article dict | reports listlengths 1 3.97k |
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{
"abstract": "A 37-year-old man was admitted to hospital for treatment of perineum damage and haematoma in the scrotum. His consciousness deteriorated after two intramuscular injections of pentazocine 15 mg. Faint low signals in the left putamin to frontal island and frontal lobe and obnubilation of the corticomedullary junction were apparent on head CT, which led to suspicion of cerebral infarction. MR angiography showed bilateral obstruction of the middle cerebral artery and moyamoya disease was diagnosed. Treatment with edaravone, argatroban and heparin was ineffective for opening the middle cerebral artery and serious after effects occurred. This case suggests that cerebrovascular accident should be suspected in a young patient with disturbance of consciousness but stable breathing and circulation, particularly if previous drug treatment has affected brain circulation. Moyamoya disease should be suspected based on medical or family history. In such a case, MR angiography is required for early diagnosis to facilitate treatment by re-establishment of blood circulation.",
"affiliations": "Department of Emergency and Critical Care Center, Kyushu University Hospital, Fukuoka, Kyushu, Japan. yoshinori216@h2.dion.ne.jp",
"authors": "Matsuoka|Yoshinori|Y|;Hashizume|Makoto|M|",
"chemical_list": "D000701:Analgesics, Opioid; D010423:Pentazocine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2010()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D002533:Cerebral Angiography; D006406:Hematoma; D006801:Humans; D020244:Infarction, Middle Cerebral Artery; D007273:Injections, Intramuscular; D018810:Magnetic Resonance Angiography; D008297:Male; D009072:Moyamoya Disease; D010343:Patient Admission; D010423:Pentazocine; D010502:Perineum; D012611:Scrotum; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "22789553",
"pubdate": "2010-11-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9409446;3748299;3069539;8609560;9412642;11201642;16685122;16788009;9099182;11118805;16179571;7974539;16645133;2351801",
"title": "Moyamoya disease in which pentazocine treatment caused cerebral infarction.",
"title_normalized": "moyamoya disease in which pentazocine treatment caused cerebral infarction"
} | [
{
"companynumb": "JP-RANBAXY-2013R1-73544",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PENTAZOCINE"
},
"drugadditional": null,
... |
{
"abstract": "Two patients with breast cancer received docetaxel-containing chemotherapy as adjuvant or neoadjuvant therapy during pregnancy. The first pregnant patient began neoadjuvant therapy with doxorubicin/cyclophosphamide at 14 weeks of gestation. After 4 cycles of doxorubicin/cyclophosphamide and surgery, she received adjuvant docetaxel for 4 cycles. The second patient began neoadjuvant therapy with doxorubicin/docetaxel at 14 weeks of gestation and received 6 cycles. The fetus of the first patient had hydrocephalus on ultrasound at 17 weeks of gestation (before docetaxel therapy) that persisted on serial follow-up ultrasounds and spontaneously regressed over several months after delivery. No fetal malformations were detected in the second fetus. These 2 cases add to the existing data on the use of taxanes during pregnancy. Although the data are limited with case reports, pregnant patients with cancer can be treated with chemotherapy including taxanes during the second and third trimesters without significant risks to the fetus. Taxanes should not be excluded, if indicated, in pregnant patients with cancer.",
"affiliations": "Department of Medicine, Louisiana State University Health Sciences Center Shreveport, 71130, USA.",
"authors": "Potluri|Vinaya|V|;Lewis|David|D|;Burton|Gary V|GV|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin; D003520:Cyclophosphamide",
"country": "United States",
"delete": false,
"doi": "10.3816/CBC.2006.n.029",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-8209",
"issue": "7(2)",
"journal": "Clinical breast cancer",
"keywords": null,
"medline_ta": "Clin Breast Cancer",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D003520:Cyclophosphamide; D000077143:Docetaxel; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D043823:Taxoids",
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "167-70",
"pmc": null,
"pmid": "16800979",
"pubdate": "2006-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Chemotherapy with taxanes in breast cancer during pregnancy: case report and review of the literature.",
"title_normalized": "chemotherapy with taxanes in breast cancer during pregnancy case report and review of the literature"
} | [
{
"companynumb": "US-SAKK-2018SA287360AA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nValidation of associations for SNPs in RAC2, NCF4 and SLC28A3, identification of a novel association with a TOP2B SNP and screening 23 SNPs putatively relevant to anthracycline-induced cardiotoxicity.\n\n\nMETHODS\nA total of 166 breast cancer patients treated with doxorubicin underwent echocardiogram, including 19 cases with systolic dysfunction (ejection fraction <55%) and 147 controls. Four high priority SNPs were tested in the primary analysis, with appropriate statistical correction, and 23 additional SNPs were screened in an uncorrected secondary analysis.\n\n\nRESULTS\nPreviously reported associations for RAC2, NCF4 and SLC28A3 could not be validated and a novel association with TOP2B was not discovered in this cohort (all p > 0.05), likely due to inadequate power. Two SNPs were identified in the uncorrected secondary analysis including a protective SNP in ABCB1 (3435C>T, p = 0.049) and a risk allele in CBR3 (V244M, p = 0.012).\n\n\nCONCLUSIONS\nThe associations reported in prior publications and those discovered in this secondary analysis require further replication in independent cohorts.",
"affiliations": "Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109, USA.;Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.;Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.;Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.;Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.;Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.;Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.;Department of Internal Medicine, Division of Cardiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.;Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.;Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.;Department of Internal Medicine, Division of Cardiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.;Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.;Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.",
"authors": "Hertz|Daniel L|DL|;Caram|Megan V|MV|;Kidwell|Kelley M|KM|;Thibert|Jacklyn N|JN|;Gersch|Christina|C|;Seewald|Nicholas J|NJ|;Smerage|Jeffrey|J|;Rubenfire|Melvyn|M|;Henry|N Lynn|NL|;Cooney|Kathleen A|KA|;Leja|Monika|M|;Griggs|Jennifer J|JJ|;Rae|James M|JM|",
"chemical_list": "C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D018943:Anthracyclines; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D026901:Membrane Transport Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C065171:cif nucleoside transporter; D000429:Alcohol Oxidoreductases; C531130:CBR3 protein, human; D019255:NADPH Oxidases; C113333:NCF4 protein, human; C116761:rac2 GTP-binding protein; D020744:rac GTP-Binding Proteins; D004250:DNA Topoisomerases, Type II; C000618814:TOP2B protein, human",
"country": "England",
"delete": false,
"doi": "10.2217/pgs.15.162",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-2416",
"issue": "17(3)",
"journal": "Pharmacogenomics",
"keywords": "ABCB1; CBR3; NCF4; RAC2; SLC28A3; TOP2B; anthracycline; cardiotoxicity; doxorubicin; pharmacogenetic; systolic dysfunction",
"medline_ta": "Pharmacogenomics",
"mesh_terms": "D018435:ATP Binding Cassette Transporter, Subfamily B; D000429:Alcohol Oxidoreductases; D018943:Anthracyclines; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D066126:Cardiotoxicity; D016022:Case-Control Studies; D002908:Chronic Disease; D003430:Cross-Sectional Studies; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D026901:Membrane Transport Proteins; D019255:NADPH Oxidases; D000075223:Poly-ADP-Ribose Binding Proteins; D020641:Polymorphism, Single Nucleotide; D020744:rac GTP-Binding Proteins",
"nlm_unique_id": "100897350",
"other_id": null,
"pages": "231-40",
"pmc": null,
"pmid": "26799497",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "16957942;17101852;23116553;23104132;8644864;22124095;21900104;26230641;18551042;21371685;16376782;11231433;19448608;20007405;25169180;24831276;26237429;15365066;23677053;26050157;19421167;18457324;16251204;23927520;18227530;16330681;25287823;17185560;11134193;15808762;15247630;23441093;22614988",
"title": "Evidence for association of SNPs in ABCB1 and CBR3, but not RAC2, NCF4, SLC28A3 or TOP2B, with chronic cardiotoxicity in a cohort of breast cancer patients treated with anthracyclines.",
"title_normalized": "evidence for association of snps in abcb1 and cbr3 but not rac2 ncf4 slc28a3 or top2b with chronic cardiotoxicity in a cohort of breast cancer patients treated with anthracyclines"
} | [
{
"companynumb": "US-JNJFOC-20160227043",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAdministration of gemcitabine together with cisplatin at cytotoxic doses in a chemoradiotherapy regimen is hampered by a high degree of local toxicity. Using the pharmacologic properties of the drug we designed a modified schedule aimed at reducing toxicity while preserving activity.\n\n\nMETHODS\nPatients with squamous cell carcinomas of the oral cavity, pharynx and larynx, bulky T4, and/or N2 to N3 were eligible. Gemcitabine was administered at a dose of 800 mg/m2 on Days 1 and 12 and cisplatin at a dose of 20 mg/m2 on Days 2 to 5, every 21 days for 3 courses. Radiotherapy, delivered with standard fractionation, was given on Days 8 to 12 and 15 to 19 and was repeated 3 times up to a total dose of > or = 60 Gy.\n\n\nRESULTS\nA total of 28 patients were selected. Grade 3 to 4 stomatitis was recorded in 25 patients (89%). Thirteen patients (46%) experienced Grade 3 to 4 neutropenia. Febrile neutropenia occurred in 8 patients (29%) and in 2 was complicated by infection and death. The overall complete response rate was 79%. At a median follow up of 71 months, 11 patients had a locoregional relapse (3-year locoregional control, 64%); 6 patients had distant metastases, among whom only 2 were without locoregional recurrence. The 3-year progression-free survival is 39% and 3-year overall survival has been 43%.\n\n\nCONCLUSIONS\nThe schedule modification did not attenuate local toxicity. Moreover, infections and especially pneumonia, were a major problem. The high activity of gemcitabine when combined with radiotherapy would most likely be better exploited in the context of modified radiation schemes.",
"affiliations": "Medical Oncology, S. Croce General Hospital, Cuneo, Italy. gianmauro.numico@fastwebnet.it",
"authors": "Numico|Gianmauro|G|;Russi|Elvio G|EG|;Vitiello|Raffele|R|;Sorrentino|Raffaele|R|;Colantonio|Ida|I|;Cipolat|Marco|M|;Taglianti|Riccardo Vigna|RV|;Pelissero|Antonio|A|;Fea|Elena|E|;Granetto|Cristina|C|;Di Costanzo|Gianna|G|;Gasco|Milena|M|;Garrone|Ornella|O|;Occelli|Marcella|M|;Merlano|Marco|M|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ijrobp.2006.05.059",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0360-3016",
"issue": "66(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; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D019583:Dose Fractionation, Radiation; D004334:Drug Administration Schedule; D005260:Female; D006258:Head and Neck Neoplasms; D006801:Humans; D007822:Laryngeal Neoplasms; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms; D009364:Neoplasm Recurrence, Local; D009503:Neutropenia; D010610:Pharyngeal Neoplasms; D013280:Stomatitis",
"nlm_unique_id": "7603616",
"other_id": null,
"pages": "731-7",
"pmc": null,
"pmid": "17011449",
"pubdate": "2006-11-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Gemcitabine and cisplatin in a concomitant alternating chemoradiotherapy program for locally advanced head-and-neck cancer: a pharmacology-guided schedule.",
"title_normalized": "gemcitabine and cisplatin in a concomitant alternating chemoradiotherapy program for locally advanced head and neck cancer a pharmacology guided schedule"
} | [
{
"companynumb": "IT-CIPLA LTD.-2016IT00302",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"d... |
{
"abstract": "Chronic migraine is a frequent, severely disabling headache that often evolves from EM. Treatment should be individualized with consideration of the patient as a whole person rather than just the headaches. Many options have been used for acute and preventive pharmacologic management, although good scientific and clinical evidence is limited to a few options. Evidence supports the efficacy and tolerability of both topiramate and onabotulinumtoxinA for prevention of CM headaches. However, only onabotulinumtoxinA is approved by the FDA for preventive treatment of CM.",
"affiliations": "Medical Director, Headache Care Center, Clinvest/a Division of Banyan Group, Inc., Springfield, MO, USA.",
"authors": "Cady|Roger K|RK|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D018696:Neuroprotective Agents; D058825:Serotonin 5-HT1 Receptor Agonists; D000077236:Topiramate; D005632:Fructose; D018170:Sumatriptan; D019274:Botulinum Toxins, Type A",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0094-3509",
"issue": "63(2 Suppl)",
"journal": "The Journal of family practice",
"keywords": null,
"medline_ta": "J Fam Pract",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D019274:Botulinum Toxins, Type A; D005260:Female; D005632:Fructose; D006801:Humans; D008881:Migraine Disorders; D018696:Neuroprotective Agents; D058825:Serotonin 5-HT1 Receptor Agonists; D018170:Sumatriptan; D000077236:Topiramate",
"nlm_unique_id": "7502590",
"other_id": null,
"pages": "S46-51",
"pmc": null,
"pmid": "24527485",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Chronic migraine in women.",
"title_normalized": "chronic migraine in women"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2014-01855",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional... |
{
"abstract": "We present the case of a young man with acute lymphoblastic leukemia who developed cytomegalovirus (CMV) appendicitis after receiving alemtuzumab for acute refractory graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (HSCT). CMV appendicitis is a rare complication; and we are reporting the first case to our knowledge of CMV appendicitis following HSCT. Our case highlights the importance of recognition of CMV viral reactivation following the use of alemtuzumab. Using a preemptive strategy of checking CMV PCR, with initiation of early effective treatment on detection of CMV replication, may be appropriate following use of alemtuzumab in hematologic malignancies in patients after HSCT.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Division of Infectious Diseases, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Division of Hematology and Oncology, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Division of Hematology and Oncology, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Division of Hematology and Oncology, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Division of Infectious Diseases, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.",
"authors": "Kothari|Atul|A|http://orcid.org/0000-0002-3236-3864;Caradine|Kari D|KD|;Rico Crescencio|Juan Carlos|JC|;Sasapu|Appalanaidu|A|;Veeraputhiran|Muthu K|MK|;Jethava|Yogesh|Y|;Burgess|Mary J|MJ|",
"chemical_list": "D000970:Antineoplastic Agents; D000998:Antiviral Agents; D015774:Ganciclovir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12747",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "19(5)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "CMV; HSCT; alemtuzumab; appendicitis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001064:Appendicitis; D003586:Cytomegalovirus Infections; D015774:Ganciclovir; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28708253",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cytomegalovirus appendicitis after hematopoietic stem cell transplantation.",
"title_normalized": "cytomegalovirus appendicitis after hematopoietic stem cell transplantation"
} | [
{
"companynumb": "US-ASTELLAS-2017US043811",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Primary hepatic lymphoma (PHL) is a very rare malignancy and constitutes 0.016% of all cases of non-Hodgkin's lymphoma and 0.4% of extranodal non-Hodgkin's lymphoma. We describe a rare case of primary hepatic lymphoma presenting as liver abscess which was complicated with the development of a hepatogastric fistula. A 58-year-old man presented with clinical signs of sepsis, high-grade fever, right upper abdominal pain, and weight loss which had progressed in the past 8 months. Noncontrast abdominal computed tomography (CT) revealed a heterogeneously hypodense lesion in the left lobe of the liver with multiple air foci within, which are seen to extend into the body of the stomach. The patient was initially misdiagnosed as a case of rupture of liver abscess into the stomach. Postoperative liver biopsy examination confirmed a diagnosis of diffuse large B-cell lymphoma. Systemic staging revealed no evidence of nodal or bone marrow involvement, so PHL was diagnosed. Chemotherapy was initiated, but discontinued due to the patient's general condition. Finally, the patient succumbed to neutropenic fever following chemotherapy. Here, we present the exceptional case of a primary hepatic lymphoma with an unusual complication, a hepatogastric fistula, and try through the existing literature to show the difficulties involved in diagnosis and treatment.",
"affiliations": "Department of Surgery, Military University Hospital Med V, University Hassan II of Casablanca, Casablanca, Morocco.;Department of Surgery, Ibn Rochd University Hospital, University Hassan II of Casablanca, Casablanca, Morocco.;Department of Pathology, Military University Hospital Med V, Rabat, Morocco.;Department of Surgery, Military University Hospital Med V, Rabat, Morocco.;Department of Surgery, Military University Hospital Med V, Rabat, Morocco.",
"authors": "Yaka|Mbarek|M|https://orcid.org/0000-0001-8083-1143;Chehab|Farid|F|;Allaoui|Mohmed|M|;Ait Ali|Abdelmonaim|A|;Zentar|Aziz|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/6647558",
"fulltext": "\n==== Front\nCase Rep Hematol\nCase Rep Hematol\nCRIHEM\nCase Reports in Hematology\n2090-6560\n2090-6579\nHindawi\n\n10.1155/2021/6647558\nCase Report\nPostsurgical Diagnosis of an Unusual Case of Primary Hepatic Lymphoma Presenting as Liver Abscess with an Uncommon Complication: A Hepatogastric Fistula\nhttps://orcid.org/0000-0001-8083-1143\nYaka Mbarek mbarekyaka@yahoo.fr\n1\nChehab Farid 2\nAllaoui Mohmed 3\nAit Ali Abdelmonaim 4\nZentar Aziz 4\n1Department of Surgery, Military University Hospital Med V, University Hassan II of Casablanca, Casablanca, Morocco\n2Department of Surgery, Ibn Rochd University Hospital, University Hassan II of Casablanca, Casablanca, Morocco\n3Department of Pathology, Military University Hospital Med V, Rabat, Morocco\n4Department of Surgery, Military University Hospital Med V, Rabat, Morocco\nAcademic Editor: Kostas Konstantopoulos\n\n2021\n24 2 2021\n2021 664755817 11 2020\n4 2 2021\n18 2 2021\nCopyright © 2021 Mbarek Yaka et al.\n2021\nThis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nPrimary hepatic lymphoma (PHL) is a very rare malignancy and constitutes 0.016% of all cases of non-Hodgkin's lymphoma and 0.4% of extranodal non-Hodgkin's lymphoma. We describe a rare case of primary hepatic lymphoma presenting as liver abscess which was complicated with the development of a hepatogastric fistula. A 58-year-old man presented with clinical signs of sepsis, high-grade fever, right upper abdominal pain, and weight loss which had progressed in the past 8 months. Noncontrast abdominal computed tomography (CT) revealed a heterogeneously hypodense lesion in the left lobe of the liver with multiple air foci within, which are seen to extend into the body of the stomach. The patient was initially misdiagnosed as a case of rupture of liver abscess into the stomach. Postoperative liver biopsy examination confirmed a diagnosis of diffuse large B-cell lymphoma. Systemic staging revealed no evidence of nodal or bone marrow involvement, so PHL was diagnosed. Chemotherapy was initiated, but discontinued due to the patient's general condition. Finally, the patient succumbed to neutropenic fever following chemotherapy. Here, we present the exceptional case of a primary hepatic lymphoma with an unusual complication, a hepatogastric fistula, and try through the existing literature to show the difficulties involved in diagnosis and treatment.\n==== Body\n1. Introduction\n\nPHL is a rare form of non-Hodgkin lymphoma (NHL), and it is a tumor confined to the liver without evidence of lymphomatous involvement of the lymph nodes, spleen, bone marrow, or other lymphoid structures. The vast majority of PHL is NHL, most often a diffuse large B-cell lymphoma type. PHL was often misdiagnosed as some other tumor and frequently diagnosed intra- or postoperatively. We report an interesting case of PHL that was difficult to discriminate from a liver abscess, with an unusual complication, hepatogastric fistula, diagnosed after postoperative biopsy report, and try through the existing literature to show the difficulties involved in diagnosis and treatment.\n\n2. Case Report\n\nA 58-year-old male with no significant past medical history presented to our emergency department with fever, right upper abdominal pain, vomiting, hematemesis, anorexia, night sweats, and unexplained weight loss. Physical examination revealed an asthenic patient with mild mucocutaneous pallor, a temperature of 38°C, pulse rate of 110/min, blood pressure of 90/60 mmHg, and respiratory rate of 17/min. There was no clinical jaundice. Per abdominal examination revealed mild tenderness in the epigastric and right hypochondriac regions, with palpable liver extending one cm below the right subcostal margin, rounded margin. The spleen and superficial lymph nodes were not palpable. Initial investigations showed hemoglobin of 7.3 g/dl, total leukocyte count of 22,000 cells/mm3 (neutrophils 82%), and platelet counts (139,000 cells/mm3). Serum lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin levels were elevated, but the levels of other tumor markers, such as alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA), were normal. Serology was negative for hepatitis B virus (HBV) surface antigen, HCV, and human immunodeficiency virus. An urgent noncontrast computed tomography (CT) examination of the abdomen and pelvis was performed which showed a heterogeneously hypodense lesion in the left lobe of the liver with multiple air foci within. The liver lesion was extending directly into the body of the stomach (Figure 1). The walls of the fundus and lesser curvature of the stomach could not be defined. These features were suggestive of rupture of left lobe liver abscess into the stomach. The spleen was remarkably normal, and the mesenteric, para-aortic, and retroperitoneal lymph nodes were not enlarged. Based on a presumptive diagnosis of liver abscess, the patient was initially treated with broad-spectrum antibiotics. The patient's clinical condition deteriorated, and a decision of surgical exploration was made. Intraoperative findings revealed dense adhesions of the left lobe of the liver with the anterior wall of the stomach and diaphragmatic surface. There was a 2 cm × 1 cm defect on the anterior wall of the stomach, and it was communicating with the abscess cavity in the left lobe of the liver. There was no peritoneal soiling. Necrosis tissues were removed from the liver, we drained the abscess cavity, and subhepatic drain was placed. The margins of the gastric perforation were freshened and primarily repaired (Figure 2). The patient was kept on nasojejunal tube for one week with broad-spectrum antibiotics and total parenteral nutrition. Histopathology of the surgical liver biopsy revealed a hepatic diffuse infiltration of large typical lymphoid B-cells, with necrosis. Immunohistochemistry was positive for CD20 and Ki-67 (80%) (Figure 3).\n\nPostoperative investigations for disseminated non-Hodgkin lymphoma (NHL) by CT scan of the thorax did not reveal any lymphadenopathy or mass lesion. FDG-PET scan and bone marrow biopsy were negative. Thus, a diagnosis of primary non-Hodgkin lymphoma of the liver, large cell type, was confirmed. The patient condition did not allow additional complementary surgery, and he was managed with six cycles of R-CHOP regimen, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. However, a persistent fever occurred 1 month after three cycles of chemotherapy. The patient succumbed to neutropenic fever following chemotherapy.\n\n3. Discussion\n\nPHL and hepatogastric fistula are extremely rare. To our knowledge, this is the first report on a primary hepatic lymphoma invading the adjacent stomach, which was complicated with the development of a hepatogastric fistula. PHL was first described in 1965 by Ata and Kamel [1]. Some authors defined primary hepatic lymphoma as a very rare malignant tumor with the features of liver involvement and without involvement of other organs and tissues including the bone marrow, lymph nodes, spleen, and peripheral blood until at least 6 months after diagnosis [2, 3].\n\nPrimary hepatic lymphoma is very rare and constitutes about 0.0016% of all cases of non-Hodgkin's lymphoma (NHL) [4]. Extranodal lymphomas account for 10%–25% of non-Hodgkin's lymphomas, in which PHL is responsible for less than 1% [5].\n\nPHL can occur at any age, and the average age of the reported patients is the fifth or sixth decade of life. It affects preferentially men with a male/female ratio of 2–3/1 [6]. PHL may be Hodgkin's or non-Hodgkin's; however, the latter is more common. Immunophenotypically, the B-cell is commoner than T-cell type [5]. The etiology of PHL is uncertain, and it may be associated with HIV, AIDS, hepatitis B and C, Epstein–Barr virus, liver cirrhosis, primary biliary cirrhosis, immunosuppressive therapy, and autoimmune diseases [7]. However, our case did not have any of the above conditions.\n\nSymptoms are usually nonspecific and include hepatomegaly, gastrointestinal symptoms (abdominal pain, vomiting, and loss of appetite), right upper quadrant, and epigastric pain. Many cases are diffuse large B-cell lymphoma, and the patients show B-symptomatology of weight loss, fever, and night sweats, as well as fatigue and lethargy. Other rare clinical manifestations include pleural effusion, jaundice, thrombocytopenia, metabolic acidosis, and hypercalcemia [8]. Laboratory abnormalities associated with PHL include anaemia, neutropenia, hypercalcemia, and variably raised LDH, one serum alkaline phosphatase, b-microglobulin, and aminotransferase activities. The tumor markers AFP and CEA are found within normal range, in almost all cases of PHL [2].\n\nOn ultrasound imaging, majority are hypoechoic as compared to surrounding normal liver parenchyma. Radiological features of PHL are usually nonspecific, and the most common presentation on the computed tomography (CT) scan is a solitary hypoattenuating lesion, which may have a central area of low intensity indicating necrosis. Other less common radiological findings are multiple lesions and diffuse infiltration patterns [9]. On MRI, the lesion appears hypointense on T1-weighted and mildly hyperintense on T2-weighted images. However, it is often difficult to distinguish hepatic lymphoma from hepatocarcinoma or gastrointestinal tract metastasis because of the rarity of this disease and the nonspecific clinical presentation, laboratory, and radiologic features [10].\n\nDiagnosis is often made upon histopathological and immunohistochemical investigation of the liver biopsy by using percutaneous needle aspiration, laparoscopy, or laparotomy [11]. In our case, liver biopsy was performed preoperatively because the lesion was profoundly symptomatic, and due to the rarity of the disease, we considered liver abscess with hepatogastric fistula in our first diagnosis.\n\nTreatment modalities include surgical resection, chemotherapy, and radiotherapy alone or in combination. Most of the reported cases are diffuse large B-cell lymphomas, but this type is usually aggressive with a relatively poor prognosis [5]. Current literature favors combination chemotherapy as the frontline treatment owing to its noninvasive nature and improved survival outcomes. The standard treatment for patients with diffuse large B-cell lymphoma is CHOP. The addition of rituximab, a monoclonal antibody targeting the pan-B-cell antigenic marker CD20, to the CHOP regimen augments the complete response rate and prolongs overall survival [11, 12]. Optimal treatment is not yet defined. However, recent series reported favorable short and midterm outcomes and longer survival rates with the use of liver resection followed by adjuvant chemotherapy and/or radiation [13]. Surgery is a better option for localized disease with adequate normal liver volume, and preoperative chemotherapy can be tried with an attempt to reduce the tumor volume [5, 14]. However, because our patient's general condition did not permit, we did not proceed with a formal liver resection as indicated in this setting.\n\nThe clinical case we present is extremely unusual because there is a coincidence of two very rare features, primary hepatic lymphoma and hepatogastric fistula. Direct invasion to the gastric wall is the basis of the formation of a hepatogastric fistula. Nevertheless, a hepatogastric fistula is a rare complication, even more so for primary liver lymphoma. Such a fistula has been described following transarterial embolization, radiotherapy for hepatocellular carcinoma, percutaneous radiofrequency of hepatocellular carcinoma, pyogenic liver abscess, iatrogenic injury of the stomach, percutaneous catheter drainage of the liver abscess, or by direct infiltration of the stomach by hepatocellular carcinoma [15].\n\n4. Conclusion\n\nIn conclusion, we have reported an exceptional case of PHL with an unusual complication that was difficult to discriminate from a liver abscess with a hepatogastric fistula. The preoperative diagnosis was difficult due to the rarity of the disease, the clinical and imaging manifestations of PHL were nonspecific, and levels of alpha-fetoprotein and carcinoembryonic antigen (CEA) were normal. The diagnosis of PHL should be strictly based on histopathology and immunophenotype. PHL should be considered in the differential diagnosis in a patient with space-occupying liver lesions. Favorable prognosis of PHL can be obtained by early surgery combined with chemotherapy in strictly selected patients.\n\nData Availability\n\nThe research article data used to support the findings of this study are available from the corresponding author upon request (mbarekyaka@yahoo.fr).\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Preoperative CT scan showing (a, b) liver cystic mass containing multiple air foci; (c, d) hepatogastric fistula.\n\nFigure 2 Operative view of the anterior surface of the left lobe of the liver showing (a) necrotic area of liver lymphoma and (b) hepatogastric fistula.\n\nFigure 3 Histopathological examination. (a) Diffuse proliferation of atypical lymphoid cells (HE, GX 40). (b) Large numbers of lymphocytes ranging in size from medium to large, with oval or round nuclei containing fine chromatin and scanty cytoplasm (HE, GX 200). (c) Immunohistochemical staining was positive for CD20 (a B-cell marker). (d) The Ki-67 index was positive in 80%.\n==== Refs\n1 Ata A. A. Kamel I. A. Primary reticulum cell sarcoma of the liver. A case report The Journal of the Egyptian Medical Association 1965 48 7 514 521 5321839\n2 Mastoraki A. Stefanou M. I. Chatzoglou E. Primary hepatic lymphoma: dilemmas in diagnostic approach and therapeutic management Indian Journal of Hematology and Blood Transfusion 2014 30 3 150 154 10.1007/s12288-013-0263-2 2-s2.0-84905589651 25114399\n3 Caccamo D. Pervez N. K. Marchevsky A. Primary lymphoma of the liver in the acquired immunode ciency syndrome Archives of Pathology and Laboratory Medicine 1986 110 553 555 3010899\n4 Yang X. W. Tan W. F. Yu W. L. Diagnosis and surgical treatment of primary hepatic lymphoma World Journal of Gastroenterology 2010 16 47 6016 6019 10.3748/wjg.v16.i47.6016 2-s2.0-78650610809 21157979\n5 Lei K. Primary non-hodgkin’s lymphoma of the liver Leukemia & Lymphoma 1998 29 3-4 293 299 9684927\n6 Avlonitis V. S. Linos D. Primary hepatic lymphoma: a review The European Journal of Surgery=Acta Chirurgica 1999 165 8 725 729 10.1080/11024159950189474 2-s2.0-0032866841 10494635\n7 Takeuchi N. Naba K. Primary hepatic lymphoma is difficult to discriminate from a liver abscess Case reports in Gastrointestinal Medicine 2014 2014 6 925307 10.1155/2014/925307\n8 Xiong F. Guan Y.-S. Primary hepatic lymphoma: is it a disease entity? Hepatoma Research 2017 3 5 73 78 10.20517/2394-5079.2017.02\n9 Mehta N. Jayapal L. Goneppanavar M. Nelamangala Ramakrishnaiah V. P. Primary hepatic lymphoma: a rare case report JGH Open 2019 3 3 261 263 10.1002/jgh3.12131 2-s2.0-85071701297 31276045\n10 Maher M. M. McDermott S. R. Fenlon H. M. Imaging of primary non-hodgkin’s lymphoma of the liver Clinical Radiology 2001 56 4 295 301 10.1053/crad.2000.0649 2-s2.0-0035323493 11286581\n11 Tatsumi G. Ukyo N. Hirata H. Tsudo M. Primary hepatic lymphoma in a patient with rheumatoid arthritis treated with methotrexate Case Reports in Hematology 2014 2014 460574 10.1155/2014/460574\n12 Masood A. Kairouz S. Hudhud K. H. Primary non-Hodg-kin lymphoma of liver Current Oncology 2009 16 74 77 10.3747/co.v16i4.443 2-s2.0-70350578563 19672429\n13 Yu Y.-D. Kim D.-S. Byun G.-Y. Primary hepatic marginal zone B cell lymphoma: a case report and review of the literature Indian Journal of Surgery 2013 75 S1 331 336 10.1007/s12262-012-0695-1 2-s2.0-84893476019\n14 Zentar A. Tarchouli M. Elkaoui H. Primary hepatic lymphoma Journal of Gastrointestinal Cancer 2014 45 3 380 382 10.1007/s12029-013-9505-7 2-s2.0-85027951962 23686662\n15 Gandham V. S. Pottakkat B. Panicker L. C. Hari R. V. Hepatogastric fistula: a rare complication of pyogenic liver abscess BMJ Case Reports 2014 2014 10.1136/bcr-2014-204175 2-s2.0-84904480146\n\n",
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"title": "Postsurgical Diagnosis of an Unusual Case of Primary Hepatic Lymphoma Presenting as Liver Abscess with an Uncommon Complication: A Hepatogastric Fistula.",
"title_normalized": "postsurgical diagnosis of an unusual case of primary hepatic lymphoma presenting as liver abscess with an uncommon complication a hepatogastric fistula"
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"abstract": "OBJECTIVE\nTo investigate the prevention and therapy of fungal infection in patients with severe acute pancreatitis (SAP).\n\n\nMETHODS\nSeventy patients with SAP admitted from Jan. 1998 to Dec. 2002 were randomly divided into garlicin prevention group, fluconazole (low dosage) prevention group and control group. The incidence of fungal infection, the fungal clearance and mortality after treatment were compared.\n\n\nRESULTS\nThe incidence of fungal infection in garlicin group and fluconazole group was lower than that in control group (16% vs 30%, P<0.05 and 9% vs 30%, P<0.01, respectively). Amphotericin B or therapy-dose fluconazole had effects on patients with fungal infection in garlicin group and control group, but had no effects on patients with fungal infection in fluconzole group.\n\n\nCONCLUSIONS\nProphylactic dosage of antifungal agents (garlicin or low dosage fluconazole) can reduce the incidence of fungal infection in patients with SAP. But once fungal infection occurs, amphotericin B should be used as early as possible if fluconazole is not effective.",
"affiliations": "Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, China. heym@medmail.com.cn",
"authors": "He|Yue-Ming|YM|;Lv|Xin-Sheng|XS|;Ai|Zhong-Li|ZL|;Liu|Zhi-Su|ZS|;Qian|Qun|Q|;Sun|Quan|Q|;Chen|Ji-Wei|JW|;Lei|Dao-Xiong|DX|;Jiang|Cong-Qing|CQ|;Yuan|Yu-Fong|YF|",
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"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D000498:Allyl Compounds; D000666:Amphotericin B; D000935:Antifungal Agents; D004220:Disulfides; D005260:Female; D015725:Fluconazole; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009181:Mycoses; D010195:Pancreatitis; D011446:Prospective Studies; D016896:Treatment Outcome",
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"title": "Prevention and therapy of fungal infection in severe acute pancreatitis: A prospective clinical study.",
"title_normalized": "prevention and therapy of fungal infection in severe acute pancreatitis a prospective clinical study"
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"abstract": "Recently, encouraging data provided long-awaited hope for gene therapy as a cure for sickle cell disease (SCD). Nevertheless, the transient suspension of the bluebird bio gene therapy trial (clinicaltrials.gov: NCT02140554) after participants developed acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) raised concerns. Potential possibilities for these cases include busulfan, insertional mutagenesis, both, or neither. Busulfan was considered the cause in the first reported case because the transgene was not present in the AML/MDS. However, busulfan is unlikely to have contributed to the most recent case. The transgene was present in the patient's malignant cells, indicating they were infused after busulfan treatment. Several lines of evidence suggest an alternative explanation for events in the bluebird bio trial, including that SCD population studies show an increased relative, but a low absolute, risk of AML/MDS. We propose a new hypothesis: after gene therapy for SCD, the stress of switching from homeostatic to regenerative hematopoiesis by transplanted cells drives clonal expansion and leukemogenic transformation of preexisting premalignant clones, eventually resulting in AML/MDS. Evidence validating our hypothesis will support prescreening individuals with SCD for preleukemic progenitors before gene therapy. While presumed viable, safe strategy has been implemented to resume gene therapy in adults with severe SCD, reasonable alternative curative therapy should be considered for children and adults with severe SCD. Currently, open multicenter clinical trials are incorporating nonmyeloablative conditioning, related haploidentical donors, and posttransplantation cyclophosphamide. Preliminary results from these trials appear promising, and National Institutes of Health-sponsored trials are ongoing in individuals with SCD using this platform.",
"affiliations": "Sidney Kimmel Cancer Center at Johns Hopkins, Johns Hopkins University, Baltimore, MD; and.;Vanderbilt-Meharry Sickle Cell Disease Center of Excellence, Vanderbilt University Medical Center, Nashville, TN.",
"authors": "Jones|Richard J|RJ|;DeBaun|Michael R|MR|0000-0002-0574-1604",
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"title": "Leukemia after gene therapy for sickle cell disease: insertional mutagenesis, busulfan, both, or neither.",
"title_normalized": "leukemia after gene therapy for sickle cell disease insertional mutagenesis busulfan both or neither"
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"abstract": "A 67-year-old woman was diagnosed with Stage ⅡA breast cancer(T2N0M0)in 2003. She underwent mastectomy and lymph node dissection. Oral fluoropyrimidine was administered for 3 years as adjuvant chemotherapy. In 2008, the patient was diagnosed with multiple bone metastases and left supraclavicular lymph node metastasis. Radiotherapy was performed on the left first rib and left supraclavicular lymph node. She was treated with chemotherapy and endocrine therapy and bone metastasis therapeutic agent. In 2013, multiple liver metastases were noted and treated with chemotherapy. Liver metastases were well-controlled. Endocrine therapy was continued for bone metastases without visceral metastasis. In 2016, the patient was diagnosed with bone marrow carcinomatosis and died 2 weeks later due to bone marrow carcinomatosis.",
"affiliations": "Dept. of Surgery, Sapporo Century Hospital.",
"authors": "Konishi|Kazuya|K|;Araya|Jun|J|;Nagabuchi|Makoto|M|;Sakamoto|Takashi|T|;Ichinokawa|Kazuomi|K|;Shikishima|Hiroyuki|H|;Mori|Akio|A|;Hirano|Satoshi|S|",
"chemical_list": null,
"country": "Japan",
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"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
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"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001853:Bone Marrow; D001943:Breast Neoplasms; D018450:Disease Progression; D005260:Female; D006801:Humans; D008408:Mastectomy",
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"title": "A Case of Bone Marrow Carcinomatosis Arising from Breast Cancer with a Rapidly Progressive Course.",
"title_normalized": "a case of bone marrow carcinomatosis arising from breast cancer with a rapidly progressive course"
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"companynumb": "JP-AMGEN-JPNSP2019205552",
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"abstract": "Abiraterone acetate has been approved for metastatic castration-resistant prostate cancer (mCRPC). Coadministration with prednisone has been recommended to prevent the toxicity from secondary mineralocorticoid excess, such as hypertension, hypokalemia, and edema. However, the use of prednisone is often not desired by patients because of the potential for detrimental effects of long-term therapy with corticosteroids, especially in those with comorbidities such as diabetes or who have received previous immunotherapeutic agents. Eplerenone is a nonsteroidal mineralocorticoid antagonist demonstrated to abrogate mineralocorticoid excess. In the present retrospective study, we report our real-world experience with the use of eplerenone with abiraterone in men with mCRPC who wished to avoid concomitant prednisone therapy.\n\n\n\nThe incidence and grade (Common Terminology Criteria for Adverse Events, version 4) of mineralocorticoid excess toxicities, baseline demographics, disease characteristics, and progression-free survival (PFS) were collected retrospectively. The patient population included men with mCRPC treated with abiraterone, who were not willing to receive corticosteroids, and thus received eplerenone. Their data were compared with the data from those treated with abiraterone and prednisone during the same period. Continuous variables were assessed using the Wilcoxon rank sum test or Student t test, and categorical variables were assessed using Fischer's exact test or χ2 test, as appropriate. PFS was compared using the Kaplan-Meier method.\n\n\n\nOf the 106 men treated with abiraterone, 40 received eplerenone and 66 received prednisone. The baseline and disease characteristics, incidence and grade of adverse events related to the syndrome of mineralocorticoid excess, and the median PFS were similar in both cohorts.\n\n\n\nIn a real-world population of men with mCRPC treated with abiraterone, corticosteroids can be avoided by concomitant treatment with eplerenone. These data require further validation.",
"affiliations": "Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.;Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.;Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT.;Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.;Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.;Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.;Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.;Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.;Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT.;Huntsman Cancer Institute, University of Utah, Salt Lake City, UT. Electronic address: oncologyus@gmail.com.",
"authors": "Gill|David|D|;Gaston|David|D|;Bailey|Erin|E|;Hahn|Andrew|A|;Gupta|Sumati|S|;Batten|Julia|J|;Alex|Anitha|A|;Boucher|Kenneth|K|;Stenehjem|David|D|;Agarwal|Neeraj|N|",
"chemical_list": "D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000077545:Eplerenone; D000069501:Abiraterone Acetate; D011241:Prednisone",
"country": "United States",
"delete": false,
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"issue": "15(4)",
"journal": "Clinical genitourinary cancer",
"keywords": "Aldosterone antagonist; Chronic glucocorticoid toxicity; mCRPC",
"medline_ta": "Clin Genitourin Cancer",
"mesh_terms": "D000069501:Abiraterone Acetate; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077545:Eplerenone; D006801:Humans; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists; D009362:Neoplasm Metastasis; D011241:Prednisone; D064129:Prostatic Neoplasms, Castration-Resistant; D012189:Retrospective Studies; D013148:Spironolactone; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "101260955",
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"pages": "e599-e602",
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"pmid": "28131750",
"pubdate": "2017-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "22411952;26025264;21632851;20159823;27491282;24647231;20159814;18645193;21612468;24150234;23228172;22170708;23582279",
"title": "Efficacy of Eplerenone in the Management of Mineralocorticoid Excess in Men With Metastatic Castration-resistant Prostate Cancer Treated With Abiraterone Without Prednisone.",
"title_normalized": "efficacy of eplerenone in the management of mineralocorticoid excess in men with metastatic castration resistant prostate cancer treated with abiraterone without prednisone"
} | [
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"abstract": "BACKGROUND\nSevere traumatic brain injury is a major public health problem that accounts for one-third of all deaths due to trauma in the United States. This case report illustrates some of the challenges faced by the elderly in accessing essential emergency services for traumatic brain injury.\n\n\nMETHODS\nA 74-year-old Caucasian man presented with head trauma at his local acute care hospital (level III/IV) in Canada at 2:30 PM. He was triaged at 4:00 PM and was seen by the emergency room physician at 4:50 PM. His vital signs were normal, and his Glasgow Coma Scale score was 15/15 upon admission. A computed tomography-based diagnosis of acute subdural hematoma was subsequently made by a radiologist at 5:00 PM. A neurosurgical transfer was requested to the nearby tertiary trauma center (level I/II), but was initially refused by the neurosurgical resident on call. The patient's condition slowly deteriorated until he became unconscious at 7:45 PM. The patient was intubated and transferred to the neurosurgical unit at 8:34 PM. He was seen by a consultant neurosurgeon at 9:30 PM, but surgery (craniotomy) was deemed not viable, given the patient's age and the fact that his pupils were now fixed and dilated (Glasgow Coma Scale score 3/15). The patient was taken off life support at 1:00 AM the following morning and died shortly thereafter. The patient's family made a formal complaint, but the decision by an independent medical review panel was that \"the patient's care was prudent, timely and professional.\"\n\n\nCONCLUSIONS\nGeriatric patients with severe head injury are less likely than their younger counterparts to be transferred to neurosurgical trauma centers. Protocol-driven care of the elderly can reduce mortality due to head trauma through the application of the Brain Trauma Foundation guidelines.",
"affiliations": "Griffith Health Institute, Griffith University, Gold Coast Campus, Gold Coast, Australia. a.ross@griffith.edu.au.",
"authors": "Ross|Allen G P|AG|",
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"doi": "10.1186/1752-1947-8-448",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 306410.1186/1752-1947-8-448Case ReportPrudent care of head trauma in the elderly: a case report Ross Allen GP a.ross@griffith.edu.au Griffith Health Institute, Griffith University, Gold Coast Campus, Gold Coast, Australia 20 12 2014 2014 8 44818 8 2014 11 11 2014 © Ross; licensee BioMed Central. 2014This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nSevere traumatic brain injury is a major public health problem that accounts for one-third of all deaths due to trauma in the United States. This case report illustrates some of the challenges faced by the elderly in accessing essential emergency services for traumatic brain injury.\n\nCase presentation\nA 74-year-old Caucasian man presented with head trauma at his local acute care hospital (level III/IV) in Canada at 2:30 PM. He was triaged at 4:00 PM and was seen by the emergency room physician at 4:50 PM. His vital signs were normal, and his Glasgow Coma Scale score was 15/15 upon admission. A computed tomography–based diagnosis of acute subdural hematoma was subsequently made by a radiologist at 5:00 PM. A neurosurgical transfer was requested to the nearby tertiary trauma center (level I/II), but was initially refused by the neurosurgical resident on call. The patient’s condition slowly deteriorated until he became unconscious at 7:45 PM. The patient was intubated and transferred to the neurosurgical unit at 8:34 PM. He was seen by a consultant neurosurgeon at 9:30 PM, but surgery (craniotomy) was deemed not viable, given the patient’s age and the fact that his pupils were now fixed and dilated (Glasgow Coma Scale score 3/15). The patient was taken off life support at 1:00 AM the following morning and died shortly thereafter. The patient’s family made a formal complaint, but the decision by an independent medical review panel was that “the patient’s care was prudent, timely and professional.”\n\nConclusions\nGeriatric patients with severe head injury are less likely than their younger counterparts to be transferred to neurosurgical trauma centers. Protocol-driven care of the elderly can reduce mortality due to head trauma through the application of the Brain Trauma Foundation guidelines.\n\nKeywords\nElderlyHealth disparitiesHealth policyTraumatic brain injuryissue-copyright-statement© The Author(s) 2014\n==== Body\nIntroduction\nGlobally, trauma ranks as the fourth leading cause of death overall and the leading cause of death among persons younger than 40 years of age [1, 2]. Each year more than 100 million people sustain traumatic injuries, resulting in close to 6 million premature deaths [1, 2]. Currently in Canada, there is an annual incidence of 200,000 patients hospitalized due to acute injury, with associated direct and indirect costs to the health-care system of close to $20 billion [2, 3].\n\nSevere traumatic brain injury (TBI) is a major public health problem that accounts for one-third of all deaths due to trauma in the United States [4]. TBI costs the Canadian government approximately $7 billion per year in terms of health-care expenditures [4]. Protocol-driven care can reduce mortality and costs due to severe TBI through the application of the Brain Trauma Foundation guidelines [4, 5]. However, only two-thirds of Canadian patients ever reach a level I/II trauma center to receive definitive care [4].\n\nDespite the Canada Health Act [6], which guarantees universal access to health care for all Canadians, significant challenges exist in delivering equitable access to trauma services across the country [3]. This case report illustrates some of the challenges faced in delivering trauma care, particularly to the elderly.\n\nCase presentation\nA 74-year-old retired Caucasian man sustained a large contusion at the base of his skull as a result of a fall at home. He presented with head trauma at 2:30 PM at his local acute care hospital in Canada (level III/IV trauma center serving a catchment population of approximately 120,000 people). The patient was taking several medications, including rosuvastatin calcium for cholesterol, hydrochlorothiazide for blood pressure and dual anti-platelet therapy with aspirin and clopidogrel for previous transient ischemic attacks.\n\nThe patient was triaged at 4:00 PM, and a neck collar was applied. He was moved to an emergency room bed at 4:29 PM. At 4:50 PM, he was seen by the emergency room physician. Upon admission, he was alert and responsive, and his vital signs (body temperature, 35.5°C; heart rate, 77 beats/min; respiratory rate, 20 breaths/min; blood pressure, 149/96 mmHg; oxygen saturation, 95%) were stable. A neurological assessment revealed a Glasgow Coma Scale (GCS) score of 15/15. His pupils were equal, round and reactive to light. In his extremities, strength, reflexes and sensation were normal and symmetrical. He had no pronator drift, no abnormal cerebellar signs and no abnormal Babinski reflex.\n\nGiven the mechanism of his injury, history of amnesia, emesis and clopidogrel use, a computed tomographic (CT) scan of the patient’s head was ordered at 4:55 PM. A large, subcutaneous hematoma extending from the posterior parietal occipital region to the upper neck was noted. He had a right-sided subdural hematoma extending from the occipital through to the frontal lobe and superoinferiorly from the convexity down to the temporal lobe region. He had an acute hemorrhage along the falx and tentorium and a crescenteric focus of hemorrhage in the left frontal and anterior parietal region extending inferiorly to the temporal region. Minimal effacement of the sulci and lateral ventricle on the right side were noted. His basal cisterns were maintained, and no evidence of blood was found in the suprasellar or quadrigeminal plate cistern. No definite parenchymal hematoma was identified. The radiologist made a diagnosis of acute subdural hematoma on the basis of the CT scan at 5:00 PM. The attending physician requested an immediate transfer to the neurosurgical service at the nearby tertiary trauma center (level I/II), situated 30 minutes away. The neurosurgical resident on call at the trauma center initially refused the transfer until he had time to review the CT images. The patient’s condition slowly deteriorated while awaiting treatment, and he became unconscious at 7:45 PM that evening. He was unresponsive, his pupils did not react to light and he had no response to pain. He was given mannitol to his lower intracerebral pressure, and he was intubated. He was approved for transfer at 8:34 PM. The patient was seen by the consultant neurosurgeon at 9:30 PM, but surgery (craniotomy) was deemed not viable, given the patient’s age and the fact that his pupils were now fixed and dilated (GCS score 3/15).\n\nThe patient was taken off life support at 1:00 AM the next morning, and he died approximately 15 minutes later. The autopsy report from the medical examiner stated that the patient’s cause of death was trauma as a result of a fall at home. The neuropathological findings were as follows: subdural hemorrhage, predominately right-sided with marked right-to-left midline shift; subfalcine and transtentorial herniation; intracerebral white matter hemorrhage, bilateral; and Duret (secondary) hemorrhages, extensive, upper brainstem, diencephalic and pons.\n\nThe patient’s family made a formal complaint to an independent medical review panel. The panel’s decision was that “[t]he patient’s care was prudent, timely and professional.” The family was told that there was no process for them to appeal.\n\nDiscussion\nIn the field of trauma, it is well known that the first hour after injury is the golden hour and that approximately 60% more lives can be saved if a patient is treated within that hour rather than later [7]. The elderly patient described in the present report waited with head trauma for 90 minutes before being triaged, and it took another 50 minutes until he was seen by an attending physician. Clearly, a “golden” opportunity to save his life was lost.\n\nIn Canada, as in many other countries in the developed world, the proportion of individuals 65 years of age and older is increasing. In Canada, the proportion of the elderly has doubled in the past 50 years, and they now number more than 5 million [7]. Research has shown that aggressive treatment of the elderly with survivable injuries results in the majority of them returning home, and 85% of these patients return to functional independence [7]. Moreover, the American College of Surgeons Committee on Trauma recommends that all trauma patients 65 years of age and older be considered for direct transport to a level I/II trauma center, regardless of injury severity [7, 8]. Despite these guidelines, however, evidence has shown that the undertriage of elderly patients to trauma centers is widespread [7], which is typified by the case of the patient reported here.\n\nConclusions\nHealth disparities occur in wealthy nations, which impacts on the provision of trauma services. Geriatric patients with severe head injuries are less likely than their younger counterparts to be transferred to neurosurgical trauma centers. However, protocol-driven care of the elderly can reduce mortality due to head trauma through the application of the Brain Trauma Foundation guidelines [5]. National trauma policies need to be put in place to ensure that elderly patients receive the quality of care they rightly deserve.\n\nConsent\nWritten informed consent was obtained from the patient’s next of kin for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nCTComputed tomography\n\nGCSGlasgow Coma Scale\n\nTBITraumatic brain injury.\n\nCompeting interests\n\nThe author declares that he has no competing interests.\n\nThe author thanks the National Health Medical Research Council of Australia for providing funding for his research.\n==== Refs\nReferences\n1. Dagal A Greer SE McCunn M International disparities in trauma care Curr Opin Anaesthesiol 2014 27 233 239 10.1097/ACO.0000000000000049 24514036 \n2. Hameed SM Schuurman N Razek T Boone D Van Heest R Taulu T Lakha N Evans DC Brown DR Kirkpatrick AW Stelfox HT Dyer D van Wijngaarden-Stephens M Logsetty S Nathens AB Charyk-Stewart T Rizoli S Tremblay LN Brenneman F Ahmed N Galbraith E Parry N Girotti MJ Pagliarello G Tze N Khwaja K Yanchar N Tallon JM Trenholm JA Tegart C Access to trauma systems in Canada J Trauma 2010 69 1350 1361 10.1097/TA.0b013e3181e751f7 20838258 \n3. Zakrison T Ball CG Kirkpatrick AW Trauma in Canada: a spirit of equity & collaboration World J Surg 2013 37 2086 2093 10.1007/s00268-013-2094-6 23652355 \n4. Sharma S Gomez D de Mestral C Hsiao M Rutka J Nathens AB Emergency access to neurosurgical care for patients with traumatic brain injury J Am Coll Surg 2014 218 51 57 10.1016/j.jamcollsurg.2013.10.005 24355876 \n5. Brain Trauma Foundation, American Association of Neurological Surgeons (AANS), Congress of Neurological Surgeons (CNS), AANS/CNS Joint Section on Neurotrauma and Critical Care Guidelines for the Management of Severe Traumatic Brain Injury 2007 3 New York Mary Ann Liebert \n6. Canada Health Act, RSC, 1985, c C-6. Updated through 29 October 2012. (accessed 19 November 2014) [http://laws-lois.justice.gc.ca/PDF/C-6.pdf]\n7. Moore L Turgeon AF Sirois MJ Lavoie A Trauma centre outcome performance: a comparison of young adults and geriatric patients in an inclusive trauma system Injury 2012 43 1580 1585 10.1016/j.injury.2011.02.010 21382620 \n8. Rotondo MF Cribari C Smith SS the Committee on Trauma, American College of Surgeons Resources for Optimal Care of the Injured Patient 2014 (v.1.1) 2014 6 Chicago American College of Surgeons\n\n",
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"mesh_terms": "D000368:Aged; D004632:Emergency Medical Services; D015577:Geriatric Assessment; D015600:Glasgow Coma Scale; D016489:Head Injuries, Closed; D006801:Humans; D015601:Injury Severity Score; D008297:Male; D019635:Neurosurgical Procedures; D010360:Patient Transfer; D011379:Prognosis; D014057:Tomography, X-Ray Computed; D014193:Trauma Centers; D014481:United States",
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"title": "Prudent care of head trauma in the elderly: a case report.",
"title_normalized": "prudent care of head trauma in the elderly a case report"
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"abstract": "Thrombotic thrombocytopenic purpura (TTP) is a rare disorder. Plasma exchange therapy has been shown to significantly reduce mortality in patients with TTP. Here, we report a case of TTP associated with ustekinumab therapy after a period of 2-3 years. Ustekinumab, a monoclonal antibody that inhibits interleukin 12 and interleukin 23, is one of the newer treatments for psoriasis. Although our patient experienced a prolonged course of TTP requiring 1 month of daily plasma exchange therapy, he recovered and remains in remission after 6 months.",
"affiliations": "The University of Western Ontario, Department of Medicine, Nephrology Division, and London Health Sciences Centre, London, Canada. shuang45@uwo.ca",
"authors": "Huang|Shih-Han S|SH|;Xenocostas|A|A|;Moist|L M|LM|;Crowther|M|M|;Moore|J C|JC|;Clark|W F|WF|",
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"title": "Ustekinumab associated thrombotic thrombocytopenic purpura.",
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"abstract": "A 69-year-old woman presented with acute kidney failure of unknown cause that ultimately required dialysis. Kidney biopsy revealed the diagnosis of oxalate nephropathy. In retrospect, the patient had several risk factors for this entity, including excessive vitamin C intake, a remote history of Roux-en-Y gastric bypass for weight loss, and chronic kidney disease. This presentation of multiple risk factors for oxalate nephropathy is especially relevant to patients and physicians considering the increase in the United States of vitamin C supplementation use and gastric bypass surgery. It is important for physicians to maintain an awareness of this diagnosis and its risk factors.",
"affiliations": "Saint Vincent Family Medicine Residency, Erie, PA. Electronic address: sunkara.vasu@gmail.com.;Saint Vincent Family Medicine Residency, Erie, PA.;Division of Nephrology, Saint Vincent Hospital, Erie, PA.;Department of Pathology, Ohio State University, Columbus, OH.",
"authors": "Sunkara|Vasu|V|;Pelkowski|Timothy D|TD|;Dreyfus|Darren|D|;Satoskar|Anjali|A|",
"chemical_list": "D002129:Calcium Oxalate; D001205:Ascorbic Acid",
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"keywords": "Oxalate; acute kidney failure; gastric bypass surgeries; oxalosis; vitamin C",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D001205:Ascorbic Acid; D001707:Biopsy, Needle; D002129:Calcium Oxalate; D004305:Dose-Response Relationship, Drug; D004636:Emergency Service, Hospital; D005260:Female; D005500:Follow-Up Studies; D015390:Gastric Bypass; D006801:Humans; D007150:Immunohistochemistry; D007677:Kidney Function Tests; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic; D018570:Risk Assessment; D016896:Treatment Outcome",
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"references": null,
"title": "Acute Kidney Disease Due to Excessive Vitamin C Ingestion and Remote Roux-en-Y Gastric Bypass Surgery Superimposed on CKD.",
"title_normalized": "acute kidney disease due to excessive vitamin c ingestion and remote roux en y gastric bypass surgery superimposed on ckd"
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"abstract": "BACKGROUND\nCalcium channel blockers and beta-blockers are among the most frequently ingested cardiovascular drugs in self-poisoning causing significant mortality. Intravenous lipid emulsion (ILE) is reported as a potentially novel antidote for treatment of acute poisoning caused by some of these drugs.\n\n\nMETHODS\nWe presented two cases of poisoning with these drugs. The case 1, a 24-year-old woman ingested amplodipine, metformin and gliclazide for self-poisoning. She presented with tachycardia and hypotension. Laboratory analyses revealed hyperglycaemia and metabolic acidosis. Despite the treatment which included fluid resuscitation, vasopressors, intravenous calcium, glucagon and ILE, circulatory shock occurred. The patient died 10 hours after admission due to cardiac arrest refractory to cardiopulmonary resuscitation. The case 2, a 41-year-old man, was found in a coma with empty packages of nifedipine, metoprolol and diazepam tablets. On admission vital signs included Glasgow Coma Scale (GCS) of 3, weak palpable pulses, undetectable blood pressure, and irregular breathing with oxygen saturation of 60%. An electrocardiography showed AV block (Mobitz II) with ventricular rate of 44/min with progression to third degree of AV block. In attempt to increase heart rate and blood pressure the following agents were administered: atropine boluses, normal saline with dopamine, glucagon, calcium chloride and ILE. Temporary transvenous pacemaker was placed, electrical capture was recorded, but without improvement in haemodynamics. Three hours after admission cardiac arrest happened and cardiopulmonary resuscitation was unsuccessful.\n\n\nCONCLUSIONS\nIntravenous lipid emulsion may be ineffective in acute poisonings with amlodipine, nifedipine or metoprolol.",
"affiliations": null,
"authors": "Jović-Stosić|Jasmina|J|;Putić|Vesna|V|;Zivanović|Dragan|D|;Mladenov|Milica|M|;Brajković|Gordana|G|;Djordjević|Snelana|S|",
"chemical_list": "D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D005217:Fat Emulsions, Intravenous; D017311:Amlodipine",
"country": "Serbia",
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"doi": "10.2298/vsp141216018j",
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"issue": "73(1)",
"journal": "Vojnosanitetski pregled",
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"mesh_terms": "D000328:Adult; D017311:Amlodipine; D002121:Calcium Channel Blockers; D066126:Cardiotoxicity; D004095:Dihydropyridines; D004630:Emergencies; D005217:Fat Emulsions, Intravenous; D017809:Fatal Outcome; D005260:Female; D006323:Heart Arrest; D006801:Humans; D008297:Male; D017211:Treatment Failure",
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"pubdate": "2016-01",
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"references": null,
"title": "Failure of intravenous lipid emulsion in treatment of cardiotoxicity caused by mixed overdose including dihydropyridine calcium channel blockers.",
"title_normalized": "failure of intravenous lipid emulsion in treatment of cardiotoxicity caused by mixed overdose including dihydropyridine calcium channel blockers"
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"abstract": "We describe a 7-week-old female infant who presented with refractory supraventricular tachycardia (SVT). During amiodarone infusion, she developed hypotension and cardiac arrest requiring extracorporeal membrane oxygenation (ECMO) support. After successful control of SVT using procainamide infusion, she was weaned from ECMO and discharged home on oral flecainide. We conclude that infants with acidosis, ventricular dysfunction, and prolonged refractory SVT may poorly tolerate intravenous amiodarone.",
"affiliations": "Department of Pediatrics, Division of Pediatric Cardiology, Doernbecher Children's Hospital, Oregon Health and Science University, Portland, U S A.;Department of Pediatrics, Division of Pediatric Cardiology, Doernbecher Children's Hospital, Oregon Health and Science University, Portland, U S A.",
"authors": "Saharan|Sunil|S|;Balaji|Seshadri|S|",
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"doi": "10.4103/0974-2069.149519",
"fulltext": "\n==== Front\nAnn Pediatr CardiolAnn Pediatr CardiolAPCAnnals of Pediatric Cardiology0974-20690974-5149Medknow Publications & Media Pvt Ltd India APC-8-5010.4103/0974-2069.149519Case ReportCardiovascular collapse during amiodarone infusion in a hemodynamically compromised child with refractory supraventricular tachycardia Saharan Sunil Balaji Seshadri Department of Pediatrics, Division of Pediatric Cardiology, Doernbecher Children's Hospital, Oregon Health and Science University, Portland, U S AAddress for correspondence: Dr. Sunil Saharan, Department of Pediatrics, Doernbecher Children's Hospital, 707 SW Gaines Road, Mail code: CDRC-P, Portland, OR, 97239, USA. E-mail: saharan@ohsu.eduJan-Apr 2015 8 1 50 52 Copyright: © Annals of Pediatric Cardiology2015This 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.We describe a 7-week-old female infant who presented with refractory supraventricular tachycardia (SVT). During amiodarone infusion, she developed hypotension and cardiac arrest requiring extracorporeal membrane oxygenation (ECMO) support. After successful control of SVT using procainamide infusion, she was weaned from ECMO and discharged home on oral flecainide. We conclude that infants with acidosis, ventricular dysfunction, and prolonged refractory SVT may poorly tolerate intravenous amiodarone.\n\nECMORefractorySVT\n==== Body\nINTRODUCTION\nMost SVT episodes can be terminated with vagal maneuvers or intravenous (IV) adenosine bolus. Rarely, SVT can be refractory to initial treatment with adenosine or be recurrent after only brief conversion.[1] There is no well-defined treatment algorithm for these cases.\n\nIntravenous amiodarone is a commonly used antiarrhythmic medication recommended for management of refractory arrhythmias in both pediatric and advanced life support algorithms (PALS, ALS).[23] The recommendation to use amiodarone for refractory arrhythmias in pediatric population is extrapolated from adult studies. The PALS algorithm is to consider either IV amiodarone (5 mg/kg IV/IO over 20-60 minutes and can be repeated twice) or procainamide for SVT if it does not respond to adenosine or electrical cardioversion. IV amiodarone does have adverse effects, including hypotension, acute liver dysfunction, and serious pulmonary toxicity.[4] There have been very few reported cases of cardiovascular collapse in literature following amiodarone infusion.[567] We report a case of severe cardiovascular collapse during amiodarone infusion that was rescued with ECMO and intravenous procainamide infusion.\n\nCASE REPORT\nA 7-week-old healthy female infant was admitted to an outside hospital with vomiting of two-week duration along with poor feeding and cold extremities noticed by her parents on the day of admission.\n\nAn initial diagnosis of SVT with left bundle branch block was made [Figure 1]. There was no evidence of either pre-excitation or non-conducted P waves on the electrocardiogram during brief periods of sinus rhythm, suggesting that it was due to an AV node-dependent mechanism. The presence of P waves suggested that it was likely due to a concealed accessory pathway [Figure 2]. The SVT briefly responded to multiple administrations of adenosine with immediate recurrence. Electrical cardioversion was not attempted because it was clear that “conversion” to sinus rhythm was not the limiting factor for this patient, and that the focus needed to be on the maintenance of sinus rhythm. Therefore, she was started on an esmolol infusion, after which she developed hypotension. At the same time, she was noted to have metabolic acidosis. At this point, she was intubated, started on mechanical ventilation, and transferred to our centre for further management.\n\nFigure 1 Narrow complex tachycardia with left bundle branch block\n\nFigure 2 Normal sinus rhythm following treatment.\n\nECMO: Extracorporeal membrane oxygenation, IV: Intravenous, PALS: Pediatric advanced life support, SVT: Supraventricular tachycardia\n\nDuring transport esmolol infusion was discontinued secondary to bradycardia and hypotension and with this, the SVT recurred. Upon arrival at our institution, the esmolol infusion was restarted, but she again developed hypotension with bradycardia; therefore, it was discontinued and an amiodarone bolus of 5 mg/kg was given IV over 60 minutes. This converted her rhythm from persistent SVT to intermittent runs of SVT. Since it appeared that amiodarone was helping to control the SVT, a second bolus of 5 mg/kg was started with a plan to infuse over 60 minutes. Throughout this time she had a significant metabolic acidosis with pH around 7.2 on the blood gas and lactate of above 15 mmol/L. Her echocardiogram showed severe left ventricular dysfunction while she was in sinus rhythm between episodes of SVT. During the second bolus of amiodarone she suddenly developed severe bradycardia and hypotension following which cardio-pulmonary resuscitation (CPR) was commenced. She was successfully placed on to venoarterial extra cardiac membrane oxygenation (ECMO) support. IV procainamide bolus (10 mg/kg) was given followed by an infusion initially at 20 mcg/kg/min with gradual increase to 60 mcg/kg/min (second bolus of 5 mg/kg in between) leading to conversion of SVT to sinus rhythm after about 14 hours from the initial bolus.\n\nShe was decannulated from the ECMO circuit on day 4 on infusions of milrinone and procainamide. On day 5, she was transitioned to oral flecainide followed by successful extubation from mechanical ventilation. A metabolic and genetic workup for cardiomyopathy was negative. During the hospital stay she also developed acute kidney injury, transient transaminitis, and thrombocytopenia all of which resolved gradually. She had normal biventricular function at discharge. At follow up 2 months post discharge, she has done well on oral flecainide and enalapril.\n\nDISCUSSION\nThere is no commonly accepted treatment regime for cases refractory to initial therapy of SVT using either vagal maneuvers or adenosine. Therapies used in the context of refractory SVT include IV and oral digoxin, IV and oral beta-blockers, oral flecainide, oral sotalol, IV procainamide, IV amiodarone, electrical cardioversion, and transesophageal overdrive pacing. Calcium channel blockers are now rarely used for acute refractory SVT in infancy as they were reported to cause acute collapse and even death in infants.[8] While IV sotalol is available, there has been very little experience with its use. Flecainide is available only in oral form in the United States. Furthermore, all the IV antiarrhythmic medications available except digoxin (beta blockers, calcium blockers, procainamide, sotalol, and amiodarone) can cause acute hypotension. While hypotension associated with amiodarone is well documented, few cases of cardiovascular collapse in neonates have been reported.[6]\n\nThere are no clear guidelines regarding management of hemodynamically unstable patients with refractory SVT other than PALS recommendation of use of amiodarone or procainamide.[2] Amiodarone is a complex drug with multiple mechanisms of action and has been called the “king” of antiarrhythmics. However, the pre-eminence of amiodarone has recently been questioned.[9]\n\nAmiodarone is thought to cause hypotension due to histamine release secondary to the solvent polysorbate 80.[10] Certain canine species, especially dogs, have been shown to be intolerant of this commonly used diluent, and some have suggested that it may be poorly tolerated by humans also.[11] Recently, a newer IV form of amiodarone (PM101) has been approved by FDA that uses cyclodextrin instead of polysorbate 80 and benzyl alcohol as solvent in order to reduce hemodynamic side effects and improve compatibility with other medications.[12]\n\nAmiodarone also has calcium channel-blocking properties, and infants have been shown to tolerate calcium channel blockers poorly.[13] A number of reports of cardiovascular collapse with IV verapamil led to recommendations against its use in infants.[814] Whether pre-treatment with IV calcium can mitigate the hemodynamic effects of amiodarone is not known. Our patient did not tolerate either esmolol or amiodarone, and this likely represents that the patient was in a fragile state with no cardiac output reserve. Radiofrequency ablation was not considered due to age and size of the child and also initial favorable response to intravenous amiodarone, which prompted us to administer the second bolus.\n\nWhile procainamide was successful in controlling the arrhythmia in our patient, it too can cause negative inotropy and be deleterious for patients with ventricular dysfunction.[15] In a recent paper, Chang et al. suggested that procainamide may be more successful in controlling SVT than amiodarone with no increase in adverse effect frequency.[16] However, as expounded in an accompanying editorial by Saul and LaPage, the study had many flaws and in particular, the two population groups were not uniformly distributed as more cases with underlying congenital heart disease were in the amiodarone group.[17]\n\nCONCLUSION\nOur case illustrates the potential dangers of using IV amiodarone in hemodynamically unstable infants with refractory SVT. It is possible that a newly released form of amiodarone (PM101) may avoid the adverse effects associated with the currently available form of amiodarone in children.\n\nSource of Support: Nil\n\nConflict of Interest: None declared\n==== Refs\nREFERENCES\n1 Salerno JC Seslar SP Supraventricular tachycardia Arch Pediatr Adolesc Med 2009 163 268 74 19255396 \n2 Kleinman ME Chameides L Schexnayder SM Samson RA Hazinski MF Atkins DL Part 14: Pediatric advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Circulation 2010 122 S876 908 20956230 \n3 Neumar RW Otto CW Link MS Kronick SL Shuster M Callaway CW Part 8: Adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Circulation 2010 122 S729 67 20956224 \n4 Connolly SJ Evidence-based analysis of amiodarone efficacy and safety Circulation 1999 100 2025 34 10556230 \n5 Veltri EP Reid PR Sinus arrest with intravenous amiodarone Am J Cardiol 1986 58 1110 1 3776867 \n6 Ng GY Hampson Evans DC Murdoch LJ Cardiovascular collapse after amiodarone administration in neonatal supraventicular tachycardia Eur J Emerg Med 2003 10 323 5 14676513 \n7 Jan SL Fu YC Lin MC Hwang B Precordial thump in a newborn with refractory supraventricular tachycardia and cardiovascular collapse after amiodarone administration Eur J Emerg Med 2012 19 128 9 22157128 \n8 Radford D Side effects of verapamil in infants Arch Dis Child 1983 58 465 6 6859944 \n9 Saul JP Scott WA Brown S Marantz P Acevedo V Etheridge SP Intravenous Amiodarone Pediatric Investigators. Intravenous amiodarone for incessant tachyarrhythmias in children: A randomized, double-blind, antiarrhythmic drug trial Circulation 2005 112 3470 7 16316969 \n10 Masini E Planchenault J Pezziardi F Gautier P Gagnol JP Histamine-releasing properties of Polysorbate 80 in vitro and in vivo : Correlation with its hypotensive action in the dog Agents Actions 1985 16 470 7 2416204 \n11 Munoz A Karila P Gallay P Zettelmeier F Messner P Mery M A randomized hemodynamic comparison of intravenous amiodarone with and without Tween 80 Eur Heart J 1988 9 142 8 3280316 \n12 Souney PF Cooper WD Cushing DJ PM101: Intravenous amiodarone formulation changes can improve medication safety Expert Opin Drug Saf 2010 9 319 33 20074019 \n13 Epstein ML Kiel EA Victorica BE Cardiac decompensation following verapamil therapy in infants with supraventricular tachycardia Pediatrics 1985 75 737 40 3982906 \n14 Perry JC Garson A Jr Diagnosis and treatment of arrhythmias Adv Pediatr 1989 36 177 99 2675568 \n15 Chapman MJ Moran JL O’Fathartaigh MS Peisach AR Cunningham DN Management of atrial tachyarrhythmias in the critically ill: A comparison of intravenous procainamide and amiodarone Intensive Care Med 1993 19 48 52 8440799 \n16 Chang PM Silka MJ Moromisato DY Bar-Cohen Y Amiodarone versus procainamide for the acute treatment of recurrent supraventricular tachycardia in pediatric patients Circ Arrhythm Electrophysiol 2010 3 134 40 20194798 \n17 Saul JP LaPage MJ Is it time to tell the emperor he has no clothes?: Intravenous amiodarone for supraventricular arrhythmias in children Circ Arrhythm Electrophysiol 2010 3 115 7 20407103\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0974-5149",
"issue": "8(1)",
"journal": "Annals of pediatric cardiology",
"keywords": "ECMO; Refractory; SVT",
"medline_ta": "Ann Pediatr Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101495459",
"other_id": null,
"pages": "50-2",
"pmc": null,
"pmid": "25684888",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "3776867;8440799;2416204;22157128;20956224;20407103;14676513;20074019;3982906;19255396;2675568;6859944;20956230;16316969;3280316;20194798;10556230",
"title": "Cardiovascular collapse during amiodarone infusion in a hemodynamically compromised child with refractory supraventricular tachycardia.",
"title_normalized": "cardiovascular collapse during amiodarone infusion in a hemodynamically compromised child with refractory supraventricular tachycardia"
} | [
{
"companynumb": "US-MYLANLABS-2015M1007103",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMIODARONE"
},
"drugadditional": null,
... |
{
"abstract": "BRAF V600E mutations occur in approximately 40% of all patients with papillary thyroid cancer (PTC) and are associated with a worse prognosis in population studies. Treatment with single-agent BRAF inhibitors can result in nondurable partial responses (PRs) in clinical trials, but resistance inevitably develops. The mechanisms of resistance are not completely understood, but in non-thyroid tumors harboring BRAF V600E mutations, resistance has been ascribed to concurrent or acquired mutations in MEK1/2, RAC1, KRAS, and NRAS. This case report describes a patient with radioactive iodine-refractory metastatic PTC treated in a clinical trial with combination BRAF and MEK inhibition who achieved a durable PR. At time of progression, biopsy revealed an acquired KRAS G12V-activating mutation. The patient subsequently went on to have a PR to cabozantinib therapy in the clinical trial. This is the first reported case of an acquired KRAS-activating mutation that developed during treatment with BRAF and MEK inhibition in a patient with BRAF-mutated PTC. The KRAS mutation was also detected in peripheral blood samples taken as part of the trial, indicating that resistant mutations may be identified through noninvasive means. The identification of resistant mutations in patients at time of progression is necessary to identify possible therapeutic options including potential clinical trials.ClinicalTrials.gov identifier: NCT01723202.",
"affiliations": "Division of Medical Oncology.;Division of Medical Oncology.;Division of Endocrinology, Diabetes, and Metabolism.;Solid Tumor Translational Service, and.;Department of Biomedical Information, The Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Columbus, Ohio; and.;Division of Endocrinology, Diabetes, and Metabolism.;Solid Tumor Translational Service, and.;Division of Medical Oncology.",
"authors": "Owen|Dwight H|DH|;Konda|Bhavana|B|;Sipos|Jennifer|J|;Liu|Tom|T|;Webb|Amy|A|;Ringel|Matthew D|MD|;Timmers|Cynthia D|CD|;Shah|Manisha H|MH|",
"chemical_list": "D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1540-1405",
"issue": "17(5)",
"journal": "Journal of the National Comprehensive Cancer Network : JNCCN",
"keywords": null,
"medline_ta": "J Natl Compr Canc Netw",
"mesh_terms": "D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D014408:Biomarkers, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases; D009154:Mutation; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D000077273:Thyroid Cancer, Papillary; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101162515",
"other_id": null,
"pages": "409-413",
"pmc": null,
"pmid": "31085763",
"pubdate": "2019-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "16174717;17126425;19156774;19255327;19883729;21196179;22007339;22402123;22437314;23020132;23406027;24265154;24463458;24768112;25265492;25285888;25549723;25671254;25673644;25977330;26456083;26608120;26636651;27127178;27312529;27460442;27525386;28423638;29431699;29742974;29996921;30256977",
"title": "KRAS G12V Mutation in Acquired Resistance to Combined BRAF and MEK Inhibition in Papillary Thyroid Cancer.",
"title_normalized": "kras g12v mutation in acquired resistance to combined braf and mek inhibition in papillary thyroid cancer"
} | [
{
"companynumb": "US-BAYER-2019-145649",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nDocetaxel-cisplatin-5-FU chemotherapy is superior to 5-FU-cisplatin in terms of response rate and survival in advanced gastric cancer (AGC), but is more toxic. Oxaliplatin is better tolerated than cisplatin, which it can effectively replace in this setting. We hypothesize that incorporating docetaxel into a simplified FOLFOX regimen should be a tolerable and effective option in first-line treatment of AGC.\n\n\nMETHODS\nData were collected at six French centers from patients with metastatic or local AGC who received docetaxel, fluorouracil, leucovorin, or oxaliplatin (TEF) as first-line treatment. TEF was administered as follows: docetaxel (50 mg/m(2)), oxaliplatin (85 mg/m(2)), and leucovorin (40 mg/m(2)) on day 1, and 5-FU continuous infusion for 48 h (2400 mg/m(2)) every 2 weeks.\n\n\nRESULTS\nForty-one patients were enrolled. Performance status was grade 0 and 1 in respectively 27 and 58 % of patients; 17 patients had adenocarcinoma of the gastroesophageal junction; 37 patients had metastatic disease, 22 had a poorly differentiated or diffuse type. Objective response rate was 66 %, with a complete response in two patients (5 %). Median progression-free survival and overall survival were respectively 6.3 and 12.1 months. Tolerability was acceptable with no treatment-related deaths. The most frequent grade 3-4 toxicities were neutropenia (30 %) and neuropathy (12.5 %). Curative intent surgery after response to TEF was performed in seven patients (17 %).\n\n\nCONCLUSIONS\nTEF is an effective first-line treatment with an acceptable toxicity profile for patients with AGC. It may allow curative resection in initially unresectable patients. TEF should now be evaluated in prospective randomized trials.",
"affiliations": "HEGP, APHP, Paris Sorbonne Cité, Université Paris Descartes, Paris, France, simon.pernot@gmail.com.",
"authors": "Pernot|Simon|S|;Mitry|Emmanuel|E|;Samalin|Emmanuelle|E|;Dahan|Laetitia|L|;Dalban|Cécile|C|;Ychou|Marc|M|;Seitz|Jean-François|JF|;Turki|Hajer|H|;Mazard|Thibault|T|;Zaanan|Aziz|A|;Lepère|Céline|C|;Vaillant|Jean-Nicolas|JN|;Landi|Bruno|B|;Rougier|Philippe|P|;Taieb|Julien|J|",
"chemical_list": "D009944:Organoplatinum Compounds; D043823:Taxoids; D000077150:Oxaliplatin; D000077143:Docetaxel; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10120-013-0266-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1436-3291",
"issue": "17(2)",
"journal": "Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association",
"keywords": null,
"medline_ta": "Gastric Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000077143:Docetaxel; D004943:Esophagogastric Junction; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D002955:Leucovorin; D008297:Male; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011379:Prognosis; D011446:Prospective Studies; D013274:Stomach Neoplasms; D015996:Survival Rate; D043823:Taxoids",
"nlm_unique_id": "100886238",
"other_id": null,
"pages": "341-7",
"pmc": null,
"pmid": "23739764",
"pubdate": "2014-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "20728210;16782930;18669868;20108336;17660494;18172173;17075117;8996151;7999410;11956258;23063354;22005144;20555102;20068567;25416687;17664467;19153121;10390007;15111344;18349393",
"title": "Biweekly docetaxel, fluorouracil, leucovorin, oxaliplatin (TEF) as first-line treatment for advanced gastric cancer and adenocarcinoma of the gastroesophageal junction: safety and efficacy in a multicenter cohort.",
"title_normalized": "biweekly docetaxel fluorouracil leucovorin oxaliplatin tef as first line treatment for advanced gastric cancer and adenocarcinoma of the gastroesophageal junction safety and efficacy in a multicenter cohort"
} | [
{
"companynumb": "FR-TEVA-530624ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nTo investigate potential drug-drug interactions between clobazam and cytochrome P450 (CYP) isoenzyme substrates, inhibitors, and inducers.\n\n\nMETHODS\nTwo, prospective, open-label, single-center, drug-drug interaction (DDI) studies and a population pharmacokinetics analysis of seven multicenter phase II-III trials.\n\n\nMETHODS\nClinical research unit.\n\n\nMETHODS\nFifty-four healthy adult volunteers were enrolled in the two drug-drug interaction studies; 53 completed the studies. The population pharmacokinetics analysis evaluated data from 171 participants from five studies with healthy volunteers and two studies with patients with Lennox-Gastaut syndrome. Participants in these studies received clobazam and stable dosages of the following antiepileptic drugs: phenobarbital, phenytoin, carbamazepine, valproic acid, lamotrigine, felbamate, or oxcarbazepine.\n\n\nMETHODS\nIn the first drug-drug interaction study, 36 participants received a single oral dose of clobazam 10 mg on day 1, followed by either ketoconazole 400 mg once/day or omeprazole 40 mg once/day on days 17-22, with a single dose of clobazam 10 mg coadministered on day 22, to study the effects of CYP3A4 or CYP2C19 inhibition, respectively, on clobazam and its active metabolite N-desmethylclobazam (N-CLB). In the second study, 18 participants received a drug cocktail consisting of caffeine 200 mg, tolbutamide 500 mg, dextromethorphan 30 mg, and midazolam 4 mg on days 1 and 19, and clobazam 40 mg/day on days 4-19, to study clobazam's effects on CYP1A2, CYP2C9, CYP2D6, and CYP3A4.\n\n\nRESULTS\nIn the first DDI study, coadministration of ketoconazole (a CYP3A4 inhibitor) and clobazam increased clobazam's area under the concentration time curve from time zero extrapolated to infinity (AUC(0-∞) ) 54% and decreased clobazam's maximum plasma concentration (C(max) ) by 15% versus administration of clobazam alone, but the combination affected these pharmacokinetic parameters for N-CLB to a lesser degree. The CYP2C19 inhibitor omeprazole increased AUC(0-∞) and C(max) of N-CLB by 36% and 15%, respectively, but did not significantly affect the pharmacokinetics of clobazam. At steady state, N-CLB has 3-4 times greater exposure than clobazam. In the second DDI study, no clinically significant drug-drug interactions were observed between clobazam 40 mg and the CYP probe substrates caffeine or tolbutamide. Exposure to midazolam and its 1-hydroxymidazolam metabolite, however, decreased by 27% and increased 4-fold, respectively. Clobazam increased dextromethorphan (CYP2D6) AUC(0-∞) by 95% and C(max) by 59%. In the population pharmacokinetics analysis, stable dosages of common antiepileptic drugs that induce CYP3A4 or CYP2C19, or inhibit CYP2C19, had negligible effects on clobazam or N-CLB. Clobazam did not affect valproic acid or lamotrigine exposures.\n\n\nCONCLUSIONS\nThese findings suggest no clinically meaningful drug-drug interactions between clobazam and drugs metabolized by CYP3A4, CYP2C19, CYP1A2, or CYP2C9. Concomitant use of drugs metabolized by CYP2D6 may require dosage adjustment. Clobazam may be administered safely as adjunctive therapy in patients with Lennox-Gastaut syndrome, without meaningful changes in clobazam pharmacokinetics that would require dosage adjustment.",
"affiliations": "Lundbeck LLC, Deerfield, Illinois 60015, USA.",
"authors": "Walzer|Mark|M|;Bekersky|Ihor|I|;Blum|Robert A|RA|;Tolbert|Dwain|D|",
"chemical_list": "D000927:Anticonvulsants; D000697:Central Nervous System Stimulants; D006993:Hypnotics and Sedatives; D007004:Hypoglycemic Agents; D007527:Isoenzymes; D014227:Triazines; D001569:Benzodiazepines; D000078306:Clobazam; D002110:Caffeine; D014635:Valproic Acid; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D008874:Midazolam; D000077213:Lamotrigine",
"country": "United States",
"delete": false,
"doi": "10.1002/j.1875-9114.2012.01028.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "32(4)",
"journal": "Pharmacotherapy",
"keywords": null,
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D019540:Area Under Curve; D001569:Benzodiazepines; D002110:Caffeine; D000697:Central Nervous System Stimulants; D017321:Clinical Trials, Phase I as Topic; D000078306:Clobazam; D003577:Cytochrome P-450 Enzyme System; D003915:Dextromethorphan; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D007004:Hypoglycemic Agents; D007527:Isoenzymes; D000077213:Lamotrigine; D008297:Male; D008874:Midazolam; D008875:Middle Aged; D015233:Models, Statistical; D010599:Pharmacokinetics; D011446:Prospective Studies; D014044:Tolbutamide; D014227:Triazines; D014635:Valproic Acid; D055815:Young Adult",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "340-53",
"pmc": null,
"pmid": "22422635",
"pubdate": "2012-04",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pharmacokinetic drug interactions between clobazam and drugs metabolized by cytochrome P450 isoenzymes.",
"title_normalized": "pharmacokinetic drug interactions between clobazam and drugs metabolized by cytochrome p450 isoenzymes"
} | [
{
"companynumb": "US-JNJFOC-20120902633",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CLOBAZAM"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nGuidelines for preventing Pneumocystis pneumonia (PCP) in HIV patients are based on CD4 below 200/mm3. Such cut-off value is suggested to guide prophylaxis in non-HIV conditions (NHIV) especially in autoimmune and inflammatory diseases (AD). We aimed to determine if CD4 could be used to guide PCP prophylaxis in AD.\n\n\nMETHODS\nCD4 and lymphocyte-count were retrospectively studied in patients diagnosed with PCP between January 2013 and February 2016.\n\n\nRESULTS\n129 patients were included. The median CD4-count was 302/mm3 in AD, which was significantly higher than in HIV patients (19/mm3; p<0.0001). Fifty percent (n=10) of AD patients had CD4 counts greater than 300/mm3.\n\n\nCONCLUSIONS\nProphylaxis for PCP cannot rely solely on CD4-count in NHIV patients especially in AD.",
"affiliations": "Department of Clinical Immunology,Saint-André Hospital, CHU de Bordeaux, France. gildas.baulier@chu-bordeaux.fr.;Department of Infectious Diseases, Saint-André Hospital, CHU de Bordeaux, France.;Department of Mycology and Parasitology, Pellegrin Hospital, CHU de Bordeaux, France.;Department of Mycology and Parasitology, Pellegrin Hospital, CHU de Bordeaux, France.;Intensive Care Unit, Saint-André Hospital, CHU de Bordeaux, France.;Department of Clinical Immunology,Saint-André Hospital, CHU de Bordeaux, France.",
"authors": "Baulier|Gildas|G|;Issa|Nahema|N|;Gabriel|Frederic|F|;Accoceberry|Isabelle|I|;Camou|Fabrice|F|;Duffau|Pierre|P|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-856X",
"issue": "36(3)",
"journal": "Clinical and experimental rheumatology",
"keywords": null,
"medline_ta": "Clin Exp Rheumatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D001172:Arthritis, Rheumatoid; D001327:Autoimmune Diseases; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes; D003449:Cryoglobulinemia; D003882:Dermatomyositis; D019468:Disease Management; D005260:Female; D013700:Giant Cell Arteritis; D015658:HIV Infections; D019693:Hepatitis, Autoimmune; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008231:Lymphopenia; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D016377:Organ Transplantation; D011020:Pneumonia, Pneumocystis; D017410:Practice Guidelines as Topic; D012189:Retrospective Studies",
"nlm_unique_id": "8308521",
"other_id": null,
"pages": "490-493",
"pmc": null,
"pmid": "29533748",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Guidelines for prophylaxis of Pneumocystis pneumonia cannot rely solely on CD4-cell count in autoimmune and inflammatory diseases.",
"title_normalized": "guidelines for prophylaxis of pneumocystis pneumonia cannot rely solely on cd4 cell count in autoimmune and inflammatory diseases"
} | [
{
"companynumb": "FR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-292299",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"dr... |
{
"abstract": "This study investigated specific substances most commonly involved in suicidal poisonings, causing severe clinical effects, and leading to intensive treatments.\n\n\n\nSuicidal poisoning cases for individuals ≥13 years old were obtained from the National Poison Data System for 2011-2015. The most common products involved in single and multiple-product poisonings were identified. Single product cases were used to calculate substances causing the largest numbers of serious clinical effects and leading to intensive treatments.\n\n\n\nMore than half of reported cases involved only a single product (54.4%), but this frequency was higher at the extremes of age (66.7% in adolescents 13-19 years old and 70.5% in individuals ≥90 years old) and among pregnant women (65.8%). The top three substances involved in single-product poisonings were over-the-counter (OTC) medications, while alcohol and prescription sedatives were most common in multiple-product poisonings. One OTC medication, diphenhydramine, was a frequent cause of several serious clinical effects and intensive treatments.\n\n\n\nSingle product suicidal poisonings were more frequent with extremes of age and in pregnancy. OTC products were more frequently used in single product attempts. Products causing serious clinical effects can be targeted for suicide prevention efforts as well as education of health care providers.",
"affiliations": "Department of Child Health and Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ, USA.",
"authors": "Kang|Aaron Min|AM|0000-0001-7784-0655",
"chemical_list": "D015386:Hazardous Substances",
"country": "England",
"delete": false,
"doi": "10.1111/sltb.12525",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-0234",
"issue": "49(5)",
"journal": "Suicide & life-threatening behavior",
"keywords": null,
"medline_ta": "Suicide Life Threat Behav",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016208:Databases, Factual; D005260:Female; D015386:Hazardous Substances; D006801:Humans; D008297:Male; D008875:Middle Aged; D011041:Poisoning; D011247:Pregnancy; D013405:Suicide; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "7608054",
"other_id": null,
"pages": "1307-1317",
"pmc": null,
"pmid": "30430638",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Substances Involved in Suicidal Poisonings in the United States.",
"title_normalized": "substances involved in suicidal poisonings in the united states"
} | [
{
"companynumb": "US-CADILA HEALTHCARE LIMITED-US-ZYDUS-049843",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
... |
{
"abstract": "We present Shewanella algea infection in a chronic suppurative otitis media (CSOM) patient with cholesteatoma in terms of clinical course and treatment. This is the first time S. algea is found as solely pathogen in a CSOM patient without history of contact with seawater in Turkey. The patient admitted to the hospital several times with complaints of otorrhoea, was diagnosed as otitis media and treated. He was hospitalized to the otorhinolaryngology department for further evaluation of recurrent infections. The patient was diagnosed as cholesteatoma according to computed tomography scan findings and was operated for cholesteatoma. As a result of surgical and medical treatment he was discharged with full recovery. Physicians must be aware of rarely seen pathogens and their unexpected ways of transmission and underlying causes such as cholesteatoma when treating patients for CSOM.",
"affiliations": "Department of Medical Biology, Bahcesehir University School of Medicine.;Department of Biochemistry, Bahcesehir University School of Medicine.;Department of Microbiology, Derince Training and Research Hospital.;Department of Otolaryngology, Derince Training and Research Hospital.",
"authors": "Ignak|Seyda|S|;Unay Demirel|Ozlem|O|;Soydan|Sevda|S|;Esen|Erkan|E|",
"chemical_list": "D002939:Ciprofloxacin",
"country": "Japan",
"delete": false,
"doi": "10.5582/ddt.2018.01014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1881-7831",
"issue": "12(2)",
"journal": "Drug discoveries & therapeutics",
"keywords": "Shewanella; cholesteatoma; chronic suppurative otitis media",
"medline_ta": "Drug Discov Ther",
"mesh_terms": "D000328:Adult; D018424:Cholesteatoma, Middle Ear; D002939:Ciprofloxacin; D006801:Humans; D008297:Male; D010035:Otitis Media, Suppurative; D013517:Otorhinolaryngologic Surgical Procedures; D020592:Shewanella; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101493809",
"other_id": null,
"pages": "108-110",
"pmc": null,
"pmid": "29681564",
"pubdate": "2018-05-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Shewanella algae in a chronic suppurative otitis media patient with cholesteatoma.",
"title_normalized": "shewanella algae in a chronic suppurative otitis media patient with cholesteatoma"
} | [
{
"companynumb": "TR-BAUSCH-BL-2018-020246",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPICILLIN SODIUM\\SULBACTAM SODIUM"
},
"druga... |
{
"abstract": "OBJECTIVE\nTo present five patients with zolpidem-induced sleep-related behavioural disorders.\n\n\nMETHODS\nEvaluation using a questionnaire designed to study sleep behaviours and past medical history in all patients.\n\n\nRESULTS\nThe patients performed complex actions while sleep-walking (telephoning, house-cleaning, feeding the dog or waxing their legs). Inappropriate feeding behaviour with excessive food intake during the night were reported by all patients. All had weight gain, which in one patient led to extreme obesity. Two patients suffered injuries (knife cuts and burns) related to attempting to prepare food. One patient took a laxative.\n\n\nCONCLUSIONS\nWithdrawal of zolpidem resolved the behaviours in all cases, highlighting the importance of an adequate diagnosis of this side effect.",
"affiliations": "Servicio de Neurologia y Unidad Multidisciplinar de Trastornos del Sueño, Hospital Clinico de Barcelona, Barcelona, Spain.",
"authors": "Pérez-Díaz|H|H|;Iranzo|A|A|;Santamaría|J|J|",
"chemical_list": "D006993:Hypnotics and Sedatives; D011725:Pyridines; D000077334:Zolpidem",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0213-4853",
"issue": "25(8)",
"journal": "Neurologia (Barcelona, Spain)",
"keywords": null,
"medline_ta": "Neurologia",
"mesh_terms": "D000328:Adult; D000368:Aged; D000818:Animals; D001519:Behavior; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D008875:Middle Aged; D009765:Obesity; D011725:Pyridines; D012890:Sleep; D012893:Sleep Wake Disorders; D011795:Surveys and Questionnaires; D015430:Weight Gain; D000077334:Zolpidem",
"nlm_unique_id": "9005460",
"other_id": null,
"pages": "491-7",
"pmc": null,
"pmid": "20965000",
"pubdate": "2010-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Zolpidem-induced sleep-related behavioural disorders.",
"title_normalized": "zolpidem induced sleep related behavioural disorders"
} | [
{
"companynumb": "ES-AUROBINDO-AUR-APL-2019-092898",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLPIDEM TARTRATE"
},
"drugadditional"... |
{
"abstract": "Multiple sclerosis (MS) is an immune mediated inflammatory disease that attacks myelinated axons in the central nervous system. Dalfampridine (4-aminopyridine) was approved by the Food and Drug Administration in January 2010 for treatment of MS. Our patient was a 34-year-old male with a history of MS, who was brought to the emergency department after being found unresponsive. His current medications were valacyclovir, temazepam, dalfampridine (4-AP) and a tysabri intravenous (IV) infusion. Fifteen minutes after arrival the patient seized. The seizures were refractory to benzodiazepines, barbiturates and phenytoin. The 4-AP level was 530 ng/mL (25 ng/mL and 49 ng/mL). The patient stopped seizing on hospital day 3 and was discharged 14 days later with normal mental status and neurologic exam. 4-AP is a potassium channel blocker that blocks the potassium ion current of repolarization following an action potential. The blockade of the potassium channel at the level of the membrane widens the action potential and enhances the release of acetylcholine, thus increasing post-synaptic action potentials. The treatment of patients with 4-AP overdose is supportive. Animal data suggest that patients with toxic levels of 4-AP may respond to phenytoin. Our case illustrates the highest recorded level of 4-AP in an overdose. Our patient appeared to be refractory to a combination of high doses of anticonvulsants and only improved with time.",
"affiliations": "North Shore University Hospital, Department of Emergency Medicine, Manhasset, New York.;Long Island Jewish Medical Center, Department of Emergency Medicine, New Hyde Park, New York.;Good Samaritan Hospital, Department of Emergency Medicine, West Islip, New York.",
"authors": "Fil|Laura J|LJ|;Sud|Payal|P|;Sattler|Steven|S|",
"chemical_list": "D000927:Anticonvulsants; D026902:Potassium Channel Blockers; D001569:Benzodiazepines; D015761:4-Aminopyridine",
"country": "United States",
"delete": false,
"doi": "10.5811/westjem.2015.8.26127",
"fulltext": "\n==== Front\nWest J Emerg MedWest J Emerg MedWestJEMWestern Journal of Emergency Medicine1936-900X1936-9018Department of Emergency Medicine, University of California, Irvine School of Medicine 10.5811/westjem.2015.8.26127wjem-16-1177Diagnostic AcumenCase ReportA Massive Overdose of Dalfampridine Fil Laura J. DO*Sud Payal MD†Sattler Steven DO‡* North Shore University Hospital, Department of Emergency Medicine, Manhasset, New York† Long Island Jewish Medical Center, Department of Emergency Medicine, New Hyde Park, New York‡ Good Samaritan Hospital, Department of Emergency Medicine, West Islip, New YorkAddress for Correspondence: Laura J Fil, DO, North Shore University Hospital, Department of Emergency Medicine, Manhasset, NY 11030. Email: LauraJFil@gmail.com.12 2015 03 12 2015 16 7 1177 1179 31 3 2015 31 7 2015 19 8 2015 Copyright © 2015 Fil et al.2015This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/Multiple sclerosis (MS) is an immune mediated inflammatory disease that attacks myelinated axons in the central nervous system. Dalfampridine (4-aminopyridine) was approved by the Food and Drug Administration in January 2010 for treatment of MS. Our patient was a 34-year-old male with a history of MS, who was brought to the emergency department after being found unresponsive. His current medications were valacyclovir, temazepam, dalfampridine (4-AP) and a tysabri intravenous (IV) infusion. Fifteen minutes after arrival the patient seized. The seizures were refractory to benzodiazepines, barbiturates and phenytoin. The 4-AP level was 530ng/mL (25ng/mL and 49ng/mL). The patient stopped seizing on hospital day 3 and was discharged 14 days later with normal mental status and neurologic exam. 4-AP is a potassium channel blocker that blocks the potassium ion current of repolarization following an action potential. The blockade of the potassium channel at the level of the membrane widens the action potential and enhances the release of acetylcholine, thus increasing post-synaptic action potentials. The treatment of patients with 4-AP overdose is supportive. Animal data suggest that patients with toxic levels of 4-AP may respond to phenytoin. Our case illustrates the highest recorded level of 4-AP in an overdose. Our patient appeared to be refractory to a combination of high doses of anticonvulsants and only improved with time.\n==== Body\nINTRODUCTION\nMultiple sclerosis (MS) is an immune-mediated inflammatory disease that attacks myelinated axons in the central nervous system. It is characterized by short-term episodes of neurologic deficits that usually resolve completely or almost completely. Patients with MS may suffer from pain due to spasticity, fatigue and progressive disability.1 There is currently no cure for the disease, but a plethora of treatments are available and are continuously being developed.\n\nOne of the more novel medications on the market is dalfampridine, or 4-aminopyridine (4-AP). 4-AP was originally developed to be used as an avicide. The chemical was studied in mammals and was shown to cause hyperexcitability, hypersalivation, tremors, muscle incoordination, convulsions, cardiac or respiratory distress.2\n\n4-AP acts as a voltage-gated potassium channel blocker that blocks the potassium ion current of repolarization in an axon following an action potential. Potassium efflux out of the axon is the ionic mechanism that results in repolarization of the axon. Repolarization must occur before the axon can generate another action potential. In MS, the myelin sheath is thinned and this results in either a weakened signal when the action potential reaches its destination or a complete block. This leads to weakness and fatigability of strength.3 The blockade of the potassium channel widens the action potential, and thus 4-AP increases the conduction of action potentials and this leads to increased strength.2 Due to the ability of 4-AP to reverse synaptic blockade it has been used as a treatment in many different neuromuscular disorders such as Alzheimer’s disease, botulism, Eaton Lambert syndrome and multiple sclerosis.4 In January 2010, 4-AP was approved by the FDA in the United States under the name dalfampridine to help patients with MS improve their gait and strength when walking.5\n\nThere are always new medications being developed for the treatment of MS, a disease with many potential comorbidities; among them, depression is the most notable. This occurs in part because MS is a chronic disease and also there are theories that it occurs because of frontal or subcortical white matter disease.6 Here we present a case of a 4-AP overdose with the highest reported level in the literature.\n\nCASE REPORT\nA 34-year-old male with a past medical history of MS was brought into the emergency department by Emergency Medical Services after being found unresponsive by his mother with three pill bottles at his side. The bottles were an empty bottle of valacyclovir, an empty bottle of temazepam and a bottle of dalfampridine still containing some pills. His mother gave the history that the patient was under multiple social stressors of late. Other than MS, the patient was diagnosed with insomnia and had no other pertinent past medical history. His current medications were valacyclovir, temazepam, dalfampridine (4-AP) and a tysabri IV infusion (all part of his MS treatment regimen).\n\nThe initial vital signs were as follows: Blood pressure: 155/82mmHg; Heart rate: 106/min; Respiratory rate: 24/min; Temperature: 97.4ºF; O2 sat: 97% 2L NC. The bedside glucose was 144mg/dl. The patient appeared extremely tremulous, was awake, but not responding to questioning nor following simple commands. He responded to tactile stimulation by localizing to the pain. He did not appear to have any focal deficits. His pupils were 4 mm, equal and reactive and his mucous membranes were moist. His heart sounds were tachycardic, with no murmurs. The patient had clear breath sounds bilaterally and no retractions. The abdomen had normoactive bowel sounds. The skin was diaphoretic with piloerection.\n\nIntravenous access was established, labs were drawn and the patient was given two liters of normal saline. Soon after arrival, the patient lost consciousness, his oxygen saturation decreased to below 90% and he began to have a tonic-clonic seizure. The patient was administered boluses of lorazepam, to a total of 8 mg, without effect in seizure resolution. He was intubated and subsequently placed on a lorazepam and propofol infusion for sedation. He was loaded with one gram of phenytoin and 300mg phenobarbital and then placed on a phenobarbital infusion. Clinically the patient continued to have frequent, recurrent seizures.\n\nThe patients lab values on arrival were significant for a white blood cell count of 31.1×103/mcL, a sodium of 143mEq/L, potassium 3.1mEq/L, chloride 107mEq/L, bicarbonate of 24mEq/L, a blood urea nitrogen of 15mg/dL and a creatinine of 1.2mg/dL. The anion gap was 12. The lactic acid was 3.4mg/dl. Total creatinine kinase was 99 units/L. Liver function tests and coagulation studies were all within normal limits. Ethanol, acetaminophen and salicylate levels were all negative. A urine toxicology screen was positive for benzodiazepines. An arterial blood gas showed pH 7.22, pCO2 65, pO2 127 and HCO3 26.6 (performed immediately after intubation). Computerized tomography of the brain and chest x-ray were both normal. The electrocardiogram showed a sinus rhythm at 88 beats per minute with normal QRS and QT intervals. Drug levels were sent for 4-AP and valacyclovir. The 4-AP level resulted at 530ng/mL (therapeutic: 25 to 49ng/mL). The valacyclovir level was 7.5mcg/mL (therapeutic 2.0–4.0mcg/mL).\n\nThe patient was admitted to the intensive care unit (ICU) and while he was there he continued to have seizures. While in the ICU the patient had two electroencephalographs (EEGs) performed. The EEG on hospital day 2 showed epileptiform activity and the other EEG was performed on hospital day 7 and was indicative of epileptiform encephalopathy.\n\nThe patient stopped seizing on hospital day 3. The patient was extubated on hospital day 12. He was discharged, with normal mental status and neurologic exam to an inpatient psychiatric facility.\n\nDISCUSSION\nDue to the fact that 4-AP is not a commonly used medication, not much is known about how it acts at toxic levels in humans. Van Diemen et al. looked at the dosage and serum level related to efficacy and safety. During this study a maximum daily dose of 0.5mg/kg body weight was not surpassed in any patient. Patients in this study experienced dizziness, paresthesias and restlessness at levels approaching 0.5mg/kg. No patient in the study had a seizure, as the level at which seizures usually occur is 0.8mg/kg body weight.7\n\n4-AP acts as a potassium channel blocker that prolongs the action potential, thus increasing neuromuscular activity. It is theorized that the increase in neuromuscular activity is therapeutic at appropriate levels, but that the same mechanism causes adverse reactions at elevated levels.8 The adverse reactions are not only of the central nervous system, but also include injury to the cardiac and skeletal muscle. One study showed that 4-AP toxicity could result in permanent damage to the hippocampus and Papez circuit affecting memory and learning.9\n\nThe 4-AP level of our patient resulted at 530ng/mL. Until now, the highest documented 4-AP level published was 233.6ng/mL.10 In that case, the patient was treated with lorazepam boluses and the seizures subsided, as opposed to our patient who was refractory to treatment with multiple anti-convulsant medications. The valacyclovir level was also elevated and valacyclovir itself can be associated with neuropsychiatric symptoms. Seizures associated with valacyclovir are not well reported in the literature, and the few case reports on valacyclovir associated seizures are in patients with renal failure, which our patient did not have.11,12\n\nThe current treatment of 4-AP overdose is supportive. Animal data suggests that patients with 4-AP toxicity will respond to phenytoin. It is hypothesized that because phenytoin acts as a sodium channel blocker it will inhibit action potentials from continuing.9 A study by Yamaguchi et al.13 showed that treatment of mice with elevated levels of 4-AP with gamma butyric acid (GABA) was comparable to other phenytoin-like therapies. Our patient did not respond to treatment with phenytoin. This raises the question of whether or not a second phenytoin load should be used, or additional anti-convulsants that have a similar mechanism of action to phenytoin should be added.\n\nUsing phenytoin to treat seizures secondary to 4-AP is an important concept because phenytoin is not usually part of the algorithm for the treatment of toxin-induced seizures. The recommendation for treating an undifferentiated toxin-induced seizure is to use a benzodiazepine or barbiturate, then pyridoxine and finally propofol.14 Toxin-induced seizures differ from seizures from other causes because they usually occur due to a global lowering of the seizure threshold in previously normal neurons, whereas seizures due to epilepsy occur in a focal lesion of abnormal neurons. Phenytoin is effective for patients with idiopathic seizure disorders or with defined structural or electrical foci of seizure activity, as phenytoin prevents the propagation of seizures (include reference). There are many reports of phenytoin used in toxin-induced seizures causing clinical detriment to the patient.14\n\nThis case illustrates the highest recorded level of 4-AP in an overdose. Optimal therapy for this overdose is unknown. Our patient appeared to be refractory to a combination of high dose intravenous benzodiazepines, phenytoin, propofol and phenobarbital and only improved with time.\n\nSection Editor: Rick A. McPheeters, DO\n\nFull text available through open access at http://escholarship.org/uc/uciem_westjem\n\nConflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n==== Refs\nREFERENCES\n1 National Multiple Sclerosis Society Who Gets MS? Available at: http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/who-gets-ms/index.aspx Accessed Oct 4, 2010 \n2 Spyker Daniel A Poisoning with 4-Aminopyridine: Report of Three Cases Clinical Toxicology 1980 16 4 487 497 6250762 \n3 Douglas J Parr E Dalfampridine Sustained-release for Symptomatic Improvement of Walking Speed in Patients with Multiple Sclerosis Core Evidence 5 2010 107 12 21468366 \n4 Van Diemen HAM 4-Aminopyridine in Patients with Multiple Sclerosis: Dosage and Serum Level Related to Efficacy and Safety Clinical Neuropharmacology 1993 16 3 195 204 8504436 \n5 MacDonald Sarah Jennifer N Clements Dalfampridine: A new agent for symptomatic management of multiple sclerosis Am J Health-Syst Pharm 12 2011 68 2335 40 22135060 \n6 Neocortical volume decrease in relapsing-remitting MS patients with mild cognitive impairment Amato MP Bartolozzi ML Zipoli V Portaccio E Mortilla M Guidi L Siracusa G Sorbi S Federico A De Stefano N Neurology 2004 \n7 Schwam Eric MD Severe Accidental Overdose Of 4-Aminopyradine Due To A Compounding Pharmacy Error Journal of Emergency Medicine 41 1 51 54 2011 19443164 \n8 Stork C Hoffman R Characterization of 4-Aminopyridine in Overdose Clinical Toxicology 1994 32 5 583 587 7932918 \n9 Badruddin A Menin R Reder A 4-Aminopyridine Toxicity Mimics Autoimmune-Mediated Limbic Encephalitis Neurology 72 3 29 2009 1100 1101 19307545 \n10 Pickett Tracy A MD Enns Robert MD Atypical Presentation of 4-Aminopyridine Overdose Ann Emerg Med 1996 27 382 385 8599505 \n11 Asahi T Tsutsui M Wakasugi M Tange D Takahashi C Tokui K Okazawa S Okudera H Valacyclovir Neurotoxicity: Clinical Experience and Review of the Literature European Journal of Neurology: Eur J Neurol 2009 4 16 4 457 60 \n12 Hoskote Sumedh S Annapureddy Narender Ramesh Atul K Rose Keith Jones James P Valacyclovir and Acyclovir Neurotoxicity With Status Epilepticus American Journal of Therapeutics 2014 1 24401701 \n13 Yamaguchi S Rogawski MA Effects of anticonvulsant drugs of 4-Aminopyridine induced seizures in mice Epilepsy Res 1992 11 9 16 1563341 \n14 Wills B Erickson T Drug- and toxin-associated seizures Med Clin North Am 2005 89 6 1297 321 16227064\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1936-900X",
"issue": "16(7)",
"journal": "The western journal of emergency medicine",
"keywords": null,
"medline_ta": "West J Emerg Med",
"mesh_terms": "D015761:4-Aminopyridine; D000328:Adult; D000927:Anticonvulsants; D001569:Benzodiazepines; D062787:Drug Overdose; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis; D026902:Potassium Channel Blockers; D012640:Seizures",
"nlm_unique_id": "101476450",
"other_id": null,
"pages": "1177-9",
"pmc": null,
"pmid": "26759675",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "6250762;8599505;22135060;19307545;21468366;24368610;19443164;15249616;7932918;16227064;8504436;19187258;1563341",
"title": "A Massive Overdose of Dalfampridine.",
"title_normalized": "a massive overdose of dalfampridine"
} | [
{
"companynumb": "US-APOTEX-2017AP017119",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DALFAMPRIDINE"
},
"drugadditional": "3",
... |
{
"abstract": "Kaposi's sarcoma is a low-grade mesenchymal angioproliferative tumor, most commonly observed in immunocompromised individuals, such as HIV-infected patients. Iatrogenic Kaposi's sarcoma occurs in patients undergoing immunosuppressive therapies. Rituximab is a chimeric monoclonal antibody targeted against the pan B cell marker CD20. Because of its immunosuppressive effects through reduction of mature B-cells, it may exacerbate Kaposi's sarcoma in HIV-positive patients. Rituximab-related Kaposi's sarcomas have been previously reported in only two HIV-negative patients and were treated surgically.\nHere, we report on a Kaposi's sarcoma that developed under rituximab treatment in a HIV-negative 55-year-old patient treated for follicular lymphoma. The lesion developed during the maintenance rituximab therapy at the rectal level with an aspect of apparent ulcerative colitis, without any cutaneous lesion. The premature stop of rituximab led to the complete regression of Kaposi's sarcoma, without any additional specific treatment.\nTo our knowledge, this is the third case of Kaposi's sarcoma diagnosed under rituximab in a HIV-negative patient, the first one at the rectal level and the first one that completely regresses after stop of rituximab. This case raises awareness of iatrogenic Kaposi's sarcoma in HIV-negative patients treated with rituximab, and further highlights the importance of immunosuppression in the pathophysiology of disease.",
