical view tract at systole. Three-dimensional transesophageal echocardiography showing coaptation defect (arrows) (c). RV: right ventricular; LV: left ventricular; RA: right atrium; LA: left atrium.\n\nFigure 2 Cardiac magnetic resonance imaging and cardiac pool scintigraphy demonstrating reduced right ventricular ejection fraction (39% and 57%, resp.). RV: right ventricular; LV: left ventricular; RA: right atrium; LA: left atrium; ESV: end-systolic volume; EDV: end-diastolic volume; RVEF: right ventricular ejection fraction.\n\nTable 1 Pre- and postoperative laboratory data.\n\n \tPreoperative\tPostoperative\n(9 months after surgery)\t\nAlb, g/dL\t3.5\t4.3\t\nAST, U/L\t8\t31\t\nALT, U/L\t23\t25\t\nTotal bilirubin, mg/dL\t0.8\t0.8\t\nChE, U/L\t279\tNot done\t\nBUN, mg/dL\t21\t23.5\t\nCreatinine, mg/dL\t1.21\t1.30\t\neGFR, mL/min/1.73 m2\t30.7\t27.0\t\nPT-INR\t2.3\t1.89\t\nAPTT, sec\t42.4\tNot done\t\nBNP, pg/mL\t129.1\t41.0\t\nAlb: albumin; AST: aspartate aminotransferase; ALT: alanine aminotransferase; ChE: cholesterol ester; BUN: blood urea nitrogen; eGFR: estimated glomerular filtration rate; PT-INR: international normalized ratio of prothrombin time; APTT: activated partial thromboplastin time; BNP: brain natriuretic peptide.\n==== Refs\n1 Schnabel R. B. Yin X. Gona P. Larson M. G. Beiser A. S. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the framingham heart study: a cohort study Lancet 2015 386 no. 9989 154 162 25960110 \n2 Nath J. Foster E. Heidenreich P. A. Impact of tricuspid regurgitation on long-term survival Journal of the American College of Cardiology 2004 43 3 405 409 10.1016/j.jacc.2003.09.036 2-s2.0-0842330731 15013122 \n3 Rodés-Cabau J. Hahn R. T. Latib A. Transcatheter therapies for treating tricuspid regurgitation Journal of the American College of Cardiology 2016 67 15 1829 1845 10.1016/j.jacc.2016.01.063 2-s2.0-84963644389 27081024 \n4 Lauten A. Figulla H. R. Willich C. Heterotopic valve replacement as an interventional approach to tricuspid regurgitation Journal of the American College of Cardiology 2010 55 5 499 500 10.1016/j.jacc.2009.09.034 2-s2.0-74549200848 20117467 \n5 Figulla H. R. Webb J. G. Lauten A. Feldman T. The transcatheter valve technology pipeline for treatment of adult valvular heart disease European Heart Journal 2016 37 28 2226 2239 2-s2.0-84991598796 10.1093/eurheartj/ehw153 27161617 \n6 Rodés-Cabau J. Taramasso M. O'Gara P. T. Diagnosis and treatment of tricuspid valve disease: current and future perspectives The Lancet 2016 388 10058 2431 2442 2-s2.0-84962069604 10.1016/S0140-6736(16)00740-6 \n7 Dreyfus G. D. Martin R. P. Chan K. M. J. Dulguerov F. Alexandrescu C. Functional tricuspid regurgitation: a need to revise our understanding Journal of the American College of Cardiology 2015 65 21 2331 2336 10.1016/j.jacc.2015.04.011 2-s2.0-84930025577 26022823 \n8 Zhou X. Otsuji Y. Yoshifuku S. Impact of atrial fibrillation on tricuspid and mitral annular dilatation and valvular regurgitation Circulation Journal 2002 66 10 913 916 2-s2.0-0036792462 10.1253/circj.66.913 12381084 \n9 Kim Y.-J. Kwon D.-A. Kim H.-K. Determinants of surgical outcome in patients with isolated tricuspid regurgitation Circulation 2009 120 17 1672 1678 2-s2.0-70350554270 10.1161/CIRCULATIONAHA.109.849448 19822809 \n10 Lee J.-W. Song J.-M. Park J. P. Lee J. W. Kang D.-H. Song J.-K. Long-term prognosis of isolated significant tricuspid regurgitation Circulation Journal 2010 74 2 375 380 2-s2.0-75849165438 10.1253/circj.CJ-09-0679 20009355 \n11 Nishimura R. A. Otto C. M. Bonow R. O. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American college of cardiology/American heart association task force on practice guidelines Circulation 2014 129 23 e521 e643 10.1161/cir.0000000000000031 24589853\n\n",
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"title": "When Is the Optimal Timing of Surgical Intervention for Severe Functional Tricuspid Regurgitation?",
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"abstract": "The purpose of this study is to determine the recommended dose (RD) of proton beam therapy (PBT) for inoperable stage III non-small cell lung cancer (NSCLC). We tested two prescribed doses of PBT: 66 Gy (relative biological effectiveness [RBE]) in 33 fractions and 74 Gy (RBE) in 37 fractions in arms 1 and 2, respectively. The planning target volume (PTV) included the primary tumor and metastatic lymph nodes with adequate margins. Concurrent chemotherapy included intravenous cisplatin (60 mg/m(2) , day 1) and oral S-1 (80, 100 or 120 mg based on body surface area, days 1-14), repeated as four cycles every 4 weeks. Dose-limiting toxicity (DLT) was defined as grade 3 or severe toxicities related to PBT during days 1-90. Each dose level was performed in three patients, and then escalated to the next level if no DLT occurred. When one patient developed a DLT, three additional patients were enrolled. Overall, nine patients (five men, four women; median age, 72 years) were enrolled, including six in arm 1 and three in arm 2. The median follow-up time was 43 months, and the median progression-free survival was 15 months. In arm 1, grade 3 infection occurred in one of six patients, but no other DLT was reported. Similarly, no DLT occurred in arm 2. However, one patient in arm 2 developed grade 3 esophageal fistula at 9 months after the initiation of PBT. Therefore, we determined that 66 Gy (RBE) is the RD from a clinical viewpoints. (Clinical trial registration no. UMIN000005585).",
"affiliations": "Radiation and Proton Therapy Center, Shizuoka Cancer Center Hospital, Shizuoka, Japan.;Radiation and Proton Therapy Center, Shizuoka Cancer Center Hospital, Shizuoka, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center Hospital, Shizuoka, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center Hospital, Shizuoka, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center Hospital, Shizuoka, Japan.;Radiation and Proton Therapy Center, Shizuoka Cancer Center Hospital, Shizuoka, Japan.;Radiation and Proton Therapy Center, Shizuoka Cancer Center Hospital, Shizuoka, Japan.;Radiation and Proton Therapy Center, Shizuoka Cancer Center Hospital, Shizuoka, Japan.;Division of Thoracic Oncology, Shizuoka Cancer Center Hospital, Shizuoka, Japan.;Radiation and Proton Therapy Center, Shizuoka Cancer Center Hospital, Shizuoka, Japan.",
"authors": "Harada|Hideyuki|H|;Fuji|Hiroshi|H|;Ono|Akira|A|;Kenmotsu|Hirotsugu|H|;Naito|Tateaki|T|;Yamashita|Haruo|H|;Asakura|Hirofumi|H|;Nishimura|Tetsuo|T|;Takahashi|Toshiaki|T|;Murayama|Shigeyuki|S|",
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"doi": "10.1111/cas.12955",
"fulltext": "\n==== Front\nCancer SciCancer Sci10.1111/(ISSN)1349-7006CASCancer Science1347-90321349-7006John Wiley and Sons Inc. Hoboken 2711095010.1111/cas.12955CAS12955Original ArticleOriginal ArticlesClinical ResearchDose escalation study of proton beam therapy with concurrent chemotherapy for stage III non‐small cell lung cancer Harada et al.Harada Hideyuki \n1\nFuji Hiroshi \n1\nOno Akira \n2\nKenmotsu Hirotsugu \n2\nNaito Tateaki \n2\nYamashita Haruo \n1\nAsakura Hirofumi \n1\nNishimura Tetsuo \n1\nTakahashi Toshiaki \n2\nMurayama Shigeyuki \n1\n1 Radiation and Proton Therapy CenterShizuoka Cancer Center HospitalShizuokaJapan2 Division of Thoracic OncologyShizuoka Cancer Center HospitalShizuokaJapan* Correspondence\n\nHideyuki Harada, Shimonagakubo 1007, Nagaizumi‐cho, Sunto‐gun, Shizuoka 411‐8777, Japan.\n\nTel: 81‐55‐989‐5222; Fax: 81‐55‐989‐5783;\n\nE‐mail: h.harada@scchr.jp\n20 6 2016 7 2016 107 7 10.1111/cas.2016.107.issue-71018 1021 27 1 2016 15 4 2016 21 4 2016 © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.The purpose of this study is to determine the recommended dose (RD) of proton beam therapy (PBT) for inoperable stage III non‐small cell lung cancer (NSCLC). We tested two prescribed doses of PBT: 66 Gy (relative biological effectiveness [RBE]) in 33 fractions and 74 Gy (RBE) in 37 fractions in arms 1 and 2, respectively. The planning target volume (PTV) included the primary tumor and metastatic lymph nodes with adequate margins. Concurrent chemotherapy included intravenous cisplatin (60 mg/m2, day 1) and oral S‐1 (80, 100 or 120 mg based on body surface area, days 1–14), repeated as four cycles every 4 weeks. Dose‐limiting toxicity (DLT) was defined as grade 3 or severe toxicities related to PBT during days 1–90. Each dose level was performed in three patients, and then escalated to the next level if no DLT occurred. When one patient developed a DLT, three additional patients were enrolled. Overall, nine patients (five men, four women; median age, 72 years) were enrolled, including six in arm 1 and three in arm 2. The median follow‐up time was 43 months, and the median progression‐free survival was 15 months. In arm 1, grade 3 infection occurred in one of six patients, but no other DLT was reported. Similarly, no DLT occurred in arm 2. However, one patient in arm 2 developed grade 3 esophageal fistula at 9 months after the initiation of PBT. Therefore, we determined that 66 Gy (RBE) is the RD from a clinical viewpoints. (Clinical trial registration no. UMIN000005585)\n\nDose escalationesophaguslate toxicitynon‐small cell lung cancerproton beam therapyShizuoka Cancer Center source-schema-version-number2.0component-idcas12955cover-dateJuly 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:15.07.2016\n\nCancer Sci \n107 (2016 ) 1018 –1021 \n27110950 \n\n\n\nFunding Information\n\n\nFunding to this study was only provided by Shizuoka Cancer Center\n==== Body\nIn stage III non‐small cell lung cancer (NSCLC), photon‐radiation is used in combination with concurrent chemotherapy with curative intent.1, 2 Ranges of 60–66 Gy have been considered standard doses for thoracic radiotherapy in several stage III non‐small cell lung cancer clinical trials. Treatment‐related toxicities of concurrent chemoradiation include pneumonitis and esophagitis. Proton beam therapy (PBT) has the advantage of sparing lung tissue from low‐dose irradiation.3 Therefore, there is room for dose escalation using PBT without resulting in severe toxicities, in particular radiation pneumonitis.