article dict | reports listlengths 1 3.97k |
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{
"abstract": "Enfuvirtide has been a cornerstone of salvage therapy for multidrug-resistant HIV. Raltegravir provides another novel class option, with the advantages of easier administration and improved tolerability. Thirty-five adults electively replaced enfuvirtide with raltegravir while the rest of their regimen was unchanged. All maintained virologic suppression after a median of 7 months except one who experienced a transiently detectable viral load after 5 months. The new regimen was well tolerated with no apparent new drug-related adverse clinical or laboratory events.",
"affiliations": "AIDS Research Programme, St Paul's Hospital, Providence Healthcare, Canada. mharris@cfenet.ubc.ca",
"authors": "Harris|Marianne|M|;Larsen|Gerene|G|;Montaner|Julio S G|JS|",
"chemical_list": "D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D011760:Pyrrolidinones; D000077560:Enfuvirtide; D000068898:Raltegravir Potassium",
"country": "England",
"delete": false,
"doi": "10.1097/QAD.0b013e328302f3b5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-9370",
"issue": "22(10)",
"journal": "AIDS (London, England)",
"keywords": null,
"medline_ta": "AIDS",
"mesh_terms": "D000328:Adult; D000368:Aged; D024921:Drug Resistance, Multiple, Viral; D000077560:Enfuvirtide; D005260:Female; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D016896:Treatment Outcome",
"nlm_unique_id": "8710219",
"other_id": null,
"pages": "1224-6",
"pmc": null,
"pmid": "18525270",
"pubdate": "2008-06-19",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Outcomes of multidrug-resistant patients switched from enfuvirtide to raltegravir within a virologically suppressive regimen.",
"title_normalized": "outcomes of multidrug resistant patients switched from enfuvirtide to raltegravir within a virologically suppressive regimen"
} | [
{
"companynumb": "CA-ROCHE-641776",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ENFUVIRTIDE"
},
"drugadditional": null,
"dru... |
{
"abstract": "A 56-year-old woman with septic shock presented with persistent hyperlactatemia, despite an adequate clinical response to treatment. Carnitine deficiency was suspected, as the patient was malnourished and chronically taking valproic acid. No other plausible cause of hyperlactatemia was found. Carnitine supplementation resulted in rapid normalization of lactatemia.",
"affiliations": "Faculté de pharmacie, Université de Montréal, Montréal, Quebec, Canada.;Faculté de pharmacie, Université de Montréal, Montréal, Quebec, Canada.;Faculté de pharmacie, Université de Montréal, Montréal, Quebec, Canada.;Department of pharmacy, Hôpital du Sacré-Cœur-de-Montréal, Montréal, Quebec, Canada.;Faculté de médecine, Université de Montréal, Montréal, Quebec, Canada.;Faculté de médecine, Université de Montréal, Montréal, Quebec, Canada.;Department of pharmacy, Hôpital du Sacré-Cœur-de-Montréal, Montréal, Quebec, Canada.",
"authors": "Hogan|Philippe|P|;Plourde|Roxane|R|;Fortier|Maude|M|;Brindamour|Dave|D|;Lagrenade-Verdant|Colin|C|;Demers-Marcil|Simon|S|;Dupuis|Sébastien|S|",
"chemical_list": "D002331:Carnitine",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190018782012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "33(1)",
"journal": "Journal of pharmacy practice",
"keywords": "carnitine deficiency; case report; hyperlactatemia; septic shock; valproic acid",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D002331:Carnitine; D005260:Female; D006801:Humans; D065906:Hyperlactatemia; D007362:Intensive Care Units; D044342:Malnutrition; D008875:Middle Aged; D012772:Shock, Septic",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "113-116",
"pmc": null,
"pmid": "29905091",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Refractory Hyperlactatemia After a Septic Shock in a Patient With Carnitine Deficiency: A Case Report.",
"title_normalized": "refractory hyperlactatemia after a septic shock in a patient with carnitine deficiency a case report"
} | [
{
"companynumb": "CA-BION-007272",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nTo demonstrate not only prevention of vision loss but also improvement in best-corrected visual acuity (BCVA) after treatment with ranibizumab on a variable-dosing regimen over 24 months in patients with age-related macular degeneration (AMD).\n\n\nMETHODS\nInterventional case series.\n\n\nMETHODS\n\n\n\nMETHODS\nInstitutional.\n\n\nMETHODS\nOne hundred and thirty-eight eyes of 138 patients treated intravitreally with 0.5 mg ranibizumab (Lucentis; Novartis, Basel, Switzerland). Age above 50 years, BCVA 0.2 to 1.2 logarithm of the minimal angle of resolution (logMAR), primary or recurrent subfoveal choroidal neovascularization (CNV) secondary to AMD.\n\n\nMETHODS\nAfter single initial treatment, monthly follow-up examination. Retreatment in case of one of the following: sign of subretinal fluid or intraretinal edema, increase in central retinal thickness (CRT) on optical coherence tomography (OCT), active CNV on fluorescein angiography, increase of metamorphopsia, and loss of BCVA > 5 letters on Early Treatment Diabetic Retinopathy Study (ETDRS) chart.\n\n\nMETHODS\nCompared with baseline: proportion of eyes gaining > or = 15 letters, proportion of eyes losing or gaining < 15 letters, change in CRT.\n\n\nRESULTS\nAfter 24 months, 30% of eyes gained > or = 15 letters. After 24 months, 55% of eyes lost or gained < 15 letters. Mean CRT of 386 +/- 145 microm at baseline was significantly reduced to 211 +/- 39 microm after 24 months (P = .036). Mean injection number per patient was 5.6 +/- 2.9 and 4.3 +/- 3.8 from baseline to month 12 and month 12 to 24, respectively.\n\n\nCONCLUSIONS\nIntravitreal ranibizumab on a variable-dosing regimen was effective in significantly increasing mean BVCA and reducing CRT. This beneficial outcome was achieved with a low-rate of mild ocular adverse effects among our patients.",
"affiliations": "Bern Photographic Reading Center, Universitätsklinik für Augenheilkunde, Inselspital, University Bern, Bern, Switzerland. simon.rothenbuehler@insel.ch",
"authors": "Rothenbuehler|Simon P|SP|;Waeber|David|D|;Brinkmann|Christian K|CK|;Wolf|Sebastian|S|;Wolf-Schnurrbusch|Ute E K|UE|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajo.2008.12.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9394",
"issue": "147(5)",
"journal": "American journal of ophthalmology",
"keywords": null,
"medline_ta": "Am J Ophthalmol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D020256:Choroidal Neovascularization; D005260:Female; D005451:Fluorescein Angiography; D005584:Fovea Centralis; D006801:Humans; D007267:Injections; D008268:Macular Degeneration; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000069579:Ranibizumab; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D014786:Vision Disorders; D014792:Visual Acuity; D014822:Vitreous Body",
"nlm_unique_id": "0370500",
"other_id": null,
"pages": "831-7",
"pmc": null,
"pmid": "19217019",
"pubdate": "2009-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effects of ranibizumab in patients with subfoveal choroidal neovascularization attributable to age-related macular degeneration.",
"title_normalized": "effects of ranibizumab in patients with subfoveal choroidal neovascularization attributable to age related macular degeneration"
} | [
{
"companynumb": "CH-ROCHE-2486880",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "This study presents follow-up of a prior study of patients with chronic symptomatic oral chronic graft-versus-host-disease (cGVHD) managed with photobiomodulation therapy (PBM therapy for 1 month. Here, we report long-term follow-up of a series of patients where PBM therapy in patients with oral cGVHD for maintenance follows the initial period of PBM therapy for continuing management. PATIENTS AND METHODS: We report continuing follow-up of 7 cases of oral cGVHD that were treated with PBM therapy. PBM therapy was continued in these patients with the goal of determining the best management schedule of PBM to maintain or improve control of each patient's symptoms and signs of oral cGVHD. RESULTS: Oral sensitivity and mucosal changes of cGVHD were controlled with a continuing schedule of PBM therapy of up to 6-8-week treatment intervals in patients with continuing GVHD. These findings suggest that PBM therapy represents an additional approach for continuing management of oral cGVHD and that the frequency of treatment should be individualized for each patient to provide best control of oral findings. In one case weekly PBM treatment was continued, while in others, management on a monthly or bimonthly basis was associated with control of the oral condition. PBM may be individualized and provided based upon best control of the symptoms and signs of oral GVHD.",
"affiliations": "City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA. jepstein@coh.org.;Department of Oral Medicine, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Amsterdam, Netherlands.;, Beverly Hills, USA.;Department of Hematology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.;Moores Cancer Center, University of California, San Diego, CA, USA.;City of Hope Comprehensive Cancer Center/Kaiser Permanente, Duarte, CA, 91010, USA.",
"authors": "Epstein|Joel B|JB|;Raber-Durlacher|Judith E|JE|;Epstein|Geena L|GL|;Hazenberg|Mette D|MD|;Tzachanis|Dimitrios|D|;Spielberger|Ricardo T|RT|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-020-05626-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "29(3)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "Induction therapy; Low level laser therapy; Maintenance therapy; Oral graft-versus-host disease; Photobiomodulation therapy",
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002908:Chronic Disease; D005260:Female; D006086:Graft vs Host Disease; D006801:Humans; D028022:Low-Level Light Therapy; D008297:Male; D008875:Middle Aged; D009059:Mouth Diseases",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "1387-1394",
"pmc": null,
"pmid": "32666212",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27957272;11726330;20977100;23605599",
"title": "Chronic oral graft-versus-host disease: induction and maintenance therapy with photobiomodulation therapy.",
"title_normalized": "chronic oral graft versus host disease induction and maintenance therapy with photobiomodulation therapy"
} | [
{
"companynumb": "NVSC2020US202546",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUDESONIDE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Postoperatively, young infants are admitted overnight in view of the risk for respiratory complications such as desaturation and apnea. This risk seems much lower than previously reported. Until what age this risk persists, and which infants might actually qualify for day-care treatment, is unknown.\n\n\n\nWe retrospectively reviewed medical charts from preterm infants <45 weeks postconceptional age (PCA), 45-60 weeks PCA, and term infants <3 months admitted overnight after inguinal hernia repair, from January 2011 to December 2015 in a large tertiary children's hospital. Postoperative complications (divided into respiratory, circulatory, neurologic, and other), recurrence, and reoperation were documented and compared between groups.\n\n\n\nMedical charts of 485 patients were reviewed. Postoperative respiratory complications (mainly desaturations or apnea) had been documented for 27 of 76 (35.5%) preterm infants <45 weeks PCA, for 13 of 221 (5.9%) preterm infants 45-60 weeks PCA, and for 3 of 188 (1.6%) term infants (P < .001). An analysis of the 221 preterm infants 45-60 weeks PCA showed statistically significantly more respiratory complications in 76 infants with a respiratory history (eg, bronchopulmonary dysplasia) compared with the others (respectively 13.2% vs 0.7%; P < .001). In these infants, lower gestational age at the time of surgery was statistically significantly predictive for the development of respiratory complications (odds ratio [OR], 0.68 [95% confidence interval {CI}, 0.52-0.89]; P = .005), but respiratory history (OR, 3.50 [0.34-36.28]; P = .294) and American Society of Anesthesiologists (ASA) physical status (OR, 1.54 [95% CI, 0.31-7.65]; P = .598 for ASA physical status II and OR, 6.11 [95% CI, 0.76-49.05]; P = .089 for ASA physical status III) were not predictive.\n\n\n\nIncidence of postoperative respiratory complications is high in preterm infants <45 weeks PCA requiring postoperative overnight saturation and heart rate monitoring. Incidence of postoperative complications in preterm born infants 45-60 weeks PCA varies. Gestational age and possibly presence of respiratory history can be used to estimate the need for overnight admission in these infants. Postoperative respiratory complications after inguinal hernia repair in ASA physical status I and II term born infants >1 month of age are uncommon, which justifies day-care admission for this type of surgical procedure.",
"affiliations": "From the Department of Pediatric Surgery, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, the Netherlands.;From the Department of Pediatric Surgery, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, the Netherlands.;From the Department of Pediatric Surgery, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, the Netherlands.;Department of Anesthesiology, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, the Netherlands.;From the Department of Pediatric Surgery, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, the Netherlands.;Department of Biostatistics, Erasmus University Medical Centre, Rotterdam, the Netherlands.;From the Department of Pediatric Surgery, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, the Netherlands.;From the Department of Pediatric Surgery, Erasmus University Medical Centre-Sophia Children's Hospital, Rotterdam, the Netherlands.",
"authors": "Massoud|Marina|M|;Kühlmann|A Y Rosalie|AYR|;van Dijk|Monique|M|;Staals|Lonneke M|LM|;Wijnen|Rene M H|RMH|;van Rosmalen|Joost|J|;Sloots|Cornelius E J|CEJ|;Keyzer-Dekker|Claudia M G|CMG|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1213/ANE.0000000000003386",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2999",
"issue": "128(3)",
"journal": "Anesthesia and analgesia",
"keywords": null,
"medline_ta": "Anesth Analg",
"mesh_terms": "D015331:Cohort Studies; D005260:Female; D006552:Hernia, Inguinal; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D010343:Patient Admission; D011183:Postoperative Complications; D012189:Retrospective Studies; D012307:Risk Factors; D047929:Term Birth",
"nlm_unique_id": "1310650",
"other_id": null,
"pages": "525-532",
"pmc": null,
"pmid": "29649028",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Does the Incidence of Postoperative Complications After Inguinal Hernia Repair Justify Hospital Admission in Prematurely and Term Born Infants?",
"title_normalized": "does the incidence of postoperative complications after inguinal hernia repair justify hospital admission in prematurely and term born infants"
} | [
{
"companynumb": "NL-PFIZER INC-2019205556",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "Candida blankii is a newly recognized human pathogen. Here we describe a case of bloodstream infection in a preterm neonate. The yeast was repeatedly isolated from blood, and its identity was confirmed by PCR sequencing of rDNA. Additionally, C. blankii DNA was detected directly in a blood sample. The isolates initially developed pink colonies on CHROMagar Candida which later turned into dark metallic blue similar to Candida tropicalis. Inaccurate identification by the VITEK 2 yeast identification system as Stephanoascus ciferrii and intrinsic resistance to fluconazole (MIC 12-16 μg/mL) underscore the need for its accurate identification for appropriate therapeutic management.",
"affiliations": "Microbiology Department, Maternity Hospital, Shuwaikh, Kuwait.;Microbiology Department, Maternity Hospital, Shuwaikh, Kuwait.;Department of Microbiology, Faculty of Medicine, Kuwait University, Safat, Kuwait.;Microbiology Department, Maternity Hospital, Shuwaikh, Kuwait.;Department of Microbiology, Faculty of Medicine, Kuwait University, Safat, Kuwait.;Department of Microbiology, Faculty of Medicine, Kuwait University, Safat, Kuwait.;Department of Microbiology, Faculty of Medicine, Kuwait University, Safat, Kuwait.",
"authors": "Al-Haqqan|A|A|;Al-Sweih|N|N|;Ahmad|S|S|;Khan|S|S|;Joseph|L|L|;Varghese|S|S|;Khan|Z|Z|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.nmni.2018.06.008",
"fulltext": "\n==== Front\nNew Microbes New InfectNew Microbes New InfectNew Microbes and New Infections2052-2975Elsevier S2052-2975(18)30054-410.1016/j.nmni.2018.06.008New Resistant Microbes in HumanAzole-resistant Candida blankii as a newly recognized cause of bloodstream infection Al-Haqqan A. 1Al-Sweih N. 12Ahmad S. 2Khan S. 1Joseph L. 2Varghese S. 2Khan Z. zkhan@hsc.edu.kw2∗1) Microbiology Department, Maternity Hospital, Shuwaikh, Kuwait2) Department of Microbiology, Faculty of Medicine, Kuwait University, Safat, Kuwait∗ Corresponding author: Z. Khan, Department of Microbiology, Faculty of Medicine, Kuwait University, PO Box 24923, Safat 13110, Kuwait. zkhan@hsc.edu.kw23 6 2018 11 2018 23 6 2018 26 25 29 22 4 2018 13 6 2018 16 6 2018 © 2018 The Author(s)2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Candida blankii is a newly recognized human pathogen. Here we describe a case of bloodstream infection in a preterm neonate. The yeast was repeatedly isolated from blood, and its identity was confirmed by PCR sequencing of rDNA. Additionally, C. blankii DNA was detected directly in a blood sample. The isolates initially developed pink colonies on CHROMagar Candida which later turned into dark metallic blue similar to Candida tropicalis. Inaccurate identification by the VITEK 2 yeast identification system as Stephanoascus ciferrii and intrinsic resistance to fluconazole (MIC 12–16 μg/mL) underscore the need for its accurate identification for appropriate therapeutic management.\n\nKeywords\nAzole resistanceCandida blankiimolecular identificationneonate\n==== Body\nIntroduction\nTwo reports have highlighted the clinical significance of Candida blankii in human infections. The first report described its isolation from respiratory specimens of a patient with repeated exacerbations of cystic fibrosis [1]. The second patient, also with cystic fibrosis, yielded a germ-tube–negative Candida species along with Aspergillus\n[2]. This patient was receiving itraconazole when the sputum culture yielded this yeast. After bilateral lung transplantation, and despite liposomal amphotericin B prophylaxis, blood cultures grew a yeast which was subsequently identified as C. blankii. Here we describe second case of C. blankii fungaemia, diagnosed by repeated isolation of the yeast in blood cultures and detection of its DNA in serum sample by PCR, thus unequivocally establishing its aetiologic role as a bloodstream pathogen.\n\nCase description\nThe patient was a 27-week-old preterm neonate. On day 8 of his birth, he presented a clinical picture simulating necrotizing enterocolitis associated with greenish gastric aspirate. The baby was maintained on total parenteral nutrition and was prescribed piperacillin/tazobactam and amphotericin B for the next 14 days, followed by 21 days of fluconazole prophylaxis. Because he continued to yield greenish gastric aspirate, an X-ray of the abdomen was performed, which revealed perforated necrotizing enterocolitis requiring surgical intervention. On day 40, ileostomy was performed. However, after surgery, he had multiple positive blood cultures for Staphylococcus epidermidis and then for Enterococcus faecalis. He was prescribed piperacillin/tazobactam and amphotericin B, and then vancomycin and liposomal amphotericin B (AmBisome). On day 76, antibiotic therapy was withdrawn, but his condition deteriorated and blood culture yielded Pseudomonas aeruginosa, which was treated with meropenem, and he continued to receive liposomal amphotericin B (AmBisome) empirically. Two days later, his blood culture grew E. faecalis, so vancomycin was prescribed for 21 days, which was replaced with teicoplanin as a result of renal toxicity. On day 117, before undergoing a second surgical procedure for prolapsed stoma, he developed septicaemia yielding S. epidermidis and a Candida species (Lab. No. Kw593/18) in blood cultures requiring addition of amikacin along with teicoplanin and liposomal amphotericin B (AmBisome) in the treatment regimen. The details of the disease progression and outcome are provided in Fig. 1. The isolate (Kw593/18) was referred to the Mycology Reference Laboratory for identification and antifungal susceptibility testing under routine patient care as a part of an ongoing study approved by ethical committee of the Ministry of Health, Kuwait. Three subsequent blood cultures on day 125 (Kw710/18), day 130 (Kw775/18) and day 133 (Kw807/18) yielded the same Candida species. Cultures of rectal swabs and endotracheal aspirates were negative for C. blankii and other Candida species.Fig. 1 Timeline and therapeutic course of Candida blankii fungaemia. AmBisome, liposomal amphotericin B; Amk, amikacin; Amp, ampicillin; AmB, amphotericin B; Cs, caspofungin; Ctx, cefotaxime; D, day; Fl, fluconazole; Mem, meropenem; NEC, necrotizing enterocolitis; NPO, nothing by mouth; Tec, teicoplanin; TPN, total parenteral nutrition; Tzp, piperacillin/tazobactam; Van, vancomycin.\n\nFig. 1\n\nResults\nAll bloodstream isolates were recovered in BACTEC Peds Plus/F culture vials after 2 to 3 days of incubation at 37°C and were identified by VITEK 2 yeast identification system as Stephanoascus ciferrii with 89% probability and remained unidentified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (VITEK MS; bioMérieux, Marcy l’Etoile, France). The isolates formed typical yeastlike cream-coloured colonies with a smooth surface and entire margins on Sabouraud dextrose agar and initially developed pink colonies (Fig. 2(A,a)) on CHROMagar Candida [3], which subsequently developed into dark metallic blue similar to Candida tropicalis (Fig. 2(A,b). Slide culture on cornmeal agar showed clusters of budding yeast cells with pseudohyphae (Fig. 2(B)). The isolate showed good growth up to 42°C. The MIC values during antifungal susceptibility testing of the four isolates by Etest were as follows: fluconazole, 12–16 μg/mL; voriconazole, 0.19–0.38 μg/mL; itraconazole, 0.75 μg/mL; posaconazole, 0.5–0.75 μg/mL; amphotericin B, 0.125 μg/mL; caspofungin, 0.25–0.5 μg/mL; micafungin, 0.125 μg/mL and anidulafungin, 0.19 μg/mL (Fig. 3(A) and (B)). Although no approved susceptibility breakpoints for C. blankii are yet available, our susceptibility results to antifungal agents are comparable with a previous report [2]. Because the isolate showed reduced susceptibility to fluconazole by Etest (≥12 μg/mL) and VITEK 2 identified it as S. ciferrii with only 89% probability, molecular identification was carried out. PCR sequencing of internally transcribed spacer (ITS) region of rDNA was performed for species-specific identification [4], [5]. The isolate (Kw593/18) was unequivocally identified as C. blankii because the ITS region of rDNA (GenBank accession no. LT993736) exhibited 100% sequence identity with the corresponding sequence from type strain (CBS1898) as well as several other (CBS6427, CBS7205, CBS1989 and CBS6788) strains, and only one nucleotide difference with a bloodstream isolate (HCFMUSP01) of C. blankii obtained from a cystic fibrosis patient in Brazil [2]. The ITS region of rDNA sequences from C. blankii CBS1898, C. blankii CBS6427 and several other closely related species [6], as well as sequences from other well-known pathogenic Candida spp. available from GenBank were retrieved. Multiple sequence alignments were performed with Clustal Omega, and the phylogenetic tree was constructed with MEGA 6.1 software using the neighbour-joining method with the Kimura two-parameter model. The robustness of tree branches was assessed by bootstrap analysis with 1000 replicates. The dendrogram (Fig. 4) showed that our isolate was identical with C. blankii CBS1898 and C. blankii CBS6427, which belong to the Stephanoascus clade, while most pathogenic Candida spp. (such as C. albicans, C. tropicalis and C. parapsilosis) belong to the CTG clade. The DNA from the blood sample yielding C. blankii Kw593/18 was also extracted as described previously; the ITS-1 region was amplified by PCR using ITS1 and ITS2 primers and sequenced by using ITS1FS and ITS2 primers [4]. The DNA sequence data of the ITS-1 region matched completely with the corresponding sequence from C. blankii Kw593/18. Despite combination antifungal therapy with amphotericin B and caspofungin for 5 days, the patient died on day 138 of life (Fig. 1).Fig. 2 (A) CHROMagar Candida showing colony characteristics of the following Candida species after 48 hours' incubation at 37°C: C. blankii (a), C. tropicalis (b), C. auris (c) and C. haemulonii (d). (B) Slide culture of C. blankii on cornmeal agar showing clusters of budding yeast cells with pseudohyphae. Original magnification, ×1000.\n\nFig. 2Fig. 3 (A) Etest susceptibility performed on RPMI 1640 medium showing minimum inhibitory concentrations. (A) Fluconazole (FL), 16 μg/mL, voriconazole (VO), 0.38 μg/mL, itraconazole (IT), 0.75 μg/mL, posaconazole (POS), 0.75 μg/mL, 5-flucytosine (FC), 0.032 μg/mL. (B) Amphotericin B (AP), 0.125 μg/mL, micafungin (MYC), 0.125, caspofungin (CS), 0.25 μg/mL, anidulafungin (AND), 0.19 μg/mL.\n\nFig. 3Fig. 4 Neighbour-joining phylogenetic tree based on internally transcribed spacer regions of rDNA sequence data for Candida blankii Kw593/18 from Kuwait together with reference strains of several other closely related as well as many well-known pathogenic Candida spp. Numbers on node branches are bootstrap frequencies.\n\nFig. 4\n\nDiscussion\nOur report unequivocally establishes the aetiologic role of C. blankii in human infections by repeatedly isolating it from blood specimens of a preterm neonate and also by demonstrating its DNA in blood. PCR sequencing of DNA isolated from blood showed 100% identity with the sequence of the bloodstream isolate. C. blankii was first described from blood of a mink in 1968 by Buckley and van Uden [7]. Two other studies have also described the isolation of this yeast from clinical specimens, including bloodstream of a fungaemia patient [1], [2].\n\nTherapeutic experience with C. blankii fungaemia is limited to only one previous case [2]. The patient experienced clearing the yeast from blood after 3 days of micafungin therapy and was discharged after 14 days of maintenance therapy with no postinfection complication. Our patient, who received antifungal prophylaxis with amphotericin B (14 days) and fluconazole (21 days) and then was treated empirically with amphotericin B, followed by combination therapy of amphotericin B and caspofungin (5 days), died of infection probably due to polymicrobial septicaemia caused by enteric pathogens possibly originating from the leaky gut together with C. blankii.\n\nC. blankii is not a regular component of human skin/mucosal microbiota and is less virulent than C. albicans\n[2]. Because of identification difficulties, it is probable that some isolates previously identified as S. ciferrii by VITEK 2 were actually C. blankii. Stephanoascus ciferrii has rarely been implicated in human infections [8], [9], [10]. Moreover, like C. blankii, it also shows reduced susceptibility to antifungal agents in previous reports [11], [12]. Candida species exhibiting reduced susceptibility to fluconazole have been implicated in breakthrough infections in patients receiving prophylaxis with this drug for prolonged periods [13]. A limitation of our study is that we determined the MIC values by Etest and not by a reference microdilution method. Although the Etest generally shows good reproducibility and correlation with the broth microdilution method, occasionally the MIC values obtained by the two methods may also show subtle variations [14].\n\nIn conclusion, this report highlights the emergence of this newly recognized azole-resistant Candida species in human infections warranting greater understanding of its epidemiology and pathogenic potential.\n\nConflict of Interest\nNone declared.\n\nAcknowledgements\nThe authors acknowledge cooperation received from the healthcare staff of the neonatal intensive care unit, and excellent technical support provided by M. Asadzadeh, S. Vayalil and O. Al-Musallam of Mycology Reference Laboratory.\n==== Refs\nReferences\n1 Zaragoza S. Galanternik L. Vazquez M. Teper A A. Cordoba S. Finquelievich J. Candida blankii: new agent in cystic fibrosis airways? J Cyst Fibros 14 Suppl. 1 2015 S140 \n2 de Almeida J.N. Jr. Campos S.V. Thomaz D.Y. Thomaz L. de Almeida R.K.G. Del Negro G.M.B. Candida blankii: an emergent opportunistic yeast with reduced susceptibility to antifungals Emerg Microbes Infect 7 2018 24 29515103 \n3 Khan Z.U. Ahmad S. Al-Sweih N. Joseph L. Alfouzan F. Asadzadeh M. Increasing prevalence, molecular characterization and antifungal drug susceptibility of serial Candida auris isolates in Kuwait PLoS One 13 2018 e0195743 \n4 Khan Z.U. Ahmad S. Hagen F. Fell J.W. Kowshik T. Chandy R. Cryptococcus randhawai sp. nov., a novel anamorphic basidiomycetous yeast isolated from tree trunk hollow of Ficus religiosa (peepal tree) from New Delhi, India Antonie Van Leeuwenhoek 97 2010 253 259 20091225 \n5 Schoch C.L. Seifert K.A. Huhndorf S. Robert V. Spouge J.L. Levesque C.A. Nuclear ribosomal internal transcribed spacer (ITS) region as a universal DNA barcode marker for fungi Proc Natl Acad Sci U S A 109 2012 6241 6246 22454494 \n6 Prasad G.S. Mayilraj S. Sood N. Singh V. Biswas K. Lal B. Candida digboiensis sp. nov., a novel anamorphic yeast species from an acidic tar sludge–contaminated oilfield Int J Syst Evol Microbiol 55 2005 967 972 15774693 \n7 Buckley H.R. van Uden N. Five new Candida species Mycopathol Mycol Appl 36 1968 257 266 5750670 \n8 Kurtzman C.P. Christie J. Robnett C.J. Multigene phylogenetic analysis of the Trichomonascus, Wickerhamiella and Zygoascus yeast clades, and the proposal of Sugiyamaella gen.nov. and 14 new species combinations FEMS Yeast Res 7 2007 141 151 17311592 \n9 Demiray T. Hafizoglu T. Koroglu M. Ozbek A. Altindis M. The first case of Stephanoascus ciferrii infection in a newborn and review of literature Nobel Medicus 11 2015 97 100 \n10 Villnueva-Lozano H. Trevino-Rangel R.D.J. Hernandez-Balbola C.L. Gonzalez G.M. Martinez-Resendez M.F. An unusual case of Candida ciferrii fungemia in an immunocompromised patient with Crohn's and Mycobacterium bovis disease J Infect Dev Ctries 10 2016 1156 1158 27801382 \n11 Agın H. Ayhan Y. Devrim I. Gülfidan G. Tulumoglu S. Kayserili E. Fluconazole-, amphotericin-B–, caspofungin-, and anidulafungin-resistant Candida ciferrii: an unknown cause of systemic mycosis in a child Mycopathologia 172 2011 237 239 21461944 \n12 Arendrup M.C. Boekhout T. Akova M. Meis J.F. Cornely O.A. Lortholary O. European Society of Clinical Microbiology and Infectious Diseases Fungal Infection Study Group; European Confederation of Medical Mycology ESCMID and ECMM joint clinical guidelines for the diagnosis and management of rare invasive yeast infections Clin Microbiol Infect 20 Suppl. 3 2014 76 98 \n13 Cuervo G. Garcia-Vidal C. Nucci M. Puchades F. Fernández-Ruiz M. Obed M. Breakthrough candidaemia in the era of broad-spectrum antifungal therapies Clin Microbiol Infect 22 2016 181 188 26460064 \n14 Cuenca-Estrella M. Gomez-Lopez A. Mellado E. Rodriguez-Tudela J.L. Correlation between the procedure for antifungal susceptibility testing for Candida spp. of the European Committee on Antibiotic Susceptibility Testing (EUCAST) and four commercial techniques Clin Microbiol Infect 11 2005 486 492 15882199\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2052-2975",
"issue": "26()",
"journal": "New microbes and new infections",
"keywords": "Azole resistance; Candida blankii; molecular identification; neonate",
"medline_ta": "New Microbes New Infect",
"mesh_terms": null,
"nlm_unique_id": "101624750",
"other_id": null,
"pages": "25-29",
"pmc": null,
"pmid": "30245830",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article",
"references": "26460064;29630658;22454494;21461944;5750670;20091225;29515103;24102785;15774693;27801382;15882199;17311592",
"title": "Azole-resistant Candida blankii as a newly recognized cause of bloodstream infection.",
"title_normalized": "azole resistant candida blankii as a newly recognized cause of bloodstream infection"
} | [
{
"companynumb": "KW-PFIZER INC-2018401490",
"fulfillexpeditecriteria": "1",
"occurcountry": "KW",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
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{
"abstract": "All-trans retinoic acid (ATRA) and Idarubicin are part of the AIDA protocol employed for the treatment of Acute promyelocytic leaukaemia (APML) and has been associated with marked improvement in the prognosis. However, it is known to worsen the haematological picture during the course of induction of therapy. Herein, we present a case of an APML patient who developed a rare documented incidence of cerebral sinus thrombosis, first noticed as an ophthalmology referral. This 22 year old lady, a known APML patient was then started on chemotherapy based on AIDA protocol but 17 days into the initiation of therapy, she began to complain of blurred vision on the right eye. Anterior segments were normal but both fundi showed papilloedema with peripapillary haemorrhages. A contrast MRI that was then ordered showed multiple filling defects in numerous venous sinuses. She was started on anticoagulant treatment and the findings resolved. Though a rare case of its side-effects, ATRA usage in APML has a multitude of presentations since its primary pathology lies in the inherent pro-coagulant potential.",
"affiliations": "Department of Ophthalmology, Faculty of Medicine, University Malaya, Jalan Lembah Pantai, 50606, Kuala Lumpur, Malaysia, kennethrohan@yahoo.com.",
"authors": "Lee|Kenneth Rohan|KR|;Subrayan|Visvaraja|V|;Win|Maung Maung|MM|;Fadhilah Mohamad|Nor|N|;Patel|Dinesh|D|",
"chemical_list": "D000970:Antineoplastic Agents; D014212:Tretinoin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-013-0988-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0929-5305",
"issue": "38(1)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": null,
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D002533:Cerebral Angiography; D005260:Female; D006801:Humans; D020767:Intracranial Thrombosis; D015473:Leukemia, Promyelocytic, Acute; D018810:Magnetic Resonance Angiography; D014212:Tretinoin",
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "87-9",
"pmc": null,
"pmid": "24046068",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23266518;9242531;15567454;12954994;9321529;8100880;8833399;16102104;9558362;8639429;22549696",
"title": "ATRA-induced cerebral sinus thrombosis.",
"title_normalized": "atra induced cerebral sinus thrombosis"
} | [
{
"companynumb": "MY-MYLANLABS-2014S1016120",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRETINOIN"
},
"drugadditional": null,
... |
{
"abstract": "Adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with conventional chemotherapy have dismal outcomes. Novel immunotherapies targeting CD19, including the bispecific T-cell engager blinatumomab and chimeric antigen-receptor T (CAR-T) cells, have revolutionized the treatment of R/R B-ALL. Robust response rates to CAR-T cell therapy after blinatumomab have recently been reported, but it is unknown whether blinatumomab can be effective following failure of anti-CD19 CAR-T cell therapy. Herein, we describe a patient with Philadelphia chromosome-positive B-ALL who relapsed after CD19-directed CAR-T therapy, but subsequently responded to the combination of blinatumomab and the tyrosine kinase inhibitor ponatinib, with the achievement of a complete remission lasting 12 months.",
"affiliations": "Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.;Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA, aemadi@umm.edu.",
"authors": "El Chaer|Firas|F|;Holtzman|Noa G|NG|;Sausville|Edward A|EA|;Law|Jennie Y|JY|;Lee|Seung Tae|ST|;Duong|Vu H|VH|;Baer|Maria R|MR|;Koka|Rima|R|;Singh|Zeba N|ZN|;Hardy|Nancy M|NM|;Emadi|Ashkan|A|",
"chemical_list": "D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D000970:Antineoplastic Agents; D007093:Imidazoles; D011724:Pyridazines; D011948:Receptors, Antigen, T-Cell; C545373:ponatinib; C510808:blinatumomab",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000495558",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "141(2)",
"journal": "Acta haematologica",
"keywords": "Acute lymphoblastic leukemia; Blinatumomab; CD19 CAR-T cell; Philadelphia chromosome; Ponatinib",
"medline_ta": "Acta Haematol",
"mesh_terms": "D000328:Adult; D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D000970:Antineoplastic Agents; D064987:Cell- and Tissue-Based Therapy; D004359:Drug Therapy, Combination; D006801:Humans; D007093:Imidazoles; D008297:Male; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011724:Pyridazines; D011948:Receptors, Antigen, T-Cell; D012008:Recurrence",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "107-110",
"pmc": null,
"pmid": "30695783",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Relapsed Philadelphia Chromosome-Positive Pre-B-ALL after CD19-Directed CAR-T Cell Therapy Successfully Treated with Combination of Blinatumomab and Ponatinib.",
"title_normalized": "relapsed philadelphia chromosome positive pre b all after cd19 directed car t cell therapy successfully treated with combination of blinatumomab and ponatinib"
} | [
{
"companynumb": "US-PFIZER INC-2019124213",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DASATINIB"
},
"drugadditional": null,
... |
{
"abstract": "Although cemiplimab has been approved for locally advanced (la) and metastatic (m) cutaneous squamous-cell carcinomas (CSCCs), its real-life value has not yet been demonstrated. An early-access program enrolled patients with la/mCSCCs to receive cemiplimab. Endpoints were best overall response rate (BOR), progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. The 245 patients (mean age 77 years, 73% male, 49% prior systemic treatment, 24% immunocompromised, 27% Eastern Cooperative Oncology Group performance status (PS) ≥ 2) had laCSCCs (35%) or mCSCCs (65%). For the 240 recipients of ≥1 infusion(s), the BOR was 50.4% (complete, 21%; partial, 29%). With median follow-up at 12.6 months, median PFS was 7.9 months, and median OS and DOR were not reached. One-year OS was 73% versus 36%, respectively, for patients with PS < 2 versus ≥ 2. Multivariate analysis retained PS ≥ 2 as being associated during the first 6 months with PFS and OS. Head-and-neck location was associated with longer PFS. Immune status had no impact. Severe treatment-related adverse events occurred in 9% of the patients, including one death from toxic epidermal necrolysis. Cemiplimab real-life safety and efficacy support its use for la/mCSCCs. Patients with PS ≥ 2 benefited less from cemiplimab, but it might represent an option for immunocompromised patients.",
"affiliations": "Centre Hospitalier Universitaire (CHU) de Lille, 59037 Lille, France.;Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris (APHP), 93000 Bobigny, France.;CHU de Bordeaux and University of Bordeaux, 33000 Bordeaux, France.;Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris (APHP), 93000 Bobigny, France.;Hôpital Saint-Louis, APHP, 75010 Paris, France.;CH Saint-Louis de la Rochelle, 17000 La Rochelle, France.;Université de Bourgogne-Franche-Comté and CHU de Besançon, 25000 Besançon, France.;CH du Mans, 72037 Le Mans, France.;Hôpital Pontchaillou, 35000 Rennes, France.;Hôpital Henri-Mondor, APHP, 94000 Créteil, France.;Institut Universitaire du Cancer de Toulouse, 31100 Toulouse, France.;Hôpital Charles-Nicolle, 76038 Rouen, France.;Hôpital Côte-de-Nacre, 14000 Caen, France.;Centre Léon-Bérard, 69008 Lyon, France.;Hôpital Saint-Joseph, 13008 Marseille, France.;CHU de Nantes and Université de Nantes, 44000 Nantes, France.;CHU de Montpellier, 34295 Montpellier, France.;CHU d'Angers, 49100 Angers, France.;APHP, Hôpital Cochin, 75014 Paris, France.;CHU de Reims, 51092 Reims, France.;CH Annecy Genevois, 74370 Annecy, France.;CHU de Nîmes, 30900 Nîmes, France.;Hôpital Lyon Sud-Hospices Civils de Lyon, 69310 Lyon, France.;CHU Amiens-Picardie, 80000 Amiens, France.;Hôpital d'Instruction des Armées Sainte-Anne, 83000 Toulon, France.;CHU F.-Mitterrand Dijon-Bourgogne, 21000 Dijon, France.;CH de Boulogne-sur-Mer, 62200 Boulogne-sur-Mer, France.;CH Robert-Ballanger, 93600 Aulnay-sous-Bois, France.;CH Côte Basque, 64109 Bayonne, France.;CHU de Grenoble-Alpes, 38700 Grenoble, France.;CHU de Brest and University of Bretagne Occidentale, 29200 Brest, France.;CHU de Clermont-Ferrand, 63100 Clermont-Ferrand, France.;CH de Cornouaille, CH Intercommunal de Quimper, 29000 Quimper, France.;APHP, Hôpital Bichat, 75018 Paris, France.;Hôpital du Scorff, 56322 Lorient, France.;CHU de Poitiers, 86021 Poitiers, France.;CH de Valence, 26000 Valence, France.;CHU de Reims, 51092 Reims, France.;Clinique Saint-Pierre, 66000 Perpignan, France.;CH Régional Universitaire Trousseau de Tours, 37170 Chambray les Tours, France.;Clinique Sainte-Anne, 67000 Strasbourg, France.;Centre d'Oncologie de Gentilly, 54000 Nancy, France.;University of Aix-Marseille and CHU de la Timone, 13005 Marseille, France.;Institut de Cancérologie de la Loire-Lucien-Neuwirth (ICLN), 42270 Saint-Priest-en-Jarez, France.;Institut Franco-Britannique, 92300 Levallois-Perret, France.;Groupe Hospitalier de St-Malo, 35400 St-Malo, France.;CH René-Dubos, 95300 Pontoise, France.;Institut de Cancérologie de l'Ouest, 44800 Saint-Herblain, France.;Pôle Santé Léonard-de-Vinci, 37170 Chambray-les-Tours, France.;Clinique Clémentville, 34070 Montpellier, France.;Hôpital Privé Toulon Hyères Saint-Jean, 83100 Toulon, France.;CHU de Saint-Denis, 97400 Saint-Denis de la Réunion, France.;CH de Niort, 79000 Niort, France.;Hôpital Louis Pasteur, 28630 Le Coudray, France.;CH Régional Metz-Thionville, 57100 Metz, France.;CHU F.-Mitterrand Dijon-Bourgogne, 21000 Dijon, France.;CHU de Nantes and Université de Nantes, 44000 Nantes, France.;CHU F.-Mitterrand Dijon-Bourgogne, 21000 Dijon, France.;Centre Hospitalier Universitaire (CHU) de Lille, 59037 Lille, France.;Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris (APHP), 93000 Bobigny, France.",
"authors": "Hober|Candice|C|;Fredeau|Lisa|L|;Pham-Ledard|Anne|A|;Boubaya|Marouane|M|;Herms|Florian|F|;Celerier|Philippe|P|;Aubin|François|F|;Beneton|Nathalie|N|;Dinulescu|Monica|M|;Jannic|Arnaud|A|;Meyer|Nicolas|N|;Duval-Modeste|Anne-Bénédicte|AB|;Cesaire|Laure|L|;Neidhardt|Ève-Marie|ÈM|;Archier|Élodie|É|;Dréno|Brigitte|B|;Lesage|Candice|C|;Berthin|Clémence|C|;Kramkimel|Nora|N|;Grange|Florent|F|;de Quatrebarbes|Julie|J|;Stoebner|Pierre-Emmanuel|PE|;Poulalhon|Nicolas|N|;Arnault|Jean-Philippe|JP|;Abed|Safia|S|;Bonniaud|Bertille|B|;Darras|Sophie|S|;Heidelberger|Valentine|V|;Devaux|Suzanne|S|;Moncourier|Marie|M|;Misery|Laurent|L|0000-0001-8088-7059;Mansard|Sandrine|S|;Etienne|Maxime|M|;Brunet-Possenti|Florence|F|0000-0003-2100-2913;Jacobzone|Caroline|C|;Lesbazeilles|Romain|R|;Skowron|François|F|;Sanchez|Julia|J|0000-0003-1658-6686;Catala|Stéphanie|S|;Samimi|Mahtab|M|;Tazi|Youssef|Y|;Spaeth|Dominique|D|;Gaudy-Marqueste|Caroline|C|;Collard|Olivier|O|;Triller|Raoul|R|;Pracht|Marc|M|0000-0001-8110-0780;Dumas|Marc|M|;Peuvrel|Lucie|L|0000-0002-4347-915X;Combe|Pierre|P|0000-0002-7321-7345;Lauche|Olivier|O|;Guillet|Pierre|P|;Reguerre|Yves|Y|;Kupfer-Bessaguet|Ingrid|I|;Solub|David|D|;Schoeffler|Amélie|A|;Bedane|Christophe|C|;Quéreux|Gaëlle|G|;Dalac|Sophie|S|;Mortier|Laurent|L|;Maubec|Ève|È|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/cancers13143547",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694\nMDPI\n\n10.3390/cancers13143547\ncancers-13-03547\nArticle\nCemiplimab for Locally Advanced and Metastatic Cutaneous Squamous-Cell Carcinomas: Real-Life Experience from the French CAREPI Study Group\nHober Candice 1†‡\nFredeau Lisa 2†‡\nPham-Ledard Anne 3‡\nBoubaya Marouane 2‡\nHerms Florian 4‡\nCelerier Philippe 5‡\nAubin François 6‡\nBeneton Nathalie 7‡\nDinulescu Monica 8‡\nJannic Arnaud 9‡\nMeyer Nicolas 1011‡\nDuval-Modeste Anne-Bénédicte 12‡\nCesaire Laure 13‡\nNeidhardt Ève-Marie 14‡\nArchier Élodie 15‡\nDréno Brigitte 161718‡\nLesage Candice 19‡\nBerthin Clémence 20‡\nKramkimel Nora 21‡\nGrange Florent 2223‡\nde Quatrebarbes Julie 24‡\nStoebner Pierre-Emmanuel 2526‡\nPoulalhon Nicolas 27‡\nArnault Jean-Philippe 28‡\nAbed Safia 29‡\nBonniaud Bertille 30‡\nDarras Sophie 31‡\nHeidelberger Valentine 32‡\nDevaux Suzanne 33‡\nMoncourier Marie 34‡\nhttps://orcid.org/0000-0001-8088-7059\nMisery Laurent 35‡\nMansard Sandrine 36‡\nEtienne Maxime 37‡\nhttps://orcid.org/0000-0003-2100-2913\nBrunet-Possenti Florence 38‡\nJacobzone Caroline 39‡\nLesbazeilles Romain 4041‡§\nSkowron François 23‡‖\nhttps://orcid.org/0000-0003-1658-6686\nSanchez Julia 22‡¶\nCatala Stéphanie 42‡\nSamimi Mahtab 4344‡\nTazi Youssef 45‡\nSpaeth Dominique 46‡\nGaudy-Marqueste Caroline 47‡\nCollard Olivier 48‡\nTriller Raoul 49‡\nhttps://orcid.org/0000-0001-8110-0780\nPracht Marc 50‡\nDumas Marc 51‡\nhttps://orcid.org/0000-0002-4347-915X\nPeuvrel Lucie 52‡\nhttps://orcid.org/0000-0002-7321-7345\nCombe Pierre 53‡\nLauche Olivier 54‡\nGuillet Pierre 55‡\nReguerre Yves 56‡\nKupfer-Bessaguet Ingrid 41‡\nSolub David 57‡\nSchoeffler Amélie 58‡\nBedane Christophe 3059‡\nQuéreux Gaëlle 161718‡\nDalac Sophie 30‡\nMortier Laurent 160‡\nMaubec Ève 26162*‡\nGutzmer Ralf Academic Editor\n1 Centre Hospitalier Universitaire (CHU) de Lille, 59037 Lille, France; candice.hober.etu@univ-lille.fr (C.H.); Laurent.MORTIER@CHRU-LILLE.FR (L.M.)\n2 Hôpital Avicenne, Assistance Publique–Hôpitaux de Paris (APHP), 93000 Bobigny, France; lisa.fredeau@aphp.fr (L.F.); marouane.boubaya@aphp.fr (M.B.)\n3 CHU de Bordeaux and University of Bordeaux, 33000 Bordeaux, France; anne.pham-ledard@chu-bordeaux.fr\n4 Hôpital Saint-Louis, APHP, 75010 Paris, France; florian.herms@aphp.fr\n5 CH Saint-Louis de la Rochelle, 17000 La Rochelle, France; Philippe.CELERIER@ght-atlantique17.fr\n6 Université de Bourgogne–Franche-Comté and CHU de Besançon, 25000 Besançon, France; faubin@chu-besancon.fr\n7 CH du Mans, 72037 Le Mans, France; nbeneton@ch-lemans.fr\n8 Hôpital Pontchaillou, 35000 Rennes, France; monica.dinulescu@chu-rennes.fr\n9 Hôpital Henri-Mondor, APHP, 94000 Créteil, France; arnaud.jannic@aphp.fr\n10 Institut Universitaire du Cancer de Toulouse, 31100 Toulouse, France; meyer.n@chu-toulouse.fr\n11 CHU de Toulouse, 31300 Toulouse, France\n12 Hôpital Charles-Nicolle, 76038 Rouen, France; ab.duval-modeste@chu-rouen.fr\n13 Hôpital Côte-de-Nacre, 14000 Caen, France; laure.cesaire@live.fr\n14 Centre Léon-Bérard, 69008 Lyon, France; eve-marie.neidhardt@lyon.unicancer.fr\n15 Hôpital Saint-Joseph, 13008 Marseille, France; earchier@hopital-saint-joseph.fr\n16 CHU de Nantes and Université de Nantes, 44000 Nantes, France; brigitte.dreno@atlanmed.fr (B.D.); gaelle.quereux@chu-nantes.fr (G.Q.)\n17 Centre d’Investigation Clinique 1413, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU de Nantes, 44000 Nantes, France\n18 Centre de Recherche en Cancérologie et Immunologie Nantes Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM), 44007 Nantes, France\n19 CHU de Montpellier, 34295 Montpellier, France; candice-lesage@chu-montpellier.fr\n20 CHU d’Angers, 49100 Angers, France; Clemence.Berthin@chu-angers.fr\n21 APHP, Hôpital Cochin, 75014 Paris, France; nora.kramkimel@aphp.fr\n22 CHU de Reims, 51092 Reims, France; fgrange@ch-valence.fr (F.G.); J.SANCHEZ@ch-stquentin.fr (J.S.)\n23 CH de Valence, 26000 Valence, France; f.skowron@hopitaux-drome-nord.fr\n24 CH Annecy Genevois, 74370 Annecy, France; jdequatrebarbes@ch-annecygenevois.fr\n25 CHU de Nîmes, 30900 Nîmes, France; pierre.stoebner@chu-nimes.fr\n26 UMR CNRS 5247, Université Montpellier I, 34090 Montpellier, France\n27 Hôpital Lyon Sud–Hospices Civils de Lyon, 69310 Lyon, France; nicolas.poulalhon@chu-lyon.fr\n28 CHU Amiens-Picardie, 80000 Amiens, France; arnault.jean-philippe@chu-amiens.fr\n29 Hôpital d’Instruction des Armées Sainte-Anne, 83000 Toulon, France; safia.abed@intradef.gouv.fr\n30 CHU F.-Mitterrand Dijon-Bourgogne, 21000 Dijon, France; bertille.bonniaud@chu-dijon.fr (B.B.); christophe.bedane@chu-dijon.fr (C.B.); sophie.dalac@chu-dijon.fr (S.D.)\n31 CH de Boulogne-sur-Mer, 62200 Boulogne-sur-Mer, France; sec_dermato@ch-boulogne.fr\n32 CH Robert-Ballanger, 93600 Aulnay-sous-Bois, France; valentine.heidelberger@aphp.fr\n33 CH Côte Basque, 64109 Bayonne, France; sdevaux@ch-cotebasque.fr\n34 CHU de Grenoble-Alpes, 38700 Grenoble, France; mmoncourier@chu-grenoble.fr\n35 CHU de Brest and University of Bretagne Occidentale, 29200 Brest, France; laurent.misery@chu-brest.fr\n36 CHU de Clermont-Ferrand, 63100 Clermont-Ferrand, France; smansard@chu-clermontferrand.fr\n37 CH de Cornouaille, CH Intercommunal de Quimper, 29000 Quimper, France; m.etienne@ch-cornouaille.fr\n38 APHP, Hôpital Bichat, 75018 Paris, France; florence.brunet-possenti@aphp.fr\n39 Hôpital du Scorff, 56322 Lorient, France; c.jacobzoneleveque@ghbs.bzh\n40 CHU de Poitiers, 86021 Poitiers, France; romain.lesbazeilles@ch-niort.fr\n41 CH de Niort, 79000 Niort, France; ingrid.kupfer@ch-niort.fr\n42 Clinique Saint-Pierre, 66000 Perpignan, France; stepscatala.2020@gmail.com\n43 CH Régional Universitaire Trousseau de Tours, 37170 Chambray les Tours, France; mahtab.samimi@univ-tours.fr\n44 ISP1282 UMR INRA-Université de Tours, 37000 Tours, France\n45 Clinique Sainte-Anne, 67000 Strasbourg, France; csaler@solcrr.org\n46 Centre d’Oncologie de Gentilly, 54000 Nancy, France; d.spaeth@ilcgroupe.fr\n47 University of Aix—Marseille and CHU de la Timone, 13005 Marseille, France; caroline.gaudy@ap-hm.fr\n48 Institut de Cancérologie de la Loire–Lucien-Neuwirth (ICLN), 42270 Saint-Priest-en-Jarez, France; olivier.collard@icloire.fr\n49 Institut Franco-Britannique, 92300 Levallois-Perret, France; rtriller@orange.fr\n50 Groupe Hospitalier de St-Malo, 35400 St-Malo, France; m.pracht@rennes.unicancer.fr\n51 CH René-Dubos, 95300 Pontoise, France; marc.dumaslattaque@aphp.fr\n52 Institut de Cancérologie de l’Ouest, 44800 Saint-Herblain, France; Lucie.Peuvrel@ico.unicancer.fr\n53 Pôle Santé Léonard-de-Vinci, 37170 Chambray-les-Tours, France; p.combe@cort37.fr\n54 Clinique Clémentville, 34070 Montpellier, France; olivier.lauche@oncoclem.org\n55 Hôpital Privé Toulon Hyères Saint-Jean, 83100 Toulon, France; pierre.guillet@clinique-st-jean.fr\n56 CHU de Saint-Denis, 97400 Saint-Denis de la Réunion, France; yves.reguerre@chu-reunion.fr\n57 Hôpital Louis Pasteur, 28630 Le Coudray, France; dsolub@ch-chartres.fr\n58 CH Régional Metz-Thionville, 57100 Metz, France; a.schoeffler@chr-metz-thionville.fr\n59 CHU de Limoges, 87000 Limoges, France\n60 INSERM U 1189, University of Lille, 59037 Lille, France\n61 Campus de Bobigny—Université Sorbonne Paris Nord, 93017 Bobigny, France\n62 UMR 1124, Campus Saint Germain des Prés, 75006 Paris, France\n* Correspondence: eve.maubec@aphp.fr\n† These authors contributed equally to this study.\n\n‡ These authors belong to French Cutaneous Squamous Cell Carcinoma Study Group.\n\n§ Present address: CH Niort, 79000 Niort, France.\n\n‖ Present address: Hôpitaux Drôme Nord, 26100 Romans-sur-Isère, France.\n\n¶ Present address: CH Saint-Quentin, 02321 Saint-Quentin, France.\n\n15 7 2021\n7 2021\n13 14 354706 6 2021\n07 7 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nSimple Summary\n\nPrognosis of advanced cutaneous squamous-cell carcinoma (CSCC) is poor. Recent clinical trials have shown that immunotherapy achieves significantly improved survival of patients with advanced CSCCs. However, few real-world data are available on treatment patterns and clinical outcomes of patients with advanced CSCCs receiving anti-programmed cell-death protein-1 (PD-1). To approach this issue, we conducted a retrospective study on 245 patients with advanced CSCCs from 58 centers who had been enrolled in an early-access program; 240 received cemiplimab. Our objectives were to evaluate, in the real-life setting, best overall response rate, progression-free survival, overall survival and safety. Results demonstrated cemiplimab efficacy in patients with advanced CSCCs, regardless of immune status. Patients with good Eastern Cooperative Oncology Group performance status benefited more from cemiplimab. The safety profile was acceptable.\n\nAbstract\n\nAlthough cemiplimab has been approved for locally advanced (la) and metastatic (m) cutaneous squamous-cell carcinomas (CSCCs), its real-life value has not yet been demonstrated. An early-access program enrolled patients with la/mCSCCs to receive cemiplimab. Endpoints were best overall response rate (BOR), progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. The 245 patients (mean age 77 years, 73% male, 49% prior systemic treatment, 24% immunocompromised, 27% Eastern Cooperative Oncology Group performance status (PS) ≥ 2) had laCSCCs (35%) or mCSCCs (65%). For the 240 recipients of ≥1 infusion(s), the BOR was 50.4% (complete, 21%; partial, 29%). With median follow-up at 12.6 months, median PFS was 7.9 months, and median OS and DOR were not reached. One-year OS was 73% versus 36%, respectively, for patients with PS < 2 versus ≥ 2. Multivariate analysis retained PS ≥ 2 as being associated during the first 6 months with PFS and OS. Head-and-neck location was associated with longer PFS. Immune status had no impact. Severe treatment-related adverse events occurred in 9% of the patients, including one death from toxic epidermal necrolysis. Cemiplimab real-life safety and efficacy support its use for la/mCSCCs. Patients with PS ≥ 2 benefited less from cemiplimab, but it might represent an option for immunocompromised patients.\n\nPD-1–blocking antibody\ncemiplimab\ncutaneous squamous cell carcinoma\nreal-life setting\nimmunocompromised\nchronic dermatosis\n==== Body\n1. Introduction\n\nCutaneous squamous-cell carcinoma (CSCC) is the second most common skin cancer after basal-cell carcinoma [1]. In Europe, the reported age-standardized CSCC incidence ranges from 15 to 77 per 100,000 individuals per year, predominantly occurring in males [2,3]. The incidence is constantly increasing, probably because of early CSCC resection, population aging and changing UV-exposure habits [4].The CSCC risk is heightened for immunocompromised patients, being about 100-times higher after organ transplantation [5,6,7,8,9], and for those CSCC oncogenic human papillomavirus-positive, or with chronic dermatitis, exposure to arsenic or ionizing radiation, or genodermatosis (e.g., dystrophic epidermolysis bullosa, xeroderma pigmentosum, albinism and Muir–Torre syndrome) [10,11,12,13,14,15]. At an early stage, CSCC prognosis is excellent, with 90% 10-year survival [16]. However, ~5% of the patients experience local recurrences, ~4% of them develop regional disease and outcomes are fatal for ~2% [16,17,18,19,20,21,22]. According to American data [23], the CSCC mortality rate is of the same order of magnitude as that of melanoma. The 5-year overall survival (OS) rate of patients with resectable, regional CSCCs was 50–60% [18,19]. The prognosis becomes more uncertain for locally advanced or metastatic disease, with either regional or distant metastases.\n\nSince 2018, anti-programed cell-death protein-1 (PD-1) monoclonal antibodies have emerged as first-line treatments for the management of unresectable, locally advanced or metastatic CSCCs. Cemiplimab was the first immunotherapy approved by the Food and Drug Administration and the European Medicines Agency [24], followed by pembrolizumab, in the United States, for patients who are not candidates for curative radiotherapy or surgery [25]. Immunotherapies have demonstrated anti-tumor activity with response rates exceeding 40% and acceptable safety profiles [24,25,26,27].\n\nIn France, an early-access program made cemiplimab available to patients with locally advanced or metastatic CSCCs during the time between completion of enrollment in cemiplimab clinical trials and its regulatory approval. This retrospective, multicenter CAREPI trial aimed to evaluate cemiplimab efficacy and safety in the real-life setting of those early-access patients. Our results confirmed cemiplimab efficacy in real life and identified clinical characteristics of those patients associated with progression-free survival (PFS) and OS.\n\n2. Materials and Methods\n\nPatients eligible for the early-access program (August 2018 to October 2019) were adults with locally advanced or metastatic CSCCs not amenable to surgery. Exclusion criteria were active autoimmune diseases or infections, uncontrolled brain metastases, pregnancy or breastfeeding. Patients received intravenous cemiplimab infusions (3 mg/kg every 2 weeks) until death from any cause, unacceptable toxicity, or patient’s or physician’s decision. Investigators were asked to complete a standardized case-report form for each patient included in the early-access program.\n\nThis retrospective study was approved by the local Avicenne Hospital Ethics Committee (CLEA-2019-75). The national database has been declared to the French data-protection agency (CNIL approval number 2215607). In compliance with French law, consent regarding non-opposition to collect and use the data was obtained from each patient.\n\nThe primary endpoint was the best overall response rate (BOR); secondary endpoints included PFS, OS, duration of response (DOR) and safety. Standard-of-care tumor assessments were carried out at the treating facility without central review. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events version 5. Efficacy and safety were assessed for all patients who received at least one cemiplimab infusion.\n\nPatient characteristics are expressed as numbers (percentages) for discrete variables, and mean ± standard deviation or median (range) for continuous variables. Data cutoff was 19 June 2020. Median follow-up was estimated using the Kaplan–Meier reverse method. OS and PFS were defined, respectively, as the times from the first cemiplimab dose to death from any cause and until disease progression or death from any cause, whichever occurred first. DOR was defined as the time from BOR to first documentation of disease progression. OS, PFS, duration of cemiplimab treatment, and DOR were censored at the date of last information update, estimated using the Kaplan–Meier method and expressed as median (95% confidence intervals (CIs)). Prognostic factors associated with PFS and OS were identified with log-rank tests. A multivariate Cox proportional hazards regression model with a step function was used because Eastern Cooperative Oncology Group performance status (PS) violated the proportional hazards assumption. PS was determined twice (< or ≥6 months). The cumulative incidence of relapses was estimated according to type of response using competing-risk analyses and were compared with Gray’s test. All tests were two-sided, with significance set at p < 0.05. Analyses were computed with R statistical software V.4.0.3 (R Foundation for Statistical Computing, Vienna, Austria).\n\n3. Results\n\n3.1. Patients\n\nAll information concerning 245 patients, from 58 French centers, was collected. Five patients died before the first infusion and were not analyzed for efficacy and safety. Baseline (pre-cemiplimab) patient characteristics are reported for the 245 intent-to-treat patients in Table 1. Their mean age was 77 years, 73% were male, 27% had PS ≥ 2 and 24% were immunocompromised. Among the 59 immunocompromised, 64% had blood disorders, including 34% with chronic lymphocytic leukemia. Among the intent-to-treat population, CSCCs were 35% localized, 39% regional disease and 26% had distant metastases; 11% had chronic dermatitis and 3% had cutaneous ulcers. Two-thirds of CSCCs were located on the head and neck. Histopathological examination revealed 23% were poorly differentiated and 11% exhibited perineural invasion.\n\nRegarding previous treatments (see Table S1), 60% of intent-to-treat patients had received radiotherapy and 79% had undergone surgical excision. Moreover, about half had received systemic treatment, which was most frequently (38%) anti-epidermal growth factor receptor (EGFR) plus chemotherapy. Three-quarters received one line of systemic therapy before cemiplimab.