"affiliations": "1INSERM UMR1068, CNRS UMR725, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, 232 Bd de Sainte-Marguerite, 13009 Marseille, France.;2Department of Hematology, Institut Paoli-Calmettes, Marseille, France.;3Department of Pathology, Institut Paoli-Calmettes, Marseille, France.;4Department of Digestive Endoscopy Centre Hospitalier Edmond Garcin, Aubagne, France.;1INSERM UMR1068, CNRS UMR725, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, 232 Bd de Sainte-Marguerite, 13009 Marseille, France.;1INSERM UMR1068, CNRS UMR725, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, 232 Bd de Sainte-Marguerite, 13009 Marseille, France.;1INSERM UMR1068, CNRS UMR725, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, 232 Bd de Sainte-Marguerite, 13009 Marseille, France.",
"authors": "Billon|Emilien|E|;Stoppa|Anne-Marie|AM|;Mescam|Lena|L|;Bocci|Massimo|M|;Monneur|Audrey|A|;Perrot|Delphine|D|;Bertucci|François|F|",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s13569-018-0097-7",
"fulltext": "\n==== Front\nClin Sarcoma ResClin Sarcoma ResClinical Sarcoma Research2045-3329BioMed Central London 9710.1186/s13569-018-0097-7ResearchReversible rituximab-induced rectal Kaposi’s sarcoma misdiagnosed as ulcerative colitis in a patient with HIV-negative follicular lymphoma Billon Emilien emilien.billon@free.fr 1Stoppa Anne-Marie stoppaam@ipc.unicancer.fr 2Mescam Lena mescaml@ipc.unicancer.fr 3Bocci Massimo mbocci@ch-aubagne.fr 4Monneur Audrey monneura@ipc.unicancer.fr 1Perrot Delphine louveld@ipc.unicancer.fr 16Bertucci François 33 4 91 22 35 37bertuccif@ipc.unicancer.fr 1561 0000 0004 0598 4440grid.418443.eINSERM UMR1068, CNRS UMR725, Department of Medical Oncology, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, 232 Bd de Sainte-Marguerite, 13009 Marseille, France 2 0000 0004 0598 4440grid.418443.eDepartment of Hematology, Institut Paoli-Calmettes, Marseille, France 3 0000 0004 0598 4440grid.418443.eDepartment of Pathology, Institut Paoli-Calmettes, Marseille, France 4 0000 0001 0069 9008grid.414047.2Department of Digestive Endoscopy Centre Hospitalier Edmond Garcin, Aubagne, France 5 0000 0001 2176 4817grid.5399.6Faculty of Medicine, Aix-Marseille University, Marseille, France 6 French Sarcoma Group, Paris, France 11 6 2018 11 6 2018 2018 8 1110 11 2017 13 3 2018 © The Author(s) 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nKaposi’s sarcoma is a low-grade mesenchymal angioproliferative tumor, most commonly observed in immunocompromised individuals, such as HIV-infected patients. Iatrogenic Kaposi’s sarcoma occurs in patients undergoing immunosuppressive therapies. Rituximab is a chimeric monoclonal antibody targeted against the pan B cell marker CD20. Because of its immunosuppressive effects through reduction of mature B-cells, it may exacerbate Kaposi’s sarcoma in HIV-positive patients. Rituximab-related Kaposi’s sarcomas have been previously reported in only two HIV-negative patients and were treated surgically.\n\nCase presentation\nHere, we report on a Kaposi’s sarcoma that developed under rituximab treatment in a HIV-negative 55-year-old patient treated for follicular lymphoma. The lesion developed during the maintenance rituximab therapy at the rectal level with an aspect of apparent ulcerative colitis, without any cutaneous lesion. The premature stop of rituximab led to the complete regression of Kaposi’s sarcoma, without any additional specific treatment.\n\nConclusions\nTo our knowledge, this is the third case of Kaposi’s sarcoma diagnosed under rituximab in a HIV-negative patient, the first one at the rectal level and the first one that completely regresses after stop of rituximab. This case raises awareness of iatrogenic Kaposi’s sarcoma in HIV-negative patients treated with rituximab, and further highlights the importance of immunosuppression in the pathophysiology of disease.\n\nKeywords\nFollicular lymphomaImmune suppressionKaposi sarcomaRituximabissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nKaposi’s sarcoma is a low-grade mesenchymal angioproliferative tumor caused by the lytic replication of human herpesvirus type 8 (HHV8), identified with Polymerase Chain Reaction (PCR) in 95% of cases. The lesions predominantly present at muco-cutaneous sites, but may involve all organs and anatomic locations. Kaposi’s sarcoma occurs most commonly in immunocompromised individuals such as HIV-infected patients. Iatrogenic Kaposi’s sarcoma occurs in patients undergoing immunosuppressive therapies for autoimmune disorders or after organ transplantation [1].\n\nRituximab is a chimeric murine/human monoclonal antibody (mAb) targeted against the pan B-cell marker CD20. It was the first mAb to receive approval by the Food and Drug Administration for use in cancer treatment. Since its approval for relapsed/refractory non-Hodgkin’s lymphoma in 1997, rituximab has been licensed for use in the treatment of numerous other B-cell malignancies, including the follicular lymphoma [2], as well as autoimmune conditions, including rheumatoid arthritis. Because of its immunosuppressive effects through action on CD20 and reduction of mature B-cells, rituximab therapy may exacerbate Kaposi’s sarcoma in HIV-positive patients [3]. Rituximab-related Kaposi’s sarcomas have been previously reported in two HIV-negative patients, without multicentric Castelman’s disease [4, 5], and were treated surgically.\n\nWe herein report a rectal Kaposi’s sarcoma that developed under rituximab treatment in a HIV-negative patient treated for follicular lymphoma, and that completely regressed upon cessation of rituximab, without any additional specific treatment.\n\nCase presentation\nIn July 2014, a 55-year-old Caucasian man with cervical and mediastinal polyadenopathies was diagnosed with a non-Hodgkin follicular lymphoma (WHO grade 2) in our institution (Fig. 1A, B). There was no clinical general symptom, and the disease stage was II. He had no specific personal or familial medical history. Because of the low malignancy grade and the low tumor mass, no treatment was introduced, and a monitoring was set up. In June 2015, because of increase in size of cervical adenopathies, therapy combining rituximab (375 mg/m2) and bendamustine (90 mg/m2) was initiated. Six monthly cycles were delivered, with good tolerance and complete metabolic response (PET-scan of October 2015), then followed by maintenance rituximab (375 mg/m2, 1 injection every 2 months) started in December 2015 and planned for 2 years (Fig. 2) [6].Fig. 1 PET-scan imaging. A, B PET-scan of July 2014 at time of diagnosis, showing hypermetabolic cervical, mediastinal and hilar lymphadenopathies (red arrows). There was no digestive localization. C, D PET-scan of October 2016, showing pulmonary FDG uptake compatible with lung infection. No suspect FDG uptake of lymphoma recurrence or digestive uptake was found\n\n\nFig. 2 Timeline of patient’s care\n\n\n\n\nIn June 2016, before the fourth maintenance injection, the patient developed diarrhea alternating with constipation, nausea, associated with weight loss. Colonoscopy showed sigmoiditis, with a 4-mm-depth rectal ulceration at 20 cm of the anal canal (Fig. 3), compatible with ulcerative colitis. Multiple biopsies were performed, and the provisional diagnosis of ulcerative colitis was retained before availability of pathological results. No fecal calprotectin measurement was done. Mesalazine therapy (2 g/day) was introduced in September 2016. Pathological analysis of the colic biopsies showed aspects of non-specific subacute colitis. However, the rectal biopsy showed a spindle-cell proliferation with high cell density. Cell atypia were moderate, the cytoplasm was scarce, and the nuclei were slightly dyscaryotic, with rare mitoses. There was no necrosis. Immunohistochemistry (IHC) revealed positive staining of cancer cells for CD34 and negative for CD117. The diagnosis of Kaposi’s sarcoma was suspected, and the samples were sent to our Department of Pathology for reviewing by expert pathologist within the French Sarcoma Network (Réseau de Référence en Pathologie des Sarcomes, RRePS). The diagnosis of rectal Kaposi’s sarcoma was confirmed in October 2016: there was an ill-defined, fasciculated to diffuse proliferation of spindle cells with little to moderate nuclear atypia and few mitoses, outlining vascular slots; IHC showed positive staining of tumor cells for CD31 and ERG endothelial markers and for HHV8, and negative staining for CD117, DOG1, and STAT6 (Fig. 4). No cutaneous lesion was present. The patient stopped mesalazine after 1 month treatment because of relief of digestive symptoms and the diagnosis of ulcerative colitis was not finally retained because of pathological results Blood tests did not detect HHV-8 viremia, and the patient was serologically negative for HIV-1 and HIV-2, hepatitis B and C, and HTLV1 viruses. The circulating CD4+ T-cell count was 387/mm3.Fig. 3 Colonoscopy imaging. Colonoscopy of June 2016 showing sigmoiditis, with a 4-mm-depth rectal ulceration (black arrow) at 20 cm of the anal canal, compatible with ulcerative colitis\n\n\nFig. 4 Pathological aspect of the rectal Kaposi’s sarcoma. a Microscopic aspect of the biopsy of rectal ulceration: the rectal mucosa is infiltrated by an ill-defined cellular fasciculated to diffuse proliferation (HES ×10). b Microscopic aspect showing spindle cells with little to moderate nuclear atypia surround vascular clefts. Few mitoses are noted. Lymphocytes and plasma cells are admixed (HES ×40). c IHC with ERG antibody: the lining cells of vascular structures and spindle cells express the ERG endothelial marker (×20). d IHC with HHV8 antibody: see the nuclear positive immunostaining of spindle tumor cells (×40)\n\n\n\n\nGiven the description in the literature of rituximab-induced Kaposi’s sarcoma in HIV-positive patients, rituximab was prematurely discontinued in October 2016 after the sixth maintenance injection. At this time, PET-scan showed neither suspect hypermetabolism of lymphomatous recurrence, nor digestive FDG uptake likely because of the disappearance of colitis after mesalazine treatment and the low proliferation rate of sarcoma. We noted only the appearance of lung lesions of infectious appearance without concomitant respiratory and infectious clinical symptoms (Fig. 1C, D). In December 2016, after complete disappearance of digestive symptoms, the patient underwent a colonoscopy, which was strictly normal without any sign of rectal Kaposi’s sarcoma or colitis. Because of the infectious images on the PET-scan, explorations were carried out with pneumocystis PCR, and CMV, HSV, and HTLV1 serologies. All these explorations remained negative, as well as a bronchoscopy. Of note, in July 2017, the colonoscopy was normal, notably at the rectal level. In October 2017, 12 months after the last dose of rituximab maintenance, our patient was still in complete remission of his lymphoma.\n\nDiscussion and conclusions\nWe report a case of rectal Kaposi’s sarcoma likely induced by rituximab therapy in a HIV-negative patient treated for a follicular lymphoma. The lesion developed while being treated with maintenance rituximab, leading to prematurely stop the treatment. Interestingly, stopping rituximab allowed the complete regression of Kaposi’s sarcoma. To our knowledge, this is the first description of such case in the literature.\n\nTwo other cases of rituximab-induced Kaposi’s sarcoma in HIV-negative patients have been reported in the literature. One case of cutaneous Kaposi’s sarcoma was described in a patient treated with rituximab for thrombotic thrombocytopenic purpura. The lesion was treated with cryodestruction [4]. Another case was reported in an 84-year-old patient after undergoing rituximab-containing chemotherapy (R-CHOP regimen) for the treatment of a diffuse large B-cell lymphoma (DLBCL); after the seventh cycle, the patient developed a severe bacterial pneumonia and subsequent CMV viremia. The cutaneous Kaposi’s sarcoma developed after the complete resolution of pneumonia and was treated with surgical resection [5]. Our case is the first rituximab-induced Kaposi’s sarcoma that developed at the mucosa level. The diagnosis of Kaposi’s sarcoma of the bowel was difficult to establish immediately in the absence of skin and oral lesions, and a provisional diagnosis of ulcerative colitis was made before availability of pathological results. We suppose that the inflammation present in the mucosa was secondary to the underlying submucosal Kaposi’s sarcoma ulceration. Kaposi’s sarcoma of the bowel presenting as apparent ulcerative colitis has already been reported in HIV-positive patients several years ago, when the pathological diagnosis used antibodies for IHC less sensitive and specific than now [7, 8]. But, intestinal Kaposi’s sarcoma has also been reported during the last decades in HIV-negative patients treated with immunosuppressive drugs for ulcerative colitis or Crohn disease, mimicking acute flare of colitis. Table 1 summarizes the cases reported since 2000 [9–22], as well as the other cases diagnosed in HIV-negative patients treated with immunosuppressive drugs after organ transplantation or for another inflammatory disease. In our case, we observed the complete resolution of Kaposi’s sarcoma 2 months after rituximab discontinuation without the use of any specific treatment. To our knowledge, this is the first case of reversible rituximab-induced KS described in the literature. In their review, Antman and Chang [23] reported several examples of Kaposi’s sarcoma regressions in renal transplant recipients after cessation, reduction or modification of immunosuppressive therapy. However, such modification led to graft rejection in approximately half of the patients. Similarly, in a HIV-negative patient treated with corticosteroid for idiopathic thrombocytopenic purpura, the skin Kaposi’ tumors regressed soon after discontinuation of corticosteroid therapy, and no recurrence was observed during the 30-month follow-up period [24]. In our case, we suppose that the rituximab cessation permitted immune restitution and regression of Kaposi’s sarcoma.Table 1 Published cases of intestinal Kaposi’s sarcoma in HIV-negative patients after 2000\n\nFirst author\tYear\tSex\tAge at diagnosis (years)\tClinical conditions\tVisceral KS localizations\tImmunosuppression therapy\tTumor HHV8 status\tBlood HHV8 status\tKS management\t\nCohen\t2001\tF\t67\tCrohn disease\tIleum\tPrednisone\tND\tND\tDiscontinuation of immunosuppressive therapy\t\nKang\t2004\tF\t60\tUlcerative colitis\tColon\tPrednisone\t+\tND\tND\t\nNepomniashchaia\t2004\tM\t41\tAllogenic kidney transplantation\tStomach, intestinal mesentery, cerebral\tND\tND\tND\tND\t\nBursics\t2005\tM\t49\tUlcerative colitis\tColon\tMethylprednisolone\t−\t−\tDiscontinuation of immunosuppressive therapy and coloprotectomy\t\nSvrcek\t2009\tM\t62\tUlcerative colitis\tRectum\tSteroid, azathioprine\t+\t+\tDiscontinuation of immunosuppressive therapy and coloprotectomy\t\nGirelli\t2009\tM\t43\tUlcerative colitis\tDescending colon\tPrednisone, mesalazine, ciclosporin\t+\t−\tDiscontinuation of immunosuppressive therapy and coloprotectomy\t\nRodriguez\t2010\tM\t65\tUlcerative colitis\tColon\tPrednisone, methotrexate\t+\t+\tDiscontinuation of immunosuppressive therapy and coloprotectomy\t\nTas\t2012\tF\t77\tChronic anemia\tColon, lymph nodes\tNone\t+\tND\tEtoposide\t\nPioche\t2013\tM\t49\tUlcerative colitis\tColon\tCorticosteroids, azathioprine, ciclosporin, infliximab\t+\t+\tColoprotectomy\t\nHamzaoui\t2013\tM\t30\tUlcerative colitis\tColorectal\tPrednisone, mesalazine, azathioprine, infliximab\t+\tND\tSubtotal colectomy\t\nHerculano\t2014\tM\t63\tUlcerative colitis\tSigmoid colon\tPrednisolone, mesalazine\t+\t−\tDiscontinuation of immunosuppressive therapy\t\nWindon\t2017\tM\t21\tCrohn disease\tColon\tPrednisone, infliximab\t−\t−\tDiscontinuation of immunosuppressive therapy\t\nDuh\t2017\tM\t48\tUlcerative colitis\tRectum\tPrednisone\t+\tND\tDiscontinuation of immunosuppressive therapy followed by subtotal colectomy\t\nKumar\t2017\tM\t70\tUlcerative colitis\tAscending colon\tNone\t+\tND\tND\t\nKS Kaposi’s sarcoma, F female, M male, ND not determined\n\n\n\n\nThe role of CD4 T-cells in the Kaposi’s sarcoma pathophysiology is suspected [25], especially in HIV-positive patients who usually present Kaposi’s sarcoma when circulating CD4+ T-cell count is under 350/mm3 under highly active antiretroviral therapy [26]. In our case as well as in Ureshino’s case, the CD4+ T-cell count was higher than 350/mm3 [5], suggesting that cellular immunodeficiency played only a minor role in the development of Kaposi’s sarcoma in these patients. As B-cells are the HHV8’s main human reservoir, another hypothesis may be that B-cell depletion induced by rituximab can expose endothelial cells to high HHV8 level, causing latent viral infection, and promoting Kaposi’s sarcoma development [23]. In HIV-positive patients, lower B-cell counts are associated with the risk of Kaposi’s sarcoma development [27], suggesting a role of humoral immune system in disease etiopathogenesis. One study, which investigated the pathological findings in a HIV-positive patient with rituximab-related Kaposi’s sarcoma who was treated for multicentric Castleman’s disease, showed depletion of intralesional B-lymphocytes accompanied with an upregulation of the HHV8 gene product K5 [28]. These authors also postulated that the diminished B-lymphocyte count interfered with the normal immune response to HHV8, allowing for viral activation. Unfortunately, the circulating CD20+ cell count and the Ig levels were not available for our patient, but they were low in the Ureshino’s case [5]. Despite the widespread use of rituximab, there has been only one case of rituximab-related Kaposi’s sarcoma in HIV-negative patients with DLBCL [5], and it was suggested that additional factors causing systemic inflammation, such as an infection, might contribute to the development of Kaposi’s sarcoma in addition to rituximab. In our patient, lung infection may have triggered Kaposi’s sarcoma progression.\n\nIn conclusion, we report the case of Kaposi’s sarcoma diagnosed under rituximab in a HIV-negative patient, the first one at the rectal level, and the first one that completely regressed after cessation of rituximab. This case further highlights the importance of immunosuppression in the pathophysiology of Kaposi’s sarcoma and how immune restitution takes part in its management. It also suggests awareness of iatrogenic Kaposi’s sarcoma in patients treated with rituximab. Even if the occurrence of Kaposi’s sarcoma is a very rare event, vigilance is needed, particularly for cancer patients often immunocompromised by disease and treatments. Patients at risk of HHV8 infection (ethnicity with high Fitzpatrick skin phototype, Mediterranean or equatorial African geographic origin, male gender, homosexuality or multiple sexual partners, immune deficiency) should be carefully screened for HHV8 before rituximab and closely monitored during treatment. Even if efforts to develop a HHV8 vaccine are ongoing [29], no prophylaxis for Kaposi’s sarcoma is available today. Finally, given the risk of lymphoma progression after rituximab cessation, further studies are needed to better understand the immunological mechanisms involved in rituximab-induced Kaposi’s sarcoma and to define optimal treatment.\n\nAbbreviations\nCMVcytomegalovirus\n\nDLBCLdiffuse large B-cell lymphoma\n\nHHV8human herpes virus type 8\n\nHIVhuman immunodeficiency virus\n\nHSVherpes simplex virus\n\nHTLV1human T-cell lymphotropic virus de type I\n\nIHCimmunohistochemistry\n\nmAbmonoclonal antibody\n\nPCRpolymerase chain reaction\n\nPET-scanpositron emission tomography scan\n\nRRePSRéseau de Référence en Pathologie des Sarcomes\n\nWHOWorld Health Organization\n\nAuthors’ contributions\nConception and design: FB; Manuscript writing: FB and EB; Final approval: FB, EB, AMS, LM, MB, AM, DP; Pathological explorations: LM; Patient’s management: AMS, MB, LM, FB. All authors read and approved the final manuscript.\n\nAcknowledgements\nOur work is supported by Institut Paoli-Calmettes.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images.\n\nEthics approval and consent to participate\nNot applicable.\n\nFunding\nNot applicable.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Geraminejad P Memar O Aronson I Rady PL Hengge U Tyring SK Kaposi’s sarcoma and other manifestations of human herpesvirus 8 J Am Acad Dermatol 2002 47 641 655 10.1067/mjd.2002.128383 12399755 \n2. Fisher RI LeBlanc M Press OW Maloney DG Unger JM Miller TP New treatment options have changed the survival of patients with follicular lymphoma J Clin Oncol Off J Am Soc Clin Oncol 2005 23 8447 8452 10.1200/JCO.2005.03.1674 \n3. Gérard L Michot J-M Burcheri S Fieschi C Longuet P Delcey V Rituximab decreases the risk of lymphoma in patients with HIV-associated multicentric Castleman disease Blood 2012 119 2228 2233 10.1182/blood-2011-08-376012 22223822 \n4. Jerdan K Brownell J Singh M Braniecki M Chan L A case report of iatrogenic cutaneous Kaposi sarcoma due to rituximab therapy for thrombotic thrombocytopenic purpura Acta Oncol 2017 56 111 113 10.1080/0284186X.2016.1253867 27885868 \n5. Ureshino H Ando T Kojima K Itamura H Jinnai S Doi K Rituximab-containing chemotherapy (R-CHOP)-induced Kaposi’s sarcoma in an HIV-negative patient with diffuse large B cell lymphoma Intern Med 2015 54 3205 3208 10.2169/internalmedicine.54.5103 26666614 \n6. Salles G Seymour JF Offner F López-Guillermo A Belada D Xerri L Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial Lancet 2011 377 42 51 10.1016/S0140-6736(10)62175-7 21176949 \n7. Biggs BA Crowe SM Lucas CR Ralston M Thompson IL Hardy KJ AIDS related Kaposi’s sarcoma presenting as ulcerative colitis and complicated by toxic megacolon Gut 1987 28 1302 1306 10.1136/gut.28.10.1302 3678959 \n8. Weber JN Carmichael DJ Boylston A Munro A Whitear WP Pinching AJ Kaposi’s sarcoma of the bowel-presenting as apparent ulcerative colitis Gut 1985 26 295 300 10.1136/gut.26.3.295 3972277 \n9. Cohen RL Tepper RE Urmacher C Katz S Kaposi’s sarcoma and cytomegaloviral ileocolitis complicating long-standing Crohn’s disease in an HIV-negative patient Am J Gastroenterol 2001 96 3028 3031 10.1111/j.1572-0241.2001.04676.x 11693345 \n10. Kang MJ Namgung KY Kim MS Ko BS Han CS Ahn HT A case of Kaposi’s sarcoma associated with ulcerative colitis Korean J Gastroenterol Taehan Sohwagi Hakhoe Chi 2004 43 316 319 15156119 \n11. Nepomniashchaia EM Gusarev SA Kirichenko IG Generalized Kaposi’s sarcoma after allogenic transplantation of cadaver kidney Arkh Patol 2004 66 55 57 15648170 \n12. Bursics A HHV-8 positive, HIV negative disseminated Kaposi’s sarcoma complicating steroid dependent ulcerative colitis: a successfully treated case Gut 2005 54 1049 1050 10.1136/gut.2005.069500 15951561 \n13. Svrcek M Tiret E Bennis M Guyot P Fléjou J-F KSHV/HHV8-associated intestinal Kaposi’s sarcoma in patient with ulcerative colitis receiving immunosuppressive drugs: report of a case Dis Colon Rectum 2009 52 154 158 10.1007/DCR.0b013e318197217f 19273971 \n14. Girelli CM Serio G Rocca E Rocca F Refractory ulcerative colitis and iatrogenic colorectal Kaposi’s sarcoma Dig Liver Dis 2009 41 170 174 10.1016/j.dld.2007.10.007 18054849 \n15. 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Iatrogenic colorectal Kaposi sarcoma complicating a refractory ulcerative colitis in a human immunodeficiency negative-virus patient. Pan Afr Med J. 2013;15. 10.11604/pamj.2013.15.154.2988.\n19. Herculano R Barreiro P Hann A Chapim I Bispo M Santos S Drug-induced colonic Kaposi’s sarcoma in a HIV-negative patient with ulcerative colitis: a case report and review of the literature Int J Colorectal Dis 2014 29 1441 1442 10.1007/s00384-014-1912-0 24898591 \n20. Windon AL Shroff SG Iatrogenic Kaposi’s sarcoma in an HIV-negative young male with Crohn’s disease and IgA nephropathy: a case report and brief review of the literature Int J Surg Pathol 2017 29169276 \n21. Duh E Fine S Human herpesvirus-8 positive iatrogenic Kaposi’s sarcoma in the setting of refractory ulcerative colitis World J Clin Cases 2017 5 423 427 10.12998/wjcc.v5.i12.423 29291200 \n22. 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Lupia R Wabuyia PB Otiato P Fang C-T Tsai F-J Risk factors for Kaposi’s sarcoma in human immunodeficiency virus patients after initiation of antiretroviral therapy: A nested case–control study in Kenya J Microbiol Immunol Infect. 2017 50 781 788 10.1016/j.jmii.2015.10.009 26712092 \n27. Stebbing J Gazzard B Newsom-Davis T Nelson M Patterson S Gotch F Nadir B cell counts are significantly correlated with the risk of Kaposi’s sarcoma Int J Cancer 2004 108 473 474 10.1002/ijc.11601 14648716 \n28. Pantanowitz L Früh K Marconi S Moses AV Dezube BJ Pathology of rituximab-induced Kaposi sarcoma flare BMC Clin Pathol 2008 8 7 10.1186/1472-6890-8-7 18651955 \n29. Wu TT Qian J Ang J Sun R Vaccine prospect of Kaposi sarcoma-associated herpesvirus Curr Opin Virol 2012 2 482 488 10.1016/j.coviro.2012.06.005 22795202\n\n",
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"title": "Reversible rituximab-induced rectal Kaposi's sarcoma misdiagnosed as ulcerative colitis in a patient with HIV-negative follicular lymphoma.",
"title_normalized": "reversible rituximab induced rectal kaposi s sarcoma misdiagnosed as ulcerative colitis in a patient with hiv negative follicular lymphoma"
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"abstract": "Dermatillomania is characterized by excessive and repeated skin picking sufficient to damage cutaneous tissue, but with no underlying dermatological disease. The condition appears as an independent diagnosis in the Obsessive-Compulsive and Related Disorders category in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. A psychiatric pathology is generally reported to accompany this symptom. Attention deficit hyperactivity disorder (ADHD) is a potentially lifelong condition involving inattentiveness, hyperactivity, and impulsiveness. Attention deficit hyperactivity disorder is one of the most common childhood psychiatric disorders. Treatment includes medication, psychotherapy, and psychosocial therapies. Psychostimulants constitute the basis of treatment of children with ADHD worldwide. We describe a case of skin picking developing after methylphenidate therapy for ADHD. Possible explanations of methylphenidate and skin picking are reviewed in the light of the current literature.",
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"authors": "Kara|Tayfun|T|;Akaltun|İsmail|İ|",
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"title": "Newly Developed Skin Picking After Methylphenidate Treatment in Attention Deficit Hyperactivity Disorder: Possible Mechanisms.",
"title_normalized": "newly developed skin picking after methylphenidate treatment in attention deficit hyperactivity disorder possible mechanisms"
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"abstract": "OBJECTIVE\nTo make through introduction of Wernicke's encephalopathy (WE) following hematopoietic stem cell transplantation (HSCT) in terms of clinical characteristics, diagnostic process and treatment.\n\n\nMETHODS\nThe clinical charactaristics, diagnostic and therapeutic process and prognostic follow-up in 4 patients diagnosed of WE following HSCT between January 2016 to January 2017 at Department of Hematology, Chinese Aerospace Center Hospital were retrospectively analyzed.\n\n\nRESULTS\nFour patients included 2 ALL and 2 AML, and 3 males and 1 female, their age ranged from 8 to 20 years old. 4 patients accouted for about 3% of all petients who received HSCT at that time. Typical triad syndrome consisting of ocular motility disorders, ataxia, global confusion was seen in only 1 patient. However, confusion and heterophthongia as onset of this complication were seen in all patients. Cerebral computed tomograph scan was universally unremarkable and useless. Cerebral MRI scan disclosed that typical involvement including thalamus, fourth ventricle, third ventricle, middle cerebral aqueduct was seen in 3, while untypical site including mamillary body was in the remaining 1 patient. All received vitamin B1 supplement therapy by intramuscular injection at a dose of 100 mg each day. Initial response was observed at 2, unknown, 3, 4 days after treatment and all obtained complete remission within 2 weeks without any event of relapse after median follow-up period of 8 (7-12) months.\n\n\nCONCLUSIONS\nAny recipient of HSCT with clinical signs or symptoms of central nervous system should receive vitamin B1 supplementary therapy immediately to decrease risk of mortality of WE even if the diagnosis of WE is uncertain.",
"affiliations": "Department of Hematology, Aerospace Center Hospital, Beijing 100049, China.;Department of Hematology, Aerospace Center Hospital, Beijing 100049, China.;Department of Hematology, Aerospace Center Hospital, Beijing 100049, China.;Department of Hematology, Aerospace Center Hospital, Beijing 100049, China.;Department of Hematology, Aerospace Center Hospital, Beijing 100049, China.;Department of Hematology, Aerospace Center Hospital, Beijing 100049, China.;Department of Hematology, Aerospace Center Hospital, Beijing 100049, China. E-mail:wangjingbo@asch.net.cn.",
"authors": "Xue|Song|S|;Yuan|Lei|L|;Cheng|Hao-Yu|HY|;Yin|Yu-Ming|YM|;Gu|Jiang-Ying|JY|;Zhang|Wei-Jie|WJ|;Wang|Jing-Bo|JB|",
"chemical_list": "D013831:Thiamine",
"country": "China",
"delete": false,
"doi": "10.7534/j.issn.1009-2137.2018.03.042",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1009-2137",
"issue": "26(3)",
"journal": "Zhongguo shi yan xue ye xue za zhi",
"keywords": null,
"medline_ta": "Zhongguo Shi Yan Xue Ye Xue Za Zhi",
"mesh_terms": "D000293:Adolescent; D002648:Child; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D012189:Retrospective Studies; D013831:Thiamine; D014899:Wernicke Encephalopathy; D055815:Young Adult",
"nlm_unique_id": "101084424",
"other_id": null,
"pages": "880-885",
"pmc": null,
"pmid": "29950237",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Four Cases of Wernicke's Encephalopathy Following Hematopoietic Stem Cell Transplantation.",
"title_normalized": "four cases of wernicke s encephalopathy following hematopoietic stem cell transplantation"
} | [
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"companynumb": "CN-MYLANLABS-2018M1091560",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "THYMOCYTE IMMUNE GLOBULIN NOS"
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"abstract": "Phaeohyphomycosis is an infection caused by a filamentous fungus that contains pigment melanin in its cell wall. We report two cases caused by Exophiala sp. emphasizing the clinical variability of the disease, as well as diagnostic and therapeutic difficulties of this opportunistic infection in immunosuppressed patients (kidney transplant).",
"affiliations": "Universidade de São Paulo, São Paulo, SP, Brazil.;Universidade de São Paulo, São Paulo, SP, Brazil.;Universidade de São Paulo, São Paulo, SP, Brazil.;Universidade de São Paulo, São Paulo, SP, Brazil.;Universidade de São Paulo, São Paulo, SP, Brazil.;Universidade de São Paulo, São Paulo, SP, Brazil.",
"authors": "de Oliveira|Walmar Roncalli Pereira|WR|;Borsato|Maria Fernanda Longo|MF|;Dabronzo|Maria Luiza Ducati|ML|;Festa Neto|Cyro|C|;Rocha|Larissa Aragão|LA|;Nunes|Ricardo Spina|RS|",
"chemical_list": "D000935:Antifungal Agents; D007166:Immunosuppressive Agents",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nAn Bras DermatolAn Bras DermatolabdAnais Brasileiros de Dermatologia0365-05961806-4841Sociedade Brasileira de Dermatologia 10.1590/abd1806-4841.20163954Case ReportPhaeohyphomycosis in renal transplantation: report of two cases* de Oliveira Walmar Roncalli Pereira 1Borsato Maria Fernanda Longo 1Dabronzo Maria Luiza Ducati 1Festa Neto Cyro 1Rocha Larissa Aragão 1Nunes Ricardo Spina 11 Universidade de São Paulo (USP) - São\nPaulo (SP), Brazil.Mailing address: Maria Fernanda Longo Borsato, Av. Dr. Enéas\nde Carvalho Aguiar, 155, 05403-900 São Paulo SP, Brazil. E-mail:\nmfernandaborsato@hotmail.comJan-Feb 2016 Jan-Feb 2016 91 1 89 92 17 8 2014 09 10 2014 © 2016 by Anais Brasileiros de\nDermatologia2016This is an Open Access article distributed under the terms of the\nCreative Commons Attribution Non-Commercial License which permits\nunrestricted non-commercial use, distribution, and reproduction in any\nmedium provided the original work is properly cited.Phaeohyphomycosis is an infection caused by a filamentous fungus that contains\npigment melanin in its cell wall. We report two cases caused by Exophiala sp.\nemphasizing the clinical variability of the disease, as well as diagnostic and\ntherapeutic difficulties of this opportunistic infection in immunosuppressed\npatients (kidney transplant).\n\nExophialaImmunosuppressive agentsKidney transplantationPhaeohyphomycosis\n==== Body\nINTRODUCTION\nPhaeohyphomycosis is a rare opportunistic infection caused by a heterogeneous group\nof pigmented filamentous fungi.1,2 These fungi are saprophytic in\nnature but may be highly pathogenic in immunocompromised individuals. In these\npatients, clinic manifestations may be quite varied.1 The disseminated form of the disease is associated\nwith severe clinical presentation and mortality rates of up to 70%. We present two\ncases of phaeohyphomycosis in kidney transplant patients. We demonstrate the\ndiagnostic and therapeutic difficulties of this opportunistic infection that may\npresent a high risk of dissemination and high mortality rates in these patients.\n\nCASE REPORT\nCASE 1\nA 57-year-old male patient presented for 2 years multiple nodules and tumors of\ncystic consistence on the back of right foot and right leg (Figure 1). The lesions exhibited a sporotrichosis-like\ndistribution pattern but there was no history of local trauma. The patient\nreceived a kidney transplant 4 years ago due to hypertensive nephropathy and his\nimmunosuppressive treatment included azathioprine, tacrolimus and prednisone.\nThe initial diagnostic hypotheses were sporotrichosis, paracoccidioidomycosis,\nleishmaniasis and phaeohyphomycosis. Direct mycological examination revealed\nirregular and septate moniliform hyphae of pigmented fungi. Culture on\nSabouraud-Agar with chloramphenicol demonstrated vegetative chambered hyphae\nwith septate annellophores, compatible with Exophiala sp. At\nthe histopathological test a granulomatous inflammatory infiltrate was observed,\nin the form of brownish walls composed of giant multinucleated cells with fungal\nstructures (Figure 2). Specific staining\ndemonstrated pheomelanin in the fungi walls (Fontana-Masson) and search for\nfungi was positive (Gridley) (Figure 3).\nThe patient was treated first with voriconazole 200mg 12/12h associated with\nsurgical excision of lesions. During treatment with voriconazole the patient\ndeveloped a severe clinical picture of hyponatremia; the drug was replaced with\nitraconazole 200mg/day, which was used during five months, with no relapses\nsince then.\n\n\nFigure 1 Nodules and tumors of cystic consistence on the right leg of a\npatient\n\n\n\n\n\nFigure 2 Inflammatory granulomatous infiltrate composed of giant\nmultinucleated cells (HE x100)\n\n\n\n\n\nFigure 3 Positive search for fungi (Gridley x400)\n\n\n\n\nCASE 2\nA 59-year-old male patient presented for 8 months an erythematous-violaceous\nplaque covered with pustules and honey-colored scabs on the right thigh (Figure 4). No history of previous local\ntrauma. The patient received a kidney transplant two years ago for hypertensive\nand diabetic nephropathy and the immunosuppressive treatment included\nmycophenolate sodium, tacrolimus and prednisone. The initial diagnostic\nhypotheses were squamous cell carcinoma, chromomycosis and phaeohyphomycosis.\nDirect mycological examination revealed irregular pigmented and septate hyphae.\nThe morphological aspect of culture on Sabouraud-Agar with chloramphenicol was\ncompatible with Exophiala sp. At the anatomopathologic\nexamination with specific staining were observed septate hyphae with acute angle\nramification (Figure 5). The established\ntreatment was surgical lesion excision associated with itraconazole 200mg/day\nduring four months. Up to this time no signs of relapse have been observed.\n\n\nFigure 4 Erythematous-violaceous plaque, covered with pustules and\nhoney-colored scabs on the right thigh of patient 2\n\n\n\n\n\nFigure 5 Septate hyphae with ramification at an acute angle (Fontana- Masson\nx400; Gridley x400)\n\n\n\n\nDISCUSSION\nPhaeohyphomycosis is an opportunistic fungal disease that predominantly affects the\nskin and may disseminate in immunocompromised patients. The incidence in\ntransplanted patients is approximately 9%, with most cases occurring after the two\nfirst years following transplant, as observed in our patients.2 This incidence has been increasing\nin the last decades due to the escalation in the number of transplant patients and\nthe use of highly immunosupressive drugs.\n\nAlthough the new immunosupressive drugs have improved survival rate of these\npatients, they are also associated with the increased morbidity and mortality due to\nopportunistic infections. Calcineurin inhibitors seem to increase susceptibility to\nfungal infections even more, when compared to other immunosuppressants.4,5\n\nThe diagnosis becomes more difficult because of clinical polymorphism of lesions and\nthe lack of serological or antigenic tests that may prove there is infection in the\nblood or tissues. The diagnosis of our patients was based on the clinical lesions\nand on direct mycological examination, on culture and anatomopathological\nexamination, which are the main diagnostic tools.(6n)\n\nIn transplanted patients, the clinical polymorphism usually present in\nphaeohyphomycosis is exacerbated by the intense iatrogenic immunosuppression used,\nmaking diagnosis extremely difficult. They may present papules, nodules,\nerythematous plaques, abscesses, ulcers and/or tumors, which have in common the\nfrequent involvement of subcutaneous tissue.\n\nUp to this time there are more than 100 species of melanotic fungi associated with\nphaeohyphomycosis. Alternaria sp, Curvularia sp and\nExophiala sp are the species most frequently found in\ntransplanted patients.3\n\nThe fungus identified in our patients was Exophiala sp., which is\nthe most common etiologic agent in subcutaneous phaeohyphomycosis.7,8 There is no correlation established until now between etiologic\nagents and the clinical presentation of phaeohyphomycosis. Despite having the same\netiologic agent, we observe a distinct clinical picture in our patients, a fact that\nmay be justified by the different moment in the progression of the disease and the\ndifferences in the immunosuppressive scheme employed.\n\nThe treatment of phaeohyphomycosis is difficult and non standardized due to the\nrarity of the disease. In transplanted patients the therapeutic approach is\nchallenging, as larger doses of antifungals are required and there is the\npossibility of drug interactions that may place at risk the functionality of the\ntransplanted organ.\n\nSurgical excision is the therapy of choice for localized and well-delimited lesions\ncaused by Exophiala sp. The use of antifungal drugs is recommended\nfor transplanted patients before and after surgery, but there is no consensus about\nthe drug of choice nor length of treatment. In severe and/or disseminated cases it\nis also recommended to reduce the immunosuppressive doses.6,9\n\nMost of the melanotic fungi are susceptible to azolics, making itraconazole and\nvoriconazole the main drugs employed, followed by amphotericin B.2\n\nIn transplanted patients, the high doses of azolics may trigger drug interaction with\ncalcineurin inhibitors and MTOR as they are important CYP3A4/5 inhibitors.10 This interaction may raise the\nserum levels of immunosuppressants to extremely toxic levels. On the other hand,\nreduction of immunosuppressant doses to extremely low levels may trigger functional\nloss of the transplanted organ.\n\nThe early clinical suspicion of phaeohyphomycosis in transplanted patients becomes\nextremely important, since immunosuppression is the main risk factor for infection\nand responsible for systemic dissemination of the disease, culminating in severe and\nfatal clinical pictures.\n\nTherefore, the importance of this article resides in the fact that it demonstrates\ntwo distinct clinical forms of phaeohyphomycosis in kidney transplant patients\n(disease with increased incidence in this population of patients) and for pointing\nout the diagnostic and therapeutic difficulties, as well as the possibility of drug\ninteraction.\n\nConflict of Interest: None.\n\nFinancial Support: None.\n\n* Study carried out at the Dermatology outpatient clinic, Teaching Hospital of the\nSchool of Medicine of the Universidade de São Paulo (HC-FMUSP) - São Paulo (SP),\nBrazil.\n==== Refs\nREFERENCES\nVásquez-del-Mercado E Lammoglia L Arenas R Subcutaneous phaeohyphomycosis due to Curvularia lunata in a\nrenal transplant patient Rev Iberoam Micol 2013 30 116 118 23153471 \nIsa-Isa R García C Isa M Arenas R Subcutaneous phaeohyphomycosis (mycotic cyst) Clin Dermatol 2012 30 425 431 22682192 \nOcampo MA Kanitakis J Bienvenu AL Chauvet C Euvrard S Phaeohyphomycosis caused by Pyrenochaeta romeroi mimicking a\nplantar wart in a kidney transplant recipient Transpl Infect Dis 2012 14 E173 E174 23121654 \nPereiro M Jr Pereiro Ferreirós MM De Hoog GS Toribio J Cutaneous infection caused by Alternaria in patients receiving\ntacrolimus Med Mycol 2004 42 277 282 15283243 \nLarsen CG Arendrup MC Krarup E Pedersen M Thybo S Larsen FG Subcutaneous phaeohyphomycosis in a renal transplant recipient\nsuccessfully treated with voriconazole Acta Derm Venereol 2009 89 657 658 19997708 \nVermeire SE de Jonge H Lagrou K Kuypers DR Cutaneous phaeohyphomycosis in renal allograft recipients: report\nof 2 cases and review of the literature Diagn Microbiol Infect Dis 2010 68 177 180 20846592 \nCosta RO Subcutaneous phaeohyphomycosis An Bras Dermatol 2010 85 727 728 21152804 \nMesa A Henao J Gil M Durango G Phaeohyphomycosis in kidney transplant patients Clin Transplant 1999 13 273 276 10383109 \nCunha D Amaro C Vieira MR Martins Mda L Maduro AP Inácio J Phaeohyphomycosis caused by Alternaria infectoria presenting as\nmultiple vegetating lesions in a renal transplant patient Rev Iberoam Micol 2012 29 44 46 21787876 \nSalido-Vallejo R Linares-Sicilia MJ Garnacho-Saucedo G Sánchez-Frías M Solís-Cuesta F Gené J Subcutaneous phaeohyphomycosis due to Alternaria infectoria in a\nrenal transplant patient: surgical treatment with no long-term\nrelapse Rev Iberoam Micol 2014 31 149-51\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0365-0596",
"issue": "91(1)",
"journal": "Anais brasileiros de dermatologia",
"keywords": null,
"medline_ta": "An Bras Dermatol",
"mesh_terms": "D000935:Antifungal Agents; D005093:Exophiala; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D060446:Phaeohyphomycosis; D012867:Skin",
"nlm_unique_id": "0067662",
"other_id": null,
"pages": "89-92",
"pmc": null,
"pmid": "26982786",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15283243;10383109;19997708;20846592;22771424;21787876;22682192;23121654;23153471;21152804",
"title": "Phaeohyphomycosis in renal transplantation: report of two cases.",
"title_normalized": "phaeohyphomycosis in renal transplantation report of two cases"
} | [
{
"companynumb": "BR-MYLANLABS-2016M1019770",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nTrigeminal neuralgia (TN) is a well-recognized facial pain syndrome. Discrete forms with disparate pain symptoms include classic and atypical. However, atypical facial pain includes neuralgiform pain along a spectrum. Most cases of TN are diagnosed in the adult population. Case reports and series of children have presented TN as a similar entity, with treatment similar to that for adults. We reviewed the pertinent data and present 2 pediatric TN cases successfully treated with microvascular decompression (MVD).\n\n\nMETHODS\nTwo pediatric patients (age 12 and 15 years) with TN refractory to previous medical therapy were identified. Both patients were deemed appropriate surgical candidates and underwent MVD to manage their TN. TN compression was arterial in both cases and involved portions of the anterior inferior cerebellar artery. Patient 1 was pain free 6 months after the procedure. Patient 2 was pain free immediately after the procedure and had been weaned off preoperative symptomatic management at the latest follow-up visit. The most recent follow-up examination was 12 and 8 months for patients 1 and 2, respectively, with both experiencing continued freedom from pain.\n\n\nCONCLUSIONS\nFew studies have reported on the effectiveness of MVD in the pediatric population for the management of TN. The supporting data and our 2 cases have demonstrated that MVD is effective for pediatric patients to treat their TN. Furthermore, the side effects appear to be minimal, with excellent pain relief after MVD in this patient population.",
"affiliations": "School of Medicine, Marian University College of Osteopathic Medicine, Indianapolis, Indiana, USA.;Section of Pediatric Neurosurgery, Riley Hospital for Children, Department of Neurological Surgery, Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, Indiana, USA.;Section of Pediatric Neurosurgery, Riley Hospital for Children, Department of Neurological Surgery, Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, Indiana, USA.;Section of Pediatric Neurosurgery, Riley Hospital for Children, Department of Neurological Surgery, Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, Indiana, USA. Electronic address: jraskin@goodmancampbell.com.",
"authors": "Chicoine|Nicole H|NH|;Yaacoub|Alan P|AP|;Jea|Andrew|A|;Raskin|Jeffrey S|JS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2018.10.074",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "121()",
"journal": "World neurosurgery",
"keywords": "Microvascular decompression in children; Pediatric facial pain; Trigeminal neuralgia",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000293:Adolescent; D002648:Child; D005157:Facial Pain; D005260:Female; D006801:Humans; D061145:Microvascular Decompression Surgery; D014277:Trigeminal Neuralgia",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "217-221",
"pmc": null,
"pmid": "30347302",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Surgical Management of Trigeminal Neuralgia in Children.",
"title_normalized": "surgical management of trigeminal neuralgia in children"
} | [
{
"companynumb": "US-TEVA-2018-US-989102",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
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"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAnaplastic lymphoma kinase (ALK) rearrangement is a well-known driver oncogene in non-small-cell lung cancer and has also been identified in other types of tumors. However, there is limited evidence on the clinical response to ALK tyrosine kinase inhibitors (TKIs), such as alectinib and crizotinib, in rare tumors with ALK fusion. We evaluated the therapeutic effect of ALK-TKIs in rare ALK-rearranged tumors.\n\n\nMETHODS\nBetween April 2012 and April 2019, clinical outcomes and characteristics of patients with ALK-rearranged nonlung solid tumors who received ALK-TKIs (alectinib and/or crizotinib) outside of clinical trials were reviewed. Expression and/or rearrangement of ALK was evaluated by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. The tumor response was assessed according to RECIST (version 1.1). Progression-free survival was estimated from initial ALK-TKI initiation until progression.\n\n\nRESULTS\nWe identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare ALK fusions, namely, CTNNA1-ALK and ITSN2-ALK, were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib.\n\n\nCONCLUSIONS\nThis study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with ALK-rearranged nonlung solid tumors.",
"affiliations": "Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.;Department of Laboratory Medicine, National Cancer Center Hospital, Tokyo, Japan.;Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.;Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.;Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan.;Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.",
"authors": "Takeyasu|Yuki|Y|;Okuma|Hitomi S|HS|;Kojima|Yuki|Y|;Nishikawa|Tadaaki|T|;Tanioka|Maki|M|;Sudo|Kazuki|K|;Shimoi|Tatsunori|T|;Noguchi|Emi|E|;Arakawa|Ayumu|A|;Mori|Taisuke|T|;Sunami|Kuniko|K|;Kubo|Takashi|T|;Kohno|Takashi|T|;Akihiko|Yoshida|Y|;Yamamoto|Noboru|N|;Yonemori|Kan|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1200/PO.20.00383",
"fulltext": "\n==== Front\nJCO Precis Oncol\nJCO Precis Oncol\npo\npo\nPO\nJCO Precision Oncology\n2473-4284\nWolters Kluwer Health\n\nPO.20.00383\n10.1200/PO.20.00383\nORIGINAL REPORTS\nTargeted Drug Therapy\nImpact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors\nTakeyasu Yuki MD 12\nOkuma Hitomi S. MD, PhD 13\nKojima Yuki MD, PhD 1\nNishikawa Tadaaki MD, PhD 1\nTanioka Maki MD, PhD 1\nSudo Kazuki MD, PhD 1\nShimoi Tatsunori MD, PhD 1\nNoguchi Emi MD, PhD 1\nArakawa Ayumu MD, PhD 4\nMori Taisuke MD, PhD 5\nSunami Kuniko MD, PhD 6\nKubo Takashi PhD 78\nKohno Takashi PhD 79\nAkihiko Yoshida MD, PhD 410\nYamamoto Noboru MD, PhD 11\nYonemori Kan MD, PhD 1\n1 Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan\n2 Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan\n3 Clinical Research Support Office, National Cancer Center Hospital, Tokyo, Japan\n4 Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan\n5 Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan\n6 Department of Laboratory Medicine, National Cancer Center Hospital, Tokyo, Japan\n7 Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan\n8 Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan\n9 Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan\n10 Rare Cancer Center, National Cancer Center Hospital, Tokyo, Japan\n11 Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan\nHitomi S. Okuma, MD, PhD, Department of Breast and Medical Oncology, Clinical Research Support Office, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo, Tokyo 104-0051, Japan; e-mail: hsumiyos@ncc.go.jp.\n2021\n03 5 2021\n03 5 2021\n5 PO.20.0038324 9 2020\n30 1 2021\n22 2 2021\n© 2021 by American Society of Clinical Oncology\n2021\nAmerican Society of Clinical Oncology\nhttps://creativecommons.org/licenses/by/4.0/ Licensed under the Creative Commons Attribution 4.0 License: https://creativecommons.org/licenses/by/4.0/\n\nPURPOSE\n\nAnaplastic lymphoma kinase (ALK) rearrangement is a well-known driver oncogene in non–small-cell lung cancer and has also been identified in other types of tumors. However, there is limited evidence on the clinical response to ALK tyrosine kinase inhibitors (TKIs), such as alectinib and crizotinib, in rare tumors with ALK fusion. We evaluated the therapeutic effect of ALK-TKIs in rare ALK-rearranged tumors.\n\nPATIENTS AND METHODS\n\nBetween April 2012 and April 2019, clinical outcomes and characteristics of patients with ALK-rearranged nonlung solid tumors who received ALK-TKIs (alectinib and/or crizotinib) outside of clinical trials were reviewed. Expression and/or rearrangement of ALK was evaluated by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. The tumor response was assessed according to RECIST (version 1.1). Progression-free survival was estimated from initial ALK-TKI initiation until progression.\n\nRESULTS\n\nWe identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare ALK fusions, namely, CTNNA1-ALK and ITSN2-ALK, were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib.\n\nCONCLUSION\n\nThis study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with ALK-rearranged nonlung solid tumors.\n==== Body\nBACKGROUND\n\nAnaplastic lymphoma kinase (ALK) rearrangement was first discovered as a potential actionable therapeutic oncogenic gene aberration in anaplastic large-cell lymphoma (ALCL).1 The next disease linked to ALK was inflammatory myofibroblastic tumor (IMT), characterized by increased expression of the ALK protein and a rearranged ALK locus in a subset of cases.2,3 Later, there were advances in ALK-targeted therapy because of the discovery of the EML4-ALK rearrangement in non–small-cell lung cancer (NSCLC),4 which led to the discovery of ALK alterations in other solid tumors such as neuroblastomas, rhabdomyosarcomas, and anaplastic thyroid cancers.5-7 Activation of the ALK gene can occur by rearrangements with partner genes, point mutations, or amplification. Ever since the discovery of the oncogenic role, ALK alterations, mainly rearrangements, have been a target for developing therapies, and Hiroyuki Mano8 proposed the collective name ALKoma to refer to tumors that develop because of ALK functioning abnormally as an oncogene.\n\nCONTEXT\n\nKey Objective\n\nThere is limited evidence on the clinical efficacy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (ALK-TKIs) in nonlung solid tumors with ALK rearrangements. This single institutional study aimed to evaluate the efficacy and tolerability of ALK-TKIs in a group of patients with ALK-rearranged rare solid tumor.\n\nKnowledge Generated\n\nAlectinib showed dramatic response for patients with ALK-rearranged nonlung solid tumors, and furthermore, sequential ALK-TKI therapy was acceptable for some patients. A patient with parotid tumor with CTNNA1-ALK rearrangement derived clinical benefit from alectinib.\n\nRelevance\n\nOur data revealed that ALK rearrangements are found in rare solid tumors and result in clinical benefit when treated with ALK-TKIs. This leads to a rationale for clinical trials targeting ALK-rearranged nonlung solid tumors to promote personalized medicine.\n\nThe first-generation ALK-tyrosine kinase inhibitor (TKI) to be approved following clinical trials was crizotinib, which also acts as a mesenchymal epithelial transition factor and receptor tyrosine kinase-1 kinase inhibitor. It showed a dramatic effect in ALK-positive solid tumors and ALCLs.9,10 A second-generation ALK inhibitor, alectinib, was subsequently approved and showed a higher response rate than crizotinib with minimal toxicity in patients with ALK-rearranged metastatic NSCLC.11 Currently, ceritinib, brigatinib, and lorlatinib are approved in the clinical setting for ALK-rearranged NSCLC.12-14\n\nIn ALKomas other than NSCLC, a small sample size of phase II studies showed that crizotinib demonstrated antitumor efficacy and achieved a durable response, as anticipated.15 However, there are limited reports on other ALK-positive solid tumors, and the efficacy and safety of alectinib for these tumors have only been described as case reports.16-19 Thus, in this case series, we summarize the efficacy and tolerability of ALK-TKIs (alectinib and crizotinib) in patients with ALKomas.\n\nPATIENTS AND METHODS\n\nWe retrospectively reviewed patients with ALK-rearranged nonlung solid tumors who received alectinib and crizotinib outside of clinical trials at the National Cancer Center Hospital between April 2012 and April 2019. Patient data were retrieved from electronic medical records. Alectinib and crizotinib were administered at the doses approved for NSCLC in Japan: 300 mg twice daily and 250 mg twice daily, respectively. Expression of ALK and/or rearrangement of ALK was evaluated by immunohistochemistry (IHC) (5A4, Abcam, Cambridge, UK, or ALK1, DAKO, Glostrup, Denmark), fluorescence in situ hybridization (FISH) using a break-apart probe (Vysis ALK Break Apart FISH Probe Kit, Abbott Molecular, Abbott Park, IL), or next-generation sequencing (NGS) using NCC Oncopanel v4.0, which detects gene rearrangements, base substitutions, short insertions or deletions, and copy number alterations in 114 genes.20 The institutional ethics committee of the National Cancer Center Hospital approved this study (#2016-086). We also obtained documented informed consent from each patient before treatment. The response to ALK-TKI was assessed by two independent oncologists according to version 1.1 of the RECIST.21 The response rate (ie, the proportion of patients with complete response (CR) or partial response [PR]) was calculated, and its 95% CI was estimated based on the Clopper-Pearson method. Time-to-event end points were summarized using the Kaplan-Meier method. Data were analyzed using JMP Pro version 13.0.0 (SAS Institute).\n\nRESULTS\n\nAmong the patients treated with an ALK-TKI outside of a clinical trial during the study period, seven had nonlung solid tumors. Initial ALK-TKI treatment consisted of alectinib in five patients and crizotinib in two patients. Patient characteristics are shown in Table 1. The median follow-up time was 15.0 months.\n\nTABLE 1. Patient Characteristics\n\nThere were five male and two female patients, and the mean age was 17 years (range, 14-60 years). The most common histology was IMT (n = 3), followed by ALK-positive histiocytosis (n = 1), histiocytic sarcoma (n = 1), osteosarcoma (n = 1), and parotid adenocarcinoma (n = 1). Three IMTs showed characteristic histology, including two epithelioid variants. In contrast to ALK-positive histiocytosis, the histiocytic sarcoma showed nuclear atypia and high mitotic activity with atypical mitoses. Osteosarcomas were of the conventional osteoblastic type with highly pleomorphic nuclei. One adenocarcinoma of the parotid gland showed a solid pattern without mucous secretion, and IHC was positive for S100, SOX10, and DOG1 and negative for NR4A3. IHC of ALK was positive for all tumors except osteosarcoma. The ALK staining patterns were nuclear membranous in patient 3 with IMT (epithelioid), plasma membranous in patient 7 with parotid adenocarcinoma, and cytoplasmic in the remaining patients (Table 2 and Fig 1).\n\nTABLE 2. Clinicopathologic Features of Patients Treated With ALK-TKI (Crizotinib and Alectinib)\n\nFIG 1. Histological features of representative cases. (A) Patient 1: histiocytic sarcoma, CLTC|ALK fusion; (B) patient 3: IMT (epithelioid); (C) patient 4: ALK-positive histiocytosis; (D) patient 5: IMT, CLTC|ALK fusion; (E) patient 6: osteosarcoma, ITSN2|ALK fusion; (F) patient 6: negative staining in ALK IHC; (G) patient 7: parotid adenocarcinoma, CTNNA1|ALK fusion; and (H) patient 7: plasma membrane staining in ALK IHC. ALK, anaplastic lymphoma kinase; IHC, immunohistochemistry; IMT, inflammatory myofibroblastic tumor.\n\nThe median number of lines of previous systemic pharmacotherapy was one (range, 0-2 lines). All seven patients showed an ALK rearrangement of some kind, and four patients were tested by NGS. Their clinicopathological features and detected fusions are listed in Table 2. The observed partner genes were KIF5B (n = 1), CLTC (n = 2), ITSN2 (n = 1), and CTNNA (n = 1) (Appendix Figs A1A-C). Table 2 and Figure 2 illustrate the patients' clinical courses. Three patients died of cancer, one was lost to follow-up, and the remainder were still alive at last follow-up.\n\nFIG 2. Trends with tumor burden (sum of target lesions) and clinical courses for each case. ADM, adriamycin; AI, adriamycin/ifosfamide; ALK, anaplastic lymphoma kinase; CAP, cyclophosphamide/adriamycin/cisplatin; CHOP, cyclophosphamide/adriamycin/oncovin/prednisolone; CR, complete response; DTX, docetaxel; GEM, gemcitabine; IFM, ifosfamide; IHC, immunohistochemistry; NGS, next-generation sequencing; PD, progressive disease; PR, partial response; SD, stable disease; TMZ, temozolomide; VP-16, etoposide.\n\nThe best objective response rate (ORR) for initial ALK-TKI was 85.7% (95% CI, 43.65 to 96.99) (6 of 7 patients) with a disease control rate of 85.7% (6 of 7 patients), as summarized in Figure 3. The median progression-free survival (PFS) was 8.1 months (range, 1.7 to not estimable). In patients receiving initial alectinib, the response rate was 80.0% (4 of 5 patients), including two patients with CR and another two with durable PR (Fig 4). In one 17-year-old patient with locally advanced bladder IMT (patient 2 in Table 2), it was possible to preserve the bladder because of the good response to crizotinib.22 Three patients were treated with a second ALK-TKI, either alectinib or ceritinib. In one patient initially treated with crizotinib (patient 1), alectinib and ceritinib were subsequently administered. In this patient, alectinib failed to achieve clinical efficacy although ceritinib achieved PR. Overall, the clinical effect of sequential ALK-TKI therapy was mild in terms of the tumor response and short response duration.\n\nFIG 3. Waterfall plot of best response to initial ALK-TKI. ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor.\n\nFIG 4. Diagnostic radiographic images of representative cases. (A and B) Patient 1: histiocytic sarcoma showing PR; (C and D) patient 3: IMT (epithelioid) showing CR; (E and F) patient 4: ALK-positive histiocytosis showing CR; (G and H) patient 5: IMT; (I and J) patient 6: osteosarcoma showing PD; and (K and L) patient 7: parotid adenocarcinoma showing PR. ALK, anaplastic lymphoma kinase; CR, complete response; PD, progressive disease; PR, partial response; IMT, inflammatory myofibroblastic tumor.\n\nRegarding the safety profile of ALK-TKI treatment, there were no treatment-related adverse events and no dose reductions or interruptions for any cause with alectinib therapy. One patient receiving crizotinib experienced grade 3 neutropenia that was considered to be drug related, and dose reduction was required.\n\nDISCUSSION\n\nThe current case series clarified the efficacy of ALK-TKIs, including alectinib, a second-generation ALK-TKI, across different tumor types and fusion partners in patients with advanced, ALK-rearranged, nonlung solid tumors. For the first time, we report the response to ALK-TKI in tumors with two rare fusions, ITSN2-ALK and CTNNA1-ALK, and the clinical benefit and safety of alectinib in a pediatric patient with a solid tumor. Previous studies have shown that crizotinib, a first-generation ALK-TKI, is effective and achieves a durable response in ALK-positive tumors, excluding NSCLC.10,23,24 In these studies, crizotinib resulted in ORRs of 66.7%-86.0% in patients with IMT and 11.8% in patients with other solid tumors excluding NSCLC. As for alectinib, a phase II trial for ALK-positive ALCL25 led to regulatory approval in Japan, but no clinical trial data for alectinib to treat solid tumors have been reported so far. In our report, the ORR for initial ALK-TKI therapy was 85.7% (6 of 7 patients), which is comparable with the efficacy in previous crizotinib trials. Our ORR results are also similar to those from alectinib trials for NSCLC, although the PFS was shorter than that of the patients with NSCLC.11 The shorter PFS could be explained by differences in histology, fusion partner genes, number of lines of previous pharmacotherapy, and number of patients. This report is the first to show the efficacy of alectinib as an initial ALK-TKI in a group of nonlung solid tumors, and the first to report the clinical benefit of alectinib in rare cancer types such as ALK-positive histiocytosis, histiocytic sarcoma, and parotid gland adenocarcinoma with CTNNA-ALK, in addition to tumors with known fusion types such as IMT with CLTC-ALK fusion.\n\nThe function of the protein derived from CTNNA1-ALK fusion was previously unknown, since only one study described CTNNA1 as a fusion partner of ALK in a patient with salivary secretory carcinoma, and the treatment outcomes were not reported.26 Our case of CTNNA-ALK–positive parotid adenocarcinoma demonstrated rearrangement in the canonical exon 20 recombination region and showed a clinical response to alectinib (Appendix Fig A1B and Table 2); this was consistent with the other cancer types in our series that had an ALK fusion in the same region and also demonstrated a response to alectinib. Also, previous studies have reported that this type of in-frame fusion to exon 20 of ALK generates an oncogenic protein, which suggests that this oncogenic protein is a possible therapeutic target of ALK inhibitors irrespective of cancer type.4,8,27,28 The positive ALK IHC staining in the tumor cells of our patient with parotid adenocarcinoma and the response to ALK inhibitors suggest that this fusion was an oncogenic driver. Interestingly, ALK plasma membrane staining was characteristic of this patient, which suggests that this staining pattern may reflect CTNNA1 function and location. α-E-catenin, the protein product of CTNNA1, functions in a complex with β-catenin and is responsible for organizing and tethering actin filaments at the zones of E-cadherin–mediated cell-cell contact, which can be seen in the cell membrane when stained by IHC for α-E-catenin.29,30 Different ALK staining patterns have been described in ALK-rearranged tumors depending on the localization of the various fusion proteins.31\n\nWe also detected an ITSN2-ALK fusion in a patient with osteosarcoma who demonstrated poor sensitivity to alectinib. Although many previous studies have reported other ALK fusion partners and breakpoints, little is still known about the true oncogenic role of fusion variants other than the common fusions found in NSCLC,32 let alone the clinical efficacy of ALK-TKIs for rare ALK fusion variants. The ITSN2-ALK fusion gene we identified by NGS resulted from a fusion between ITSN2 (exon 32) and ALK (exon 14). However, IHC was negative despite FISH positivity with predominant isolated ALK 3′ signals, suggesting that this fusion may not be an activating alteration despite genomic rearrangement. Although our NGS analysis detected ALK-ITSN2 fusion reads, that is, the possible reciprocal counterpart of ITSN2-ALK, it is possible that an ITSN2-ALK gene fusion also occurs. Since the fusion gene maintained the ALK kinase domain and the ITSN2 portion of the fusion gene included the coiled coil domain, the rearranged gene might have resulted in production of an oncogenic fusion protein. However, given the negative IHC results and the poor response to alectinib, the rearrangement is unlikely to have produced the ITSN2-ALK fusion gene (Appendix Fig A1C). Only one other ITSN2 (exon 29)-ALK (exon 18) fusion has been reported so far, specifically in a patient with thyroid cancer.33 In that case, RNA-Seq showed overexpression of ALK exons 18-29 downstream of the fusion point; however, neither IHC results nor the therapeutic effects of ALK-TKIs were reported.\n\nNext-generation ALK-TKIs such as alectinib, ceritinib, and lorlatinib have shown antitumor activity in patients with ALK-positive NSCLC who were previously treated with a different ALK-TKI.34,35 In our study, two patients (one with CLTC-ALK and the other with CTNAA-ALK) who progressed on alectinib were treated with ceritinib. One patient (CLTC-ALK) achieved PR, confirming the clinical efficacy of ceritinib. This patient had initially responded to crizotinib, but did not show a response to subsequent alectinib. Since a previous study found that ceritinib was effective in patients with NSCLC treated with first-line alectinib, our results are in line with expectations about rechallenging with ALK-TKIs.34 We could not examine the molecular mechanism of resistance to previous ALK-TKI treatment or the efficacy of lorlatinib, a third-generation ALK-TKI. Resistance to ALK inhibitors in ALK-rearranged NSCLC is known to result from secondary mutations such as gatekeeper mutations or the emergence of fusion-negative tumor cells.36-38 Therefore, we conducted plasma NGS (Guardant360) in the patient with CTNNA1-ALK fusion–positive parotid adenocarcinoma at disease progression after he was treated with alectinib. We identified TP53 T253A and PIK3CA E547A mutations but did not detect any ALK-related alterations, including the ALK fusion found in the tumor tissue. The failure to identify this ALK fusion in the serial biopsy may be a result of the alectinib treatment or the limited detection power of NGS when using cell-free DNA. Moreover, Petros et al reported that detection of TP53 mutations was associated with poor TKI-response in patients with ALK-positive NSCLC.39 These factors may explain the poor outcome after treatment with ceritinib in our patient with parotid adenocarcinoma.\n\nThis case series has several limitations. First, this was a retrospective study conducted at a single institution with a small sample size and a variety of malignant solid tumors. In addition, because of the lack of systematic strategy at the time to identify patients with rare cancer with a specific genomic characteristic, we did not systematically identify ALK-positive solid tumors. Therefore, there might have been ALK-positive cases that did not receive ALK-TKIs outside of this case series. However, these study characteristics are not unusual because of the nature of rare cancers and we have made improvements in the process by building a registry study for rare cancers. Second, we did not perform NGS sequencing in all patients, and therefore, it was not possible to demonstrate a clear correlation between the efficacy of ALK-TKI treatment and each ALK fusion partner. In the era of personalized medicine involving the idea of the $1,000 genome, such precise mechanisms may gradually become clarified, since only FISH was performed before the development of NGS. The MASTER KEY project40 is a platform study being conducted in Japan that includes a prospective registry study and multiple clinical trials (UMIN000027552). One of the clinical trials is an investigator-initiated, single-arm, open-label, phase II trial of alectinib for patients with ALK-positive rare cancers (JMA-IIA00364). These platforms are essential since they centrally accumulate limited data in a comprehensive manner, as opposed to instances in which each patient with rare cancer is treated with a driver-directed therapy at a local hospital, and the valuable patient data are scattered.\n\nIn conclusion, our data suggest that ALK fusions are found in rare solid tumors outside of NSCLC and will lead to clinical benefit for patients in the era of personalized medicine. The ongoing clinical phase II trial is expected to result in new evidence and treatment options for this small patient population.\n\nACKNOWLEDGMENT\n\nThe authors would like to thank the TOP-GEAR project members (UMIN 000011141) for conducting the NGS tests, Dr Satoshi Ota of Teine Keijinkai Hospital, Dr Kengo Takeuchi of Cancer Institute Hospital, and Dr Naoya Nakamura of the Department of Diagnostic Pathology, Tokai University, for diagnosing patient 1.\n\nAUTHOR CONTRIBUTIONS\n\nConception and design: Hitomi S. Okuma, Yuki Kojima, Kazuki Sudo, Noboru Yamamoto, Kan Yonemori\n\nAdministrative support: Noboru Yamamoto\n\nProvision of study material or patients: Taisuke Mori, Noboru Yamamoto\n\nCollection and assembly of data: Yuki Takeyasu, Hitomi S. Okuma, Tadaaki Nishikawa, Maki Tanioka, Kazuki Sudo, Taisuke Mori, Takashi Kubo, Yoshida Akihiko, Noboru Yamamoto, Kan Yonemori\n\nData analysis and interpretation: Yuki Takeyasu, Hitomi S. Okuma, Kazuki Sudo, Tatsunori Shimoi, Emi Noguchi, Ayumu Arakawa, Kuniko Sunami, Takashi Kohno, Yoshida Akihiko, Noboru Yamamoto, Kan Yonemori\n\nManuscript writing: All authors\n\nFinal approval of manuscript: All authors\n\nAccountable for all aspects of the work: All authors\n\nAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\n\nThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.\n\nOpen Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).\n\nAppendix\n\nFIG A1. (A) Schematic figures of gene fusions detected by NGS (patients 1 and 5): patient 1: CLTC|ALK fusion chr17:57, 769, 218-chr2:29, 447, 574 (exon 31: exon 20) and patient 5: CLTC|ALK fusion chr 17:57, 768, 627-chr 2:29,446,555 (exon 31: exon 20); (B) NGS sequencing results and schematic figure of patient 7: CTNNA1-ALK fusion. Patient 7: CTNNA1|ALK fusion chr5:138, 259, 019-chr2:29, 446, 464 (exon 10: exon 20); (C) NGS sequencing results and schematic figure of patient 6: ITSN-ALK fusion. Patient 6: ITSN2|ALK fusion chr2:29,462,361-chr2:24,438,831 (exon 14: exon 32); ALK, anaplastic lymphoma kinase; chr2, chromosome 2; DH, Dbl homology domain; EH, Eps15 homology domain; IMT, inflammatory myofibroblastic tumor; ITSN2, intersectin 2; NGS, next-generation sequencing; SH3, Src three homology domain; TM, transmembrane domain; TrD, trimerization domain; VH1, vinculin homology one domain; VH2, vinculin homology two domain.\n\nSee accompanying editorial https://doi.org.10.1200/po.21.00078.\n\nTadaaki Nishikawa\n\nHonoraria: AstraZeneca, Eisai\n\nConsulting or Advisory Role: Eisai\n\nSpeakers' Bureau: AstraZeneca, Eisai\n\nKazuki Sudo\n\nHonoraria: AstraZeneca, Pfizer\n\nEmi Noguchi\n\nHonoraria: Nippon Kayaku\n\nSpeakers' Bureau: Sysmex, AstraZeneca, Pfizer, Eisai, Lilly Japan, Taiho Pharmaceutical, Chugai Pharma\n\nAyumu Arakawa\n\nResearch Funding: Chugai Pharma\n\nTravel, Accommodations, Expenses: Amgen\n\nKuniko Sunami\n\nHonoraria: Sysmex, Chugai Pharma, AstraZeneca, Novartis, Eisai, Riken Genesis, Lilly\n\nTakashi Kubo\n\nConsulting or Advisory Role: Sysmex\n\nTakashi Kohno\n\nConsulting or Advisory Role: LOXO Oncology, Lilly Japan\n\nResearch Funding: Daiichi Sankyo, Sysmex\n\nNoboru Yamamoto\n\nHonoraria: AstraZeneca, Pfizer, Chugai Pharma, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, Sysmex\n\nConsulting or Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheimm, CMIC, Chugai Pharma\n\nResearch Funding: Chugai Pharma, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, IQVIA, Merck Sharp & Dohme, Abbvie, Bristol Myers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience, Otsuka\n\nKan Yonemori\n\nHonoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical\n\nConsulting or Advisory Role: Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai\n\nResearch Funding: Ono Pharmaceutical\n\nNo other potential conflicts of interest were reported.\n\nTadaaki Nishikawa\n\nHonoraria: AstraZeneca, Eisai\n\nConsulting or Advisory Role: Eisai\n\nSpeakers' Bureau: AstraZeneca, Eisai\n\nKazuki Sudo\n\nHonoraria: AstraZeneca, Pfizer\n\nEmi Noguchi\n\nHonoraria: Nippon Kayaku\n\nSpeakers' Bureau: Sysmex, AstraZeneca, Pfizer, Eisai, Lilly Japan, Taiho Pharmaceutical, Chugai Pharma\n\nAyumu Arakawa\n\nResearch Funding: Chugai Pharma\n\nTravel, Accommodations, Expenses: Amgen\n\nKuniko Sunami\n\nHonoraria: Sysmex, Chugai Pharma, AstraZeneca, Novartis, Eisai, Riken Genesis, Lilly\n\nTakashi Kubo\n\nConsulting or Advisory Role: Sysmex\n\nTakashi Kohno\n\nConsulting or Advisory Role: LOXO Oncology, Lilly Japan\n\nResearch Funding: Daiichi Sankyo, Sysmex\n\nNoboru Yamamoto\n\nHonoraria: AstraZeneca, Pfizer, Chugai Pharma, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, Sysmex\n\nConsulting or Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheimm, CMIC, Chugai Pharma\n\nResearch Funding: Chugai Pharma, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, IQVIA, Merck Sharp & Dohme, Abbvie, Bristol Myers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience, Otsuka\n\nKan Yonemori\n\nHonoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical\n\nConsulting or Advisory Role: Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai\n\nResearch Funding: Ono Pharmaceutical\n\nNo other potential conflicts of interest were reported.\n==== Refs\nREFERENCES\n\n1. 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Nagumo Y Maejima A Toyoshima Y et al Neoadjuvant crizotinib in ALK-rearranged inflammatory myofibroblastic tumor of the urinary bladder: A case report Int J Surg Case Rep 48 1–4 2018 29758320\n23. Mossé YP Lim MS Voss SD et al Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: A Children's Oncology Group phase 1 consortium study Lancet Oncol 14 472–480 2013 23598171\n24. Mossé YP Voss SD Lim MS et al Targeting ALK with crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: A Children's Oncology Group study J Clin Oncol 35 3215–3221 2017 28787259\n25. Nagai H Fukano R Sekimizu M et al Phase II trial of CH5424802 (alectinib hydrochloride) for recurrent or refractory ALK-positive anaplastic large cell lymphoma: Study protocol for a non-randomized non-controlled trial Nagoya J Med Sci 79 407–413 2017 28878445\n26. Sasaki E Masago K Fujita S et al Salivary secretory carcinoma harboring a novel ALK fusion: Expanding the molecular characterization of carcinomas beyond the ETV6 gene Am J Surg Pathol 44 962–969 2020 32205481\n27. Sasaki T Rodig SJ Chirieac LR et al The biology and treatment of EML4-ALK non-small cell lung cancer Eur J Cancer 46 1773–1780 2010 20418096\n28. Yakirevich E Resnick MB Mangray S et al Oncogenic ALK fusion in rare and aggressive subtype of colorectal adenocarcinoma as a potential therapeutic target Clin Cancer Res 22 3831–3840 2016 26933125\n29. Rimm DL Koslov ER Kebriaei P et al Alpha 1(E)-catenin is an actin-binding and -bundling protein mediating the attachment of F-actin to the membrane adhesion complex Proc Natl Acad Sci U S A 92 8813–8817 1995 7568023\n30. Majewski IJ Kluijt I Cats A et al An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer J Pathol 229 621–629 2013 23208944\n31. Pulford K Lamant L Morris SW et al Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1 Blood 89 1394–1404 1997 9028963\n32. Rosenbaum JN Bloom R Forys JT et al Genomic heterogeneity of ALK fusion breakpoints in non-small-cell lung cancer Mod Pathol 31 791–808 2018 29327716\n33. Panebianco F Nikitski AV Nikiforova MN et al Characterization of thyroid cancer driven by known and novel ALK fusions Endocr Relat Cancer 26 803–814 2019 31539879\n34. Hida T Seto T Horinouchi H et al Phase II study of ceritinib in alectinib-pretreated patients with anaplastic lymphoma kinase-rearranged metastatic non-small-cell lung cancer in Japan: ASCEND-9 Cancer Sci 109 2863–2872 2018 29959809\n35. Gadgeel SM Gandhi L Riely GJ et al Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): Results from the dose-finding portion of a phase 1/2 study Lancet Oncol 15 1119–1128 2014 25153538\n36. Choi YL Soda M Yamashita Y et al EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors N Engl J Med 363 1734–1739 2010 20979473\n37. Katayama R Friboulet L Koike S et al Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib Clin Cancer Res 20 5686–5696 2014 25228534\n38. Katayama R Shaw AT Khan TM et al Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers Sci Transl Med 4 120ra17 2012\n39. Christopoulos P Dietz S Kirchner M et al Detection of TP53 mutations in tissue or liquid rebiopsies at progression identifies ALK+ lung cancer patients with poor survival Cancers (Basel) 11 120 2019\n40. Okuma HS Yonemori K Narita SN et al MASTER KEY project: Powering clinical development for rare cancers through a platform trial Clin Pharmacol Ther 108 596–605 2020 32112563\n\n",
"fulltext_license": "CC BY",
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"journal": "JCO precision oncology",
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"medline_ta": "JCO Precis Oncol",
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"nlm_unique_id": "101705370",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34036223",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "12405914;9028963;29352732;28586279;17625570;32112563;29669701;10383129;28878445;29327716;30742731;19097774;23208944;30669647;29439172;31539879;7568023;25228534;28977547;28787259;29685646;30790150;22614325;29079636;20979473;21596819;28126333;22367537;30280657;29758320;23598171;10934142;26933125;25153538;29959809;32205481;8122112;30413378;20418096;22277784",
"title": "Impact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors.",
"title_normalized": "impact of alk inhibitors in patients with alk rearranged nonlung solid tumors"
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"abstract": "Wilms tumor is the most common renal tumor in children. However, tumor extension into the ureter is exceedingly rare. We present a case of bilateral Wilms tumor with unilateral ureteral extension into the bladder. This case illustrates the importance of thoughtful diagnostic evaluation and surgical planning to obtain a good oncologic outcome while preserving renal function.",
"affiliations": "Department of Surgery, Division of Pediatric Urology, Connecticut Children's Medical Center, Hartford, CT; School of Medicine, University of Connecticut, Farmington, CT. Electronic address: glockwood@connecticutchildrens.org.;School of Medicine, University of Connecticut, Farmington, CT.;Department of Surgery, Division of Pediatric Urology, Connecticut Children's Medical Center, Hartford, CT; School of Medicine, University of Connecticut, Farmington, CT.",
"authors": "Lockwood|Gina|G|;Ferrer|Fernando|F|;Makari|John|J|",
"chemical_list": "D000970:Antineoplastic Agents",
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"medline_ta": "Urology",
"mesh_terms": "D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D007223:Infant; D007668:Kidney; D007677:Kidney Function Tests; D007680:Kidney Neoplasms; D008197:Lymph Node Excision; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009392:Nephrectomy; D018714:Radiotherapy, Adjuvant; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014463:Ultrasonography; D014513:Ureter; D009396:Wilms Tumor",
"nlm_unique_id": "0366151",
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"pages": "219-221",
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"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral Wilms Tumor With Ureteral Extension.",
"title_normalized": "bilateral wilms tumor with ureteral extension"
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"abstract": "To describe a case of invasive ductal carcinoma of the breast in a transgender male receiving testosterone therapy for gender-affirming treatment.\nA 28-year-old transgender male receiving intramuscular testosterone was found to have a breast mass on ultrasound after self-exam revealed a palpable breast lump. Ultrasound-guided breast biopsy revealed estrogen receptor/progesterone receptor (ER/PR) negative, human epidermal growth factor receptor-2 (HER-2) positive, invasive ductal carcinoma of the left breast. He underwent neoadjuvant and adjuvant chemotherapy along with bilateral mastectomy. At patient request, his testosterone injections were permanently discontinued.\nFewer than 20 cases of breast cancer in transgender male patients have been reported in medical literature. While studies have shown increased risk of breast cancer in postmenopausal women with higher testosterone levels, data regarding premenopausal women is conflicting and little is known about breast cancer risk in transgender individuals receiving gender-affirming hormone therapy (GAHT), with inconclusive results regarding correlation between testosterone therapy and breast cancer. More research is required to evaluate whether a possible increased risk of breast cancer exists for transgender men receiving gender-affirming therapy.",
"affiliations": "Department of Endocrinology, West Virginia University, Morgantown, WV, USA.;Department of Medicine, West Virginia University, Morgantown, WV, USA.;Department of Endocrinology, West Virginia University, Morgantown, WV, USA.",
"authors": "Barghouthi|Nadia|N|0000-0002-5314-3035;Turner|Jennifer|J|;Perini|Jessica|J|",
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"delete": false,
"doi": "10.1155/2018/3652602",
"fulltext": "\n==== Front\nCase Rep EndocrinolCase Rep EndocrinolCRIECase Reports in Endocrinology2090-65012090-651XHindawi 10.1155/2018/3652602Case ReportBreast Cancer Development in a Transgender Male Receiving Testosterone Therapy http://orcid.org/0000-0002-5314-3035Barghouthi Nadia nbarghou@mix.wvu.edu\n1\nTurner Jennifer \n2\nPerini Jessica \n1\n\n1Department of Endocrinology, West Virginia University, Morgantown, WV, USA\n2Department of Medicine, West Virginia University, Morgantown, WV, USAAcademic Editor: John Broom\n\n2018 31 12 2018 2018 36526021 10 2018 23 12 2018 Copyright © 2018 Nadia Barghouthi et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Context\n To describe a case of invasive ductal carcinoma of the breast in a transgender male receiving testosterone therapy for gender-affirming treatment.\n\n Case Description\n A 28-year-old transgender male receiving intramuscular testosterone was found to have a breast mass on ultrasound after self-exam revealed a palpable breast lump. Ultrasound-guided breast biopsy revealed estrogen receptor/progesterone receptor (ER/PR) negative, human epidermal growth factor receptor-2 (HER-2) positive, invasive ductal carcinoma of the left breast. He underwent neoadjuvant and adjuvant chemotherapy along with bilateral mastectomy. At patient request, his testosterone injections were permanently discontinued.\n\n Conclusion\n Fewer than 20 cases of breast cancer in transgender male patients have been reported in medical literature. While studies have shown increased risk of breast cancer in postmenopausal women with higher testosterone levels, data regarding premenopausal women is conflicting and little is known about breast cancer risk in transgender individuals receiving gender-affirming hormone therapy (GAHT), with inconclusive results regarding correlation between testosterone therapy and breast cancer. More research is required to evaluate whether a possible increased risk of breast cancer exists for transgender men receiving gender-affirming therapy.\n==== Body\n1. Introduction\nTestosterone is used in the transgender male population in order to induce masculinization; however the association between testosterone and breast cancer risk is not well defined. There are a small number of cases documenting breast cancer in transgender male patients receiving masculinizing GAHT with current studies showing a possible but inconclusive correlation between higher doses of testosterone and increased breast cancer risk.\n\n2. Case Presentation\nA 28-year-old transgender man who had been receiving masculinizing hormone therapy presented with a self-palpated left breast mass. Past medical history included gender incongruence for which the patient had been receiving weekly testosterone injection therapy for one year prior to presentation. Gynecological history was unremarkable and menses had stopped approximately one month into gender-affirming therapy. Home medications included intramuscular testosterone enanthate 100 mg weekly, multivitamin, and vitamin D supplement. He had never smoked and denied alcohol or illicit drug use. Family history included mother with hypertension, father with diabetes mellitus, paternal great grandmother with breast cancer, maternal great grandmother with ovarian cancer, maternal grandmother with lung cancer, and maternal grandfather with gastric cancer.\n\nOn physical exam, the patient was a well-appearing male with moderate growth of facial hair. Cardiac, pulmonary, abdominal, neurologic, and musculoskeletal exam were all unremarkable. Breast exam revealed a palpable left upper breast lump without skin dimpling or changes in pigmentation. His lab values included total testosterone ranging over the year from 544 to 970 ng/dL (reference range for men: 270-1,734), hemoglobin and hematocrit of 15.1 g/dL (reference range for men: 12.5-16.3) and 44.2% (reference range for men: 36.7-47.0), and normal hepatic function panel.\n\n3. Investigation\nBreast ultrasound revealed a 1.4 × 0.8 × 1.1 cm oval, hypoechoic left upper breast mass with indistinct margins which was suspicious for malignancy and corresponded to the palpable lump on physical exam (Figure 1). Ultrasound-guided breast biopsy was performed with pathology revealing nuclear grade 3, estrogen receptor (ER)/progesterone receptor (PR) negative, human epidermal growth factor receptor 2 (HER-2) positive, invasive ductal carcinoma of left breast. Genetic testing was negative for androgen receptor (AR) mutation and breast cancer type 1 and 2 (BRCA-1 and BRCA-2) mutations but did show a variant of undetermined significance (VUS).\n\n4. Treatment and Outcome\nAfter diagnosis of invasive ductal carcinoma of the left breast, a lengthy discussion was held with the patient regarding potential risks of continuing testosterone therapy versus risks to the patient's well-being from cessation of gender-affirming hormone therapy. The patient opted to discontinue the testosterone. He underwent neo-adjuvant chemotherapy with docetaxel, carboplatin, pertuzumab, and trastuzumab. He then underwent bilateral nipple-sparing mastectomy with surgical pathology showing left breast ductal carcinoma in situ with negative margins and no lymph node involvement. The patient later had a total laparoscopic hysterectomy with bilateral salpingo-oophorectomy and remains on trastuzumab therapy at this time.\n\n5. Discussion\nTransgender male patients typically achieve masculinization through gender-affirming therapy with testosterone. Although there is strong evidence to link higher estrogen levels with breast cancer development [1, 2], there is mounting but inconclusive evidence suggesting a link between higher circulating androgen levels and the development of breast cancer [3–9]. The patient population in these studies has been female and, to date, there have been fewer than 20 reported cases of breast cancer related to testosterone therapy in transgender men [3–7, 10]. Two proposed mechanisms of excess androgen-related breast cancer development include aromatization of testosterone to estrogens in peripheral tissues and the activation of androgen receptors which leads to cellular growth and proliferation, particularly in mammary tissues [1–4, 8, 9]. Conversely, a few studies suggest protective effects of androgens possibly via competitive blockade of estrogen receptors in mammary epithelium [8].\n\nStudies have noted that some breast cancers which are negative for ER and PR expression are positive for AR expression, suggesting increased androgen receptor positivity as its own risk factor in the development of breast cancers [3]. In our case, expressions of ER, PR, and AR were all negative however HER-2 expression was positive. Some case reports of breast cancer development in transgender men receiving testosterone therapy noted increased expression of HER-2 but the mechanism of testosterone-related overexpression of HER-2 is unknown [3, 11]. Of the cases revealed in the literature, the types of breast cancer were variable, consisting of invasive ductal carcinoma, neuroendocrine carcinoma, and tubular adenocarcinoma [3–7, 11]. The strongest correlation of androgen levels and risk of breast cancer was in hormone receptor positive tumors including ER/PR and androgen receptor (AR) positivity [2, 3]. One study which followed five transgender male patients two years after initiation of testosterone therapy found upregulation of over 200 genes associated with breast cancer-unique expression [3].\n\nNo consistent guidelines exist regarding the continuation of GAHT following breast cancer treatment in transgender men [3–7, 10]. Published reports suggest that most patients are restarted on low-dose testosterone therapy with or without an aromatase inhibitor to prevent peripheral conversion of testosterone to estrogens [3, 4, 6, 7, 11]; however the available evidence on the risk of breast cancer recurrence with continuation of masculinizing GAHT is conflicting. Prophylactic use of aromatase inhibitors is currently under investigation and its effectiveness is unknown [3–7]. None of the patients who resumed low-dose testosterone therapy had breast cancer recurrent at 2-5 years' follow-up in a limited number of case reports [3–7]. Other studies of recurrence among transgender men receiving masculinizing GAHT have indicated that bilateral mastectomy does not negate future risk of cancer development in residual breast tissue [4, 5]. In individual high-risk cases, such as in this case with extensive family history of cancer, pretreatment screening with breast imaging may be warranted prior to initiating GAHT. In our particular case, the patient elected to permanently discontinue testosterone therapy. Whether such cessation of therapy was necessary is uncertain and more research is required to assess benefits of therapy versus risk of breast cancer recurrence.\n\nData Availability\nThe review of collective case report data used to support the discussion findings in this case report are included within the article within the following references [1–11].\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest that are relevant to the subject matter or materials included in this work.\n\nFigure 1 Breast ultrasound: lobulated solid left breast mass at 11:00, approximately 0.8 × 1.1 × 1.4 cm.\n==== Refs\n1 Yager J. D. Davidson N. E. Estrogen carcinogenesis in breast cancer The New England Journal of Medicine 2006 354 3 270 282 10.1056/nejmra050776 2-s2.0-30944469849 16421368 \n2 Eliassen A. H. Missmer S. A. Tworoger S. S. Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women Journal of the National Cancer Institute 2006 98 19 1406 1415 2-s2.0-33749538836 10.1093/jnci/djj376 17018787 \n3 Shao T. Grossbard M. L. Klein P. Breast cancer in female-to-male transsexuals: Two cases with a review of physiology and management Clinical Breast Cancer 2011 11 6 417 419 2-s2.0-82255191385 10.1016/j.clbc.2011.06.006 21831723 \n4 Burcombe R. J. Makris A. Pittam M. Finer N. Breast cancer after bilateral subcutaneous mastectomy in a female-to-male trans-sexual The Breast 2003 12 4 290 293 2-s2.0-0042130370 10.1016/S0960-9776(03)00033-X 14659317 \n5 Nikolic D. V. Djordjevic M. L. Granic M. Importance of revealing a rare case of breast cancer in a female to male transsexual after bilateral mastectomy World Journal of Surgical Oncology 2012 10, article no. 280 2-s2.0-84872819613 10.1186/1477-7819-10-280 23273269 \n6 Gooren L. Bowers M. Lips P. Konings I. R. Five new cases of breast cancer in transsexual persons Andrologia 2015 47 10 1202 1205 2-s2.0-84946496220 10.1111/and.12399 25611459 \n7 Katayama Y. Motoki T. Watanabe S. A very rare case of breast cancer in a female-to-male transsexual Breast Cancer 2016 23 6 939 944 2-s2.0-84949644238 10.1007/s12282-015-0661-4 26660332 \n8 Kotsopoulos J. Narod S. A. Androgens and breast cancer Steroids 2012 77 1-2 1 9 2-s2.0-83655167086 10.1016/j.steroids.2011.10.002 22015396 \n9 Dimitrakakis C. Bondy C. Androgens and the breast Breast Cancer Research: BCR 2009 11 5 p. 212 2-s2.0-77449140006 \n10 Hembree W. C. Cohen-Kettenis P. T. Gooren L. Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline The Journal of Clinical Endocrinology & Metabolism 2017 102 11 3869 3903 10.1210/jc.2017-01658 28945902 \n11 Hartley R. L. Stone J. P. Temple-Oberle C. Breast Cancer in transgender patients: A systematic review. Part 2: Female to Male European Journal of Surgical Oncology in press\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-651X",
"issue": "2018()",
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"title": "Breast Cancer Development in a Transgender Male Receiving Testosterone Therapy.",
"title_normalized": "breast cancer development in a transgender male receiving testosterone therapy"
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"abstract": "Hematopoietic stem cell transplantation is an established treatment for many malignant and non-malignant haematological disorders. In the current case report, we describe the first haploidentical stem cell transplantation, used for the first time in Romania, the case of a 33 year-old young woman diagnosed with Hodgkin's lymphoma that has underwent a haploSCT after she relapsed from several chemotherapy regimens, as well as after an autologous stem cell transplantation. This success represents a prèmiere in Romanian clinical hematology, being the first case of a haploSCT in Romania, as well as in South-Eastern Europe.",
"affiliations": null,
"authors": "Tănase|Alina|A|;Tomuleasa|C|C|;Mărculescu|Alexandra|A|;Bardaş|A|A|;Coliţă|Anca|A|;Ciurea|Ş O|ŞO|",
"chemical_list": null,
"country": "Germany",
"delete": false,
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"issn_linking": "1220-4749",
"issue": "54(3)",
"journal": "Romanian journal of internal medicine = Revue roumaine de medecine interne",
"keywords": null,
"medline_ta": "Rom J Intern Med",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease; D006801:Humans; D012008:Recurrence; D012383:Romania; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous",
"nlm_unique_id": "9304507",
"other_id": null,
"pages": "194-200",
"pmc": null,
"pmid": "27658169",
"pubdate": "2016-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21527933;20871781;1383821;21527516;3897863;17229633;12802024;26524730;12171484;2386744;6131300;15632410;16479735;14734093;25263628;26670632;26806585;15549304;23423745;15759115;15598948",
"title": "First Successful Haploidentical Stem Cell Transplantation in Romania.",
"title_normalized": "first successful haploidentical stem cell transplantation in romania"
} | [
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"companynumb": "RO-ACCORD-044719",
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"abstract": "Recent attention on the possible use of hydroxychloroquine and chloroquine to treat COVID-19 disease has potentially triggered a number of overdoses from hydroxychloroquine. Toxicity from hydroxychloroquine manifests with cardiac conduction abnormalities, seizure activity, and muscle weakness. Recognizing this toxidrome and unique management of this toxicity is important in the COVID-19 pandemic.\n\n\n\nA 27-year-old man with a history of rheumatoid arthritis presented to the emergency department 7 hours after an intentional overdose of hydroxychloroquine. Initial presentation demonstrated proximal muscle weakness. The patient was found to have a QRS complex of 134 ms and QTc of 710 ms. He was treated with early orotracheal intubation and intravenous diazepam boluses. Due to difficulties formulating continuous diazepam infusions, we opted to utilize an intermitted intravenous bolus strategy that achieved similar effects that a continuous infusion would. The patient recovered without residual side effects.\n\n\n\nHydroxychloroquine toxicity is rare but projected to increase in frequency given its selection as a potential modality to treat COVID-19 disease. It is important for clinicians to recognize the unique effects of hydroxychloroquine poisoning and initiate appropriate emergency maneuvers to improve the outcomes in these patients.",
"affiliations": "Division of Medical Toxicology, Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA. pchai@bwh.harvard.edu.;Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.;Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.;Department of Emergency Medicine, Harvard Medical School, Boston, MA, USA.;Division of Medical Toxicology, Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.;Division of Medical Toxicology, Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.;Division of Medical Toxicology, Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.",
"authors": "Chai|Peter R|PR|0000-0003-0955-4117;Ferro|E G|EG|;Kirshenbaum|J M|JM|;Hayes|B D|BD|;Culbreth|S E|SE|;Boyer|E W|EW|;Erickson|T B|TB|",
"chemical_list": "D006886:Hydroxychloroquine; D003975:Diazepam",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-020-00790-8",
"fulltext": null,
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"issn_linking": "1556-9039",
"issue": "16(3)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": "Adverse Reactions; COVID-19; Chloroquine; Drug-Related Side Effects; hydroxycholorquine",
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D018352:Coronavirus Infections; D003975:Diazepam; D062787:Drug Overdose; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D006886:Hydroxychloroquine; D008297:Male; D058873:Pandemics; D011024:Pneumonia, Viral; D013406:Suicide, Attempted; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "314-320",
"pmc": null,
"pmid": "32514696",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "26819720;16162774;6088933;11555803;3179169;6408923;29225688;32034323;32194981;3795134;2512694;32450107;32194152;4739691;932536;32150618;8343674;8986493;10991709;16115318;3336379;26351590;3799616;3183189;450030",
"title": "Intentional Hydroxychloroquine Overdose Treated with High-Dose Diazepam: an Increasing Concern in the COVID-19 Pandemic.",
"title_normalized": "intentional hydroxychloroquine overdose treated with high dose diazepam an increasing concern in the covid 19 pandemic"
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"activesubstancename": "DIAZEPAM"
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"drugaddition... |
{
"abstract": "OBJECTIVE\nTo estimate risk of death due to cardiac arrhythmia during methadone maintenance treatment.\n\n\nBACKGROUND\nThere is evidence that methadone prolongs the QT interval, and has been associated with ventricular tachycardia in some individuals.\n\n\nMETHODS\nWe identified 51 deaths occurring during methadone treatment, occurring in a cohort with a defined exposure to methadone treatment. We obtained consent to access coronial records to investigate these in-treatment deaths in detail, to identify potential cases of fatal arrhythmia--those cases in which sudden death occurred without clear evidence of an alternate cause of death. We obtained consent to access clinic records of dosing. Two physicians reviewed the coronial files and circumstances of death. The total number of person-years exposure to methadone treatment was calculated.\n\n\nRESULTS\nThere were extensive missing data in coronial and clinic files, making definitive assessment difficult in many cases. No definite case of death due to cardiac arrhythmia was identified. There were two cases in which arrhythmia seemed possible, and 10 cases in which arrhythmia could not be excluded. The study covered 14,500 patient-years (pys) in methadone treatment, yielding an estimate from 0 to 0.069 deaths per 100 pys, with a best estimate of fatal arrhythmia occurring at a rate of 0.014 per 100 pys. Overdose is a more common cause of death. Both potential arrhythmias and overdoses were associated with use of other drugs in addition to methadone—usually, prescription drugs or methamphetamine.\n\n\nCONCLUSIONS\nThe risk of fatal cardiac arrhythmia in methadone maintenance patients appears to be low. The major risk factor for death was use of prescription drugs, and methamphetamine, in addition to methadone.",
"affiliations": "University of New SouthWales, Sydney, Australia, 2 South Eastern Sydney Illawarra Health Service, Sydney, Australia.",
"authors": "Butler|Bethany|B|;Rubin|George|G|;Lawrance|Anne|A|;Batey|Robert|R|;Bell|James|J|",
"chemical_list": "D008691:Methadone",
"country": "Australia",
"delete": false,
"doi": "10.1111/j.1465-3362.2010.00213.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-5236",
"issue": "30(2)",
"journal": "Drug and alcohol review",
"keywords": null,
"medline_ta": "Drug Alcohol Rev",
"mesh_terms": "D000328:Adult; D001145:Arrhythmias, Cardiac; D015331:Cohort Studies; D016208:Databases, Factual; D006556:Heroin Dependence; D006801:Humans; D008691:Methadone; D008875:Middle Aged; D058850:Opiate Substitution Treatment; D012307:Risk Factors; D013223:Statistics as Topic; D055815:Young Adult",
"nlm_unique_id": "9015440",
"other_id": null,
"pages": "173-80",
"pmc": null,
"pmid": "21355903",
"pubdate": "2011-03",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Estimating the risk of fatal arrhythmia in patients in methadone maintenance treatment for heroin addiction.",
"title_normalized": "estimating the risk of fatal arrhythmia in patients in methadone maintenance treatment for heroin addiction"
} | [
{
"companynumb": "GB-BAUSCH-BL-2019-002350",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHAMPHETAMINE"
},
"drugadditional": null,
... |
{
"abstract": "Warfarin continues to be the mainstay therapy for preventing thrombus formation. Although pharmacogenetic algorithms have shown higher predictability of the optimal warfarin dose and lower occurrence of bleeding episodes, they often do not include ethno-specific genetic variants relevant to non-Europeans. This case report describes a rare missense variant at exon 9 of CYP2C9 (rs202201137; c.1370A>G transition; p.Asn457Ser) found in a Puerto Rican patient with low warfarin dose requirements (3 mg/day). The haplotype characterized by two amino acid changes, Asn457Ser and Arg144Cys (rs1799853; c.430C>T), has been designated CYP2C9*61 by the Pharmacogene Variation Consortium. According to prediction scores assessed with the Combined Annotation Dependent Depletion tool, CYP2C9*61 (p.Asn457Ser) was classified as nondeleterious, therefore its impact on CYP2C9 enzymatic activity cannot be postulated.",
"affiliations": "Department of Pharmacotherapy and Translational Research, University of Florida, College of Pharmacy, Gainesville, FL 36611, USA.;Department of Pharmacology, School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936, Puerto Rico.;Department of Biochemistry, School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936, Puerto Rico.;Department of Chemistry, Rio Piedras Campus, University of Puerto Rico, San Juan, PR 00931, Puerto Rico.;Research Centers for Minorities Institutions (RCMI) - Integrated Informatics Services University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, Puerto Rico.;Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, MO 64108, USA.;Research Centers for Minorities Institutions (RCMI) - Integrated Informatics Services University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, Puerto Rico.;Department of Pharmaceutical Sciences, School of Pharmacy, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936, Puerto Rico.",
"authors": "Claudio-Campos|Karla I|KI|;González-Santiago|Pablo|P|;Renta|Jessica Y|JY|;Rodríguez|Jovaniel|J|;Carrasquillo|Kelvin|K|;Gaedigk|Andrea|A|;Roche|Abiel|A|;Ducongé|Jorge|J|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9",
"country": "England",
"delete": false,
"doi": "10.2217/pgs-2018-0143",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-2416",
"issue": "20(1)",
"journal": "Pharmacogenomics",
"keywords": " ; Hispanics; anticoagulation; haplotype; next-generation sequencing; pharmacogenetics (PGx); warfarin",
"medline_ta": "Pharmacogenomics",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D065729:Cytochrome P-450 CYP2C9; D005838:Genotype; D006630:Hispanic or Latino; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010597:Pharmacogenetics; D014859:Warfarin",
"nlm_unique_id": "100897350",
"other_id": null,
"pages": "3-8",
"pmc": null,
"pmid": "30518301",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "20375999;17924348;17047216;29134625;23215886;19663669;19794411;24657685;11455026;2687096;23215885;26745506;19228618;22274142;14676821;28638342;18305455;20072124;19300499;21110192;22491019",
"title": "CYP2C9*61, a rare missense variant identified in a Puerto Rican patient with low warfarin dose requirements.",
"title_normalized": "cyp2c9 61 a rare missense variant identified in a puerto rican patient with low warfarin dose requirements"
} | [
{
"companynumb": "US-TEVA-2019-US-1001591",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "1",
"... |
{
"abstract": "Drug induced hyperthermia is a rare presentation which can rapidly lead to gross metabolic abnormality and death. These presentations are further complicated by the wide range of potentially causative agents. We present a case of rigidity and hyperthermia, following overdose of an initially unknown substance leading to challenging management decisions in the Emergency Department. This case was later identified as Serotonin Syndrome. The patient presented with trismus which was managed with rapid sequence induction of anaesthesia to allow airway protection. On extubation a significant degree of laryngeal oedema complicated weaning, a possible complication of Serotonin Syndrome not previously described in the literature. We discuss the pathophysiology of Serotonin Syndrome, important differentials and practical considerations in managing hypertonicity of unknown origin in a young person.",
"affiliations": "Core Trainee in Emergency Medicine, Morriston Hospital, Swansea, UK.;Specialist Registrar in Anaesthetics, Morriston Hospital, Swansea, UK.;Specialist Registrar in Emergency Medicine, Morriston Hospital, Swansea, UK.;Consultant in Emergency and Intensive Care Medicine, Morriston Hospital, Swansea, UK.",
"authors": "Dean-Paccagnella|Rose|R|;Creed|Matthew|M|;Kakollu|Mahendra|M|;Gopala Pillai|Suresh Kumar|SK|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": "10.29252/beat-060311",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2322-2522",
"issue": "6(3)",
"journal": "Bulletin of emergency and trauma",
"keywords": "Hyperthermia; Hypertonicity; Overdose; Serotonin syndrome",
"medline_ta": "Bull Emerg Trauma",
"mesh_terms": null,
"nlm_unique_id": "101614018",
"other_id": null,
"pages": "249-252",
"pmc": null,
"pmid": "30090822",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports",
"references": "28979436;25622200;22719217;24455378;24358002;25860609;29207768;25689750;27999518;26019424;16923659",
"title": "Hyperthermia and Rigidity Following Overdose of an Unknown Drug; A Case Report and Literature Review.",
"title_normalized": "hyperthermia and rigidity following overdose of an unknown drug a case report and literature review"
} | [
{
"companynumb": "GB-BAUSCH-BL-2018-028808",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nAcute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Relapse of ALL occurs in 15%-20% of patients, with 2%-6% occurring exclusively in extramedullary sites. Relapse of ALL in gynecologic organs is extremely rare.\n\n\nMETHODS\nWe present a case of a 12-year-old girl with a history of ALL who was referred to the pediatric gynecology clinic with abnormal uterine bleeding. She was determined to have an extramedullary uterine relapse of her ALL.\n\n\nCONCLUSIONS\nAbnormal uterine bleeding in the setting of childhood malignancy is a frequent reason for consultation to pediatric and adolescent gynecology services. This bleeding is commonly attributed to thrombocytopenia due to bone marrow suppressive chemotherapeutic agents. However, as shown in this report, abnormal uterine bleeding might be a manifestation of an extramedullary relapse.",
"affiliations": "Division of Pediatric and Adolescent Gynecology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama.;Division of Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.;Division of Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama; Pediatric Blood and Marrow Transplant Program, University of Alabama at Birmingham, Birmingham, Alabama.;Division of Pediatric and Adolescent Gynecology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama. Electronic address: jarbuckle@uabmc.edu.",
"authors": "Robillard|Diana T|DT|;Kutny|Matthew A|MA|;Chewning|Joseph H|JH|;Arbuckle|Janeen L|JL|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpag.2016.12.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-3188",
"issue": "30(3)",
"journal": "Journal of pediatric and adolescent gynecology",
"keywords": "Abnormal uterine bleeding; Acute lymphoblastic leukemia; Adolescent; Extramedullary relapse",
"medline_ta": "J Pediatr Adolesc Gynecol",
"mesh_terms": "D000970:Antineoplastic Agents; D002648:Child; D005260:Female; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012008:Recurrence; D014592:Uterine Hemorrhage; D014594:Uterine Neoplasms; D014599:Uterus",
"nlm_unique_id": "9610774",
"other_id": null,
"pages": "431-434",
"pmc": null,
"pmid": "28062243",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Extramedullary Relapse of Acute Lymphoblastic Leukemia Presenting as Abnormal Uterine Bleeding: A Case Report.",
"title_normalized": "extramedullary relapse of acute lymphoblastic leukemia presenting as abnormal uterine bleeding a case report"
} | [
{
"companynumb": "US-RECORDATI RARE DISEASES-US-R13005-17-00102",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPARAGINASE"
},
"drugad... |
{
"abstract": "BACKGROUND\nPlasmablastic myeloma is an aggressive subtype of multiple myeloma with overall poor prognosis. Spinal cord compression and hyperammonemic encephalopathy are two grave complications of multiple myeloma with significantly poor survival outcomes.\n\n\nMETHODS\nA 49-year-old male presented with a 5-day history of worsening abdominal distention with inability to walk, urinate or defecate. Imaging findings of innumerable spinal osteolytic lesions with paraspinal masses coupled with a bone marrow biopsy of ≥70% plasmablasts confirmed the diagnosis of plasmablastic myeloma. Despite spinal decompression surgery, the patient remained paraplegic. Three myeloma-directed chemotherapies failed, eventually leading to him developing hyperammonemic encephalopathy culminating in his death.\n\n\nCONCLUSIONS\nPlasmablastic myeloma is a rare entity which poses therapeutic challenges especially in patients with negative prognosticators, including high-risk cytogenetic markers, extraosseous involvement with cord compression and hyperammonemic encephalopathy. Early aggressive management with consideration of novel therapeutic alternatives, especially in treatment refractory disease, can be worthwhile.",
"affiliations": "Department of Internal Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, U.S.A.; da1ha@hotmail.com.;Department of Pathology, Texas Tech University Health Sciences Center El Paso, El Paso, TX, U.S.A.;Department of Internal Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, U.S.A.",
"authors": "Dah|Kingsley|K|;Lavezo|Jonathan L|JL|;Dihowm|Fatma|F|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.15403",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "41(11)",
"journal": "Anticancer research",
"keywords": "Multiple myeloma; hyperammonemic encephalopathy; plasmablastic myeloma; spinal cord compression",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000970:Antineoplastic Agents; D001927:Brain Diseases; D019299:Decompression, Surgical; D018450:Disease Progression; D017809:Fatal Outcome; D006801:Humans; D022124:Hyperammonemia; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D013117:Spinal Cord Compression; D017211:Treatment Failure",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "5839-5845",
"pmc": null,
"pmid": "34732460",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Aggressive Plasmablastic Myeloma With Extramedullary Cord Compression and Hyperammonemic Encephalopathy: Case Report and Literature Review.",
"title_normalized": "aggressive plasmablastic myeloma with extramedullary cord compression and hyperammonemic encephalopathy case report and literature review"
} | [
{
"companynumb": "US-drreddys-LIT/USA/21/0144603",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": null,
... |
{
"abstract": "We present a patient with systemic lupus erythematosus receiving long-term steroid therapy, who had myometrial thinning, markedly thickened placenta, and fetal growth restriction (FGR). Blood flow profiles of the myometrium, decidua and placental villous vessels (VV) were described using superb microvascular imaging (SMI) at 35 weeks' gestation. Images showed no decidual blood flow underneath the placenta sitting on a thin myometrium and sparse VV distribution and non-visualization of peripheral VV flow. Emergency cesarean hysterectomy was performed at 36 weeks. Histological findings showed missing decidua on the thin myometrium, which indicated placenta accreta spectrum, and massive perivillous fibrin deposition and increased numbers of syncytial knots in the placenta. We speculated that the thick placenta and peculiar VV flow profiles resulted from congestion of the intervillous space and intervillous underperfusion/low intraplacental oxygenation, respectively, resulting in FGR. Superb microvascular imaging is useful for diagnosing placenta accreta spectrum and understanding the pathophysiology of thick placenta and FGR.",
"affiliations": "Department of Obstetrics and Gynecology, School of Medicine, Kurume University, Kurume, Japan.;Department of Obstetrics and Gynecology, School of Medicine, Kurume University, Kurume, Japan.;Department of Obstetrics and Gynecology, School of Medicine, Kurume University, Kurume, Japan.;Department of Pathology, School of Medicine, Kurume University, Kurume, Japan.;Department of Obstetrics and Gynecology, School of Medicine, Kurume University, Kurume, Japan.;Department of Obstetrics and Gynecology, School of Medicine, Kurume University, Kurume, Japan.",
"authors": "Inoue|Asami|A|;Horinouchi|Takashi|T|;Yoshizato|Toshiyuki|T|;Kojiro-Sanada|Sakiko|S|;Kozuma|Yutaka|Y|;Ushijima|Kimio|K|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.14502",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": null,
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "chorion; myometrium; placenta accreta; systemic lupus erythematosus, ultrasonography",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": null,
"nlm_unique_id": "9612761",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33047457",
"pubdate": "2020-10-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Peculiar blood flow profiles among placental chorionic villous vessels of an abnormally thick placenta in a case of systemic lupus erythematosus characterized using microvascular imaging.",
"title_normalized": "peculiar blood flow profiles among placental chorionic villous vessels of an abnormally thick placenta in a case of systemic lupus erythematosus characterized using microvascular imaging"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1871986",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Endogenous Endophthalmitis (EE) is a rare cause of blindness in the pediatric age group and this may account for the paucity of management guidelines in the literature. In this report, we describe our experience with a 10-year-old immunocompetent female who developed EE and became blind because of rapidly progressive and destructive inflammatory changes in her eye in spite of seemingly timely treatment.",
"affiliations": "Department of Basic Medical Sciences, Neurosciences and Sense Organs, Institute of Ophthalmology, University of Bari, Bari, Italy.;Department of Basic Medical Sciences, Neurosciences and Sense Organs, Institute of Ophthalmology, University of Bari, Bari, Italy.;Department of Basic Medical Sciences, Neurosciences and Sense Organs, Institute of Ophthalmology, University of Bari, Bari, Italy.;Department of Basic Medical Sciences, Neurosciences and Sense Organs, Institute of Ophthalmology, University of Bari, Bari, Italy.;Department of Basic Medical Sciences, Neurosciences and Sense Organs, Institute of Ophthalmology, University of Bari, Bari, Italy.;Department of Basic Medical Sciences, Neurosciences and Sense Organs, Institute of Ophthalmology, University of Bari, Bari, Italy.;Department of Basic Medical Sciences, Neurosciences and Sense Organs, Institute of Ophthalmology, University of Bari, Bari, Italy.",
"authors": "Guerriero|Silvana|S|;Dammacco|Rosanna|R|;Albano|Valeria|V|https://orcid.org/0000-0002-6193-3299;Rizzo|Tiziana|T|;Cassano|Flavio|F|;Boscia|Francesco|F|;Alessio|Giovanni|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/11206721211037825",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": null,
"journal": "European journal of ophthalmology",
"keywords": "Aspergillus infection; Endophthalmitis; endogenous fungal endophthalmitis; fungal orbital infection; pediatric endophthalmitis",
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "11206721211037825",
"pmc": null,
"pmid": "34405721",
"pubdate": "2021-08-18",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A 10-year-old immunocompetent girl with endogenous fungal endophthalmitis: Report of a case and review of the literature.",
"title_normalized": "a 10 year old immunocompetent girl with endogenous fungal endophthalmitis report of a case and review of the literature"
} | [
{
"companynumb": "IT-GLAXOSMITHKLINE-IT2022GSK026053",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BECLOMETHASONE DIPROPIONATE"
},
"dru... |
{
"abstract": "Membranoproliferative glomerulonephritis is known to recur after kidney transplantation and may lead to allograft loss. Although an optimal treatment has not been determined, B-cell targeted therapies are now increasingly used as first-line agents, based on growing data showing antibodies as key players in the pathogenesis of membranoproliferative glomerulonephritis. Here, we report a case of recurrent immune complex-mediated membranoproliferative glomerulonephritis 3 years after a living-donor kidney transplant. Treatment with plasmapheresis and rituximab resulted in immediate and sustained improvement in allograft function.