\n\nAt the time of planning of this trial, the results of several prospective phase I and II trials to establish the safety and efficacy of increasing the total radiation dose, in the setting of concurrent chemotherapy and photon radiotherapy, had been reported.4, 5 Each of these trials showed that a maximum radiation dose of 74 Gy, given with concurrent weekly paclitaxel and carboplatin, was safe and resulted in a median overall survival of approximately 24 months. Furthermore, our previous phase I study also demonstrated that photon radiotherapy at a dose of 74 Gy in 37 fractions, combined with cisplatin (CDDP) and S‐1, was both safe and therapeutically promising.6 Thereafter we aimed to establish the recommended dose (RD) of PBT, when combined with concurrent chemotherapy using CDDP and S‐1, for stage III NSCLC patients.\n\nPatients and Methods\nThis is a single‐institutional, open label, dose escalation phase I trial. All the patients gave written informed consent. Eligible patients were required to have histologically or cytologically proven inoperable stage IIIA or IIIB NSCLC as defined in the TNM Classification of Malignant Tumors (6th edition), no previous chemotherapy or radiation therapy, a performance status of 0–1 on the Eastern Cooperative Oncology Group scale, adequate bone marrow reserves, as well as normal liver and renal function. Patients were excluded if they had malignant pleural or pericardial effusion, supraclavicular lymphnode metastasis, active secondary cancer, or a concomitant serious illness that contraindicated chemotherapy or PBT. For staging, all the patients underwent computed tomography (CT) of the thorax and either CT or magnetic resonance imaging (MRI) of the brain. Fludeoxyglucose (18F)‐positron emission tomography was also performed in all patients.\n\nStudy design\nThe clinical protocol and consent form were approved by the institutional review board. The dose escalation of PBT was decided based on consultation with the Independent Efficacy and Safety Evaluation Committee. Two total dose levels were tested in this study. The total doses were 66 Gy in arm 1 as the standard dose and 74 Gy (12% higher) in arm 2 as the elevated dose. The protocol was to treat three patients at a given dose of PBT and perform follow‐up for at least 90 days, and then to escalate to the next level if no dose‐limiting toxicities (DLT) occurred. If one patient developed a DLT, then up to three additional patients were treated at the same dose. Dose escalation was stopped if two or more DLT occurred at a given dose level among six patients, and a maximum tolerated dose and RD was determined at the previous dose level. If a dose of 74 Gy (relative biological effectiveness; RBE) did not cause DLT, then the actual maximum tolerated dose was not determined; rather, 74 Gy (RBE) was defined as the RD. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. DLT was defined as PBT‐related toxicities occurring within 1–90 days from the start of radiotherapy and included grade 3 non‐hematologic toxicity, excluding nausea, vomiting and esophagitis, as well as grade 4 toxicity, excluding neutropenia.\n\nProton beam therapy\nProton beam therapy was delivered with a variable energy synchrotron. Volumetric CT images at the end of the exhalation phase were obtained for treatment planning using a respiratory gating system. External respiratory signals were obtained by monitoring abdominal wall movement throughout simulation on CT, and carried out at every treatment session. Each patient was positioned in an immobilization device in the treatment position on a flat table.\n\nThe primary tumor and clinically positive lymph nodes, seen either on the planning CT (short‐axis diameter >1 cm) or pretreatment positron emission tomography images, constituted the gross tumor volume. The clinical target volume was equal to the gross tumor volume in this study. The total planning target volume (PTV) included the clinical target volume plus a total margin of at least 1.0 cm. Elective nodal irradiation was not conducted in this study. Normalization of the treatment plan covered 95% of the PTV with the prescription dose. PBT started on day 1 of the first cycle of chemotherapy and was delivered once daily for 5 days per week. The total dose of PBT was 66 Gy (RBE) in 33 fractions in arm 1 and 74 Gy (RBE) in 37 fractions in arm 2. The spinal cord dose was limited to below 48 Gy (RBE). The volume of both lungs that received 20 Gy (RBE) or more of PBT was kept below 30% of the total volume of the lungs, and brachial plexus doses were limited to below 66 Gy (RBE). The mean dose to the esophagus and heart were optimally kept below 34 Gy (RBE) and 40 Gy (RBE), respectively. If the treatment volume is larger than the field size limit, PTV is divided into several PTV that are smaller than the maximum field size.\n\nChemotherapy\nTreatment in eligible patients began with the administration of two cycles of concurrent chemoradiotherapy and two cycles of consolidation chemotherapy. This consisted of oral administration of S‐1 twice daily from day 1 to 14, along with a 60‐min intravenous infusion of CDDP (60 mg/m2) on day 1 and, thereafter, at 4‐week intervals. The patients received one of three fixed oral doses of S‐1 based on their body surface area. The three doses administered were 40 mg (body surface area <1.25 m2), 50 mg (body surface area, 1.25–1.50 m2) and 60 mg (body surface area ≥1.50 m2).\n\nResults\nNine patients were enrolled in this study, six in arm 1 and three in arm 2. The patient cohort consisted of five men and four women, with a median age of 72 years. The characteristics and disease outcomes of these patients are summarized in Table 1.\n\nTable 1 Patient characteristics and outcomes\n\nNumber\tAge (years)\tSex\tPS\tT, N\tHistology\tDose (Gy, RBE)\tStatus\tOS (months)\tPFS (months)\tFirst relapse site\t\n1\t72\tM\t0\tT1N2\tAd\t66\tNED\t49\t49\t\t\n2\t73\tF\t1\tT2N3\tAd\t60\tDOD\t38\t9\tPleural effusion, brain\t\n3\t73\tF\t1\tT4N0\tNOS\t66\tNED\t49\t49\t\t\n4\t74\tM\t0\tT2N2\tSq\t66\tFollow off\t24\t15\tPrimary site\t\n5\t65\tM\t1\tT3N2\tAd\t66\tAWD\t43\t11\tAdrenal gland\t\n6\t56\tF\t1\tT2N3\tAd\t66\tAWD\t43\t29\tBone, supraclavicular lymph node\t\n7\t72\tF\t0\tT1N2\tAd\t74\tNED\t35\t35\t\t\n8\t74\tM\t1\tT1N2\tAd\t74\tAWD\t37\t10\tAdrenal gland\t\n9\t67\tM\t1\tT3N2\tSq\t74\tDOD\t12\t8\tPrimary site, kidneys, adrenal gland\t\nAd, adenocarcinoma; AWD, alive with disease; DOD, dead on disease; NED, no evidence of disease (recurrence); NOS, no specific; OS, overall survival; PFS, progression‐free survival; Sq, squamous cell carcinoma; M, male; F, female; PS, performance status.\n\nJohn Wiley & Sons, LtdThe median follow‐up time was 43 months for surviving patients and the median progression‐free survival was 15 months. In arm 1, grade 3 infection occurred in one patient who then stopped PBT at 60 Gy (RBE) and chemotherapy at one cycle. No other DLT occurred in arm 1. Similarly, no DLT occurred in arm 2. All patients without DLT in arm 1, and all patients in arm 2, completed their PBT up to the prescribed dose, together with four cycles of chemotherapy. However, one patient developed grade 3 esophageal fistula 9 months after the initiation of PBT (Fig. 1). Among three patients in arm 2, the maximum esophageal dose of PBT did not exceed 74 Gy (RBE), with the exception of the patient with esophageal fistula, who received a dose of 75.8 Gy (RBE). This patient also experienced recurrence in the primary tumor site, but not in the lymph nodes, and second‐line chemotherapy (docetaxel) had started 1 month before the appearance of esophageal fistula. None of the patients experienced grade 2 or severe lung toxicities. The overall toxicities are summarized in Table 2.\n\nFigure 1 Grade 3 esophageal fistula occurring in a patient 9 months after the initiation of PBT. Upper left: (a) CT image at pre‐treatment. Upper middle: (b) CT image at 2 months after the initiation of PBT. Upper right: (c) CT image at 9 months after the initiation of PBT. Lower left: (d) PBT dose distribution. Lower middle: (e) Upper GI endoscopy at 9 months after the initiation of PBT. Lower right: (f) Bronchial endoscopy at 9 months after the initiation of PBT. CT, computed tomography; GI, gastrointestinal; PBT, proton beam therapy.\n\nTable 2 Overall toxicities experienced by patients following therapy\n\nToxicity\tArm 1 (n = 6)\tArm 2 (n = 3)\t\nG2\tG3\tG2\tG3\t\nAnorexia\t3\t1\t1\t0\t\nEsophagus\t2\t0\t1\t1\t\nMucositis\t0\t0\t1\t0\t\nDiarrhea\t0\t1\t0\t0\t\nConstipation\t2\t0\t1\t0\t\nDermatitis\t2\t0\t1\t0\t\nFatigue\t3\t0\t0\t0\t\nThromboembolic event\t1\t0\t0\t0\t\nInfection\t1\t1\t0\t0\t\nJohn Wiley & Sons, LtdTo explain our results, we compared the PBT plans with those of 3‐Dimensional conformal photon radiotherapy (3DCRT) using the same targets and prescribed doses. For all patients, planning images and targets used in PBT were registered to the Pinnacle treatment planning system (Phillips, Milpitas, CA, USA). 3DCRT plans were typically generated using a five‐field technique. Dose–volume histograms were obtained for each plan. All plans were normalized such that 95% of the PTV received the same dose of PBT. The lung and heart doses are summarized in Table 3, and the esophageal doses for each patient are listed in Table 4.