\n\nCemiplimab administration lasted a median of 5.5 (95% CI 4.6–8.8) months, for a median of 10 (1–40) infusions for each per-protocol patient, with 29% (95% CI 23–36) of the patients still being treated beyond 12 months.\n\n3.2. Efficacy Evaluation\n\nResponses of the 240 assessable patients are detailed in Table 2: 21% complete responses and 29% partial responses, for a BOR of 50% (95% CI 44–57). Only 64% of responses were confirmed. The BORs did not differ according to immunocompromised versus immunocompetent status (50% versus 51%, respectively), with prior systemic treatment versus without (51% versus 50%, respectively; p = 0.9), or according to local, regional or distant disease (48%, 56% or 46%, respectively; p = 0.41). However, the BORs were lower for patients with PS ≥ 2 versus <2 (37% versus 56%, respectively; p = 0.01). Patients with chronic dermatitis tended to have poorer responses than those without (32% versus 52%, respectively; p = 0.06). The disease-control rate was 59.6% (95% CI 53.1–65.8).\n\nThe median time to complete response was 5.9 (range 1.7–13.6) months. Complete responders’ median treatment duration was 11.3 months (range 13–516 days), versus 7.5 months (range 43–595 days) for partial responders. The reasons for cemiplimab discontinuation were not fully available for these patients. Among the 51 complete responders, only three (6%) progressed during follow-up: two progressed on cemiplimab after 318 or 471 days of treatment and one progressed 3 months after stopping cemiplimab, which had been administered for 241 days (see Figure S1). A median of 61 days of follow-up were available for 27 (53%) complete responders after cemiplimab discontinuation: only one of them relapsed. At 1 year, relapses were significantly more frequent for partial responders (53%) than complete responders (9%) (p = 0.007).\n\nWith global median follow-up at 12.6 months, median PFS lasted 7.9 (95% CI, 4.9–10.7) months and 1-year PFS was 38.7%; median global OS was not reached and the 1-year OS was 63.1%; and median global DOR was not reached and the 1-year DOR rate was 62.9% (Figure 1, Figure 2 and Figure 3). The 1-year PFS and OS rates did not differ according to immune status or previous systemic treatment status (p > 0.21). However, their durations were significantly shorter for patients with PS ≥ 2 versus PS < 2, with respective estimated percentages (95% CI) of 25.1% (15.0–41.8%) and 43.5% (36.3–52.3%) (p < 0.0001) for PFS, and 36% (25–52%) and 73% (66–81%) (p < 0.0001) for OS. The highly significant impact of PS ≥ 2 on PFS and OS was confirmed during the first 6 months, after adjustment for age, sex, chronic dermatitis, primary CSCC site and disease stage (Table 3). After 6 months, PS was no longer associated with PFS or OS. Primary head-and-neck CSCC was also associated with a better PFS.\n\n3.3. Adverse Events\n\nOne-third of the patients experienced treatment-related AEs (TRAEs; Table 4), with the most common being (in decreasing order): fatigue, arthralgias/myalgias, hepatic disorders, diarrhea and pruritus. They led to treatment discontinuation for 16 (7%) patients. Twenty-two patients experienced at least one grade-3 or higher TRAE, as detailed in Table 5. They were mostly hepatic disorders and fatigue, but also renal impairment, arthralgias/myalgias, and two kidney-transplant rejections. The death of one patient from toxic epidermal necrolysis (Lyell’s syndrome) was attributed to cemiplimab. A median of 6 (range 0–70) weeks separated cemiplimab onset and the first AE. The response rates for patients with TRAEs (54.7%) and those without (47.3%) did not differ significantly (p = 0.45).\n\n4. Discussion\n\nThis retrospective study on 240 CSCC patients confirmed cemiplimab efficacy in the real-life setting as a curative treatment for unresectable, locally advanced or metastatic disease. Patients in this series share characteristics with the 193 patients enrolled in the phase II trial evaluating cemiplimab that led to its approval [24,26,28,29]: predominantly men, older age, 29% poorly differentiated tumors [26], and mostly head-and-neck primary locations. Unlike those study participants, our population included 24% immunocompromised patients, with 16% having blood disorders (i.e., chronic lymphocytic leukemia and other hemopathies), and 27% with PS ≥ 2. Notably, in our series, 49% had received systemic treatment before starting cemiplimab, versus 34% in the phase II trial [28], 3% had a genodermatosis and 11% had an underlying chronic dermatitis, most frequently chronic wounds. The BOR herein was 50%, including 21% complete responses, which is of the same order of magnitude as in other trials evaluating anti-PD-1 [24,25,26,27,28,29].\n\nOur results suggest that immunocompromised patients, including those with blood disorders, respond and survive as well as immunocompetent patients, meaning they apparently benefit from anti-PD-1, despite usually being excluded from trials. However, management of these patients, particularly transplant recipients, must be extremely attentive so as to avoid rejection, as highlighted by the two kidney-transplant rejections observed herein; nonetheless, they should be included in trials. Indeed, anti-PD-1 increased the risk of graft rejection and, when rejection occurred, mortality was recently estimated at 36%, with a high risk for liver-transplant recipients [30]. An ongoing trial is evaluating the safety and efficacy of cemiplimab with everolimus/sirolimus plus prednisone or without as treatment for advanced CSCCs in kidney transplantees (NCT04339062).\n\nOur findings also support that systemic treatment-naïve patients responded as well as pretreated patients. They also showed that frail patients with poor PS responded less well. However, because more than one-third of them responded to cemiplimab, anti-PD-1 should remain the first-line systemic treatment of choice. It is now critical to identify factors predictive of response in these frail patients. Our observations indicate that patients with underlying chronic dermatitis might respond less well to cemiplimab than patients without, but that outcome remains to be confirmed by a larger study.\n\nRemarkably, our complete responders rarely relapsed (6%), even after stopping cemiplimab. Notably, although disease progression after an objective response was observed in 21% of responders, the risk of relapse was markedly higher for partial responders than complete responders, as previously reported for melanoma patients [31,32]. Determining responders’ factors predictive of relapse and optimal treatment duration for partial responders would contribute greatly to improving their management.\n\nAlthough direct comparison is impossible, for our entire population, 1-year PFS (38.7%) and OS (63.1%) were substantially lower than in Migden et al.’s phase II study [24]. Indeed, their patients’ 1-year PFS and OS ranged between 47% and 58%, and 76% and 93%, respectively, according to the different patient subgroups [28,33]. One factor that could explain this difference would be our overestimation of the response rate, attributable to either the high frequency of unconfirmed responses or the lack of independent central review. Indeed, in Migden et al.’s phase II study [26], the response rate was overestimated by investigators (53%) compared to blinded independent central reviewers (44%), as recently demonstrated by the analysis of 20 trials that had central and investigators’ BOR assessments available [34]. However, our series’ BOR was very close to the investigators’ estimated response rate in Migden et al.’s trial [26].\n\nAnother hypothesis might be that our lower-than-expected PFS and OS might reflect our patients’ characteristics, i.e., 27% with PS ≥ 2, whose 1-year OS at 36% was significantly shorter, as reported for lung cancer [35], whereas that OS rate for patients with PS < 2 reached the lower threshold of the OS estimated in the cemiplimab phase II CSCC trial [28,33]. Our best model for OS included only PS, while our best model for PFS included PS and primary head-and-neck. Although it is difficult to attribute a protective effect to head-and-neck CSCCs, it can be hypothesized that the tumor mutational burden would be increased in CSCCs located at that site, a chronically sun-exposed area, compared to other cutaneous areas not chronically sun-exposed. Because high tumor mutational burden predicts prolonged survival in patients receiving anti PD-1 [36], such a higher burden might help explain the association between longer PFS and head-and-neck site retained by our multivariate analysis. Further molecular studies are needed to confirm this hypothesis. Notably, PFS and OS did not differ according to CSCC stage, prior systemic treatment status or immune status, thereby suggesting that it would be of interest to enroll immunocompromised patients in trials evaluating anti-PD-1.\n\nThe cemiplimab-safety profile for our series was comparable with that in other studies on PD-1–blocking agents to treat CSCC [24,26,37]. Most AEs were manageable, except for 16 (7% of the patients) that necessitated cemiplimab discontinuation. One cemiplimab-related death from toxic epidermal necrolysis occurred. About 20 Stevens–Johnson syndrome/toxic epidermal necrolysis cases have been reported with other inhibitors of PD-1 or its ligand [38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55]. Toxic epidermal necrolysis is responsible for high mortality [56]. According to the American Society of Clinical Oncology guidelines, cyclosporine or intravenous immunoglobulins combined with corticosteroids should be initiated when toxic epidermal necrolysis is diagnosed [57]. Indeed, with the increasing use of immune-checkpoint inhibitors, physicians should be aware of this very rare AE. Twenty-two (9%) of our patients developed severe grade-3 or -4 TRAEs, a rate consistent with previous studies on PD-1–blocking agents [24,25,26,50]. One early-onset cemiplimab-induced grade-4 drug reaction with eosinophilia and systemic symptoms with a favorable outcome occurred in a 76-year-old woman. Considering these frail patients, the safety profile seems acceptable.\n\nLimitations of this study are its retrospective design, the lack of central assessment of disease response, the too short follow-up that precluded accurate determinations of OS, DOR, and the long-term outcomes of responders after stopping anti-PD-1. Indeed, longer follow-up would be helpful. Moreover, PFS results may not be very accurate because assessments were made according to standard of care and may have been performed at different timepoints.\n\n5. Conclusions\n\nThe results of this retrospective study confirm cemiplimab’s strong anti-tumor activity and manageable safety, meaning it should be offered to patients with unresectable, locally advanced or metastatic CSCCs. Our analysis of the characteristics of CSCC patients who received cemiplimab in the real-life setting demonstrated the poor prognosis associated with PS ≥ 2. The association between head-and-neck involvement and longer PFS requires additional molecular prognostic studies to determine whether or not that site has a protective effect on PFS for patients with locally advanced or metastatic disease. Moreover, the results of this analysis indicate that cemiplimab might be beneficial for immunocompromised patients.\n\nAcknowledgments\n\nThe authors would like to thank Elisa Funck-Brentano from Hôpital Ambroise Paré, AP-HP, Boulogne, who included 3 cases in this study, for her contribution to this study. They would like to thank all members of the Groupe Français de Cancérologie and of the French Cutaneous Squamous Cell Carcinoma Study Group (CAREPI). They would like to thank other physicians involved in the study and the patients who participated in this early access program. Editorial assistance was provided by Janet Jacobson. The authors thank Margot Denis for technical assistance.\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/article/10.3390/cancers13143547/s1, Figure S1. The responses for each cemiplimab-recipient and the times at which they and other events occurred are reported. Table S1. Therapies given to the 245 intent-to-treat patients before cemiplimab.\n\nClick here for additional data file.\n\nAuthor Contributions\n\nConceptualization, S.D. (Sophie Dalac), L.M. (Laurent Mortier) and È.M.; formal analysis, M.B. and È.M.; investigation, C.H., L.F. and È.M.; methodology, M.B.; project administration, È.M.; resources, C.H., L.F., A.P.-L., F.H., P.C. (Philippe Celerier), F.A., N.B., M.D. (Monica Dinulescu), A.J., N.M., A.-B.D.-M., L.C., È.-M.N., É.A., B.D., C.L., C.B. (Clémence Berthin), N.K., F.G., J.d.Q., P.-E.S., N.P., J.-P.A., S.A., B.B., S.D. (Sophie Darras), V.H., S.D. (Suzanne Devaux), M.M., L.M. (Laurent Misery), S.M., M.E., F.B.-P., C.J., R.L., F.S., J.S., S.C., M.S., Y.T., D.S. (Dominique Spaeth), C.G.-M., O.C., R.T., M.P., M.D. (Marc Dumas), L.P., P.C. (Pierre Combe), O.L., P.G., Y.R., I.K.-B., D.S. (David Solub), A.S., C.B. (Christophe Bedane) and G.Q.; software, M.B.; supervision, È.M.; visualization, C.H., L.F. and È.M.; writing—review and editing, C.H., L.F., A.P.-L., M.B., F.H., P.C. (Philippe Celerier), F.A., N.B., M.D. (Monica Dinulescu), A.J., N.M., A.-B.D.-M., L.C., È.-M.N., É.A., B.D., C.L., C.B. (Clémence Berthin), N.K., F.G., J.d.Q., P.-E.S., N.P., J.-P.A., S.A., B.B., S.D. (Sophie Darras), V.H., S.D. (Suzanne Devaux), M.M., L.M. (Laurent Misery), S.M., M.E., F.B.-P., C.J., R.L., F.S., J.S., S.C., M.S., Y.T., D.S. (Dominique Spaeth), C.G.-M., O.C., R.T., M.P., M.D. (Marc Dumas), L.P., P.C. (Pierre Combe), O.L., P.G., Y.R., I.K.-B., D.S. (David Solub), A.S., C.B. (Christophe Bedane), G.Q., S.D. (Sophie Dalac), L.M. (Laurent Mortier) and È.M. 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 in accordance with the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of AVICENNE HOSPITAL (protocol code CLEA-2019-75; date of approval 27 September 2019). The national database has been declared to the French data-protection agency (CNIL approval number 2215607).\n\nInformed Consent Statement\n\nIn compliance with French law, consent regarding non-opposition to collect and use the data was obtained from each patient.\n\nData Availability Statement\n\nRelevant data supporting the findings of this study are available within the article and Supplementary Materials and are available from the authors upon reasonable request.\n\nConflicts of Interest\n\nM. Samimi received fees from Janssen Cilag for speaking at an educational meeting and has received reimbursement for travel and accommodation expenses for attending national and international medical congresses from Abbvie, Amgen SAS, Bristol Myers Squibb, Celgene SAS, Galderma International, Lilly France SAS, MSD France. N. Meyer: Investigator and/or consultant and/or speaker and/or research grants from BMS, MSD, Roche, Novartis, Pierre Fabre, Merck, Sanofi, Sun Pharma. J.-P. Arnault: Novartis (boards), speaker (BMS and MSD). E. Maubec: Investigator and/or consultant and/or research grants from BMS, MSD, Novartis, Pierre Fabre, Sanofi. F. Herms reports receiving fees for consulting, advisory boards and travel accommodations for attending congresses from Sanofi et SUN Pharma. S. Mansard reports participation on boards and having received support for travel accommodations for attending congresses from Sanofi, Novartis, Pierre Fabre, MSD, BMS. G. Quereux reports receiving fees for consulting, advisory boards and being an investigator from Sanofi, Novartis, Pierre Fabre, MSD, Roche and BMS.\n\nFigure 1 Kaplan–Meier estimations of the 6-month and 1-year probabilities of progression-free survival for the per-protocol population (n = 240).\n\nFigure 2 Kaplan–Meier estimations of the 6-month and 1-year probabilities of overall survival for the per-protocol population (n = 240).\n\nFigure 3 Kaplan–Meier estimations of the 6-month and 1-year probabilities of duration of response after cemiplimab treatment for the per-protocol population (n = 240).\n\ncancers-13-03547-t001_Table 1 Table 1 Baseline characteristics of all 245 intent-to-treat CSCC patients.\n\nCharacteristic\tValue\t\nAge, years\t77.1 ± 13.3\t\nMale sex\t178 (73)\t\nECOG performance status\t\t\n0\t60 (25)\t\n1\t118 (48)\t\n≥2\t66 (27)\t\nUnknown\t1 (0.4)\t\nImmunocompromised\t59 (24)\t\nHuman immunodeficiency virus-positive\t8 (3)\t\nOrgan transplant\t7 (3)\t\nChronic lymphocytic leukemia\t20 (8)\t\nOther blood disorders a\t18 (7)\t\nImmunosuppressive drugs\t6 (3)\t\nGenodermatosis\t8 (3)\t\nInherited epidermolysis bullosa\t2 (0.8)\t\nMuir–Torre syndrome\t2 (0.8)\t\nXeroderma pigmentosum\t1 (0.4)\t\nIchthyosis\t2 (0.8)\t\nEpidermodysplasia verruciformis\t1 (0.4)\t\nChronic dermatitis\t28 (11)\t\nBurns\t4 (1.6)\t\nScars\t2 (0.8)\t\nLichen planus\t2 (0.8)\t\nChronic wounds\t9 (4)\t\nWarts/condylomas\t4 (1.6)\t\nArsenic keratosis\t2 (0.8)\t\nRadiodermatitis\t3 (1.2)\t\nOthers b\t2 (0.8)\t\n≥3 primary CSCCs\t80 (33)\t\nPrimary CSCC site\t\t\nHead-and-neck c\t164 (70)\t\nTrunk\t9 (4)\t\nAnorectal and/or genital\t12 (5)\t\nArm or leg\t58 (24)\t\nUnknown\t3 (1.2)\t\nHistopathological characteristics\t\t\nPoor differentiation\t57 (23)\t\nPerineural invasion\t26 (11)\t\nBoth\t9 (4)\t\nNone\t69 (28)\t\nUnknown\t84 (34)\t\nCSCC stage\t\t\nLocalized\t85 (35)\t\nRegional\t95 (39)\t\nDistant metastases\t64 (26)\t\nUnknown\t1 (0.4)\t\nResults are expressed as mean ± standard deviation or number (%). ECOG, Eastern Cooperative Oncology Group; CSCC, cutaneous squamous-cell carcinoma. a Other blood disorders included: polycythemia vera, four; Waldenström’s macroglobulinemia, three; two each: mantle-cell lymphoma or myelodysplastic syndrome; one each: large B-cell lymphoma, cutaneous T-cell lymphoma, essential thrombocythemia, multiple myeloma associated with amyloid light-chain amyloidosis, IgM monoclonal gammopathy, thrombopenia of unspecified cause or idiopathic CD4 lymphocytopenia. b Carcinomas due to phototherapy or erosive pustular dermatosis of the scalp. c Including two CSCCs located on the lips.\n\ncancers-13-03547-t002_Table 2 Table 2 Best overall responses (n = 240) as assessed by investigators.\n\nOutcome\tn (%)\t\nComplete response\t51 (21)\t\nConfirmed\t36 (15)\t\nUnconfirmed\t15 (6)\t\nPartial response\t70 (29)\t\nConfirmed\t41 (17)\t\nUnconfirmed\t29 (12)\t\nStable disease\t22 (9)\t\nProgressive disease\t84 (35)\t\nNot assessable\t13 (5)\t\nBest overall response rate, n (% [95% CI])\t121 (50.4 [43.9–56.9])\t\nConfirmed\t77 (32)\t\nUnconfirmed\t44 (18)\t\nBest overall disease control rate, n (% [95% CI])\t143 (59.6 [53.1–65.8])\t\nResults are expressed as number (%), unless stated otherwise.\n\ncancers-13-03547-t003_Table 3 Table 3 Factors associated with progression-free survival or overall survival in univariate and multivariate analyses.\n\nFactor\tUnivariate\tMultivariate\t\nHR (95% CI)\tp\tHR (95% CI)\tp\t\nProgression-free survival\t\t\t\t\t\nAge\t1.00 (0.98–1.01)\t0.62\t1.00 (0.98–1.01)\t0.63\t\nMale sex\t0.79 (0.55–1.15)\t0.22\t0.91 (0.61–1.37)\t0.66\t\nImmunocompromised\t1.03 (0.7–1.51)\t0.89\t1.15 (0.76–1.76)\t0.5\t\nECOG PS ≥ 2\t\t\t\t\t\n≤6 months\t2.3 (1.53–3.44)\t<0.0001\t2.33 (1.52–3.55)\t0.0001\t\n6 months\t0.88 (0.31–2.51)\t0.81\t0.85 (0.3–2.46)\t0.77\t\nChronic dermatitis\t1.67 (1.02–2.71)\t0.04\t1.07 (0.61–1.87)\t0.8\t\nPrimary head-or-neck CSCC\t0.58 (0.41–0.81)\t0.0002\t0.52 (0.34–0.79)\t0.0025\t\nLocalized disease\t1.16 (0.82–1.64)\t0.41\t0.72 (0.49–1.05)\t0.09\t\nPrevious systemic treatment\t0.88 (0.62–1.23)\t0.44\t1.03 (0.71–1.50)\t0.88\t\nOverall survival\t\t\nAge\t1.00 (0.99–1.02)\t0.81\t0.99 (0.98–1.01)\t0.46\t\nMale sex\t0.9 (0.56–1.44)\t0.66\t1.01 (0.61–1.67)\t0.97\t\nImmunocompromised\t0.82 (0.49–1.35)\t0.43\t0.91 (0.53–1.56)\t0.72\t\nECOG PS ≥ 2\t\t\n≤6 months\t4.39 (2.62–7.33)\t<0.0001\t4.56 (2.64–7.85)\t0.0001\t\n>6 months\t1.61 (0.61–4.27)\t0.34\t1.69 (0.63–4.52)\t0.3\t\nChronic dermatitis\t0.98 (0.49–1.95)\t0.95\t0.7 (0.32–1.51)\t0.36\t\nPrimary head-or-neck CSCC\t0.76 (0.49–1.18)\t0.22\t0.67 (0.4–1.13)\t0.13\t\nLocalized disease\t1.02 (0.66–1.58)\t0.94\t0.74 (0.45–1.2)\t0.22\t\nPrevious systemic treatment\t0.76 (0.5–1.17)\t0.21\t1.09 (0.68–1.76)\t0.72\t\nECOG PS, Eastern Cooperative Oncology Group performance status; CSCC, cutaneous squamous-cell carcinoma.\n\ncancers-13-03547-t004_Table 4 Table 4 Each cemiplimab-related adverse event occurred in at least two of the 240 treated patients.\n\nAdverse Event\tAny Grade\tGrade ≥ 3\t\nAny\t75 (31)\t22 (9)\t\nLed to cemiplimab discontinuation\t16 (7)\t12 (5)\t\nFatigue\t21 (9)\t4 (2)\t\nArthralgias/myalgias\t17 (7)\t2 (1)\t\nCholestasis/cytolysis/hepatitis\t10 (4)\t5 (2)\t\nDiarrhea\t7 (3)\t0\t\nPruritus\t6 (3)\t0\t\nRash\t5 (2)\t0\t\nHypothyroidism\t5 (2)\t0\t\nRenal failure\t5 (2)\t3 (1)\t\nHyperthyroidism\t4 (2)\t0\t\nLymphopenia\t3 (1)\t0\t\nDecreased appetite\t3 (1)\t1 (0.4)\t\nPeripheral neuropathy\t3 (1)\t0\t\nAnemia\t2 (1)\t0\t\nNeutropenia\t2 (1)\t0\t\nMyocarditis\t2 (1)\t1 (0.4)\t\nCorticotropic insufficiency\t2 (1)\t0\t\nColitis\t2 (1)\t2 (1)\t\nVomiting\t2 (1)\t1 (0.4)\t\nLoss of weight\t2 (1)\t0\t\nBalance disorder\t2 (1)\t0\t\nTransplant rejection\t2 (1)\t2 (1)\t\nResults are expressed as number (%).\n\ncancers-13-03547-t005_Table 5 Table 5 Serious cemiplimab-related adverse events in the 240 treated patients.\n\nAdverse Event\tSeverity Grade\t\nAny\tGrade 3\tGrade 4\tGrade 5\t\nCholestasis/cytolysis/hepatitis\t5 (2)\t3\t2\t0\t\nFatigue\t4 (2)\t4\t0\t0\t\nRenal impairment\t3 (1)\t2\t1\t0\t\nArthralgias/myalgias\t2 (1)\t2\t0\t0\t\nColitis\t2 (1)\t2\t0\t0\t\nTransplant rejection\t2 (1)\t1\t1\t0\t\nDecreased appetite\t1 (0.4)\t1\t0\t0\t\nMyocarditis\t1 (0.4)\t1\t0\t0\t\nVomiting\t1 (0.4)\t1\t0\t0\t\nAcute pancreatitis\t1 (0.4)\t1\t0\t0\t\nInterstitial lung disease\t1 (0.4)\t1\t0\t0\t\nDrug reaction with eosinophilia and systemic symptoms\t1 (0.4)\t0\t1\t0\t\nToxic epidermal necrolysis\t1 (0.4)\t0\t0\t1\t\nResults are expressed as number (%) or number.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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Genet. 2019 51 202 206 10.1038/s41588-018-0312-8 30643254\n37. Wang Y. Zhou S. Yang F. Qi X. Wang X. Guan X. Shen C. Duma N. Vera Aguilera J. Chintakuntlawar A. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: A systematic review and meta-analysis JAMA Oncol. 2019 5 1008 1019 10.1001/jamaoncol.2019.0393 31021376\n38. Nayar N. Briscoe K. Penas P.F. Toxic epidermal necrolysis-like reaction with severe satellite cell necrosis associated with nivolumab in a patient with ipilimumab refractory metastatic melanoma J. Immunother. 2016 39 149 152 10.1097/CJI.0000000000000112 26938948\n39. Saw S. Lee H.Y. Ng Q.S. Pembrolizumab-induced Stevens-Johnson syndrome in non-melanoma patients Eur. J. Cancer 2017 81 237 239 10.1016/j.ejca.2017.03.026 28438440\n40. Demirtas S. El Aridi L. Acquitter M. Fleuret C. Plantin P. Toxic epidermal necrolysis due to anti-PD1 treatment with fatal outcome Ann. Dermatol. Venereol. 2017 144 65 66 10.1016/j.annder.2016.11.012 28011090\n41. Vivar K.L. Deschaine M. Messina J. Epidermal programmed cell death-ligand 1 expression in TEN associated with nivolumab therapy J. Cutan. Pathol. 2017 44 381 384 10.1111/cup.12876 28000240\n42. Rouyer L. Bursztejn A.C. Charbit L. Schmutz J.L. Moawad S. Stevens-Johnson syndrome associated with radiation recall dermatitis in a patient treated with nivolumab Eur. J. Dermatol. 2018 28 380 381 10.1684/ejd.2018.3295 29952288\n43. Shah K.M. Rancour E.A. Al-Omari A. Rahnama-Moghadam S. Striking enhancement at the site of radiation for nivolumab-induced Stevens-Johnson syndrome Dermatol. Online J. 2018 24 10.5070/D3246040713\n44. Haratake N. Tagawa T. Hirai F. Toyokawa G. Miyazaki R. Maehara Y. Stevens-Johnson syndrome induced by pembrolizumab in a lung cancer patient J. Thorac. Oncol. 2018 13 1798 1799 10.1016/j.jtho.2018.05.031 29885481\n45. Chirasuthat P. Chayavichitsilp P. Atezolizumab-induced Stevens-Johnson syndrome in a patient with non-small cell lung carcinoma Case Rep. Dermatol. 2018 10 198 202 10.1159/000492172 30186133\n46. Griffin L.L. Cove-Smith L. Alachkar H. Radford J.A. Brooke R. Linton K.M. Toxic epidermal necrolysis (TEN) associated with the use of nivolumab (PD-1 inhibitor) for lymphoma JAAD Case Rep. 2018 4 229 231 10.1016/j.jdcr.2017.09.028 29687056\n47. Salati M. Pifferi M. Baldessari C. Bertolini F. Tomasello C. Cascinu S. Barbieri F. Stevens-Johnson syndrome during nivolumab treatment of NSCLC Ann. Oncol. 2018 29 283 284 10.1093/annonc/mdx640 29045532\n48. Hwang A. Iskandar A. Dasanu C.A. Stevens-Johnson syndrome manifesting late in the course of pembrolizumab therapy J. Oncol. Pharm. Pract. 2019 25 1520 1522 10.1177/1078155218791314 30086678\n49. Dasanu C.A. Late-onset Stevens-Johnson syndrome due to nivolumab use for hepatocellular carcinoma J. Oncol. Pharm. Pract. 2019 25 2052 2055 10.1177/1078155219830166 30782092\n50. Cohen E.E.W. Soulières D. Le Tourneau C. Dinis J. Licitra L. Ahn M.J. Soria A. Machiels J.P. Mach N. Mehra R. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): A randomised, open-label, phase 3 study Lancet 2019 393 156 167 10.1016/S0140-6736(18)31999-8 30509740\n51. Cai Z.R. Lecours J. Adam J.P. Toxic epidermal necrolysis associated with pembrolizumab J. Oncol. Pharm. Pract. 2020 26 1259 1265 10.1177/1078155219890659 31810421\n52. Keerty D. Koverzhenko V. Belinc D. LaPorta K. Haynes E. Immune-mediated toxic epidermal necrolysis Cureus 2020 12 e9587 10.7759/cureus.9587 32923193\n53. Cassaday R.D. Garcia K.A. Fromm J.R. Phase 2 study of pembrolizumab for measurable residual disease in adults with acute lymphoblastic leukemia Blood Adv. 2020 4 3239 3245 10.1182/bloodadvances.2020002403 32692850\n54. Riano I. Cristancho C. Treadwell T. Stevens-Johnson syndrome-like reaction after exposure to pembrolizumab and recombinant zoster vaccine in a patient with metastatic lung cancer J. Investig. Med. High Impact Case Rep. 2020 8 10.1177/2324709620914796 32207346\n55. Maloney N.J. Ravi V. Cheng K. Bach D.Q. Worswick S. Stevens-Johnson syndrome and toxic epidermal necrolysis-like reactions to checkpoint inhibitors: A systematic review Int. J. Dermatol. 2020 59 e183 e188 10.1111/ijd.14811 32052409\n56. Dodiuk-Gad R.P. Chung W.H. Valeyrie-Allanore L. Shear N.H. Stevens-Johnson syndrome and toxic epidermal necrolysis: An update Am. J. Clin. Dermatol. 2015 16 475 493 10.1007/s40257-015-0158-0 26481651\n57. Brahmer J.R. Lacchetti C. Schneider B.J. Atkins M.B. Brassil K.J. Caterino J.M. Chau I. Ernstoff M.S. Gardner J.M. Ginex P. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline J. Clin. Oncol. 2018 36 1714 1768 10.1200/JCO.2017.77.6385 29442540\n\n",
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"keywords": "PD-1–blocking antibody; cemiplimab; chronic dermatosis; cutaneous squamous cell carcinoma; immunocompromised; real-life setting",
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"title": "Cemiplimab for Locally Advanced and Metastatic Cutaneous Squamous-Cell Carcinomas: Real-Life Experience from the French CAREPI Study Group.",
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"abstract": "Chronic frontal sinus infection is managed with a combination of medical and surgical interventions. Frontal bone osteomyelitis due to recurrent infection following trauma or prior open surgery may require more significant debridement. Free tissue transfer may allow for extensive debridement with replacement of tissue, and definitive eradication of osteomyelitis.\n\n\n\nRetrospective chart review.\n\n\n\nPatients undergoing free flap obliteration of the frontal sinus for frontal bone osteomyelitis at a single institution were included in the study. Clinical, radiologic, and surgical data were collected. Surgeries before and after free flap obliteration were compared by Wilcoxon signed rank test.\n\n\n\nFifteen patients were identified; however, one patient had less than 6 months of follow-up and was excluded from analysis. Of the remaining 14 patients, mean follow-up duration was 26 months (range, 6-120 months). Mean number of surgeries prior to free flap was 3.7 (range, 1-8 surgeries). Free flap obliteration resolved chronic frontal sinusitis in all patients. Two patients experienced postoperative infection, and the overall complication rate was 29%. Eight patients underwent cranioplasty (six immediate, two delayed) without complication. All patients received planned courses of postoperative antibiotics. A statistically significant decrease in the number of surgeries after free flap obliteration was observed P ≤ .01).\n\n\n\nExtensive debridement followed by free tissue transfer and antibiotics offers a definitive treatment for complicated, recurrent frontal osteomyelitis. Simultaneous cranioplasty provides immediate protective and aesthetic benefit without complication. Consideration should be given for free tissue transfer and cranioplasty earlier in the algorithm for treatment of refractory frontal sinus osteomyelitis.\n\n\n\n4 Laryngoscope, 129:1497-1504, 2019.",
"affiliations": "Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.;Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.;Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Department of Neurological Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Department of Neurological Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.;Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.",
"authors": "Rimmer|Ryan A|RA|0000-0002-9010-8183;Duffy|Alexander N|AN|;Knops|Alexander M|AM|;Rabinowitz|Mindy R|MR|;Koszewski|Ian J|IJ|;Rosen|Marc R|MR|;Ortlip|Timothy|T|;Heffelfinger|Ryan N|RN|;Garcia|Hermes G|HG|;Evans|James J|JJ|;Nyquist|Gurston G|GG|;Curry|Joseph M|JM|",
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"keywords": "Osteomyelitis; free tissue transfer; frontal sinus",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D002908:Chronic Disease; D003131:Combined Modality Therapy; D003646:Debridement; D005260:Female; D058752:Free Tissue Flaps; D005626:Frontal Sinus; D015522:Frontal Sinusitis; D006801:Humans; D008297:Male; D008875:Middle Aged; D010019:Osteomyelitis; D012189:Retrospective Studies; D016896:Treatment Outcome",
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"title": "The Role of Free Tissue Transfer in the Management of Chronic Frontal Sinus Osteomyelitis.",
"title_normalized": "the role of free tissue transfer in the management of chronic frontal sinus osteomyelitis"
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"abstract": "COVID-19 in cancer patients on immunosuppressive agents for the treatment of immune-related adverse events of immune checkpoint inhibitors can rapidly deteriorate. The combination therapy with methylprednisolone, baricitinib, and remdesivir may be effective for critical COVID-19, and further clinical trials are warranted.",
"affiliations": "Department of Internal Medicine Fukuyama City Hospital Fukuyama Japan.;Department of Respiratory Medicine Fukuyama Medical Center Fukuyama Japan.;Department of Respiratory Medicine Fukuyama Medical Center Fukuyama Japan.;Department of Respiratory Medicine Fukuyama Medical Center Fukuyama Japan.;Department of Internal Medicine Fukuyama City Hospital Fukuyama Japan.;Department of Internal Medicine Fukuyama City Hospital Fukuyama Japan.;Department of Respiratory Medicine Fukuyama Medical Center Fukuyama Japan.;Department of Internal Medicine Fukuyama City Hospital Fukuyama Japan.",
"authors": "Oda|Naohiro|N|https://orcid.org/0000-0001-8112-9233;Miyoshi|Keiji|K|;Morichika|Daisuke|D|;Beika|Yuka|Y|;Taki|Takahiro|T|;Mitani|Reo|R|;Okada|Toshiaki|T|;Takata|Ichiro|I|",
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"doi": "10.1002/ccr3.4459",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4459\nCCR34459\nCase Report\nCase Reports\nSuccessful treatment of critical coronavirus disease 2019 in a patient with lung cancer concomitant with pembrolizumab‐induced arthritis by methylprednisolone, baricitinib, and remdesivir\nODA et al.\nOda Naohiro https://orcid.org/0000-0001-8112-9233\n1 dancingqueen121212@gmail.com\n\nMiyoshi Keiji 2\nMorichika Daisuke 2\nBeika Yuka 2\nTaki Takahiro 1\nMitani Reo 1\nOkada Toshiaki 2\nTakata Ichiro 1\n1 Department of Internal Medicine Fukuyama City Hospital Fukuyama Japan\n2 Department of Respiratory Medicine Fukuyama Medical Center Fukuyama Japan\n* Correspondence\nNaohiro Oda, Department of Internal Medicine, Fukuyama City Hospital, 5‐23‐1 Zao‐cho, Fukuyama 721‐8511, Japan.\nEmail: dancingqueen121212@gmail.com\n\n06 7 2021\n7 2021\n9 7 10.1002/ccr3.v9.7 e0445908 5 2021\n31 5 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nCOVID‐19 in cancer patients on immunosuppressive agents for the treatment of immune‐related adverse events of immune checkpoint inhibitors can rapidly deteriorate. The combination therapy with methylprednisolone, baricitinib, and remdesivir may be effective for critical COVID‐19, and further clinical trials are warranted.\n\nbaricitinib\nCOVID‐19\nimmune checkpoint inhibitor\nimmune‐related adverse event\nlung cancer\nsource-schema-version-number2.0\ncover-dateJuly 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:06.07.2021\nOda N , Miyoshi K , Morichika D , et al. Successful treatment of critical coronavirus disease 2019 in a patient with lung cancer concomitant with pembrolizumab‐induced arthritis by methylprednisolone, baricitinib, and remdesivir. Clin Case Rep. 2021;9 :e04459. 10.1002/ccr3.4459\n==== Body\n1 INTRODUCTION\n\nCancer patients have been reported to have a more than twice higher risk of death from coronavirus disease 2019 (COVID‐19) than healthy individuals. 1 , 2 Lung cancer has been reported to be the second cancer type with the highest risk of severe COVID‐19 after hematologic malignancies. 2 In an observational study of thoracic cancer patients (mostly metastatic nonsmall cell lung cancer [NSCLC] patients) with COVID‐19, the following were associated with an increased risk of death: aged >65 years, a current or former smoker, having received chemotherapy treatment within 3 months, and the presence of any comorbidities; conversely, having received treatment with tyrosine kinase inhibitor (TKI) or immune checkpoint inhibitor (ICI) was not associated with an increased risk of death. 3 However, it is uncertain if patients on immunosuppressive agents for the treatment of immune‐related adverse events (irAEs) are at a greater risk of severe COVID‐19.\n\nHere, we report a case of critical COVID‐19 in a patient with NSCLC concomitant with refractory pembrolizumab‐induced arthritis who was successfully treated with methylprednisolone, baricitinib, and remdesivir.\n\n2 CASE REPORT\n\nA 50‐year‐old man with a 31 pack‐year smoking history was diagnosed with lung squamous cell carcinoma (T4N1M1c, stage IVB) with left adrenal metastasis. Molecular examination of the tumor genes showed that EGFR and BRAF were wild type, and ALK and ROS‐1 fusion gene rearrangement were not detected. The programmed death‐ligand 1 (PD‐L1) tumor proportion score stained with the PD‐L1 22C3 pharmDx assay was 80%. The patient was treated with four cycles of carboplatin, nab‐paclitaxel, and pembrolizumab, and four cycles of pembrolizumab maintenance. Subsequently, the tumor significantly decreased in size (Figure 1A, B). After four cycles of pembrolizumab maintenance, the patient developed right shoulder and knee arthritis (CTCAE grade 3). Treatment with prednisolone 20 mg was started; however, the arthritis did not improve, and the dose of prednisolone was increased to 70 mg. As 70 mg prednisolone and repeated joint injections of betamethasone reduced arthralgia, the prednisolone dose was tapered to 40 mg.\n\nFIGURE 1 Chest computed tomography showing the primary lesion in the right upper lobe at the time of diagnosis of lung cancer (A) and after four cycles of carboplatin, nab‐paclitaxel, and pembrolizumab and four cycles of pembrolizumab maintenance (B)\n\nThirty days after the administration of prednisolone for immune‐related arthritis (52 days after the last dose of pembrolizumab), the patient developed COVID‐19, as diagnosed by nucleic acid amplification test for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) using a nasopharyngeal swab. On the 2nd day of COVID‐19 onset, treatment with favipiravir was initiated and prednisolone 40 mg was withheld. On the 7th day of COVID‐19 onset, the patient required oxygen and was transferred to our hospital due to rapid worsening of his respiratory condition within several hours. The patient presented high fever, cough, dyspnea, and arthralgia, and his body mass index was 31.8. His oxygen saturation measured using a pulse oximeter under oxygen inhalation at 8 L/min was 96%. The following blood test results were obtained: white blood cells, 9600/μl; neutrophils, 8611/μl; lymphocytes, 854/μl; hemoglobin, 13.5 g/dl; platelet, 186,000 /μl; D‐dimmer, 2.0 μg/ml; albumin, 3.4 g/dl; creatine kinase, 16 U/L; aspartate aminotransferase, 16 U/L; lactate dehydrogenase (LDH), 375 U/L; creatinine, 0.85 mg/dl; blood urea nitrogen, 14 mg/dl; C‐reactive protein (CRP), 29.07 mg/dl; procalcitonin, 0.31 ng/ml; hemoglobin A1c, 7.0%; and ferritin, 2349 ng/ml. Chest computed tomography (CT) revealed diffuse ground‐glass opacities in both lungs (Figure 2A‐C). Nasal high‐flow oxygen therapy and treatment with 1 g of methylprednisolone, remdesivir, and heparin calcium were started. However, tracheal intubation and invasive mechanical ventilation were required on the 9th day of COVID‐19 onset, and prone ventilation and treatment with 4 mg of baricitinib were started. Thereafter, his respiratory condition gradually improved, and he was extubated on the 14th day of COVID‐19 onset. Chest CT showed that the ground‐glass opacities in both lungs were reduced, but linear and reticular shadows remained (Figure 2D‐F). The patient was discharged on the 33th day of COVID‐19 onset (Figure 3). Prednisolone has been tapered to 10 mg, but there has been no relapse of arthritis. Lung cancer had not progressed at 4 months after cessation of pembrolizumab.\n\nFIGURE 2 Chest computed tomography showing diffuse ground‐glass opacities in both lungs on the 6th day of COVID‐19 onset (A‐C). Chest computed tomography revealing that ground‐glass opacities in both lungs reduced, but linear and reticular shadows remained on the 29th day of COVID‐19 onset (D‐F)\n\nFIGURE 3 Clinical course. CRP: C‐reactive protein, LDH: lactate dehydrogenase, PSL: prednisolone, mPSL: methylprednisolone, COVID‐19: coronavirus disease 2019, RM: reservoir mask, NHF: nasal high flow, IMV: invasive mechanical ventilation, NC: nasal cannula, and FIO2: fraction of inspiratory oxygen\n\n3 DISCUSSION\n\nThe present case is of a patient with NSCLC who developed severe COVID‐19 while receiving prednisolone 40 mg for refractory pembrolizumab‐induced arthritis. Methylprednisolone pulse and remdesivir could partially suppress the cytokine storm indicated by his serum CRP levels; however, the respiratory condition did not improve, which necessitated invasive mechanical ventilation. After the addition of baricitinib, clinical recovery was achieved. This clinical course suggested that a combination therapy with methylprednisolone, baricitinib, and remdesivir may be effective in rapidly deteriorating patients with critical COVID‐19.\n\nThere is no clear consensus about the impact of ICIs on the clinical course of COVID‐19. In the TERAVOLT study, it has been reported that ICIs did not increase the risk of death in thoracic cancer patients with COVID‐19, 3 and Luo et al 4 . reported that receiving PD‐1 inhibitors did not affect the severity of COVID‐19. Conversely, Robilotti EV et al 5 . reported that ICI administration may increase the risk of severe COVID‐19; there is also a report that ICIs administered within 40 days may increase the risk of death or severe COVID‐19. 2\n\nLung pathological findings in a fatal case of COVID‐19 revealed overactivation of cytotoxic CD8+ T cells. 6 A cytokine storm caused by an excessive immune response is considered responsible for the severe acute respiratory distress syndrome in COVID‐19. 7 On the other hand, blockade of the PD‐1/PD‐L1 axis induced by ICIs could break the self‐tolerance, reactivating autoimmune CD8+ T cells and leading to irAEs. 8 There are similarities in the mechanisms of severe COVID and irAEs of ICIs from the perspective of activation of CD8+ T cells. In addition, corticosteroid use ≥20 mg per day equivalent of prednisone was associated with an increased risk of hospitalization of cancer patients with COVID‐19. 5 Therefore, patients on immunosuppressive agents for the treatment of irAEs of ICIs may be primed for severe COVID‐19, as in the present case.\n\nCorticosteroids have been the mainstay of treatment for COVID‐19 since dexamethasone 6 mg was reported to reduce mortality in hospitalized COVID‐19 patients in the RECOVERY trial. 9 In this trial, in the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51–0.81) and among those receiving oxygen (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72–0.94). However, even in the dexamethasone group, the mortality of severe COVID‐19 was very high and the optimal regimen of corticosteroid and the combination therapy with other agents remains to be investigated. Edalatifard M et al 10 . have reported that a methylprednisolone pulse reduced mortality in severe COVID‐19 patients (not intubated) compared to standard care (5.9% vs. 42.9%; hazard ratio, 0.29; 95% CI, 0.15–0.56), suggesting the efficacy of high‐dose corticosteroid in severe COVID‐19.\n\nBaricitinib, a selective inhibitor of Janus kinase 1 and 2, not only interrupts the passage and intracellular assembly of SARS‐CoV‐2 into the target cells via disruption of AP2‐associated protein kinase 1 signaling, but also inhibits the intracellular signaling pathway of cytokines known to be elevated in severe COVID‐19, including interleukin (IL)‐2, IL‐6, IL‐10, interferon‐γ, and granulocyte‐macrophage colony‐stimulating factor. 11 In the ACTT2 trial, baricitinib plus remdesivir was shown to shorten the time to clinical recovery in hospitalized COVID‐19 patients compared to remdesivir alone. 12 In this trial, corticosteroid use rate after enrollment was only 10.9%‐12.9%, and the benefit of adding corticosteroids to baricitinib plus remdesivir was uncertain. One observational study reported possible synergistic effect of a combination therapy with corticosteroid and baricitinib on severe COVID‐19. 13 Further studies are required to determine the optimal timing of baricitinib administration, in combination with or without corticosteroids.\n\nRheumatic irAEs are often persistent and can require long‐term treatment with immunosuppressive agents. 14 Conventional synthetic disease‐modifying antirheumatic drugs (DMARD) should be considered in patients with insufficient response to acceptable dose of corticosteroid or requiring corticosteroid sparing. 15 The patient in the present case required high‐dose corticosteroid for refractory arthritis, although the corticosteroid dose could be tapered after treatment for COVID‐19. The clinical efficacy and safety of baricitinib, which is a targeted synthetic DMARD, in the context of rheumatic irAEs have yet to be proven. 16 Intensive immunosuppressive therapy with methylprednisolone pulse and baricitinib for critical COVID‐19 may have led to remission of refractory immune‐related arthritis.\n\nIn conclusion, COVID‐19 in cancer patients on immunosuppressive agents for the treatment of irAEs of ICIs can rapidly deteriorate. The combination therapy with methylprednisolone, baricitinib, and remdesivir may be effective for critical COVID‐19, and further clinical trials are warranted.\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHOR CONTRIBUTIONS\n\nNO: drafted the manuscript. All authors: have read and approved the final manuscript, and contributed substantially to the revision.\n\nETHICAL APPROVAL\n\nThe patient provided written informed consent for the publication.\n==== Refs\nREFERENCES\n\n1 Mehta V , Goel S , Kabarriti R , et al. Case fatality rate of cancer patients with COVID‐19 in a New York hospital system. Cancer Discov. 2020;10 :935‐941. 10.1158/2159-8290.cd-20-0516 32357994\n2 Dai M , Liu D , Liu M , et al. Patients with cancer appear more vulnerable to SARS‐CoV‐2: a multicenter study during the CVID‐19 outbreak. Cancer Discov. 2020;10 :783‐791. 10.1158/2159-8290.cd-20-0422 32345594\n3 Garassino MC , Whisenant JG , Huang L‐C , et al. COVID‐19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry based, cohort study. Lancet Oncol. 2020;21 :914‐922. 10.1016/s1470-2045(20)30314-4 32539942\n4 Luo J , Rizvi H , Egger JV , et al. Impact of PD 1 blockade on severity of COVID‐19 in patients with lung cancers. Cancer Discov. 2020;10 :1121‐1128. 10.1158/2159-8290.cd-20-0596 32398243\n5 Robilotti EV , Babady NE , Mead PA , et al. Determinants of COVID‐19 disease severity in patients with cancer. Nat Med. 2020;26 :1218‐1223. 10.1038/s41591-020-0979-0 32581323\n6 Mehta P , McAuley DF , Brown M , et al. COVID‐19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395 :1033‐1034. 10.1016/s0140-6736(20)30628-0 32192578\n7 Xu Z , Shi L , Wang Y , et al. Pathological findings of COVID‐19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8 :420‐422. 10.1016/s2213-2600(20)30076-x 32085846\n8 Russano M , Citarella F , Napolitano A , et al. COVID‐19 pneumonia and immune‐related pneumonitis: critical issues on differential diagnosis, potential interactions, and management. Expert Opin Biol Ther. 2020;20 :959‐964. 10.1080/14712598.2020.1789097 32588674\n9 Recovery Collaborative Group , Horby P , Lim WS , et al. Dexamethasone in hospitalized patients with Covid‐19–preliminary report. N Engl J Med. 2021;384 :693‐704. 10.1056/NEJMoa2021436 32678530\n10 Edalatifard M , Akhtari M , Salehi M , et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID‐19 patients: results from a randomised controlled clinical trial. Eur Respir J. 2020;56 :2002808. 10.1183/13993003.02808-2020 32943404\n11 Stebbing J , Phelan A , Griffin I , et al. COVID‐19: combining antiviral and anti‐inflammatory treatments. Lancet Infect Dis. 2020;20 :400‐402. 10.1016/s1473-3099(20)30132-8 32113509\n12 Kalil AC , Patterson TF , Mehta AK , et al. Baricitinib plus remdesivir for hospitalized adults with Covid‐19. N Engl J Med. 2021;384 :795‐807. 10.1056/NEJMoa2031994 33306283\n13 Rodriguez‐Garcia JL , Sanchez‐Nievas G , Arevalo‐Serrano J , et al. Baricitinib improves respiratory function in patients treated with corticosteroids for SARS‐CoV‐2 pneumonia: an observational cohort study. Rheumatology. 2021;60 :399‐407. 10.1093/rheumatology/keaa587 33020836\n14 Ghosh N , Tirpack A , Chan KK , et al. Impact of COVID‐19 on patients with rheumatic complications of cancer immunotherapy: results of a registry survey. J Immunother Cancer. 2020;8 :e001550. 10.1136/jitc-2020-001550 33067320\n15 Kostine M , Finckh A , Bingham CO , et al. EULAR points to consider for the diagnosis and management of rheumatic immune‐related adverse events due to cancer immunotherapy with checkpoint inhibitors. Ann Rheum Dis. 2021;80 :36‐48. 10.1136/annrheumdis-2020-217139 32327425\n16 Chatzidionysiou K , Liapi M , Tsakonas G , et al. Treatment of rheumatic immune‐related adverse events due to cancer immunotherapy with immune checkpoint inhibitors—is it time for a paradigm shift? Clin Rheumatol. 2021;40 :1687‐1695. 10.1007/s10067-020-05420-w 32989505\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "9(7)",
"journal": "Clinical case reports",
"keywords": "COVID‐19; baricitinib; immune checkpoint inhibitor; immune‐related adverse event; lung cancer",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "e04459",
"pmc": null,
"pmid": "34257986",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "32085846;32357994;32588674;32113509;32539942;33020836;32581323;32192578;32678530;32345594;32398243;33306283;32989505;32943404;33067320;32327425",
"title": "Successful treatment of critical coronavirus disease 2019 in a patient with lung cancer concomitant with pembrolizumab-induced arthritis by methylprednisolone, baricitinib, and remdesivir.",
"title_normalized": "successful treatment of critical coronavirus disease 2019 in a patient with lung cancer concomitant with pembrolizumab induced arthritis by methylprednisolone baricitinib and remdesivir"
} | [
{
"companynumb": "JP-009507513-2107JPN005612",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Recurrent miscarriage (RM) has a multifactorial etiology mainly due to chromosomal abnormalities and immunological factors. Treating RM has remained to be a challenging issue and the role of intravenous immunoglobulin (IVIG) in treating RM is still controversial.\n\n\n\nThis study aimed to evaluate the changes in natural killer (NK) cells' frequency and cytotoxicity in patients with RM who received the IVIG therapy. A total of 78 women with a history of three or more recurrent miscarriages were included and their peripheral blood was drawn in case of positive pregnancy test. On the same date, 400 mg/kg of IVIG was administrated intravenously in 38 women and it continued every four weeks through weeks 30-32 of gestation. The remaining 40 patients with RM were included to be the untreated control group. Then, the effects of IVIG on NK cell frequency, cytotoxic activity, and the expression of inhibitory and activating receptors in the patients with RM, pre and posttreatment were assessed.\n\n\n\nNK cells percentage and cytotoxicity were significantly reduced in the IVIG-treated patients after 32 weeks of gestation (p < 0.0001). Expression levels of inhibitory receptors was increased, however, the expression levels of activating receptors were significantly decreased after the IVIG therapy. Pregnancy outcome after the treatment was significantly higher (86.8%) in the IVIG-treated patients than controls (45%; p = 0.0006).\n\n\n\nOur results suggested that women with RM may benefit from IVIG as a therapeutic approach and the frequency and functional status of peripheral NK cells may serve as a valuable predictive factor of therapy response.",
"affiliations": "Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.;Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.;Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.;Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.;Reproductive Biology Department, Tabriz University of Medical Sciences, Tabriz, Iran.;Department of Gynecology, Eastern Azerbaijan ACECR ART Center, Eastern Azerbaijan Branch of ACECR, Tabriz, Iran.;Department of Gynecology, Eastern Azerbaijan ACECR ART Center, Eastern Azerbaijan Branch of ACECR, Tabriz, Iran.;Department of Gynecology, Eastern Azerbaijan ACECR ART Center, Eastern Azerbaijan Branch of ACECR, Tabriz, Iran.;Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.;Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.;Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.;Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.;Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.;Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.;Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.",
"authors": "Ahmadi|Majid|M|;Ghaebi|Mahnaz|M|;Abdolmohammadi-Vahid|Samaneh|S|;Abbaspour-Aghdam|Sanaz|S|;Hamdi|Kobra|K|;Abdollahi-Fard|Sedigheh|S|;Danaii|Shahla|S|;Mosapour|Parisa|P|;Koushaeian|Ladan|L|;Dolati|Sanam|S|;Rikhtegar|Reza|R|;Oskouei|Farnaz Dabiri|FD|;Aghebati-Maleki|Leili|L|;Nouri|Mohammad|M|0000-0002-5367-9956;Yousefi|Mehdi|M|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D012333:RNA, Messenger",
"country": "United States",
"delete": false,
"doi": "10.1002/jcp.27627",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-9541",
"issue": "234(6)",
"journal": "Journal of cellular physiology",
"keywords": "IVIG therapy; NK cell; live birth; recurrent miscarriage; recurrent pregnancy loss (RPL)",
"medline_ta": "J Cell Physiol",
"mesh_terms": "D000026:Abortion, Habitual; D000328:Adult; D002452:Cell Count; D003602:Cytotoxicity, Immunologic; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D016756:Immunoglobulins, Intravenous; D020014:K562 Cells; D007694:Killer Cells, Natural; D011247:Pregnancy; D011256:Pregnancy Outcome; D012333:RNA, Messenger",
"nlm_unique_id": "0050222",
"other_id": null,
"pages": "9428-9437",
"pmc": null,
"pmid": "30317625",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "NK cell frequency and cytotoxicity in correlation to pregnancy outcome and response to IVIG therapy among women with recurrent pregnancy loss.",
"title_normalized": "nk cell frequency and cytotoxicity in correlation to pregnancy outcome and response to ivig therapy among women with recurrent pregnancy loss"
} | [
{
"companynumb": "IR-SHIRE-IR201842823",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThere is very limited evidence concerning phenytoin-related mydriasis.\n\n\nMETHODS\nA 59-year-old male was hospitalized in the intensive care unit due to a head injury. During his hospitalization, phenytoin was administrated. Some days later he presented bilateral mydriasis. At that time he had impaired creatinine clearance 7 ml/min, albumin levels 3.4 gr/dl, and phenytoin serum concentration 19.94 μg/dl. Evaluation with brain computed tomography and magnetic resonance imaging did not reveal any potential cause of mydriasis, while none of the co-administrated drugs have been reported to cause significant mydriasis. After initiation of continuous venovenous hemodiafiltration and discontinuation of phenytoin, mydriasis was reversed.\n\n\nCONCLUSIONS\nClinicians should be aware that mydriasis due to a toxic concentration of phenytoin may be manifested. Hippokratia 2016, 20(2): 166-168.",
"affiliations": "Department of Clinical Pharmacy, Hygeia Hospital, Athens, Greece.;Department of Clinical Pharmacy, Hygeia Hospital, Athens, Greece.;Department of Intensive Care Unit, Hygeia Hospital, Athens, Greece.;Department of Clinical Pharmacy, Hygeia Hospital, Athens, Greece.;Department of Intensive Care Unit, Hygeia Hospital, Athens, Greece.",
"authors": "Ioannidis|K|K|;Papachristos|A|A|;Athanassa|Z|Z|;Skarlatinis|I|I|;Paskalis|H|H|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1108-4189",
"issue": "20(2)",
"journal": "Hippokratia",
"keywords": "Phenytoin; adjusted concentrations; concentration-related; mydriasis; renal dysfunction",
"medline_ta": "Hippokratia",
"mesh_terms": null,
"nlm_unique_id": "101296613",
"other_id": null,
"pages": "166-168",
"pmc": null,
"pmid": "28416916",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "11696132;16510741;19718399;599408;16966571;7249508;9471951;1992618",
"title": "Concentration-related mydriasis in a patient with renal dysfunction treated with phenytoin.",
"title_normalized": "concentration related mydriasis in a patient with renal dysfunction treated with phenytoin"
} | [
{
"companynumb": "GR-MYLANLABS-2017M1027016",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "REMIFENTANIL"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nCase reports suggest that long-term, high-dose fluconazole treatment for severe fungal infections during pregnancy causes a pattern of birth defects. It is unclear whether commonly used lower doses increase the risk of specific birth defects.\n\n\nMETHODS\nIn a registry-based cohort of liveborn infants in Denmark, we evaluated first-trimester oral fluconazole exposure and the risk of birth defects overall and of birth defects previously linked to azole antifungal agents.\n\n\nRESULTS\nThe majority of fluconazole-exposed pregnancies were in women who received common therapeutic doses of 150 mg (56% of pregnancies) or 300 mg (31%). Oral fluconazole exposure was not associated with an increased risk of birth defects overall (210 birth defects among 7352 fluconazole-exposed pregnancies [prevalence, 2.86%] and 25,159 birth defects among 968,236 unexposed pregnancies [prevalence, 2.60%]; adjusted prevalence odds ratio, 1.06; 95% confidence interval [CI], 0.92 to 1.21). In addition, oral fluconazole exposure was not associated with a significantly increased risk of 14 of 15 types of birth defects previously linked to azole antifungal agents: craniosynostosis, other craniofacial defects, middle-ear defects, cleft palate, cleft lip, limb defects, limb-reduction defects, polydactyly, syndactyly, diaphragmatic hernia, heart defects overall, pulmonary-artery hypoplasia, ventricular septal defects, and hypoplastic left heart. A significantly increased risk of tetralogy of Fallot was observed (7 cases in fluconazole-exposed pregnancies [prevalence, 0.10%] as compared with 287 cases in unexposed pregnancies [prevalence, 0.03%]; adjusted prevalence odds ratio, 3.16; 95% CI, 1.49 to 6.71).\n\n\nCONCLUSIONS\nOral fluconazole was not associated with a significantly increased risk of birth defects overall or of 14 of the 15 specific birth defects of previous concern. Fluconazole exposure may confer an increased risk of tetralogy of Fallot. (Funded by the Danish Medical Research Council.).",
"affiliations": "Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. dnl@ssi.dk",
"authors": "Mølgaard-Nielsen|Ditte|D|;Pasternak|Björn|B|;Hviid|Anders|A|",
"chemical_list": "D000935:Antifungal Agents; D015725:Fluconazole",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1301066",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "369(9)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents; D015331:Cohort Studies; D003718:Denmark; D005260:Female; D015725:Fluconazole; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D012042:Registries; D012306:Risk; D013771:Tetralogy of Fallot",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "830-9",
"pmc": null,
"pmid": "23984730",
"pubdate": "2013-08-29",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Use of oral fluconazole during pregnancy and the risk of birth defects.",
"title_normalized": "use of oral fluconazole during pregnancy and the risk of birth defects"
} | [
{
"companynumb": "DK-JNJFOC-20130914358",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Acute generalized exanthematous pustulosis (AGEP) is a rare, severe, pustular, cutaneous reaction. We report a case in which a patient developed AGEP after the intake of 3 different antitussive agents containing dextromethorphan as the only ingredient in common.",
"affiliations": "Complejo Asistencial Universitario de Leon. Motero@aedv.es.",
"authors": "Otero Rivas|M M|MM|;Sánchez Sambucety|P|P|;García-Ruiz de Morales|J M|JM|;Pérez Paredes|G|G|;Rodríguez Prieto|M A|MA|",
"chemical_list": "D000996:Antitussive Agents; D003915:Dextromethorphan",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "19(10)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000328:Adult; D000996:Antitussive Agents; D003915:Dextromethorphan; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D011565:Psoriasis",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": "20030",
"pmc": null,
"pmid": "24139370",
"pubdate": "2013-10-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute generalized exanthematous pustulosis due to dextromethorphan.",
"title_normalized": "acute generalized exanthematous pustulosis due to dextromethorphan"
} | [
{
"companynumb": "GB-ACELLA PHARMACEUTICALS, LLC-1064525",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BROMPHENIRAMINE MALEATE\\DEXTROMETHORPHAN HYDROBROMI... |
{
"abstract": "BACKGROUND\nThe electronic health record and electronic prescribing have transformed the practice of medicine. Both have led to improved efficacy and safety in medication management. However, dangers may arise when electronic prescription requests are filled by default and when electronic health record medication lists are presumed accurate. In this case, our patient underwent 2 days of inpatient evaluation before a thorough medication reconciliation revealed that his symptoms had likely resulted from a medication that had been refilled reflexively.\n\n\nMETHODS\nA 69-year-old man presented with worsening weakness, weight loss, decreased appetite, and nonbloody diarrhea. Imaging revealed a large right pleural effusion and a nonspecific colitis. Lab workup revealed significant bicytopenia, hypogammaglobulinemia, and hypolipidemia. Initial evaluation and diagnoses were focused toward causes of malnutrition and malabsorption. However, on hospital day 2, a pharmacist discovered that the patient had been taking long-term oral linezolid for unclear reasons. With cessation of linezolid, the patient's myriad symptoms resolved and all lab values progressively normalized.\n\n\nCONCLUSIONS\nThe side effects of linezolid have been well documented and include reversible myelosuppression and gastrointestinal symptoms. However, medication reconciliation was imperative in diagnosing and treating our patient. Further, reflexive refilling of this patient's medication likely explains why he was taking linezolid for such a long period of time, as other forms of automation bias are known to introduce errors in electronic prescribing.\n\n\nCONCLUSIONS\nThis case calls attention to the importance of medication reconciliation, the danger of overreliance on electronic health record medication lists, and the pitfalls in not maintaining vigilance with electronic prescribing. It also highlights the necessity of patient and caregiver education regarding their medications.",