.",
"affiliations": null,
"authors": "Yango|Angelito F|AF|;Fischbach|Bernard V|BV|;Ruiz|Richard|R|;Mudrovich|Steven|S|;Klintmalm|Goran|G|",
"chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab",
"country": "Germany",
"delete": false,
"doi": "10.5414/CN109451",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0430",
"issue": "91(1)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D005260:Female; D015432:Glomerulonephritis, Membranoproliferative; D006801:Humans; D007155:Immunologic Factors; D016030:Kidney Transplantation; D008875:Middle Aged; D010956:Plasmapheresis; D012008:Recurrence; D000069283:Rituximab; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "52-58",
"pmc": null,
"pmid": "30431428",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Treatment of recurrent, post-kidney transplant membranoproliferative glomerulonephritis with plasmapheresis and rituximab: A case report and literature review
.",
"title_normalized": "treatment of recurrent post kidney transplant membranoproliferative glomerulonephritis with plasmapheresis and rituximab a case report and literature review"
} | [
{
"companynumb": "US-ASTELLAS-2019US005441",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nErenumab, a calcitonin gene-related peptide (CGRP) receptor monoclonal antibody, has been well tolerated with good efficacy for the preventive treatment of episodic and chronic migraine in phase 2 and phase 3 clinical trials. Limited post-market observations are available to validate these findings in a real-world tertiary headache clinic population with complex comorbidities and refractory migraine.\n\n\nOBJECTIVE\nThe goal of this study is to demonstrate the real-world performance of erenumab among patients in a tertiary care headache clinic by describing patient selection, experience, and clinical characteristics after 6 months of erenumab therapy.\n\n\nMETHODS\nA retrospective, exploratory, observational study was conducted on patients receiving at least 1 erenumab injection (70 or 140 mg). Baseline data obtained by chart review and telephone calls were compared to 6-month follow-up telephone calls. The primary outcome was the reduction in self-reported headache days per month at baseline compared to 6 months for those with complete 6-month data. The significance level was set at P < .05. Secondary analyses explored the distribution of headache severity, responder rates, Migraine Disability Assessment scores, adverse effects, ineffective preventives, comorbidities, wearing-off, and discontinuation.\n\n\nRESULTS\nOf the 101 patients who consented to participate, 89.1% (90/101) were women, and the mean age of all patients was 49 years (range, 19-80 years). At baseline, 94.1% (95/101) of patients had chronic migraine, 5.0% (5/101) had episodic migraine, and 18.8% (19/101) had medication overuse headache. The mean (SD) number of baseline headache and migraine days per month for the entire cohort were 24.3 (8.2) and 18.2 (9.3) days, respectively. Participants had numerous comorbidities and had tried a mean of 11.2 unique oral medications and 4.8 unique medication categories before receiving erenumab, including 83.2% (84/101) who had also received onabotulinumtoxinA. Six-month post-erenumab follow-up data were available for 42.6% (43/101) of participants. For these 43 participants, the number of headache days per month decreased significantly by 6.5 days from a baseline mean (SD) of 24.8 (6.47) days to 18.3 (12) days at 6-month follow-up (P < .001); similarly, the monthly migraine days decreased significantly by 8.4 days from a baseline mean of 19.1 (9.3) days to 10.7 days at 6-month follow-up (P < .001). The 50% responder rate was 34.9% (15/43) for monthly headache days and 54.8% (23/43) for monthly migraine days. Of all 101 participants, 28 (27.7%) discontinued erenumab, primarily because it was ineffective (39.3%, 11/28) or because of adverse effects (42.9%, 12/28).\n\n\nCONCLUSIONS\nThis post-market observational study of patient experience describes response to erenumab in a real-world tertiary headache clinic with a complex patient population. Overall, these complex patients had a significant positive clinical response to erenumab, but with high rates of discontinuation. This study also noted a 1-week wearing-off response and high rates of constipation. Further post-market studies are needed to better characterize patient selection and real-world response to erenumab.",
"affiliations": "Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.;Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA.;Division of Neurology, Mayo Clinic, Scottsdale, AZ, USA.;Division of Neurology, Mayo Clinic, Scottsdale, AZ, USA.;Division of Neurology, Mayo Clinic, Scottsdale, AZ, USA.;Division of Neurology, Mayo Clinic, Scottsdale, AZ, USA.",
"authors": "Robblee|Jennifer|J|https://orcid.org/0000-0002-2556-1125;Devick|Katrina L|KL|;Mendez|Natasha|N|;Potter|Jamie|J|;Slonaker|Jennifer|J|;Starling|Amaal J|AJ|https://orcid.org/0000-0003-1334-1157",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C000605816:erenumab",
"country": "United States",
"delete": false,
"doi": "10.1111/head.13951",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-8748",
"issue": "60(9)",
"journal": "Headache",
"keywords": "erenumab; headache; migraine; monoclonal antibody; preventive treatment",
"medline_ta": "Headache",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders; D000071066:Patient Reported Outcome Measures; D012189:Retrospective Studies; D062606:Tertiary Care Centers; D055815:Young Adult",
"nlm_unique_id": "2985091R",
"other_id": null,
"pages": "2014-2025",
"pmc": null,
"pmid": "32920850",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Real-World Patient Experience With Erenumab for the Preventive Treatment of Migraine.",
"title_normalized": "real world patient experience with erenumab for the preventive treatment of migraine"
} | [
{
"companynumb": "US-AMGEN-USASP2020153540",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERENUMAB-AOOE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe treatment of newly diagnosed type 2 diabetes mellitus is diverse, with no clear consensus regarding the initial drug regimen or dosing to achieve optimal glycemic control.\n\n\nMETHODS\nWe treated 44 consecutive patients with newly diagnosed type 2 diabetes with maximally tolerated doses of pioglitazone 45 mg/day, metformin 1000-2000 mg/day, and repaglinide 1-4 mg before meals. The doses and drugs were subsequently decreased (\"subtraction therapy\") to achieve optimal glycemic control and minimize side effects. Three primary outcomes were measured: the short term HbA1c response, the long term HbA1c response, and the incidence of hypoglycemia.\n\n\nRESULTS\nAll 44 patients responded with a rapid, progressive decline in their HbA1c levels from 11.43±2.3% to 6.17±0.72% (101±25.1 mmol/mol to 44±7.9 mmol/mol) by three months, and remained stable thereafter. An HbA1c ≤7.0% (≤53 mmol/mol) was reached within 1-4 months in 42 of 44 patients, and in every patient by 12 months. Each patient's lowest HbA1c level, 5.65±0.6% (38±6.6 mmol/mol), was reached over 6.3±2.9 months. Patients with initial HbA1c levels >10% (>86 mmol/mol) (n=33) responded similarly as those with HbA1c levels <10% (<86 mmol/mol) (n=11). Combination drug therapy maintained HbA1c levels between 5.0 and 7.0% (31 and 53 mmol/mol) for up to 14.83 years. Only one clinically significant hypoglycemic event occurred during 261.08 person-years of follow-up.\n\n\nCONCLUSIONS\nIn our experience, combination drug \"subtraction therapy\" was safe and effective for treating all newly diagnosed type 2 diabetic patients.",
"affiliations": "Virtua Health System, Covered Bridge Medical Center, 27 Covered Bridge Rd., Cherry Hill, NJ, 08034. Electronic address: anthonysjennings111@gmail.com.;Harvard Neurology Partners Program, Massachusetts General Hospital/Brigham and Women's Hospital, 55 Fruit St., WACC 720, Boston, MA, 02114.;Virtua Health System, Covered Bridge Medical Center, 27 Covered Bridge Rd., Cherry Hill, NJ, 08034.;Virtua Health System, Covered Bridge Medical Center, 27 Covered Bridge Rd., Cherry Hill, NJ, 08034.",
"authors": "Jennings|Anthony S|AS|;Lovett|Alexandra J|AJ|;George|Tina M|TM|;Jennings|Jonathan S|JS|",
"chemical_list": "D002219:Carbamates; D006442:Glycated Hemoglobin A; D007004:Hypoglycemic Agents; D010880:Piperidines; D045162:Thiazolidinediones; C072379:repaglinide; D008687:Metformin; D000077205:Pioglitazone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0026-0495",
"issue": "64(9)",
"journal": "Metabolism: clinical and experimental",
"keywords": "Combination drug therapy; Durability; Subtraction therapy; Treatment efficacy; Type 2 diabetes",
"medline_ta": "Metabolism",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002219:Carbamates; D003924:Diabetes Mellitus, Type 2; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006442:Glycated Hemoglobin A; D006040:Goals; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D008875:Middle Aged; D000077205:Pioglitazone; D010880:Piperidines; D045162:Thiazolidinediones; D016896:Treatment Outcome",
"nlm_unique_id": "0375267",
"other_id": null,
"pages": "1005-12",
"pmc": null,
"pmid": "26003501",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Getting to goal in newly diagnosed type 2 diabetes using combination drug \"subtraction therapy\".",
"title_normalized": "getting to goal in newly diagnosed type 2 diabetes using combination drug subtraction therapy"
} | [
{
"companynumb": "US-TAKEDA-2015TEU009839",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "REPAGLINIDE"
},
"drugadditional": null,
... |
{
"abstract": "We report the first case of enterovirus-D68 infection in an adult living-donor kidney transplant recipient who developed rapidly progressive bulbar weakness and acute flaccid limb paralysis following an upper respiratory infection. We present a 45-year-old gentleman who underwent pre-emptive living-donor kidney transplantation for IgA nephropathy. Eight weeks following transplantation, he developed an acute respiratory illness from enterovirus/rhinovirus that was detectable in nasopharyngeal (NP) swabs. Within 24 h of onset of respiratory symptoms, the patient developed binocular diplopia which rapidly progressed to multiple cranial nerve dysfunctions (acute bulbar syndrome) over the next 24 h. Within the next 48 h, asymmetric flaccid paralysis of the left arm and urinary retention developed. While his neurological symptoms were evolving, the Centers for Disease Control reported that the enterovirus strain from the NP swabs was, in fact, Enterovirus-D68 (EV-D68). Magnetic resonance imaging of the brain demonstrated unique gray matter and anterior horn cell changes in the midbrain and spinal cord, respectively. Constellation of these neurological symptoms and signs was suggestive for postinfectious encephalomyelitis (acute disseminated encephalomyelitis [ADEM]) from EV-D68. Treatment based on the principles of ADEM included intensive physical therapy and other supportive measures, which resulted in a steady albeit slow improvement in his left arm and bulbar weakness, while maintaining stable allograft function.",
"affiliations": "Department of Surgery and Medicine, Inova Transplant Center, Falls Church, VA.;Department of Radiology, Inova Health System, Falls Church, VA.;Department of Nephrology, George Washington School of Medicine, Washington, DC.;Department of Surgery, Inova Transplant Center, Falls Church, VA.;Department of Surgery, Inova Transplant Center, Falls Church, VA.;Department of Infectious Disease, Inova Health System, Falls Church, VA.;Department of Infectious Disease, Inova Health System, Falls Church, VA.;Department of Surgery, Inova Transplant Center, Falls Church, VA.;Department of Medicine, Virginia Commonwealth University, Richmond, VA.;Department of Neurology, Inova Health System, Falls Church, VA.;Department of Neurology, Inova Health System, Falls Church, VA.;Department of Pulmonary and Critical Care, Inova Health System, Falls Church, VA.",
"authors": "Wali|R K|RK|;Lee|A H|AH|;Kam|J C|JC|;Jonsson|J|J|;Thatcher|A|A|;Poretz|D|D|;Ambardar|S|S|;Piper|J|J|;Lynch|C|C|;Kulkarni|S|S|;Cochran|J|J|;Djurkovic|S|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.13398",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "15(12)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "Clinical research/practice; complication: infectious; diagnostic techniques and imaging: magnetic resonance imaging; encephalopathy; infection and infectious agents; infectious disease; kidney transplantation/nephrology; viral",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D001927:Brain Diseases; D030016:Enterovirus D, Human; D004769:Enterovirus Infections; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D010264:Paraplegia; D011183:Postoperative Complications; D011379:Prognosis; D012307:Risk Factors; D066027:Transplant Recipients",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "3224-8",
"pmc": null,
"pmid": "26228743",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Neurological Illness in a Kidney Transplant Recipient Following Infection With Enterovirus-D68: An Emerging Infection?",
"title_normalized": "acute neurological illness in a kidney transplant recipient following infection with enterovirus d68 an emerging infection"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0055808",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe aim of this prospective study was to evaluate the efficacy and safety of extracorporeal photopheresis (ECP) in patients with bronchiolitis obliterans syndrome (BOS) after lung transplantation and to identify factors predicting treatment response.\n\n\nMETHODS\nThe study was performed at a single center and consisted of a cohort of 1,012 lung transplant recipients (November 1989-June 2010). A total of 194 patients developed BOS after a mean of 1,293 ± 1,008 days (range, 99-4,949 days) and received established treatment, and 51 patients received additional ECP.\n\n\nRESULTS\nThirty-one (61%) of the ECP-treated patients responded to the therapy and showed sustained stabilization (forced expiratory volume in 1 second range, -5% to 5% vs baseline at start of ECP) of lung function over 6 months. Responders to ECP showed significantly greater survival and less need for retransplantation (p = 0.001) than non-responders. Factors associated with an inferior treatment response were cystic fibrosis as underlying lung disease and a longer time between transplantation and development of BOS. No side effects were observed after ECP. Compared with BOS patients not treated with ECP, the ECP responders showed an improved graft survival (p = 0.05).\n\n\nCONCLUSIONS\nThese results confirm and suggest that early use of ECP could be an effective adjunct treatment for patients who develop BOS after lung transplantation.",
"affiliations": "Department of Thoracic Surgery, University Hospital Vienna, Vienna, Austria. peter.jaksch@meduniwien.ac.at",
"authors": "Jaksch|Peter|P|;Scheed|Axel|A|;Keplinger|Maya|M|;Ernst|Mai-Britt|MB|;Dani|Theresa|T|;Just|Ulrike|U|;Nahavandi|Hesam|H|;Klepetko|Walter|W|;Knobler|Robert|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.healun.2012.05.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-2498",
"issue": "31(9)",
"journal": "The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation",
"keywords": null,
"medline_ta": "J Heart Lung Transplant",
"mesh_terms": "D001989:Bronchiolitis Obliterans; D005260:Female; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D017893:Photopheresis; D011446:Prospective Studies; D013577:Syndrome",
"nlm_unique_id": "9102703",
"other_id": null,
"pages": "950-7",
"pmc": null,
"pmid": "22884382",
"pubdate": "2012-09",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A prospective interventional study on the use of extracorporeal photopheresis in patients with bronchiolitis obliterans syndrome after lung transplantation.",
"title_normalized": "a prospective interventional study on the use of extracorporeal photopheresis in patients with bronchiolitis obliterans syndrome after lung transplantation"
} | [
{
"companynumb": "AT-MALLINCKRODT-T201803623",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional":... |
{
"abstract": "C3 glomerulopathy, a newly designated entity, is characterized by glomerular disease associated with dysregulation of the alternative complement pathway and is a rare cause of end-stage kidney disease. Overall disease characteristics that include clinical presentation, laboratory assessment, histopathology and genetic background have only been unravelled in recent years and have led to the development of anti-complement therapies targeting different levels of the alternative pathway. We describe the long-term outcomes following kidney transplantation in an Irish family with familial C3 glomerulopathy due to a hybrid CFHR3-1 gene.",
"affiliations": "Department of Nephrology , Beaumont Hospital , Dublin , Ireland.;Department of Nephrology , Beaumont Hospital , Dublin , Ireland.;Department of Nephrology , Tallaght Hospital , Dublin , Ireland.;Department of Renal Pathology, Beaumont Hospital, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland.;Department of Nephrology, Beaumont Hospital, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland.",
"authors": "Wong|Limy|L|;Moran|Sarah|S|;Lavin|Peter J|PJ|;Dorman|Anthony M|AM|;Conlon|Peter J|PJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ckj/sfw020",
"fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjndtplusClinical Kidney Journal2048-85052048-8513Oxford University Press 10.1093/ckj/sfw020sfw020Transplantation and GlomerulonephritisKidney transplant outcomes in familial C3 glomerulopathy Wong Limy 1Moran Sarah 1Lavin Peter J. 2Dorman Anthony M. 34Conlon Peter J. 141 Department of Nephrology, Beaumont Hospital, Dublin, Ireland2 Department of Nephrology, Tallaght Hospital, Dublin, Ireland3 Department of Renal Pathology, Beaumont Hospital, Dublin, Ireland4 Royal College of Surgeons in Ireland, Dublin, IrelandCorrespondence and offprint requests to: Limy Wong; E-mail: limywong@gmail.com6 2016 14 4 2016 14 4 2016 9 3 403 407 2 1 2016 29 2 2016 © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.2016This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comC3 glomerulopathy, a newly designated entity, is characterized by glomerular disease associated with dysregulation of the alternative complement pathway and is a rare cause of end-stage kidney disease. Overall disease characteristics that include clinical presentation, laboratory assessment, histopathology and genetic background have only been unravelled in recent years and have led to the development of anti-complement therapies targeting different levels of the alternative pathway. We describe the long-term outcomes following kidney transplantation in an Irish family with familial C3 glomerulopathy due to a hybrid CFHR3-1 gene.\n\ncomplementgraft functiongraft survivalkidney transplantation\n==== Body\nIntroduction\nC3 glomerulopathy is a new clinical entity describing complement-mediated glomerular pathology as a result of genetic or acquired defects in the regulation of the alternative complement pathway and is pathologically characterized by the deposition of C3 in the glomerulus in the absence of significant immunoglobulin [1]. The term encompasses dense deposit disease (DDD), previously known as membranoproliferative glomerulonephritis (MPGN) type II, C3 glomerulonephritis (C3GN) and complement factor H-related protein 5 (CFHR5) nephropathy. Electron dense deposits are seen within the glomerulus in all forms of C3 glomerulopathy. DDD is distinguished by the presence of intensely osmiophilic, ribbon-like electron dense material in the intramembranous location with associated transformation of the glomerular basement membrane [2]. In C3GN, the deposits are less discrete, more ill-defined and found in the mesangium and capillary walls in various combinations including subendothelial, intramembranous and subepithelial locations, with a similar description designated for MPGN type III [3, 4].\n\nThe age of presentation for C3 glomerulopathy can vary widely. DDD is frequently diagnosed in children and young adults while the other forms are found in an older age group. Presenting features consist of proteinuria, haematuria, hypertension and progressive renal failure, leading to end-stage kidney disease (ESKD) in 36–50% of patients [3, 5]. Genetic factors have been identified in cohorts of patients with C3 glomerulopathy and these include mutations in the complement regulatory protein factor H (CFH), factor I (CFI), CD46 (also known as membrane cofactor protein) [3], C3 [6], as well as genomic rearrangements within the complement factor H-related (CFHR) genes, such as internal duplication of the CFHR5 gene [7] and CFHR1 gene [8] and chromosomal deletion of the CFHR gene cluster leading to expression of a CFHR2-CFHR5 hybrid plasma protein [9]. An Irish family was first reported with autosomal dominant MPGN type III and linkage to the regulators of complement activation locus (chromosome 1q) was demonstrated more than a decade ago [10, 11]. A hybrid CFHR3-1 gene was subsequently identified, encoding an abnormal CFHR3-1 protein in eight affected family members over three generations (Figure 1) [12], of which five received kidney transplants. The outcomes of kidney transplantation in patients with C3G are generally favourable, although recurrence of disease in the allograft is common, reducing the overall allograft survival [13–16]. We describe the outcomes of kidney transplantation in this family (Table 1).\nTable 1. Characteristics of all five affected family members who underwent kidney transplantation\n\n\tCase index\t\nCharacteristics\t103\t105\t212\t213\t214\t\nAge of diagnosis (years)\t25\t51\t28\t4\t21\t\nNumber of kidney transplants\t2\t1\t1\t3\t1\t\nAge at 1st tx (years)\t51\t59\t34\t11\t31\t\nStatus of 1st tx\tNF\tF\tF\tNF\tF\t\nAge at 2nd tx (years)\t72\t–\t–\t24\t–\t\nStatus of 2nd tx\tF\t–\t–\tNF\t–\t\nAge at 3rd tx (years)\t–\t–\t–\t41\t–\t\nStatus of 3rd tx\t–\t–\t–\tF\t–\t\n1st graft survival (months)\t116\t129 (follow-up)\t105 (follow-up)\t79\t49 (follow-up)\t\n2nd graft survival (months)\t9 (follow-up)\t–\t–\t170\t–\t\n3rd graft survival (months)\t–\t–\t–\t5 (follow-up)\t–\t\nRecurrence in graft\tYes (bx proven)\t–\tYes (bx proven)\tYes (bx proven)\t–\t\nTime to recurrence (months)\t101\t–\t93\t0.5\t–\t\nCreatinine (µmol/L)\t90\t137\t105\t120\t74\t\nUPCR (mg/mmol)\t39\t10\t179\t10\t13\t\nbx, biopsy; tx, transplant; Status of transplant: NF, non-functioning; F, functioning.\n\n\nFig. 1. Pedigree with familial C3 glomerulopathy. Affected individuals were confirmed on renal biopsy and probable affected members had abnormal urinalysis with either significant proteinuria (at least 3+ or >300 mg over 24 h) or haematuria (at least 3+ on two occasions).\n\n\n\nCase presentation\nCase index 103\nShe was first diagnosed with C3GN at the age of 25 years and progressed to end-stage kidney disease (ESKD) when she was 47 years old. She was on haemodialysis for 4 years prior to her first deceased donor kidney transplant [human leucocyte antigen mismatch (HLA MM) 1-1-0; panel reactive antibody (PRA) 5%; donation after brain death (DBD); donor age 20 years; donor creatinine 139 µmol/L]. She was noted to have slowly rising creatinine and proteinuria (3.2 g/24 h) approximately 8 years post-transplant. Transplant biopsy revealed features of a membranoproliferative pattern of injury. A large number of electron dense deposits were seen both in the mesangial regions and in the subendothelial aspect of the capillary walls that correlated with the findings of significant amounts of C3 by the direct immunofluorescence (DIF) technique, confirming disease recurrence in the allograft. Her allograft continued to deteriorate and she eventually returned to haemodialysis 9 years and 8 months post-transplant. The time from transplant to disease recurrence in the allograft was 101 months. Following this, she underwent a second deceased donor kidney transplant at the age of 72 years (HLA MM 0-1-2; PRA 100%; DBD; donor age 44 years; donor creatinine 60 µmol/L). At her most recent follow-up, her serum creatinine was 93 µmol/L (eGFR 51 mL/min) and urine protein:creatinine ratio (UPCR) was 39 mg/mmol. Her current immunosuppressive regimen consists of tacrolimus, mycophenolate mofetil (MMF) and prednisolone (Table 2).\nTable 2. Characteristics of the donor kidneys\n\nCase index\tTransplant\tHLA MM\tPRA (%)\tDonor type\tDonor age (years)\tDonor creatinine (µmol/L)\t\n103\t1st\t1-1-0\t5\tDBD\t20\t139\t\n103\t2nd\t0-1-2\t100\tDBD\t44\t60\t\n105\t1st\t1-2-1\t10\tDBD\t52\t68\t\n212\t1st\t0-1-0\t5\tDBD\t22\t105\t\n213\t1st\t1-1-1\t84\tLD\t39\tNormal rangea\t\n213\t2nd\t1-1-2\t85\tDBD\t43\t76\t\n213\t3rd\t0-0-0\t100\tLD\t33\t77\t\n214\t1st\t1-2-2\t5\tDBD\t18\t48\t\nHLA MM, human leucocyte antigen mismatch; PRA, panel reactive antibody; DBD, donation after brain death; LD, living donation.\n\naActual figure is not available.\n\n\n\nCase index 105\nHe was first diagnosed with C3GN at the age of 51 years when he presented with hypertension, proteinuria, haematuria and renal impairment. He had previously donated a kidney to his son (case index 213) 12 years prior to presentation. A native kidney biopsy showed a membranoproliferative pattern of injury with large amounts of capillary wall C3 by DIF. On electron microscopy, immune deposits were seen in the distribution of the mesangial regions as well as the subendothelial, intramembranous and subepithelial aspects of the capillary loops. Despite treatment with prednisolone and pulsed cyclophosphamide, he progressed to ESKD and began peritoneal dialysis (PD). He received a deceased donor kidney transplant 1 year later (HLA MM 1-2-1; PRA 10%; DBD; donor age 52 years; donor creatinine 68 µmol/L). His graft function remains stable at his most recent follow-up (129 months post-transplantation) with a serum creatinine of 137 µmol/L (eGFR 43 mL/min) and UPCR of 10 mg/mmol. His immunosuppressive regimen consists of tacrolimus, MMF and prednisolone.\n\nCase index 212\nHe was first diagnosed with C3GN at the age of 28 years. He progressed to ESKD within a 5-year period and was commenced on PD. He subsequently received a deceased donor kidney transplant (HLA MM 0-1-0; PGEN 5%; DBD; donor age 22 years; donor creatinine 105 µmol/L). His immunosuppressive regimen consists of tacrolimus and MMF. He developed significant proteinuria (1.8 g/24 h) a few years following transplant and a transplant biopsy showed features of recurrence of MPGN. This was confirmed by electron microscopy, with electron dense deposits seen in many capillary loops, predominantly in a subendothelial location with some also seen in a subepithelial location (Figure 2A and B). There were no clinical or pathologic features of allograft rejection. The time from kidney transplant to disease recurrence was 93 months. His most recent serum creatinine at follow-up was 105 µmol/L (eGFR >60 mL/min).\nFig. 2. The electron micrographs illustrate features in keeping with recurrence of C3 MPGN in the allograft of case index 212. They show the presence of electron dense deposits in many capillary loops in a predominantly subendothelial location (black arrows) and mesangium (white arrows) under direct (A) ×6000 magnification and (B) ×10 000 magnification. In addition, there appears to be global increase in thickness of the basement membranes, most probably related to calcineurin inhibitor.\n\n\n\nCase index 213\nHe presented at the age of 4 years with steroid-resistant nephrotic syndrome and MPGN type III was demonstrated on initial kidney biopsy. He progressed to ESKD 4 years later when he presented with malignant hypertension and stroke resulting in left-sided hemiparesis. He received a living donor kidney transplant from case index 105. Two weeks post-transplant he had a transplant biopsy that showed an acute diffuse proliferative glomerulonephritis, with the presence of subendothelial as well as subepithelial deposits suggestive of early recurrence of his original disease. A repeat biopsy was performed 2 years following transplant due to a slow but progressive rise in serum creatinine and proteinuria. This showed a C3 membranoproliferative pattern of injury, with a large number of deposits seen both in the mesangial regions and in the capillary loops, which confirmed recurrence of disease. There was no evidence of graft rejection. He progressed to allograft failure 6.5 years post-transplant and was commenced on PD. He received a second deceased donor kidney transplant at the age of 24 years that lasted for 14 years (HLA MM 1-1-2; PRA 85%; DBD; donor age 43 years; donor creatinine 76 µmol/L). In addition, he has a significant cardiac history with an episode of myocardial infarction, previous coronary artery bypass grafting and an implantable cardioverter defibrillator inserted. More recently, he received a third kidney transplant from his brother who was genetically screened and was negative for the familial mutation (HLA MM 0-0-0; PRA 100%; living donor; donor age 33 years; donor creatinine 77 µmol/L). His graft function remains stable with a creatinine of 120 µmol/L (eGFR 55 mL/min).\n\nCase index 214\nShe was first diagnosed with C3GN at the age of 21 years. She progressed to ESKD and received a deceased donor kidney transplant 10 years later (HLA MM 1-2-2; PRA 5%; DBD; donor age 18 years; donor creatinine 48 µmol/L). Her graft function has been very stable over the years, with a serum creatinine of 74 µmol/L (eGFR >60 mL/min) and UPCR of 13 mg/mmol at her most recent follow-up (49 months post-transplantation). Her maintenance immunosuppressive regimen consists of tacrolimus, azathioprine and prednisolone. She has no clinical or biochemical evidence of disease recurrence.\n\nDiscussion\nThe CFHR3-1 hybrid gene is a unique cause of C3 glomerulopathy, most probably due to an abnormal crossover event during meiosis, as there are frequent interspersed repeat elements within the CFH-CFHR locus [12]. This is inherited in an autosomal dominant fashion and the exact cause in this family remains to be elucidated. In a previous study, a chromosomal deletion in the CFHR2 gene led to production of a hybrid CFHR21,2-CFHR5 plasma protein that stabilized C3 convertase and reduced the factor H-mediated convertase decay, enhancing alternative pathway activation and ultimately an increase in C3b deposition along the glomerular basement membrane and glomerular damage [9]. In addition, Gale et al. [7] also demonstrated that the mutant CHFR5 protein was associated with reduced affinity towards surface-bound complement. Thus, it was speculated that the mutant CFHR3-1 protein might have caused an abnormal accumulation of C3 within the kidneys through disruption of alternative pathway regulation by CFH and CFHR [12].\n\nTo our knowledge, this is the first description of renal transplant outcomes of hybrid CFHR3-1 gene–associated C3 glomerulopathy. In our cohort, five patients received a total of eight kidney transplants. Four renal allografts had disease recurrence (50%), of which three had biopsy-proven recurrence in the allografts, with time to recurrence ranging from as early as 2 weeks following living related donor transplantation (case index 213) to 93 and 101 months for the two remaining allografts, respectively. Similarly, Vernon et al. [17] previously reported one case of histological recurrence of CFHR5 nephropathy as early as 46 days after deceased donor kidney transplantation. In contrast, Andresdottir et al. [14] showed a biopsy-proven recurrence rate of 100% in DDD, with one recurrence occurring 12 days post-transplantation. There is inevitably an inherent bias in reporting the time of recurrence, as it is dependent on the timing of transplant biopsy, which may not be performed if the allograft remained stable with no clinical signs of acute or chronic rejection. The longest graft survival in our series was 170 months and the median graft survival was 92 months. A retrospective review of paediatric transplant recipients reported graft survival rates of 50% at 5 years in a cohort of 75 children with DDD, which was significantly lower than in transplanted children with all-cause ESKD and non-DDD forms of glomerulonephritis (74 and 72% 5-year graft survival rates, respectively) [15]. Moreover, the outcome of kidney transplantation in the Irish cohort with primary idiopathic MPGN was previously reported by Little et al. [16], where 49% of transplant recipients had evidence of disease recurrence after a median of 4.7 years (with a trend towards a greater likelihood of recurrence in DDD than MPGN), and within this group, 67% eventually lost their graft after a median time of 7.5 years.\n\nThere is always a concern over the use of a living related donor as an organ source in familial renal disease, owing to an increased lifetime risk to a genetically related potential donor of developing significant renal disease. In this large kindred, familial MPGN was first seen when case index 105 developed renal impairment following living donor nephrectomy. By recognizing that this familial renal disease is inherited in an autosomal dominant fashion with a wide range of disease onset, many of the first-degree relatives would have been precluded as potential living kidney donors. Fortunately, the underlying familial mutation was identified in recent years and we were able to provide genetic screening to case index 215, who was clinically asymptomatic. He successfully donated a kidney to his HLA-identical brother (case index 214), who has a PRA of 100%, and therefore a very low probability of receiving a third transplant from the deceased donor pool. Our study serves to highlight how advances in the genomic sciences can influence clinical practice and patient care at an individual level. Presently, it is recommended by the C3 glomerulopathy consensus group that all patients, regardless of being diagnosed with disease affecting the native or transplant kidney, should have serological investigations comprising measurements of serum C3, C4, factor H, paraprotein and C3 nephritic factor. Other tests that should be considered on an individual basis include measurement of serum factor B, C5, markers of C3/C5 activation, anti-factor H antibodies, anti-factor B antibodies and mutation screening of complement regulatory genes (such as CFH, CFI and CD46), activation protein gene (C3, CFB) and copy number variation across the CFH-CFHR locus [4]. These investigations should also be considered in potential living kidney donors with a strong family history.\n\nTo date, no treatment has been proven to be beneficial in C3 glomerulopathy. The Kidney Disease: Improving Global Outcomes clinical practice guideline for glomerulonephritis recommend that adults or children with presumed idiopathic MPGN accompanied by nephrotic syndrome and progressive decline in kidney function should receive oral cyclophosphamide or MMF with low-dose alternate day or daily corticosteroids with initial therapy limited to <6 months, which is based on level 2D evidence [18]. Recent advancements in our understanding of complement-mediated kidney injury have prompted the use of eculizumab, an anti-C5 humanized monoclonal antibody that inhibits formation of membrane attack complex, as a disease modifying agent. Results from anecdotal cases and open-label studies have shown modest benefits in some patients, although further evidence is awaited [19–22]. In conclusion, recurrence of disease is common in all forms of C3 glomerulopathy following kidney transplantation. Although disease recurrence was high in our cohort, overall transplant graft survival was good and transplantation remains a viable treatment option for ESKD secondary to C3 glomerulopathy.\n\nConflict of interest statement\nNone declared.\n==== Refs\nReferences\n1 Fakhouri F , Fremeaux-Bacchi V , Noel LH et al \nC3 glomerulopathy: a new classification . Nat Rev Nephrol \n2010 ; 6 : 494 –499 20606628 \n2 Smith RJ , Alexander J , Barlow PN et al \nNew approaches to the treatment of dense deposit disease . J Am Soc Nephrol \n2007 ; 18 : 2447 –2456 17675665 \n3 Servais A , Noel LH , Roumenina LT et al \nAcquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies . Kidney Int \n2012 ; 82 : 454 –464 22456601 \n4 Pickering MC , D'Agati VD , Nester CM et al \nC3 glomerulopathy: consensus report . Kidney Int \n2013 ; 84 : 1079 –1089 24172683 \n5 Appel GB , Cook HT , Hageman G et al \nMembranoproliferative glomerulonephritis type II (dense deposit disease): an update . J Am Soc Nephrol \n2005 ; 16 : 1392 –1403 15800116 \n6 Martinez-Barricarte R , Heurich M , Valdes-Canedo F et al \nHuman C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation . J Clin Invest \n2010 ; 120 : 3702 –3712 20852386 \n7 Gale DP , de Jorge EG , Cook HT et al \nIdentification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis . Lancet \n2010 ; 376 : 794 –801 20800271 \n8 Tortajada A , Yebenes H , Abarrategui-Garrido C et al \nC3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation . J Clin Invest \n2013 ; 123 : 2434 –2446 23728178 \n9 Chen Q , Wiesener M , Eberhardt HU et al \nComplement factor H-related hybrid protein deregulates complement in dense deposit disease . J Clin Invest \n2014 ; 124 : 145 –155 24334459 \n10 Neary J , Dorman A , Campbell E et al \nFamilial membranoproliferative glomerulonephritis type III . Am J Kidney Dis \n2002 ; 40 : E1 12087587 \n11 Neary JJ , Conlon PJ , Croke D et al \nLinkage of a gene causing familial membranoproliferative glomerulonephritis type III to chromosome 1 . J Am Soc Nephrol \n2002 ; 13 : 2052 –2057 12138136 \n12 Malik TH , Lavin PJ , Goicoechea de Jorge E et al \nA hybrid CFHR3-1 gene causes familial C3 glomerulopathy . J Am Soc Nephrol \n2012 ; 23 : 1155 –1160 22626820 \n13 Angelo JR , Bell CS , Braun MC \nAllograft failure in kidney transplant recipients with membranoproliferative glomerulonephritis . Am J Kidney Dis \n2011 ; 57 : 291 –299 21215503 \n14 Andresdottir MB , Assmann KJ , Hoitsma AJ et al \nRenal transplantation in patients with dense deposit disease: morphological characteristics of recurrent disease and clinical outcome . Nephrol Dial Transplant \n1999 ; 14 : 1723 –1731 10435883 \n15 Braun MC , Stablein DM , Hamiwka LA et al \nRecurrence of membranoproliferative glomerulonephritis type II in renal allografts: the North American Pediatric Renal Transplant Cooperative Study experience . J Am Soc Nephrol \n2005 ; 16 : 2225 –2233 15888559 \n16 Little MA , Dupont P , Campbell E et al \nSeverity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk . Kidney Int \n2006 ; 69 : 504 –511 16395262 \n17 Vernon KA , Gale DP , de Jorge EG et al \nRecurrence of complement factor H-related protein 5 nephropathy in a renal transplant . Am J Transplant \n2011 ; 11 : 152 –155 21114651 \n18 Kidney Disease: Improving Global Outcomes . KDIGO clinical practice guideline for glomerulonephritis . Kidney Int \n2012 ; 2 (Suppl 2 ): 198 –199 \n19 Bomback AS , Smith RJ , Barile GR et al \nEculizumab for dense deposit disease and C3 glomerulonephritis . Clin J Am Soc Nephrol \n2012 ; 7 : 748 –756 22403278 \n20 Daina E , Noris M , Remuzzi G \nEculizumab in a patient with dense-deposit disease . N Engl J Med \n2012 ; 366 : 1161 –1163 22435382 \n21 Radhakrishnan S , Lunn A , Kirschfink M et al \nEculizumab and refractory membranoproliferative glomerulonephritis . N Engl J Med \n2012 ; 366 : 1165 –1166 22435384 \n22 Le Quintrec M , Lionet A , Kandel C et al \nEculizumab for treatment of rapidly progressive C3 glomerulopathy . Am J Kidney Dis \n2015 ; 65 : 484 –489 25530108\n\n",
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"issn_linking": "2048-8505",
"issue": "9(3)",
"journal": "Clinical kidney journal",
"keywords": "complement; graft function; graft survival; kidney transplantation",
"medline_ta": "Clin Kidney J",
"mesh_terms": null,
"nlm_unique_id": "101579321",
"other_id": null,
"pages": "403-7",
"pmc": null,
"pmid": "27274824",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports",
"references": "23728178;10435883;22435382;12087587;25530108;22403278;20852386;12138136;20800271;17675665;20606628;24334459;15800116;22456601;15888559;24172683;22435384;22626820;16395262;21114651;21215503",
"title": "Kidney transplant outcomes in familial C3 glomerulopathy.",
"title_normalized": "kidney transplant outcomes in familial c3 glomerulopathy"
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"abstract": "BACKGROUND\nLimy bile syndrome (LBS) is an unusual condition in which gallbladder and/or bile ducts are filled with paste-like radiopaque material with a high calcium carbonate content. It can be rarely associated with PTH disorder and hypercalcemia.\n\n\nMETHODS\nA 35-year-old woman presented with epigastric and right hypochondrium pain since a few hours. Similar attacks occurred in the past months soon after a pregnancy with vaginal delivery. Laboratory findings were not significant. The abdominal ultrasound highlighted a micro-lithiasis of gallbladder without complications. Considering the recurrent biliary attacks, laparoscopic cholecystectomy was performed with intraoperative diagnosis of LBS. A subsequent endocrinological screening highlighted a normocalcemic hyperparathyroidism associated with Vitamin D deficiency, likely related to the recent pregnancy and not to LBS.\n\n\nCONCLUSIONS\nLBS is a rare condition with not clear etiology, frequently associated with cholelithiasis, of which it shares clinical presentation and potential complications. Diagnosis of LBS is based on abdominal X-ray/computed tomography scan, or it could be an intraoperative finding. The gold standard treatment is represented by laparoscopic cholecystectomy. The pregnancy with its related cholestatic phenotype could facilitate the LBS manifestation. An endocrinological screening should be performed to rule out a concomitant calcium metabolism disorder.\n\n\nCONCLUSIONS\nKnowledge of this rare condition could help general surgeons handle it properly.",
"affiliations": "Department of Surgery, General and Oncologic Surgery Unit, Santa Croce e Carle Hospital, Cuneo, Italy. Electronic address: marco.migliore88@gmail.com.;Department of Surgery, General and Oncologic Surgery Unit, Santa Croce e Carle Hospital, Cuneo, Italy.;Division of Endocrinology Diabetology and Metabolism, S. Croce and Carle Hospital, Cuneo, Italy.;Department of Surgery, General and Oncologic Surgery Unit, Santa Croce e Carle Hospital, Cuneo, Italy.;Department of Surgery, General and Oncologic Surgery Unit, Santa Croce e Carle Hospital, Cuneo, Italy.",
"authors": "Migliore|Marco|M|;Giraudo|Giorgio|G|;Gianotti|Laura|L|;Testa|Valentina|V|;Borghi|Felice|F|",
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"doi": "10.1016/j.ijscr.2021.105976",
"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612\nElsevier\n\nS2210-2612(21)00478-8\n10.1016/j.ijscr.2021.105976\n105976\nCase Report\nPost-pregnancy recurrent biliary colic with intraoperative diagnosis of limy bile syndrome\nMigliore Marco marco.migliore88@gmail.com\na⁎\nGiraudo Giorgio a\nGianotti Laura b\nTesta Valentina a\nBorghi Felice a\na Department of Surgery, General and Oncologic Surgery Unit, Santa Croce e Carle Hospital, Cuneo, Italy\nb Division of Endocrinology Diabetology and Metabolism, S. Croce and Carle Hospital, Cuneo, Italy\n⁎ Corresponding author at: Department of Surgery, General and Oncologic Surgery Unit, Santa Croce e Carle Hospital, 12100 Cuneo, Italy. marco.migliore88@gmail.com\n13 5 2021\n6 2021\n13 5 2021\n83 10597618 4 2021\n7 5 2021\n9 5 2021\n© 2021 The Author(s). Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nIntroduction\n\nLimy bile syndrome (LBS) is an unusual condition in which gallbladder and/or bile ducts are filled with paste-like radiopaque material with a high calcium carbonate content. It can be rarely associated with PTH disorder and hypercalcemia.\n\nPresentation of case\n\nA 35-year-old woman presented with epigastric and right hypochondrium pain since a few hours. Similar attacks occurred in the past months soon after a pregnancy with vaginal delivery. Laboratory findings were not significant. The abdominal ultrasound highlighted a micro-lithiasis of gallbladder without complications. Considering the recurrent biliary attacks, laparoscopic cholecystectomy was performed with intraoperative diagnosis of LBS. A subsequent endocrinological screening highlighted a normocalcemic hyperparathyroidism associated with Vitamin D deficiency, likely related to the recent pregnancy and not to LBS.\n\nDiscussion\n\nLBS is a rare condition with not clear etiology, frequently associated with cholelithiasis, of which it shares clinical presentation and potential complications. Diagnosis of LBS is based on abdominal X-ray/computed tomography scan, or it could be an intraoperative finding. The gold standard treatment is represented by laparoscopic cholecystectomy. The pregnancy with its related cholestatic phenotype could facilitate the LBS manifestation. An endocrinological screening should be performed to rule out a concomitant calcium metabolism disorder.\n\nConclusion\n\nKnowledge of this rare condition could help general surgeons handle it properly.\n\nHighlights\n\n• LBS is a rare condition characterized by a gallbladder and/or bile ducts filled with a a high calcium carbonate content\n\n• LBS could be an incidental finding during cholecistectomy or preoperative diagnosed by abdominal X-ray/CT scan\n\n• The gold standard of treatment for LBS is laparoscopic cholecystectomy\n\n• A postoperative endocrinological screening should be performed to rule out a concomitant calcium metabolism disorder\n\nKeywords\n\nLimy bile syndrome\nCholelithiasis\nLaparoscopic cholecystectomy\nIncidental finding\nPregnancy\nCase report\n==== Body\n1 Introduction\n\nLimy bile (also known as milk of calcium bile) syndrome (LBS) is an unusual condition in which gallbladder and/or bile ducts are filled with paste-like radiopaque material with a high calcium carbonate content. It could be diagnosed by abdominal X-ray/computed tomography (CT) scan or it could represent an incidental finding after cholecystectomy. It can be rarely associated with PTH disorder and hypercalcemia. We report the clinical case of LBS in a young women who underwent cholecystectomy for recurrent biliary colic appeared soon after pregnancy. The case report was realized according to international SCARE checklist [1].\n\n2 Presentation of case\n\nA 36-year-old woman with no comorbidities and no drug history presented at our Emergency Department with an important epigastric and right hypochondrium pain since a few hours, without vomit and fever. In the past months, soon after pregnancy, she already experienced several similar pain attacks and therefore she had an abdominal ultrasound which demonstrated a micro-lithiasis of gallbladder. Since this finding, she has been prescribed ursodeoxycholic acid with no benefit. At the examination, she presented with mild tenderness in the right hypochondrium with negative Murphy's sign and no jaundice. Laboratory findings are listed in Table 1 and were not significant. Because of patient's age and the high clinical diagnostic suspicion of biliary colic, we didn't perform abdominal X-ray or abdominal CT scan. We only repeated an abdominal ultrasound which confirmed the presence of millimetric stones in the gallbladder without inflammation figures and with no common bile duct dilatation (Fig. 1).Table 1 Laboratory findings at the Emergency Department access.\n\nTable 1Laboratory test\tFinding\tNormal range\t\nWBC count\t6.03 K/μl\t4.00–10.80\t\nHemoglobin\t13.20 g/dL\t12.00–16.00\t\nPLT count\t192 K/μl\t130–424\t\nINR\t0.93\t0.80–1.20\t\nCRP\t0.50 mg/L\t<5.00\t\nALT\t11 U/L\t<49\t\nAST\t25 U/L\t<34\t\nBilirubin\t0.5 mg/dL\t0.3–1.2\t\nALP\t77 U/L\t33–98\t\nGGT\t9 U/L\t<38\t\nWBC: White Blood Cells; PLT: platelet; INR: International Normalized Ratio; CRP: C-reactive protein; ALT: Alanine Amonotransferase; AST: Aspartate Transaminase; ALP: Alkaline Phosphatase; GGT: Gamma-glutamyltransferase.\n\nFig. 1 An ultrasound picture which shows the presence of millimetric stones in the gallbladder without inflammation figures.\n\nFig. 1\n\nConsidering the recurrent biliary attacks resulting in impairment of quality of life, even if in absence of acute cholecystitis, laparoscopic cholecystectomy was performed during the same recovery. Surgery was done by a well versed surgeon experienced in minimally invasive surgery. At the gallbladder check at the end of surgery we noticed a gallbladder filled with a white unusual paste-like material with interposed micro-stones (<5 mm) and therefore the LBS diagnosis was made (Fig. 2). Histological examination of the gallbladder showed a chronic cholecystitis with acute exacerbation.Fig. 2 The gallbladder check at the end of intervention showed a gallbladder filled with a white unusual paste-like material with interposed micro-stones (<5 mm).\n\nFig. 2\n\nThe postoperative course was uneventful and she was discharged on the first postoperative day. Through a literature search, we became aware of the rare but possible association between LBS and primary hyperparathyroidism [2,3] and therefore an endocrine-metabolic screening was performed with biochemical evidence of normocalcemic hyperparathyroidism and Vitamin D deficiency (Table 2). A neck ultrasound was negative for parathyroid hyperplasia or adenomas.Table 2 Laboratory findings of endocrine-metabolic screening.\n\nTable 2Laboratory test\tFinding\tNormal range\t\nSerum calcium\t9.1 mg/dL\t8.7–10.4\t\nSerum phosphorus\t3.8 mg/dL\t2.4–5.1\t\nUrinary calcium excretion\t150 mg/24 h\t50–150\t\nVitamin D (25OHD)\t21.1 ng/mL\t25–80\t\nParathormone\t40.2 pg/mL\t6.5–36.8\t\n\n3 Discussion\n\nPrevalence of LBS varies between 0.1 and 1.7% of cholecystectomy for benign gallbladder disease, being more frequent among young female [4,5]. Even if the exact etiopathogenetic mechanism is not known, calcium carbonate precipitation seems to be facilitated by the bile stasis [6]. Bile stasis can also be affected by gonadal steroids and their dramatic increase during pregnancy; a cholestatic effect of estrogen is known and in addition to estrogen, progesterone and its metabolites are of considerable importance in the modulation of bile acid signalling pathways, thus having an impact on the cholestatic phenotype [7]. In our patient, the recent pregnancy with its related bile stasis, have probably played a key role in the micro-stones formation and calcium carbonate accumulation with LBS manifestation. The chronic inflammatory changes at the histological examination could be either a contributing factor of calcium carbonate deposition or not specific and secondary.\n\nIn a few exceptional case reports [2,3], bile calcium deposition has been correlated to a primary hyperparathyroidism with parathyroid adenoma. However, in these exceptional reports characterized by high serum calcium levels related to hyperparathyroidism, obstruction of cystic duct and inflammation of the gallbladder seemed to be also present, facilitating calcium deposition. An endocrinological screening is therefore recommended in patients affected by LBS, also after surgery. In our case, the endocrinological laboratory tests highlighted a normocalcemic hyperparathyroidism secondary to Vitamin D deficiency probably not related to the LBS and therefore it could be considered an incidental finding probably related to the recent pregnancy. Note that vitamin D deficiency is quite common but underestimated in pregnancy leading to hyperparathyroidism, calcium bone mobilization and osteopenia.\n\nThe main symptoms of LBS (right hypochondrium and epigastrium pain) and its potential complications (cholecystitis, pancreatitis and obstructive jaundice) are the same of cholelithiasis. Actually, symptoms and complications are mainly caused by the frequent concomitant cholelitiasis, more than the calcium carbonate precipitation. Moreover, LBS is a rare condition. In view of this considerations, it's quite difficult to identify an algorithm for LBS diagnosis, even considering that the surgical treatment of symptomatic LBS is laparoscopic cholecystectomy, the same of symptomatic or complicated cholelithiasis.\n\nThe preoperative diagnosis of LBS could be done with abdominal X-ray/CT scan [8] while abdominal ultrasound is much less specific, but could reveal the concomitant cholelithiasis and its potential complications. Considering the higher frequency of LBS among young female, abdominal X-ray/CT scan are often avoided, leading to the possibility of an intraoperative diagnosis by checking the gallbladder content, as in our specific report. Note that abdominal X-ray and especially abdominal CT scan could help in the differential diagnosis from porcelain gallbladder in which the calcification is limited to the gallbladder wall instead of its entire content. Magnetic resonance cholangiopancreatography (MRCP) should be done in case of clinical and/or laboratory findings of cholestasis. In case of obstruction of common bile duct, laparoscopic cholecystectomy has to be associated to a concomitant endoscopic retrograde cholangiopancreatography (ERCP).\n\n4 Conclusion\n\nLBS is a rare condition. In our patient the recent pregnancy with its related bile stasis have probably played a key role on its etiopathogenesis. Abdominal X-ray/CT scan are the gold standard for preoperative diagnosis even if not pivotal. The treatment of choice of LBS is laparoscopic cholecystectomy, eventually associated to ERCP in case of common bile duct obstruction. A following endocrinological screening should be performed to rule out a concomitant calcium metabolism disorder. Knowledge of this rare condition could help general surgeons handle it properly.\n\nSources of funding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\n\nEthical approval was not required for this case report.\n\nInformed consent\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nRegistration of research studies\n\nNot applicable.\n\nGuarantor\n\nMarco Migliore and Giorgio Giraudo act as guarantors for the report and accept responsibility for the work.\n\nProvenance and peer review\n\nNot commissioned, externally peer-reviewed.\n\nCRediT authorship contribution statement\n\nMarco Migliore, MD conceived, designed and drafted the article.\n\nGiorgio Giraudo, MD, Laura Gianotti, MD, Valentina Testa, MD and Felice Borghi, MD contributed to conception of the work and contributed to critical revision of the manuscript for intellectual content.\n\nAll authors listed above gave final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nDeclaration of competing interest\n\nThe authors report no declarations of interest.\n==== Refs\nReferences\n\n1 Agha R. Franchi T. Sohrabi C. Ginimol M. Kerwan A. SCARE Group The SCARE 2020 guideline: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 84 2020 226 230 33181358\n2 Koca Y.S. Koca T. Barut I. Limy bile syndrome complicated with primary hyperparathyroidism Case Rep. Surg. 2015 2015 928217 25821626\n3 Takatori Y. Yamauchi K. Negoro Y. Noro K. Yoshida A. Nanamiya W. Tamai M. Kobayashi T. Yamane Y. Akamoto S. Suzaki N. Sasaki A. Limy bile syndrome complicated with primary hyperparathyroidism Intern. Med. 42 1 2003 44 47 12583617\n4 Sudhakar Krishnan M.M. Lim K.H. Limy bile: case report and review of literature Singap. Med. J. 24 1983 374 376\n5 Masuda Y. Mizuguchi Y. Kanda T. Furuki H. Mamada Y. Taniai N. Nakamura Y. Yoshioka M. Matsushita A. Kawano Y. Shimizu T. Uchida E. Successful treatment of limy bile syndrome extending to the common bile duct by laparoscopic cholecystectomy and common bile duct exploration: a case report and literature review Asian J. Endosc. Surg. 10 1 2017 59 62 27554920\n6 Naryshkin S. Trotman B.W. Raffensperger E.C. Milk of calcium bile: evidence that gallbladder stasis is a key factor Dig. Dis. Sci. 32 9 1987 1051 1055 3622186\n7 Dixon P.H. Williamson C. The pathophysiology of intrahepatic cholestasis of pregnancy Clin. Res. Hepatol. Gastroenterol. 40 2 2016 141 153 26823041\n8 Peroux E. Geffroy Y. Potet J. Unenhanced computed tomography to identify intrahepatic and extrahepatic limy bile Clin. Gastroenterol. Hepatol. 10 3 2012 e27 e28 22056298\n\n",
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"journal": "International journal of surgery case reports",
"keywords": "Case report; Cholelithiasis; Incidental finding; Laparoscopic cholecystectomy; Limy bile syndrome; Pregnancy",
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"title": "Post-pregnancy recurrent biliary colic with intraoperative diagnosis of limy bile syndrome.",
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"abstract": "BACKGROUND\nThe risk of thromboembolism associated with combined oral contraceptives (COCs) in Japanese women is not clear yet. The aim of this study is to estimate the current risk of thromboembolism among COC users in Japan.\n\n\nMETHODS\nWe used the Pharmaceuticals and Medical Devices Agency (PMDA) database disclosed by PMDA from April 2004 to December 2013, and extracted thromboembolic events among adverse events from the adverse event information of COC products.\n\n\nRESULTS\nOf the 581 thromboembolic events, venous thromboembolism (VTE) accounted for 394 events, arterial embolism and thrombosis (ATE) were 154, and thrombosis of unspecified sites was 33. In VTE, deep vein thrombosis and pulmonary embolism were the most frequent (78.4%), followed by cerebral vein thrombosis (11.4%). In ATE, cerebral infarction was the most frequent (76.0%) and approximately 6.9-fold higher than coronary heart diseases. The annual estimated incidence per 10,000 person-years of VTE, ATE and all thromboembolisms in current users of all COCs were 1.11 (95% confidence interval: 1.00-1.24), 0.37 (0.30-0.44), and 1.56 (1.42-1.71), respectively. The frequency of all thromboembolic events that developed within 90 days from the start of COCs was 45.5%, and that within 360 days was 81.2%. Sixteen deceased cases were suspected to be associated with thromboembolism, and the estimated mortality rate between 2009 and 2013 was 0.50 (0.30-0.84) per 100,000 person-years.\n\n\nCONCLUSIONS\nIncidence rates of thromboembolism, particularly VTE, in Japanese current COC users became clear for the first time, being slightly lower than people in Western countries.",
"affiliations": "Department of Reproductive Health Nursing/Midwifery, Nagoya City University Graduate School of Nursing, Nagoya, Japan; Department of Community Health and Preventive Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address: sugiura@med.nagoya-cu.ac.jp.;Department of Obstetrics and Gynecology, Hamamatsu Medical Center, Hamamatsu, Japan. Electronic address: tkoba@hmedc.or.jp.;Department of Community Health and Preventive Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address: ojima@hama-med.ac.jp.",
"authors": "Sugiura|Kazuko|K|;Kobayashi|Takao|T|;Ojima|Toshiyuki|T|",
"chemical_list": "D003277:Contraceptives, Oral, Combined",
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"journal": "Thrombosis research",
"keywords": "Arterial embolism and thrombosis; Combined oral contraceptives; Progestin; Venous thromboembolism",
"medline_ta": "Thromb Res",
"mesh_terms": "D003277:Contraceptives, Oral, Combined; D005260:Female; D006801:Humans; D015994:Incidence; D013997:Time Factors; D054556:Venous Thromboembolism",
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"title": "Thromboembolism as the adverse event of combined oral contraceptives in Japan.",
"title_normalized": "thromboembolism as the adverse event of combined oral contraceptives in japan"
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"companynumb": "JP-JNJFOC-20151219122",
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"abstract": "BACKGROUND\nGynaecomastia is a fairly common condition in puberty but is rare in prepubertal boys. While it is necessary to exclude possible endocrinopathay in prepubertal gynaecomastia, medication is an important and potentially reversible cause to consider in new onset gynaecomastia. Isoniazid-induced gynaecomastia has been reported in adult males, but none was reported in the paediatric population and general paediatricians may not be aware of this uncommon side effect.\n\n\nMETHODS\nWe hereby report a 11-year-old prepubertal boy who developed gynaecomastia while taking anti-tuberculosis drugs. Investigations excluded endocrinopathies. Gynaecomastia subsided 8 weeks after stopping isoniazid.\n\n\nCONCLUSIONS\nThis case is the first paediatric case report describing the association of gynaecomastia with isoniazid use. It is important for general paediatricians to recognize this entity, as prompt diagnosis and cessation of the offending drug can lead to resolution of the problem.",
"affiliations": "Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Pok Fu Lam, Hong Kong. sarahpoonwy@gmail.com.;Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Pok Fu Lam, Hong Kong.;Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Pok Fu Lam, Hong Kong.",
"authors": "Poon|Sarah Wing Yiu|SWY|http://orcid.org/0000-0003-0818-9699;Siu|Ka Ka|KK|;Tsang|Anita Man Ching|AMC|",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid",
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"doi": "10.1186/s12902-020-00639-9",
"fulltext": "\n==== Front\nBMC Endocr Disord\nBMC Endocr Disord\nBMC Endocrine Disorders\n1472-6823 BioMed Central London \n\n639\n10.1186/s12902-020-00639-9\nCase Report\nIsoniazid-induced gynaecomastia: report of a paediatric case and review of literature\nhttp://orcid.org/0000-0003-0818-9699Poon Sarah Wing Yiu sarahpoonwy@gmail.com Siu Ka Ka Tsang Anita Man Ching Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Pok Fu Lam, Hong Kong \n27 10 2020 \n27 10 2020 \n2020 \n20 16025 4 2020 20 10 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nGynaecomastia is a fairly common condition in puberty but is rare in prepubertal boys. While it is necessary to exclude possible endocrinopathay in prepubertal gynaecomastia, medication is an important and potentially reversible cause to consider in new onset gynaecomastia. Isoniazid-induced gynaecomastia has been reported in adult males, but none was reported in the paediatric population and general paediatricians may not be aware of this uncommon side effect.\n\nCase presentation\nWe hereby report a 11-year-old prepubertal boy who developed gynaecomastia while taking anti-tuberculosis drugs. Investigations excluded endocrinopathies. Gynaecomastia subsided 8 weeks after stopping isoniazid.\n\nConclusion\nThis case is the first paediatric case report describing the association of gynaecomastia with isoniazid use. It is important for general paediatricians to recognize this entity, as prompt diagnosis and cessation of the offending drug can lead to resolution of the problem.\n\nKeywords\nGynaecomastiaIsoniazidPaediatricissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nIsoniazid has selective bactericidal activity for mycobacteria [1]. It is a key component of anti-tuberculosis therapy and is well tolerated by children and adolescents with low rates of serious adverse effects. Common side effects include rash, fever, hepatitis, peripheral neuropathy and gastrointestintal upset. Gynaecomastia is a rare adverse effect. There were ten case reports of isoniazid-induced gynaecomastia in adults, while none was reported in children. Here we describe a case of gynaecomastia in an 11-year-old prepubertal boy after receiving therapeutic dose of isoniazid for 4 months. This case highlights the importance of recognizing the temporal association of this rare side effect of isoniazid during the course of anti-tuberculosis therapy.\n\nCase presentation\nAn 11-year-old boy, who has good past health and normal development, presented with 4-day history of fever, cough and haemoptysis. Appetite was maintained and he did not have any chills or rigors. There was no sick contact. Examination showed body weight 26.3 kg (10th centile) and height 140.9 cm (55th centile) according to the local growth chart [2]. There was decreased air-entry over right middle and lower zone on chest examination. Investigations showed normal white cell count 13.8 × 10^9/L but elevated erythrocyte sedimentation rate (ESR) 29 mm/hr. (ref < 12 mm/hr) and lactate dehydrogenase (LDH) 1078u/L (ref 380-750u/L). Mantoux test was positive with 10 mm induration. Chest x ray showed volume loss over the right lung field with consolidation over right middle and lower zone with tracheal deviation to the right. He was initially treated with augmentin but consolidation persisted. Bronchoscopy was then performed which showed suspicious stenosis at the right middle lobe bronchus. Smear for acid-fast bacilli and polymerase chain reaction (PCR) for Mycobacterium tuberculosis (MTB) of sputum, early morning gastric aspirate, early morning urine (EMU) and bronchoalveolar lavage (BAL) were all negative. The child was initially treated as latent tuberculosis and started on isoniazid 250 mg daily (10 mg/kg). In view of the abnormal bronchoscopy findings, computerised tomography (CT) thorax was arranged which revealed segmental collapse of the apical segment of right lower lobe with matted lymph nodes. In view of the CT changes, he was treated as active pulmonary tuberculosis. Rifampicin 400 mg daily, Pyrazinamide 800 mg daily and Ethambutol 400 mg daily, were added in addition to isoniazid. Subsequent cultures of sputum, gastric aspirate, EMU and BAL for MTB were negative.\n\nFour months after isoniazid treatment (i.e. 3 months after full anti-tuberculosis treatment), he complained of painful left breast swelling. Clinical examination showed a 1.5 cm × 1 cm firm glandular tissue around the nipple-areola complex on the left side and a 0.5 × 0.5 cm glandular tissue on the right side. Both swellings were mildly tender on palpation. There were no skin changes or nipple retraction. There were no palpable axillary lymph nodes. Abdominal examination was normal. He did not have significant weight gain during that period and his body weight was 27.5 kg (10th centile). He was pre-pubertal with Tanner stage 1 genitalia, testes 3 ml in volume and of normal consistency and no pubic hair development. There was no history of exposure to any other drugs, exogenous forms of estrogens or topical use of essential oils. There was no family history of gynaecomastia. Laboratory investigations showed normal renal, liver and thyroid functions; prepubertal levels of leutinizing hormone < 0.1 IU/L (< 1.0–12 IU/L), follicle stimulating hormone 0.36 IU/L (1.0–12 IU/L) and testosterone 0.2 nmol/L (adult range 10–35 nmol/L). Estradiol was slightly elevated at 30 pmol/L (adult range 20–160 pmol/L, prepubertal < 20 pmol/L). Prolactin level was normal at 229 mIU/L (45–375 mIU/L). Tumour markers including alpha fetoprotein and beta-human chorionic gonadotropin (b-HCG) were unremarkable. Ultrasound breasts showed bilateral small discs of retroareolar fibroglandular tissue compatible with gynaecomastia. With the above normal investigation results, we suspected isoniazid was the culprit. Isoniazid was then withheld and rifampicin, pyrazinamide and ethambutol were continued for a total of 6 months. Breast tissue subsided 8 weeks after withholding isoniazid.\n\nDiscussion and conclusion\nGynaecomastia is defined as presence of palpable breast tissue in males and histologically characterised by benign glandular proliferation of breast tissue. Clinically it appears as a rubbery or firm, concentric mass at the areolar-nipple complex, in contrast to “pseudogynaecomastia” or fatty breast that occurs frequently in obese men, which is soft in consistency due to fat deposition without glandular proliferation. Gynaecomastia is common particularly in the newborn period, at puberty, and in the elderly. It occurs in up to 70% of all boys at pubertal period [3]. It may cause psychological distress due to change in body image or even painfulness.\n\nGynaecomastia primarily results from an imbalance of androgenic and estrogenic influence on breast tissue. Estrogen stimulates the proliferation of breast tissue whereas androgen inhibits it. Gynaecomastia occurs when there is an increase in circulating or tissue level of estrogen, decrease in circulating or tissue level of androgen, altered serum androgen/estrogen ratio, increased breast tissue sensitivity to estrogen (e.g. due to increased number of estrogen receptors) or decreased breast tissue sensitivity to androgen (e.g. androgen receptor defect or drugs). Common causes of gynaecomastia include obesity, ageing, primary or secondary hypogonadism, liver or renal failure, hyperthyroidism and less commonly feminizing adrenal or testicular tumour (e.g. Leydig or Sertoli cell tumour), gonadal or extragonadal HCG producing tumours and genetic conditions resulting in aromatase excess or androgen insensitivity [3].\n\nIn contrast to pubertal gynaecomastia which is common, prepubertal gynaecomastia is rare. Medical evaluation is warranted to rule out endocrinopathies, estrogen or HCG producing tumours or aromatase excess. History of exposure to lavendar oil or tea tree oils should be sought as the components in these essential oils had been demonstrated in vitro to have estrogenic and anti-androgenic effects and their use had been reported to cause prepubertal gynaecomastia [4].\n\nMedication is a reversible cause of gynaecomastia and a careful drug history has to be taken. In healthy young males, particular attention should be made to use of anabolic steroid in body-builders and recreational use of marijuana. Drugs can cause gynaecomastia by its estrogenic activity (e.g. digitoxin), by decreasing serum testosterone (e.g. ketoconazole, metronidazole by damaging or inhibiting Leydig cells), blocking androgen receptor (e.g. spironolactone, cimetidine, marijuana), increasing serum prolactin (e.g. antipsychotics, metoclopramide) or via unknown mechanisms (e.g. antidepressants, human growth hormone, highly active antiretroviral therapy, proton pump inhibitors) [3]. Among the drugs in the standard tuberculosis regimen, only isoniazid has been reported to be associated with gynaecomastia.\n\nIn our patient, clinical examination and laboratory studies showed no evidence of liver, renal or thyroid disorder. Tumour markers were also taken to rule out the possibility of a HCG-producing tumour which may cause stimulation of Leydig cells. He was not obese and did not have excessive weight gain during the course of treatment, making obesity and refeeding gynaecomastia less likely. His gonadotrophins were within the pre-pubertal range while estradial was mildly elevated for his age and sex.\n\nIsoniazid is known to induce pyridoxine (vitamin B6) deficiency by inhibitng pyridoxal phosphokinase and by combining with pyridoxine to form isonicotinylhydrazide which is excreted in urine [5]. Apart from causing the well-known side effect of peripheral neuropathy, isoniazid was also postulated to cause altered estrogen-androgen metabolism. The physiologically active form of vitamin B6, pyridoxal 5-phosphate (PLP), acts as a modulator of steroid hormone receptor- mediated gene expression. Elevation of intracellular PLP leads to a decreased transcriptional response to glucocorticoid hormones, progesterone, androgens, and estrogens, while cells in a vitamin B6-deficient state exhibit enhanced responsiveness to steroid hormone [6]. This might thus account for the elevated estradial level in our patient. Another possible mechanism is “refeeding gynaecomastia” associated with weight gain during anti-tuberculosis therapy, but this was not seen in our case.\n\nWe performed a literature search in Pubmed and Medline using text terms “isoniazid” and “gyneacomastia”. Animal studies and articles written in a language other than English were excluded. Ten articles describing such phenomenon in adult patients were found (Table 1) [7–16]. Age of presentation ranges from 18 to 72 years old, with mean age of 40.9 years old. Gynaecomastia occurred 3–6 months (mean 4.5 months) after isoniazid treatment, and subsided at variable time frame ranging from 1 month to 1 year. Bilateral breasts were involved in 60% (n = 6) of the cases. Our reported case is the youngest among all and is the only reported pre-pubertal case. Like most of the reported cases, there was bilateral involvement of the breasts. The clinical course of our patient resembles the reported adult cases, with gynaecomastia occurring 4 months after isoniazid intake. Breast enlargement resolved 8 weeks upon cessation of medication in our case. The relatively quick resolution might be related to the absence of pre-existing breast tissue in pre-pubertal males.\nTable 1 Case reports of isoniazid-induced gynecomastia in the English literature\n\nAuthor (yr of publication)\tAge (in yr)\tDiagnosis\tTreatment\tOnset of gynaecomastia after ATT\tClinical features\tOutcome\t\n1. Khanna et al. (2003) [7]\t25\tRight TB pleural effusion\t2HRZE/2HR, H 300 mg, R 450 mg, Z 1500 mg, E 800 mg\t4 m\tRight painful breast 5x4cm Left painless nipple swelling\tBilateral breast swellings persisted for 3 m after ATT stopped, but decreased slightly and non-tender; subsided at 1 yr\t\n2. Dixit et al. (2008) [8]\t42\tTB cervical lymph node\t2H3R3Z3/2H3R3/2REC, H 600 mg, R 450 mg, Z 1500 mg\t4 m\tLeft painful breast 6x8cm\tH stopped at 4th m and breast swelling subsided after 6 months\t\n3. Morrone et al. (2008) [9]\t18\tCavitatory pulmonary TB (2 episodes)\t1st episode: 2HRZ/4HR\n\n2nd episode: 2HRZ/4HR/6R, H 400 mg, R 600 mg, Z 2000 mg\n\n\t1st episode: 3 m;\n\n2nd episode: 6 m\n\n\t1st episode: mildly tender small breast swellings\n\n2nd episode: Right tender breast swelling 5 cm\n\n\tGynaecomastia remained 2 months after H stopped and resolved 2 m after 1 yr of ATT\t\n4. Garg et al. (2009) [10]\t60\tPulmonary TB\t2HRZE/3HRE/4RE, H 300 mg, R 450 mg, Z 1000 mg, E 800 mg\t5 m\tBilateral tender breast swellings 5x6cm\tBreast swellings became non-tender after H stopped and resolved 6 m after 9 m of ATT\t\n5. Mansoor et al. (2009) [11]\t50\tTB epididymo-orchitis\t2HRZE/4HR, H 300 mg, R 450 mg, Z 1500 mg, E 800 mg\t4 m\tBilateral painful breast swellings\tAfter H stopped, breast swellings resolved at 6 m of ATT\t\n6. Lee et al. (2009) [12]\t72\tPulmonary TB\t2HRZ3E3/2 HRE3/5 RE3, H 300 mg, R 600 mg, Z 1000 mg, E 400 mg\t4 m\tBilateral painful breast swellings 4 cm\tBreast swellings resolved 1.5 m after H stopped\t\n7. Agrawal et al. (2011) [13]\t28\tPulmonary TB\t2HRZE/4HR, H: 300 mg, R: 450 mg, Z: 1500 mg, E: 800 mg\t3 m\tBilateral tender breast swellings 3x4cm\tBreast pain and swellings subsided 2 m after H stopped\t\n8. Goud et al.(2012) [14]\t45\tPulmonary TB\t2HRZE/2HR/5RE, H 300 mg, R 450 mg, Z 1500 mg, E 800 mg\t4 m\tLeft painful breast swelling 5x4cm\tBreast swelling resolved 1 m after H stopped\t\n9. Khan (2012) [15]\t45\tBilateral TB cervical lymph node\t2H3R3Z3/1H3R3/3R3E3, H 600 mg, R 600 mg, Z 1500 mg\t3 m\tLeft painful breast swelling 4 cm\tPain subsided 1 m after H stopped and breast swelling decreased by 25% at 3 m after H stopped\t\n10. Neki (2016) [16]\t24\tPulmonary TB\t2HRZE/2.5HRE/4.5RE, H: 300 mg, R: 450 mg, Z: 1500 mg, E: 800 mg\t4.5 m\tBilateral tender breast swellings 4x3cm\tBreast pain and swelling subsided 1 m after H stopped\t\nATT anti-tuberculosis therapy\n\nDrugs, H Isoniazid, R Rifampicin, Z Pyrazinamide, E Ethambutol, C Cirpofloxacin\n\nDuration: Shown by the number (in months) in front of the drugs, separated by the slash “/” to indicate another phase of treatment\n\nFrequency: Shown by the subscript attached to the individual drug (i.e. subscript “3” indicates thrice weekly administration and no subscript indicates daily administration)\n\n\n\nMost patients with drug induced gynaecomastia do not require treatment other than discontinuation of the offending agent. Likewise, no treatment was initiated in all the reported cases and our case. Reassurance is especially important in adolescents, and follow up should be arranged to document regression of breast tissue after the drug is withdrawn. Medical therapy, for example, antiestrogen and aromatase inhibitors are only indicated in those with significant pain or in those with considerable social anxiety due to breast enlargement.\n\nThis case is the first paediatric case report describing the association of gynaecomastia with isoniazid use. It is important for general paediatricians to recognize this entity, as prompt diagnosis and cessation of the offending drug can lead to resolution of the problem.\n\nAbbreviations\nESRErythrocyte sedimentation rate\n\nLDHLactate dehydrogenase\n\nPCRPolymerase chain reaction\n\nMTBMycobacterium tuberculosis\n\nEMUEarly morning urine\n\nBALBronchoalveolar lavage\n\nCTComputerised tomography\n\nPLPPyridoxal 5-phosphate\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nKKS is the attending paediatrician of this patient. SWYP and AMCT are involved in composition and revision of the manuscript. All authors have read and approved the manuscript.\n\nFunding\nThis publication receives no funding.\n\nAvailability of data and materials\nThe datasets used during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nNeed for ethical approval was waived.\n\nConsent for publication\nWritten informed consent has been obtained from the patient’s mother regarding this publication. A copy can be made available upon request.\n\nCompeting interests\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.\n==== Refs\nReferences\n1. Timmins GS Deretic V Mechanisms of action of isoniazid Mol Microbiol 2006 62 5 1220 1227 10.1111/j.1365-2958.2006.05467.x 17074073 \n2. Leung SSF Tse LY Wong GWK Standards for the anthropometric assessment of nutritional status of Hong Kong children HKJ Paediatr 1995 12 5 15 \n3. Narula HS Carlson HE Gynaecomastia—pathophysiology, diagnosis and treatment Nat Rev Endocrinol 2014 10 11 684 698 10.1038/nrendo.2014.139 25112235 \n4. Henley DV Lipson N Korach KS Bloch CA Prepubertal gynecomastia linked to lavender and tea tree oils N Engl J Med 2007 356 5 479 485 10.1056/NEJMoa064725 17267908 \n5. Mandel W Pyridoxine and the isoniazid-induced neuropathy Dis Chest 1959 36 293 296 10.1378/chest.36.3.293 14420556 \n6. Oka T Modulation of gene expression by vitamin B6 Nutr Res Rev 2001 14 2 257 266 10.1079/095442201108729231 19087426 \n7. Khanna P Panjabi C Maurya V Shah A Isoniazid associated, painful, bilateral gynaecomastia Ind J Chest Dis Allied Sci 2003 45 277 279 \n8. Dixit R Sharma S Nawal CL Gynaecomastia during antituberculosis chemotherapy with isoniazid J Assoc Physicians India 2008 56 390 391 18700651 \n9. Morrone N Morrone N Junior BAG Maia JA Gynecomastia: a rare adverse effect of isoniazid J Bras Pneumol 2008 34 978 981 10.1590/S1806-37132008001100014 19099106 \n10. Garg R Vaibha V Mehra S Prasad R Isoniazid induced gynaecomastia: A case report Indian J Tuberc 2009 56 51 54 19402273 \n11. Mansoor T, Rizvi SA, Khurram F, Ali W. Isoniazid-Induced Gynaecomastia. Internet J Surg. 2009. p. 18. [Available from: http://www.ispub.com/journal/the-internet-journal-of-surgery/volume-18-number-1/isoniazid-induced-gynaecomastia.html].\n12. Lee MK Jib Na D Jeon H Lee YD Cho YS Han MS A case of isoniazid induced Gynecomastia Tuberc Respir Dis 2009 66 33 36 10.4046/trd.2009.66.1.33 \n13. Agrawal P Gupta AK Goyal V Handa A Gupta A Isoniazid-induced gynaecomastia J Indian Acad Clin Med 2011 12 4 332 333 \n14. Goud BKM Devi OS Nayal B Devaki RN A rare case of unilateral gynecomastia during antituberculous chemotherapy with isoniazid Indian J Pharmacol 2012 44 4 521 522 10.4103/0253-7613.99340 23087519 \n15. Khan A Agarwal R Isoniazid related gynecomastia: description of a case and systematic review of literature Lung India Off Organ Indian Chest Soc 2012 29 2 189 191 10.4103/0970-2113.95343 \n16. Neki NS Isoniazid-induced gynaecomastia J Indian Acad Clin Med 2016 17 4 332 333\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1472-6823",
"issue": "20(1)",
"journal": "BMC endocrine disorders",
"keywords": "Gynaecomastia; Isoniazid; Paediatric",
"medline_ta": "BMC Endocr Disord",
"mesh_terms": "D000995:Antitubercular Agents; D002648:Child; D006177:Gynecomastia; D006801:Humans; D007538:Isoniazid; D008297:Male; D011379:Prognosis; D028761:Withholding Treatment",
"nlm_unique_id": "101088676",
"other_id": null,
"pages": "160",
"pmc": null,
"pmid": "33109161",
"pubdate": "2020-10-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "19087426;19099106;25112235;12962465;19402273;23087519;17267908;22628943;14420556;17074073;18700651",
"title": "Isoniazid-induced gynaecomastia: report of a paediatric case and review of literature.",
"title_normalized": "isoniazid induced gynaecomastia report of a paediatric case and review of literature"
} | [
{
"companynumb": "HK-ALKEM LABORATORIES LIMITED-HK-ALKEM-2020-07877",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PYRAZINAMIDE"
},
"dr... |
{
"abstract": "This case provides support for electroconvulsive therapy as a safe treatment in adolescents with a feeding tube. The patient presented to our hospital with symptoms of catatonia with minimal oral intake. She had stopped eating, had minimal interaction with her environment, and spent weeks with a nasogastric tube for nutritional support. She had been referred for electroconvulsive therapy but was unable to find a local provider who would perform it on an adolescent with a nasogastric tube. She came to our hospital and received 9 rounds of electroconvulsive therapy with improvement of her catatonia and no aspiration or adverse events.",
"affiliations": "Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, 1601 23rd Avenue South, Nashville, TN 37212, USA. Electronic address: paul.a.fuchs@vumc.org.;Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, 1601 23rd Avenue South, Nashville, TN 37212, USA.;Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, 1601 23rd Avenue South, Nashville, TN 37212, USA.",
"authors": "Fuchs|Paul A|PA|;Peters|Todd E|TE|;Benningfield|Margaret M|MM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.chc.2018.08.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1056-4993",
"issue": "28(1)",
"journal": "Child and adolescent psychiatric clinics of North America",
"keywords": "Adolescent; ECT; Feeding tube; Nasogastric tube; Neuromodulation",
"medline_ta": "Child Adolesc Psychiatr Clin N Am",
"mesh_terms": "D000293:Adolescent; D002389:Catatonia; D004565:Electroconvulsive Therapy; D005260:Female; D020042:Histiocytic Necrotizing Lymphadenitis; D006801:Humans; D007441:Intubation, Gastrointestinal; D016896:Treatment Outcome",
"nlm_unique_id": "9313451",
"other_id": null,
"pages": "121-125",
"pmc": null,
"pmid": "30389072",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Electroconvulsive Therapy as a Safe, Effective Treatment for Catatonia in an Adolescent with a Nasogastric Tube: A Case Report.",
"title_normalized": "electroconvulsive therapy as a safe effective treatment for catatonia in an adolescent with a nasogastric tube a case report"
} | [
{
"companynumb": "US-JNJFOC-20181137505",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": "3",
"... |
{
"abstract": "OBJECTIVE\nIntracameral mydriatics using epinephrine associated with lidocaine have been reported as efficacious in reducing intraoperative floppy iris syndrome (IFIS) complications during cataract surgery. The aim of this study was to verify the efficacy of intracameral epinephrine without intracameral lidocaine as prophylaxis against IFIS in patients on tamsulosin.\n\n\nMETHODS\nThis was a retrospective study on the results of cataract surgery in 18 patients on therapy with tamsulosin. Patients had undergone routine phacoemulsification in one eye. Successively, they underwent phacoemulsifcation in the fellow eye using non preserved intracameral epinephrine 1:4000 diluted with BSS. Intraoperative complications during cataract surgery had been documented and IFIS was graded based on iris billowing, miosis or iris prolapse. Follow-up was 3 months.\n\n\nRESULTS\nThirty-six eyes of 18 patients were included in the evaluation. The incidence of IFIS was significantly higher in the eyes where routine phacoemulsificaton had been performed (100%) with respect to eyes where phacoemulsification was carried out using intracameral epinephrine (33%) (Chi Square test =15.12, p<0.001). In routine phacoemulsification 16 eyes showed iris billowing, 14 eyes had some extent of miosis and 14 eyes had tendency to iris prolapse. In phacoemulsification with the use of intracameral epinephrine 5 eyes showed iris billowing, 4 eyes presented some extent of miosis and 2 eyes had tendency to iris prolapse. There were no serious intraoperative complications.\n\n\nCONCLUSIONS\nIntracameral epinephrine without the addition of lidocaine was efficacious in the management of IFIS in patients on tamsulosin.",
"affiliations": "Ophthalmology Unit, NESMOS Department, Sant'Andrea Hospital.;Ophthalmology Unit, DAI Head/Neck, Policlinico Umberto I Hospital, University Sapienza, Rome, Italy.;Ophthalmology Unit, NESMOS Department, Sant'Andrea Hospital.;Ophthalmology Unit, NESMOS Department, Sant'Andrea Hospital.;Ophthalmology Unit, NESMOS Department, Sant'Andrea Hospital.;Ophthalmology Unit, DAI Head/Neck, Policlinico Umberto I Hospital, University Sapienza, Rome, Italy.;Ophthalmology Unit, NESMOS Department, Sant'Andrea Hospital.",
"authors": "Fenicia|V|V|;Abdolrahimzadeh|S|S|;Scuderi|G|G|;Fabrizio|L|L|;Maurizi Enrici|M|M|;Cruciani|F|F|;Recupero|S M|SM|",
"chemical_list": "D058668:Adrenergic alpha-1 Receptor Antagonists; D009184:Mydriatics; D013449:Sulfonamides; D008012:Lidocaine; D000077409:Tamsulosin; D004837:Epinephrine",
"country": "Italy",
"delete": false,
"doi": "10.7417/CT.2015.1862",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9074",
"issue": "166(4)",
"journal": "La Clinica terapeutica",
"keywords": "Intracameral lidocaine; Intraoperative floppy iris syndrome, intracameral epinephrine; Tamsulosin; α1-adrenergic receptor antagonists",
"medline_ta": "Clin Ter",
"mesh_terms": "D058668:Adrenergic alpha-1 Receptor Antagonists; D000368:Aged; D004837:Epinephrine; D005500:Follow-Up Studies; D006801:Humans; D007431:Intraoperative Complications; D007499:Iris Diseases; D008012:Lidocaine; D008297:Male; D009184:Mydriatics; D018918:Phacoemulsification; D012189:Retrospective Studies; D013449:Sulfonamides; D013577:Syndrome; D000077409:Tamsulosin; D016896:Treatment Outcome",
"nlm_unique_id": "0372604",
"other_id": null,
"pages": "158-61",
"pmc": null,
"pmid": "26378751",
"pubdate": "2015",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Intracameral epinephrine without the addition of intracameral lidocaine in the management of tamsulosin associated intraoperative floppy iris syndrome.",
"title_normalized": "intracameral epinephrine without the addition of intracameral lidocaine in the management of tamsulosin associated intraoperative floppy iris syndrome"
} | [
{
"companynumb": "IT-TEVA-746702ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TAMSULOSIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "The clinical importance of neoadjuvant chemotherapy (NAC) followed by definitive surgery was retrospectively investigated in clinical Stage III/IV oral squamous cell carcinoma (OSCC).\nSurgery was performed for OSCC in 164 patients, including 72 patients who had received NAC (two cycles of cisplatin and fluorouracil) prior to surgery from January 2004 to December 2014. The clinical characteristics and survival parameters of the groups that received and did not receive NAC were evaluated. The pathological response was classified as Grade 0 (no effect), 1a (very slight effect), 1b (slight effect), 2 (moderate effect) or 3 (marked effect), and its correlation with prognosis was investigated.\nThere were no statistical differences in survival indicators between patients who received NAC and those who did not (overall survival, P = 0.75). The proportion of patients who received NAC in the effective NAC group (Grades 1b, 2, and 3) was 52.8%. After a median follow-up of 35 months, overall survival (P = 0.01), disease-free survival (P = 0.002), locoregional disease-free survival (P = 0.003), and distant disease-free survival (P = 0.01) were significantly better in the effective NAC group than in the less effective NAC group (Grades 0 and 1a).\nAlthough NAC had a limited effect on disease prognosis in OSCC, the pathological response to NAC could be an important prognostic indicator for advanced OSCC.",
"affiliations": "Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara-cho, Okinawa.;Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan.;Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan.;Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara-cho, Okinawa.;Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan.;Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Nishihara-cho, Okinawa.",
"authors": "Hirakawa|Hitoshi|H|;Hanai|Nobuhiro|N|;Suzuki|Hidenori|H|;Nishikawa|Daisuke|D|;Matayoshi|Sen|S|;Hasegawa|Yasuhisa|Y|;Suzuki|Mikio|M|",
"chemical_list": "D002945:Cisplatin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyx097",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "47(11)",
"journal": "Japanese journal of clinical oncology",
"keywords": "neoadjuvant chemotherapy; oral squamous cell carcinoma; pathological response; prognosis; surgery",
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms; D011379:Prognosis; D012189:Retrospective Studies; D000077195:Squamous Cell Carcinoma of Head and Neck",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "1038-1046",
"pmc": null,
"pmid": "28985398",
"pubdate": "2017-11-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prognostic importance of pathological response to neoadjuvant chemotherapy followed by definitive surgery in advanced oral squamous cell carcinoma.",
"title_normalized": "prognostic importance of pathological response to neoadjuvant chemotherapy followed by definitive surgery in advanced oral squamous cell carcinoma"
} | [
{
"companynumb": "JP-TEVA-2017-JP-838284",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
... |
{
"abstract": "Recurrent respiratory papillomatosis is an increasingly common disease which leads to organic and functional limitations. Clinical symptoms depend on the location and extent of the papillomatosis. They include hoarseness, cough, and, in some cases, significant narrowing of the respiratory and digestive tracts. The present report describes a fatal case of a young man (28 years old) who developed a very dynamic papilloma infection of the larynx, which spread to the trachea, the oesophagus, the soft tissues of the neck, and the mediastinum. Multimodal treatment did not stop the progression of the disease. The papillomatous lesion was removed with a CO2 laser used in a Kleinsasser microlaryngoscopy and under a microscope using a electrocoagulation loop with argon plasma during the gastroscopy. Antiviral treatment with cidofovir was introduced, as well as in further follow-up radiotherapy. Congenital or acquired immunodeficiency was also excluded. Despite multimodal treatment, successful eradication of the infection was not possible. In our case, aggressive progression of the disease was observed. We were unable to confirm malignant transformation. Papillomatosis was the only disease, and its aggressive development led to the patient's death. In the case of aggressive, uncontrolled progression - when the infiltration spreads beyond the larynx and the hypopharynx - there are no alternative treatment methods that would lead to an effective cure.",
"affiliations": "Bartosz Szybiak, Head and Neck Department, Greater Poland Cancer Center, Garbary 15, 61-866 Poznan, Poland, e-mail: bartek.szybiak@wp.pl.",
"authors": "Szybiak|Bartosz|B|;Marszałek|Andrzej|A|;Łuczewski|Łukasz|Ł|;Golusinski|Pawel|P|;Pazdrowski|Jakub|J|;Majchrzak|Ewa|E|;Pieńkowski|Piotr|P|;Golusinski|Wojciech|W|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5114/pjp.2015.51158",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1233-9687",
"issue": "66(1)",
"journal": "Polish journal of pathology : official journal of the Polish Society of Pathologists",
"keywords": null,
"medline_ta": "Pol J Pathol",
"mesh_terms": "D001706:Biopsy; D003131:Combined Modality Therapy; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D030361:Papillomavirus Infections; D012141:Respiratory Tract Infections; D014057:Tomography, X-Ray Computed; D017211:Treatment Failure",
"nlm_unique_id": "9437432",
"other_id": null,
"pages": "80-5",
"pmc": null,
"pmid": "26017885",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Uncontrolled human papilloma virus infection in a 28-year-old man leading to death - case report and review of literature.",
"title_normalized": "uncontrolled human papilloma virus infection in a 28 year old man leading to death case report and review of literature"
} | [
{
"companynumb": "PL-GILEAD-2015-0157684",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIDOFOVIR"
},
"drugadditional": null,
... |
{
"abstract": "Between September 1st, 1994, and the end of August, 1995, 3% of all inpatients (21 of 731) were treated with electroconvulsive therapy (ECT) at the Department of General Psychiatry at the University Hospital for Psychiatry in Vienna. These patients suffered from psychotic and/or therapy-resistant depression (n = 15), therapy-resistant schizoaffective psychosis (n = 3), and catatonic schizophrenia (n = 3). ECT was administered in short-time anaesthetised and muscle relaxed patients. On average, each patient was treated with ECT on 9 non-consecutive days. As a rule, electrodes were placed unilaterally over the non-dominant hemisphere at the beginning. In four cases electrodes were placed bifronto-temporally. To be considered as effective the seizure had to last for at least 25 s. In shorter seizure duration ECT was repeated up to a maximum of three times in one session. With this procedure a reduction in clinical global impressions of -3.7 points was achieved in ECT-treated patients, who had been considered to be \"severely\" to \"most severely\" ill according to CGI before starting ECT. ECT proved to be effective for treating severe depression and catatonic schizophrenia, with only minor and reversible side effects. For establishing a favorable relation between good clinical outcome and remarkable few side effects, the following factors seem to be of importance, in accordance with the literature: (1) application of biphasic short-impulse stimuli in anaesthetised and muscle relaxed patients; (2) measurement of static impedance to avoid high skin impedance and short circuits. (3) at the beginning of each ECT series unilateral electrode placement over the non-dominant hemisphere; (4) ECT three times weekly on non-consecutive days.",
"affiliations": "Klinische Abteilung für Allgemeine Psychiatrie, Universitätsklinik für Psychiatrie, Wien.",
"authors": "Tauscher|J|J|;Neumeister|A|A|;Fischer|P|P|;Frey|R|R|;Kasper|S|S|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s001150050143",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2804",
"issue": "68(5)",
"journal": "Der Nervenarzt",
"keywords": null,
"medline_ta": "Nervenarzt",
"mesh_terms": "D000328:Adult; D001931:Brain Mapping; D002540:Cerebral Cortex; D003866:Depressive Disorder; D004292:Dominance, Cerebral; D004565:Electroconvulsive Therapy; D004569:Electroencephalography; D004576:Electromyography; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011618:Psychotic Disorders; D012560:Schizophrenia, Catatonic; D016896:Treatment Outcome",
"nlm_unique_id": "0400773",
"other_id": null,
"pages": "410-6",
"pmc": null,
"pmid": "9280851",
"pubdate": "1997-05",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Electroconvulsive therapy in clinical practice.",
"title_normalized": "electroconvulsive therapy in clinical practice"
} | [
{
"companynumb": "PL-ACCORD-046040",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "The objective of this study is to perform an open, prospective study on various aspects of comparative effectiveness of newer-generation antiepileptic drugs as add-on therapy in Bulgarian patients with drug-resistant epilepsy.\n\n\n\nThe study was performed with the participation of 1259 patients with epilepsy who attended the Clinic of Neurology at the University Hospital in Plovdiv, Bulgaria for regular visits and completed diaries about seizure frequency, severity, and adverse events.\n\n\n\nOxcarbazepine was used in 82 patients, topiramate in 120 patients, lamotrigine in 73 patients, levetiracetam in 135 patients, pregabalin in 47 patients, tiagabine in 43 patients, gabapentin in 18 patients, lacosamide in 12 patients, and retigabine in 6 patients. During the first 24 months of study, improvement of seizure severity and frequency was most frequent in patients on treatment with pregabalin and levetiracetam and rarest in those on treatment with oxcarbazepine. The retention rate of patients on pregabalin and tiagabine was significantly lower compared to the retention rate of patients on most of the other antiepileptic drugs. The frequency of adverse events was higher in patients on treatment with tiagabine and pregabalin.\n\n\n\nDespite some similar characteristics of newer-generation antiepileptic drugs' effectiveness, levetiracetam stands out with better dynamic improvement of seizure severity and frequency and satisfactory tolerability; typical for pregabalin is a very good dynamic improvement of seizure severity and frequency mainly in patients with focal seizures, but a lower tolerability, and the main advantage of oxcarbazepine is a good tolerability, efficacy, however, is less satisfactory.",
"affiliations": "Department of Neurology, Medical University - Plovdiv, Bulgaria, 15A Vasil Aprilov str., 4002 Plovdiv, Bulgaria. Electronic address: eiviteva@abv.bg.;Department of Neurology, Medical University - Plovdiv, Bulgaria, 15A Vasil Aprilov str., 4002 Plovdiv, Bulgaria.",
"authors": "Viteva|Ekaterina|E|;Zahariev|Zahari|Z|",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D000077287:Levetiracetam; D000077206:Gabapentin; D000077213:Lamotrigine; D000078330:Oxcarbazepine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.yebeh.2018.07.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-5050",
"issue": "87()",
"journal": "Epilepsy & behavior : E&B",
"keywords": "Adverse events; Efficacy; Epilepsy; Newer-generation antiepileptic drugs; Tolerability",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D002031:Bulgaria; D000069279:Drug Resistant Epilepsy; D004359:Drug Therapy, Combination; D005260:Female; D000077206:Gabapentin; D006801:Humans; D000077213:Lamotrigine; D000077287:Levetiracetam; D008297:Male; D000078330:Oxcarbazepine; D011446:Prospective Studies; D000077236:Topiramate; D016896:Treatment Outcome",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "137-145",
"pmc": null,
"pmid": "30097339",
"pubdate": "2018-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Comparative effectiveness of add-on therapy with newer-generation antiepileptic drugs in Bulgarian patients with refractory epilepsy.",
"title_normalized": "comparative effectiveness of add on therapy with newer generation antiepileptic drugs in bulgarian patients with refractory epilepsy"
} | [
{
"companynumb": "BG-UCBSA-2018038038",
"fulfillexpeditecriteria": "1",
"occurcountry": "BG",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "Cardiovascular disease is the leading cause of peripartum death in the United States during pregnancy. The presence of concomitant diagnoses may complicate or conflict with the management of the primary cardiovascular diagnosis and further complicate pregnancy and delivery. We describe the management of a 29-year-old, gravida 5, para 1 woman with severe peripartum cardiomyopathy during this and a previous pregnancy complicated by multiple endocrine neoplasia type and factor V Leiden thrombophilia, limiting therapeutic options and contributing to considerable perioperative management challenges.",
"affiliations": "From the Department of Anesthesiology, University of Virginia, Charlottesville, Virginia.",
"authors": "Kleiman|Amanda M|AM|;Sheeran|Jessica L|JL|;Tiouririne|Mohamed|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000659",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "10(8)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": null,
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "195-197",
"pmc": null,
"pmid": "29652683",
"pubdate": "2018-04-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Case Report of Recurrent Severe Peripartum Cardiomyopathy Complicated by Factor V Leiden and Multiple Endocrine Neoplasia Type 1: A Management Conundrum.",
"title_normalized": "a case report of recurrent severe peripartum cardiomyopathy complicated by factor v leiden and multiple endocrine neoplasia type 1 a management conundrum"
} | [
{
"companynumb": "US-PFIZER INC-2019087224",
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"activesubstancename": "SPIRONOLACTONE"
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"abstract": "OBJECTIVE\nVascular pythiosis is a life-threatening infection caused by the oomycete Pythium insidiosum. This article reports the clinical presentation, serodiagnosis, pathology, and outcomes seen at the authors' institution.\n\n\nMETHODS\nThe cases of patients with proven vascular pythiosis at Ramathibodi Hospital, Mahidol University, Bangkok, Thailand from January 2006 to December 2016 were analyzed retrospectively.\n\n\nRESULTS\nThirteen patients were analyzed, eight of whom had underlying thalassemias. Of the remaining five patients, one had aplastic anemia, one had myelodysplasia, one had acute leukemia, one had cirrhosis, and one had alcoholism. Neutropenic patients showed a rapid clinical deterioration. Atypical presentations including carotid arteritis, aneurysm, brain abscess, and stroke occurred in the non-thalassemic patients. Serology yielded positive results in all cases, with a rapid turnaround time. Serology has the advantage of providing a presurgical diagnosis, which allows prompt surgery and clinical cure to be achieved. Pathology revealed a neutrophilic response in the acute phase and a later shift to granuloma. Immunotherapy in combination with itraconazole and terbinafine was given. The amputation rate was 77%, and disease-free surgical margins were achieved in five cases (38%). The mortality rate was 31%.\n\n\nCONCLUSIONS\nThis study highlights new aspects of pythiosis, such as the unusual host, clinical presentation, serology as a marker for rapid diagnosis, histopathology, and outcomes. Early recognition of the disease with prompt multimodality treatment may improve survival.",
"affiliations": "Division of Infectious Disease, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 270 Rama VI Road, Ratchathewi, Bangkok 10400, Thailand. Electronic address: maria.cht@mahidol.ac.th.;Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Ratchathewi, Bangkok, Thailand. Electronic address: noppadol.lar@mahidol.ac.th.;Mycology Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Electronic address: cariya@chula.ac.th.;Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Ratchathewi, Bangkok, Thailand. Electronic address: theerapong.kra@mahidol.ac.th.",
"authors": "Chitasombat|Maria Nina|MN|;Larbcharoensub|Noppadol|N|;Chindamporn|Ariya|A|;Krajaejun|Theerapong|T|",
"chemical_list": "D000935:Antifungal Agents; D009281:Naphthalenes; D017964:Itraconazole; D000077291:Terbinafine",
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2018.03.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "71()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Arteritis; Pythiosis; Pythium insidiosum",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000671:Amputation; D000818:Animals; D000935:Antifungal Agents; D005260:Female; D006801:Humans; D007167:Immunotherapy; D017964:Itraconazole; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes; D058968:Pythiosis; D011775:Pythium; D012189:Retrospective Studies; D000077291:Terbinafine; D013785:Thailand; D055815:Young Adult",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "33-41",
"pmc": null,
"pmid": "29653202",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinicopathological features and outcomes of pythiosis.",
"title_normalized": "clinicopathological features and outcomes of pythiosis"
} | [
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"companynumb": "PHHY2018TH012138",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
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"activesubstance": {
"activesubstancename": "TERBINAFINE"
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"drugadditional": null,
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{
"abstract": "BACKGROUND\nThe diagnosis of gonorrhea and/or chlamydia in a prepubertal child beyond the neonatal period is confirmatory of mucosal contact with infective bodily secretions and therefore highly concerning for sexual abuse. When such a diagnosis is made, a report to protective authorities is warranted so that safety and potential criminal activity may be evaluated concurrent with the medical management. Occasionally, despite perceived adequate medical management and protective safety plans, a child may present with a repeat positive result for sexually transmitted infections. In this scenario, it is important for medical providers to carefully consider and be aware of the possible reasons for the repeat positive result: (1) treatment failure, (2) a new infection from repeated abuse, or (3) a false-positive result due to the limitations of nonculture testing.\n\n\nMETHODS\nPrepubertal sisters were diagnosed with gonorrhea and Chlamydia and treated with antibiotics, and the individual identified as having sexually abused them was removed from the home.\n\n\nCONCLUSIONS\nOver a 4-month period, both children continued to have positive testing for chlamydia via the nucleic acid amplification test and/or culture. Concurrent with using alternate antibiotic treatment options, protective authorities were alerted to the fact that this was likely a reinfection. The investigative team later determined that a second adult, who tested positive for gonorrhea and chlamydia, was also sexually abusing both girls. Disclosures of abuse regarding both adult individuals were deemed credible by authorities and supported with collateral information.",
"affiliations": "New York Medical College, Valhalla, New York; Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, New York.;New York Medical College, Valhalla, New York; Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, New York. Electronic address: jcanter@wihd.org.",
"authors": "Rao|Vinod|V|;Canter|Jennifer|J|",
"chemical_list": "D004269:DNA, Bacterial",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-3188",
"issue": "28(4)",
"journal": "Journal of pediatric and adolescent gynecology",
"keywords": "Child abuse; Chlamydia; Cultures; Delayed disclosure; Follow-up in sexual abuse; Gonorrhea; HPV; Human papilloma virus; Nucleic acid amplification test (NAAT); Sexual abuse; Sibling testing with sexually transmitted infections (STIs); Time frame for chlamydia; Time frame for gonorrhea; Treatment failure; Warts",
"medline_ta": "J Pediatr Adolesc Gynecol",
"mesh_terms": "D000328:Adult; D002648:Child; D002650:Child Abuse, Sexual; D002690:Chlamydia Infections; D002692:Chlamydia trachomatis; D004269:DNA, Bacterial; D005260:Female; D005500:Follow-Up Studies; D006069:Gonorrhea; D006801:Humans; D008297:Male; D009344:Neisseria gonorrhoeae; D021141:Nucleic Acid Amplification Techniques; D012749:Sexually Transmitted Diseases",
"nlm_unique_id": "9610774",
"other_id": null,
"pages": "e109-12",
"pmc": null,
"pmid": "26119074",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The Interpretation of Repeat Positive Results for Gonorrhea and Chlamydia in Children.",
"title_normalized": "the interpretation of repeat positive results for gonorrhea and chlamydia in children"
} | [
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"companynumb": "US-JNJFOC-20150712045",
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"activesubstancename": "LEVOFLOXACIN"
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{
"abstract": "The purpose of this study is to evaluate the in-hospital mortality of community-acquired pneumonia (CAP) treated with ceftaroline in comparison with standard therapy. This was a retrospective observational study in two centers. Hospitalized patients with CAP were grouped according to the empiric regimen (ceftaroline versus standard therapy) and analyzed using a propensity score matching (PSM) method to reduce confounding factors. Out of the 6981 patients enrolled, 5640 met the inclusion criteria, and 89 of these received ceftaroline. After PSM, 78 patients were considered in the ceftaroline group (cases) and 78 in the standard group (controls). Ceftaroline was mainly prescribed in cases with severe pneumonia (67% vs. 56%, p = 0.215) with high suspicion of Staphylococcus aureus infection (9% vs. 0%, p = 0.026). Cases had a longer length of hospital stay (13 days vs. 10 days, p = 0.007), while an increased risk of in-hospital mortality was observed in the control group compared to the case group (13% vs. 21%, HR 0.41; 95% CI 0.18 to 0.62, p = 0.003). The empiric use of ceftaroline in hospitalized patients with severe CAP was associated with a decreased risk of in-hospital mortality.",
"affiliations": "Department of Pneumology, Hospital Clinic of Barcelona, August Pi I Sunyer Biomedical Research Institute - IDIBAPS, University of Barcelona, Biomedical Research Networking Centers in Respiratory Diseases (CIBERES), Barcelona, Spain. catiacilloniz@yahoo.com.;Department of Pneumology, Hospital La Fe de Valencia, Valencia, Spain.;Internal Medicine Department, Respiratory Medicine Unit and Emergency Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.;Department of Infectious Diseases, Hospital Clinic of Barcelona, C/Villarroel 170, 08036, Barcelona, Spain.;Department of Infectious Diseases, Hospital Clinic of Barcelona, C/Villarroel 170, 08036, Barcelona, Spain.;Department of Pneumology, Hospital Clinic of Barcelona, August Pi I Sunyer Biomedical Research Institute - IDIBAPS, University of Barcelona, Biomedical Research Networking Centers in Respiratory Diseases (CIBERES), Barcelona, Spain.;Department of Pneumology, Hospital La Fe de Valencia, Valencia, Spain.;Department of Pneumology, Hospital Clinic of Barcelona, August Pi I Sunyer Biomedical Research Institute - IDIBAPS, University of Barcelona, Biomedical Research Networking Centers in Respiratory Diseases (CIBERES), Barcelona, Spain.;Department of Infectious Diseases, Hospital Clinic of Barcelona, C/Villarroel 170, 08036, Barcelona, Spain. asoriano@clinic.cat.",
"authors": "Cilloniz|Catia|C|http://orcid.org/0000-0002-4646-9838;Mendez|Raúl|R|;Peroni|Héctor|H|;Garcia-Vidal|Carolina|C|;Rico|Verónica|V|;Gabarrus|Albert|A|;Menéndez|Rosario|R|;Torres|Antoni|A|;Soriano|Alex|A|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s10096-021-04378-0",