\n\nTable 3 Lung and heart doses for proton and photon radiotherapy\n\n\tProton (clinical use)\tPhoton\t\nP‐value\t\nLung V5 (mean)\t31.1%\t44.3%\t<0.01\t\nLung V20 (mean)\t20.9%\t26.6%\t0.11\t\nMLD\t11.1 Gy(RBE)\t13.9 Gy\t0.06\t\nMHD\t12.0 Gy(RBE)\t16.9 Gy\t0.10\t\nLung V5, relative lung volume irradiated more than 5 Gy; Lung V20, relative lung volume irradiated more than 20 Gy; MHD, mean heart dose; MLD, mean lung dose; RBE, relative biological effectiveness.\n\nJohn Wiley & Sons, LtdTable 4 Esophageal proton dose (RBE) and volume (cc)\n\nArm\tPatient#\tV66\tV70\tV74\t\n1\t1\t0.00\t0.00\t0.00\t\n2\t8.27\t3.26\t0.00\t\n3\t3.95\t2.41\t0.00\t\n4\t5.52\t0.00\t0.00\t\n5\t0.00\t0.00\t0.00\t\n6\t3.11\t0.00\t0.00\t\n2\t7\t0.00\t0.00\t0.00\t\n8\t0.00\t0.00\t0.00\t\n9a\n\t11.38\t10.02\t7.81\t\na Patient #9 experienced esophageal fistula. RBE, relative biological effectiveness; V66, V70 and V74, the esophageal volume irradiated more than 66 Gy (RBE), 70 Gy (RBE) and V74 (RBE), respectively.\n\nJohn Wiley & Sons, LtdDiscussion\nProton beam therapy has an advantage over other radiation therapies in that the dose drops off and it is, therefore, utilized to reduce the risk to surrounding structures, particularly the low‐dose regions in critical structures such as the heart, lungs and esophagus.7 Indeed, only radiation pneumonitis below grade 2 occurred in this PBT trial. Explanatory analyses revealed that lung V20 is significantly reduced in PBT compared to 3DCRT.\n\nIn general, sparing of normal tissues in the low‐to‐moderate dose range is superior with proton therapy compared to photon therapy. However, we noted a case with severe esophageal toxicity resulting in a thoraco‐esophageal fistula without local recurrence in this lesion. There are several possible explanations for this toxicity. First, the esophageal dose may have been too high to avoid a late toxicity probably because the esophagus was within the PTV of this patient, and was, hence, irradiated more than the prescribed dose. Moreover, an adaptive planning strategy generally improves sparing of the esophagus;8 however, this was not performed in our study. Thus, the esophagus may be irradiated more than the planning dose.\n\nA second potential reason for the observed toxicity is that combination with concurrent CDDP and S‐1 chemotherapy was not feasible with high‐dose radiotherapy. A previous phase I study demonstrated that 74 Gy photon radiotherapy, together with CDDP and S‐1, was feasible and promising.6 However, other reports regarding high‐dose thoracic radiotherapy adopted carboplatin and paclitaxel chemotherapy.4, 5, 9, 10.\n\nA third reason for the toxicity could be the second‐line chemotherapy started 1 month before the esophageal fistula, which may have caused a recall phenomenon in the esophageal mucosa.11 After accounting for all possible factors, it is most likely that the high esophageal PBT dose is the main reason for this late esophageal toxicity. In fact, the esophageal dose in other patients without esophageal late toxicities did not exceed 74 Gy (RBE). For stage III NSCLC, lymphnodes are located in the mediastinum, which may lead to maximum esophagus doses to prescribed dose or more and it appears to be at a greater risk of severe esophageal toxicity. For the dose to serial organs in the mediatinum such as the esophagus and the bronchus, is a limiting factor in dose escalation. Actually, a recent study comparing 74‐Gy and 60‐Gy photon radiotherapy showed no advantage in both local recurrence and overall survival.10 We assumed that overall toxicities were unacceptably high by photon 74 Gy irradiation.\n\nIn this study, the pre‐defined DLT were toxicities occurring up to 90 days after proton beam therapy. When this study was planned, we thought that longer observation periods in the 66‐Gy arm were not necessary to assess the need for dose escalation because 66 Gy is considered a standard and safe dose. However, if we had set a period longer than 90 days for DLT observation, we could have detected late toxicity in arm 2. Future study should have a longer observation period so that the need for dose escalation can be properly assessed.\n\nIn conclusion, considering these issues, we maintain that PBT at a dose of 66 Gy (RBE) is more appropriate to reduce overall toxicity and improve therapeutic ratios, and identified this as the RD for future clinical trials.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n==== Refs\nReferences\n1 \n\nLe Chevalier \nT \n, \nArriagada \nR \n, \nQuoix \nE \n\net al\nRadiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non‐small‐cell lung cancer: first analysis of a randomized trial in 353 patients . J Natl Cancer Inst \n1991 ; 83 : 417 –23 .1847977 \n2 \nChemotherapy in non‐small cell lung cancer: a meta‐analysis using updated data on individual patients from 52 randomized clinical trials. Non‐small Cell Lung Cancer Collaborative Group . BMJ \n1995 ; 311 : 899 –909 .7580546 \n3 \n\nAllen \nAM \n, \nPawlicki \nT \n, \nDong \nL \n\net al\nAn evidence based review of proton beam therapy: the report of ASTRO's emerging technology committee . Radiother Oncol \n2012 ; 103 : 8 –11 .22405807 \n4 \n\nBradley \nJD \n, \nBae \nK \n, \nGraham \nMV \n\net al\nPrimary analysis of the phase II component of a phase I/II dose intensification study using three‐dimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non‐small‐cell lung cancer: RTOG 0117 . J Clin Oncol \n2010 ; 28 : 2475 –80 .20368547 \n5 \n\nSocinski \nMA \n, \nBlackstock \nAW \n, \nBogatt \nJA \n\net al\nRandomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose‐escalated thoracic conformal radiotherapy (74 Gy) in stage III non‐small‐cell lung cancer: CALGB 30105 . J Clin Oncol \n2008 ; 26 : 2457 –63 .18487565 \n6 \n\nHarada \nH \n, \nNishio \nM \n, \nMurakami \nH \n\net al\nDose‐escalation study of three‐dimensional conformal thoracic radiotherapy with concurrent S‐1 and cisplatin for inoperable stage III non‐small‐cell lung cancer . Clin Lung Cancer \n2013 ; 14 : 440 –5 .23540866 \n7 \n\nChang \nJ \n, \nZhang \nX \n, \nWang \nX \n\net al\nSignificant reduction of normal tissue dose by proton radiotherapy compared with three‐dimensional conformal or intensity‐modulated radiation therapy in stage I or stage III non‐small‐cell lung cancer . Int J Radiat Oncol Biol Phys \n2006 ; 65 : 1087 –96 .16682145 \n8 \n\nKoay \nEJ \n, \nLege \nD \n, \nMohan \nR \n\net al\nAdaptive/non‐adaptive proton radiation planning and outcome in a phase II trial for locally advanced non‐small cell lung cancer . Int J Radiat Oncol Biol Phys \n2012 ; 84 : 1093 –100 .22543217 \n9 \n\nChang \nJ \n, \nKomaki \nR \n, \nLu \nC \n\net al\nPhase II study of high‐dose proton therapy with concurrent chemotherapy for unresectable stage III non‐small cell lung cancer . Cancer \n2011 ; 117 : 4707 –13 .21437893 \n10 \n\nBradley \nJD \n, \nPaulus \nR \n, \nKomaki \nR \n\net al\nStandard‐dose versus high‐dose conformal radiotherapy with concurrent and carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non‐small‐cell lung cancer (RTOG 0617): a randomised, two‐by‐two factorial phase 3 study . Lancet Oncol \n2015 ; 16 : 187 –99 .25601342 \n11 \n\nCulp \nLR \n, \nPou \nAM \n, \nJones \nDV \n\net al\nA case of radiation recall mucositis associated with docetaxel . Head Neck \n2004 ; 26 : 197 –200 .14762890\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1347-9032",
"issue": "107(7)",
"journal": "Cancer science",
"keywords": "Dose escalation; esophagus; late toxicity; non-small cell lung cancer; proton beam therapy",
"medline_ta": "Cancer Sci",
"mesh_terms": "D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D004307:Dose-Response Relationship, Radiation; D004947:Esophagus; D005260:Female; D006321:Heart; D006801:Humans; D008168:Lung; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D061766:Proton Therapy; D011879:Radiotherapy Dosage",
"nlm_unique_id": "101168776",
"other_id": null,
"pages": "1018-21",
"pmc": null,
"pmid": "27110950",
"pubdate": "2016-07",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": "18487565;21437893;14762890;1847977;20368547;7580546;16682145;22543217;23540866;27110950;22405807;25601342",
"title": "Dose escalation study of proton beam therapy with concurrent chemotherapy for stage III non-small cell lung cancer.",
"title_normalized": "dose escalation study of proton beam therapy with concurrent chemotherapy for stage iii non small cell lung cancer"
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"companynumb": "JP-SA-2016SA132332",
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"activesubstancename": "CISPLATIN"
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"abstract": "OBJECTIVE\nTo report 6 months of results of combined treatment of intravitreal bevacizumab and triamcinolone in patients with retinal vein occlusion (RVO).\n\n\nMETHODS\nRetrospective consecutive case series. Intravitreal bevacizumab (1.25 mg) combined with intravitreal triamcinolone (2 mg) was injected to 16 patients with RVO: eight with branch retinal vein occlusion (BRVO) and eight with central retinal vein occlusion (CRVO). Patient's charts were reviewed for age, sex, previous ocular interventions, duration of follow-up, number of intraocular injections, intraocular pressure (IOP) and central macular thickness measured by optical coherence tomography (OCT). We included only patients that completed 6 months of follow-up.\n\n\nRESULTS\nMean age and number of injections were 72.9 +/- 11.99 years, and 2 +/- 0.81 respectively. In eight patients with CRVO, initial visual acuity was logMAR 1.09 +/- 0.67 and mean visual acuity at 1, 3 and 6 months was logMAR 0.98 +/- 0.55 (p = 0.59), 1.33 +/- 1.05 (p = 0.4) and 1.4 +/- 1.2 (p = 0.34) respectively. In eight patients with BRVO, initial visual acuity was logMAR 1.025 +/- 0.58 and mean visual acuity at 1, 3, and 6 months was 0.56 +/- 0.21 (p = 0.05), 0.61 +/- 0.17 (p = 0.03) and 0.66 +/- 0.34 (p = 0.12) respectively. Mean initial central macular thickness for the whole group was 527 +/- 182 microm and mean central macular thickness at 6 months was 379 +/- 156 microm (p < 0.001).\n\n\nCONCLUSIONS\nThis study suggests that combined treatment with intravitreal bevacizumab and intravitreal triamcinolone improves structural outcome in patients with retinal vein occlusion. In our study, the combination of triamcinolone acetonide and bevacizumab offered no advantage over previously published results with intravitreal bevacizumab injections alone for improving vision at 6 months.",