"affiliations": "Medical College of Wisconsin, Milwaukee, Wisconsin.;The Brooklyn Hospital Center, Brooklyn, New York.;Department of Medicine; Gundersen Lutheran Medical Center, La Crosse, Wisconsin, pabergl@gundersenhealth.org.",
"authors": "McCarty|Olivia R|OR|;Pertzborn|Margaret|M|;Bergl|Paul A|PA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1098-1861",
"issue": "120(3)",
"journal": "WMJ : official publication of the State Medical Society of Wisconsin",
"keywords": null,
"medline_ta": "WMJ",
"mesh_terms": "D000368:Aged; D064420:Drug-Related Side Effects and Adverse Reactions; D057286:Electronic Health Records; D006801:Humans; D008297:Male; D008508:Medication Errors; D059065:Medication Reconciliation; D010595:Pharmacists",
"nlm_unique_id": "9716054",
"other_id": null,
"pages": "237-240",
"pmc": null,
"pmid": "34710309",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The Risks of Reflexive Refilling.",
"title_normalized": "the risks of reflexive refilling"
} | [
{
"companynumb": "US-MYLANLABS-2021M1085722",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": "1",
... |
{
"abstract": "Renal transplant recipients are at a higher risk of malignancy. We report our experience and the critical differences in the presentation of malignancy in kidney transplant patients performed at our tertiary care center and followed up over the period of 1990-2015. A total of 338 live donor transplants performed in 332 patients were analyzed. Induction immunosuppression was used in 22 cases with interleukin-2 (IL-2) receptor antibody. Overall 299 patients were continued on calcineurin inhibitor (CNI)-based triple drug immunosuppression, 33 were off CNI with 13 of them receiving sirolimus additionally. A total of 16 malignancies including post transplant lymphoproliferative disease (5), oral cancer (5), lung cancer (2), hepatobiliary cancer (2), colon cancer (1), and skin cancer (1) were diagnosed in 15 patients. Over the 26-year follow up, 138 patients died of whom 12 died due to cancer. Cancer occurred in 4.7% of patients but accounted for 9.4% of deaths. Oral cancer occurred after a significantly longer latency of over 10 years (212 vs. 94 months, P = 0.00652). Despite the longer latency, oral cancer patients were younger at diagnosis (44.0 vs. 52 years, P = 0.01016) and had better outcome (Fisher's exact test, P = 0.0275). This was despite a longer overall follow-up for the oral cancer patients, reflecting the better outcome for these patients (24 vs. 4 months, P = 0.0278). This might be the result of relatively early diagnosis of oral cancers.",
"affiliations": "Department of Nephrology, Medwin Hospitals, Hyderabad, Telangana, India.;Department of Nephrology, Virinchi Hospital, Hyderabad, Telangana, India.;Department of Nephrology, Medwin Hospitals, Hyderabad, Telangana, India.;Department of Urology, Apollo Hospital, Hyderabad, Telangana, India.;Department of Pathology, Apollo Hospital, Hyderabad, Telangana, India.;Department of Surgical Oncology, Basavatarakam Indo American Cancer Hospital and Research Centre, Hyderabad, Telangana, India.",
"authors": "Narayan|G|G|;Jha|R|R|;Srikant|P|P|;Sinha|S|S|;Swarnalata|G|G|;Raju|K V V N|KVVN|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijn.IJN_354_16",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-28-11910.4103/ijn.IJN_354_16Original ArticleCarcinoma of the Tongue in Renal Transplant Recipients: An Unusual Spectrum of De novo Malignancy at a Tertiary Care Center in India Over a Period of 26 Years Narayan G. Jha R. 1Srikant P. Sinha S. 2Swarnalata G. 3Raju K. V. V. N. 4Department of Nephrology, Medwin Hospitals, Hyderabad, Telangana, India1 Department of Nephrology, Virinchi Hospital, Hyderabad, Telangana, India2 Department of Urology, Apollo Hospital, Hyderabad, Telangana, India3 Department of Pathology, Apollo Hospital, Hyderabad, Telangana, India4 Department of Surgical Oncology, Basavatarakam Indo American Cancer Hospital and Research Centre, Hyderabad, Telangana, IndiaAddress for correspondence: Dr. R. Jha, Department of Nephrology, Virinchi Hospital, Road No. 1, Banjara Hills, Hyderabad - 500 034, Telangana, India. E-mail: jharatan08@gmail.comMar-Apr 2018 28 2 119 126 Copyright: © 2018 Indian Journal of Nephrology2018This 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.Renal transplant recipients are at a higher risk of malignancy. We report our experience and the critical differences in the presentation of malignancy in kidney transplant patients performed at our tertiary care center and followed up over the period of 1990–2015. A total of 338 live donor transplants performed in 332 patients were analyzed. Induction immunosuppression was used in 22 cases with interleukin-2 (IL-2) receptor antibody. Overall 299 patients were continued on calcineurin inhibitor (CNI)-based triple drug immunosuppression, 33 were off CNI with 13 of them receiving sirolimus additionally. A total of 16 malignancies including post transplant lymphoproliferative disease (5), oral cancer (5), lung cancer (2), hepatobiliary cancer (2), colon cancer (1), and skin cancer (1) were diagnosed in 15 patients. Over the 26-year follow up, 138 patients died of whom 12 died due to cancer. Cancer occurred in 4.7% of patients but accounted for 9.4% of deaths. Oral cancer occurred after a significantly longer latency of over 10 years (212 vs. 94 months, P = 0.00652). Despite the longer latency, oral cancer patients were younger at diagnosis (44.0 vs. 52 years, P = 0.01016) and had better outcome (Fisher's exact test, P = 0.0275). This was despite a longer overall follow-up for the oral cancer patients, reflecting the better outcome for these patients (24 vs. 4 months, P = 0.0278). This might be the result of relatively early diagnosis of oral cancers.\n\nCarcinoma tonguemalignancyrenal transplant\n==== Body\nIntroduction\nSolid organ transplant patients are at an increased risk of malignancy as compared to general population (nearly 3–5 times) with serious consequences.[1] With significantly improved survival due to potent immunosuppressive drugs, better control of infectious complications, and cardiovascular events, there is an increase in incidence (average 5%–6%, range 1%–30%) of malignancies in these patients.[23] It is now emerging as one of the important causes of morbidity and mortality in a kidney transplant recipient (KTR) in the recent decade with functioning graft.[45] Their immunosuppressed state makes them more vulnerable to develop various malignancies, which also have wide geographical variation.[567] Predominant malignancies reported are epithelial (approximately 40%) and lymphoproliferative (approximately 20%). The common epithelial malignancies reported include non-melanoma skin cancer, lip cancer, carcinoma of genitourinary tract, and anorectal cancers while non-Hodgkin's lymphoma (post transplant lymphoproliferative diseases [PTLD]) is the other common malignancy.[289] Squamous cell carcinoma of the tongue is not commonly reported in KTRs with only isolated case reports published so far unlike lip, mouth, and tonsil cancers.[8] We present our retrospective analysis of single-center patients' data over 26 years with respect to incidence of malignancy, its spectrum, presentation, association, and survival.\n\nMaterials and Methods\nA total of 338 live donor transplants were performed over the 26-year period (1990–2015) in 332 patients, with six patients having undergone second transplant. Details of malignancies developing in recipients and the outcome were analyzed retrospectively along with other causes of death such as infection, renal dysfunction, or cardiac events. Immunosuppression varied over the years. Initially, all received triple drug therapy. It consisted of prednisolone (332), azathioprine (AZA) (201), mycophenolate mofetil (MMF) (131), calcineurin inhibitor (CNI) either cyclosporine (260) or tacrolimus (72), and sirolimus in 13 patients. Induction immunosuppression was used in 22 cases with IL-2 receptor antibodies (basiliximab). Overall 299 patients were continued on conventional triple drug therapy. In 33 patients where graft biopsy showed changes of CNI toxicity, and in some with well-matched allograft, for economic reasons, CNI was gradually withdrawn and patients were maintained only on AZA/MMF with prednisolone, though 13 of them with no proteinuria received sirolimus additionally.\n\nAppropriate evaluation was done to identify the malignant lesion and localize it. Histopathological examination including immunohistochemistry (Epstein–Barr virus/human papillomavirus [EBV/HPV]) was performed as deemed appropriate. Imaging including routine radiology, computed tomography scan, magnetic resonance imaging scan, and positron emission tomography scan was done depending on the need. Standard care of malignancy was given along with reduction of immunosuppression. The outcome was correlated with nature of immunosuppression, any induction, viral infections, renal dysfunction, rejection, or any known risk factors. A comparison was made between the nonoral malignancies (Group A) with oral cancers involving tongue (Group B) with respect to age, sex, time after transplant, duration of follow-up, and survival.\n\nStatistical analysis\nMedian for all data was used instead of mean for statistical analysis. Nonparametric tests using median were used in view of the small numbers, outliers in data, and lack of normal distribution. Difference between patients characteristics were assessed with Fisher's exact test or Mann–Whitney test as appropriate. Fisher's exact test (two-tailed) with the P < 0.05 when comparing parametric data or Mann–Whitney test (two-tailed) with P < 0.05 for nonparametric data was considered statistically significant. Statistical analysis was done for both parametric and nonparametric data using an online calculator http://www.socscistatistics.com/tests/mannwhitney/default2.aspx accessed on 09 November 2016.\n\nResults\nSixteen malignancies [Tables 1 and 2] were diagnosed in 15 patients (4.7%). Five patients had PTLD (33%) of which one developed it as second malignancy 5 years after initial hepatobiliary carcinoma. There were two cases of adenocarcinoma of the lung and another case of adenocarcinoma from sigmoid colon. The mean age of individuals developing malignancy at transplant was 38.4 ± 14.8 years (median 32) and at the time of malignancy was 51.5 ± 11.9 years (median 46). There were 138 deaths in the follow-up among 332 patients over 26 years with only 13 (9.4%) due to malignancy. The most common cause of death noted was infection in 54 persons (39%) followed by death arising from complications of renal allograft loss with uraemia 51 (36%) and cardiac 17 (12%).\n\nTable 1 Details of 10 patients with nonoral malignancy (11 malignancies)\n\nTable 2 Details of five patients with carcinoma tongue\n\nDemographic characteristics showed oral cancer developed in younger individuals (mean age at malignancy 44 ± 1.58 years/median 52) as compared to other group (mean age at the time of diagnosis of malignancy 53.8 ± 13.6/median 44). Patients in both Groups had reasonable and similar glomerular filtration rate (GFR) (median 54.5 vs. 53.6 ml/m). There was no significant difference in the number of rejection episodes and immunosuppressive therapy in both groups. All patients developing malignancy were getting prednisolone, AZA with or without cyclosporine as indicated in Tables 1 and 2 with none on tacrolimus or MMF. None of the patients who developed malignancy had received any depleting agent in our study.\n\nAll PTLD patients [Table 1] presented with either constitutional symptoms, fever, weight loss, or local organ-specific symptoms such as proptosis, dyspnea, and acute pain abdomen with perforation. All were late-onset PTLD. They were mostly located to gastrointestinal tract (GIT) (3/5) and extranodal (4/5). All displayed morphologically monomorphic population of large atypical lymphoid cells with CD20 positive marker with negative EBV status where tested (2/5) in tissue sample by in situ hybridization. Patients with adenocarcinoma of the lung or gut had local organ-specific symptoms [Table 1]. Patient with carcinoma of the skin had multiple warts such as lesions on legs with local lymphadenopathy. All patients in group A were treated with appropriate chemotherapeutic regimens along with reduction of immunosuppression (cyclosporine withdrawn and AZA reduced by 50%).\n\nFive patients (33%) developed squamous cell carcinoma of the tongue [Table 2]. All the patients were in fifth decade (mean age 44 ± 1.58 years/median 44 years) and were on minimal immunosuppression. Three patients were of triple drug regimen (cyclosporine + AZA + prednisolone) and two patients only on AZA and prednisolone. They presented with nonhealing ulcer over tongue with no regional lymph nodes or distant metastasis. All five patients were maintaining fairly good graft functions with their mean serum creatinine of 1.3 mg% (median 1.3 mg/dl) (estimated GFR mean 55/median 54.5 ml/min). There were no obvious risk factors such as sharp tooth, tobacco or “pan-chewing” (betel leaf), and alcohol intake. All patients were treated with reduction of immunosuppression (cyclosporine withdrawn and AZA reduced by 50%). They underwent hemiglossectomy or wide local excision of the tumor along with regional lymph node resection. On histology, the resected margins were free from tumor, and in only one case, there was perineural and lymphovascular involvement. In all the cases, the resected lymph nodes were reported free from malignancy. Staging of T1N0M0 was made in four cases and one had T2N0M0. Immunohistochemistry for P16 antigen for HPV infection was done in four patients and it was positive in two. Follow-up radiotherapy was given in three cases along with adjuvant appropriate chemotherapy. Two cases had recurrence of growth at 2 and 4½ years after initial surgery needing second time local excision with radiotherapy and chemo-therapy. One patient died at 56 months with distant metastasis after her initial diagnosis and another at 13 months due to other coincidental illness. Three patients were still under follow up at 8, 24, and 80 months, respectively, after diagnosis.\n\nStatistical analysis showed oral cancer patients were significantly younger at the time of diagnosis (44.0 vs. 52 years, Z-score 2.572, P = 0.01016). They developed it after longer latency (212 months vs. 94 months, Z-score −2.7189, P = 0.00652). Oral cancer patients had a longer follow-up (24 months vs. 4 months, Z-score −2.2045, P = 0.0278) and had better survival after diagnosis and treatment [Figure 1] compared to other cancer group with 3 out of five patients alive in oral cancer group at last follow-up as compared to 100% mortality in all the other non-oral cancer patients (Fisher's exact test P = 0.0275).\n\nFigure 1 Kaplan–Meier survival curves for oral and all other cancers with confidence intervals\n\nDiscussion\nEarly diagnosis of post transplant malignancies is an important and emerging challenge in the field of transplantation medicine and an even greater challenge is the prevention and management of malignancies. Long-term outcome of renal transplant recipients is improving due to better management of infections, cardiovascular complications, and immunological problems all over the world. At the same time, malignancy has emerged as an important cause for long-term morbidity and mortality.[45] Currently, malignancy is an important factor limiting life expectancy of transplant recipients with functioning allograft in the developed countries second only to cardiovascular events.[4569] However, scenario in South Asian region and a developing country like India is quite different where infections followed by chronic allograft loss from immunological and other causes are responsible for vast majority of death in the post transplant period. Cardiovascular complications and malignancy rank as other two less important causes of death.[10111213]\n\nCompared to the risk of malignancy in the aging general population, KTRs have an earlier, higher, distinctive variable risk of usual and unusual malignancy.[1415] The chronic use of immunosuppressive agents to prevent allograft rejection increases the long-term risk of wide range of malignancy in solid organ transplantation depending on the nature of organ-transplanted and geographical location. The reported incidence of cancer in transplant cases varies from 1% to 30% in literature with recent data on occurrence of cancer after transplant are mainly derived from Israel Penn International Transplant Tumor Registry and Australia New Zealand Therapeutic Products Authority registry.[6161718] Recently, standardized incidence ratio (SIR) in various registries was calculated by comparing risk of malignancy among KTR to risk among general population matched for age, sex, year of diagnosis, which gives more meaningful reliable estimate than nonstandardized percent incidence[61416] and has characterized risk in KTR as high/medium/low risk based on SIR (>5, 1–5, <1). Overall, the risk of malignancy in KTR is 3–5 times than general population.[1]\n\nCancers in KTR could be characterized as de novo, preexisting or rarely donor derived due to unintended transmission of malignant cells from a donor that may result in metastasis. The risk of inadvertent transplantation of malignant cells appears to depend on the type and extent of the donor's cancer and is rare in live renal transplantation. Several factors have been linked to the increased incidence of malignancies among transplant recipients including age of transplant, genetic diversity, environment factors such as sun exposure, extent and duration of immunosuppression, concomitant viral infection, and duration of pretransplantation dialysis.[19] One of the important reasons for differential increase is due to increased propensity for various viral infections such as hepatitis B virus (HBV), hepatitis C virus, HPV, EBV, human herpes virus (HHV), cytomegalovirus, and Merkel cell polyomavirus (MCV) which are well known carcinogenic viruses in general population.[12021] Other microbial agents such as Helicobacter pylori have also been implicated in lymphoma associated with gastric mucosa.\n\nCertain cancers have high incidence in KTR across the world such as skin cancer (non-melanoma), lip cancer, non-Hodgkin's lymphoma, Kaposi's sarcoma (KS), and genital and anorectal cancers unlike low incidence breast and prostate cancers.[151920] Although risk of oral cancers especially of lip have been reported to be increased in many such studies, carcinoma tongue has not been reported to be so. There seems to be some geographical variability in malignancy among renal transplant recipient with most common cancer being reported as skin cancer from Australia, Germany, and Hong Kong, while lymphoma from UK, Sweden, Germany, South Africa, India, and Pakistan.[61617182223] Increased incidence of KS from Saudi Arabia and gastrointestinal cancer from Japan has been reported.[24] However, there is no mention of increased risk of oral cancer involving tongue in any of such reports even from the South Asian region unlike the present study where carcinoma tongue was as common as PTLD. Most of the centers from India have reported high incidence of PTLD with low incidence of skin cancers.[222526] There have been only isolated reports of carcinoma tongue in various other studies and single case reports have been published from India.[222728]\n\nCollett et al., in their study of 25,100 KTR of a large UK Registry data, reported only 34 cases of oral cancers that included palate, gum, floor of the mouth, tongue, and other part of mouth.[18] In Australia and New Zealand Dialysis and Transplant (ANZDATA) 2013 data of 25,700 patients, oral cancer was reported in 126 patients (4.6%) but no separate data were mentioned for carcinoma tongue.[16]\n\nIn contrast to most of the data reported from various regions in India, the present study has incidence of 4.7% that is 2–3 times higher but still less than that reported in transplant registries from other developed countries.[2223] Our study's overall low incidence of malignancy could be due to lower age of recipient at time of renal transplant, lower immunosuppression, no use of antithymocyte globulin, except for resistant rejection, missing follow-up data, relatively lower post renal transplant survival, and inadequate follow-up. There is a striking paucity of skin cancer though equally impressive is the presence of tongue cancer and late-onset PTLD with negative EBV status unlike reports from other centers of India and developed countries.\n\nAlthough higher immunosuppression due to acute rejection is considered as risk factor for having malignancy in predisposed individuals, absence of any rejection could also mean a more immunosuppressed state, suggesting the need to reduce the immunosuppression further down to a minimum. This may be difficult to decide during routine clinical follow-up. The concept of scaling down immunosuppression to the lowest level should be aimed in such individuals who are at low immunological risk with stable renal function and no rejections. Use of mechanistic target of rapamycin (m-TOR) inhibitors may reduce the risk of malignancies in such recipients.[19] None of our patients who were on m-TOR inhibitors had malignancy.\n\nAt least four viruses may be considered co-carcinogenic in transplanted patients, including EBV, HHV-8, HPV, and MCV. We had noted this association in four of our patients (two patients with HBV and two with HPV). Two with carcinoma tongue had HPV co infection, one patient with hepatocellular carcinoma, and another with PTLD involving liver had chronic HBV infection. Known viral association of EBV infection was not seen in any of our patients of PTLD where it was checked. The cause for such high incidence of carcinoma tongue in the present study is not obvious. All the patients were relatively young (40–45 years) at the time of diagnosis. Many patients with oropharyngeal squamous cell carcinomas, particularly those arising in the base of the tongue and in the tonsillar region, do not have any of the traditional risk factors associated with head and neck cancers (e.g., smoking, smokeless tobacco, and alcohol consumption). Epidemiologic and molecular studies have identified the HPV-16 genotype of HPV as a causative agent in many of these patients.[21] In the present study, staining for P16 antigen for HPV infection was positive in two of the four specimens. None of these five patients had received induction therapy with lymphocyte depleting agents or IL-2 receptor blockers. All of them were on minimal immunosuppression. There was no correlation between any immunosuppression drugs to the occurrence of a specific cancer in follow-up population. Such high incidence of oral cancer was restricted geographically to a particular local population of southern part of India (Telangana and Andhra Pradesh) and only isolated cases are reported from other parts of India. We speculate therefore the role of diet in its causation though viral infection like HPV could be one such additional risk. The diagnosis of malignancy was after long duration of 12–22 years after transplantation. Even in other case reports from India, carcinoma tongue was diagnosed 9 and 11 years after transplant.[2829] This suggests that this malignancy is possibly more common in long-term survivors who have been immunosuppressed for a long period.\n\nCancers if diagnosed early continue to have better outcome as seen in oral cancer, which is a surface lesion. The diagnosis was made relatively early in all the five tongue cancer patients staged as T1 or T2 with no nodal involvement or metastasis. The prognosis of carcinoma of tongue in this setting of renal transplant seems to be better compared to some other malignancies. Though two patients died, one nearly 5 years after initial diagnosis with metastasis and another after 13 months with an unrelated illness, three patients have remained in remission and are alive. Hence, high index of suspicion in any nonhealing ulcer over tongue in a transplant patient is required to establish early diagnosis and get the best outcome. Other cancers of gut, lung, and lymphoma where the diagnosis is usually late have dismal prognosis. Survival after post renal transplant malignancy is poorer compared to transplant alone or cancer alone as evident from ANZDATA registry data. Conversely, the same registry showed increased death risk as high as four-fold in patients above age of 30 years both in males and female as compared to general, transplant, or cancer population.[9]\n\nThe presentation of PTLD is a highly variable and has different localization pattern for kidneys, lung, liver, central nervous system, lymph nodes, GIT/disseminated status needing high index of suspicion. Most common presentation of PTLD was nonlocalizing fever, pain abdomen, weight loss or chronic diarrhea. Though presentation is usually chronic, occasionally, it presented with acute features of viscus perforation or obstructive jaundice needing emergency surgery when the real diagnosis is unfolded. Associated local symptoms (breathlessness, hemoptysis, skin lesions, malabsorption) gave the clue to the potential site of malignancy in some instances. Hence, a patient having fever, weight loss, malaise if unremitting needs to be evaluated for its presence if other etiologies such as viral infection and tuberculosis have been excluded.\n\nCancer in KTRs is an enigmatic issue with limited choice of immunosuppression.[9] The ability to prevent and detect solid organ malignancies in the transplant patient, particularly early-stage carcinomas, relies on periodic screening and strict adherence to prophylactic measures.\n\nInformation about screening, treatment, monitoring strategies for such high-risk population is limited and largely extrapolated from information in general population. However, various published guidelines recommend for cancer screening periodically in KTR, which needs to be adhered to. The approach to post transplant malignancies begins with adopting general preventive measures such as avoiding excess immunosuppression or repeated exposure to antilymphocyte drugs, preferring immunosuppressive drugs, such as m-TOR inhibitors and IL-2 receptor antibodies to probably reduce the risk. Measures such as reduction or cessation of immunosuppressive therapy may result in tumor regression in lymphoma and skin cancers. In KS, reducing the CNI exposure may be particularly important. Periodic focused oral health and hygiene check and screening may be useful in addition to conventional screening for other malignancies such as cervix, gut, and lung.[9143031]\n\nThe major limitations of this study include the retrospective nature of the analysis, lack of information on tissue markers of EBV/HPV infection uniformly, and heterogeneity of immunosuppression used since these patients were transplanted at different times over three decades.\n\nConclusion\nIn our experience, PTLD and carcinoma of the tongue were the most common malignancies seen in kidney transplant recipients. While PTLD was seen usually early (within first decade of transplant) and was associated with dismal prognosis, carcinoma tongue was seen much beyond first decade with less aggressive course. Patients with oral cancer had a better outcome and are more likely to survive for longer periods of time following their diagnosis. We suggest that oral cancers could be related to dietary factors because it was seen in local population only and none in the non-local transplant. Viral infection could be a contributor in some patients and the role of vaccination needs exploration.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgment\nWe thank our colleague Lt. Col. (Dr.) J. Muthukrishnan, Classified Specialist (Med and Endocrinology), Southern Command Hospital, Pune, for helping statistical analysis and manuscript preparation.\n==== Refs\n1 Andrés A Cancer incidence after immunosuppressive treatment following kidney transplantation Crit Rev Oncol Hematol 2005 56 71 85 15978827 \n2 Engels EA Pfeiffer RM Fraumeni JF Jr Kasiske BL Israni AK Snyder JJ Spectrum of cancer risk among US solid organ transplant recipients JAMA 2011 306 1891 901 22045767 \n3 Tremblay F Fernandes M Habbab F deB Edwardes MD Loertscher R Meterissian S Malignancy after renal transplantation: Incidence and role of type of immunosuppression Ann Surg Oncol 2002 9 785 8 12374662 \n4 Kahwaji J Bunnapradist S Hsu JW Idroos ML Dudek R Cause of death with graft function among renal transplant recipients in an integrated healthcare system Transplantation 2011 91 225 30 21048529 \n5 Collins AJ Foley RN Chavers B Gilbertson D Herzog C Johansen K 'United States Renal Data System 2011 Annual Data Report: Atlas of chronic kidney disease & end-stage renal disease in the United States Am J Kidney Dis 2012 59 1 Suppl 1 A7, e1 420 22177944 \n6 Witherow BA Roth GS Carrozza MA Freyberg RW Kopke JE Alloway RR The Israel Penn International Transplant Tumor Registry AMIA Annu Symp Proc 2003 1053 14728556 \n7 Moosa MR Racial and ethnic variations in incidence and pattern of malignancies after kidney transplantation Medicine (Baltimore) 2005 84 12 22 15643296 \n8 Vajdic CM McDonald SP McCredie MR van Leeuwen MT Stewart JH Law M Cancer incidence before and after kidney transplantation JAMA 2006 296 2823 31 17179459 \n9 Wong G Webster AC Turner N Lamier N Goldsmith DJ Winearls CG Himmelfarb J Remuzzi G Cancer after kidney transplant Oxford Textbook of Clinical Nephrology 2016 3 4th ed Oxford, UK Oxford University Press 2483 90 \n10 John GT Infections after renal transplantation in India J Nephrol Ren Transplant [Review] 2009 2 71 88 \n11 Prakash J Ghosh B Singh S Soni A Rathore SS Causes of death in renal transplant recipients with functioning allograft Indian J Nephrol 2012 22 264 8 23162269 \n12 Jha V Post-transplant infections: An ounce of prevention Indian J Nephrol 2010 20 171 8 21206677 \n13 Basu G Infections after kidney transplantation: The bug bear of kidney transplantation in tropics Open Urol Nephrol J 2015 8 76 87 \n14 Kasiske BL Zeier MG Chapman JR Craig JC Ekberg H Garvey CA KDIGO clinical practice guideline for the care of kidney transplant recipients: A summary Kidney Int 2010 77 299 311 19847156 \n15 Shang W Huang L Li L Li X Zeng R Ge S Cancer risk in patients receiving renal replacement therapy: A meta-analysis of cohort studies Mol Clin Oncol 2016 5 315 25 27602224 \n16 Wong G Grace B Clayton P Craig JC Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry Report 2013, 36th Report Last assessed on 2016 Nov 21 Available from: http://www.anzdata.org.au/anzdata/AnzdataReport/36thReport/ANZDATA_36th_Annual%20_Report.pdf \n17 Birkeland SA Løkkegaard H Storm HH Cancer risk in patients on dialysis and after renal transplantation Lancet 2000 355 1886 7 10866449 \n18 Collett D Mumford L Banner NR Neuberger J Watson C Comparison of the incidence of malignancy in recipients of different types of organ: A UK Registry audit Am J Transplant 2010 10 1889 96 20659094 \n19 Wimmer CD Rentsch M Crispin A Illner WD Arbogast H Graeb C The janus face of immunosuppression – de novo malignancy after renal transplantation: The experience of the Transplantation Center Munich Kidney Int 2007 71 1271 8 17332737 \n20 Adami J Gäbel H Lindelöf B Ekström K Rydh B Glimelius B Cancer risk following organ transplantation: A nationwide cohort study in Sweden Br J Cancer 2003 89 1221 7 14520450 \n21 Chung CH Zhang Q Kong CS Harris J Fertig EJ Harari PM p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma J Clin Oncol 2014 32 3930 8 25267748 \n22 Sakhuja V Ramachandran R Kohli HS Jha V Gupta KL Rathi M Spectrum of lymphoproliferative disorders following renal transplantation in North India Indian J Nephrol 2013 23 287 91 23960346 \n23 Yunus M Aziz T Mubarak M Posttransplant malignancies in renal transplant recipients: 22-years experience from a single center in Pakistan Asian Pac J Cancer Prev 2012 13 575 8 22524827 \n24 Harzallah K Abderrahim E Chareffedine K Yeich S Belhadj R Skhiri H Cancers after renal transplantation: Multicenter experience Saudi J Kidney Dis Transpl 2008 19 825 30 18711309 \n25 Madhivanan S John GT Rajasekar T Nair S Kirubakaran MG Jacob CK Lymphoproliferative disorders in renal transplant recipients: A single-centre experience Natl Med J India 2006 19 50 1 \n26 Jain M Badwal S Pandey R Srivastava A Sharma RK Gupta RK Post-transplant lymphoproliferative disorders after live donor renal transplantation Clin Transplant 2005 19 668 73 16146560 \n27 Kasiske BL Snyder JJ Gilbertson DT Wang C Cancer after kidney transplantation in the United States Am J Transplant 2004 4 905 13 15147424 \n28 Prakash J Prabhakar Kumar M Aralapuram K Carcinoma of the tongue in a renal transplant recipient: A rare post-transplant malignancy Saudi J Kidney Dis Transpl 2015 26 103 6 25579725 \n29 Malleshappa P Aghariya M Tampi C Shah BV Squamous cell carcinoma of tongue in a renal transplant recipient Indian J Med Paediatr Oncol 2009 30 136 7 20838555 \n30 Asch WS Perazella MA Cancer and mortality in solid-organ transplantation: Preventable or inevitable? Am J Kidney Dis 2016 68 839 42 27405594 \n31 Kasiske BL Vazquez MA Harmon WE Brown RS Danovitch GM Gaston RS Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation J Am Soc Nephrol 2000 11 Suppl 15 S1 86 11044969\n\n",
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"title": "Carcinoma of the Tongue in Renal Transplant Recipients: An Unusual Spectrum of De novo Malignancy at a Tertiary Care Center in India Over a Period of 26 Years.",
"title_normalized": "carcinoma of the tongue in renal transplant recipients an unusual spectrum of de novo malignancy at a tertiary care center in india over a period of 26 years"
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"affiliations": "University of California, San Francisco, CA 94110, USA. kdrasner@anesthesia.ucsf.edu",
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"abstract": "We provide a unique case of haemorrhagic shock complicating a corticosteroid-resistant diffuse ulcerative enteritis in a patient treated with a combination of an anti CTLA-4 and an anti PD-1 for metastatic melanoma. Immunotherapy has changed the perspective for the management of patients with metastatic melanoma but are also responsible for digestive complications mainly represented by immunomediated colitis. Digestive bleeding is common in patients with extensive colonic lesions but has never been described in enteritis independent of colitis. The patient with acute intestinal obstruction related ileitis without evidence of stricture on imaging and then had a gastro-intestinal bleed. In the absence of haemorrhagic lesions on upper gastrointestinal endoscopy, colonoscopy and CT angiography, a surgical exploration with enteroscopy was performed. This revealed an extensive ulcerated jejunoileitis, with active bleeding, within a Meckel's diverticulum. Management included resection of the Meckel diverticulum with a transient double barrel ileostomy. Two infliximab infusions were given due to persistent bleeding. We observed a dramatic improvement after infliximab treatment with complete cessation of bleeding and no further need for transfusions. A complete mucosal healing has been achieved on enteroscopy at 3 months with disappearance of histological inflammatory lesions. This observation suggests that infliximab represents a therapeutic option in severe enteritis and may be as effective as in more moderate immune-mediated enterocolitis.",
"affiliations": "Université de Paris, Department of Gastroenterology, AP-HP Hôpital Saint Louis, Paris, France.;Université de Paris, Department of Dermatology, AP-HP Hôpital Saint Louis, Paris, France.;Université de Paris, Department of Pathology, AP-HP Hôpital Saint Louis, Paris, France.;Université de Paris, Department of Dermatology, AP-HP Hôpital Saint Louis, Paris, France.;Université de Paris, Department of Gastroenterology, AP-HP Hôpital Saint Louis, Paris, France.;Université de Paris, Department of Gastroenterology, AP-HP Hôpital Saint Louis, Paris, France.",
"authors": "Trystram|Noémie|N|;Laly|Pauline|P|;Bertheau|Philippe|P|;Baroudjian|Barouyr|B|;Aparicio|Thomas|T|;Gornet|Jean-Marc|JM|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/apm-21-58",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2224-5820",
"issue": null,
"journal": "Annals of palliative medicine",
"keywords": "Metastatic melanoma; case report; gastrointestinal haemorrhage; immune checkpoint inhibitors; immune-mediated enterocolitis",
"medline_ta": "Ann Palliat Med",
"mesh_terms": null,
"nlm_unique_id": "101585484",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34118829",
"pubdate": "2021-06-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Haemorrhagic shock secondary to a diffuse ulcerative enteritis after Ipilimumab and Nivolumab treatment for metastatic melanoma: a case report.",
"title_normalized": "haemorrhagic shock secondary to a diffuse ulcerative enteritis after ipilimumab and nivolumab treatment for metastatic melanoma a case report"
} | [
{
"companynumb": "FR-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-064748",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "Acute liver failure (ALF), characterized by sudden onset of coagulopathy (international normalized ratio [INR] ≥ 1.5) and encephalopathy, may occur during pregnancy either as a pregnancy-associated etiology or an unrelated and coincidental liver injury. The U.S. Acute Liver Failure Study Group, comprised of 33 tertiary care liver centers, has enrolled consecutive patients with ALF or acute liver injury (ALI; INR ≥ 2.0 with no encephalopathy), over two decades.\n\n\n\nEtiologies, clinical features, and outcomes of 70 of 3,155 patients (2.2%) who developed ALF or ALI during pregnancy were reviewed to determine how many were pregnancy associated (pregnancy-associated liver disease; PAALD) and how many were attributed to other etiologies. Thirty-five of the 70 were considered PAALD, of whom nearly half were attributed to hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome and half to acute fatty liver of pregnancy (AFLP), although, in some instances, the distinction was unclear. Virtually all with PAALD had been delivered before hepatology referral, mostly by cesarean section. Acetaminophen toxicity accounted for 21 (60% of the remaining cases), with the remainder resulting from a variety of other causes, but not including viral hepatitis A through E. Although recovery with delivery or supportive measures was possible in most cases, 11 of 70 (16%) required liver transplantation and 8 (11%) died. Swansea criteria to diagnose AFLP were met by all patients with PAALD and also by virtually all women with other forms of ALF.\n\n\n\nOnly half of those with ALF during pregnancy appeared to have HELLP or AFLP. Morbidity and mortality for mother and fetus are strongly associated with etiology of liver failure.",
"affiliations": "Division of Digestive and Liver Diseases, UT Southwestern Medical Center at Dallas, Dallas, TX.;Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI.;Division of Digestive and Liver Diseases, UT Southwestern Medical Center at Dallas, Dallas, TX.;Department of Obstetrics and Gynecology, UT Southwestern Medical Center at Dallas, Dallas, TX.;Division of Digestive and Liver Diseases, UT Southwestern Medical Center at Dallas, Dallas, TX.;Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC.;Department of Medicine, University of Texas Medical Branch, Galveston, TX.;Division of Digestive and Liver Diseases, UT Southwestern Medical Center at Dallas, Dallas, TX.",
"authors": "Casey|Lisa C|LC|;Fontana|Robert J|RJ|;Aday|Ariel|A|;Nelson|David B|DB|;Rule|Jody A|JA|;Gottfried|Michelle|M|;Tran|Minh|M|;Lee|William M|WM|0000-0002-2783-5441;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/hep.31144",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0270-9139",
"issue": "72(4)",
"journal": "Hepatology (Baltimore, Md.)",
"keywords": null,
"medline_ta": "Hepatology",
"mesh_terms": "D000328:Adult; D005260:Female; D017359:HELLP Syndrome; D006801:Humans; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D011247:Pregnancy; D011248:Pregnancy Complications",
"nlm_unique_id": "8302946",
"other_id": null,
"pages": "1366-1377",
"pmc": null,
"pmid": "31991493",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "9329933;16317692;27641661;26408081;20977643;11376667;30151988;27911262;31017355;18332072;10331463;18318440;9262493;27174330;27043883;20159293;17906043;26658682;30731196;18825709;30947881;3565968;8678935;28734939;12427793;27878648;27085756;27215797;29946176;27586034;16530510;10352164;10368478;23860212;23857305;12237653;18265410",
"title": "Acute Liver Failure (ALF) in Pregnancy: How Much Is Pregnancy Related?",
"title_normalized": "acute liver failure alf in pregnancy how much is pregnancy related"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-271073",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"d... |
{
"abstract": "BACKGROUND\nThe treatment of patients with acute leukemia, who due to their religious beliefs refuse to accept blood transfusion, is a great challenge for hematologists.\n\n\nMETHODS\nWe present a case of acute pre-T-lymphoblastic leukemia in a Jehovah's Witness who did not accept blood transfusion during chemotherapy. Standard induction and consolidation chemotherapy was used (according to the PALG ALL-6 regiment).\n\n\nRESULTS\nDuring consolidation cycles, darbepoietin alfa, intravenous iron, and total parenteral nutrition was administered. Extreme (Hb < 5 g/dL), long-lasting (41 days) anemia was observed with the lowest Hb concentration amounting to 1.3 g/dL (lasting 7 days).\n\n\nCONCLUSIONS\nWe believe this to be the lowest Hb value observed, particularly one that persisted for such a long period of time and resulted in the patient surviving without consequences. The patient remains in complete remission for more than 2 years after diagnosis.",
"affiliations": "Department of Hemostasis, Medical University of Łódź, and the, Łódź, Poland.;Department of Hematology, Copernicus Memorial Hospital, Łódź, Poland.;Department of Hematology, Copernicus Memorial Hospital, Łódź, Poland.;Department of Hemostasis, Medical University of Łódź, and the, Łódź, Poland.;Department of Hemostasis, Medical University of Łódź, and the, Łódź, Poland. jacek.trelinski@umed.lodz.pl.",
"authors": "Chojnowski|Krzysztof|K|;Janus|Agnieszka|A|;Bliźniewska|Katarzyna|K|;Robak|Marta|M|;Treliński|Jacek|J|",
"chemical_list": "D006397:Hematinics; D006454:Hemoglobins; D000068256:Darbepoetin alfa; D007501:Iron",
"country": "United States",
"delete": false,
"doi": "10.1111/trf.13703",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1132",
"issue": "56(10)",
"journal": "Transfusion",
"keywords": null,
"medline_ta": "Transfusion",
"mesh_terms": "D000740:Anemia; D000971:Antineoplastic Combined Chemotherapy Protocols; D001803:Blood Transfusion; D000068256:Darbepoetin alfa; D006397:Hematinics; D006454:Hemoglobins; D006801:Humans; D007501:Iron; D033221:Jehovah's Witnesses; D008297:Male; D010289:Parenteral Nutrition, Total; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012074:Remission Induction; D016312:Treatment Refusal; D055815:Young Adult",
"nlm_unique_id": "0417360",
"other_id": null,
"pages": "2438-2442",
"pmc": null,
"pmid": "27385671",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Long-lasting extreme anemia during the therapy of acute lymphoblastic leukemia in a Jehovah's Witness patient.",
"title_normalized": "long lasting extreme anemia during the therapy of acute lymphoblastic leukemia in a jehovah s witness patient"
} | [
{
"companynumb": "PL-MYLANLABS-2016M1056888",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "1",
... |
{
"abstract": "This was a phase II study of capecitabine in substitution of 5-fluorouracil (5-FU) in the chemoradiotherapy regimen for patients with localized squamous cell carcinoma of the anal canal.\n\n\nBACKGROUND\nCombined chemoradiation with infusional 5-FU and mitomycin is the standard treatment for localized squamous cell carcinoma (SCC) of the anal canal. Capecitabine is an oral fluoropirimidine that has been shown to be equally effective to 5-FU in many solid tumors. However, the efficacy of the substitution of 5-FU for capecitabine in anal SCC needs confirmation.\n\n\nMETHODS\nPatients with SCC of anal cancer T2-4N0M0 or T (any) N1-3M0, with good performance status and normal blood and renal function, were treated with capecitabine 825 mg/m(2) bid during radiotherapy associated with a single dose of mitomycin 15 mg/m(2) on day 1. The primary objective was local control rate at 6 months determined by clinical examination and radiological assessment. Sample size was calculated using the Fleming single-stage design.\n\n\nRESULTS\nFrom November 2010 to February 2014, N = 51 patients were initially included; however, 43 patients were assessed. Seventeen patients (39.5%) were stage II, 11 patients (25.6%) stage IIIA, and 15 patients (34.9%) stage IIIB. Four patients (9.3%) were HIV positive. With a median follow-up of 23.1 months (range 4 to 44.4 months), 3 patients (7%) presented partial response, 37 (86%) had complete response, and 3 patients developed progression of the disease (7%) at 6 months. The colostomy rate was 18.6%. It was observed a locoregional control of 86% in 6 months (CI 95% 0.72-0.94). The main grade 3-4 toxicities were grade 3 radiodermitis in 10 patients (23.2%), grade 3 lymphopenia in 5 patients (11.6%), and grade 3 neutropenia in 2 patients (6.9%). One HIV-positive patient had septic shock, pneumonia, herpetic encephalitis, atrial fibrillation, and macrophage activation syndrome.\n\n\nCONCLUSIONS\nCapecitabine can safely substitute infusional 5-FU in the standard chemoradiation regimen for SCC of the anal cancer, with a locoregional control of 86% in 6 months (CI 95% 0.72-0.94).",
"affiliations": "Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil. suilanecr@yahoo.com.br.;Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil.;Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil.;Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil.;Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil.;Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil.;Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil.;Universidade de Sao Paulo, Sao Paulo, Sao Paulo, Brazil.",
"authors": "Oliveira|Suilane Coelho Ribeiro|SC|;Moniz|Camila Motta Venchiarutti|CM|;Riechelmann|Rachel|R|;Alex|Alexandra Kichfy|AK|;Braghirolli|Maria Ignez|MI|;Bariani|Giovanni|G|;Nahas|Caio|C|;Hoff|Paulo Marcelo Gehm|PM|",
"chemical_list": "D016685:Mitomycin; D000069287:Capecitabine; D002945:Cisplatin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1007/s12029-015-9790-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "47(1)",
"journal": "Journal of gastrointestinal cancer",
"keywords": "Anus neoplasms/drug therapy; Anus neoplasms/radiotherapy; Capecitabine; Mitomycin; Squamous cell carcinoma",
"medline_ta": "J Gastrointest Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001005:Anus Neoplasms; D000069287:Capecitabine; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D002945:Cisplatin; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D016685:Mitomycin; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D012074:Remission Induction; D015996:Survival Rate",
"nlm_unique_id": "101479627",
"other_id": null,
"pages": "75-81",
"pmc": null,
"pmid": "26691173",
"pubdate": "2016-03",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "25167226;9166533;8874455;18430910;12504657;25001200;8690640;26374429;9164216;17721920;18472366;9336145;24885554;23517808;23150704;4830803;24638005;22503032;8823332;21328328",
"title": "Phase II Study of Capecitabine in Substitution of 5-FU in the Chemoradiotherapy Regimen for Patients with Localized Squamous Cell Carcinoma of the Anal Canal.",
"title_normalized": "phase ii study of capecitabine in substitution of 5 fu in the chemoradiotherapy regimen for patients with localized squamous cell carcinoma of the anal canal"
} | [
{
"companynumb": "BR-ROCHE-1736511",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Lymphoid malignancies represent 0. 008% of all cervical tumours. While uncommon, lymphoid malignancies of the gynaecological tract require careful diagnosis and classification to ensure appropriate treatment. We present a case of a 54-year-old woman with HIV who presented with urinary and faecal incontinence for 2 weeks, associated with the feeling of a mass in her vagina. A smooth flesh-coloured pelvic mass was seen on physical examination, and a transvaginal biopsy revealed infiltration of atypical lymphoid cells with fluorescence in situ hybridisation positive for MYC and BCL6, and negative for IGH/BCL2. Bone marrow and cerebral spinal fluid analysis also showed involvement by atypical lymphocytes. She was diagnosed with stage IV high-grade B-cells lymphoma (HGBLs) with MYC and BCL6 rearrangements. She was given R-CODOX-M plus IVAC with no evidence of disease at 4-month follow-up. To our knowledge, this is the first literature report of a HGBL with MYC and BCL6 rearrangement presenting as a cervical mass.",
"affiliations": "Internal Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA philippos500ac@hotmail.com.;Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.;Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA.;Hematology and Oncology, Sylvester Comprehensive Cancer Center at University of Miami, Miami, Florida, USA.",
"authors": "Costa|Philippos Apolinario|PA|http://orcid.org/0000-0001-9681-0515;Needelman|Brandon S|BS|;Tjendra|Youley|Y|;Hoffman|James E|JE|",
"chemical_list": "C084103:BCL6 protein, human; C489427:MYC protein, human; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-235451",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(8)",
"journal": "BMJ case reports",
"keywords": "cervical cancer; gynaecological cancer; haematology (incl blood transfusion); malignant disease and immunosuppression",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D015448:Leukemia, B-Cell; D008228:Lymphoma, Non-Hodgkin; D008875:Middle Aged; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32843454",
"pubdate": "2020-08-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "High-grade B-cell lymphoma with MYC and BCL6 rearrangements presenting as a cervical mass.",
"title_normalized": "high grade b cell lymphoma with myc and bcl6 rearrangements presenting as a cervical mass"
} | [
{
"companynumb": "US-ACCORD-204938",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "1",
"druga... |
{
"abstract": "Venous thromboembolism occurs when a deep vein thrombosis travels to the lungs and forms a pulmonary embolism. Low-molecular-weight heparins are a mainstay in the treatment and prevention of venous thromboembolism and should be initiated promptly due to substantial morbidity and mortality. A rare side effect of low-molecular-weight heparins is major bleeding, which also carries a significant morbidity and mortality rate. Here, we present a case of a fatal retroperitoneal hematoma in a patient being treated with enoxaparin for bilateral pulmonary emboli.",
"affiliations": "William Carey University College of Osteopathic Medicine, Hattiesburg, MS, USA.;Internal Medicine Residency Program, Baptist Memorial Hospital-Golden Triangle, Columbus, MS, USA.;Internal Medicine Residency Program, Baptist Memorial Hospital-Golden Triangle, Columbus, MS, USA.;Internal Medicine Residency Program, Baptist Memorial Hospital-Golden Triangle, Columbus, MS, USA.;Department of Pulmonary and Critical Care, Baptist Memorial Hospital-Golden Triangle, Columbus, MS, USA.",
"authors": "Sexe|Jordan|J|https://orcid.org/0000-0003-2339-8528;McCarthy|Robin|R|;Dara|Navid|N|;Brown|Lyon|L|;Dutta|Gaurav|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/4805967",
"fulltext": "\n==== Front\nCase Rep Hematol\nCase Rep Hematol\nCRIHEM\nCase Reports in Hematology\n2090-6560 2090-6579 Hindawi \n\n10.1155/2020/4805967\nCase Report\nFatal Retroperitoneal Hematoma in a Patient Receiving Enoxaparin for Bilateral Pulmonary Emboli\nhttps://orcid.org/0000-0003-2339-8528Sexe Jordan jordanmichaelsexe@gmail.com\n1\n McCarthy Robin \n2\n Dara Navid \n2\n Brown Lyon \n2\n Dutta Gaurav \n3\n \n1William Carey University College of Osteopathic Medicine, Hattiesburg, MS, USA\n\n2Internal Medicine Residency Program, Baptist Memorial Hospital-Golden Triangle, Columbus, MS, USA\n\n3Department of Pulmonary and Critical Care, Baptist Memorial Hospital-Golden Triangle, Columbus, MS, USA\nAcademic Editor: Håkon Reikvam\n\n\n2020 \n29 5 2020 \n2020 480596713 2 2020 30 4 2020 4 5 2020 Copyright © 2020 Jordan Sexe 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.Venous thromboembolism occurs when a deep vein thrombosis travels to the lungs and forms a pulmonary embolism. Low-molecular-weight heparins are a mainstay in the treatment and prevention of venous thromboembolism and should be initiated promptly due to substantial morbidity and mortality. A rare side effect of low-molecular-weight heparins is major bleeding, which also carries a significant morbidity and mortality rate. Here, we present a case of a fatal retroperitoneal hematoma in a patient being treated with enoxaparin for bilateral pulmonary emboli.\n==== Body\n1. Introduction\nA venous thromboembolism (VTE) occurs when a deep vein thrombosis (DVT) migrates to a pulmonary artery, forming a pulmonary embolism (PE). A subsegmental pulmonary embolism (SSPE) involves subsegmental pulmonary artery branches and spares major vessels. Enoxaparin is a low-molecular-weight heparin (LMWH) commonly used in both the treatment and prevention of PE. LMWHs are a highly effective and popular treatment option due to lack of required laboratory monitoring, low cost, and ease of subcutaneous dosing [1]. For these reasons, LMWHs are a preferred initial agent in the treatment of PE in the acute setting. Direct oral anticoagulants (DOACs), such as rivaroxaban and apixaban, are another popular treatment for PE due to their fast onset of action, affordability, and oral administration. DOACs are a preferred treatment for stable PE in the outpatient setting but are not indicated for treating unstable PE. Unfractionated heparin is the preferred treatment for hemodynamically unstable PE due to its shorter half-life and presence of a well-established reversibility agent, protamine sulfate [1].\n\nA potential consequence of enoxaparin therapy is major bleeding, which has been reported to occur in about 3.79 per 1,000 patients [2]. Major bleeding has been defined as requiring transfusion, causing symptoms in an essential organ/body region, necessitating hospitalization, or fatal [2]. Though very rare, case reports exist of rectus sheath and retroperitoneal hematoma development secondary to enoxaparin administration. Here, we present a patient receiving therapeutic enoxaparin who developed a rectus sheath hematoma and subsequent fatal retroperitoneal hematoma.\n\n2. Case Presentation\nA 50-year-old female presented to the ED with the complaint of near syncope for the past week. Her past medical history included anxiety, hypertension, migraines, depression, and gastric bypass 10 years priorly. Her home medications were amitriptyline, clonazepam, erenumab, metoprolol, mirtazapine, montelukast, myrbetriq, pantoprazole, ropinirole, and estradiol, which had been started by the patient's PCP one month priorly. The review of systems was positive for nausea and lightheadedness.\n\nPertinent physical exam findings were hypotension and moderate obesity, with a weight of 146.6 kg. Urinalysis revealed positive nitrites and numerous bacteria. Initial lactic acid was 2.8 mmol/L. Hemoglobin was 12.7 g/dL and hematocrit 40%. The serum creatinine was 1.3 mg/dL. A CT chest/abdomen/pelvis revealed bilateral subsegmental pulmonary emboli. Ultrasound of the lower extremities demonstrated a right-sided DVT of the femoral and popliteal veins. A transthoracic echocardiogram (TTE) showed no evidence of right heart strain, no right atrial dilation, a left ventricle ejection fraction of 55–60%, and left ventricular hypertrophy. An arterial blood gas (ABG) was performed and is shown in Table 1. The HAS-BLED score was 1, indicating a low risk for major bleeding. The aPTT was 26.4 seconds. She was started on therapeutic subcutaneous enoxaparin injections at a dose of 1 mg/kg, totaling 160 mg twice daily. Despite fluid resuscitation, the patient remained hypotensive and was admitted to the ICU for vasopressor support, anticoagulation, and intravenous antibiotics.\n\nOver the next 48 to 72 hours, the patient improved and was moved to the general medicine floor. However, on day 8, the patient developed sudden, profound hypotension requiring dual pressor support. CBC revealed a hemoglobin of 5.2 g/dL and hematocrit of 16.7%. An ABG revealed a pH of 6.95 and lactate of 14.3 mmol/L (Table 1). Repeat CT imaging revealed a right-sided rectus sheath, and pelvic hematoma presumed to be of inferior epigastric artery origin (Figure 1). A coil embolization was performed with successful ligation of the vessel.\n\nOver the next 24 hours, the patient remained hemodynamically unstable despite dual pressor support requiring repeat imaging, which revealed a new left retroperitoneal hematoma (Figure 2). CT imaging and diagnostic angiography were unable to find a source of the retroperitoneal hematoma. Due to severe hemodynamic instability and an indeterminate source of bleeding, the patient was deemed a poor surgical candidate. Over the next 3 days, the patient required triple pressor therapy and mass transfusion protocol for worsening hemorrhagic shock. Attempts at reversal of anticoagulation with protamine, vitamin K, desmopressin, and tranexamic acid were unsuccessful. The patient died 2 days later.\n\n3. Discussion\nEnoxaparin is a LMWH commonly used in the treatment and prevention of VTE. A meta-analysis found that LMWH had a lower rate of major hemorrhage compared to intravenous heparin and subcutaneous unfractionated heparin during initial VTE treatment [3]. Bleeding is considered major when it is located within the retroperitoneum or cranium, or if it leads to transfusion, hospitalization, or death [4]. Retroperitoneal hemorrhage constitutes 1% of all adverse bleeding events [4]. Though more common in patients with renal impairment, the rarity of rectus sheath and retroperitoneal hematomas makes well-established conclusions difficult [5, 6].\n\nDiagnosis is commonly confirmed with CT imaging [7]. Treatment consists of fluid resuscitation, blood transfusions, FFP, and discontinuing anticoagulation. Administration of protamine has questionable benefit with a 40–70% effectiveness in reversing LMWH [8]. If conservative therapy fails, surgical intervention may be explored if a bleeding vessel is identified [7].\n\nHere, it is believed that an enoxaparin injection pierced the patient's inferior epigastric artery. There have been numerous reports of rectus sheath hematoma development secondary to accidental injection of intramuscular tissue or the inferior epigastric artery with enoxaparin [9, 10]. This patient's rectus sheath hematoma was not present on initial CT imaging performed in the ED but became apparent on CT imaging 8 days after initiation of enoxaparin. This vessel was fortunately able to be identified and successfully coil embolized. However, the ultimate fatal retroperitoneal hematoma was likely secondary to cannulation of the femoral artery during embolization of the rectus sheath hematoma in a partially heparinized patient.\n\nIt is also possible that discontinuing the patient's anticoagulation provoked clinical deterioration. The enoxaparin was discontinued after the patient developed major bleeding in the presence of acute hypotension on day 8. However, it could be possible that stopping anticoagulation in a patient with bilateral subsegmental pulmonary emboli while immobilized during hospitalization may have worsened the underlying pulmonary emboli and/or elicited formation of a new PE from one of the patient's proximal DVTs. Regardless, this patient developed a massive retroperitoneal hematoma and ultimately died of complications from hemorrhagic shock.\n\nProper administration of subcutaneous enoxaparin injections relies on pinching a segment of subcutaneous tissue and injecting the needle into the isolated area. Some practitioners may administer the injection by simply pressing into the anterior abdominal wall without isolating a secure subcutaneous fat pad. Such a technique could compress the superficial fat and lead to injection of intramuscular tissue or a blood vessel. In Figure 1, we show the depth of this patient's inferior epigastric artery in relation to the length of needle typically used in enoxaparin injections. This shows the plausibility of a routine enoxaparin injection piercing the inferior epigastric artery if not administered correctly.\n\n4. Conclusion\nIt is imperative to closely monitor for hemodynamic instability and symptomatic changes related to potential hemorrhaging in patients receiving enoxaparin. In addition, proper training of medical staff with regard to administration is of the utmost importance in preventing complications. Though rare, LMWHs such as enoxaparin may precipitate adverse hematologic events that may contribute to morbidity and mortality.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 CT performed on day 8 showing right-sided rectus sheath and pelvic hematomas. The inferior epigastric artery was measured approximately 25.9 mm below the skin. A standard enoxaparin injection needle at our facility has a length of 15.9 mm. Photo of the needle was adapted from https://tinylittlehuman.wordpress.com/2012/11/02/lovenox/.\n\nFigure 2 CT performed on day 9 showing development of a massive left-sided retroperitoneal hematoma.\n\nTable 1 The patient's ABG results.\n\n \tpH\tpO2 (mmHg)\tpCO2 (mmHg)\tHCO3 (mmol/L)\tO2 saturation\t\nDay 1\t7.45\t93\t28 (L)\t19.5 (L)\t98\t\nDay 8\t6.95\t361 (H)\t18 (L)\t4.0 (L)\t98\t\nDay 11\t7.40\t49 (L)\t43\t26.2\t91 (L)\t\nThe ABG on day 8 was performed just after the patient developed acute hypotension and demonstrates a severe acidosis. The ABG on day 11 was performed about 3 hours prior to death and demonstrates marked hypoxemia despite high-flow oxygen therapy.\n==== Refs\n1 Lip G. Y. H. Hull R. D. Post T. Venous Thromboembolism: Initiation of Anticoagulation (First 10 Days) 2020 Waltham, MA, USA UpToDate \n2 Rein N. Biedermann J. S. Meer F. J. M. Major bleeding risks of different low-molecular-weight heparin agents: a cohort study in 12 934 patients treated for acute venous thrombosis Journal of Thrombosis and Haemostasis 2017 15 7 1386 1391 10.1111/jth.13715 2-s2.0-85019757571 28440008 \n3 Robertson L. Jones L. E. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for the initial treatment of venous thromboembolism Cochrane Database of Systematic Reviews 2017 2 10.1002/14651858.cd001100.pub4 2-s2.0-85012060183 \n4 Shah R. D. Nagar S. Shanley C. J. Janczyk R. J. Factors affecting the severity of spontaneous retroperitoneal hemorrhage in anticoagulated patients The American Journal of Surgery 2008 195 3 410 413 10.1016/j.amjsurg.2007.12.003 2-s2.0-40749103374 18241833 \n5 Ahuja T. Altshuler J. Papadopoulos J. Risk factors for bleeding events with enoxaparin, dabigatran and fondaparinux in hospitalized patients with varying levels of renal impairment Journal of Pharmaceutical Care & Health Systems 2017 4 3 2376 2419 10.4172/2376-0419.1000178 \n6 DeCarolis D. D. Thorson J. G. Clairmont M. A. Leuthner A. M. Rector T. S. Johnson G. J. Enoxaparin outcomes in patients with moderate renal impairment Archives of Internal Medicine 2012 172 22 1713 1718 10.1001/2013.jamainternmed.369 2-s2.0-84871365801 23128835 \n7 Salemis N. S. Oikonomakis I. Lagoudianakis E. Enoxaparin-induced spontaneous massive retroperitoneal hematoma with fatal outcome The American Journal of Emergency Medicine 2014 32 12 e1 e1559 10.1016/j.ajem.2014.05.026 2-s2.0-84916896541 \n8 Lee M. C. Nickisch F. Limbird R. S. Massive retroperitoneal hematoma during enoxaparin treatment of pulmonary embolism after primary total hip arthroplasty: case reports and review of the literature The Journal of Arthroplasty 2006 21 8 1209 1214 10.1016/j.arth.2006.01.018 2-s2.0-33845336448 17162185 \n9 Kayrak M. Bacaksiz A. Yazici M. Is enoxaparin injection from the abdominal wall safe in elderly people?: a fatal case of rectus sheath hematoma Canadian Family Physician 2008 54 9 1246 1248 18791099 \n10 Holmes S. J. Yale S. H. Mazza J. J. Rectus sheath hematoma as a cause of acute abdominal pain American Family Physician 2001 64 64 1681 1682 11759076\n\n",