"fulltext": "\n==== Front\nEur J Clin Microbiol Infect Dis\nEur J Clin Microbiol Infect Dis\nEuropean Journal of Clinical Microbiology & Infectious Diseases\n0934-9723\n1435-4373\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n34767120\n4378\n10.1007/s10096-021-04378-0\nOriginal Article\nImpact on in-hospital mortality of ceftaroline versus standard of care in community-acquired pneumonia: a propensity-matched analysis\nhttp://orcid.org/0000-0002-4646-9838\nCilloniz Catia catiacilloniz@yahoo.com\n\n1\nMendez Raúl 2\nPeroni Héctor 3\nGarcia-Vidal Carolina 4\nRico Verónica 4\nGabarrus Albert 1\nMenéndez Rosario 2\nTorres Antoni 1\nSoriano Alex asoriano@clinic.cat\n\n4\n1 Department of Pneumology, Hospital Clinic of Barcelona, August Pi I Sunyer Biomedical Research Institute - IDIBAPS, University of Barcelona, Biomedical Research Networking Centers in Respiratory Diseases (CIBERES), Barcelona, Spain\n2 grid.84393.35 0000 0001 0360 9602 Department of Pneumology, Hospital La Fe de Valencia, Valencia, Spain\n3 grid.414775.4 0000 0001 2319 4408 Internal Medicine Department, Respiratory Medicine Unit and Emergency Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina\n4 grid.410458.c 0000 0000 9635 9413 Department of Infectious Diseases, Hospital Clinic of Barcelona, C/Villarroel 170, 08036 Barcelona, Spain\n12 11 2021\n12 11 2021\n2022\n41 2 271279\n18 8 2021\n4 11 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/.\nThe purpose of this study is to evaluate the in-hospital mortality of community-acquired pneumonia (CAP) treated with ceftaroline in comparison with standard therapy. This was a retrospective observational study in two centers. Hospitalized patients with CAP were grouped according to the empiric regimen (ceftaroline versus standard therapy) and analyzed using a propensity score matching (PSM) method to reduce confounding factors. Out of the 6981 patients enrolled, 5640 met the inclusion criteria, and 89 of these received ceftaroline. After PSM, 78 patients were considered in the ceftaroline group (cases) and 78 in the standard group (controls). Ceftaroline was mainly prescribed in cases with severe pneumonia (67% vs. 56%, p = 0.215) with high suspicion of Staphylococcus aureus infection (9% vs. 0%, p = 0.026). Cases had a longer length of hospital stay (13 days vs. 10 days, p = 0.007), while an increased risk of in-hospital mortality was observed in the control group compared to the case group (13% vs. 21%, HR 0.41; 95% CI 0.18 to 0.62, p = 0.003). The empiric use of ceftaroline in hospitalized patients with severe CAP was associated with a decreased risk of in-hospital mortality.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1007/s10096-021-04378-0.\n\nKeywords\n\nCommunity-acquired pneumonia\nSevere pneumonia\nCeftaroline\nPneumonia\nAntimicrobials\nCIBERESCIBERES CB06/06/0028 http://dx.doi.org/10.13039/501100007509 Sociedad Española de Neumología y Cirugía Torácica Aspire: INSPIIRE WI244153Universitat de BarcelonaOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature.\n\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2022\n==== Body\npmcIntroduction\n\nApproximately 10 to 18% of hospitalized patients with community-acquired pneumonia (CAP) present with severe pneumonia that requires admission to the intensive care unit (ICU) [1]. Severe CAP is associated with high mortality, ranging from 25 to more than 50% [2, 3]. Prompt identification of severe pneumonia and early, adequate antibiotic therapy are crucial in managing these cases. Based on this observation, early, adequate antibiotic therapy could reduce mortality in severe CAP.\n\nSeveral studies have reported the beneficial effects on the patient outcomes by using ceftriaxone plus macrolide regimen as empiric therapy [4, 5]. However, this combination is not good enough to cover Staphylococcus aureus, which is increasingly identified as a cause of severe pneumonia with high associated mortality, particularly in cases related to influenza virus co-infection or COVID-19 [1, 6, 7]. Also, the increasing prevalence of methicillin-resistant S. aureus and penicillin- and ceftriaxone-resistant Streptococcus pneumoniae in severe CAP has made this combination of antibiotics less effective [8, 9]. Ceftaroline is a broad-spectrum cephalosporin that covers gram-positive bacteria (including methicillin-susceptible and methicillin-resistant S. aureus and drug-resistant S. pneumoniae) and third-generation-susceptible gram-negative bacilli [10]. Results of the FOCUS 1 and 2 trials demonstrated the superiority of ceftaroline against ceftriaxone in bacterial CAP; however, these studies did not include severe cases and the mortality rate was low [10]. In comparison with ceftriaxone, ceftaroline has shown to have superior in vitro activity against S. aureus (≥ 16-fold more potent than ceftriaxone against MSSA and active against MRSA), S. pneumoniae, and other common CAP pathogens [11, 12].\n\nUsing the propensity score matching (PSM) method, we aim to evaluate in-hospital mortality of CAP treated with ceftaroline in comparison with standard therapy (Supplementary Table 1) in our cohort of severe CAP.\n\nMethods\n\nStudy design\n\nThis was a retrospective analysis of prospectively collected data conducted at two Spanish hospitals (Hospital 1 from 1996 to 2020, and Hospital 2 from 2017 to 2020). The collection method was systematic, and all patients with CAP admitted to both hospitals were enrolled in the study.\n\nSelection of patients\n\nWe enrolled all consecutive adult patients with a diagnosis of CAP admitted to hospital via the emergency department. We included patients from nursing homes, as we previously demonstrated that the microbial aetiology in this population is similar to that of CAP arising in people living in their own homes [13].\n\nExclusion criteria were as follows: (a) severe immunosuppression (AIDS, chemotherapy, immunosuppressive drugs [e.g., oral corticosteroid ≥ 10 mg prednisone or equivalent per day for at least 2 weeks]); (b) active tuberculosis; (c) cases with a confirmed alternative diagnosis.\n\nThe study was approved by the Ethics Committees of both institutions (Register: 2009/5451). The need for written informed consent was waived due to the non-interventional design.\n\nDefinitions\n\nCAP was defined as a new pulmonary infiltrate on chest x-ray performed at hospital admission, combined with symptoms and signs consistent with a lower respiratory tract infection (e.g., fever, cough, sputum production, and pleuritic chest pain) in patients with no recent hospitalization or regular exposure to a healthcare system. Severe CAP was diagnosed by the presence of at least one major or three minor criteria, as set out by the Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guideline [14]. Prior antibiotic treatment was defined as antibiotics taken within the week before disease presentation. Polymicrobial pneumonia was defined as pneumonia due to more than one pathogen.\n\nData collection\n\nDemographic variables, comorbidities, and physiologic parameters were collected in the emergency department within 24 h of admission. Comorbidities of interest included chronic respiratory disease (e.g., chronic obstructive pulmonary disease, asthma, and bronchiectasis), diabetes mellitus, chronic cardiovascular disease, neurologic disease (e.g., dementia, coma, stroke, degenerative diseases, Parkinson’s disease, and Down syndrome), chronic renal disease, chronic liver disease, and previous neoplasm.\n\nThe Pneumonia Severity Index (PSI), CURB-65 score (i.e., confusion, urea nitrogen, respiratory rate, blood pressure, and age ≥ 65 years), and SOFA score were calculated at admission. During hospitalization, we recorded whether the patients had specific complications, including multilobar infiltration, pleural effusions, acute respiratory distress syndrome (ARDS), septic shock, or acute renal failure. Further details are reported elsewhere [15]. All surviving patients were visited or contacted by telephone 30 days after discharge.\n\nMicrobiologic evaluation\n\nMicrobiologic examination was performed on respiratory, urinary, and blood samples. Cultures were collected before the initiation of empiric antibiotic therapy in the emergency department. Criteria for making an aetiologic diagnosis have been reported previously[15].\n\nBlood cultures, sputum cultures, and urine samples for S. pneumoniae and Legionella pneumophila antigen detection were obtained within 24 h of hospital admission. When available, pleural fluid, tracheobronchial aspirates, and bronchoalveolar lavage samples were collected for Gram and Ziehl–Neelsen staining and processed for bacterial, fungal, and mycobacterial pathogen detection. The results of susceptibility testing were interpreted according to EUCAST guidance (http://www.eucast.org). Blood samples for serology of atypical pathogens and respiratory virus were collected at admission and between the third and sixth week thereafter.\n\nRespiratory viruses were diagnosed by serology, immunofluorescence assay (IFA), and isolation in cell cultures between 2005 and 2007. However, between 2008 and 2019, polymerase chain reaction (PCR) and/or cultures of nasopharyngeal swab samples were used instead. Two independent nested multiplex real-time PCR tests were performed to detect human influenza viruses (A, B, and C), respiratory syncytial virus, adenoviruses, parainfluenza viruses (1–4), coronaviruses (229E and OC43), enteroviruses, and rhinoviruses (A, B, and C).\n\nOutcomes\n\nPrimary outcomes were in-hospital and 30-day mortality. Secondary outcomes included length of hospital stay, ICU mortality, length of stay in ICU, need of mechanical ventilation, and 30-day and 1-year mortality.\n\nStatistical analysis\n\nWe report the number and percentage of patients for categorical variables, the median (first quartile; third quartile) for continuous variables with non-normal distributions, and the mean (standard deviation) for continuous variables with normal distributions. Categorical variables were compared using the chi-squared test or Fisher’s exact test, whereas continuous variables were compared using the t test or nonparametric Mann–Whitney U test.\n\nPatients receiving ceftaroline in monotherapy or in combination as empirical therapy were considered the case group, whereas the remaining cohort was considered as controls. PSM was used to obtain a balance between patients in the case and control groups. To match the two cohorts, we used a 1:1 nearest neighbor matching without replacement within a match tolerance width of 0.005. Variables were chosen for inclusion in the PSM calculation according to methods set forth by Brookhart et al. [16]. Variables included were associated with the case group and outcomes (age, gender, chronic respiratory disease, chronic cardiovascular disease, diabetes mellitus, neurologic disease, chronic renal disease, chronic liver disease, previous neoplasm, fever, confusion, C-reactive protein, PaO2/FiO2, polymicrobial, bacteremia, multilobar, septic shock, ICU admission, and mechanical ventilation). An adequate model fit with discrimination and calibration of the PSM was demonstrated by the logistic model including covariates yielded a goodness-of-fit p = 0.867.\n\nCox proportional hazard regression models were used for in-hospital, 3-day, and 30-day mortality. The hazard ratio (HR) and its 95% confidence intervals (CI) were calculated.\n\nWe used the multiple imputation method for missing data in the covariates of the PSM model.\n\nThe level of significance was set at 0.05 (two-tailed). All statistical analyses were performed using IBM SPSS Statistics 26.0 (Armonk, NY, USA).\n\nResults\n\nGeneral clinical characteristics\n\nDuring the study period, 6981 patients with CAP were enrolled. Of these, 5640 (80%) patients met the inclusion criteria. In the full cohort, a total of 5551 (99%) received standard empiric antibiotic treatment and 89 (1%) received ceftaroline (3% monotherapy and 97% in combination therapy [46% ceftaroline + azithromycin; 16% ceftaroline + levofloxacin; and 38% other combinations]). After PSM was performed, 156 patients were finally included in the study (78 cases and 78 controls) (Fig. 1).Fig. 1 Flow diagram of study population\n\nTable 1 summarizes the demographics and clinical characteristics of patients between case and control groups in the full cohort and after PSM. In the full cohort, and when compared to the control group, the case group was more likely to be younger and have a lower rate of influenza vaccines and a higher rate of pneumococcal vaccine. Also, the case group was less likely to have previously received inhaled corticosteroids and more frequently had chronic renal disease and a previous neoplasm. At admission, the case group less frequently presented with fever and purulent sputum than the control group. At admission, the case group had higher levels of C-reactive protein, lower lymphocyte counts, and worse oxygenation. Also, the case group at days 2 and 3 had higher levels of C-reactive protein and neutrophils, yet a lower rate of lymphocyte counts. In comparison with the control group, the case group also had a higher percentage of patients with severe CAP, with more cases of complications including bacteremia, multilobar involvement, ARDS, and acute renal failure. Pneumococcal vaccination, purulent sputum, and pleuritic pain were the only general variables not adequately balanced between both groups after PSM.Table 1 Patient characteristics and outcomes\n\n\tCAP (full cohort)\tCAP (propensity score matching)\t\nVariable\t(N = 5640)\t(N = 156)\t\nCase (n = 89)\tControl (n = 5551)\tp value\tCase (n = 78)\tControl (n = 78)\tp value\t\nAge, mean (SD), years\t64 (17)\t70 (17)\t0.001\t64 (17)\t65 (19)\t0.673\t\nMale sex, n (%)\t52 (58)\t3,456 (62)\t0.460\t48 (62)\t50 (64)\t0.740\t\nCurrent smoker, n (%)\t18 (31)\t1,223 (22)\t0.129\t18 (31)\t20 (26)\t0.518\t\nCurrent alcohol use, n (%)\t4 (7)\t787 (14)\t0.097\t4 (7)\t10 (13)\t0.240\t\nPrevious antibiotic, n (%)\t16 (19)\t1,222 (23)\t0.391\t15 (20)\t17 (23)\t0.690\t\nInfluenza vaccine, n (%)\t23 (29)\t1,833 (45)\t0.004\t20 (29)\t19 (35)\t0.543\t\nPneumococcal vaccine, n (%)\t26 (32)\t822 (20)\t0.010\t24 (34)\t10 (18)\t0.045\t\nPrevious inhaled corticosteroids, n (%)\t9 (10)\t1,053 (19)\t0.034\t7 (9)\t15 (19)\t0.065\t\nPrevious systemic corticosteroids, n (%)\t3 (3)\t217 (5)\t0.525\t3 (4)\t4 (6)\t0.701\t\nPrevious episode of pneumonia, n (%)\t16 (18)\t745 (14)\t0.291\t15 (19)\t9 (12)\t0.232\t\nComorbidities, n (%) a\t55 (62)\t4,074 (74)\t0.013\t48 (62)\t55 (71)\t0.237\t\n Chronic respiratory disease\t32 (36)\t2,472 (45)\t0.080\t29 (37)\t32 (41)\t0.623\t\n Chronic cardiovascular disease\t10 (11)\t918 (17)\t0.176\t9 (12)\t14 (18)\t0.259\t\n Diabetes mellitus\t16 (18)\t1,178 (21)\t0.433\t13 (17)\t13 (17)\t > 0.999\t\n Neurologic disease\t10 (11)\t1,007 (19)\t0.079\t9 (12)\t13 (17)\t0.357\t\n Chronic renal disease\t13 (15)\t473 (9)\t0.044\t11 (14)\t14 (18)\t0.513\t\n Chronic liver disease\t5 (6)\t272 (5)\t0.627\t5 (6)\t3 (4)\t0.719\t\n Previous neoplasm\t16 (18)\t512 (10)\t0.008\t14 (18)\t15 (19)\t0.837\t\nNursing home, n (%)\t2 (3)\t364 (7)\t0.434\t2 (3)\t4 (5)\t0.696\t\nCough, n (%)\t68 (77)\t4,270 (78)\t0.882\t58 (75)\t60 (7)\t0.815\t\nPurulent sputum, n (%)\t40 (45)\t3,097 (57)\t0.024\t32 (42)\t51 (68)\t0.001\t\nDyspnea, n (%)\t62 (70)\t3,907 (72)\t0.818\t54 (70)\t59 (78)\t0.291\t\nPleuritic pain, n (%)\t23 (26)\t1,889 (35)\t0.109\t18 (24)\t34 (44)\t0.009\t\nFever, n (%)\t56 (63)\t4,157 (76)\t0.006\t46 (59)\t48 (62)\t0.744\t\nConfusion, n (%)\t12 (13)\t1,147 (21)\t0.090\t11 (14)\t10 (13)\t0.815\t\nC-reactive protein at baseline, median (IQR), mg/dL\t25.3 (13.9; 39.4)\t17.8 (8.5; 27.3)\t < 0.001\t22.6 (10.3; 31.6)\t25.1 (16.4; 33.9)\t0.244\t\nC-reactive protein at days 2 and 3, median (IQR), mg/dL\t25.3 (15.5; 31)\t15.3 (7.4; 24.1)\t < 0.001\t24.5 (15.5; 30.6)\t20.6 (8.5; 28)\t0.269\t\nNeutrophils at baseline, median (IQR), cell/mm3\t9,810 (4,686; 15,032)\t10,160 (6,622; 14,661)\t0.380\t9,626 (5,376; 14,711)\t10,640 (7,304; 14,280)\t0.388\t\nNeutrophils at days 2 and 3, median (IQR), cell/mm3\t11,550 (7,650; 17,606)\t8,306 (5,465; 12,466)\t0.009\t11,659 (7,769; 17,606)\t8,835 (5,192; 12,220)\t0.081\t\nLymphocytes at baseline, median (IQR), cell/mm3\t660 (380; 1192)\t900 (543; 1,386)\t0.001\t661 (386; 1,152)\t900 (428; 1,463)\t0.135\t\nLymphocytes at days 2 and 3, median (IQR), cell/mm3\t600 (387; 816)\t902 (531; 1,379)\t0.003\t592 (387; 753)\t722 (520; 1,122)\t0.057\t\nPaO2/FiO2, median (IQR)\t238 (173; 295)\t276 (233; 316)\t < 0.001\t241 (177; 300)\t248 (184; 310)\t0.656\t\nPSI score, median (IQR)\t104 (76; 135)\t101 (78; 126)\t0.664\t105.5 (70; 137.5)\t114.5 (83; 134)\t0.568\t\nPSI risk class IV–V, n (%) b\t58 (66)\t2,366 (62)\t0.411\t53 (69)\t34 (68)\t0.922\t\nSOFA score, median (IQR)\t3 (2; 4)\t2 (1; 3)\t0.087\t3 (2; 4)\t3 (2; 5)\t0.685\t\nSevere CAP, n (%)\t46 (69)\t1,337 (32)\t < 0.001\t43 (67)\t35 (56)\t0.215\t\n Major criteria\t11 (16)\t254 (6)\t0.002\t11 (17)\t8 (13)\t0.502\t\n ≥ 3 minor criteria\t18 (27)\t752 (18)\t0.053\t16 (25)\t12 (19)\t0.446\t\n Major and ≥ 3 minor criteria\t17 (25)\t331 (8)\t < 0.001\t16 (25)\t15 (24)\t0.916\t\nBacteremia, n (%) c\t22 (29)\t554 (13)\t < 0.001\t20 (26)\t25 (32)\t0.377\t\nPleural effusion, n (%)\t13 (22)\t837 (15)\t0.156\t13 (22)\t15 (20)\t0.706\t\nMultilobar involvement, n (%)\t51 (57)\t1,485 (27)\t < 0.001\t44 (56)\t44 (56)\t > 0.999\t\nARDS, n (%)\t21 (26)\t271 (5)\t < 0.001\t18 (25)\t14 (19)\t0.423\t\nAcute renal failure, n (%)\t31 (44)\t1,510 (28)\t0.002\t28 (42)\t34 (44)\t0.888\t\nSeptic shock, n (%)\t10 (11)\t396 (7)\t0.150\t10 (13)\t9 (12)\t0.807\t\nLength of hospital stay, median (IQR), days\t12 (9; 24)\t7 (5; 11)\t < 0.001\t13 (9; 25)\t10 (6.5; 15.5)\t0.007\t\nICU admission, n (%)\t56 (63)\t1,040 (19)\t < 0.001\t54 (69)\t46 (59)\t0.182\t\n ICU mortality, n (%) d\t5 (9)\t116 (11)\t0.605\t5 (9)\t10 (22)\t0.082\t\n Length of ICU stay, median (IQR), days d\t15.5 (10.5; 29.5)\t12 (8; 20)\t0.005\t15.5 (10; 30)\t12 (8; 23)\t0.074\t\nMechanical ventilation, n (%) e\t\t\t < 0.001\t\t\t0.198\t\n Non-invasive\t3 (5)\t183 (4)\t0.491\t5 (6)\t12 (15)\t0.040\t\n Invasive\t24 (40)\t360 (7)\t < 0.001\t27 (35)\t24 (31)\t0.308\t\nIn-hospital mortality, n (%)\t11 (12)\t432 (8)\t0.112\t10 (13)\t16 (21)\t0.197\t\n3-day mortality, n (%)\t1 (1)\t82 (1)\t > 0.999\t1 (1)\t4 (5)\t0.367\t\n30-day mortality, n (%)\t10 (13)\t439 (8)\t0.113\t9 (12)\t15 (19)\t0.183\t\n1-year mortality, n (%)\t13 (23)\t600 (11)\t0.004\t12 (18)\t16 (21)\t0.664\t\nARDS, acute respiratory distress syndrome; CAP, community-acquired pneumonia; IQR, interquartile range; ICU, intensive care unit; PSI, Pneumonia Severity Index; SD, standard deviation. Percentages calculated with non-missing data only. aPossibly > 1 comorbidity. bStratified by 30-day mortality risk for CAP: classes I–III (≤ 90 points) had low mortality risk, while classes IV–V (> 90 points) had the highest mortality risk. cCalculated only for patients with blood samples. dCalculated only for patients admitted to intensive care. ePatients who initially received non-invasive ventilation yet subsequently needed intubation were included in the invasive mechanical ventilation group\n\nBold numbers refers to statistically significant differences\n\nMicrobial aetiology\n\nIn the full cohort, microbiologic diagnosis was more frequent in the case group (70% vs. 41%, p < 0.001) than in the control group. A higher prevalence of polymicrobial aetiology and Staphylococcus aureus, as well as a lower prevalence of Legionella pneumophila, was observed in the case group when compared to the control group. After PSM, no differences in microbiologic diagnoses were observed (73% vs. 76%, p = 0.714); however, Staphylococcus aureus was more frequent in the case group than in the control group (Table 2).Table 2 Microbial aetiology\n\n\tCAP (full cohort)\tCAP (propensity score matching)\t\nVariable\t(N = 5,640)\t(N = 156)\t\nCase (n = 89)\tControl (n = 5,551)\tp value\tCase (n = 78)\tControl (n = 78)\tp value\t\nPatients with defined aetiology\t62 (70)\t2,302 (41)\t < 0.001\t57 (73)\t59 (76)\t0.714\t\nStreptococcus pneumoniae\t22 (35)\t982 (43)\t0.259\t19 (33)\t25 (42)\t0.316\t\nRespiratory virus\t13 (21)\t335 (15)\t0.159\t13 (23)\t6 (10)\t0.066\t\nPolymicrobial\t21 (34)\t320 (14)\t < 0.001\t19 (33)\t20 (34)\t0.949\t\nAtypical\t0 (0)\t119 (5)\t0.073\t0 (0)\t2 (3)\t0.496\t\n Mycoplasma pneumoniae\t0 (0)\t54 (2)\t0.401\t0 (0)\t1 (2)\t > 0.999\t\n Coxiella burnetii\t0 (0)\t22 (1)\t > 0.999\t0 (0)\t1 (2)\t > 0.999\t\n Chlamydophila pneumoniae\t0 (0)\t41 (2)\t0.626\t0 (0)\t0 (0)\t-\t\n Chlamydophila psittaci\t0 (0)\t2 (0.1)\t > 0.999\t0 (0)\t0 (0)\t-\t\nLegionella pneumophila\t0 (0)\t151 (7)\t0.031\t0 (0)\t0 (0)\t-\t\n Staphylococcus aureus\t5 (8)\t61 (3)\t0.028\t5 (9)\t0 (0)\t0.026\t\n Haemophilus influenzae\t0 (0)\t97 (4)\t0.180\t0 (0)\t1 (2)\t > 0.999\t\n Pseudomonas aeruginosa\t1 (2)\t87 (4)\t0.728\t1 (2)\t2 (3)\t > 0.999\t\n Gram-negative Enterobacteriaceae\t0 (0)\t51 (2)\t0.643\t0 (0)\t1 (2)\t > 0.999\t\n Moraxella catarrhalis\t0 (0)\t6 (0.3)\t > 0.999\t0 (0)\t0 (0)\t-\t\nOther Streptococcus species\t0 (0)\t6 (0.3)\t > 0.999\t0 (0)\t0 (0)\t-\t\nOthers\t0 (0)\t82 (4)\t0.275\t0 (0)\t2 (3)\t0.496\t\nCAP, community-acquired pneumonia. Results are given as n (%). Percentages calculated on non-missing data. Pathogen percentages are related to the number of patients with an aetiologic diagnosis in each group\n\nOutcomes\n\nIn the full cohort, the case group had more ICU admissions; longer length of hospital stay; longer length of ICU stay; more invasive mechanical ventilation; and higher 1-year mortality (Table 1). Cox regression (Table 3) showed that the risks of in-hospital, 3-day, and 30-day mortality did not differ between patients of either the case or control groups. After PSM, the case group was associated with a lower in-hospital mortality (adjusted HR 0.41 [95% CI 0.18 to 0.92]) and a longer length of hospital stay in comparison to the control group (Table 1 and Table 3, respectively).Table 3 Cox regression models evaluating the risk of in-hospital and 30-day mortality in the case group\n\nVariable\tHR\t95% CI\tp value\t\nIn-hospital mortality\t\n Crude (full cohort)\t0.72\t0.39 to 1.31\t0.279\t\n Propensity score matching\t0.41\t0.18 to 0.92\t0.031\t\n3-day mortality\t\n Crude (full cohort)\t0.76\t0.11 to 5.44\t0.782\t\n Propensity score matching\t0.24\t0.03 to 2.19\t0.208\t\n30-day mortality\t\n Crude (full cohort)\t1.41\t0.75 to 2.63\t0.286\t\n Propensity score matching\t0.54\t0.24 to 1.24\t0.149\t\nHR, hazard ratio; CI, confidence interval\n\nDiscussion\n\nThere are 3 main findings of this study. First, ceftaroline was mainly prescribed in cases of severe pneumonia with high suspicion of S. aureus infection. Second, in-hospital mortality of the PSM cohort was 13% in the ceftaroline group, and 21% in the control group. Third, after confounding variables were adjusted, the use of ceftaroline was associated with a lower in-hospital mortality rate.\n\nImplementing new antibiotics into clinical practice often implies use of such drugs in the most severe cases, and a simple analysis of its effectiveness could be biased. Ceftaroline has been proposed as a better alternative to ceftriaxone during influenza season when S. aureus is more prevalent [17]. Severe infections characterize this population [18, 19], and it explains why ceftaroline was used mainly in critically ill patients in our cohort (67% presented with severe CAP). These patients had a higher prevalence of S. aureus and a recent history of pneumococcal vaccine. Ceftaroline is 16 times more active against MSSA (MIC90 0.25 versus 4 mg/L) than ceftriaxone and is active against MRSA as well [11]. Furthermore, available data about critically ill patients suggest that 2 g of ceftriaxone does not reach adequate plasma concentrations [20]. In the case of ceftaroline, pharmacokinetic/pharmacodynamic (PK/PD) target is achieved with a standard dosage, although PK data in critically ill patients is lacking. In addition, an animal model of pneumonia due to MRSA-producing Panton-Valentine leukocidin (PVL) showed that ceftaroline was bactericidal and also significantly reduced PVL concentration in the lung [21]. All of this data could explain why better results were obtained in 3 randomized controlled trials (RCT) [22–24] comparing the clinical efficacy of ceftaroline vs. ceftriaxone. In a meta-analysis of these studies, which included 1916 patients, ceftaroline (600 mg/12 h) was superior to ceftriaxone (1–2 g/24 h) in terms of clinical recovery (OR 1.66; 95% CI 1.34, 2.06) [25]; however, mortality rate in these studies was low (1.5% in each group) [25].\n\nIn our study, in-hospital mortality of the PSM cohort was 15%. This is a high mortality for CAP [26, 27], clearly demonstrating the severity of patients included in the analysis. Interestingly, in-hospital mortality was lower in the ceftaroline group (13% vs. 21%, p = 0.197). After we adjusted the analysis for confounding variables, in-hospital mortality was significantly lower in the ceftaroline group (adjusted HR 0.41 [95% CI 0.18 to 0.92]). The same trend was observed in results obtained for 30-day and 1-year mortality (adjusted HR 0.54 [95% CI 0.24 to 1.24]); however, the small number of patients may have not allowed for significance to be reached. Longer in-hospital survival in the case group may explain extended hospital stay.\n\nThere is a continuous debate about which antibiotic, a macrolide or fluoroquinolone, is the best companion to β-lactams. Both options are included as first-line choices in recent ATS guidelines [1]. Several studies have reported an association between the use of the combination of β-lactams plus macrolide and lower mortality in CAP, when compared to the use of β-lactams in monotherapy [28, 29]. However, Postma et al. [30]. found that β-lactam monotherapy was not inferior to the treatment with combination of β-lactams and macrolides or fluoroquinolone monotherapy with respect to 90-day mortality in patients with non-severe CAP. The main benefits of macrolides include a reduction in pneumolysin, immunomodulation, and activity against atypical pathogens, albeit not against S. aureus [31]. An association of macrolide with levofloxacin offers activity against S. aureus, but there is little data about its efficacy and some studies have even shown a worse prognosis [28]. In addition, the use of fluoroquinolones is associated with severe adverse effects [32, 33]. The potent activity of ceftaroline against S. aureus, the possibility to combine it with a macrolide, and the present article showing good outcomes in patients with severe CAP highlight how such a combination could offer broad-spectrum coverage, potent bactericidal activity, and the potential benefits of macrolides.\n\nWe believe that our statistical approach using a PSM is a strength in this study. There are, however, some limitations due to the final total sample size. In this study, we were able to analyze only 78 patients in each group (total N = 156). This sample size may result in a large type II error, and conclusions that can be drawn are limited. This aside, though, the rigorous approach to the study underpins our confidence in its findings and their clinical relevance. Another limitation of this study is the analysis of empiric antibiotic therapy, without consideration of dose or duration of the treatment.\n\nOur data showed that ceftaroline was associated with a decreased risk of mortality in hospitalized patients with severe CAP. Ceftaroline is a very active β-lactam against S. pneumoniae and S. aureus, which can be associated with a macrolide without a loss of beneficial effects. This explains why ceftaroline was recommended by current ATS/IDSA guidelines [1] in the management of CAP. Our experience supports the use of ceftaroline in patients with severe CAP.\n\nSupplementary Information\n\nBelow is the link to the electronic supplementary material.Supplementary file1 (DOCX 16 KB)\n\nAuthor contribution\n\nAS had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: AS, AT, RM, and CC. Acquisition of data: CC, RM, HP, CG, VR, and AG. Analysis and interpretation of data: CC, HP, RM, RM, VR, CG, AT, and AS. Drafting of the manuscript: AS, CC, AT, RM, RM, CG, HP, VR, and AG. Critical revision of the manuscript for important intellectual content: AS, CC, AT, RM, CG. Statistical analysis: AG. Study supervision: AS, AT, RM, and CC.\n\nFunding\n\nOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This study was supported by a grant from Pfizer (Aspire: INSPIIRE WI244153), by CIBER de Enfermedades Respiratorias (CIBERES CB06/06/0028), and by 2009 Support to Research Groups of Catalonia 911, IDIBAPS. Dr. Soriano received a grant from Pfizer (Aspire). Dr. Cilloniz received a SEPAR fellowship 2018, and a grant from the Fondo de Investigación Sanitaria (PI19/00207). SEPAR integrated respiratory infections program.\n\nDeclarations\n\nEthics approval\n\nThe study was approved by the Ethics Committees of both institutions (Register: 2009/5451 and 2011/0219). The need for written informed consent was waived due to the non-interventional design.\n\nConflict of interest\n\nThe authors declare that they have no conflicts of interest with the study. AS has received a grant from Pfizer and honoraria for lectures and advisory meetings from Pfizer, MSD, Menarini, Shionogi, Gilead, and Angelini. CGV has received honoraria for talks on behalf of Gilead Science, MSD, Novartis, Pfizer, Janssen, and Lilly, as well as a grant from Gilead Science, Pfizer, and MSD. RM has received honoraria for lectures from Pfizer.\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. Metlay JP Waterer GW Long AC Anzueto A Brozek J Crothers K Diagnosis and treatment of adults with community-acquired pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America Am J Respir Crit Care Med 2019 200 e45 67 10.1164/rccm.201908-1581ST 31573350\n2. Cillóniz C Dominedò C Garcia-Vidal C Torres A Community-acquired pneumonia as an emergency condition Curr Opin Crit Care 2018 24 531 539 10.1097/MCC.0000000000000550 30239410\n3. 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Zhong NS Sun T Zhuo C D’Souza G Lee SH Lan NH Ceftaroline fosamil versus ceftriaxone for the treatment of Asian patients with community-acquired pneumonia: a randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial Lancet Infect Dis 2015 15 161 171 10.1016/S1473-3099(14)71018-7 25539586\n23. File TM Low DE Eckburg PB Talbot GH Friedland HD Lee J FOCUS 1: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia J Antimicrob Chemother 2011 66 iii19 32 10.1093/jac/dkr096 21482566\n24. Low DE File TM Eckburg PB Talbot GH David Friedland H Lee J FOCUS 2: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia J Antimicrob Chemother 2011 66 Suppl 3 iii33 44 10.1093/jac/dkr097 21482568\n25. Taboada M Melnick D Iaconis JP Sun F Zhong NS File TM Ceftaroline fosamil versus ceftriaxone for the treatment of community-acquired pneumonia: individual patient data meta-analysis of randomized controlled trials J Antimicrob Chemother 2016 71 1748 1749 10.1093/jac/dkw136 27076104\n26. Ramirez JA Wiemken TL Peyrani P Arnold FW Kelley R Mattingly WA Adults hospitalized with pneumonia in the United States: incidence, epidemiology, and mortality Clin Infect Dis 2017 13 65 1806 1812 10.1093/cid/cix647\n27. Cillóniz C Polverino E Ewig S Aliberti S Gabarrús A Menéndez R Impact of age and comorbidity on cause and outcome in community-acquired pneumonia Chest 2013 144 999 1007 10.1378/chest.13-0062 23670047\n28. Lee JH Kim HJ Kim YH Is β-lactam plus macrolide more effective than β-lactam plus fluoroquinolone among patients with severe community-acquired pneumonia?: a systemic review and meta-analysis J Korean Med Sci 2017 32 77 84 10.3346/jkms.2017.32.1.77 27914135\n29. Gilbert TT Arfstrom RJ Mihalovic SW Dababneh AS Varatharaj Palraj BR Dierkhising RA Effect of β-lactam plus macrolide versus fluoroquinolone on 30-day readmissions for community-acquired pneumonia Am J Ther 2020 27 e177 e182 10.1097/MJT.0000000000000788 30418221\n30. Postma DF van Werkhoven CH van Elden LJR Thijsen SFT Hoepelman AIM Kluytmans JAJW Antibiotic treatment strategies for community-acquired pneumonia in adults N Engl J Med 2015 2 372 1312 1323 10.1056/NEJMoa1406330\n31. Murphy DM Forrest IA Curran D Ward C Macrolide antibiotics and the airway: antibiotic or non-antibiotic effects? Expert Opin Investig Drugs 2010 19 401 414 10.1517/13543781003636480 20151856\n32. Stahlmann R Lode H Safety considerations of fluoroquinolones in the elderly: an update Drugs Aging 2010 1 27 193 209 10.2165/11531490-000000000-00000\n33. Vouga Ribeiro N Gouveia Melo R Guerra NC Nobre  Fernandes RM Pedro LM Fluoroquinolones are associated with increased risk of aortic aneurysm or dissection: systematic review and meta-analysis Semin Thorac Cardiovasc Surg 2020 9 20 30404 30414 10.1053/j.semtcvs.2020.11.011\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0934-9723",
"issue": null,
"journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology",
"keywords": "Antimicrobials; Ceftaroline; Community-acquired pneumonia; Pneumonia; Severe pneumonia",
"medline_ta": "Eur J Clin Microbiol Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "8804297",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34767120",
"pubdate": "2021-11-12",
"publication_types": "D016428:Journal Article",
"references": "31173864;16624967;33144192;23670047;21482568;31573350;21067350;27914135;32739491;31404620;25830421;21257985;31508159;17278083;20210367;29278281;29020164;33181305;22487223;30850010;11266414;25539586;32745596;30239410;24395236;32351925;20388763;30418221;29370285;22444785;20151856;27076104;21482566",
"title": "Impact on in-hospital mortality of ceftaroline versus standard of care in community-acquired pneumonia: a propensity-matched analysis.",
"title_normalized": "impact on in hospital mortality of ceftaroline versus standard of care in community acquired pneumonia a propensity matched analysis"
} | [
{
"companynumb": "ES-ALLERGAN-2139211US",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFTAROLINE FOSAMIL"
},
"drugadditional": "4",
... |
{
"abstract": "We describe a case of a 70-year old man with sensorimotor chronic inflammatory demyelinating polyneuropathy (CIDP) with small-fibre involvement resulting in severe diffuse neuropathic pain which was refractory to immunotherapy and anti-neuropathic medication. His pain was successfully treated with implantation of a spinal cord stimulation (SCS) system comprising bilateral cervical and lumbar epidural leads. Following SCS programming, he experienced a 50% reduction in average pain severity with substantial improvement in quality of life, persisting at 18 months after surgery. SCS has been employed to treat a variety of neuropathic pain syndromes. However, this is the first report to our knowledge of SCS utilised effectively for pain in CIDP. This therapy should be considered in painful CIDP for neuropathic pain refractory to medical management, though further studies are required to evaluate its efficacy.",
"affiliations": "Atkinson Morley Regional Neurosciences Centre, St George's Hospital, London SW17 0QT, UK; Neurosciences Research Centre, Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW17 0RE, UK. Electronic address: amostofi@sgul.ac.uk.;Atkinson Morley Regional Neurosciences Centre, St George's Hospital, London SW17 0QT, UK.;Atkinson Morley Regional Neurosciences Centre, St George's Hospital, London SW17 0QT, UK.;Atkinson Morley Regional Neurosciences Centre, St George's Hospital, London SW17 0QT, UK.;Atkinson Morley Regional Neurosciences Centre, St George's Hospital, London SW17 0QT, UK; Neurosciences Research Centre, Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW17 0RE, UK.",
"authors": "Mostofi|Abteen|A|;Tavakkoli|Moein|M|;Bedran|Hadi|H|;Nirmalananthan|Niranjanan|N|;Pereira|Erlick A C|EAC|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2019.06.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "67()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Chronic inflammatory demyelinating polyradiculoneuropathy; Pain; Spinal cord stimulation",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000368:Aged; D006801:Humans; D008297:Male; D009437:Neuralgia; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; D011788:Quality of Life; D062187:Spinal Cord Stimulation",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "255-257",
"pmc": null,
"pmid": "31221583",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spinal cord stimulation in the treatment of neuropathic pain in chronic inflammatory demyelinating polyneuropathy.",
"title_normalized": "spinal cord stimulation in the treatment of neuropathic pain in chronic inflammatory demyelinating polyneuropathy"
} | [
{
"companynumb": "GB-ACCORD-153687",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMITRIPTYLINE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "In adult patients with ESRD, calcific uremic arteriolopathy (CUA) is an uncommon but life-threatening complication. No effective therapy exists, although anecdotal case reports highlight the use of sodium thiosulfate (STS), a calcium-chelating agent with antioxidant properties. CUA is rare in children, and STS use has not been reported. The objective of this study was to determine the influence of STS treatment on three patients with CUA in a pediatric chronic dialysis unit. The patients were between 12 and 21 yr of age; two were male; and primary diagnoses were obstructive uropathy, renal dysplasia, and calcineurin nephrotoxicity. Time from ESRD to CUA diagnosis was 1, 9, and 20 yr. Diagnosis was made by tissue biopsy and three-phase bone scan. Pain was the presenting symptom. Initial treatment included discontinuation of calcitriol and use of non-calcium-based phosphate binders and low-calcium dialysate concentration. STS dosage was 25 g/1.73 m(2) per dose intravenously after each hemodialysis session. For optimization of removal of calcium deposits, patient three received a combination of STS and continuous venovenous hemofiltration for the first 10 d. All patients demonstrated rapid pain relief. Within weeks, skin induration and joint mobility of the extremities improved. Radiographic evidence of reduction in the calcium deposits occurred within 3 mo of initiation of STS. The only complication was prolonged QT interval in one patient as a result of hypocalcemia, who was resolved by use of a higher dialysate calcium concentration. STS seems well tolerated in children and young adults with CUA and has mild adverse effects. For determination of its efficacy, optimum dosage, duration of therapy, and dialysis modality, controlled trials are needed.",
"affiliations": "Division of Pediatric Nephrology, Department of Pediatrics, University of Florida Health Science Center, Gainesville, FL 32610-0296, USA.",
"authors": "Araya|Carlos E|CE|;Fennell|Robert S|RS|;Neiberger|Richard E|RE|;Dharnidharka|Vikas R|VR|",
"chemical_list": "D000975:Antioxidants; D013885:Thiosulfates; C017717:sodium thiosulfate",
"country": "United States",
"delete": false,
"doi": "10.2215/CJN.01520506",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1555-9041",
"issue": "1(6)",
"journal": "Clinical journal of the American Society of Nephrology : CJASN",
"keywords": null,
"medline_ta": "Clin J Am Soc Nephrol",
"mesh_terms": "D000328:Adult; D000975:Antioxidants; D001161:Arteriosclerosis; D002115:Calciphylaxis; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D013885:Thiosulfates; D014511:Uremia",
"nlm_unique_id": "101271570",
"other_id": null,
"pages": "1161-6",
"pmc": null,
"pmid": "17699342",
"pubdate": "2006-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sodium thiosulfate treatment for calcific uremic arteriolopathy in children and young adults.",
"title_normalized": "sodium thiosulfate treatment for calcific uremic arteriolopathy in children and young adults"
} | [
{
"companynumb": "US-AMGEN-USASP2019203312",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CINACALCET HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "We report two patients with Panayiotopoulos syndrome (PS) who developed encephalopathy related to status epilepticus during slow sleep (ESES) at the peak of their clinical course. Clinical charts and EEG data were reviewed. The patients exhibited nocturnal autonomic seizures and occipital EEG foci, the latter of which later evolved into multifocal EEG foci with synchronous frontopolar and occipital spikes (Fp-O EEG foci), and finally into continuous spikes-waves during sleep (CSWS; spike-wave index >85% based on whole-night sleep recording) at eight years and seven years of age, respectively. The occipital spikes always preceded frontopolar spikes by 30∼50 mseconds based on the analysis of CSWS. Neuropsychological ability, including IQ, deteriorated during the CSWS period in both patients. The autonomic seizures and focal to bilateral tonic-clonic seizures were initially resistant to antiepileptic drugs (AEDs), and occurred more than 10 times in both patients. However, the seizures and EEG findings gradually resolved, and AEDs were successfully terminated in both patients. PS can progress to ESES if the clinical course exhibits atypical evolution. The initial autonomic symptom of the seizures and interictal Fp-O EEG foci should be carefully monitored in patients with CSWS or ESES.",
"affiliations": "Department of Pediatrics, Tokyo Women's Medical University, Tokyo.;Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Yotsugi Medical Center for the Severely Disabled, Tokyo, Japan.;Department of Pediatrics, Tokyo Women's Medical University, Tokyo.",
"authors": "Oguni|Hirokazu|H|;Hirano|Yoshiko|Y|;Nagata|Satoru|S|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1684/epd.2020.1128",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "22(1)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "Atypical evolution; CSWS; ESES; Fp-O EEG pattern; Panayiotopoulos syndrome; epileptic encephalopathy",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D000293:Adolescent; D001927:Brain Diseases; D004569:Electroencephalography; D004828:Epilepsies, Partial; D005260:Female; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D000077310:Sleep, Slow-Wave; D013226:Status Epilepticus",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "67-72",
"pmc": null,
"pmid": "32020894",
"pubdate": "2020-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Encephalopathy related to status epilepticus during slow sleep (ESES) as atypical evolution of Panayiotopoulos syndrome: an EEG and neuropsychological study.",
"title_normalized": "encephalopathy related to status epilepticus during slow sleep eses as atypical evolution of panayiotopoulos syndrome an eeg and neuropsychological study"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-246030",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLOBAZAM"
},
"drugad... |
{
"abstract": "BACKGROUND\nThe overall survival of patients with localised osteosarcoma has dramatically improved with the introduction of multidrug chemotherapeutic regimens into the treatment paradigm. However, despite optimal treatment, all-cause mortality remains higher among osteosarcoma survivors than in the general population. The development of second malignant neoplasms contributes to this higher mortality rate.\n\n\nMETHODS\nWe present three cases of patients definitively treated for osteosarcoma who subsequently developed a second malignant neoplasm. The first case describes a 17-year-old female with osteosarcoma of her right femur treated with surgical resection and perioperative chemotherapy. Ten years later, she was diagnosed with metastatic HER2-positive breast cancer. Genetic testing identified a germline TP53 mutation, confirming the presence of Li-Fraumeni syndrome. The second case details an 18-year-old male with osteosarcoma of his right humerus treated with definitive resection and perioperative chemotherapy. He was diagnosed with appendiceal adenocarcinoma after presenting with acute abdominal pain 17 years later. The third case reviewed is of a 36-year-old male with osteosarcoma of his right femur treated with definitive resection and adjuvant chemotherapy. A diagnosis of leiomyosarcoma was made 7 years later following surveillance imaging.\n\n\nCONCLUSIONS\nThe risk of second malignant neoplasms in osteosarcoma may relate to previous oncological treatment, an inherited cancer predisposition syndrome or a spontaneous new neoplasm. Although screening for a second malignancy is not routinely recommended for osteosarcoma survivors, a high degree of clinical suspicion should be maintained during surveillance.",
"affiliations": "Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin, D07 R2WY, Ireland. gearyr@tcd.ie.;Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin, D07 R2WY, Ireland.;Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin, D07 R2WY, Ireland.;Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin, D07 R2WY, Ireland.",
"authors": "Geary|R L|RL|http://orcid.org/0000-0002-2695-1889;Corrigan|L R|LR|;Carney|D N|DN|;Higgins|M J|MJ|",
"chemical_list": null,
"country": "Ireland",
"delete": false,
"doi": "10.1007/s11845-019-02027-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-1265",
"issue": "188(4)",
"journal": "Irish journal of medical science",
"keywords": "Osteosarcoma; Second primary",
"medline_ta": "Ir J Med Sci",
"mesh_terms": "D000230:Adenocarcinoma; D000293:Adolescent; D000328:Adult; D001859:Bone Neoplasms; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D005260:Female; D005269:Femur; D006801:Humans; D007890:Leiomyosarcoma; D016864:Li-Fraumeni Syndrome; D008297:Male; D016609:Neoplasms, Second Primary; D012516:Osteosarcoma",
"nlm_unique_id": "7806864",
"other_id": null,
"pages": "1163-1167",
"pmc": null,
"pmid": "31054046",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20922787;27498913;14583457;24179373;21703851;15659502;9333268;12697883;12891382;17159192;21454129;19332714;21837677;21216138;25989269;11920786;19130300;26175892;20934517;12365021",
"title": "Osteosarcoma and second malignant neoplasms: a case series.",
"title_normalized": "osteosarcoma and second malignant neoplasms a case series"
} | [
{
"companynumb": "IE-PFIZER INC-2019518079",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "The present case report describes a case of recurrent and advanced urachal carcinoma including neuroendocrine features with iliac bone metastasis after partial cystectomy and adjuvant chemotherapy consisting of irinotecan and cisplatin in a 32-year-old man. He received gemcitabine/cisplatin/ paclitaxel (GCP) combination chemotherapy, consisting of gemcitabin (1,000mg/m2) on day 1, 8, cisplatin (70mg/m2) on day 1, and paclitaxel (80mg/m2) on day 1 and 8. After three cycles of chemotherapy, PET-CT showed complete regression of the disease. So the patient underwent total cystourethrectomy, and histological examination showed an almost complete pathological response. External beam radiation therapy was also given to the ileac bone metastasis regions. However, PET-CT taken 17 months after the external beam radiation showed multiple lung metastases. He received GCP chemotherapy again, which resulted in a complete response again after three cycles of chemotherapy. This is the first report on GCP chemotherapy used not only as a salvage chemotherapy but also as a rechallenge regimen for metastatic urachal cancer including a neuroendocrine component.",
"affiliations": "Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.pjcr7j4j@cc.okayama-u.ac.jp.",
"authors": "Ebara|Shin|S|;Kobayashi|Yasuyuki|Y|;Sasaki|Katsumi|K|;Araki|Motoo|M|;Sugimoto|Morito|M|;Wada|Koichiro|K|;Fujio|Kei|K|;Takamoto|Atsushi|A|;Watanabe|Toyohiko|T|;Yanai|Hiroyuki|H|;Nasu|Yasutomo|Y|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.18926/AMO/54423",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0386-300X",
"issue": "70(3)",
"journal": "Acta medica Okayama",
"keywords": null,
"medline_ta": "Acta Med Okayama",
"mesh_terms": null,
"nlm_unique_id": "0417611",
"other_id": null,
"pages": "223-227",
"pmc": null,
"pmid": "27339213",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A Case of Metastatic Urachal Cancer Including a Neuroendocrine Component Treated with Gemcitabine, Cisplatin and Paclitaxel Combination Chemotherapy.",
"title_normalized": "a case of metastatic urachal cancer including a neuroendocrine component treated with gemcitabine cisplatin and paclitaxel combination chemotherapy"
} | [
{
"companynumb": "JP-CIPLA LTD.-2017JP13285",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Valproic acid is a broad-spectrum anticonvulsant that has also gained attention in the psychiatric setting. With respect to safety, valproic acid may induce a seemingly rare condition, hyperammonemia, which can induce a wide variety of symptoms ranging from irritability to coma. The proposed mechanism of hyperammonemia involves depletion of carnitine and overproduction of a toxic metabolite, 4-en-valproic acid, both of which impair the urea cycle and thus ammonia elimination. Carnitine is a commonly used antidote for acute intoxication of valproic acid, but is not a therapeutic option for management of chronic adults with adverse effects related to valproic acid. We herein report a case involving a woman with epilepsy who developed hyperammonemia after a change in her anticonvulsant therapy. She reported increased seizures and gastrointestinal disturbances. Her ammonia, valproic acid, 4-en-valproic acid, and carnitine levels were monitored. Her ammonia level was elevated and her carnitine level was at the inferior limit of the population range. She was supplemented with carnitine at 1 g/day. After 1 month, her ammonia level decreased, her carnitine level increased, and her seizures were better controlled. Carnitine supplementation was useful for reversal of her hyperammonemia, allowing her to continue valproic acid for seizure control.",
"affiliations": "1 Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la República, Montevideo, Uruguay.;1 Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la República, Montevideo, Uruguay.;2 Department of Neuropsychology of the Neurology Institute, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay.;1 Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la República, Montevideo, Uruguay.;1 Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la República, Montevideo, Uruguay.",
"authors": "Maldonado|Cecilia|C|;Guevara|Natalia|N|;Silveira|Alicia|A|;Fagiolino|Pietro|P|;Vázquez|Marta|M|",
"chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid; D002331:Carnitine",
"country": "England",
"delete": false,
"doi": "10.1177/0300060517703278",
"fulltext": "\n==== Front\nJ Int Med ResJ. Int. Med. ResIMRspimrThe Journal of International Medical Research0300-06051473-2300SAGE Publications Sage UK: London, England 2842582110.1177/030006051770327810.1177_0300060517703278Case ReportsL-Carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: A case report Maldonado Cecilia 1Guevara Natalia 1Silveira Alicia 2Fagiolino Pietro 1Vázquez Marta 11 Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la República, Montevideo, Uruguay2 Department of Neuropsychology of the Neurology Institute, Hospital de Clínicas, Universidad de la República, Montevideo, UruguayMarta Vázquez, Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la República, Avenida General Flores 2124, PO Box 1157, 11800 Montevideo, Uruguay. Email: mvazquez@fq.edu.uy20 4 2017 6 2017 45 3 1268 1272 8 2 2017 15 3 2017 © The Author(s) 20172017SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) 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 page(https://us.sagepub.com/en-us/nam/open-access-at-sage).Valproic acid is a broad-spectrum anticonvulsant that has also gained attention in the psychiatric setting. With respect to safety, valproic acid may induce a seemingly rare condition, hyperammonemia, which can induce a wide variety of symptoms ranging from irritability to coma. The proposed mechanism of hyperammonemia involves depletion of carnitine and overproduction of a toxic metabolite, 4-en-valproic acid, both of which impair the urea cycle and thus ammonia elimination. Carnitine is a commonly used antidote for acute intoxication of valproic acid, but is not a therapeutic option for management of chronic adults with adverse effects related to valproic acid. We herein report a case involving a woman with epilepsy who developed hyperammonemia after a change in her anticonvulsant therapy. She reported increased seizures and gastrointestinal disturbances. Her ammonia, valproic acid, 4-en-valproic acid, and carnitine levels were monitored. Her ammonia level was elevated and her carnitine level was at the inferior limit of the population range. She was supplemented with carnitine at 1 g/day. After 1 month, her ammonia level decreased, her carnitine level increased, and her seizures were better controlled. Carnitine supplementation was useful for reversal of her hyperammonemia, allowing her to continue valproic acid for seizure control.\n\nValproic acidhyperammonemiacarnitine\n==== Body\nIntroduction\nValproic acid (VPA) is a widely used broad-spectrum anticonvulsant.1 In the last several years, it has also gained attention in the psychiatric setting as a mood stabilizer.2 It is usually well tolerated, although hepatic function impairment necessitates tight control in children.3 VPA has also been associated with metabolic disorders leading to weight gain and occasionally with hyperammonemia. The latter may develop asymptomatically or lead to encephalopathy.4,5 The prevalence of symptomatic hyperammonemia caused by VPA is unknown, and the condition is thought to be rare in adults. However, in a study carried out by our group,6 almost one-third of adult patients (8 of 28 patients) developed ammonia levels higher than the reference range, although only one of these patients exhibited unequivocal symptoms (encephalopathy). L-Carnitine (LCAR) is commonly used as an antidote in acute intoxication with VPA,7 but its use in chronic treatment is reserved for the pediatric setting.8\n\nWe herein report a case in which VPA-induced hyperammonemia during chronic treatment was reverted by the use of LCAR as adjuvant therapy.\n\nCase report\nA 42-year-old woman had an 18-year history of seizures. She was a current smoker. In 1995, she first developed focal somatosensory seizures (paresthesia in the right limbs); these evolved to dysphasic seizures and loss of consciousness. Neuroimaging revealed a left temporoparietal arteriovascular malformation. Her primary pharmacological treatment was carbamazepine (600 mg/day) and VPA (1500 mg/day); however, the seizures persisted. The carbamazepine was stopped and lamotrigine (LTG) was added at 300 mg/day. After several months of treatment, the patient presented with increased seizures, cephalea, and nausea and was referred to our service for monitoring. Her hepatic and renal function was normal. At that time point, she was receiving 1500 mg of VPA. Her morning trough VPA level was measured using a previously described validated high-performance liquid chromatography (HPLC) technique with minor modifications,9 and her 2-propyl-4-pentenoic acid (4-en-VPA) level was determined using the same technique. Thirty microliters of internal standard (octanoic acid) was added to 1 mL of plasma. A Phenomenex Luna CN 5 µm column (150 × 4.6 mm) was used for the stationary phase. The mobile phase was a mixture of potassium phosphate monobasic (40 mM, pH 3.4) and acetonitrile (90/10) pumped at a flow rate of 1.5 mL/min. The column compartment was kept at 36℃, and the wavelength detection was 210 nm. Under these conditions, the retention times of the analytes were 3.8, 4.9, and 6.8 min for 4-en-VPA, VPA, and octanoic acid, respectively. The HPLC method was linear between 1.1 and 133 mg/L for VPA and between 0.78 and 16.5 mg/L for 4-en-VPA. The within-day and between-day precision (coefficient of variation) for the low, intermediate, and high concentration of both analytes was <15%. The accuracy at the same concentrations was within 92% and 108%. The blood ammonia concentration was determined with a Cobas c311 (Roche Laboratories), and LCAR and its acyl derivatives were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Extraction was performed on 3.2-mm filter paper disks punched out from dried blood spot specimens using 100% methanol solution containing the internal standards. The internal standards used were the Cambridge isotope internal standards NSK sets A and B, which contained the following stable isotopes: acylcarnitines d9-C0, d3-C2, d3-C3, d3-C4, d9-C5, d3-C8, d9-C14, and d3-C16. The extracted samples underwent derivatization with 3 N butanolic HCl at 65℃ and were finally reconstituted in an acetonitrile/water (50/50) solution containing 0.02% formic acid (mobile phase). The samples were analyzed with HPLC-MS/MS (Dionex-AB Sciex 3200 triple quadrupole) using the precursor ion spectra of 85 m/z.6 The results are depicted in Table 1.\nTable 1. Effect of LCAR supplementation at 1 g/day\n\n\tWithout LCAR\tWith LCAR\t\nBlood VPA (mg/L)\t86.6\t46.3\t\n4-en VPA (mg/L)\t3.6\t0.7\t\n4-en-VPA/VPA metabolic ratio\t0.042\t0.015\t\nAmmonium (NH4+) (µg/dL)\t295\t75\t\nLCAR (µmol/L)\t20.9\t29.3\t\nACYLCAR/LCAR ratio\t0.45\t0.23\t\nLCAR, L-carnitine; VPA, valproic acid; ACYLCAR/LCAR, acylcarnitine/L-carnitine\n\n\n\nThe LCAR levels were minimal according the population reference ranges10 and as evidenced by a high acylcarnitine/LCAR (ACYLCAR/LCAR) ratio of >0.4, which is a good biomarker of LCAR deficiency.11\n\nBecause of the patient’s high ammonia concentration (>94 µg/mL), LCAR was added at 1 g/day. The patient was then monitored 2 months later at the doctor’s request; the results are shown in Table 1. With addition of the LCAR, the ammonia level decreased to within the reference range. The metabolite concentration also decreased, while the LCAR level increased after supplementation, as expected, from a borderline-low concentration to a normal value.10 Finally, the ACYLCAR/LCAR ratio decreased due to resolution of the LCAR deficiency.\n\nThis study was conducted in accordance with the principles of good clinical practice and the Declaration of Helsinki and was approved by the Ethics Review Committee of the Faculty of Chemistry (Uruguay). The patient provided written informed consent for publication.\n\nDiscussion\nVPA has been on the market for almost 40 years now. It was initially considered to be a safer alternative to first-generation anticonvulsants and free of serious side effects. However, some reports have associated VPA with fulminant hepatitis, a Reye-like syndrome, and encephalopathy. Although hyperammonemia has also been reported, little attention has been paid to its prevalence. One report stated that up to 50% of patients taking VPA developed hyperammonemia, although they were asymptomatic.12\n\nWith respect to its pharmacokinetics, VPA is highly protein-bound and undergoes extensive liver metabolism. During its elimination, VPA follows three main routes: glucuronidation (50%), β-oxidation in the mitochondria (40%), and ω-oxidation (10%); the latter leads to formation of a toxic metabolite, 4-en-VPA.13 This metabolite impairs the function of carbamoyl phosphate synthetase (CPS), which catalyzes the conversion of ammonia in the first step of the urea cycle.14 Consequently, the ammonia level rises. However, this is not the only factor affecting ammonia elimination. In the β-oxidation pathway, VPA must cross the mitochondrial membrane via the carnitine shuttle, as fatty acids do. LCAR depletion may occur in patients receiving high doses of VPA or who experience acute intoxication, which may in turn result in less β-oxidation of fatty acids (including VPA), less acetyl-CoA production, and decreased synthesis of N-acetyl glutamic acid, an allosteric activator of CPS.15 As β-oxidation decreases, ω-oxidation of VPA is favored and higher levels of 4-en-VPA are formed, which enhances CPS inhibition as described above.\n\nA well-established risk factor for hyperammonemia in the neurological literature is the combination of VPA with other antiepileptic medications, particularly phenobarbital, phenytoin, and carbamazepine. The mechanisms of action are thought to be related to an increase in the production of toxic VPA metabolites because all of them are inducers of the ω-oxidative pathway.16 Case reports have also raised the possibility that hyperammonemia results from an interaction between the effects of VPA and topiramate17 and VPA and LTG.18\n\nIn our patient, no VPA or ammonia monitoring was performed while she was taking carbamazepine and VPA. LTG is mainly eliminated by glucuronidation and competes with VPA for this metabolic route. The addition of LTG may have enhanced deviation of VPA metabolism to oxidative routes favoring the production of 4-en-VPA (by ω-oxidation) because β-oxidation was impaired by LCAR depletion.19 All of these processes in combination could have led to the development of hyperammonemia, the consequences of which (seizures) are difficult to differentiate from the pathology itself (epilepsy) and that can be misdiagnosed as therapeutic failure instead of an adverse drug reaction related to the use of VPA. Hence, seizures might be seen as the final step of the excitatory symptoms of hyperammonemia due to the increase in glutamate neurotransmitter synthesis.20\n\nExogenous supplementation of LCAR has been proposed to prevent the development of hyperammonemia. In Uruguay, however, this strategy has only been applied in the pediatric setting. Collectively, the available evidence provides a reasonable argument for the role of LCAR supplementation in certain cases of childhood-onset epilepsy.21,22 However, well-designed studies of LCAR replacement therapy in children with epilepsy are still needed. LCAR supplementation was useful for resolution of our patient’s VPA-related adverse drug reaction. This is important knowledge for clinicians, who might otherwise change the therapeutic strategy in such patients.\n\nLCAR supplementation not only favors ammonia elimination but also restores VPA metabolism to normal routes, increasing β-oxidation and thus decreasing ω-oxidation and therefore 4-en-VPA formation. The metabolic ratio decreased after LCAR addition. This can be explained by the higher impact that the decrease in carnitine has on the kinetics of 4-en-VPA, which is also a fatty acid. The ACYLCAR/LCAR ratio also decreased and was maintained within the reference ranges reported in the literature.11 The ammonia level also returned to the reference range (25–94 µg/mL).\n\nWide variation exists in the doses and routes of administration of LCAR, making it challenging to identify the optimal dosing strategy.23 A dose of 1 g/day was proposed as the initial dose in the present case, but as the patient’s condition improved, this dose was maintained as long as the VPA treatment continued.\n\nThe patient’s renal and liver function remained normal despite her elevated ammonia, VPA, and 4-en-VPA levels.\n\nMonitoring of the ammonia level is advisable in adult patients undergoing chronic VPA treatment, and LCAR supplementation could be a solution to this VPA-associated adverse drug reaction.\n\nThe main limitation of this study is that the case report included only one patient. Despite the usefulness of this intervention, more patients still need to be studied to draw stronger conclusions.\n\nDeclaration of conflicting interest\nThe authors declare that there is no conflict of interest.\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n1 Löscher W \nBasic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy . CNS Drugs \n2002 ; 16 : 669 –694 .12269861 \n2 Bowden CL Brugger AM Swann AC \nEfficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group . JAMA \n1994 ; 271 : 918 –924 .8120960 \n3 Powel-Jackson PR Tredger JM Williams R \nHepatotoxicity to sodium valproate: a review . Gut \n1984 ; 25 : 673 –681 .6428980 \n4 Gerster T Buesing D Longin E \nValproic induced encephalopathy-19 new cases in Germany from 1994 to 2003- a side effect associated to VPA therapy not only in young children . Seizure \n2006 ; 15 : 443 –448 .16787750 \n5 Baganz M Dross P \nValproic acid-induced hyperammonemic encephalopathy MR appearance . AJNR Am J Neuroradiol \n1994 ; 15 : 1779 –1781 .7847228 \n6 Maldonado C Guevara N Queijo C \nCarnitine and/or Acetylcarnitine Deficiency as a Cause of Higher Levels of Ammonia . Biomed Res Int \n2016 ; 2016 : 2920108 –2920108 . http://dx.doi.org/10.1155/2016/2920108 .26998483 \n7 Murakami K Sugimoto T Woo M \nEffect of L-carnitine supplementation on acute valproate intoxication . Epilepsia \n1996 ; 37 : 687 –689 .8681902 \n8 Chung S Choi J Hyun T \nAlteration in the carnitine metabolism in epileptic children treated with valproic acid . J Korean Med Sci \n1999 ; 12 : 553 –558 .\n9 Amini H Javan M Ahmadiani A \nDevelopment and validation of a sensitive assay of valproic acid in human plasma by high-performance liquid chromatography without prior derivatization . J Chromatogr B Analyt Technol Biomed Life Sci \n2006 ; 830 : 368 –371 .\n10 University of California, San Francisco Clinical Laboratories. Lab Manual. http://labmed.ucsf.edu/labmanual/db/data/tests/169.html (2017, accessed 26 January 2017) .\n11 Reuter SE Evans AM \nCarnitine and acylcarnitines: pharmacokinetic, pharmacological and clinical aspects . Clin Pharmacokinet \n2012 ; 51 : 553 –572 .22804748 \n12 Raja M Azzoni A \nValproate-induced hyperammonemia . J Clin Psychopharmacol \n2002 ; 22 : 631 –633 .12454569 \n13 Siemes H Nau H Schultze K \nValproate (VPA) metabolites in various clinical conditions of probable VPA-associated hepatotoxicity . Epilepsia \n1993 ; 34 : 332 –346 .8453944 \n14 Mehndiratta MM Mehndiratta P Phul P \nValproate induced non hepatic hyperammonaemic encephalopathy (VNHE)—a study from tertiary care referral university hospital, North India . J Pak Med Assoc \n2008 ; 58 : 627 –631 .19024136 \n15 Ohtani Y Endo F Matsuda I \nCarnitine deficiency and hyperammonemia associated with valproic acid therapy . J Pediatr \n1982 ; 101 : 782 –785 .6813444 \n16 Carr RB Shrewsbury K \nHyperammonemia due to valproic acid in the psychiatric setting . Am J Psychiatry \n2007 ; 164 : 1020 –1027 .17606652 \n17 Hamer HM Knake S Schomburg U \nValproate-induced hyperammonemic encephalopathy in the presence of topiramate . Neurology \n2000 ; 54 : 230 –232 .10636156 \n18 Fan CC Huang MC Liu HC \nLamotrigine might potentiate valproic acid-induced hyperammonemic encephalopathy . Prog Neuropsychopharmacol Biol Psychiatry \n2008 ; 32 : 1747 –1748 .18602440 \n19 Anderson GD Yau MK Gidal BE \nBidirectional interaction of valproate and lamotrigine in healthy subjects . Clin Pharmacol Ther \n1996 ; 60 : 145 –156 .8823232 \n20 Vázquez M Fagiolino P Maldonado C \nHyperammonemia associated with valproic acid concentrations . Biomed Res Int \n2014 ; 2014 : 217269 –217269 . http://dx.doi.org/10.1155/2014/217269 .24868521 \n21 De Vivo DC Bohan TP Coulter DL \nL-Carnitine supplementation in childhood epilepsy: current perspectives . Epilepsia \n1998 ; 39 : 1216 –1225 .9821988 \n22 Raskind JY El-Chaar GM \nThe role of carnitine supplementation during valproic acid therapy . Ann Pharmacother \n2000 ; 34 : 630 –638 .10852092 \n23 Perrott J Murphy NG Zed PJ \nL-Carnitine for acute Valproic acid overdose: a systematic review of published cases . Ann Pharmacother \n2010 ; 44 : 1287 –1293 .20587742\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "45(3)",
"journal": "The Journal of international medical research",
"keywords": "Valproic acid; carnitine; hyperammonemia",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D002331:Carnitine; D005260:Female; D006801:Humans; D022124:Hyperammonemia; D012640:Seizures; D014635:Valproic Acid",
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"pages": "1268-1272",
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"pmid": "28425821",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17606652;10636156;9821988;8823232;12454569;18602440;12269861;7847228;8453944;26998483;8681902;16324890;19024136;24868521;8120960;10852092;6428980;9443096;20587742;16787750;22804748;6813444",
"title": "L-Carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: A case report.",
"title_normalized": "l carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment a case report"
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"abstract": "Pigmented villonodular synovitis (PVNS) is a rare synovial proliferative disease featuring hemosiderin deposits. Calcium pyrophosphate deposition (CPPD) is a crystal-induced inflammatory arthritis common in the elderly. We reported the case of a 78-year-old male who was under stroke rehabilitation when acute inflammatory and hemorrhagic knee arthritis of his paretic lower limb occurred. CPPD was proven by synovial analysis. Ultrasonography showed widespread synovial nodular lesions in the affected knee and helped guiding difficult arthrocentesis. These led to a rapid diagnosis of PVNS with magnetic resonance imaging. In elderly stroke patients, knee pain, being a common complaint, warrants a careful diagnosis including adequate imaging. This case demonstrates that ultrasonography is an accessible and useful diagnostic tool.",
"affiliations": "Department of Physical and Rehabilitation Medicine, MacKay Memorial Hospital, Taipei, Taiwan.;Department of Physical and Rehabilitation Medicine, Asia University Hospital, Taichung, Taiwan.;Department of Radiology, Cheng Hsin General Hospital, Taipei, Taiwan.;Department of Orthopaedics Surgery, MacKay Memorial Hospital, Taipei, Taiwan.",
"authors": "Hsieh|Shiau-Fu|SF|;Wu|Shu-Yih|SY|;Hung|Yu-Chung|YC|;Wang|Guo-Shou|GS|",
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"doi": "10.4103/JMU.JMU_107_19",
"fulltext": "\n==== Front\nJ Med Ultrasound\nJ Med Ultrasound\nJMU\nJournal of Medical Ultrasound\n0929-6441 2212-1552 Wolters Kluwer - Medknow India \n\nJMU-28-188\n10.4103/JMU.JMU_107_19\nCase Report\nConcurrence of Pigmented Villonodular Synovitis with Calcium Pyrophosphate Deposition in a Postacute Stroke Patient\nHsieh Shiau-Fu 1* Wu Shu-Yih 2 Hung Yu-Chung 3 Wang Guo-Shou 4 1 Department of Physical and Rehabilitation Medicine, MacKay Memorial Hospital, Taipei, Taiwan\n2 Department of Physical and Rehabilitation Medicine, Asia University Hospital, Taichung, Taiwan\n3 Department of Radiology, Cheng Hsin General Hospital, Taipei, Taiwan\n4 Department of Orthopaedics Surgery, MacKay Memorial Hospital, Taipei, Taiwan\nAddress for correspondence: Dr. Shiau-Fu Hsieh, No. 92, Section 2, Chung-Shan North Road, Taipei, Taiwan. E-mail: sfhpmr@gmail.com\nJul-Sep 2020 \n26 3 2020 \n28 3 188 191\n07 11 2019 15 12 2019 18 12 2019 Copyright: © 2020 Journal of Medical Ultrasound2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Pigmented villonodular synovitis (PVNS) is a rare synovial proliferative disease featuring hemosiderin deposits. Calcium pyrophosphate deposition (CPPD) is a crystal-induced inflammatory arthritis common in the elderly. We reported the case of a 78-year-old male who was under stroke rehabilitation when acute inflammatory and hemorrhagic knee arthritis of his paretic lower limb occurred. CPPD was proven by synovial analysis. Ultrasonography showed widespread synovial nodular lesions in the affected knee and helped guiding difficult arthrocentesis. These led to a rapid diagnosis of PVNS with magnetic resonance imaging. In elderly stroke patients, knee pain, being a common complaint, warrants a careful diagnosis including adequate imaging. This case demonstrates that ultrasonography is an accessible and useful diagnostic tool.\n\nCalcium pyrophosphate depositionkneemagnetic resonance imagingpigmented villonodular synovitisultrasonography\n==== Body\nINTRODUCTION\nPigmented villonodular synovitis (PVNS) is a benign rare disease involving the proliferation of joint synovium.[1] It typically presents as joint swelling, pain, and hemarthrosis. Calcium pyrophosphate deposition (CPPD) is a common inflammatory arthritis in the elderly due to calcium pyrophosphate (CPP) dihydrate crystal deposits.[2] Like PVNS, its most frequently involved joint is the knee.[34]\n\nWe present the case of a 78-year-old male, who was taking dual-antiplatelet treatment after stroke. He presented with acute severe knee pain at his paretic leg during inpatient rehabilitation. Through evidences from arthrocentesis, well-correlated musculoskeletal ultrasound (US), and magnetic resonance images, a rare diagnosis, coexistence of PVNS and CPPD, is made apart from other common causes of knee pain in this time frame.\n\nCASE REPORT\nA 78-year-old male had acute pain, swelling, and heat at the knee of his paralyzed left lower limb after 1 month of inpatient rehabilitation for a new ischemic stroke at his right periventricular region. He also started dual-antiplatelet (aspirin and clopidogrel) treatment because of stroke recurrence. The patient had a history of hypertension, dyslipidemia, diabetes, gout, and chronic kidney disease but denied previous joint problems or recent trauma.\n\nAcute severe pain, swelling, redness, and heat without ecchymosis of his left paretic knee led to the discontinuation of stroke rehabilitation. The passive and active ranges of the knee were limited. No particular point tenderness was identified. Neither valgus nor varus stress test was positive. Anterior and posterior drawer tests were not performed due to pain. No sign of new neurologic deficit was noticed. Laboratory tests showed mild leukocytosis (leukocyte = 11.90 × 103/μL) and high C-reactive protein (=12.91 mg/dL) level. A 0.2 ng/mL of procalcitonin level was within the 0.1–0.25 ng/mL cutoff level. The levels of antinuclear antibody, rheumatoid factor, and uric acid were within the normal range. Repeated US-guided knee arthrocentesis yielded massive bloody joint fluid. These two synovial fluid analyses had similar profiles. The second analysis showed that leukocyte was 17,600/mm3 (neutrophil = 80% and lymphocyte = 4%). Synovial fluid cultures were negative. CPP crystal was found in one of the two samples.\n\nKnee radiography [Figure 1] identified soft-tissue swelling, osteophytes, joint space narrowing, and chondrocalcinosis at medial joint space. Furthermore, bone erosions at lateral femur and lateral border of the medial femur condyle were worth noticing. US examinations [Figure 2] provided important diagnostic clues including interspersed fluid and proliferative synovium of multiple, villus-like, heterogeneous projections with hyperemia at the suprapatellar bursa and knee joint. A thin layer of hyperechoic signal within the intercondylar cartilage correlated with chondrocalcinosis on radiography. US allowed for evaluation of major knee structures, including unremarkable patella tendon, menisci, and collateral ligaments, aside from a synovial plica.\n\nFigure 1 X-ray of the patient's affected left knee, (a) Coronal view. Joint space narrowing at the lateral aspect of the knee. Chondrocalcinosis at the medial joint space (arrowhead). Bone erosions were discovered at the lateral femur and the lateral border of medial femur condyle. (arrow), (b) Sagittal view. Increased suprapatellar bursal effusions and periarticular soft-tissue and subcutaneous swelling were seen. Calcification in popliteal artery identified\n\nFigure 2 Ultrasound and magnetic resonance images of the patient's affected left knee at the similar level. (a) Magnetic resonance imaging proton density fat-suppressed sequence (sagittal) with high-signal intensity synovial proliferations with obscured internal contents (asterisk), (b) Ultrasound scan showing villus-like heterogeneous nodules. Septum-like structure separating the nodules (asterisk), possibly an embryologic remnant, a synovial plicae, (c) T2-weighted fat-suppressed gradient echo sequence (coronal) showing exaggerated low-signal intensity contents of the proliferated synovial nodules. The signal change from Figure 2a-c is characteristic of the hemosiderin components of pigmented villonodular synovitis in magnetic resonance imaging and is termed as “Blooming effect,” (d) Ultrasound scan at suprapatellar region along the short axis (almost corresponding to the yellow dash box) in (c) also reveals proliferated synovial tissue (asterisk) with fluid collection. Chondrocalcinosis (arrowhead) of the calcium pyrophosphate deposition is noted at the femoral condyle and in the X-ray. The arrow indicates the “cartilage interface sign” or “the double-contour sign of gouty arthritis” as one of the patient's past history\n\nMagnetic resonance imaging (MRI) [Figure 2] confirmed PVNS as the most possible cause of proliferative synovium and hemarthrosis. Proton density fat-suppressed sequence outlined multifocal low-signal intensity nodules in the knee joint, suprapatellar bursa, and popliteal fossa with bone erosions. These structures showed further decreased signal intensity under T2-weighted fat-suppressed gradient echo sequence, compatible with a characteristic MRI “blooming artifact” of hemosiderin.\n\nAntibiotics were temporarily used early in the course to cover possible septic arthritis. Colchicine and oral prednisolone were started for acute CPP arthritis later. Symptoms and laboratory findings improved dramatically thereafter. Repeated arthrocentesis also helped relieving knee swelling. The patient refused surgical excision or adjuvant intra-articular instillation of radioactive isotopes or adjuvant external beam radiotherapy for diffuse PVNS of the knee due to his high anesthetic risk and the possibility of recurrence. Watchful waiting with periodic follow-up was decided as a patient-centered treatment plan. His knee remained symptom free 9 months later while he remained wheelchair bound due to poor stroke recovery.\n\nDISCUSSION\nWe reported the coexistence of PVNS and CPPD causing acute knee arthritis with hemarthrosis in a postacute stroke patient. Poststroke knee pain is common and osteoarthritis is the most frequent diagnosis.[5] However, in this case, disproportionate inflammation and atraumatic hemarthrosis raised our suspicions for atypical causes. Blood and joint fluid analyses confirmed CPP existence and excluded septic arthritis, gouty arthritis, rheumatoid arthritis, or seronegative arthritis. Radiography revealed characteristic CPPD and excluded late-stage rheumatoid arthritis and gouty arthritis. Musculoskeletal ultrasonography showed finding of hemarthrosis and synovial proliferation and led to the early confirmative diagnosis of PVNS by MRI which is the gold standard diagnostic tool. Differential diagnoses of acute atraumatic knee effusions are summarized in Table 1.\n\nTable 1 Diagnostic features of acute atraumatic knee effusions\n\nConditions\tHistory\tLaboratory study\tSynovial analysis\tImage\t\nPigmented villonodular synovitis\tMost frequently in the fourth decade \nMost often at the knee followed by hip, ankle, shoulder, and elbow\tNonspecific\tHemorrhagic in appearance \nNoninflammatory: <2000 leukocyte/mm3\tSynovial thickening with heterogeneous projections/mass \nMRI gradient echo sequence: “Blooming artifact” \nBone erosions or cysts\t\nCalcium pyrophosphate deposition\tMost common among the elderly \nOften involves the knee, wrist, shoulder, and hip \nPrevious attack with spontaneous resolution \nFever if severe\tElevated CRP and ESR\tMaybe cloudy in appearance \nCalcium pyrophosphate dihydrate crystal (positive birefringence) \nInflammatory: >2,000 leukocyte/mm3\tPossible chondrocalcinosis \nSometimes associated osteoarthritis\t\nGouty arthritis\tMore often at the first metatarsophalangeal joint, followed by the midfoot, ankle, and knee \nPrevious attack with spontaneous resolution \nFever if severe \nPresence of tophi \nUse of diuretics\tElevated uric acid \nElevated CRP and ESR\tMaybe cloudy in appearance \nMonosodium urate crystal (negative birefringence) \nInflammatory: >2000 leukocyte/mm3\tTophi \nTophaceous erosion if severe, with characteristic “overhanging edge”\t\nSeptic arthritis\tHistory of joint surgery \nPrevious or concurrent urinary infection \nSkin infection or lesion (e.g., vesiculopustular lesion) \nFever \nSequential monoarthritis in several joints\tLeukocytosis \nElevated CRP and ESR \nPossible elevation of procalcitonin \nBlood culture may be positive\tMaybe cloudy in appearance \nInflammatory: >10,000 leukocyte/mm3\n\nPositive finding in Gram stain \nSynovial culture may be positive\t\t\nOsteoarthritis\tMore common in the elderly \nCrepitus during ROM\t\tTransparent in appearance \nNoninflammatory: <2000 leukocyte/mm3\tJoint space narrowing \nSclerosis \nOsteophytosis \nSubchondral cyst\t\nRheumatic arthritis\tSequential monoarthritis in several joints\tPositive rheumatoid factor and/or anti-CCP elevated CRP and ESR\tInflammatory: >2000 WBC/mm3\tSynovitis \nTenosynovitis \nBone erosion \nBursitis \nTendon rupture and resulted in deformity as swan-neck or boutonniere deformities\t\nSeronegative arthritis\t“Sausage toe” appearance \nEye lesion \nSkin lesion (as in psoriatic arthritis) \nHistory of gastrointestinal or urinary infection (as in reactive arthritis)\tNegative rheumatoid factor \nPossible HLA-B27 positive \nElevated CRP and ESR\tInflammatory: >2000 leukocyte/mm3\tSyndesmophyte \nPossible bamboo spine (as in ankylosing spondylitis) \nPossible sacroiliitis (as in ankylosing spondylitis)\t\nMRI: Magnetic resonance imaging, ESR: Erythrocyte sedimentation rate, CRP: C-reactive protein, ROM: Range of motion, HLA: Human leukocyte antigen\n\nPVNS is a rare benign proliferative disease of the synovium with hemosiderin deposition. Knee joint is most frequently affected, followed by hip, ankle, shoulder, and elbow.[34] Diagnosis may be difficult and late as clinical manifestations are nonspecific, including joint pain, warmth, swelling, and limitation of mobility. PVNS is classified into localized type and diffuse type.[1] Hemarthrosis is a feature of PVNS, especially in its diffuse type. The multinodular thickening of synovium is infiltrated with synovial cells, macrophages, histiocytes, giant cells, and plasma cells with characteristic granular hemosiderin deposits in phagocytic cells microscopically.[6] Bone erosion is possible in the advanced stage.\n\nThe US and MRI findings of PVNS in this case correlate well. In PVNS, US can be used to (1) provide clues to support advanced imaging such as MRI, (2) exclude other conditions, (3) monitor disease activity through change of synovium and effusion, (4) detect early osteochondral change, and (5) guide knee arthrocentesis and focus on invasive treatment in complicated cases with indications. US could demonstrate joint effusion and proliferative synovium of PVNS, but MRI remains the gold standard of imaging diagnosis. In MRI, the proliferative synovium has low signal in T1 and T2 sequences. In gradient echo sequence, scattered hemosiderin granules in the synovium show further decrease in signal intensity due to the magnetic susceptibility of hemosiderin.[4] This is called the “blooming effect” and aids in the diagnosis of PVNS in MRI. Imaging features of PVNS and a summary of other causes of atraumatic hemarthrosis are listed [Table 2]. Another common diagnosis of hemarthrosis is hemophilia. Recent studies had advocated US scoring systems be used as a part of comprehensive periodic monitoring.[7] The essential US screening items are similar for hemophilia and PVNS. Both diseases would cause proliferating synovial tissue, but currently, we are not certain if there is any specific US sign to differentiate these two diseases.\n\nTable 2 Ultrasonography and magnetic resonance imaging findings of pigmented villonodular synovitis and differential diagnosis of atraumatic hemarthrosis\n\nPVNS\t\n\t\nPossible US findings\tPossible MRI findings\t\nJoint effusion\t\t\n Anechoic or hypoechoic depending on the stage of blood content\tJoint effusion with possible “hematocrit effect”\t\nSynovial proliferation\t\t\n Heterogeneous hypoechoic projections\tWell-demarcated mass lesion with signal characteristics based on components of hemosiderin, lipids, and inflammatory fibrosis\t\n\tLipid-laden macrophage or hemorrhage as high-signal areas on T1\t\n\tInflammatory fibrotic synovial linings as low-signal capsule on T1\t\n\tIntense enhancement postgadolinium is common\t\n Focal or diffuse distribution\tFocal or diffuse distribution\t\nSynovial hyperemia\t\t\n Increased signal under Doppler\t\t\nHemosiderin deposition\tHemosiderin as low signal on T1 and “blooming effect” low signal in gradient echo sequences\t\nBone erosions\t\t\n Extra-articular bone can be identified\tBoth extra-articular and intra-articular bone erosion may be identified\t\n Intra-articular bone erosion may not be seemed due to blockage of ultrasound\t\t\nClinical relevance\t\t\nA tool for fast and early differential diagnosis\tCurrent “gold standard” image diagnosis\t\n Guidance of aspiration and monitoring tool\t\t\n Other differential diagnoses of atraumatic hemarthrosis\t\t\n Hemophilia\tDrug related\t\n Hemangioma\tOther synovial tumors\t\n Osteoarthritis\tSeptic arthritis\t\nPVNS: Pigmented villonodular synovitis, US: Ultrasonography, MRI: Magnetic resonance imaging\n\nCPPD features intra-articular CPP dihydrate deposits in cartilage, synovium, joint capsule, and ligaments.[2] It is the third most common inflammatory arthritis and a major cause of acute monoarticular arthritis in the elderly. Synovial fluid CPPD crystal showing weak-positive birefringence is diagnostic. Characteristic chondrocalcinosis may be demonstrated by US and radiography but is mostly nonspecific [Figure 2].[8]\n\nBoth PVNS and CPPD may attribute to the clinical manifestations of this case. Dual-antiplatelet treatment may be another possible contributor of hemarthrosis. To our understanding, this is the first case reported in the English literature of concurrent PVNS and CPPD and the first report discussing the image features of PVNS under US and MRI.\n\nEthical statement\nThis study was approved by IRB of Mackay Memorial Hospital (approved no. 19MMHIS150e obtained on Sep. 16th, 2019) and informed consent was waived by IRB.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Myers BW Masi AT Pigmented villonodular synovitis and tenosynovitis: A clinical epidemiologic study of 166 cases and literature review Medicine (Baltimore) 1980 59 223 38 7412554 \n2 Ferrone C Andracco R Cimmino MA Calcium pyrophosphate deposition disease: Clinical manifestations Reumatismo 2012 63 246 52 22303531 \n3 Al-Nakshabandi NA Ryan AG Choudur H Torreggiani W Nicoloau S Munk PL Pigmented villonodular synovitis Clin Radiol 2004 59 414 20 15081846 \n4 Bravo SM Winalski CS Weissman BN Pigmented villonodular synovitis Radiol Clin North Am 1996 34 311 8633118 \n5 Doruk P The impact of knee osteoarthritis on rehabilitation outcomes in hemiparetic stroke patients J Back Musculoskelet Rehabil 2013 26 207 11 23640323 \n6 Botez P Sirbu PD Grierosu C Mihailescu D Savin L Scarlat MM Adult multifocal pigmented villonodular synovitis-clinical review Int Orthop 2013 37 729 33 23361936 \n7 Di Minno MND Pasta G Airaldi S Zaottini F Storino A Cimino E Ultrasound for early detection of joint disease in patients with hemophilic arthropathy J Clin Med 2017 6 pii: E77 \n8 Paparo F Fabbro E Ferrero G Piccazzo R Revelli M Camellino D Imaging studies of crystalline arthritides Reumatismo 2012 63 263 75 22303533\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0929-6441",
"issue": "28(3)",
"journal": "Journal of medical ultrasound",
"keywords": "Calcium pyrophosphate deposition; knee; magnetic resonance imaging; pigmented villonodular synovitis; ultrasonography",
"medline_ta": "J Med Ultrasound",
"mesh_terms": null,
"nlm_unique_id": "9423829",
"other_id": null,
"pages": "188-191",
"pmc": null,
"pmid": "33282666",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "7412554;8633118;22303531;28758960;15081846;22303533;23361936;23640323",
"title": "Concurrence of Pigmented Villonodular Synovitis with Calcium Pyrophosphate Deposition in a Postacute Stroke Patient.",
"title_normalized": "concurrence of pigmented villonodular synovitis with calcium pyrophosphate deposition in a postacute stroke patient"
} | [
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"companynumb": "TW-ACCORD-209276",
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"actiondrug": "5",
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"activesubstancename": "ASPIRIN"
},
"drugadditional": "3",
"drugadmi... |
{
"abstract": "JC virus (JCV)-associated nephropathy has been increasingly recognized as a cause of allograft dysfunction with graft loss in renal transplant recipients. Like many other opportunistic viral infections in transplant recipients, there are currently limited therapeutic options for this condition. Fusidic acid has previously been reported to exhibit antiviral activity against JCV in in vitro assays. We report the first in vivo study to document the rapid reduction of JC viruria and stabilization of allograft function by oral fusidic acid (fusidate sodium) in a deceased donor renal transplant recipient with JCV-associated nephropathy and acute allograft dysfunction which did not improve initially to surgical relief of hydronephrosis and reduction of immunosuppressants. Rapid reduction of JC viruria detected by quantitative PCR and stabilization of renal function were observed. Fusidic acid has several practical advantages in this clinical setting, including a low EC50 against JCV, high plasma C max, long half-life, availability of both oral and intravenous formulations, excellent oral bioavailability, good patient tolerability, and lack of serious drug interactions with other drugs taken by renal transplant recipients. Further mechanistic and clinical studies are necessary to evaluate this treatment option for JCV-associated nephropathy.",
"affiliations": "State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, China.;Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China.;Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China.;Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China.;Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China.;Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China.;Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China.;Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China.;Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong Special Administrative Region, China.;State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong Special Administrative Region, China. kyyuen@hku.hk.",
"authors": "Chan|Jasper Fuk-Woo|JF|;Ma|Maggie Kam-Man|MK|;Chan|Gavin Shueng-Wai|GS|;Chan|Gary Chi-Wang|GC|;Choi|Garnet Kwan-Yue|GK|;Chan|Kwok-Hung|KH|;Cheng|Vincent Chi-Chung|VC|;Chan|Kwok-Wah|KW|;Choy|Bo-Ying|BY|;Yuen|Kwok-Yung|KY|",
"chemical_list": "D000890:Anti-Infective Agents; D005672:Fusidic Acid",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-015-0721-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "43(5)",
"journal": "Infection",
"keywords": "Fusidic acid; JC virus; Nephropathy; Polyomavirus; Renal transplant",
"medline_ta": "Infection",
"mesh_terms": "D000284:Administration, Oral; D064591:Allografts; D000890:Anti-Infective Agents; D005672:Fusidic Acid; D006801:Humans; D007577:JC Virus; D016030:Kidney Transplantation; D008297:Male; D027601:Polyomavirus Infections; D060888:Real-Time Polymerase Chain Reaction; D066027:Transplant Recipients; D016896:Treatment Outcome; D014556:Urine",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "577-81",
"pmc": null,
"pmid": "25944568",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19258267;19022546;24264833;24119828;20562463;11535537;23182496;21299772;17700156;24175200;23733308;20667770;23424601;15712075;14981772;14702550;16527364;24096239",
"title": "Rapid reduction of viruria and stabilization of allograft function by fusidic acid in a renal transplant recipient with JC virus-associated nephropathy.",
"title_normalized": "rapid reduction of viruria and stabilization of allograft function by fusidic acid in a renal transplant recipient with jc virus associated nephropathy"
} | [
{
"companynumb": "HK-ACCORD-155932",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "We herein report a case in which an IgG4-producing lymphoma arose in a patient with a previous diagnosis consistent with an IgG4-related disease. A 43-year-old man presented with enlarged cervical lymph nodes and was treated with steroids and radiation for what was initially assumed to be Kimura's disease, although the lesions were later histologically re-diagnosed as IgG4-related lymphadenopathy. Fourteen years later, when the patient was 58-years-old, he presented with retroperitoneal fibrosis and swollen lymph nodes. The suspicious lesions were not histologically examined as the patient did not give consent. However, the serum IgG4 concentration was high (1400 mg/dL) and he was clinically diagnosed with systemic IgG4-related disease. Although steroid administration reduced the size of the lesions, tapering the dose finally resulted in systemic, prominently enlarged lymph nodes. Analysis of the biopsy specimen revealed that these multiple lymph node lesions were marginal zone B cell lymphomas that themselves expressed IgG4. Complete remission was achieved after a total of six courses of chemotherapy including rituximab. This case suggests that the infiltrating IgG4-expressing cells observed in IgG4-related disease can clonally expand to malignant lymphomas.",
"affiliations": "Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.;Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.;Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.;Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.;Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.;Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.;Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.;Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. satou-y@okayama-u.ac.jp.",
"authors": "Igawa|Takuro|T|;Hayashi|Toshiaki|T|;Ishiguro|Kazuya|K|;Maruyama|Yumiko|Y|;Takeuchi|Mai|M|;Takata|Katsuyoshi|K|;Yoshino|Tadashi|T|;Sato|Yasuharu|Y|",
"chemical_list": "D007074:Immunoglobulin G",
"country": "Japan",
"delete": false,
"doi": "10.1007/s00795-016-0139-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1860-1499",
"issue": "49(4)",
"journal": "Medical molecular morphology",
"keywords": "IgG4-producing lymphoma; IgG4-related disease; Immunohistochemical staining; Malignant lymphoma; Marginal zone B cell lymphoma",
"medline_ta": "Med Mol Morphol",
"mesh_terms": "D000328:Adult; D018450:Disease Progression; D006801:Humans; D007074:Immunoglobulin G; D008223:Lymphoma; D008297:Male; D012185:Retroperitoneal Fibrosis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101239023",
"other_id": null,
"pages": "243-249",
"pmc": null,
"pmid": "27068526",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18344866;18580683;26111022;22481280;22596100;22706531;23765244;22716304;22719769;23749941;21894525;20403026;15534090;18705764;17043351;24559103;16405665;26311608;18839275;23813646",
"title": "IgG4-producing lymphoma arising in a patient with IgG4-related disease.",
"title_normalized": "igg4 producing lymphoma arising in a patient with igg4 related disease"
} | [
{
"companynumb": "JP-CONCORDIA PHARMACEUTICALS INC.-E2B_00008139",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugad... |
{
"abstract": "The use of levetiracetam (LEV) in the management of drug-induced seizures has not been systematically investigated. Repetitive and continuous seizures that do not respond to benzodiazepines require second line therapy. Levetiracetam has a unique receptor binding site, rapid absorption, no known cardiac effects at therapeutic doses, and is theoretically a good candidate for use in drug-induced seizures. We evaluate the safety of LEV and its association with seizure cessation in this retrospective chart review of patients who received LEV as a control agent in drug-induced seizures.\n\n\n\nWe identified the medical records of patients presenting to an urban, level 1 trauma center between 1 January 2010 and 31 May 2015 by ICD-9 codes based on the following: (1) a poisoning diagnosis, (2) a seizure diagnosis, and (3) administration of LEV. We included patients with a drug-induced seizure based on history, electroencephalogram results, blood alcohol concentrations, urine drug screens, and adequate documentation. We excluded patients with alcohol withdrawal, anoxic brain injury, subtherapeutic concentrations of other antiepileptics, hypoglycemia, and pseudoseizures. Primary outcomes of interest included cessation of active seizures or the prevention of seizure recurrence. We assessed safety by the presence or absence of adverse drug effects (ADE) attributed to the administration of LEV.\n\n\n\nThirty-four patients met inclusion and exclusion criteria. Half of the study cohort (17) presented with generalized tonic-clonic seizures (TCS); half (17) presented in generalized convulsive status epilepticus (GCSE). Six patients in GCSE received LEV during their seizures; 2 also received fosphenytoin. One improved immediately following LEV administration, and the remaining 5 had seizure control. Eleven GCSE patients (65%) remained seizure free after LEV therapy. The patients with TCS (17) received LEV after seizure(s) control. Sixteen (94%) were seizure-free during their hospital course. We found no adverse drug effects. In total, 27 of 34 patients (79%) had a return to baseline neurological and physical health. Six had long-term sequelae; none of which are known LEV side-effects. We identified 46 toxic substances and 22 known seizurogenic agents (48%). The median length of stay was 3.7 days (0.4-96), and the median duration of in-hospital LEV therapy was 1.6 days (0-49).\n\n\n\nLevetiracetam used as a second-line agent was associated with control of drug-induced seizures and prevention of seizure recurrence without obvious adverse effects. A prospective study is needed to confirm these results.",
"affiliations": "a Department of Emergency Medicine , University of New Mexico Hospital , Albuquerque , NM , USA.;a Department of Emergency Medicine , University of New Mexico Hospital , Albuquerque , NM , USA.;a Department of Emergency Medicine , University of New Mexico Hospital , Albuquerque , NM , USA.;c Department of Neurosurgery , University of New Mexico Hospital , Albuquerque , NM , USA.;a Department of Emergency Medicine , University of New Mexico Hospital , Albuquerque , NM , USA.;b New Mexico Poison and Drug Information Center , Albuquerque , NM , USA.;b New Mexico Poison and Drug Information Center , Albuquerque , NM , USA.",
"authors": "Lee|Ted|T|;Warrick|Brandon J|BJ|;Sarangarm|Preeyaporn|P|;Alunday|Robert L|RL|;Bussmann|Silas|S|;Smolinske|Susan C|SC|;Seifert|Steven A|SA|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2017.1355056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "56(3)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Levetiracetam; drug-induced seizure; toxic seizure",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D009516:New Mexico; D012189:Retrospective Studies; D012640:Seizures; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "175-181",
"pmc": null,
"pmid": "28753046",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Levetiracetam in toxic seizures.",
"title_normalized": "levetiracetam in toxic seizures"
} | [
{
"companynumb": "US-BAYER-2018-030882",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BORIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Pramipexole is a dopamine agonist with higher affinity for D3 receptors. Treatment with pramipexole in clinical conditions such as restless legs syndrome, fibromyalgia, and parkinsonism has been found to significantly improve measures of pain and sleep along with the other symptoms. There is no research data available that explores the usefulness of pramipexole in somatoform/functional pain syndromes. We report a case of a 65-year-old male with bilateral functional shoulder pain associated with insomnia and zolpidem dependence effectively treated with pramipexole.",
"affiliations": "Department of Psychiatry, Smt. N.H.L. Municipal Medical College and Sheth V.S. General Hospital, Ahmedabad, Gujarat, India.;Department of Psychiatry, Smt. N.H.L. Municipal Medical College and Sheth V.S. General Hospital, Ahmedabad, Gujarat, India.;Department of Psychiatry, Smt. N.H.L. Municipal Medical College and Sheth V.S. General Hospital, Ahmedabad, Gujarat, India.",
"authors": "Kandre|Dhiraj|D|;Banwari|Girish|G|;Sharma|Prateek|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4103/0253-7176.168591",
"fulltext": "\n==== Front\nIndian J Psychol MedIndian J Psychol MedIJPsyMIndian Journal of Psychological Medicine0253-71760975-1564Medknow Publications & Media Pvt Ltd India IJPsyM-37-44310.4103/0253-7176.168591Case ReportComorbid Functional Shoulder Pain and Zolpidem Dependence Treated with Pramipexole Kandre Dhiraj Banwari Girish Sharma Prateek Department of Psychiatry, Smt. N.H.L. Municipal Medical College and Sheth V.S. General Hospital, Ahmedabad, Gujarat, IndiaAddress for correspondence: Dr. Girish H. Banwari, Department of Psychiatry, Smt. N.H.L. Municipal Medical College and Sheth V.S. General Hospital, Ahmedabad, Gujarat, India. E-mail: drgirishbanwari@yahoo.comOct-Dec 2015 37 4 443 445 Copyright: © Indian Journal of Psychological Medicine2015This is an open access article distributed under the terms of the Creative Commons Attribution NonCommercial ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non commercially, as long as the author is credited and the new creations are licensed under the identical terms.Pramipexole is a dopamine agonist with higher affinity for D3 receptors. Treatment with pramipexole in clinical conditions such as restless legs syndrome, fibromyalgia, and parkinsonism has been found to significantly improve measures of pain and sleep along with the other symptoms. There is no research data available that explores the usefulness of pramipexole in somatoform/functional pain syndromes. We report a case of a 65-year-old male with bilateral functional shoulder pain associated with insomnia and zolpidem dependence effectively treated with pramipexole.\n\nFunctional paininsomniapramipexolezolpidem dependence\n==== Body\nINTRODUCTION\nThere is growing evidence supporting the role of central dopaminergic neurotransmission in modulating pain perception, although the exact mechanisms by which dopamine influences pain processing remain to be determined.[123] Several novel classes of medication with analgesic properties have bearing on dopaminergic activity as evident in the capacity of dopamine antagonists to attenuate their analgesic capacity.[3] Activation of mesolimbic dopamine neurons, arising from the cell bodies of the ventral tegmental area and projecting to the nucleus accumbens, plays an important role in mediating the suppression of tonic pain.[4] D3 receptors are predominantly located in the mesolimbus.[5] This plausibly explains the role of pramipexole, a dopamine agonist with 7- to 10-fold higher affinity for D3 receptor subtypes than for either D2 or D4 receptors, in reducing pain.[6] It additionally has a moderate opioid affinity and minimal alpha 2-adrenoceptor activity.[6] Treatment with pramipexole in clinical conditions such as restless legs syndrome,[7] fibromyalgia,[8] and parkinsonism[9] has been found to significantly improve measures of pain along with the other symptoms. There is no research data available that looks into the usefulness of pramipexole in somatoform/functional pain syndromes. Here, we report a single case of bilateral functional shoulder pain associated with insomnia and zolpidem dependence achieving remission with pramipexole monotherapy.\n\nCASE REPORT\nA 65-year-old male presented with history of taking 70-80 mg zolpidem/day in 6-8 divided doses. One year back, the patient had an insidious onset of pain in both shoulders for which he had consulted an orthopedic surgeon. He also complained of difficulty in initiating and maintaining sleep, attributing it to be secondary to the shoulder pain. Investigations were done that included complete blood counts; renal, hepatic and thyroid function tests; fasting and postprandial blood sugar; vitamin B12 and D3 assay; serum uric acid, all of which were within the normal range. He tested negative for human immunodeficiency virus. Magnetic resonance imaging of both shoulders as well as clinical examination revealed no abnormality. Analgesics, including nonsteroidal antiinflammatory drugs and oral opioids (tramadol) reduced the pain only by 10% as reported by the patient. A psychiatric referral was sought as the pain was deemed to be functional. The patient was diagnosed as having pain disorder and was prescribed 40 mg duloxetine in two divided doses and 10 mg zolpidem HS. He discontinued duloxetine in 5 days of starting due to excessive nausea experienced each time after taking duloxetine, but continued zolpidem. Since, he also felt relieved of the shoulder pain with zolpidem apart from improved sleep; he started taking it in the daytime. He remained virtually free of pain for 1-2 h after taking zolpidem, following which the pain would gradually reappear. He increased the frequency of zolpidem intake to once every 2-3 h so that for the last 6 months, he took 7-8 tablets of 10 mg zolpidem in a day. On not taking zolpidem for 4-5 h, he felt anxious, diaphoretic, restless, and tremulous, agitated and had a resurgence of intense shoulder pain; all of these would subside after taking zolpidem. He had no past or family history of psychiatric illness or substance use. A physician evaluation affirmed the absence of any significant current medical illness.\n\nAt the time of presentation, the patient was diagnosed as having zolpidem dependence and was treated as an inpatient. Zolpidem was tapered off over a period of 10 days. He was instructed to maintain strict sleep hygiene. Along with, pregabalin was started at a dose of 75 mg HS, which was discontinued in 2 days as the patient had intolerable giddiness on it. Quetiapine 50 mg HS was then started, which also had to be discontinued as it caused physical weakness and lethargy in excess of the patient's tolerability. Thereafter, he was put on pramipexole sustained release (SR) preparation 0.26 mg HS for 5 days. As there was favorable response in the form of reduction in the intensity of pain and no adverse effects reported, the dose was increased to 1.05 mg of pramipexole SR. On follow-up for the next 6 months, the patient was maintained on the same dose of pramipexole. He no longer complained of pain or insomnia and reported of being abstinent from zolpidem.\n\nDISCUSSION\nZolpidem, a nonbenzodiazepine hypnotic has higher abuse and dependence potiential than previously documented,[10] and our case adds to the existing literature. Based upon previous reports,[1112] we initially tried detoxification with pregabalin and quetiapine, but were unsuccessful due to tolerability issues. Since, the patient had co morbid pain disorder and insomnia, pramipexole was started for its putative role in pain control as well as in improving sleep.\n\nInvolvement of central nervous system in the form of autonomic nervous system dysregulation has been implicated in the pathophysiology of functional pain syndromes.[13] Adrenergic arousal arising from the locus ceruleus (central sympathetic stimulation) alters nociception and fragments deep sleep. Mesolimbic dopaminergic neurotransmission has an inhibitory role, thus attenuating this central adrenergic arousal. This may enable pramipexole, a D3 receptor agonist to reduce pain and restore sleep by augmenting the mesolimbic control of excessive adrenergic arousal.[8] Pain syndromes such as migraine[14] and burning mouth syndrome[15] have been reported to improve with pramipexole. Besides, pramipexole improves sleep in patients with parkinsonism[16] and restless legs syndrome[17] as well as is effective in treating rapid eye movement sleep behavior disorder[18] and sleep related eating disorder,[19] suggesting its possible role in restoration of normal sleep.\n\nSince this is a single case report, we do not exclude the possibility of the beneficial effect of pramipexole in our patient to be either placebo or coincidental. Placebo-controlled blinded studies are needed to establish the effectiveness of pramipexole in functional pain syndromes and associated insomnia.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Hagelberg N Jääskeläinen SK Martikainen IK Mansikka H Forssell H Scheinin H Striatal dopamine D2 receptors in modulation of pain in humans: A review Eur J Pharmacol 2004 500 187 92 15464032 \n2 Potvin S Grignon S Marchand S Human evidence of a supra-spinal modulating role of dopamine on pain perception Synapse 2009 63 390 402 19173266 \n3 Wood PB Role of central dopamine in pain and analgesia Expert Rev Neurother 2008 8 781 97 18457535 \n4 Altier N Stewart J The role of dopamine in the nucleus accumbens in analgesia Life Sci 1999 65 2269 87 10597883 \n5 Vallone D Picetti R Borrelli E Structure and function of dopamine receptors Neurosci Biobehav Rev 2000 24 125 32 10654668 \n6 Benbir G Guilleminault C Pramipexole: New use for an old drug - The potential use of pramipexole in the treatment of restless legs syndrome Neuropsychiatr Dis Treat 2006 2 393 405 19412489 \n7 Partinen M Hirvonen K Jama L Alakuijala A Hublin C Tamminen I Open-label study of the long-term efficacy and safety of pramipexole in patients with Restless Legs Syndrome (extension of the PRELUDE study) Sleep Med 2008 9 537 41 18276187 \n8 Holman AJ Myers RR A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications Arthritis Rheum 2005 52 2495 505 16052595 \n9 Letvinenko IV Odinak MM Mogil’naia VI Pain and depression in Parkinson's disease: New therapeutic possibilities of pramipexole Zh Nevrol Psikhiatr Im S S Korsakova 2008 108 36 8 19008798 \n10 Victorri-Vigneau C Dailly E Veyrac G Jolliet P Evidence of zolpidem abuse and dependence: Results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey Br J Clin Pharmacol 2007 64 198 209 17324242 \n11 Mariani JJ Levin FR Quetiapine treatment of zolpidem dependence Am J Addict 2007 16 426 17882616 \n12 Oulis P Nakkas G Masdrakis VG Pregabalin in zolpidem dependence and withdrawal Clin Neuropharmacol 2011 34 90 1 21407000 \n13 Petzke F CNS processing of pain in functional somatic syndromes Schmerz 2010 24 146 55 20376603 \n14 Suzuki K Suzuki S Miyamoto M Miyamoto T Numao A Watanabe Y Does pramipexole treatment improve headache in patients with concomitant migraine and restless legs syndrome? Tremor Other Hyperkinet Mov (N Y) 2013 3 176 \n15 Stuginski-Barbosa J Rodrigues GG Bigal ME Speciali JG Burning mouth syndrome responsive to pramipexol J Headache Pain 2008 9 43 5 18219443 \n16 Nodel’ MR Effects of the dopamine agonist mirapex (pramipexole) therapy on sleep disorders in Parkinson's disease Zh Nevrol Psikhiatr Im S S Korsakova 2010 110 42 7 20517225 \n17 Ferini-Strambi L Aarskog D Partinen M Chaudhuri KR Sohr M Verri D Effect of pramipexole on RLS symptoms and sleep: A randomized, double-blind, placebo-controlled trial Sleep Med 2008 9 874 81 18952497 \n18 Schmidt MH Koshal VB Schmidt HS Use of pramipexole in REM sleep behavior disorder: results from a case series Sleep Med 2006 7 418 23 16815751 \n19 Provini F Albani F Vetrugno R Vignatelli L Lombardi C Plazzi G A pilot double-blind placebo-controlled trial of low-dose pramipexole in sleep-related eating disorder Eur J Neurol 2005 12 432 6 15885046\n\n",
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"journal": "Indian journal of psychological medicine",
"keywords": "Functional pain; insomnia; pramipexole; zolpidem dependence",
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"title": "Comorbid Functional Shoulder Pain and Zolpidem Dependence Treated with Pramipexole.",
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"abstract": "Epileptogenicity following brain insult depends on various factors including severity of the resulting lesion and extent of brain damage. We report a 54-year-old female patient who developed medically refractory epilepsy resulting from the interplay of pre-existing and post-insult pathologies. She presented with subarachnoid hemorrhage (SAH) due to a ruptured aneurysm and underwent clipping surgery. Seizures started 3 months post-operatively. MRI revealed cerebral ischemia and hemosiderin deposits in the left temporal lobes, and left hippocampal atrophy was suspected. As anti-seizure medications and vagus nerve stimulation failed to control her seizures, she underwent left temporal lobe resection and placement of a ventriculoperitoneal shunt for the post-operative complication of hydrocephalus. She remains seizure-free to date. Neuropathology revealed a previously undiagnosed focal cortical dysplasia (FCD) type 1a. Brain insult likely had a second hit effect in the late onset of epilepsy in this patient with pre-existing mild MCD, in whom secondary epilepsy can be attributed to the interplay of multiple underlying pathologies.",
"affiliations": "Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.;Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.;Department of Pathology, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.;Department of Pathology, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.;Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.;Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.;Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.;Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.",
"authors": "Ikawa|Anna|A|;Fujimoto|Ayataka|A|;Arai|Yoshifumi|Y|;Otsuki|Yoshiro|Y|;Nozaki|Toshiki|T|;Baba|Shimpei|S|;Sato|Keishiro|K|;Enoki|Hideo|H|",