"affiliations": "Department of Ophthalmology, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, IN 46202, USA. ritaehrlich@gmail.com",
"authors": "Ehrlich|Rita|R|;Ciulla|Thomas A|TA|;Moss|Adam M|AM|;Harris|Alon|A|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005938:Glucocorticoids; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D014222:Triamcinolone Acetonide",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00417-009-1211-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0721-832X",
"issue": "248(3)",
"journal": "Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie",
"keywords": null,
"medline_ta": "Graefes Arch Clin Exp Ophthalmol",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007267:Injections; D008297:Male; D011379:Prognosis; D012170:Retinal Vein Occlusion; D012189:Retrospective Studies; D016896:Treatment Outcome; D014222:Triamcinolone Acetonide; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity; D014822:Vitreous Body",
"nlm_unique_id": "8205248",
"other_id": null,
"pages": "375-80",
"pmc": null,
"pmid": "19898827",
"pubdate": "2010-03",
"publication_types": "D016428:Journal Article",
"references": "18040239;18211942;18940262;18040237;16508427;18293182;18362932;12938661;19752419;16133018;15105817;15302653;18696094;18507724;19277242;6383055;17031288;17585312;19752420;15860292;19672216;19074916;18294608;16329061;19218991;12470137;19174717;19696805;7533959;19065973;19584649;15577566;17420692",
"title": "Combined treatment of intravitreal bevacizumab and intravitreal triamcinolone in patients with retinal vein occlusion: 6 months of follow-up.",
"title_normalized": "combined treatment of intravitreal bevacizumab and intravitreal triamcinolone in patients with retinal vein occlusion 6 months of follow up"
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"companynumb": "US-ROCHE-2005663",
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{
"abstract": "Fatalities following intravenous recombinant tissue-type plasminogen activator therapy have been reported. Major fatal complications following intravenous recombinant tissue-type plasminogen activator therapy include intracranial hemorrhage, aortic dissection, and extracranial bleeding. However, the possibility that intravenous recombinant tissue-type plasminogen activator therapy itself paradoxically induces synchronized multiple cerebral novel infarctions has never been considered. We herein report the first case of bilateral internal carotid artery infarction with onset seizure following intravenous recombinant tissue-type plasminogen activator therapy for a vertebral-basilar artery infarction. A 75-year-old man was transferred to our hospital and diagnosed with acute ischemic stroke in the basilar artery. His National Institute of Health Stroke Scale score was 4. The intravenous recombinant tissue-type plasminogen activator therapy was initiated 234 minutes after stroke onset because no contraindications were present. Almost 2 hours after the intravenous recombinant tissue-type plasminogen activator therapy, the patient suddenly fell into a deep coma with generalized convulsions. A huge secondary infarction was found in the bilateral anterior circulation territories, and he died 7 days after stroke onset. This case alerts clinicians to the possibility of synchronized multiple cerebral infarctions following intravenous recombinant tissue-type plasminogen activator therapy as a dangerous complication in patients with multiple severe stenoses in the cerebral arteries.",
"affiliations": "Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan. Electronic address: kmatsuzono51@jichi.ac.jp.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan.",
"authors": "Matsuzono|Kosuke|K|;Nagaoka|Lisa|L|;Suzuki|Masayuki|M|;Kim|Younhee|Y|;Ozawa|Tadashi|T|;Mashiko|Takafumi|T|;Shimazaki|Haruo|H|;Koide|Reiji|R|;Fujimoto|Shigeru|S|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2018.12.045",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "28(4)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "complication; intracranial arterial stenosis; multiple infarctions; onset seizure; rt-PA",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000368:Aged; D020520:Brain Infarction; D002343:Carotid Artery, Internal; D016893:Carotid Stenosis; D002533:Cerebral Angiography; D002560:Cerebrovascular Circulation; D038524:Diffusion Magnetic Resonance Imaging; D017809:Fatal Outcome; D005343:Fibrinolytic Agents; D006801:Humans; D007262:Infusions, Intravenous; D018810:Magnetic Resonance Angiography; D008297:Male; D012640:Seizures; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D018615:Ultrasonography, Doppler, Color; D017585:Ultrasonography, Doppler, Transcranial; D014715:Vertebrobasilar Insufficiency",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "e24-e26",
"pmc": null,
"pmid": "30655041",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Catastrophic Secondary Infarctions with Onset Seizure Following Tissue Plasminogen Activator Therapy.",
"title_normalized": "catastrophic secondary infarctions with onset seizure following tissue plasminogen activator therapy"
} | [
{
"companynumb": "JP-MTPC-MTPC2019-0047848",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EDARAVONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nBisphosphonates use is a recognised cause of atypical femur fractures. Intramedullary nailing is the first line of treatment for these fractures, but failure is a common problem due to altered biology, resulting in a non-union and a challenging problem.\n\n\nOBJECTIVE\nThere is lack of evidence in the literature on revision surgery for the management of non-union after failed nailing in atypical femur fracture. We present our experience of treating this complex problem.\n\n\nMETHODS\nA retrospective review of all consecutive cases of revision surgery for non-union of bisphosphonate related subtrochanteric fractures was undertaken. All procedures were performed between 2012 and 2017 by a single surgeon. Revision surgery included removal of failed metalwork, resection of non-union, bone grafting and double plating with a lateral DCS plate and anterior locking compression plate.\n\n\nRESULTS\nTen patients (9 females, 1 male) were included with a mean age of 71.5 years and mean BMI of 34 at the time of revision. All patients received previous Bisphosphonate treatment on average for 6.2 years. One patient was lost to follow up. Mean time for non-weight bearing (NWB) mobilization was 7 months and mean time for union was 14 months.\n\n\nCONCLUSIONS\nFracture healing can be achieved with bone grafting and compression plating in all patients. However, a prolonged time to achieve union and a long follow-up duration should be expected.",
"affiliations": "Department of Trauma and Orthopaedic Surgery, Whiston Hospital, Prescot, UK. Electronic address: dr.nagy@gmx.net.;University of Nicosia Medical School, Cyprus.;Department of Trauma and Orthopaedic Surgery, Whiston Hospital, Prescot, UK.;Department of Trauma and Orthopaedic Surgery, Whiston Hospital, Prescot, UK.",
"authors": "Nagy|Mathias T|MT|;Pydisetty|Gaurav|G|;Kwaees|Tariq A|TA|;Saldanha|Kiran|K|",
"chemical_list": "D004164:Diphosphonates",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.injury.2020.09.051",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-1383",
"issue": "52(3)",
"journal": "Injury",
"keywords": "Atypical femur fracture; Bisphosphonates; Nonunion; Revision surgery",
"medline_ta": "Injury",
"mesh_terms": "D000368:Aged; D001858:Bone Nails; D001860:Bone Plates; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D005594:Fracture Fixation, Intramedullary; D017102:Fracture Healing; D006620:Hip Fractures; D006801:Humans; D008297:Male; D012086:Reoperation; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0226040",
"other_id": null,
"pages": "582-588",
"pmc": null,
"pmid": "33092855",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Outcome of revision surgery for bisphosphonate related subtrochanteric fracture non-union following failed intramedullary nailing.",
"title_normalized": "outcome of revision surgery for bisphosphonate related subtrochanteric fracture non union following failed intramedullary nailing"
} | [
{
"companynumb": "NVSC2021GB084857",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Persistent migraine aura without infarction is a rare but debilitating condition. Treatment options are mostly anecdotal and limited due to inefficacy and side effects. We present a 16-year-old female patient with triple X syndrome, having persistent aura symptoms for over 2 years, consisting of continuous visual and sensory sensations. Previous treatments with seven different migraine preventatives were not successful. The patient successfully responded to zonisamide against refractory prolonged aura and remained symptom-free under the ongoing treatment without any relevant side effects. Zonisamide may be considered a new and safe treatment option for patients with persistent migraine aura.",