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"title": "Fatal Retroperitoneal Hematoma in a Patient Receiving Enoxaparin for Bilateral Pulmonary Emboli.",
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"abstract": "BACKGROUND\nMucormycosis is a rare opportunistic fungal infection with poor prognosis. The incidence of mucormycosis has been increasing, and it is a threat to immunocompromised hosts. We present a case of gastric mucormycosis complicated by a gastropleural fistula during immunosuppressive treatment for adult-onset Still disease (AOSD).\nAn 82-year-old woman diagnosed with AOSD who developed gastric ulcers during the administration of an immunosuppressive therapy with corticosteroids, cyclosporine, and tocilizumab complained of melena and epigastralgia. Esophagogastroduodenoscopy showed multiple ulcers covered with grayish or greenish exudates.\nThe patient diagnosed with mucormycosis based on culture and biopsy of the ulcers, which showed nonseptate hyphae branching at wide angles. Mucor indicus was identified using polymerase chain reaction.\n\n\nRESULTS\nAlthough liposomal amphotericin B was administered, gastric mucormycosis was found to be complicated by a gastropleural fistula. The patient died because of pneumonia due to cytomegalovirus infection, and autopsy revealed the presence of Mucorales around the fistula connecting the stomach and diaphragm.\n\n\nCONCLUSIONS\nGastric mucormycosis is refractory to treatment and fatal. Surgical resection, if possible, along with antifungal drugs can result in better outcomes.",
"affiliations": "Department of Rheumatology.;Department of Rheumatology.;Department of Rheumatology.;Department of Gastroenterology.;Department of Rheumatology.;Department of Infectious Disease, Japan Community Healthcare Organization, Isahaya General Hospital, Isahaya.;Department of Infectious Disease, Japan Community Healthcare Organization, Isahaya General Hospital, Isahaya.;Department of Gastroenterology.;Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki.;Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki.;Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki.;Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo.;Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyo.;Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.",
"authors": "Uchida|Tomohisa|T|;Okamoto|Momoko|M|;Fujikawa|Keita|K|;Yoshikawa|Daisuke|D|;Mizokami|Akinari|A|;Mihara|Tomo|T|;Kondo|Akira|A|;Ohba|Kazuo|K|;Kurohama|Kazuhiro|K|;Nakashima|Masahiro|M|;Sekine|Ichiro|I|;Nakamura|Shigeki|S|;Miyazaki|Yoshitsugu|Y|;Kawakami|Atsushi|A|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31770250MD-D-19-0240110.1097/MD.0000000000018142181424500Research ArticleClinical Case ReportGastric mucormycosis complicated by a gastropleural fistula A case report and review of the literatureUchida Tomohisa MDaOkamoto Momoko MDaFujikawa Keita MD, PhDa∗Yoshikawa Daisuke MD, PhDbMizokami Akinari MD, PhDaMihara Tomo MD, PhDcKondo Akira MD, PhDcOhba Kazuo MD, PhDbKurohama Kazuhiro MDdNakashima Masahiro MD, PhDdSekine Ichiro MD, PhDdNakamura Shigeki MD, PhDeMiyazaki Yoshitsugu MD, PhDeKawakami Atsushi MD, PhDfNA. a Department of Rheumatologyb Department of Gastroenterologyc Department of Infectious Disease, Japan Community Healthcare Organization, Isahaya General Hospital, Isahayad Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, Nagasakie Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Tokyof Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.∗ Correspondence: Keita Fujikawa, Department of Rheumatology, Japan Community Hearthcare Organization, Isahaya General Hospital, 24-1 Eishohigashi-machi, Isahaya 854-0071, Japan (e-mail: keitafj@gmail.com).11 2019 27 11 2019 98 48 e1814224 3 2019 13 10 2019 30 10 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nMucormycosis is a rare opportunistic fungal infection with poor prognosis. The incidence of mucormycosis has been increasing, and it is a threat to immunocompromised hosts. We present a case of gastric mucormycosis complicated by a gastropleural fistula during immunosuppressive treatment for adult-onset Still disease (AOSD).\n\nPatient concerns:\nAn 82-year-old woman diagnosed with AOSD who developed gastric ulcers during the administration of an immunosuppressive therapy with corticosteroids, cyclosporine, and tocilizumab complained of melena and epigastralgia. Esophagogastroduodenoscopy showed multiple ulcers covered with grayish or greenish exudates.\n\nDiagnoses:\nThe patient diagnosed with mucormycosis based on culture and biopsy of the ulcers, which showed nonseptate hyphae branching at wide angles. Mucor indicus was identified using polymerase chain reaction.\n\nInterventions and outcomes:\nAlthough liposomal amphotericin B was administered, gastric mucormycosis was found to be complicated by a gastropleural fistula. The patient died because of pneumonia due to cytomegalovirus infection, and autopsy revealed the presence of Mucorales around the fistula connecting the stomach and diaphragm.\n\nLessons:\nGastric mucormycosis is refractory to treatment and fatal. Surgical resection, if possible, along with antifungal drugs can result in better outcomes.\n\nKeywords\nadult-onset Still diseasegastric mucormycosisgastropleural fistulatocilizumabOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nMucormycosis is a rare but fatal fungal infection caused by Mucorales with an acute course. Recently, as the incidence of mucormycosis has been increasing, it has been considered an important infectious disease observed among immunocompromised patients.[1,2] Its common infection sites include the skin, paranasal sinus, and lungs, but gastrointestinal manifestations are rare.[3] Mucormycosis is diagnosed based on histologic findings or positive culture from affected lesions owing to the lack of validated serologic biomarkers. Management guidelines for mucormycosis recommend a combination treatment with antifungal drugs and surgical resection of the devitalized tissue.[4] Herein, we describe a case of gastric mucormycosis complicated by a gastropleural fistula during immunosuppressive treatment for adult-onset Still disease (AOSD).\n\n2 Case report\nAn 82-year-old woman developed fever, sore throat, general malaise, and polyarthralgia and was admitted to our hospital. At hospitalization, her vital signs were as follows: blood pressure, 109/84 mm Hg; pulse rate, 92 beats/min; and temperature, 37.3°C. She presented with cervical lymphadenopathy, salmon-colored rash on the torso and extremities, and bilateral tenderness of the shoulder, elbow, and ankle joints. She had no relevant medical and family histories. Laboratory data revealed a white blood cell count of 17,110/μL with 92% neutrophils, C-reactive protein (CRP) level of 28.57 mg/dL, serum ferritin level of 9899 ng/mL, and elevated liver enzyme levels. Rheumatoid factor, anticitrullinated protein antibody, and antinucleolar antibody were tested to be negative, and whole body computed tomography (CT) revealed no abnormalities. Subsequently, she was diagnosed with AOSD based on Yamaguchi criteria[5] and was prescribed oral prednisolone (50 mg/d) and oral cyclosporine (200 mg/d). Her symptoms and serum ferritin levels remarkably improved on day 10. On day 36, she developed high fever with elevated CRP and serum ferritin levels. Because AOSD relapse was suspected, she was intravenously administered 400 mg tocilizumab (8 mg/kg) after methylprednisolone pulse therapy at a dose of 1 g/d for 3 days. This regimen improved her symptoms and serum ferritin levels. However, during this therapy, she complained of epigastralgia and melena, and esophagogastroduodenoscopy (EGD) showed peptic ulcers at the pylorus. Therefore, she was prescribed vonoprazan instead of lansoprazole, resulting in immediate symptomatic relief. However, epigastralgia and melena relapsed on day 47. On day 51, a repeat EGD showed multiple ulcers covered with grayish or greenish exudates spreading from the upper body of the stomach toward the fundus (Fig. 1A). Biopsy showed nonseptate hyphae branching at wide angles, indicative of the presence of Mucorales in the gastric mucosa (Fig. 1C) that were stained with Grocott methenamine silver (Fig. 1D). Colony obtained from exudates around gastric ulcers culturing on the Sabouraud dextrose agar at 35°C for 2 days and after that culturing at 25°C for 9 days was white and fuzzy mold colony (Fig. 2A). Colony on the potato dextrose agar plate incubated at 30°C for 4 days was fluffy and white (Fig. 2B). Nonseptate hyphae with round sporangia were observed microscopically (Fig. 2C). The internal transcribed spacer (ITS) region and D1/D2 region of the ribosomal RNA gene of the isolates were sequenced to provide further support.[6,7] As a result, sequences of both the ITS and D1/D2 regions were found to have 100% similarity with Mucor indicus, CBS423.71. The patient was diagnosed with gastric mucormycosis, and intravenous liposomal amphotericin B (L-AMB) was administered at a dose of 200 mg/d (5 mg/kg/d). During the antifungal therapy, oral prednisolone was carefully tapered to 17.5 mg/d, but high serum ferritin levels were sustained between 1789 and 4010 ng/mL. On day 92, EGD revealed shrinking of the ulcers (Fig. 1B). However, the patient complained of left-sided chest pain on day 102, and chest CT identified a pneumothorax that was relieved by inserting a drainage tube into the chest cavity. Additionally, chest CT after the administration of diluted amidotrizoate showed it to be leaking from the stomach into the thoracic cavity, suggesting the presence of a gastropleural fistula (Fig. 3A, B). Surgical correction of the fistula was impossible considering the patient's worsening general condition. Although her thoracic cavity was drained and she was treated with broad-spectrum antibacterial drugs and L-AMB, she died pneumonia on day 159. Autopsy revealed Mucorales infection near the gastric perforation (Fig. 4), and cytomegalovirus pneumonia was considered the possible direct cause of death.\n\nFigure 1 Esophagogastroduodenoscopy findings and biopsy specimens of the gastric mucosa. Necrotic ulcer is covered with gray-greenish exudate at the fornix of stomach (A). The size of the ulcer has reduced after administration of an antifungal drug (B). Histopathologic findings of the gastric ulcer following staining with hematoxylin and eosin stain (C) and Grocott methenamine silver stain (D). White arrowheads indicate nonseptate, right-angle, branched fungal hyphae.\n\nFigure 2 Cultures from exudates of gastric ulcers. Colony on Sabouraud dextrose agar plate cultured 35°C for 2 days and after that culturing at 25°C for 9 days (A). Colony on potato dextrose agar plate cultured at 30°C for 4 days (B). Direct mount from a culture fixed with lactophenol cotton blue at 1000× magnification (C).\n\nFigure 3 Chest computed tomography after administration of diluted amidotrizoate in the coronal (A) and transverse (B) planes. White arrows indicate the gastropleural fistula.\n\nFigure 4 Histopathologic findings on autopsy. Yellow circle indicates invasions of Mucorales at the muscularis propria near the gastropleural fistula.\n\n3 Discussion\nWe describe a case of gastric mucormycosis secondary to immunosuppressive treatment for AOSD. Although the patient was treated with antifungal drugs, the gastric ulcer developed into a gastropleural fistula and the patient died due to pneumonia. Autopsy identified the cause of the fistula to be gastric perforation due to the spread of Mucorales infection from gastric ulcers.\n\nMucormycosis is an acute and fatal fungal infection with a mortality rate of 54% in the world.[3] The risk factors for mucormycosis primarily include neutropenia, diabetes mellitus (DM, especially with ketoacidosis), malignancies, hematopoietic stem-cell transplantation, solitary organ transplantation (SOT), corticosteroid use, iron overload, deferoxamine use, and trauma.[8] In addition, there are several case reports on mucormycosis in patients undergoing biologic therapies,[9,10] for example, one report describes the presence of pulmonary mucormycosis during treatment with tocilizumab.[11] In the case described here, the immunosuppressive therapy administered with high-dose corticosteroids, cyclosporine A, and tocilizumab is a possible risk factor for mucormycosis.\n\nGastrointestinal manifestations of mucormycosis account for only 7% of all cases,[3] with the stomach being the most frequently affected organ.[8] We reviewed 20 reports on gastric mucormycosis (Table 1).[12–30] We identified common symptoms to be melena, hematemesis, and abdominal distention or pain, and most patients had predisposing factors such as DM, SOT, or corticosteroid use. The common site of infection is the upper body of the stomach, and the ulcers have been characterized as having greenish, grayish, or black exudate or necrosis during EGD.\n\nTable 1 A review of previous reports and our case regarding gastric mucormycosis.\n\nAngioinvasion is a characteristic of mucormycosis progression, which probably contributes to its hematogenous dissemination to other organs.[31] Our literature review revealed that 7 of the 9 cases with vessel invasions as per histologic examination resulted in death, suggesting that vessel invasion is a poor prognostic factor. Almyroudis et al reported that a combination of surgery with AMB therapy yielded a better outcome than AMB administration alone in SOT recipients, with mortality rates being 34.3% and 62.5%, respectively.[32] However, during literature review, we found that 5 of 10 cases treated with antifungal drugs and surgical intervention resulted in death. Thus, it is possible that gastric mucormycosis has poor prognosis even with the combined use of surgical treatment and antifungal drug therapy. Notably, we found only 1 case report that described a gastropleural fistula secondary to gastric mucormycosis.[30] In this report, an HIV-positive male developed gastric mucormycosis after experiencing an abdominal trauma, and a postoperative gastropleural fistula developed due to gastric perforation. In our case, the ulcers initially seemed to have improved upon treatment with an antifungal drug, but the outcome remained unfavorable. Nonetheless, it is possible that a combination of surgical resection for gastric mucormycosis and antifungal therapy during the early stages of the disease improves outcomes and prognosis.\n\nMucorales require host iron for hyphal growth during host cell invasion,[33] and 10 of the 20 reported cases on gastric mucormycosis involved peptic ulcers.[34] Possibly, gastric bleeding from peptic ulcers provides iron to Mucorales for growth and a route for angioinvasion. Additionally, hyperferritinemia is a reported poor prognostic factor for mucormycosis,[35] and inflammation due to infection increases storage iron levels through various cytokines and hepcidin.[36] Thus, hyperferritinemia may reflect inflammation due to mucormycosis. Meanwhile, hyperferritinemia mirrors the disease activity of AOSD and is a risk factor for macrophage activation syndrome.[37] In our case, hyperferritinemia was sustained during the clinical course, and it was difficult to distinguish between the disease activity of AOSD and inflammation due to mucormycosis. In such cases, we are of the opinion that the significance of serum ferritin levels should be carefully judged based on clinical course.\n\nIn conclusion, we reported a case of gastric mucormycosis complicated by a gastropleural fistula. In an immunocompromised host, gastric mucormycosis should be considered a cause of refractory gastric ulcers, and it is recommended to confirm Mucorales infection by gastric biopsy and culture of exudates. A mucormycosis is a fatal fungal infection, and antifungal drugs and timely surgical resection are important to manage the disease.\n\nAcknowledgment\nThe authors thank the patient and the family as well as the medical staff for their contribution to the case report.\n\nAuthor contributions\nInvestigation: Momoko Okamoto, Daisuke Yoshikawa, Tomo Mihara, Akira Kondo, Kazuhiro Kurohama, Masahiro Nakashima, Ichiro Sekine, Shigeki Nakamura.\n\nSupervision: Daisuke Yoshikawa, Akinari Mizokami, Kazuo Ohba, Yoshitsugu Miyazaki, Atsushi Kawakami.\n\nWriting – original draft: Tomohisa Uchida.\n\nWriting – review & editing: Keita Fujikawa.\n\nKeita Fujikawa orcid: 0000-0003-2907-5359.\n\nHow to cite this article: Uchida T, Okamoto M, Fujikawa K, Yoshikawa D, Mizokami A, Mihara T, Kondo A, Ohba K, Kurohama K, Nakashima M, Sekine I, Nakamura S, Miyazaki Y, Kawakami A. Gastric mucormycosis complicated by a gastropleural fistula: A case report and review of the literature. Medicine. 2019;98:48(e18142).\n\nAbbreviations: AMB = amphotericin B, AOSD = adult-onset Still disease, CT = computed tomography, DM = diabetes mellitus, EGD = esophagogastroduodenoscopy, ITS = internal transcribed spacer, L-AMB = liposomal amphotericin B, SOT = solitary organ transplantation.\n\nInstitutional ethics review board approval is not required for observational case reports that do not alter patient management. Written informed consent was obtained from the family for publication of this article.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Bitar D Van Cauteren D Lanternier F \nIncreasing incidence of zygomycosis (mucormycosis), France, 1997-2006 . Emerg Infect Dis \n2009 ;15 :1395 –401 .19788806 \n[2] Guinea J Escribano P Vena A \nIncreasing incidence of mucormycosis in a large Spanish hospital from 2007 to 2015: epidemiology and microbiological characterization of the isolates . PLoS One \n2017 ;12 :e0179136 .28591186 \n[3] Roden MM Zaoutis TE Buchanan WL \nEpidemiology and outcome of zygomycosis: a review of 929 reported cases . Clin Infect Dis \n2005 ;41 :634 –53 .16080086 \n[4] Skiada A Lanternier F Groll AH \nDiagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3) . Haematologica \n2013 ;98 :492 –504 .22983580 \n[5] Yamaguchi M Ohta A Tsunematsu T \nPreliminary criteria for classification of adult Still's disease . J Rheumatol \n1992 ;19 :424 –30 .1578458 \n[6] White TJ Bruns T Lee S \nInnis MA Gelfand DH Sninsky JJ White TJ \nAmplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics . PCR Protocols: A Guide to Methods and Applications . New York, NY : Academic Press, Inc ; 1990 \n315 –22 .\n[7] O’Donnell K \nReynolds DR Taylor JW \nFusarium and its near relatives . The Fungal Holomorph: Mitotic, Meiotic and Pleomorphic Speciation in Fungal Systematics . Wallingford, UK : CAB International ; 1993 \n225 –33 .\n[8] Petrikkos G Skiada A Lortholary O \nEpidemiology and clinical manifestations of mucormycosis . Clin Infect Dis \n2012 ;54 :S23 –34 .22247442 \n[9] Abidi MZ Coelho-Prabhu N Hargreaves J \nMucormycosis in patients with inflammatory bowel disease: case series and review of the literature . Case Rep Med \n2014 ;2014 :637492 .24872818 \n[10] Wright AJ Steiner T Bilawich AM \nPulmonary mucormycosis in a patient with Crohn disease on immunosuppressive medications including infliximab . Can J Infect Dis Med Microbiol \n2013 ;24 :67 –8 .24421803 \n[11] Mori S Yoshitama T Hidaka T \nEffectiveness and safety of tocilizumab therapy for patients with rheumatoid arthritis and renal insufficiency: a real-life registry study in Japan (the ACTRA-RI study) . Ann Rheum Dis \n2015 ;74 :627 –30 .25561361 \n[12] Winkler S Susani S Willinger B \nGastric mucormycosis due to Rhizopus oryzae in a renal transplant recipient . J Clin Microbiol \n1996 ;34 :2585 –7 .8880524 \n[13] Corley DA Lindeman N Ostroff JW \nSurvival with early diagnosis of invasive gastric mucormycosis in a heart transplant patient . Gastrointest Endosc \n1997 ;46 :452 –4 .9402122 \n[14] Barroso F Forcelledo JL Mayorga M \nA fatal case of gastric mucormyosis in a heart transplant recipient . Endoscopy \n1999 ;31 :S2 .10223379 \n[15] Cherney CL Chutuape A Fikrig MK \nFatal invasive gastric mucormycosis occurring with emphysematous gastritis: case report and literature review . Am J Gastroenterol \n1999 ;94 :252 –6 .9934766 \n[16] Tinmouth J Baker J Gardiner G \nGastrointestinal mucormycosis in a renal transplant patient . Can J Gastroenterol \n2001 ;15 :269 –71 .11331930 \n[17] Park YS Lee JD Kim TH \nGastric mucormycosis . Gastrointest Endosc \n2002 ;56 :904 –5 .12447307 \n[18] Shahapure AG Patankar RV Bhatkhande R \nGastric mucormycosis . Indian J Gastroenterol \n2002 ;21 :231 –2 .12546179 \n[19] Manchikalapati P Canon CL Jhala N \nGastrointestinal zygomycosis complicating heart and lung transplantation in a patient with Eisenmenger's syndrome . Dig Dis Sci \n2005 ;50 :1181 –3 .15986881 \n[20] Prasad N Ram R Satti Reddy V \nNon-fatal gastric mucormycosis in a renal transplant patient and review of the literature . Transpl Infect Dis \n2006 ;8 :237 –41 .17116140 \n[21] Deja M Wolf S Weber-Carstens S \nGastrointestinal zygomycosis caused by Mucor indicus in a patient with acute traumatic brain injury . Med Mycol \n2006 ;44 :683 –7 .17071566 \n[22] Johnson CB Ahmeti M Tyroch AH \nGastric mucormycosis as a cause of life-threatening upper gastrointestinal bleeding in a trauma patient . Am Surg \n2010 ;76 :E76 –7 .21683003 \n[23] Rudler M Barret M Poynard T \nGastric mucormycosis: a rare cause of gastrointestinal bleeding in cirrhosis . Clin Res Hepatol Gastroenterol \n2012 ;36 :e32 –3 .22138061 \n[24] Ryan O Frohlich S Crotty TB \nRhizopus microsporus infection in an immunocompetent host: a case of immunoparalysis? \nAnaesth Intensive Care \n2012 ;40 :367 –8 .22417051 \n[25] Bini R Addeo A Maganuco L \nThe role of surgery in a case of diffuse mucormycosis with haematemesis and gastric necrosis . Ann R Coll Surg Engl \n2014 ;96 :e31 –3 .24992411 \n[26] Kaiser P Maggio EM Pfammatter T \nHistopathological evidence of invasive gastric mucormycosis after transarterial chemoembolization and liver transplantation . Infection \n2014 ;42 :779 –83 .24595492 \n[27] Raviraj KS Miglani P Garg A \nGastric mucormycosis with hemolytic uremic syndrome . J Assoc Physicians India \n2015 ;63 :75 –6 .\n[28] Tathe SP Dani AA Chawhan SM \nGastric mucormycosis: diagnosis by imprint cytology . Diagn Cytopathol \n2016 ;44 :820 –2 .27321416 \n[29] Sanchez Velazquez P Pera M Gimeno J \nMucormycosis: an unusual cause of gastric perforation and severe bleeding in immunocompetent patients . Rev Esp Enferm Dig \n2017 ;109 :223 –5 .27088595 \n[30] Chow KL McElmeel DP Brown HG \nInvasive gastric mucormycosis: a case report of a deadly complication in an immunocompromised patient after penetrating trauma . Int J Surg Case Rep \n2017 ;40 :90 –3 .28946029 \n[31] Ibrahim AS Spellberg B Walsh TJ \nPathogenesis of mucormycosis . Clin Infect Dis \n2012 ;54 :S16 –22 .22247441 \n[32] Almyroudis NG Sutton DA Linden P \nZygomycosis in solid organ transplant recipients in a tertiary transplant center and review of the literature . Am J Transplant \n2006 ;6 :2365 –74 .16925570 \n[33] Baldin C Ibrahim AS \nMolecular mechanisms of mucormycosis—the bitter and the sweet . PLoS Pathog \n2017 ;13 :e1006408 .28771587 \n[34] Thomson SR Bade PG Taams M \nGastrointestinal mucormycosis . Br J Surg \n1991 ;78 :952 –4 .1913115 \n[35] Spellberg B Kontoyiannis DP Fredricks D \nRisk factors for mortality in patients with mucormycosis . Med Mycol \n2012 ;50 :611 –8 .22435877 \n[36] Weiss G Schett G \nAnaemia in inflammatory rheumatic diseases . Nat Rev Rheumatol \n2013 ;9 :205 –15 .23147894 \n[37] Mitrovic S Fautrel B \nNew markers for adult-onset Still's disease . Joint Bone Spine \n2018 ;85 :285 –93 .28529117\n\n",
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"issn_linking": "0025-7974",
"issue": "98(48)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000369:Aged, 80 and over; D005260:Female; D005747:Gastric Fistula; D006801:Humans; D007166:Immunosuppressive Agents; D009091:Mucormycosis; D009894:Opportunistic Infections; D010994:Pleura; D016156:Respiratory Tract Fistula; D016706:Still's Disease, Adult-Onset; D013276:Stomach Ulcer",
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"title": "Gastric mucormycosis complicated by a gastropleural fistula: A case report and review of the literature.",
"title_normalized": "gastric mucormycosis complicated by a gastropleural fistula a case report and review of the literature"
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"abstract": "OBJECTIVE\nThe purpose of this report is to describe the management and outcome of an unusual complication of a commonly used chemotherapeutic agent. Gemcitabine is a known risk factor for hemolytic uremic syndrome (HUS), which can often have a rapidly fatal clinical course despite intervention with steroids, plasmapheresis and hemodialysis.\n\n\nMETHODS\nA retrospective report of the first case of gemcitabine-related HUS, in a patient with metastatic pancreatic adenocarcinoma, treated with a variety of standard therapies in addition to rituximab is presented. The hematologic response parameters and clinical outcomes to each of the therapies given are described.\n\n\nRESULTS\nChemotherapy-induced HUS was aggressively treated with plasmapheresis, high-dose steroids, vincristine and rituximab. Platelet recovery and clinical improvement coincided with administration of rituximab. In addition, aggressive supportive measures to manage renal failure (hemodialysis) and labile hypertension, allowed this patient to have an extended survival as a result of successful therapy for this complication despite an underlying rapidly fatal malignancy.\n\n\nCONCLUSIONS\nThis case highlights the importance of timely application of aggressive measures even in patients with known diagnosis of a fatal malignancy as these interventions can prolong life and be of palliative benefit.",
"affiliations": "Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.",
"authors": "Bharthuar|Anubha|A|;Egloff|Lori|L|;Becker|Joanne|J|;George|Marina|M|;Lohr|James W|JW|;Deeb|George|G|;Iyer|Renuka V|RV|",
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"mesh_terms": "D000230:Adenocarcinoma; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D005260:Female; D005938:Glucocorticoids; D006463:Hemolytic-Uremic Syndrome; D006801:Humans; D007155:Immunologic Factors; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D010956:Plasmapheresis; D012189:Retrospective Studies; D000069283:Rituximab; D014750:Vincristine",
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"title": "Rituximab-based therapy for gemcitabine-induced hemolytic uremic syndrome in a patient with metastatic pancreatic adenocarcinoma: a case report.",
"title_normalized": "rituximab based therapy for gemcitabine induced hemolytic uremic syndrome in a patient with metastatic pancreatic adenocarcinoma a case report"
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"abstract": "Ischaemic colitis (IC) is the most frequent form of ischaemia of the digestive tract. Due to the worldwide increasing use of medications, there is a growing interest in drug-induced IC. This study reports a rare case of IC directly due to amoxicillin-clavulanate intake. The objective of the study was to describe the evolution of this novel manifestation. An 18-year-old man, non-smoker, with an insignificant medical history, presented with diarrhoea and cramping abdominal pain that started the day following the end of a 10-day amoxicillin-clavulanate course for recent upper respiratory tract infection. Stool cultures including Clostridium difficile toxin testing were negative. Colonoscopy documented an erosive-ulcerative colitis of the sigmoid and the descending colon. Histological examination of the colon biopsies revealed an IC with focal pseudomembranous areas in the descending-sigmoid colon. Thrombophilia screening tests were negative. The patient was discharged from the hospital without symptoms, and another colonoscopy was performed 3 weeks after the previous one, which documented normal endoscopic and histological findings. Amoxicillin-clavulanate IC is a very rare condition and should be suspected once infectious diseases, vascular/haemodynamic causes and a prothrombotic/hypercoagulable state have been excluded. Immediate discontinuation of the antibiotic leads to rapid disease remission.",
"affiliations": "Gastroenterology Unit, Department of Clinical and Experimental Sciences, University of Brescia and Spedali Civili, Brescia, Italy.;Gastroenterology Unit, Department of Clinical and Experimental Sciences, University of Brescia and Spedali Civili, Brescia, Italy.;Gastroenterology Unit, Department of Clinical and Experimental Sciences, University of Milan and Spedali Civili, Brescia, Italy.;Gastroenterology Unit, Department of Clinical and Experimental Sciences, University of Brescia and Spedali Civili, Brescia, Italy.;Digestive Endoscopy Unit, Department of Clinical and Experimental Sciences, University of Brescia and Spedali Civili, Brescia, Italy.;Pathological Anatomy Division, Department of Molecular and Translational Medicine, University of Brescia and Spedali Civili, Brescia, Italy.;Gastroenterology Unit, Department of Clinical and Experimental Sciences, University of Brescia and Spedali Civili, Brescia, Italy.",
"authors": "Alonge|Marco|M|;Benini|Federica|F|;Cannatelli|Rosanna|R|;Pozzi|Alessandro|A|;Missale|Guido|G|;Villanacci|Vincenzo|V|;Ricci|Chiara|C|",
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"fulltext": "\n==== Front\nCase Rep Gastroenterol\nCase Rep Gastroenterol\nCRG\nCase Reports in Gastroenterology\n1662-0631 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000507014\ncrg-0014-0242\nSingle Case\nAmoxicillin-Clavulanate-Induced Ischaemic Colitis\nAlonge Marco a* Benini Federica a Cannatelli Rosanna b Pozzi Alessandro a Missale Guido c Villanacci Vincenzo d Ricci Chiara a aGastroenterology Unit, Department of Clinical and Experimental Sciences, University of Brescia and Spedali Civili, Brescia, Italy\nbGastroenterology Unit, Department of Clinical and Experimental Sciences, University of Milan and Spedali Civili, Brescia, Italy\ncDigestive Endoscopy Unit, Department of Clinical and Experimental Sciences, University of Brescia and Spedali Civili, Brescia, Italy\ndPathological Anatomy Division, Department of Molecular and Translational Medicine, University of Brescia and Spedali Civili, Brescia, Italy\n*Chiara Ricci, Gastroenterology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili, Piazzale Spedali Civili, 1, IT–25123 Brescia (Italy), chiara.ricci@unibs.it\nJan-Apr 2020 \n29 4 2020 \n29 4 2020 \n14 1 242 247\n15 2 2020 5 3 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Ischaemic colitis (IC) is the most frequent form of ischaemia of the digestive tract. Due to the worldwide increasing use of medications, there is a growing interest in drug-induced IC. This study reports a rare case of IC directly due to amoxicillin-clavulanate intake. The objective of the study was to describe the evolution of this novel manifestation. An 18-year-old man, non-smoker, with an insignificant medical history, presented with diarrhoea and cramping abdominal pain that started the day following the end of a 10-day amoxicillin-clavulanate course for recent upper respiratory tract infection. Stool cultures including Clostridium difficile toxin testing were negative. Colonoscopy documented an erosive-ulcerative colitis of the sigmoid and the descending colon. Histological examination of the colon biopsies revealed an IC with focal pseudomembranous areas in the descending-sigmoid colon. Thrombophilia screening tests were negative. The patient was discharged from the hospital without symptoms, and another colonoscopy was performed 3 weeks after the previous one, which documented normal endoscopic and histological findings. Amoxicillin-clavulanate IC is a very rare condition and should be suspected once infectious diseases, vascular/haemodynamic causes and a prothrombotic/hypercoagulable state have been excluded. Immediate discontinuation of the antibiotic leads to rapid disease remission.\n\nKeywords\nIschaemic colitisAmoxicillin-clavulanatePseudomembranesPseudomembranous ischaemic colitis\n==== Body\nIntroduction\nIschaemic colitis (IC) is the most frequent form of ischaemia of the digestive tract, even if it is often misdiagnosed because of its temporary, mild clinical manifestation and the similarity to other diseases such as infectious colitis or inflammatory bowel disease. The incidence of IC has considerably risen over the years: from 6.1 cases/100,000 person-years in 1976–1980 to 22.9/100,000 in 2005–2009 [1]. Its prevalence increases with age and comorbidity [1]. It is usually difficult to determine the precise site of the ischaemic insult; however, we should suspect IC in elderly patients with small vessel disease and various comorbidities. Most of cases occur in patients over 60 years, although younger patients may also be affected [2].\n\nA lot of conditions may induce IC: arterial emboli, thrombosis or trauma [3]; hypoperfusion states and shock due to a variety of causes such as hypovolaemia or sepsis [4]; and mechanical colonic obstruction due to tumours, adhesions, volvuli, hernias, diverticulitis or prolapse [4]. Drug-induced IC is also a well-represented entity. Several classes of pharmacologic agents are associated with IC [5]: appetite suppressants like phentermine, chemotherapeutic agents like vinca alkaloids and taxanes, constipation-inducing medications, decongestants like pseudoephedrine, cardiac glucosides, diuretics, ergot alkaloids, hormonal therapies, statins, illicit drugs, immunosuppressive agents, laxatives, non-steroidal anti-inflammatory drugs, psychotropic medications, serotonin agonists/antagonists, vasopressors and antibiotics. IC is a rising condition among drug-induced adverse effects and diseases.\n\nThis study reports a rare case of pseudomembranous IC directly due to amoxicillin-clavulanate intake. Pseudomembranes, seen on histological examination, represented an early manifestation of IC. The objectives of the study were to describe the evolution of this novel manifestation. Even if more studies on this issue are required, we documented complete clinical and histological remission after antibiotic discontinuation. There is only 1 case of amoxicillin-related IC in the literature, but it is described as an effect of anaphylactic shock due to antibiotic allergy [6].\n\nCase Report\nThis is a report on an 18-year-old man with an insignificant past medical history, non-smoker, and with recent upper respiratory tract infection, treated with a course of antibiotics. One amoxicillin-clavulanate 875/125 mg film-coated tablet had been administered orally twice daily for 10 days, according to the general practitioner's prescription. During the night following the final day of antibiotic course, the patient developed diarrhoea with cramping and stabbing abdominal pain, mostly localised in the lower abdominal quadrants. The following days, the patient experienced passing of frequent watery stools, about 15 times a day, with bowel movement-induced abdominal pain, in the absence of nausea, fever or vomiting. For this reason, the patient decided to go to the hospital. He referred regular intestinal transit, with no abdominal distress or discomfort, in the past years, but also a family history of colorectal cancer and Crohn's disease. The patient denied eating unsafe food, recent trips abroad or non-steroidal anti-inflammatory drug intake.\n\nThe standard haematologic tests and blood chemistry tests showed leucocytosis (WBC 13,520/μL), a slight increase in C-reactive protein (CRP) levels (CRP 9.2 mg/L) and hypokalaemia (K+ 3.1 mmol/L). We then performed a colonoscopy, which documented erosive-ulcerative colitis of the sigmoid and the descending colon (Fig. 1), with a normal rectal mucosal surface. Histological examination of the colon biopsies revealed a normal rectal mucosa with prolapsed areas and an IC appearance (coagulative necrosis of the superficial epithelium) with focal pseudomembranous areas (aggregates of hyaline material intermingled with eosinophils) in the descending-sigmoid colon (Fig. 2). During hospitalisation, the laboratory tests showed a rapid decrease in CRP (CRP <2.90 mg/L) and leucocyte count (WBC 4,550/μL), as well as clinical remission of symptoms like diarrhoea and abdominal pain. Stool cultures, including Clostridium difficile (CD) toxin testing, were negative. Thrombophilia screening tests (protein C, protein S, lupus anticoagulant, D-dimer test, factor II mutation, factor V mutation and anti-cardiolipin antibodies) were also performed to exclude a prothrombotic/hypercoagulable state, with negative results.\n\nThe patient was asymptomatic when discharged from the hospital. Colonoscopy performed 3 weeks after antibiotic discontinuation did not reveal any pathological finding. The colonic luminal surface seen during the colonoscopy and the histological examination of the biopsies were both totally normal.\n\nDiscussion\nBeta-lactams represent the most commonly prescribed antibiotic class and are often associated with various adverse manifestations: immunoglobulin E-mediated type I reactions, serum sickness, and dermatologic, neurologic, pulmonary, hepatobiliary, renal, haematologic and gastrointestinal reactions. Diarrhoea is a common complication of antibiotic therapy, most frequently caused by oral antibiotics such as ampicillin or amoxicillin [7]. All antibiotics can predispose to CD colitis, especially ampicillin among the class of beta-lactams [8].\n\nAmong amoxicillin-clavulanate-related reactions, diarrhoea is the most frequent manifestation (3–34% of cases) and its incidence varies depending on the dose and regimen used. A very small percentage (<1%) of adverse manifestations are presented in post-marketing and case reports. Only 1 case of IC secondary to amoxicillin-clavulanate has been reported in the literature, even if caused by the hypotensive state suffered during the anaphylactic episode induced by antibiotic intake [6].\n\nIt is well known that the spectrum of clinical IC manifestations is heterogeneous, including mild and reversible forms, acute forms like pseudomembranous colitis (PMC), chronic diseases and fulminant pancolitis. The same heterogeneity is seen on histological examination, and the diverse microscopic aspects are surely influenced by the severity of ischaemic damage and by the time elapsed since the initial injury. Pseudopolyps are a direct effect of submucosal injury, whereas pseudomembranes occur subsequently, when rapid mucosal reperfusion leads to a localised inflammatory response. The pseudomembranes on the mucosa are formed by expulsion of inflammatory infiltrate from the lamina propria onto the luminal surface. PMC tends to be usually associated with CD infection, but it is also associated and caused by ischaemia. Ischaemia-related PMC is rarer and more difficult to diagnose, because pseudomembranes are mostly seen in the early phases of the ischaemic process [9]. A prospective, multicentre study on 364 patients diagnosed with IC showed ulcers with pseudomembranes in 13.1% of the endoscopic biopsies and 24% of the surgical biopsies; this finding was statistically significantly more common in the first 48 h of presentation [9].\n\nAccording to these data, in our case the colonoscopy with biopsies was performed within the first 48 h after symptom onset, and the pseudomembranes were detected only by histological microscopic examination. In this case, the relationship between antibiotic intake and symptom onset helped us to suspect an adverse drug reaction. Given the recent medical history of the patient, our suspicion was an adverse reaction to amoxicillin-clavulanate, which was the only drug administered immediately before the IC outbreak; the antibiotic may have triggered a local vascular reaction that damaged the colonic mucosa. After excluding any smoking habit, which is a well-known risk factor for IC, thrombophilia screening tests were performed to be sure that no prothrombotic state underlay the ischaemic condition of the colitis. In addition, the sudden remission from the symptoms with a rapid decrease in inflammatory indexes as well as the histological report let us exclude an onset of inflammatory bowel disease. The two aspects confirming the hypothesis of a drug-related condition were the histological finding of a pseudomembranous IC (CD negative) and the complete endoscopic remission after a brief period of 3 weeks since amoxicillin-clavulanate withdrawal. In this specific case, the IC went rapidly into remission with antibiotic discontinuation; the pseudomembranes seen only on microscopic examination represented an early marker of IC.\n\nIn conclusion, IC is a widely heterogeneous disease which may highlight vascular or haemodynamic problems. Once these causes have been assessed and excluded, drug-induced IC should be considered. Amoxicillin-clavulanate may cause antibiotic-induced IC, which, according to our experience, tends to be self-limiting after drug discontinuation. The described clinical report underlines the potential unusual side effects of antibiotics routinely used; prompt withdrawal of the medication may limit significant disease morbidity and mortality.\n\nStatement of Ethics\nAll procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent for publication of the clinical details and clinical images was obtained from the patient. A copy of the consent form is available for review by the editor of this journal.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nThis case report received no funding support for its preparation.\n\nAuthor Contributions\nM.A.: literature research, writing and editing the manuscript; F.B.: clinical management of the patient, revision and final approval of the manuscript; A.P., G.M. and V.V.: revision and final approval of the manuscript; C.R.: revision and critical review and approval of the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgments\nThe authors received no financial support for the research, authorship and/or publication of this article.\n\nFig. 1 Colonoscopy image showing an oedematous and hyperaemic mucosa of the sigmoid tract with multiple erosions and ulcerations, tending to be confluent and circumferential.\n\nFig. 2 Histological examination of the descending-sigmoid colon biopsies showed ischaemic colitis (A, arrow) with focal pseudomembranous areas (B, arrows): highly hyperplastic glandular elements mixed with atrophic crypt elements immersed in a homogeneously inflamed and vascularised lamina propria with erosion of the surface's coat, in which there were mixed inflammatory elements like neutrophils and most of all eosinophils. HE. ×20.\n==== Refs\nReferences\n1 Yadav S Dave M Edakkanambeth Varayil J Harmsen WS Tremaine WJ Zinsmeister AR A population-based study of incidence, risk factors, clinical spectrum, and outcomes of ischemic colitis Clin Gastroenterol Hepatol 2015 4 13 (4) 731 8.e1 25130936 \n2 Binns JC Isaacson P Age-related changes in the colonic blood supply: their relevance to ischaemic colitis Gut 1978 5 19 (5) 384 90 658768 \n3 Gandhi SK Hanson MM Vernava AM Kaminski DL Longo WE Ischemic colitis Dis Colon Rectum 1996 1 39 (1) 88 100 8601363 \n4 Green BT Tendler DA Ischemic colitis: a clinical review South Med J 2005 2 98 (2) 217 22 15759953 \n5 Hass DJ Kozuch P Brandt LJ Pharmacologically mediated colon ischemia Am J Gastroenterol 2007 8 102 (8) 1765 80 17488249 \n6 Pérez-Carral C Carreira J Vidal C Acute ischaemic colitis due to hypotension and amoxicillin allergy Postgrad Med J 2004 5 80 (943) 298 9 15138324 \n7 Gillies M Ranakusuma A Hoffmann T Thorning S McGuire T Glasziou P Common harms from amoxicillin: a systematic review and meta-analysis of randomized placebo-controlled trials for any indication CMAJ 2015 1 187 (1) E21 31 25404399 \n8 Kelly CP Pothoulakis C LaMont JT Clostridium difficile colitis N Engl J Med 1994 1 330 (4) 257 62 8043060 \n9 Montoro MA Brandt LJ Santolaria S Gomollon F Sánchez Puértolas B Vera J Workgroup for the Study of Ischaemic Colitis of the Spanish Gastroenterological Association (GTECIE-AEG) Clinical patterns and outcomes of ischaemic colitis: results of the Working Group for the Study of Ischaemic Colitis in Spain (CIE study) Scand J Gastroenterol 2011 2 46 (2) 236 46 20961178\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "14(1)",
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"keywords": "Amoxicillin-clavulanate; Ischaemic colitis; Pseudomembranes; Pseudomembranous ischaemic colitis",
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"title": "Amoxicillin-Clavulanate-Induced Ischaemic Colitis.",
"title_normalized": "amoxicillin clavulanate induced ischaemic colitis"
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"abstract": "A 72-year-old man presented with a short history of headache, jaw claudication, double vision, amaurosis fugax and distended temporal arteries. A diagnosis of giant cell arteritis (GCA) was confirmed on temporal artery ultrasound and temporal artery biopsy. Despite treatment with high-dose oral glucocorticoid (GC) and multiple pulses of intravenous methylprednisolone, his vision deteriorated to hand movements in one eye. 8 mg/kg intravenous tocilizumab, a humanised, recombinant anti-IL-6 receptor antibody, was administered within 48 hours of vision loss and continued monthly, resulting in marked visual improvement within days, as well as sustained remission of GCA. This case suggests a possible role for tocilizumab as a rescue therapy to prevent or recover visual loss in patients with GCA resistant to GC treatment, termed refractory GCA. Further research is required to elucidate the role of intravenous administration of tocilizumab in this setting.",
"affiliations": "Ophthalmology, Luton and Dunstable University Hospital NHS Foundation Trust, Luton, UK.;Neuro-Ophthalmology Unit, Ophthalmology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.;Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, UK.;Rheumatology, Luton and Dunstable University Hospital NHS Foundation Trust, Luton, UK.",
"authors": "Svasti-Salee|Carl Richard|CR|;Mollan|Susan P|SP|;Morgan|Ann W|AW|;Quick|Vanessa|V|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005938:Glucocorticoids; C502936:tocilizumab",
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"issue": "12(10)",
"journal": "BMJ case reports",
"keywords": "Ophthalmology; Rheumatology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D003937:Diagnosis, Differential; D004172:Diplopia; D004334:Drug Administration Schedule; D004351:Drug Resistance; D013700:Giant Cell Arteritis; D005938:Glucocorticoids; D006261:Headache; D006801:Humans; D008297:Male; D013699:Temporal Arteries",
"nlm_unique_id": "101526291",
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"pmid": "31586951",
"pubdate": "2019-10-05",
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"references": "10852275;30287521;28745999;1469092;28499892;12190776;28905861;17665429;20210989;12792130;2202311;15878052;23240123;20371504;22693300;21360492;29112741;29982779;9063237;27925577;26952547;17009270;9433866;27599663;16884778;25081291;12623817;22965672;11520757;15106952;15525846;15885780;18413441;15818722",
"title": "Rapid visual recovery following intravenous tocilizumab in glucocorticoid resistant refractory giant cell arteritis.",
"title_normalized": "rapid visual recovery following intravenous tocilizumab in glucocorticoid resistant refractory giant cell arteritis"
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"druga... |
{
"abstract": "The established treatment algorithms for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are currently challenged by novel classes of drugs, with ibrutinib being one of the most effective. Published data suggest that patients with early progression under ibrutinib often emerge as having Richter's transformation (RT) with a rapidly fatal prognosis, mostly developing diffuse large B-cell lymphoma (DLBCL). In this respect, it is known that RT to large DLBCL occurs in about 5% of patients with CLL during the disease course and less frequently to Hodgkin lymphoma (HL). Here, we report a patient with CLL who presented with HL transformation while still receiving therapy with ibrutinib stressing the need for clinical vigilance in any case with persisting or enlarging lymph nodes during treatment with this agent, as prompt modification of therapy is most important.",
"affiliations": "Department of Hematology, Athens Medical Center, Psychikon Branch, Athens, Greece ssachanas@gmail.com.;Department of Hematology, Athens Medical Center, Psychikon Branch, Athens, Greece.;Department of Hematology, Athens Medical Center, Psychikon Branch, Athens, Greece.;Department of Hematology, Athens Medical Center, Psychikon Branch, Athens, Greece.;Department of Hematology, Athens Medical Center, Psychikon Branch, Athens, Greece.;Department of Hematology, Athens Medical Center, Psychikon Branch, Athens, Greece.;Department of Hematology, Heraklion University Hospital, University of Crete, Heraklion, Greece.;Department of Anatomic Pathology, Evangelismos General Hospital, University of Athens, Athens, Greece.",
"authors": "Sachanas|Sotirios|S|;Pangalis|Gerassimos A|GA|;Moschogiannis|Maria|M|;Yiakoumis|Xanthi|X|;Koulieris|Efstathios|E|;Tsirkinidis|Pantelis|P|;Kalpadakis|Christina|C|;Rontogianni|Dimitra|D|",
"chemical_list": "D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.11692",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "37(6)",
"journal": "Anticancer research",
"keywords": "Chronic lymphocytic leukemia; Hodgkin lymphoma; Richter's syndrome; ibrutinib",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000225:Adenine; D000368:Aged; D000970:Antineoplastic Agents; D001706:Biopsy; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D006689:Hodgkin Disease; D006801:Humans; D007150:Immunohistochemistry; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "3277-3280",
"pmc": null,
"pmid": "28551676",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hodgkin Lymphoma Transformation of Chronic Lymphocytic Leukemia Under Ibrutinib Therapy: Chance Association or Therapy-related?",
"title_normalized": "hodgkin lymphoma transformation of chronic lymphocytic leukemia under ibrutinib therapy chance association or therapy related"
} | [
{
"companynumb": "GR-TEVA-783664ROM",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null,
... |
{
"abstract": "T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T-LBL/T ALL) is an aggressive hematological malignancy arising from malignant transformation of T-cell progenitors with poor prognosis in adult patients. Outcomes are particularly dismal in the relapsed/refractory setting, and therapeutic options are limited in this context. Genomic profiling has shown frequent aberrations in the JAK-STAT pathway, including recurrent mutations in JAK3 (15%-20% of T-ALL cases), suggesting that JAK kinase inhibition may be a promising therapeutic approach. Activating JAK3 mutations are capable of transforming cytokine-dependent progenitor cells in vitro and causing T-ALL-like disease when expressed in hematopoietic progenitors in vivo. We describe a case of relapsed T-ALL in an adult patient, with two JAK3 activating mutations identified by whole-exome sequencing (WES), leading to hypothesis-based treatment with the JAK1 and JAK3 inhibitor, tofacitinib, following failure of salvage chemotherapy reinduction. Despite the molecularly targeted rationale, tofacitinib did not induce an objective clinical response. Our report suggests that the presence of activating JAK3 mutations does not necessarily confer sensitivity to pharmacological JAK3 inhibition.",
"affiliations": "Department of Hematology, Monash Health, Clayton, 3168, Victoria, Australia.;School of Clinical Sciences, Monash University, Clayton, 3168, Victoria, Australia.;Department of Hematology, Monash Health, Clayton, 3168, Victoria, Australia.;Monash Pathology, Monash Health, Clayton, 3168, Victoria, Australia.;Department of Hematology, Monash Health, Clayton, 3168, Victoria, Australia.;Department of Hematology, Monash Health, Clayton, 3168, Victoria, Australia.;Department of Hematology, Monash Health, Clayton, 3168, Victoria, Australia.",
"authors": "Wong|Jonathan|J|0000-0003-2974-8023;Wall|Meaghan|M|0000-0001-9711-0705;Corboy|Gregory Philip|GP|0000-0001-9888-5203;Taubenheim|Nadine|N|;Gregory|Gareth Peter|GP|0000-0002-4170-0682;Opat|Stephen|S|0000-0002-0308-6458;Shortt|Jake|J|0000-0003-3185-6488",
"chemical_list": "C092513:MLLT10 protein, human; D010880:Piperidines; D011743:Pyrimidines; D014157:Transcription Factors; C479163:tofacitinib; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases",
"country": "United States",
"delete": false,
"doi": "10.1101/mcs.a004994",