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"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295 Frontiers Media S.A. \n\n10.3389/fneur.2021.599130\nNeurology\nCase Report\nCase Report: Late-Onset Temporal Lobe Epilepsy Following Subarachnoid Hemorrhage: An Interplay Between Pre-existing Cortical Development Abnormality and Tissue Damage\nIkawa Anna 12 Fujimoto Ayataka 12* Arai Yoshifumi 3 Otsuki Yoshiro 3 Nozaki Toshiki 1 Baba Shimpei 1 Sato Keishiro 1 Enoki Hideo 1 1Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital, Hamamatsu, Japan\n2Department of Neurosurgery, Seirei Hamamatsu General Hospital, Hamamatsu, Japan\n3Department of Pathology, Seirei Hamamatsu General Hospital, Hamamatsu, Japan\nEdited by: Eliane Kobayashi, McGill University, Canada\n\nReviewed by: Ricardo Silva Centeno Centeno, Universidade Federal de São Paulo, Brazil; Giovanni Pellegrino, McGill University, Canada\n\n*Correspondence: Ayataka Fujimoto afujimotoscienceacademy@gmail.comThis article was submitted to Epilepsy, a section of the journal Frontiers in Neurology\n\n\n09 2 2021 \n2021 \n12 59913026 8 2020 19 1 2021 Copyright © 2021 Ikawa, Fujimoto, Arai, Otsuki, Nozaki, Baba, Sato and Enoki.2021Ikawa, Fujimoto, Arai, Otsuki, Nozaki, Baba, Sato and EnokiThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Epileptogenicity following brain insult depends on various factors including severity of the resulting lesion and extent of brain damage. We report a 54-year-old female patient who developed medically refractory epilepsy resulting from the interplay of pre-existing and post-insult pathologies. She presented with subarachnoid hemorrhage (SAH) due to a ruptured aneurysm and underwent clipping surgery. Seizures started 3 months post-operatively. MRI revealed cerebral ischemia and hemosiderin deposits in the left temporal lobes, and left hippocampal atrophy was suspected. As anti-seizure medications and vagus nerve stimulation failed to control her seizures, she underwent left temporal lobe resection and placement of a ventriculoperitoneal shunt for the post-operative complication of hydrocephalus. She remains seizure-free to date. Neuropathology revealed a previously undiagnosed focal cortical dysplasia (FCD) type 1a. Brain insult likely had a second hit effect in the late onset of epilepsy in this patient with pre-existing mild MCD, in whom secondary epilepsy can be attributed to the interplay of multiple underlying pathologies.\n\ncase reportepileptogenicityparenchymal hemosiderosishippocampal atrophymalformation of cortical developmentmultiple pathology\n==== Body\nHighlights\n- Pre-existing and post-insult pathologies induced epileptogenicity\n\n- Late-onset medically refractory epilepsy with undiagnosed FCD\n\nBackground\nParenchymal hemosiderosis is a risk factor for focal epilepsy after intracerebral bleeding (1, 2). Epileptogenicity due to hemosiderosis is well-known and can be related to cavernous malformation (3), brain tumor (4), or intracranial hemorrhage (5, 6). The mechanism of epileptogenicity due to hemosiderosis includes abnormalities in neurotransmission and free radical formation (7).\n\nIn neuropathology of temporal lobe epilepsy, epileptogenicity has been attributed to various lesions including hippocampal sclerosis, malformation of cortical development (focal cortical dysplasia—FCD—and gray matter heterotopia), as well low-grade tumors (8, 9).\n\nIn daily practice, acute or remote damage resulting from a previous insult is considered as the sole cause of epileptogenicity. As many patients do not require surgery, information on etiology derives solely from magnetic resonance imaging (MRI). However, many pre-existing and yet undiagnosed factors as well as complications from an acute insult can impact the establishment of an epilepsy network by affecting the neurotransmitter system and intracellular and extracellular homeostasis. Indeed, it is common clinical experience that some patients develop epilepsy following an insult and others do not, even though they have the same degree of brain damage.\n\nWe have previously identified the presence of an underlying FCD as a significant factor associated with epilepsy in patients who developed post-traumatic epilepsy following severe head trauma (10). We postulated that multifactorial mechanisms might be involved in epileptogenicity following an insult, and this further applies to patients with chronic seizures following subarachnoid hemorrhage (SAH).\n\nHere, we describe the management of a patient who developed epilepsy and who initially presented for medical care due to a ruptured aneurysmal SAH. In addition to multiple complications due to her SAH (which included acute ischemic stroke with hemorrhagic transformation, hemosiderosis and hydrocephalus), her seizures became medically refractory and warranted resection surgery, leading to the discovery of a previously unknown area suggestive of FCD type 1a.\n\nCase Presentation\nA 54-year-old right-handed female was evaluated at the Comprehensive Epilepsy Center, Seirei Hamamatsu General Hospital (Hamamatsu, Japan) due to medically refractory weekly epileptic seizures.\n\nPast medical history was relevant for a SAH due to a ruptured left middle cerebral artery aneurysm and status post-aneurysm clipping 11 months prior. Her clinical evolution during acute care was complicated by a hemorrhagic cerebral infarction in the left temporal lobes due to symptomatic cerebral vasospasm.\n\nFocal aware and unaware seizures started 3 months after the surgery. Seizure semiology consisted of an epigastric sensation followed by aphasia and then loss of awareness, with occasional focal to bilateral tonic-clonic seizures. The electroencephalogram (EEG) showed interictal epileptiform discharges over the left fronto-temporal region, in keeping with topography of the bleeding and complications.\n\nLevetiracetam, Zonisamide, Valproic acid, and Lamotrigine did not control her seizures, thus fulfilling criteria for drug-resistant seizures (11, 12). The patient was considered a candidate for surgical intervention and was offered the option of either resection surgery or vagus nerve stimulation (VNS). In view of focal aware seizures, the possibility of effective application of the magnet at the onset of seizures to abort their progression was preferred by the patient and her family. Therefore, she underwent VNS implantation at the age of 55-years and 3 months. VNS reduced her seizure intensity and frequency from weekly to monthly, and aiming at seizure freedom, the patient thereafter elected to undergo resection surgery.\n\nPre-surgical evaluation included MRI, 2-[18F]fluoro-2-deoxy-D-glucose (18FDG)-positron emission tomography (PET), and video EEG monitoring (VEEG). MRI showed T2 signal hyperintensity lesions in the frontal and temporal lobes, with hemosiderin deposits in the temporal area, as well as severe left hippocampal atrophy. 18FDG-PET showed hypometabolism in the left frontal and temporal lobe (Figure 1). VEEG captured her habitual seizures with loss of awareness preceded by an epigastric sensation and aphasia, arising electrographically from the left fronto-temporal area.\n\nFigure 1 Pre-operative and post-operative neuroimaging. MRI FLAIR axial image (A) showing a hyperintense signal at the left temporal pole (arrow) and hippocampal atrophy (arrowhead). T2-weighted coronal image (B) showing a hypointense signal along the lower insula cortex and the roof of the inferior horn. Positron emission tomography (C,D) showing reduced glucose uptake in the left frontal and temporal lobes (arrow). T2-weighted coronal image (E) at the level of the hippocampal body showing hippocampal atrophy (arrow). T2-weighted coronal image at frontal region (F) showing a change in intensity.\n\nBased on the comprehensive pre-surgical evaluation, we hypothesized that her seizures were consistent with mesial temporal lobe epilepsy with a generator in the mesial temporal lobe structures from her dominant hemisphere, and we performed Spencer's anteromedial temporal lobectomy (a left hippocampal and amygdala resection with a temporal lobectomy from the middle temporal gyrus) (13, 14) at age 56. Surgery was complicated by subacute hydrocephalus at post-operative week 1, and she underwent ventriculoperitoneal shunting. She has remained seizure-free for more than 2-years, and remains on Levetiracetam monotherapy.\n\nNeuropathology revealed a small number of ectopic neurons in the white matter of the temporal lobe, as well as satellite oligogenesis growth, suggestive of FCD type 1a (Figure 2). Despite MRI evidence of hippocampal atrophy, the hippocampal specimen showed no neuronal loss or gliosis in CA sectors or in the dentate gyrus, and thus, no neuropathological diagnosis of hippocampal sclerosis could be confirmed.\n\nFigure 2 Histopathology of the left temporal lobe. The cortical-white matter border is ill-defined and indicated as a dotted line (A). Sporadic ectopic neurons accompanied by glial cell proliferation (satellite oligogenesis equivalent to oligodendrocytes) surrounding the neurons (arrows) are seen at high magnification (×200) (B).\n\nDiscussion\nIn this patient, her late-onset epilepsy was at first attributed to prior SAH complicated with left frontal and temporal ischemic stroke with hemorrhagic transformation due to severe vasospasm. However, upon development of drug resistance and partial response to VNS, a full work-up for possible resection surgery, including resection of a generator in the mesial temporal structures, was postulated based on MRI signs that indicated hippocampal atrophy. Although hippocampal pathology did not confirm the presence of hippocampal sclerosis, the decision for resection surgery as the next step in this patient's management revealed FCD 1a in the temporal neocortex. This pre-existing and not yet diagnosed epileptogenic lesion could play a role in the development of epilepsy in this patient, as not all patients with a prior vascular insult will present with chronic unprovoked seizures.\n\nMany patients, like ours, will present with recurrent seizures that develop following the diagnosis of an insult, such as stroke, head trauma, or tumors (15–21). The current use of terms such as “post-stroke epilepsy,” “post-traumatic epilepsy,” and “brain tumor-related epilepsy” can guide our management decisions and allows us to provide patients and families an overview of the predicted outcome. However, the interplay with other underlying known and unknown neuropathological factors might lead to unexpected directions, and attention needs to be paid to patients with rather poor clinical evolution.\n\nAn imbalance between excitatory and inhibitory neurotransmission causing epileptic seizures (22–24) is a common mechanism in the various etiologies of epilepsy. It is however possible that even in the presence of a highly epileptogenic brain lesion such as FCD, epileptogenicity and clinically manifested seizures in some patients only occur after a second hit/insult. Indeed, the “two-hit theory” (25) or “multiple-hit theory” (26) may explain this situation (27, 28). In our patient, seizures became controlled after resection surgery, including resection of the cortical malformation and of areas bearing hemosiderin deposits.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Submission of this case report was approved by the ethics review board at Seirei Hamamatsu General Hospital, and written informed consent was obtained from the patient. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nAll authors made substantial contributions to the conception, validation, design, acquisition of data, or analysis and interpretation of data.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAbbreviations\nEEGelectroencephalogram\n\n18FDG2-[18F]fluoro-2-deoxy-D-glucose\n\nMCDmalformation of cortical development\n\nMRImagnetic resonance imaging\n\nPETpositron emission tomography\n\nSAHsubarachnoid hemorrhage\n\nVEEGvideo electroencephalogram\n\nVNSvagus nerve stimulation.\n==== Refs\nReferences\n1. Hammen T Romstöck J Dörfler A Kerling F Buchfelder M Stefan H . Prediction of postoperative outcome with special respect to removal of hemosiderin fringe: a study in patients with cavernous haemangiomas associated with symptomatic epilepsy\n. Seizure . (2007 ) 16 :248 –53\n. 10.1016/j.seizure.2007.01.001 17276092 \n2. Hirano T Enatsu R Iihoshi S Mikami T Honma T Ohnishi H . Effects of hemosiderosis on epilepsy following subarachnoid hemorrhage\n. Neurol Med Chir. (2019 ) 59 :27 –32\n. 10.2176/nmc.oa.2018-0125 30568071 \n3. Schuss P Marx J Borger V Brandecker S Güresir Á Hadjiathanasiou A . Cavernoma-related epilepsy in cavernous malformations located within the temporal lobe: surgical management and seizure outcome\n. Neurosurg Focus . (2020 ) 48 :E6 . 10.3171/2020.1.FOCUS19920 32234980 \n4. Roelcke U Boxheimer L Fathi AR Schwyzer L Ortega M Berberat J . Cortical hemosiderin is associated with seizures in patients with newly diagnosed malignant brain tumors\n. J Neurooncol . (2013 ) 115 :463 –8\n. 10.1007/s11060-013-1247-7 24045969 \n5. Lahti AM Saloheimo P Huhtakangas J Salminen H Juvela S Bode MK . Poststroke epilepsy in long-term survivors of primary intracerebral hemorrhage\n. Neurology . (2017 ) 88 :2169 –75\n. 10.1212/WNL.0000000000004009 28476758 \n6. Räty S Sallinen H Virtanen P Haapaniemi E Wu TY Putaala J . Occipital intracerebral hemorrhage-clinical characteristics, outcome, and post-ICH epilepsy\n. Acta Neurol Scand . (2020 ). 10.1111/ane.13303 . [Epub ahead of print].32602110 \n7. Kraemer DL Awad IA . Vascular malformations and epilepsy: clinical considerations and basic mechanisms\n. Epilepsia. (1994 ) 35 (Suppl. 6 ):S30 –43\n. 10.1111/j.1528-1157.1994.tb05987.x 8206013 \n8. Li LM Cendes F Andermann F Watson C Fish DR Cook MJ . Surgical outcome in patients with epilepsy and dual pathology\n. Brain. (1999 ) 122 (Pt. 5 ):799 –805\n. 10.1093/brain/122.5.799 10355666 \n9. Salanova V Markand O Worth R . Temporal lobe epilepsy: analysis of patients with dual pathology\n. Acta Neurol Scand . (2004 ) 109 :126 –31\n. 10.1034/j.1600-0404.2003.00183.x 14705975 \n10. Sakakura K Fujimoto A Arai Y Ichikawa N Sato K Baba S . Posttraumatic epilepsy may be a state in which underlying epileptogenicity involves focal cortical dysplasia\n. Epilepsy Behav . (2020 ) 114 :107352 . 10.1016/j.yebeh.2020.107352 32843304 \n11. Kwan P Brodie MJ \nEarly identification of refractory epilepsy\n. N Engl J Med . (2000 ) 342 :314 –9\n. 10.1056/NEJM200002033420503 10660394 \n12. Berg AT Vickrey BG Testa FM Levy SR Shinnar S DiMario F . How long does it take for epilepsy to become intractable? A prospective investigation\n. Ann Neurol . (2006 ) 60 :73 –9\n. 10.1002/ana.20852 16685695 \n13. Spencer DD Spencer SS Mattson RH Williamson PD Novelly RA . Access to the posterior medial temporal lobe structures in the surgical treatment of temporal lobe epilepsy\n. Neurosurgery . (1984 ) 15 :667 –71\n. 10.1227/00006123-198411000-00005 6504282 \n14. Al-Otaibi F Baeesa SS Parrent AG Girvin JP Steven D . Surgical techniques for the treatment of temporal lobe epilepsy\n. Epilepsy Res Treat . (2012 ) 2012 :374848 . 10.1155/2012/374848 22957228 \n15. Olivecrona M Zetterlund B Rodling-Wahlström M Naredi S Koskinen LO . Absence of electroencephalographic seizure activity in patients treated for head injury with an intracranial pressure-targeted therapy\n. J Neurosurg . (2009 ) 110 :300 –5\n. 10.3171/2008.4.17538 18759609 \n16. Kim HJ Lee SA Kim HW Kim SJ Jeon SB Koo YS . The timelines of MRI findings related to outcomes in adult patients with new-onset refractory status epilepticus\n. Epilepsia . (2020 ) 61 :1735 –48\n. 10.1111/epi.16620 32715470 \n17. Severino M Geraldo AF Utz N Tortora D Pogledic I Klonowski W . Definitions and classification of malformations of cortical development: practical guidelines\n. Brain . (2020 ) 143 :2874 –94\n. 10.1093/brain/awaa174 32779696 \n18. Sales F Chaves J McMurray R Loureiro R Fernandes H Villanueva V . Eslicarbazepine acetate in post-stroke epilepsy: clinical practice evidence from Euro-Esli\n. Acta Neurol Scand . (2020 ) 142 :563 –73\n. 10.1111/ane.13323 32691850 \n19. Siig Hausted H Nielsen JF Odgaard L . Epilepsy after severe traumatic brain injury: frequency and injury severity\n. Brain Inj . (2020 ) 34 :889 –94\n. 10.1080/02699052.2020.1763467 32506958 \n20. Uluduz D Midi I Duman T Yayla V Karahan AY Afsar N . Epileptic seizures in cerebral venous sinus thrombosis: subgroup analysis of VENOST study\n. Seizure . (2020 ) 78 :113 –7\n. 10.1016/j.seizure.2020.02.017 32353818 \n21. Ersoy TF Ridwan S Grote A Coras R Simon M . Early postoperative seizures (EPS) in patients undergoing brain tumour surgery\n. Sci Rep . (2020 ) 10 :13674 . 10.1038/s41598-020-70754-z 32792594 \n22. Lotan E Tomer O Tavor I Blatt I Goldberg-Stern H Hoffmann C . Widespread cortical dyslamination in epilepsy patients with malformations of cortical development\n. Neuroradiology . (2020 ). 10.1007/s00234-020-02561-2 . [Epub ahead of print].32975591 \n23. Sarnat HB Hader W Flores-Sarnat L Bello-Espinosa L . Synaptic plexi of U-fibre layer beneath focal cortical dysplasias: role in epileptic networks\n. Clin Neuropathol . (2018 ) 37 :262 –76\n. 10.5414/NP301103 30232955 \n24. Brenet A Hassan-Abdi R Somkhit J Yanicostas C Soussi-Yanicostas N . Defective excitatory/inhibitory synaptic balance and increased neuron apoptosis in a zebrafish model of dravet syndrome\n. Cells . (2019 ) 8 :1199 . 10.3390/cells8101199 31590334 \n25. Hamelin S Depaulis A . Revisiting hippocampal sclerosis in mesial temporal lobe epilepsy according to the “two-hit” hypothesis\n. Rev Neurol. (2015 ) 171 :227 –35\n. 10.1016/j.neurol.2015.01.560 25748332 \n26. Galanopoulou AS . Basic mechanisms of catastrophic epilepsy – overview from animal models\n. Brain Dev . (2013 ) 35 :748 –56\n. 10.1016/j.braindev.2012.12.005 23312951 \n27. Chang YC Huang CC Huang SC . Long-term neuroplasticity effects of febrile seizures in the developing brain\n. Chang Gung Med J . (2008 ) 31 :125 –35\n.18567412 \n28. Colciaghi F Finardi A Frasca A Balosso S Nobili P Carriero G . Status epilepticus-induced pathologic plasticity in a rat model of focal cortical dysplasia\n. Brain. (2011 ) 134 (Pt. 10 ):2828 –2843\n. 10.1093/brain/awr045 21482549\n\n",
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"title": "Case Report: Late-Onset Temporal Lobe Epilepsy Following Subarachnoid Hemorrhage: An Interplay Between Pre-existing Cortical Development Abnormality and Tissue Damage.",
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"abstract": "We report a case of anaphylactic shock following topical administration of moxifloxacin for endophthalmitis prophylaxis prior to cataract surgery. Immunoglobulin E (IgE) serology and IgE skin testing confirmed the anaphylactic etiology. Phacoemulsification with posterior chamber intraocular lens implantation was later performed with identical preoperative preparation except for the exclusion of moxifloxacin; no anaphylactic response occurred. To our knowledge, this is the first report of an anaphylactic response to topical moxifloxacin.\n\n\n\nNone of the authors has a financial or proprietary interest in any material or method mentioned.",
"affiliations": "From the Department of Ophthalmology (M.A. Ullman, Midgley, Kim), MedStar Washington Hospital Center, and the Department of Ophthalmology (M.A.Ullman, Midgley, Kim), MedStar Georgetown University Hospital, Washington, DC; Ullman Eye Consultants (S. Ullman), Pensacola, Florida, USA. Electronic address: mullman@gmail.com.;From the Department of Ophthalmology (M.A. Ullman, Midgley, Kim), MedStar Washington Hospital Center, and the Department of Ophthalmology (M.A.Ullman, Midgley, Kim), MedStar Georgetown University Hospital, Washington, DC; Ullman Eye Consultants (S. Ullman), Pensacola, Florida, USA.;From the Department of Ophthalmology (M.A. Ullman, Midgley, Kim), MedStar Washington Hospital Center, and the Department of Ophthalmology (M.A.Ullman, Midgley, Kim), MedStar Georgetown University Hospital, Washington, DC; Ullman Eye Consultants (S. Ullman), Pensacola, Florida, USA.;From the Department of Ophthalmology (M.A. Ullman, Midgley, Kim), MedStar Washington Hospital Center, and the Department of Ophthalmology (M.A.Ullman, Midgley, Kim), MedStar Georgetown University Hospital, Washington, DC; Ullman Eye Consultants (S. Ullman), Pensacola, Florida, USA.",
"authors": "Ullman|Michael A|MA|;Midgley|Kirsten J|KJ|;Kim|Jocelyn|J|;Ullman|Saul|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D000077266:Moxifloxacin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jcrs.2016.11.004",
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"issn_linking": "0886-3350",
"issue": "42(12)",
"journal": "Journal of cataract and refractive surgery",
"keywords": null,
"medline_ta": "J Cataract Refract Surg",
"mesh_terms": "D000369:Aged, 80 and over; D000707:Anaphylaxis; D000900:Anti-Bacterial Agents; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D019654:Lens Implantation, Intraocular; D000077266:Moxifloxacin; D018918:Phacoemulsification",
"nlm_unique_id": "8604171",
"other_id": null,
"pages": "1836-1837",
"pmc": null,
"pmid": "28007117",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anaphylactic reaction secondary to topical preoperative moxifloxacin.",
"title_normalized": "anaphylactic reaction secondary to topical preoperative moxifloxacin"
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"abstract": "The antipsychotic drug olanzapine may be subject to postmortem redistribution. This complicates the toxicological evaluation in postmortem cases and a supplementary analysis of brain tissue may be an advantage. We report reference brain and blood concentrations of olanzapine from 40 forensic autopsy cases. Each case was assigned to one of three groups according to the cause of death: (A) fatal intoxication by olanzapine alone; (B) fatal intoxication by olanzapine in combination with other drugs and (C) olanzapine was not related to the cause of death. Quantification of olanzapine in brain and blood was performed by ultra-performance liquid chromatography with tandem mass spectrometry using a validated method. A linear correlation between concentrations in blood and brain from 40 cases was found with a correlation coefficient of 0.87. The median brain:blood ratio was 2.5 (10-90%: 1.2-5.8, range: 0.72-10.4). For the A cases (n = 2), the concentrations in brain (Br) and femoral blood (FB) were: Br: 2.1-3.6 mg/kg, FB: 0.99-1.2 mg/kg; for the B cases (n = 17) the 10-90% were: Br: 0.27-1.0 mg/kg (range: 0.13-1.3 mg/kg) FB: 0.11-0.57 mg/kg (range: 0.096-0.65 mg/kg) and the 10-90% of the C cases (n = 21): Br: 0.05-0.49 mg/kg (range: 0.040-0.87 mg/kg) FB: 0.02-0.14 mg/kg (range: 0.008-0.15 mg/kg). These results can serve as reference concentrations for the interpretation of postmortem forensic cases.",
"affiliations": "Department of Forensic Medicine, University of Copenhagen, Frederik V's vej 11, 3. Floor, Copenhagen Ø, Denmark.;Department of Forensic Medicine, University of Copenhagen, Frederik V's vej 11, 3. Floor, Copenhagen Ø, Denmark.;Department of Forensic Medicine, University of Copenhagen, Frederik V's vej 11, 3. Floor, Copenhagen Ø, Denmark.",
"authors": "Nedahl|Michael|M|;Johansen|Sys|S|;Linnet|Kristian|K|",
"chemical_list": "D014150:Antipsychotic Agents; D000077152:Olanzapine",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bky036",
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"issue": "42(9)",
"journal": "Journal of analytical toxicology",
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"medline_ta": "J Anal Toxicol",
"mesh_terms": "D014150:Antipsychotic Agents; D002851:Chromatography, High Pressure Liquid; D053593:Forensic Toxicology; D066128:Gray Matter; D006801:Humans; D000077152:Olanzapine; D011180:Postmortem Changes; D015203:Reproducibility of Results; D013048:Specimen Handling; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "7705085",
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"pages": "650-654",
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"pubdate": "2018-11-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Reference Brain and Blood Concentrations of Olanzapine in Postmortem Cases.",
"title_normalized": "reference brain and blood concentrations of olanzapine in postmortem cases"
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"abstract": "Primary neuroendocrine carcinoma of the breast (NECB) is a very rare type of invasive breast carcinoma. Most NECBs appear on breast imaging as solid masses of varied shapes and margins, and have worse clinical outcomes than does invasive ductal carcinoma, not otherwise specified. However, there have been no reports to date regarding NECB with features of inflammatory breast carcinoma. Here, we describe the clinical, radiol-ogic, and pathologic findings of the first reported case of primary NECB presenting as inflammatory breast carcinoma. The patient complained of diffuse right breast enlargement and erythema. Mammography identified severe breast edema and axillary lymphadenopathy. Ultrasound detected an irregular, angular, hypoechoic mass with dermal lymphatic dilatation. On magnetic resonance imaging, the mass had rim enhancement and the entire right breast showed heterogeneous enhancement with malignant kinetic features. Pathology identified the mass as a primary NECB with positive for synaptophysin, CD56, estrogen and progesterone receptors.",
"affiliations": "Department of Radiology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea.;Department of Radiology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea.; Kangwon National University Graduate School, Chuncheon, Korea.;Department of Radiology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea.;Department of Pathology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea.;Department of Radiology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea.;Department of Radiology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea.",
"authors": "Lee|Do Hyung|DH|;Park|Ah Young|AY|;Seo|Bo Kyoung|BK|;Kim|Young Sik|YS|;Lee|Ki Yeol|KY|;Cha|Sang Hoon|SH|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4048/jbc.2015.18.4.404",
"fulltext": "\n==== Front\nJ Breast CancerJ Breast CancerJBCJournal of Breast Cancer1738-67562092-9900Korean Breast Cancer Society 10.4048/jbc.2015.18.4.404Case ReportPrimary Neuroendocrine Carcinoma of the Breast with Clinical Features of Inflammatory Breast Carcinoma: A Case Report and Literature Review Lee Do Hyung 1Park Ah Young 12Seo Bo Kyoung 1Kim Young Sik 3Lee Ki Yeol 1Cha Sang Hoon 11 Department of Radiology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea.2 Kangwon National University Graduate School, Chuncheon, Korea.3 Department of Pathology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea.Correspondence to: Ah Young Park. Department of Radiology, Korea University Ansan Hospital, Korea University College of Medicine, 123 Jeokgeum-ro, Danwon-gu, Ansan 15355, Korea. Tel: +82-31-412-6872, Fax: +82-31-412-5224, pay526@naver.com12 2015 23 12 2015 18 4 404 408 28 8 2015 26 10 2015 © 2015 Korean Breast Cancer Society. All rights reserved.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Primary neuroendocrine carcinoma of the breast (NECB) is a very rare type of invasive breast carcinoma. Most NECBs appear on breast imaging as solid masses of varied shapes and margins, and have worse clinical outcomes than does invasive ductal carcinoma, not otherwise specified. However, there have been no reports to date regarding NECB with features of inflammatory breast carcinoma. Here, we describe the clinical, radiol-ogic, and pathologic findings of the first reported case of primary NECB presenting as inflammatory breast carcinoma. The patient complained of diffuse right breast enlargement and erythema. Mammography identified severe breast edema and axillary lymphadenopathy. Ultrasound detected an irregular, angular, hypoechoic mass with dermal lymphatic dilatation. On magnetic resonance imaging, the mass had rim enhancement and the entire right breast showed heterogeneous enhancement with malignant kinetic features. Pathology identified the mass as a primary NECB with positive for synaptophysin, CD56, estrogen and progesterone receptors.\n\nBreast neoplasmsMagnetic resonance imagingNeuroendocrine carcinomaUltrasonography\n==== Body\nINTRODUCTION\nPrimary neuroendocrine carcinoma of the breast (NECB) is an extremely rare tumor, accounting for 0.27% to 0.5% of histopathologically proven breast cancers [12]. It exhibits morphological features similar to those of neuroendocrine tumors of both the gastrointestinal tract and lung [3]. The standard diagnostic method for NECB is immunohistochemical staining for neuroendocrine markers, including synaptophysin, chromogranin, and neuron-specific enolase [23]. The 2003 World Health Organization (WHO) histologic classification of tumors of the breast and female genital organs defined NECB as breast carcinoma with more than 50% of the cell population expressing these neuroendocrine markers. Furthermore, the diagnosis of primary neuroendocrine carcinoma of the breast can be established when either an in situ component is found or extramammary sites are excluded [45]. In 2012, the WHO histologic classification was upgraded and these tumors were divided into three subtypes: neuroendocrine carcinoma, well-differentiated; neuroendocrine carcinoma, poorly-differentiated/small cell carcinoma; and invasive breast carcinoma with neuroendocrine differentiation [6].\n\nThere have been some publications describing the pathologic findings in NECB, but few regarding the radiologic findings. Furthermore, there is debate regarding clinical outcomes for NECB. Some authors reported clinical outcome similar to that of invasive ductal carcinoma (IDC), while other large-scale population studies showed higher local recurrence rates and worse overall survival, compared with IDC [278].\n\nTo our knowledge, there has been no report of NECB with clinical features of inflammatory breast carcinoma at the time of diagnosis. In this article, we report the radiologic and pathologic findings of the first reported case of primary NECB presenting as inflammatory breast carcinoma, with a brief review of the relevant literature.\n\nCASE REPORT\nA 48-year-old woman presented to our clinic with diffuse enlargement and erythema of the right breast of 2 weeks duration. She had no risk factors for breast cancer and was taking only oral medication for diabetes mellitus. On physical examination, the right breast was diffusely enlarged and the skin had a peau d'orange appearance. Mediolateral oblique and craniocaudal mammograms showed diffuse skin thickening and edema of the right breast, dense dystrophic calcification in the right subareolar area, and enlarged lymph nodes in both axillae (Figure 1). Breast ultrasound (US) examination was performed with a 6-15-MHz linear transducer (LOGIQ 9 unit; GE Medical Systems, Milwaukee, USA). On US, the normal architecture of breast parenchyma was lost in the right breast. The skin thickness reached up to 6 mm thick and the dermal lymphatics were dilated (Figure 2A). A 24×14 mm, irregular-shaped, angular-margined, hypoechoic mass was observed in the right 9 o'clock position (Figure 2B). Multiple level I and II lymph nodes were enlarged in the right axilla, with level I enlargement in the left axilla (Figure 2C). The lymph nodes had cortical thickening or loss of the fatty hilum. The largest level I node in the right axilla measured 15 mm. These findings were compatible with inflammatory breast cancer with axillary lymph node metastasis.\n\nTo assess the tumor extent, magnetic resonance imaging (MRI) was performed using a 3T MRI unit (MAGNETOM Skyra 3.0 T; Siemens Healthcare, Erlangen, Germany). The precontrast T2-weighted scan demonstrated an indistinct, irregular high signal intensity mass in the right 9 o'clock position with skin and chest wall edema (Figure 3A). On the postcontrast T1-weighted image, the mass in the right 9 o'clock position was irregular, and had internal rim enhancement with skin invasion (Figure 3B). The parenchyma of the entire right breast showed heterogeneous enhancement with early rapid and delayed washout enhancement, suggestive of extensive involvement of the cancer.\n\nUS-guided core needle biopsy was performed for the right 9 o'clock mass. The pathologic examination of the core biopsy specimen revealed irregular nests or interconnected trabecular formation of tumor cells with fine granular chromatin and indistinct nucleoli on hematoxylin and eosin stain (Figure 4A). There was no other component suggestive of a different subtype of invasive breast carcinoma, such as the mucinous or not otherwise specified type. Immunohistochemical staining was positive for synaptophysin and CD56 (neural cell adhesion molecule) (Figure 4B, C). In addition, the tumor was positive for estrogen receptor and progesterone receptor, but negative for human epidermal growth factor receptor (Figure 4D). The Ki-67 labeling index was 10% to 20%. These pathologic findings were compatible with a diagnosis of primary NECB, poorly-differentiated carcinoma.\n\nThe patient underwent chemotherapy, with six cycles of cisplatin and etoposide, six cycles of docetaxel, and three cycles of eribulin. However, on follow-up imaging, the primary cancer in her right breast and metastatic ipsilateral axillary lymph nodes were enlarged, and new metastatic lesions had developed in the left breast. She received endocrine therapy with goserelin acetate and tamoxifen, plus palliative radiation therapy. On follow-up MRI images, multicentric enhancement of the right breast had partially regressed, suggesting a partial response to radiation therapy and/or endocrine therapy. However, multifocal metastatic lesions in the left breast and metastatic axillary lymph nodes had progressed.\n\nDISCUSSION\nThere are a few reports of the radiologic findings in primary NECB [145]. Based on these reports, all primary NECBs present as solid masses. On mammography, the tumors were hyperdense, round or irregularly shaped masses with variable margins that were spiculated, indistinct, circumscribed, or obscured [145]. On US, the tumors were oval or irregularly shaped, heterogeneous or homogeneous hypoechoic masses with variable margins, as in mammography. Most masses had normal US transmission [145]. A few reports of MRI findings in primary NECB demonstrated that the tumors were irregular masses with rim enhancement and malignant kinetic characteristics, and early rapid and delayed washout enhancement [4,5].\n\nIn our case, the radiologic findings were unique in that the tumor was accompanied by features of inflammatory breast carcinoma. Inflammatory carcinoma is a form of breast carcinoma with a distinct clinical presentation including diffuse erythema, edema, peau d'orange appearance, tenderness, induration, warmth, enlargement, and a palpable ill-defined mass in some cases [6]. It has prominent dermal lymphatic infiltration from an underlying invasive carcinoma, and is a form of advanced breast carcinoma classified as T4d in the TNM classification [9]. In the majority of cases, the underlying carcinoma is diagnosed as IDC, not otherwise specified, but any histologic type of carcinoma can be present. We believe our patient is the first reported case of primary NECB. The case showed typical clinical and radiologic features of inflammatory breast carcinoma. She complained of enlargement, erythema, and peau d'orange appearance of the entire right breast, and radiological examination revealed diffuse skin thickening, dilated dermal lymphatics, and extensive cancer involvement of the right breast on mammography, US, and MRI. On mammography, we could not identify a discrete mass because of severe breast edema. US and MRI demonstrated breast parenchymal findings in detail. An angularmargined, irregular-shaped, hypoechoic mass was found in the 9 o'clock position of her right breast on US. MRI demonstrated that the mass had rim enhancement with early rapid and delayed washout, a malignant kinetic feature. In addition, MRI visualized extensive right breast involvement with heterogeneous enhancement. Axillary lymph node metastases were also found on radiological examination.\n\nWith regard to clinical outcome, several recent studies showed higher local recurrence and worse overall survival for NECB than for IDC [278]. In addition, patients with NECB tend to present at an older age (mean age, 65 years) and with a higher T stage (stage T2 in 50.5% of patients) than those with IDC (54 years, stage T1 in 59.2%) at the time of diagnosis, according to the most recent large-scale investigation [2]. Although there have been reports that the incidence of advanced NECB cases presenting with skin or chest wall invasion (stage T4) is 0% to 8%, there has been no reported case of NECB with clinical features of inflammatory carcinoma [27].\n\nThe treatment of NECB is not standardized and most patients receive conventional breast cancer management. Therefore, surgery may be considered as first-line therapy when possible [4]. A few case studies have demonstrated the effectiveness of endocrine therapy for hormone receptor-positive NECB or of platinum-based chemotherapy for small cell NECB [1011]. A recent large-scale study of 74 patients with NECB indicated that endocrine and radiation therapy tended to improve overall survival, while chemotherapy had the opposite effect. However, none of these differences reached statistical significance [7]. In our case, chemotherapy with various regimens was attempted first, because of the advanced stage at diagnosis. However, the response was poor. The primary cancer progressed and new metastatic lesions developed in the contralateral breast. As second-line treatment, endocrine therapy with palliative radiation therapy was attempted considering the expression of estrogen and progesterone receptors, but metastatic cancer involving the contralateral breast and axilla progressed. According to recent prognostic research about NECB, higher T and M classification, advanced TNM stage, increased expression of Ki-67, and the absence of progesterone expression all are associated with poor prognosis [2]. Presentation as inflammatory breast carcinoma (T4d stage) and node metastases at diagnosis were poor prognostic factors in our case.\n\nIn conclusion, primary NECB is extremely rare, and most NECBs have been detected as solid masses. In this article, we describe the clinical, radiological, and pathological findings of the first reported case of primary NECB presenting as inflammatory breast carcinoma. Inflammatory breast carcinoma presents with dermal lymphatic infiltration by cancer cells. Although the majority of the underlying malignancy in inflammatory breast carcinoma is IDC, we should be aware that NECB, which is an extremely rare malignancy, can present with unique symptoms and radiologic features suggestive of an inflammatory breast lesion.\n\nCONFLICT OF INTEREST: The authors declare that they have no competing interests.\n\nFigure 1 Mammographic findings. Craniocaudal (CC) view (A), mediolateral oblique (MLO) view (B). Both CC and MLO views show severe skin thickening (arrowheads) in the right breast. There is dense dystrophic calcification in the right subareolar area. Enlarged lymph A B nodes (arrows) are also noted in both axilla.\nFigure 2 Breast ultrasound (US) findings. (A) A breast US image shows diffuse skin thickening and dilatation of dermal lymphatics (arrowheads). (B) There is an angular-margined, irregular-shaped, hypoechoic mass (arrows) in the 9 o'clock position of the right breast. (C) There are enlarged lymph nodes with loss of internal fatty hila in the right axilla (arrows).\nFigure 3 Breast magnetic resonance imaging findings. (A) Axial precontrast T2-weighted image shows an indistinct irregular high signal intensity mass (arrow) in the right 9 o'clock position and diffuse skin and chest wall edema (arrowheads). (B) Sagittal postcontrast T1-weighted image shows the mass (arrows) in the right 9 o'clock direction with rim enhancement. Multiple enlarged lymph nodes (white arrowheads) are seen in the right axilla. In the right subareolar area, there is a dark round lesion which corresponds to a calcification (black arrowhead). The entire breast parenchyma has heterogeneous enhancement.\nFigure 4 Pathologic findings of the core biopsy specimen. (A) H&E staining shows irregular nests or interconnected trabecular formation of tumor cells with fine granular chromatin and indistinct nucleoli (×400). On immunohistochemistry, tumor cells show diffuse positive staining for synaptophysin (B), CD56 (C), and estrogen receptor markers (D) (×400).\n==== Refs\n1 Kim JW Woo OH Cho KR Seo BK Yong HS Kim A Primary large cell neuroendocrine carcinoma of the breast: radiologic and pathologic findings J Korean Med Sci 2008 23 1118 1120 19119462 \n2 Zhang Y Chen Z Bao Y Du Z Li Q Zhao Y Invasive neuroendocrine carcinoma of the breast: a prognostic research of 107 Chinese patients Neoplasma 2013 60 215 222 23259792 \n3 Ellis IO Schnitt SJ Sastre-Garau X Invasive breast carcinoma Tavassoli FA Devilee P International Agency for Research on Cancer World Health Organization Pathology and Genetics of Tumours of the Breast and Female Genital Organs Lyon IARC Press 2003 13 59 \n4 Valentim MH Monteiro V Marques JC Primary neuroendocrine breast carcinoma: a case report and literature review Radiol Bras 2014 47 125 127 25741062 \n5 Günhan-Bilgen I Zekioglu O Ustün EE Memis A Erhan Y Neuroendocrine differentiated breast carcinoma: imaging features correlated with clinical and histopathological findings Eur Radiol 2003 13 788 793 12664118 \n6 Bussolati G Badve S Carcinomas with neuroendocrine features Lakhani SR Schnitt SJ Tan PH van de Vijver MJ WHO Classification of Tumours of the Breast 4th ed Lyon IARC Press 2012 62 63 \n7 Wei B Ding T Xing Y Wei W Tian Z Tang F Invasive neuroendocrine carcinoma of the breast: a distinctive subtype of aggressive mammary carcinoma Cancer 2010 116 4463 4473 20572042 \n8 Kwon SY Bae YK Gu MJ Choi JE Kang SH Lee SJ Neuroendocrine differentiation correlates with hormone receptor expression and decreased survival in patients with invasive breast carcinoma Histopathology 2014 64 647 659 24117859 \n9 Breast cancer staging, 7th edition American Joint Committee on Cancer Accessed April 24th, 2015 https://cancerstaging.org/references-tools/quickreferences/Documents/BreastMedium.pdf \n10 Buttar A Mittal K Khan A Bathini V Effective role of hormonal therapy in metastatic primary neuroendocrine breast carcinoma Clin Breast Cancer 2011 11 342 345 21729664 \n11 Ochoa R Sudhindra A Garcia-Buitrago M Romilly AP Cortes J Gomez H Small-cell cancer of the breast: what is the optimal treatment? A report and review of outcomes Clin Breast Cancer 2012 12 287 292 22520734\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1738-6756",
"issue": "18(4)",
"journal": "Journal of breast cancer",
"keywords": "Breast neoplasms; Magnetic resonance imaging; Neuroendocrine carcinoma; Ultrasonography",
"medline_ta": "J Breast Cancer",
"mesh_terms": null,
"nlm_unique_id": "101314183",
"other_id": null,
"pages": "404-8",
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"title": "Primary Neuroendocrine Carcinoma of the Breast with Clinical Features of Inflammatory Breast Carcinoma: A Case Report and Literature Review.",
"title_normalized": "primary neuroendocrine carcinoma of the breast with clinical features of inflammatory breast carcinoma a case report and literature review"
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"abstract": "Lipofuscin deposition is a characteristic manifestation of aging. There is very limited literature in humans and in animals describing these deposits in native kidneys. Overall, it is thought to be non-pathogenic and successful transplants from a donor with lipofuscin deposits have been reported. We present the case of a patient who underwent a kidney transplant and a for-cause biopsy post-transplantation incidentally revealed lipofuscin deposition.\n\n\n\nA 48-year old gentleman with a past medical history of diabetes, hypertension, coronary artery disease, and ischemic and then hemorrhagic cardiovascular accident underwent a successful kidney transplant. His donor was an expanded criteria donor with no major past medical history. Post-transplant course was complicated by delayed graft function requiring one dialysis treatment for hyperkalemia. After that he had an uneventful course and achieved a baseline creatinine of 1.2 mg/dL, with no proteinuria. On a routine 19-month follow-up he was noted to have proteinuria and an antibody against the major-histocompatibility-complex class I-related chain A. A graft biopsy revealed acute antibody-mediated rejection and impressive lipofuscin deposition. He was subsequently treated with an antibody-mediated rejection protocol that included high dose steroids, Rituximab, plasmapheresis, and intravenous immunoglobulin, but responded poorly to this regimen. A 6-month follow up biopsy continued to show lipofuscin deposition, with similar microvascular injury scores and 12-months later his creatinine remained stable but his proteinuria worsened. Patient was struggling with recurrent infectious episodes requiring hospitalizations and thus no further diagnostic or therapeutic treatments were pursued.\n\n\n\nLipofuscin deposition has been reported in solid organ transplants but the significance and cause are not well understood. Several physiologic and some pathologic causes to these deposits have been reported including age, diabetes, medications and a genetic syndrome. We propose that immunologic causes such as rejection in the presence of other risk factors could potentiate the oxidative stress leading to excessive lipofuscin deposition in kidney transplants. In the case of our patient, we conclude that these deposits were likely recipient-derived, and postulate that the cumulative burden of inflammation from rejection, and underlying medical conditions led to increased lipofuscin deposition. We speculate them to be an innocent bystander.",
"affiliations": "Faculty of Medicine, McGill University, 1001 boul Decarie, Montreal, Quebec, H4A 3J1, Canada.;Department of Pathology, McGill University Health Centre, 1001 boul Decarie, Montreal, Quebec, H4A 3J1, Canada.;Department of Pathology, McGill University Health Centre, 1001 boul Decarie, Montreal, Quebec, H4A 3J1, Canada.;Division of Nephrology, Department of Medicine, McGill University Health Centre, 1001 boul Decarie, Montreal, Quebec, H4A 3J1, Canada. shaifali.sandal@mcgill.ca.",
"authors": "Leung|Vivian W Y|VWY|;Pilon|Sarah-Jeanne|SJ|;Fiset|Pierre O|PO|;Sandal|Shaifali|S|0000-0003-1941-0598",
"chemical_list": "D008062:Lipofuscin",
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"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 156910.1186/s12882-019-1569-6Case ReportA case report on lipofuscin deposition in a graft biopsy two years after kidney transplantation: an insignificant bystander or a pathogenic benefactor? Leung Vivian W. Y. vivian.leung2@mail.mcgill.ca 1Pilon Sarah-Jeanne sarah-jeanne.pilon@mail.mcgill.ca 2Fiset Pierre O. pierre-olivier.fiset@muhc.mcgill.ca 2http://orcid.org/0000-0003-1941-0598Sandal Shaifali (514) 934-1934shaifali.sandal@mcgill.ca 3451 0000 0004 1936 8649grid.14709.3bFaculty of Medicine, McGill University, 1001 boul Decarie, Montreal, Quebec H4A 3J1 Canada 2 0000 0000 9064 4811grid.63984.30Department of Pathology, McGill University Health Centre, 1001 boul Decarie, Montreal, Quebec H4A 3J1 Canada 3 0000 0000 9064 4811grid.63984.30Division of Nephrology, Department of Medicine, McGill University Health Centre, 1001 boul Decarie, Montreal, Quebec H4A 3J1 Canada 4 0000 0000 9064 4811grid.63984.30Research Institute of the McGill University Health Centre, 1001 boul Decariel, Montrea, Quebec H4A 3J1 Canada 5 0000 0004 0646 3575grid.416229.aRoyal Victoria Hospital Glen Site, D05-7176, 1001 boul Decarie, Montreal, QC H4A 3J1 Canada 17 10 2019 17 10 2019 2019 20 37614 4 2019 27 9 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nLipofuscin deposition is a characteristic manifestation of aging. There is very limited literature in humans and in animals describing these deposits in native kidneys. Overall, it is thought to be non-pathogenic and successful transplants from a donor with lipofuscin deposits have been reported. We present the case of a patient who underwent a kidney transplant and a for-cause biopsy post-transplantation incidentally revealed lipofuscin deposition.\n\nCase presentation\nA 48-year old gentleman with a past medical history of diabetes, hypertension, coronary artery disease, and ischemic and then hemorrhagic cardiovascular accident underwent a successful kidney transplant. His donor was an expanded criteria donor with no major past medical history. Post-transplant course was complicated by delayed graft function requiring one dialysis treatment for hyperkalemia. After that he had an uneventful course and achieved a baseline creatinine of 1.2 mg/dL, with no proteinuria. On a routine 19-month follow-up he was noted to have proteinuria and an antibody against the major-histocompatibility-complex class I-related chain A. A graft biopsy revealed acute antibody-mediated rejection and impressive lipofuscin deposition. He was subsequently treated with an antibody-mediated rejection protocol that included high dose steroids, Rituximab, plasmapheresis, and intravenous immunoglobulin, but responded poorly to this regimen. A 6-month follow up biopsy continued to show lipofuscin deposition, with similar microvascular injury scores and 12-months later his creatinine remained stable but his proteinuria worsened. Patient was struggling with recurrent infectious episodes requiring hospitalizations and thus no further diagnostic or therapeutic treatments were pursued.\n\nConclusions\nLipofuscin deposition has been reported in solid organ transplants but the significance and cause are not well understood. Several physiologic and some pathologic causes to these deposits have been reported including age, diabetes, medications and a genetic syndrome. We propose that immunologic causes such as rejection in the presence of other risk factors could potentiate the oxidative stress leading to excessive lipofuscin deposition in kidney transplants. In the case of our patient, we conclude that these deposits were likely recipient-derived, and postulate that the cumulative burden of inflammation from rejection, and underlying medical conditions led to increased lipofuscin deposition. We speculate them to be an innocent bystander.\n\nKeywords\nKidney transplantationLipofuscin depositionGraft biopsyAmiodaroneRejectionMICAissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nLipofuscin is a brown-yellow, electron-dense and autofluorescent deposit composed mainly of protein and lipids that is seen in many post-mitotic cells, and rarely in proliferating cell populations [1]. A decline in the lysosomal degradative capacity or abnormalities in lipid peroxidation leads to lipofuscin deposition (LD) in these cells [1]. This can be physiologic. For instance, LD is a characteristic manifestation of aging; thus, it is also called the “age pigment” [1–4]. However, rapid and more pronounced deposition is seen in some pathogenic processes, such as lysosomal storage diseases and neurodegenerative disorders [1, 5].\n\nThere is very limited literature in humans and in animals describing LD in the native kidneys (Table 1) [2–23]. Aging is considered to be the most common cause, and except in the case of Hermansky-Pudlak syndrome, [9–11] LD is thought to be non-pathogenic [12, 23]. Thus, LD in the kidneys of a donor is not a contraindication to kidney transplantation (KT) [4, 23]. However, there is very limited literature of LD developing after KT [8]. We present the case of a patient who underwent KT and post-transplantation, a for-cause biopsy incidentally revealed LD. The potential etiology and pathologic role of these deposits are explored.\nTable 1 Potential etiology of lipofuscin deposits in the kidney\n\nCauses\tCommentary\t\n\nPhysiological\n\t\n Aging [6–8]\tStrongest correlate of lipofuscin levels and deposition\t\n\nCongenital\n\t\n Hermansky-Pudlak syndrome [9–11]\tDiffuse tubulopathy from deposition of cytoplasmic irregular waxy brown-yellow ceroid-lipofuscin-like pigment accumulations. This is thought to be pathogenic and leads to chronic kidney disease\t\n\nMedical Conditions\n\t\n Diabetes Mellitus [3, 8, 12]\tPatients have more lipofuscin deposits that are larger in size\t\n Hypertension [3, 12]\tLipofuscin deposits may increase in number\t\n Uremia [13]\tHigh oxidative stress is presumed to be the cause\t\n Beta-Thalassemia Major [14]\tThis feature may be related to vitamin E deficiency secondary to fat malabsorption or hyper-consumption of Vitamin E\t\n Vitamin E deficiency [15]\tLarge amount of lipid peroxides that was produced in the kidney for the period of vitamin E deficiency reacted with amino acids or protein-amino acids to produce lipofuscin by glutathione depletion.\t\n Neurodegenerative disorders [5]\tStudies have focused on increased lipofuscin deposits in neuronal cells only\t\n\nMedications and other chemicals\n\t\n Amiodarone [2, 16, 17]\tCutaneous deposition occurs after 20 months of amiodarone use (dose: ≥160 mg/day) and is considered reversible\t\n Aluminum Exposure [18, 19]\tChronic exposure to aluminum sulfate (33 mg/day) in rats led to lipofuscin depositions. In hemodialysis patient, increased membrane lipid peroxidation of red blood cells has been described\t\n Analgesics [20, 21]\tSeen with large doses of Acetophenetidin, Phenacetin and Acetaminophen\t\n Estrogen [22]\tOnly described in rats\t\n\nImmunologic\n\t\n Rejection\tCurrent case\t\n\n\nCase presentation\nPatient information\nA 48-year-old male patient with end-stage renal disease on hemodialysis underwent an expanded criteria donor KT. The donor’s age was in the early 60s and cause of death was a cerebrovascular event. The donor did not have a history of diabetes or hypertension and terminal creatinine was 1 mg/dL. Our patient received Alemtuzumab and one dose of steroids as induction therapy, and the cold and warm ischemia times were 26 h and 1 h and 15 min, respectively. His primary kidney disease was presumed to be hypertension and diabetes. Three years prior to KT, he presented with an episode of hypertensive urgency, paroxysmal atrial fibrillation and an ischemic cardiovascular accident involving the right posterior corona radiata. Following this, he was placed on anticoagulation therapy with warfarin and a few months later suffered an intraventricular haemorrhage. This left him with significant deficits, in particular, mild cognitive impairment and Broca’s aphasia. Two years after this episode, he also underwent a coronary artery bypass graft surgery. Post-operatively, he was on amiodarone for 11 months and this was stopped after KT.\n\nTimeline\nPost-KT, our patient experienced delayed graft function and required dialysis once, within 24 h of transplantation due to hyperkalemia. Following that, he had renal function recovery and achieved a baseline creatinine of 1.2 mg/dL, with no proteinuria. He had a human leukocyte antigen mismatch of six on the A, B and DR loci and had a pre-transplantation panel reactive antibody of 0. Thus, he was maintained on dual immunosuppression: tacrolimus with a trough target of 4–8 ng/mL and mycophenolic acid 720 mg twice a day. On a routine urine test 19-months post-transplant, he was noted to have proteinuria of 0.088 g/mmol (normal ≤0.017 g/mmol); thus a graft biopsy was pursued.\n\nPathology presentation\nThe graft specimen consisted of five cores, with ¾ cortex and ¼ medulla, for a total of 76 glomeruli (three globally sclerosed) and 11 arteries. The technician noted a brown discoloration while processing the sample. Given the patient’s post-transplant status, the Banff criteria were applied [24]. The biopsy showed endocapillary inflammatory cells in the glomeruli and in the peritubular spaces, which was given a score of moderate glomerulitis (Fig. 1a) and peritubular capillaritis (Fig. 1b), but there was no significant staining for C4d in the peritubular capillaries. Also noted, were tubular changes of acute tubular necrosis or acute drug toxicity. The immunofluorescence was non-contributory. A diagnosis suspicious for acute antibody-mediated rejection was rendered. However, in addition to this, diffuse brown granular pigments in the tubular epithelial cells were seen on hematoxylin and eosin stain. The pigment was found in the cytoplasm of the tubular epithelial cells, ranging from 1 to 4 μm (Fig. 1c). Upon subsequent histologic examination with special stains, the granules were magenta on Masson Trichrome (Fig. 1d) and periodic acid Schiff (Fig. 1e), blue on Schmorl reaction (Fig. 1f), and dark black on Fontana stain (Fig. 1g). They were not reactive with iron staining by Prussian blue (Fig. 1h) and negative on Jone’s silver (Fig. 1i). The tubular cells showed autofluorescence (Fig. 1j). Electron microscopy examination revealed intracellular lamellar inclusions that had a granular matrix and were surrounded by mitochondria (Fig. 1k). All of these features were characteristic of LD (Fig. 2) [7, 25–27].\nFig. 1 Pathology specimen of the graft biopsy of a patient who received a kidney transplant 19 month prior and now had proteinuria (200X magnification unless otherwise specified). a Hematoxylin and eosin: Endocapillary proliferation is seen in the glomeruli. b Hematoxylin and eosin: A peritubular capillary involved by numerous lymphocytes and arrow showing ptc2. c Hematoxylin and eosin: brown granular pigments of 2 μm on average are seen. d Masson-Trichrome: The granules are darker than the surrounding cytoplasm in the tubular cells. e Periodic-acid Schiff: Tubular epithelium with light brown to magenta granules. f Schmorl reaction: The blue coloration of the granules is highlighted. g Fontana: The black coloration of the granules is highlighted. h Prussian blue: the granules are negative for iron staining. i Jone’s silver: the granules are negative for silver staining. j Immunofluorescence (400x magnification): The granules show autofluorescence, exhibited by molecules with fluorophore-like property upon excitation. k Electron microscopy (700x magnification): Tubular cell with intracytoplasmic inclusions, compatible with lipofuscin. They have a lamellar arrangement and a granular matrix (arrow), usually surrounded by mitochondria (arrowhead)\n\n\nFig. 2 Diagnostic approach to black pigments on hematoxylin and eosin stain\n\n\n\nDiagnostic assessment and therapeutic intervention\nSince the transplant and during the biopsy intervals, the patient had fairly good metabolic parameters: hemoglobin A1c < 7.2%, total cholesterol < 3 mmol/L, and BMI < 25 kg/m2. Overall, his BP was well controlled on 2 to 3 agents. No donor-specific antibody to the human leukocyte antigen was noted except that the patient had an indeterminate antibody level against the major-histocompatibility-complex class I-related chain A (MICA). He was treated with our antibody-mediated rejection protocol which entailed three doses of steroids intravenously, two doses of Rituximab 375 mg/m2, and six treatments with plasmapheresis. Following this, we increased his maintenance immunosuppression regimen by increasing the target tacrolimus trough to 8–10 ng/mL and adding prednisone 5 mg to his maintenance immunosuppression. We also started monthly intravenous immunoglobulin. Unfortunately, a protocol biopsy at 6-months did not show much improvement in his inflammatory scores; although the MICA antibody was no longer present (Table 2). In conjunction with this, significant LD was still noted despite augmented immunosuppression.\nTable 2 Comparing the pathology reports of the index for-cause biopsy done 19-months post kidney transplant and a follow-up 6-month biopsy\n\nIndex biopsy\t6-month follow up biopsy\t\nGross description:5 cores, ¾ renal cortex, 76 glomeruli, 3 globally sclerosed, 11 arteries\tGross description: 3 cores, all cortex, 22 glomeruli, 3 globally sclerosed, 9 arteries\t\nBanff lesion scores:a\n\n • i1, t0, v0, ti1, i-IFTA1\n\n • g2, ptc2, v0, C4d0, cg0, mm1\n\n • ci1, ct1, ah2, cv3\n\n\tBanff lesion scores:a\n\n• i0–1, t0–1, v0, ti1, i-IFTA?, t0\n\n• g2, ptc1–2, v0, C4d0, cg0–1, mm1\n\n• ci1–2, ct1–2, ah1, cv1\n\n\t\nMiscellaneous: lipofuscin deposition, polyoma virus immunostaining negative, immunofluorescence negative to non-specific\n\nIndeterminate antibody level against the major-histocompatibility-complex class I-related chain A\n\n\tMiscellaneous: lipofuscin deposition, immunofluorescence negative to non-specific\n\nNo donor specific antibody\n\n\t\naClassification based on Haas et al. Am J Transplant. 2018;18 (2):293–307\n\n\n\nFollow-up and outcomes\nAfter his second biopsy, we discussed initiating the same protocol again, or using Bortezomib and/or Tocilizumab. However, the patient was tolerating augmented immunosuppression poorly, with recurrent infectious episodes requiring hospitalizations. Hence, it was decided that we will be pragmatic with his care and treat him with anti-proteinuric therapy only. At the 12-month mark post the first biopsy, his creatinine was stable and at his baseline but he had nephrotic range proteinuria of 0.4–0.5 g/mmol.\n\nDiscussion\nRenal deposits of lipofuscin in the native kidneys of humans and animals have been described in a very limited number of cases in the literature (Table 1) [2–7, 9–23]. These deposits are considered to be non-pathogenic; thus, successful transplants from donors with LD have been reported [4, 23]. These deposits have also been described in other solid organ transplants [6, 28]. In heart transplants, LD was noted in almost 50% of the patients by three years [6]. Higher serum levels of lipofuscin were tested in KT recipients [13]. In a case series of 201 living donor kidney transplant, Kawaguchi and colleagues reviewed 260 allograft biopsies and reported prevalence of LD was 58.8% [8]. However, it is not clear from the text how the authors ensured that the granules they saw were in fact lipofuscin. In addition, this cohort included living donor KT recipients in Japan that has a high rate of performing ABO incompatible transplants [29]. The implications of previous rejection episodes, desensitization protocols and heme deposits were not accounted for. Lastly, the authors do not report whether what they reported as massive LD led to gross discoloration of core biopsy samples, which was the case in our patient. At our center, while we have not stained every biopsy sample for LD, a gross discoloration of the biopsy sample necessitating investigation has not happened before.\n\nThe significance and cause of LD in a transplanted organ is not well understood. In heart transplant recipients, the presence of lipofuscin in a 12-month endomyocardial biopsy specimen was predictive of the development of angiographically confirmed cardiac allograft vasculopathy [6]. LD is thought to decrease cellular functional capacity leading to cell death by apoptosis or autophagy [30]. On the other hand, some speculate that in the presence of stress, cells are able to respond appropriately to cellular damage and initiate a protective autophagocytic response leading to LD [31]. What is peculiar about our case is the presence of an antibody to the MICA antigen that is associated with decreased renal-allograft survival [32]. MICA antigen expression is known to increase with stress, and its role in autophagy is speculated [33, 34]. However, we reviewed available biopsy samples of other patients who had a MICA antibody and did not note any LD. Thus, having an antibody to MICA alone likely does not lead to excessive LD. We, however, propose that there might be immunologic causes to LD as rejection is known to augment the oxidative stress in a transplanted graft [35]. Thus, immunologic factors may be at play and this needs to be further explored.\n\nKawaguchi and colleagues concluded that LD in the renal allograft tubular epithelium is not a surrogate marker for kidney allograft aging [8]. Although, older age of the recipients but not the donor was speculated to be involved in lipofuscin deposition. Despite his younger age, we postulate that the extensive LD in our patient was the result of the cumulative burden of medical co-morbidities and rejection that caused increased oxidative and inflammatory stress [6, 12, 35]. These medical comorbidities include hypertension, diabetes and a history of neurologic disease. The role of amiodarone is possible as well. However, cutaneous pigmentation typically occurs after many months of continuous treatment with amiodarone, and is reversible [2, 16]. In our patient, the history of amiodarone use was only 11-months, and it was stopped at the time of KT. We did not note any cutaneous discoloration in our patient. In addition, some have characterized amiodarone-associated inclusions to be quite different, morphologically, from lipofuscin [17]. There is low suspicion of these deposits being donor-derived as intra-operative surgical reports do not mention altered pigmentation of the transplanted kidney. The recipient who received the contralateral donor kidney is doing very well and currently does not meet the criteria of a for-indication biopsy. In addition, if donor-derived, LD decreases with time, [23] which was not the case in the two biopsy specimens performed 6-months apart in our patient. The donor was a smoker, but otherwise, had no significant past medical history or risk factors as reported in Table 1 which would have contributed to excess LD. Thus, we believe that LD in the case of our patient was likely not donor derived.\n\nIn conclusion, we report the case of a kidney transplant recipient who had LD in the transplanted graft two years after KT that are likely recipient derived. We present a thorough differential of how we concluded these deposits to indeed be lipofuscin. We also summarize the current literature and list the potential causes to LD. We propose exploring immunologic causes such as rejection as potentiating the oxidative stress that could cause more lipofuscin in the presence of other risk factors. Last, we speculate that LD is more likely to be a bystander and a manifestation of other pathogenic causes that potentiate inflammation.\n\nAbbreviations\nKTKidney transplantation\n\nLDLipofuscin deposition\n\nMICAMajor-histocompatibility-complex class I-related chain A\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable\n\nAuthors’ contributions\nVY: Involved with the acquisition and interpretation of data; drafted the manuscript; approved the submitted version; agree both to be personally accountable for their contributions and to ensure that questions related to the accuracy or integrity of any part of the work. SP: Involved with the acquisition, analysis, and interpretation of data; helped draft and revise the manuscript; approved the submitted version; agree both to be personally accountable for their contributions and to ensure that questions related to the accuracy or integrity of any part of the work. PF: Involved with the conception and the design, and the analysis and interpretation of data; substantively revised the manuscript; approved the submitted version; agree both to be personally accountable for their contributions and to ensure that questions related to the accuracy or integrity of any part of the work. SS: Involved with the conception and the design, and the analysis and interpretation of data; drafted the manuscript; approved the submitted version; agree both to be personally accountable for their contributions and to ensure that questions related to the accuracy or integrity of any part of the work [29].\n\nFunding\nThis work was supported using clinical research funding from the Department of Medicine at the McGill University Health Center. The funding organization had no role in the design, and preparation, writing, review, or approval of the manuscript.\n\nAvailability of data and materials\nNot applicable\n\nEthics approval and consent to participate\nNot indicated as this case report only includes pathology images that are entirely unidentifiable and there are no significant details on the individual whose case is presented.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s guardians for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nDr. Sandal has received an education grant from Amgen to increase living donor kidney transplantation. Dr. Fiset has received honoraria from Pfizer Canada, Merck Canada and AstraZeneca Canada. Otherwise, the authors have no other relevant financial interests or conflict of interests to report.\n==== Refs\nReferences\n1. 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"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "20(1)",
"journal": "BMC nephrology",
"keywords": "Amiodarone; Graft biopsy; Kidney transplantation; Lipofuscin deposition; MICA; Rejection",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D064591:Allografts; D001706:Biopsy; D006084:Graft Rejection; D006801:Humans; D033162:Incidental Findings; D007668:Kidney; D016030:Kidney Transplantation; D008062:Lipofuscin; D008297:Male; D055806:Microvessels; D008875:Middle Aged",
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"other_id": null,
"pages": "376",
"pmc": null,
"pmid": "31623557",
"pubdate": "2019-10-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "9531959;2813197;30317187;29243394;12884641;14096390;1880635;9497295;3033032;9562579;21755057;18497567;22057066;3299917;1713494;19680649;22153555;31076149;18209173;19577082;23368870;21159450;16213475;7573188;25820564;16329037;24839502;5954049;17898098;3989014;29624848;14333519",
"title": "A case report on lipofuscin deposition in a graft biopsy two years after kidney transplantation: an insignificant bystander or a pathogenic benefactor?",
"title_normalized": "a case report on lipofuscin deposition in a graft biopsy two years after kidney transplantation an insignificant bystander or a pathogenic benefactor"
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"abstract": "Tacrolimus is the most widely used immunosuppressant in liver transplant (LT) patients. However, the ideal long-term target level for these patients is unknown. This retrospective study aimed to investigate the impact of tacrolimus blood concentration five years after LT on long-term patient survival outcomes in adult LT recipients. Patients who underwent LT between January 2004 and July 2014 at a tertiary medical center were included in this study (n = 189). The mean tacrolimus blood concentrations of each patient during the fifth year after LT were recorded and the overall survival rate was determined. A multivariate analysis of factors associated with long-term survival was conducted using a Cox's model. The median follow-up period was 9.63 years, and 144 patients (76.2%) underwent live donor LT. Sixteen patients died within 5 years of LT. In the Cox's model, patients with a mean tacrolimus blood trough level of 4.6-10.2 ng/mL had significantly better long-term survival than those with a mean tacrolimus blood trough level outside this range (estimated hazard ratio = 4.76; 95% confidence interval: 1.34-16.9, p = 0.016). Therefore, a tacrolimus level no lower than 4.6 ng/mL would be recommended in adult LT patients.",
"affiliations": "Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei City 110, Taiwan.;Department of Surgery, National Taiwan University College of Medicine, Taipei City 110, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei City 110, Taiwan.;Department of Surgery, National Taiwan University College of Medicine, Taipei City 110, Taiwan.;Department of Surgery, National Taiwan University Hospital, Taipei City 110, Taiwan.;Department of Surgery, National Taiwan University College of Medicine, Taipei City 110, Taiwan.",
"authors": "Hsiao|Chih-Yang|CY|0000-0003-2494-7007;Ho|Ming-Chih|MC|;Ho|Cheng-Maw|CM|0000-0003-1874-7615;Wu|Yao-Ming|YM|;Lee|Po-Huang|PH|;Hu|Rey-Heng|RH|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jpm11020090",
"fulltext": "\n==== Front\nJ Pers Med\nJ Pers Med\njpm\nJournal of Personalized Medicine\n2075-4426\nMDPI\n\n33535628\n10.3390/jpm11020090\njpm-11-00090\nArticle\nLong-Term Tacrolimus Blood Trough Level and Patient Survival in Adult Liver Transplantation\nhttps://orcid.org/0000-0003-2494-7007\nHsiao Chih-Yang 1234\nHo Ming-Chih 23\nhttps://orcid.org/0000-0003-1874-7615\nHo Cheng-Maw 3\nWu Yao-Ming 23\nLee Po-Huang 35\nHu Rey-Heng 234*\nBell Aaron W. Academic Editor\n1 Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei City 110, Taiwan; cyhsiao1102@gmail.com\n2 Department of Surgery, National Taiwan University College of Medicine, Taipei City 110, Taiwan; mcho1215@ntu.edu.tw (M.-C.H.); wyaoming@gmail.com (Y.-M.W.)\n3 Department of Surgery, National Taiwan University Hospital, Taipei City 110, Taiwan; miningho@ntu.edu.tw (C.-M.H.); pohuang1115@ntu.edu.tw (P.-H.L.)\n4 Department of Traumatology, National Taiwan University Hospital, Taipei City 110, Taiwan\n5 Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung 886, Taiwan\n* Correspondence: rhhu@ntu.edu.tw; Tel.: +886-2-2312-3456 (ext. 65106)\n01 2 2021\n2 2021\n11 2 9030 12 2020\n29 1 2021\n© 2021 by the authors.\n2021\nLicensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).\nTacrolimus is the most widely used immunosuppressant in liver transplant (LT) patients. However, the ideal long-term target level for these patients is unknown. This retrospective study aimed to investigate the impact of tacrolimus blood concentration five years after LT on long-term patient survival outcomes in adult LT recipients. Patients who underwent LT between January 2004 and July 2014 at a tertiary medical center were included in this study (n = 189). The mean tacrolimus blood concentrations of each patient during the fifth year after LT were recorded and the overall survival rate was determined. A multivariate analysis of factors associated with long-term survival was conducted using a Cox’s model. The median follow-up period was 9.63 years, and 144 patients (76.2%) underwent live donor LT. Sixteen patients died within 5 years of LT. In the Cox’s model, patients with a mean tacrolimus blood trough level of 4.6–10.2 ng/mL had significantly better long-term survival than those with a mean tacrolimus blood trough level outside this range (estimated hazard ratio = 4.76; 95% confidence interval: 1.34–16.9, p = 0.016). Therefore, a tacrolimus level no lower than 4.6 ng/mL would be recommended in adult LT patients.\n\nCox’s model\nimmunosuppressant\nliver transplantation\nsurvival\ntacrolimus\n==== Body\n1. Introduction\n\nLiver transplantation (LT) has become a mature treatment of end-stage liver disease in clinical practice [1]. The continuous improvement of effective immunosuppression treatments has led to a significant improvement in patient and graft survival in recent years [2]. Calcineurin inhibitors are the cornerstone of immunosuppression in LT [3], and tacrolimus is currently the mainstay of initial and maintenance immunosuppression therapies [4,5,6]. Tacrolimus reduces the incidence and severity of early and late T-cell mediated rejection by inhibiting T-cell production of interleukin-2 [5,6]. However, the long-term use of immunosuppressants leads to an increasing burden of toxicity. The reported toxic effects of calcineurin inhibitors include infections, chronic renal insufficiency, metabolic diseases (such as hyperlipidemia, hypertension, and diabetes mellitus), and malignancy [7,8,9], which, along with cardiovascular diseases, have been reported to be the major causes of morbidity and mortality after LT [3,10]. However, most LT patients cannot withdraw from lifelong immunosuppression therapy; the only exceptions are a few selected patients participating in experimental trials [11,12].\n\nIt is a clinical challenge to design a well-balanced immunosuppressive regimen for LT recipients. Tacrolimus has a narrow therapeutic dose range and its blood levels should be carefully monitored. The Advagraf (tacrolimus prolonged-release hard capsules) recommendation for adult LT patients is a blood trough level of 5–20 ng/mL in the early post-transplant period and 5–15 ng/mL during subsequent maintenance therapy. Nevertheless, the current recommendations from the clinical practice guidelines for the ideal tacrolimus level in adults after LT remain controversial. The American Association for the Study of Liver Diseases (AASLD) recommends a target blood trough level of 5–10 ng/mL for tacrolimus three months after LT [13]. The Consensus on Managing Modifiable Risk in Transplantation Group (COMMIT) recommends that the target tacrolimus blood trough levels be 6–10 ng/mL during the first month after LT and decrease to 4–8 ng/mL thereafter, except when used in combination with mammalian target of rapamycin (mTOR) inhibitors [14]. Moreover, the International Liver Transplant Society (ILTS) consensus statement on immunosuppression in LT recipients recommends the target blood trough levels of tacrolimus be 6–10 ng/mL three months after LT, lower than 5 ng/mL 12 months after LT, and decrease to 3 ng/mL thereafter, resulting in a blood trough level just above the lower limit of detection five years after LT [15]. However, the impact of the long-term tacrolimus blood trough level on the outcomes of the LT recipients remains unclear. This study aimed to suggest an appropriate tacrolimus blood trough level for adult patients five years after LT.\n\n2. Materials and Methods\n\nThis study was approved by the Institutional Review Board of National Taiwan University Hospital and was conducted according to the Declaration of Helsinki. A total of 286 patients who underwent LT at 18 years or older at a tertiary medical center from January 2004 to July 2014 were recruited for this study. Patients who died within 5 years of LT, were lost to follow-up, or did not use tacrolimus-based calcineurin inhibitor for immunosuppressant therapy were excluded from this study (Figure 1). In addition, those who received mTOR inhibitor treatment were excluded, as mTOR inhibitors are typically used as a combination therapy to reduce the required dose of tacrolimus. The final analysis included 189 patients. All eligible patients were followed up for more than five years until August 2019. Patients who underwent a LT due to liver cancer met the Milan criteria (before 2006) or the criteria of the University of California, San Francisco (since 2006) at the time of LT. All patients received regular monthly or bi-monthly follow-ups at the outpatient clinic after LT. Routine blood examinations for the tacrolimus blood trough level, liver function, and renal function were conducted at each visit, and abdominal sonography was performed every 6 to 12 months.\n\nThe patients’ medical records were reviewed retrospectively to extract demographic and clinical data, including patient characteristics, laboratory tests, and survival outcomes. The serum bilirubin and creatinine data at the end of the fifth year after LT were used in this study. The tacrolimus level used in this study was the mean of the values obtained at the three follow-up visits during the fifth year after LT.\n\nThe immunosuppression protocol for adult LT patients consisted of tacrolimus, mycophenolate mofetil, and steroids. Tacrolimus was administered orally beginning on the first day after LT, and the dose was adjusted to achieve the desired therapeutic drug level. Basiliximab was administered immediately before graft reperfusion and on the fourth day after LT for induction therapy. A 500-mg intravenous bolus of methylprednisolone was administered immediately before reperfusion of the liver graft and was tapered to oral prednisolone over one week and reduced to withdrawal after six months.\n\nAll statistical analyses were performed using R 4.0.2 software (R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was set at p ≤ 0.05. Continuous variables are presented as mean ± standard deviation (SD) and median (interquartile range, IQR), and categorical variables are presented as frequency (percentage, %). The survival curve was estimated by the Kaplan-Meier method. A univariate analysis was conducted to examine the differences in the distributions of continuous variables, categorical variables, and survival outcomes between the surviving and deceased liver recipients five years after LT using the Wilcoxon rank-sum test, Chi-square test, Fisher’s exact test, or log-rank test as appropriate for the data type. A multivariate analysis was performed to estimate the adjusted effects of risk factors or prognostic factors on the survival outcome using a multiple Cox’s proportional hazards model.\n\nTo ensure a good quality of regression analysis, the model-fitting techniques for variable selection, goodness-of-fit (GOF) assessment, and regression diagnostics and remedies were used in our regression analysis. Specifically, the stepwise variable selection procedure (with iterations between the forward and backward steps) was applied to obtain the best final regression model using the My.stepwise package of the R software [16]. All significant and non-significant relevant covariates from the univariate analysis (listed in Table 1) and some of the interaction terms were used in the multivariate analysis. The significance levels for entry and for stay were set to 0.15 for being conservative. With the aid of substantive knowledge, the best candidate final regression model was identified manually by dropping the covariates with p value > 0.05 one at a time until all regression coefficients were significantly different from 0. To assess the GOF of the fitted Cox’s model, the concordance and adjusted generalized R2 [17] were examined. A concordance ≥ 0.7 and an adjusted generalized R2 > 0.15 indicated an acceptable level of discrimination, power, and fitness.\n\nMoreover, the smoothing option “pspline” (for the smoothing splines using a “p-spline” basis) was specified inside the coxph function of the survival package to smooth the effects of continuous covariates on the log-hazard rate of the simple and multiple Cox’s proportional hazards models in R. Then, the termplot function of the stats package was used to plot the smoothed effects of the continuous covariates on the log-hazard rate in R [18]. The regression diagnostics for the verification of proportional hazards assumption, residual analysis, detection of influential cases, and a multicollinearity check were applied to discover any model or data problems. A variance inflating factor (VIF) ≥ 10 in continuous covariates or VIF ≥ 2.5 in categorical covariates indicated the occurrence of the multicollinearity problem among some of the covariates in the fitted regression model.\n\n3. Results\n\n3.1. Patients’ Demographic and Clinical Characteristics\n\nThe median follow-up duration was 9.63 years (IQR: 7.2–11.4 years), and the mean follow-up was 9.58 ± 2.74 years. A total of 121 males (64.0%) and 68 females (36.0%) were included in this study (Table 1). The median age at LT was 54.26 years (IQR: 48.63–58.58 years, range: 18.3–73.1 years), and the mean age at LT was 52.7 ± 9.6 years. Among the 189 patients, 114 (76.2%) underwent living donor transplants and 45 (23.8%) underwent deceased donor transplants. The main indications for LT were hepatitis B virus (HBV) cirrhosis (52.9%), hepatocellular carcinoma (38.1%), hepatitis C virus (HCV) cirrhosis (22.2%), and fulminant hepatitis (12.2%). The median of the mean tacrolimus blood trough level during the fifth year after LT was 5.0 ng/mL (IQR: 4.12–6.33 ng/mL), and the mean tacrolimus blood trough level was 5.249 ± 1.71 ng/mL. The mean tacrolimus blood trough level was ≥ 5 ng/mL in 96 patients (50.8%) and < 5 ng/mL in 93 patients (49.2%), including 44 patients (23.3%) with a mean tacrolimus blood trough level < 4 ng/mL and 11 patients (5.8%) with a mean tacrolimus blood trough level < 3 ng/mL. No significant differences in gender, age at LT, body weight, blood type, graft type, etiology of LT, or serum total bilirubin were found between the deceased and surviving LT recipients (p > 0.05). However, serum creatinine levels > 1.5 mg/dL (23/173 vs. 8/16, p = 0.001), end-stage renal disease (2/173 vs. 3/16, p = 0.005), and mean tacrolimus blood trough levels < 4 ng/mL (36/173 vs. 8/16, p = 0.014) were significantly more common among deceased LT recipients compared to survivors. The causes of death included malignancies (n = 5), graft failures (n = 4), infection (n = 4), cerebrovascular accidents (n = 2), and duodenal ulcer bleeding (n = 1) (Table 2). The distribution of the tacrolimus trough level stratified by the etiology and cause of death among the 16 dead patients was shown in the box plot of Figure 2. There was no statistical significance in the tacrolimus trough level between the different causes of death (p = 0.3823).\n\n3.2. Predictors of Patients’ Long-Term Survival\n\nThe Cox’s model fitted to the survival data for the multivariate analyses of the time to death after five years of LT is shown in Table 3. After adjusting for the effects of the other covariates, age at LT ≤ 27.011 years (estimated hazard ratio [HR] = 168.79, 95% confidence interval [C.I.]: 11.13–2559.51), pre-transplant autoimmune liver disease (HR = 8.12, 95% C.I.: 1.97–33.43), pre-transplant HCV infection × survival time in years (HR = 1.34, 95% C.I.: 1.12–1.60), serum creatinine level > 1.311 mg/dL × serum total bilirubin level > 1.411 mg/dL (HR = 921.69, 95% C.I.: 43.40–19,573.71), serum creatinine level > 1.311 mg/dL × serum total bilirubin level ≤ 0.792 mg/dL (HR = 105.68, 95% C.I.: 7.81–1430.79), serum creatinine level ≤ 1.311 mg/dL × serum total bilirubin level > 0.882 mg/dL (HR = 30.49, 95% C.I.: 2.98–312.34), and the mean tacrolimus trough level during the fifth year after LT ≤ 4.609 ng/mL or > 10.168 ng/mL (HR = 4.76, 95% C.I.: 1.34–16.94) were associated with a higher long-term mortality five years after LT. The time-dependent interaction term, HCV × survival time in years, was added to the Cox’s model to account for the non-proportional hazards problem between the patients with and without HCV, and its positive-valued regression coefficient estimate, 0.292, indicates that the risk of mortality in patients with HCV increases with time five years post-LT. Moreover, the three second-order interaction terms between the serum creatinine and total bilirubin levels were compared to the other two possible combinations, serum creatinine level > 1.311 mg/dL × (0.792 mg/dL < serum total bilirubin level ≤ 1.411 mg/dL) and serum creatinine level ≤ 1.311 mg/dL × serum total bilirubin level ≤ 0.882 mg/dL, as the reference group (i.e., HR = 1.0), where the cross sign × can be literally interpreted as “and”.\n\nAll cut-off values of the continuous covariates (such as age at LT) were estimated by applying the p-spline smoothing techniques in fitting simple and multiple Cox’s proportional hazards models. As shown in Figure 3, the optimal cut-off values of the mean tacrolimus trough level, 4.609 ng/mL and 10.168 ng/mL, were estimated directly in the “p-spline plot,” which allowed the visualization of the nonlinear effect of the averaged dosage of the tacrolimus-based immunosuppressant during the fifth year after LT on log(λ), where λ was the hazard rate of time to death five years after LT. Then, the Kaplan-Meier estimates of survival curves for time to death five years after LT were determined for the 66 patients with mean tacrolimus trough levels ≤ 4.609 ng/mL or > 10.168 ng/mL and the 123 patients with mean tacrolimus trough levels between 4.609 ng/mL and 10.168 ng/mL (log-rank test, p = 0.009) (Figure 4). In an additional subgroup analysis, we found that a mean tacrolimus trough level between 4.431 ng/mL and 6.332 ng/mL for patients with a serum creatinine level > 1.311 mg/dL improved survival. Finally, this Cox’s model had a concordance of 0.904 and an adjusted generalized R2 of 0.388, indicating that it fit the survival data very well.\n\n4. Discussion\n\nThis is the first study to report an association between long-term tacrolimus blood trough level and long-term patient survival in adult LT recipients. We found that a long-term tacrolimus blood trough level of 4.6–10.2 ng/mL in adult LT recipients is associated with a lower mortality rate. In patients with a serum creatinine > 1.3 mg/dL, a mean tacrolimus blood trough level of 4.4–6.3 ng/mL is associated with a lower mortality rate.\n\nDecreasing tacrolimus use during long-term follow-up in LT recipients is a general concept in clinical practice. In this study, only one patient had the mean level > 10 ng/mL and a few patients had the mean level > 8 ng/mL (Figure 3). Patients with such high drug levels were most likely because of their poor compliance (not must because of they have truly such high trough level). Poor compliance indicates that a patient takes incorrect dosage of immunosuppressant that their physician prescribed, or takes immunosuppressant or blood exam at the wrong time, either of which might clearly be important factors that influence graft and survival outcome of LT patients during long-term follow-ups. We found that a long-term tacrolimus blood trough level of 4.6–10.2 ng/mL is associated with lower mortality rate; however, the upper limit of 10.2 ng/mL suggested by the regression analysis was merely a value for caution, but not a recommended upper limit in real clinical practice. The long-term hazard of high level of tacrolimus is already widely known; therefore, we would focus more on the findings that it appears to increase the survival risks in LT recipients if their tacrolimus levels are maintained below 4.6 ng/mL during the long-term follow-ups.\n\nInadequate immunosuppression is associated with higher risks of graft rejection [19], while excess immunosuppression increases the risks of malignancy and infection and increases the adverse effects of drug toxicity. The tailored use of immunosuppressants should be considered based on the patient’s risks of graft rejection and infection and the patient’s medical comorbidities and liver disease status prior to LT [14]. Patients with autoimmune liver diseases may require more immunosuppression to prevent disease recurrence and graft rejection [20]. By contrast, lower doses of immunosuppression are recommended in patients who have undergone LT due to HCV, as high levels of immunosuppression are related to increased viral replication [21,22]. Rejection results in abnormal liver function and is one of the most important factors associated with poor long-term graft and patient outcomes [23,24,25]. Tacrolimus reduces the risk of T-cell mediated rejection to protect graft function and is the cornerstone of a successful LT. However, short and long-term adverse effects of tacrolimus such as infection, chronic renal insufficiency, metabolic diseases (hyperlipidemia, hypertension, and diabetes mellitus), and malignancy have been widely reported and influence patients’’ long-term outcomes [7,8,9]. The early causes of death after LT within one year are infection and graft loss, and the late causes of death three years post-LT are malignancy, cardiovascular disease, and renal failure [10]. As graft function typically stabilizes, factors associated with the long-term outcome are often patient-related factors (such as chronic medical diseases) that are usually associated with tacrolimus.\n\nPrevious studies have reported that minimizing tacrolimus use in the early post-LT period is associated with a lower risk of new-onset diabetes mellitus [26], a lower incidence of hyperlipidemia [27], and better long-term survival [19,28]. In recent years, studies have focused on the reduction or complete withdrawal of long-term immunosuppressants in LT recipients [12,29,30,31,32,33,34]. One study reported satisfactory outcomes with the combined use of tacrolimus and mycophenolate mofetil, which allowed for the tacrolimus dose to be reduced [35]. Other studies demonstrated that the concomitant use of everolimus may reduce the required dose of tacrolimus while having potential renal benefits [29,36]. However, only some LT recipients were able to discontinue the use of immunosuppressants, and these patients more frequently experienced biopsy-proven acute rejection [29]. The risk of chronic rejection during long-term follow-up remains in patients with inadequate immunosuppression [30,33]. The tacrolimus blood concentration in LT recipients may play a key role in long-term outcomes, as it is associated with long-term graft function and its adverse effects are related to several chronic medical diseases. However, to the best of our knowledge, this is the first report regarding the effect of long-term tacrolimus levels on the long-term survival outcomes of LT recipients.\n\nSeveral factors are associated with the long-term outcomes of adult LT recipients, including pre-transplant primary sclerosing cholangitis, immunosuppression therapies, acute and chronic rejections, malignancy, and metabolic syndrome [37,38]. As listed in Table 3, we found several independent risk factors of long-term mortality in this study. Only four patients aged <27 years at the time of LT were included in this study, and one died due to pneumonia 6.3 years after LT. Patients who underwent LT due to autoimmune liver diseases had worse outcomes, as they were more likely to experience acute rejections [39] and suffer disease recurrence, leading to graft loss. Patients who underwent LT due to HCV infections had relatively poor post-LT outcomes due to the disease recurrence followed by graft dysfunction and failure [40]. As direct-acting antiviral agents have advanced [41], the survival outcomes of HCV patients should improve in the near future. Long-term renal and liver functions are reflected by serum creatinine and total bilirubin levels, respectively. We found that abnormal serum creatinine levels have a bigger impact than abnormal serum total bilirubin levels on the survival outcomes of LT recipients. The graft function of adult LT recipients is chronically stable five years after LT. While some patients may experience asymptomatic hyperbilirubinemia at this time, the long-term outcomes remain favorable. By contrast, the gradual deterioration of renal function may lead to chronic kidney disease or end-stage renal disease, affecting the long-term survival, especially in patients with long-term use of tacrolimus.\n\nThis study had some limitations. First, the data were obtained from a single medical center in Asia, which provided a relatively small number of eligible patients with single ethnicity and fewer death events. Second, the study spanned a long time period, and therefore the improvements in surgical and medical expertise and advances in immunosuppression therapies may have influenced the patient outcomes. Third, we did not collect or analyze the time-dependent tacrolimus blood trough level during the follow-up visits five years after LT.\n\nIn summary, we found an association between the long-term tacrolimus blood trough levels and the long-term survival five years after LT. A mean tacrolimus blood trough level outside the range of 4.6–10.2 ng/mL appeared to be an independent risk factor for long-term mortality. Further studies with larger sample sizes are needed to verify these results and to further identify an appropriate tacrolimus blood trough level for maintenance use.\n\nAcknowledgments\n\nWe thank the coordinators (Hui-Ying Lin and Min-Heuy Lin) for their helpful efforts in data collection.\n\nAuthor Contributions\n\nC.-Y.H. drafted the manuscript and R.-H.H. designed the study. C.-Y.H., M.-C.H., and Y.-M.W. conducted data processing, and C.-Y.H. and C.-M.H. performed data analysis. P.-H.L. and R.-H.H. were the directors responsible for general organization and instruction. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of National Taiwan University Hospital.\n\nInformed Consent Statement\n\nPatient consent was waived due to retrospective design of the study.\n\nData Availability Statement\n\nThe datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Patient flow diagram.\n\nFigure 2 The box plot of tacrolimus mean trough level stratified by the etiology and cause of death among the 16 dead patients. There was no statistical difference of tacrolimus level between the different causes of death (p = 0.3823).\n\nFigure 3 The p-spline plot for the nonlinear effect of the long-term tacrolimus blood trough levels on time to death. The tacrolimus blood trough level is shown on the X-axis, and the log(λ), where λ is the hazard rate of time to death five years after liver transplantation, is shown on the Y-axis. In this p-spline plot, the intersection between the horizontal green line (Y = 0) and the red curve yields the estimated optimal cut-off values for long-term tacrolimus blood trough levels at which the values of log(λ) will not change (4.609 ng/mL and 10.168 ng/mL). When the level is ≤4.609 ng/mL or >10.168 ng/mL, the value of log(λ) increases, indicating an increasing λ. When the level is >4.609 ng/mL and ≤10.168 ng/mL, the value of log(λ) decreases, indicating a decreasing λ. The vertical bars above the X-axis represent the patients’ actual mean tacrolimus blood trough levels obtained at the three follow-up visits during the fifth year after LT.\n\nFigure 4 The Kaplan-Meier curve for time to death five years after liver transplantation. The survival curve of the 66 patients with a mean tacrolimus blood trough level ≤ 4.609 ng/mL or >10.168 ng/mL is shown in red while the survival curve of the 123 patients with a mean tacrolimus blood trough level > 4.609 ng/mL or ≤10.168 ng/mL is shown in green.\n\njpm-11-00090-t001_Table 1 Table 1 Univariate analysis for comparing the distributions of the demographic and clinical characteristics between the alive and dead adult liver recipients after five years of liver transplantations.\n\nVariable\tAll Patients\n(n = 189)\tAlive\n(n = 173)\tDead\n(n = 16)\tp Value\t\nGender\t\t\t\t0.7899\t\nMale\t121 (64.0)\t110 (90.9)\t11 (9.1)\t\t\nFemale\t68 (36.0)\t63 (92.6)\t5 (7.4)\t\t\nAge at LT (years)\t52.7 ± 9.6\t52.6 ± 9.5\t53.4 ± 10.7\t0.6672\t\nBody weight at LT (kg)\t64.9 ± 12.2\t65.0 ± 12.3\t63.7 ± 12.1\t0.4459\t\nBlood type\t\t\t\t0.8719\t\nO\t79 (41.8)\t73 (92.4)\t6 (7.6)\t\t\nA\t51 (27.0)\t46 (90.2)\t5 (9.8)\t\t\nB\t42 (22.2)\t39 (92.9)\t3 (7.1)\t\t\nAB\t17 (9.0)\t15 (88.2)\t2 (11.8)\t\t\nGraft type\t\t\t\t1.0000\t\nLiving donor\t144 (76.2)\t132 (91.7)\t12 (8.3)\t\t\nDeceased donor\t45 (23.8)\t41 (91.1)\t4 (8.9)\t\t\nEtiology for LT\t\t\t\t\t\nLiver malignancy (HCC)\t72 (38.1)\t66 (91.7)\t6 (8.3)\t1.0000\t\nAlcoholic cirrhosis\t17 (9.0)\t16 (94.1)\t1 (5.9)\t1.0000\t\nHBV cirrhosis\t100 (52.9)\t92 (92.0)\t8 (8.0)\t1.0000\t\nHCV cirrhosis\t42 (22.2)\t38 (90.5)\t4 (9.5)\t0.7577\t\nFulminant hepatitis\t23 (12.2)\t23 (100)\t0 (0)\t0.2259\t\nAutoimmune disease\t14 (7.4)\t11 (78.6)\t3 (21.4)\t0.1017\t\nBiliary atresia\t5 (2.6)\t5 (100)\t0 (0)\t1.0000\t\nOther\t10 (5.3)\t9 (90)\t1 (10)\t0.5964\t\nTotal bilirubin (mg/dL)\t0.973 ± 0.51\t0.958 ± 1.53\t1.133 ± 0.69\t0.6260\t\nTotal bilirubin > 1 mg/dL\t60 (31.7)\t53 (88.3)\t7 (11.7)\t0.2770\t\nTotal bilirubin > 2 mg/dL\t11 (5.8)\t9 (81.8)\t2 (18.2)\t0.2360\t\nCreatinine (mg/dL)\t1.391 ± 1.25\t1.279 ± 0.96\t2.6 ± 2.74\t0.0201 *\t\nCreatinine > 1.5 mg/dL\t31 (16.4)\t23 (74.2)\t8 (25.8)\t0.0010 *\t\nESRD\t5 (2.6)\t2 (40.0)\t3 (60.0)\t0.0050 *\t\nTacrolimus mean level (ng/mL)\t5.249 ± 1.71\t5.263 ± 1.53\t5.096 ± 3.12\t0.9787\t\nTacrolimus level < 5 ng/mL\t93 (49.2)\t82 (88.2)\t11 (11.8)\t0.1216\t\nTacrolimus level < 4 ng/mL\t44 (23.3)\t36 (81.8)\t8 (18.2)\t0.0136 *\t\nTacrolimus level < 3 ng/mL\t11 (5.8)\t9 (81.8)\t2 (18.2)\t0.2356\t\nData are presented as mean ± standard deviation (SD) for continuous variables and frequency (percentage, %) for categorical variables. The p-values of statistical tests were calculated using the Wilcoxon rank-sum test for continuous variables and the Fisher’s exact test for categorical variables. * p value ≤ 0.05. Abbreviations: LT, liver transplantation; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; Total bilirubin, serum total bilirubin level; Creatinine, serum creatinine level; and ESRD, end-stage renal disease (defined by receiving hemodialysis regularly).\n\njpm-11-00090-t002_Table 2 Table 2 The causes of 16 deaths since 5 years after adult liver transplantations.\n\nCauses of Deaths\tNumber of Subjects\t\nMalignancy\t5 (31.25%)\t\nDe novo: Multiple myeloma, bladder cancer, colon cancer, prostate cancer\t4\t\nRecurrent: Hepatocellular carcinoma\t1\t\nGraft failure\t4 (25.00%)\t\nChronic rejection\t3\t\nAutoimmune hepatitis\t1\t\nInfection\t4 (25.00%)\t\nPneumonia\t3\t\nUrinary tract infection\t1\t\nCerebral vascular event (intracerebral hemorrhage)\t2 (12.50%)\t\nPeptic ulcer bleeding\t1 (6.25%)\t\n\njpm-11-00090-t003_Table 3 Table 3 Multivariate analysis for identifying the predictors of long-term overall survival after 5 years of liver transplantations by fitting a multiple Cox’s Model in the adult liver transplant recipients 1.\n\nCovariate 2\tEstimate\tStandard\nError\tWald’s\nz Test\tp Value\tHazard\nRatio (HR)\t95% Confidence\nInterval (C.I.)\t\nAge at LT ≤ 27.011 years\t5.1286\t1.3872\t3.6970\t0.0002\t168.7851\t11.130–2559.512\t\nAutoimmune (including PBC)\t2.0946\t0.7219\t2.9015\t0.0037\t8.1221\t1.973–33.431\t\nHCV × Overall survival years\t0.2924\t0.0914\t3.1978\t0.0014\t1.3397\t1.120–1.603\t\nCre > 1.311 × T-Bil > 1.411 mg/dL\t6.8262\t1.5591\t4.3784\t<0.0001\t921.6940\t43.401–19,573.712\t\nCre > 1.311 × T-Bil ≤ 0.792 mg/dL\t4.6604\t1.3294\t3.5056\t0.0005\t105.6778\t7.805–1430.790\t\nCre ≤ 1.311 × T-Bil > 0.882 mg/dL\t3.4174\t1.1871\t2.8788\t0.0040\t30.4913\t2.977–312.341\t\nTacrolimus mean ≤ 4.609 or > 10.168 ng/mL\t1.5599\t0.6479\t2.4076\t0.0161\t4.7581\t1.336–16.940\t\n1 The above multiple Cox’s model was fitted to the 189 adult patients who underwent liver transplantations with 16 death events, for modeling the hazard rate of the right-censored overall survival time five years after liver transplantations. All the cut-off values of the continuous covariates (e.g., age at liver transplantations) were estimated by choosing the option of applying the p-spline smoothing techniques in fitting simple and multiple Cox’s proportional hazards models (e.g., Figure 3). The time-dependent interaction term, HCV × Overall survival year, was added to the Cox’s model for handling the non-proportional hazards problem between the patients with and without HCV, and its positive-valued regression coefficient estimate, 0.2924, indicated that the risk of dying in the patients with HCV would increase as time elapsed five years after liver transplantations. Moreover, the three second-order interaction terms, Cre > 1.311 × T-Bil > 1.411, Cre > 1.311 × T-Bil ≤ 0.792, and Cre ≤ 1.311 × T-Bil > 0.882, were compared to the other two possible combinations, Cre > 1.311 × (0.792 < T-Bil ≤ 1.411) and Cre ≤ 1.311 × T-Bil ≤ 0.882, as the reference group (i.e., HR = 1.0), where the cross sign × can be literally interpreted as “and.” Finally, both goodness-of-fit (GOF) measures, concordance = 0.9041 (se = 0.0265) > 0.7 and adjusted generalized R2 = 0.3878 > 0.15, indicated an excellent fit of this multiple Cox’s model to the observed survival data. 2 Abbreviations: LT, liver transplantation; PBC, primary biliary cirrhosis; HCV, hepatitis C viral infection; Cre, serum creatinine level (mg/dL); T-Bil, serum total bilirubin level (mg/dL); and Tacrolimus mean, the averaged dosage of the tacrolimus-based immunosuppressant (ng/mL).\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Adam R. Karam V. Delvart V. O’Grady J. Mirza D. Klempnauer J. Burroughs A. Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR) J. Hepatol. 2012 57 675 688 10.1016/j.jhep.2012.04.015 22609307\n2. Fung J. Kelly D. Kadry Z. Patel-Tom K. Eghtesad B. Immunosuppression in liver transplantation: Beyond calcineurin inhibitors Liver Transpl. 2005 11 267 280 10.1002/lt.20373 15719409\n3. European Association for the Study of the Liver Electronic address EEE. EASL Clinical Practice Guidelines: Liver transplantation J. Hepatol. 2016 64 433 485 10.1016/j.jhep.2015.10.006 26597456\n4. Wiesner R.H. Fung J.J. Present state of immunosuppressive therapy in liver transplant recipients Liver Transpl. 2011 17 Suppl. 3 S1 S9 10.1002/lt.22410 21850697\n5. McAlister V.C. Haddad E. Renouf E. Malthaner R.A. Kjaer M.S. Gluud L.L. Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: A meta-analysis Am. J. Transplant. 2006 6 1578 1585 10.1111/j.1600-6143.2006.01360.x 16827858\n6. O’Grady J.G. Hardy P. Burroughs A.K. Elbourne D. UK and Ireland Liver Transplant Study Group Randomized controlled trial of tacrolimus versus microemulsified cyclosporin (TMC) in liver transplantation: Poststudy surveillance to 3 years Am. J. Transplant. 2007 7 137 141 10.1111/j.1600-6143.2006.01576.x 17109723\n7. Gonwa T.A. Mai M.L. Melton L.B. Hays S.R. Goldstein R.M. Levy M.F. End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: Risk of development and treatment Transplantation 2001 72 1934 1939 10.1097/00007890-200112270-00012 11773892\n8. Dantal J. Soulillou J.P. Immunosuppressive drugs and the risk of cancer after organ transplantation N. Engl. J. Med. 2005 352 1371 1373 10.1056/NEJMe058018 15800234\n9. Halloran P.F. Immunosuppressive drugs for kidney transplantation N. Engl. J. Med. 2004 351 2715 2729 10.1056/NEJMra033540 15616206\n10. Watt K.D. Pedersen R.A. Kremers W.K. Heimbach J.K. Charlton M.R. Evolution of causes and risk factors for mortality post-liver transplant: Results of the NIDDK long-term follow-up study Am. J. Transplant. 2010 10 1420 1427 10.1111/j.1600-6143.2010.03126.x 20486907\n11. Benitez C. Londono M.C. Miquel R. Manzia T.M. Abraldes J.G. Lozano J.J. Prospective multicenter clinical trial of immunosuppressive drug withdrawal in stable adult liver transplant recipients Hepatology 2013 58 1824 1835 10.1002/hep.26426 23532679\n12. Londono M.C. Rimola A. O’Grady J. Sanchez-Fueyo A. Immunosuppression minimization vs. complete drug withdrawal in liver transplantation J. Hepatol. 2013 59 872 879 10.1016/j.jhep.2013.04.003 23578883\n13. Lucey M.R. Terrault N. Ojo L. Hay J.E. Neuberger J. Blumberg E. Long-term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation Liver Transpl. 2013 19 3 26 10.1002/lt.23566 23281277\n14. Neuberger J.M. Bechstein W.O. Kuypers D.R. Burra P. Citterio F. De Geest S. Duvoux C. Jardine A.G. Kamar N. Krämer B.K. Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients: A Guidance Report and Clinical Checklist by the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) Group Transplantation 2017 101 Suppl. 2 S1 S56 10.1097/TP.0000000000001651 28328734\n15. Charlton M. Levitsky J. Aqel B. O’Grady J. Hemibach J. Rinella M. Saliba F. International Liver Transplantation Society Consensus Statement on Immunosuppression in Liver Transplant Recipients Transplantation 2018 102 727 743 10.1097/TP.0000000000002147 29485508\n16. Hu F.C. My Stepwise: Stepwise Variable Selection Procedures for Regression Analysis. R Package, Version 0.1.0 Available online: https://CRAN.R-project.org/package=My.stepwise (accessed on 12 October 2020)\n17. Nagelkerke N. A note on a general definition of the coefficient of determination Biometrika 1991 78 691 692 10.1093/biomet/78.3.691\n18. Moore D.F. Applied Survival Analysis Using R Springer International Publishing Cham, Switzerland 2016 84 85\n19. Rodriguez-Peralvarez M. Germani G. Papastergiou V. Tsochatzis E. Thalassinos E. Luong T.V. Early tacrolimus exposure after liver transplantation: Relationship with moderate/severe acute rejection and long-term outcome J. Hepatol. 2013 58 262 270 10.1016/j.jhep.2012.09.019 23023010\n20. Khalaf H. Mourad W. El-Sheikh Y. Abdo A. Helmy A. Medhat Y. Liver transplantation for autoimmune hepatitis: A single-center experience Transplant. Proc. 2007 39 1166 1170 10.1016/j.transproceed.2007.02.030 17524922\n21. Grassi A. Ballardini G. Post-liver transplant hepatitis C virus recurrence: An unresolved thorny problem World J. Gastroenterol. 2014 20 11095 11115 10.3748/wjg.v20.i32.11095 25170198\n22. Moini M. Schilsky M.L. Tichy E.M. Review on immunosuppression in liver transplantation World J. Hepatol. 2015 7 1355 1368 10.4254/wjh.v7.i10.1355 26052381\n23. Adams D.H. Neuberger J.M. Patterns of graft rejection following liver transplantation J. Hepatol. 1990 10 113 119 10.1016/0168-8278(90)90081-2 2407770\n24. Mor E. Gonwa T.A. Husberg B.S. Goldstein R.M. Klintmalm G.B. Late-onset acute rejection in orthotopic liver transplantation--associated risk factors and outcome Transplantation 1992 54 821 824 10.1097/00007890-199211000-00010 1279849\n25. Thurairajah P.H. Carbone M. Bridgestock H. Thomas P. Hebbar S. Gunson B.K. Shah T. Neuberger J. Late acute liver allograft rejection; a study of its natural history and graft survival in the current era Transplantation 2013 95 955 959 10.1097/TP.0b013e3182845f6c 23442806\n26. Song J.L. Gao W. Zhong Y. Yan L.N. Yang J.Y. Wen T.F. Yang J. Minimizing tacrolimus decreases the risk of new-onset diabetes mellitus after liver transplantation World J. Gastroenterol. 2016 22 2133 2141 10.3748/wjg.v22.i6.2133 26877618\n27. Li H.Y. Li B. Wei Y.G. Yan L.N. Wen T.F. Zhao J.C. Higher tacrolimus blood concentration is related to hyperlipidemia in living donor liver transplantation recipients Dig. Dis. Sci. 2012 57 204 209 10.1007/s10620-011-1817-5 21743990\n28. Jia J.J. Lin B.Y. He J.J. Geng L. Kadel D. Wang L. Yu D.-D. Shen T. Yang Z. Ye Y.-F. “Minimizing tacrolimus” strategy and long-term survival after liver transplantation World J. Gastroenterol. 2014 20 11363 11369 10.3748/wjg.v20.i32.11363 25170223\n29. Saliba F. Duvoux C. Gugenheim J. Kamar N. Dharancy S. Salame E. Efficacy and Safety of Everolimus and Mycophenolic Acid with Early Tacrolimus Withdrawal after Liver Transplantation: A Multicenter Randomized Trial Am. J. Transplant. 2017 17 1843 1852 10.1111/ajt.14212 28133906\n30. Girlanda R. Rela M. Williams R. O’Grady J.G. Heaton N.D. Long-term outcome of immunosuppression withdrawal after liver transplantation Transplant. Proc. 2005 37 1708 1709 10.1016/j.transproceed.2005.03.070 15919439\n31. Oike F. Yokoi A. Nishimura E. Ogura Y. Fujimoto Y. Kasahara M. Complete withdrawal of immunosuppression in living donor liver transplantation Transplant. Proc. 2002 34 1521 10.1016/S0041-1345(02)02980-9 12176465\n32. Mazariegos G.V. Reyes J. Marino I.R. Demetris A.J. Flynn B. Irish W. Starzl T.E. Weaning of immunosuppression in liver transplant recipients Transplantation 1997 63 243 249 10.1097/00007890-199701270-00012 9020325\n33. Takatsuki M. Uemoto S. Inomata Y. Egawa H. Kiuchi T. Fujita S. Hayashi M. Kanematsu T. Tanaka K. Weaning of immunosuppression in living donor liver transplant recipients Transplantation 2001 72 449 454 10.1097/00007890-200108150-00016 11502975\n34. Tisone G. Orlando G. Cardillo A. Palmieri G. Manzia T.M. Baiocchi L. Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence J. Hepatol. 2006 44 702 709 10.1016/j.jhep.2005.11.047 16473433\n35. Boudjema K. Camus C. Saliba F. Calmus Y. Salame E. Pageaux G. Ducerf C. Duvoux C. Mouchel C. Renault A. Reduced-dose tacrolimus with mycophenolate mofetil vs. standard-dose tacrolimus in liver transplantation: A randomized study Am. J. Transplant. 2011 11 965 976 10.1111/j.1600-6143.2011.03486.x 21466650\n36. Fischer L. Saliba F. Kaiser G.M. De Carlis L. Metselaar H.J. De Simone P. Three-year Outcomes in De Novo Liver Transplant Patients Receiving Everolimus with Reduced Tacrolimus: Follow-Up Results from a Randomized, Multicenter Study Transplantation 2015 99 1455 1462 10.1097/TP.0000000000000555 26151607\n37. Imai D. Yoshizumi T. Sakata K. Ikegami T. Itoh S. Harada N. Maehara Y. Long-Term Outcomes and Risk Factors after Adult Living Donor Liver Transplantation Transplantation 2018 102 e382 e391 10.1097/TP.0000000000002324 29912047\n38. Durand F. How to improve long-term outcome after liver transplantation? Liver Int. 2018 38 Suppl. 1 134 138 10.1111/liv.13651 29427483\n39. Edmunds C. Ekong U.D. Autoimmune Liver Disease Post-Liver Transplantation: A Summary and Proposed Areas for Future Research Transplantation 2016 100 515 524 10.1097/TP.0000000000000922 26447505\n40. Pruthi J. Medkiff K.A. Esrason K.T. Donovan J.A. Yoshida E.M. Erb S.R. Steinbrecher U.P. Fong T.-L. Analysis of causes of death in liver transplant recipients who survived more than 3 years Liver Transpl. 2001 7 811 815 10.1053/jlts.2001.27084 11552217\n41. Suraweera D. Sundaram V. Saab S. Treatment of Hepatitis C Virus Infection in Liver Transplant Recipients Gastroenterol. Hepatol. (N. Y.) 2016 12 23 30 27330501\n\n",
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"title": "Long-Term Tacrolimus Blood Trough Level and Patient Survival in Adult Liver Transplantation.",
"title_normalized": "long term tacrolimus blood trough level and patient survival in adult liver transplantation"
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"abstract": "The article reports the case history of a patient with baclofen intoxication and burst suppression activity in the EEG several hours after baclofen ingestion. With symptomatic treatment the patient recovered within 5 days and the EEG became normal, again.",
"affiliations": "Department of Neurology and Clinical Neurophysiology, Medizinische Hochschule, Hannover, FRG.",
"authors": "Weissenborn|K|K|;Wilkens|H|H|;Hausmann|E|E|;Degen|P H|PH|",
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"mesh_terms": "D000328:Adult; D001418:Baclofen; D003128:Coma; D062787:Drug Overdose; D004569:Electroencephalography; D005260:Female; D006801:Humans; D013406:Suicide, Attempted",
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"title": "Burst suppression EEG with baclofen overdose.",
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"abstract": "OBJECTIVE\nThe aim of this study was to compare the outcomes of pancreatic transplantation from pediatric donors younger than 15 years of age to the outcomes of pancreatic transplantation from adult donors.\n\n\nMETHODS\nSixty patients underwent pancreatic transplantation in our facility from August 2012 to June 2019. These patients were divided into two groups according to the age of the donor: Cases in which the donor was younger than 15 years of age were classified into the PD group (n = 7), while those in which the donor was older than 15 years of age were classified into the AD group (n = 53). The outcomes of pancreas transplantation were retrospectively compared between the two groups.\n\n\nRESULTS\nPancreatic graft survival did not differ between the PD and AD groups. Furthermore, there were no differences in the HbA1c and serum creatinine levels at three months, with good values maintained in both groups. The results of oral glucose tolerance tests (OGTTs) revealed that the blood glucose concentration did not differ between the two groups. However, the serum insulin concentration at 30 min after 75 g glucose loading was significantly higher in the PD group.\n\n\nCONCLUSIONS\nThe outcomes of pancreatic transplantation from pediatric donors may be comparable to those of pancreatic transplantation from adult donors and the insulin secretion ability after transplantation may be better.",
"affiliations": "Department of Transplantation and Regenerative Medicine, Fujita Health University, School of Medicine, Dengakugakubo 1-98, Kutsukakecho, Toyoake-shi, Aichi 470-1192, Japan. i-taihei@fujita-hu.ac.jp.;Department of Transplantation and Regenerative Medicine, Fujita Health University, School of Medicine, Dengakugakubo 1-98, Kutsukakecho, Toyoake-shi, Aichi 470-1192, Japan.;Department of Transplantation and Regenerative Medicine, Fujita Health University, School of Medicine, Dengakugakubo 1-98, Kutsukakecho, Toyoake-shi, Aichi 470-1192, Japan.;Department of Transplantation and Regenerative Medicine, Fujita Health University, School of Medicine, Dengakugakubo 1-98, Kutsukakecho, Toyoake-shi, Aichi 470-1192, Japan.;Department of Transplantation and Regenerative Medicine, Fujita Health University, School of Medicine, Dengakugakubo 1-98, Kutsukakecho, Toyoake-shi, Aichi 470-1192, Japan.;Department of Endocrinology and Metabolism, Fujita Health University, School of Medicine, Dengakugakubo 1-98, Kutsukakecho, Toyoake-shi, Aichi 470-1192, Japan.;Department of Endocrinology and Metabolism, Fujita Health University, School of Medicine, Dengakugakubo 1-98, Kutsukakecho, Toyoake-shi, Aichi 470-1192, Japan.;Department of Endocrinology and Metabolism, Fujita Health University, School of Medicine, Dengakugakubo 1-98, Kutsukakecho, Toyoake-shi, Aichi 470-1192, Japan.;Department of Nephrology, Fujita Health University School of Medicine, Dengakugakubo 1-98, Kutsukakecho, Toyoake-shi, Aichi 470-1192, Japan.",
"authors": "Ito|Taihei|T|;Kenmochi|Takashi|T|;Aida|Naohiro|N|;Kurihara|Kei|K|;Kawai|Akihiro|A|;Suzuki|Atsushi|A|;Shibata|Megumi|M|;Hiratsuka|Izumi|I|;Hasegawa|Midori|M|",