"affiliations": "Neurology, Innsbruck Medical University Department of Neurology, Innsbruck, Austria.;Neurology, Innsbruck Medical University Department of Neurology, Innsbruck, Austria.;Neurology, Innsbruck Medical University Department of Neurology, Innsbruck, Austria gregor.broessner@i-med.ac.at.",
"authors": "Kaltseis|Katharina|K|;Frank|Florian|F|;Broessner|Gregor|G|",
"chemical_list": "D000078305:Zonisamide",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240783",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(4)",
"journal": "BMJ case reports",
"keywords": "drugs: CNS (not psychiatric); headache (including migraines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000293:Adolescent; D064420:Drug-Related Side Effects and Adverse Reactions; D004827:Epilepsy; D005260:Female; D006801:Humans; D008881:Migraine Disorders; D020325:Migraine with Aura; D000078305:Zonisamide",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33846185",
"pubdate": "2021-04-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Zonisamide as treatment option in persistent migraine aura.",
"title_normalized": "zonisamide as treatment option in persistent migraine aura"
} | [
{
"companynumb": "AT-NOVARTISPH-NVSC2021AT121943",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "1",... |
{
"abstract": "Human Herpes Virus-8 (HHV-8) may reactivate in immunocompromised patients including recipients of solid organ transplants. Reactivation of HHV-8 may result in Kaposi sarcoma (KS). KS typically occurs with dermatologic involvement but can affect virtually any other organ; most commonly the gastrointestinal tract. We present a diagnostically challenging case of KS in a South American woman 7 months after kidney transplant. She presented with recurrent urinary tract infection manifested by pelvic pain and dysuria. Imaging studies revealed bladder thickening with pelvic lymphadenopathy. Findings on tissue biopsied from the bladder and lymph nodes were consistent with KS. Her skin was not affected. This case illustrates that KS and other HHV-8-related diseases should be on the differential diagnosis as a cause of mass lesions as well as lymphadenopathy in transplant recipients. The case exemplifies the need to pursue a tissue diagnosis in immunocompromised patients when a diagnosis is uncertain.",
"affiliations": "Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York.;Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York.;Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York.;Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York.;Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York.;Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York.;Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York.;Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York.;Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York.;Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York.",
"authors": "Nair|Vinay|V|https://orcid.org/0000-0002-4427-165X;Sheikh|Fatima|F|;Hirschwerk|David|D|;Fahmy|Ahmed|A|;Bhaskaran|Madhu|M|;Grodstein|Elliot|E|;Winnick|Aaron|A|;Maki|Robert|R|;Teperman|Lewis|L|;Molmenti|Ernesto|E|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13132",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "21(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Immunosuppression; Kaposi sarcoma; human herpes virus-8; kidney transplantation; lymphadenopathy",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D003556:Cystitis; D003937:Diagnosis, Differential; D005260:Female; D006566:Herpesviridae Infections; D019288:Herpesvirus 8, Human; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation; D000072281:Lymphadenopathy; D012514:Sarcoma, Kaposi; D066027:Transplant Recipients; D001743:Urinary Bladder",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13132",
"pmc": null,
"pmid": "31220395",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "An unusual case of Kaposi sarcoma masquerading as cystitis in a kidney transplant recipient.",
"title_normalized": "an unusual case of kaposi sarcoma masquerading as cystitis in a kidney transplant recipient"
} | [
{
"companynumb": "US-MYLANLABS-2019M1112680",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "... |
{
"abstract": "Corticosteroid-refractory (SR) acute graft-versus-host disease (aGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Multiple agents have been evaluated in this setting, but the benefit of pentostatin has not been described well. We report a single-center experience of pentostatin salvage therapy for SR aGVHD. Fifteen patients received pentostatin for SR aGVHD from March 2005 till March 2010 after failure to respond to methylprednisolone ≥ 2 mg/kg/d for at least seven d. All patients had grade III-IV aGVHD prior to pentostatin therapy. Thirteen (87%), 10 (67%), and six (40%) patients had gastrointestinal (GI), skin, and liver involvement of aGVHD, respectively. Pentostatin was given at a median of 33 d after steroid therapy initiation. The dose of pentostatin was 1.4 mg/m(2) daily for three d, repeated every two wk. Eight (53%) patients also received additional therapies. Complete responses were noted in two patients (both in skin). However, one patient relapsed and did not respond to additional salvage treatment. Partial responses were seen in three patients. Fourteen died of GVHD-related causes. This study suggested that pentostatin is of limited benefit in the treatment for SR grade III-IV aGVHD.",
"affiliations": "Allogeneic Blood and Marrow Transplant Program, Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada.",
"authors": "Alam|Naheed|N|;Atenafu|Eshetu G|EG|;Tse|Garwin|G|;Viswabandya|Auro|A|;Gupta|Vikas|V|;Kim|Dennis|D|;Lipton|Jeffrey H|JH|;Messner|Hans A|HA|;Kuruvilla|John|J|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D015649:Pentostatin; D008775:Methylprednisolone",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.12268",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "27(6)",
"journal": "Clinical transplantation",
"keywords": "graft-versus-host disease; hematopoietic cell transplant; pentostatin",
"medline_ta": "Clin Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D004351:Drug Resistance; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007938:Leukemia; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D015649:Pentostatin; D011379:Prognosis; D016879:Salvage Therapy; D014184:Transplantation, Homologous; D055815:Young Adult",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "930-7",
"pmc": null,
"pmid": "24304375",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Limited benefit of pentostatin salvage therapy for steroid-refractory grade III-IV acute graft-versus-host disease.",
"title_normalized": "limited benefit of pentostatin salvage therapy for steroid refractory grade iii iv acute graft versus host disease"
} | [
{
"companynumb": "CA-SA-2014SA130476",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PENTOSTATIN"
},
"drugadditional": null,
"... |
{
"abstract": "Neuralgic amyotrophy (NA), also known as Parsonage-Turner syndrome is often triggered by mechanical stress or viral infections. We reported 2 cases of shoulder weakness and amyotrophy related to spinal accessory nerve (SAN) palsy due to neuralgic amyotrophy occurring after COVID-19 infection.\n\n\n\nFor both patients, clinical history, clinical examination, electrodiagnostic (EDX), and imaging examinations invalidated other diagnoses but confirmed NA diagnosis.\n\n\n\nThe NA involved only the SAN in both cases. EDX revealed a characteristic axonal lesion found in NA. SAN conduction study revealed normal latencies and low compound motor action potential amplitude for trapezius muscle when needle examination demonstrated a neurogenic pattern and denervation signs in the trapezius muscle. Both patient's MRI revealed denervation T2 hyper signal in impaired muscles, without any mass, cyst, injury, fibrous band, or tearing signs along SAN course.\n\n\n\nThe COVID-19 infection could be the trigger for NA as many other viruses, and as it is a possible trigger for Guillain-Barré syndrome.",
"affiliations": "Locomotor functional rehabilitation department, Robert-Ballanger hospital, boulevard Robert-Ballanger, 93602 Aulnay-sous-Bois, France. Electronic address: clemence.coll@ght-gpne.fr.;Locomotor functional rehabilitation department, Robert-Ballanger hospital, boulevard Robert-Ballanger, 93602 Aulnay-sous-Bois, France. Electronic address: muriel.tessier@ght-gpne.fr.;Radiology department, fondation ophtalmologique de Rothschild, 29, rue Manin, 75019 Paris, France; RMX-medical center, 80, avenue Felix-Faure, 75015 Paris, France.;Electroneuromyography laboratory, 146, avenue Ledru-Rollin, 75011 Paris, France; Private hospital of eastern Paris, 93600 Aulnay-sous-Bois, France.",
"authors": "Coll|Clemence|C|;Tessier|Muriel|M|;Vandendries|Christophe|C|;Seror|Paul|P|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.jbspin.2021.105196",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1297-319X",
"issue": "88(5)",
"journal": "Joint bone spine",
"keywords": "COVID-19; Neuralgic amyotrophy; Parsonage–Turner syndrome; Peripheral neuropathy; Spinal accessory nerve; Trapezius muscle palsy",
"medline_ta": "Joint Bone Spine",
"mesh_terms": "D000055:Accessory Nerve; D020968:Brachial Plexus Neuritis; D000086382:COVID-19; D006801:Humans; D010243:Paralysis; D000086402:SARS-CoV-2",
"nlm_unique_id": "100938016",
"other_id": null,
"pages": "105196",
"pmc": null,
"pmid": "33901661",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports",