"fulltext": "\n==== Front\nCold Spring Harb Mol Case Stud\nCold Spring Harb Mol Case Stud\ncshmcs\ncshmcs\ncshmcs\nCold Spring Harbor Molecular Case Studies\n2373-2873 Cold Spring Harbor Laboratory Press \n\n32843425\n10.1101/mcs.a004994\nMCS004994Won\nResearch Report\nFailure of tofacitinib to achieve an objective response in a DDX3X-MLLT10 T-lymphoblastic leukemia with activating JAK3 mutations\nTofacitinib in JAK3-mutated T-lymphoblastic leukemiaTofacitinib in JAK3-mutated T-lymphoblastic leukemiahttp://orcid.org/0000-0003-2974-8023Wong Jonathan 12 http://orcid.org/0000-0001-9711-0705Wall Meaghan 2345 http://orcid.org/0000-0001-9888-5203Corboy Gregory Philip 126 Taubenheim Nadine 57 http://orcid.org/0000-0002-4170-0682Gregory Gareth Peter 12 http://orcid.org/0000-0002-0308-6458Opat Stephen 12 http://orcid.org/0000-0003-3185-6488Shortt Jake 12 1 Department of Hematology, Monash Health, Clayton, 3168, Victoria, Australia;\n2 School of Clinical Sciences, Monash University, Clayton, 3168, Victoria, Australia;\n3 Victorian Cancer Cytogenetics Service, St Vincent's Hospital, Fitzroy, 3065, Victoria, Australia;\n4 St Vincent's Institute, Fitzroy, 3065, Victoria, Australia;\n5 Monash Pathology, Monash Health, Clayton, 3168, Victoria, Australia;\n6 Department of Clinical Pathology, The University of Melbourne, Parkville, 3010, Victoria, Australia;\n7 Center for Cancer Research, Hudson Institute of Medical Research, Clayton, 3168, Victoria, Australia\nCorresponding author: jonathan.wong@monashhealth.org\n8 2020 \n6 4 a00499419 11 2019 5 6 2020 © 2020 Wong et al.; Published by Cold Spring Harbor Laboratory Press2020This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T-LBL/T ALL) is an aggressive hematological malignancy arising from malignant transformation of T-cell progenitors with poor prognosis in adult patients. Outcomes are particularly dismal in the relapsed/refractory setting, and therapeutic options are limited in this context. Genomic profiling has shown frequent aberrations in the JAK-STAT pathway, including recurrent mutations in JAK3 (15%–20% of T-ALL cases), suggesting that JAK kinase inhibition may be a promising therapeutic approach. Activating JAK3 mutations are capable of transforming cytokine-dependent progenitor cells in vitro and causing T-ALL-like disease when expressed in hematopoietic progenitors in vivo. We describe a case of relapsed T-ALL in an adult patient, with two JAK3 activating mutations identified by whole-exome sequencing (WES), leading to hypothesis-based treatment with the JAK1 and JAK3 inhibitor, tofacitinib, following failure of salvage chemotherapy reinduction. Despite the molecularly targeted rationale, tofacitinib did not induce an objective clinical response. Our report suggests that the presence of activating JAK3 mutations does not necessarily confer sensitivity to pharmacological JAK3 inhibition.\n\nhematological neoplasmleukemiaT-cell acute lymphoblastic leukemiasState Government of Victoria 10.13039/501100004752Monash Health Emerging Researcher Fellowship\n==== Body\nINTRODUCTION\nT-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T-LBL/T-ALL) is an aggressive hematological malignancy arising from malignant transformation of T-cell progenitors that accounts for 15% of pediatric and 25% adult ALL cases (Borowitz et al. 2017). Although childhood T-ALL remission rates and long-term survival have steadily improved, prognosis in adult patients remains poor, particularly in relapsed or refractory cases. Consequently, more effective treatment is urgently needed in this patient group, and recently developed therapies with novel mechanisms of action are currently under investigation.\n\nThe DDX3X-MLLT10 fusion is a primary abnormality in T-ALL and cases harboring this fusion cluster within the HOXA subgroup by gene expression profiling (Brandimarte et al. 2013). Genomic profiling studies in T-ALL have shown frequent aberrations within the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, such as recurrent mutations in JAK1 and JAK3, suggesting that JAK kinase inhibition may be a promising therapeutic approach. JAK1/JAK3 mutations are recurrent and enriched in the HOXA subgroup and in patients with MLLT10 gene rearrangements, but JAK1/JAK3 mutations do not appear to have been described previously in DDX3X-MLLT10 T-ALL (Liu et al. 2017). JAK3 mutations are present in 15%–20% of T-ALL cases (Bains et al. 2012; De Keersmaecker et al. 2012; Kalender Atak et al. 2012, 2013; Zhang et al. 2012; Yin et al. 2014; Greenplate et al. 2018). Activating (gain-of-function) JAK3 mutations induce constitutive JAK activation and STAT phosphorylation and have also been identified in other hematological malignancies including T-cell and myeloid neoplasms (Cornejo et al. 2009). Mutant JAK3 is capable of transforming cytokine-dependent progenitor cells in vitro and causing T-ALL-like disease when expressed in hematopoietic progenitors in vivo (Degryse et al. 2014).\n\nHere, we report the identification of two JAK3 activating mutations by whole-exome sequencing (WES) in a patient presenting with relapsed T-ALL with DDX3X-MLLT10 fusion, leading to hypothesis-based treatment with the JAK1 and JAK3 inhibitor, tofacitinib. Despite the molecularly targeted rationale, tofacitinib did not induce an objective clinical response. We conclude that the presence of activating JAK3 mutations does not necessarily evoke sensitivity to pharmacological JAK3 inhibition.\n\nRESULTS\nClinical Presentation\nA 69-yr-old woman presented with exertional dyspnea and pruritus. A mediastinal mass was identified on computerized tomography (CT) imaging.\n\nTransbronchial cryobiopsy of the mediastinal mass identified diffuse sheets of intermediate-sized, atypical lymphoid cells with minimal cytoplasm and enlarged hyperchromatic nuclei, expressing CD3, CD4, CD7, CD10, and TdT by immunohistochemical staining, consistent with a diagnosis of T-lymphoblastic lymphoma (T-LBL). Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging confirmed nodal disease limited to the mediastinum and left hilum, in keeping with Ann Arbor stage II. There was no evidence of extranodal involvement on bone marrow biopsy and magnetic resonance imaging of the central nervous system. She commenced treatment with HyperCVAD/methotrexate-cytarabine induction chemotherapy (Kantarjian et al. 2004) and achieved complete structural and metabolic remission after four cycles, followed by consolidative radiotherapy to the mediastinal mass. Allogeneic stem cell transplant was discussed with the patient at this point but was not pursued on the basis of her advanced age and treatment preferences.\n\nThe patient presented eight months later with fatigue. Full blood examination revealed circulating medium-sized blasts comprising 81% of nucleated cellularity accompanied by pancytopenia: hemoglobin 6.4 g/dL, absolute neutrophil count 0.01 × k/µL, platelet count 9 × k/µL. A bone marrow aspirate and trephine biopsy were obtained for morphologic assessment, flow cytometry, fluorescence in situ hybridization (FISH), and chromosome studies. The marrow was markedly hypercellular (90%) and predominantly composed of lymphoblasts (90%–95% of marrow cellularity) with reduced trilineage hematopoiesis (Fig. 1A). Flow cytometry of the bone marrow aspirate demonstrated a blast population comprising 99% of leukocytes, which expressed the following antigens: CD1a (partial dim), cCD3, CD4 (dim), CD5 (dim), CD7, CD10, and TdT. Blasts were negative for CD19 and MPO. The morphologic and immunophenotypic features confirmed relapsed T-ALL.\n\nFigure 1. (A) Routinely stained bone marrow aspirate specimen obtained at relapse demonstrates marked hypercellularity predominantly comprised of medium-sized blasts. Magnification, 40×. (B–D) Immunohistochemical stain performed with anti-BCL2 antibody (clone SP66, Ventana Roche) on formalin-fixed, paraffin-embedded tissue of bone marrow core biopsy specimen obtained at relapse demonstrates uniformly strong BCL2 expression in leukemic blasts (B); normal bone marrow core biopsy specimen as control (C); bone marrow core biopsy specimen with follicular non-Hodgkin lymphoma demonstrating BCL2 positive lymphoma cells (D). Magnification, 40×.\n\nTreatment Outcomes\nThe patient commenced FLAG (fludarabine, cytarabine, filgrastim) salvage chemotherapy (Montillo et al. 2009). Her treatment was complicated by febrile neutropenia attributable to a urinary tract infection. Despite intensive chemotherapy, the patient failed to clear blasts from her peripheral blood, which were confirmed to be T-ALL by immunophenotyping. At this point, no clinical trials were available and it was deemed futile to administer further intensive chemotherapy. Given the finding of activating JAK3 mutations identified on sequencing at diagnosis and at relapse (see Methods section and Tables 1 and 2), we hypothesized that JAK-inhibition with tofacitinib might rationally evoke an anti-tumor response. Tofacitinib (marketed as Xeljanz) has potent inhibitory activity against JAK1 and JAK3 (Flanagan et al. 2010; Meyer et al. 2010). We posited that this was preferable to the more JAK2-selective agent, ruxolitinib, which does not inhibit JAK3 activity. The patient was informed that tofacitinib treatment was not approved for leukemia treatment and consented to a trial of therapy after considering the potential risks. Tofacitinib was supplied under a Pfizer non-commercial supply compassionate access program following notification of the Monash Health Drug and Therapeutic Committee and Australian Therapeutic Goods Administration. She commenced treatment with tofacitinib at a dose of 5 mg BD on Day 17 post-FLAG. A bone marrow aspirate was performed on Day 21 post-FLAG, which showed persistent marrow infiltration with blasts (97% of nucleated cellularity). She started weekly oral dexamethasone 40 mg and continued on tofacitinib. In the absence of any further evidence of an objective response, tofacitinib was ceased from day 36 post-FLAG (Fig. 2).\n\nFigure 2. Timeline of treatment and peripheral blood leukemic blast percentages. (BM) Bone marrow, (D) day, (FLAG) fludarabine, cytarabine, filgrastim (G-CSF), (PB) peripheral blood.\n\nTable 1. At diagnosis (left hilar mass)\n\nGene symbol\tChr\tDNA locus and change (GRCh37/hg19)\tTranscript\tcDNA variation\tHGVS protein reference\tVariant type\tVAF\t\nDNMT3A\t2\tg.25466766C > T\tNM_022552.4\tc.1936 + 1G > A\tp.?\tCanonical splice donor site SNV\t39%\t\nNOTCH1\t9\tg.139391782_139391785 delinsCTTGTCGCTGGC\tNM_017617.3\tc.6406_6409delinsGCCAGCGACAAG\tp.(Ser2136AlafsTer115)\tTruncating frameshift deletion-insertion variant\t20%a\t\nNOTCH1\t9\tg.139397700C > T\tNM_017617.3\tc.5101G > A\tp.(Ala1701Thr)\tMissense SNV\t40%\t\nTP53\t17\tg.7577084_7577103 delinsCCCCAAGG\tNM_000546.5\tc.835_854delinsCCTTGGGG\tp.(Gly279_Glu285delinsProTrpGly)\tIn-frame deletion-insertion variant\t19%a\t\nGNA13\t17\tg.63010721T > A\tNM_006572.4\tc.788A > T\tp.(Asn263Ile)\tMissense SNV\t39%\t\nJAK3\t19\tg.17945970G > A\tNM_000215.3\tc.1969C > T\tp.(Arg657Trp)\tMissense SNV\t37%\t\nJAK3\t19\tg.17949108C > T\tNM_000215.3\tc.1533G > A\tp.(Met511Ile)\tMissense SNV\t33%\t\nWT1\t11\tg.32417914delinsCC\tNM_024426.4\tc.1138delinsGG\tp.(Arg380GlyfsTer5)\tTruncating frameshift deletion-insertion variant\t35%a\t\nFBXW7\t4\tg.153249385G > A\tNM_033632.3\tc.1393C > T\tp.(Arg465Cys)\tMissense SNV\t43%\t\n(HGVS) Human Genome Variation Society, (VAF) variant allele frequency, (SNV) single-nucleotide variant.\n\naNote: bioinformatics bias against deletion containing reads.\n\nTable 2. At relapse (bone marrow)\n\nGene symbol\tChr\tDNA locus and change (GRCh37/hg19)\tTranscript\tcDNA Variation\tHGVS protein reference\tVariant type\tVAF\t\nDNMT3A\t2\tg.25466766C > T\tNM_022552.4\tc.1936 + 1G > A\tp.?\tCanonical splice donor site SNV\t50%\t\nNOTCH1\t9\tg.139391782_139391785 delinsCTTGTCGCTGGC\tNM_017617.3\tc.6406_6409delinsGCCAGCGACAAG\tp.(Ser2136AlafsTer115)\tTruncating frameshift deletion-insertion variant\t43%\t\nNOTCH1\t9\tg.139397700C > T\tNM_017617.3\tc.5101G > A\tp.(Ala1701Thr)\tMissense SNV\t11%\t\nNOTCH1\t9\tg.139397646_139397647insGCG\tNM_017617.3\tc.5154_5155insCGC\tp.(Ile1718_Glu1719insArg)\tIn-frame insertion variant\t18%\t\nTP53\t17\tg.7577084_7577103 delinsCCCCAAGG\tNM_000546.5\tc.835_854delinsCCTTGGGG\tp.(Gly279_Glu285delinsProTrpGly)\tIn-frame deletion-insertion variant\t86%\t\nJAK3\t19\tg.17945970G > A\tNM_000215.3\tc.1969C > T\tp.(Arg657Trp)\tMissense SNV\t93%\t\nJAK3\t19\tg.17949108C > T\tNM_000215.3\tc.1533G > A\tp.(Met511Ile)\tMissense SNV\t97%\t\nWT1\t11\tg.32417914delinsCC\tNM_024426.4\tc.1138delinsGG\tp.(Arg380GlyfsTer5)\tTruncating frameshift deletion-insertion variant\t50%\t\nFBXW7\t4\tg.153249385G > A\tNM_033632.3\tc.1393C > T\tp.(Arg465Cys)\tMissense SNV\t53%\t\nKaryotype\t\n46,X,t(X;10;2)(p11.4;p12;q31),del(9)(p?13p?21)[7]/47,idem,+20[4]/46,idem,?t(4;14)(q13;q21),t(12;22)(p12;q11.2)[7]/46,X,der(X)t(X;2)(p11.4;q31),der(1)t(1;2)(q21;p23),der(2)t(1;2)(q21;p23)t(2;10)(q31;p12),add(3)(p13),add(5)(q13),add(9)(q22),del(9)(p?13p?21),der(10)t(X;10)(p11.4;p12),-13,-13,+mar1,+mar2[3]\t\n(HGVS) Human Genome Variation Society, (VAF) variant allele frequency, (SNV) single-nucleotide variant.\n\nMutations in DNA-methylation regulators (e.g., DNMT3A, TET2) induce epigenetic changes that may be modulated by DNA-methyltransferase inhibitors such as decitabine and azacitidine. In particular, TET2 mutations predict a higher response rate to hypomethylating agents in myelodysplasia (Bejar et al. 2014). JAK-STAT pathway activation increases anti-apoptotic BCL2 family protein expression in lymphoid cancer (Waibel et al. 2014), and we noted high BCL2 expression in our patient's bone marrow trephine (Fig. 1B). Moreover, combination therapy with decitabine and the BCL2 inhibitor, venetoclax, was recently reported to induce clinical remission in another patient with relapsed and refractory T-ALL (Rahmat et al. 2018).\n\nHaving received a cycle of azacitidine, venetoclax was obtained through the AbbVie compassionate access program and commenced at 100 mg daily. There was no evidence of tumor lysis syndrome, but venetoclax dose escalation was not attempted as the patient was receiving posaconazole antifungal prophylaxis (which inhibits venetoclax metabolism). A second cycle of azacitidine was commenced on Day 40 post-FLAG. At this point there had still been no objective evidence of an antileukemic response and the patient developed febrile neutropenia with significant clinical deterioration. A further bone marrow biopsy (Day 54 post-FLAG) showed ongoing leukemia with 87% blasts. In view of her poor response to treatment, the decision was made to withdraw active treatment and the patient died shortly after this.\n\nDISCUSSION\nDisease-free survival is poor in adults with a diagnosis of T-ALL, particularly when compared to pediatric T-ALL patients. Outcomes are particularly dismal in the relapsed/refractory setting, and <10% of patients survive long-term (Marks and Rowntree 2017). There are limited therapeutic options available in this context. Here, we describe a patient initially diagnosed with mediastinal T-LBL who achieved remission with induction chemotherapy but relapsed with T-ALL within eight months. WES on the diagnostic biopsy specimen identified two JAK3 hotspot missense variants, p.Met511Ile and p.Arg657Trp, both previously established as activating mutations (Degryse et al. 2014). Targeted gene sequencing on the bone marrow aspirate specimen at relapse confirmed the persistence of these mutations. Subsequently, targeted JAK-STAT pathway inhibition with tofacitinib was introduced following salvage chemotherapy reinduction.\n\nInterleukin 7 (IL7) signaling is essential for normal T-cell development and plays a major role in differentiation and homeostasis. IL7 interacts with heterodimeric IL7 receptor (IL7R), which induces reciprocal JAK1 and JAK3 phosphorylation and subsequent recruitment and activation of STAT5. Phosphorylated STAT5 dimerizes and translocates to the nucleus where it regulates gene transcription (e.g., BCL2 family genes) (Waibel et al. 2014). Unlike other JAK family kinases, JAK3 expression and function is mostly restricted to the hematopoietic compartment (Cornejo et al. 2009; Degryse and Cools 2015; Girardi et al. 2017).\n\nActivating mutations in this pathway (ILR7, JAK1, JAK3, STAT5) are present in 20%–30% of T-ALL cases (Zhang et al. 2012; Vicente et al. 2015; Girardi et al. 2017). JAK3 mutations are most frequently seen (Bains et al. 2012; De Keersmaecker et al. 2012; Kalender Atak et al. 2012, 2013; Zhang et al. 2012; Yin et al. 2014; Greenplate et al. 2018). Functional studies investigating the oncogenic role of JAK3 in T-ALL have shown the JAK3 p.Met511Ile pseudokinase domain mutant to be the most efficient oncokinase with the highest transforming properties (Yamashita et al. 2010). In vivo data support the transforming role of mutant JAK3 in a mouse bone marrow transplant model of JAK3-induced T-ALL (Degryse et al. 2014). One-third of JAK3-mutated T-ALL cases harbor two JAK3 mutations, which can be monoallelic or less frequently biallelic (Degryse et al. 2018). JAK3 p.Met511Ile increases oncogenic potential via acquisition of additional mutations in the mutant JAK3 allele (Degryse et al. 2018). Double JAK3 mutants show increased STAT5 activation compared to single JAK3 mutants, suggesting that progression of JAK3 mutant T-ALL cases may be associated with acquisition of additional JAK3 mutations and subsequent increase in JAK/STAT signaling (Degryse et al. 2018).\n\nIn our patient, all variants identified by WES demonstrated concordant allele frequency, including both JAK3 variants, suggesting they were present in the same leukemic cells, rather than separate clones. The p.Met511Ile and p.Arg657Trp variants had concordant variant allele frequencies (VAFs) of 31% and 37%, respectively, at diagnosis, and concordant VAFs of 97% and 93%, respectively in the relapsed leukemia sample, suggesting that both variants are likely on the same allele with either copy-neutral loss of heterozygosity of 19p13 or deletion of the second JAK3 allele. The two JAK3 variants are 436 bp apart and are too far apart to phase on short-read sequencing. Large-fragment amplification of JAK3 encompassing both variants was performed to experimentally validate the hypothesis that both variants were present on the same allele, but was unsuccessful.\n\nLoss-of-function mutations affecting JAK3 signaling in patients with severe combined immunodeficiency disease have been shown to severely impair lymphoid development (Pesu et al. 2005). On this basis, the potential therapeutic effect of JAK3 inhibition has been investigated as targeted immunosuppression for prevention of solid organ graft rejection and in autoimmune inflammatory diseases such as rheumatoid arthritis. A number of JAK inhibitors have been studied, with variable selectivity against JAK3 compared to other JAK family members. Originally described as a selective JAK3 inhibitor, tofacitinib also inhibits JAK1 and its efficacy may be due to the combined inhibition of both kinases (Thoma et al. 2014). Tofacitinib has received U.S. Federal Drug Administration (FDA) approval for the treatment of refractory rheumatoid arthritis.\n\nDifferent activating mutations of JAK3 confer differential sensitivity to JAK inhibitors (Losdyck et al. 2015; Steven Martinez et al. 2016). Preclinical data suggest that most, but not all, JAK3 mutants transform T-ALL cell lines to cytokine-independent proliferation in vitro and cause leukemia in vivo. However, JAK3 pseudokinase domain mutants (including p.Met511Ile and p.Arg657Trp mutants, identified in our patient) require JAK1 for their transforming potential. In contrast, JAK3 kinase domain mutations can induce cell transformation independent from JAK1. In line with these findings, JAK3 pseudokinase domain mutants demonstrated more sensitivity to ruxolitinib (a JAK1/JAK2 inhibitor) than JAK3 kinase domain mutants, whereas both JAK3 pseudokinase and kinase domain mutants were sensitive to tofacitinib. Tofacitinib and ruxolitinib demonstrated synergistic inhibition in JAK3 pseudokinase domain mutants (Degryse et al. 2014). The effect of double JAK3 mutants on sensitivity to JAK inhibitors is unclear. Degryse and colleagues identified two cases of p.Met511Ile and p.Arg657Trp double mutants but did not test sensitivity to ruxolitinib (Degryse et al. 2018). To the best of our knowledge, there are no reports of tofacitinib sensitivity testing for this double mutant so it is unknown if tofacitinib is active against the double mutant.\n\nActivating JAK3 mutations have been identified in other T-cell malignancies and are seen most frequently in T-cell prolymphocytic leukemia (T-PLL) at a rate of 30%–40% (Bellanger et al. 2013; Bergmann et al. 2014; Kiel et al. 2014; Stengel et al. 2015; López et al. 2016). Targeted JAK3 inhibition with tofacitinib has elicited responses in several cases of T-PLL, both as a single agent (Li et al. 2017) and in combination with ruxolitinib (Gomez-Arteaga et al. 2019). Interestingly, both of these cases harbored the JAK3 hotspot activating mutation, p.Met511Ile, as well as a second JAK3 missense mutation in each case (p.Ala573Val pseudokinase domain mutation and p.Leu875His kinase domain mutation, respectively). JAK3 mutations are not common in T-cell large granular lymphocytic leukemia (T-LGLL), but a proportion of patients demonstrate activating STAT3 mutations; in a cohort of nine patients with T-LGLL (four harboring STAT3 mutations), tofacitinib induced a hematologic response in six patients (Bilori et al. 2015).\n\nTo our knowledge, this is the first report describing tofacitinib in a patient with T-ALL harboring gain-of-function JAK3 mutations. We cannot conclude that the tofacitinib exposure did not have a cytostatic (rather than apoptotic) effect, but no significant clinical activity was observed either as a single agent or when combined with dexamethasone. It is possible that therapeutic levels of tofacitinib were not achieved, although this seems unlikely as the patient did not have any signs or symptoms of malabsorption and was taking concurrent potent cytochrome p450 inhibitors (i.e., posaconazole). In a preclinical mouse model, in vivo response was observed within 6 days of commencing treatment with tofacitinib, suggesting sufficient duration of exposure to tofacitinib in our patient (Degryse et al. 2014). This case may indicate that established leukemia may become independent of JAK3 signaling or that unimpeded JAK2 signaling was a pro-survival mechanism in this case. Indeed, one report evaluating the ex vivo sensitivity of T-PLL patient samples to JAK inhibitors showed poor correlation between specific mutations in the JAK-STAT pathway and response (Andersson et al. 2017). Furthermore, in a preclinical model, pSTAT5 expression in M511I + A573V and M511I + A572T double mutants in Ba/F3 were higher than pSTAT5 expression in single mutants, so it is possible that drug concentrations may have been inadequate for inhibition of JAK-STAT signaling in the presence of JAK3 double mutants (Degryse et al. 2018).\n\nThe role of other mutations in potential resistance to tofacitinib is speculative. The TP53 mutation variant allele frequency increased between diagnosis and relapse from 19% (Table 1) to 86% (Table 2), consistent with copy-neutral loss of heterozygosity (CN-LOH) or deletion of the second allele. TP53 loss-of-function mutation is known to drive resistance to DNA damaging agents and is a predictor of poor prognosis in adults treated with chemotherapy, but its impact on response to tofacitinib remains unknown (Diccianni et al. 1994; Hof et al. 2011). However, Tp53 null mice with B-ALL and oncogene addiction to JAK-STAT signaling still responded to tofacitinib and ruxolitinib (Cheng et al. 2016). This would indicate that responses to JAK inhibition may be agnostic to p53 status; however, more functional studies and preclinical models are needed.\n\nJAK-STAT pathway activation has been shown to up-regulate anti-apoptotic BCL2 family protein expression in lymphoid cancer (Waibel et al. 2014). In this case, high BCL2 protein expression was seen on immunohistohemical staining of the patient's bone marrow trephine (Fig. 1B). Venetoclax (ABT-199) is a highly specific BCL-2 inhibitor. Preclinical studies have shown in vitro and in vivo sensitivity of some T-ALL cell lines to venetoclax, either alone or in combination with other agents (Peirs et al. 2014). A report of venetoclax combined with low-intensity chemotherapy reported a durable response in one patient with early T-cell precursor ALL, and a complete but transient response in one patient with T-ALL (Numan et al. 2018). This was consistent with preclinical data demonstrating particular susceptibility of ETP-ALL to BCL2 inhibition, because of lesser dependence on BCL-XL compared to more mature subtypes of T-ALL (Chonghaile et al. 2014). In our case there was no apparent response to venetoclax, indicating BCL2-independent pro-survival mechanisms that could be explained by the up-regulation of BCL-XL in JAK-STAT dysregulated neoplasms (Waibel et al. 2014). Although it is possible the lack of efficacy of venetoclax could be attributable to underdosing, it was postulated that there would be a p450 interaction with concurrent posaconazole administration, reducing the metabolism of venetoclax and thereby increasing the therapeutic level. The patient's limited exposure to azacitidine (only two cycles) makes it inappropriate to speculate as to whether ongoing hypomethylating agent treatment in combination with venetoclax might have yielded a disease response.\n\nAlthough this case report indicates that activating JAK3 mutations do not necessarily sensitize to tofacitinib therapy, further preclinical and clinical exploration of JAK inhibition in JAK-STAT dysregulated acute leukemia is clearly warranted. Furthermore, gene expression data and pathway analysis would potentially have assisted with targeted approaches to management in this case, supporting the role of robust and representative assays in clinical management.\n\nMETHODS\nWES with targeted analysis of genes related to lymphoid malignancies was performed on DNA extracted from the initial diagnostic left hilar lung mass cryobiopsy and genomic DNA derived from buccal swab normal specimens. Tumor purity was estimated as 90%, assessed on hematoxylin and eosin–stained tissue obtained by cryobiopsy. Libraries were prepared using Agilent Clinical Research Exome 1 (CRE1) (Agilent) followed by massively parallel sequencing using a HiSeq 3000 instrument (Illumina) with 100-bp paired-end reads. Tumor-normal comparison to generate somatic variant calls was conducted using the Seqliner bioinformatic pipeline (http://seqliner.org). Mean target region sequencing coverage was 140× (tumor) and 60× (germline) (Supplemental Table S1).\n\nA list of target genes was selected following a review of the literature regarding recurrent mutations in lymphoid malignancies, performed by three independent contributors (Supplemental Table S2). After filtering, seven nonsynonymous somatic variants presumed to be functionally important were identified in the tumor: five single-nucleotide variants (SNVs) and two short insertions and deletions (indels) involving DNMT3A, GNA13, JAK3, NOTCH1, and TP53 (Table 1). We identified two JAK3 hotspot missense SNVs: NM_000215.3: c.1533G > A, p.Met511Ile and NM_000215.3: c.1969C > T, p.Arg657Trp. Both variants occur in the pseudokinase (JH2) domain (Fig. 3) and have been established as activating mutations in JAK3 (Degryse et al. 2014). The two JAK3 variants are 436 bp apart and were thus too far apart to phase on short-read sequencing. Large-fragment amplification of JAK3 encompassing both variants was unsuccessful.\n\nFigure 3. Missense mutations in JAK3 identified in our patient. Schematic shows JAK3 protein domain structures. Amino acid numbers are shown below. Missense mutations are denoted by circles with codon changes shown. (FERM) The conserved domain named for its founding members (band 4.2, exrin, radixin, and moesin), (JH1) JAK homology domain 1, the functional kinase domain, (JH2) JAK homology domain 2, also known as the pseudokinase domain, (SH2) Src homology domain 2.\n\nGenomic studies were performed on the bone marrow aspirate specimen taken at relapse. Conventional chromosome studies showed the following karyotype: 46,X,t(X;10;2)(p11.4;p12;q31),del(9)(p?13p?21)[7]/47,idem,+20[4]/46,idem, ?t(4;14)(q13;q21),t(12;22)(p12;q11.2)[7]/46,X,der(X)t(X;2)(p11.4;q31), der(1)t(1;2)(q21;p23),der(2)t(1;2)(q21;p23)t(2;10)(q31;p12),add(3)(p13), add(5)(q13),add(9)(q22),del(9)(p?13p?21),der(10)t(X;10)(p11.4;p12),−13,−13,+mar1,+mar2[3] (Table 2). This identified a three-way X;10;2 translocation and deletion of part of 9p in all 22 metaphases analyzed. Multiple subclones were present. Four metaphases also showed trisomy 20, whereas another seven contained reciprocal 4;14 and 12;22 translocations. Three metaphases were more complex. They showed a reciprocal 1;2 translocation involving 1q and the short arm of the derivative chromosome 2, abnormalities of 3p, 5q, 9q, and apparent nullisomy 13 with two marker chromosomes. The t(X;10;2) appeared to be a variant of the X;10 translocation that forms a DDX3X-MLLT10 gene fusion. The t(X;10) is a rare but recurrent translocation in T-LBL/T-ALL and has an association with NOTCH1 mutation and deletion of 9p (Brandimarte et al. 2014).\n\nTargeted massively parallel sequencing of 76 genes with diagnostic, prognostic, and therapeutic relevance in hematological malignancies was performed on DNA derived from the bone marrow aspirate specimen obtained at time of relapse. Libraries were prepared using the KAPA Hyper Prep Kit (KAPA Biosystems) and then enriched using a SureSelectXT Custom Capture Panel (Agilent) and sequenced on a NextSeq 500 instrument (Illumina) with 75-bp paired-end reads. This confirmed the presence of the variants identified on WES of the initial diagnostic biopsy, including the two JAK3 hotspot missense variants (Table 2). Three additional variants were identified. Two variants were in genes not included in the target gene review list for exome analysis: a WT1 frameshift mutation, NM_024426.4: c.1138delinsGG, p.Arg380Glyfs*5, and a FBXW7 hotspot missense mutation, NM_ 033632.3: c.1393C > T, p.Arg465Cys. However, retrospective review of the exome sequencing data showed that both WT1 and FBXW7 mutations were present in the diagnostic sample (Table 1). A third NOTCH1 variant was also identified, an in-frame insertion, NM_017617.3: c.5154_5155insCGC, p.Ile1718_Glu1719insArg. This variant was not present on WES performed on the initial diagnostic specimen.\n\nADDITIONAL INFORMATION\nData Deposition and Access\nThe variants were submitted to COSMIC (https://cancer.sanger.ac.uk/cosmic) and can be found under accession number COSP48326. Patient consent was not obtained for deposition of raw sequencing data. The Melbourne Genomics Health Alliance can be contacted for anonymized cohort data release via their data release program.\n\nEthics Statement\nThe whole-exome sequencing performed in this study was approved by the Melbourne Health Human Research Ethics Committee as an amendment to the Melbourne Genomics Protocol Number 2013.245.\n\nInformed consent was obtained in writing from the patient prior to collection of blood, tumor, and buccal swab samples. On enrollment into the study, the patient signed a patient information and consent form approved by central and local human research ethics committees. The consent included use of patient data for publication. Postmortem consent for publication was also obtained from the deceased patient's next of kin.\n\nThe authors report no pertinent disclosures, and no conflict of interest concerning the materials or methods used in this study or findings described in this paper.\n\nAuthor Contributions\nJ.W. acquired clinical data and images, created the table and figures, and developed the manuscript with the assistance of J.S. G.P.C. performed and interpreted whole-exome sequencing analysis. N.T. performed targeted JAK3 sequencing analysis. M.W. performed and interpreted conventional chromosome analysis. G.P.G. and S.O. supervised the whole-exome sequencing project. All authors critically edited and approved the final manuscript.\n\nFunding\nThe Melbourne Genomics Health Alliance is supported financially by the State Government of Victoria (Department of Health and Human Services) and by its member institutions. J.W. was supported by a Monash Health Emerging Researcher Fellowship.\n\nCompeting Interest Statement\nThe authors have declared no competing interest.\n\nSupplementary Material\nSupplemental Material\n [Supplemental material is available for this article.]\n==== Refs\nREFERENCES\nAndersson \nEI , Pützer \nS , Yadav \nB , Dufva \nO , Khan \nS , He \nL , Sellner \nL , Schrader \nA , Crispatzu \nG , Oleś \nM , \n2017 \nDiscovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling\n. Leukemia \n32 : 774 –787\n. 10.1038/leu.2017.252 28804127 \nBains \nT , Heinrich \nMC , Loriaux \nMM , Beadling \nC , Nelson \nD , Warrick \nA , Neff \nTL , Tyner \nJW , Dunlap \nJ , Corless \nCL , \n2012 \nNewly described activating JAK3 mutations in T-cell acute lymphoblastic leukemia\n. 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"fulltext_license": "CC BY-NC",
"issn_linking": "2373-2873",
"issue": "6(4)",
"journal": "Cold Spring Harbor molecular case studies",
"keywords": "T-cell acute lymphoblastic leukemias; hematological neoplasm; leukemia",
"medline_ta": "Cold Spring Harb Mol Case Stud",
"mesh_terms": "D000368:Aged; D002471:Cell Transformation, Neoplastic; D053487:DEAD-box RNA Helicases; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D010880:Piperidines; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011743:Pyrimidines; D014157:Transcription Factors; D000073359:Whole Exome Sequencing",
"nlm_unique_id": "101660017",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32843425",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25193870;22675565;28115373;26208852;21747090;26206799;15661026;23673860;30225152;26917488;30997845;29296924;19747563;20400977;24825865;28804127;26493028;30079384;29046866;25224413;26974155;26449659;24446122;28671688;28115371;24048415;22425895;29187379;7949183;23263491;26446793;25301704;9250830;25217444;25146434;31080940;20701804;24994123;21105711;24584351;15481055;24367274;22237106;24811162",
"title": "Failure of tofacitinib to achieve an objective response in a DDX3X-MLLT10 T-lymphoblastic leukemia with activating JAK3 mutations.",
"title_normalized": "failure of tofacitinib to achieve an objective response in a ddx3x mllt10 t lymphoblastic leukemia with activating jak3 mutations"
} | [
{
"companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-271310",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"dr... |
{
"abstract": "OBJECTIVE\nIntravenous (IV) infusion of aminobisphosphonates (ABP) induces cytokine release by peripheral blood Vγ9δ2 T cells, resulting in an immediate short-term inflammatory response in up to 50% of patients. We evaluated possible long-term pro-inflammatory effects of IV ABP.\n\n\nMETHODS\nRetrospective case-series study from one rheumatology specialist's clinic. 2261 electronic charts were reviewed for administration of 'zoledronate' or different brand names of zoledronic acid, and relevant clinical data was retrieved for patients who had received the infusion.\n\n\nRESULTS\nThirteen patients had recieved zoledronate. In six, new-onset or exacerbation of a previous inflammatory/autoimmune disorder was diagnosed within 3 months following infusion. Of these, one patient developed new-onset rheumatoid arthritis (RA), two polymyalgia rheumatica (PMR), two suffered a flare of Crohn's disease-related and aromatase inhibitor-induced arthralgias, and one patient acquired autoimmune hemophilia. Pre-existing malignancy and immediate inflammatory response following zoledronate were more frequent in patients experiencing new or worsening immunologic manifestations (3/6 vs. 0/7, and 5/6 vs. 2/7, respectively).\n\n\nCONCLUSIONS\nIntravenous ABP may trigger induction of persistent autoimmune syndromes, especially when accompanied by an immediate adverse reaction or pre-existing malignancy.",
"affiliations": "Institute of Clinical Pharmacology, Chaim Sheba Medical Center, Tel Hashomer, Israel. noamarkovits@gmail.com.;Institute of Clinical Pharmacology, Chaim Sheba Medical Center, Tel Hashomer, Israel.;Autoimmunity Institute and Laboratory for Immunoregulation, Chaim Sheba Medical Center, Tel Hashomer, Israel.",
"authors": "Markovits|Noa|N|;Loebstein|Ronen|R|;Bank|Ilan|I|",
"chemical_list": "D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid",
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s10787-017-0365-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-4692",
"issue": "25(6)",
"journal": "Inflammopharmacology",
"keywords": "Aminobisphosphonates; Vγ9δ2 T cells; Zoledronic acid; γδ T cells",
"medline_ta": "Inflammopharmacology",
"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D001327:Autoimmune Diseases; D003424:Crohn Disease; D004164:Diphosphonates; D005260:Female; D006801:Humans; D007093:Imidazoles; D007249:Inflammation; D007262:Infusions, Intravenous; D008297:Male; D011111:Polymyalgia Rheumatica; D012189:Retrospective Studies; D013577:Syndrome; D000077211:Zoledronic Acid",
"nlm_unique_id": "9112626",
"other_id": null,
"pages": "665-671",
"pmc": null,
"pmid": "28567535",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": "24008306;25991474;25617367;27619996;21069948;3755221;3487737;19188178;27012367;21519826;25250025;21406498;20681408;22450805;23074158;17291279;17265022;18624305;11780560;22139198;24120862;1386549;20554708;26168223;19409955;12538656;16984888;19016713;15611247;23184667;25657647;25540645;10837080",
"title": "Immune-mediated syndromes following intravenous bisphosphonate therapy.",
"title_normalized": "immune mediated syndromes following intravenous bisphosphonate therapy"
} | [
{
"companynumb": "IL-INFO-000414",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nIn severe hyperkalemia, neurologic symptoms are described more rarely than cardiac manifestations. We report a clinical case; present a systematic review of available literature on secondary hyperkalemic paralysis (SHP); and also discuss pathogenesis, clinical effects, and therapeutic options.\n\n\nMETHODS\nA 75-year-old woman presented to the emergency department complaining of tetraparesis. Her serum potassium level was 11.4 mEq/L. Electrocardiogram (ECG) showed a pacemaker (PMK)-induced rhythm, with loss of atrial capture and wide QRS complexes. After emergency treatment to restore cell membrane potential threshold and lower serum potassium, neurologic and ECG signs completely disappeared. An acute myocardial infarction subsequently occurred, possibly linked to tachycardia induced by salbutamol therapy. We reviewed 99 articles (119 patients). Mean serum potassium was 8.8 mEq/L. In most cases, ECG showed the presence of tall T waves; loss of PMK atrial capture was documented in 5 patients. In 94 patients, flaccid paralysis was described and in 25, severe muscular weakness; in 65 patients, these findings were associated with other symptoms. Concurrent renal failure was often documented. The most frequent treatments were dialysis and infusion of insulin and glucose. Eighty-seven percent of patients had complete resolution of symptoms. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Severe hyperkalemia is always a life-threatening medical emergency, as it can precipitate fatal dysrhythmias and paralysis. SHP should be considered in the differential diagnosis of neurologic signs and symptoms of uncertain etiology, especially in a subject with kidney failure or who is taking medications that may worsen renal function. The presence of a PMK does not necessarily impede hyperkalemic cardiac toxicity.",
"affiliations": "School of Nursing, University of Trieste, Trieste, Italy.;High Dependency Unit, Azienda Ospedaliero-Universitaria, Trieste, Italy.;School of Emergency Medicine, University of Trieste, Trieste, Italy.;High Dependency Unit, San Paolo Hospital, Naples, Italy.",
"authors": "Sanson|Gianfranco|G|;Russo|Savino|S|;Iudicello|Alessandra|A|;Schiraldi|Fernando|F|",
"chemical_list": "D011188:Potassium",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "48(5)",
"journal": "The Journal of emergency medicine",
"keywords": "hyperkalemia; kidney failure; pacemaker capture failure; paralysis",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000368:Aged; D004562:Electrocardiography; D004868:Equipment Failure; D005260:Female; D006801:Humans; D006947:Hyperkalemia; D010138:Pacemaker, Artificial; D011188:Potassium; D011782:Quadriplegia; D051436:Renal Insufficiency, Chronic",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "555-61.e3",
"pmc": null,
"pmid": "25766426",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": null,
"title": "Tetraparesis and failure of pacemaker capture induced by severe hyperkalemia: case report and systematic review of available literature.",
"title_normalized": "tetraparesis and failure of pacemaker capture induced by severe hyperkalemia case report and systematic review of available literature"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-94664",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PIROXICAM"
},
"drugad... |
{
"abstract": "A 56-year-old man with diabetes mellitus and cadaveric renal transplantation had vancomycin-resistant Enterococcus faecium tricuspid valve endocarditis. Relapse followed 6 weeks of treatment with intravenous gentamicin and high-dose ampicillin. On the basis of previous data suggesting the potential for synergistic activity of quinupristin/dalfopristin plus high-dose ampicillin, therapy with this combination was administered for 63 days. Cure was achieved and later confirmed at 2-year follow-up.",
"affiliations": "Infectious Disease Section, Group Health Cooperative of Puget Sound, Seattle, WA 98112, USA. thompson.rl@ghc.org",
"authors": "Thompson|Robert L|RL|;Lavin|Bruce|B|;Talbot|George H|GH|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005839:Gentamicins; D010406:Penicillins; D014769:Virginiamycin; C113825:quinupristin; D000667:Ampicillin; C113826:dalfopristin",
"country": "United States",
"delete": false,
"doi": "10.1097/01.SMJ.0000047962.61701.57",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0038-4348",
"issue": "96(8)",
"journal": "Southern medical journal",
"keywords": null,
"medline_ta": "South Med J",
"mesh_terms": "D000667:Ampicillin; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D003922:Diabetes Mellitus, Type 1; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D004697:Endocarditis, Bacterial; D016984:Enterococcus faecium; D005839:Gentamicins; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010406:Penicillins; D012008:Recurrence; D016896:Treatment Outcome; D020713:Vancomycin Resistance; D014769:Virginiamycin",
"nlm_unique_id": "0404522",
"other_id": null,
"pages": "818-20",
"pmc": null,
"pmid": "14515928",
"pubdate": "2003-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Endocarditis due to vancomycin-resistant Enterococcus faecium in an immunocompromised patient: cure by administering combination therapy with quinupristin/dalfopristin and high-dose ampicillin.",
"title_normalized": "endocarditis due to vancomycin resistant enterococcus faecium in an immunocompromised patient cure by administering combination therapy with quinupristin dalfopristin and high dose ampicillin"
} | [
{
"companynumb": "US-IBIGEN-2018.05145",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMPICILLIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report the clinical outcome of nicotine exposure in patients with autosomal dominant sleep-related hypermotor epilepsy (ADSHE), along with serum concentrations of the major nicotine metabolite cotinine.\n\n\nMETHODS\nWe recruited 17 ADSHE patients with CHRNA4 mutations (12 with p.S280F and 5 with p.L291 dup). Clinical characteristics were collected from hospital records. A telephone interview was performed on the use and seizure-reducing effect of nicotine applying a six-point rating scale from \"none\" to very good\". Serum concentrations of cotinine were measured in 14 nicotine users.\n\n\nRESULTS\nAll patients but one had ever used nicotine. Nine had used snuff; seven were current users. Eleven had used transdermal nicotine; nine were current users. Seven reported long-lasting seizure control, all used nicotine, four transdermal nicotine and three snuff. In 78% of patients using continuous transdermal nicotine, the effect was rated as good or very good. Cotinine concentrations were 453 ± 196 (mean ± SD) nmol/l in seven patients using transdermal nicotine only vs. 1241 ± 494 nmol/l in seven using other forms of nicotine. No correlation with seizure control was found. Three patients experienced improvement with transdermal delivery compared to snuff.\n\n\nCONCLUSIONS\nThis is the hitherto largest observational study supporting a favorable effect of nicotine in this specific seizure disorder. Better seizure control from transdermal nicotine compared to only day-time consumption suggests benefit from exposure throughout the night. According to current clinical experience, patients with uncontrolled ADSHE harboring relevant mutations should be offered precision treatment with transdermal nicotine.",
"affiliations": "Department of Neurology and Clinical Neurophysiology, St. Olav University Hospital, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: eylert.brodtkorb@ntnu.no.;Department of Neurology and Clinical Neurophysiology, St. Olav University Hospital, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway; Kavli Institute for Systems Neuroscience and Centre for Neural Computation, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: sverre.myren-svelstad@ntnu.no.;The National Center for Epilepsy, Oslo University Hospital, Sandvika, Norway. Electronic address: kristinmkb@gmail.com.;The National Center for Epilepsy, Oslo University Hospital, Sandvika, Norway. Electronic address: karln@ous-hf.no.;Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: Olav.Spigset@stolav.no.",
"authors": "Brodtkorb|Eylert|E|;Myren-Svelstad|Sverre|S|;Knudsen-Baas|Kristin Marie|KM|;Nakken|Karl Otto|KO|;Spigset|Olav|O|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.eplepsyres.2021.106792",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-1211",
"issue": "178()",
"journal": "Epilepsy research",
"keywords": "Autosomal dominant sleep-related hypermotor epilepsy; Cotinine; Nicotine; Precision treatment; Seizures; Transdermal",
"medline_ta": "Epilepsy Res",
"mesh_terms": null,
"nlm_unique_id": "8703089",
"other_id": null,
"pages": "106792",
"pmc": null,
"pmid": "34763266",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Precision treatment with nicotine in autosomal dominant sleep-related hypermotor epilepsy (ADSHE): An observational study of clinical outcome and serum cotinine levels in 17 patients.",
"title_normalized": "precision treatment with nicotine in autosomal dominant sleep related hypermotor epilepsy adshe an observational study of clinical outcome and serum cotinine levels in 17 patients"
} | [
{
"companynumb": "NO-GLAXOSMITHKLINE-NOCH2022GSK020350",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NICOTINE"
},
"drugadditional": nul... |
{
"abstract": "Blastomyces dermatitidis is a dimorphic fungus endemic to the midwestern, south-central, and southeastern United States known to cause disseminated infection in immunocompromised individuals. We report a case of B. dermatitidis peritonitis in a renal allograft recipient with new-onset ascites and cytomegalovirus encephalitis. Peritoneal blastomycosis is a rare clinical entity and, to our knowledge, this patient represents the first known case of peritoneal blastomycosis in a solid organ transplant recipient. We review the clinical characteristics of B. dermatitidis peritonitis as well as the literature on fungal peritonitis with emphasis on dimorphic fungal pathogens. Clinical features suggestive of fungal peritonitis include new-onset ascites, abdominal pain, and fevers, especially with antecedent or concomitant pneumonia. A high index of clinical suspicion, along with the use of culture and non-culture diagnostics, is needed for early diagnosis and prompt initiation of therapy.",
"affiliations": "Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.",
"authors": "Barocas|J A|JA|;Gauthier|G M|GM|",
"chemical_list": "D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12234",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "16(4)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Blastomyces dermatitidis; Peritonitis; solid organ transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D000666:Amphotericin B; D000935:Antifungal Agents; D001758:Blastomyces; D001759:Blastomycosis; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D010538:Peritonitis",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "634-41",
"pmc": null,
"pmid": "24862205",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Peritonitis caused by Blastomyces dermatitidis in a kidney transplant recipient: case report and literature review.",
"title_normalized": "peritonitis caused by blastomyces dermatitidis in a kidney transplant recipient case report and literature review"
} | [
{
"companynumb": "US-CUBIST PHARMACEUTICAL, INC.-2014CBST001221",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nAntifungal prophylaxis after heart transplantation is usually targeted to high-risk recipients, but the duration is normally fixed and empirical. Our purpose was to assess the efficacy of a personalized prophylactic approach based on the duration of the risk factors.\n\n\nMETHODS\nIn a prospective cohort, from 2003 to 2010, prophylaxis was only administered to patients with risk factors (13 of 133) and duration was personalized, starting with the risk factor and continued a median of 20 days after its resolution.\n\n\nRESULTS\nAntifungal prophylaxis was prescribed only in 9.8% of the recipients and was effective in all but one patient who should have received a higher dose of caspofungin due to his obesity. Despite suffering an outbreak of invasive aspergillosis (IA) in the intensive care unit due to extremely high concentration of spores in the air (three cases with no personal risk factors), there was a reduction in the incidence of IA (8.6% vs. 2.2%; P=0.01) and Aspergillus-related mortality (5.75% vs. 1.5%; P=0.06).\n\n\nCONCLUSIONS\nTargeted prophylaxis for IA in heart recipients provided only to patients with risk factors and maintained for a median of 20 days after their disappearance is effective and safe. A high environmental load of Aspergillus spores in the intensive care unit would also indicate the need for antifungal prophylaxis in all exposed patients.",
"affiliations": "1 Department of Clinical Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 2 Department of Cardiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 3 Department of Experimental Medicine, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 4 Department of Medicine, Universidad Complutense de Madrid, Madrid, Spain. 5 Red Española de Investigación en Patología Infecciosa (REIPI), Madrid, Spain. 6 CIBER de Enfermedades Respiratorias (CIBER RES), Palma de Mallorca, Spain. 7 Spanish Study Group of Infections in Transplant Recipients (GESITRA), Madrid, Spain. 8 Department of Bioengineering and Aerospace Engineering, Universidad Carlos III de Madrid. 9 Address correspondence to: Patricia Muñoz, M.D., Ph.D., or Maricela Valerio, M.D., Servicio de Microbiología Clínica y Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañón, Doctor Esquerdo 46, 28007 Madrid, Spain.",
"authors": "Muñoz|Patricia|P|;Valerio|Maricela|M|;Palomo|Jesús|J|;Giannella|Maddalena|M|;Yañez|Juan F|JF|;Desco|Manuel|M|;Bouza|Emilio|E|",
"chemical_list": "D000935:Antifungal Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/TP.0b013e31829e6d7b",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1337",
"issue": "96(7)",
"journal": "Transplantation",
"keywords": null,
"medline_ta": "Transplantation",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D003428:Cross Infection; D004196:Disease Outbreaks; D004334:Drug Administration Schedule; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis; D008297:Male; D008875:Middle Aged; D009181:Mycoses; D018579:Patient Selection; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0132144",
"other_id": null,
"pages": "664-9",
"pmc": null,
"pmid": "23921444",
"pubdate": "2013-10-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Targeted antifungal prophylaxis in heart transplant recipients.",
"title_normalized": "targeted antifungal prophylaxis in heart transplant recipients"
} | [
{
"companynumb": "PHHY2015ES024218",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditional": ... |
{
"abstract": "Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by isolated thrombocytopenia. While first-line treatments focus on inhibiting autoantibodies and platelet destruction, second- and third-line treatments include splenectomy and thrombopoietin receptor agonists. In this study, we aimed to compare the efficiency and toxicities of splenectomy and eltrombopag as second-line treatments in ITP.\n\n\n\nWe retrospectively analyzed patients who were diagnosed with ITP and followed between 2015 and 2020. Patients who underwent splenectomy or received eltrombopag treatment as second-line or further therapy were included. For subgroup analyses, patients were further stratified according to whether they received eltrombopag in the second or third line of treatment.\n\n\n\nThere were 38 patients in the splenectomy group and 47 patients in the eltrombopag group. The mean age of patients in the splenectomy and eltrombopag groups was 43.2 and 50.5 years, respectively. Time to response was significantly shorter in the splenectomy arm (p=0.001). However, response rates at the 3rd, 6th, 12th, and 24th months did not exhibit a statistically significant difference between groups; nor did total duration of response and adverse events. Response rates at the 1st, 3rd, 6th, 12th, and 24th months and the total duration of response did not exhibit a statistically significant difference between eltrombopag subgroups. Eltrombopag treatment was ceased for 20 patients after a median of 54.1 months (range: 1-151). Among them, 12 patients (60%) did not experience a loss of response.\n\n\n\nComparing the splenectomy and eltrombopag arms, even though time to achieve response was in favor of the splenectomy group, this advantage disappeared when overall response rates and response rate at the 2nd year were considered. Using eltrombopag in the second or third line of therapy does not yield any difference in terms of time to achieving response.",
"affiliations": "University of Health Sciences Turkey, İzmir Bozyaka Training and Research Hospital, Clinic of Hematology, İzmir, Turkey;University of Health Sciences Turkey, İzmir Bozyaka Training and Research Hospital, Clinic of Hematology, İzmir, Turkey;University of Health Sciences Turkey, Prof. Dr. Cemil Taşçıoğlu Training and Research Hospital, Clinic of Hematology, İstanbul, Turkey;University of Health Sciences Turkey, İzmir Dr. Lütfi Kırdar Training and Research Hospital, Clinic of Hematology, İstanbul, Turkey;İzmir Çiğli Training and Research Hospital, Clinic of Internal Medicine, İzmir, Turkey;University of Health Sciences Turkey, İzmir Bozyaka Training and Research Hospital, Clinic of Hematology, İzmir, Turkey;University of Health Sciences Turkey, İzmir Bozyaka Training and Research Hospital, Clinic of Hematology, İzmir, Turkey",
"authors": "Uğur|Mehmet Can|MC|0000-0002-5600-3169;Namdaroğlu|Sinem|S|0000-0002-8074-7301;Doğan|Esma Evrim|EE|0000-0003-0635-2966;Turan Erkek|Esra|E|0000-0001-7206-6699;Nizam|Nihan|N|0000-0002-0378-4686;Eren|Rafet|R|0000-0003-0973-6279;Bilgir|Oktay|O|0000-0001-9579-0583",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.4274/tjh.galenos.2021.2021.0216",