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"fulltext": "\n==== Front\nJ Clin MedJ Clin MedjcmJournal of Clinical Medicine2077-0383MDPI 10.3390/jcm8091386jcm-08-01386ArticleThe Outcomes of Pancreatic Transplantation from Pediatric Donors–A Single Institution Experience Ito Taihei 1*Kenmochi Takashi 1Aida Naohiro 1Kurihara Kei 1Kawai Akihiro 1https://orcid.org/0000-0003-0807-199XSuzuki Atsushi 2Shibata Megumi 2Hiratsuka Izumi 2Hasegawa Midori 31 Department of Transplantation and Regenerative Medicine, Fujita Health University, School of Medicine, Dengakugakubo 1-98, Kutsukakecho, Toyoake-shi, Aichi 470-1192, Japan2 Department of Endocrinology and Metabolism, Fujita Health University, School of Medicine, Dengakugakubo 1-98, Kutsukakecho, Toyoake-shi, Aichi 470-1192, Japan3 Department of Nephrology, Fujita Health University School of Medicine, Dengakugakubo 1-98, Kutsukakecho, Toyoake-shi, Aichi 470-1192, Japan* Correspondence: i-taihei@fujita-hu.ac.jp; Tel.: +562-93-2000; Fax: 562-93-512504 9 2019 9 2019 8 9 138625 7 2019 02 9 2019 © 2019 by the authors.2019Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Objectives: The aim of this study was to compare the outcomes of pancreatic transplantation from pediatric donors younger than 15 years of age to the outcomes of pancreatic transplantation from adult donors. Methods: Sixty patients underwent pancreatic transplantation in our facility from August 2012 to June 2019. These patients were divided into two groups according to the age of the donor: Cases in which the donor was younger than 15 years of age were classified into the PD group (n = 7), while those in which the donor was older than 15 years of age were classified into the AD group (n = 53). The outcomes of pancreas transplantation were retrospectively compared between the two groups. Results: Pancreatic graft survival did not differ between the PD and AD groups. Furthermore, there were no differences in the HbA1c and serum creatinine levels at three months, with good values maintained in both groups. The results of oral glucose tolerance tests (OGTTs) revealed that the blood glucose concentration did not differ between the two groups. However, the serum insulin concentration at 30 min after 75 g glucose loading was significantly higher in the PD group. Conclusion: The outcomes of pancreatic transplantation from pediatric donors may be comparable to those of pancreatic transplantation from adult donors and the insulin secretion ability after transplantation may be better.\n\npancreas transplantationpediatric donorbrain-dead donor\n==== Body\n1. Introduction\nSince the revision of the organ transplantation law, pancreas transplantation from brain-dead donors has increased and 30–40 pancreas transplants are performed annually [1]. At the same time, organ donation from children under 15 years of age is also increasing. Among the 358 pancreas transplants performed in Japan by the end of 2018, 13 involved transplants from pediatric donors of <15 years of age. Seven of these procedures were performed in our facility.\n\nRegarding pancreatic transplantation from small child donors, the following questions remain. Does the difficulty of vascular anastomosis increase and do such donors influence pancreatic graft survival due to associated postoperative complications, such as thrombosis? In addition, since the pancreatic graft volume is small, does size mismatch with adult recipients sometimes result in insufficient insulin secretion?\n\nIn the United States, en bloc grafting, including dual kidney and pancreatic grafts, has been successfully utilized for simultaneous pancreas and kidney transplantation from small pediatric donors [2,3,4]. However, the utilization of dual kidneys should be limited to cases involving very small donors because of a severe donor shortage in Japan and the difficultly associated with the use of en bloc grafts, including the pancreas and the use of the donor’s aorta for arterial anastomosis from the viewpoint of blood vessel sharing with liver transplantation.\n\nIn this study, we compared the outcomes of pancreatic transplantation from pediatric donors of less than 15 years of age to the outcomes of pancreatic transplantation from adult donors and clarified the usefulness of these procedures. All patients were treated in our facility.\n\n2. Patients and Methods\n2.1. Patients\nAll pancreatic transplant cases in Japan are registered in the Japan Organ Transplant Network. Patients waiting for transplantation are selected according to the following conditions, regardless of whether the cases involve pediatric or adult donors. Blood type compatibility and negativity on a direct crossmatch test are prerequisites for recipient selection. Priority for recipient selection is determined as follows: 1. The order of the recipients is arranged based on the number of HLA mismatches, with priority given to cases involving smaller numbers of HLA mismatches. 2. Cases are then prioritized in the order of simultaneous pancreas-kidney transplant (SPK), pancreas transplantation after kidney transplantation (PAK), pancreas transplantation alone (PTA). 3. Priority is given according to the length of the waiting period, with priority given to cases involving a longer waiting period. 4. Cases are prioritized in ascending order according to the estimated transport time, with priority given to cases with a shorter estimated transport time.\n\nThe criteria for accepting pediatric donor pancreas transplant in our facility were as follows: No history of diabetes, HbA1c ≤ 6.2%, and well-controlled blood glucose during ICU stay. In the case of SPK, the following conditions were also required: A normal serum creatinine level on admission or after sufficient fluid replacement and bodyweight ≥15 kg.\n\n2.2. The Study Design\nSixty cases, in which pancreatic transplantation from brain-dead donors were performed at Fujita Medical University from August 2012 to June 2019, were divided into two groups according to the age of the donors. Cases involving donors of <15 years of age were classified into the pediatric donor group (PD group; n = 7), while those involving donors of >15 years of age were classified into the adult donor group (AD group; n = 53). The outcomes of pancreas transplantation were compared retrospectively.\n\nThe following items were compared as donor background factors: Age, sex, body weight, body mass index (BMI), cause of death, HbA1c, blood glucose, serum creatinine, LDH, Na, CRP, pancreatic graft weight, and total ischemic time of both the pancreas and kidney grafts. Pancreatic graft survival, as defined by a basal CPR level of >0.3 ng/mL, the insulin free rate at three months post-transplantation, the time course of the HbA1c and serum creatinine levels, and the 75 g-OGTT and glucagon tolerance test results at one month post-transplantation in the cases of graft survival were compared between the two groups as the outcomes of pancreatic transplantation.\n\n2.3. Transplantation Methods and Immunosuppression Protocols\nThe transplantation methods applied in the PD group included SPK (n = 6) and PTA (n = 1). The transplantation methods applied in the AD group included SPK (n = 44), PAK (n = 7), and PTA (n = 2). All cases involved brain-dead donors. In all cases in which SPK was performed, it was performed with a single kidney graft. Both pancreatic and kidney grafts were transplanted from the same donor in all cases involving SPK recipients. Although blood vessel sharing is determined in consultation with the liver transplant team, most arterial reconstruction was anastomosed between a Carrel patch that included the roots of the celiac artery (CEA) and superior mesenteric artery (SMA) with the external iliac artery. In some cases, Y-graft anastomosis was required to anastomose the sphenopalatine artery (SPA) and SMA. The portal vein was extended as needed. Intestinal drainage was performed in all cases. In all cases involving pediatric or adult donors, vascular anastomosis for pancreatic transplantation was performed by the same surgeon, who was trained in microvascular techniques.\n\nFor induction therapy, basiliximab (20 mg/body) was administered on day 0 and 4 to all patients who underwent SPK, while anti-thymocyte globulin (1.5 mg/kg) was administered from day 0 to 4 to all patients who underwent either PAK or PTA. In all cases, tacrolimus (0.15 mg/kg [adjust to trough level: 3–8 ng/mL]), mycophenolate mofetil (1500 mg/body), and prednisolone (5 mg/body) were administered to maintain immunosuppression. During the perioperative period and the follow-up period after transplantation, all pancreatic transplantation recipients in both the PD and AD groups were managed by the same surgical team.\n\n2.4. Statistical Analyses\nAll statistical analyses were performed using the EZR software program (freely distributed from the homepage of Saitama Medical Center Jichi Medical University), which extends the functionality of R and R commander [5]. The categorical variables were analyzed with an x2 test, the continuous variables were analyzed using the Mann-Whitney U-test. Kaplan-Meier curves and a log-rank test were used to analyze graft survival. p values of <0.05 were considered to indicate statistical significance.\n\n2.5. Ethical Aspects\nBefore registration, all subjects gave their informed consent to the secretariat of islet transplants in Japan and information on the opt-out procedure was published on the Fujita Health University website (https://www.fujita-hu.ac.jp/). The study was conducted in accordance with the Declaration of Helsinki and the protocol was approved by the Ethics Committee of Fujita Health University (HM19-140).\n\n3. Results\n3.1. Background Factors and the Outcomes of Transplantation from Pediatric Donors\nThe backgrounds of the pediatric donors are summarized in Table 1. The youngest donor was 4 years of age, while the oldest was 11 years of age. The minimum weight was 18.5 kg. The pancreatic graft weight was 61–114 g. The donor’s HbA1c levels ranged from 4.7 to 5.5% and were within the normal range in all cases. The serum creatinine level was slightly high in Case 4 (0.82 mg/dl) but was normal in all other cases.\n\nThe backgrounds of the recipients and the results of transplantation are summarized in Table 2. PTA was performed in Case 2. In all other cases, simultaneous pancreas and kidney transplantation was performed. As arterial reconstruction, Cases 1 and 2 required Y-graft anastomosis. Carrel patches, which consisted of the celiac artery and superior mesenteric artery, were used in all other cases. Cases 1 and 2 also required portal vein prolongation. In Case 3, although no stenosis was found at the sites of portal vein anastomosis, blood flow stagnation between the splenic vein and the pancreatic graft was observed after reperfusion, and additional vein bypass was created by the placement of a vein graft between the splenic vein of the graft and the external iliac vein of the recipient.\n\nIn all cases, insulin withdrawal was achieved immediately after transplantation. In all cases of simultaneous pancreas and kidney transplantation, hemodialysis withdrawal was also achieved. However, acute rejection was observed in Cases 2 and 5. Despite treatment for rejection, Case 2 had a CPR level of <0.3 ng/mL at six months post-transplantation, leading to pancreatic graft loss. In all other cases, a good pancreatic and renal graft function was maintained.\n\n3.2. Background Factors of the Pediatric Donor and Adult Donor Groups\nTable 3 compares the backgrounds of the donors and recipients for the pediatric donor (PD) and adult donor (AD) groups. The donor body weight and body mass index (BMI) were significantly lower and the ICU stay was longer in the PD group. Laboratory analyses before procurement surgery revealed that the HbA1c, blood glucose, serum creatinine, and serum C-peptide (CRP) levels were significantly lower and the LDH level was significantly higher in the PD group. There were no differences in terms of the total ischemic time and the number of HLA-mismatches. However, the pancreatic graft weight was significantly lower in the PD group.\n\nOn the other hand, while the median HbA1c levels of the recipients were significantly higher before transplantation in the PD group, no differences in other background factors were observed between the two groups.\n\n3.3. Pancreatic Graft Survival\nOnly one patient in the PD group experienced pancreatic graft loss due to rejection at six months post-transplantation, while in other cases, the graft function was well-maintained. On the other hand, 12 cases of pancreatic graft losses were experienced in the AD groups, including 10 cases of SPK and 2 cases of PTA. The causes of pancreatic graft loss in the AD groups were death with a functioning graft (n = 5 [myocardial infarction, n = 2; malignant neoplasm, n = 1; death due to accident, n = 1; multiple organ failure, n = 1), thrombosis (n = 4), rejection (n = 2), and other reasons (n = 1). In comparison to the AD group, there were no differences between the two groups in overall pancreatic graft survival (Figure 1a) or death-censored pancreatic graft survival (Figure 1b). With regard to the perioperative surgical complications, no cases of graft loss due to thrombosis were experienced in the pediatric donor group, while graft loss due to thrombosis occurred in 4 out of 53 cases (7.5%) in the adult donor group. Furthermore, perforation of the graft duodenum, which necessitated reoperation was observed in 4 of the 53 cases (7.5%) in the adult donor group, while there were no cases of perforation of the graft duodenum in the pediatric donor group.\n\nThe insulin free rate at three months after transplantation is shown in the Figure 2. Two cases in the AD group required insulin for glycemic control despite CPR positivity, while all recipients in the PD group achieved an insulin free status.\n\nThe time courses of the median HbA1c (Figure 3a) and serum creatinine level (Figure 3b) in the PD and AD groups are shown in Figure 3. The median preoperative HbA1c of recipients in the PD group was significantly higher than that in the AD group (PD group = 8.1% vs. AD group = 6.9, p = 0.043). Thus, the median HbA1c at one month post-transplantation was significantly higher in the PD group (PD group = 6.1 vs. AD group = 5.45, p = 0.008). However, there were no differences between the two groups after three months (PD group = 5.1 vs. AD group = 5.0, p = 0.874), with good values maintained in both groups.\n\nNo difference in the time course of the median serum creatinine level was observed between the two groups of patients who underwent simultaneous pancreas and kidney transplantation, and all patients maintained a good renal graft function.\n\n3.4. The OGTT and Glucagon Stimulation Test Results at One Month after Transplantation\nA 75 g oral glucose tolerance test (OGTT) (Figure 4) and glucagon stimulation test (Figure 5) were performed at one month after transplantation. Regarding the OGTT results, changes in the blood glucose concentration (Figure 4a) and the area under the curve (AUC) (Figure 4b) did not differ between the two groups. However, the serum insulin concentration at 30 min after 75 g glucose loading was significantly higher in the PD group (Figure 4c) (PD group = 82.8μU/mL vs. AD group = 34.3 p = 0.024). As a result, although the difference was not statistically significant, the AUC for insulin tended to be higher in the PD group (Figure 4d) (PD group = 195.3μU/mL vs. AD group = 148.9 p = 0.0577).\n\nOn the other hand, in the glucagon stimulation test, no significant differences were observed between the two groups before or after glucagon loading (Figure 5a), or in the ΔCPR (Figure 5b) (PD group = 2.66 ng/mL vs. AD group = 2.43 p = 0.374).\n\n4. Discussion\nIn the United States, pancreas transplantation from pediatric donors has been performed since the 1980s, and its usefulness has been reported. Nghiem DD et al. [6] reported seven cases of pancreatic transplantation from pediatric donors of 3–11 years of age. In these cases, the rates of thrombosis and early graft loss were 14% and 28%, respectively, while the rates in cases involving adult donors were 17.6% and 11.7%, respectively. They also indicated that the OGTT results at three months post-transplantation were similar to those of adult donors, but that the serum glucose level at 30 min after glucose loading was significantly higher in the pediatric group, despite the patients showing higher insulin secretion. These findings were somewhat different from the results that we experienced in procedures involving pediatric donors, as our patients showed better insulin secretion.\n\nSince that time, there have been reports on pancreatic transplantation from pediatric donors from several institutions [2,3,4,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22], and the results were comparable to those of adult donors. The youngest reported case (reported by Sageshima et al. [3]) involved a pediatric donor of 14 months of age; while the lowest donor body weight (reported by Nghiem et al. [6]) was 8.2 kg. Once the blood flow of the transplanted pancreatic graft can be secured, the smallness of the pancreas is unlikely to be a problem. The reason why there were no episodes of thrombosis or perforation of the graft duodenum in the PD group in our study, despite the difficulty of vascular anastomosis, was the relatively better tissue perfusion in the early period after transplantation. Aida et al. [23]. reported that early perioperative graft pancreatic tissue perfusion, as assessed by contrast-enhanced ultrasonography, tended to be better in younger donors. Better tissue perfusion is considered to be associated with faster the blood flow velocity in the splenic vein and portal vein in the pancreatic graft, and this is thought to reduce the risk of thrombus and to guarantee the blood flow of the graft duodenum.\n\nOne potential factor was the size of the anastomosed vessels and the distribution of kidney grafts, as 80% of pancreas transplants involve simultaneous pancreas and kidney transplantation. In the United States, Pelletier et al. [10]. and Kayler et al. [24,25]. reported that the outcomes of kidney transplantation from single kidney grafts from donors of <21 kg were significantly poor based on the Scientific Registry of Transplant Recipients (SRTR) data. Based on these results, a transplantation method using an en bloc graft including the bilateral kidneys and the pancreas was adopted in cases involving very small donors (e.g., donors of <21 kg). This en bloc graft also makes both arterial and vein anastomosis easier, as both the aorta and inferior vena cava are used as anastomotic orifices, which avoids narrow anastomosis.\n\nThe relatively small number of cases was one limitation of the present study. However, in Japan, even the number of cases of single kidney transplantation from brain-dead donors is limited, and it is unclear—as it is in the United States—whether the performance of single kidney transplantation from donors of ≤21 kg is associated with poor outcomes. In Japan, recipients are expected to weigh less than those in the United States. Thus, it is likely that the outcomes of single kidney transplantation from smaller pediatric donors would be better. Single kidney transplantation from small donors should be considered from the viewpoint of the donor shortage in Japan. However, a donor weight of ≥15 kg was required for SPK based on the consideration that single kidney transplantation from a donor of <15 kg would not provide a sufficient function for adult SPK recipients. Thus, dual kidney transplantation might be necessary. From this viewpoint, we consider that for kidney donation from a donor of <15 kg, priority should be given to age-matched pediatric kidney transplantation rather than adult SPK. The further accumulation of cases is expected in the future.\n\n5. Conclusions\nIn conclusion, the outcomes of pancreatic transplantation from pediatric donors may be comparable to those pancreatic transplantation from adult donors, and the insulin secretion ability after transplantation may be better. The distribution of renal grafts remains a problem to be solved in the future, as >80% of pancreatic transplants involve simultaneous pancreas and kidney transplantation. It is necessary to properly consider the allocation according to the accumulation of kidney transplant results from pediatric donors and the numbers of donors in each country.\n\nAuthor Contributions\nConceptualization: T.I. and T.K.; Methodology, T.I. Validation: K.K., A.K. and N.A. Formal Analysis: K.K., A.K. and N.A. Investigation, T.I. Data Curation: T.I., A.S., M.S., I.H. and M.H. Writing—Original Draft Preparation: T.I. Writing—Review & Editing: K.K., A.K., N.A., A.S., M.S., I.H. and M.H. Supervision: T.K. Project Administration: A.S., M.S. and I.H.\n\nFunding\nThe authors of this manuscript have not received any financial support for this study.\n\nConflicts of Interest\nThe authors declare no conflict of interest in association with the present study.\n\nAbbreviations\nAD: Adult donor; AUC, Area under the curve; BMI, Body mass index; BW, Body weight; CEA, Celiac artery; CPR, C-peptide; CVA, Cerebrovascular accident; HLA, Human Leukocyte Antigen; ICU, Intensive care unit; OGTT, Oral glucose tolerance test; PAK, Pancreas transplantation after kidney transplantation. PTA, Pancreas transplantation alone; PD, Pediatric donors; s-Cre, serum creatinine; SMA, Superior mesenteric artery; SPK, Simultaneous pancreas and kidney transplantation; SPV, Splenic vein; TIT, Total ischemic time.\n\nFigure 1 Comparison of pancreatic graft survival. There was no significant difference between the PD and AD groups in overall (a) or death-censored (b) pancreatic graft survival. Only one patient in the PD group experienced pancreatic graft loss due to rejection at six months post-transplantation. The graft function was well-maintained in the other cases.\n\nFigure 2 The insulin free rate at three months post-transplantation. Two cases in the AD group required insulin for glycemic control despite a positive CPR level (≥0.3 ng/ml), while all recipients in the PD group achieved an insulin free status.\n\nFigure 3 The time course of the HbA1c (a) and serum creatinine (b) levels after transplantation. The median preoperative HbA1c level of the recipients in the PD group was significantly higher than that in the AD group. The median HbA1c at one month post-transplantation was significantly higher in the PD group. However, there were no differences between the two groups after three months, with good values maintained in both groups. There were no differences between the two groups in the time course of the median serum creatinine level in cases in which simultaneous pancreas and kidney transplantation was performed, and a good renal graft function was maintained in all cases.\n\nFigure 4 The 75 g Oral glucose tolerance test (OGTT) results at one month post-transplantation. The changes in blood glucose concentration (a) and the area under the curve (AUC) (b) did not differ between the two groups. However, the change in the serum insulin concentration (c) at 30 min after 75 g glucose loading was significantly higher in the PD group. As a result, although there was no significant difference, the AUC for insulin (d) tended to be higher in the PD group.\n\nFigure 5 The glucagon stimulation test results at one month after transplantation. The glucagon stimulation test at one month post-transplantation showed that there was no significant difference between the two groups before or after glucagon loading (a) and the ΔCPR did not differ to a statistically significant extent (b).\n\njcm-08-01386-t001_Table 1Table 1 Donor characteristics.\n\nCase\tAge\tSex\tCause of Death\tBW (kg)\tHbA1c (%)\ts-Cre (mg/dl)\tNumber of HLA Mismatches\tTIT (Pancreas, min)\tTIT (Kidney, min)\tGraft Weight (Pancreas, g)\t\n1\t6\tMale\tHypoxia\t20.0\t4.7\t0.33\t3\t891\t676\t95\t\n2\t5\tFemale\tTrauma\t20.8\t5.5\t0.19\t3\t630\tN/A\t71\t\n3\t9\tMale\tTrauma\t27.0\t5.4\t0.41\t5\t714\t597\t64\t\n4\t11\tFemale\tHypoxia\t43.0\t5.3\t0.82\t2\t969\t704\t114\t\n5\t5\tMale\tHypoxia\t21.0\t4.9\t0.22\t2\t729\t522\t63\t\n6\t4\tFemale\tHypoxia\t18.5\t5.2\t0.17\t3\t974\t680\t61\t\n7\t10\tFemale\tCVA\t29.1\t5.4\t0.47\t2\t801\t606\t75\t\nBW, Body weight; CVA, Cerebrovascular accident; HLA, Human Leukocyte Antigen; s-Cre, serum creatinine; TIT, Total ischemic time.\n\njcm-08-01386-t002_Table 2Table 2 Recipient background and the results of transplantation.\n\nCase\tRecipient Age\tRecipient Sex\tRecipient BW (kg)\tOperation Type\tArterial Reconstruction\tPortal Vein Elongation\tEpisode of Rejection\tGraft Survival\tHbA1c *\ts-Cre * (mg/dl)\tBasal CRP ** (ng/mL)\tCPR after Glucagon Load ** (ng/mL)\tΔCPR ** (ng/mL)\t\n(%)\t\n1\t61\tMale\t61.3\tSPK\tY-graft\t+\t-\tSurvive (43 M)\t5.2\t1.42\t2.44\t5.1\t2.66\t\n2\t34\tMale\t55.1\tPTA\tY-graft\t+\t+\tGraft failure due to rejection (6 M)\t5.3\tN/A\t1.19\t4.01\t2.82\t\n3\t36\tFemale\t49.3\tSPK\tCarrel patch\tSPV bypass\t-\tSurvive (27 M)\t5.1\t0.76\t2.44\t7.66\t5.22\t\n4\t50\tMale\t59.8\tSPK\tCarrel patch\t-\t-\tSurvive (14 M)\t4.7\t1.47\t1.48\t3.22\t1.74\t\n5\t34\tFemale\t56\tSPK\tCarrel patch\t-\t+\tSurvive (12 M)\t5.1\t0.94\t1.3\t3.46\t2.16\t\n6\t56\tMale\t65.7\tSPK\tCarrel patch\t-\t-\tSurvive (5 M)\t5\t1.4\t1.79\t5.68\t3.89\t\n7\t44\tFemale\t51.9\tSPK\tCarrel patch\t-\t-\tSurvive (4 M)\t4.2\t0.91\t1.43\t3.57\t2.14\t\nBW, Body weight; CPR, C-peptide; s-Cre, serum creatinine; PTA, Pancreas transplantation alone; SPK, Simultaneous pancreas and kidney transplantation; SPV, Splenic vein. * at three months post-transplantation, ** at one month post-transplantation.\n\njcm-08-01386-t003_Table 3Table 3 The donor and recipient backgrounds of the pediatric donor (PD) group and the adult donor (AD) group.\n\n\n\tGroup\tPediatric Donors\tAdult Donors\tp Value\t\n\nn\n\t7\t53\t\n\t\nDonor factors\tAge\t6 (4–11)\t48 (17–67)\t\n<0.001\n\t\nSex\tMale (%)\t3 (42.9)\t26 (49.1)\t1\t\nFemale (%)\t4 (57.1)\t27 (50.9)\t\nBW (kg)\t21.0 (18.5–43.0)\t59.7 (40.0–94.1)\t\n<0.001\n\t\nBMI (kg/m2)\t16.0 (12.8–20.8)\t22.2 (16.6–30.0)\t\n<0.001\n\t\nCause of death\tCVA (%)\t1 (14.3)\t27 (52.9)\t0.104\t\nOthers (%)\t6 (85.7)\t24 (47.1)\t\nICU stay (days)\t24 (7–35)\t7 (2–34)\t\n0.005\n\t\nPreoperative HbA1c (%)\t5.3 (4.7–5.5)\t5.5 (4.9–6.3)\t\n0.017\n\t\nPreoperative BG (mg/dl)\t97 (80–117)\t128 (81–237)\t\n0.003\n\t\nPreoperative s-Cre (mg/dl)\t0.33 (0.17–0.82)\t0.68 (0.23–6.93)\t\n0.004\n\t\nPreoperative LDH (U/l)\t1249 (871–2211)\t688 (248–2323)\t\n0.002\n\t\nPreoperative Na (mmol/l)\t139 (130–143)\t141 (114–166)\t0.213\t\nPreoperative CRP (mg/dl)\t7.43 (0.15–22.53)\t17.51 (0.38–39.57)\t\n0.025\n\t\nPancreatic graft weight (g)\t71 (61–114)\t191 (95–352)\t\n<0.001\n\t\nTIT (pancreas, min)\t801 (630–974)\t886 (494–1383)\t0.189\t\nTIT (kidney, min)\t641 (522–704)\t706 (474–1124)\t0.244\t\nRecipient factors\tAge\t44 (34–61)\t44 (31–62)\t0.926\t\nSex\tMale (%)\t4 (57.1)\t17 (32.1)\t0.226\t\nFemale (%)\t3 (42.9)\t36 (67.9)\t\nPreoperative HbA1c (%)\t8.1 (6.3–12.3)\t6.9 (4.9–9.8)\t\n0.043\n\t\nPeriod of diabetic history (year)\t29 (21–38)\t29 (11–43)\t0.926\t\nPeriod of hemodialysis history (year)\t6.0 (1.5–11.0)\t6.0 (0–20.0)\t0.893\t\nBMI, Body mass index; BW, Body weight; CVA, Cerebrovascular accident; HLA, Human Leukocyte Antigen; ICU, Intensive care unit; s-Cre, serum creatinine; TIT, Total ischemic time. Categorical variables were analyzed with the x2 test. Continuous variables were analyzed with the Mann-Whitney U-test.\n==== Refs\nReferences\n1. Asaoka T. Ito T. Kenmochi T. The Japan Society for Pancreas and Islet Transplantation, The registry of Japanese pancreas and islet transplantation 2018 Ishoku 2018 53 139 147 \n2. Buggenhout A. Hoang A.D. Hut F. Lekeufack J.B. Bali M.A. De Pauw L. Pediatric en bloc dual kidney-pancreas transplantation into an adult recipient: A simplified technique. Benefits of the en bloc kidney-pancreas transplantation technique in pediatric donors Am. J. Transpl. 2004 4 663 665 10.1111/j.1600-6143.2004.00371.x 15023161 \n3. Sageshima J. Ciancio G. Chen L. Selvaggi G. Nishida S. Akpinar E. Nesher E. Romano A. Misawa R. Burke G.W. 3rd Combined pancreas and en bloc kidney transplantation using a bladder patch technique from very small pediatric donors Am. J. Transpl. 2010 10 2168 2172 10.1111/j.1600-6143.2010.03229.x 20883550 \n4. Waldner M. Bachler T. Schadde E. Schiesser M. Immer F. Clavien P.A. Brockmann J.G. New surgical technique for pediatric en-bloc kidney and pancreas transplantation: The pancreas piggy-back Transpl. Int. 2013 26 30 33 10.1111/j.1432-2277.2012.01569.x 23072376 \n5. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics Bone Marrow Transpl. 2013 48 452 458 10.1038/bmt.2012.244 23208313 \n6. Nghiem D.D. Corry R.J. Cottington E.M. Function of simultaneous kidney and pancreas transplants from pediatric donors Transplantation 1989 47 1075 1079 2660348 \n7. Abouna G.M. Kumar M.S. Miller J.L. Rose L.I. Brezin J. Chvala R. Lyons P. Katz S.M. McSorley M. Combined kidney and pancreas transplantation from pediatric donors into adult diabetic recipients Transpl. Proc. 1994 26 441 442 \n8. Van der Werf W.J. Odorico J. D’Alessandro A.M. Knechtle S. Becker Y. Collins B. Pirsch J. Hoffman R. Sollinger H.W. Utilization of pediatric donors for pancreas transplantation Transpl. Proc. 1999 31 610 611 10.1016/S0041-1345(98)01578-4 \n9. Rhein T. Metzner R. Uhlmann D. Serr F. Caca K. Weinert D. Hauss J. Witzigmann H. Pediatric donor organs for pancreas transplantation: An underutilized resource? Transplant. Proc. 2003 35 2145 2146 10.1016/S0041-1345(03)00749-8 14529870 \n10. Fernandez L.A. Turgeon N.A. Odorico J.S. Leverson G. Pirsch J.D. Becker B.N. Chin L.T. Becker Y.T. Knechtle S.J. Foley D.P. Superior long-term results of simultaneous pancreas-kidney transplantation from pediatric donors Am. J. Transpl. 2004 4 2093 2101 10.1046/j.1600-6143.2004.00599.x \n11. Pelletier S.J. Guidinger M.K. Merion R.M. Englesbe M.J. Wolfe R.A. Magee J.C. Sollinger H.W. Recovery and utilization of deceased donor kidneys from small pediatric donors Am. J. Transpl. 2006 6 1646 1652 10.1111/j.1600-6143.2006.01353.x 16827866 \n12. Mazor R. Baden H.P. Trends in pediatric organ donation after cardiac death Pediatrics 2007 120 e960 e966 10.1542/peds.2006-3550 17908751 \n13. Illanes H.G. Quarin C.M. Maurette R. Sanchez N.G. Reniero L. Casadei D.H. Use of small donors (<28 kg) for pancreas transplantation Transpl. Proc. 2009 41 2199 2201 10.1016/j.transproceed.2009.05.025 19715872 \n14. Schenker P. Flecken M. Vonend O. Wunsch A. Traska T. Viebahn R. En bloc retroperitoneal pancreas-kidney transplantation with duodenoduodenostomy using pediatric organs Transpl. Proc. 2009 41 2643 2645 10.1016/j.transproceed.2009.06.113 19715992 \n15. Socci C. Orsenigo E. Santagostino I. Caumo A. Caldara R. Parolini D. Aldrighetti L. Castoldi R. Frasson M. Carvello M. Pancreata from pediatric donors restore insulin independence in adult insulin-dependent diabetes mellitus recipients Transpl. Proc. 2010 42 2068 2070 10.1016/j.transproceed.2010.05.120 \n16. Biglarnia A.R. Bennet W. Nilsson T. Larsson E. Magnusson A. Yamamoto S. Lorant T. Sedigh A. von Zur-Muhlen B. Backman L. Utilization of small pediatric donors including infants for pancreas and kidney transplantation: Exemplification of the surgical technique and the surveillance Ann. Surg. 2014 260 e5 e7 10.1097/SLA.0000000000000751 24854454 \n17. Fisher R.A. Commentary on “Utilization of small pediatric donors including infants for pancreas and kidney transplantation” Ann. Surg. 2014 260 e8 10.1097/SLA.0000000000000752 25350654 \n18. Chiari D. Bissolati M. Gazzetta P.G. Guarneri G. Tomanin D. Maffi P. Secchi A. Rosati R. Socci C. Pancreas Transplantation from Very Small Pediatric Donor Using the “Cephalic Placement” Technique: A Case Report Transpl. Proc. 2016 48 435 437 10.1016/j.transproceed.2016.01.012 \n19. Spaggiari M. Bissing M. Campara M. Yeh C.C. Tzvetanov I. Jeon H. Benedetti E. Pancreas Transplantation from Pediatric Donors: A United Network for Organ Sharing Registry Analysis Transplantation 2017 101 2484 2491 10.1097/TP.0000000000001736 28319566 \n20. Christensen K. Kennedy A. Kim R. Martinez E. Campsen J. Pancreatic Grafts from Pediatric Donors Do Not Appear to Grow After Transplantation into Adults Cureus 2018 10 e3363 10.7759/cureus.3363 30510873 \n21. Spaggiari M. Di Bella C. Di Cocco P. Campara M. Galen K. Gheza F. Oberholzer J. Benedetti E. Tzvetanov I. Pancreas Transplantation from Pediatric Donors: A Single-Center Experience Transplantation 2018 102 1732 1739 10.1097/TP.0000000000002208 29620617 \n22. Dobbs S. Shapey I.M. Summers A. Moinuddin Z. van Dellen D. Augustine T. Simultaneous en-bloc pancreas and kidney transplantation from a small pediatric donor after circulatory death Am. J. Transpl. 2019 19 929 932 10.1111/ajt.15044 30063123 \n23. Aida N. Kenmochi T. Ito T. Nishikawa T. Hiratsuka I. Shibata M. Suzuki A. Hasegawa M. Kawai A. Kusaka M. Prediction of Insulin Secretion Ability with Microcirculation Evaluated by Contrast-enhanced Ultrasonography in Pancreas Transplantation Pancreas 2018 47 617 624 10.1097/MPA.0000000000001051 29683975 \n24. Kayler L.K. Magliocca J. Fujita S. Kim R.D. Zendejas I. Hemming A.W. Howard R. Schold J.D. Recovery factors affecting utilization of small pediatric donor kidneys Am. J. Transpl. 2009 9 210 216 10.1111/j.1600-6143.2008.02447.x 18976301 \n25. Kayler L.K. Magliocca J. Kim R.D. Howard R. Schold J.D. Single kidney transplantation from young pediatric donors in the United States Am. J. Transpl. 2009 9 2745 2751 10.1111/j.1600-6143.2009.02809.x 20021480\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "8(9)",
"journal": "Journal of clinical medicine",
"keywords": "brain-dead donor; pancreas transplantation; pediatric donor",
"medline_ta": "J Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101606588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31487959",
"pubdate": "2019-09-04",
"publication_types": "D016428:Journal Article",
"references": "25350654;10083258;19715872;23072376;28319566;20021480;17908751;20692410;7513453;2660348;29683975;24854454;15575914;15023161;18976301;16827866;27109972;23208313;30510873;14529870;20883550;30063123;29620617;19715992",
"title": "The Outcomes of Pancreatic Transplantation from Pediatric Donors-A Single Institution Experience.",
"title_normalized": "the outcomes of pancreatic transplantation from pediatric donors a single institution experience"
} | [
{
"companynumb": "NVSC2019JP068254",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
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{
"abstract": "Összefoglaló. A Bruton-féle tirozin-kinázt gátló ibrutinib és a B-sejtes lymphoma-2-t gátló venetoklax a krónikus lymphoid leukaemia (CLL) kezelésének egyre korábbi vonalában alkalmazható, és ezek mellett a progressziómentes túlélés növekedése figyelhető meg. A célzott kismolekulákkal végzett kezelés nemcsak a CLL lefolyását, de a betegek gondozását is alapvetően megváltoztatta. A tartósan adagolt orális szerek mellett a betegek nagyobb valószínűséggel jelennek meg a panaszaiknak megfelelő szakrendeléseken. Az új típusú szerek hatásai és mellékhatásai mellett az alapvető gyógyszer-interakciókra is fel kell hívni a figyelmet. Kiemelt fontosságú az ibrutinib hypertoniát provokáló hatása, illetve a 6-16%-ban megjelenő pitvarfibrilláció. Ez utóbbi ellátását a gyógyszer-interakciókon túl az ibrutinib vérzékenységet okozó hatása is nehezíti. A CLL-lel, illetve annak kezelésével kapcsolatos ismeretek a másodlagos daganatok, néhány gastrointestinalis és bőrgyógyászati betegség megközelítése szempontjából is fontosak. A venetoklax mellett potenciálisan kialakuló tumorlízis-szindróma alkalmanként a nefrológusok bevonását igényli. A betegek gondozása, megfelelő szakszerű ellátása és a betegutak optimalizálása érdekében a háziorvosok, a sürgősségi ellátók és az egyéb szakellátó helyek szoros együttműködése szükséges szakorvosi konzultáció keretei között. Orv Hetil. 2021; 162(9): 336-343. Summary. Chronic lymphocytic leukemia (CLL) is ubiquitously treated with novel agents. The Bruton's tyrosine kinase inhibitor ibrutinib and the B-cell lymphoma 2 inhibitor venetoclax can be used increasingly in earlier lines of treatment with improved progression-free survival. Treatment with targeted small molecules fundamentally changed not only the course of CLL but also the care of patients. With the administration of long-term oral medications, patients are more likely to show up at specialist clinics that match their complaints. In addition to the effects and side effects of the new drugs, attention should also be drawn to basic drug interactions. The effect of ibrutinib on blood pressure and the ability to provoke atrial fibrillation in 6-16% of cases are of paramount importance. In addition to drug interactions, the treatment of the latter is also complicated by the hemorrhagic effect of ibrutinib. Knowledge on CLL and its treatment is also important in the approach to secondary tumors, some gastrointestinal and dermatological diseases. The potential for tumor lysis syndrome of venetoclax requires close collaboration with nephrologists. In order to provide appropriate professional care and optimize patient pathways, close co-operation between GPs, emergency care providers and other specialist care facilities is required within the framework of professional consultation. Orv Hetil. 2021; 162(9): 336-343.",
"affiliations": "1 Debreceni Egyetem, Általános Orvostudományi Kar, Belgyógyászati Intézet, Hematológiai Tanszék, Debrecen, Nagyerdei krt. 98., 4032.;1 Debreceni Egyetem, Általános Orvostudományi Kar, Belgyógyászati Intézet, Hematológiai Tanszék, Debrecen, Nagyerdei krt. 98., 4032.",
"authors": "Szász|Róbert|R|;Illés|Árpád|Á|",
"chemical_list": null,
"country": "Hungary",
"delete": false,
"doi": "10.1556/650.2021.31948",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-6002",
"issue": "162(9)",
"journal": "Orvosi hetilap",
"keywords": "chronic lymphocytic leukemia; ibrutinib; idelalisib; idelaliszib; kezelés; krónikus lymphoid leukaemia; therapy; venetoclax; venetoklax",
"medline_ta": "Orv Hetil",
"mesh_terms": "D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D010348:Patient Care Team",
"nlm_unique_id": "0376412",
"other_id": null,
"pages": "336-343",
"pmc": null,
"pmid": "33640875",
"pubdate": "2021-02-28",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Interdisciplinary approach to the current management of chronic lymphocytic leukemia",
"title_normalized": "interdisciplinary approach to the current management of chronic lymphocytic leukemia"
} | [
{
"companynumb": "HU-ABBVIE-21K-076-3902042-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "HU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBRUTINIB"
},
"drugadditional": "3",
... |
{
"abstract": "While many guidelines recommend a 10-day course of oral erythromycin following preterm prelabour rupture of membranes (PPROM) as derived from the ORACLE I trial, evidence is emerging that this may encourage a state of antenatal genital tract dysbiosis. In addition, erythromycin's lack of efficacy toward Gram-negative microorganisms may promote colonisation and infection, conveying more significant unrecognised risk for very and extremely preterm newborns.\n\n\n\nTo define patterns of placental infection or colonisation in newborns born before 30 completed weeks gestation following PPROM.\n\n\n\nRetrospective cohort study of mother-infant dyads who delivered at < 30 completed weeks gestation following PPROM in a South Australian tertiary perinatal centre between January 2012 and December 2015. Main outcome measures included placental and neonatal culture and sensitivities within 72 h of delivery and histologic chorioamnionitis. Categorical characteristics were analysed using two-sided Fisher's exact test and numerical characteristics via analysis of variance.\n\n\n\nDuring the four years studied, 126 infant-mother dyads were identified. Where a placental swab was taken, 23.9% cultured Gram-negative organisms and the majority (58.8%) were antimicrobial-resistant. Those that received erythromycin had increased incidence of antimicrobial-resistant Gram-negative organisms on placental swab (P = 0.02). All cases of neonatal early-onset sepsis (EOS), including two cases of multi-resistant Gram-negative EOS, occurred in those who received erythromycin.\n\n\n\nThe current antibiotic recommendations for PPROM may promote selection of unhindered antimicrobial-resistant Gram-negative organisms and may increase risk of Gram-negative EOS in very and extremely preterm newborns. Further wide-scale examination of antibiotic recommendations in PPROM is necessary.",
"affiliations": "Department of Neonatal Medicine, Women's and Children's Hospital, Adelaide, South Australia, Australia.;Department of Neonatal Medicine, Women's and Children's Hospital, Adelaide, South Australia, Australia.;Department of Neonatal Medicine, Women's and Children's Hospital, Adelaide, South Australia, Australia.",
"authors": "Axford|Samuel B|SB|0000-0002-7106-316X;Andersen|Chad C|CC|;Stark|Michael J|MJ|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajo.13087",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-8666",
"issue": "60(4)",
"journal": "The Australian & New Zealand journal of obstetrics & gynaecology",
"keywords": "Gram-negative; antimicrobial resistance; dysbiosis; erythromycin; preterm prelabour rupture of membrane",
"medline_ta": "Aust N Z J Obstet Gynaecol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001315:Australia; D024881:Drug Resistance, Bacterial; D005260:Female; D005322:Fetal Membranes, Premature Rupture; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D011256:Pregnancy Outcome; D047928:Premature Birth; D012189:Retrospective Studies",
"nlm_unique_id": "0001027",
"other_id": null,
"pages": "509-513",
"pmc": null,
"pmid": "31650540",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Patterns of placental antimicrobial resistance in preterm birth before 30 completed weeks gestation complicated by preterm prelabour rupture of membranes.",
"title_normalized": "patterns of placental antimicrobial resistance in preterm birth before 30 completed weeks gestation complicated by preterm prelabour rupture of membranes"
} | [
{
"companynumb": "AU-MYLANLABS-2020M1085491",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ERYTHROMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "This study reports the treatment and local control of advanced breast cancer with a giant ulcer. A 53-year-old woman presented with a large left breast tumor and an associated giant ulcer, with massive exudates, bleeding, and an offensive odor. Histopathological examination revealed an invasive ductal carcinoma(Luminal B type). Computed tomography(CT) showed multiple metastases to the lymph nodes, lungs, liver and bones. The patient received chemotherapy with a combina- tion of paclitaxel(PTX 90mg/m / 2)and bevacizumab(BEV 10 mg/kg). After 4 courses of chemotherapy, there was a significant reduction in the tumor size, the discharge of exudates and bleeding as well as lumbago and femoral pain. High CEA and CA15-3 levels had been normalized and CT showed a remarkable decrease in metastases. Compared to the tumor itself, the ulcer associated with it had shown a smaller decrease in size, and there was the possibility of perforation in the thin chest wall. Suspecting these outcomes to the adverse events of BEV, its use was discontinued, and starting with course 5 of chemothera- py, we administrated only PTX(90mg/m2). Subsequently, the ulcer showed obvious granulation and was infected. CT of the chest prior to the second course of PTX revealed pleurisy, pneumonia and atelectasis. Following the administration of antibiotics, while infection in the ulcer had subsided, pleurisy and pneumonia continued, with increased right pleural effusion, which finally required drainage. We had to discontinue the administration of PTX. BEV, although effective as first-line therapy, has the adverse effect of slowing wound healing. Therefore, even though the combination therapy of BEV and PTX is markedly effective for systemic therapy, it should be altered for local wound healing as in this case.",
"affiliations": "Dept. of Breast Surgery, Kansai Medical Hospital.",
"authors": "Inoue|Tomoo|T|;Shimomura|Atsushi|A|;Sugimoto|Takuji|T|;Wakamiya|Shiori|S|;Chou|Ukou|U|;Fujiwara|Akira|A|;Uchikoshi|Fumihiro|F|;Watanabe|Tarou|T|;Kitamura|Natsuko|N|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "44(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D001706:Biopsy; D001943:Breast Neoplasms; D044584:Carcinoma, Ductal; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D014456:Ulcer",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1062-1064",
"pmc": null,
"pmid": "29394534",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Local Control of Advanced Breast Cancer with Giant Ulcer.",
"title_normalized": "local control of advanced breast cancer with giant ulcer"
} | [
{
"companynumb": "JP-ROCHE-1982795",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
"dru... |
{
"abstract": "Ovarian cancer is the leading cause of death among gynecologic malignancies. Combining cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) can benefit patients with advanced ovarian cancer. We evaluate the role of small bowel peritoneal cancer index (sb-PCI) score as a prognostic factor. We retrospectively analyzed characteristics and clinical outcomes of patients that underwent intermediate cytoreductive surgery combined with HIPEC after neoadjuvant chemotherapy and patient's characteristics underwent debulking surgery plus HIPEC for recurrence disease. One hundred thirty patients were included. Eighty-five of them (65.4%) were treated for recurrent ovarian cancer, while 45 (34.6%) underwent intermediate cytoreductive surgery after neoadjuvant chemotherapy with a mean age of 52 years. Mean intraoperative peritoneal cancer index (PCI) was 11.84 with a mean sb-PCI score of 5.57. Univariate analysis revealed that PCI, sb-PCI, and completeness of cytoreduction (CC) were parameters that correlated significantly with overall survival, while after multivariate analysis sb-PCI and CC were identified as independent prognostic factors of survival. A statistically significant correlation between sb-PCI score and overall survival of patients with advanced ovarian cancer was revealed. Further larger future studies are required to confirm our conclusion in order to change the treatment of advanced ovarian cancer patients.",
"affiliations": "Department of Gynecological Oncology, Metaxa Cancer Hospital, 51, Botasi Str., Piraeus, Greece.;Department of Gynecological Oncology, Metaxa Cancer Hospital, 51, Botasi Str., Piraeus, Greece.;Department of Gynecological Oncology, Metaxa Cancer Hospital, 51, Botasi Str., Piraeus, Greece.;Department of Gynecological Oncology, Metaxa Cancer Hospital, 51, Botasi Str., Piraeus, Greece.;Plastic Surgery Department, Southmead Hospital, Bristol, UK.;Department of Surgical Oncology and HIPEC, Athens Medical Centre, Athens, Greece.",
"authors": "Iavazzo|Christos|C|;Fotiou|Alexandros|A|0000-0003-2428-3992;Psomiadou|Victoria|V|;Lekka|Sofia|S|;Katsanos|Dimitrios|D|;Spiliotis|John|J|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s13193-021-01304-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0975-7651",
"issue": "12(2)",
"journal": "Indian journal of surgical oncology",
"keywords": "Cytoreductive surgery; Hyperthermic intraperitoneal chemotherapy (HIPEC); Ovarian cancer; Overall survival; Peritoneal cancer index (PCI); Small bowel peritoneal cancer index (sb-PCI)",
"medline_ta": "Indian J Surg Oncol",
"mesh_terms": null,
"nlm_unique_id": "101532448",
"other_id": null,
"pages": "258-265",
"pmc": null,
"pmid": "34295068",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "25391263;11870167;28830230;29324538;31101436;31744887;31118829;1234624;17617518;29887688;16239238;25061539;26051329;17072675;28468520;27594911;16515565;18083650;20818904;20864305;29342393;25376916;9887245;28540829;27065704;20336386;22494563;10549956;25019568;21757333;25086990;29873689;20734422;30207593;31937926;16515561",
"title": "Small Bowel PCI Score as a Prognostic Factor of Ovarian Cancer Patients Undergoing Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC), a Retrospective Analysis of 130 Patients.",
"title_normalized": "small bowel pci score as a prognostic factor of ovarian cancer patients undergoing cytoreductive surgery crs with hyperthermic intraperitoneal chemotherapy hipec a retrospective analysis of 130 patients"
} | [
{
"companynumb": "GR-TEVA-2021-GR-1989559",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "4",
... |
{
"abstract": "Dexmedetomidine is a promising sedative and analgesic for newborns with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Pharmacokinetics and safety of dexmedetomidine were evaluated in a phase I, single-center, open-label study to inform future trial strategies. We recruited 7 neonates ≥36 weeks' gestational age diagnosed with moderate-to-severe HIE, who received a continuous dexmedetomidine infusion during TH and the 6 h rewarming period. Time course of plasma dexmedetomidine concentration was characterized by serial blood sampling during and after the 64.8 ± 6.9 hours of infusion. Noncompartmental analysis yielded descriptive pharmacokinetic estimates: plasma clearance of 0.760 ± 0.155 L/h/kg, steady-state distribution volume of 5.22 ± 2.62 L/kg, and mean residence time of 6.84 ± 3.20 h. Naive pooled and population analyses according to a one-compartment model provided similar estimates of clearance and distribution volume. Overall, clearance was either comparable or lower, distribution volume was larger, and mean residence time or elimination half-life was longer in cooled newborns with HIE compared to corresponding estimates previously reported for uncooled (normothermic) newborns without HIE at comparable gestational and postmenstrual ages. As a result, plasma concentrations in cooled newborns with HIE rose more slowly in the initial hours of infusion compared to predicted concentration-time profiles based on reported pharmacokinetic parameters in normothermic newborns without HIE, while similar steady-state levels were achieved. No acute adverse events were associated with dexmedetomidine treatment. While dexmedetomidine appeared safe for neonates with HIE during TH at infusion doses up to 0.4 μg/kg/h, a loading dose strategy may be needed to overcome the initial lag in rise of plasma dexmedetomidine concentration.",
"affiliations": "Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.;Department of Pharmacy, Seattle Children's Hospital, Seattle, WA, USA.;Clinical Pharmacology Sciences, Eisai Inc., Woodcliff Lake, NJ, USA.;Pharmacokinetics Laboratory, Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.;Pharmacokinetics Laboratory, Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA.",
"authors": "McAdams|Ryan M|RM|https://orcid.org/0000-0002-9579-1698;Pak|Daniel|D|;Lalovic|Bojan|B|;Phillips|Brian|B|;Shen|Danny D|DD|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/2582965",
"fulltext": "\n==== Front\nAnesthesiol Res Pract\nAnesthesiol Res Pract\nARP\nAnesthesiology Research and Practice\n1687-6962 1687-6970 Hindawi \n\n10.1155/2020/2582965\nClinical Study\nDexmedetomidine Pharmacokinetics in Neonates with Hypoxic-Ischemic Encephalopathy Receiving Hypothermia\nhttps://orcid.org/0000-0002-9579-1698McAdams Ryan M. mcadams@pediatrics.wisc.edu\n1\n Pak Daniel \n2\n Lalovic Bojan \n3\n Phillips Brian \n4\n Shen Danny D. \n4\n \n1Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA\n\n2Department of Pharmacy, Seattle Children's Hospital, Seattle, WA, USA\n\n3Clinical Pharmacology Sciences, Eisai Inc., Woodcliff Lake, NJ, USA\n\n4Pharmacokinetics Laboratory, Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA\nAcademic Editor: Ronald G. Pearl\n\n\n2020 \n25 2 2020 \n2020 25829659 4 2019 26 12 2019 16 1 2020 Copyright © 2020 Ryan M. McAdams et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Dexmedetomidine is a promising sedative and analgesic for newborns with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Pharmacokinetics and safety of dexmedetomidine were evaluated in a phase I, single-center, open-label study to inform future trial strategies. We recruited 7 neonates ≥36 weeks' gestational age diagnosed with moderate-to-severe HIE, who received a continuous dexmedetomidine infusion during TH and the 6 h rewarming period. Time course of plasma dexmedetomidine concentration was characterized by serial blood sampling during and after the 64.8 ± 6.9 hours of infusion. Noncompartmental analysis yielded descriptive pharmacokinetic estimates: plasma clearance of 0.760 ± 0.155 L/h/kg, steady-state distribution volume of 5.22 ± 2.62 L/kg, and mean residence time of 6.84 ± 3.20 h. Naive pooled and population analyses according to a one-compartment model provided similar estimates of clearance and distribution volume. Overall, clearance was either comparable or lower, distribution volume was larger, and mean residence time or elimination half-life was longer in cooled newborns with HIE compared to corresponding estimates previously reported for uncooled (normothermic) newborns without HIE at comparable gestational and postmenstrual ages. As a result, plasma concentrations in cooled newborns with HIE rose more slowly in the initial hours of infusion compared to predicted concentration-time profiles based on reported pharmacokinetic parameters in normothermic newborns without HIE, while similar steady-state levels were achieved. No acute adverse events were associated with dexmedetomidine treatment. While dexmedetomidine appeared safe for neonates with HIE during TH at infusion doses up to 0.4 μg/kg/h, a loading dose strategy may be needed to overcome the initial lag in rise of plasma dexmedetomidine concentration.\n\nSeattle Children's Hospital Academic Enrichment Fund\n==== Body\n1. Introduction\nWorldwide, hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal brain injury and neonatal mortality [1]. In high-income countries, therapeutic hypothermia (TH) is the standard therapy to mitigate brain damage in newborns with HIE. While TH appears to increase survival without increasing major disability in survivors, 1 in 4 neonates with moderate-to-severe HIE die despite receiving TH [2]. Newborns with moderate-to-severe HIE often have multiorgan failure and may demonstrate seizures, respiratory failure, and cardiovascular instability. They commonly receive morphine for sedation and to prevent shivering [3]. However, efficacy of morphine as an adjunctive therapy during TH has not been evaluated in clinical trials. Morphine also requires dosing adjustments to avoid toxicity due to altered pharmacokinetics during TH [4]. Safety concerns with morphine include short-term side effects such as depressed ventilation and questionable effects on long-term neurodevelopmental outcomes [5–7].\n\nDexmedetomidine, a highly lipophilic α2-adrenergic receptor agonist metabolized in the liver and primarily excreted by the kidney, may be a promising alternative to morphine for newborns with HIE treated with TH. Dexmedetomidine provides sedation and prevents shivering but does not suppress ventilation [8–11]. Information on the safety and efficacy of dexmedetomidine in infants is limited, and the drug is not approved for this age group by the Food and Drug Administration. However, dexmedetomidine is increasingly being used off-label for sedation in infants [11–14]. Considerable variation in dexmedetomidine dosing has been reported in studies involving infants, ranging from 0.05 to 1 μg/kg for loading dose and from 0.1 to 2.5 μg/kg/h for continuous infusion [12, 13, 15–17]. Although pharmacokinetic-pharmacodynamic data to inform dexmedetomidine dosing in neonates are limited, available studies have demonstrated decreased dexmedetomidine clearance in infants compared to adults [13, 15, 17].\n\nCurrently, dexmedetomidine pharmacokinetic data in neonates with HIE receiving hypothermia are lacking and pharmacokinetic data from cooled neonatal animals [14, 18] are insufficient to guide clinical practice. Neonates with HIE receiving TH often have altered pharmacokinetics and dosing needs [4, 19, 20]. In the setting of neonatal HIE, whether hypoxia-induced liver injury and hypothermia alter dexmedetomidine pharmacokinetics remains unknown. Therefore, the overall objective of the current prospective clinical study is to evaluate the pharmacokinetics and safety of dexmedetomidine in neonates with HIE receiving TH, which will inform the design of future clinical efficacy trials in this population. The pharmacokinetic portion of the trial is aimed primarily on the question of whether dexmedetomidine pharmacokinetics in HIE neonates undergoing TH differ from those reported for normothermic, non-HIE neonates and secondarily to provide initial pharmacokinetic data in designing a comprehensive population PK-PD study later in a larger patient population.\n\n2. Methods\n2.1. General Study Design\nThis study received Seattle Children's Hospital Institutional Review Board approval and was registered with the US Food and Drug Administration (Investigational New Drug 127874) and ClinicalTrials.gov (NCT02529202). Informed parental consent was obtained for each neonate enrolled. This is a phase I, single-center, prospective, open-label clinical study of dexmedetomidine pharmacokinetics and safety in neonates with HIE receiving TH. This study was conducted in Seattle Children's Hospital level IV neonatal intensive care unit (NICU), a center with expertise in caring for outborn neonates with HIE and using TH.\n\n2.2. Patients\nThe study population consisted of intubated neonates who were ≥36 weeks' gestational age, diagnosed with moderate-to-severe perinatal HIE, and treated with TH (target temperature 33.5°C) for a planned duration of 72 h. Neonates meeting inclusion and exclusion criteria were enrolled consecutively. Criteria for TH were similar to those in the CoolCap [21] or National Institute of Child Health and Human Development studies [22]. Intubated neonates could be extubated any time during the study period at the discretion of the neonatology team. Exclusion criteria included known chromosomal anomalies, cyanotic congenital heart defects, lack of an indwelling central intravenous line, neonates participating in another clinical trial, neonates who received dexmedetomidine prior to study enrollment, withdrawal of care being considered because of moribund condition, or a decision made to withhold full support.\n\n2.3. Dexmedetomidine Administration\nThe study drug, dexmedetomidine hydrochloride injection (100 mg/mL base), was administered in a primed intravenous line via a computer-controlled infusion device programmed by trained NICU nurses. At the time of study, the Seattle Children's Hospital Pharmacy and Therapeutics Committee had established a dexmedetomidine dosing range of 0.2–1.2 μg/kg/h in critical care areas. For the current study, a maximum dexmedetomidine dose of 0.4 μg/kg/h was used, a dose that was well tolerated without significant adverse side effects based on our clinical experience with normothermic neonates. Given that all potential study candidates were outborn neonates, the window for enrollment was within the first 24 h after TH was started. After study enrollment, dexmedetomidine infusion was started at 0.2 μg/kg/h, increased to 0.3 μg/kg/h after one hour, then increased to 0.4 μg/kg/h after 2.5 h, and maintained at that dose until the neonate had completed the 6 h rewarming period following 72 h of TH. After rewarming and once normothermia was reestablished, dexmedetomidine was discontinued without weaning the dose. Adjustment of the dexmedetomidine dose (i.e., decreasing or holding the dose) during TH was based on the discretion of the treating clinical team. Open-label morphine was available for rescue analgesia or to prevent shivering as per the discretion of the medical team. The incidence, dose, and duration of treatment with adjunctive sedation medications were recorded.\n\n2.4. Pharmacokinetic Sampling\nThe blood-sampling schedule was designed to capture the rise in blood dexmedetomidine concentration during the titration phase, the maximum or plateau level reached during maintenance infusion, and the washout kinetics after discontinuation. A total of 17 blood samples (0.3 mL whole blood each) were collected from each neonate's central line, which was in three periods: a single baseline sample (1) prior to dexmedetomidine initiation, (2) during dexmedetomidine infusion at 15, 30, 60, 120, 180, and 270 min and 6, 10, 24, and 48 h after start of infusion, and (3) at 0, 1, 2, 4, 18, and 42 h after dexmedetomidine discontinuation. The dexmedetomidine infusion occurred in a separate intravenous line from the neonate's central line, where blood samples were drawn. Over the 5-day (120 h) study period, a total blood volume of up to 5.1 mL (17 × 0.3 mL) was withdrawn for research purposes. Blood samples were collected in 1 mL sterile cryogenic vials (Globe Scientific CryoClear™ vials, Paramus, New Jersey); plasma was separated by centrifuging sample vials at 1,200 rpm for 15 min, then frozen, and stored at −80°C in 1 mL sterile cryogenic vials for subsequent analysis.\n\n2.5. Analytical Quantification\nA sensitive liquid chromatography-tandem mass spectrometry method was developed for analyzing dexmedetomidine concentration in 100 μL volume of plasma. Dexmedetomidine and the internal standard medetomidine-d3 (Toronto Research Chemicals, Toronto, ON) were extracted from plasma samples using Bond Elut Certify cartridges (Agilent Technologies, Santa Clara, CA). For chromatographic separation, extracts were injected onto a Restek Ultra Aqueous C18 column, 2.1 mm × 200 mm × 5 μ (Bellefonte, PA), operated with an isocratic mobile phase consisting of a 45 : 55 mix of 0.1% formic acid in water (mobile phase A) and methanol (mobile phase B) at a flow rate of 0.25 mL/min and temperature of 35°C. For quantification, the eluent was directed to an AB Sciex 6500 Q-Trap triple-quadrupole mass spectrometer using an electrospray ion source operating in the positive ion mode. Transitions for single reaction monitoring of dexmedetomidine and internal standard are detailed in Supplementary . Quality control samples were run with each batch of plasma samples. The lower limit of quantitation was 1 ± 0.6 pg/mL. The interday coefficient of variation was <7% for both the low and high QCs.\n\n2.6. Pharmacokinetic Analysis\nTwo types of pharmacokinetic analyses were performed, i.e., an initial noncompartmental (descriptive) analysis followed by naïve pooled and initial population-based compartmental modeling.\n\nPlasma concentration data collected during and after discontinuing dexmedetomidine infusion in each of the 7 HIE newborns were subject to noncompartmental analysis. The highest observed plasma dexmedetomidine concentration (Cmax (pg/mL)) and time of its occurrence (Tmax (h)) during dexmedetomidine infusion were noted. The decline in plasma concentration with time after discontinuing the dexmedetomidine infusion was fitted to either a monoexponential or biexponential function to yield an estimate of terminal exponential rate constant (λz (h−1)) using the numerical module of SAAM II (v2.0; University of Washington, Seattle, WA). Area under the plasma concentration-time curve from time zero (i.e., infusion start time) to time infinity (AUC0–∞ (pg/mL·h)) was calculated by a linear trapezoidal rule up to the last sampling time, and area beyond the last observed concentration (Clast) was extrapolated by Clast/λz. Plasma clearance (CLcor (L/h/kg)) was calculated by the total dose infused/AUC0–∞; the infused dose was corrected for sorptive loss of dexmedetomidine to microbore tubing (see below). Area under the first moment curve (AUMC0–∞ (pg/mL·h [2])) was also calculated by a linear trapezoidal rule up to the last sampling time, and area beyond was extrapolated as the sum of Clast·tlast/λz and Clast/λz2. The mean residence time (MRT (h)) was calculated from the ratio of AUMC0–∞ and AUC0-∞ corrected for infusion time (i.e., Tinf/2). Steady-state distribution volume (Vss) was further calculated from the product of MRT and CLcor.\n\nThe available set of dexmedetomidine pharmacokinetic data for the 7 HIE newborns was then analyzed by nonlinear mixed-effects (population) modeling. The analysis was performed using NONMEM software (version 7.4.1; ICON Development Solutions, Ellicott City, MD) using the first-order conditional estimation method with residual variability (η–ε) interaction (FOCEI). Given the small dataset, a naïve pooled analysis was initially performed and subsequently expanded to include a random-effect parameter. The objective function value (OFV, the −2 log likelihood) was used to judge goodness of fit when comparing nested models. While the difference in model OFVs (ΔOFV) is often assumed to approximate a chi-squared distribution, the assumption may not apply to the current small dataset; hence, no critical ΔOFV for a given level of probability significance was assumed. In addition to consideration of standard nonlinear mixed-effects diagnostics, the model condition number (ratio of the largest to the smallest eigenvalue of the variance-covariance matrix) served as a guide against overparametrization (i.e., models with a high degree of collinearity amongst model parameters); only models with condition number below 1000 were considered acceptable [23].\n\nTwo additional adjustments to the population model were implemented. First, as dictated by the clinical circumstance and as allowed under the study protocol, dexmedetomidine infusion deviated from protocol design in three of the 7 subjects; hence, dosing input consisting of escalating, body weight-normalized constant-rate (0-order) infusion was individually specified according to the record of dexmedetomidine infusion. Furthermore, the input rate of dexmedetomidine was corrected for loss due to sorption to microbore tubing as described in a later section. Additionally, dexmedetomidine concentrations in 14.7% of samples, those primarily collected early on during dexmedetomidine infusion, fell below the lower limit of quantification likely due to sorptive loss and slow accumulation. Therefore, we examined the impact of censoring of dexmedetomidine pharmacokinetic data based on the “NONMEM M3 method” [24, 25].\n\nBoth one-compartment and two-compartment models were initially evaluated; the reasonableness and precision of the parameter estimates, as well as several graphical goodness-of-fit diagnostic plots, were considered. All covariates were analyzed as univariate predictors of dexmedetomidine clearance or distribution volume in a stepwise process; they included body weight, gestational and postmenstrual ages, serum alanine transferase (ALT), and maximum creatinine concentration (CrMax). Two physiologically relevant covariates on either clearance or distribution volume were also evaluated: duration of cooling prior to initiation of dexmedetomidine infusion and variation of body temperature over the course of study. It should be noted that addition of either of these covariates would result in changes in clearance or distribution volume over time; hence, this was an attempt to discern the presence of time-varying or nonstationary dexmedetomidine pharmacokinetics as a result of hypothermia and rewarming. A more empirical approach to modeling such time-varying pharmacokinetic processes was also attempted by allowing either exponential or linear change in clearance or distribution volume over time.\n\nPharmacokinetic data and the NONMEM code for the modeling analyses are available to other investigators upon request.\n\n2.7. Infusate Sampling to Assess Microbore Tubing Dexmedetomidine Sorption\nIn 4 of the 7 cooled neonates with HIE, plasma dexmedetomidine concentration remained low or undetectable during the initial 1 to 3 hours of infusion, which led to the question of whether some portion of the dexmedetomidine dose may be lost through sorption to intravenous tubing during dexmedetomidine infusion. To test this possibility, infusates were serially collected in three mock infusion experiments performed with an intravenous pump and tubing setup identical to the setup used with all 7 cooled neonates with HIE in the study. An Alaris model 8100 infusion pump (CareFusion, San Diego, CA) driven by an Alaris model 8015 PC unit was coupled to a microbore tubing (213 cm in length) extension set (CareFusion) using MaxZero minibore extension set intravenous connectors (CareFusion).\n\nFor experiment 1, a time zero sample was taken from the dexmedetomidine syringe and 8 additional infusate samples were collected from the outflow of the microbore tubing at times corresponding to the clinical study time points through the first 6 h of dexmedetomidine infusion. For experiments 2 and 3, preinfusion samples were drawn from the dexmedetomidine syringe and immediately from the outflow after priming the microbore tubing. Serial collection of the outflow infusate was extended to 18 h and included 12 total time points to capture the sorptive loss beyond the titration phase and into the plateau phase during maintenance infusion. At the end of all three experiments, a sample of the infusate left in the syringe was collected immediately upon stopping the infusion pump. Any loss in dexmedetomidine while the infusate was held in the syringe or flowing through the microbore tubing was expressed as fraction of nominal concentration (FNC), which is the ratio of assayed concentration in the sampled infusate to the originally prepared concentration of 4 μg/mL. FNC in the serially sampled outflow from the microbore tubing was plotted against time.\n\nIn the noncompartment analysis, for each neonate, the actual dexmedetomidine dose delivered during successive intervals between blood sampling or between change in infusion rate and the next blood sampling was calculated by multiplying the intended infused dose (i.e., nominal infusion rate × interval duration) by the average FNC at the mid-time point as estimated by linear interpolation of the FNC vs. time plot up to the last time point and extrapolation to the time when sorptive loss stopped based on projection of the last two data points (Figure 1). The total delivered dexmedetomidine dose over the duration of TH and rewarming (i.e., Dcor or total dose corrected for sorptive loss to microbore tubing) was calculated by summing the corrected doses from all the successive sampling intervals. Clearance corrected for sorptive loss of infused dose to microbore tubing (CL, L/h/kg) was estimated by Dcor/AUC0–∞.\n\nIn the naïve pooled and population compartmental modeling, dexmedetomidine infusion rates during successive intervals between blood samplings or between the time of a change in infusion rate and the next blood sampling were adjusted for sorptive loss using the F1 parameter in NONMEM, which was assumed to be the same for every individual. Values of F1 were derived from linear interpolation of the plot of the observed FNC over time (Figure 1) to yield FNC estimates at the mid-time points of successive sampling intervals. Also, the time of return to 100% FNC (i.e., ending of sorptive loss) was estimated to be 25.1 h by extrapolation of the last two data points at 12 and 18 h.\n\n2.8. Clinical Assessments\nShivering was assessed and recorded using a modified version of the Bedside Shivering Assessment Scale described by Badjatia et al. that has been validated in brain-injured adults, but not neonates [26]. A 4-point scale was used, which rated shivering as none: no shivering noted (0), mild: shivering localized to the neck and/or chest only (1), moderate: shivering involves upper extremities, plus neck and chest (3), or severe: shivering involves upper and lower extremities, plus neck and chest (4). For any shivering episodes noted during TH, newborn shivering assessment scores were recorded along with the date, time, and duration of the episode and whether morphine was given.\n\nFor each neonate in the study, Neonatal Pain, Agitation, and Sedation Scale (N-PASS) scores were evaluated prior to and during dexmedetomidine exposure to determine sedation and analgesia effectiveness. The N-PASS tool, which has been validated in neonates [27], uses 5 assessment criteria (crying/irritability, behavior/state, facial expression, extremities/tone, and vital signs); each criterion is graded 0, –1, or –2 for sedation and 0, 1, or 2 for pain/agitation. An N-PASS total score >3 was thought to reflect significant pain or agitation, at which point supplemental sedation or analgesia therapy could be administered at the discretion of the medical team.\n\n2.9. Safety Evaluations\nSafety evaluations included continuous heart rate and blood pressure monitoring, laboratory measurements including complete blood count, basic metabolic panel, and liver function tests, and monitoring for any adverse events or serious adverse events. Adverse events included bradycardia (<70 beats per min), hypotension (<32 mm Hg mean arterial pressure), atrial fibrillation and renal failure (creatinine > 1.4 mg/dL), acute respiratory failure (requiring mechanical ventilation), or a central line-associated blood stream infection during dexmedetomidine infusion. Serious adverse events included severe cardiorespiratory decompensation (e.g., sinus arrest) or death related to dexmedetomidine infusion. An Internal Safety Monitoring Committee reviewed the NICU clinical course of all enrolled neonates; their review started after enrollment of the first 4 neonates.\n\n2.10. Statistical Analyses\nGroup data are presented as means ± standard deviations. Mean estimates of descriptive, noncompartmental pharmacokinetic parameters for our cohort of cooled newborns with HIE were compared to a similar set of parameters for normothermic, full-term neonates without HIE reported by Chrysostomou et al. [15] using unpaired, 2-tailed t-tests for samples with unequal variance. Additional comparisons were also conducted with two other parallel sets of individual-level (adjusted for covariates of postmenstrual age and body weight), descriptive pharmacokinetic parameters that were generated from population compartmental models reported by Greenberg et al. [13] and Potts et al. [28] based upon dexmedetomidine pharmacokinetic data collected from mixed populations of neonates, infants, and young children. All calculations were performed using the statistical programming language R [29].\n\n3. Results\nIn total, 7 HIE neonates treated with TH were enrolled in the study. Five other neonates were identified but were not included in the study, three whose parents declined enrollment and two whom the neonatology team deemed likely to have early withdrawal of care due to severe HIE. All infants were cooled to the target temperature of 72 h using whole body cooling; target cooling temperatures were achieved at 5.2 ± 1.6 h after delivery (range: 3.7 to 8.5 h). TH had already begun in all 7 neonates by the time parental consent was obtained; dexmedetomidine infusions were initiated at an average of 14 ± 6.5 h after TH was started (i.e., pre-dexmedetomidine cooling duration, range: 5.5 to 23.8 h). Neonates received dexmedetomidine infusion for an average of 64.8 ± 6.9 h (range: 54.3 to 74 h).\n\n3.1. Time Course of Plasma Dexmedetomidine during and after Infusion\nA total of 94 blood samples were collected for dexmedetomidine pharmacokinetic analyses from the 7 neonates with HIE who underwent TH. The time course of observed plasma drug concentration during and after dexmedetomidine infusion for all 7 neonates with HIE is displayed in Figure 2. In 4 of the 7 neonates, dexmedetomidine concentration in plasma remained low or undetectable over the first few hours. In all subjects, plasma concentrations rose gradually; near plateau levels, ranging from 300 to 900 pg/mL, were approached only after 12 to 24 h of infusion (i.e., >10 h after the final step of infusion to 0.4 μg/kg/h at 2.5 h). Upon discontinuation of dexmedetomidine infusion at 6 h after rewarming, plasma dexmedetomidine concentration declined exponentially and remained detectable up to as long as 43 h after infusion ceased. Descriptive pharmacokinetic parameters derived from the noncompartmental analysis are presented in Table 1.\n\n3.2. Dexmedetomidine Loss to Infusion Tubing\nDue to unexpectedly low plasma concentrations observed during initial hours of dexmedetomidine infusion, mock infusion experiments were conducted to investigate possible drug loss from the intravenous infusion setup. Dexmedetomidine concentrations in samples collected either directly from the syringe or microbore tubing outflow immediately before initiation of infusion or from the syringe at termination of infusion were all close to the nominal concentration of 4 μg/mL; their FNC averaged 0.98 (±0.02). This indicates negligible loss of dexmedetomidine while the infusate was held in the syringe and during quick priming of the microbore tubing.\n\nLoss of dexmedetomidine through sorption to the microbore tubing was observed over the 18 h of infusion (Figure 1). Dexmedetomidine concentration in the outflow infusate declined steadily over the first 6 h; FNC reached a nadir of 0.73 (±0.11). Thereafter, outflow infusate concentration began to recover towards the expected value; by 18 h, FNC had returned to 0.90 (±0.04) when dexmedetomidine sorption apparently became saturated. Linear extrapolation suggests that infusate should attain nominal concentration by 25.1 h. Overall, there was an average 5% cumulative loss of dose delivered over the 54.3 to 74.0 h of dexmedetomidine infusion.\n\n3.3. Pharmacokinetic Modeling\nA one-compartment model incorporating variable, subject-specific infusion rates adequately described the available pharmacokinetic dataset. The model included adjustments for dexmedetomidine infusion rates for the estimated loss to infusion tubing, censoring due to observations below the lower limit of quantification, and additive residual error. The population model was examined after consideration of a naïve pooled fit; similar pharmacokinetic estimates were obtained under both approaches. The population model included a between-subject variability term on K. Use of the “M3 method” to account for censored PK observations at the start of the infusion (most likely on account of sorptive loss) had a negligible impact; parameter estimates differed by <10% when this approach was not used. For the population fit, the random (variance) components of the model featured an additive residual error parameter and included an exponential between-subject variability in the elimination rate parameter (K). As would be expected for a population model with only seven subjects, the between-subject variability was not estimated with high precision. More complex or alternate variance components (such as an additional, proportional residual error parameter or models with the between-subject variability parameter on CL and/or V) did not appreciably improve goodness of fit; that is, these models resulted in only slightly smaller decreases in the OFV and similar goodness-of-fit diagnostics while exhibiting considerably a higher condition number and large SE of parameter estimates.\n\nAs the washout data on a semilogarithmic plot showed convex features in some subjects, we also examined fit of a two-compartment model to the data. The two-compartment model offered only marginal improvements over the one-compartment model counterpart in ΔOFV (−0.8) and goodness-of-fit plots while resulting in a very high condition number (>1000). Under the two-compartment model, dexmedetomidine distribution was predominantly (94%) ascribed to the peripheral compartment (V2), along with a very fast intercompartmental CL (14 L/h/kg), some 20 times higher than the elimination CL from the central compartment (0.69 L/h/kg). The latter observation indicates near collapse of the two-compartment model to the one-compartment model. Hence, the present set of data does not support the use of a two-compartment model.\n\nWe also investigated the possible presence of nonstationarity in dexmedetomidine pharmacokinetics by featuring time-varying model parameters. Per TH protocol body temperature and duration of cooling prior to dexmedetomidine infusion were deemed to represent informative, mechanistic patient-level covariate information, an alternative to the more-commonly employed, empirical, stepwise, linear, or exponential time functions. Inclusion of body temperature as a physiological covariate on CL resulted in a relatively small change in OFV (−2.5) compared to the more empirical stepwise change in CL upon discontinuation of TH (−4.8 ΔOFV) or when CL was assumed to change monoexponentially or linearly after the start of infusion (−13.2 or −14.2 ΔOFV). Incorporation of duration of cooling prior to the start of infusion as a covariate for CL was noted to result in a small OFV decrease (−4.2), and a model exhibiting high SE of the estimate for this parameter. While mechanistically appealing, we cannot conclude that time-varying pharmacokinetics occurred in this small cohort of HIE neonates. Further studies will be required to address this possible complexity of dexmedetomidine pharmacokinetics. At present, the conventional (time-invariant) one-compartment model appears to adequately describe dexmedetomidine pharmacokinetics.\n\nAll the demographic or clinical variables: gestational age, postmenstrual age, body weight, serum CrMax, and serum ALT, when incorporated into the final model as covariates of CL resulted in very small decreases in OFV (<3.4). Models with these covariates on V resulted in even smaller ΔOFVs. In view of the limited number of subjects, the small effect size of these covariate estimates, and a generally high condition number of models with two or more covariates, we concluded that none of these patient-specific factors appear to significantly influence dexmedetomidine pharmacokinetics.\n\n\nTable 2 presents the parameter estimates for both the naïve pooled and population models, along with their absolute and relative standard errors; parameter estimates are similar between the two compartmental modeling approaches. Population estimates of CL and V for the one compartment model, 0.697 L/h/kg and 7.48 L/kg, respectively, are also reasonably consistent with estimates derived from noncompartmental analysis in Table 1. The elimination half-life corresponding to the typical CL and V is 7.3 h.\n\n\nFigure 2 shows the population (typical subject) and individual-level predictions of the one-compartment model; they describe the observed data well. As expected, the naïve pooled model predictions followed the population predictions quite closely. Figure 3 compares the standard goodness-of-fit plots between the population and naïve pooled approaches, indicating that only a very modest improvement in goodness of fit was observed for the population model. Observations, typical subject (population-average) predictions and quantiles of the observed and simulated data are presented as a visual predictive check (VPC) in Figure 4, illustrating that the central tendency of the data is well captured with the current population model.\n\n3.4. Clinical Characteristics\nAll enrolled neonates had moderate-to-severe HIE. The mean gestational age was 39 ± 1.3 weeks and mean birth weight was 3501 ± 588 grams. Most of the neonates were of white race (6/7, plus 1 native Hawaiian/Pacific Islander). Over half (4/7; 57%) of neonates were delivered via emergent cesarean section. Table 3 presents the NICU hospital course characteristics of the study neonates. Five neonates (71%) had a 10-minute APGAR score ≤5. Three (43%) neonates required chest compressions, 2 of whom received epinephrine during newborn resuscitation. Most of the neonates (5/7; 71%) had seizures; 4 had seizures prior to starting dexmedetomidine. One neonate had a single, brief seizure not requiring treatment that occurred 5 h after dexmedetomidine was started; thereafter, no further seizure activity was noted. Four neonates required mechanical ventilation for >12 h, but all the surviving neonates were sent home on room air. Of the 7 neonates in our study, 3 required no inotropic support during dexmedetomidine treatment, and one (patient #2) was weaned off dopamine within 1 h after starting dexmedetomidine. Patient #3, who was titrated off dopamine prior to starting dexmedetomidine, was placed back on dopamine 18 h after starting dexmedetomidine and then was weaned off dopamine 18.5 h later. Patient #5 was placed on dopamine 12 h after starting dexmedetomidine and was weaned off dopamine 27 h later. Patient #1, who had severe HIE with multiorgan failure and was treated with dopamine and epinephrine infusions during dexmedetomidine treatment, continued to require dopamine for 3 additional days after dexmedetomidine was discontinued. This neonate died at 10 days of age after her life support was withdrawn per parental request.\n\nBreakthrough shivering episodes treated with morphine were recorded in 29% (2/6) of neonates during TH. One neonate (patient #4), who had 7 shivering episodes, received 3 total doses of morphine, each for a shivering episode that lasted 5 min. Another neonate (patient #5) had 2 mild shivering episodes (duration not documented) and received a dose of morphine for each episode.\n\nPrior to starting dexmedetomidine, the baseline average N-PASS score ranged between 0 and 2 (63 time points recorded) for patients #2–7 and was −6 (3 time points) for patient #1. During the dexmedetomidine infusion period, 244 N-PASS scores were collected over time. Most neonates were without signs of pain or agitation, with only 3.7% (9/244) of N-PASS scores >3 at any time point. The majority of neonates (85.2%; 208/244 time points) had N-PASS scores between −5 and +3. Of the 11.1% (27/244) of scores between −6 and −10, reflecting deeper sedation levels, most of these (25/27) were accounted for by one neonate with severe global brain injury (patient #1). Patient #7 received 5 morphine doses prior to starting dexmedetomidine and 4 morphine doses while receiving dexmedetomidine during TH for elevated N-PASS scores (≥3). In addition to morphine, lorazepam was used once for placement of a peripherally inserted central catheter (0.05 mg/kg; patient #2) and once for an elevated N-PASS score of 4 (0.1 mg/kg; patient #5). No other benzodiazepines were used while the neonates were receiving dexmedetomidine infusions.\n\n3.5. Adverse Events\nTo assess any study safety concerns, the NICU clinical course of every neonate enrolled in the study was reviewed by the Internal Safety Monitoring Committee during and after study completion. Overall, no adverse events or serious adverse events were associated with dexmedetomidine. No neonates had hypertension or bradycardia episodes associated with dexmedetomidine. Following a dose of lorazepam for placement of a peripherally inserted central catheter, one neonate (patient #2) in our study had a transient bradycardia that prompted a temporary dexmedetomidine rate reduction to 0.3 μg/kg/h; further bradycardic events were not noted after the dexmedetomidine rate was increased back to 0.4 μ/kg/h. During dexmedetomidine treatment, three neonates (patients #1, 3, and 5) had hypotension that was responsive to inotropic support. These three neonates did not have hypotension below the cutoff considered to be an adverse event (<32 mm Hg mean arterial pressure) based on the study safety guidelines approved by the Seattle Children's Hospital Institutional Review Board. None of the neonates had atrial fibrillation or cardiorespiratory decompensation. The one neonate who died suffered from severe multiorgan failure and had care withdrawn electively at 10 days of age, per parental request. None of the 7 neonates had positive blood cultures or central line-associated blood stream infections.\n\n4. Discussion\nThis is the first report of a clinical study on the pharmacokinetics of dexmedetomidine in neonates with HIE undergoing TH. The key question raised in this study was whether the clinical complications of HIE and abnormal physiology induced by TH altered dexmedetomidine pharmacokinetics. We identified three reported studies in the literature that allowed for comparison of our data to findings in non-HIE, normothermic newborns.\n\nThe most comparable set of dexmedetomidine pharmacokinetic data for normothermic term neonates without HIE was reported by Chrysostomou et al. [15] (see summary in Table 1). This was a phase II/III, open-label, multicenter safety, efficacy, and pharmacokinetic study of dexmedetomidine that included 24 term neonates. Evaluable pharmacokinetic data were available from 13 term neonates; they received 3 escalating dexmedetomidine dose levels, including a loading dose (LD, μg/kg) followed by a maintenance dose (MD, μg/kg/h) for a median of 6 h (range, 6–14.4 h): level 1, 0.05/0.05 LD/MD (n = 1); level 2, 0.1/0.1 LD/MD (n = 5); and level 3, 0.2/0.2 LD/MD (n = 7). Chrysostomou et al. reported their findings based on a noncompartmental pharmacokinetic analysis, which are directly comparable to results of our noncompartmental analysis presented in Table 1. The mean clearance (0.91 ± 0.50 L/h/kg) reported by Chrysostomou et al. [15] for normothermic neonates without HIE of similar gestational and premenstrual age was somewhat higher but not statistically different than the mean CL corrected for the sorptive loss in dose (CLcor, 0.76 ± 0.16 L/h/kg) in our cohort of HIE neonates undergoing TH. MRT was shorter (4.26 ± 3.90 vs. 6.84 ± 3.20 h) and Vss was smaller (4.57 ± 4.26 vs. 5.22 ± 2.62 L/kg) in the non-HIE, normothermic cohort; again, neither of these differences reached statistical significance, most likely due to the large variability reported in Chrysostomou's study.\n\nAdditional dexmedetomidine pharmacokinetic data were extracted from studies by Greenberg et al. [13] and Potts et al. [28] in pediatric populations of broader age range (i.e., including infants and young children). The study by Greenberg et al. was an open-label, single-center pharmacokinetic study of dexmedetomidine involving 20 infants (median gestational age of 39 weeks, range 27–40 weeks; postnatal age of 43 days, range 4–203 days), who received continuous dexmedetomidine intravenous infusions (median 1 μg/kg/h, range 0.1–2.5 μg/kg/h), with additional intravenous bolus doses when needed (median 0.5 μg/kg, range 0.1–3.0 μg/kg) [13]. Potts et al. reported a population pharmacokinetic analysis of pooled plasma concentration-time data derived from four earlier (pre-2009) studies on 95 non-HIE pediatric intensive care patients (mean age of 3.8 years), who received either a dexmedetomidine intravenous bolus (1 μg/kg) or infusion (0.2 μg/kg/h) regimen [28].\n\nIn both studies, the investigators performed population pharmacokinetic modeling using premenstrual age and body weight as covariates to account for the influence of age and development. Hence, their models afforded individual-level predictions for non-HIE, normothermic counterparts (external model “controls”) to our 7 neonatal subjects. Figure 5 compares predicted plasma concentration-time profiles based on our present population model for the 7 HIE, hypothermic newborns to those based on the population pharmacokinetic models of Greenberg et al. and Potts et al. for the non-HIE, normothermic counterparts. The models of Greenberg et al. and Potts et al. predicted that dexmedetomidine concentration in normothermic neonates without HIE would rise quickly and reasonably in step with the upward titration in dexmedetomidine infusion rate. The plateau plasma concentrations predicted by the Greenberg model were consistently lower than those predicted by our model, whereas predictions by the Potts model were generally higher. Since plateau or steady-state plasma concentration during intravenous infusion is entirely governed by plasma clearance, the above observations are consistent with the comparison of mean corrected CL observed in our cooled neonates (0.761 ± 0.155 L/h/kg) with those predicted for normothermic counterparts based on the population models of Greenberg et al. (vs. 1.23 ± 0.08 L/h/kg, p < 0.01) and Potts et al. (vs. 0.548 ± 0.032 L/h/kg, p=0.02), as presented in Table 1. The average Cmax predicted by the Greenberg model (304 ± 49 pg/mL) was lower than our observed average by ∼43% (537 ± 180 pg/mL, p=0.02), whereas the average Cmax predicted by the Potts model (670 ± 128 pg/mL) was higher but did not reach statistical significance. Both Greenberg et al. and Potts et al. models predicted significantly shorter MRTs (1.24 ± 0.09 and 3.28 ± 0.19 h vs. 6.84 ± 3.20 h, p < 0.01 and p=0.03, respectively) and smaller Vss (1.51 and 1.79 vs. 5.22 ± 2.62, p < 0.01 and p=0.02, respectively).\n\nOverall, the above analysis suggested some distinction in dexmedetomidine pharmacokinetics between cooled neonates with HIE and normothermic neonates without HIE. Mean dexmedetomidine CL in the current study cohort was comparable to or slightly lower than values for normothermic newborns without HIE reported by Chrysostomou et al. [15] and predicted from the population model of Greenberg et al. [13] (Table 1). In contrast, mean CL for our HIE cohort was higher than that for a corresponding normothermic cohort predicted by the population model of Potts et al. [28]. It should be noted that Potts et al. performed a pooled analysis of earlier literature data collected in mostly older infants (>1 month of age) and young children; there were only 4 neonates out of a study population of 94 subjects. Thus, the Potts population model may be biased towards older infants and children. Therefore, our conclusions should rely largely upon comparisons with the data of Chrysostomou et al. [15] and Greenberg et al. [13]. Our analysis further indicated that HIE newborns undergoing TH have larger distribution volumes and shorter MRTs than anticipated in a comparable cohort of non-HIE, normothermic newborns.\n\nSeveral caveats are worth noting. First, our analysis is based on a very limited dataset from just 7 subjects; hence, our observations will need to be confirmed by further studies in larger cohorts of HIE newborns. Second, the comparisons with dexmedetomidine pharmacokinetics reported in earlier studies may be biased by study design differences in blood sampling; the present study is exceptional in that washout kinetics of dexmedetomidine after discontinuation of drug infusion was followed for an extended period of 42 h. In all previous studies in normothermic neonates without HIE, blood sampling was limited to a time span of no more than 24 h after either bolus intravenous dose or short-term infusion.\n\nThe reason for dexmedetomidine CL tending to be lower in HIE newborns undergoing TH compared to normothermic, non-HIE newborns needs further investigation. Dexmedetomidine is cleared in adult humans almost exclusively by metabolism through direct N-glucuronidation and cytochrome P450 metabolism (hydroxylation, mediated by CYP2A6) [30]. Minimal dexmedetomidine dose is recovered in urine or feces as an unchanged drug; hence, renal function is not an important consideration in this context. Depressed hepatic drug metabolism in the HIE newborns undergoing TH could be an explanation for its lower clearance. In this regard, it is interesting to note that Frymoyer et al. reported markedly lower morphine clearance in neonates with HIE receiving hypothermia compared with reports in full-term normothermic neonates <7 days old without HIE [4]. Clearance of morphine, which mainly occurs through UGT2B7-mediated O-glucuronidation in the liver, was not correlated with liver injury (based on elevated alanine aminotransferase levels) in their study. We also did not find the liver enzyme marker, serum alanine aminotransferase, to be a significant covariate for dexmedetomidine clearance in our population modeling.\n\nIn practical terms, our current study suggests that the standard dexmedetomidine maintenance infusion rates recommended for typical newborns in an intensive care setting may be reasonably appropriate for neonates with HIE undergoing TH, at least with respect to achieving similar or slightly higher steady-state plasma drug concentrations. Our study does suggest that a loading dose may be needed to overcome the initial lag in achieving effective plasma levels of dexmedetomidine due to a longer elimination half-life in HIE newborns; the elimination half-life predicted by the compartmental model is about 7.3 hours (i.e., estimated from CL and V reported in Table 2), which is longer than the generally accepted value of 3 hours for normothermic, non-HIE neonates. This means dexmedetomidine steady state would not be achieved until about 28 hours (i.e., 4 half-lives) after initiation of or change in infusion rate in HIE neonates undergoing TH compared to only 13 hours in normothermic, non-HIE neonates. The delay in achieving an infusion steady state may be further complicated by drug loss through sorption to intravenous microbore tubing; the latter could result in as much as 30% lower actual infusion rate than intended during the first 6 hours of infusion (Figure 3). Sorptive loss of dexmedetomidine to plastic intravenous tubing, which effectively lowers the dose delivered, is probably dependent on the particular infusion set; this potential issue should always be considered when patients treated with standard doses of dexmedetomidine do not respond with the anticipated sedative, analgesic, anxiolytic, and antishivering effects in a timely fashion. While a loading dose may lead to a faster attainment of steady-state level, the current dosing regimen appeared to provide effective sedation and appeared safe, so a bolus dose should probably be reserved for cases where sedation or preventing shivering is ineffective.\n\nThe neonates in the current study were critically ill, evidenced by their severe metabolic acidosis with a mean pH of 6.90 and base deficit of 22 after birth. In addition to neonatal encephalopathy related to moderate-to-severe HIE, the majority of neonates had seizures and elevated alanine aminotransferase levels, required mechanical ventilation, and needed inotropic support for hypotension. Although it is unclear if dexmedetomidine treatment resulted in the need for inotropic support, clinicians considering dexmedetomidine treatment for neonates with HIE during TH should closely monitor hypotension as a potential side effect. Despite their clinical lability, titration of intravenous dexmedetomidine infusion up to 0.4 μg/kg/h was well tolerated, without apparent adverse events. Based on N-PASS scores, the neonates had adequate sedation with dexmedetomidine for the majority of the study, with only one neonate (patient #1, who had severe global brain injury) being potentially oversedated, but that neonate also had an N-PASS score of −6 prior to starting dexmedetomidine. The predetermined maximum study dosage was much lower than dexmedetomidine doses commonly used in critically ill neonates in the Seattle Children's NICU (e.g., doses up to 1.2 μg/kg/h; unpublished data); this maximum dosage of 0.4 μg/kg/h was chosen to avoid potential adverse side effects since neonates with HIE often have multiorgan failure.\n\nSmall sample size is a limitation of our present study. The current study was designed to assess the pharmacokinetics and safety of dexmedetomidine in neonates with HIE treated with TH and was not powered to evaluate dexmedetomidine efficacy, and therefore, any safety-related results should be carefully considered. Only one neonate had multiorgan dysfunction, so our ability to describe the pharmacokinetic profile and clinical response to dexmedetomidine in the setting of multiorgan dysfunction is limited. Despite a limited number of subjects, a total of 94 pharmacokinetic samples were collected from the 7 neonates with HIE who underwent TH, which are comparable to the total samples collected from 20 infants in the study by Greenberg et al. (n = 89) [13]. We believe that rich sampling in select subjects is preferable to sparse sampling in a larger number of subjects, given the unknown effects of TH on dexmedetomidine pharmacokinetics prior to this study. We could not have discerned the time-dependent kinetics of dexmedetomidine in our HIE cohort undergoing TH if our study had followed a sparse blood sampling design.\n\n5. Conclusions\nDifferences in dexmedetomidine pharmacokinetics were observed in the current small cohort of newborns with HIE undergoing TH compared to reported literature data for normothermic neonates without HIE. Dexmedetomidine clearance in our 7 HIE neonates is comparable to or lower than reported clearance in normothermic, non-HIE neonates. Our HIE newborns also exhibited a larger volume distribution and a longer mean residence time or elimination half-lives compared to their non-HIE counterparts. There was a notable delay or slow initial rise in plasma drug concentration upon dexmedetomidine infusion due to a combination of longer elimination half-life and sorptive loss during delivery through the microbore infusion tubing. These findings suggest that, in cooled neonates with HIE, a loading dose or more rapid escalation in initial titration of dexmedetomidine infusion may be needed in order to achieve effective levels in a timely manner. Safety is suggested by our data; however, considering the limitations of our small sample size and lack of a control group, further evaluation of dexmedetomidine in neonates with HIE treated with TH is warranted. A larger, well-powered trial is needed to determine the effectiveness of dexmedetomidine vs. morphine at providing sedation and preventing shivering and to elucidate any long-term neurodevelopmental impact in neonates with HIE treated with TH.\n\nAcknowledgments\nThe authors thank all the families for their participation and the neonatologists at Seattle Children's Hospital who helped consent families for the study. This study was supported by a local award from the Seattle Children's Hospital Academic Enrichment Fund.\n\nData Availability\nThe data used to support the findings of this study are available from the corresponding author upon request.\n\nDisclosure\nThe funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was originally presented in the abstract/poster form at the Pediatric Academic Societies Meeting on May 5–8, 2018, in Toronto, Canada.\n\nConflicts of Interest\nThe authors have no conflicts of interest to declare.\n\nSupplementary Materials\nSupplementary Materials Supplementary Table S1: optimized mass spectrometry parameters for analytes and dexmedetomidine.\n\nClick here for additional data file.\n\n Figure 1 Sorptive loss of dexmedetomidine to IV microbore tubing assessed over an 18-h mock infusion experiment. The mean ± standard deviation of the fraction of nominal concentration (FNC) in the outflow infusate from 3 separate experiments is plotted against time.\n\nFigure 2 Comparison of the observed plasma dexmedetomidine time course (OBS, open circles) to typical subject prediction (PRED, black solid line) and individual-level prediction (IPRED, black dash line) based on the respective population model. Predictions based on the naïve pooled compartmental model (blue solid line) are overlaid for comparison. Body weight-normalized dexmedetomidine-infused rates, which varied across subjects, are also depicted (red dotted-dash line). Upper and lower panels present the respective semilogarithmic and rectilinear plots; the former is better in showing the model fit to data in the postinfusion phase, whereas the latter shows the fit during infusion more clearly. Variation in the infusion regimen across the subjects is also more evident in the rectilinear plots.\n\nFigure 3 Goodness-of-fit plots for the one-compartment naïve pooled model (a) and population model (b). (a) and (b) depict plots of observed (DV) vs. population prediction (PRED) or individual prediction (IPRED) and plots of conditional weighted residuals (CWRES) vs. time or PRED. PREDs are equal to IPREDs for the case of the naïve pooled model.\n\nFigure 4 Visual predictive check (VPC) plot of the final dexmedetomidine population model providing a comparison of observed and predicted data. Individual concentrations are depicted using black points, with the median for the observed concentration-time course being depicted as a solid red line and its simulated 5th and 95th percentiles. The median for model predictions is depicted as a black solid line, with corresponding simulated 5th and 95th percentiles being depicted as a dotted black line. The simulated 90% prediction intervals for the 5th, 50th, and 95th levels are depicted using light blue polygons (prediction area overlaps appear as darker polygons).\n\nFigure 5 Comparison of individual-level predictions based on the dexmedetomidine population model from the current study (black) and those reported by Greenberg et al. (green) and Potts et al. (orange). Simulations for the Greenberg and Potts models took into account individual-level covariates (postnatal age and body weight) from the present study.\n\nTable 1 Comparison of dexmedetomidine pharmacokinetics in 7 neonates with HIE undergoing TH to literature data in normothermic, non-HIE neonates.\n\n \tSubject #\tPresent\tChrysostomou [15]\tGreenberg [13]\tPotts [28]\t\n1\t2\t3\t4\t5\t6\t7\tMean ± SD or median (range)\t\nSubject characteristics\t \t \t \t \t \t \t \t \t \t \t \t\n Gestational age (wks; days)\t39 5 d\t41 5 d\t37 3 d\t40 4 d\t40 6 d\t38 0 d\t39 0 d\t39.6 ± 1.4\t39.1 ± 1.6\t39 (27–40)\tNR\t\n Postnatal age (d, wks, or yrs)\t \t \t \t \t \t \t \t1.7 ± 0.5 d\t2.23 ± 1.60 wks\t6.14 (0.57–29) wks\t3.8 (0.02–14) yrs\t\n Body weight (kg)\t3.83\t3.47\t2.41\t3.84\t3.08\t4.13\t3.81\t3.51 ± 0.54\t3.40 ± 0.60\t4.02 (2.00–6.00)\t16.1 (3.1–58.9)\t\n Time from birth to TH (h)\t4.55\t4.78\t4.60\t8.50\t3.65\t5.78\t4.7\t5.22 ± 1.57\tNA\tNA\tNA\t\n\n\n\t\nDexmedetomidine dosing\t \t \t \t \t \t \t \t \t \t \t \t\n Time from TH to infusion start (h)\t4\t9.7\t16.2\t12.5\t5.5\t23.7\t20.7\t13.19 ± 7.44\tNA\tNA\tNA\t\n Duration of infusion (h)\t74.0\t68.3\t61.8\t65.5\t72.5\t54.3\t57.3\t64.8 ± 6.9\t6–24\tVariable\tBolus or 8 h inf.\t\n Maintenance infusion rate (μg/kg/h)\t0.4\t0.4\t0.4\t0.4\t0.4\t0.4\t0.4\t0.4\t0.2\t0.5–2.5 (max)\t0.4 (under age 1 yr)\t\n Nominal infused dose (μg/kg)\t24.1\t25.9\t18.5\t25.9\t14.2\t21.4\t22.6\t21.8 ± 3.9\tNR\tNR\tNR\t\n Corrected infused dose (μg/kg)\t22.8\t25.0\t17.8\t24.9\t13.5\t19.8\t21.1\t20.7 ± 3.8\tNA\tNA\tNA\t\n\n\n\t\nDescriptive PK parameters\t \t \t \t \t \t \t \t \t \t \t \t\n Cmax (pg/mL)\t929\t562\t501\t523\t295\t517\t433\t537 ± 180\t968 ± 1011a\t304 ± 49b,∗\t670 ± 128b\t\n Tmax (h)\t48.0\t24.0\t24.0\t24.0\t0.2\t48.3\t48.3\t31.0 ± 16.8\tNR\tEnd of infusion\tEnd of infusion\t\n AUC0–∞ (ng/mL·h)\t47.4\t32.3\t25.5\t26.0\t19.5\t26.4\t21.8\t28.4 ± 8.6\tNR\tNR\tNR\t\n CL (L/h/kg)\t0.480\t0.775\t0.699\t0.958\t0.694\t0.752\t0.968\t0.761 ± 0.155\t0.907 ± 0.502\t1.23 ± 0.08∗∗\t0.548 ± 0.032∗\t\n MRT (h)\t4.05\t11.4\t4.73\t2.64\t6.85\t11.3\t6.79\t6.84 ± 3.20\t4.26 ± 3.90\t1.24 ± 0.09∗∗\t3.28 ± 0.19∗\t\n Vss (L/kg)\t1.95\t8.88\t3.31\t2.53\t4.75\t8.54\t6.57\t5.22 ± 2.62\t4.57 ± 4.26\t1.51c,†\t1.79d,†\t\nAbbreviations: NR, not reported; NA, not applicable or available; TH, therapeutic hypothermia (33.5°C); PK, pharmacokinetics; Cmax, maximum observed plasma concentration; Tmax, time of Cmax; AUC0–∞, area under the plasma concentration-time curve from time 0 to infinity; CL, clearance based upon the infused dose corrected for sorptive loss; MRT, mean residence time; Vss, steady-state distribution volume. Note that, for all the pharmacokinetic parameters, estimates presented in the Potts et al. and Greenberg et al. columns are mean ± SD for the 7 normothermic counterparts predicted based upon the reported population pharmacokinetic models. aExtrapolated from an infusion rate of 0.2 μg/kg/h, i.e., multiplying reported mean ± SD by 2. bAverage of simulations for normothermic counterparts to each of our 7 cooled newborns without HIE at the maximum infusion rate of 0.4 μg/kg/h. cGreenberg et al. were only able to provide the population mean estimate of distribution volume because of insufficient data in the initial accumulation or washout phases of DEX infusion, i.e., no modeling of interindividual variation. dDistribution volume was scaled to body weight; hence, volume per kg did not differ between the normothermic counterparts. ∗p < 0.05 for a 2-tailed, 2-sample t-test between reported values for normothermic, non-HIE newborns and presently observed values for cooled newborns with HIE. ∗∗p < 0.01 for a 2-tailed, 2-sample t-test between reported values for normothermic, non-HIE newborns and presently observed values for cooled newborns with HIE. †p < 0.02 for a 2-tailed, one-sample t-test between the reported fixed value for normothermic, non-HIE newborns and presently observed values for cooled newborns with HIE.\n\nTable 2 Parameter estimates, along with their standard error and relative standard error, for the naïve pooled model and the population one-compartment model.\n\nParameter\tEstimate\tStandard error\tRelative standard error\t\nNaïve pooled model\t\nClearance (CL) (L/h/kg)\t0.726\t0.0253\t0.0349\t\nVolume of distribution (V) (L/kg)\t7.90\t1.05\t0.133\t\nAdditive residual error (pg/mL)\t109\t6.86\t0.0630\t\n\n\n\t\nPopulation model\t\nClearance (CL) (L/h/kg)\t0.697\t0.0869\t0.125\t\nVolume of distribution (V) (L/kg)\t7.48\t1.17\t0.157\t\nAdditive residual error (pg/mL)\t94.3\t8.83\t0.0936\t\nBetween-subject variance on K\t0.0394\t0.116\t2.95\t\nTable 3 Hospital course characteristics of neonates with hypoxic-ischemic encephalopathy treated with dexmedetomidine during hypothermia.\n\nCharacteristics\t1\t2\t3\t4\t5\t6\t7\tMean or no.\tSD (±)\t\nFemale, n (%)\tF\tM\tM\tF\tM\tM\tM\t \t \t\nAPGAR\t \t \t \t \t \t \t \t \t \t\n 5 min\t4\t6\t0\t2\t4\t0\t4\t3\t2\t\n 10 min\t4\t7\t0\t3\t4\t5\t8\t4\t3\t\nResuscitation\t \t \t \t \t \t \t \t \t \t\n Chest compressions\tYes\tNo\tYes\tNo\tNo\tYes\tNo\t \t \t\n Intubation after birth\tYes\tYes\tYes\tYes\tYes\tYes\tYes\t \t \t\n Epinephrine (bolus number)\tNo\tNo\tYes (7)\tNo\tNo\tYes (1)\tNo\t \t \t\n Normal saline (bolus number)\tNo\tNo\tYes (2)\tNo\tNo\tYes (1)\tNo\t \t \t\nFirst arterial or capillary pH\t6.65\t6.98\t7.04\t6.98\t7.06\t6.7\t6.9\t6.90\t0.16\t\nBase deficit, mmol/L\t34\t18\t23\t17\t17\t27\t19\t22\t6\t\nAdmission rectal temp. (Celsius)\t30.9\t35\t33.6\t34.7\t34.5\t34.5\t34.7\t34.0\t1.4\t\nCrMax, mg/dL\t3.7\t1.1\t0.5\t0.8\t1.4\t1.9\t0.8\t1.5\t1.1\t\nLowest platelet level\t95\t201\t106\t234\t75\t62\t97\t124\t66\t\nALTmax, U/L\t482\t439\t127\t160\t583\t129\t28\t278\t217\t\nHighest INR\t3\t2.1\t2.6\t1.3\t1.8\t1.8\t1.1\t2.0\t0.7\t\nLowest fibrinogen\t110\t273\t62\t185\t169\t118\t397\t188\t114\t\nIntubation > 12 h, n (%)\tYes\tNo\tYes\tNo\tYes\tYes\tNo\t4/7 (57%)\t \t\nClinical seizure, n (%)\tYes\tNo\tYes\tYes\tYes\tYes\tNo\t5/7 (71%)\t \t\nAnticonvulsants\tYes (P, F, Lev)\tNo\tYes (P, Lev)\tYes (P)\tNo\tNo\tNo\t3/7 (43%)\t \t\nInotropic support, n (%)\tYes (Dop, Epi, HC)\tYes (Dop)\tYes (Dop, HC)\tNo\tYes (Dop)\tYes (Dop)\tNo\t5/7 (71%)\t \t\nBreakthrough shivering\tNo\tNo\tNo\tYes, X7 (2 sev, 2 mod, 2 mild)\tYes, X2 (mild)\tNo\tNR\t2/6 (33%)\t \t\n Duration\t \t \t \t1–5 min\tNR\t \t \t \t \t\n Morphine doses given\t0\t0\t0\t3\t2\t0\t0\t \t \t\nBradycardia (<70 bpm)\tNo\t1 episode\tNo\tNo\tNo\tNo\tNo\t1/7 (14%)\t \t\nDeath during hospitalization, n (%)\tYes\tNo\tNo\tNo\tNo\tNo\tNo\t1/7 (14%)\t \t\nSD, standard deviation; CrMax, maximum creatinine; ALTmax, maximum alanine aminotransferase; INR, international normalized ratio; P, phenobarbital; F, fosphenytoin; Lev, levetiracetam; Dop, dopamine; Epi, epinephrine; HC, hydrocortisone; NR, not reported.\n==== Refs\n1 Ariff S. Lee A. C. Lawn J. Bhutta Z. A. Global burden, epidemiologic trends, and prevention of intrapartum-related deaths in low-resource settings Clinics in Perinatology 2016 43 3 593 608 10.1016/j.clp.2016.05.001 2-s2.0-84981710224 27524456 \n2 McAdams R. M. Juul S. E. Neonatal encephalopathy Clinics in Perinatology 2016 43 3 485 500 10.1016/j.clp.2016.04.007 2-s2.0-84981743386 27524449 \n3 Simbruner G. Mittal R. A. Rohlmann F. Muche R. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT Pediatrics 2010 126 4 e771 e778 10.1542/peds.2009-2441 2-s2.0-77957704402 20855387 \n4 Frymoyer A. Bonifacio S. L. Drover D. R. Su F. Wustoff C. J. Van Meurs K. P. Decreased morphine clearance in neonates with hypoxic ischemic encephalopathy receiving hypothermia The Journal of Clinical Pharmacology 2017 57 1 64 76 10.1002/jcph.775 2-s2.0-84977138703 27225747 \n5 Anand K. Hall R. W. Desai N. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial The Lancet 2004 363 9422 1673 1682 10.1016/s0140-6736(04)16251-x 2-s2.0-2442691352 \n6 Molina P. E. Opioids and opiates: analgesia with cardiovascular, haemodynamic and immune implications in critical illness Journal of Internal Medicine 2006 259 2 138 154 10.1111/j.1365-2796.2005.01569.x 2-s2.0-33644857240 16420543 \n7 Attarian S. Tran L. Moore A. Stanton G. Meyer E. Moore R. The neurodevelopmental impact of neonatal morphine administration Brain Sciences 2014 4 2 321 334 10.3390/brainsci4020321 2-s2.0-84921754999 24961764 \n8 Talke P. Tayefeh F. Sessler D. I. Jeffrey R. Noursalehi M. Richardson C. Dexmedetomidine does not alter the sweating threshold, but comparably and linearly decreases the vasoconstriction and shivering thresholds Anesthesiology 1997 87 4 835 841 10.1097/00000542-199710000-00017 2-s2.0-0030709295 9357885 \n9 Madden C. J. Tupone D. Cano G. Morrison S. F. 2 adrenergic receptor-mediated inhibition of thermogenesis Journal of Neuroscience 2013 33 5 2017 2028 10.1523/jneurosci.4701-12.2013 2-s2.0-84873043752 23365239 \n10 Lewis S. R. Nicholson A. Smith A. F. Alderson P. Alpha-2 adrenergic agonists for the prevention of shivering following general anaesthesia The Cochrane Database of Systematic Reviews 2015 8 CD011107 10.1002/14651858.CD011107.pub2 2-s2.0-84991227405 \n11 O’Mara K. Gal P. Wimmer J. Dexmedetomidine versus standard therapy with fentanyl for sedation in mechanically ventilated premature neonates The Journal of Pediatric Pharmacology and Therapeutics 2012 17 3 252 262 10.5863/1551-6776-17.3.252 23258968 \n12 Lam F. Bhutta A. T. Tobias J. D. Gossett J. M. Morales L. Gupta P. Hemodynamic effects of dexmedetomidine in critically ill neonates and infants with heart disease Pediatric Cardiology 2012 33 7 1069 1077 10.1007/s00246-012-0227-6 2-s2.0-84867877845 22327182 \n13 Greenberg R. G. Wu H. Laughon M. Population pharmacokinetics of dexmedetomidine in infants Journal of clinical pharmacology 2017 57 1174 1182 28444697 \n14 McAdams R. M. McPherson R. J. Kapur R. Phillips B. Shen D. D. Juul S. E. Dexmedetomidine reduces cranial temperature in hypothermic neonatal rats Pediatric Research 2015 77 6 772 778 10.1038/pr.2015.45 2-s2.0-84929896035 25751572 \n15 Chrysostomou C. Schulman S. R. Herrera Castellanos M. A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates The Journal of Pediatrics 2014 164 2 276 282 10.1016/j.jpeds.2013.10.002 2-s2.0-84892822970 24238862 \n16 Dilek O. Yasemin G. Atci M. Preliminary experience with dexmedetomidine in neonatal anesthesia Journal of Anaesthesiology, Clinical Pharmacology 2011 27 27 17 22 \n17 Su F. Nicolson S. C. Gastonguay M. R. Population pharmacokinetics of dexmedetomidine in infants after open heart surgery Anesthesia & Analgesia 2010 110 5 1383 1392 10.1213/ane.0b013e3181d783c8 2-s2.0-77951729054 20418300 \n18 Ezzati M. Broad K. Kawano G. Pharmacokinetics of dexmedetomidine combined with therapeutic hypothermia in a piglet asphyxia model Acta Anaesthesiologica Scandinavica 2014 58 6 733 742 10.1111/aas.12318 2-s2.0-84903124582 24724965 \n19 Frymoyer A. Juul S. E. Massaro A. N. Bammler T. K. Wu Y. W. High-dose erythropoietin population pharmacokinetics in neonates with hypoxic-ischemic encephalopathy receiving hypothermia Pediatric Research 2017 81 6 865 872 10.1038/pr.2017.15 2-s2.0-85020469008 28099423 \n20 Frymoyer A. Meng L. Bonifacio S. L. Verotta D. Guglielmo B. J. Gentamicin pharmacokinetics and dosing in neonates with hypoxic ischemic encephalopathy receiving hypothermia Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 2013 33 7 718 726 10.1002/phar.1263 2-s2.0-84885407041 \n21 Gluckman P. Wyatt J. Azzopardi D. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial The Lancet 2005 365 9460 663 670 10.1016/s0140-6736(05)17946-x 2-s2.0-13844321255 \n22 Shankaran S. Laptook A. R. Ehrenkranz R. A. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy New England Journal of Medicine 2005 353 15 1574 1584 10.1056/nejmcps050929 2-s2.0-26444452073 16221780 \n23 Bonate P. L. Strougo A. Desai A. Guidelines for the quality control of population pharmacokinetic-pharmacodynamic analyses: an industry perspective The AAPS Journal 2012 14 4 749 758 10.1208/s12248-012-9387-9 2-s2.0-84869127348 22826033 \n24 Bergstrand M. Karlsson M. O. Handling data below the limit of quantification in mixed effect models The AAPS Journal 2009 11 2 371 380 10.1208/s12248-009-9112-5 2-s2.0-68249141539 19452283 \n25 Ahn J. E. Karlsson M. O. Dunne A. Ludden T. M. Likelihood based approaches to handling data below the quantification limit using NONMEM VI Journal of Pharmacokinetics and Pharmacodynamics 2008 35 4 401 421 10.1007/s10928-008-9094-4 2-s2.0-52549112649 18686017 \n26 Badjatia N. Strongilis E. Gordon E. Metabolic impact of shivering during therapeutic temperature modulation Stroke 2008 39 12 3242 3247 10.1161/strokeaha.108.523654 2-s2.0-58149347205 18927450 \n27 Hummel P. Puchalski M. Creech S. D. Weiss M. G. Clinical reliability and validity of the N-PASS: neonatal pain, agitation and sedation scale with prolonged pain Journal of Perinatology 2008 28 1 55 60 10.1038/sj.jp.7211861 2-s2.0-38049050785 18165830 \n28 Potts A. L. Anderson B. J. Warman G. R. Lerman J. Diaz S. M. Vilo S. Dexmedetomidine pharmacokinetics in pediatric intensive care—a pooled analysis Pediatric Anesthesia 2009 19 11 1119 1129 10.1111/j.1460-9592.2009.03133.x 2-s2.0-70350552006 19708909 \n29 Team R. C. A Language and Environment for Statistical Computing 2017 Vienna, Austria R Foundation for Statistical Computing \n30 Gertler R. Brown H. C. Mitchell D. H. Silvius E. N. Dexmedetomidine: a novel sedative-analgesic agent Baylor University Medical Center Proceedings 2001 14 1 13 21 10.1080/08998280.2001.11927725 16369581\n\n",
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"title": "Dexmedetomidine Pharmacokinetics in Neonates with Hypoxic-Ischemic Encephalopathy Receiving Hypothermia.",
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"abstract": "Background. Natalizumab treatment is frequently discontinued and replaced by alternative medication in multiple sclerosis (MS) patients having a high risk of progressive multifocal leukoencephalopathy (PML). Case Presentation. We report a PML case that was missed on magnetic resonance imaging (MRI) at the time Natalizumab treatment was discontinued. The patient subsequently developed a PML-immune reconstitution inflammatory syndrome after the initiation of Fingolimod treatment, suggesting that immune reconstitution may occur even during Fingolimod induced lymphopenia. Conclusion. This report highlights the need for strict drug surveillance using MRI of Natalizumab-associated MS patients at the time of drug discontinuation and beyond. This is important with respect to pharmacovigilance purposes not only for Natalizumab, but also for alternative drugs used after Natalizumab discontinuation.",
"affiliations": "Department of Neurology, MS Center Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.;Department of Neurology, MS Center Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.;Department of Neurology, ZGT, Almelo, The Netherlands.;Department of Radiology, ZGT, Almelo, The Netherlands.;Department of Neurology, ZGT, Almelo, The Netherlands.;Department of Radiology, Nuclear Medicine & PET Research, MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.",
"authors": "Killestein|J|J|;Vennegoor|A|A|;van Golde|A E L|AE|;Bourez|R L J H|RL|;Wijlens|M L B|ML|;Wattjes|M P|MP|",