"references": "32593341;29314072;32345343;32147283;33001471;33190028;32622375;32275288;32710672;16371410;27864983;32725449;21692917;3187305",
"title": "Neuralgic amyotrophy and COVID-19 infection: 2 cases of spinal accessory nerve palsy.",
"title_normalized": "neuralgic amyotrophy and covid 19 infection 2 cases of spinal accessory nerve palsy"
} | [
{
"companynumb": "FR-LUPIN PHARMACEUTICALS INC.-2021-22189",
"fulfillexpeditecriteria": "2",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugad... |
{
"abstract": "Many cancer patients use integrative therapies with a combination of natural products and diets. In the Western world, integrative medicine is often not shared with oncologists even during antineoplastic treatments. This behavior stems from the unmet needs of cancer patients who may feel oncologists' underestimation of their symptoms and spiritual aspects. This case report demonstrates the potential harm of inadequate diet and nutraceutical intake in a 68-year-old woman with metastatic estrogen receptor-positive, human epidermal growth factor receptor-2-negative breast cancer. Her care team recommended hormone therapy with abemaciclib plus fulvestrant. Her diarrhea started after 10 days of therapy and did not disappear, despite the use of loperamide, causing a significant reduction in adherence and dose intensity of abemaciclib. The patient finally disclosed to her oncologist she was following a detoxifying diet and taking several nutraceuticals. Her diarrhea was correlated with abemaciclib but most probably exacerbated and prolonged by the diet. Evaluation of disease after 3 months showed progressive disease. Integrative medicine should be in the multidisciplinary management of cancer patients to avoid potentially harmful events and ameliorate patients' quality of life in a holistic approach.",
"affiliations": "Medical Oncology Unit, La Maddalena Clinic for Cancer, Palermo, Italy.;GSTU Foundation, Palermo, Italy.;Medical Oncology Unit, Policlinic Paolo Giaccone, University of Palermo, Palermo, Italy.",
"authors": "Gebbia|Vittorio|V|;Piazza|Dario|D|;Valerio|Maria Rosaria|MR|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000518779",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575\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\n10.1159/000518779\ncro-0014-1399\nCase Report\nHarmful Interference of Detoxifying Diets and Nutraceuticals with Adherence to Abemaciclib in Advanced Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor-2-Negative Breast Cancer: A Case Report\nGebbia Vittorio a b *\nPiazza Dario c\nValerio Maria Rosaria d\naMedical Oncology Unit, La Maddalena Clinic for Cancer, Palermo, Italy\nbDepartment of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties ProMISE, University of Palermo, Palermo, Italy\ncGSTU Foundation, Palermo, Italy\ndMedical Oncology Unit, Policlinic Paolo Giaccone, University of Palermo, Palermo, Italy\n*Vittorio Gebbia, vittorio.gebbia@gmail.com\nSep-Dec 2021\n23 9 2021\n23 9 2021\n14 3 13991406\n6 7 2021\n26 7 2021\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nMany cancer patients use integrative therapies with a combination of natural products and diets. In the Western world, integrative medicine is often not shared with oncologists even during antineoplastic treatments. This behavior stems from the unmet needs of cancer patients who may feel oncologists' underestimation of their symptoms and spiritual aspects. This case report demonstrates the potential harm of inadequate diet and nutraceutical intake in a 68-year-old woman with metastatic estrogen receptor-positive, human epidermal growth factor receptor-2-negative breast cancer. Her care team recommended hormone therapy with abemaciclib plus fulvestrant. Her diarrhea started after 10 days of therapy and did not disappear, despite the use of loperamide, causing a significant reduction in adherence and dose intensity of abemaciclib. The patient finally disclosed to her oncologist she was following a detoxifying diet and taking several nutraceuticals. Her diarrhea was correlated with abemaciclib but most probably exacerbated and prolonged by the diet. Evaluation of disease after 3 months showed progressive disease. Integrative medicine should be in the multidisciplinary management of cancer patients to avoid potentially harmful events and ameliorate patients' quality of life in a holistic approach.\n\nKeywords\n\nMetastatic breast cancer\nEstrogen receptor\nAbemaciclib\nDetoxifying diet\nNutraceuticals\n==== Body\npmcIntroduction\n\nMetastatic breast cancer still represents a major cause of death in women [1]. To date, patients with estrogen receptor-positive, human epidermal growth factor receptor-2-negative (her-2) breast carcinoma are best managed with a combination of antihormonal agents and cyclin-dependent kinase 4 and 6 inhibitors. Among the latter class, abemaciclib is the most potent in preclinical studies [2]. Such combination therapy may achieve a median disease-free survival of 46 months with good tolerability in breast cancer patients progressing during endocrine therapy [3].\n\nRecently, the role of integrative medicine has gained popularity in a more open, multidisciplinary, holistic way of interpreting oncology and unmet patients' needs [4, 5, 6]. Many patients follow detoxifying or anticancer diets and take nutraceuticals often without discussion with their treating oncologists [7]. This attitude toward the use of nutraceuticals should be carefully evaluated in a team of integrative medicine since natural products does not always correspond to safety in oncology [8]. This article reports a negative interaction between detoxifying diet and nutraceuticals with adherence to antihormonal therapy in a woman with advanced estrogen receptor-positive, her-2-negative breast cancer.\n\nCase Report\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A 68-year-old woman − a housewife − presented with suspect progressive breast cancer while taking adjuvant letrozole for 3 years. In February 2018, she was diagnosed with breast cancer and received conservative left breast surgery with axillary dissection after sentinel lymph node analysis was positive for cancer. The systemic staging was negative for metastatic disease. Pathology showed a ductal infiltrating carcinoma estrogen receptor 80%, progestin receptor 35%, her-2 score 1, and Ki67 40%. The clinical and pathological stage was pT2, N1, M0. She received an adjuvant chemotherapy regimen with epirubicin and cyclophosphamide every 3 weeks for 4 cycles, followed by paclitaxel for 12 weeks, complementary radiotherapy on the left breast and the homolateral axilla, and started adjuvant letrozole. In May 2020, she was admitted to our outpatients' clinic because of a Ca15.3 increase. A positron emission tomography/CT (PET/CT) showed progressive disease at nodes, bone, and an unspecific liver uptake. Physical examination was nonsignificant, and the patient denied any symptoms of the disease but moderate fatigue. She was classified as an estrogen receptor-positive, her-2/neu-negative, hormone-resistant breast carcinoma.\n\nThe oncologist quitted letrozole. Based on scientific data, the oncologist proposed a systemic treatment with fulvestrant 500 mg every 2 weeks as a loading dose 3 times and then every 4 weeks, plus abemaciclib 150 mg bid on a continuous schedule [3]. The patient's performance status was adequate for abemaciclib plus fulvestrant regimen with an Eastern Cooperative Oncology Group Performance Status score of 1. The oncologist carefully interviewed the patient for concomitant gastrointestinal diseases that could contraindicate abemaciclib use and other drug assumptions. The oncologist performed a drug-drug interaction evaluation employing a drug checker tool and explained in detail abemaciclib to the patient and her daughter, including written precise suggestions concerning potential side effects. More specifically, the oncologist stressed the precocious use of loperamide and dietary modification in case of diarrhea. He recommended immediately taking loperamide at first or second liquid stool and contacting the medical oncology team via a WhatsApp messenger system (Fig. 1).\n\nAfter 10 days, she complained of grade 2 diarrhea, according to the National Cancer Institute Common Toxicity Criteria version 5.0 [9]. Nurses called the patient to assure she was following a correct astringent diet and loperamide assumption. A blood test showed only a mild increase in serum creatinine. Since she reported intermittent diarrhea, the oncologist reduced the abemaciclib dose to 100 mg bid, but intestinal movements remained unchanged and stopped abemaciclib for 3 days. Such drug-free periods occurred every 2 weeks, with no other significant side effects.\n\nAt this point, the patient disclosed she was following a detoxifying diet prescribed by a dietician. Oncologists were not aware of it. The dietician did not make any effort to contact the managing oncologists. Table 1 depicts the diet components. As shown in Table 2, she was also taking several integrative agents such as broccoli extracts (250 mg bid), garlic extracts (500 mg bid), high-dose vitamin D, curcumin plus black pepper (526 mg bid), green tea (3 serving/day), vitamin C (500 mg/day), lipoic acid 100 mg/day, coenzyme q10 100 mg/day, vitamin K (250 mcg/day), selenium (75 mcg/day), and iodine (150 mcg/day). The dietary prescription also reported that “people may experience weakness, stool modification including diarrhea, and generalized pain, which are positive signs of detoxification.” Accordingly, the patient showed evident difficulties in decoding her gastrointestinal symptoms. The oncologist stopped the diet, and diarrhea frequency reduced in 2 weeks. The dose intensity of abemaciclib was 68.5% of the planned one, according to the Hyrnuk and Bush formula [10]. After 3 months of abemaciclib and fulvestrant, a new PET/CT showed progressive disease according to the RECIST criteria. Besides reversible diarrhea G3 and renal toxicity (creatinine) G1, no other significant adverse events were observed according to the NCCN-CTC criteria [9]. The oncologist's decision was to withheld fulvestrant and abemaciclib and proposed a second-line treatment of everolimus and exemestane. She is still alive during the time of writing.