"fulltext": "\n==== Front\nTurk J Haematol\nTurk J Haematol\nTJH\nTurkish Journal of Hematology\n1300-7777\n1308-5263\nGalenos Publishing\n\n34162173\n10.4274/tjh.galenos.2021.2021.0216\n48674\nResearch Article\nComparison of Splenectomy and Eltrombopag Treatment in the Second-Line Treatment of Immune Thrombocytopenic Purpura\nİmmün Trombositopenik Purpuranın İkinci Basamak Tedavisinde Splenektomi ve Eltrombopag Tedavilerinin KarşılaştırılmasıUğur Mehmet Can 1*https://orcid.org/0000-0002-5600-3169\n\nNamdaroğlu Sinem 1https://orcid.org/0000-0002-8074-7301\n\nDoğan Esma Evrim 2https://orcid.org/0000-0003-0635-2966\n\nTuran Erkek Esra 3https://orcid.org/0000-0001-7206-6699\n\nNizam Nihan 4https://orcid.org/0000-0002-0378-4686\n\nEren Rafet 1https://orcid.org/0000-0003-0973-6279\n\nBilgir Oktay 1https://orcid.org/0000-0001-9579-0583\n\n1 University of Health Sciences Turkey, İzmir Bozyaka Training and Research Hospital, Clinic of Hematology, İzmir, Turkey\n2 University of Health Sciences Turkey, Prof. Dr. Cemil Taşçıoğlu Training and Research Hospital, Clinic of Hematology, İstanbul, Turkey\n3 University of Health Sciences Turkey, İzmir Dr. Lütfi Kırdar Training and Research Hospital, Clinic of Hematology, İstanbul, Turkey\n4 İzmir Çiğli Training and Research Hospital, Clinic of Internal Medicine, İzmir, Turkey\n* Address for Correspondence: University of Health Sciences Turkey, İzmir Bozyaka Training and Research Hospital, Clinic of Hematology, İzmir, Turkey Phone: +90 505 886 11 26 E-mail:med.can@hotmail.com\n9 2021\n25 8 2021\n38 3 181187\n4 4 2021\n22 6 2021\n© Copyright 2021 by Turkish Society of Hematology / Turkish Journal of Hematology, Published by Galenos Publishing House.\n2021\nhttps://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nObjective:\n\nPrimary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by isolated thrombocytopenia. While first-line treatments focus on inhibiting autoantibodies and platelet destruction, second- and third-line treatments include splenectomy and thrombopoietin receptor agonists. In this study, we aimed to compare the efficiency and toxicities of splenectomy and eltrombopag as second-line treatments in ITP.\n\nMaterials and Methods:\n\nWe retrospectively analyzed patients who were diagnosed with ITP and followed between 2015 and 2020. Patients who underwent splenectomy or received eltrombopag treatment as second-line or further therapy were included. For subgroup analyses, patients were further stratified according to whether they received eltrombopag in the second or third line of treatment.\n\nResults:\n\nThere were 38 patients in the splenectomy group and 47 patients in the eltrombopag group. The mean age of patients in the splenectomy and eltrombopag groups was 43.2 and 50.5 years, respectively. Time to response was significantly shorter in the splenectomy arm (p=0.001). However, response rates at the 3rd, 6th, 12th, and 24th months did not exhibit a statistically significant difference between groups; nor did total duration of response and adverse events. Response rates at the 1st, 3rd, 6th, 12th, and 24th months and the total duration of response did not exhibit a statistically significant difference between eltrombopag subgroups. Eltrombopag treatment was ceased for 20 patients after a median of 54.1 months (range: 1-151). Among them, 12 patients (60%) did not experience a loss of response.\n\nConclusion:\n\nComparing the splenectomy and eltrombopag arms, even though time to achieve response was in favor of the splenectomy group, this advantage disappeared when overall response rates and response rate at the 2nd year were considered. Using eltrombopag in the second or third line of therapy does not yield any difference in terms of time to achieving response.\n\nAmaç:\n\nPrimer immün trombositopeni (İTP), izole trombositopeni ile karakterize, edinsel bir otoimmün hastalıktır. Birinci basamak tedaviler otoantikorları ve trombosit yıkımını inhibe etmeye odaklanırken, ikinci ve üçüncü basamak tedaviler arasında splenektomi ve trombopoietin reseptör agonistleri bulunur. Bu çalışmada, İTP’de ikinci basamak tedaviler olarak splenektomi ve eltrombopagın etkinlik ve toksisitelerinin karşılaştırılması amaçlanmıştır.\n\nGereç ve Yöntemler:\n\n2015-2020 yılları arasında İTP tanısı alan ve takip edilen hastaları retrospektif olarak analiz ettik. Splenektomi yapılan ve 2. veya daha ileri basamaklarda eltrombopag tedavisi alan hastalar çalışmaya dahil edildi. Alt grup analizleri için, hastalar ikinci veya üçüncü tedavi hattında eltrombopag alıp almadıklarına göre gruplandırıldı.\n\nBulgular:\n\nSplenektomi grubunda 38 hasta, eltrombopag grubunda 47 hasta vardı. Splenektomi ve eltrombopag gruplarındaki hastaların ortalama yaşı sırasıyla 43,2 ve 50,5’di. Splenektomi kolunda yanıt süresi anlamlı olarak daha kısaydı (p=0,001). Bununla birlikte, 3., 6., 12. ve 24. aylardaki yanıt oranları, toplam yanıt süresi ve yan etkiler açısından gruplar arasında istatistiksel olarak anlamlı fark bulunmadı. Birinci, 3., 6., 12. ve 24. aylardaki yanıt oranları ve toplam yanıt süresi, eltrombopag alt grupları arasında istatistiksel olarak anlamlı değildi. Eltrombopag tedavisi medyan 54,1 ay (1-151) sonra 20 hastada kesildi. Bunlardan 12 hastada (%60) yanıt kaybı yaşanmadı.\n\nSonuç:\n\nSplenektomi ve eltrombopag kolları karşılaştırıldığında yanıt alma süresi splenektomi lehine olsa da, genel yanıt oranları ve 2. yıldaki yanıt oranları dikkate alındığında bu avantaj ortadan kalkmaktadır. İkinci veya 3. basamak tedavide eltrombopag kullanılması, yanıt alma süresi açısından herhangi bir fark oluşturmamaktadır.\n\nThrombocytopenia\nEltrombopag\nSplenectomy\n==== Body\nIntroduction\n\nPrimary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by isolated thrombocytopenia caused by T-cell-mediated platelet destruction, with immunoglobulin G autoantibodies binding to platelets and megakaryocytes, and megakaryocyte dysfunction. Patients may present with petechiae, purpura, mucosal bleeding, and life-threatening organ bleeding [1,2,3]. The aim of treatment is to prevent serious or life-threatening bleeding. Treatment modalities employed in ITP target various stages in its pathophysiology, including the inhibition of autoantibody synthesis, modulation of T-cell activity, and stimulation of platelet production. While first-line treatments mainly focus on inhibiting autoantibodies and platelet destruction, second- and third-line treatments include immunosuppression, splenectomy, and megakaryocyte stimulation for increased platelet production [4].\n\nSplenectomy is an effective treatment choice for steroid-refractory or steroid-dependent ITP because the spleen is the major site of platelet clearance. Macrophages express the FcγR function in the phagocytosis of antibody-coated platelets via SYK signaling pathways [5,6]. They also present antigenic peptides, including glycoproteins IIa/IIIb and Ib/IX, to CD4+ T cells, causing activation and expansion of autoreactive B- and T-cells [7,8]. The spleen also acts as a reservoir for long-lived plasma cells producing antiplatelet antibodies [9]. However, there is no reliable predictor for splenectomy response. Considering the associated risk of infection and cardiovascular complications, splenectomy is being replaced by immunosuppressive agents and thrombopoietin receptor agonists (TPO-RAs) as the second-line treatment of ITP [10].\n\nThe TPO-RAs romiplostim and eltrombopag have been widely used since 2008 [11]. These agents bind to the TPO receptor, cause conformational changes, and activate the JAK2/STAT5 pathway, increasing megakaryocyte progenitor proliferation and platelet production [12,13]. Randomized controlled studies with TPO-RAs have reported response rates of 50% to 90%, as well as efficiency in preventing bleeding and decreased need to use additional medication. Data on toxicity indicate reversible reticulin fibrosis and increased risk of venous thromboembolism (VTE) [11].\n\nStudies that directly compare the long-term efficacy of second-line treatments for ITP are limited and treatment decisions are therefore mostly patient-based. In this study, we aimed to compare the efficiency and toxicities of splenectomy and eltrombopag, a TPO-RA, as second-line treatments for ITP.\n\nMaterials and Methods\n\nIn our study, we retrospectively analyzed patients who were diagnosed with ITP after the evaluation of complete blood count, peripheral blood smear, blood biochemistry, viral serologies including human immunodeficiency virus and hepatitis C virus, abdominal sonography, and antinuclear antibody testing and who were followed between 2015 and 2020. Bone marrow aspiration and biopsy were performed for patients as deemed necessary by the clinician to confirm the diagnosis of ITP. Among these cases, patients who were steroid-resistant, who were steroid-refractory, or who experienced relapse after response and who had undergone splenectomy or received eltrombopag treatment as second-line or third-line therapy as the next step after only splenectomy were included in the study. Included subjects were divided into splenectomy and eltrombopag groups. For subgroup analyses, patients receiving eltrombopag were further stratified according to whether they received eltrombopag as the second or third line of treatment.\n\nPatient data were recorded, including age, sex, ITP bleeding score, white blood cell (WBC) count, neutrophil and lymphocyte counts, hemoglobin level, mean corpuscular volume (MCV), platelet count, mean platelet volume (MPV), serum creatinine, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels at the time of splenectomy or initiation of eltrombopag therapy, as well as the dates of diagnosis and last visit. The ITP bleeding score was assessed according to the World Health Organization Bleeding Scale [14]. Cases were classified using a simple five-point scale in which no bleeding was scored as 0, petechiae as grade 1, mild blood loss as grade 2, gross blood loss as grade 3, and debilitating blood loss as grade 4. The following comparisons between the splenectomy and eltrombopag groups were also performed: time to achieve response; response at the 1st, 3rd, 6th, 12th, and 24th months; total duration of response; and complications. Response evaluation was performed according to the American Society of Hematology’s 2009 International Working Group Report [15]. Platelet count below 30,000/mm3 was considered as no response, above 30,000/mm3 as response, and above 100,000/mm3 as complete response.\n\nThe compliance of the study with ethical rules was confirmed by the İzmir Bozyaka Training and Research Hospital Ethics Committee and approval was granted. Also, the consent was obtained from the volunteers included in the study.\n\nStatistical Analysis\n\nSPSS 21 was used for statistical tests. Data were represented as mean ± standard deviation for numeric variables and as frequency and percentage for categorical variables. Normality of numeric variables was assessed by Shapiro-Wilk test. Comparisons of normally distributed variables were performed using t-tests, while the Mann-Whitney U test was used for nonnormally distributed nonparametric variables. The chi-square test was used to determine whether there was a relationship and dependency between two variables. Values of p<0.05 were considered statistically significant.\n\nResults\n\nEighty-five patients were included in the study. Bone marrow aspiration and biopsy were performed for 67 patients who required confirmation of the diagnosis of ITP. Among those, 49 were female and 36 were male. The median ages of the patients in the splenectomy and eltrombopag groups were 43.2 and 50.5 years, respectively. There were 38 patients in the splenectomy group and 47 patients in the eltrombopag group. There was no statistically significant difference between the two groups in terms of age, sex, comorbidities, bleeding score, WBC count, neutrophil and lymphocyte counts, hemoglobin, MCV, or platelet count. Characteristics of the treatment groups are summarized in Table 1.\n\nTable 2 presents data on the time to achieve response (R) or complete response (CR) in the second line of treatment; R/CR at the 1st, 3rd, 6th, 12th, and 24th months of second-line therapy; and the total duration of R/CR of the treatment groups. Time to R/CR was significantly shorter in the splenectomy group (p=0.001). The R/CR rate at the 1st month was also significantly higher in the splenectomy group (p=0.023). However, R/CR rates at the 3rd, 6th, 12th, and 24th months and total duration of R/CR did not exhibit statistically significant differences between the groups.\n\nOne patient in the splenectomy group developed deep vein thrombosis. In the eltrombopag group, one patient experienced headache, one patient had elevated liver enzymes, one patient developed bone marrow fibrosis, one patient developed chronic myelomonocytic leukemia (CMML), one patient developed basal cell carcinoma, and one patient developed pancreatic cancer. There was no statistically significant difference in adverse events between treatment groups (p=0.105). Bone marrow fibrosis was detected in the patient who underwent bone marrow biopsy 3 years after eltrombopag treatment because platelet increase could not be achieved despite increasing the dose of eltrombopag. The diagnosis of CMML was made 14 months after the patient started eltrombopag. A blast count below 5% was considered as CMML-0 and the patient was followed without treatment.\n\nPatients receiving eltrombopag were stratified according to whether they received the treatment in the second or third line. Table 3 provides data on age and sex; comorbidities; bleeding score; WBC, neutrophil, and lymphocyte counts; hemoglobin, MCV, MPV, and platelet count; time to achieve R/CR; R/CR at the 1st, 3rd, 6th, 12th, and 24th months of second-line treatment; and the total duration of R/CR. Patients who received eltrombopag in the third line had significantly higher WBC counts (p=0.002). On the other hand, no significant difference was observed between the groups in terms of age, sex, comorbidities, bleeding score, neutrophil and lymphocyte counts, hemoglobin, MCV, or platelet count. The R/CR rates at the 1st, 3rd, 6th, 12th, and 24th months and the total duration of R/CR also did not exhibit statistically significant differences between the groups.\n\nEltrombopag treatment was discontinued with no tapering due to adverse effects or the patient’s refusal for various reasons in 20 patients after a median of 54.1 months (range: 1-151). Among them, 12 patients (60%) did not experience a loss of response. The median duration of eltrombopag treatment was 25.6 (range: 2-64) months and median follow-up was 67.9 (range: 20-151) months in these patients. The follow-up period after discontinuation of eltrombopag was 12.4 months, median platelet count was 159,000/mm3, and bleeding score was 0.0.\n\nDiscussion\n\nAs highlighted in the updated international consensus report, initial treatments for patients with newly diagnosed ITP are usually corticosteroid-based regimens, intravenous immunoglobulin (IVIg), and anti-D. However, the most commonly preferred treatments are corticosteroids. IVIg can also be added to the treatment for patients with active bleeding, patients who are scheduled to undergo emergency interventions, or patients who experience adverse events with glucocorticoids, even though this approach is not standardized [16,17,18].\n\nBecause there are no randomized controlled studies that directly compare second-line treatment options in ITP, treatment decisions are mostly based on patient characteristics and clinical preferences. Second-line medical treatments supported by robust evidence are rituximab and TPO-RAs. Splenectomy is still also preferred as a surgical option today [18,19,20].\n\nSplenectomy is among the second-line treatment options with the greatest likelihood of achieving long-term remission and changing the course of the disease [21]. Provan et al. [18] recommended waiting at least 12 months after the diagnosis to rule out possible spontaneous remission. As new drugs are available for ITP, splenectomy is often postponed. If the patient is working in a risky profession or has a thrombotic history or immunosuppression, splenectomy is considered as the second line. In developing countries, and especially for younger patients, it is still recommended for financial reasons and the difficulties in obtaining novel drugs. Kojouri et al. [22] conducted a systematic review of 47 case series including 2623 adult patients undergoing splenectomy and found rates of 66% complete response and 88% overall response. The mean duration of response was approximately 12 years in this patient group [22]. Platelet count often tends to rise within 1 to 2 days after splenectomy, while a delayed response can be observed at up to 8 weeks [23]. The only clinical parameter predicting splenectomy response is the patient’s age, with younger patients achieving higher response rates [22]. Even though there is no distinct age cut-off, splenectomy was recommended for patients younger than 50 years in two different studies [24,25]. In our study, the median age of the patients in the splenectomy group was 43.2 years. The higher median age of the patients in the eltrombopag group was due to elderly patients ineligible for splenectomy inevitably being in this treatment arm.\n\nThe most common complications after splenectomy, which is an irreversible procedure, are infections and venous thromboembolism. In the review by Kojouri et al. [22], complications occurred in 88 of 921 patients (9.6%) undergoing laparoscopic splenectomy and in 318 of 2465 patients (12.9%) undergoing open splenectomy. The risk of infection is highest in the early postoperative period. In another series of 3812 patients undergoing splenectomy for various indications, the rate of infections was 10.2% in the first 90 days [26]. However, this rate declines to 1%-3% in the long term [27]. In our study, no infectious side effects were found. The risk of VTE also increases after splenectomy. In the aforementioned cohort of 3812 patients undergoing splenectomy, the risk of VTE in the first year was reported to be 1.9%. Observed thromboses in that study were deep vein thrombosis in half of the patients, pulmonary embolism in a quarter, and portal or splenic vein thrombosis in the remaining quarter [26]. Considering these potential complications as well as the possibility of spontaneous remission in ITP, postponing splenectomy for 6 to 12 months after diagnosis may help avoid needless interventions. However, this duration may be shortened for symptomatic patients with severe thrombocytopenia [28]. In our study, response was observed at a mean of 1.9 days in 38 patients undergoing splenectomy and this response was durable for a mean of 43 months. One patient (2.6%) experienced deep vein thrombosis.\n\nStudies assessing the efficiency of eltrombopag have reported overall response rates of about 80%, including temporary responses. The RAISE study, which randomized 197 adult patients into eltrombopag and placebo arms, showed that the mean platelet count of patients receiving eltrombopag was 74,000/mm3 and their response rate was 79%. This rate showed no difference among patients who underwent splenectomy and those who received other therapies prior to eltrombopag. The long-term response rate was 51% in patients with splenectomy and 66% in patients without splenectomy [29]. In another study with 110 adult patients, rates of response to eltrombopag and a placebo were found to be 59% and 16%, respectively [30]. The EXTEND study revealed that the 3-year response rates of 299 patients using eltrombopag were 80% for splenectomized and 89.3% for non-splenectomized patients [31]. In a recent study assessing real-life data, the researchers reported that rates of response to eltrombopag were not affected by factors including splenectomy status or initial platelet count. Six of those patients stopped eltrombopag after a median sustained response of 796 days and remained in remission for a median follow-up of 624 days [32]. Similarly, González-López et al. [33] reported that 51% of patients remained in remission in the 6th month after eltrombopag cessation after sustained response.\n\nEltrombopag is usually well tolerated. The most common side effects are headache, gastrointestinal complaints, elevated liver enzymes, thrombosis, and bone marrow fibrosis. In the EXTEND study, 14% of patients had to cease medication due to adverse events. Among these, hepatobiliary adverse events were observed in 7 patients, cataract in 4 patients, deep vein thrombosis in 3 patients, cerebral infarction in 2 patients, headache in 2 patients, and myelofibrosis in 2 patients. The rate of thromboembolic events and hepatobiliary adverse events did not show any increase with 1 year of therapy [29,34]. In our study, median duration of response was 34.9 months in patients receiving eltrombopag and only 55% maintained response into the 2nd year. There was no significant difference in the response rates of patients with and without a history of splenectomy prior to eltrombopag. Twelve of 20 patients who stopped eltrombopag treatment remained in remission. The observed adverse events were consistent with those reported in the literature; however, malignancy development in 3 (6.3%) patients was noteworthy. The EXTEND study did not reveal a significant difference between the treatment and placebo arms in terms of malignancies [34]. In a multicenter study from Turkey that reported the 12-month data of 40 patients on eltrombopag, there were also no eltrombopag-associated malignancies [35]. We could not identify a direct association between the observed malignancies and eltrombopag use, but we think that these malignancies may be incidental due to the higher median age in the eltrombopag group. Furthermore, a statistically significant difference was found in our study in terms of pretreatment leukocyte counts between administration of eltrombopag as second-line and as third-line treatment. This difference may be attributable to splenectomy, as the patients receiving third-line eltrombopag had previously undergone splenectomy.\n\nConclusion\n\nComparing the splenectomy and eltrombopag arms of the present study, even though time to achieve response and the response rate at the 1st month were in favor of splenectomy, this advantage disappeared when overall response rates and response rate at the 2nd year were considered. However, more adverse events were observed in the eltrombopag group. Observed malignancies in 3 patients are inconsistent with the reported data in the literature. Using eltrombopag in the second or third line of therapy does not yield any difference in terms of time to achieve response. The overall response rate was higher when eltrombopag was used as the third-line treatment after splenectomy compared to second-line treatment, but this difference did not reach statistical significance. Randomized prospective studies comparing treatment options such as splenectomy, immunosuppressive therapies, and eltrombopag head-to-head are required for the standardization of second-line and more advanced therapies for immune thrombocytopenia.\n\nTable 1 Patient characteristics.\n\nTable 2 Comparison of treatment response between splenectomy and eltrombopag groups.\n\nTable 3 Eltrombopag as second-line or third-line treatment.\n\nEthics\n\nEthics Committee Approval: The compliance of the study with ethical rules was confirmed by the İzmir Bozyaka Training and Research Hospital Ethics Committee and approval was granted.\n\nInformed Consent: Consent was obtained from the volunteers included in the study.\n\nAuthorship Contributions\n\nSurgical and Medical Practices: M.C.U., E.E.D., E.T.E.; Concept: S.N., R.E., O.B.; Design: S.N., R.E.; Data Collection or Processing: M.C.U., E.E.D., E.T.E.; Analysis or Interpretation: M.C.U., R.E., O.B.; Literature Search: M.C.U., N.N.; Writing: N.N.\n\nConflict of Interest: No conflict of interest was declared by the authors.\n\nFinancial Disclosure: The authors declared that this study received no financial support.\n==== Refs\nReferences\n\n1 Khodadi E Asnafi AA Shahrabi S Shahjahani M Saki N Bone marrow niche in immune thrombocytopenia: a focus on megakaryopoiesis Ann Hematol 2016 95 1765 1776 27236577\n2 Olsson B Andersson PO Jernås M Jacobsson S Carlsson B Carlsson LM Wadenvik H T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura Nat Med 2003 9 1123 1124 12937414\n3 Moulis G Palmaro A Montastruc JL Godeau B Lapeyre-Mestre M Sailler L Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France Blood 2014 124 3308 3315 25305203\n4 Blickstein D Treatment of immune thrombocytopenic purpura in adults: update Harefuah 2019 15 196 199\n5 Audia S Santegoets K Laarhoven AG Vidarsson G Facy O Ortega-Deballon P Samson M Janikashvili N Saas P Bonnotte B 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15217831\n23 Gigot JF Healy ML Ferrant A Michaux JL Njinou B Kestens PJ Laparoscopic splenectomy for idiopathic thrombocytopenic purpura Am J Surg 2004 187 720 723 15191864\n24 Duperier T Brody F Felsher J Walsh RM Rosen M Ponsky J Predictive factors for successful laparoscopic splenectomy in patients with immune thrombocytopenic purpura Arch Surg 2004 139 61 66 14718278\n25 Tastaldi L Krpata DM Prabhu AS Petro CC Haskins IN Perez AJ Alkhatib H Colturato I Tu C Lichtin A Rosen MJ Rosenblatt S Laparoscopic splenectomy for immune thrombocytopenia (ITP): long-term outcomes of a modern cohort Surg Endosc 2019 33 475 485 29987573\n26 Thomsen RW Schoonen WM Farkas DK Riis A Jacobsen J Fryzek JP Sørensen HT Risk for hospital contact with infection in patients with splenectomy: a population-based cohort study Ann Intern Med 2009 151 546 555 19841456\n27 Bisharat N Omari H Lavi I Raz R Risk of infection and death among post-splenectomy patients J Infect 2001 43 182 186 11798256\n28 Rodeghiero F A critical appraisal of the evidence for the role of splenectomy in adults and children with ITP Br J Haematol 2018 181 183 195 29479668\n29 Cheng G Saleh MN Marcher C Vasey S Mayer B Aivado M Arning M Stone NL Bussel JB Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study Lancet 2011 377 393 402 20739054\n30 Bussel JB Provan D Shamsi T Cheng G Psaila B Kovaleva L Salama A Jenkins JM Roychowdhury D Mayer B Stone N Arning M Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial Lancet 2009 373 641 648 19231632\n31 Saleh MN Bussel JB Cheng G Meyer O Bailey CK Arning M Brainsky A; EXTEND Study Group Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study Blood 2013 121 537 545 23169778\n32 Mishra K Pramanik S Jandial A Sahu KK Sandal R Ahuja A Yanamandra U Kumar R Kapoor R Verma T Sharma S Singh J Das S Chatterjee T Sharma A Nair V Real-world experience of eltrombopag in immune thrombocytopenia Am J Blood Res 2020 10 240 251 33224568\n33 González-López TJ Alvarez-Román MT Pascual C Sánchez-González B Fernández-Fuentes F Jarque I Pérez-Rus G Pérez-Crespo S Bernat S Hernández-Rivas JA Andrade MM Cortés M Gómez-Nuñez M Olivera P Martínez-Robles V Fernández-Rodríguez A Fuertes-Palacio MA Fernández-Miñano C de Cabo E Fisac R Aguilar C Bárez A Peñarrubia MJ García-Frade LJ González-Porras JR Eltrombopag safety and efficacy for primary chronic immune thrombocytopenia in clinical practice Eur J Haematol 2016 97 297 302 26709028\n34 Wong RSM Saleh MN Khelif A Salama A Portella MSO Burgess P Bussel JB Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study Blood 2017 130 2527 2536 29042367\n35 Özdemirkıran F Payzın B Kiper HD Kabukçu S Akgün Çağlıyan G Kahraman S Sevindik ÖG Ceylan C Kadıköylü G Şahin F Keskin A Arslan Ö Özcan MA Kabukçu G Görgün G Bolaman Z Büyükkeçeci F Bilgir O Alacacıoğlu İ Vural F Tombuloğlu M Gökgöz Z Saydam G Eltrombopag for the treatment of immune thrombocytopenia: the Aegean Region of Turkey experience Turk J Hematol 2015 32 323 328\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1300-7777",
"issue": "38(3)",
"journal": "Turkish journal of haematology : official journal of Turkish Society of Haematology",
"keywords": "Thrombocytopenia; Eltrombopag; Splenectomy",
"medline_ta": "Turk J Haematol",
"mesh_terms": null,
"nlm_unique_id": "9606065",
"other_id": null,
"pages": "181-187",
"pmc": null,
"pmid": "34162173",
"pubdate": "2021-08-25",
"publication_types": "D016428:Journal Article",
"references": "20739054;15191864;19841456;29042367;33224568;19005182;26709028;12937414;12149222;25914025;31770441;29295846;19231632;29987573;14693160;19038790;27236577;11798256;27135647;30264861;30916510;22117897;23169778;27189086;21067388;19096013;23241960;31073079;15217831;28142207;29479668;29574922;11907134;14718278;25305203",
"title": "Comparison of Splenectomy and Eltrombopag Treatment in the Second-Line Treatment of Immune Thrombocytopenic Purpura",
"title_normalized": "comparison of splenectomy and eltrombopag treatment in the second line treatment of immune thrombocytopenic purpura"
} | [
{
"companynumb": "TR-NOVARTISPH-NVSC2022TR122504",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ELTROMBOPAG"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPersistent genital arousal disorder (PGAD) is an uncommon condition resulting in intrusive, unwanted and distressing symptoms of genital arousal. Presentation can vary and most cases do not have an immediately identifiable etiology.\n\n\nOBJECTIVE\nTo present evaluation and treatment recommendations for PGAD from a multidisciplinary perspective and provide case examples.\n\n\nMETHODS\nA focused review of the literature on diagnosis, workup, and treatment of PGAD was completed. A case series of 3 varying presentations of PGAD is offered.\n\n\nRESULTS\nPGAD results in high levels of patient distress and is best managed with a multidisciplinary treatment approach. Identification and management of co-occurring symptoms or disease states is imperative, particularly psychologic and psychiatric comorbidities. With appropriate intervention, patients may achieve improvement of their physical symptoms and a decrease in associated psychological distress.\n\n\nCONCLUSIONS\nPGAD is an uncommon and highly distressing condition that requires thoughtful evaluation for appropriate diagnosis and treatment. Multidisciplinary treatment approaches provide the best opportunity to address the needs of patients and optimizing treatment response. Pease ER, Ziegelmann M, Vencill JA, et al. Persistent Genital Arousal Disorder (PGAD): A Clinical Review and Case Series in Support of Multidisciplinary Management. Sex Med Rev 2021;XX:XXX-XXX.",
"affiliations": "Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.;Department of Urology, Mayo Clinic, Rochester, MN, USA. Electronic address: ziegelmann.matthew@mayo.edu.;Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA; Division of General Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA.;Division of General Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA.;Division of General Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.",
"authors": "Pease|Eric R|ER|;Ziegelmann|Matthew|M|;Vencill|Jennifer A|JA|;Kok|Susan N|SN|;Collins|C Scott|CS|;Betcher|Hannah K|HK|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.sxmr.2021.05.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2050-0521",
"issue": null,
"journal": "Sexual medicine reviews",
"keywords": "Genital Arousal; PGAD; Sexual Disorder; Sexual Function; Sexual Health; Sexual Medicine; Somatic Symptoms",
"medline_ta": "Sex Med Rev",
"mesh_terms": null,
"nlm_unique_id": "101614773",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34362711",
"pubdate": "2021-08-03",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Persistent Genital Arousal Disorder (PGAD): A Clinical Review and Case Series in Support of Multidisciplinary Management.",
"title_normalized": "persistent genital arousal disorder pgad a clinical review and case series in support of multidisciplinary management"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2022-07145",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DULOXETINE"
},
"drugadditional... |
{
"abstract": "The aim of our work is to promote the awareness about the development of sarcoidosis after antineoplastic therapy in order to avoid diagnostic errors with FDG-PET/CT findings. We report the observation of three women with breast, cervix and stomach treated cancers who developed a sarcoidosis after the end of anti-neoplastic therapy. The utility of FDG-PET/CT is in pinpointing the organs candidates for diagnostic biopsy and not distinguishing between the malignancy and granulomatous or inflammatory diseases.",
"affiliations": "Departamento de Cirugía Torácica, Centro Hospitalario Universitario Mohammed V, Rabat, Marruecos. Electronic address: hamoumimassine@hotmail.fr.;Departamento de Radioterapia, Centro Hospitalario Universitario Mohammed V, Rabat, Marruecos.;Departamento de Ginecología y Obstetricia, Centro Hospitalario Universitario Mohammed V, Rabat, Marruecos.;Departamento de Medicina Nuclear, Centro Hospitalario Universitario Mohammed V, Rabat, Marruecos.;Departamento de Radioterapia, Centro Hospitalario Universitario Mohammed V, Rabat, Marruecos.;Departamento de Cirugía Torácica, Centro Hospitalario Universitario Mohammed V, Rabat, Marruecos.",
"authors": "El Hammoumi|Massine|M|;El Marjany|Mohamed|M|;Moussaoui|Driss|D|;Doudouh|Aberahim|A|;Mansouri|Hamid|H|;Kabiri|El Hassane|el H|",
"chemical_list": "D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2896",
"issue": "51(7)",
"journal": "Archivos de bronconeumologia",
"keywords": "Malignancy; Malignidad; Mediastin; Mediastino; Mediastinoscopia; Mediastinoscopy; Reacciones sarcoideas; Sarcoid reaction; Sarcoidosis",
"medline_ta": "Arch Bronconeumol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D001943:Breast Neoplasms; D002277:Carcinoma; D003937:Diagnosis, Differential; D003951:Diagnostic Errors; D005260:Female; D019788:Fluorodeoxyglucose F18; D005743:Gastrectomy; D006099:Granuloma; D006801:Humans; D007044:Hysterectomy; D015182:Lymphatic Irradiation; D008207:Lymphatic Metastasis; D015412:Mastectomy, Segmental; D008477:Mediastinal Diseases; D008875:Middle Aged; D064847:Multimodal Imaging; D009364:Neoplasm Recurrence, Local; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D012507:Sarcoidosis; D013274:Stomach Neoplasms; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "0354720",
"other_id": null,
"pages": "e33-5",
"pmc": null,
"pmid": "25294405",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mediastinal sarcoidosis mimicking lymph malignancy recurrence after anti-neoplastic therapy.",
"title_normalized": "mediastinal sarcoidosis mimicking lymph malignancy recurrence after anti neoplastic therapy"
} | [
{
"companynumb": "MA-MYLANLABS-2017M1075700",
"fulfillexpeditecriteria": "1",
"occurcountry": "MA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "There is a paucity of data regarding outcomes and response to standard therapy in patients with limited-stage (LS) agressive B-cell lymphoma (LS-ABCL) who harbor MYC rearrangement (MYC-R) with or without BCL2 and/or BCL6 rearrangements. We conducted a multicenter retrospective study of MYC-R LS-ABCL patients who received either rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), or more intensive immunochemotherapy (IIC) plus or minus consolidative involved-field radiation therapy (IFRT). One hundred four patients from 15 academic centers were included. Forty four patients (42%) received R-CHOP, of whom 52% had IFRT. Sixty patients (58%) received IIC, of whom 40% had IFRT. Overall response rate was 91% (84% complete response [CR]; 7% partial response). Patients with double-hit lymphoma (DHL; n = 40) had a lower CR rate compared with patients with MYC-R only (75% vs 98%; P = .003). CR rate was higher in the IFRT vs no-IFRT group (98% vs 72%; P < .001). Median follow-up was 3.2 years; 2-year progression-free survival (PFS) and overal survival (OS) were 78% and 86% for the entire cohort, and 74% and 81% for the DHL patients, respectively. PFS and OS were similar across treatment groups (IFRT vs no IFRT, R-CHOP vs IIC) in the entire cohort and in DHL patients. Our data provide a historical benchmark for MYC-R LS-ABCL and LS-DHL patients and show that outcomes for this population may be better than previously recognized. There was no benefit of using IIC over R-CHOP in patients with MYC-R LS-ABCL and LS-DHL.",
"affiliations": "Roswell Park Comprehensive Cancer Center, Buffalo, NY.;Department of Medicine, Yale University, New Haven, CT.;Roswell Park Comprehensive Cancer Center, Buffalo, NY.;The University of Texas MD Anderson Cancer Center, Houston, TX.;The University of Texas MD Anderson Cancer Center, Houston, TX.;Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.;Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.;The Ohio State University Cancer Center, Columbus, OH.;The Ohio State University Cancer Center, Columbus, OH.;Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC.;Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC.;Lymphoma Division, Stanford University, Stanford, CA.;Lymphoma Division, Stanford University, Stanford, CA.;Fox Chase Cancer Center, Philadelphia, PA.;Fox Chase Cancer Center, Philadelphia, PA.;University of Nebraska Medical Center, Omaha, NE.;Winship Cancer Institute, Emory University, Atlanta, GA.;Winship Cancer Institute, Emory University, Atlanta, GA.;Feinberg School of Medicine, Northwestern University, Chicago, IL.;Feinberg School of Medicine, Northwestern University, Chicago, IL.;Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL.;Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL.;Department of Medicine, Alpert Medical School, Brown University, Providence, RI.;Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH.;Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH.;Dartmouth-Hitchcock Medical Center, Lebanon, NH; and.;Dartmouth-Hitchcock Medical Center, Lebanon, NH; and.;Division of Hematology & Oncology, University of Illinois at Chicago, Chicago, IL.;Division of Hematology & Oncology, University of Illinois at Chicago, Chicago, IL.;Roswell Park Comprehensive Cancer Center, Buffalo, NY.;Roswell Park Comprehensive Cancer Center, Buffalo, NY.;Roswell Park Comprehensive Cancer Center, Buffalo, NY.",
"authors": "Torka|Pallawi|P|;Kothari|Shalin K|SK|;Sundaram|Suchitra|S|;Li|Shaoying|S|;Medeiros|L Jeffrey|LJ|;Ayers|Emily C|EC|;Landsburg|Daniel J|DJ|;Bond|David A|DA|;Maddocks|Kami J|KJ|;Giri|Anshu|A|;Hess|Brian|B|;Pham|Luu Q|LQ|;Advani|Ranjana|R|;Liu|Yang|Y|;Barta|Stefan Klaus|SK|;Vose|Julie M|JM|;Churnetski|Michael C|MC|;Cohen|Jonathon B|JB|;Burkart|Madelyn|M|;Karmali|Reem|R|;Zurko|Joanna|J|;Mehta|Amitkumar|A|;Olszewski|Adam J|AJ|;Lee|Sarah|S|;Hill|Brian T|BT|;Burns|Timothy F|TF|;Lansigan|Frederick|F|;Rabinovich|Emma|E|;Peace|David|D|;Groman|Adrienne|A|;Attwood|Kristopher|K|;Hernandez-Ilizaliturri|Francisco J|FJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1182/bloodadvances.2019000875",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2473-9529",
"issue": "4(2)",
"journal": "Blood advances",
"keywords": null,
"medline_ta": "Blood Adv",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003582:Cytogenetics; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008875:Middle Aged; D009367:Neoplasm Staging; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101698425",
"other_id": null,
"pages": "253-262",
"pmc": null,
"pmid": "31945157",
"pubdate": "2020-01-28",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "27382104;22252721;19704118;9647875;26373676;24943107;26456939;29061568;26980727;19151788;22851565;15210738;14504078;17228021;31498031;28475457;25161267;22002575;18413640;20498406;25687653;19597184;16648042;31285189;30501868;30939090",
"title": "Outcomes of patients with limited-stage aggressive large B-cell lymphoma with high-risk cytogenetics.",
"title_normalized": "outcomes of patients with limited stage aggressive large b cell lymphoma with high risk cytogenetics"
} | [
{
"companynumb": "US-BAXTER-2020BAX008479",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Acquired factor X (FX) deficiency is a rare but serious complication of primary amyloidosis, presumably caused by the binding of amyloid proteins to the clotting factors. The prolonged prothrombin time, partial thromboplastin time, and low FX level, which are correctable by mixing study, are the disease hallmarks. An immediate goal of care is to stop bleeding. Clotting factor replacement requires close monitoring of coagulogram and FX levels due to varying FX clearance among patients. High-purity FX is currently approved for hereditary FX deficiency and has been successfully used in some acquired FX deficiency cases. Ongoing bleeding risk complicates the treatment decision. Novel therapies yielding rapid and deep response reduce amyloid protein production and improve long-term outcome.",
"affiliations": "1 Indiana University School of Medicine, Indianapolis, IN, USA.;1 Indiana University School of Medicine, Indianapolis, IN, USA.",
"authors": "Dejhansathit|Siroj|S|0000-0001-7679-831X;Suvannasankha|Attaya|A|",
"chemical_list": "D058227:Amyloidogenic Proteins; D000970:Antineoplastic Agents; D001779:Blood Coagulation Factors; D007166:Immunosuppressive Agents; D005170:Factor X",
"country": "United States",
"delete": false,
"doi": "10.1177/2324709619832332",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961983233210.1177_2324709619832332Case ReportAcquired Factor X Deficiency in Patients With Primary Light Chain Amyloidosis https://orcid.org/0000-0001-7679-831XDejhansathit Siroj MD1Suvannasankha Attaya MD11 Indiana University School of Medicine, Indianapolis, IN, USAAttaya Suvannasankha, MD, Division of Hematology and Oncology, Department of Medicine, Indiana University School of Medicine, 980 West Walnut Street, Indianapolis, IN 46202, USA. Email: asuvanna@iupui.edu04 4 2019 Jan-Dec 2019 7 232470961983233216 1 2019 19 1 2019 24 1 2019 © 2019 American Federation for Medical Research2019American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Acquired factor X (FX) deficiency is a rare but serious complication of primary amyloidosis, presumably caused by the binding of amyloid proteins to the clotting factors. The prolonged prothrombin time, partial thromboplastin time, and low FX level, which are correctable by mixing study, are the disease hallmarks. An immediate goal of care is to stop bleeding. Clotting factor replacement requires close monitoring of coagulogram and FX levels due to varying FX clearance among patients. High-purity FX is currently approved for hereditary FX deficiency and has been successfully used in some acquired FX deficiency cases. Ongoing bleeding risk complicates the treatment decision. Novel therapies yielding rapid and deep response reduce amyloid protein production and improve long-term outcome.\n\nfactor X deficiencyblood coagulation disordersAL amyloidosiscover-dateJanuary-December 2019\n==== Body\nCase Series\nCase 1\nA 42-year-old woman presented to the emergency department with acute abdominal pain and was diagnosed with a hemoperitoneum from a ruptured ovarian cyst. The laparoscopic evaluation was complicated by continuous bleeding. Additional workup confirmed a partial thromboplastin time (PTT) of 42 seconds (normal 20-36 seconds), which was corrected by mixing study, suggesting factor deficiency. Factor X (FX) activity was 11%, while others were normal. She required multiple units of fresh frozen plasma (FFP) and aminocaproic acid for bleeding control. FX activity did not significantly improve after FFP infusion but improved transiently with prothrombin complex concentrates (PCC). However, to maintain a FX activity over 20%, a higher dose and more frequent infusions were required. Serum protein electrophoresis showed IgG kappa monoclonal protein of 0.4 g/dL, and serum-free kappa and lambda light chain levels were 14.5 and 72.2 g/dL, respectively. Bone marrow aspiration and biopsy showed 3% kappa-restricted plasma cells. Congo red staining of bone marrow was negative, but rectal biopsy tissue was positive. Immunofluorescent staining confirmed kappa-restricted amyloid protein. Amyloidosis of the kidney was also suspected based on 3 g/24 h proteinuria, though kidney biopsy was not performed. She had no hepatosplenomegaly. Troponin, pro-BNP levels, and echocardiogram were normal. The patient had ongoing bleeding complications including heavy periods requiring uterine ablation and intermittent lower gastrointestinal bleeding. She started induction therapy using bortezomib, cyclophosphamide, and dexamethasone regimen (CyborD). She developed grade 2 painful sensory neuropathy and only achieved marginal response after 3 cycles of therapy. Her FX activity remained between 10% and 15%. She proceeded to stem cell collection, followed by high-dose melphalan and autologous stem cell transplantation. During the myelosuppressive period, she received PCC and platelet transfusion to keep the platelet level over 20 × 109/mL. She achieved complete remission as evidenced by the normalized serum lambda light chain and correspondingly had a gradual improvement of FX level.\n\nCase 2\nA 67-year-old man presented with an ankle swelling and cutaneous purpura. Additional workup showed 7 g/dL of albuminuria, and kidney biopsy confirmed lambda-restricted amyloid protein deposition. The patient had a bleeding complication from kidney biopsy, which led to additional investigations confirming a low serum FX activity (20%). Splenomegaly was noted on the computed tomography of the abdomen. He had no bleeding history but reported easy bruising for the past 3 months. Serum protein electrophoresis showed 1.0 g/dL of IgG lambda monoclonal protein. Serum-free kappa and lambda light chain levels were 18 and 34 g/dL, respectively. Bone marrow aspiration and biopsy confirmed 5% of lambda-restricted plasma cells. The patient opted against stem cell transplantation and underwent induction therapy with the bortezomib-based regimen. He achieved complete hematologic remission. Serum FX level improved but remained low at 35%. The patient was in an auto accident resulting in a splenic rupture. He underwent emergent splenectomy and required red blood cell transfusion during the procedure. The serum FX level improved to 52% within 1 month after the surgery.\n\nDiscussion\nBleeding complications are common in patients with primary amyloidosis (AL amyloidosis; AL). Multifactorial causes include vasculopathy due to amyloid protein deposition, production defect of clotting factors due to liver failure, and, less commonly, clotting factor deficiency due to adsorption of clotting factors by amyloid protein.1 This case series illustrates an unusual presentation of acquired FX deficiency in systemic amyloidosis. FX deficiency is the most common coagulation factor deficiency in amyloidosis, occurring in 6.3% to 14% of patients.2 AL is the only described cause for acquired isolated deficiency of FX.\n\nFX involves both the intrinsic and extrinsic pathways of coagulation cascades3; therefore, the prolonged prothrombin time and PTT, and low FX levels, corrected by mixing study, are clues to FX deficiency rather than the presence of clotting inhibitors.4 Acquired FX deficiency in patients with primary amyloidosis is secondary to the adsorption of FX to amyloid fibrils in the reticuloendothelial system leading to a shortened half-life.5,6 While in congenital FX deficiency bleedings tend to occur only in severe cases with FX level <10% (0.01 IU/mL), patients with AL-related FX deficiency can develop bleeding complications at higher FX levels. In our case series, spontaneous bleeding occurred when FX levels were between 10% and 25%. The above-mentioned evidence highlights the more complicated bleeding diathesis in primary amyloidosis where other variables such as vascular integrity, clot lysis rate, platelet count, and function may also play a role.7 In a series of acquired clotting deficiency in AL amyloidosis, serious bleeding can occur in up to 56% of patients.1 This includes excessive bleeding after invasive procedures, intracranial, umbilical cord, joint, and muscle bleeding.3\n\nFor acute bleeding, correction of factor deficiency is the primary goal. FFP, PCCs, activated PCCs, recombinant factor VIIa (rFVIIa), and most recently available high-purity FX have been successfully used. FFP, PCCs, and activated PCCs have a varying amount of FX concentration (Table 1). Advantages of PCCs versus FFP include more rapid correction of FX deficiency due to higher FX concentration in PCCs; greater increase in other clotting factors, which may benefit patients with acquired deficiency of other clotting factors in addition to FX case of combined clotting factor deficiency; fewer complications secondary to fluid overload; and shortened preparation time since PCCs do not need to be thawed and do not require blood typing. While recommended dosing of these products are based on factor IX concentration in the product, the dose required for acquired FX deficiency is not known, and therefore, the measurement of FX activity post infusion is needed. High-purity FX concentrations (Factor X P Behring; CSL Behring, King of Prussia, PA; and Coagadex; Bio Products Laboratory, Elstree, England) have recently received an Food and Drug Administration approval for the treatment of hereditary FX deficiency, but not yet for acquired FX deficiency, despite its successful application in a small case series. It is not available locally; therefore, its use may be limited to large medical centers.\n\nTable 1. Factor Compositions in the Prothrombin Complex Concentrates (PCC), as Ratio to Factor IX.\n\n\tFII\tFVII\tFIX\tFX\tDosea\t\n\n3-Factor PCC\n\t\nBebulin (USA)\t120 units\t13 units\t100 units\t139 units\t25-35 units/kg (minor bleed); 40-55 units/kg (moderate bleed); 60-70 units/kg (serious bleed)\t\nProthrombinex HT (Australia)\t100 units\t—\t100 units\t100 units\t25-50 units/kg\t\nCofact (Europe and UK)\t~75 units\t~25 units\t100 units\t~75 units\t25-50 units/kg\t\nProfilnine SD (USA)\t148 units\t11 units\t100 units\t64 units\t25-50 units/kg\t\n\n4-Factor PCCs\n\t\nBeriplex (UK), KCentra (US)\t128 units\t68 units\t100 units\t152 units\t25-50 units/kg\t\nProthromplex T (Austria)\t100 units\t85 units\t100 units\t100 units\t25-50 units/kg\t\nOctaplex (UK and Europe)\t44-152units\t36-96 units\t100 units\t72-120 units\t25-50 units/kg\t\na Dose of PCC product is based on factor IX component.\n\nDue to the variation in the adsorption and clearance of FX by amyloid protein, it is mandatory to monitor and adjust the frequency as well as the concentrations of these products based on the levels of PTT as well as FX activity after each transfusion, as shown in Case 1. At present, the optimal target after replacement for the FX levels in patients with primary amyloidosis is not known; however, it can be derived from that of patients with congenital FX deficiency: 10 to 15 IU/dL for minor bleeding and >50 IU/dL for major bleeding, trauma, or surgery.8 Physician needs to exert extra caution for volume overload particularly in AL amyloid patients with cardiac involvement when a large volume of factor replacement is used.\n\nOther therapies with reported use in acquired FX deficiency include activated rFVIIa. rFVIIa binds to tissue factor exposed on injured tissue to activate factor IX, factor X, and platelets.9 In addition, high concentrations of factor VIIa can directly activate platelets and local thrombin formation.10 rFVIIa may be effective in treating persistent skin and muscle bleeding, and intraoperative bleeding.11 However, successful thrombin generation requires activation of FX downstream of FVII, and rFVIIa may be ineffective in cases of severe FX deficiency. Both rFVIIa and PCC increase the risk of thrombosis, particularly in patients with nephrotic proteinuria whose thrombotic risk is already high; therefore, close observation for thrombosis is warranted.\n\nPlasma exchange has been used to remove clotting inhibitors.6 Plasma exchange with FFP allows a transient replacement of FX while avoiding volume overload, but the benefit is short-lived due to adsorption of the replaced FX by the amyloid protein. Central venous access needed for plasma exchange increases bleeding risk. Antithrombotic agents including aminocaproic acid or tranexamic acid do not directly correct FX deficiency but provide clot stabilization. They can be used together with clotting factor replacement in serious bleeding and can be adequate to use in mucosal bleeding particularly in an outpatient setting.\n\nA majority of FX adsorption is believed to occur within the reticuloendothelial system. Rapid correction of FX levels has been reported post-splenectomy and extensive amyloid deposition seen in the removed spleen.5 However, splenectomy carries a high bleeding risk, which can be attenuated by factor replacement. In Case 2, the patient had a mild FX deficiency and had already responded to induction therapy. Splenectomy yielded a rapidly improved FX activity.\n\nThe long-term outcome of amyloidosis-related FX deficiency depends on the response to treatment of primary amyloidosis. High-dose chemotherapy and stem cell transplantation have been a standard of care for young and fit patients with limited organ involvement. Patients with cardiac involvement or extensive organ involvement are typically treated with combination chemotherapy. Newer agents including proteasome inhibitors and immunomodulatory agents yield rapid response, while having low toxicities, and have been incorporated into AL amyloidosis algorithms at diagnosis and relapse. FX activity improvement may lack behind hematologic response, so the risk of bleeding continues long after hematologic remission. Serial FX levels and factor replacement for bleedings and prophylaxis prior to invasive procedures are recommended.12 Patients are recommended to wear medical alert bracelets highlighting their underlying bleeding disorder, in case of bleeding emergency.\n\nIn summary, we report the case series of acquired FX deficiency and review the current standard of care, where early recognition and factor replacement is lifesaving.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: VA merit award I01CX000977 (to AS).\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iD: Siroj Dejhansathit \nhttps://orcid.org/0000-0001-7679-831X\n==== Refs\nReferences\n1 \nChoufani EB Sanchorawala V Ernst T et al \nAcquired factor X deficiency in patients with amyloid light-chain amyloidosis: incidence, bleeding manifestations, and response to high-dose chemotherapy . Blood . 2001 ;97 :1885 -1887 .11238135 \n2 \nGreipp PR Kyle RA Bowie EJ. \nFactor X deficiency in amyloidosis: a critical review . Am J Hematol . 1981 ;11 :443 -450 .7036713 \n3 \nMannucci PM. \nRare inherited coagulation disorders . In: Leung LLK Tirnauer JS eds. UpToDate . Waltham, MA : UpToDate Inc ; 2019 \nhttp://www.uptodate.com/contents/rare-inherited-coagulation-disorders#H4350607\n4 \nMumford AD O’Donnell J Gillmore JD Manning RA Hawkins PN Laffan M. \nBleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis . Br J Haematol . 2000 ;110 :454 -460 .10971408 \n5 \nFurie B Voo L McAdam KP Furie BC. \nMechanism of factor X deficiency in systemic amyloidosis . N Engl J Med . 1981 ;304 :827 -830 .7207512 \n6 \nBeardell FV Varma M Martinez J. \nNormalization of plasma factor X levels in amyloidosis after plasma exchange . Am J Hematol . 1997 ;54 :68 -71 .8980263 \n7 \nGatel A Cacoub P Piette JC. \nAL amyloidosis combined with acquired factor V deficiency . Ann Intern Med . 1998 ;128 :604 -605 .\n8 \nBrown DL Kouides PA. \nDiagnosis and treatment of inherited factor X deficiency . Haemophilia . 2008 ;14 :1176 -1182 .19141158 \n9 \nHender U Lee CA. \nFirst 20 years with recombinant FVIIa (NovoSeven) . Haemophilia . 2011 ;17 :e172 -e182 .20609014 \n10 \nMonroe DM Hoffman M Oliver JA Roberts HR. \nPlatelet activity of high-dose factor VIIa is independent of tissue factor . Br J Haematol . 1997 ;99 :542 -547 .9401063 \n11 \nBoggio L Green D. \nRecombinant human factor VIIa in the management of amyloid-associated factor X deficiency . Br J Haematol . 2001 ;112 :1074 -1075 .11298609 \n12 \nThompson CA Kyle R Gertz M Heit J Pruthi R Pardanani A. \nSystemic AL amyloidosis with acquired factor X deficiency: a study of perioperative bleeding risk and treatment outcomes in 60 patients . Am J Hematol . 2010 ;85 :171 -173 .20052750\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "7()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "AL amyloidosis; blood coagulation disorders; factor X deficiency",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000328:Adult; D000368:Aged; D058227:Amyloidogenic Proteins; D000970:Antineoplastic Agents; D001779:Blood Coagulation Factors; D005170:Factor X; D005171:Factor X Deficiency; D005260:Female; D006470:Hemorrhage; D006801:Humans; D000075363:Immunoglobulin Light-chain Amyloidosis; D007166:Immunosuppressive Agents; D008297:Male; D010314:Partial Thromboplastin Time",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709619832332",
"pmc": null,
"pmid": "30947547",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "10971408;11238135;11298609;19141158;20052750;20609014;7036713;7207512;8980263;9401063;9518420",
"title": "Acquired Factor X Deficiency in Patients With Primary Light Chain Amyloidosis.",
"title_normalized": "acquired factor x deficiency in patients with primary light chain amyloidosis"
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"abstract": "Bullous pemphigoid (BP) is the most prevalent autoimmune blistering skin disease in the Western world affecting mainly the elderly population. The diagnosis is based on clinical assessment along with specific immunopathologic findings on skin biopsy. Risk factors include genetic factors, environmental exposures, and several infections including hepatitis B, hepatitis C, Helicobacter pylori, Toxoplasma gondi, and cytomegalovirus. A variety of drugs have been associated with BP including but not limited to dipeptidyl peptidase-4 inhibitors, loop diuretics, spironolactone, and neuroleptics. Associated neurologic disorders (dementia, Parkinson's disease, bipolar disorder, previous stroke history, and multiple sclerosis) have also been described. Common clinical presentation consists of extremely pruritic inflammatory plaques that resemble eczematous dermatitis or urticaria, followed by formation of tense bullae with subsequent erosions. Typical distribution involves the trunk and extremities. Mucosa is typically spared affecting only 10% to 30% of patients. Several unusual clinical presentations of BP have been described such as nonbullous forms with erythematous excoriated papules, plaques, and nodules. Other reported findings include urticarial lesions, prurigo-like nodules, multiple small vesicles resembling dermatitis herpetiformis or pompholyx, vegetating and purulent lesions localized in intertriginous areas, and even exfoliative erythroderma. Recognition and management of such cases can present a diagnostic challenge to clinicians. In this article, we describe another variant which to our knowledge is the first case to present with a cellulitis-like presentation in a patient with a known history of BP.",
"affiliations": "Texas Tech University Health Sciences Center, Amarillo, TX, USA.;Texas Tech University Health Sciences Center, Amarillo, TX, USA.;Texas Tech University Health Sciences Center, Amarillo, TX, USA.;Amarillo VA Health Care System, Amarillo, TX, USA.;Texas Tech University Health Sciences Center, Amarillo, TX, USA.",
"authors": "Ivyanskiy|Ilya|I|;Dave|Dhara|D|;Dweik|Anass|A|;Yeary|James|J|;Naguib|Tarek M|TM|",
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"doi": "10.1177/23247096211008585",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096\nSAGE Publications Sage CA: Los Angeles, CA\n\n33847152\n10.1177/23247096211008585\n10.1177_23247096211008585\nCase Report\nBullous Pemphigoid Mimicking Cellulitis\nIvyanskiy Ilya 1\nDave Dhara 1\nDweik Anass 1\nYeary James 2\nNaguib Tarek M. 1\n1 Texas Tech University Health Sciences Center, Amarillo, TX, USA\n2 Amarillo VA Health Care System, Amarillo, TX, USA\nIlya Ivyanskiy, 3101 SW 58th Avenue, Apt 5103, Amarillo, TX 79118, USA. Email: Ilya.ivyanskiy@ttuhsc.edu\n13 4 2021\nJan-Dec 2021\n9 2324709621100858531 1 2021\n31 1 2021\n9 3 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\nhttps://creativecommons.org/licenses/by-nc/4.0/ 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 page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nBullous pemphigoid (BP) is the most prevalent autoimmune blistering skin disease in the Western world affecting mainly the elderly population. The diagnosis is based on clinical assessment along with specific immunopathologic findings on skin biopsy. Risk factors include genetic factors, environmental exposures, and several infections including hepatitis B, hepatitis C, Helicobacter pylori, Toxoplasma gondi, and cytomegalovirus. A variety of drugs have been associated with BP including but not limited to dipeptidyl peptidase-4 inhibitors, loop diuretics, spironolactone, and neuroleptics. Associated neurologic disorders (dementia, Parkinson’s disease, bipolar disorder, previous stroke history, and multiple sclerosis) have also been described. Common clinical presentation consists of extremely pruritic inflammatory plaques that resemble eczematous dermatitis or urticaria, followed by formation of tense bullae with subsequent erosions. Typical distribution involves the trunk and extremities. Mucosa is typically spared affecting only 10% to 30% of patients. Several unusual clinical presentations of BP have been described such as nonbullous forms with erythematous excoriated papules, plaques, and nodules. Other reported findings include urticarial lesions, prurigo-like nodules, multiple small vesicles resembling dermatitis herpetiformis or pompholyx, vegetating and purulent lesions localized in intertriginous areas, and even exfoliative erythroderma. Recognition and management of such cases can present a diagnostic challenge to clinicians. In this article, we describe another variant which to our knowledge is the first case to present with a cellulitis-like presentation in a patient with a known history of BP.\n\nbullous pemphigoid\natypical presentation\nautoimmune blistering disease\nclinical variants\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nBullous pemphigoid (BP) is the most common autoimmune blistering disease in the elderly that is associated with multiple environmental and genetic factors. It has various cutaneous manifestations and may imitate other conditions. To our knowledge, cellulitis-like picture has never been previously reported.\n\nCase Report\n\nAn 85-year-old man with a history of BP presented with right forearm swelling and erythema for 3 days. The patient had a history of atrial fibrillation, chronic obstructive pulmonary disease, and diabetes mellitus. He was diagnosed with BP about 7 years ago when he presented with a similar rash. The diagnosis of BP was made based on a punch biopsy showing subepidermal bullae containing a dense inflammatory infiltrate with prominent eosinophils. Direct immunofluorescence revealed a strong linear staining pattern of the basement membrane zone with immunoglobulin G and C3. Since then, he has been having similar although less severe recurrent episodes about once every 1 to 2 years involving lower and upper extremities with complete remission in between, every time treated successfully with short courses of intramuscular, oral, and topical steroids. He also required methotrexate maintenance therapy for the initial episode. Medications included insulin, metoprolol, gabapentin, simvastatin, warfarin, lisinopril, tamsulosin, and furosemide. Examination revealed swelling, erythema, and warmth of the right upper extremity from the mid upper arm all the way to the hand (Figures 1 and 2) along with a few deep tense bullae formation of 2 to 3 cm (Figure 3). Laboratory investigations revealed the following: leukocytes 9.3 × 10 9/L, hemoglobin 13.7 g/dL, creatinine 1.83 mg/dL, platelets 248 × 10 9/L, procalcitonin <0.05 ng/mL, lactic acid 2.3 mmol/L, and negative blood cultures. The patient was initially started on broad-spectrum antibiotics due to suspicion of infectious etiology. However, due to the absence of fever and elevated inflammatory markers, the antibiotics were discontinued, and oral prednisone 40 mg daily was initiated with tremendous and rapid response. His eruption had cleared with no new bullae at the 1-week outpatient follow-up with his dermatologist. The prednisone was tapered accordingly.\n\nFigure 1. An extensive erythematous and edematous plaque on the right arm and post inflammatory hypo- and hyperpigmentation.\n\nFigure 2. An extensive erythematous and edematous plaque on the right arm and post inflammatory hypo- and hyperpigmentation.\n\nFigure 3. A close-up of large deep-seated tense bullae on the right forearm.\n\nDiscussion\n\nBullous pemphigoid is the most frequent autoimmune blistering disorder in Western Hemisphere with increased incidence in the last decades. It particularly affects the elderly population. The incidence has been reported to be 24 cases per million per year in the United States, with the highest incidence of 42.8 cases per million per year in the United Kingdom.1 The disease is characterized by autoantibody formation against the hemidesmosome. Several antigens have been identified as potential targets of autoantibodies, mainly BP antigen 180 (BP180) and BP antigen 230 (BP230).2 Antibody-mediated activation of the complement apparently contributes to bullae formation. Inflammatory cell recruitment and release of proinflammatory mediators and proteases are also involved in the process. Other potential contributory factors have been described including environmental, genetic, and the so-called phenomenon of epitope spreading. Association with hepatitis B, hepatitis C, Helicobacter pylori, Toxoplasma gondi, and cytomegalovirus were more prevalent in one small case-control study.3 A variety of drugs have been associated with BP including a few antihypertensive medications (amlodipine, losartan, lisinopril, and clonidine), glucose-lowering (dipeptidyl peptidase-4 inhibitors), nonsteroidal anti-inflammatory drugs (ibuprofen celecoxib), selective serotonin reuptake inhibitors (fluoxetine), several diuretics (furosemide, spironolactone), proton-pump inhibitors (omeprazole), neuroleptics (risperidone), antibiotics (penicillins, fluoroquinolones, rifampin, and cephalexin), and many others.4 The epitope spreading phenomenon is an autoimmune response against normal host antigens as a result of the immune-mediated damage secondary to tissue inflammation in the setting of other diseases. This phenomenon has also been implicated in certain neurological disorders such as multiple sclerosis and Alzheimer’s disease.5\n\nThe typical hallmark is an intensely pruritic eruption consisting of excoriated urticarial or eczematous plaques with subsequent formation of tense bullae 1 to 3 cm diameter with negative Nikolsky’s sign and subsequent erosions.6 Resolution appears to be without scarring. The course is usually chronic with spontaneous flare-ups and remissions. On the other hand, BP may be extremely polymorphic with nonbullous lesions, prurigo-like nodules, vegetating and purulent lesions, and many other subtypes mimicking other common cutaneous diseases.7 Therefore, BP should be considered in every pruritic inflammatory skin eruption in the elderly. The diagnosis is usually confirmed by the immunopathologic findings that are both highly sensitive and specific. Serologic studies for anti-basement zone antibodies are also useful supporting the diagnosis. Nevertheless, detection of those antibodies is not necessarily indicative of the disease and could be found in patients without clinical or laboratory evidence of BP.\n\nTo our knowledge, there have been no reported cases with a presentation resembling cellulitis. In our patient, the history of BP was the main clue in helping to sort out the diagnosis. Contacting his dermatologist who is a staff physician at our facility and reviewing his previous history played a crucial role in the correct approach and management. It is important to note that the patient was a very poor historian making the correct diagnosis difficult. He sought medical attention at times in emergency departments where he was treated with antibiotics for a presumptive diagnosis of cellulitis with minimal improvement in symptoms and several recurrences. He showed a definite and drastic response to steroids, which helped confirm the suspicion that the cellulitis-like lesions were indeed a manifestation of his underlying BP. Another feature worth mentioning was completely nonpruritic rash as opposed to typical BP being extremely itchy.\n\nBullous pemphigoid remains the disease without clear guidelines regarding treatment. Even assessment of the severity of the disease seems to differ in different countries. However, most guidelines agree that the mainstay of treatment are corticosteroids with various adjuvant options. In mild disease, topical glucocorticoids could be used as a monotherapy. Moderate disease usually warrants an addition of systemic glucocorticoids. Anti-inflammatory antibiotics such as tetracyclines are preferred by some dermatologists. In cases where maintenance therapy is required, immunosuppressive agents may be implemented. Among them are mycophenolate mofetil, azathioprine, dapsone, and methotrexate.8 New therapies including biologics have been studied showing some promising results.\n\nDespite the unusual presentation of a nonpruritic exacerbation of BP, it should always be among the differential diagnosis in each elderly patient presenting with inflammatory skin disease.\n\nConclusion\n\nDespite the unusual presentation of a nonpruritic exacerbation of BP, it should always be among the differential diagnosis in elderly presenting with inflammatory skin eruption. By reporting this case, we would like to make the readers aware of this unique presentation that was initially misdiagnosed as cellulitis.\n\nAuthors’ Note: This article has been submitted as an abstract for the SRM 2021 Conference.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.\n==== Refs\nReferences\n\n1 Kridin K Ludwig RJ. The growing incidence of bullous pemphigoid: overview and potential explanations. Front Med (Lausanne). 2018;5 :220. doi:10.3389/fmed.2018.00220 30177969\n2 Wieland CN Comfere NI Gibson LE Weaver AL Krause PK Murray JA. Anti-bullous pemphigoid 180 and 230 antibodies in a sample of unaffected subjects. Arch Dermatol. 2010;146 :21-25. doi:10.1001/archdermatol.2009.331 20083688\n3 Sagi L Baum S Agmon-Levin N , et al . Autoimmune bullous diseases the spectrum of infectious agent antibodies and review of the literature. Autoimmun Rev. 2011;10 :527-535. doi:10.1016/j.autrev.2011.04.003 21527361\n4 Stavropoulos PG Soura E Antoniou C. Drug-induced pemphigoid: a review of the literature. J Eur Acad Dermatol Venereol. 2014;28 :1133-1140. doi:10.1111/jdv.12366 24404939\n5 Bouras C Riederer BM Kövari E Hof PR Giannakopoulos P. Humoral immunity in brain aging and Alzheimer’s disease. Brain Res Brain Res Rev. 2005;48 :477-487. doi:10.1016/j.brainresrev.2004.09.009 15914253\n6 Di Zenzo G Marazza G Borradori L . Bullous pemphigoid: physiopathology, clinical features and management. Adv Dermatol. 2007;23 :257-288. doi:10.1016/j.yadr.2007.07.013 18159905\n7 Cozzani E Gasparini G Burlando M Drago F Parodi A. Atypical presentations of bullous pemphigoid: clinical and immunopathological aspects. Autoimmun Rev. 2015;14 :438-445. doi:10.1016/j.autrev.2015.01.006 25617817\n8 Daniel BS Borradori L Hall RP 3rd Murrell DF. Evidence-based management of bullous pemphigoid. Dermatol Clin. 2011;29 :613-620. doi:10.1016/j.det.2011.06.003 21925006\n\n",