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"fulltext": "\n==== Front\nCase Rep Neurol MedCase Rep Neurol MedCRINMCase Reports in Neurological Medicine2090-66682090-6676Hindawi Publishing Corporation 10.1155/2014/307872Case ReportPML-IRIS during Fingolimod Diagnosed after Natalizumab Discontinuation Killestein J. \n1\n\n*\nVennegoor A. \n1\nvan Golde A. E. L. \n2\nBourez R. L. J. H. \n3\nWijlens M. L. B. \n2\nWattjes M. P. \n4\n1Department of Neurology, MS Center Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands2Department of Neurology, ZGT, Almelo, The Netherlands3Department of Radiology, ZGT, Almelo, The Netherlands4Department of Radiology, Nuclear Medicine & PET Research, MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands*J. Killestein: j.killestein@vumc.nlAcademic Editor: Filippo Martinelli Boneschi\n\n2014 23 11 2014 2014 30787219 8 2014 11 11 2014 Copyright © 2014 J. Killestein et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. Natalizumab treatment is frequently discontinued and replaced by alternative medication in multiple sclerosis (MS) patients having a high risk of progressive multifocal leukoencephalopathy (PML). Case Presentation. We report a PML case that was missed on magnetic resonance imaging (MRI) at the time Natalizumab treatment was discontinued. The patient subsequently developed a PML-immune reconstitution inflammatory syndrome after the initiation of Fingolimod treatment, suggesting that immune reconstitution may occur even during Fingolimod induced lymphopenia. Conclusion. This report highlights the need for strict drug surveillance using MRI of Natalizumab-associated MS patients at the time of drug discontinuation and beyond. This is important with respect to pharmacovigilance purposes not only for Natalizumab, but also for alternative drugs used after Natalizumab discontinuation.\n==== Body\n1. Introduction\nProgressive multifocal leukoencephalopathy (PML) is a serious adverse event in multiple sclerosis (MS) patients treated with Natalizumab (Tysabri, Biogen Idec, MA, USA) [1]. Many patients who display anti-JCV antibodies decide to switch to Fingolimod (Gilenya, Novartis) or alternative drugs. There are unaddressed issues regarding the best possible regimen for switchers, including the right time point to start Fingolimod after Natalizumab discontinuation to avoid possible MS rebound. Recent studies suggest less prominent rebound disease breakthrough with shorter Natalizumab wash-out periods [2–4]. No PML cases related to Fingolimod monotherapy have been reported so far. Natalizumab-associated PML after drug discontinuation is a rather infrequent phenomenon, although the drug may remain detectable up to 200 days after cessation of therapy and induces shifts in circulating T-cell subpopulations that persist over several months [5–8].\n\nHere we report a patient with an initially missed diagnosis of Natalizumab-associated PML at the time of drug discontinuation, who developed PML-immune reconstitution inflammatory syndrome (IRIS) after initiating Fingolimod treatment.\n\n2. Case Report \nA 52-year-old relapsing-remitting MS patient switched to Natalizumab treatment in 2011, due to a breakthrough of MS disease activity while being treated with Glatiramer (Copaxone, Teva). Due to a positive STRATIFY JCV antibody test (Unilabs) in the spring of 2013, Natalizumab was discontinued and Fingolimod initiated. At that time (22-04-2013), brain MRI showed a new, small lesion in the cortical grey matter of the right precentral gyrus, which, according to recently published PML imaging characteristics [9, 10], can be interpreted retrospectively as PML onset (see Figure 1). After 3 months of wash-out, Fingolimod (0.5 mg) was initiated on 31 July 2013. By early September 2013, the patient presented with partial epileptic seizures of the left arm, which responded well to carbamazepine. However, in the following days after the seizures ceased, he developed an increase in fatigue and difficulties in fine hand movements, as well as mild weakness of his left arm, initially interpreted as MS exacerbation. Subsequently, he received IV methylprednisolone (1000 mg) for three days from 8 September 2013. MRI was repeated on 10 September 2013 and showed lesions highly suggestive of PML. At that stage, the patient fulfilled the diagnostic criteria of “possible PML” according to the AAN diagnostic criteria [11]. Fingolimod was discontinued. On 16 September 2013, brain MRI showed evolution and an enhancement pattern suggestive of PML-IRIS (Figure 1). IV methylprednisolone (1000 mg) for three days was repeated weekly until the 19th of October 2013.\n\nCerebrospinal fluid multiplex quantitative polymerase chain reaction performed at the US National Institute of Health Laboratory of Molecular Medicine and Neuroscience on 11 September 2013 did not reveal JCV DNA copies. However, radiological characteristics and the disease course make alternative diagnoses very unlikely.\n\nLymphocyte counts were measured before, during, and after Fingolimod treatment (see Table 1), suggesting that immune reconstitution may occur even during Fingolimod induced lymphopenia.\n\n3. Discussion\nNo cases of PML have been described in patients using Fingolimod monotherapy most likely because it clearly differs from Natalizumab in pharmacodynamic immune mechanisms of action and subsequently its safety profile. This case study documenting the development of PML-IRIS during Fingolimod treatment after Natalizumab discontinuation backs up our conviction that a suspicion of a possible Fingolimod-associated PML in this setting has to be analysed very carefully. Current Natalizumab surveillance programs use MRI as a sensitive screening tool for PML detection preferably in the presymptomatic/asymptomatic stage, which is associated with a better prognosis [9, 10]. Our case is another argument that MRI surveillance should not stop at the time of Natalizumab discontinuation. Asymptomatic Natalizumab-associated PML can present with small lesions on MRI and may show a rather mild progression, staying asymptomatic for several months [12]. A recently published case series of 17 patients developing PML after Natalizumab discontinuation showed that this phenomenon is highly clinically relevant [7]. Interestingly, the majority of these patients developed PML within the first few months after drug discontinuation, suggesting that PML might already have occurred at the time of drug discontinuation or shortly thereafter [8]. In addition, small PML lesions can be missed, like in our case, or misinterpreted as a new MS lesion, supporting our opinion that Natalizumab surveillance, particularly the MRI assessment, should be committed to experienced centres. The need for professional drug surveillance in patients switching from one therapy to another is also relevant in terms of pharmacovigilance of drugs used after Natalizumab discontinuation. As the drug remains detectable in the blood up to 200 days after cessation of Natalizumab [5] and early detection of asymptomatic PML has a much better prognosis than symptomatic PML [9], we believe that MRI surveillance of high risk patients in terms of Natalizumab-associated PML should be performed every three months and continued at least 6 months after Natalizumab discontinuation.\n\nOur case may also imply that the PML-IRIS phenomenon seems to start independently of the usage of Fingolimod, suggesting that lymphocytic cellular host-defence against JCV reactivation might not be (totally) impaired during Fingolimod treatment [13]; Fingolimod reduced CSF CD4+ T cells and B cells. However, the decrease was less pronounced than in the peripheral blood. In addition, the proportion of CSF CD8+ T cells, NK cells, and monocytes even increased compared to treatment-naive patients [13], supporting the use of Fingolimod after Natalizumab-associated PML in active MS.\n\nRebound disease activity after cessation of Natalizumab is well recognized and breakthroughs have been reported even in patients who switched to Fingolimod [2, 14]. Our observation confirms, however, that clinical deterioration after Natalizumab discontinuation should not automatically lead to the conclusion that we are dealing with a rebound of MS activity. The risk of further evolvement of Natalizumab-associated PML after stopping the drug is not imaginary. Since both situations can be clinically and radiologically difficult to differentiate, this is another strong argument to leave this challenging and potentially life threatening diagnostic issue in the hands of experienced physicians.\n\nAcknowledgment\nThe authors wish to thank Phil Riley for the critical reading of the paper.\n\nDisclosure\nDr. J. Killestein has accepted consulting fees from Merck-Serono, Teva, Biogen Idec, Genzyme, and Novartis. VU Medical Center has received financial support for research activities from Bayer Schering Pharma, Biogen Idec, GlaxoSmithKline, Merck Serono, Novartis, and Teva. Dr. A. Vennegoor has accepted speaking fees from Teva. Dr. M. P. Wattjes serves as a consultant for Biogen Idec and Roche. He serves on the Editorial Board of European Radiology.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nAuthors’ Contribution\nJ. Killestein, A. Vennegoor, A. E. L. van Golde, R. L. J. H. Bourez, M. L. B. Wijlens, and M. P. Wattjes contributed to drafting/revising the paper, study concept or design, and analysis or interpretation of the data. A.E. L. van Golde, R. L. J. H. Bourez, and M. L. B. Wijlens contributed to acquisition of the data. J. Killestein contributed to study supervision or coordination.\n\nFigure 1 Axial T2-weighted (top row) and contrast-enhanced T1-weighted images (bottom row) obtained during Natalizumab treatment (3 December 2012), at the time of Natalizumab discontinuation (22 April 2013), at the time of PML-IRIS occurrence (16 September 2013), and after PML-IRIS treatment (21 October 2013). A small lesion suggestive of PML was already visible at the time of Natalizumab discontinuation (arrow). During Fingolimod treatment, this lesion progressed and changed to a PML-IRIS manifestation with slight mass effect and contrast enhancement (arrows) leading to posttreatment sequelae (arrow).\n\nTable 1 Lymphocyte counts before, during, and after Fingolimod treatment.\n\n06-06-2013\t3.2\t\n17-08-2013\t1.4\t\n17-09-2013\t0.9\t\n24-09-2013\t0.8\t\n01-10-2013\t0.8\t\n04-10-2013\t0.6\t\n08-10-2013\t2.8\t\nLymphocyte counts 2 × 109/L (normal range 0.6–2.9). The final Fingolimod dose was administered on 11 September 2013. Increase in lymphocyte counts long after IRIS phase started (16 September 2013), suggesting that immune reconstitution occurs even in low lymphocyte state under Fingolimod.\n==== Refs\n1 Bloomgren G. Richman S. Hotermans C. Subramanyam M. Goelz S. Natarajan A. Lee S. Plavina T. Scanlon J. V. Sandrock A. Bozic C. Risk of natalizumab-associated progressive multifocal leukoencephalopathy The New England Journal of Medicine 2012 366 20 1870 1880 10.1056/NEJMoa1107829 2-s2.0-84861022041 22591293 \n2 Pilz G. Harrer A. Wipfler P. Oppermann K. Sellner J. Fazekas F. Trinka E. Kraus J. Tumefactive MS lesions under fingolimod: a case report and literature review Neurology 2013 81 1914 1921 10.1212/01.wnl.0000435293.34351.11 2-s2.0-84888238788 24186912 \n3 Cohen M. Maillart E. Tourbah A. De Sèze J. Vukusic S. Brassat D. Anne O. Wiertlewski S. Camu W. Courtois S. Ruet A. Debouverie M. Le Page E. Casez O. Heinzlef O. Stankoff B. Bourre B. Castelnovo G. Rico A. Berger E. Camdessanche J.-P. Defer G. Clavelou P. Al Khedr A. Zephir H. Fromont A. Papeix C. Brochet B. Pelletier J. Lebrun C. Barth P. Blanc F. Boulay C. Chambaud L. Collongues N. Coustans M. Creange A. Derouiche F. Edan G. Fleury M. Gout O. Guennoc A. M. Kopf A. Labauge P. Lallement F. Laplaud D. Louiset P. Malikova I. Moreau T. Ouallet J. C. Pittion S. Rouhart F. Rumbach L. Seeldrayers P. Taithe F. Taurin G. Thouvenot E. Vermersch P. Zaenker C. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study JAMA Neurology 2014 71 4 436 441 10.1001/jamaneurol.2013.6240 2-s2.0-84899004764 24566807 \n4 Jokubaitis V. G. Li V. Kalincik T. Fingolimod after natalizumab and the risk of short-term relapse Neurology 2014 82 14 1204 1211 10.1212/WNL.0000000000000283 24610329 \n5 Rispens T. Vennegoor A. Wolbink G. J. Polman C. H. Killestein J. Natalizumab remains detectable in patients with multiple sclerosis long after treatment is stopped Multiple Sclerosis Journal 2012 18 6 899 901 2-s2.0-84861807320 10.1177/1352458511431073 22183929 \n6 Stüve O. Marra C. M. Jerome K. R. Cook L. Cravens P. D. Cepok S. Frohman E. M. Phillips T. Arendt G. Hemmer B. Monson N. L. Racke M. K. Immune surveillance in multiple sclerosis patients treated with natalizumab Annals of Neurology 2006 59 5 743 747 10.1002/ana.20858 2-s2.0-33646347610 16634029 \n7 Fine A. J. Sorbello A. Kortepeter C. Scarazzini L. Progressive multifocal leukoencephalopathy after natalizumab discontinuation Annals of Neurology 2014 75 1 108 115 10.1002/ana.24051 2-s2.0-84894102134 24242357 \n8 Wattjes M. P. Killestein J. Progressive multifocal leukoencephalopathy after natalizumab discontinuation: few and true? Annals of Neurology 2014 75 3, article 462 10.1002/ana.24110 2-s2.0-84897989231 \n9 Wattjes M. P. Richert N. D. Killestein J. de Vos M. Sanchez E. Snaebjornsson P. Cadavid D. Barkhof F. The chameleon of neuroinflammation: magnetic resonance imaging characteristics of natalizumab-associated progressive multifocal leukoencephalopathy Multiple Sclerosis Journal 2013 19 14 1826 1840 10.1177/1352458513510224 2-s2.0-84888627559 24192217 \n10 Wattjes M. P. Barkhof F. Diagnosis of natalizumab-associated progressive multifocal leukoencephalopathy using MRI Current Opinion in Neurology 2014 27 3 260 270 10.1097/WCO.0000000000000099 2-s2.0-84900474314 24739400 \n11 Berger J. R. Aksamit A. J. Clifford D. B. Davis L. Koralnik I. J. Sejvar J. J. Bartt R. Major E. O. Nath A. PML diagnostic criteria: consensus statement from the AAN neuroinfectious disease section Neurology 2013 80 15 1430 1438 10.1212/WNL.0b013e31828c2fa1 2-s2.0-84876266893 23568998 \n12 Blinkenberg M. Sellebjerg F. Leffers A.-M. Madsen C. G. Sørensen P. S. Clinically silent PML and prolonged immune reconstitution inflammatory syndrome in a patient with multiple sclerosis treated with natalizumab Multiple Sclerosis Journal 2013 19 9 1226 1229 10.1177/1352458513481010 2-s2.0-84880154812 23508652 \n13 Kowarik M. C. Pellkofer H. L. Cepok S. Korn T. Kümpfel T. Buck D. Hohlfeld R. Berthele A. Hemmer B. Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS Neurology 2011 76 14 1214 1221 2-s2.0-79954611536 10.1212/WNL.0b013e3182143564 21464424 \n14 Rinaldi F. Seppi D. Calabrese M. Perini P. Gallo P. Switching therapy from natalizumab to fingolimod in relapsing-remitting multiple sclerosis: clinical and magnetic resonance imaging findings Multiple Sclerosis Journal 2012 18 11 1640 1643 10.1177/1352458512464282 2-s2.0-84868036448 23100526\n\n",
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"references": "23508652;24097813;24442606;23568998;24610329;24242357;22183929;22591293;23100526;24739400;21464424;16634029;24566807;24192217",
"title": "PML-IRIS during Fingolimod Diagnosed after Natalizumab Discontinuation.",
"title_normalized": "pml iris during fingolimod diagnosed after natalizumab discontinuation"
} | [
{
"companynumb": "NL-BIOGENIDEC-2013BI087919",
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"activesubstancename": "FINGOLIMOD"
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"abstract": "BACKGROUND\nSinusoidal obstructive syndrome (SOS) is well associated with the use oxaliplatin-based chemotherapy, and represents a spectrum of hepatotoxicity, with nodular regenerative hyperplasia (NRH) representing the most significant degree of injury. The aim of this study was to determine the prevalence of NRH in patients undergoing resection of colorectal liver metastases (CRLM) and to determine its impact on outcome.\n\n\nMETHODS\nFrom January 2000 to December 2010, some 978 first primary liver resections were performed for CRLM. A prospectively maintained database was analysed to identify all patients with evidence of NRH in the non-tumour portion of their histopathology specimens. Clinical data of these patients was reviewed and outcomes assessed.\n\n\nRESULTS\nFive patients exhibited NRH (four males, one female) with a median age of 69 years (range: 35-74). Three patients presented with synchronous hepatic metastases, and two with metachronous lesions. All received at least 6 cycles of oxaliplatin as either adjuvant or neo-adjuvant chemotherapy. Only one patient developed a post-operative complication namely transient hepatic failure that required a 4-day stay in the intensive care unit. The median hospital stay was 6 days (range: 6-14 days). There were no 90-day mortalities. One patient is alive and disease free at 55 months, the remaining 4 died of recurrent disease between 37 and 70 months following diagnosis of their primary tumours.\n\n\nCONCLUSIONS\nNRH is not an uncommon finding amongst patients with SOS with all patients having received oxaliplatin-based chemotherapy. Data on outcome would suggest no increased morbidity and mortality associated with the presence of NRH.",
"affiliations": "Department of Hepatobiliary and Transplant Surgery, St James' University Hospital, Leeds LS9 7TF, UK.;Department of Hepatobiliary and Transplant Surgery, St James' University Hospital, Leeds LS9 7TF, UK.;Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Derby Road, Nottingham NG7 2UH, UK.;Department of Hepatobiliary and Pancreatic Surgery, Queen's Medical Centre, Derby Road, Nottingham NG7 2UH, UK.;Department of Hepatobiliary and Transplant Surgery, St James' University Hospital, Leeds LS9 7TF, UK.;Department of Hepatobiliary and Transplant Surgery, St James' University Hospital, Leeds LS9 7TF, UK.;Department of Hepatobiliary and Transplant Surgery, St James' University Hospital, Leeds LS9 7TF, UK.;Department of Hepatobiliary and Transplant Surgery, St James' University Hospital, Leeds LS9 7TF, UK. Electronic address: raj.prasad@leedsth.nhs.uk.",
"authors": "Morris-Stiff|G|G|;White|A D|AD|;Gomez|D|D|;Cameron|I C|IC|;Farid|S|S|;Toogood|G J|GJ|;Lodge|J P A|JP|;Prasad|K R|KR|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"country": "England",
"delete": false,
"doi": null,
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"issn_linking": "0748-7983",
"issue": "40(8)",
"journal": "European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology",
"keywords": "Colorectal liver metastases; Nodular regenerative hyperplasia; Oxaliplatin; Sinusoidal obstruction syndrome",
"medline_ta": "Eur J Surg Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms; D016208:Databases, Factual; D004334:Drug Administration Schedule; D005260:Female; D020518:Focal Nodular Hyperplasia; D006498:Hepatectomy; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D008099:Liver; D008113:Liver Neoplasms; D008115:Liver Regeneration; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011446:Prospective Studies; D012189:Retrospective Studies",
"nlm_unique_id": "8504356",
"other_id": null,
"pages": "1016-20",
"pmc": null,
"pmid": "24370284",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Nodular regenerative hyperplasia (NRH) complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases.",
"title_normalized": "nodular regenerative hyperplasia nrh complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases"
} | [
{
"companynumb": "GB-MYLANLABS-GB2014013023",
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"patient": {
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"activesubstancename": "OXALIPLATIN"
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... |
{
"abstract": "BACKGROUND\nDrug patch tests (PTs) can reproduce delayed hypersensitivity to drugs and entail a moderate re-exposure of patients to offending drugs.\n\n\nOBJECTIVE\nTo determine the value of PTs for identifying the responsible drug in severe cutaneous adverse drug reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).\n\n\nMETHODS\nIn a multicentre study, PTs were conducted on patients referred for DRESS, AGEP or SJS/TEN within 1 year of their SCAR. All drugs administered in the 2 months prior to and the week following the onset of the SCAR were tested.\n\n\nRESULTS\nAmong the 134 patients included (48 male, 86 female; mean age 51·7 years), positive drug PTs were obtained for 24 different drugs. These included positive tests for 64% (46/72) of patients with DRESS, 58% (26/45) of those with AGEP and 24% (4/17) of those with SJS/TEN, with only one relapse of AGEP. The value of PTs depended on the type of drug and the type of SCAR (e.g. carbamazepine was positive in 11/13 DRESS cases but none of the five SJS/TEN cases). PTs were frequently positive for beta lactams (22 cases), pristinamycin (11 cases) and in DRESS with pump proton inhibitors (five cases), but were usually negative for allopurinol and salazopyrin. Of 18 patients with DRESS, eight had virus reactivation and positive PTs. In DRESS, multiple drug reactivity was frequent (18% of cases), with patients remaining sensitized many years later.\n\n\nCONCLUSIONS\nPTs are useful and safe for identifying agents inducing SCAR.",
"affiliations": "Dermatology Department, University Hospital of Nancy, Pôle des Spécialités Médicales, Université de Lorraine, Brabois Hospital, 6 Rue du Morvan, Vandoeuvre-lès-Nancy 54500, France. a.barbaud@chu-nancy.fr",
"authors": "Barbaud|A|A|;Collet|E|E|;Milpied|B|B|;Assier|H|H|;Staumont|D|D|;Avenel-Audran|M|M|;Grange|A|A|;Amarger|S|S|;Girardin|P|P|;Guinnepain|M-T|MT|;Truchetet|F|F|;Lasek|A|A|;Waton|J|J|;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bjd.12125",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0963",
"issue": "168(3)",
"journal": "The British journal of dermatology",
"keywords": null,
"medline_ta": "Br J Dermatol",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003875:Drug Eruptions; D004347:Drug Interactions; D004802:Eosinophilia; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010328:Patch Tests; D013262:Stevens-Johnson Syndrome; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "0004041",
"other_id": null,
"pages": "555-62",
"pmc": null,
"pmid": "23136927",
"pubdate": "2013-03",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions.",
"title_normalized": "a multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions"
} | [
{
"companynumb": "FR-ROXANE LABORATORIES, INC.-2014-BI-49014GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditi... |
{
"abstract": "OBJECTIVE\nReport of an acquired immunodeficiency syndrome (AIDS) patient with Epstein-Barr virus (EBV)-associated iris smooth muscle tumor.\n\n\nMETHODS\nA 14-year-old African American female diagnosed with AIDS developed a painless iris mass in the right eye for 10 months. Iridocyclectomy was performed, and the pathology indicated EBV-associated iris smooth muscle tumor with epithelioid morphology. Immunohistochemical stains and in situ hybridization for EBV-encoded ribonucleic acid are very useful diagnostic tools for definite diagnosis. At 14-month follow-up, the patient did not have any tumor recurrence.\n\n\nCONCLUSIONS\nThis is the case report of EBV-associated iris smooth muscle tumor in a person diagnosed with AIDS with a unique epithelioid morphologic feature.",
"affiliations": "Department of Ophthalmology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Department of Ophthalmology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Department of Ophthalmology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Department of Pathology, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand.",
"authors": "Suwan|Yanin|Y|;Rojanaporn|Duangnate|D|;Teekhasaenee|Chaiwat|C|;Keelawat|Somboon|S|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IMCRJ.S96837",
"fulltext": "\n==== Front\nInt Med Case Rep JInt Med Case Rep JInternational Medical Case Reports JournalInternational Medical Case Reports Journal1179-142XDove Medical Press 10.2147/IMCRJ.S96837imcrj-9-083Case ReportEpstein–Barr virus-associated iris smooth muscle tumor with epithelioid morphology in AIDS patients: a case report Suwan Yanin 1Rojanaporn Duangnate 1Teekhasaenee Chaiwat 1Keelawat Somboon 21 Department of Ophthalmology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand2 Department of Pathology, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, ThailandCorrespondence: Yanin Suwan, Department of Ophthalmology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, Tel +66 2 201 2729, Fax +66 2 354 7280, Email yanin.suwan@gmail.com2016 30 3 2016 9 83 86 © 2016 Suwan et al. This work is published and licensed by Dove Medical Press Limited2016The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Importance\nReport of an acquired immunodeficiency syndrome (AIDS) patient with Epstein–Barr virus (EBV)-associated iris smooth muscle tumor.\n\nObservations\nA 14-year-old African American female diagnosed with AIDS developed a painless iris mass in the right eye for 10 months. Iridocyclectomy was performed, and the pathology indicated EBV-associated iris smooth muscle tumor with epithelioid morphology. Immunohistochemical stains and in situ hybridization for EBV-encoded ribonucleic acid are very useful diagnostic tools for definite diagnosis. At 14-month follow-up, the patient did not have any tumor recurrence.\n\nConclusion\nThis is the case report of EBV-associated iris smooth muscle tumor in a person diagnosed with AIDS with a unique epithelioid morphologic feature.\n\nKeywords\nhuman immunodeficiency virus (HIV)acquired immunodeficiency syndrome (AIDS)iris tumorEpstein-Barr virussmooth muscle tumorleiomyosarcoma\n==== Body\nIntroduction\nAcquired immunodeficiency syndrome (AIDS) patients have an increased susceptibility to develop multiple malignant neoplasms. One of the well-recognized lesion in AIDS is Epstein–Barr virus (EBV)-induced smooth muscle tumor (SMT).1 They can occur in several anatomic sites. However, uveal tract EBV-associated SMTs are extremely rare, to the best of knowledge only seven cases have been described in the English literature.2–8 This report describes another documented AIDS patient with EBV-associated iris SMT, which is unique for its prominent epithelioid morphology.\n\nMethods\nA case of EBV-associated iris SMT was diagnosed and followed up in Ramathibodi Hospital, a tertiary referral center, between May 2014 and June 2014.\n\nCase report\nA 14-year-old African American female developed a painless iris mass in the right eye for 10 months. She had a vertically transmitted human immunodeficiency virus (HIV) infection since birth. As a result of poor compliance, the most recent CD4 count was 27 cell/mm3 without previous opportunistic infections. HIV viral load was 60,261 copies/mL. The patient had been taking antiretroviral drugs (nevirapine, zidovudine, and lamivudine) and trimethoprim/sulfamethoxazole at the time of visit.\n\nShe complained of blurred vision in the right eye. Her best-corrected visual acuity was 20/70 OD and 20/25 OS. Slit-lamp biomicroscopy in the right eye revealed an oval, yellowish, highly vascularized iris mass with 6 mm horizontal diameter and 10 mm vertical diameter extending from the 4:00 to 11:00 positions (Figure 1). Multiple iris pigment epithelial cysts were found adhering to the posterior iris surface. Slit-lamp biomicroscopy of the left eye and dilated ophthalmoscopies of both eyes demonstrated no significant findings. Gonioscopy showed a tumor occupying the entire iris surface and obstructing the temporal anterior chamber angle. The anterior surface of the tumor adhered to the corneal endothelium. Ultrasound biomicroscopy revealed a hypoechoic mass coalesced with iris stroma and multiple underlying posterior iris pigment epithelial cysts (Figure 2). The largest diameter was 5.6 (horizontal) and 9.3 mm (vertical) by ultrasonic measurements. Since the tumor was confined within the iris tissue with ciliary body extension, an iridocyclectomy was performed to remove the entire mass. The neoplastic lesion that was removed was solid with homogeneous gray–white cut surfaces.\n\nHistology revealed the specimen consisting of iris tissue with an attached tumor mass. The tumor lesion consisted of plump-shaped and epithelioid-appearing cells containing mildly pleomorphic, vesicular nuclei with inconspicuous nucleoli, and ill-defined eosinophilic cytoplasm. Vague fascicular arranging pattern was observed. Mitotic count was ∼8/10 high-power fields (HPF). Tumor necrosis was not found. Because of its epithelioid shape, tumors with such morphology, eg, malignant melanoma, undifferentiated carcinoma, and EBV-SMT were included in the lists of differential diagnoses with immunohistochemical studies which were performed accordingly. The neoplastic cells were strongly reactive to smooth muscle actin but negative to cytokeratin (AE1/AE3), S-100, desmin, epithelial membrane antigen, and HMB-45. In situ hybridization for EBV-encoded ribonucleic acid revealed a positive reaction in most regions of the tumor (Figure 3). The final diagnosis was, therefore, concluded as “EBV-associated SMT”.\n\nAt 14-month follow-up, the patient was free of disease. The visual acuity was 20/25 OD (Figure 4).\n\nThis study was approved by the Ramathibodi Hospital, Mahidol University Ethic committee. Written, informed consent was obtained from all subjects and the study adhered to the tenets of the Declaration of Helsinki.\n\nDiscussion\nEBV-induced SMTs have been described in AIDS as well as in organ transplantation.3 The pathogenesis of this change appears to be related to the viral infection that induces neoplastic transformation of infected smooth muscle cells. However, it is unclear as to how these microorganisms can lead to such tumorigenesis.9\n\nSeveral anatomical locations have been involved by these tumors1,10,11 of which the central nervous system is the most common site, followed by the soft tissue.9 Of these patients, many of them have multiple organ involvement.9\n\nAlthough several cases of SMTs have been reported in the iris, only seven cases were proven to be associated with an EBV infection.2,4,12 Herein, we present the case of EBV-SMT. The tumor is believed to arise from the dilator and sphincter muscles, which are of neuroectoderm in origin. The unique feature for our case is its dominant epithelioid morphology, different from the typical plump spindle (cigar-shaped) cells that comprise the major part of those described in other reports. This appearance likely represents a histologic variant, similar to its non-EBV related, SMT counterpart.\n\nWe prefer to use the term “EBV-associated SMT” for our case rather than EBV-associated leiomyosarcoma as reported by some authors,9 since the criteria for distinction between benign and malignant neoplasms for EBV-SMT, so far, have not yet been well established.9 In the review article by Purgina et al9 in which 64 published cases of EBV-SMT were analyzed, there was no difference in clinical outcomes between the groups diagnosed with leiomyoma and leiomyosarcoma using the same criteria with the soft tissue counterpart of non-EBV-related SMTs. As such, until when there are generally accepted criteria to separate benign from malignant EBV-related SMTs, the diagnostic term and criteria used for EBV-related SMTs should not be similar to the usual type of non-EBV-associated neoplasms at present.\n\nHistologically, the iris EBV-SMT should be distinguished from amelanotic spindle cell melanoma which can be difficult without the assistance of immunohistochemical studies owing to their overlapped morphologic features. Foss et al reported 24 cases of patients with SMTs all of which turned out to be melanocytic neoplasms when studied with appropriate immunohistochemistry.13 In this particular case, most tumor cells were of epithelioid shape, therefore, epithelial tumors and several epithelioid mesenchymal neoplasms were included for differential diagnosis. However, with the history of HIV infection in this patient, EBV-SMT was suspected and immunohistochemistries as well as in situ hybridization for EBV were performed to confirm such diagnosis.\n\nWhen compared with the classic, non-EBV-related leiomyosarcomas, the histology of EBV-SMT is somewhat different to the former. They hardly achieve the level of atypia noted in the classic leiomyosarcomas, although many display some levels of mitotic activity.14 In addition, primitive rounded smooth muscle cell nodules can be identified as a minor part among interlacing fascicles of differentiated cigar-shaped smooth muscle cells in about half of the cases.14 Intralesional T-lymphocytes are also a common feature of this entity.14\n\nEBV is also implicated in the pathogenesis of a number of hematological and nonhematological neoplasms.15 Studied results indicated that the other EBV-related neoplasms, for example, lymphoid neoplasms, were the consequence of a second, independent EBV infection, due to the persistent immunodeficiency of the patient.16\n\nDue to the lightly pigmented nature of these tumors, transillumination defects might be difficult to determine tumor extension.7 It has been suggested that fluorescein angiography is probably a better tool for achieving this purpose.17\n\nIn general, EBV-SMT appears to have a variable aggressiveness and clinical outcomes. Compared with conventional, non-EBV-related leiomyosarcoma that often progresses with hematogenous spread and distant metastasis, EBV-SMT tends to have more favorable clinical courses. Patients who develop such lesions have rarely died as a direct consequence of the tumors. From one previous report,9 tumor-related deaths from EBV-SMT occurred in only 6%. Surgical resection was the main therapeutic approach in the previously published studies.\n\nFor the iris tumors, there are limited data about the natural course of disease since only eight iris EBV-SMTs have been described including this case. Three patients acquired HIV infection since birth.2,4 The latter two cases were 10 years and more older than the first case who was a 4-year-old female.2,4 The delay in presentation of disease might be explained by more effective antiretroviral regimens against HIV virus. From our last report,4 serial slit-lamp photography documented a 100% enlargement of the tumor dimension within 2 months. Although the iris mass in our patient was much larger than that of the previous reports, it was surprisingly indolent and it minimally disturbed the patient. All patients shared a common feature of a very low CD4 count, which might indicate a tendency of this condition to occur in a severely compromised host. Mean CD4 count was ∼60 cells/μL from the previous report.9\n\nConclusion\nIn conclusion, we present a case of an iris EBV-SMT, which is unique in its epithelioid morphology as a dominant feature. Although relatively rare, this entity should be regarded as one differential diagnosis in HIV-infected patients who have spindle or epithelioid neoplastic lesions for which confirmatory immunohistochemistry and EBV study are necessary.\n\nAcknowledgments\nThe authors would like to thank Kirsten Russell for manuscript revision.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 A well-circumscribed amelanotic iris mass with underlying multiple posterior pigment epithelial cysts.\n\nFigure 2 UBM revealed a hypoechoic mass coalesced with iris stroma with 5.6 mm horizontal diameter and 9.3 mm vertical diameter.\n\nAbbreviation: UBM, ultrasound biomicroscopy.\n\nFigure 3 Histopathology and Immunohistochemical stain.\n\nNotes: (A) Histopathology of the surgical specimen showing attached iridic tissue (H&E ×40). (B) Tumor cells having plump shape and epithelioid appearance with mildly pleomorphic and vesicular nuclei (H&E ×400). (C) Immunohistochemical stain for alpha smooth muscle actin (IHC ×100). (D) In situ hybridization for EBER shows positive reaction (EBER ×400).\n\nAbbreviations: EBER, Epstein–Barr virus-encoded RNA; H&E, hematoxylin and eosin; IHC, immunohistochemistry.\n\nFigure 4 Final slit-lamp biomicroscopy at 8 months revealed the absence of tumor recurrence.\n==== Refs\nReferences\n1 McClain KL Leach CT Jenson HB Association of Epstein-Barr virus with leiomyosarcomas in children with AIDS N Engl J Med 1995 332 1 12 18 7990860 \n2 Tulvatana W Pancharoen C Mekmullica J Epstein-Barr virus-associated leiomyosarcoma of the iris in a child infected with human immunodeficiency virus Arch Ophthalmol 2003 121 10 1478 1481 14557189 \n3 Yu L Aldave AJ Glasgow BJ Epstein-Barr virus-associated smooth muscle tumor of the iris in a patient with transplant: a case report and review of the literature Arch Pathol Lab Med 2009 133 8 1238 1241 19653717 \n4 Suwan YRD Teekhasaenee C Aroonroch R Epstein-Barr virus-associated iris leiomyosarcoma in an AIDS patient: a case report J Clin Exp Ophthalmol 2014 5 342 \n5 Okamoto N Sotani T Shimo-Oku M Sashikata T A case with leiomyoma of iris extirpated with cryosurgery and its pathological findings Acta Ophthalmol (Copenh) 1982 60 2 183 189 7136532 \n6 Jellie HG Gonder JR Willis NR Green L Tokarewicz AC Leiomyoma of the iris Can J Ophthalmol 1989 24 4 169 171 2743204 \n7 Eide N Farstad IN Roger M A leiomyoma of the iris documented by immunohistochemistry and electron microscopy Acta Ophthalmol Scand 1997 75 4 470 473 9374264 \n8 Tuncer S Peksayar G Demiryont M Gozum N Long term follow-up of a patient with iris leiomyoma treated with partial lamellar iridocyclectomy Acta Ophthalmol Scand 2004 82 1 112 114 14738498 \n9 Purgina B Rao UN Miettinen M Pantanowitz L AIDS-related EBV-associated smooth muscle tumors: a review of 64 published cases Patholog Res Int 2011 2011 561548 21437186 \n10 Zevallos-Giampietri EA Yanes HH Orrego Puelles J Barrionuevo C Primary meningeal Epstein-Barr virus-related leiomyosarcoma in a man infected with human immunodeficiency virus: review of literature, emphasizing the differential diagnosis and pathogenesis Appl Immunohistochem Mol Morphol 2004 12 4 387 391 15536343 \n11 Zetler PJ Filipenko JD Bilbey JH Schmidt N Primary adrenal leiomyosarcoma in a man with acquired immunodeficiency syndrome (AIDS). Further evidence for an increase in smooth muscle tumors related to Epstein-Barr infection in AIDS Arch Pathol Lab Med 1995 119 12 1164 1167 7503667 \n12 Dugmore WN 11-year follow up of a case of iris leiomyosarcoma Br J Ophthalmol 1972 56 4 366 367 5038724 \n13 Foss AJ Pecorella I Alexander RA Hungerford JL Garner A Are most intraocular “leiomyomas” really melanocytic lesions? Ophthalmology 1994 101 5 919 924 8190481 \n14 Goldblum J Folpe A Weiss A Enzinger and Weiss’s Soft Tissue Tumors 6 ed Philadelphia, PA Elsevier Saunders 2014 549 568 \n15 Hsu JL Glaser SL Epstein-Barr virus-associated malignancies: epidemiologic patterns and etiologic implications Crit Rev Oncol Hematol 2000 34 1 27 53 10781747 \n16 Petrilli G Lorenzi L Paracchini R Epstein-Barr virus-associated adrenal smooth muscle tumors and disseminated diffuse large B-cell lymphoma in a child with common variable immunodeficiency: a case report and review of the literature Int J Surg Pathol 2014 22 8 712 721 21454372 \n17 Sevel D Tobias B The value of fluorescein iridography with lleiomyoma of the iris Am J Ophthalmol 1972 74 3 475 478 5053692\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-142X",
"issue": "9()",
"journal": "International medical case reports journal",
"keywords": "Epstein-Barr virus; acquired immunodeficiency syndrome (AIDS); human immunodeficiency virus (HIV); iris tumor; leiomyosarcoma; smooth muscle tumor",
"medline_ta": "Int Med Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101566269",
"other_id": null,
"pages": "83-6",
"pmc": null,
"pmid": "27099533",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "14557189;2743204;15536343;19653717;5053692;9374264;7503667;8190481;21437186;7990860;5038724;21454372;7136532;14738498;10781747",
"title": "Epstein-Barr virus-associated iris smooth muscle tumor with epithelioid morphology in AIDS patients: a case report.",
"title_normalized": "epstein barr virus associated iris smooth muscle tumor with epithelioid morphology in aids patients a case report"
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"activesubstancename": "NEVIRAPINE"
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{
"abstract": "An unexpected increased HCC recurrence and occurrence rate among HCV patients treated with direct acting antivirals combination has been reported. Aim of the study was the evaluation of early HCC occurrence rate and its risk factors in a HCV infected population, treated with direct-acting-antivirals.\n\n\n\nAccording to the Italian ministerial guidelines for direct-acting-antivirals treatment, 1022 consecutive HCV patients treated with direct-acting-antivirals were enrolled. Patients either with active HCC at imaging or history of previous treated HCC, HBV or HIV co-infection, or liver transplant recipients were excluded. The SVR, defined as the persistent absence of detectable serum HCV-RNA 12 weeks after the end of treatment (SVR12), was assessed for all enrolled patients. Abdominal ultrasound was performed before starting antiviral therapy, and repeated every 6 months. HCC was diagnosed according to the international guidelines. Patients showing either nodular patterns suggestive of HCC or with uncertain dynamic vascular behaviour were excluded from a further follow-up.\n\n\n\nNine hundred and eighty-five patients completed the 48 weeks follow-up after the end of treatment. A Sofosbuvir-based regimen was administered in the 74.9% of patients, among whom, the 71.6% underwent a simultaneous Ribavirin administration. A sustained virological response at 12 weeks off treatment was documented in 966 patients (98.2%). During the post treatment follow-up HCC was detected in 35 patients, with a cumulative incidence rate of the 3.55%. At multivariate analysis, four variables resulted independently associated with HCC development, both in a cirrhosis based and a class B Child based model, respectively: cirrhosis/class B Child, therapeutic schedule including Sofosbuvir without Ribavirin, liver stiffness values, male gender and presence of diabetes. A multivariate analysis performed on Child A cirrhotic patients, showed that Sofosbuvir based therapeutic treatment without Ribavirin had a HCC occurrence 5.7 higher than Ribavirin-based schedules with or without Sofosbuvir (p < 0.0001, OR: 5.686, 95% CI 2.455-13.169).\n\n\n\nOur data suggest that early HCC occurrence appears more frequently related to Sofosbuvir-based therapy without Ribavirin which, indeed, seems to play a protective role on HCC onset. Therefore, a careful follow-up should be mandatory, especially in those regimens including Sofosbuvir without Ribavirin.",
"affiliations": "Department of Advanced Medical and Surgical Sciences, University of Campania \"Luigi Vanvitelli\", Naples, Italy. luca.rinaldi@unicampania.it.;Immunological and Neurological Infectious Diseases Unit, Cotugno Hospital, Naples, Italy.;Department of Clinical Medicine and Surgery, Gastroenterology Unit, Federico II University, Naples, Italy.;Hepatology and Pancreas Unit, Cardarelli Hospital, Naples, Italy.;Liver Diseases and Transplant Unit, Department of Medical Sciences, S. Anna and S. Sebastiano Hospital, Caserta, Italy.;Department of Precision Medicine, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Department of Advanced Medical and Surgical Sciences, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Department of Precision Medicine, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Department of Precision Medicine, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Department of Precision Medicine, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Liver Diseases and Transplant Unit, Department of Medical Sciences, S. Anna and S. Sebastiano Hospital, Caserta, Italy.;Department of Advanced Medical and Surgical Sciences, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Department of Precision Medicine, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Liver Diseases and Transplant Unit, Department of Medical Sciences, S. Anna and S. Sebastiano Hospital, Caserta, Italy.;Medical Unit, New Hospital of Marcianise, Marcianise, CE, Italy.;Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori Aviano, Aviano, PN, Italy.;Department of Advanced Medical and Surgical Sciences, University of Campania \"Luigi Vanvitelli\", Naples, Italy.;Department of Clinical Medicine and Surgery, Gastroenterology Unit, Federico II University, Naples, Italy.;Immunological and Neurological Infectious Diseases Unit, Cotugno Hospital, Naples, Italy.;Department of Advanced Medical and Surgical Sciences, University of Campania \"Luigi Vanvitelli\", Naples, Italy.",
"authors": "Rinaldi|Luca|L|0000-0002-6541-3821;Perrella|Alessandro|A|;Guarino|Maria|M|;De Luca|Massimo|M|;Piai|Guido|G|;Coppola|Nicola|N|;Pafundi|Pia Clara|PC|;Ciardiello|Fortunato|F|;Fasano|Morena|M|;Martinelli|Erika|E|;Valente|Giovanna|G|;Nevola|Riccardo|R|;Monari|Caterina|C|;Miglioresi|Lucia|L|;Guerrera|Barbara|B|;Berretta|Massimiliano|M|;Sasso|Ferdinando Carlo|FC|;Morisco|Filomena|F|;Izzi|Antonio|A|;Adinolfi|Luigi Elio|LE|",
"chemical_list": "D000998:Antiviral Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s12967-019-2033-x",
"fulltext": "\n==== Front\nJ Transl MedJ Transl MedJournal of Translational Medicine1479-5876BioMed Central London 203310.1186/s12967-019-2033-xResearchIncidence and risk factors of early HCC occurrence in HCV patients treated with direct acting antivirals: a prospective multicentre study http://orcid.org/0000-0002-6541-3821Rinaldi Luca luca.rinaldi@unicampania.it 1Perrella Alessandro 2Guarino Maria 3De Luca Massimo 4Piai Guido 5Coppola Nicola 6Pafundi Pia Clara 1Ciardiello Fortunato 6Fasano Morena 6Martinelli Erika 6Valente Giovanna 5Nevola Riccardo 1Monari Caterina 6Miglioresi Lucia 5Guerrera Barbara 7Berretta Massimiliano 8Sasso Ferdinando Carlo 1Morisco Filomena 3Izzi Antonio 2Adinolfi Luigi Elio 11 0000 0001 2200 8888grid.9841.4Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy 2 Immunological and Neurological Infectious Diseases Unit, Cotugno Hospital, Naples, Italy 3 0000 0001 0790 385Xgrid.4691.aDepartment of Clinical Medicine and Surgery, Gastroenterology Unit, Federico II University, Naples, Italy 4 grid.413172.2Hepatology and Pancreas Unit, Cardarelli Hospital, Naples, Italy 5 Liver Diseases and Transplant Unit, Department of Medical Sciences, S. Anna and S. Sebastiano Hospital, Caserta, Italy 6 0000 0001 2200 8888grid.9841.4Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy 7 Medical Unit, New Hospital of Marcianise, Marcianise, CE Italy 8 0000 0004 1757 9741grid.418321.dDepartment of Medical Oncology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori Aviano, Aviano, PN Italy 28 8 2019 28 8 2019 2019 17 29220 4 2019 18 8 2019 © The Author(s) 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nAn unexpected increased HCC recurrence and occurrence rate among HCV patients treated with direct acting antivirals combination has been reported. Aim of the study was the evaluation of early HCC occurrence rate and its risk factors in a HCV infected population, treated with direct-acting-antivirals.\n\nMethods\nAccording to the Italian ministerial guidelines for direct-acting-antivirals treatment, 1022 consecutive HCV patients treated with direct-acting-antivirals were enrolled. Patients either with active HCC at imaging or history of previous treated HCC, HBV or HIV co-infection, or liver transplant recipients were excluded. The SVR, defined as the persistent absence of detectable serum HCV-RNA 12 weeks after the end of treatment (SVR12), was assessed for all enrolled patients. Abdominal ultrasound was performed before starting antiviral therapy, and repeated every 6 months. HCC was diagnosed according to the international guidelines. Patients showing either nodular patterns suggestive of HCC or with uncertain dynamic vascular behaviour were excluded from a further follow-up.\n\nResults\nNine hundred and eighty-five patients completed the 48 weeks follow-up after the end of treatment. A Sofosbuvir-based regimen was administered in the 74.9% of patients, among whom, the 71.6% underwent a simultaneous Ribavirin administration. A sustained virological response at 12 weeks off treatment was documented in 966 patients (98.2%). During the post treatment follow-up HCC was detected in 35 patients, with a cumulative incidence rate of the 3.55%. At multivariate analysis, four variables resulted independently associated with HCC development, both in a cirrhosis based and a class B Child based model, respectively: cirrhosis/class B Child, therapeutic schedule including Sofosbuvir without Ribavirin, liver stiffness values, male gender and presence of diabetes. A multivariate analysis performed on Child A cirrhotic patients, showed that Sofosbuvir based therapeutic treatment without Ribavirin had a HCC occurrence 5.7 higher than Ribavirin-based schedules with or without Sofosbuvir (p < 0.0001, OR: 5.686, 95% CI 2.455–13.169).\n\nConclusions\nOur data suggest that early HCC occurrence appears more frequently related to Sofosbuvir-based therapy without Ribavirin which, indeed, seems to play a protective role on HCC onset. Therefore, a careful follow-up should be mandatory, especially in those regimens including Sofosbuvir without Ribavirin.\n\nKeywords\nHCCDirect acting antiviralsHCV cirrhosisImmune-surveillanceissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nDirect acting antiviral (DAA) based treatment dramatically changed the natural history of hepatitis C virus (HCV) chronic infection. In fact, whereas previous antiviral regimens were characterized by a sustained virological response (SVR) rate of the 55–65%, these new therapies schedules, according to several clinical trials and the available real practice reports, reached more than 90% of SVR [1]. Indeed, the viral clearance embodies a fundamental turning point in the chronic HCV infection, as it may prevent the most part of severe complications and disease evolution of persistent infection, since these are related to immune system imbalance because of viral replication [2, 3].\n\nNew DAAs schedule activity on immune system is still unknown. However, DAA treatment seems to exert a certain effect on immune response [4, 5].\n\nHepatocellular carcinoma (HCC) represents one of the most important complications of chronic liver disease, with an incidence rate of the 1–6% per year, and is mainly related to two well-known pathways: (a) to fibrosis due to continuous necrosis and (b) to immune-surveillance failures attributable to persistent viral replication with immune system escape mechanisms [6]. A direct carcinogenic effect of HCV proteins, which deregulate host cell cycle checkpoints and the virus and immune-mediated oxidative stress, thus leading to DNA mutations in liver cells, is also known [7]. Therefore, according to all these evidences, HCV eradication and its necro-inflammation activity may be crucial in HCC prevention.\n\nSo far, several long-term studies on patients treated with Interferon and Ribavirin-based regimens globally reported a reduced HCC incidence in about the 75% of patients achieving a SVR, and a residual risk of HCC development, mainly associated with comorbidities, such as metabolic syndrome and type 2 diabetes [8, 9].\n\nRecently, an unexpected increased HCC recurrence and occurrence rate among HCV patients treated with DAAs combination has been reported, raising some concerns about a possible indirect role of the new antiviral drugs [10–13]. Conversely, other studies showed either a stable or a decreased overall HCC incidence [14, 15].\n\nThese controversial data are triggering an interesting debate on the residual risk of HCC development after DAAs treatment, especially about the possible involvement of DAAs in liver carcinogenesis.\n\nAccording to the aforementioned evidences [7–9], our study assessed DAAs efficacy and early HCC occurrence rate and risk factors in a real life setting on a well-studied HCV population regularly followed during and after an antiviral treatment with DAAs.\n\nPatients and methods\nStudy design and patients population\nFrom February 2015 to February 2017 a group of 6 Hospital and Academic Centres in Southern Italy (Campania Region) conducted a prospective, real-life study on efficacy of DAAs treatment schedule. 1022 consecutive HCV patients treated with IFN-free DAAs regimens were enrolled.\n\nAccording to the Italian ministerial guidelines for DAAs treatment, inclusion criteria were HCV-RNA serum positivity and fibrosis stage ≥ F3 according to Metavir score (the Italian reimbursement criteria were applicable only for patients with F3–F4 fibrosis), assessed either by liver biopsy or transient elastography (TE). The TE was performed by Fibroscan® (Echosens, Paris, France), according to standard criteria.\n\nIn this real life population study, patients with either active HCC at imaging or history of previous treated HCC, HBV or HIV co-infection, or liver transplant recipients were excluded.\n\nThe baseline HCC screening for all patients enrolled in our cohort was performed according to the European Association for the Study of Liver (EASL) guidelines [16].\n\nAn abdominal ultrasound (US) was performed before starting the antiviral therapy (within 1 month). Each US was performed by an experienced operator [more than 5000 exams performed following SIUMB (Italian Society of Ultrasound Medicine) certification], to minimize the bias of a multicenter, unmonitored study. Either a contrast-enhanced ultrasonography (CEUS), a dynamic computed tomography (CT) scan or dynamic magnetic resonance imaging (MRI) was performed to characterize incidental hepatic lesions. Patients showing either nodular patterns suggestive of HCC or with uncertain dynamic vascular behaviour at treatment enrolment were instead excluded from a further follow-up.\n\nHCV-RNA was assessed by real-time PCR (COBAS® TaqMan, AmpliPrep, Roche), with a detection limit of 15 IU/mL.\n\nCirrhosis diagnosis was based on clinical, biochemical, ultrasonographic, elastographic and, where available, histological parameters. In particular, among cirrhotic patients, liver function was graded according to the Child–Turcotte–Pugh (CTP) score system.\n\nDemographic characteristics and clinical parameters at baseline, were recorded and reported (Fig. 1).Fig. 1 Study flow\n\n\n\n\nThe study was performed according to the 1976 Declaration of Helsinki and its later amendments and approved by our local Ethic Committee. All patients gave their informed consent to the study.\n\nAntiviral treatment\nPatients eligibility to HCV treatment with IFN-free DAAs regimens was assessed following the priority criteria established in February 2015 by the National Scientific Society and Registry of the Italian Medicines Agency Committee (AIFA). The prescribing clinicians chose the treatment regimen in accordance with the National and International Guidelines and its most recent updates at that time [17, 18].\n\nThe treatment duration (12/24 weeks) was established based on the severity of liver disease, with a longer treatment reserved to cirrhotic patients.\n\nPatients were treated either with Sofosbuvir + Ribavirin (SOF/RBV-dual), Simeprevir + Sofosbuvir ± Ribavirin, Daclatasvir + Sofosbuvir ± Ribavirin, Ledipasvir + Sofosbuvir ± Ribavirin or Ombitasvir/Paritaprevir/Ritonavir (2D) ± Dasabuvir (3D) ± Ribavirin.\n\nSuccessively, therapeutic regimens were categorized as follows: Sofosbuvir (SOF)-based, Ribavirin (RBV)-included and all treatment Sofosbuvir + Ribavirin based (SOF/RBV-all). Ribavirin dosage was never reduced (according to adverse events) below 600 mg day in all therapeutic schedules.\n\nPatients follow-up\nNine hundred and eighty-five (n = 985) of the 1022 enrolled patients completed the 48 weeks follow-up after the end of treatment. Thirty-five patients were excluded from the analysis due to incomplete follow-up data, whilst three died during the antiviral therapy (due to causes unrelated to DAAs).\n\nVirological response to the therapy was assessed by real-time PCR, with HCV-RNA detection at the end of the treatment, 12 and 24 weeks after its end. The SVR, defined as the persistent absence of detectable serum HCV-RNA 12 weeks after the end of treatment (SVR12), was assessed for all enrolled patients. Any relapse of serum HCV-RNA during follow-up was also recorded.\n\nAt least three ultrasound examinations were performed on every enrolled patient during the established follow-up period (before starting therapy and every 6 months), according to the HCC surveillance program and the study design. Any detected liver lesion was evaluated by imaging technique workup (CEUS, or dynamic CT scan or dynamic MRI) according to EASL guidelines [16].\n\nThe diagnosed HCC were recorded and scored according to Barcelona Clinic Liver Cancer (BCLC) staging system [19]. Once a patient was diagnosed with HCC, the follow-up was discontinued.\n\nEndpoints of study\nPrimary endpoint was the assessment of HCC occurrence rate in HCV patients within 48 weeks after DAAs-IFN free treatment, whilst secondary endpoint was the evaluation of risk factors associated with HCC occurrence.\n\nAs an additional end-point, a sub-analysis exclusively focused on cirrhotic patients was performed, to reduce any possible selection bias. Similarly, an additional sub-analysis within cirrhotic patients focused on Child A or Child B patients, most of all to obtain an indication to the prescription of 3D–2D therapies only in Child A patients.\n\nStatistical analysis\nBaseline characteristics and measures of clinical and demographic variables were expressed as absolute and percentage (for categorical variables) or median and interquartile range (IQR) for continuous variables. Categorical data were compared using either the Pearson Chi-square test (with Mantel–Haenszel common odds ratio estimate) or Fisher Exact test when indicated, and continuous variables by non-parametric Mann–Whitney U test or Kruskal–Wallis test, where indicated. A logistic binary regression model (backward step-wise model) was performed to evaluate independent factors associated with HCC occurrence. Moreover, a stratification analysis was also performed, in order to better assess the much higher HCC occurrence with respect to duration of therapy.\n\nTo avoid a collinearity bias, the presence of cirrhosis and the class B CTP were evaluated separately in two different models. For all statistical comparisons, a two-tailed significance level of 0.05 was used, with a 95% confidence interval. All analyses were performed using SPSS software, version 24.0 (IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY:IBM Corp.).\n\nResults\nNine hundred and eighty-five patients completed treatment and follow-up, according to the study design, from February 2015 to February 2017. Data were equally distributed among the participant Centres. The baseline demographic characteristics of the enrolled population are reported in Tables 1 and 2.Table 1 Overall baseline characteristics according to SVR status\n\nParameters\tOverall\n(n = 985)\tSVR\n(n = 966)\tNo SVR\n(n = 19)\t\nSex, n (%)\t\n M\t543 (55.1)\t529 (54.8)\t14 (73.7)\t\n F\t442 (44.9)\t437 (45.2)\t5 (26.3)\t\nAge, years, median [IQR]\t67 [59–73]\t67 [59–73]\t66 [60–71]\t\nBMI, kg/m2, median [IQR]\t26 [24–28.4]\t26 [24–28.3]\t27 [23.3–30.6]\t\nDiabetes, n (%)\t131 (13.3)\t129 (13.4)\t2 (10.5)\t\nMetabolic syndrome, n (%)\t69 (8)\t69 (8.1)\t–\t\nLiver disease stage, n (%)\t\n Advanced fibrosis\t254 (25.8)\t252 (26.1)\t2 (10.5)\t\n Cirrhosis\t731 (74.2)\t714 (73.9)\t17 (89.5)\t\nHCV genotype, n (%)\t\n 1\t765 (77.7)\t754 (78.1)\t12 (63.2)\t\n 2\t160 (16.2)\t155 (16.1)\t4 (21.1)\t\n 3\t50 (5.1)\t47 (4.9)\t3 (15.8)\t\n 4\t10 (1.0)\t10 (1.0)\t0\t\nLiver stiffness, kPa, median [IQR]\t17.3 [11.9–35.3]\t16 [11.8–23]\t23.4 [14.6–41.7]\t\nTreatment duration, n (%) (weeks)\t\n 12\t612 (62.1)\t603 (62.4)\t9 (47.4)\t\n 24\t373 (37.9)\t363 (37.6)\t10 (52.6)\t\nSVR12, n (%)\t966 (98.1)\t\t\t\nDAAs regimen, n (%)\t\n SOF/RBV (dual)\t417 (42.3)\t408 (42.2)\t10 (52.6)\t\n SOF/LDV ± RBV\t183 (18.6)\t186 (19.3)\t3 (15.8)\t\n SOF/DCV ± RBV\t39 (4.0)\t33 (3.4)\t0 (0.0)\t\n SOF/SIM ± RBV\t99 (10.1)\t97 (10)\t2 (10.5)\t\n 2D/3D ± RBV\t247 (25.0)\t242 (25.1)\t4 (21.1)\t\nTreatment classes, n (%)\t\n SOF based\t738 (74.9)\t723 (74.8)\t15 (78.9)\t\n RBV included\t705 (71.6)\t693 (71.7)\t12 (63.2)\t\n SOF/RBV (all)\t573 (58.2)\t561 (58.1)\t12 (63.2)\t\nHCC occurrence, n (%)\t35 (3.6)\t35 (3.6)\t0 (0)\t\n\nTable 2 Overall baseline characteristics according to liver disease stage\n\nParameters\tCirrhosis (n = 731)\tAdvanced liver fibrosis (n = 254)\t\nSex, n (%)\t\n M\t391 (53.5)\t152 (59.8)\t\n F\t340 (46.5)\t102 (40.2)\t\nAge, years, median [IQR]\t68 [60–74]\t66 [58–72]\t\nBMI, kg/m2, median [IQR]\t26 [23.9–28.4]\t26.1 [24.1–28.3]\t\nDiabetes, n (%)\t99 (13.6)\t32 (12.6)\t\nMetabolic syndrome, n (%)\t53 (8.2)\t16 (7.5)\t\nChild–Turcotte–Pugh, n (%)\t\n Class A\t649 (88.8)\t–\t\n Class B\t82 (11.2)\t–\t\nHCV genotype, n (%)\t\n 1\t561 (76.7)\t205 (80.7)\t\n 2\t121 (16.6)\t38 (15)\t\n 3\t43 (5.9)\t7 (2.8)\t\n 4\t6 (0.8)\t4 (1.6)\t\nLiver stiffness, kPa, median [IQR]\t21 [15.6–27.2]\t10.7 [10–11.8]\t\nTreatment duration, n (%) (weeks)\t\n 12\t401 (54.9)\t211 (83.1)\t\n 24\t330 (45.1)\t43 (16.9)\t\nSVR12, n (%)\t714 (97.7)\t252 (99.2)\t\nDAAs regimen, n (%)\t\n SOF/RBV\t322 (44)\t96 (37.8)\t\n SOF/LDV ± RBV\t158 (21.6)\t31 (12.2)\t\n SOF/DCV ± RBV\t26 (3.6)\t7 (2.8)\t\n SOF/SIM ± RBV\t78 (10.7)\t21 (8.3)\t\n 2D/3D ± RBV\t147 (20.1)\t109 (39)\t\nTreatment classes, n (%)\t\n SOF based\t584 (79.9)\t154 (60.6)\t\n RBV included\t549 (75.1)\t156 (24.2)\t\n SOF/RBV\t450 (61.6)\t123 (48.4)\t\nHCC occurrence, n (%)\t35 (4.8)\t0 (0)\t\n\n\n\nWithin the subgroup of cirrhotic patients (n = 731), four hundred and eighty-five (74.8%) CTP A and 64 (78%) of the CTP B patients underwent a RBV scheduled treatment. An overall successful treatment outcome, with SVR achievement, was obtained in 966 patients (98.1%).\n\nDuring the post treatment follow-up, HCC onset was reported in 35 patients, with a cumulative incidence rate of the 3.55%, which raised till the 4.65% considering only the cirrhotic subset of patients. Two HCC cases were recorded at the end of treatment, 16 cases 12–24 weeks after treatment, and 17 cases 36–48 weeks after treatment.\n\nAll patients with HCC occurrence did not show any viral relapse, achieving a SVR. The median diameter of lesions was 33 mm (range 18–57 mm). None of the patients with HCC was an active alcohol consumer, whilst three subjects (8.5%) were smokers (about 10 cigarettes/day).\n\nAccording to BCLC classification, patients were stratified as follows: 27 patients as stage A, 4 patients as stage B, 4 patients as stage C. Among HCC patients, 31 of them (88.5%) underwent a SOF-based treatment and 19 (61.3%) were treated without RBV.\n\nBased on univariate analysis, gender (p = 0.048), age (p = 0.045), CTP B stage (p = 0.001), presence of diabetes as comorbidity (p = 0.007), presence of cirrhosis (p = 0.002), and liver stiffness value (p < 0.0001) were significantly associated with HCC occurrence. A SOF-based therapeutic regimen without RBV was significantly associated with HCC development (p = 0.003). Conversely, the use of Ribavirin was associated with a reduced risk of HCC development (p < 0.0001), regardless of the DAAs regimen (Table 3).Table 3 Clinical and demographic characteristics in patients with and without HCC occurrence—univariate and multivariate analysis\n\nParameters\tUnivariate analysis\tMultivariate analysis (cirrhosis)\tMultivariate analysis (Child–Pugh)\t\nPatients without HCC (n = 950)\tPatients with HCC (n = 35)\tp\tO.R. [95% C.I.]\tp\tO.R. [95% C.I.]\tp\t\nMale gender, n (%)\t518 (54.5)\t25 (71.4)\t0.048\t2.852 [1.162–6.999]\t0.022\t2.738 [1.109–6.762]\t0.029\t\nAge, years, median [IQR]\t67 [59–73]\t69 [64–74]\t0.045\t\t\t\t\t\nBMI, kg/m2, median [IQR]\t26 [24–28.4]\t25.4 [23.4–28]\t0.17\t\t\t\t\t\nPresence of diabetes, n (%)\t121 (12.8)\t10 (28.6)\t0.007\t0.392 [0.155–0.988]\t0.047\t0.369 [0.146–0.931]\t0.047\t\nPresence of cirrhosis, n (%)\t696 (73.4)\t35 (100)\t0.002\t0.153 [0.019–1.239]\t0.079\t\t\t\nCTP B classa n (%)\t72/696 (10.3)\t10/34 (29.4)\t0.001\t\t\t0.430 [0.170–1.086]\t0.074\t\nHCV genotype 1, n (%)\t724 (77.3)\t29 (82.9)\t0.44\t\t\t\t\t\n24 weeks treatment duration, n (%)\t354 (37.3)\t19 (54.3)\t0.041\t\t\t\t\t\nBaseline HCV-RNA, UI/ml, median [IQR]\t995,500 [350,000–2,646,500]\t729,000 [290,000–1,238,000]\t0.123\t\t\t\t\t\nLiver stiffness, kPa, median [IQR]\t14.9 [11.8–22]\t32 [18.5–44.4]\t< 0.0001\t1.048 [1.020–1.077]\t0.001\t1.057 [1.031–1.084]\t0.000\t\nSVR12, n (%)\t933 (98.2)\t33 (94.3)\t0.09\t\t\t\t\t\nDAA-SOF based, n (%)\t707 (74.6)\t31 (88.6)\t0.09\t\t\t\t\t\nDAA-RBV included, n (%)\t690 (72.8)\t15 (42.9)\t< 0.0001\t\t\t\t\t\nDAA-SOF + RBV, n (%)\t562 (59.2)\t12 (34.3)\t0.003\t\t\t\t\t\nDAA-SOF without RBV, n (%)\t145 (20.5)\t19 (61.3)\t0.003\t15.363 [6.668–35.396]\t0.000\t0.059 [0.025–0.137]\t0.000\t\naComputed based on number of cirrhotic patients\n\n\n\n\nMoreover, the duration of therapy also resulted significantly associated with HCC occurrence (p = 0.041). Nevertheless, the greatest percentage of HCC occurrence in the group 24 weeks (5.1%) versus the group 12 weeks (2.6%) suggested us to perform a stratified analysis for each group of duration therapy. The 24 weeks group underwent more SOF therapy than the 12 weeks group (96.7% vs 61.8%). However, a stratification for duration of therapy (12 vs 24 weeks) and type of treatment (SOF-without-RBV vs all other Tx) showed a statistically significant association between that variable and HCC onset in both group: 12 weeks group (11.3% vs 1.3%, p = 0.001) and 24 weeks group (12.3% vs 3.1%, p = 0.005), independently from the duration of treatment.\n\nWe then performed two different multivariate models, in order to assess separately the presence of cirrhosis and the class B CTP, in order to avoid a collinearity bias.\n\nThe first model, built based on the presence of cirrhosis, showed four variables resulted independently associated with HCC development: the use of a SOF-based regimen without RBV (p = 0.000, O.R.: 15.363, 95% C.I. 6.668–35.396), liver stiffness values (p = 0.001, O.R.: 1.048, 95% C.I. 1.020–1.077), male gender (p = 0.022, O.R.: 2.852, 95% C.I. 1.162–6.999) and presence of diabetes as comorbidity (p = 0.047, O.R.: 0.392, 95% C.I. 0.155–0.988), whilst presence of cirrhosis just showed a trend at multivariate analysis, without reaching the statistical significance (p = 0.079; O.R.: 0.153; 95% C.I. 0.019–1.239) (Table 3).\n\nThe second model, built instead considering the CTP class B, similarly showed the same four variables as independently associated with HCC development: the use of a SOF-based regimen without RBV (p = 0.000, O.R.: 0.059, 95% C.I. 0.025–0.137), liver stiffness values (p = 0.000, O.R.: 1.057, 95% C.I. 1.031–1.084), male gender (p = 0.029, O.R.: 2.738, 95% C.I. 1.109–6.762) and presence of diabetes as comorbidity (p = 0.047, O.R.: 0.369, 95% C.I. 0.146–0.931), whilst presence of CTP class B just showed a trend at multivariate analysis, without reaching the statistical significance (p = 0.074; O.R.: 0.430; 95% C.I. 0.170–1.086) (Table 3).\n\nA further sub-analysis, focusing only on cirrhotic patients was performed. In this subset of patients, at univariate analysis (Table 4) male gender (p = 0.04), presence of diabetes (p = 0.006), CTP class B (p = 0.001), liver stiffness ≥ 20 kPa (p = 0.01), and the use of SOF-based regimen without RBV (p < 0.0001), were significantly associated with HCC occurrence. At multivariate analysis, four variables resulted independently associated with HCC development: the use of a SOF-based regimen without RBV (p < 0.0001, OR: 6.145, 95% CI 2.97–12.73), CTP class B (p = 0.004, OR: 3.29, 95% CI 1.46–7.44), male gender (p = 0.019, OR: 2.58, 95% CI 1.17–5.69) and presence of diabetes as comorbidity (p = 0.043, OR: 2.3, 95% CI 1.03–5.16) (Table 5).Table 4 Clinical and demographic characteristics in cirrhotic patients subgroup with and without HCC occurrence (N = 731)—univariate analysis\n\nVariables\tCirrhotic patients without HCC (n = 696)\tCirrhotic patients with HCC (n = 35)\tp\t\nMale gender, n (%)\t367 (52.7)\t24 (70.6)\t0.04\t\nAge, years, ≥ 67, n (%)\t373 (53.6)\t23 (67.6)\t0.11\t\nBMI, kg/m2 ≥ 26, n (%)\t285 (51.4)\t14 (42.4)\t0.32\t\nPresence of diabetes, n (%)\t89 (12.8)\t10 (29.4)\t0.006\t\nCTP B class, n (%)\t72 (10.3)\t10 (29.4)\t0.001\t\nHCV genotype 1, n (%)\t524 (76.2)\t28 (82.4)\t0.41\t\n24 weeks treatment duration, n (%)\t311 (44.6)\t19 (55.9)\t0.19\t\nBaseline HCV-RNA, UI/ml, ≥ 1 × 106, n (%)\t381 (54.7)\t13 (38.2)\t0.06\t\nLiver stiffness, kPa ≥ 20, n (%)\t176 (49.7)\t24 (72.7)\t0.01\t\nSVR12, n (%)\t682 (97.8)\t32 (94.1)\t0.16\t\nDAA-SOF based, n (%)\t555 (79.6)\t30 (88.2)\t0.31\t\nDAA-RBV included, n (%)\t535 (76.8)\t15 (44.1)\t< 0.0001\t\nDAA-SOF + RBV, n (%)\t438 (63.0)\t12 (35.3)\t0.001\t\nDAA-SOF without RBV, n (%)\t113 (16.2)\t18 (52.9)\t< 0.0001\t\n\nTable 5 Multivariable logistic regression analysis of risk factors for HCC occurrence in the cirrhotic patients subgroup (N = 731)\n\nVariables associated with HCC\tBeta coefficient\tp-value\tOdds ratio\tC.I. 95%\t\nLow\tUpper\t\nSOF without RBV\t1.82\t< 0.0001\t6.145\t2.97\t12.73\t\nChild–Turcotte–Pugh B class\t1.19\t0.004\t3.29\t1.46\t7.44\t\nMale gender\t0.95\t0.019\t2.58\t1.17\t5.69\t\nPresence of diabetes\t0.83\t0.043\t2.30\t1.03\t5.16\t\n\n\n\nSubsequently, we analysed HCC occurrence only in the 649 CTP class A cirrhotic patients, according to the therapeutic schedule. The multivariate analysis showed that SOF-based therapeutic treatment without Ribavirin had a HCC occurrence 5.7 higher than with Ribavirin in the schedule or compared to schedules without Sofosbuvir (2D–3D based therapy) (Table 6).Table 6 Multivariable logistic regression analysis of risk factors for HCC occurrence in the Child–Turcotte–Pugh Class A subgroup (N = 649)\n\nVariables associated with HCC\tBeta coefficient\tp-value\tOdds ratio\tC.I. 95%\t\nLow\tUpper\t\nMale gender\t1.166\t0.017\t3.210\t1.237\t8.332\t\nSOF without RBV\t1.738\t< 0.0001\t5.686\t2.455\t13.169\t\n\n\n\nA logistic regression was used to compare multiple causal variables on HCC development, also correcting for the potential confounding effects.\n\nBased on our findings, in order to avoid any possible bias, we established a further univariate statistical analysis on patients undergoing a 2D–3D treatment schedule, verifying the presence of any difference with respect to patients who had undergone SOF-based antiviral regimens, with respect to gender, CTP class, albumin serum level, bilirubin, INR, diabetes, liver stiffness and platelets. According to our results, we did not find any significant statistical difference in our real life population.\n\nDiscussion\nHepatitis C virus pathogenesis and its natural history are characterized by several factors, among which those implicating immune system activity. This, in fact, involves regulatory and effector environments, since the acute phase of infection plays an important role [20]. In this latter case, the chronic infection underlies a persistent activity of the immune system, with a specific cytokines environment leading first to a liver necro-inflammation, and then to HCC onset (which may still occur over the years, as previously suggested) [21]. HCC onset, in particular, was recently related to a persistent inflammatory network mainly supported by IL-17, TGF-beta and deactivation of T Regulatory cells [22]. Based on these findings, one of the most important purposes of the antiviral treatment in persistent infection is represented by the virus eradication in order to prevent HCC occurrence.\n\nPreviously, in interferon-based regimens, the reduction of HCC incidence, but not its disappearance, had been associated with several factors, among which: the cirrhotic persistence stage, advanced age, presence of latent HCV mutations, presence of comorbidities such as diabetes [8, 9]. The approval of second wave DAA represents a recent event and still does not allow for a long-term assessment of SVR impact on HCC incidence [23].\n\nRecently, two interesting studies have suggested some mechanisms as possible HCC inducers after DAA treatment. Debes et al. [24] identified, in patients who developed HCC de novo after DAA treatment, an higher value of 9 inflammatory cytokines, measured in serum before treatment (MIG, IL22, TRAIL, APRIL, VEGF, IL3, TWEAK, SCF, IL21), assuming a possible role in carcinogenesis.\n\nFaillaci et al. [25] showed that the DAAs-mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, i.e. who already have abnormal activation of neo-angiogenetic pathways in liver tissues, as showed by an increase in angiopoietin-2, studied in neoplastic and cirrhotic tissue.\n\nThis independent, real life study showed that the 61% of patients who developed a HCC had either a single small or 2–3 small nodules, while the remaining 39% were diagnosed with larger and infiltrative cancers. According to our data, early HCC occurrence seems to be associated with to well-known factors like diabetes, liver stiffness and advanced CTP stage. Furthermore, we also found that second wave HCV DAA therapy without a contemporary RBV treatment also seems to be related to an early HCC onset. Particularly, and more interestingly, this association with neoplasms onset seems strongly occurring among CTP A patients, hence suggesting that fibrosis might not represent the only factor possibly associated with HCC occurrence in this setting of patients.\n\nPatients who showed HCC onset achieved SVR. Our data, according to previous findings, while proving that DAAs treatment does not increase the overall risk of HCC, also appear to demonstrate that the successful antiviral therapy is not able to prevent HCC onset even though patients achieve SVR [26]. More interestingly, this latter scenario, upon a multivariate analysis, seems to be more frequently related to SOF based regimens without Ribavirin, whose use, conversely, appears associated with a reduced HCC risk.\n\nThese data could be in part explained with the well-known immune-modulating activity of RBV, independently from the dosage, which may improve immune surveillance, while both boosting Th1 response and switching from Th2 to a Th1 CD4 pattern too [27]. Moreover, some kind of protective activity of RBV against HCC, when associated with Doxorubicin, most likely implicating the immune-surveillance, has also been recently demonstrated [28].\n\nIt could also be speculated that a rapid reduction in the HCV viral load may impact the tumor immunity, since it might affect the balance between pro-tumor and anti-tumor immune functions previously reported [29].\n\nNonetheless, despite this scientific evidence and the possible suggestion of a pathogenetic model, the related fine mechanisms still remain unclear and are most likely associated with several factors.\n\nFurther mechanisms that could explain these events may be related to the mitochondrial dysregulation these new drugs may induce, even though literature data regarding this issue are contradictory [30, 31].\n\nConsistently with our data, the duration of therapy did not result significantly associated with HCC occurrence. Though a much higher percentage of HCC occurrence in the 24 weeks group versus the 12 weeks group, the stratification for duration of therapy did not affect the statistically significance between HCC onset and type of treatment.\n\nIt could be argued that our findings may be related to HCC micro nodules already placed in the liver before treatment, since the majority of nodules are bigger than 2 cm, as such rapid HCC growth seems really unusual. Of note, we found one patient having a 5 cm lesion at the onset of HCC. The possible reason of a close HCC onset after SVR and the difference in lesion size could be related not only to immune system but also intrinsically correlated to HCC. Indeed previously has been demonstrated that HCC size could explain phenotypic diversity within proliferative and non-proliferative HCCs and be associated to vascular invasion according to dimension [32]. Therefore patients with largest tumor are correlated to different metabolic path of tumor with related poor prognosis [33].\n\nIn addition, one of the major bias of the study is the limited number of cases and the short follow-up time, but early HCC occurrence was the primary endpoint of the study and, for that reason, long term assessment was not part of this research protocol.\n\nThese results seem to be corroborated by the absence of any statistically significant difference in clinical and laboratory results between patients who underwent 2D–3D based treatment compared to other antiviral regimens, as well as in the use of ribavirin in CTP class A and B.\n\nNevertheless, during the follow-up of our patients the aim was mainly focused on the early appearance of HCC after treatment and, fascinatingly, this event occurred at all times of this short term follow-up period. Therefore, our findings significantly underline that we still have no large data on the possible effect of some DAAs treatment schedule on physiopathology of HCC natural history and that Ribavirin, probably due to its immunomodulatory properties, may represents a protective factor on HCC risk.\n\nIn these patients, others rigorous studies on molecular mechanisms and immune system on are necessary to better elucidate and understand subtended mechanisms of early HCC occurrence in this cohort. In particular, a limitation of this study is the lack of an external validation cohort for confirming our results.\n\nConclusions\nEarly HCC occurrence appears to be associated with an advanced CTP stage, male gender, higher liver stiffness value and diabetes. However, interestingly, it is also more often correlated to SOF based therapy without Ribavirin, in CTP A, whereas the use of this latter antiviral seems exert a protective effect on HCC onset, as some literature also suggests [27, 28].\n\nWe therefore firmly believe that a careful selection during antiviral schedule evaluation, as well as follow-up, is mandatory, particularly in patients undergoing a SOF without RBV antiviral regimen.\n\nAbbreviations\nDAAdirect acting antiviral\n\nHCVhepatitis C virus\n\nSVRsustained virological response\n\nHCChepatocellular carcinoma\n\nTEtransient elastography\n\nEASLEuropean Association for the Study of Liver\n\nUSabdominal ultrasound\n\nSIUMBItalian Society of Ultrasound Medicine\n\nCEUScontrast-enhanced ultrasonography\n\nCTcomputed tomography\n\nMRImagnetic resonance imaging\n\nCTPChild–Turcotte–Pugh\n\nBMIbody mass index\n\nAIFAItalian Medicines Agency Committee\n\nSOFSofosbuvir\n\nRBVRibavirin\n\nBCLCBarcelona Clinic Liver Cancer\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\n“Programma Valere” University of Campania Luigi Vanvitelli.\n\nAuthors' contributions\nLR and LEA designed the study. AP, MG, GV, LM, CM, RN, BG collected the data. LR, LEA, AP, MG interpreted data. MDL and PCP analyzed and interpreted the data. LR, AP and MG wrote the manuscript. GP, NC, FM, AI, LEA, MB, FC, EM, MF revised the manuscript. All authors reviewed the manuscript. All authors read and approved the final manuscript.\n\nFunding\nDepartment of Advanced Medical and Surgical Sciences, University of Campania, Luigi Vanvitelli. The funders had no role in the writing of the manuscript or the decision to submit it for publication.\n\nAvailability data\nData available if requested.\n\nEthics approval and consent to participate\nUniversity of Campania Luigi Vanvitelli Ethic Committee (protoc. number 647).\n\nConsent approval\nNon individual data is shown.\n\nCompeting interests\nThe authors declare that they have no actual or potential competing interests, including any financial aspects, personal or other relationships with other people or organizations within it that may not be appropriate influence (prejudices) on their work.\n==== Refs\nReferences\n1. Pawlotsky JM Feld JJ Zeuzem S Hoofnagle JH From non-A, non-B hepatitis to hepatitis C virus cure J Hepatol 2015 62 S87 S99 10.1016/j.jhep.2015.02.006 25920094 \n2. Shi J Li Y Chang W Zhang X Wang FS Current progress in host innate and adaptive immunity against hepatitis C virus infection Hepatol Int 2017 11 374 383 10.1007/s12072-017-9805-2 28643186 \n3. Perrella A Sbreglia C Atripaldi L Esposito C D’Antonio A Perrella O Rapid virological response in peripheral blood mononuclear cells with an increase of hepatitis C virus-specific interferon-gamma production predisposes to sustained virological response in patients with chronic hepatitis C genotype 1 undergoing treatment with pegylated-interferon alpha 2a plus ribavirin Scand J Gastroenterol 2010 45 250 255 10.3109/00365520903428614 19968615 \n4. Van der Ree MH Stelma F Willemse SB Brown A Swadling L van der Valk M Immune responses in DAA treated chronic hepatitis C patients with and without prior RG-101 dosing Antiviral Res 2017 146 139 145 10.1016/j.antiviral.2017.08.016 28844749 \n5. Hou XJ Ye F Li XY Liu WT Jing YY Han ZP Immune response involved in liver damage and the activation of hepatic progenitor cells during liver tumorigenesis Cell Immunol 2018 326 52 59 10.1016/j.cellimm.2017.08.004 28860007 \n6. Wirth TC Manns MP The impact of the revolution in hepatitis C treatment on hepatocellular carcinoma Ann Oncol 2016 27 1467 1474 10.1093/annonc/mdw219 27226385 \n7. Lemon SM McGivern DR Is hepatitis C virus carcinogenic? Gastroenterology 2012 142 1274 1278 10.1053/j.gastro.2012.01.045 22537433 \n8. El-Serag HB Kanwal F Richardson P Kramer J Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection Hepatology 2016 64 130 137 10.1002/hep.28535 26946190 \n9. Nahon P Layese R Bourcier V Cagnot C Marcellin P Guyader D ANRS CO12 Cir Vir group Incidence of hepatocellular carcinoma after direct antiviral therapy for HCV in patients with cirrhosis included in surveillance programs Gastroenterology 2018 155 1436 1450 10.1053/j.gastro.2018.07.015 30031138 \n10. Reig M Mariño Z Perelló C Iñarrairaegui M Ribeiro A Lens S Unexpected early tumor recurrence in patients with hepatitis C virus-related hepatocellular carcinoma undergoing interferon-free therapy: a note of caution J Hepatol 2016 65 719 726 10.1016/j.jhep.2016.04.008 27084592 \n11. Rinaldi L Di Francia R Coppola N Guerrera B Imparato M Monari C Hepatocellular carcinoma in HCV cirrhosis after viral clearance with direct acting antiviral therapy: preliminary evidence and possible meanings WCRJ 2016 3 e748 \n12. Conti F Buonfiglioli F Scuteri A Crespi C Bolondi L Caraceni P Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct acting antivirals J Hepatol 2016 65 727 733 10.1016/j.jhep.2016.06.015 27349488 \n13. Kozbial K Moser S Schwarzer R Laferl H Al-Zoairy R Stauber R Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with sustained virologic response following interferon-free direct-acting antiviral treatment J Hepatol 2016 65 856 858 10.1016/j.jhep.2016.06.009 27318327 \n14. Romano A Angeli P Piovesan S Noventa F Anastassopoulos G Chemello L Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: a prospective population study J Hepatol 2018 69 345 352 10.1016/j.jhep.2018.03.009 29551707 \n15. Calvaruso V Cabibbo G Cacciola I Petta S Madonia S Bellia A Rete Sicilia Selezione Terapia-HCV (RESIST-HCV) Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting antiviral agents Gastroenterology 2018 155 411 421 10.1053/j.gastro.2018.04.008 29655836 \n16. 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Jin Z Kinkade A Behera I Chaudhuri S Tucker K Dyatkina N Rajwanshi VK Structure–activity relationship analysis of mitochondrial toxicity caused by antiviral ribonucleoside analogs Antiviral Res 2017 143 151 161 10.1016/j.antiviral.2017.04.005 28412183 \n32. Pawlik TM Delman KA Vauthey JN Nagorney DM Ng IO Ikai I Yamaoka Y Tumor predicts vascular invasion and histologic grade: implications for selection of surgical treatment for size hepatocellular carcinoma Liver Transpl 2005 11 1086 1092 10.1002/lt.20472 16123959 \n33. Wang X Wang Z Wu L Combined measurement of tumor number and size helps estimate the outcome of resection of Barcelona clinic liver cancer stage B hepatocellular carcinoma BMC Surg 2016 16 22 10.1186/s12893-016-0135-4 27094483\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1479-5876",
"issue": "17(1)",
"journal": "Journal of translational medicine",
"keywords": "Direct acting antivirals; HCC; HCV cirrhosis; Immune-surveillance",
"medline_ta": "J Transl Med",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D006528:Carcinoma, Hepatocellular; D005260:Female; D019698:Hepatitis C, Chronic; D006801:Humans; D015994:Incidence; D008103:Liver Cirrhosis; D008113:Liver Neoplasms; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011446:Prospective Studies; D012307:Risk Factors; D000072230:Sustained Virologic Response",
"nlm_unique_id": "101190741",
"other_id": null,
"pages": "292",
"pmc": null,
"pmid": "31462268",
"pubdate": "2019-08-28",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "16123959;16905711;16929323;19968615;20175034;22424438;22537433;22891772;25911336;25920094;26946190;27084592;27094483;27226385;27318327;27349488;27645237;28035203;28412183;28643186;28837142;28844749;28860007;28867970;29102620;29112301;29551707;29604220;29655836;29686274;30031138",
"title": "Incidence and risk factors of early HCC occurrence in HCV patients treated with direct acting antivirals: a prospective multicentre study.",
"title_normalized": "incidence and risk factors of early hcc occurrence in hcv patients treated with direct acting antivirals a prospective multicentre study"
} | [
{
"companynumb": "IT-GILEAD-2019-0427267",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SOFOSBUVIR"
},
"drugadditional": null,
... |
{
"abstract": "Platelet-derived growth factor receptor B (PDGFRB) gene rearrangements define a unique subgroup of myeloid and lymphoid neoplasms frequently associated with eosinophilia and characterized by high sensitivity to tyrosine kinase inhibition. To date, various PDGFRB/5q32 rearrangements, involving at least 40 fusion partners, have been reported. However, information on genomic and clinical features accompanying rearrangements of PDGFRB is still scarce. Here, we characterized a series of 14 cases with a myeloid neoplasm using cytogenetic, single nucleotide polymorphism array, and next-generation sequencing. We identified nine PDGFRB translocation partners, including the KAZN gene at 1p36.21 as a novel partner in a previously undescribed t(1;5)(p36;q33) chromosome change. In all cases, the PDGFRB recombination was the sole cytogenetic abnormality underlying the phenotype. Acquired somatic variants were mainly found in clinically aggressive diseases and involved epigenetic genes (TET2, DNMT3A, ASXL1), transcription factors (RUNX1 and CEBPA), and signaling modulators (HRAS). By using both cytogenetic and nested PCR monitoring to evaluate response to imatinib, we found that, in non-AML cases, a low dosage (100-200 mg) is sufficient to induce and maintain longstanding hematological, cytogenetic, and molecular remissions.",
"affiliations": "Department of Medicine and Surgery, Center for Hemato-Oncology Research (C.R.E.O.), University of Perugia, Perugia, Italy.;Department of Medicine and Surgery, Center for Hemato-Oncology Research (C.R.E.O.), University of Perugia, Perugia, Italy.;Department of Medicine and Surgery, Center for Hemato-Oncology Research (C.R.E.O.), University of Perugia, Perugia, Italy.;Department of Medicine and Surgery, Center for Hemato-Oncology Research (C.R.E.O.), University of Perugia, Perugia, Italy.;Department of Medicine and Surgery, Center for Hemato-Oncology Research (C.R.E.O.), University of Perugia, Perugia, Italy.;Department of Medicine and Surgery, Center for Hemato-Oncology Research (C.R.E.O.), University of Perugia, Perugia, Italy.;Department of Medicine and Surgery, Center for Hemato-Oncology Research (C.R.E.O.), University of Perugia, Perugia, Italy.;Department of Medicine and Surgery, Center for Hemato-Oncology Research (C.R.E.O.), University of Perugia, Perugia, Italy.;Division of Hematology, AOU Policlinico-San Marco, Catania, Italy.;Department of Pediatric Oncology-Hematology, Meyer Children's Hospital, Florence, Italy.;Hematology Unit, ASST-Spedali Civili, Brescia, Italy.;Hematology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.;Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy.;Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy.;Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy.;Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy.;Hematology, Department of Medical Sciences, St. Anna University Hospital, 44124, Ferrara, Italy.;Hematology Unit, ASST-Spedali Civili, Brescia, Italy.;Department of Medicine and Surgery, Center for Hemato-Oncology Research (C.R.E.O.), University of Perugia, Perugia, Italy. cristina.mecucci@unipg.it.",
"authors": "Di Giacomo|Danika|D|;Quintini|Martina|M|;Pierini|Valentina|V|;Pellanera|Fabrizia|F|;La Starza|Roberta|R|;Gorello|Paolo|P|;Matteucci|Caterina|C|;Crescenzi|Barbara|B|;Fiumara|Paolo Fabio|PF|;Veltroni|Marinella|M|;Borlenghi|Erika|E|;Albano|Francesco|F|;Forghieri|Fabio|F|;Maccaferri|Monica|M|;Bettelli|Francesca|F|;Luppi|Mario|M|;Cuneo|Antonio|A|;Rossi|Giuseppe|G|;Mecucci|Cristina|C|http://orcid.org/0000-0002-1623-0148",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-021-04712-8",
"fulltext": "\n==== Front\nAnn Hematol\nAnn Hematol\nAnnals of Hematology\n0939-5555\n1432-0584\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n34859285\n4712\n10.1007/s00277-021-04712-8\nOriginal Article\nGenomic and clinical findings in myeloid neoplasms with PDGFRB rearrangement\nDi Giacomo Danika 1\nQuintini Martina 1\nPierini Valentina 1\nPellanera Fabrizia 1\nLa Starza Roberta 1\nGorello Paolo 12\nMatteucci Caterina 1\nCrescenzi Barbara 1\nFiumara Paolo Fabio 3\nVeltroni Marinella 4\nBorlenghi Erika 5\nAlbano Francesco 6\nForghieri Fabio 7\nMaccaferri Monica 7\nBettelli Francesca 7\nLuppi Mario 7\nCuneo Antonio 8\nRossi Giuseppe 5\nhttp://orcid.org/0000-0002-1623-0148\nMecucci Cristina cristina.mecucci@unipg.it\n\n1\n1 grid.9027.c 0000 0004 1757 3630 Department of Medicine and Surgery, Center for Hemato-Oncology Research (C.R.E.O.), University of Perugia, Perugia, Italy\n2 grid.9027.c 0000 0004 1757 3630 Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy\n3 Division of Hematology, AOU Policlinico-San Marco, Catania, Italy\n4 grid.413181.e 0000 0004 1757 8562 Department of Pediatric Oncology-Hematology, Meyer Children’s Hospital, Florence, Italy\n5 grid.412725.7 Hematology Unit, ASST-Spedali Civili, Brescia, Italy\n6 grid.7644.1 0000 0001 0120 3326 Hematology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy\n7 grid.7548.e 0000000121697570 Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy\n8 grid.416315.4 Hematology, Department of Medical Sciences, St. Anna University Hospital, 44124 Ferrara, Italy\n2 12 2021\n2 12 2021\n2022\n101 2 297307\n20 10 2021\n26 10 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/.\nPlatelet-derived growth factor receptor B (PDGFRB) gene rearrangements define a unique subgroup of myeloid and lymphoid neoplasms frequently associated with eosinophilia and characterized by high sensitivity to tyrosine kinase inhibition. To date, various PDGFRB/5q32 rearrangements, involving at least 40 fusion partners, have been reported. However, information on genomic and clinical features accompanying rearrangements of PDGFRB is still scarce. Here, we characterized a series of 14 cases with a myeloid neoplasm using cytogenetic, single nucleotide polymorphism array, and next-generation sequencing. We identified nine PDGFRB translocation partners, including the KAZN gene at 1p36.21 as a novel partner in a previously undescribed t(1;5)(p36;q33) chromosome change. In all cases, the PDGFRB recombination was the sole cytogenetic abnormality underlying the phenotype. Acquired somatic variants were mainly found in clinically aggressive diseases and involved epigenetic genes (TET2, DNMT3A, ASXL1), transcription factors (RUNX1 and CEBPA), and signaling modulators (HRAS). By using both cytogenetic and nested PCR monitoring to evaluate response to imatinib, we found that, in non-AML cases, a low dosage (100–200 mg) is sufficient to induce and maintain longstanding hematological, cytogenetic, and molecular remissions.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1007/s00277-021-04712-8.\n\nKeywords\n\nPDGFRB\nChromosome translocations\nImatinib\nMolecular monitoring\nKAZN\nAIRC 5 × 1000#21267 MYNERVA project Mecucci Cristina Sergio Luciani Association, Fabriano, ItalyConsorzio Internazionale per le Biotecnologie, CIBhttp://dx.doi.org/10.13039/100014805 Roche Italia Roche per la Medicina di Precisione bando 2020 Di Giacomo Danika issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2022\n==== Body\npmcIntroduction\n\nThe PDGFRB gene, at 5q32, encodes for the ß chain of the cell surface receptor for platelet-derived growth factor (PDGFRß), a class III receptor tyrosine kinase (RTK) that activates signaling pathways involved in cell growth and differentiation [1]. PDGFRB is a frequent target of chromosomal translocations in a subgroup of hematological malignancies recognized in the 2017 World Health Organization (WHO) as a stand-alone category under “Myeloproliferative neoplasms with eosinophilia and gene rearrangement” [2. These disorders are presenting as chronic myeloid neoplasms, frequently as chronic myelomonocytic leukemia with eosinophilia [2], although (hyper)-eosinophilia is not invariably present [3, 4]. Less frequently, PDGFRB is rearranged in lymphoid malignancies, including cases of both B- and T-cell acute lymphoblastic leukemia/lymphoma (ALL) [1, 4–6]. In addition, in the same patient, a PDGFRB rearrangement may underlie the occurrence of two different malignancies of both myeloid and lymphoid lineages, which may be diagnosed concomitantly or sequentially [7, 8]. To date, at least 40 fusion translocation partners of PDGFRB have been identified. Among them, ETV6 is the most frequently involved gene as a consequence of the t(5;12)(q32;p13) [4], while all other partners are rare and often found in single cases [9]. Whatever the partner, the PDGFRB gene always participates in the fusion with its 3′ end tyrosine kinase domain, resulting in the constitutive activation and in the deregulation of downstream signaling cascades, including Ras/mitogen-activated protein kinase, phosphatidylinositol 3′-kinase, and phospholipase-5γ pathways [4]. Information on somatic gene variants in cases with a PDGFRB rearrangement is still scarce mainly affecting ASXL1, TET2, STAG2, DNMT3A, NRAS, ZRSR2, BCOR, and STAT5B [4, 7, 10, 11]. Male predominance and a median age at onset in the late 40 s [2] have been established. Most patients have splenomegaly and/or hepatomegaly [2]. Rapid response and long-term remission are obtained with tyrosine kinase inhibitors. In particular, imatinib is the treatment of choice for this group of neoplasms [3, 4, 9]. Although this treatment is successful, few series of cases with clinical and molecular monitoring have been reported [3, 4, 12].\n\nWe carried out an in-depth characterization of genomic events accompanying the 5q32 rearrangement in a series of 14 PDGFRB-positive cases recruited in our center during the last 23 years. In addition, we evaluated the response to imatinib by cytogenetic and molecular monitoring.\n\nMaterials and methods\n\nPatients\n\nPatients with a myeloid neoplasm and a rearrangement of PDGFRB were recruited from the files of the Laboratory of Cytogenetics at the Department of Medicine and Surgery-Hematology section of the University of Perugia (Table 1). Data collection was done in accordance with the Declaration of Helsinki and its later amendments. The study was approved by the Bioethics Committee University of Perugia (number 2014–0259). All patients or their parents/guardians have provided informed consent for sample collection and use in approved research studies. Table 1 Demographic, clinical, and hematological features of 14 cases with PDGFRB rearrangement\n\nCase\tSex/age\tPresentation\tClinical and hematological diagnosis\tOrganomegaly\tLymphadenopathy\tLDH (U/L)\tKaryotype\tFusion gene\tTreatment before imatinib\tResponse\tPreviously reported\t\nWBC (× 109/L)\tHGB (g/dL)\tMCV (fL)\tPLT (× 109/L)\tEosinophils (× 109/L)\tMonocytes (× 109/L)\t\nChronic presentations\t\n1\tM/41\t85.4\t11.1\t68.3\t183\t6.5\t2.2\tMDS/MPN-U\tSplenomegaly\n\nHepatomegaly\n\n\tSuperficial\t364\t46,XY,t(5;12)(q33;p13)[17]\tETV6::PDGFRB\tHydroxyurea\tNo\tNo\t\n2\tM/68\t57.2\t12.9\t91\t240\t3.4\t1.7\tMDS/MPN-U\tHepatomegaly\tNo\t695\t46,XY,t(5;12)(q33;p13)[16]/46,XY[4]\tETV6::PDGFRB\tSteroids and hydroxyurea (3 months)\tNo\tNo\t\n3\tM/45\t40.3\t14.3\tn.a\t187\t3.2\t2\tCMML\tSplenomegaly\tn.a\tn.a\t46,XY,add(1)(p36),del(5)(q33q35), der(12)del(12)(p13)add(12)(q22 ~ q24) [18]. ish\n\nt(1;12;5;12)(WCP1 + ,WCP12 + ;WCP12\n\n + ,WCP1 + ;WCP5 + ,WCP12 + ;WCP12 + , WCP5 +)/46,XY[2]\n\n\tETV6::PDGFRB\tα-IFN (1 month)\tNo\tYes [20]\t\n4\tM/26\t60.8\t7.8\t90.7\t9\t1.89\t2.91\tMDS/MPN-U\tSplenomegaly Hepatomegaly\tSuperficial\t581\t46,XY,t(5;12)(q31;p13)[10]/46,XY[1]\tERC1::PDGFRB\tNo\t-\tNo\t\n5\tM/21\t21.6\t16.4\tn.a\t190\t8\tn.a\tCEL\tSplenomegaly\tNo\tn.a\t46,XY,t(1;5)(q21;q33)[29]/46,XY[1]\tTPM3::PDGFRB\tα-IFN (10 years)\tHR\tYes [17, 18]\t\n6\tF/31\t15.4\t14.2\tn.a\t171\t3.2\tn.a\tCEL\tSplenomegaly\tn.a\t153\t46,XX,t(5;14)(q33;q32)\tCCDC88C::PDGFRB\tNo\t–\tYes [19]\t\n7\tF/2\t23\t12.2\t85\t346\t2.3\t1.33\tMDS/MPN-U\tSplenomegaly\tn.a\t288\t46,XX,t(5;14)(q33;q32)\tCCDC88C::PDGFRB\tThioguanine (6 months)\tNo\tNo\t\n8\tF/75\t11.2\t12.8\t100.6\t236\t2\t1.34\tMDS/MPN-U\tNo\tn.a\tn.a\t46,XX,t(5;9)(q33;q34)[20]\tTSC1::PDGFRB\tNo\t–\tNo\t\n9\tF/35\t38.6\t13.5\tn.a\t336\t14.4\t13.1\tCMML\tSplenomegaly\tn.a\tn.a\t46,XX,t(5;16)(q33;p13)[11]/46,XX[4]\tNDE1::PDGFRB\tSteroids and hydroxyurea (5 months)\tHR\tYes [21, 23]\t\n10\tM/49\t33\t10.3\tn.a\t398\t2\t1\taCML\tNo\tNo\tn.a\t46,XY,t(5;10)(q33;q22)[17]/46,XY[1]\tCCDC6::PDGFRB\tHydroxyurea (18 weeks) -cytarabine + steroids (7 days)-hydroxyurea + thioguanine\tNo\tYes [16]\t\n11\tM/40\t16.3\t10\t90.6\t246\t2.2\t1.11\tMDS/MPN-U\tSplenomegaly\tn.a\tn.a\t46,XY\tTNIP1::PDGFRB\tNo\t–\tYes [24]\t\nAggressive/unusual presentations\t\n12\tM/66\t12.6\t13.7\t91\t256\tn.a\tn.a\tMyeloid sarcoma\tNo\tSuperficial\tNormal\t46,XY,t(5;12)(q33;p13)[14]/46,XY[3]\tETV6::PDGFRB\tnilg aml 06.02 (5 months)\tHR, CCR, CMR\tNo\t\n13\tM/36\t3.1\t11.4\tn.a\t97\tn.a\t0.34\tRelapsed-AML*\tSplenomegaly\n\nHepatomegaly\n\n\tn.a\tn.a\t46,XY,t(5;12)(q33;p13.3)[9]/92,XXYY\n\n,t(5;12)(q33;p13.3)X2[12]\n\n\tERC1::PDGFRB\tNo\t–\tYes [22]\t\n14\tM/33\t106.8\t7.9\t111.3\t43\t1.1\t12.8\tAML\tSplenomegaly\tNo\t1604\t46,XY,t(1;5)(p35;q33)\tKAZN::PDGFRB\tNo\t–\tNo\t\nMDS/MPN-U myelodysplastic/myeloproliferative neoplasm-unclassifiable, CMML chronic myelomonocytic leukemia, AML acute myeloid leukemia, CEL chronic eosinophilia leukemia, aCML atypical chronic myeloid leukemia, WBC white blood cells, HGB hemoglobin, MCV mean corpuscular volume, PLT platelet, HR hematological remission, CCR complete cytogenetic remission, CMR complete molecular remission, n.a. not available\n\n*The previous diagnosis was of AML M5a 4 years before, followed by auto-HSCT [22]\n\nFISH\n\nFluorescence in situ hybridization (FISH) was used to investigate PDGFRB involvement in our cohort, to identify translocation partners, and to assess cytogenetic response. A complete list of the genomic probes is reported in Supplementary Table 1. PDGFRB was studied by using either a commercial break-apart probe (LSI PDGFRB Break Apart, Abbott Molecular Diagnostics, Rome, Italy) or home-brew FISH assays with bac probes (RP11-759G10, 149,562,887–149,746,958, for the 5′, and RP11-100O5, 149,274,400–149,455,385, for the 3′) and even more specific cosmid clones: cosmid 4–1, for the 5′, and 9–4, for the 3′ of the gene [13]. The 1p36/KAZN breakpoint was characterized using a series of locus-specific probes mapping at 1p36–1p35 regions (Supplementary Table 1). Genomic coordinates are referred to GRCh37/hg19 assembly. One to two hundred nuclei and at least 7 abnormal metaphases were analyzed in each experiment. Follow-up analyses were carried out in one thousand nuclei. Cutoffs were assumed at the upper limit value obtained in 500 cells from a normal donor. FISH was used to assess the cytogenetic response in 13/14 cases (nos. 1–9, 11–14) with a monitoring range of 1–12 months.\n\nSingle nucleotide polymorphism array (SNPa)\n\nCopy number variations (CNVs), gains, losses, and copy neutral loss of heterozygosity (cnLOH) were studied by SNP array in 9 cases with available material at diagnosis (nos. 1–4, 7–8, 11, 13–14) using a Cytoscan HD Array Kit (Affymetrix/Thermo Fisher Scientific, Santa Clara, CA, USA) following manufacturer’s instructions. Data were analyzed by Chromosome Analysis Suite (ChAS 4.1) software with hg19 build as reference. Filters were set at 400 kb, 50 markers for CNVs, and 10 Mb, 50 markers for cnLOH. Polymorphic copy number variants were excluded from the analysis by comparing with the Database of Genomic Variants (http://dgv.tcag.ca/dgv/app/home).\n\nRT-PCR\n\nTotal RNA was extracted by Trizol reagent (Invitrogen, Carlsbad, CA, USA), according to the manufacturer’s protocol. One microgram was retrotranscribed using 50 U of SuperscriptII (Invitrogen). Nested PCR was performed to identify the fusion transcripts in 13/14 cases (nos. 1–9, 11–14) and for monitoring the minimal residual disease in 11 cases (nos. 1–4, 7–9, 11–14) with a monitoring range of 1–12 months (primer details are reported in Supplementary Table 2).\n\nTreatment\n\nTherapeutic regimens and responses for all patients are reported in Table 1 and .Table 2 Cytoreductive treatment was administered in eight cases (nos. 1–3, 5, 7, 9–11; Table 1) before the cytogenetic finding of a PDGFRB involvement was available. Thereafter, imatinib was administered as monotherapy in 13/14 cases (Table 2). Seven cases (nos. 1–2, 4, 6–8, 11) received a low dosage (100–200 mg/die), whereas 4 cases (nos. 3, 9, 13–14) received a high dosage (400 mg/die). In 2 cases (nos. 3 and 9), the dosage was reduced during follow-up. In 2 cases (nos. 5 and 12), the dosage was not available. Table 2 Imatinib regimens and monitoring after treatment\n\nCase\tImatinib dosage at diagnosis\tImatinib dosage at follow-up\tCCR (months from imatinib)\tCMR (months from imatinib)\tRelapse\tLast follow-up (months after imatinib)\t\n1\t100 mg\t200 mg\t + 24\t + 24\tNo\t + 30a\t\n2\t100 mg\t100 mg\t + 4\t + 18\tNo\t + 30a\t\n3\t400 mg\t200 mg\t + 1\t + 25\tNo\t + 222a\t\n4\t100 mg\t100 mg\t + 9\t + 9\tNo\t + 61a\t\n5\tn.a\tn.a\t + 11\tn.a\tn.a\t + 33*\t\n6\t100 mg\t200 mg\t + 24\tn.a\tNo\t + 155*\t\n7\t100 mg\t200 mg\t + 8\t + 32\tNo\t + 109a\t\n8\t100 mg\t200 mg\t + 40§\t + 40§\tNo\t + 42a\t\n9\t400 mg\t100 mg\t + 12\t + 44\tNo\t + 129†\t\n11\t100 mg\t200 mg\t + 12\tNo\tNo\t + 72a\t\n12\tn.a\tn.a\tMaintained after CHT\tMaintained after CHT\tB-ALL\t + 11†\t\n13\t400 mg\t400 mg\t + 4\tNo\tNo\t + 9†\t\n14\t400 mg\t400 mg\t + 7\t + 10#\tAML\t + 36†\t\nCCR complete cytogenetic remission, CMR complete molecular remission, CHT chemotherapy, B-ALL B cell acute lymphoblastic leukemia, n.a. not available\n\naAlive\n\n§First evaluation after treatment\n\n#Obtained after 8 months of imatinib therapy followed by 2 months of induction chemotherapy\n\n†Death\n\n*Lost at follow up\n\nTargeted NGS\n\nMutational analysis of thirty genes mutated in myeloid malignancies and included in the Myeloid Solution SOPHiA GENETICS (Saint‐Sulpice, Switzerland) was performed following the manufacturer’s instructions on 13 cases at diagnosis (patient nos. 1–4, 6–14), in 8 cases (nos. 1, 4, 7–8, 11–14) also at cytogenetic and/or molecular remission, and in one case (no. 14) also after HSCT. The resulting captured libraries were further processed on a Miseq® sequencing platform (Illumina, San Diego, CA, USA). FASTQ sequencing files were uploaded to SOPHiA DDM® platform version 4 and, following adapter trimming and quality filtering, reads were aligned to the human reference genome (hg19 assembly) through the artificial SOPHiA™ intelligence. Variant calling of the resulted alignments was then performed using an in-house somatic variant caller, which takes into account the background noise level at each region. Only exonic and splice sites variants with MAF < 0.01 were taken into consideration and classified according to ACMG criteria [14] using the Varsome database [15]. Mutations with a variant allele frequency (VAF) of 40–60% or > 90% and/or associated with a clinical phenotype reported in OMIM (Online Mendelian Inheritance in Man, https://omim.org/) were defined as germline. All other variants were defined as somatic.\n\nResults\n\nFourteen cases were collected. The median age at diagnosis was 38 years (range: 2–75) with a male/female ratio of 2.5 (Table 1). Eleven of fourteen patients were first observed in a non-aggressive phase (6 MPN/MDS, 2 CEL, 2 CMML, 1 aCML), 2 cases were first diagnosed as acute myeloid leukemia, and 1 case was diagnosed as myeloid sarcoma (Table 1). Thirteen of fourteen cases (93%) presented with leukocytosis (range: 11.2–106.8 × 109/L); eosinophilia (≥ 0.5 × 109/L) or hyper-eosinophilia (≥ 1.5 × 109/L) was demonstrated in 12 of them (range: 1.07–14.4 × 109/L) (Table 1). Six cases showed monocytosis (≥ 1.5 × 109/L). Anemia was seen in seven cases and thrombocytopenia in three. Hepatomegaly and/or splenomegaly was present in eleven cases (Table 1), and lymphadenopathy was noticed in three (Table 1). The serum lactate dehydrogenase level was available in seven cases and resulted increased in five (288–1604 U/L). Skin lesions have been noticed at diagnosis in two cases (nos. 7 and 9, Table 1).\n\nCytogenetics and molecular findings\n\nInvolvement of 5q32 was detected by conventional cytogenetics in 13/14 patients while it was cryptic in case no. 11 (Table 1). In case no. 13, with t(5;12), hyperdiploidy was predominant. FISH revealed PDGFRB involvement and identified the translocation partner in all cases. Seven partners were already reported [16–24]. RT-PCR confirmed the presence of the corresponding fusion transcript in all cases with available material (12/14; nos. 1–4, 6–9, 11–14). Nine different partner genes were found (Table 1). Among them, ETV6 (n = 4), ERC1 (n = 2), and CCDC88C (n = 2) were recurrent partners. Moreover, in case no. 14, we identified KAZN at 1p36.21 as a novel partner gene of PDGFRB. Metaphase FISH identified the 1p breakpoint between RP11-1079F4, flanking the 5′, and RP11-317H5, covering the 3′ of the gene. Additional experiments, showing the splitting of WI2-0883F15 and WI2-0968K05 fosmids, narrowed the breakpoint between exons 4 and 5 of KAZN (Fig. 1a). RT-PCR confirmed an in-frame fusion between exon 4 of KAZN (NM_201628.3) and exon 12 of PDGFRB (NM_002609.3) (Fig. 1b) Fig. 1 Cytogenetic and molecular characterization of the novel KAZN::PDGFRB fusion. a FISH break-apart assay with fosmids WI2-0883F15 (spectrum green) and WI2-0968K05 (spectrum orange) for KAZN/1p36.21 showed a fusion signal on normal chromosome 1, a red signal on der(1), and a green signal on der(5) in case no. 14 (Table 1). b Direct sequencing showed an in-frame fusion joining exon 4 of KAZN to exon 12 of PDGFRB. GenBank accession numbers: NM_201628.3 for KAZN and NM_002609.3 for PDGFRB. nl, normal; ex, exon\n\nSNParray\n\nSNPa revealed a total of 13 events (3 gains, 8 losses, and 2 copy neutral LOH, Supplementary Table 3) in nine investigated cases. However, they were mainly concentrated in case no. 13 showing nine imbalances (gains at 3q and 8q, and losses at 1p, 2q, 4q, and 5q; Supplementary Table 3). Four events were distributed in case nos. 1, 3, 11, and 14 (Supplementary Table 3). The remaining four cases (nos. 2, 4, 7, and 8) were normal (Supplementary Table 3).\n\nMutational analysis\n\nNGS was applied in 13 cases at diagnosis. Seven of them showed a total of 16 variants (range: 0–5 per case) (Fig. 2 and Table 3). One germline mutation at PTPN11 was confirmed in patient no. 9 (Fig. 2 and Table 3). A total of five somatic variants affecting HRAS (n = 2), TET2, DNMT3A, and CEBPA (n = 1 each) were found in 5 out of the 10 cases with chronic presentation (nos. 4, 8–11; 1 mutation/case). Longitudinal studies showed disappearance of HRAS and TET2 variants at remission in case nos. 4 and 8, respectively, whereas DNMT3A mutation load increased at cytogenetic remission in case no. 11 (Table 3). In the two cases with AML at presentation (nos. 13 and 14), we found a total of 10 somatic mutations (5 mutation/case) (Fig. 2 and Table 3). In both cases, RUNX1 was affected by multiple variants (n = 9), while one mutation at ASXL1 was found in case no. 14 (see Fig. 2, Table 3, and below for details). Table 3 Sequence variants identified in PDGFRB-positive cases and their longitudinal monitoring\n\n\tCase no 4\tCase no 8\tCase no 9\tCase no 10\tCase no 11\tCase no 13\tCase no 14\t\nDiagnosis\tCCR/CMR\tDiagnosis\tCCR/CMR\tDiagnosis\tDiagnosis\tDiagnosis\tCCR\tDiagnosis\tCCR\tDiagnosis\tCCR\tPost-HSCT\t\nFLT3\t\t\t\t\t\t\t\t\t\t\tAbsent\tc.1804_1805ins120, p.Leu601_Lys602ins40 (2.6%)\tAbsent\t\nPTPN11\t\t\t\t\tc.178 G > T, p.Gly60Cys (43.3%)\t\t\t\t\t\t\t\t\t\nASXL1\t\t\t\t\t\t\t\t\t\t\tc.2277C > A, p.Cys759* (45.4%)\tc.2277C > A, p.Cys759* (42.7%)\tc.2277C > A, p.Cys759* (1.4%)\t\nDNMT3A\t\t\t\t\t\t\tc.2645G > A, p.Arg882His (8.5%)\tc.2645G > A, p.Arg882His (25.9%)\t\t\t\t\t\t\nTET2\t\t\tc.1123G > T, p.Glu375* (29.7%)\tAbsent\t\t\t\t\t\t\t\t\t\t\nCEBPA\t\t\t\t\tc.646A > G, p.Thr216Ala (2.5%)\t\t\t\t\t\t\t\t\t\nRUNX1\t\t\t\t\t\t\t\t\tc.500G > T, p.Ser167Ile (17.8%)\tAbsent\tc.777dupT, p.Asn260* (41.6%)\tc.777dupT, p.Asn260* (16%)\tAbsent\t\nc.586A > C, p.Thr196Pro (17.1%)\tAbsent\tc.497G > A, p.Arg166Gln (1.3%)\tc.497G > A, p.Arg166Gln (4.8%)\tc.497G > A, p.Arg166Gln (1.5%)\t\nc.496C > T, p.Arg166* (16.7%)\tAbsent\tc.472_473insGG, p.Phe158Trpfs*19 (1.9%)\tc.472_473insGG, p.Phe158Trpfs*19 (13.3%)\tAbsent\t\nc.1011del, p.Ala338Argfs*256 (7.3%)\tAbsent\tc.941_942insCT, p.Ala315Leufs*14 (0.7%)\tc.941_942insCT, p.Ala315Leufs*14 (2.2%)\tAbsent\t\nc.424_445dup, p.Ala149Glyfs*2 (6.8%)\tAbsent\t\nHRAS\tc.404G > A, p.Arg135Gln (7.1%)\tAbsent\t\t\t\tc.412G > T, p.Gly138Cys (2.8%)\t\t\t\t\t\t\t\t\nVariance allele frequency (VAF) is indicated in brackets\n\nCCR complete cytogenetic remission of the PDGFRB rearrangement, CMR complete molecular remission of the PDGFRB rearrangement, HSCT hematopoietic stem cell transplant\n\nAggressive and unusual presentations\n\nTwo cases of our cohort presented as acute myeloid leukemia (nos. 13 and 14) and one case as myeloid sarcoma (no. 12).\n\nCase no. 12\n\nA 66-year-old man was diagnosed with myeloid sarcoma in another center based on a lymph node biopsy. At the same time, we found t(5;12)/PDGFRB::ETV6 and the absence of somatic mutations in bone marrow cells. Hematological, cytogenetic, and molecular response were achieved after 2 cycles of chemotherapy [25]. Remission was maintained by imatinib which was discontinued after 5 months because of iatrogenic interstitial infiltrates and pulmonary fibrosis. Four months later, the patient developed a B-ALL but material was not available for our cytogenetic-molecular studies. He died in aplasia after chemotherapy.\n\nCase no. 13\n\nA 36-year-old man received imatinib only at relapse, occurring 4 years after the first identification of a t(5;12)-positive AML that underwent chemotherapy and autologous transplant. At relapse, in addition to the PDGFRB translocation, we found five somatic variants at the RUNX1 gene (Fig. 2 and Table 3). The patient was treated with imatinib (400 mg/day) followed by chemotherapy. The disappearance of hematological and cytogenetic remissions and RUNX1 mutations was observed, followed by an unrelated HSCT. The patient died because of transplant-related events.\n\nCase no. 14\n\nA 33-year-old man was first observed because of marked splenomegaly and leukocytosis (Table 1) with 22% of circulating myeloblasts and promonocytes, and bone marrow blasts < 20%. A t(1;5) translocation plus four somatic variants at RUNX1 and one at ASXL1 (Fig. 2 and Table 3) was documented. Cytogenetic remission was observed after 6 months of imatinib at 400 mg/die although increased blast cells (20–30%) were found in the bone marrow aspirate. At that time, a complex mutational landscape was identified. The ASXL1-positive cells persisted with unchanged VAF, while involvement of RUNX1 showed a decrease of the non-sense variant c.777dupT, p.Asn260*, but an increase of the three additional variants already found at diagnosis (Table 3). Moreover, a FLT3-ITD was identified in a small-size cell population. Treatment was standard chemotherapy and subsequent HSCT from an HLA-identical sibling donor. AML relapsed 1 year after HSCT, when bone marrow cells were negative for both PDGFRB and RUNX1 c.777dupT, p.Asn260*, but still positive for ASXL1 and for 1 out of the 3 RUNX1 variants identified at diagnosis (c.497G > A, p.Arg166Gln) (Table 3). Unfortunately, massive splenomegaly and CNS involvement occurred, requiring palliative splenic and cranio-spinal irradiation. The patient died of progressive disease 24 months after HSCT.\n\nImatinib dosage\n\nIn 10/11 cases first observed with a non-aggressive disease phase, imatinib was administered as sole treatment. Six cases (nos. 1–3, 5, 7, and 9) received a cytoreductive therapy before imatinib while four cases (nos. 4, 6, 8, and 11) received imatinib as front-line therapy (Table 1). In nine cases, precise information on dosage, response, and follow-up was available. A dosage of 100 mg/die induced complete cytogenetic and molecular remission in three cases (nos. 2, 4, and 7) while an increase to 200 mg/die was necessary in four other cases (nos. 1, 6, 8, and 11). In two cases (nos. 3 and 9), a higher dosage (400 mg/die) induced cytogenetic and molecular remission that was maintained by a dosage of 200 mg in case no. 3 and 100 mg in case no. 9. Case no. 3, still in monitoring, has the longest follow-up of 18 years, while case no. 9 died of sepsis of unknown origin in disease remission at + 129 months. A long-standing history was observed in our pediatric case (no. 7) who was started on a dosage of 100 mg/die and obtained a molecular remission after 32 months. However, after an additional 19 months, we detected molecular relapse and imatinib was increased to 200 mg/die, obtaining a second molecular remission after 10 months. The disease is stable with negative cytogenetic and molecular tests at + 44 months from the second remission and at + 105 months from the first imatinib administration. The median survival from the start of imatinib treatment in the nine chronic cases is 66.5 months (range: 30–222 months). Eight cases are still in follow-up.\n\nMonitoring of PDGFRB rearrangements\n\nBoth FISH and nested or semi-nested RT-PCR were used for disease monitoring during imatinib treatment. FISH documented complete cytogenetic remission in all 13 cases with a median of 9 months after start of treatment. Molecular remission was also documented in 9 of 11 tested cases with a median of 24 months after start of treatment. In case no. 13, positivity disappeared only after HSCT, while case no. 11, who discontinued imatinib for 10 weeks due to kidney transplantation, was positive at last follow-up (+ 72 months from imatinib administration).\n\nIn four cases with complete monitoring (nos. 2–3, 7, and 9), the median time lapse between cytogenetic and molecular remission was 24 months (range: 14–32). The earliest cytogenetic remission was obtained in case no. 3 after 1 month of treatment, although the disease persisted at molecular level up to month 25. In case nos. 1 and 4, remission was simultaneously documented by FISH and RT-PCR after 24 and 9 months of treatment, respectively. The median overall survival after molecular remission in nine cases was 42 months (range: 6–197), with ongoing follow-up in seven cases.\n\nDiscussion\n\nChromosomal rearrangements involving PDGFRB in myeloid malignancies are rare events. Here, we characterized a series of 14 cases with a myeloid neoplasm at diagnosis and a rearrangement of PDGFRB, providing data from in-depth genomic characterization by SNPa and NGS analysis. At cytogenetics, the 5q32/PDGFRB rearrangement involved multiple partners identified by banding in all cases but one with a cryptic change. Notably, in one case, complex chromosome rearrangements corresponded to a PDGFRB::ETV6 fusion underlying a four-break translocation. These results confirm the clinical relevance of FISH studies for PDGFRB gene rearrangements in patients with myeloid neoplasms, especially when associated with eosinophilia, even in the absence of karyotypic abnormalities. Notably, the 5q32/PDGFRB rearrangement was the sole cytogenetic abnormality in our cohort and SNPa confirmed a low burden of co-occurring abnormalities in all cases with chronic disease, strongly supporting the driver role of PDGFRß tyrosine kinase activation to address the clinical phenotype.\n\nThis study first identified the KAZN gene at 1p36 as a novel partner of PDGFRB in one case with a t(1;5)(p36;q33). The KAZN gene is involved in intercellular adhesion, cell differentiation, signal transduction, cytoskeletal organization, and apoptosis [26]. To date, PTBP2, TMEM51, and MTOR have been found as fusion partners of KAZN by RNA sequencing studies in solid tumors [27, 28], while, as far as we know, rearrangements of KAZN have never been described in hematological malignancies. Recurrent KAZN variants have not been specifically associated with human tumors (COSMIC, Catalogue of Somatic Mutation in Cancer [29]).\n\nIn a literature review, we found only 8 cases in chronic phase with information on the mutational background that showed variants at TET2, ASXL1, and STAG2 genes [4, 7, 10]. In our cases presenting with a chronic clinical phenotype, we found a low burden of somatic mutations involving TET2, DNMT3A, HRAS, and CEBPA. Notably, five and four variants affected the RUNX1 gene in our AML case no. 13 and no. 14, respectively. These findings suggest that instability at RUNX1 is a nonrandom event accompanying an acute clinical phenotype in PDGFRB + malignancies. This hypothesis is supported by the work of Stengel et al. [30], who rarely (< 1%) found more than three variants of the RUNX1 gene in a large series of mutated de novo AML cases. With respect to the nature of RUNX1 mutations in our acute cases, they are all predicted to be pathogenic. Six of them fell in the Runt-Homology DNA binding Domain (RHD), one fell in the Trans-Activation Domain (TAD), and two non-sense mutations truncated the protein between RHD and TAD.\n\nLongitudinal studies helped us to characterize the behavior of somatic mutations over the disease course. In particular, both HRAS and TET2 gene variants disappeared concomitantly to cytogenetic and molecular remission of the PDGFRB abnormality. These cases, in addition to one case with somatic mutation at the BCOR gene that disappeared at remission of the PDGFRB rearrangement [11], suggest that all these acquired mutations were present in the PDGFRB + clonal population sensitive to imatinib. Instead, a peculiar dynamics of somatic gene variants, as compared to the PDGFRB rearrangement, was seen in our case no. 14, in which one of the RUNX1 variants (c.777dupT, p.Asn260*) decreased concomitantly to cytogenetic remission, whereas both the ASXL1 and the c.497G > A RUNX1 variants appeared as the leukemic fil rouge over the whole disease course in this case, from diagnosis till post-transplant relapse, when PDGFRB was absent. Altogether, these results raise the question whether AML in the last case was a second malignancy instead of an acute phase originated by linear clonal evolution [31] of the PDGFRB-positive cells. Single-cell analysis will be helpful to better understand the origin of AML in PDGFRB-positive cases. Finally, the increased clonal size of DNMT3A in another responder (case no. 11) with cytogenetic disappearance of the PDGFRB rearrangement is consistent with clonal hematopoiesis, similar to that observed in other myeloid malignancies [32].\n\nOur study confirmed that prognosis in cases with PDGFRB rearrangement is deeply influenced by the clinical presentation [3], as our cases first seen with acute disease had a more unfavorable outcome compared to cases with less aggressive hematological phenotypes at diagnosis.\n\nA consensus on the posology of the TKI inhibitor in PDGFRB-related disorders presenting in chronic phase is still not available. The present series underlines the low dosage of 100–200 mg as a successful approach to inducing and maintaining cytogenetic and molecular remission. Moreover, molecular analysis is essential to carefully monitoring response to therapy, to evaluate the amount of residual disease, and to address changes of imatinib dosage over the disease course.\n\nFig. 2 The mutational background of PDGFRB-positive cases. Oncoprint heatmap showing mutations found at diagnosis in cases with a rearrangement of PDGFRB. Somatic mutations are reported in red and germline mutations in green; gray, non-mutated genes\n\nSupplementary Information\n\nBelow is the link to the electronic supplementary material. Supplementary file1 (XLS 35 KB)\n\nSupplementary file2 (XLS 34 KB)\n\nSupplementary file3 (XLS 37 KB)\n\nAuthor contribution\n\nD.D.G. and P.G. performed molecular studies and monitoring. V.P., R.L.S., B.C., and C.M. performed and analyzed cytogenetics, FISH, and SNP arrays. F.P. and Ca. Ma. performed and analyzed NGS data. M.Q., R.L.S., P.F.F., M.V., E.B., F.A., F.F. M.M., F.B., M.L., A.C., G.R., and C.M. collected samples and patient data. C.M. conceived the study. C.M. and D.D.G. collected all of the data and wrote the manuscript. All of the authors read and approved the final paper.\n\nFunding\n\nThis work was supported by AIRC 5 × 1000, MYNERVA project, #21267 (MYeloid NEoplasms Research Venture Airc, http://www.progettoagimm.it) (CM); Sergio Luciani Association, Fabriano, Italy (CM); Consorzio Internazionale per le Biotecnologie, CIB (CM); Roche per la Medicina di Precisione, bando 2020 (DDG)., #21267 (MYeloid NEoplasms Research Venture Airc, http://www.progettoagimm.it) (CM); Sergio Luciani Association, Fabriano, Italy (CM); Consorzio Internazionale per le Biotecnologie, CIB (CM); Roche per la Medicina di Precisione, bando 2020 (DDG).\n\nData availability\n\nAll datasets generated during the current study were deposited in NCBI Gene Expression Omnibus (GEO) under accession number GSE182820 (GSE182785 for SNParray and GSE182817 for Sequencing data).\n\nDeclarations\n\nEthics approval\n\nThe study was approved by the Bioethics Committee of the University of Perugia (number 2014–0259). The study was performed in accordance with the Declaration of Helsinki and its later amendments.\n\nConsent to participate\n\nInformed consent was obtained for all individual participants included in the study.\n\nCompeting interests\n\nThe authors declare 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. Ondrejka SL Jegalian AG Kim AS Chabot-Richards DS Giltnane J Czuchlewski DR Shetty S Sekeres MA Yenamandra A Head D Jagasia M His ED PDGFRB-rearranged T-lymphoblastic leukemia/lymphoma occurring with myeloid neoplasms: the missing link supporting a stem cell origin Haematologica 2014 99 e148 e151 10.3324/haematol.2014.105452 24951465\n2. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J (2017) WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France\n3. Jawhar M Naumann N Schwaab J Baurmann H Casper J Dang TA Dietze L Döhner K Hänel A Lathan B Link H Lotfi S Maywald O Mielke S Müller L Platzbecker U Prümmer O Thomssen H Töpelt K Panse J Vieler T Hofmann WK Haferlach T Haferlach C Fabarius A Hochhaus A Cross NCP Reiter A Metzgeroth G Imatinib in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB in chronic or blast phase Ann Hematol 2017 96 1463 1470 10.1007/s00277-017-3067-x 28725989\n4. Fang H Tang G Loghavi S Greipp P Wang W Verstovsek S Medeiros LJ Reichard KK Miranda RN Wang SA Systematic use of fluorescence in-situ hybridisation and clinicopathological features in the screening of PDGFRB rearrangements of patients with myeloid/lymphoid neoplasms Histopathology 2020 76 1042 1054 10.1111/his.14097 32083752\n5. Zabriskie MS Antelope O Verma AR Draper LR Eide CA Pomicter AD Tran TH Druker BJ Tyner JW Miles RR Graham JM Hwang JH Varley KE Toydemir RM Deininger MW Raetz EA O'Hare T A novel AGGF1-PDGFRb fusion in pediatric T-cell acute lymphoblastic leukemia Haematologica 2018 103 e87 e91 10.3324/haematol.2017.165282 29284681\n6. Heilmann AM Schrock AB He J Nahas M Curran K Shukla N Cramer S Draper L Verma A Erlich R Ross J Stephens P Miller VA Ali SM Verglio JA Tallman MS Mughal TI Novel PDGFRB fusions in childhood B- and T-acute lymphoblastic leukemia Leukemia 2017 31 1989 1992 10.1038/leu.2017.161 28552906\n7. Pozdnyakova O Orazi A Kelemen K King R Reichard KK Craig FE Quintanilla-Martinez L Rimsza L George TI Horny HP Wang SA Myeloid/lymphoid neoplasms associated with eosinophilia and rearrangements of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2 Am J Clin Pathol 2021 155 160 178 10.1093/ajcp/aqaa208 33367495\n8. Chen X Wang F Wang T Zhang Y Ma X Yuan L Teng W Guo L Liu M Liu M Chen J Nie D Zhang Y Zhou X Wang M Chen KN Zhu P Liu H The incidence, genetic characteristics, and prognosis of leukemia with concurrent pathogenic fusion genes: a series of 25 cases from a large cohort of leukemia patients Cancer Gene Ther 2020 27 89 97 10.1038/s41417-019-0147-1 31645680\n9. Appiah-Kubi K Lan T Wang Y Qian H Wu M Yao X Wu Y Chen Y Platelet- derived growth factor receptors (PDGFRs) fusion genes involvement in hematological malignancies Crit Rev Oncol Hematol 2017 109 20 34 10.1016/j.critrevonc.2016.11.008 28010895\n10. Zimmermann N Nassiri M Zhou J Miller AM Zhang S Myeloid neoplasm with a novel cryptic PDGFRB rearrangement detected by next-generation sequencing Cancer Genet 2020 244 55 59 10.1016/j.cancergen.2020.03.002 32442889\n11. Baer C Muehlbacher V Kern W Haferlach C Haferlach T Molecular genetic characterization of myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2 Haematologica 2018 103 e348 e350 10.3324/haematol.2017.187302 29567772\n12. Cheah CY Burbury K Apperley JF Huguet F Pitini V Gardembas M Ross DM Forrest D Genet P Rousselot P Patton N Smith G Dunbar CE Ito S Aguiar RCT Odenike O Gimelfarb A Cross NCP Seymour JF Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib Blood 2014 123 3574 3577 10.1182/blood-2014-02-555607 24687085\n13. Baxter EJ Kulkarni S Vizmanos J-L Jaju R Martinelli G Testoni N Hughes G Salamanchuk Z Calasanz MJ Lahortiga I Pocock CF Dang R Fidler C Wainscoat JS Boultwood J Cross NCP Novel translocations that disrupt the platelet-derived growth factor receptor β (PDGFRB) gene in BCR-ABL-negative chronic myeloproliferative disorders Br J Haematol 2003 120 251 256 10.1046/j.1365-2141.2003.04051.x 12542482\n14. Richards S Aziz N Bale S Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genet Med 2015 17 405 423 10.1038/gim.2015.30 25741868\n15. Kopanos C Tsiolkas V Kouris A VarSome: the human genomic variant search engine Bioinformatics 2019 35 1978 1980 10.1093/bioinformatics/bty897 30376034\n16. Siena S Sammarelli G Grimoldi MG Schiavo R Nozza A Roncalli M Mecucci C Santoro A Carlo-Stella C New reciprocal translocation t(5;10)(q33;q22) associated with atypical chronic myeloid leukemia Haematologica 1999 84 369 372 10190953\n17. Luciano L Catalano L Sarrantonio C Guerriero A Califano C Rotoli B AlphaIFN- induced hematologic and cytogenetic remission in chronic eosinophilic leukemia with t(1;5) Haematologica 1999 84 651 653 10406909\n18. Rosati R La Starza R Luciano L Gorello P Matteucci C Pierini V Romoli S Crescenzi B Rotoli B Martelli MF Pane F Mecucci C TPM3/PDGFRB fusion transcript and its reciprocal in chronic eosinophilic leukemia Leukemia 2006 20 1623 1624 10.1038/sj.leu.2404307 16838028\n19. Albano F Anelli L Zagaria A Lonoce A La Starza R Liso V Rocchi M Specchia G Bosi A, Martelli MF, Marynen P, Mecucci C (2007) Molecular cytogenetic findings in a four- way t(1;12;5;12)(p36;p13;q33;q24) underlying the ETV6-PDGFRB fusion gene in chronic myelomonocytic leukemia Cancer Genet Cytogenet 2008 176 67 71 10.1016/j.cancergencyto.2007.03.004\n20. Crescenzi B La Starza R Nozzoli C Ciolli S Matteucci C Romoli S Rigacci L Gorello P Bosi A Martelli MF Marynen P Mecucci C Molecular cytogenetic findings in a four-way t(1;12;5;12)(p36;p13;q33;q24) underlying the ETV6-PDGFRB fusion gene in chronic myelomonocytic leukemia Cancer Genet Cytogenet 2007 176 67 71 10.1016/j.cancergencyto.2007.03.004 17574967\n21. La Starza R Rosati R Roti G Gorello P Bardi A Crescenzi B Pierini V Calabrese O Baens M Folens C Cools J Marynen P Martelli MF Mecucci C Cuneo A A new NDE1/PDGFRB fusion transcript underlying chronic myelomonocytic leukaemia in Noonan Syndrome Leukemia 2007 21 830 833 10.1038/sj.leu.2404541 17301821\n22. Gorello P La Starza R Brandimarte L Trisolini SM Pierini V Crescenzi B Limongi MZ Nanni M Belloni E Tapinassi C Gerbino E Martelli MF Foà R Meloni G Pelicci PG Mecucci C A PDGFRB-positive acute myeloid malignancy with a new t(5;12)(q33;p13.3) involving the ERC1 gene Leukemia 2008 22 216 218 10.1038/sj.leu.2404894 17690697\n23. Cavazzini F Bardi A Ciccone M Rigolin GM Gorello P La Starza R Mecucci C Cuneo A Trisomy 8 in PDGFRB-negative cells in a patient with imatinib-sensitive chronic myelomonocytic leukemia and t(5;16)(q33;p13), PDGFRB–NDE1 fusion Cancer Genet Cytogenet 2009 194 67 69 10.1016/j.cancergencyto.2009.04.026 19737658\n24. Maccaferri M Pierini V Di Giacomo D Zucchini P Forghieri F Bonacorsi G Paolini A Quadrelli C Giacobbi F Fontana F Cappelli G Potenza L Marasca R Luppi M Mecucci C The importance of cytogenetic and molecular analyses in eosinophilia-associated myeloproliferative neoplasms: an unusual case with normal karyotype and TNIP1- PDGFRB rearrangement and overview of PDGFRB partner genes Leuk Lymphoma 2017 58 489 493 10.1080/10428194.2016.1197396 27337990\n25. Caprioli C, Lussana F, Salmoiraghi S, et al (2020) Clinical significance of chromatin- spliceosome acute myeloid leukemia: a report from the Northern Italy Leukemia Group (NILG) randomized trial 02/06. Haematologica haematol 2020 252825. 10.3324/haematol.2020.252825\n26. Le Pennec S Konopka T Gacquer D Fimereli D Tarabichi M Tomás G Savagner F Decaussin-Petrucci M Trésallet C Andry G Larsimont D Detours V Maenhaut C Intratumor heterogeneity and clonal evolution in an aggressive papillary thyroid cancer and matched metastases Endocr Relat Cancer 2015 22 205 216 10.1530/ERC-14-0351 25691441\n27. Yoshihara K Wang Q Torres-Garcia W Zheng S Vegesna R Kim H Verhaak RGW The landscape and therapeutic relevance of cancer-associated transcript fusions Oncogene 2015 34 4845 4854 10.1038/onc.2014.406 25500544\n28. Stransky N Cerami E Schalm S Kim JL Lengauer C The landscape of kinase fusions in cancer Nat Commun 2014 5 4846 10.1038/ncomms5846 25204415\n29. Tate JG Bamford S Jubb HC COSMIC: the Catalogue Of Somatic Mutations In Cancer Nucleic Acids Res 2019 47 D941 D947 10.1093/nar/gky1015 30371878\n30. Stengel A Kern W Meggendorfer M Nadarajah N Perglerovà K Haferlach T Haferlach C Number of RUNX1 mutations, wild-type allele loss and additional mutations impact on prognosis in adult RUNX1-mutated AML Leukemia 2018 32 295 302 10.1038/leu.2017.239 28751771\n31. Vosberg S Greif PA Clonal evolution of acute myeloid leukemia from diagnosis to relapse Genes, Chromosom Cancer 2019 58 839 849 10.1002/gcc.22806 31478278\n32. Pløen GG Nederby L Guldberg P Hansen M Ebbesen LH Jensen UB Hokland P Aggerholm A Persistence of DNMT3A mutations at long-term remission in adult patients with AML Br J Haematol 2014 167 478 486 10.1111/bjh.13062 25371149\n\n",