\n\nDiscussion\n\nAbemaciclib may be administered with or without food, and food-drug interaction analysis showed that diet has modest effects on the pharmacokinetics of abemaciclib [11]. A high-fat, high-calorie meal administered to healthy subjects increased the C-max and AUC of abemaciclib plus its active metabolites by 26% and 9%, respectively. Grapefruit juice may increase the plasma concentrations of abemaciclib and therefore should be avoided. The possible mechanism is the inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. According to product labeling, abemaciclib systemic exposure (AUC) is predicted to increase up to 16-fold when administered with the potent CYP450 3A4 inhibitor ketoconazole.\n\nIn this study, we report the inappropriate use of a detoxifying diet with a massive daily administration of herbal and nutraceutical agents in a female patient treated with fulvestrant plus abemaciclib for metastatic breast cancer. This patient showed poor response to antihormonal therapy, as shown by PET/CT, and reported chronic diarrhea, which hampered treatment adherence and drug dose intensity by one-third of the planned dose. Neither the patient nor the family caregiver or the dietician informed the oncology center. Suspension of the diet by the treating oncologist resulted in the weakening of diarrhea. Although usual diet habits seem not to influence abemaciclib pharmacokinetics, an incorrect diet may cause gastrointestinal disturbances. These may favor the occurrence of abemaciclib-related diarrhea, causing dose reductions and poor adherence and eventually negatively influencing patients' outcomes and quality of life.\n\nOur patient was taking many compounds with possible negative interaction on treatment outcome. Supplementation with coenzyme q10 and vitamins caused a more unsatisfactory outcome in patients with metastatic breast cancer treated with chemotherapy in a Southwest Oncology Group trial [12]. Although the herb-drug interaction risk for short-term use of garlic is low, prolonged exposure to concentrated garlic extracts may counteract the efficacy of drugs whose disposition depends on the human efflux transporter ABCB1 which may occur in tumor cells [13, 14]. Even if the check for interactions between the single nutraceuticals and antihormonal agents employed in our patient was negative, knowledge on the possible effects of the whole “orchestra” of agents is poor.\n\nIn clinical practice, oncologists commonly check drug-drug interactions when prescribing modern targeted therapies. On the other hand, herb-drug or food/diet-drug is far less explored, even if herb-drug interaction checkers are available [15]. In this patient, while such a check did not show negative interaction between antihormonal agents and supplements, the diet followed caused a sharpening and prolongation of liquid stools, causing poor adherence and dose reduction of abemaciclib. Moreover, the reckless pieces of information about possible effects of diet, such as fatigue and loose stools, elicited confusion in the patient. Today, herbal supplements and nutraceuticals in various forms can be easily purchased over the counter and widely employed by cancer patients, often without discussing with their oncologists. This hidden behavior is probably related to sometimes justified patients' perception that their needs in terms of quality of life are underweighted by most oncologists far more concentrated on therapy management [16]. Herbal supplements and nutraceuticals are often self-prescribed or suggested by friends, other patients, or prescribed by professionals other than oncologists. Such prescriptions are often not shared, even if patients should discuss its use with the managing oncologist and pharmacist. The regulatory agencies do not pay the same attention for pharmaceutical drugs to herbals, dietary supplements, and their manufacturers.\n\nConclusion\n\nAlthough integrative medicine has a significant positive role in managing people affected by cancer, a careful approach is advisable since herbal supplements and nutraceuticals may enhance prescription medications' side effects and block the intended therapeutic drug efficacy. It is then advisable that deep and correct information be delivered to patients about the potential benefits but especially about the possible interactions of herbal supplements and nutraceuticals that may occur with the standard therapies administered. For this purpose, a multidisciplinary approach is essential to treat this kind of patients.\n\nStatement of Ethics\n\nThe study is exempt from ethics committee approval because every diagnostic and therapeutic action for the primary pathology was performed according to the current standards and guidelines. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nConflict of Interest Statement\n\nThe authors declared no potential conflicts of interest concerning the research, authorship, and/or publication of this article.\n\nFunding Sources\n\nThe authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this study was supported by the Network in Integrative Medicine in Oncology Program of the GSTU Foundation, Palermo, Italy.\n\nAuthor Contributions\n\nV.G. and M.R.V. contributed to study concept and design. V.G. and D.P. contributed to drafting of the manuscript. All authors contributed to acquisition, analysis, and interpretation of data, critical revision of the manuscript, and read and approved the final manuscript.\n\nData Availability Statement\n\nAll data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.\n\nAcknowledgment\n\nThis study was conducted at the La Maddalena Cancer Center, Palermo, Italy.\n\nFig. 1 Treatment timeline.\n\nTable 1 Diet composition\n\nBreakfast, g\t\t\n Almond milk\t200\t\n Coconut yogurt\t200\t\n Puffed cereals\t30\t\nMidmorning snack, g\t\t\n Carrots\t100\t\n Avocado\t40\t\n Olives\t10\t\n Dried fruit\t10\t\nLunch, g\t\t\n Cooked greens\t200\t\n Quinoa\t80\t\n Cooked legumes\t100\t\n Olive oil\t40\t\n Oily dried fruit\t20\t\nAfternoon snack, g\t\t\n Avocado\t80\t\n Olives\t20\t\n Oily dried fruit\t20\t\n Fresh coconut\t50\t\n Coconut yogurt\t125\t\nDinner, g\t\t\n Fish\t150\t\n Egg\t120 (2 eggs)\t\n Cooked vegetables\t200\t\n Olive oil\t40\t\nBanned aliments\t\t\n Lemon\t\t\n Cheese\t\t\n Chocolate\t\t\n Tomato\t\t\n Eggplant\t\t\n Maize\t\t\n Potato\t\t\n Peppers\t\t\n Cooked carrots\t\t\n Alcohol drinks\t\t\n Dried figs\t\t\n Dried plums\t\t\n Peanuts\t\t\n\nTable 2 Nutraceuticals\n\nAgent\tDosage\t\nBroccoli extracts\t250 mg bid\t\nGarlic extracts\t500 mg bid\t\nCurcumin\t526 mg bid\t\nCoenzyme q10\t100 mg/once a day\t\nVitamin K\t250 mcg/once a day\t\nVitamin C\t500 mg/once a day\t\nLipoic acid\t100 mg/once a day\t\nSelenium\t75 mcg/once a day\t\nIodine\t150 mcg/once a day\t\nGreen tea\tThree serving/day\n==== Refs\nReferences\n\n1 Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2018 68 (6) 394 424 30207593\n2 Gebbia V Valerio MR Firenze A Vigneri P Abemaciclib: safety and effectiveness of a unique cyclin-dependent kinase inhibitor Expert Opin Drug Saf 2020 8 19 (8) 945 54 32552035\n3 Sledge GW Toi M Neven P Sohn J Inoue K Pivot X The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial JAMA Oncol 2020 Jan 1 6 (1) 116 24 31563959\n4 Seely DM Weeks LC Young S A systematic review of integrative oncology programs Curr Oncol 2012 12 19 (6) e436 61 23300368\n5 Chiesi F Bonacchi A Primi C Miccinesi G Assessing unmet needs in patients with cancer: an investigation of differential item functioning of the needs evaluation questionnaire across gender, age and phase of the disease PloS One 2017 12 (7) e0179765 28742867\n6 Ben-Arye E Portalupi E Keshet Y Bonucci M Can G Kading Y Enhancing palliative care with mindful touch: impact of a manual and movement therapy training program in an international multidisciplinary integrative oncology setting J Pain Sympt Manag 2021 8 61 (2) 229\n7 Berretta M Della Pepa C Tralongo P Fulvi A Martellotta F Lleshi A Use of complementary and alternative medicine (CAM) in cancer patients: an Italian multicenter survey Oncotarget 2017 4 8 (15) 24401 14 28212560\n8 Schiff E Levy I Arnon Z Ben-Arye E Attias S First, keep it safe: integration of a complementary medicine service within a hospital Int J Clin Pract 2018 5 72 (5) e13082 29665222\n9 U.S. Department of Health and Human Services Common Terminology Criteria for Adverse Events (CTCAE) [Internet] 2017 Cancer.gov [cited 2021 Jun 11]. Available from: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5×11.pdf\n10 Hryniuk W Bush H The importance of dose intensity in chemotherapy of metastatic breast cancer J Clin Oncol 1984 11 2 (11) 1281 8 6387060\n11 Verzenios-epar-product-information_en.pdf [Internet]. [cited 2020 Nov 11]. Available from: https://www.ema.europa.eu/en/documents/product-information/verzenios-epar-product-information_en.pdf\n12 Ambrosone CB Zirpoli GR Hutson AD McCann WE McCann SE Barlow WE Dietary supplement use during chemotherapy and survival outcomes of patients with breast cancer enrolled in a cooperative group clinical trial (SWOG S0221) J Clin Oncol 2020 10 38 (8) 804 14 31855498\n13 Bayan L Koulivand PH Gorji A Garlic: a review of potential therapeutic effects Avicenna J Phytomed 2014 1 4 (1) 1 14 25050296\n14 Choi KH Chen CJ Kriegler M Roninson IB An altered pattern of cross-resistance in multidrug-resistant human cells results from spontaneous mutations in the mdr1 (P-glycoprotein) gene Cell 1988 5 53 (4) 519 29 2897240\n15 Drug-nutrient interactions [Internet]. Available from: https://www.integrativepro.com/Resources/Drug-Nutrient-Interaction-Checker [cited 2020 Nov 11].\n16 van der Sluijs C Lombardo FL Lesi G Bensoussan A Cardini F Social and Cultural Factors Affecting Complementary and Alternative Medicine (CAM) use during menopause in Sydney and Bologna Evid Based Complement Alternat Med 2013 2013 836234 24459531\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "14(3)",