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"issn_linking": "2324-7096",
"issue": "9()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "atypical presentation; autoimmune blistering disease; bullous pemphigoid; clinical variants",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000368:Aged; D001768:Blister; D002481:Cellulitis; D006801:Humans; D010391:Pemphigoid, Bullous; D012867:Skin",
"nlm_unique_id": "101624758",
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"pages": "23247096211008585",
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"pmid": "33847152",
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"references": "20083688;18159905;15914253;24404939;25617817;30177969;21925006;21527361",
"title": "Bullous Pemphigoid Mimicking Cellulitis.",
"title_normalized": "bullous pemphigoid mimicking cellulitis"
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"abstract": "Due to their efficient osteoclastic inhibitor effect in bone metabolism and antiangiogenic activity, bisphosphonates are widely used in many cancer diseases particularly in prostate cancers with bone metastasis, lung cancer, breast cancer and multiple myeloma, as well as in systemic diseases such as osteoporosis, osteopenia, Paget disease and osteogenesis imperfect for the last 13 years. Prostate cancer is a common cancer in males and it is the leading cause of bone metastasis. Mandibular metastasis is rarely encountered during the course of prostate cancer. Mandibular osteonecrosis as well has begun to be observed along with the availability of more efficient and stronger formulations developed following the use of bisphosphonates. Zolendronic acid, which has been used also by our patient, has widely come into practice as a 3(rd) generation bisphosphonate. Because of prostate cancer and widespread bone metastases, our patient has been receiving zolendronic acid with maximum androgen blockage for 4 years. Tomography of the patient, who has undergone intensive treatment because of submandibular abscess, demonstrated extensive osteonecrosis in the fovea sublingual region of the mandible corpus. In large series, although, mandibular osteonecrosis was widely seen due to bisphosphonate use for the metastases of lung and breast cancers, this rate was between 9.6% and 11% for prostate cancer within the series. Although our patient had no mandibular metastasis before, mandibular necrosis was observed due to long-term bisphosphonate use. We are going to present our patient who had this rare complication with his clinical picture.",
"affiliations": "Department of Urology, Konya Hospital, Konya, Turkey.;Department of Pathology, Bağcılar Training and Research Hospital, İstanbul, Turkey.",
"authors": "Şalvarcı|Ahmet|A|;Altınay|Serdar|S|",
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"country": "Turkey",
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"issue": "41(1)",
"journal": "Turkish journal of urology",
"keywords": "Bisphosphonate; mandibular; metastatic prostate cancer; osteonecrosis",
"medline_ta": "Turk J Urol",
"mesh_terms": null,
"nlm_unique_id": "101643563",
"other_id": null,
"pages": "43-7",
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"pmid": "26328198",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article",
"references": "9797474;18686751;24023329;10898342;18061527;15345179;15758064;12430099;19531406;24281463;12669737;20871729;9494781;12183663;16314620;17307580;15767788;15883944;15122554;15984412;16243172",
"title": "Mandibular osteonecrosis due to bisphosphonate use.",
"title_normalized": "mandibular osteonecrosis due to bisphosphonate use"
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"abstract": "We report the case of Niemann-Pick disease type C with extensive phenotypic heterogeneity in two monozygotic twins. One of the twins presented with a history of obsessive-compulsive disorder and slowly progressive inferior limb clumsiness, dysphagia and dysarthria. Neurological examination revealed a broad-based ataxic gait, limb dysmetria, downward vertical gaze palsy, brisk lower limb reflexes and ankle clonus, while neuropsychological assessment revealed global cognitive deficits in multiple domains. Complete neurological and neuropsychological evaluation in the asymptomatic monozygotic twin brother only revealed mild neurological impairment. In the hypothesis of Niemann-Pick disease type C, Filipin test, measurement of plasma oxysterols levels and genetic analysis were carried out in both twins. Filipin staining showed massive intracellular accumulation of non-esterified cholesterol, plasma oxysterols levels were elevated and genetic analysis revealed a homozygous c.2662 C > T (p.P888S) mutation in the NPC1 gene (18q11.2) in both twins. 18F-FDG-PET imaging with single-subject analysis revealed a reduced frontal and temporal glucose metabolism, which correlated with disease progression. This case supports the phenotypic variability of Mendelian inherited disorders in monozygotic twins, likely due to epigenetic differences and post-zygotic mutagenesis.",
"affiliations": "Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.",
"authors": "Benussi|Alberto|A|;Alberici|Antonella|A|;Premi|Enrico|E|;Bertasi|Valeria|V|;Cotelli|Maria Sofia|MS|;Turla|Marinella|M|;Dardis|Andrea|A|;Zampieri|Stefania|S|;Marchina|Eleonora|E|;Paghera|Barbara|B|;Gallivanone|Francesca|F|;Castiglioni|Isabella|I|;Padovani|Alessandro|A|;Borroni|Barbara|B|",
"chemical_list": "D019788:Fluorodeoxyglucose F18",
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"keywords": null,
"medline_ta": "J Neurol",
"mesh_terms": "D001921:Brain; D004252:DNA Mutational Analysis; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D052556:Niemann-Pick Disease, Type C; D010375:Pedigree; D010641:Phenotype; D049268:Positron-Emission Tomography; D014430:Twins, Monozygotic; D055815:Young Adult",
"nlm_unique_id": "0423161",
"other_id": null,
"pages": "642-7",
"pmc": null,
"pmid": "25536905",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D018486:Twin Study",
"references": "24952892;19440707;10521290;2715172;1287434;8312368;16720792;20468073;20525256;16009939;19363805;21343899;9211849;24343124;21518695;11125141;11479732;3865225;17689147;22572546;11349231;17003072;22476655;19741716;10942596;21783023;19656703;21048217;3609608;18304490;21147389",
"title": "Phenotypic heterogeneity of Niemann-Pick disease type C in monozygotic twins.",
"title_normalized": "phenotypic heterogeneity of niemann pick disease type c in monozygotic twins"
} | [
{
"companynumb": "IT-WATSON-2015-19146",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional": nul... |
{
"abstract": "A 65-year-old Polish immigrant named T. J. was diagnosed with metastatic colon cancer in January 2012 when he presented with obstructing sigmoid colon cancer and liver metastases. A diverting colostomy as well as biopsy of his liver metastases was performed and chemotherapy with FOLFOX (5-fluorouracil [5-FU], leucovorin, oxaliplatin) and bevacizumab was initiated. After three months, he transitioned to maintenance therapy with infusional 5-FU and bevacizumab until he progressed in August 2012. Oxaliplatin was reintroduced and he responded until he developed progressive neuropathy in November and his therapy was changed to FOLFIRI (5-FU, leucovorin, irinotecan) and bevacizumab. T. J. developed liver progression after three months and, because he was Kras wild type, irinotecan and panitumumab were initiated. Liver-directed therapy also was pursued and he underwent radioembolization with yittrium-90 followed by chemoembolization with irinotecan-eluded beads. At the time of these procedures, T. J.'s portal and hepatic venous systems were patent (i.e., no thrombosis or obstruction causing portal hypertension).",
"affiliations": "Gastrointestinal Oncology Division, John Theurer Cancer Center, Hackensack University Medical Center in New Jersey.",
"authors": "Flaherty|Anne Marie C|AM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1188/15.ONF.96-99",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-535X",
"issue": "42(1)",
"journal": "Oncology nursing forum",
"keywords": null,
"medline_ta": "Oncol Nurs Forum",
"mesh_terms": "D000368:Aged; D001201:Ascites; D006801:Humans; D008113:Liver Neoplasms; D008297:Male",
"nlm_unique_id": "7809033",
"other_id": null,
"pages": "96-9",
"pmc": null,
"pmid": "25542326",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of malignancy-related ascites.",
"title_normalized": "management of malignancy related ascites"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US00301",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "The effects of empagliflozin, a sodium-glucose co-transporter 2 inhibitor, on neointimal response after drug-eluting-stent (DES) implantation remains unknown. Insufficiently controlled diabetes patients with coronary artery disease planned for DES stenting were consecutively enrolled. The patients were assigned to receive empagliflozin in addition to standard therapy or intensive therapy using other glucose-lowering drugs (oGLD). The primary endpoint was thickness of neointimal hyperplasia (NIH) 12 months after stenting assessed by optical coherence tomography (OCT). A total of 28 patients were analyzed (n = 15 in the empagliflozin group, n = 13 in the oGLD group). The levels of glucose profile were not significantly different between both groups at follow-up [HbA1c; 7.2 ± 0.8 vs 7.3 ± 0.9%, p = 0.46]. In OCT analysis, neointima was significantly less in the empagliflozin group than the oGLD group [mean NIH thickness: 137 ± 32 vs 168 ± 39 μm, p = 0.02]. Changes of systolic and diastolic blood pressure (BP), changes of body mass index, and changes of hematocrit after additional treatment were significantly associated with NIH attenuation, whereas no correlation was observed in changes in blood glucose parameters. Multivariate logistic regression analysis revealed that changes in systolic BP was the strongest predictor for NIH attenuation, followed by changes in diastolic BP. In patients with type 2 diabetes, standard plus empagliflozin attenuated neointimal progression as compared with intensive standard therapy after DES implantation. Our data possibly support a beneficial effect of empagliflozin in type 2 diabetes required for coronary revascularization therapy.",
"affiliations": "Department of Cardiology, NTT Medical Center Tokyo, 5-9-22 Higashigotanda, Shinagawa, Tokyo, 141-0022, Japan. t_hashikata@med.kitasato-u.ac.jp.;Department of Cardiology, NTT Medical Center Tokyo, 5-9-22 Higashigotanda, Shinagawa, Tokyo, 141-0022, Japan.;Department of Cardiology, NTT Medical Center Tokyo, 5-9-22 Higashigotanda, Shinagawa, Tokyo, 141-0022, Japan.;Department of Cardiology, NTT Medical Center Tokyo, 5-9-22 Higashigotanda, Shinagawa, Tokyo, 141-0022, Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Department of Cardiology, NTT Medical Center Tokyo, 5-9-22 Higashigotanda, Shinagawa, Tokyo, 141-0022, Japan.;Department of Cardiology, NTT Medical Center Tokyo, 5-9-22 Higashigotanda, Shinagawa, Tokyo, 141-0022, Japan.;Department of Cardiology, NTT Medical Center Tokyo, 5-9-22 Higashigotanda, Shinagawa, Tokyo, 141-0022, Japan.;Department of Cardiology, NTT Medical Center Tokyo, 5-9-22 Higashigotanda, Shinagawa, Tokyo, 141-0022, Japan.;Department of Cardiology, NTT Medical Center Tokyo, 5-9-22 Higashigotanda, Shinagawa, Tokyo, 141-0022, Japan.",
"authors": "Hashikata|Takehiro|T|http://orcid.org/0000-0001-9633-1303;Ikutomi|Masayasu|M|;Jimba|Takahiro|T|;Shindo|Akito|A|;Kakuda|Nobutaka|N|;Katsushika|Susumu|S|;Yokoyama|Masaaki|M|;Kishi|Mikio|M|;Sato|Takahiro|T|;Matsushita|Masashiro|M|;Ohnishi|Satoshi|S|;Yamasaki|Masao|M|",
"chemical_list": "D001559:Benzhydryl Compounds; D005960:Glucosides; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570240:empagliflozin",
"country": "Japan",
"delete": false,
"doi": "10.1007/s00380-020-01621-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0910-8327",
"issue": "35(10)",
"journal": "Heart and vessels",
"keywords": "Diabetes mellitus; Drug-eluting stent; Empagliflozin; Neointimal hyperplasia; Optical coherence tomography",
"medline_ta": "Heart Vessels",
"mesh_terms": "D000368:Aged; D001559:Benzhydryl Compounds; D003324:Coronary Artery Disease; D003331:Coronary Vessels; D003924:Diabetes Mellitus, Type 2; D054855:Drug-Eluting Stents; D005260:Female; D005960:Glucosides; D006801:Humans; D006965:Hyperplasia; D007564:Japan; D008297:Male; D008875:Middle Aged; D058426:Neointima; D062645:Percutaneous Coronary Intervention; D011446:Prospective Studies; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013997:Time Factors; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome",
"nlm_unique_id": "8511258",
"other_id": null,
"pages": "1378-1389",
"pmc": null,
"pmid": "32399662",
"pubdate": "2020-10",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Empagliflozin attenuates neointimal hyperplasia after drug-eluting-stent implantation in patients with type 2 diabetes.",
"title_normalized": "empagliflozin attenuates neointimal hyperplasia after drug eluting stent implantation in patients with type 2 diabetes"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-025199",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EMPAGLIFLOZIN"
},
... |
{
"abstract": "Amantadine is an antiviral agent that is also used in the treatment of parkinsonism and neuroleptic-induced extrapyramidal symptoms. Toxic effects of amantadine relate primarily to the central nervous system and range from mild symptoms to disorientation and hallucinations. Anti-cholinergic agents may exacerbate these effects. We report a case of unsuspected amantadine overdose in a previously healthy 35-year-old woman who presented with acute psychosis manifested by delirium and visual hallucinations. Concomitant use of diphenhydramine contributed to the clinical presentation. Amantadine toxicity should be considered in the differential diagnosis of altered mental status in patients known to be taking the drug or with conditions commonly treated with amantadine.",
"affiliations": "Department of Emergency Medicine, Harbor-UCLA Medical Center, Torrance 90509.",
"authors": "Snoey|E R|ER|;Bessen|H A|HA|",
"chemical_list": "D004155:Diphenhydramine; D000547:Amantadine",
"country": "United States",
"delete": false,
"doi": "10.1016/s0196-0644(05)82473-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0644",
"issue": "19(6)",
"journal": "Annals of emergency medicine",
"keywords": null,
"medline_ta": "Ann Emerg Med",
"mesh_terms": "D000328:Adult; D000547:Amantadine; D003937:Diagnosis, Differential; D004155:Diphenhydramine; D004357:Drug Synergism; D005260:Female; D006212:Hallucinations; D006801:Humans; D011605:Psychoses, Substance-Induced; D012141:Respiratory Tract Infections",
"nlm_unique_id": "8002646",
"other_id": null,
"pages": "668-70",
"pmc": null,
"pmid": "2344084",
"pubdate": "1990-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute psychosis after amantadine overdose.",
"title_normalized": "acute psychosis after amantadine overdose"
} | [
{
"companynumb": "US-SA-2020SA362531",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nTyrosine kinase inhibitors (TKIs) are associated with prolongation of the QTc interval on the electrocardiogram (ECG). The QTc-interval prolongation increases the risk of life-threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and only consist of small patient numbers.\n\n\nMETHODS\nIn this multicentre trial in four centres in the Netherlands and Italy we screened all patients who were treated with any TKI. To evaluate the effects of TKIs on the QTc interval, we investigated ECGs before and during treatment with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib.\n\n\nRESULTS\nA total of 363 patients were eligible for the analyses. At baseline measurement, QTc intervals were significantly longer in females than in males (QTcfemales=404 ms vs QTcmales=399 ms, P=0.027). A statistically significant increase was observed for the individual TKIs sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib, after the start of treatment (median ΔQTc ranging from +7 to +24 ms, P<0.004). The CTCAE grade for QTc intervals significantly increased after start of treatment (P=0.0003). Especially patients who are treated with vemurafenib are at increased risk of developing a QTc of ⩾470 ms, a threshold associated with an increased risk for arrhythmias.\n\n\nCONCLUSIONS\nThese observations show that most TKIs significantly increase the QTc interval. Particularly in vemurafenib-treated patients, the incidence of patients at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, ECG monitoring in patients treated with TKIs is strongly recommended.",
"affiliations": "Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 5201, 3075EA Rotterdam, The Netherlands.;Department of Medical Oncology, Fondazione S. Maugeri, Via Maugeri 10, 27100 Pavia, Italy.;Department of Clinical Oncology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands.;Laboratory of Informatics and Systems Engineering for Clinical Research, Salvatore Maugeri Research and Care Institute, Pavia, Italy.;Department of Molecular Cardiology, IRCCS Fondazione S. Maugeri, Via Maugeri 10, 27100 Pavia, Italy.;Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 5201, 3075EA Rotterdam, The Netherlands.;1] Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 5201, 3075EA Rotterdam, The Netherlands [2] Cancer Genomics Netherlands, Amsterdam, The Netherlands.;Department of Medical Oncology, Netherlands Cancer Institute, PO Box 90203, 1006 BE Amsterdam, The Netherlands.;Department of Medical Oncology, Ospedale Papa Giovanni XXIII, P.zza OMS n 1, 24127 Bergamo, Italy.;Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 5201, 3075EA Rotterdam, The Netherlands.",
"authors": "Kloth|J S L|JS|;Pagani|A|A|;Verboom|M C|MC|;Malovini|A|A|;Napolitano|C|C|;Kruit|W H J|WH|;Sleijfer|S|S|;Steeghs|N|N|;Zambelli|A|A|;Mathijssen|R H J|RH|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases",
"country": "England",
"delete": false,
"doi": "10.1038/bjc.2015.82",
"fulltext": "\n==== Front\nBr J CancerBr. J. CancerBritish Journal of Cancer0007-09201532-1827Nature Publishing Group bjc20158210.1038/bjc.2015.8225742483Clinical StudyIncidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors TKI-induced QTc prolongationKloth J S L 19*Pagani A 29Verboom M C 3Malovini A 4Napolitano C 5Kruit W H J 1Sleijfer S 16Steeghs N 7Zambelli A 8Mathijssen R H J 11 Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 5201, 3075EA Rotterdam, The Netherlands2 Department of Medical Oncology, Fondazione S. Maugeri, Via Maugeri 10, 27100 Pavia, Italy3 Department of Clinical Oncology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands4 Laboratory of Informatics and Systems Engineering for Clinical Research, Salvatore Maugeri Research and Care Institute, Pavia, Italy5 Department of Molecular Cardiology, IRCCS Fondazione S. Maugeri, Via Maugeri 10, 27100 Pavia, Italy6 Cancer Genomics Netherlands, Amsterdam, The Netherlands7 Department of Medical Oncology, Netherlands Cancer Institute, PO Box 90203, 1006 BE Amsterdam, The Netherlands8 Department of Medical Oncology, Ospedale Papa Giovanni XXIII, P.zza OMS n 1, 24127 Bergamo, Italy* E-mail: j.kloth@erasmusmc.nl9 These authors contributed equally to this work.\n\n17 03 2015 05 03 2015 112 6 1011 1016 15 09 2014 19 01 2015 05 02 2015 Copyright © 2015 Cancer Research UK2015Cancer Research UKFrom twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/Background:\nTyrosine kinase inhibitors (TKIs) are associated with prolongation of the QTc interval on the electrocardiogram (ECG). The QTc-interval prolongation increases the risk of life-threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and only consist of small patient numbers.\n\nMethods:\nIn this multicentre trial in four centres in the Netherlands and Italy we screened all patients who were treated with any TKI. To evaluate the effects of TKIs on the QTc interval, we investigated ECGs before and during treatment with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib.\n\nResults:\nA total of 363 patients were eligible for the analyses. At baseline measurement, QTc intervals were significantly longer in females than in males (QTcfemales=404 ms vs QTcmales=399 ms, P=0.027). A statistically significant increase was observed for the individual TKIs sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib, after the start of treatment (median ΔQTc ranging from +7 to +24 ms, P<0.004). The CTCAE grade for QTc intervals significantly increased after start of treatment (P=0.0003). Especially patients who are treated with vemurafenib are at increased risk of developing a QTc of ⩾470 ms, a threshold associated with an increased risk for arrhythmias.\n\nConclusions:\nThese observations show that most TKIs significantly increase the QTc interval. Particularly in vemurafenib-treated patients, the incidence of patients at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, ECG monitoring in patients treated with TKIs is strongly recommended.\n\ntyrosine kinase inhibitorsQTc intervalarrhythmiaECG\n==== Body\nLong QT syndrome (LQTS) is a myocardial repolarisation disorder characterised by prolongation of the QT interval on the surface electrocardiogram (ECG). The clinical presentation of LQTS consists of palpitations, syncope, seizures, and sudden cardiac death due to a characteristic arrhythmia known as torsades de pointes (TdP) (El-Sherif and Turitto, 2003; Moss, 2003; Trinkley et al, 2013).\n\nThe QT interval represents the total duration of ventricular depolarisation and repolarisation. It is measured on the ECG from the first deflection of the QRS complex to the end of the T-wave. Prolongation of the QT interval usually results from delayed repolarisation. This can be caused by drugs or inherited ion channel abnormalities, which block or result in loss of function of potassium channels (IKr, IKs, and IKl), or opening or gain of function of sodium (Ina) or calcium channels (Grant, 2009). The QT interval is usually corrected for heart rate, leading to the corrected QT interval QTc.\n\nSeveral factors such as gender, age, electrolyte disturbances, cardiovascular diseases (CVD), and different types of drugs can affect the duration of the QT interval (Yetkin et al, 2001; Benoit et al, 2005). Due to the risk of fatal arrhythmias, the US Food and Drug Administration (FDA) now requires thorough studies to evaluate the potency of new drugs to induce QT-interval prolongation in preclinical and early phase I clinical trials in healthy individuals (El-Sherif and Turitto, 2003). However, for new anticancer drugs these studies are usually not performed in healthy individuals because of their toxicity profile (Curigliano et al, 2008; de Jonge and Verweij, 2008).\n\nAs with many drugs, tyrosine kinase inhibitors (TKIs) are reported to prolong the QT interval (Strevel et al, 2007; Bello et al, 2009; Lee et al, 2010; Tolcher et al, 2011; Dogan et al, 2012; Doherty et al, 2013; Dong et al, 2013; Heath et al, 2013; Shah et al, 2013). In vitro studies demonstrated that lapatinib and imatinib interact with the phosphorylation of the cardiac hERG channel. This results in a reduction of the repolarising current (IKr), which can lead to action potential prolongation and subsequent QT-interval prolongation (Lee et al, 2010; Dong et al, 2013).\n\nIn a small prospective clinical study to evaluate the cardiac safety of lapatinib in 21 patients, a mean QTc increase of 8.63 ms was seen (Dogan et al, 2012). In three prospective post-marketing studies in patients with solid tumours treated with sorafenib (N=31), pazopanib (N=48), and sunitinib (N=24) a modest increase of 9.0 ms of QTc interval with the use of sorafenib, 4.4 ms after start of pazopanib and 9.6 ms after start of sunitinib was seen (Bello et al, 2009; Tolcher et al, 2011; Heath et al, 2013).\n\nThese drugs have been approved by the FDA because they appear highly effective in situations where treatment options are limited. With an increasing number of TKIs on market, a relatively long on-treatment time, and the application in the adjuvant setting, which is already standard for imatinib in patients with localised GIST with a high risk of relapse, and which is being explored for other TKIs in various tumour types, thorough QTc studies in this group of drugs are necessary to get more insight into their cardiac safety. In this multicentre study performed in four centres in the Netherlands and Italy, we describe the incidence and relevance of QTc-interval prolongation in patients with cancer treated with different types of TKIs.\n\nPatients and methods\nStudy design\nWe undertook a retrospective study in patients with solid malignancies, who were treated with any type of TKI. Patients from four centres in the Netherlands (Erasmus MC Cancer Institute, Rotterdam, Leiden University Medical Centre, Leiden, and Netherlands Cancer Institute—Antoni van Leeuwenhoek, Amsterdam) and Italy (Salvatore Maugeri Foundation, Pavia) were included.\n\nThis study was reviewed and approved by the Erasmus MC Medical Ethical Board (MEC 2013-148). All ECGs were obtained as standard clinical care. Demographic and clinical characteristics of the analysed cohort were collected using clinical record forms designed for this study.\n\nPatients were considered eligible if they were aged ⩾18 years, were treated for solid tumours with any type of TKI and if at least one ECG before start of TKI treatment and one ECG during treatment with TKI were available. Exclusion criteria were as follows: ECGs that do not match criteria for accurate QTc-interval measurements (intra-ventricular conduction delay and/or pacemaker driven rhythm), missing ECGs at baseline or during therapy, and patients with a time-lapse between baseline ECG and start of TKI treatment of more than 1 year. Patients who were subsequently treated with different TKIs were included once. All standard 12-lead ECGs analysed in this study were reviewed by a single expert cardiologist (CN). The QT interval was measured from the beginning of the QRS complex until the point where the deflection of the T wave crosses the iso-electric line. A description of the statistical method is presented in the Supplementary Material.\n\nDefinition of QTc prolongation\nSince increases in heart rate result in shortening of the QT interval, a correction for heart rate was applied using the Bazett formula (Sagie et al, 1992):\n\n \n\nIn this formula, RR is the interval between two subsequent R waves. The Bazett formula is the most frequently applied correction in clinical practice, leading to the corrected QT interval or QTc interval (Sagie et al, 1992).\n\nA prolonged QT interval is associated with an increased risk of polymorphic ventricular tachycardia, torsade de pointes (TdP). This study defined a prolonged QT interval corrected for heart rate (QTc) as ⩾470 ms, which represents <0.5% of the healthy population (Kobza et al, 2009) and has been shown to be associated with an increased risk of TdP (Trinkley et al, 2013). A clinically relevant increase in QTc (ΔQTc) was defined as an increase of ⩾30 ms between a patient's baseline and subsequent ECG as this has also been shown to be associated with increased risk (Li et al, 2010). The QTc was also categorised according to the Common terminology criteria for adverse events (CTCAE) guidelines version 4.03 (grade 0, QTc<450; grade 1, QTc 450–479 ms; grade 2, QTc 480–499 ms; grade 3, QTc⩾500 ms; grade 4, QTc⩾500 ms with life-threatening signs or symptoms; grade 5, death). Relevant CVD was defined as myocardial infarction and/or heart failure.\n\nOutcome measures used in this study were (i) the quantitative difference in QTc interval between on therapy and baseline ECG measurements (ΔQTc, ms), (ii) the transition from a condition of normal repolarisation to a condition in which QTc is prolonged to an extent with high risk of arrhythmia as a consequence of the TKI therapy (i.e., from QTc<470 to QTc⩾470 ms) (Kobza et al, 2009; Trinkley et al, 2013), (iii) clinically relevant ΔQTc (defined as ΔQTc⩾30 ms, above which the risk for TdP is significantly increased) (Li et al, 2010) and (iv) QTc-interval CTCAE grade increase during TKI therapy.\n\nResults\nPatient characteristics\nA total of 1933 cases of TKI use were screened in this study. In 644 cases at least one ECG before treatment and one ECG during treatment were available. Among these cases, 18 patients were included twice, with subsequent use of different TKIs. One patient had a pacemaker-driven rhythm. In 262 patients, the time lapse between baseline ECG and start of treatment was more than 1 year and patients were therefore excluded from the analysis. The remaining study cohort consisted of 363 patients. The median age at start of treatment was 60 years (interquartile range (IQR) 51–67), and 59% of patients were male. Sunitinib was the most frequently used TKI in our study cohort, with a total of 110 treated patients. The median QTc interval at baseline visit was 401 ms (IQR 388–415), where 346 patients (95.3%) had a normal QTc interval (CTCAE grade 0), 14 (3.9%) had grade 1, 2 patients (0.6%) had grade 2, and 1 patient (0.3%) had a grade 3 QTc interval. A total number of 37 patients (10.2%) had a known history of relevant CVD, while 34 patients (9.4%) used co-medication, that can lead to QTc-interval prolongation (Strevel et al, 2007). Patients' demographics and disease characteristics are presented in Table 1.\n\nVariables modulating QTc interval at baseline visit\nAt baseline measurements, QTc was slightly, but significantly greater in females than in males (QTcfemales=404 ms (IQR 392–417) vs QTcmales=399 ms (IQR 385–414), P=0.027), which is consistent with previous studies (Strevel et al, 2007). Patients treated with co-medication known to prolong the QTc interval, such as anti-depressants, anti-epileptics, and anti-emetics, had a statistically significant higher baseline QTc interval than the patients who did not use such co-medication (409 ms (IQR 398–424) vs 400 ms (IQR 387–414), respectively, P=0.035). Consistent with previous studies, patients suffering from hypokalaemia had longer median QTc intervals than patients with normokalaemia and hyperkalaemia (median QTc in hypokalaemic, normokalaemic, and hyperkalaemic patients 416 ms (IQR 376–431), 401 ms (IQR 389–415), and 391 ms (IQR 381–408), P=0.028, respectively). A more detailed report about baseline QTc intervals according to the evaluated variables is found in Supplementary Table 1.\n\nQuantitative variations of the QTc interval\nThe median on treatment time before the ECG was performed was 43 days (IQR 26–118 days). In the entire population of 363 patients, the start of a TKI resulted in a statistically significant increase in QTc interval, with a median ΔQTc of +11 ms (P<0.00001). The distribution of ΔQTc was significantly different across TKIs (P=0.0001). When analysing subgroups of patients treated with specific TKIs, patients treated with sunitinib (N=110), vemurafenib (N=67), sorafenib (N=52), imatinib (N=41), and erlotinib (N=21) showed a statistically significant increase in QTc interval after start of treatment (median ΔQTc ranging from +7 to +24 ms, P<0.004; Figure 1). For lapatinib (N=16) and pazopanib (N=46), no statistically significant increase in QTc interval after start of treatment was found (Table 2).\n\nIncrease in CTCAE grade and prevalence of high-risk patients\nA statistically significant increase in CTCAE grade for QTc intervals was observed after start of TKI therapy in the whole cohort (P=0.0003). In detail, 33 patients (9.1%) were characterised by an increased CTCAE grade. Of these, 31 passed from grade 0 to grade⩾1, while the remaining 2 individuals passed from grade 1 to grade 2 or 3. Of the remaining patients, 321 (88.4%) did not have an increase or decrease in CTCAE grade after start of TKI treatment, while 9 patients (2.5%) had a reduced CTCAE grade for QTc interval (Table 3).\n\nSimilarly, a statistically significant increase in the prevalence of high-risk patients was observed after TKI therapy start (QTcbaseline⩾470 ms=1.7% vs QTctherapy⩾470 ms=5.8%, P=0.005), with 20 individuals (5.5%) who transitioned from a low-risk to a high-risk condition. Moreover, 5 patients (1.4%) developed QTc⩾500 ms (CTCAE grade 3) after therapy start, and 76 patients (20.9%) experienced a clinically relevant QTc increase after TKI start. All five patients who developed QTc⩾500 ms after start of therapy had a ΔQTc of ⩾100 ms.\n\nWhen focusing on specific TKI subgroups, we observed that individuals treated with vemurafenib (N=67) were characterised by a statistically significant increase both in terms of CTCAE grade for QTc intervals (P=0.008) and in the probability of becoming high-risk patients (P=0.023), also showing the greatest probability of clinically relevant QTc increase (34.3%). No statistically significant variations in the evaluated outcomes were observed in the other TKI subgroups.\n\nCharacterisation of TKI-induced QTc variability\nThe median age of patients who had a worsening of the CTCAE grade for QTc interval was significantly higher than that of patients who did not (62 years (IQR 59–72) vs 60 years (IQR 51–67), respectively, P=0.023). These patients also more often suffered from hypokalaemia (20.7% vs 3.1%, P=0.0009; Table 4). Multivariate logistic regression confirmed that age and hypokalaemia were independent predictors of worsened CTCAE grade for QTc interval (OR=1.10, 95% CI=1.05–1.16, P=0.0002 and OR=10.30, 95% CI=2.22–4.64, P=0.002).\n\nSimilarly, patients who had QTc prolongation to ⩾470 ms after start of TKI treatment were significantly older than patients who did not (66 years (IQR 60–76) and 60 years (IQR 51–66), respectively, P=0.007) and were more frequently treated with QTc-prolonging co-medication (25% vs 8.5%, P=0.030). This was confirmed by multivariate logistic regression (OR=1.10, 95% CI=1.04–1.15, P=0.0004 and OR=4.38, 95% CI=1.14–15.25, P=0.023).\n\nWe did not identify variables that have a statistically significant impact on quantitative ΔQTc or on the probability of clinically relevant ΔQTc (Supplementary Table 2).\n\nDiscussion\nWe found a significant increase in QTc intervals after start of treatment with sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib. In most cases, the increase in QTc interval is only modest and under normal conditions not clinically relevant. However, in 76 of the 363 patients the start of TKI treatment resulted in a clinically relevant increase of the QTc interval of ⩾30 ms. The incidence of high-risk patients, defined as QTc⩾470 ms (Trinkley et al, 2013), increased during treatment with a TKI. Still, only the subgroup receiving vemurafenib showed a statistically significant increase in the number of patients with QTc>470 ms.\n\nIn the entire cohort, 21% of patients showed a clinically relevant increase in QTc of ⩾30 ms with TKI treatment, but as most had a normal baseline QTc interval, only 5% had a QTc of ⩾470 ms, which is associated with increased risk of arrhythmias. Although older patients, patients with low potassium and patients taking co-medication which can prolong the QTc interval are at higher risk of QTc-interval prolongation, it is still not possible to differentiate which patient is at risk at the start of treatment.\n\nTherefore, treating physicians should anticipate this possible increase in QTc intervals and perform ECGs during treatment with TKI, and be aware of symptoms, such as palpitation, seizures, and collapse, which may be the result of drug-induced LQTS. In those diseases where alternative treatment is available, such as in metastatic renal cell carcinoma where sunitinib and pazopanib have equivalent efficacy (Motzer et al, 2013), consideration should be given to use a TKI with less QTc prolongation effects if the QTc is prolonged at baseline or develops during treatment.\n\nFurthermore, many patients use co-medication during TKI treatment. As drugs of a broad variety are known for drug-induced QTc-interval prolongation, it is likely that patients use several drugs which can lead to QTc-interval prolongation and thereby intensifying the effect on the QTc interval. This was shown in this study, where 14 patients (4%) using such co-medication were more likely to develop QTc prolongation. In those cases, extra awareness may be necessary and switching to drugs that are not likely to have an effect on QTc interval should be considered.\n\nThis study has several limitations. This was a retrospective study in patients treated with cancer, and therefore in most cases ECGs were not performed at predefined times before, during, and after TKI therapy. Since fluctuations in QTc interval are frequent and may be caused by many factors (Yetkin et al, 2001; Benoit et al, 2005), this is a weakness of our study, and may have influenced outcome (Molnar et al, 1996). Also, only patients treated with a TKI were included and there was no control group given non-TKI treatment in which the variation in the QTc interval could be examined. Furthermore, there may be a bias in patient selection since patients with cardiac events may be more likely to have had ECGs performed. Patients who died from arrhythmia may not have been included in analyses when no ECGs were available. One patient taking a TKI in the study died suddenly. This did not occur in a hospital and no cause of death was reported so it is unknown whether this was related to QTc-interval prolongation. Possible effects from electrolyte disorders on the QTc interval may have been missed, because of missing data. However, we showed in a large group of patients treated with TKIs that there is an overall increase in QTc interval after start of treatment, which may possibly be harmful for patients treated with these drugs. Future prospective studies could improve the current knowledge about TKI-induced QTc prolongation.\n\nOverall, we may conclude that most TKIs tend to cause an increase in QTc intervals. In some cases, this increase is clinically relevant, and therefore the QTc interval should be verified in patients before starting TKI treatment and during therapy. Monitoring QTc intervals during TKI treatment is particularly important in patients with a history of QTc-interval prolongation, in patients using co-medication which can prolong the QTc interval, in patients with electrolyte disorders, and in patients with pre-existing CVD. Furthermore, during treatment with TKIs physicians should be aware of clinical symptoms, which may be attributed to QTc-interval prolongation.\n\nSupplementary Information accompanies this paper on British Journal of Cancer website (http://www.nature.com/bjc)\n\nThis work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License.\n\nThis study was presented at the 2014 ASCO Annual Meeting in Chicago, Illinois.\n\nSupplementary Material\nSupplementary Information Click here for additional data file.\n\n Supplementary Tables Click here for additional data file.\n\n Figure 1 ΔQTc in the whole cohort and in specific TKIs. Blue bars represent the median baseline QTc interval and red bars represent the median QTc interval during treatment. At the y axis, the QTc interval is expressed in ms.\n\nTable 1 Patient characteristics\nVariable\tN (%) or median (IQR)\t\nGender\t\nMale\t215 (59)\t\nFemale\t148 (41)\t\nAge (years)\t60 (51–67)\t\nQTc-interval baseline\t401 (388–415)\t\nQTc-interval therapy\t415 (397–431)\t\nTumour type\t\nRCC\t101 (27.8)\t\nGIST\t49 (13.5)\t\nHCC\t45 (12.4)\t\nLung cancer\t27 (7.4)\t\nBreast cancer\t16 (4.4)\t\nMelanoma\t69 (19.0)\t\nOther\t56 (15.4)\t\nType of TKI\t\nSunitinib\t110 (30.3)\t\nVemurafenib\t67 (18.5)\t\nSorafenib\t52 (14.3)\t\nPazopanib\t46 (12.7)\t\nImatinib\t41 (11.3)\t\nErlotinib\t21 (5.8)\t\nLapatinib\t16 (4.4)\t\nGefitinib\t10 (2.8)\t\nWHO PS baseline\t\n0\t155 (42.7)\t\n1\t195 (53.7)\t\n2\t12 (3.3)\t\n3\t1 (0.3)\t\nCVD\t37 (10.2)\t\nQTc co-medications\t34 (9.4)\t\nRace\t\nCaucasian\t349 (96.1)\t\nOther\t14 (3.5)\t\nSite\t\nEMC\t184 (50.7)\t\nNKI\t118 (32.5)\t\nLUMC\t54 (14.9)\t\nSMF\t7 (1.9)\t\nAbbreviations: CVD=cardiovascular disease; EMC=Erasmus MC—Cancer Institute; GIST=gastro-intestinal stromal tumour; HCC=hepatocellular carcinoma; LUMC=Leiden University Medical Centre; NKI=Netherlands Cancer Institute—Antoni van Leeuwenhoek; RCC=renal cell cancer; SMF=Salvatore Maugeri Foundation; TKI=tyrosine kinase inhibitor; WHO PS=World Health Organisation performance score.\n\nTable 2 TKI-induced change in QTc interval\n \t \tQTc interval (ms) \nMedian (IQR)\t \t\nTKI\tn\tBaseline\tTherapy\tP-value\t\nWhole\t363\t401 (388–415)\t415 (397–431)\t<0.00001\t\nSunitinib\t110\t393 (380–410)\t406 (390–424)\t<0.00001\t\nVemurafenib\t67\t401 (394–417)\t427 (415–442)\t<0.00001\t\nSorafenib\t52\t400 (386–412)\t410 (394–425)\t0.0004\t\nPazopanib\t46\t402 (390–411)\t412 (395–431)\t0.079\t\nImatinib\t41\t410 (396–424)\t425 (410–439)\t0.002\t\nErlotinib\t21\t412 (398–430)\t421 (414–440)\t0.004\t\nLapatinib\t16\t413 (405–423)\t414 (397–428)\t0.982\t\nGefitinib\t10\t403 (396–417)\t409 (390–429)\t0.919\t\nAbbreviations: IQR=interquartile range; n=number of patients within each TKI group; ΔQTc=median difference between QTc interval during TKI treatment and QTc interval at baseline; TKI=tyrosine kinase inhibitor. Bold values are statistically significant.\n\nTable 3 Increase in CTCAE grade and prevalence of high-risk patients\n \t \t \tChange in CTCAE Grade after start of therapy\tQTc⩾470\t\nTKI\tN\tΔQTc⩾30 ms\nN (%)\tIncreased N (%)\tUnchanged N (%)\tReduced N (%)\tP-value\tBaseline N (%)\tTherapy N (%)\tP-value\t\nWhole\t363\t76 (20.9)\t33 (9.1)\t321 (88.4)\t9 (2.5)\t0.0003\t6 (1.7)\t21 (5.8)\t0.005\t\nSunitinib\t110\t22 (20.0)\t4 (3.6)\t104 (95.6)\t2 (1.8)\t0.746\t1 (0.9)\t3 (2.7)\t0.617\t\nVemurafenib\t67\t23 (34.3)\t9 (13.4)\t58 (86.6)\t0 (0)\t0.008\t1 (1.5)\t8 (11.9)\t0.023\t\nSorafenib\t52\t11 (21.2)\t6 (11.6)\t45 (86.6)\t1 (1.9)\t0.073\t1 (1.9)\t2 (3.9)\t1\t\nPazopanib\t46\t6 (13.0)\t3 (6.5)\t41 (89.1)\t2 (4.4)\t0.410\t1 (2.2)\t2 (4.4)\t1\t\nImatinib\t41\t8 (19.5)\t5 (12.2)\t34 (82.9)\t2 (4.9)\t0.430\t1 (2.4)\t1 (2.4)\t1\t\nErlotinib\t21\t3 (14.3)\t3 (14.3)\t18 (85.7)\t0 (0)\t0.174\t0 (0)\t2 (9.5)\tNA\t\nLapatinib\t16\t1 (6.3)\t1 (6.3)\t14 (87.5)\t1 (6.3)\t1\t1 (6.3)\t1 (6.3)\t1\t\nGefitinib\t10\t2 (20.0)\t2 (20.0)\t7 (70.0)\t1 (10.0)\t0.423\t0 (0)\t2 (20.0)\tNA\t\nAbbreviations: CTCAE=common terminology criteria for adverse events; N=number of patients; NA=not applicable; TKI=tyrosine kinase inhibitor; ΔQTc=difference between QTc interval during TKI treatment and QTc interval at baseline measurement. Bold values are statistically significant.\n\nTable 4 Variables influencing CTCAE grade for QTc interval and the probability to become a high-risk patient\n \t \tCTCAE grade during TKI\tTransition to high risk (QTc⩾470 ms)\t\nVariable\tN\tIncreased (n=33)\nmedian (IQR) \nor N (%)\tUnchanged/Reduced (n=330)\nmedian (IQR) \nor N (%)\tP-value\tYes (n=20)\nmedian (IQR) \nor N (%)\tNo (n=343)\nmedian (IQR) \nor N (%)\tP-value\t\nAge (years)\t363\t62 (59–72)\t60 (51–67)\t0.026\t66 (60–76)\t60 (51–66)\t0.007\t\nGender\t\nMales\t215\t22 (66.7)\t193 (58.5)\t0.458\t14 (70)\t201 (58.6)\t0.358\t\nFemales\t148\t11 (33.3)\t137 (41.5)\t \t6 (30)\t142 (41.4)\t \t\nCo-medication\t\nYes\t34\t6 (18.2)\t28 (8.5)\t0.107\t5 (25)\t29 (8.4)\t0.030\t\nNo\t329\t27 (81.8)\t302 (91.5)\t \t15 (75)\t314 (91.6)\t \t\nCVD\t\nYes\t37\t5 (15.2)\t32 (9.7)\t0.360\t4 (20)\t33 (9.6)\t0.134\t\nNo\t326\t28 (84.9)\t298 (90.3)\t \t16 (80)\t310 (90.4)\t \t\nDM\t\nYes\t43\t3 (9.1)\t40 (12.1)\t0.782\t1 (5)\t42 (12.2)\t0.489\t\nNo\t320\t30 (90.9)\t290 (87.9)\t \t19 (95)\t301 (87.8)\t \t\nCa2+\t\nNormo/Hyper\t169\t13 (61.9)\t156 (71.6)\t0.451\t8 (80)\t161 (70.3)\t0.728\t\nHypo\t70\t8 (38.1)\t62 (28.4)\t \t2 (20)\t68 (29.7)\t \t\nK+\t\nNormo/Hyper\t304\t23 (79.3)\t281 (96.9)\t0.0009\t16 (88.9)\t288 (95.7)\t0.204\t\nHypo\t15\t6 (20.7)\t9 (3.1)\t \t2 (11.1)\t13 (4.3)\t \t\nAbbreviations: Ca2+=calcium level at time of QTc measurement during treatment; CVD=cardiovascular disease; CTCAE, common terminology criteria for adverse events; DM=diabetes mellitus; IQR, interquartile range; K+, potassium level at time of QTc measurement during treatment; N, number of analysed patients with non-missing values; TKI, tyrosine kinase inhibitor. Bold values are statistically significant.\n==== Refs\nBello CL Mulay M Huang X Patyna S Dinolfo M Levine S Van Vugt A Toh M Baum C Rosen L 2009 Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic- pharmacodynamic evaluation of sunitinib Clin Cancer Res 15 7045 7052 19903787 \nBenoit SR Mendelsohn AB Nourjah P Staffa JA Graham DJ 2005 Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey Eur J Cardiovasc Prev Rehabil 12 363 368 16079644 \nCommittee for Proprietary Medicinal Products (CPMP) Points to consider: The Assessment of the Potential for QT Interval Prolongation by non-Cardiovascular Medicinal Products Vol. 1997The European Agency for the Evaluation of Medicinal Products: London, UK \nCommon Terminology Criteria for Adverse Events (CTCAE), Version 4.03 U.S. Department of Health and Human Services National Institutes of Health, National Cancer Institute published 14 June 2010.\nCurigliano G Spitaleri G Fingert HJ de Braud F Sessa C Loh E Cipolla C De Pas T Goldhirsch A Shah R 2008 Drug-induced QTc interval prolongation: a proposal towards an efficient and safe anticancer drug development Eur J Cancer 44 494 500 18024014 \nde Jonge M Verweij J 2008 QTc prolongation and/or oncology drug development: who's in danger Eur J Cancer 44 486 487 18272360 \nDogan E Yorgun H Petekkaya I Ozer N Altundag K Ozisik Y 2012 Evaluation of cardiac safety of lapatinib therapy for ErbB2-positive metastatic breast cancer: a single center experience Med Oncol 29 3232 3239 22729366 \nDoherty KR Wappel RL Talbert DR Trusk PB Moran DM Kramer JW Brown AM Shell SA Bacus S 2013 Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes Toxicol Appl Pharmacol 272 245 255 23707608 \nDong Q Fu XX Du LL Zhao N Xia CK Yu KW Cheng LX Du YM 2013 Blocking of the human ether-a-go-go-related gene channel by imatinib mesylate Biol Pharm Bull 36 268 275 23196655 \nEl-Sherif N Turitto G 2003 Torsade de pointes Curr Opin Cardiol 18 6 13 12496496 \nGrant AO 2009 Cardiac ion channels Circ Arrhythm Electrophysiol 2 185 194 19808464 \nHeath EI Infante J Lewis LD Luu T Stephenson J Tan AR Kasubhai S LoRusso P Ma B Suttle AB Kleha JF Ball HA Dar MM 2013 A randomized, double-blind, placebo-controlled study to evaluate the effect of repeated oral doses of pazopanib on cardiac conduction in patients with solid tumors Cancer Chemother Pharmacol 71 565 573 23344712 \nKobza R Roos M Niggli B Abacherli R Lupi GA Frey F Schmid JJ Erne P 2009 Prevalence of long and short QT in a young population of 41,767 predominantly male Swiss conscripts Heart Rhythm 6 652 657 19303371 \nLee HA Kim EJ Hyun SA Park SG Kim KS 2010 Electrophysiological effects of the anti-cancer drug lapatinib on cardiac repolarization Basic Clin Pharmacol Toxicol 107 614 618 20406211 \nLi EC Esterly JS Pohl S Scott SD McBride BF 2010 Drug-induced QT-interval prolongation: considerations for clinicians Pharmacotherapy 30 684 701 20575633 \nMolnar J Zhang F Weiss J Ehlert FA Rosenthal JE 1996 Diurnal pattern of QTc interval: how long is prolonged? Possible relation to circadian triggers of cardiovascular events J Am Coll Cardiol 27 76 83 8522713 \nMoss AJ 2003 Long QT Syndrome JAMA 289 2041 2044 12709446 \nMotzer RJ Hutson TE Cella D Reeves J Hawkins R Guo J Nathan P Staehler M de Souza P Merchan JR Boleti E Fife K Jin J Jones R Uemura H De Giorgi U Harmenberg U Wang J Sternberg CN Deen K McCann L Hackshaw MD Crescenzo R Pandite LN Choueiri TK 2013 Pazopanib versus sunitinib in metastatic renal-cell carcinoma N Engl J Med 369 722 731 23964934 \nSagie A Larson MG Goldberg RJ Bengtson JR Levy D 1992 An improved method for adjusting the QT interval for heart rate (the Framingham Heart Study) Am J Cardiol 70 797 801 1519533 \nShah RR Morganroth J Shah DR 2013 Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT interval) Drug Saf 36 295 316 23620167 \nStrevel EL Ing DJ Siu LL 2007 Molecularly targeted oncology therapeutics and prolongation of the QT interval J Clin Oncol 25 3362 3371 17664484 \nTolcher AW Appleman LJ Shapiro GI Mita AC Cihon F Mazzu A Sundaresan PR 2011 A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer Cancer Chemother Pharmacol 67 751 764 20521052 \nTrinkley KE Page RL 2ndLien H Yamanouye K Tisdale JE 2013 QT interval prolongation and the risk of torsades de pointes: essentials for clinicians Curr Med Res Opin 29 1719 1726 24020938 \nYetkin E Senen K Ileri M Atak R Topaloglu S Ergun K Yanik A Tandogan I Cehreli S Duru E Demirkan D 2001 Diurnal variation of QT dispersion in patients with and without coronary artery disease Angiology 52 311 316 11386381\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0007-0920",
"issue": "112(6)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": "D000368:Aged; D001145:Arrhythmias, Cardiac; D004562:Electrocardiography; D005260:Female; D006801:Humans; D015994:Incidence; D007558:Italy; D029593:Jervell-Lange Nielsen Syndrome; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D012189:Retrospective Studies; D012306:Risk",
"nlm_unique_id": "0370635",
"other_id": null,
"pages": "1011-6",
"pmc": null,
"pmid": "25742483",
"pubdate": "2015-03-17",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "23964934;23707608;24020938;11386381;12496496;12709446;1519533;8522713;16079644;17664484;18024014;18272360;19303371;19808464;19903787;20575633;20406211;20521052;22729366;23196655;23344712;23620167",
"title": "Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors.",
"title_normalized": "incidence and relevance of qtc interval prolongation caused by tyrosine kinase inhibitors"
} | [
{
"companynumb": "NL-ASTELLAS-2014US005679",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SORAFENIB"
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"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate maternal tolerance to digoxin, used alone or associated to other antiarrhythmic drugs in the management of fetal tachycardia.\n\n\nMETHODS\nThis retrospective study was conducted at Rouen University Hospital between January 2009 and July 2016. All women who have received a treatment by either digoxin alone or associated with another antiarrhythmic drug for fetal tachycardia were included in the study. Maternal cardiac and extracardiac adverse effects were reported and comparisons between electrocardiograms before and during treatment with digoxin alone were performed.\n\n\nRESULTS\nEighteen women were treated by digoxin, either alone or associated with another antiarrhythmic (sotalol, flecainide or amiodarone). During treatment, digoxin overdosing (>2ng/mL) was observed in 11 women (61%), among which 4 women had toxic levels of digoxinemia (>3ng/mL) that was symptomatic in 3 women. Cardiac complications such as sinus bradycardia, first-degree auriculo-ventricular block and Mobitz I second-degree auriculo-ventricular block were reported in four women (18.2%). Extracardiac side effects i.e. neurosensorial or digestive were diagnosed in 35.3% of women. The parameters of the electrocardiogram were not altered before and after treatment with digoxin alone.\n\n\nCONCLUSIONS\nAntiarrhythmics can cause maternal cardiac complications and extracardiac side effects that can sometimes be severe but rapidly reversible upon treatment arrest.",
"affiliations": "Department of Gynecology and Obstetrics, Rouen University Hospital, 76031 Rouen, France.;Department of Gynecology and Obstetrics, Rouen University Hospital, 76031 Rouen, France.;Department of Pediatric-Cardiology, Rouen University Hospital, 76031 Rouen, France.;Department of Pediatric-Radiology, Rouen University Hospital, 76031 Rouen, France.;Department of Gynecology and Obstetrics, Rouen University Hospital, 76031 Rouen, France.;Department of Pediatric-Cardiology, Rouen University Hospital, 76031 Rouen, France.;Department of Gynecology and Obstetrics, Rouen University Hospital, 76031 Rouen, France. Electronic address: eric.verspyck@chu-rouen.fr.",
"authors": "Moatassim|S|S|;Touleimat|S|S|;Hazelzet|T|T|;Brasseur|M D|MD|;Diguet|A|A|;Durand|I|I|;Verspyck|E|E|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D004077:Digoxin",
"country": "France",
"delete": false,
"doi": "10.1016/j.jogoh.2017.11.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2468-7847",
"issue": "47(2)",
"journal": "Journal of gynecology obstetrics and human reproduction",
"keywords": "Fetal tachycardia; Fetal therapy; Maternal complications",
"medline_ta": "J Gynecol Obstet Hum Reprod",
"mesh_terms": "D000328:Adult; D000889:Anti-Arrhythmia Agents; D004077:Digoxin; D004562:Electrocardiography; D005260:Female; D005315:Fetal Diseases; D006801:Humans; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D013610:Tachycardia",
"nlm_unique_id": "101701588",
"other_id": null,
"pages": "35-38",
"pmc": null,
"pmid": "29208503",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Maternal complications induced by digoxin treatment of fetal tachycardia: A retrospective series of 18 cases.",
"title_normalized": "maternal complications induced by digoxin treatment of fetal tachycardia a retrospective series of 18 cases"
} | [
{
"companynumb": "FR-CONCORDIA PHARMACEUTICALS INC.-E2B_00010454",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadditio... |
{
"abstract": "Case. We report a rare case of hydralazine-induced anti-neutrophil cytoplasmic antibody-associated vasculitis. A 75-year-old African American woman with history of high blood pressure on hydralazine for 3 years presented with acute onset of shortness of breath and hemoptysis. Lab workup revealed a severe normocytic anemia and a serum creatinine of 5.09 mg/dL (baseline 0.9). Bronchoscopy demonstrated active pulmonary hemorrhage. A urine sample revealed red cell casts and a renal biopsy demonstrated pauci-immune, focally necrotizing glomerulonephritis with small crescents consistent with possible anti-neutrophil cytoplasmic antibody-positive renal vasculitis. Serologies showed high-titer MPO-ANCA and high-titer anti-histone antibodies. She was treated with intravenous steroids and subsequently with immunosuppression after cessation of hydralazine. The patient was subsequently discharged from hospital after a rapid clinical improvement. Conclusion. Hydralazine-induced anti-neutrophil cytoplasmic antibody-positive renal vasculitis is a rare adverse effect and can present as a severe vasculitic syndrome with multiple organ involvement. Features of this association include the presence of high titer of anti-myeloperoxidase anti-neutrophil cytoplasmic antibody with multiantigenicity, positive anti-histone antibodies, and the lack of immunoglobulin and complement deposition. Prompt cessation of hydralazine may be sufficient to reverse disease activity but immunosuppression may be needed.",
"affiliations": "Department of Internal Medicine, Division of Rheumatology, Henry Ford Hospital, Wayne State University, Detroit, MI 48202, USA ; Department of Internal Medicine, Division of Rheumatology, University of Michigan, 1150 W. Medical Center Drive, SPC 5680, Ann Arbor, MI 48109, USA.;Department of Internal Medicine, Division of Rheumatology, Henry Ford Hospital, Wayne State University, Detroit, MI 48202, USA.;Department of Pathology, Henry Ford Hospital, Wayne State University, Detroit, MI 48202, USA.;Department of Internal Medicine, Division of Rheumatology, Henry Ford Hospital, Wayne State University, Detroit, MI 48202, USA.",
"authors": "Namas|Rajaie|R|;Rubin|Bernard|B|;Adwar|Wamidh|W|0000-0003-1673-4351;Meysami|Alireza|A|0000-0002-8608-1010",
"chemical_list": null,
"country": "United States",
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"doi": "10.1155/2014/516362",