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"issue": null,
"journal": "Annals of hematology",
"keywords": "Chromosome translocations; Imatinib; KAZN; Molecular monitoring; PDGFRB",
"medline_ta": "Ann Hematol",
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"pmid": "34859285",
"pubdate": "2021-12-02",
"publication_types": "D016428:Journal Article",
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"title": "Genomic and clinical findings in myeloid neoplasms with PDGFRB rearrangement.",
"title_normalized": "genomic and clinical findings in myeloid neoplasms with pdgfrb rearrangement"
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"abstract": "BACKGROUND\nParadoxical adverse drug reactions (ADRs) are defined as being opposing reactions to the pharmacological effect of drugs in relation to its pharmacodynamic properties. Their diagnosis is difficult as they are relatively rare with atypical clinical presentation (with the possibility of being confused with drug ineffectiveness or the worsening of the underlying disease). This kind of ADR may be particularly subject to under-notification. The aim of the present study is to describe paradoxical ADRs using the French PharmacoVigilance DataBase (FPVDB).\n\n\nMETHODS\nWe analysed all reports recorded in the FPVDB with drugs defined as \"suspect\" and which included the term \"paradoxical reaction\" (PR) (according to MedDRA classification) from 01/01/1984 to 12/31/2018. The drugs were classified according to the Chemical Therapeutic Anatomical Classification (ATC).\n\n\nRESULTS\nWe found 57 reports of PR, with half of them recorded between 2015 and 2018. The median age of patients was 46 years, mainly male (54%). The most frequently involved drugs were immunomodulating agents (n = 28, 49%) and psychotropics (n = 28, 49%). The leading paradoxical ADRs were psychiatric (anxiety, sleep and behavioural disorders) and skin-related. In 19 cases (33%), PR was related to benzodiazepines mainly occurring in patients in extreme ages (five cases in children and patients > 70, respectively, 53%). For psychotropic-induced PR (n = 28), known contributory factors (alcohol consumption, underlying psychiatric diseases) were found in 18 cases (64%). Paradoxical reactions with immunomodulating agents were mainly related to skin ADRs (n = 25). For psychotropics, paradoxical ADRs occurred rapidly after a mean delay of 1 day, predominantly following high doses. We also identified several \"unexpected\" paradoxical reactions, such as cognitive degradation with donepezil, or a return to impulsive smoking addiction with varenicline.\n\n\nCONCLUSIONS\nThis study highlights that pharmacovigilance databases like the French database make it possible to investigate the main characteristics of paradoxical reactions to drugs. This ADR was mainly found in the FPVDB with psychotropic drugs and immunomodulating agents. Moreover, pharmacovigilance databases enable the identification of some signs of \"unexpected paradoxical reactions\". In order to identify this type of ADR more effectively, work on awareness and harmonization is required to register these reports. The addition of the term \"paradoxical reaction to the drug\" to the list of other symptoms would facilitate their identification and analysis.",
"affiliations": "Centre De Pharmacovigilance, De Pharmacoépidémiologie Et D'informations Sur Le Médicament, Inserm UMR 1027, Faculté De Médecine, Centre Hospitalier Universitaire, Toulouse, France.;Centre Régional De Pharmacovigilance-Service De Pharmacologie Clinique, Toxicologie CHRU, De Nancy, France.;Département De Pharmacologie Médicale et Toxicologie, Centre Régional De Pharmacovigilance Occitanie-Est, Montpellier, France.;Centre De Pharmacovigilance, De Pharmacoépidémiologie Et D'informations Sur Le Médicament, Inserm UMR 1027, Faculté De Médecine, Centre Hospitalier Universitaire, Toulouse, France.;Centre De Pharmacovigilance, De Pharmacoépidémiologie Et D'informations Sur Le Médicament, Inserm UMR 1027, Faculté De Médecine, Centre Hospitalier Universitaire, Toulouse, France. haleh.bagheri@univ-tlse3.fr.",
"authors": "Hakimi|Yan|Y|;Petitpain|Nadine|N|;Pinzani|Véronique|V|;Montastruc|Jean-Louis|JL|;Bagheri|Haleh|H|http://orcid.org/0000-0001-9585-9341",
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"issue": "76(8)",
"journal": "European journal of clinical pharmacology",
"keywords": "Benzodiazepines; Drug safety; Immunomodulating agents; Paradoxical adverse drug reactions; Pharmacovigilance",
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D016208:Databases, Factual; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D055815:Young Adult",
"nlm_unique_id": "1256165",
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"pmid": "32418024",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Paradoxical adverse drug reactions: descriptive analysis of French reports.",
"title_normalized": "paradoxical adverse drug reactions descriptive analysis of french reports"
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"companynumb": "FR-PRINSTON PHARMACEUTICAL INC.-2020PRN00199",
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"abstract": "Amiodarone is used commonly and effectively in the treatment of arrhythmia; however, it may cause thyrotoxicosis categorized into two types: iodine-induced hyperthyroidism (type 1 amiodarone-induced thyrotoxicosis (AIT)) and destructive thyroiditis (type 2 AIT). We experienced a case of type 2 AIT, in which high-dose steroid was administered intravenously, and we finally decided to perform total thyroidectomy, resulting in a complete cure of the AIT. Even though steroid had been administered to the patient (maximum 80 mg of prednisolone), the operation was performed safely and no acute adrenal crisis as steroid withdrawal syndrome was found after the operation. Few cases of type 2 AIT that underwent total thyroidectomy with high-dose steroid administration have been reported. The current case suggests that total thyroidectomy should be taken into consideration for patients with AIT who cannot be controlled by medical treatment and even in those under high-dose steroid administration.",
"affiliations": "Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan ; Department of Preemptive Medicine and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.;Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.;Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.;Department of Thoracic Visceral Organ Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.;Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.;Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.;Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.;Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.;Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.;Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.;Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.;Department of Thoracic Visceral Organ Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.;Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.;Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.",
"authors": "Hashimoto|Koshi|K|;Ota|Masaki|M|;Irie|Tadanobu|T|;Takata|Daisuke|D|;Nakajima|Tadashi|T|;Kaneko|Yoshiaki|Y|;Tanaka|Yuko|Y|;Matsumoto|Shunichi|S|;Nakajima|Yasuyo|Y|;Kurabayashi|Masahiko|M|;Oyama|Tetsunari|T|;Takeyoshi|Izumi|I|;Mori|Masatomo|M|;Yamada|Masanobu|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2015/416145",
"fulltext": "\n==== Front\nCase Rep EndocrinolCase Rep EndocrinolCRIECase Reports in Endocrinology2090-65012090-651XHindawi Publishing Corporation 10.1155/2015/416145Case ReportA Case of Type 2 Amiodarone-Induced Thyrotoxicosis That Underwent Total Thyroidectomy under High-Dose Steroid Administration Hashimoto Koshi \n1\n\n2\n\n*\nOta Masaki \n3\nIrie Tadanobu \n3\nTakata Daisuke \n4\nNakajima Tadashi \n3\nKaneko Yoshiaki \n3\nTanaka Yuko \n5\nMatsumoto Shunichi \n1\nNakajima Yasuyo \n1\nKurabayashi Masahiko \n3\nOyama Tetsunari \n5\nTakeyoshi Izumi \n4\nMori Masatomo \n1\nYamada Masanobu \n1\n1Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan2Department of Preemptive Medicine and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan3Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan4Department of Thoracic Visceral Organ Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan5Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan*Koshi Hashimoto: khashimoto.mem@tmd.ac.jpAcademic Editor: Takeshi Usui\n\n2015 13 1 2015 2015 41614517 10 2014 15 12 2014 Copyright © 2015 Koshi Hashimoto et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Amiodarone is used commonly and effectively in the treatment of arrhythmia; however, it may cause thyrotoxicosis categorized into two types: iodine-induced hyperthyroidism (type 1 amiodarone-induced thyrotoxicosis (AIT)) and destructive thyroiditis (type 2 AIT). We experienced a case of type 2 AIT, in which high-dose steroid was administered intravenously, and we finally decided to perform total thyroidectomy, resulting in a complete cure of the AIT. Even though steroid had been administered to the patient (maximum 80 mg of prednisolone), the operation was performed safely and no acute adrenal crisis as steroid withdrawal syndrome was found after the operation. Few cases of type 2 AIT that underwent total thyroidectomy with high-dose steroid administration have been reported. The current case suggests that total thyroidectomy should be taken into consideration for patients with AIT who cannot be controlled by medical treatment and even in those under high-dose steroid administration.\n==== Body\n1. Introduction\nAmiodarone, a benzofuranic acid derivative, is a potent class III antiarrhythmic drug that is used in the treatment of paroxysmal supraventricular tachycardia, malignant ventricular tachyarrhythmia, atrial flutter, and fibrillation [1]. It is an iodine-rich (37% of its weight) compound with a molecular structure similar to thyroxine (T4) and triiodothyronine (T3). It is also a fat-soluble drug with a long half-life (107 days), which allows the effects to be seen months after discontinuation [2]. Conventional doses of 100 to 600 mg of amiodarone per day provide 37 to 222 mg of organic iodine, which is up to 50–100 times the optimal daily iodine intake, and greatly expand the systemic and thyroidal iodine pools [3]. Although it may reduce cardiac-related mortality and improve survival rates, amiodarone can also cause the development of serious thyroid dysfunction in patients with or without underlying thyroid disease [4, 5]. The rate of occurrence of thyroid dysfunction, either thyrotoxicosis (amiodarone-induced thyrotoxicosis: AIT) or hypothyroidism, is 15–20% [6]. AIT is more prevalent in iodine-deficient areas and is currently known to be catabolized by two mechanisms: iodine-induced hyperthyroidism (type 1 AIT) and destructive thyroiditis (type 2 AIT), caused by amiodarone itself and its high iodine content. Type 1 AIT develops in subjects with underlying thyroid disease and is exacerbated by iodine loading of thyroid autonomous function; on the other hand, type 2 AIT occurs in patients with no history of thyroid disease and is probably consequent to drug-induced destructive thyroiditis. Moreover, the two mechanisms may occur in the same patient (mixed type) [4, 7]. AIT may develop early during amiodarone treatment or even several months after it has been discontinued. This is due to the fact that amiodarone and its metabolites have a long half-life and are stored in various tissues, particularly in fat, from which they are released very slowly. The onset of AIT is often sudden and explosive [8]. AIT worsens ventricular arrhythmia because of the hyperthyroid state. Medical management including steroid administration against AIT may produce a temporary response but often fails to resolve the thyrotoxicosis [9]. Here, we experienced a case of type 2 AIT, in which high-dose steroid was administered intravenously, and we finally decided to perform total thyroidectomy, resulting in complete cure of the AIT. Even though steroid had been administered to the patient (maximum 80 mg of prednisolone: PSL), the operation was performed safely and no acute adrenal crisis as steroid withdrawal syndrome was found after the operation. Few cases of AIT with steroid administration that underwent total thyroidectomy have been reported. The current case suggests that total thyroidectomy should be taken into consideration for patients with AIT who cannot be controlled by medical treatment and even in those under steroid administration.\n\n2. Case Presentation\nA 40-year-old man suffering from dilated cardiomyopathy had been prescribed amiodarone for 2.5 years. Seven weeks before the consultation at our department, his serum-free T4 levels increased above the upper limit and thyrotoxicosis developed. His thyroid status was as shown in Figure 1. An attending cardiologist consulted at our thyroid clinic about the patient's thyrotoxicosis, but he had no complaints. He did not show any tachycardia or finger tremor, despite the thyrotoxicosis. His thyroid gland was not swollen and ultrasonic study revealed a slightly enlarged thyroid gland with almost monotonous echogenicity (Figure 2(a)). The Doppler flow rate inside the thyroid gland was not increased (Figure 2(b)). To differentiate the diagnosis of thyrotoxicosis, we planned to investigate thyroid iodine uptake. Ten days after the first visit, he showed symptoms of acute heart failure and was admitted to the intensive care unit of our hospital. His thyrotoxicosis had worsened by the time of admission, with increased levels of thyroglobulin, suggesting destructive thyroiditis (Table 1). Amiodarone administration was stopped and inorganic iodine administration (189 mg/day) was started upon admission; however, his thyrotoxicosis was prolonged and worsened. His cardiac function also worsened, with the thyrotoxicosis being exacerbated (Figure 3). On admission, his heart rate was over 180 bpm and systolic blood pressure was 220 mmHg. Oxygen saturation rate was 70% under 10 L/min of oxygen administration with a venturi mask. Intra-arterial balloon pumping was performed to maintain the circulation. On the day after admission, administration of 200 mg of hydrocortisone was started, in addition to inorganic iodine. After the hydrocortisone administration, free T3 levels were somewhat improved, but free T4 levels remained high. To control and suppress the destruction of the thyroid, 40 mg of PSL was administered instead of hydrocortisone. Subsequently, 60 mg of PSL improved the serum-free T4 levels, so we tapered the dose of PSL gradually. However, at a dose of 20 mg of PSL, the thyrotoxicosis relapsed. At this point, TSH receptor antibody (TRAb) became positive (Figure 1), so we decided to prescribe 15 mg of methimazole (MMI) together with 40 mg of PSL. Two days after these prescriptions, his free T4 levels increased to above the normal range. Thirty milligrams of MMI, 40 mg of PSL, and inorganic iodine (189 mg/day) did not suppress the destructive thyroiditis. On the 17th day of admission, thyroid 99mTc uptake was investigated, but none was observed (Figure 2(c)). At this point, we made a final diagnosis of type 2 amiodarone-induced thyrotoxicosis (AIT). On the 23rd day of admission, MMI was discontinued and the administration of 80 mg of PSL was maintained. Subsequently, we attempted to taper the dose of PSL, but under a dose of 80 mg of PSL, overt thyrotoxicosis was not controlled (Figure 1). Since over 2.5 months had passed since a high dose of PSL had been administered, we decided to perform total thyroidectomy. The administration of 80 mg of PSL was continued until the operation. With informed consent from the patient and his wife, total thyroidectomy was performed on the 78th day of admission. Intravenous administration of 40 mg of PSL and 200 mg of hydrocortisone was performed during the operation. The operation was safely performed and 25.6 g of thyroid was resected. After the operation, PSL was discontinued and the dose of hydrocortisone was carefully tapered. Two days after the thyroidectomy, hydrocortisone was tapered to 100 mg and administered orally. Then, hydrocortisone was again gradually tapered to 15 mg eleven days after the surgery. Twenty-five days after the operation, hydrocortisone was tapered to 5 mg, and it was discontinued on the forty-sixth day after the thyroidectomy. During the tapering of hydrocortisone and after its discontinuation, the patient demonstrated no symptoms of adrenal insufficiency. Pathological findings of the excised thyroid gland are as shown in Figure 4. Grossly, the lobes became firm in consistency but maintained their normal shape (Figure 4(a)). On microscopy, several sizes of follicles were regularly lined with flattened follicular epithelium. The lumen was filled with colloid. Scattered disrupted follicles with enlarged epithelium and cytoplasmic vacuoles were observed (Figure 4(b)). It is of note that macrophages had infiltrated and multinucleated giant cells were also found in the follicular lumen (Figure 4(c)). Immunostaining with anti-KP1 (CD68) and antithyroglobulin antibodies confirmed that the infiltrated cells were macrophages but not follicular cells (Figures 4(d) and 4(e)). These findings characterized by scattered follicle disruption, vacuoles in epithelial cells, and macrophage infiltration are compatible with amiodarone toxicity [10].\n\nAfter the operation, the patient's thyrotoxicosis rapidly disappeared and the thyroid function was normalized with 100 μg of levothyroxine (L-T4). Thirty-six days after the thyroidectomy, implantation of a left ventricular epicardial lead was performed under the administration of 5 mg of hydrocortisone. We administered 200 mg of hydrocortisone intravenously during the procedure and the implantation was performed safely. After the implantation, his cardiac function was dramatically improved. On the 130th day of admission, the administration of hydrocortisone was discontinued and he was discharged from the hospital on foot.\n\n3. Discussion\nWe have experienced a severe case of type 2 AIT, which was uncontrollable with high-dose PSL. The final diagnosis was difficult since TRAb was positive at one time in the clinical course, which led us to consider that this case may be type 1 and type 2 mixed AIT. Therefore, we administered MMI to the patient at some points in the clinical course. However, taken together with the findings from a thyroid scan and laboratory data, this case should be classified as type 2 AIT, even though it has been reported that the features of hyperthyroidism and destructive thyroiditis may concomitantly be present. Thionamides such as methimazole and propylthiouracil are not effective in type 2 AIT [7]. It was a very difficult decision to perform the total thyroidectomy since a maximum of 80 mg of PSL had been administered. However, considering the side effects, including infection, of long-term use of high-dose steroid, we did not have an alternative approach other than thyroidectomy. Moreover, in view of his cardiac status, implantation of a left ventricular epicardial lead needed to be performed as soon as possible.\n\nType 2 AIT may be self-limiting, and some reports recommend continuation of amiodarone for the cardiac effect [11]. Steroid is the best treatment for type 2 AIT [12]. As other treatments, the use of lithium, potassium perchlorate, and iopanoic acid has been proposed for type 2 AIT, but the evidence is too limited to support their effectiveness [7]. Plasmapheresis can provide acute relief from type 2 AIT but is not generally used because of its transient effects, its cost, and the impossibility of maintaining its use over the long term [5, 7]. In addition, radioactive iodine therapy is in principle not feasible in type 2 AIT patients because iodine uptake is usually suppressed, as shown in this case [5, 7]. The initial PSL dose is about 0.5–0.7 mg/kg body weight per day and the treatment is usually continued for 3 months [6]. The current case can be considered rare because a maximum of 80 mg per day of PSL was required to control the thyrotoxicosis. Therefore, we were very careful to taper the dose of steroid after the total thyroidectomy and the tapering was performed successfully. Total thyroidectomy with general anesthesia is not the first-line treatment for type 2 AIT, since there may be potential risks, such as severe arrhythmia, in the perioperative period in these patients with underlying cardiac disorders [7]. However, this approach may be required in patients who are resistant to medical treatments [5, 9, 13, 14]. Minimally invasive thyroidectomy with local anesthesia may further reduce the risk [15]; however, its use has not yet spread widely.\n\nThyroidectomy is an efficacious approach for type 2 AIT patients who are resistant to high-dose PSL to control thyrotoxicosis. Physicians should not be reluctant to make a decision to perform the surgery and total thyroidectomy can be performed more safely than expected, even if high-dose PSL has been administered to the patients.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Clinical course of the case.\n\nFigure 2 (a) Ultrasonic study of the thyroid revealing mild swelling with 6.9 mm isthmus diameter. (b) Doppler flow study of the thyroid gland revealing no blood flow increase. (c) Thyroid 99mTc scintigraphy revealing no uptake.\n\nFigure 3 (a) Chest X-ray on admission demonstrating severe cardiomegaly. (b) Electrocardiogram on admission showing wide QRS pattern and tachycardia.\n\nFigure 4 (a) Gross pathological findings of the excised thyroid gland. (b, c) H-E staining of the thyroid gland in low-power (b) and high-power fields (c). Several sizes of follicle were regularly lined with flattened follicular epithelium. The lumen was filled with colloid. Scattered disrupted follicles with enlarged epithelium and cytoplasmic vacuoles were observed (b). Macrophages had infiltrated and multinucleated giant cells were found in follicular lumen (c). Immunostaining with anti-KP-1 (CD68) antibody (d). Immunostaining with antithyroglobulin antibody (e).\n\nTable 1 Laboratory data on admission.\n\nHematology\tBiochemistry\tCardiology\t\nRBC\t494 × 104/μL\tT.P.\t6.6 g/dL\tTroponin I\t0.53 ng/mL\t(<0.1)\t\nHb.\t16.4 g/dL\tAlb.\t3.7 g/dL\tBNP\t579.0 pg/mL\t(0–18.4)\t\nHt.\t47.4%\tT.Bil.\t0.8 mg/dL\t\nThyroid function\n\t\nWBC\t16100/μL\tGOT\t115 IU/L\tTSH\t<0.05 μU/mL\t(0.35–4.94)\t\nPlt.\t27.8 × 104/mL\tGPT\t138 IU/L\tFree T4\t3.39 ng/dL\t(0.70–1.48)\t\nFib.\t372 mg/dL\tLDH\t356 IU/L\tFree T3\t6.61 pg/mL\t(1.71–3.71)\t\nPT\t93%\tALP\t223 IU/L\tThyglobulin\t1025.0 ng/mL\t(0–32.7)\t\nAPTT\t27.8 sec\t\nγ-GTP\t310 IU/L\tTGHA \t<100X\t \t\nFDP\t13.6 mg/dL\tAMY\t293 IU/L\tMCHA \t<100X\t \t\n \t \tLDL-Cho\t136 mg/dL\tTRAb\t0.9 IU/L\t(<1.0)\t\n \t \tUA\t5.1 mg/dL\t \t \t \t\n \t \tGlu\t226 mg/dL\t \t \t \t\n \t \tCRP\t0.23 mg/dL\t \t \t \t\n \t \tBUN\t24 mg/dL\t \t \t \t\n \t \tCr\t0.89 mg/dL\t \t \t \t\n \t \tNa\t139 mEq/L\t \t \t \t\n \t \tK\t5.1 mEq/L\t \t \t \t\n \t \tCl\t105 mEq/L\t \t \t \n==== Refs\n1 Roy D. Talajic M. Dorian P. Amiodarone to prevent recurrence of atrial fibrillation New England Journal of Medicine 2000 342 13 913 920 10.1056/nejm200003303421302 2-s2.0-0007356262 10738049 \n2 Zipes D. P. Prystowsky E. N. Heger J. J. Amiodarone: electrophysiologic actions, pharmacokinetics and clinical effects Journal of the American College of Cardiology 1984 3 4 1059 1071 2-s2.0-0021336827 10.1016/s0735-1097(84)80367-8 6368644 \n3 Rao R. H. McCready V. R. Spathis G. S. Iodine kinetic studies during amiodarone treatment Journal of Clinical Endocrinology and Metabolism 1986 62 3 563 568 10.1210/jcem-62-3-563 2-s2.0-0022637902 3944239 \n4 Piga M. Serra A. Boi F. Tanda M. L. Martino E. Mariotti S. Amiodarone-induced thyrotoxicosis: a review Minerva Endocrinologica 2008 33 3 213 228 2-s2.0-58149377805 18846027 \n5 Franzese C. B. Stock B. C. Jr. Amiodarone-induced thyrotoxicosis: a case for surgical management American Journal of Otolaryngology—Head and Neck Medicine and Surgery 2002 23 6 358 361 10.1053/ajot.2002.128042 2-s2.0-0036856304 \n6 Martino E. Bartalena L. Bogazzi F. Braverman L. E. The effects of amiodarone on the thyroid Endocrine Reviews 2001 22 2 240 254 10.1210/er.22.2.240 2-s2.0-0006353759 11294826 \n7 Bogazzi F. Bartalena L. Martino E. Approach to the patient with amiodarone-induced thyrotoxicosis Journal of Clinical Endocrinology and Metabolism 2010 95 6 2529 2535 10.1210/jc.2010-0180 2-s2.0-77954484535 20525904 \n8 Conen D. Melly L. Kaufmann C. Amiodarone-induced thyrotoxicosis: clinical course and predictors of outcome Journal of the American College of Cardiology 2007 49 24 2350 2355 10.1016/j.jacc.2007.02.054 2-s2.0-34249987933 17572251 \n9 Birkedal C. Touliatos J. Gaskin T. Spence R. K. Surgical considerations for treatment of amiodarone-induced thyrotoxicosis Current Surgery 2001 58 5 478 480 10.1016/s0149-7944(01)00478-0 2-s2.0-0346510197 16093070 \n10 Nakazawa T. Murata S.-I. Kondo T. Histopathology of the thyroid in amiodarone-induced hypothyroidism Pathology International 2008 58 1 55 58 2-s2.0-36649023948 10.1111/j.1440-1827.2007.02189.x 18067642 \n11 Franklyn J. A. Gammage M. D. Treatment of amiodarone-associated thyrotoxicosis Nature Clinical Practice Endocrinology and Metabolism 2007 3 9 662 666 10.1038/ncpendmet0592 2-s2.0-34548092159 \n12 Bartalena L. Brogioni S. Grasso L. Bogazzi F. Burelli A. Martino E. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study Journal of Clinical Endocrinology and Metabolism 1996 81 8 2930 2933 2-s2.0-0029787591 8768854 \n13 Houghton S. G. Farley D. R. Brennan M. D. Van Heerden J. A. Thompson G. B. Grant C. S. Surgical management of amiodarone-associated thyrotoxicosis:mayo clinic experience World Journal of Surgery 2004 28 11 1083 1087 10.1007/s00268-004-7599-6 2-s2.0-12144261848 15490061 \n14 Franzese C. B. Fan C. Y. Stack B. C. Surgical management of amiodarone-induced thyrotoxicosis Otolaryngology—Head and Neck Surgery 2003 129 5 565 570 10.1016/s0194-5998(03)01590-0 2-s2.0-0242411009 14595280 \n15 Berti P. Materazzi G. Bogazzi F. Ambrosini C. E. Martino E. Miccoli P. Combination of minimally invasive thyroid surgery and local anesthesia associated to iopanoic acid for patients with amiodarone-induced thyrotoxicosis and severe cardiac disorders: a pilot study Langenbeck's Archives of Surgery 2007 392 6 709 713 2-s2.0-35448978350 10.1007/s00423-006-0112-y\n\n",
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"title": "A Case of Type 2 Amiodarone-Induced Thyrotoxicosis That Underwent Total Thyroidectomy under High-Dose Steroid Administration.",
"title_normalized": "a case of type 2 amiodarone induced thyrotoxicosis that underwent total thyroidectomy under high dose steroid administration"
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"abstract": "BACKGROUND\nIt has been proposed that pregnant women and their fetuses may be particularly at risk for poor outcomes due to the coronavirus (COVID-19) pandemic. From the few case series that are available in the literature, women with high risk pregnancies have been associated with higher morbidity. It has been suggested that pregnancy induced immune responses and cardio-vascular changes can exaggerate the course of the COVID-19 infection.\n\n\nMETHODS\nA 26-year old Somalian woman (G2P1) presented with a nine-day history of shortness of breath, dry cough, myalgia, nausea, abdominal pain and fever. A nasopharyngeal swab returned positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Her condition rapidly worsened leading to severe liver and coagulation impairment. An emergency Caesarean section was performed at gestational week 32 + 6 after which the patient made a rapid recovery. Severe COVID-19 promptly improved by the termination of the pregnancy or atypical HELLP (Hemolysis, Elevated Liver Enzymes and Low Platelet Count) exacerbated by concomitant COVID-19 infection could not be ruled out. There was no evidence of vertical transmission.\n\n\nCONCLUSIONS\nThis case adds to the growing body of evidence which raises concerns about the possible negative maternal outcomes of COVID-19 infection during pregnancy and advocates for pregnant women to be recognized as a vulnerable group during the current pandemic.",
"affiliations": "Department of Obstetrics & Gynaecology, Skåne University Hospital, Malmö/Lund, Sweden.;Department of Clinical Sciences Lund, Paediatrics/Neonatology, Lund University, Skåne University Hospital, Malmö/Lund, Sweden.;Department of Obstetrics & Gynaecology, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, 205 01, Malmö/Lund, Sweden.;Department of Obstetrics & Gynaecology, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, 205 01, Malmö/Lund, Sweden.;Department of Obstetrics & Gynaecology, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, 205 01, Malmö/Lund, Sweden.;Department of Obstetrics & Gynaecology, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, 205 01, Malmö/Lund, Sweden. mehreen.zaigham@med.lu.se.",
"authors": "Ronnje|Louise|L|;Länsberg|John-Kalle|JK|;Vikhareva|Olga|O|;Hansson|Stefan R|SR|;Herbst|Andreas|A|;Zaigham|Mehreen|M|",
"chemical_list": "D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D; D000990:Antithrombin III; D007770:L-Lactate Dehydrogenase",
"country": "England",
"delete": false,
"doi": "10.1186/s12884-020-03172-8",
"fulltext": "\n==== Front\nBMC Pregnancy Childbirth\nBMC Pregnancy Childbirth\nBMC Pregnancy and Childbirth\n1471-2393 BioMed Central London \n\n3172\n10.1186/s12884-020-03172-8\nCase Report\nComplicated COVID-19 in pregnancy: a case report with severe liver and coagulation dysfunction promptly improved by delivery\nRonnje Louise 1 Länsberg John-Kalle 2 Vikhareva Olga 3 Hansson Stefan R. 3 Herbst Andreas 3 Zaigham Mehreen mehreen.zaigham@med.lu.se 3 1 grid.411843.b0000 0004 0623 9987Department of Obstetrics & Gynaecology, Skåne University Hospital, Malmö/Lund, Sweden \n2 Department of Clinical Sciences Lund, Paediatrics/Neonatology, Lund University, Skåne University Hospital, Malmö/Lund, Sweden \n3 grid.411843.b0000 0004 0623 9987Department of Obstetrics & Gynaecology, Institute of Clinical Sciences Lund, Lund University and Skåne University Hospital, 205 01 Malmö/Lund, Sweden \n4 9 2020 \n4 9 2020 \n2020 \n20 51112 5 2020 12 8 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nIt has been proposed that pregnant women and their fetuses may be particularly at risk for poor outcomes due to the coronavirus (COVID-19) pandemic. From the few case series that are available in the literature, women with high risk pregnancies have been associated with higher morbidity. It has been suggested that pregnancy induced immune responses and cardio-vascular changes can exaggerate the course of the COVID-19 infection.\n\nCase presentation\nA 26-year old Somalian woman (G2P1) presented with a nine-day history of shortness of breath, dry cough, myalgia, nausea, abdominal pain and fever. A nasopharyngeal swab returned positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Her condition rapidly worsened leading to severe liver and coagulation impairment. An emergency Caesarean section was performed at gestational week 32 + 6 after which the patient made a rapid recovery. Severe COVID-19 promptly improved by the termination of the pregnancy or atypical HELLP (Hemolysis, Elevated Liver Enzymes and Low Platelet Count) exacerbated by concomitant COVID-19 infection could not be ruled out. There was no evidence of vertical transmission.\n\nConclusions\nThis case adds to the growing body of evidence which raises concerns about the possible negative maternal outcomes of COVID-19 infection during pregnancy and advocates for pregnant women to be recognized as a vulnerable group during the current pandemic.\n\nKeywords\nCOVID-19CoronavirusSARS-CoV-2NeonatePregnancyDifferential diagnosisHELLP syndromeLiverCoagulationMorbidityFeverMortalityObstetric managementPandemicRespiratory distress syndromeRespiratory failureSepsisSusceptibilityVirusSwedish Medical Research Council Medicinska Fakulteten, Lunds Universitet (SE)issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nThe pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has exposed vulnerable populations to an unprecedented global health crisis. From the knowledge gained from previous human coronavirus outbreaks, it has been proposed that pregnant women and their fetuses are particularly at risk for poor outcomes [1]. The maternal and neonatal outcomes of pregnant women with COVID-19 is limited to a handful of case reports which present diverse results. Obstetricians are still learning about COVID-19 presentation and progression in pregnancy and even though the majority of pregnancies infected by COVID-19 have good outcomes, a recent systematic analysis [1] showed that up to 3% of pregnancies were associated with severe maternal morbidity. It was indicated that mothers with a complicated medical history could be at increased risk for severe outcomes. Furthermore, experts are of the opinion that the clinical recommendations for managing COVID-19 in pregnancy should be based on lessons learned from the current epidemic [2] which emphasizes the importance of presenting COVID-19 cases associated with complex clinical management.\n\nWe therefore present a case report of a young woman, pregnant in the third trimester, diagnosed with COVID-19, showing severe liver and coagulation impairment.\n\nCase presentation\nA 26-year-old Somalian woman (Gravida 2, Para 1) who had been living in Sweden for a year presented at the Emergency Department of Skåne University Hospital in Malmö on April 17th, 2020 pregnant at 32 + 1 weeks of gestation. She was transferred to the Infectious Diseases Department with suspicion of COVID-19. A diagnostic test, based on quantitative real time polymerase chain reaction (qRT-PCR), from a nasopharyngeal swab, was positive for SARS-CoV-2.\n\nShe had recently moved from Stockholm to Malmö. In 2015 she had a normal vaginal delivery in Somalia. The patient had an appendectomy and a cholecystectomy in Somalia. Her medical history also included hypothyroidism, currently treated with 150 ug Levothyroxine daily. The body mass index (BMI) on admission to prenatal care was 47 kg/m2 with length 163 centimetres (cm), weight 126 kg (kg). Apart from the obesity, her pregnancy had been without complications. She had received an intramuscular injection of Anti-D immunoglobulin at 28 + 5 weeks of gestation since she was Rhesus D (RhD) negative and the fetus was RhD positive.\n\nOn admission, the patient described a nine-day history of shortness of breath, dry cough, myalgia, nausea, abdominal pain and fever (Fig. 1). She had significant abdominal pain on admission but the surgeon did not find any signs of an acute abdominal event. The patient had also noticed reduced fetal movements for the last two days. Obstetric examination including cardio-tocography (CTG) and an abdominal ultrasound showed no abnormalities.\n\n\nFig. 1 Timeline of the patient’s admission in to tertiary care\n\n\n\nThe patient’s respiratory rate was 22 breaths/minute, oxygen saturation 95%, blood pressure 116/71, pulse 113 beats/minute and temperature 37.2 degrees Celsius (oC). The laboratory tests are shown in Table 1. The patient was given morphine, paracetamol and oxycodone for pain relief and also received thromboprophylaxis, Dalteparin 7500 units /day subcutaneously. No additional oxygen was needed.\n\n\nTable 1 Maternal laboratory results during admission and readmission\n\nVariable\tReference Range\tAdmission Day 1\n(4/17/2020)\tReadmission Day 2\n(4/22/2020)\nPrior to Cesarean Section\tReadmission Day 3\n(4/23/2020)\t\nHemoglobin\n\n(Hb) g/L\n\n\t117–153\t113\t95\t101\t\nPlatelet count\n\nx109/L\n\n\t165–387\t209\t122\t179\t\nWhite cell count\n\nx109/L\n\n\t3.5–8.8\t5.1\t4.4\t7.0\t\nNeutrophil count\n\nx109/L\n\n\t1.8–7.5\t2.8\t3.1\t6.1\t\nLymphocyte count\n\nx109/L\n\n\t1.0–4.0\t1.9\t0.3\t0.5\t\nReticulocyte\n\nx109/L\n\n\t28–120\t-\t38\t53\t\nHaptoglobin\n\ng/L\n\n\t0.24–1.90\t-\t2.02\t-\t\nFerritin\n\nµmol/L\n\n\t13–148\t-\t875\t370\t\nC-reactive protein\n\n(CRP) mg/L\n\n\t< 5\t37\t102\t136\t\nInterleukin-6\n\nng/L\n\n\t< 1.8\t-\t211\t-\t\nProcalcitonin\n\nµg/L\n\n\t< 0.05\t-\t149\t209\t\nP-NT-pro-BNP\n\nng/L\n\n\t< 150\t-\t71\t-\t\nTroponin-T\n\nng/L\n\n\t< 5\t< 5\t-\t-\t\nMyoglobin\n\nµg/L\n\n\t25–58\t< 22\t34\t-\t\nGlucose\n\nmmol/L\n\n\t4.2-6.0\t-\t4.3\t4.4\t\nAspartate aminotransferase (ASAT) µkat/L\t0.25–0.6\t0.38\t28\t11\t\nAlanine aminotransferase\n\n(ALAT) µkat/L\n\n\t0.15–0.75\t0.84\t5.8\t3.5\t\nAlkaline phosphatase\n\n(ALP) µkat/L\n\n\t0.70–1.9\t-\t4.6\t3.9\t\nGamma-glutamyl transferase\n\n(GGT) µkat/L\n\n\t0.15–0.75\t-\t5.4\t5.7\t\nBilirubin\n\nµmol/L\n\n\t5–25\t-\t21\t21\t\nLactate Dehydrogenase\n\n(LDH) µkat/L\n\n\t1.8–3.4\t-\t34\t9.9\t\nPancreatic amylase\n\nµkat/L\n\n\t0.15–1.1\t0.30\t0.15\t0.12\t\nCreatinine\n\nµmol/L\n\n\t45–90\t50\t59\t63\t\nUrea\n\nmmol/L\n\n\t2.6-6-4\t-\t1.3\t1.0\t\nUric acid\n\nµmol/L\n\n\t155–350\t-\t312\t267\t\nSodium\n\nmmol/L\n\n\t137–145\t136\t135\t136\t\nPotassium\n\nmmol/L\n\n\t3.5–4.4\t3.5\t2.8\t3.6\t\nChloride\n\nmmol/L\n\n\t98–110\t-\t107\t103\t\nCalcium ion\n\nmmol/L\n\n\t1.15–1.33\t-\t1.10\t1.06\t\nMagnesium\n\nmmol/L\n\n\t0.70–0.95\t-\t0.62\t0.73\t\nPlasma Paracetamol concentration µmol/L\t< 200\t-\t67\t-\t\nD-dimer\n\nmg/L\n\n\t< 0.5\t5.4\t4.3\t5.6\t\nProthrombin-complex International Normalized Ratio (P-INR)\t0.9–1.2\t0.9\t1.0\t1.0\t\nActivated Partial Thromboplastin Time (APTT) in seconds (s)\t26–33\t39\t46\t45\t\nFibrinogen\n\ng/L\n\n\t2.0–4.0\t-\t2.7\t2.2\t\nAntithrombin (IIa)\n\nkIE/L\n\n\t0.8–1.2\t-\t-\t0.66\t\nArterial blood gases\t\n pH\t7.35–7.45\t-\t7.43\t7.40\t\n Partial pressure of carbon dioxide\n\npCO2 in kPa\n\n\t4.6-6.0\t-\t4.1\t5.1\t\n Partial pressure of oxygen\n\npO2 in kPa\n\n\t10.0–13.0\t-\t8.6\t9.9\t\n Base Excess\n\nmmol/l\n\n\t22–27\t-\t22\t23\t\n Bicarbonate\n\nHCO3−mmol/l\n\n\t-3.0-3.0\t-\t-3.2\t-1.7\t\n Lactate\n\nmmol/L\n\n\t0.5–1.6\t-\t1.5\t0.7\t\n Saturation of oxygen\n\n%\n\n\t97–100\t-\t92\t93\t\n\n\nOn day 2 (18/4/2020), the patient was relatively stable apart from two short episodes of fever up to 38.9 oC. Due to risk for preterm labour, the patient received 12 milligrams (mg) of Betamethasone intramuscularly to aid fetal lung maturity. Daily fetal monitoring using CTG showed no signs of fetal distress.\n\nThe patient was discharged on day 3 (19/4/2020) with a planned obstetric follow-up including fetal growth assessment after recovery. She was prescribed dalteparin for four weeks.\n\nThe patient returned to the Emergency Department the next day (20/4/2020) with a sore throat and severe difficulties in swallowing. Apart from tachypnoea (25–35 breaths/minute) and tachycardia (118 beats/minute), other vital signs were normal. After examination, she was discharged with a prescription of Betamethasone tablets for three days (6, 4 and 3 mg) for swallowing difficulties and potassium supplements for the hypokalaemia noted in the blood tests (Table 1).\n\nThe patient was readmitted to the Infectious Diseases Department the next day (21/4/2020) (Fig. 1). Her COVID-19 symptoms (cough, myalgia, abdominal pain and fever) had worsened and she now presented with dyspnoea. At readmission, the patient’s respiratory rate 42 breaths/minute, blood pressure 114/61, pulse was 120 beats/minute and temperature 38.9 oC. During episodes of coughing, her oxygen saturation fell to 86%, but with 5 L of oxygen on mask the saturation rose to 99%. Laboratory tests are shown in Table 1.\n\nHer condition deteriorated on day 2 (22/4/2020) of the readmission. In addition to the generalized pain and tenderness, the pain in her right upper abdomen had worsened. Blood tests showed elevation of aspartate aminotransferase (ASAT), interleukin-6 (IL-6) and ferritin concentrations. There was impaired coagulation as shown by a prolonged activated partial thromboplastin time (APTT), high D-dimer, falling platelet count and decreased level of Anti-thrombin III (Table 1). Hemolysis was indicated by a fall in the hemoglobin concentration and rising lactate dehydrogenase levels although haptoglobin concentrations only were slightly elevated (Table 1). Despite her worsening condition, the patient felt active fetal movements and normal intermittent CTG controls were registered. Intravenous antibiotic treatment with Cefotaxime (2 g, 3 times daily) was initiated due to suspicion of concomitant bacterial infection (Table 1). Blood and urine cultures were taken but since the general condition of the patient had worsened, a decision was made to deliver by Caesarean section (32 + 6 gestational weeks), on maternal indication. The operation was performed in spinal analgesia in an operating theatre with negative air ventilation. The local hospital guidelines were followed to prevent the spread of COVID-19 [3]. An uncomplicated operation was completed within 40 min and the total blood loss was 200 millilitres (mL).\n\nAfter two hours in the post-operative unit, the patient returned to the ward and received thromboprophylaxis, dalteparin at a total dose of 10.000 units divided in two doses. A computed tomography (CT) lung scan, performed later the same day, showed bilateral diffuse, ground-glass opacities with both peripheral and perihilar distribution, but no signs of pulmonary embolism (Fig. 2).\nFig. 2 Computed tomography (CT) thorax scan showing bilateral diffuse, ground-glass opacities with both peripheral and perihilar distribution and no signs of pulmonary embolism. Two segments from the same session post-partum on day 2 of readmission (22/4/2020). 1 Pulmonary vein. 2 Pulmonary artery. 3 Aorta. 4 Right ventricle\n\n\n\nPost-operative pain management\nDue to deranged liver values, the patient was unable to receive paracetamol and due to the COVID-19 infection not able to receive ibuprofen [4]. The pain relief was managed by administering 2.5 mL of intravenous morphine as needed. However, the patient’s condition worsened during the night and on examination, the patient was somnolent and lethargic but answered adequately when woken up (Reaction Level Scale 2). The patient’s pain was mostly localized to the upper right quadrant of the abdomen and epigastrium. Her uterus was well contracted and there were no signs of postoperative complications such as bleedings and local infection. On examination, the patient had miotic pupils that reacted poorly to light stimulation. Even though the patient only was given 7.5 mg of morphine over the course of 8 h, a morphine over-dose was suspected, and intravenous morphine was replaced by a combination of orally administered Naloxone and Oxycodone. Post-operative mobilization was initiated one day after surgery where after the patient made a steady recovery.\n\nTable 1 illustrates the drastic improvement in the patient’s blood tests on day 3 (23/4/2020) of the readmission. The patient was discharged in good health on the 30th of April, 2020 with thromboprophylaxis planned for 6 weeks postpartum and a follow-up visit to the Obstetrics Clinic.\n\nThe neonate\nA male baby was delivered with birth weight 2085 g (37th percentile), birth length 48 cm (99th percentile) and head circumference 33.5 cm (99th percentile). The cord was clamped immediately after birth and the baby was shown briefly to the mother before being taken to a neonatal resuscitation station. At 1-minute after delivery, the baby had a normal heart rate but was gasping and had absent tone and no spontaneous movements. Positive pressure ventilation by a T-piece (neopuff) was given with peak inspiratory pressure (PIP) 20 cmH2O and positive end expiratory pressure (PEEP) between 5 and 7 cmH2O intermittently during the first seven minutes of life. At ten minutes, the baby was spontaneously breathing, albeit grunting, through T-piece continuous positive airway pressure (CPAP) with preductal oxygen saturation between 90–95% at FiO2 (fraction of inspired oxygen) 0.4. Fine crackles could be heard on lung auscultation. Intermittent intercostal retractions were also seen. Skin colour, tone and reflex irritability improved gradually during the stabilisation process. Apgar score; 1 min: 4 (appearance 1, pulse 2, reflex irritability 0, activity 1, respiration 0), 5 min: 6 (appearance 1, pulse 2, reflex irritability 1, activity 1, respiration 1), 10 min: 8 (appearance 2, pulse 2, reflex irritability 1, activity 1, respiration 2). Vitamin K was given intramuscularly and a nasogastric tube was inserted. Nasal CPAP with PEEP 6 cmH2O was started.\n\nArterial umbilical cord blood gas showed mild combined respiratory and metabolic acidosis with pH 7.28, partial pressure of oxygen (pO2) 3.45 (kilopascal) kPa, partial pressure of carbon dioxide (pCO2) 6.97 kPa and base excess − 6.8.\n\nThe baby was put in an incubator and transferred to the neonatal intensive care unit (NICU) and placed in an airborne infection isolation room (AIIR) with negative pressure ventilation. It was given preterm formula supplemented with intravenous glucose infusion. Venous blood gas was analysed at 4 h of age: pH 7.27, pO2 5 kPa, pCO2 7.3 kPa, BE -1.8, Hb 184 g/l and lactate 2.7 mmol/l.\n\nAfter parental consent, formula was changed to donated breast milk. The mother was supplied with a breast pump and instructed in its use. After the initial need of breathing support and supplemental oxygen during day one of life the baby has enjoyed an uneventful clinical course. Nasopharyngeal swabs for SARS-CoV-2 detection were collected at 48 and 96 h of life and were found to be negative in both instances.\n\nDiscussion and conclusions\nWe report a case of severe COVID-19 during in third trimester pregnancy, which led to an emergency Caesarean section and preterm delivery at 32 + 6 weeks of gestational age. This case adds to the growing body of evidence which raises concerns about the possible negative maternal outcomes of COVID-19 infection during pregnancy [1, 5–8]. Whilst most mothers with COVID-19 infection have mild symptoms which resolve without treatment, a number of cases have now emerged in the literature, where mothers have required intensive care admission, and one case requiring invasive ventilation with extracorporeal membrane oxygenation [8]. It has been suggested that pregnancy induced immune responses and cardio-vascular changes can exaggerate the course of the COVID-19 infection [1]. Mothers with prior medical conditions may be at higher risk for poor outcomes. In this case, there were several risk factors for preeclampsia such as Somalian origin and high BMI [9].\n\nOur patient was severely obese (BMI 47 kg/m2) and her condition deteriorated drastically 12 days after her initial symptoms. Atypical HELLP (Haemolysis, Elevated Liver Enzymes, and Low Platelet Count) syndrome or Mississippi class 3 [10] can present itself with platelets between 100 and 150 × 109/L, aspartate aminotransferase (ASAT)/alanine aminotransferase (ALT) ≥ 0.68 µkat/L and lactate dehydrogenase (LDH) > 10.2 µkat/L but it is seldom associated with coagulation impairment [10]. In addition, the patient had remarkably high levels of ASAT (28 µkat/L), as compared to the other liver tests, which is not consistent with the generalized liver dysfunction seen in HELLP or acute fatty liver of pregnancy [11].\n\nLiver injury has been reported by a number of studies in patients with severe COVID-19 [12–15] making this organ the most commonly affected besides the respiratory system. Transient elevation of serum aminotransferases is often seen and a number of factors have been implicated for acute liver damage in severe COVID-19, including severe hypoxemia due to acute respiratory failure, drug interactions, septic shock and multiorgan dysfunction [12]. On readmission, the plasma paracetamol concentration was well within the therapeutic reference interval (Table 1) and liver injury secondary to a paracetamol overdose was therefore not suspected. Although there is insufficient evidence for direct SARS-CoV-2 virus-related hepatocyte injury, liver dysfunction has been continuingly related to severe COVID-19 infection [15] and intensive care admission [16, 17].\n\nThe patient also presented with elevated concentrations of several active-phase proteins (APPs) including IL-6, procalcitonin and ferritin, which may have indicated concomitant bacterial infection or severe systemic inflammation due to COVID-19. Subsequent blood and urine cultures were negative but the patient still received prophylactic treatment with broad spectrum antibiotics intravenously from day 1–5 of the readmission.\n\nThe hyperactive immune responses characteristic of severe COVID-19 can lead to stress-induced tissue injury and multiorgan impairment [18]. Ruan et al. [19] found that elevated levels of IL-6 were associated with a significantly increased risk of mortality in COVID-19 patients but in this case the inflammatory markers (and liver enzyme tests) decreased significantly after the Caesarean section. We can only speculate whether this indicated that severe COVID-19 in pregnancy may improve promptly by the termination of the pregnancy or that the patient’s condition was a combination of atypical HELLP and COVID-19 which subsequently improved after the Caesarean section. Considering the latter option, the patient showed some typical characteristics of HELLP syndrome; including right upper abdominal pain, epigastric pain, nausea and vomiting but a normal blood pressure [20]. Furthermore, she had no past obstetric history of preeclampsia or HELLP. Her platelet count was only marginally decreased and although subtle signs of haemolysis were present (decreased haemoglobin concentration and elevated LDH), haptoglobin concentration was not decreased [10] (Table 1). Given that pregnancy itself is a hypercoagulable state, it has been suggested that COVID-19 infection during pregnancy is associated with high risk of maternal thrombotic complications [15–17]. High levels of D-dimer in combination with elevated liver enzymes supports the likelihood that the patient’s liver injury and coagulation dysfunction were secondary to the severe COVID-19 infection.\n\nConsidering the neonate, we found no evidence for any vertical transmission of COVID-19 between mother and the baby. However, there have been reported cases of early COVID-19 detection in newborns, implying the potential risk of vertical transmission [21], although in the vast majority of cases, no such evidence has been identified [22, 23]. Since only a handful of cases have been reported in the literature, vertical transmission cannot be ruled out until systematic studies have been undertaken.\n\nOur report has some limitations. We were unable to report a complete panel of coagulation tests due to errors in lab analysis. Similarly, the presence of antiphospholipid antibodies to rule out antiphospholipid syndrome were not investigated. We did not evaluate the presence of SARS-CoV-2 in amniotic fluid, cord blood, or placental tissue which could further clarify the possibility of vertical transmission.\n\nIn summary, we describe a severe case of maternal COVID-19 during the third trimester of pregnancy which led to liver and coagulation impairment and preterm delivery. We believe these findings have important public implications both due to the severity of the disease progression but also due to the rapid nature of the improvement after delivery. Atypical presentation of HELLP could not be ruled out and the importance of a multidisciplinary team in the treatment and management of severe COVID-19 during pregnancy is critical for positive patient outcome. Pregnant women should be considered a vulnerable group in the population in which exposure to COVID-19 should be avoided at all costs.\n\nAbbreviations\nASATAspartate aminotransferase\n\nBMIBody mass index\n\nCTGCardio-tocography\n\ncmCentimetre\n\nCTComputed tomography\n\nCOVID-19Novel coronavirus 2019\n\nHELLPHemolysis, Elevated Liver Enzymes and Low Platelet Count\n\nIl-6Interleukin-6\n\nmgMilligrams\n\nSARS-CoV-2Severe acute respiratory syndrome coronavirus 2\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors want to thank Daisey Lee for her contribution in editing Fig. 2.\n\nAuthors’ contributions\nLR: planning, data collection, analyzing and writing the manuscript. JKL: planning, data collection, writing the manuscript. OV: conception, planning, data collection and revising the manuscript. SRH: conception, planning, data collection and revising the manuscript. AH: conception, planning, data collection and revising the manuscript. MZ: conception, planning, data collection, writing and revising the manuscript. All authors have read and approved the manuscript.\n\nFunding\nThis work was supported by the Swedish Medical Research Council – S.R.H (2018–03156_4, 2018–04840_3)(www.vr.se), Government ALF research grants from Lund University and Lund University Hospital – S.R.H, M.Z (www.med.lu.se/alf), Skåne University Hospital Foundations and Donations – S.R.H (93602, 93603, 93607) (https://susforskningsmedel.skane.se/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Open access funding provided by Lund University.\n\nEthics approval and consent to participate\nEthical approval was not sought due to the nature of the case report. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nConsent for publication\nThe patient provided written informed consent for the publication of potentially identifying images and clinical details on behalf of themselves and their child.\n\nAvailability of data and materials\nThe datasets used and analysed during the current study available from the corresponding author on reasonable request.\n\nCompeting interests\nA.H. is a board member and shareholder in Amniotics AB, a start-up company developing treatment for severe lung disease in COVID-19. S.R.H. holds patents for the diagnosis and treatment of preeclampsia. S.R.H. is also a co-founder of the company Guard Therapeutics International formerly named A1M Pharma AB (https://guardtherapeutics.com).\n==== Refs\nReferences\n1. Zaigham M, Andersson O. 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The spectrum of severe preeclampsia: comparative analysis by HELLP (hemolysis, elevated liver enzyme levels, and low platelet count) syndrome classification. Am J Obstet Gynecol. 1999 Jun;180(6 Pt 1):1373–84.\n11. Naoum EE Leffert LR Chitilian HV Gray KJ Bateman BT Acute Fatty Liver of Pregnancy: Pathophysiology, Anesthetic Implications, and Obstetrical Management Anesthesiology 2019 130 3 446 61 10.1097/ALN.0000000000002597 30707120 \n12. Li J Fan JG Characteristics and Mechanism of Liver Injury in 2019 Coronavirus Disease J Clin Transl Hepatol 2020 8 1 13 7 10.14218/JCTH.2020.00019 32274341 \n13. Zu ZY, Jiang MD, Xu PP, Chen W, Ni QQ, Lu GM, et al. Coronavirus disease 2019 (COVID-19): A perspective from China. Radiology. 2020;296(2):E15–25.\n14. Ren M, Jie L, Jun S, Subrata G, Liang-Ru Z, Hong Y, et al. Implications of COVID-19 for patients with pre-existing digestive diseases. Lancet Gastroenterol Hepatol. 2020.\n15. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020.\n16. Huang C Wang Y Li X Ren L Zhao J Hu Y Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 2020 395 497 506 10.1016/S0140-6736(20)30183-5 31986264 \n17. Wang D Hu B Hu C Zhu F Liu X Zhang J Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China JAMA 2020 323 11 1061 1069 10.1001/jama.2020.1585 \n18. Henderson LA, Canna SW, Schulert GS, Volpi S, Lee PY, Kernan K, et al. On the alert for cytokine storm: Immunopathology in COVID-19. Arthritis Rheumatol. 2020. Accepted Author Manuscript. [Epub ahead of print].\n19. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intens Care Med 2020 [Epub ahead of print].\n20. Dusse LM Alpoim PN Silva JT Rios DR Brandão AH Cabral AC Revisiting HELLP syndrome Clin Chim Acta 2015 451 Pt B 117 20 10.1016/j.cca.2015.10.024 26525965 \n21. Zhang ZJ, Yu XJ, Fu T, Liu Y, Jiang Y, Yang BX, Bi Y. Novel Coronavirus Infection in Newborn Babies Under 28 Days in China. Eur Respir J. 2020 Apr 8. pii: 2000697. [Epub ahead of print].\n22. Yang P, Wang X, Liu P, Wei C, He B, Zheng J, Zhao D. Clinical characteristics and risk assessment of newborns born to mothers with COVID-19. J Clin Virol. 2020 Apr 10;127:104356. [Epub ahead of print].\n23. Liu W, Wang J, Li W, Zhou Z, Liu S, Rong Z. Clinical characteristics of 19 neonates born to mothers with COVID-19. Front Med. 2020 Apr 13. [Epub ahead of print].\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2393",
"issue": "20(1)",
"journal": "BMC pregnancy and childbirth",
"keywords": "COVID-19; Coagulation; Coronavirus; Differential diagnosis; Fever; HELLP syndrome; Liver; Morbidity; Mortality; Neonate; Obstetric management; Pandemic; Pregnancy; Respiratory distress syndrome; Respiratory failure; SARS-CoV-2; Sepsis; Susceptibility; Virus",
"medline_ta": "BMC Pregnancy Childbirth",
"mesh_terms": "D000328:Adult; D000990:Antithrombin III; D001034:Apgar Score; D000073640:Betacoronavirus; D001778:Blood Coagulation Disorders; D000086382:COVID-19; D002585:Cesarean Section; D018352:Coronavirus Infections; D003937:Diagnosis, Differential; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products; D017359:HELLP Syndrome; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007770:L-Lactate Dehydrogenase; D008107:Liver Diseases; D008168:Lung; D008297:Male; D000079262:Obesity, Maternal; D058873:Pandemics; D010314:Partial Thromboplastin Time; D010976:Platelet Count; D011024:Pneumonia, Viral; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D000086402:SARS-CoV-2; D013548:Sweden; D014057:Tomography, X-Ray Computed",
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"title": "Complicated COVID-19 in pregnancy: a case report with severe liver and coagulation dysfunction promptly improved by delivery.",
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"abstract": "Pediatric Burkitt lymphoma has historically been treated with intensive methotrexate-based chemotherapy, which improves patient survival while causing severe toxicities. Young patients typically have better outcomes with intensive therapies, while adults and immunocompromised patients have higher toxicities and worse outcomes. Newer treatment regimens, including etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab (EPOCH-R), show promise for these patients. However, few studies exist to demonstrate efficacy and improved toxicity profile with EPOCH-R. We present 2 cases: a 25-year-old male with Down syndrome and an 18-year-old male with Burkitt lymphoma and significant renal injury who were successfully treated with EPOCH-R with minimal toxicities.",
"affiliations": "Department of Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO.",
"authors": "Ross|Savannah|S|;Eisenman|Kristen|K|;Maloney|Kelly W|KW|",
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"fulltext": "\n==== Front\nJ Pediatr Hematol OncolJ. Pediatr. Hematol. OncolMPHJournal of Pediatric Hematology/Oncology1077-41141536-3678Lippincott Williams & Wilkins 10.1097/MPH.000000000000128700017Clinical and Laboratory ObservationsSuccessful Use of EPOCH-R in 2 Young Adult Patients With Burkitt Lymphoma and Acute Kidney Injury: A Case Report Ross Savannah MDEisenman Kristen MDMaloney Kelly W. MDDepartment of Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, COReprints: Savannah Ross, MD, 13123 E., 16th Ave, B 115, Aurora, CO 80045 (e-mail: savannah.ross@childrenscolorado.org).8 2019 24 7 2019 41 6 498 500 13 2 2018 12 7 2018 Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/Pediatric Burkitt lymphoma has historically been treated with intensive methotrexate-based chemotherapy, which improves patient survival while causing severe toxicities. Young patients typically have better outcomes with intensive therapies, while adults and immunocompromised patients have higher toxicities and worse outcomes. Newer treatment regimens, including etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab (EPOCH-R), show promise for these patients. However, few studies exist to demonstrate efficacy and improved toxicity profile with EPOCH-R. We present 2 cases: a 25-year-old male with Down syndrome and an 18-year-old male with Burkitt lymphoma and significant renal injury who were successfully treated with EPOCH-R with minimal toxicities.\n\nKey Words:\nEPOCH-RBurkitt lymphomaacute kidney injuryDown syndromeOPEN-ACCESSTRUE\n==== Body\nBurkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma that comprises 1% to 2% of lymphomas in the United States, but up to 30% to 50% of pediatric lymphomas.1,2 Most cases present with a rapidly growing tumor and tumor lysis syndrome (TLS).3 Typical therapeutic approaches for BL involve short, intensive chemotherapies including methotrexate, cytarabine, prednisone, and anthracycline.4 These regimens are associated with severe grade 3-4 toxicities, including neutropenia, mucositis, sepsis, and nephrotoxicity.5 In children, toxicities are usually manageable, allowing the necessary intensity.\n\nAnother treatment approach used in adults with BL is similar to that of acute lymphoblastic leukemia (ALL), with induction, consolidation, and maintenance chemotherapy, given over a prolonged period. An example of this approach is hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone (Hyper-CVAD), which causes significant myelosuppression.6 Patients unable to tolerate toxicities have previously received less intensive regimens, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). However, overall survival is substantially lower in patients who receive CHOP (38.8% vs. 82.8% with Hyper-CVAD).7\n\nRecently, studies have looked at whether prolonged, less intense doses of chemotherapy are as effective in BL. Treatment with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab (EPOCH-R) adjusted based on neutrophil count has been studied, mostly in acquired immunodeficiency syndrome–related BL. The rate of neutropenic fevers was 10% to 22%, which is substantially lower than that seen with more intensive regimens.1 Patients treated with EPOCH-R showed an overall survival rate of 90% to 100% at 7 years.1 More intensive regimens have survival rates of 80% to 90% at 2 years.7 Therefore, EPOCH-R may be an effective alternative for patients who do not tolerate intensive therapies, as published in the adult literature. There is little data for this approach in the pediatric and adolescent young adult populations. This case report supports the successful use of this approach in 2 adolescent young adult patients, suggesting that treatment with lower intensity EPOCH-R can be considered in younger patients who are more medically fragile.\n\nRESULTS\nCase Description #1\nA 25-year-old male with Down syndrome (DS) presented to an outside hospital (OSH) with 3 days of nausea, vomiting, and evidence of acute kidney injury (AKI) secondary to dehydration and prerenal injury (creatinine, 3.2 mg/dL). Computed tomographic (CT) scan of abdomen with contrast showed dilated loops of small bowel with transmural thickening and diffuse peritoneal caking, suspicious for lymphoma. There was no involvement of the kidneys on imaging.\n\nHe underwent exploratory laparoscopy with biopsy, and pathology was consistent with BL, stage II. Cytogenetics and fluorescence in situ hybridization revealed a MYC-IGH rearrangement. He had a significant intra-abdominal tumor burden that placed him at risk for TLS, with elevated uric acid requiring treatment with rasburicase initially. He was also treated with intravenous fluids for dehydration, after which creatinine improved to 2.1 mg/dL. A chest x-ray demonstrated right pleural effusion with possible infiltrate. He was started on antibiotics for suspected pneumonia, and underwent thoracentesis, which showed an exudative effusion.\n\nHe was started on prephase chemotherapy with steroids and cyclophosphamide, after which he developed worsening TLS and resulting renal injury requiring continuous venovenous hemofiltration, and pneumonia requiring intubation. As he was treated at an OSH, specific creatinine and electrolyte values were not available. He then received treatment with Hyper-CVAD 1A with pegfilgrastim for neutropenia. In addition to renal and pulmonary complications, he developed hypertension due to AKI, perianal herpes simplex virus dermatitis and diarrhea. There was no concern for posterior reversible encephalopathy syndrome despite his hypertension.\n\nBecause of his DS and concerns that he would not tolerate additional intensive chemotherapy, his parents decided to transfer to our institution, a pediatric hospital. He had a positron emission tomography (PET)-CT, bone marrow biopsy and lumbar puncture performed, which showed no evidence of metastasis. Although on presentation to our institution he had a normal potassium, phosphorus, and uric acid, these subsequently increased (potassium, 5.1 mmol/L; phosphorus, 5.5 mg/dL; and uric acid, 10 mg/dL) within a few days of arrival, requiring treatment with intravenous fluids and allopurinol with resolution of abnormalities. His creatinine also improved to 1.39 mg/dL after continuous venovenous hemofiltration at OSH and intravenous fluids. After review of his course, he was initiated on therapy with EPOCH-R per ANHL1131 in order to avoid further nephrotoxicity with methotrexate. He developed neutropenia, but responded well to pegfilgrastim. His course was notable for resolution of his AKI, TLS, perianal dermatitis, and pneumonia.\n\nHe was admitted 5 times thereafter for EPOCH-R and pegfilgrastim. His main side effects were nausea, AKI that improved with hydration, and hyperglycemia associated with steroids. He also experienced headaches associated with fluid overload. Between cycles, he only had grade 1-2 toxicities with headache, nausea, anorexia, mucositis, and peripheral neuropathy. He had no readmissions for fever and neutropenia.\n\nFollow-up PET-CT after completion of 6 cycles of EPOCH-R demonstrated a small area of increased activity in the small bowel, with questionable bowel wall thickening, concerning for inflammatory or malignant process. Magnetic resonance imaging enterography showed no bowel wall thickening. Repeat imaging 3 months later demonstrated no evidence of recurrence. Of note, his creatinine remains persistently elevated around 1.5 mg/dL, although his electrolytes, fluid balance, and blood pressures remain normal. He is currently 3.5 years off therapy, and is clinically well without recurrence.\n\nCase Description #2\nAn 18-year-old male presented to an OSH with abdominal pain, distention, and evidence of AKI. Kidney injury was initially thought to be due to dehydration and NSAID use for pain. A CT abdomen with contrast showed small bowel obstruction, diffuse edema, free fluid, bilateral pleural effusions, and hydroureteronephrosis. There were no masses within the kidney, though the kidneys had abnormal enhancement suggestive of pyelonephritis, for which he was started on antibiotics. Initially, an oncologic process was not identified.\n\nHis OSH course was complicated by worsening AKI (maximum creatinine, 9.1 mg/dL), obstructive uropathy requiring hemodialysis, hyperuricemia (maximum uric acid, 17.1 mg/dL; requiring treatment with rasburicase), small bowel obstruction, hepatobiliary obstruction, respiratory insufficiency, and hypertension. His obstructive uropathy and worsening AKI were thought to be due to lymphadenopathy causing obstruction. Because of concern for abdominal lymphadenopathy, with imaging showing multiple nodes of varying sizes, measuring up to 8 cm in circumference, he underwent paracentesis, which demonstrated multiple lymphocytes concerning for lymphoma. He was transferred to the intensive care unit at our hospital for further management.\n\nUpon transfer, cytology from the ascites fluid was reviewed, which showed both C-MYC and MYC-IGH rearrangements, confirming the diagnosis of BL. Lumbar puncture and bone marrow biopsy showed clear cerebrospinal fluid and <1% bone marrow involvement. He was thus classified as stage IV. He was initially started on COP therapy (cyclophosphamide, vincristine, methylprednisolone) according to Children’s Cancer Group 5961.\n\nMoreover, upon transfer, he had significant TLS with uric acid of 14.4 mg/dL, potassium of 5.1 mmol/L, although phosphorus was normal. Creatinine improved to 1.76 mg/dL with hemodialysis at the OSH. However, given ongoing electrolyte abnormalities, he required initiation of continuous renal replacement therapy (CRRT) for 12 days, followed by intermittent hemodialysis for 1 month. He was started on CRRT in conjunction with initiation of chemotherapy to prevent further electrolyte abnormalities. After CRRT, electrolytes normalized and creatinine improved to 1.09 mg/dL. Following completion of intermittent hemodialysis, which was required due to recurrent moderate elevations in potassium, phosphorus, and uric acid, electrolytes stabilized and creatinine normalized to 0.49 mg/dL.\n\nIn addition to his kidney injury, he developed respiratory failure with bilateral pleural effusions requiring intubation. His AKI and pleural effusions were a contraindication to methotrexate administration, so he was given another cycle of COP with rituximab. Repeat imaging showed substantial reduction of tumor burden.\n\nBecause of multiple significant toxicities, and concern that he would not tolerate methotrexate, he was transitioned to treatment with dose-adjusted EPOCH-R with filgrastim. He tolerated this regimen well, and did not require further hemodialysis. His creatinine has remained normal. PET-CT after cycle 2 showed complete remission. He was admitted 4 times thereafter to complete 6 total cycles of chemotherapy. He experienced minimal toxicities, including hypertension related to fluid overload, neuropathic pain, and brief episodes of pancytopenia without associated infection. He did not require any dose reductions despite cytopenias. He is currently 3 years off therapy, and is doing well without evidence of disease recurrence.\n\nDISCUSSION\nAlthough treatment of pediatric BL is standardized, some pediatric patients and patients with underlying immunodeficiency may not tolerate the standard, more intensive regimens. Recent studies identified treatment with EPOCH-R as an alternative regimen. A few studies exist to indicate that this regimen is effective and less toxic, with similar overall survival rates and fewer hematologic and infectious toxicities.1\n\nOur cases present further evidence of the utility of EPOCH-R, and expand upon the patient population that may benefit from this chemotherapy regimen. It should be considered in pediatric patients who will not tolerate toxicities from more intensive regimens, or who are presenting critically ill with evidence of significant end organ damage. Both of our patients presented with significant AKI, limiting use of the standard pediatric approach with regimens that include methotrexate. After transitioning to EPOCH-R, both patients had near resolution of their renal injury. Both patients experienced little toxicity during subsequent cycles, most notably no serious infections related to neutropenia, demonstrating the safety of this regimen. Finally, both patients achieved remission after completing 6 cycles of EPOCH-R.\n\nIt has been well documented in children with DS and ALL that these patients have increased toxicities with methotrexate.8,9 Rabin et al10 showed that patients with DS had longer neutrophil nadirs, more frequent infections, and more severe mucositis. As such, it is important to consider less toxic, non–methotrexate-based therapies for these patients in order to minimize chemotherapy-associated morbidity and mortality.\n\nGiven that our patients achieved remission and had minimal severe toxicities from treatment with EPOCH-R, other patients with similar risk factors should be considered as candidates for this treatment regimen. Long-term outcomes must be monitored to ensure that recurrence rates and late effects are comparable with those regimens currently used.\n\nThe authors declare no conflict of interest.\n==== Refs\nREFERENCES\n1 Dunleavy K Pittaluga S Shovlin M \nLow-intensity therapy in adults with Burkitt’s lymphoma . N Engl J Med . 2013 ;369 :915 –1925 .\n2 Said J Lones M Yea S \nBurkitt lymphoma and MYC: what else is new? \nAdv Anat Pathol . 2014 ;21 :160 –165 .24713985 \n3 Blum KA Lozanski G Byrd JC \nAdult Burkitt leukemia and lymphoma . Blood . 2004 ;104 :3009 –3020 .15265787 \n4 Allen CE Kelly KM Bollard CM \nPediatric lymphomas and histiocytic disorders of childhood . Pediatr Clin North Am . 2015 ;62 :139 –165 .25435117 \n5 Ylinen E Jahnukainen K Saarinen-Pihkala UM \nAssessment of renal function during high dose methotrexate treatment in children with acute lymphoblastic leukemia . Pediatr Blood Cancer . 2014 ;61 :2199 –2202 .25174822 \n6 Kantarjian HM O’Brien S Smith TL \nResults of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia . J Clin Oncol . 2000 ;18 :547 –561 .10653870 \n7 Wasterlid T Brown PN Hagberg O \nImpact of chemotherapy regimen and rituximab in adult Burkitt lymphoma: a retrospective population-based study from the Nordic Lymphoma Group . Ann Oncol . 2013 ;24 :1879 –1886 .23446093 \n8 Maloney KW \nAcute lymphoblastic leukaemia in children with Down Syndrome: an updated review . Br J Haematol . 2011 ;155 :420 –425 .21933171 \n9 Maloney KW Taub JW Ravindranath Y \nDown syndrome preleukemia and leukemia . Pediatr Clin North Am . 2015 ;62 :121 –137 .25435116 \n10 Rabin KR Smith J Kozinetx CA \nMyelosuppression and Infectious complications in children with Down Syndrome and acute lymphoblastic leukemia . Pediatr Blood Cancer . 2012 ;58 :633 –635 .22106003\n\n",
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"issn_linking": "1077-4114",
"issue": "41(6)",
"journal": "Journal of pediatric hematology/oncology",
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"mesh_terms": "D058186:Acute Kidney Injury; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002051:Burkitt Lymphoma; D003520:Cyclophosphamide; D004314:Down Syndrome; D004317:Doxorubicin; D005047:Etoposide; D006801:Humans; D008297:Male; D011241:Prednisone; D011379:Prognosis; D000069283:Rituximab; D014750:Vincristine",
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"title": "Successful Use of EPOCH-R in 2 Young Adult Patients With Burkitt Lymphoma and Acute Kidney Injury: A Case Report.",
"title_normalized": "successful use of epoch r in 2 young adult patients with burkitt lymphoma and acute kidney injury a case report"
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"abstract": "Clozapine is an antipsychotic without the extra-pyramidal adverse effects associated with currently marketed antipsychotics. In animals, this drug has not been shown to induce catalepsy and only weakly antagonizes the stereotypic movements induced by apomorphine and the amphetamines. Clozapine is rapidly absorbed after both single and repeated oral doses, with steady-state concentrations attained within eight to ten days after beginning therapy. It is metabolized to N-oxideclozapine and N-desmethylclozapine, which have less pharmacological activity than the parent compound and are excreted in the urine and, to a lesser extent, in the feces. Clozapine has overall therapeutic efficacy and/or superiority to currently marketed antipsychotics in the treatment of refractory schizophrenia. Usual doses (25-900 mg/d) of clozapine cause fewer extrapyramidal adverse reactions than available antipsychotics. Hypotension, dizziness, salivation, and sedation are the most frequently reported adverse effects and tend to subside over time. Agranulocytosis is the most serious adverse reaction, and those receiving clozapine should undergo weekly white blood cell count determinations. Clozapine is useful for those treatment-resistant patients who have not responded to adequate trials of other antipsychotics.",
"affiliations": "College of Pharmacy, University of Rhode Island, Kington 02881.",
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"abstract": "Adequate intravascular volume maintenance is essential to ensure early graft function during renal transplantation. Various recommendations on optimum fluid therapy are based, at best, on sparse evidence, and that too only from observational studies. This prospective randomized controlled study was done to evaluate the effect of 20% human albumin on the early graft function in living donor renal transplantation. Eighty patients undergoing renal transplantation were randomly assigned to one of the intraoperative fluid regimens, 0.9% normal saline with 20% human albumin (albumin group) or 0.9% normal saline alone (saline group), after confirming the exclusion criteria. Intravenous fluid infusion was given to keep central venous pressure (CVP) between 12 to 15 mm Hg. The statistical package of social sciences, SPSS version 12, was used for statistical analysis. The intraoperative fluid volume infused [albumin group--3381±1021.2 vs. saline group--3487±978.5 (mL)] to maintain target CVP was comparable between the two groups (P value>0.05). Statistically, no significant difference was found between the two groups in terms of post transplant serum creatinine [day one; 2.76±1.0 vs. 2.58±0.94, day three; 1.48±0.53 vs. 1.43±0.71, day seven; 1.42±0.6 vs. 1.42±0.53 (mg/dL)] and urine output [day one; 13122.5±5767.8 vs. 13909.4±5324.7, day three; 9233.9±3267.4 vs. 9250±4794.2, day seven; 7517.6±3043.6 vs. 6921.4±3170 (mL)] (P value>0.05). Postoperative change in body weight [1.89±3.82 vs. 2.48±3.89 (kg)], tissue edema (10% vs. 7.5%), and pulmonary edema (2.5% vs. 5%) did not differ significantly (P>0.05). Twenty percent human albumin given intraoperatively, as a volume expander, does not improve early graft function in living donor renal transplantation. It should be used selectively rather than as a routine protocol.",
"affiliations": "Department of Anesthesiology and Critical Care, Institute of Kidney Diseases and Research Center, Civil Hospital Campus, Ahmedabad, Gujarat, India.",
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"title": "Effect of intraoperative human albumin on early graft function in renal transplantation.",
"title_normalized": "effect of intraoperative human albumin on early graft function in renal transplantation"
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"abstract": "We herein describe an 18-month-old boy who underwent initially successful surgical and antibiotic treatment of complicated appendicitis with postoperative occurrence of hemolytic uremic syndrome (HUS). This complication was due to Shiga toxin-producing Escherichia coli (STEC) found secondarily in rectal swabs but not in the peritoneal cavity. The literature indicates that a causal link may exist between these two entities, and HUS could be considered an iatrogenic complication of appendicitis management due to a multimodal stress effect in non-symptomatic STEC carriers.",
"affiliations": "Pediatric Surgery Department, Hôpital Mère-Enfant, University Hospital Centre of Limoges, 8 Avenue Dominique Larrey, Limoges, France.;Pediatric Intensive Care Department, Hôpital Mère-Enfant, University Hospital Centre of Limoges, 8 Avenue Dominique Larrey, Limoges, France.;Microbiology Department, Limoges University Hospital, Limoges, France.;Pediatric Intensive Care Department, Hôpital Mère-Enfant, University Hospital Centre of Limoges, 8 Avenue Dominique Larrey, Limoges, France.;Pediatric Intensive Care Department, Hôpital Mère-Enfant, University Hospital Centre of Limoges, 8 Avenue Dominique Larrey, Limoges, France.;Pediatric Surgery Department, Hôpital Mère-Enfant, University Hospital Centre of Limoges, 8 Avenue Dominique Larrey, Limoges, France.",
"authors": "Belgacem|Alexis|A|;Miane|Hortense|H|;Fillali|Wasfi|W|;Hangard|Pauline|P|;Ponthier|Laure|L|;Ballouhey|Quentin|Q|https://orcid.org/0000-0002-9655-4029",
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"fulltext": "\n==== Front\nJ Int Med Res\nJ Int Med Res\nIMR\nspimr\nThe Journal of International Medical Research\n0300-0605\n1473-2300\nSAGE Publications Sage UK: London, England\n\n33840247\n10.1177/03000605211006952\n10.1177_03000605211006952\nCase Reports\nHemolytic uremic syndrome following complicated appendicitis in a child: what is the missing link?\nBelgacem Alexis 1\nMiane Hortense 2\nFillali Wasfi 3\nHangard Pauline 2\nPonthier Laure 2\nhttps://orcid.org/0000-0002-9655-4029\nBallouhey Quentin 1\n1 Pediatric Surgery Department, Hôpital Mère-Enfant, University Hospital Centre of Limoges, 8 Avenue Dominique Larrey, Limoges, France\n2 Pediatric Intensive Care Department, Hôpital Mère-Enfant, University Hospital Centre of Limoges, 8 Avenue Dominique Larrey, Limoges, France\n3 Microbiology Department, Limoges University Hospital, Limoges, France\nQuentin Ballouhey, Service de chirurgie pédiatrique, Hôpital Mère-Enfant, Centre Hospitalier Universitaire de Limoges, 8 Avenue Dominique Larrey 87042 Limoges, France. Email: q.ballouhey@gmail.com\n12 4 2021\n4 2021\n49 4 0300060521100695227 1 2021\n9 3 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by-nc/4.0/ Creative 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).\nWe herein describe an 18-month-old boy who underwent initially successful surgical and antibiotic treatment of complicated appendicitis with postoperative occurrence of hemolytic uremic syndrome (HUS). This complication was due to Shiga toxin-producing Escherichia coli (STEC) found secondarily in rectal swabs but not in the peritoneal cavity. The literature indicates that a causal link may exist between these two entities, and HUS could be considered an iatrogenic complication of appendicitis management due to a multimodal stress effect in non-symptomatic STEC carriers.\n\nHemolytic uremic syndrome\nShiga toxin\nchildren\nappendicitis\nsurgery\ncase report\nEscherichia coli\ntypesetterts2\n==== Body\nIntroduction\n\nAppendicitis is the most common surgical emergency in children, with an incidence of 1 per 1000 and a peak at approximately 10 years of age.1 Most cases are due to isolated appendiceal infections with digestive aerobic bacteria such as Escherichia coli or Klebsiella pneumoniae.2 In some cases, specific bacteria3 or even viruses are isolated. In children aged <5 years, appendicitis is often complicated by perforation, abscess, and peritonitis because of a delayed diagnosis, secondary or nonspecific presentation, difficulty in communication, or symptoms that overlap with other pediatric illnesses.4\n\nHemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by thrombocytopenia, hemolytic anemia, and kidney failure due to Shiga toxins from Shiga toxin-producing E. coli (STEC).5 There is currently no specific treatment for this rare entity.\n\nThe diagnosis and management of HUS can be a dilemma for the pediatric surgeon6 because the clinical presentation of HUS may be indistinguishable from that of acute surgical diseases of the abdomen, such as appendicitis or postoperative complications.7 Actual surgical complications due to STEC species such as E. coli O157:H7 are very uncommon.8 The relationship between the type of appendicitis and the development of HUS has not yet been clearly identified. Several cases of perforated appendicitis with secondary HUS,8 and vice versa,9 have been reported. Several cases of appendicitis with8 or without a perforated appendix10 have also been associated with the presence of E. coli O157:H7 but without HUS development.\n\nWe herein describe an 18-month-old boy who underwent surgical treatment of peritonitis and developed secondary HUS. The bacteriological analysis identified two microorganisms: a non-enteropathogenic E. coli found in the peritoneal cavity during the appendectomy and a STEC in the stools. The aim of this report is to highlight the link between peritonitis and the occurrence of typical HUS. Is it logical to expect a causal link between appendicitis and HUS?\n\nCase report\n\nAn 18-month-old boy was referred to our emergency department with abdominal pain and a 2-day history of fever despite amoxicillin treatment for suspected otitis. He had no bloody diarrhea. He had no medical history, and all of his other family members were healthy.\n\nPhysical examination revealed a temperature of 38°C, abdominal bloating, and tiredness. A computed tomography scan indicated appendicitis (Figure 1). Blood examination revealed an inflammatory syndrome with a high C-reactive protein level of 236 mg/L (reference range, <5 mg/L). His blood cell count was 9.42 × 109/L (reference range, 4.5–14.5 × 109/L) with 75% neutrophils, his hemoglobin level was 9.5 g/dL, and his platelet count was 252 G/L.\n\nFigure 1. Abdominal computed tomography scan before surgery. (a) Fluid collection was present in the peritoneum (arrow) before the first surgical procedure. (b) An abscess was present in the parietal wall before the second surgical procedure.\n\nThe patient was managed in the operating room of the emergency department. Acute appendicitis with perforation was found at laparotomy. Postoperative intravenous antibiotic therapy with gentamycin, cefotaxime, and metronidazole was initiated. The initial postoperative sequelae were straightforward. The intraoperative swabs recovered wild-type E. coli with false membranes, Clostridium ramosum, Bifidobacterium spp., and Bacteroides thetaiotaomicron. The abdominal silicone drainage tube was removed on postoperative day 4.\n\nThe patient developed a persistent fever and progressive abdominal bloating on postoperative day 2. A computed tomography scan revealed peritoneal effusion in the right iliac fossa and parietal wall (Figure 1) on postoperative day 6. After a multidisciplinary discussion, redo surgery was performed to exclude a surgical complication. Twenty mL of pus were evacuated from the abdominal wall on day 7, and the antibiotic therapy was switched to piperacillin/tazobactam (Tazocilin™; Pfizer, Paris, France). Wild-type E. coli was found in the pus specimen of the parietal wall. Biological tests the day after the redo surgery revealed thrombocytopenia (platelet count of 35 G/L), hemolysis and nonregenerative anemia (hemoglobin of 8.9 g/dL, the presence of schistocytes, collapsed haptoglobin, and high lactate dehydrogenase of 1967 IU/L [reference range, 180–430 IU/L]), and renal failure (serum creatinine of 73 µmol/L [reference range, 15–31 µmol/L]). STEC was suspected and the patient was admitted to the intensive care unit for monitoring. The diagnosis was confirmed by rectal swabbing, which revealed the presence of E. coli with Shiga toxin Stx-2.\n\nA water compensation was performed for the zero input/output balance sheet, and the antibiotic therapy was bolstered by the addition of azithromycin. The patient’s subsequent clinical course was favorable, and he was discharged 10 days after the redo surgery. Tazocilin™ was continued for a total of 7 days. Both of the patient’s brothers (3 months and 3 years of age, respectively) were positive for the Shiga toxin eae, and the older brother was also positive for Stx-2; however, both were asymptomatic. Azithromycin was administered to the older brother for 5 days.\n\nDiscussion\n\nThe identification of eae or Stx-2 Shiga toxin in patients with HUS associated with appendicitis has been described in a small number of case reports in the literature, but a clear link has yet to be made between these two entities.\n\nMost published cases refer to atypical HUS. Reported risk factors for typical HUS include other stress conditions such as burn injuries11 and the post-partum period.12 Acute appendicitis is rare in children under 3 years of age and often presents with a deceptive clinical picture. The diagnosis is often delayed, resulting in a high rate of appendicular perforation (>80%).1 In our case, the patient had complicated appendicitis with no obvious pathogenic bacteria. During the first operative management, wild-type E. coli was identified in the peritoneal fluid; it was also identified in the parietal abscess during the redo surgery. No STEC was found in the perioperative samples. Our hypothesis of asymptomatic prior presence of STEC in this patient is based on the presence of the same STEC in the patient’s two young brothers.\n\nThe presence of certain bacteria in the microbiota in conjunction with the use of antibiotics influences the patient’s susceptibility to STEC infection and increases the risk of typical HUS. The intestinal microbiota of healthy individuals normally has the ability to repress the expression of virulence factors. There are many variants of Stx-2 with different STEC strains that could exhibit pathogen and contamination diversification.13 In our case, the patient’s young age and thus intestinal immaturity was a risk factor for HUS occurrence.13\n\nAntibiotic therapy increases the risk of HUS occurrence,14 given the presence of E. coli O157:H7 in the intestinal tract. The addition of gentamycin during the first surgical management may have placed a degree of stress on the bacteria. Bactericidal antibiotics such as gentamycin are more likely to give rise to the development of HUS than are bacteriostatic antibiotics.14 In vitro data have shown that E. coli O157 cultured with gentamycin produces more Stx Shiga toxin than does E. coli O157 alone.15 This stress probably allows for acquisition of the Stx-2 gene by transduction with phages16 and might explain the occurrence of the HUS symptoms 48 hours after the first surgery in our patient. One study showed that an increase in temperature can also induce phages when associated with other inducers.17 Antibiotic treatment of STEC is still a matter of debate, although azithromycin appears to be the most effective agent.18 Azithromycin is thought to be able to inhibit Stx-stimulated cytokine production by human peripheral blood mononuclear cells and monocytes.18 The efficacy of azithromycin against STEC has been demonstrated in mice.19 In contrast, ciprofloxacin treatment has been shown to increase stress and the production of Stx.20 The survival rate of affected neonatal pigs treated with azithromycin was higher than that of ciprofloxacin-treated animals and untreated controls.21\n\nThus, in summary, this case of typical HUS was probably an adverse effect of the antibiotic treatment and the stressful context of the peritonitis management (Figure 2). The risk factors were the patient’s young age and adjunction of bactericidal antibiotics. When children develop postoperative thrombocytopenia with schistocytes, HUS should be suspected. Detection of STEC in stools is warranted for diagnosis, and the administration of azithromycin may favor rapid recovery.\n\nFigure 2. Pathophysiology of the hemolytic uremic syndrome after peritonitis in our patient. STEC, Shiga toxin-producing Escherichia coli.\n\nEthics and consent: Written informed consent for publication was obtained from the patient’s parents. The requirement for ethics committee approval was waived because of the nature of this study (case report).\n\nDeclaration of conflicting interest: The authors declare that there is no conflict of interest.\n\nFunding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nAuthors’ contributions: All of the authors contributed equally to the manuscript and read and approved the final version of the manuscript.\n\nORCID iD: Quentin Ballouhey https://orcid.org/0000-0002-9655-4029\n==== Refs\nReferences\n\n1 Holcomb GW Murphy JP St Peter SD. Holcomb and Ashcraft’s pediatric surgery. 7th ed. Amsterdam: Elsevier, 2019, pp.549–556.\n2 Lob SH Badal RE Bouchillon SK , et al . Epidemiology and susceptibility of Gram-negative appendicitis pathogens: SMART 2008-2010. Surg Infect (Larchmt) 2013; 14 : 203–208.23540793\n3 Arda IS Ergin F Varan B , et al . Acute abdomen caused by Salmonella typhimurium infection in children. J Pediatr Surg 2001; 36 : 1849–1852.11733922\n4 Almaramhy HH. Acute appendicitis in young children less than 5 years: review article. Ital J Pediatr 2017; 43 : 15.28257658\n5 Wong CS Jelacic S Habeeb RL , et al . The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157: H7 infections. N Engl J Med 2000; 342 : 1930–1936.10874060\n6 Smith CD Schuster SR Gruppe WE , et al . Hemolytic-uremic syndrome: a diagnostic and therapeutic dilemma for the surgeon. J Pediatr Surg 1978; 13 : 597–604.731358\n7 Edmonson MB Chesney RW. Hemolytic-uremic syndrome confused with acute appendicitis. Arch Surg 1978; 113 : 754–755.655853\n8 Cimolai N Blair GK Murphy JJ , et al . Impact of infection by verotoxigenic Escherichia coli O157: H7 on the use of surgical services in a children's hospital. Can J Surg 1997; 40 : 28–32.9030080\n9 Fenton SJ Kastenmeier A Pysher TJ , et al . Acute appendicitis in a patient with hemolytic uremic syndrome: an unusual clinical scenario. Pediatr Surg Int 2008; 24 : 439–441.17410368\n10 Cimolai N Anderson JD Bhanji NM , et al . Escherichia coli O157: H7 infections associated with perforated appendicitis and chronic diarrhoea. Eur J Pediatr 1990; 149 : 259–260.2406150\n11 Emil S Rockstad R Vannix D. Hemolytic uremic syndrome in a child with burn injuries. J Burn Care Rehabil 1998; 19 : 135–137.9556316\n12 Anacleto FE Cifra CL Elises JS. Postpartum hemolytic uremic syndrome in a 17-year-old Filipina primigravid. Pediatr Nephrol 2003; 18 : 1283–1285.14564496\n13 Bruyand M Mariani-Kurkdjian P Gouali M , et al . Hemolytic uremic syndrome due to Shiga toxin-producing Escherichia coli infection. Med Mal Infect 2018; 48 : 167–174.29054297\n14 Kakoullis L Papachristodoulou E Chra P , et al . Shiga toxin-induced haemolytic uraemic syndrome and the role of antibiotics: a global overview. J Infect 2019; 79 : 75–94.31150744\n15 McGannon CM Fuller CA Weiss AA. Different classes of antibiotics differentially influence shiga toxin production. Antimicrob Agents Chemother 2010; 54 : 3790–3798.20585113\n16 Xiaoli L Figler HM Banerjee KG , et al . Non-pathogenic escherichia coli enhance Stx2a production of E. coli O157:H7 through both bamA-dependent and independent mechanisms. Front Microbiol 2018; 9 : 1325.29973923\n17 Bonanno L Delubac B Michel V , et al . Influence of stress factors related to cheese-making process and to STEC detection procedure on the induction of Stx phages from STEC O26: H11. Front Microbiol 2017; 8 : 296.28316592\n18 Ohara T Kojio S Taneike I , et al . Effects of azithromycin on shiga toxin production by Escherichia coli and subsequent host inflammatory response. Antimicrob Agents Chemother 2002; 46 : 3478–3483.12384353\n19 Amran MY Fujii J Kolling GL , et al . Proposal for effective treatment of Shiga toxin-producing Escherichia coli infection in mice. Microb Pathog 2013; 65 : 57–62.24120399\n20 Nitschke M Sayk F Härtel C , et al . Association between azithromycin therapy and duration of bacterial shedding among patients with Shiga toxin-producing enteroaggregative Escherichia coli O104: H4. JAMA 2012; 307 : 1046–1052.22416100\n21 Zhang Q Donohue-Rolfe A Krautz-Peterson G , et al . Gnotobiotic piglet infection model for evaluating the safe use of antibiotics against Escherichia coli O157: H7 infection. J Infect Dis 2009; 199 : 486–493.19125676\n\n",
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"issue": "49(4)",
"journal": "The Journal of international medical research",
"keywords": "Escherichia coli; Hemolytic uremic syndrome; Shiga toxin; appendicitis; case report; children; surgery",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001064:Appendicitis; D002648:Child; D004927:Escherichia coli Infections; D006463:Hemolytic-Uremic Syndrome; D006801:Humans; D007223:Infant; D008297:Male; D054323:Shiga-Toxigenic Escherichia coli",
"nlm_unique_id": "0346411",
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"pages": "3000605211006952",
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"title": "Hemolytic uremic syndrome following complicated appendicitis in a child: what is the missing link?",
"title_normalized": "hemolytic uremic syndrome following complicated appendicitis in a child what is the missing link"
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"abstract": "Granular cell astrocytoma (GCA) is an uncommon malignant glial tumour that is associated with a poor prognosis. GCA cells have some morphological and immunohistochemical similarities to macrophages. In this case, a small biopsy contained no typical astrocytoma and large rounded lesional cells were interpreted as negative for glial fibrillary acidic protein and S100 and positive for CD68, a commonly used marker for macrophages. A diagnosis of a histiocytosis was made. When the patient failed to respond to first and second line therapy, tumour resection was undertaken and the pathology then showed typical morphologic and immunohistochemical features of glioblastoma (astrocytoma World Health Organization grade IV).",
"affiliations": "Joint Austin-Ludwig Oncology Unit, Level 4 Olivia Newton-John Cancer & Wellness Centre, Austin Hospital, 145 Studley Road, Heidelberg, VIC 3084, Australia.;Joint Austin-Ludwig Oncology Unit, Level 4 Olivia Newton-John Cancer & Wellness Centre, Austin Hospital, 145 Studley Road, Heidelberg, VIC 3084, Australia.;Joint Austin-Ludwig Oncology Unit, Level 4 Olivia Newton-John Cancer & Wellness Centre, Austin Hospital, 145 Studley Road, Heidelberg, VIC 3084, Australia.;Joint Austin-Ludwig Oncology Unit, Level 4 Olivia Newton-John Cancer & Wellness Centre, Austin Hospital, 145 Studley Road, Heidelberg, VIC 3084, Australia; Neurology Unit, Austin Health, VIC, Australia. Electronic address: lmcher@mac.com.",
"authors": "Campbell|Robert N|RN|;Liew|Mun Sem|MS|;Gan|Hui K|HK|;Cher|Lawrence|L|",
"chemical_list": "D015415:Biomarkers",
"country": "Scotland",
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"issn_linking": "0967-5868",
"issue": "21(8)",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Erdheim-Chester disease; Glioma; Granular cell astrocytoma",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D001254:Astrocytoma; D015415:Biomarkers; D001706:Biopsy; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D015614:Histiocytosis; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "1457-9",
"pmc": null,
"pmid": "24594450",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mistaken identity: granular cell astrocytoma masquerading as histiocytosis of the central nervous system.",
"title_normalized": "mistaken identity granular cell astrocytoma masquerading as histiocytosis of the central nervous system"
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"companynumb": "AU-JNJFOC-20140720359",
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"abstract": "OBJECTIVE\nUnstable clinical course characterizes the first 24 hours after thrombolysis for anterior circulation stroke, including early neurological deterioration (END), a secondary complication consistently predictive of poor outcome. Apart from straightforward causes, such as intracerebral hemorrhage and malignant edema, the mechanism of END remains unclear in the majority of cases (ENDunexplained). Based on the core/penumbra model, we tested the hypothesis that ENDunexplained is caused by infarct growth beyond the initial penumbra and assessed the associated vascular patterns.\n\n\nMETHODS\nFrom our database of consecutive thrombolyzed patients (n=309), we identified 10 ENDunexplained cases who had undergone both admission and 24-hour MRI. Diffusion-weighted imaging lesion growth both within and beyond the acute penumbra (Tmax>6 seconds) was mapped voxelwise. These 10 cases were compared with 30 no-END controls extracted from the database blinded to 24-hour diffusion-weighted imaging to individually match cases (3/case) according to 4 previously identified clinical and imaging variables.\n\n\nRESULTS\nAs predicted, lesion growth beyond initial penumbra was present in 9 of 10 ENDunexplained patients (substantial in 8) and its volume was significantly larger in cases than controls (2P=0.047). All ENDunexplained cases had proximal arterial occlusion initially, of which only 2 had recanalized at 24 hours.\n\n\nCONCLUSIONS\nIn this exploratory study, most instances of ENDunexplained were related to diffusion-weighted imaging growth beyond acute penumbra. Consistent presence of proximal occlusion at admission and lack of recanalization at 24 hours in most cases suggest that hemodynamic factors played a key role, via for instance systemic instability/collateral failure or secondary thromboembolic processes. Preventing END after tissue-type plasminogen activator using, eg, early antithrombotics may therefore be feasible.",
"affiliations": "From the INSERM UMR S894, Sorbonne Paris Cité, Service de Neuroradiologie (M.T., L.L., M.-A.L., S.C., J.-F.M., C.O.) and INSERM UMR S894, Sorbonne Paris Cité, Service de Neurologie (P.S., G.T., J.-L.M., J.-C.B.), Centre Hospitalier Sainte-Anne, Paris, France.;From the INSERM UMR S894, Sorbonne Paris Cité, Service de Neuroradiologie (M.T., L.L., M.-A.L., S.C., J.-F.M., C.O.) and INSERM UMR S894, Sorbonne Paris Cité, Service de Neurologie (P.S., G.T., J.-L.M., J.-C.B.), Centre Hospitalier Sainte-Anne, Paris, France.;From the INSERM UMR S894, Sorbonne Paris Cité, Service de Neuroradiologie (M.T., L.L., M.-A.L., S.C., J.-F.M., C.O.) and INSERM UMR S894, Sorbonne Paris Cité, Service de Neurologie (P.S., G.T., J.-L.M., J.-C.B.), Centre Hospitalier Sainte-Anne, Paris, France.;From the INSERM UMR S894, Sorbonne Paris Cité, Service de Neuroradiologie (M.T., L.L., M.-A.L., S.C., J.-F.M., C.O.) and INSERM UMR S894, Sorbonne Paris Cité, Service de Neurologie (P.S., G.T., J.-L.M., J.-C.B.), Centre Hospitalier Sainte-Anne, Paris, France.;From the INSERM UMR S894, Sorbonne Paris Cité, Service de Neuroradiologie (M.T., L.L., M.-A.L., S.C., J.-F.M., C.O.) and INSERM UMR S894, Sorbonne Paris Cité, Service de Neurologie (P.S., G.T., J.-L.M., J.-C.B.), Centre Hospitalier Sainte-Anne, Paris, France.;From the INSERM UMR S894, Sorbonne Paris Cité, Service de Neuroradiologie (M.T., L.L., M.-A.L., S.C., J.-F.M., C.O.) and INSERM UMR S894, Sorbonne Paris Cité, Service de Neurologie (P.S., G.T., J.-L.M., J.-C.B.), Centre Hospitalier Sainte-Anne, Paris, France.;From the INSERM UMR S894, Sorbonne Paris Cité, Service de Neuroradiologie (M.T., L.L., M.-A.L., S.C., J.-F.M., C.O.) and INSERM UMR S894, Sorbonne Paris Cité, Service de Neurologie (P.S., G.T., J.-L.M., J.-C.B.), Centre Hospitalier Sainte-Anne, Paris, France.;From the INSERM UMR S894, Sorbonne Paris Cité, Service de Neuroradiologie (M.T., L.L., M.-A.L., S.C., J.-F.M., C.O.) and INSERM UMR S894, Sorbonne Paris Cité, Service de Neurologie (P.S., G.T., J.-L.M., J.-C.B.), Centre Hospitalier Sainte-Anne, Paris, France.;From the INSERM UMR S894, Sorbonne Paris Cité, Service de Neuroradiologie (M.T., L.L., M.-A.L., S.C., J.-F.M., C.O.) and INSERM UMR S894, Sorbonne Paris Cité, Service de Neurologie (P.S., G.T., J.-L.M., J.-C.B.), Centre Hospitalier Sainte-Anne, Paris, France.;From the INSERM UMR S894, Sorbonne Paris Cité, Service de Neuroradiologie (M.T., L.L., M.-A.L., S.C., J.-F.M., C.O.) and INSERM UMR S894, Sorbonne Paris Cité, Service de Neurologie (P.S., G.T., J.-L.M., J.-C.B.), Centre Hospitalier Sainte-Anne, Paris, France. jean-claude.baron@inserm.fr.",
"authors": "Tisserand|Marie|M|;Seners|Pierre|P|;Turc|Guillaume|G|;Legrand|Laurence|L|;Labeyrie|Marc-Antoine|MA|;Charron|Sylvain|S|;Méder|Jean-François|JF|;Mas|Jean-Louis|JL|;Oppenheim|Catherine|C|;Baron|Jean-Claude|JC|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1161/STROKEAHA.114.006745",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0039-2499",
"issue": "45(12)",
"journal": "Stroke",
"keywords": "magnetic resonance imaging; physiopathology; stroke; thrombolysis",
"medline_ta": "Stroke",
"mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D008297:Male; D008875:Middle Aged; D020521:Stroke; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "0235266",
"other_id": null,
"pages": "3527-34",
"pmc": null,
"pmid": "25336515",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Mechanisms of unexplained neurological deterioration after intravenous thrombolysis.",
"title_normalized": "mechanisms of unexplained neurological deterioration after intravenous thrombolysis"
} | [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
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{
"abstract": "Melanoma with cartilaginous differentiation is a rare histologic subtype that has been reported in the literature. It often presents clinically different than conventional melanomas and can be diagnostically challenging. Molecular alterations in previously reported cases have not been published. We present a case of melanoma with chondroid stroma from a 70-year-old man that was found to contain an NRAS mutation (c.182A>G (p.Q61R)) via Illumina TruSight Tumor 15 (TST15) next generation sequencing assay.",
"affiliations": "Department of Pathology, Walter Reed National Military Medical Center, Bethesda, MD; and.;Division of Dermatopathology, Joint Pathology Center, Silver Spring, MD.",
"authors": "Sweeney|Shane P|SP|;Royer|Michael C|MC|",
"chemical_list": "D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human",
"country": "United States",
"delete": false,
"doi": "10.1097/DAD.0000000000001608",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0193-1091",
"issue": "42(8)",
"journal": "The American Journal of dermatopathology",
"keywords": null,
"medline_ta": "Am J Dermatopathol",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D002280:Carcinoma, Basal Cell; D020558:GTP Phosphohydrolases; D006801:Humans; D008297:Male; D008545:Melanoma; D008565:Membrane Proteins; D009154:Mutation; D016609:Neoplasms, Second Primary; D011471:Prostatic Neoplasms; D012878:Skin Neoplasms",
"nlm_unique_id": "7911005",
"other_id": null,
"pages": "608-611",
"pmc": null,
"pmid": "32701697",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "NRAS Mutation Detected in a Melanoma With Chondroid Stroma: A Case Report With Molecular Evaluation and Literature Review of a Rare Form of Melanoma.",
"title_normalized": "nras mutation detected in a melanoma with chondroid stroma a case report with molecular evaluation and literature review of a rare form of melanoma"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-086372",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
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