"journal": "Case reports in oncology",
"keywords": "Abemaciclib; Detoxifying diet; Estrogen receptor; Metastatic breast cancer; Nutraceuticals",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "1399-1406",
"pmc": null,
"pmid": "34720948",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "31855498;32552035;2897240;24459531;31563959;23300368;28212560;32795608;29665222;25050296;6387060;30207593;28742867",
"title": "Harmful Interference of Detoxifying Diets and Nutraceuticals with Adherence to Abemaciclib in Advanced Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor-2-Negative Breast Cancer: A Case Report.",
"title_normalized": "harmful interference of detoxifying diets and nutraceuticals with adherence to abemaciclib in advanced estrogen receptor positive human epidermal growth factor receptor 2 negative breast cancer a case report"
} | [
{
"companynumb": "IT-drreddys-LIT/ITL/22/0146267",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FULVESTRANT"
},
"drugadditional": "4",
... |
{
"abstract": "Exon 18-T719X EGFR mutation in non-small cell lung cancer is rare, only 1-5% of all EGFR mutations. The efficacy of EGFR tyrosin kinase inhibitors in tumours with uncommon mutations is still unclear and the prediction of response of such tumours to therapy remains unexplored.\n\n\n\nA 71-year-old woman with no previous smoking history with disseminated lung adenocarcinoma with exon 18-T719X EGFR mutation was treated with afatinib. A partial response was achieved in 2 months, progression-free survival was 19 months. The dose of afatinib was reduced to 30mg/day after 3 months due to skin toxicity and stomatitis grade 2. Next reduction to 20mg/day was performed after 10 subsequent months due to leucopenia and neutropenia grade 2.\n\n\n\nWith this patient, a partial response which lasted 19 months despite 50% reduction of the afatinib dose was achieved. Key words: afatinib - non-small cell lung cancer - epidermal growth factor-mutation receptor - treatment outcome - drug toxicity This article was supported by Boehringer Ingelheim. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 27. 9. 2018 Accepted: 1. 10. 2018.",
"affiliations": null,
"authors": "Čoupková|Helena|H|;Vyzula|Rostislav|R|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "Czech Republic",
"delete": false,
"doi": "10.14735/amko2018380",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0862-495X",
"issue": "31(5)",
"journal": "Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti",
"keywords": "afatinib - non-small cell lung cancer - epidermal growth factor-mutation receptor - treatment outcome - drug toxicity\n\nThis article was supported by Boehringer Ingelheim.\n\nThe authors declare they have no potential conflicts of interest concerning drugs; or services used in the study.\n\nThe Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.\n\nSubmitted: 27. 9. 2018\n\nAccepted: 1. 10. 2018; products",
"medline_ta": "Klin Onkol",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000077716:Afatinib; D000368:Aged; D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D018572:Disease-Free Survival; D066246:ErbB Receptors; D005091:Exons; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D009154:Mutation; D047428:Protein Kinase Inhibitors; D016896:Treatment Outcome",
"nlm_unique_id": "9425213",
"other_id": null,
"pages": "380-383",
"pmc": null,
"pmid": "30541326",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Afatinib in the Treatment of Advanced Non-Small Cell Lung Cancer with Rare EGFR (in exon 18-T179X) Mutation - a Case Report.",
"title_normalized": "afatinib in the treatment of advanced non small cell lung cancer with rare egfr in exon 18 t179x mutation a case report"
} | [
{
"companynumb": "CZ-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-037477",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AFATINIB"
},
"dr... |
{
"abstract": "This article is a practical guide to identifying uncommon causes of stroke and offers guidance for evaluation and management, even when large controlled trials are lacking in these rarer forms of stroke.\n\n\n\nFabry disease causes early-onset stroke, particularly of the vertebrobasilar system; enzyme replacement therapy should be considered in affected patients. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), often misdiagnosed as multiple sclerosis, causes migraines, early-onset lacunar strokes, and dementia. Moyamoya disease can cause either ischemic or hemorrhagic stroke; revascularization is recommended in some patients. Cerebral amyloid angiopathy causes both microhemorrhages and macrohemorrhages, resulting in typical stroke symptoms and progressive dementia. Pregnancy raises the risk of both ischemic and hemorrhagic stroke, particularly in women with preeclampsia/eclampsia. Pregnant women are also at risk for posterior reversible encephalopathy syndrome (PRES), reversible cerebral vasoconstriction syndrome, and cerebral venous sinus thrombosis. Experts recommend that pregnant women with acute ischemic stroke not be systematically denied the potential benefits of IV recombinant tissue plasminogen activator.\n\n\n\nNeurologists should become familiar with these uncommon causes of stroke to provide future risk assessment and family counseling and to implement appropriate treatment plans to prevent recurrence.",
"affiliations": null,
"authors": "Majersik|Jennifer Juhl|JJ|",
"chemical_list": "D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1212/CON.0000000000000432",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1080-2371",
"issue": "23(1, Cerebrovascular Disease)",
"journal": "Continuum (Minneapolis, Minn.)",
"keywords": null,
"medline_ta": "Continuum (Minneap Minn)",
"mesh_terms": "D000328:Adult; D000368:Aged; D016657:Cerebral Amyloid Angiopathy; D005260:Female; D006801:Humans; D020300:Intracranial Hemorrhages; D008297:Male; D008875:Middle Aged; D054038:Posterior Leukoencephalopathy Syndrome; D011247:Pregnancy; D011248:Pregnancy Complications; D020521:Stroke; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "9509333",
"other_id": null,
"pages": "211-237",
"pmc": null,
"pmid": "28157751",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Inherited and Uncommon Causes of Stroke.",
"title_normalized": "inherited and uncommon causes of stroke"
} | [
{
"companynumb": "US-ROCHE-1895328",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "To evaluate the long-term outcomes of rituximab in the treatment of pemphigus and the influence of disease duration and different dose of rituximab on the clinical response, 45 patients with refractory pemphigus treated with at least one cycle of two infusions of rituximab (375 mg/m2 per infusion weekly) were retrospectively studied. All patients were followed up for more than 2 years. All patients achieved complete or partial remission within 8 months of the first cycle. Thirty-four (76%) patients relapsed at a median of 17 months. All patients who received additional cycles after relapse achieved new remissions. Early use of rituximab within 1 year of disease duration and high-dose therapy induced better outcomes, although the results in early use were not statistically significant. Acute respiratory distress syndrome occurred in one patient. Rituximab is effective in treating pemphigus, but relapses are frequent during long-term follow up, and additional cycles are beneficial in relapsed cases. Early and high-dose rituximab therapy may be more effective.",
"affiliations": "Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.;Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.;Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.;Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.;Department of Dermatology, Gangnam Severance Hospital, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.",
"authors": "Kim|Tae Hyung|TH|;Choi|Yuri|Y|;Lee|Sang Eun|SE|;Lim|Jung Min|JM|http://orcid.org/0000-0002-0223-5933;Kim|Soo-Chan|SC|",
"chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.13757",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "44(6)",
"journal": "The Journal of dermatology",
"keywords": "early use; pemphigus; relapse; retreatment; rituximab",
"medline_ta": "J Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D010392:Pemphigus; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "615-620",
"pmc": null,
"pmid": "28186358",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Adjuvant rituximab treatment for pemphigus: A retrospective study of 45 patients at a single center with long-term follow up.",
"title_normalized": "adjuvant rituximab treatment for pemphigus a retrospective study of 45 patients at a single center with long term follow up"
} | [
{
"companynumb": "KR-ROCHE-1902773",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
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