"fulltext": "\n==== Front\nCase Rep RheumatolCase Rep RheumatolCRIRHCase Reports in Rheumatology2090-68892090-6897Hindawi Publishing Corporation 10.1155/2014/516362Case ReportA Challenging Twist in Pulmonary Renal Syndrome Namas Rajaie \n1\n\n2\n\n*\nRubin Bernard \n1\nhttp://orcid.org/0000-0003-1673-4351Adwar Wamidh \n3\nhttp://orcid.org/0000-0002-8608-1010Meysami Alireza \n1\n1Department of Internal Medicine, Division of Rheumatology, Henry Ford Hospital, Wayne State University, Detroit, MI 48202, USA2Department of Internal Medicine, Division of Rheumatology, University of Michigan, 1150 W. Medical Center Drive, SPC 5680, Ann Arbor, MI 48109, USA3Department of Pathology, Henry Ford Hospital, Wayne State University, Detroit, MI 48202, USA*Rajaie Namas: rajainammas@gmail.comAcademic Editor: Masataka Kuwana\n\n2014 27 11 2014 2014 5163625 6 2014 30 8 2014 Copyright © 2014 Rajaie Namas 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.\nCase. We report a rare case of hydralazine-induced anti-neutrophil cytoplasmic antibody-associated vasculitis. A 75-year-old African American woman with history of high blood pressure on hydralazine for 3 years presented with acute onset of shortness of breath and hemoptysis. Lab workup revealed a severe normocytic anemia and a serum creatinine of 5.09 mg/dL (baseline 0.9). Bronchoscopy demonstrated active pulmonary hemorrhage. A urine sample revealed red cell casts and a renal biopsy demonstrated pauci-immune, focally necrotizing glomerulonephritis with small crescents consistent with possible anti-neutrophil cytoplasmic antibody-positive renal vasculitis. Serologies showed high-titer MPO-ANCA and high-titer anti-histone antibodies. She was treated with intravenous steroids and subsequently with immunosuppression after cessation of hydralazine. The patient was subsequently discharged from hospital after a rapid clinical improvement. Conclusion. Hydralazine-induced anti-neutrophil cytoplasmic antibody-positive renal vasculitis is a rare adverse effect and can present as a severe vasculitic syndrome with multiple organ involvement. Features of this association include the presence of high titer of anti-myeloperoxidase anti-neutrophil cytoplasmic antibody with multiantigenicity, positive anti-histone antibodies, and the lack of immunoglobulin and complement deposition. Prompt cessation of hydralazine may be sufficient to reverse disease activity but immunosuppression may be needed.\n==== Body\n1. Case Report\nA 75-year-old African American female with history of hypertension and Type 2 DM presented to the emergency room with acute onset of shortness of breath and hemoptysis of 2-day duration. She denied fever, chest pain, recent hospitalizations, new medications, or travel history. Medications include gabapentin 100 mg at bedtime, hydralazine 50 mg every 8 hours for the past 3 years, and simvastatin 20 mg at bedtime. Four months ago, she was evaluated in the rheumatology clinic for multiple joint pains and swelling including hands and ankles. She denied fever, dry cough, dyspnea, chest pain, or hemoptysis. She also denied patchy alopecia, photosensitivity, mucosal or nasal ulcers, skin rash, or inflammatory eye disease. She was lost to followup before lab was done.\n\nPhysical exam in the emergency room revealed an intubated patient on mechanical ventilation who was hypertensive, tachypneic, and afebrile. Lung exam demonstrated diffuse coarse rales bilaterally. The rest of the physical exam was unremarkable. Laboratory findings on admission revealed ESR: 98 mm/hr, CRP: 7 mg/L, hemoglobin: 4.9 g/dL (baseline 11 g/dL), leukocytosis, lymphopenia, and serum creatinine of 5.09 mg/dL (baseline 0.9 mg/dL). Urine analysis demonstrated 3+ blood, 2+ protein, and red blood cell casts. Chest X-ray revealed bilateral perihilar air space opacity and a tiny right pleural effusion with thickening or fluid within the fissures (Figure 1).\n\nDuring the hospital stay she received 2 units of blood and a bronchoscopy was consistent with active pulmonary hemorrhage. She was treated with 1 gram of methyl prednisolone IV; she was then switched to 1 mg/kg for possible pulmonary renal syndrome. Extensive evaluation with cultures (sputum, bronchoalveolar lavage, blood, and urine) and serologies for atypical infections including viral and fungal diseases failed to demonstrate an infectious etiology. Further workup demonstrated ANA of 1 : 320 (homogenous pattern), P-ANCA positive with anti-MPO of 52 and anti-PR3 of 28, and a strongly positive histone antibody (2.6, normal value 0–0.9). Anti-Smith (anti-Sm) antibody test was negative, and C3 and C4 complement levels were normal. Transthoracic echocardiography revealed severely elevated pulmonary artery systolic pressure (61 mmHg) with an ejection fraction of 55–60%. Ultrasound of the kidneys was normal.\n\nDue to her critical condition a kidney biopsy was not obtained on the day of admission but on day 5 her condition stabilized and a kidney biopsy was obtained which demonstrated necrotizing glomerulonephritis with fibrocellular crescents (66%) (Figure 2(a)), global glomerulosclerosis (33%), focal infiltration of polymorphonuclear cells within the glomerulus (arrow) (Figure 2(b)), tubular hemorrhage (Figure 2(c)), sclerosed glomeruli (Figure 2(d)), and interstitial inflammation with infiltration of lymphocytes, plasma cells, and polymorphonuclear cells (Figure 2(e)) on H&E stain. Direct immunofluorescence microscopy revealed peripheral granular positive staining, +1 of IgG, IgM, and C3, peripheral and mesangial positive staining, 1+ of IgA, and negative staining of fibrinogen, C1 and C4. There was peripheral granular positive staining, 1+ of kappa and lambda light chains, and nonspecific positive staining of albumin. Linear positivity was not seen with IgG or C3. Immunofluorescence studies and electron microscopy (Figure 3) were negative for immune complex deposition, consistent with pauci-immune glomerulonephritis.\n\nA diagnosis of hydralazine-induced anti-neutrophil cytoplasmic antibody-positive renal vasculitis presenting with a pulmonary renal syndrome was established. To assess the probability that hydralazine caused the adverse event in our patient, we used the Naranjo adverse drug reaction probability scale patient's score which indicated that the association of hydralazine to pulmonary-renal syndrome was probable. Hydralazine was stopped and she was started on 750 mg of cyclophosphamide IV every 2 weeks and then was switched to oral cyclophosphamide (100 mg/day). Plasmapheresis was initiated on admission and she received a total of 7 cycles over 14 days of 60 mL/kg per session using 3% to 5% albumin as a replacement solution. The volumes were calculated using the estimated plasma volume (in liters) = 0.07 × wt (kg) × (1 − hematocrit). She was extubated on the 3rd day of admission. She received hemodialysis 3 times per week. Repeating chest X-ray and bronchoscopy 2 weeks later did not reveal any signs of pulmonary hemorrhage.\n\nThe patient was discharged on tapering dose of oral steroids, and an oral dose of 2 mg per kg of cyclophosphamide (100 mg/day) daily for 6 months with a cumulative dose was 21600 calculated based on the weight (weight (kg) × 2 mg) × 180 (days). One month later, she was asymptomatic, and the microscopic hematuria had resolved. Prednisone was weaned off over 3 months. One year later MPO-ANCA normalized, but the ANA remained positive.\n\n2. Discussion\nThis case describes a patient with hydralazine-induced ANCA who presented with pauci-immune glomerulonephritis and the simultaneous presence of multiple autoantibodies (ANAs, anti-histone antibodies, and P-ANCA positive with anti-MPO and anti-PR3).\n\nHydralazine is a direct-acting smooth muscle vasodilator that is often used in the treatment of hypertension. Anti-neutrophil cytoplasmic antibody-associated vasculitis has been associated with many drugs such as allopurinol, sulfasalazine, and propylthiouracil and is a relatively rare side effect of hydralazine. The etiology of ANCA-associated vasculitis (AAV) is not always clear and this association is less well recognized compared to drug-induced lupus, which is well documented in the literature [1]. The diagnosis and management of patients may be challenging because of its relative infrequency. The incidence of hydralazine-induced vasculitis is dose dependent. It is reported to be 5.4% in patients on 100 mg/d of hydralazine versus 10.4% with 200 mg of daily dosing for ≥3 years duration, particularly in individuals who are slow acetylators. The key to the diagnosis is resolution of symptoms with discontinuation of the drug [2].\n\nThe spectrum of AAV can range from cutaneous rashes and petechiae or single organ involvement to fatal multiorgan involvement with death commonly from massive pulmonary hemorrhage. A latency of several years can occur before the development of vasculitis with a variable delay in the full clinical manifestations [3] therefore posing a challenge for clinicians to achieve a clear diagnosis and treatment strategy. The presence of high titers of P-ANCA and anti-MPO with multiantigenicity, the positive anti-histone antibodies, and the lack of immunoglobulin and complement deposition histopathologically are features that have been described with drug-induced ANCA vasculitis [3, 4] rather than with drug-induced lupus or with primary vasculitis.\n\nRisk factors that have been identified as predisposing factors for hydralazine-induced AAV include a cumulative dose of more than 100 grams, female sex, and a history of thyroid disease [5] as seen in our patient. Other risk factors include the human leukocyte antigen (HLA)-DR4 genotype, slow hepatic acetylation, and the null gene for C4 [6].\n\nThe mechanism for hydralazine-induced AAV is not fully understood but might be multifactorial. Hypotheses of immune system activation by drug metabolites with autoimmunity towards neutrophil proteins (including elastase and lactoferrin) and upregulation of ANCA antigens have been suggested [6]. The hydralazine dosage ranged from 50 to 300 mg per day, and the treatment duration varied from 0.73 to 120 months. Almost all the patients in the literature were positive for MPO antibodies and all of the patients in whom anti-histone antibodies were checked had positive results.\n\n3. Conclusion\nThe diagnosis of drug-induced lupus and drug-induced vasculitis is challenging to the physician. In the former, characteristic symptoms include arthralgia, myalgia, fever, and serositis that improve after discontinuation, whereas the latter is predominantly an anti-neutrophil cytoplasmic antibody (ANCA) positive small vessel vasculitis involving the kidneys, skin, and lungs that resembles idiopathic ANCA-associated vasculitides, such as granulomatosis with polyangiitis and microscopic polyangiitis. Discontinuation of the offending agent must be the first intervention and rechallenging using the same medication after resolution of the symptoms should be avoided in addition to avoiding similar drug classes.\n\nAcknowledgments\nThe patient and her family are acknowledged for giving the authors the trust to manage her medical condition.\n\nAbbreviations\nAAV:ANCA-associated vasculitis\n\nH&E:Hematoxylin and eosin stain.\n\nDisclosure\nThe case report was accepted and presented for Thieve’s Market at the American College of Rheumatology Annual meeting in San Diego, 2013.\n\nDisclaimer\nAll authors take responsibility for the information in the review, which has not been published elsewhere.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Chest X-ray revealing bilateral perihilar air space opacity. Tiny right pleural effusion with thickening or fluid within the fissures.\n\nFigure 2 (a) Necrotizing glomerulonephritis with fibrocellular crescents (66%). (b) Global glomerulosclerosis (33%), focal infiltration of polymorphonuclear cells within the glomerulus (arrow). (c) Tubular hemorrhage (arrow). (d) Sclerosed glomeruli (arrow). (e) Interstitial inflammation lymphocytes, plasma cells, and polymorphonuclear cells (arrow).\n\nFigure 3 No evidence of electron dense, immune complex deposits by electron microscopy.\n==== Refs\n1 Choi H. K. Merkel P. A. Walker A. M. Niles J. L. Drug-associated antineutrophil cytoplasmic antibody-positive vasculitis Arthritis & Rheumatology 2000 43 2 405 413 \n2 Suneja M. Baiswar S. Vogelgesang S. A. Hydralazine associated pauci-immune glomerulonephritis Journal of Clinical Rheumatology 2014 20 2 99 102 10.1097/RHU.0000000000000049 2-s2.0-84896730278 24561415 \n3 Luxton G. Langham R. ANCA serology in the diagnosis and management of ANCA-associated renal vasculitis Nephrology 2008 13 S17 S23 10.1111/j.1440-1797.2008.00994.x 2-s2.0-47749124271 18713120 \n4 Radić M. Kaliterna D. M. Radić J. Drug-induced vasculitis: a clinical and pathological review Netherlands Journal of Medicine 2012 70 1 12 17 2-s2.0-84856353784 22271809 \n5 Lionaki S. Hogan S. L. Falk R. J. Joy M. S. Chin H. Jennette C. E. Jennette J. C. Nachman P. H. Association between thyroid disease and its treatment with ANCA small-vessel vasculitis: a case-control study Nephrology Dialysis Transplantation 2007 22 12 3508 3515 10.1093/ndt/gfm493 2-s2.0-36749009179 \n6 McKinnon R. A. Nebert D. W. Possible role of cytochromes P450 in lupus erythematosus and related disorders Lupus 1994 3 6 473 478 10.1177/096120339400300608 2-s2.0-0028572410 7704004\n\n",
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"title": "A challenging twist in pulmonary renal syndrome.",
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"abstract": "Sweet's syndrome and eosinophilic folliculitis are aseptic inflammatory dermatitis mainly because of infiltrated neutrophils and eosinophils on skin, respectively. These diseases rarely overlap or coexist in the same patient, especially co-occur in HIV infected patient. Here, we report a rare case of an AIDS patient who developed eosinophilic folliculitis and Sweet's syndrome within 1 month of initial antiretroviral therapy, presumably due to immune reconstitution inflammatory syndrome. The CD4+ T cell counts increased dramatically from 70 to 249 cells/μL within a period of 1 month. Interestingly, the patient was rapidly and strikingly responsive to thalidomide, which has anti-inflammatory, immune regulation, inhibition of neutrophil chemotaxis etc. Moreover, we focused our attention on discussing the clinical, pathological, and possible pathogenic aspects of the rare overlap of HIV complicated with neutrophilic and eosinophilic dermatosis.",
"affiliations": "Department of Dermatology and Venereology, First Affiliated Hospital of Kunming Medical University, Kunming, China.;Yunnan Provincial Hospital of Infectious Disease/Yunnan AIDS Care Center (YNACC), Anning, China.;Department of Dermatology and Venereology, First Affiliated Hospital of Kunming Medical University, Kunming, China.;Department of Medical Imaging, First Affiliated Hospital of Kunming Medical University, Kunming, China.;Department of Dermatology and Venereology, Jining Second People's Hospital, Jining, China.;Department of Dermatology and Venereology, First Affiliated Hospital of Kunming Medical University, Kunming, China.",
"authors": "Dong|Rong-Jing|RJ|;Huang|Shi-Zhen|SZ|;Upadhyay|Pratishtha|P|;Shrestha|Samip|S|;Zhai|Ya-Jie|YJ|;Li|Yu-Ye|YY|",
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"doi": "10.3389/fmed.2019.00343",
"fulltext": "\n==== Front\nFront Med (Lausanne)Front Med (Lausanne)Front. Med.Frontiers in Medicine2296-858XFrontiers Media S.A. 10.3389/fmed.2019.00343MedicineCase ReportThalidomide in the Treatment of Sweet's Syndrome and Eosinophilic Folliculitis Associated With Immune Reconstitution Inflammatory Syndrome Dong Rong-Jing 1Huang Shi-Zhen 2Upadhyay Pratishtha 1Shrestha Samip 3Zhai Ya-Jie 4Li Yu-Ye 1*1Department of Dermatology and Venereology, First Affiliated Hospital of Kunming Medical University, Kunming, China2Yunnan Provincial Hospital of Infectious Disease/Yunnan AIDS Care Center (YNACC), Anning, China3Department of Medical Imaging, First Affiliated Hospital of Kunming Medical University, Kunming, China4Department of Dermatology and Venereology, Jining Second People's Hospital, Jining, ChinaEdited by: Ivan V. Litvinov, McGill University, Canada\n\nReviewed by: Hassanin Al-Aasam, Luebeck University of Applied Sciences, Germany; Feras M. Ghazawi, University of Ottawa, Canada\n\n*Correspondence: Yu-Ye Li yyeli2000@126.comThis article was submitted to Dermatology, a section of the journal Frontiers in Medicine\n\n21 1 2020 2019 6 34318 9 2019 27 12 2019 Copyright © 2020 Dong, Huang, Upadhyay, Shrestha, Zhai and Li.2020Dong, Huang, Upadhyay, Shrestha, Zhai and LiThis 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.Sweet's syndrome and eosinophilic folliculitis are aseptic inflammatory dermatitis mainly because of infiltrated neutrophils and eosinophils on skin, respectively. These diseases rarely overlap or coexist in the same patient, especially co-occur in HIV infected patient. Here, we report a rare case of an AIDS patient who developed eosinophilic folliculitis and Sweet's syndrome within 1 month of initial antiretroviral therapy, presumably due to immune reconstitution inflammatory syndrome. The CD4+ T cell counts increased dramatically from 70 to 249 cells/μL within a period of 1 month. Interestingly, the patient was rapidly and strikingly responsive to thalidomide, which has anti-inflammatory, immune regulation, inhibition of neutrophil chemotaxis etc. Moreover, we focused our attention on discussing the clinical, pathological, and possible pathogenic aspects of the rare overlap of HIV complicated with neutrophilic and eosinophilic dermatosis.\n\nAIDSthalidomidesweet's syndromeeosinophilic folliculitisIRIS\n==== Body\nBackground\nEosinophilic folliculitis (EF) has been regarded as a significant marker of advanced AIDS (1), reportedly occurs in 9–10% HIV infected patients (2, 3). HIV-associated eosinophilic folliculitis (HIV-EF) was first reported in 1986 by Soeprono and Schinella (4), which is a variant of eosinophilic pustular folliculitis (EPF) (known as Ofuji disease) (5) and characterized by pruritic, erythematous, follicular papules distributed on face, trunk, and limbs. Histopathology of HIV-EF lesion shows eosinophil infiltration in the epithelium of the follicular infundibulum. The specific etiology and pathogenesis of HIV-EF is still unclear. Recently, more reports have suggested HIV-EF is associated with immune reconstitution inflammatory syndrome (IRIS) after commencing anti-retroviral therapy (ART) (6–9), especially when patients with a low baseline CD4 cells count increased rapidly after ART. Maybe due to immune reconstitution recognized antigens from past or ongoing infections (8). Furthermore, accumulated evidence confirmed that Th2 shift and produced cytokines/chemokines play a role in Ofuji disease and a possible pathogenic mechanism of HIV-EF (10), especially interleukin (IL)-4, IL-5, Eotaxin and intercellular adhesion molecule 1 (ICAM-1), which could promote activity, proliferation, and recruitment of eosinophils (11).\n\nAnother pro-inflammatory neutrophilic dermatoses (ND) with the predominance of mature neutrophils infiltrate diffusely in the papillary and upper reticular dermis on histopathology, is Sweet's syndrome (also known as acute febrile neutrophilic dermatosis). It can manifest with fever, neutrophilia, tender and painful skin lesions like pseudovesicular nodules and plaques on the face, neck, and upper extremities (12). It was initially proposed by British dermatologist Sweet in 1964 (13). The etiologies and pathogenesis may be multifactorial. It may be associated with tumor antigens (especially hematologic malignancies and underlying malignancy), drugs (granulocyte-colony stimulating factor), infections (bacterial, viral) etc. that can induce cytokine cascade (12). It is classified as classical, drug-induced, and malignancy-associated Sweet's syndrome (14). It has been increasingly reported with co-occurring immunodeficiencies (15, 16). However, Sweet's syndrome has not been well-established associations with HIV. Scattered cases had reported that Sweet's syndrome was associated with IRIS (6, 8, 9). In addition, the immunohistochemistry and serological tests suggested that Th1 (17) and Th17 cells (18) secreted pro-inflammatory cytokines (IL-2, INF-γ, and IL-17) played a dominant role in the pathogenesis of Sweet's syndrome, which could activate and recruit neutrophils to the site of inflammation. Besides, other neutrophil recruiters and activators, such as TNF-α, IL-6, and IL-8 are potential cytokine candidates in the pathogenesis of Sweet's syndrome (14, 19, 20). And some authors have speculated that IL-6 may also be a potential target for the treatment of ND (21).\n\nBoth eosinophilic folliculitis and Sweet's syndrome are chronic recurrent and have no specific treatment. But they are sensitive to anti-inflammatory drugs such as glucocorticoids and Non-steroidal anti-inflammatory drugs (NSAIDs) (5, 12). Here, we first reported a case of occurrence of eosinophilic folliculitis and Sweet's syndrome after ART. And first attempted successful treatment with thalidomide and discuss the clinical, pathological, and possible pathogenic aspects of the rare overlap of these three diseases.\n\nCase Presentation\nA 47-year-old Chinese woman confirmed HIV-seropositive for 6 years had a history of 3 years of irregular ART, and stopped taking any antiviral medications for the next 3 years because of non-compliance. In September 11 2017, as the CD4+ T cells counts was only 70 cells/μL and initiation of ART (tenofovir, lamivudine, and dolutegravir) was started. However, 3 weeks after the onset of ART, there were dense, red follicular papules with itching involving the face, neck and upper trunk, ranging from 2 to 5 mm in diameter (Figure 1a). Routine examination of blood showed white blood cell count of 6.23 × 109/L, the percentage of neutrophils and eosinophils were 58.10% and 8.7%, respectively. The counts of neutrophils and eosinophils were 3.62 × 109/L and 0.54 × 109/L, respectively. She hadn't received any treatment for skin lesions but continued ART.\n\nFigure 1 Clinical and histopathological images of the patient before and after treatment. (a) Neck and upper chest with erythema and red papules. (b) Left forearm with raised, pseudovesicular cysts, and infiltrated plaques. (c) Hematoxylin–eosin (HE) staining of skin biopsy from papule at back of neck showing edema of hair follicle epithelial cells in the dermis, surrounded by eosinophils, lymphocytes, and neutrophils inflammatory infiltration. And neutrophils and eosinophils were seen migrated into the hair follicle epithelium (original magnification ×100). (d) HE staining of skin biopsy from left forearm plaque showing obvious edema in the superficial dermis, neutrophils, and lymphocytes infiltrated diffusely in the superficial and middle layers of dermis, and nuclear sedimentation were present significantly (×100). (e) Neck and upper chest papules resolved completely. (f) Forearm with scars formation.\n\nThen, she had persistent fever for 1 week and the highest temperature was 39°C. She then developed painful, raised, infiltrated plaques, and pseudovesicular on her left forearm (Figure 1b). Re-examination of blood (Table 1) revealed a white blood cell count of 4.54 × 109/L, with 78% neutrophils and 0.4% eosinophils. The neutrophil count was 3.54 × 109/L, the eosinophils count was 0.02 × 109/L; ESR was 68 mm/h, C reactive protein (CRP) was 18.12 mg/L, procalcitonin (PCT) was 0.141 ng/mL and IL-6 was 18.13 pg/ml. The CD4+ T lymphocytes counts increased sharply from 70 to 249 cells/μL (Table 1).\n\nTable 1 Basic information of the patient.\n\nLaboratory findings\tSeptember 11, 2017\tOctober 3, 2017\tOctober 11, 2017\tNovember 12, 2017\t\nCD4+ T (cells/ul)\t70\t–\t249\t–\t\nCD8+ T (cells/ul)\t197\t–\t577\t–\t\nWBC (109/L)\t–\t6.23\t4.54\t3.90\t\nNeutrophil (109/L)\t—\t3.62\t3.54\t1.97\t\nNeutrophil (%)\t–\t58.1\t78↑\t50.6\t\nEosinophils (109/L)\t–\t0.54\t0.02\t0.05\t\nEosinophils (%)\t–\t8.7↑\t0.4\t1.3\t\nIL−6 (pg/ml)\t–\t–\t18.13↑\t6.22\t\nCRP(mg/L)\t–\t–\t18.12↑\t4.02\t\nESR(mm/h)\t–\t–\t68↑\t12\t\nPCT (ng/ml)\t–\t–\t0.141↑\t0.022\t\n(HE) staining\t–\t–\tConfirmed Sweet's syndrome and HIV–EF\t–\t\nWBC, white blood cell; IL, interleukin; CRP, C–Reactive Protein; ESR, erythrocyte sedimentation rate; PCT, procalcitonin.\n\nShe underwent dermatopathology biopsies in two sites from her left forearm plaque and the back of neck papules. The pathological examination of the papules confirmed the diagnosis of eosinophilic folliculitis, edema of hair follicle epithelial cells in the dermis, surrounded by eosinophils, lymphocytes, and neutrophils inflammatory infiltration. And neutrophils and eosinophils were seen migrated into the hair follicle epithelium (Figure 1c). Pathological examination of the left forearm biopsy confirmed the diagnosis of Sweet's syndrome with obvious edema in the superficial dermis, neutrophils and lymphocytes infiltrated diffusely in the superficial and middle layers of dermis, and nuclear sedimentation were present significantly (Figure 1d). No obvious abnormality was found in the examination of lung, liver, renal etc. and without any other systemic manifestations.\n\nConsidering the CD4+ T cells count increased sharply, the IL-6 and C-reactive protein in peripheral blood were increased. Combined with clinical manifestations and pathological examination results, the patient was diagnosed as AIDS complicated with Sweet's syndrome and eosinophilic folliculitis. We speculate that the patient's symptoms were attributable to IRIS. The patient received thalidomide 100 mg/day combined with ART. On follow-up half month later, the follicular papules on face, neck and trunk were improved and about 1 month after the onset of treatment the plaques were also improved significantly (Figures 1e,f). The patient developed scars at the site of plaque on the forearm after treatment and are present till now. Re-examination laboratory tests showed CRP was 4.02 mg/L, PCT was 0.022 ng/mL and IL-6 was 6.22 pg/ml, all of which returned to their normal levels. The blood tests returned to normal (Table 1). ART was continued during the treatment of thalidomide. There is no sign of relapsing pruritic papules and plaque up till now.\n\nDiscussion\nAnecdotally, Sweet's syndrome and eosinophilic folliculitis co-occurring with immunodeficiencies is very rare. It may be related through an overlap in immunopathogenesis. There are different postulated pathogeneses for them, but the patient suffered Sweet's syndrome followed by EF successively within 1 month of initial ART, accompanied by a sharp increase in CD4+ T cells. It indicated that her immunity state switched from disease of predominant Th2 activation—EF—to disease of predominant Th1 activation—Sweet's syndrome. There seems to be a shift of Th2 cytokines production and a decline in Th1 cytokines as CD4+ T cells decreased with AIDS progression (22), which may first contribute to EF, and then developed Sweet's syndrome with increase in Th1 cytokines secretion. In addition, rapid recovery of effector memory CD4+T cells in the first phase of CD4 cell recovery (23) also restored immunity to previously non-pathogenic infectious state (8, 14), possibly resulting in Sweet's syndrome and eosinophilic folliculitis. It still needs to be explored whether the rapidly increased and newly distributed CD4+ T cells could directly or indirectly regulate neutrophils and eosinophils and inflammatory agents and may contribute to Sweet's syndrome and EF.\n\nART restores the Th1/Th2 cell balance, which allows the adaptive immune system to overcome some dermatosis. However, new appearance or paradoxical worsening of existing dermatosis may attribute to dramatic immune restoration because of IRIS which occurs in about 15–25% of patients in the early stage of ART (24). IRIS is the excessive inflammatory response to the existing pathogens or underlying antigens in the early stage of ART. The increased levels of IL-6, TNF-a, and CRP can be potential biomarkers for IRIS (25, 26). The rapidly increased of circulating CD4 cells leads to the increase of Th1 and Th2 cells and their secreted cytokines (IL-4, IL-5, IL-6, IL-8, TNF-a ect) (22), which may promote the occurrence and development of Sweet's syndrome and eosinophilic folliculitis. Taken together, we speculate that the presence of Sweet's syndrome and EF after ART may be closely related to IRIS. Although it has been reported that ART drug abacavir can cause Sweet's syndrome (27). We affirmed that the patient suffered Sweet's syndrome was not caused by ART drugs, because the patient's skin lesions improved when the ART was not stopped during the treatment of thalidomide. At the same time, comprehensive laboratory tests have also ruled out malignancy related Sweet's syndrome.\n\nThere are many methods of treatment for HIV-EF and Sweet's syndrome, co-treatment included anti-inflammatory agents of glucocorticoids and NSAIDs. Thalidomide is a strong non-steroid anti-inflammatory drug and immunomodulatory which seems to have been forgotten or abandoned due to the side effects of “seal-leg deformity” since 1961 (28). Thalidomide is contraindicated in pregnant females because of its adverse teratogenic side effects. Prolonged administration of thalidomide can cause peripheral neuropathy, drowsiness and fatigue (29). In addition, venous thrombosis, neutropenia and cardiovascular side effects have also been reported in clinical practice (30). Therefore, baseline electrophysiological examinations, coagulation function, absolute neutrophil count, and cardiac function should be monitored carefully during thalidomide treatment.\n\nRecently, it has been approved and used in the field of dermatology, such as leprosy nodular erythema, vascular lupus erythematosus, and refractory inflammatory bowel disease (29). Although thalidomide had been reported for treatment of HIV/AIDS-related oral ulcers (30) or Kaposi's sarcoma (31). But there have been no reports concerning thalidomide treatment for AIDS associated Sweet's syndrome or EF. Only one report on thalidomide had achieved good curative effect without relapse after ineffective systemic corticosteroids therapy in Sweet's syndrome associated with myelodysplasia (32).\n\nThalidomide could inhibit TNF-a, IL-1β, and IL-6 production (33, 34). This benefits not only by inhibiting SS and EF associated cytokines (IL-4, IL-5, IL-6, IL-8, TNF-a etc.), but also by inhibiting IRIS induced release of inflammatory cytokines (TNF-a, IL-6 etc.). More importantly, pro-inflammatory cytokine TNF-a could not only mediate the recruitment and activation of eosinophils by expressing adhesion molecules such as ICAM-1, but also activates and chemotactic neutrophils directly (35). Therefore, the use of TNF-a inhibitor infliximab or etanercept has been effective in the treatment of EF and Sweet's syndrome (36, 37). In addition, TNF-α induces viral replication via NF-κB-dependent transcriptional pathway (38), the anti-TNF activity of thalidomide may reduce HIV viral replication (39), which also benefits HIV infected patients. In this case, it significantly improved HIV associated with eosinophilic and neutrophilic dermatoses lesions, which means another weapon to be considered in the novel therapeutic strategies.\n\nTo our knowledge, this was the first report of AIDS patient co-incidental occurrence of Sweet's syndrome and eosinophilic folliculitis. Moreover, it was the first to report on the efficacy of old drug thalidomide for treatment of HIV-EF and Sweet's syndrome. This case provides a new perspective for the dialectical understanding of pharmaceutical value of thalidomide rather than its complete negation. Thalidomide may be an effective and safe treatment strategy for HIV patients with eosinophilic and (or) neutrophilic dermatitis.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by the studies involving human participants were reviewed and approved by The Ethics committe of First Affiliated Hospital of Kunming Medical University. The patients/participants provided their written informed consent to participate in this study. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\nR-JD, Y-YL, and Y-JZ contributed conception and design of the study. S-ZH performed the statistical analysis. SS wrote the first draft of the manuscript. PU wrote sections of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nWe are grateful to the patients and medical staffs participated in this study.\n\nFunding. This work was partially supported by the Science and Technology Innovation Team of Sexually Transmitted Diseases of Kunming Medical University (2018HC005), the Joint Special Fund of Science and Technology Department of Yunnan—Kunming Medical University [2017FE467-(005)], the Medical Leadership Foundation of Health and Family Planning Commission of Yunnan Province, China (L-201613), the National Natural Science Foundation of China (81860553).\n==== Refs\nReferences\n1. Meyer T Lopez-Navarro N Herrera-Acosta E Gallego E Bosch RJ Herrera E . Human immunodeficiency virus (HIV)-associated eosinophilic folliculitis and follicular mucinosis in a black woman . Int J Dermatol. (2010 ) 49 :1308 –10 . 10.1111/j.1365-4632.2009.04257.x 20964654 \n2. Yokobayashi H Sugaya M Miyagaki T Kai H Suga H Yamada D . Analysis of serum chemokine levels in patients with HIV-associated eosinophilic folliculitis . J Eur Acad Dermatol Venereol. (2013 ) 27 :e212 –6 . 10.1111/j.1468-3083.2012.04592.x 22672135 \n3. 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(2007 ) 2 :34 . 10.1186/1750-1172-2-34 17655751 \n13. Sweet RD . An acute febrile neutrophilic dermatosis . Br J Dermatol. (1964 ) 76 :349 –56 . 10.1111/j.1365-2133.1964.tb14541.x 14201182 \n14. Heath MS Ortega-Loayza AG . Insights into the pathogenesis of sweet's syndrome . Front Immunol. (2019 ) 10 :414 . 10.3389/fimmu.2019.00414 30930894 \n15. Abbott JK Gelfand EW . Common variable immunodeficiency: diagnosis, management, and treatment . Immunol Allergy Clin North Am. (2015 ) 35 :637 –58 . 10.1016/j.iac.2015.07.009 26454311 \n16. Elbuluk N Martiniuk F Levis WR . Erythema nodosum leprosum, Sweet's syndrome, and human immunodeficiency virus may be related through an overlap in immunopathogenesis . Int J Dermatol. (2010 ) 49 :1344 –5 . 10.1111/j.1365-4632.2009.04066.x 20964666 \n17. Giasuddin AS El-Orfi AH Ziu MM El-Barnawi NY . Sweet's syndrome: is the pathogenesis mediated by helper T cell type 1 cytokines? \nJ Am Acad Dermatol. 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Mechanisms of inflammation in neutrophil-mediated skin diseases . Front Immunol. (2019 ) 10 :1059 . 10.3389/fimmu.2019.01059 31139187 \n22. Klein SA Dobmeyer JM Dobmeyer TS Pape M Ottmann OG Helm EB . Demonstration of the Th1 to Th2 cytokine shift during the course of HIV-1 infection using cytoplasmic cytokine detection on single cell level by flow cytometry . AIDS. (1997 ) 11 :1111 –8 . 10.1097/00002030-199709000-00005 9233457 \n23. Smiatacz T . Immune mechanisms in HIV infection and their role in antiretroviral therapy . Przeglad Epidemiologiczny. (2003 ) 57 :309 –16 .12910599 \n24. Ratnam I Chiu C Kandala NB Easterbrook PJ . Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV type 1-infected cohort . Clin Infect Dis. (2006 ) 42 :418 –27 . 10.1086/499356 16392092 \n25. Morlese JF Orkin CM Abbas R Burton C Qazi NA Nelson MR . Plasma IL-6 as a marker of mycobacterial immune restoration disease in HIV-1 infection . AIDS. (2003 ) 17 :1411 –3 . 10.1097/00002030-200306130-00025 12799572 \n26. Narendran G Andrade BB Porter BO Chandrasekhar C Venkatesan P Menon PA . Paradoxical tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) in HIV patients with culture confirmed pulmonary tuberculosis in India and the potential role of IL-6 in prediction . PLoS ONE. (2013 ) 8 :e63541 . 10.1371/journal.pone.0063541 23691062 \n27. Del Giudice P Vandenbos F Perrin C Bernard E Marq L Dellamonica P . Sweet's syndrome following abacavir therapy . J Am Acad Dermatol. (2004 ) 51 :474 –5 . 10.1016/j.jaad.2003.09.033 15337997 \n28. Neri P . The Pandora's box of thalidomide analogs and their substrates . Blood. (2019 ) 134 :105 –6 . 10.1182/blood.2019001420 31296542 \n29. Chen M Doherty SD Hsu S . Innovative uses of thalidomide . Dermatol Clin. (2010 ) 28 :577 –86 . 10.1016/j.det.2010.03.003 20510766 \n30. Ramirez-Amador VA Esquivel-Pedraza L Ponce-de-Leon S Reyes-Teran G Gonzalez-Guevara M Ponce-de-Leon S . Thalidomide as therapy for human immunodeficiency virus-related oral ulcers: a double-blind placebo-controlled clinical trial . Clin Infect Dis. (1999 ) 28 :892 –4 . 10.1086/515222 10825055 \n31. Little RF Wyvill KM Pluda JM Welles L Marshall V Figg WD . Activity of thalidomide in AIDS-related Kaposi's sarcoma . J. Clin. Oncol. (2000 ) 18 :2593 –602 . 10.1200/JCO.2000.18.13.2593 10893291 \n32. Browning CE Dixon JE Malone JC Callen JP . Thalidomide in the treatment of recalcitrant Sweet's syndrome associated with myelodysplasia . J Am Acad Dermatol. (2005 ) 53 (2 Suppl 1 ):S135 –8 . 10.1016/j.jaad.2004.12.041 16021163 \n33. Kumar V Chhibber S . Thalidomide: an old drug with new action . J Chemother. (2011 ) 23 :326 –34 . 10.1179/joc.2011.23.6.326 22233815 \n34. Casal JJ Bollini M Lombardo ME Bruno AM . Thalidomide analogues: tumor necrosis factor-alpha inhibitors and their evaluation as anti-inflammatory agents . Eur J Pharmaceut Sci. (2016 ) 83 :114 –9 . 10.1016/j.ejps.2015.12.017 26692341 \n35. Ferrante A Hauptmann B Seckinger P Dayer JM . Inhibition of tumour necrosis factor alpha (TNF-alpha)-induced neutrophil respiratory burst by a TNF inhibitor . Immunology. (1991 ) 72 :440 –2 .1851135 \n36. Hasegawa A Kobayashi N Fukumoto T Asada H . A case of eosinophilic pustular folliculitis with response to infliximab . J Am Acad Dermatol. (2012 ) 67 :e136 –7 . 10.1016/j.jaad.2011.10.023 22980264 \n37. Yamauchi PS Turner L Lowe NJ Gindi V Jackson JM . Treatment of recurrent Sweet's syndrome with coexisting rheumatoid arthritis with the tumor necrosis factor antagonist etanercept . J Am Acad Dermatol. (2006 ) 54 (3 Suppl 2 ):S122 –6 . 10.1016/j.jaad.2005.11.1089 16488324 \n38. Pomerantz RJ Feinberg MB Trono D Baltimore D . Lipopolysaccharide is a potent monocyte/macrophage-specific stimulator of human immunodeficiency virus type 1 expression . J Exp Med. (1990 ) 172 :253 –61 . 10.1084/jem.172.1.253 2193097 \n39. Vergara TRC Samer S Santos-Oliveira JR Giron LB Arif MS Silva-Freitas ML . Thalidomide is associated with increased t cell activation and inflammation in antiretroviral-naive HIV-infected individuals in a randomised clinical trial of efficacy and safety . EBioMed. (2017 ) 23 :59 –67 . 10.1016/j.ebiom.2017.08.007 28822719\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-858X",
"issue": "6()",
"journal": "Frontiers in medicine",
"keywords": "AIDS; IRIS; eosinophilic folliculitis; sweet's syndrome; thalidomide",
"medline_ta": "Front Med (Lausanne)",
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"pages": "343",
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"pmid": "32039221",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "26692341;22449621;14201182;11501668;16392092;30930894;28822719;31139187;31296542;16021163;19373005;9390338;12799572;22233815;2193097;12910599;20636397;20964654;20964666;16488324;20510766;9233457;17655751;10893291;1851135;4193219;10825055;26454311;28609645;21658319;21050684;22672135;3722478;9843005;10780726;16230559;23691062;22980264;15337997",
"title": "Thalidomide in the Treatment of Sweet's Syndrome and Eosinophilic Folliculitis Associated With Immune Reconstitution Inflammatory Syndrome.",
"title_normalized": "thalidomide in the treatment of sweet s syndrome and eosinophilic folliculitis associated with immune reconstitution inflammatory syndrome"
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"abstract": "BACKGROUND\nPisa syndrome (PS) is characterized by an abnormally sustained posture, with flexion of the body and head to one side and slight rotation of the trunk. Although PS most commonly arises as an adverse effect of antipsychotic drugs, choline-esterase inhibitors (ChEIs) are also sometimes known to induce PS. Despite the fact that the precise mechanism remains unclear, cholinergic-dopaminergic imbalance has been considered as a possible pathophysiologic mechanism underlying the genesis of PS.\n\n\nMETHODS\nWe hereby report the case of a 60-year-old woman with Alzheimer's disease who presented with the signs of PS after her treatment was switched to galantamine, a type of ChEI, even though she had received donepezil, another type of ChEI, for 5 years without any complications. To the best of our knowledge, this is the first report of PS associated with treatment switch from one to another type of ChEI. Galantamine, but not other ChEIs, can enhance striatal dopamine release through allosteric modulation of the nicotinic acetylcholine receptor, and has weaker muscarinic effects than donepezil. Therefore, we propose two novel hypotheses to explain the development of PS, as follows; galantamine, which enhances dopamine release, can induce imbalance of dopamine levels in the striatum of patients with dementia, resulting in PS, and the weaker muscarinic effects of the drug could be one of the factors predisposing to the development of PS.\n\n\nCONCLUSIONS\nThe present case suggests that treatment with galantamine is associated with a higher risk of development of PS than that with other ChEIs, such as donepezil, despite the pharmacological profile of galantamine as a dopamine modulator. Also, this report provides novel insight into another plausible mechanism underlying the development of PS, besides cholinergic-dopaminergic imbalance, namely, dopamine imbalance in the striatum with muscarinic-nicotinic imbalance.",
"affiliations": "Department of Neuropsychiatry, Japanese Red Cross Ashikaga Hospital, 49-1 Yobe, Ashikaga, Tochigi, Japan. yu.mimura@keio.jp.;Department of Neuropsychiatry, Japanese Red Cross Ashikaga Hospital, 49-1 Yobe, Ashikaga, Tochigi, Japan.;Department of Neuropsychiatry, Japanese Red Cross Ashikaga Hospital, 49-1 Yobe, Ashikaga, Tochigi, Japan.;Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, Japan.;Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, Japan.;Department of Neuropsychiatry, Japanese Red Cross Ashikaga Hospital, 49-1 Yobe, Ashikaga, Tochigi, Japan.",
"authors": "Mimura|Yu|Y|http://orcid.org/0000-0003-0538-6785;Kurose|Shin|S|;Takata|Taketo|T|;Tabuchi|Hajime|H|;Mimura|Masaru|M|;Funayama|Michitaka|M|",
"chemical_list": "D002800:Cholinesterase Inhibitors; D005702:Galantamine; D000077265:Donepezil",
"country": "England",
"delete": false,
"doi": "10.1186/s12883-020-01769-2",
"fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377 BioMed Central London \n\n1769\n10.1186/s12883-020-01769-2\nCase Report\nPisa syndrome induced by switching of a choline-esterase inhibitor treatment from donepezil to galantamine: a case report\nhttp://orcid.org/0000-0003-0538-6785Mimura Yu yu.mimura@keio.jp 12 Kurose Shin 12 Takata Taketo 1 Tabuchi Hajime 2 Mimura Masaru 2 Funayama Michitaka 1 1 Department of Neuropsychiatry, Japanese Red Cross Ashikaga Hospital, 49-1 Yobe, Ashikaga, Tochigi, Japan \n2 grid.26091.3c0000 0004 1936 9959Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, Japan \n13 5 2020 \n13 5 2020 \n2020 \n20 1833 1 2020 6 5 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\nPisa syndrome (PS) is characterized by an abnormally sustained posture, with flexion of the body and head to one side and slight rotation of the trunk. Although PS most commonly arises as an adverse effect of antipsychotic drugs, choline-esterase inhibitors (ChEIs) are also sometimes known to induce PS. Despite the fact that the precise mechanism remains unclear, cholinergic-dopaminergic imbalance has been considered as a possible pathophysiologic mechanism underlying the genesis of PS.\n\nCase presentation\nWe hereby report the case of a 60-year-old woman with Alzheimer’s disease who presented with the signs of PS after her treatment was switched to galantamine, a type of ChEI, even though she had received donepezil, another type of ChEI, for 5 years without any complications. To the best of our knowledge, this is the first report of PS associated with treatment switch from one to another type of ChEI. Galantamine, but not other ChEIs, can enhance striatal dopamine release through allosteric modulation of the nicotinic acetylcholine receptor, and has weaker muscarinic effects than donepezil. Therefore, we propose two novel hypotheses to explain the development of PS, as follows; galantamine, which enhances dopamine release, can induce imbalance of dopamine levels in the striatum of patients with dementia, resulting in PS, and the weaker muscarinic effects of the drug could be one of the factors predisposing to the development of PS.\n\nConclusion\nThe present case suggests that treatment with galantamine is associated with a higher risk of development of PS than that with other ChEIs, such as donepezil, despite the pharmacological profile of galantamine as a dopamine modulator. Also, this report provides novel insight into another plausible mechanism underlying the development of PS, besides cholinergic-dopaminergic imbalance, namely, dopamine imbalance in the striatum with muscarinic-nicotinic imbalance.\n\nKeywords\nPisa syndromeCholine-esterase inhibitorGalantamineDopamineNicotinic effectsExtra-pyramidal symptomAlzheimer’s diseaseissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nPisa syndrome (PS) or pleurothotonus, is characterized by a marked lateral trunk flexion that can be reduced by passive mobilization or supine positioning [1], and was originally described by Ekbom in 1972 [2]. PS is observed in patients with neurodegenerative diseases, mainly Parkinson’s disease [3]. PS is also considered as one of the rare types of tardive dystonias caused by drugs such as choline-esterase inhibitors (ChEIs) [4–18], antipsychotics [19–21], antidepressants [22, 23], lithium [24], and valproic acid [25]. However, the precise pathophysiology of PS has not yet been established. PS induced by ChEIs and antipsychotics has been assumed to be induced by cholinergic-dopaminergic imbalance. In other words, antipsychotics can decrease dopaminergic neurotransmission, and ChEIs can increase both the levels and actions of acetylcholine in the synaptic clefts to cause choline-dominance imbalance [3, 11, 17]. Decrease of dopaminergic functions with enhanced cholinergic functions cause the tonic influence on posture and locomotion to change toward the direction of immobility, because cholinergic-dopaminergic balance in the nigrostriatal neuronal system maintains normal muscle tone in the human body [26]. Disruption of the cholinergic-dopaminergic balance could result in an asymmetric axial muscle tone activation, and this is the hypothesized pathogenic mechanism underlying the development of drug-induced PS. Herein, we present the case report of a patient who presented with signs of PS following switching of ChEI treatment from donepezil to galantamine. Our case might shed some light on the onset of PS induced by ChEIs.\n\nCase presentation\nA 57-year-old Japanese woman visited the memory clinic affiliated to our hospital with a 2-year history of visual memory loss. Examination revealed that the patient had agraphia as well as left-right agnosia. Her insights into her cognitive dysfunction, however, were relatively well-preserved. She showed no signs of parkinsonism. Magnetic resonance imaging and single- photon emission computed tomography of the head revealed bilaterally symmetric atrophy of the occipitoparietal lobes and decreased blood flow to the same areas. She was clinically diagnosed as having posterior cortical atrophy, a visual variant of early-onset Alzheimer’s disease.\n\nShe was prescribed donepezil at the dose of 3 mg per day, which was later increased to 10 mg per day, in the absence of any side effects. Her visuospatial function gradually deteriorated during the treatment. In the following year, she presented with dressing apraxia. At the age of 60, she had difficulty in positioning herself to sit on a chair; her attempts to take a seat often resulted in her missing the chair and she found herself trying to sit on air instead. She was unable to find her way out of our examination room. She became dependent for her activities of daily living. She also became so impulsive and agitated that she was always talking to herself, without daily fluctuations in cognitive functions. Donepezil was discontinued in view of her agitation. Instead, she was started on augmentation therapy with the combination of galantamine and memantine to improve her psychiatric symptoms and maintain her cognitive function status. However, two weeks after the treatment switch from donepezil to galantamine plus memantine, she was admitted to the neuropsychiatric unit of our hospital, because her psychiatric symptoms did not improve, and she began to show signs of parkinsonism.\n\nOn admission, she presented with frozen gait and a mask-like expression. No rigidity, tremor or other neurological signs, such as paralysis or sensory impairment, were apparent. There were no remarkable changes of the vital signs or abnormalities on physical and laboratory examinations. Cerebrospinal fluid (CSF) examination revealed no increase of the cell count or protein levels, and the IgG index was within normal limits. The CSF amyloid beta 1–42(Aβ 1–42) level was 116 pg/mL and that of phosphorylated tau(P-tau) was 41 pg/mL, consistent with the diagnosis of Alzheimer’s disease [27]. To examine the possibility of Lewy body disease, 123I-(3meta)-iodobenzylguanidine myocardial scintigraphy and dopamine-transporter scanning were performed, which showed early and delayed heart/mediastinum ratios of 3.96 and 3.88, and specific binding ratios of 5.76 (right) and 5.78 (left), respectively, excluding Lewy body disease. Also, corticobasal syndrome was ruled out, because of the absence of laterality.\n\nHer medications on admission included galantamine 4 mg bid, memantine 10 mg qd, suvorexant 20 mg qd. Her parkinsonism signs deteriorated after she was hospitalized. In particular, she showed sustained flexion of both the head and body trunk, with slight rotation of the body to the right side, consistent with the diagnosis of PS, which was exacerbated while walking; these symptoms remained fixed until the 13th hospital day. Based on the suspicion that the PS in this patient had developed as a side effect of galantamine, this drug was stopped on the 13th hospital day. After discontinuation of galantamine while continuing memantine monotherapy, the characteristic posture of PS gradually improved within 2–3 days. In accordance with improvements on posturing, her freezing of gait also disappeared so that she was able to walk without any assistance. Meanwhile, her masked face was preserved. Finally, her posturing almost thoroughly disappeared over the subsequent 14-day period (Fig. 1).\nFig. 1 Left: Sustained flexion of both head and body trunk, with slight rotation of the body to right side. Right: 14 days after discontinuation of galantamine while continuing memantine therapy, the characteristic posture of Pisa syndrome disappeared\n\n\n\nFor the agitation and insomnia, the patient was prescribed 5 mg of asenapine, an antipsychotic, which was effective without any side effects in terms of extrapyramidal symptoms (EPS), including PS. By the 93rd hospital day, her neuropsychiatric symptoms had markedly improved and the patient was discharged home, where she was taken care of by her family members in her daily life.\n\nDiscussion and conclusion\nTo the best of our knowledge, this is the first case report of PS induced by a treatment switch of a ChEI to galantamine, despite prior long-term use, for 5 years, of donepezil without any complications. As for PS induced by ChEIs, a large pharmacovigilance study reported 52 cases of PS [28]. According to the previous report, PS occurs most frequently with galantamine, followed by rivastigmine and donepezil [28]. Our case report on PS is consistent with their findings. We reviewed and summarized all case reports that described PS linked to ChEIs initiation in Table 1.\nTable 1 All previous case reports that described PS linked to ChEIs initiation in Table 1\n\n\n\nThe mechanisms underlying the development of PS are not yet fully understood. Many past reports have suggested that cholinergic-dopaminergic balance in the direction of cholinergic dominance is the main cause of PS [3]. This hypothesis is widely accepted and based on the fact that the symptoms most often develop with the use of antipsychotics and ChEIs, and improve with the use of anticholinergics [3].\n\nHowever, the notion that galantamine, among the ChEIs is associated with the highest risk of development of PS is inconsistent with the results of a recent animal study on the effects of galantamine. Galantamine is not only a ChEI, but also an allosteric potentiating ligand (APL) for the nicotinic acetylcholine receptor. In experiments conducted using a hemiparkinsonian rat model, galantamine was found to facilitate striatal dopamine release by acting as an APL at the α4 nicotinic acetylcholine receptor [29]. This seems to be inconsistent with galantamine as a risk factor for PS, because EPS are primarily caused by blockade of the dopamine D2 receptor. On the other hand, in the experiment conducted by Inden et al., both methamphetamine, which enhances dopamine release, and the combination of a dopamine reuptake inhibitor plus galantamine induced the same rotational behavior, indicating that galantamine enhances dopamine release on the contralateral side of the striatum in the hemiparkinsonian model of rats [29]. From this point of view, dopamine imbalance triggered by galantamine in the striatum would induce rotation and flexion of the body to one side like PS. In our presented case, even though the dopamine transporter scan was negative, this imbalance might become worse by dopamine release induced on one side by galantamine.\n\nIn another mouse study conducted by Shimizu et al., the results were consistent with galantamine as a strong risk factor for PS [30]. According to this study on the effects of donepezil-, galantamine-, and antipsychotic drug-induced EPS, galantamine induced and augmented EPS more potently than donepezil [30]. In this experiment, EPS induced by galantamine was completely ameliorated by a muscarinic antagonist, but not by a nicotinic antagonist, suggesting that ChEI-induced EPS primary involves muscarinic effects and is improved by muscarinic antagonists. In addition, galantamine has a weaker antagonistic effect against the muscarinic receptor as compared to donepezil [31]. Taken together, weaker effect on the muscarinic receptors is associated with an increase in the risk of development of EPS.\n\nIn our case, memantine was the better alternative, because the patient showed good tolerability to memantine. In order to not only maintain the patient’s cognitive functions, but also to resolve the symptoms, memantine, which acts by non-competitive binding to the N-methyl-D-aspartate (NMDA) receptor, is an effective, reasonable, and safe treatment agent [5]. In fact, mouse experiments support this notion, in that memantine significantly reduced EPS induced by haloperidol, as compared to galantamine and donepezil, through its antagonistic effect on the NMDA receptor [32].\n\nIn addition to switching ChEIs, the patient’s impaired visuo-spatial function might be related to PS in the presented case. According to previous reports, visuo-spatial dysfunction assessed by Benton’s judgement line orientation test was a strong and significant predictor for developing PS [33, 34]. Given the abnormal posture in PS, however, disruption in body schema, rather than visuo-spatial dysfunction, might influence the development of PS because the main atrophic area involved the bilateral parietal lobe, which is considered the neural basis for body schema [35]. Still, switching was a major cause because posturing was completely resolved after discontinuation of galantamine.\n\nThis case report has some limitations. First of all, no electromyography was performed, because we were not sure whether we could perform the examinations safely. Also, there is a possibility that the symptoms represented delayed effects of donepezil in our case. However, we are reasonably certain about our diagnosis based on the fact that our patient presented with the symptoms of PS soon after (2 weeks later) her treatment was switched to galantamine and her symptoms disappeared soon after (2 weeks later) galantamine was discontinued. The Naranjo score of 5 indicates that galantamine was the probable cause of PS in our case [36]. Additionally, to the best of our knowledge, the longest period between the initiation of ChEI treatment and the onset of PS is 24 months [14]. Finally, a major limitation is that this was just a single case report. Further cases should be collected to better understand the pathophysiology of PS.\n\nIn conclusion, we present the first case report of PS that developed soon after the patient’s treatment was switched to galantamine from donepezil, even though the patient had shown good tolerability to 10 mg of donepezil for 5 years. This case suggests additional possible mechanisms underlying the development of PS, besides the conventional cholinergic-dopaminergic imbalance theory, including dopamine imbalance in the striatal system and muscarine-nicotine imbalance.\n\nAbbreviations\nPSPisa syndrome\n\nChEIsCholine-esterase inhibitors\n\nCSFCerebrospinal fluid\n\nAPLAllosteric potentiating ligand\n\nEPSExtrapyramidal symptoms\n\nNMDAN-Methyl-D-Aspartate\n\nMMale\n\nFFemale\n\nADAlzheimer’s disease\n\nPDParkinson’s disease\n\nDLBDementia with Lewy body\n\nTBITraumatic brain injury\n\nNANot available\n\nHDS-RHasegawa Dementia Scale Revised\n\nWAISWechsler adult intelligence scale\n\nFIQFull scale intelligence quotient\n\nCDRClinical dementia rating\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nNone.\n\nAuthors’ contributions\nYM acquired case data and drafted the manuscript. MF, SK, and TT acquired case data. MF, HT, and MM supervised the study and substantively revised the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article and its supplementary information files.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from family member of the patient for publication of this report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Doherty KM Van De Warrenburg BP Peralta MC Silveira-moriyama L Azulay J Gershanik OS Postural deformities in Parkinson’s disease Lancet Neurol 2011 10 538 549 10.1016/S1474-4422(11)70067-9 21514890 \n2. Ekbom K Lindholm H Ljungberg L New dystonic syndrome associated with butyrophenone therapy Z Neurol 1972 202 94 103 4115928 \n3. Suzuki T Matsuzaka H Drug-induced Pisa syndrome (Pleurothotonus) CNS Drugs 2002 16 165 174 10.2165/00023210-200216030-00003 11888337 \n4. Kwak YT Han IIW Baik J Koo MS Relation between cholinesterase inhibitor and Pisa syndrome Lancet. 2000 355 2222 10.1016/S0140-6736(00)02412-0 10881902 \n5. Chen CF, Hsu HC, Ouyang WC, Lin YC. Galantamine-induced pisa syndrome: Memantine as an alternative. Int J Geriatr Psychiatry. 2008;23:660–1.\n6. Vanacore N Suzzareddu G Maggini M Casula A Capelli P Raschetti R Pisa syndrome in a cohort of Alzheimer’s disease patients Acta Neurol Scand 2005 111 199 201 10.1111/j.1600-0404.2005.00388.x 15691290 \n7. Chao PC Li JC Yeh TC Bin YC A very low dose of rivastigmine-induced Pisa syndrome in a clozapine-treated patient Aust N Z J Psychiatry 2018 52 204 205 10.1177/0004867417741983 29119798 \n8. Hsu CW Lee Y Lee CY Lin PY Reversible Pisa syndrome induced by rivastigmine in a patient with early-onset Alzheimer disease Clin Neuropharmacol 2017 40 147 148 10.1097/WNF.0000000000000215 28452906 \n9. Pollock D Cunningham E Mcguinness B Passmore AP Pisa syndrome due to donepezil: pharmacokinetic interactions to blame? Age Ageing 2017 46 529 530 28104598 \n10. Panagiotis I Pantelis M George B Dimitris K Acute Pisa syndrome after administration of a single dose of donepezil J Neuropsychiatry Clin Neurosci. 2012 24 2012 10.1176/appi.neuropsych.11070158 \n11. Shinfuku M Nakajima S Uchida H Watanabe K Kocha H Kashima H Pisa syndrome caused by an acetylcholinesterase inhibitor in a patient with dementia with Lewy bodies Psychiatry Clin Neurosci 2011 65 299 10.1111/j.1440-1819.2011.02196.x \n12. Cossu G Melis M Melis G Maccioni E Putzu V Catte O Reversible Pisa syndrome (Pleurothotonus) due to the cholinesterase inhibitor galantamine: case report Mov Disord 2004 19 1243 1244 10.1002/mds.20164 15389998 \n13. Miyaoka T Seno H Yamamori C Inagaki T Itoga M Tsubouchi KHJ Pisa syndrome due to a cholinesterase inhibitor (donepezil): a case report J Clin Psychiatry 2001 62 573 574 10.4088/JCP.v62n07d13 \n14. Villarejo A Camacho A Garcia-Ramos R Moreno T Penas M Juntas R Case report: cholinergic-dopaminergic imbalance in Pisa syndrome Clin Neuropharmacol 2003 26 119 121 10.1097/00002826-200305000-00004 12782913 \n15. Huvent-Grelle D Roche J Camus FE Dewailly PH Puisieux F Relation between cholinesterase inhibitors and Pisa syndrome in a cohort of five French patients with Alzheimer’s disease JAGS. 2007 55 1472 1487 10.1111/j.1532-5415.2007.01283.x \n16. Huvent-Grelle D Roche J Gaxatte C Dewailly P Puisieux F Relation between Pisa syndrome and choline esterase inhibitors in a cohort of Alzheimer's disease patients Presse Med 2009 38 1 150 153 10.1016/j.lpm.2008.08.007 18986791 \n17. Leelavathi M Rosdinom R Suguna M Pisa syndrome secondary to rivastigmine: a case report Clin Ter 2012 163 31 32 22362231 \n18. Mukku SSR Achary U Sivakumar PT Varghese M Reccurent truncal dystonia (Pisa syndrome) due to donepezil — A case report Asian J Psychiatr 2018 35 47 49 10.1016/j.ajp.2018.05.003 29783133 \n19. Kumar RNS Gopalakrishnan A Clozapine-associated Pisa syndrome: a rare type of tardive dystonia Indian J Psychiatry 2017 59 390 391 10.4103/psychiatry.IndianJPsychiatry_308_16 29085106 \n20. Faridhosseini F Omidi-Kashani F Baradaran A Pisa syndrome associated with clozapine: a rare case report and literature review Spine Deform 2015 3 386 389 10.1016/j.jspd.2015.02.003 27927486 \n21. Yassa R Nastase C Cvejic J Laberge G The Pisa syndrome (or pleurothotonus): prevalence in a psychogeriatric population Biol Psychiatry 1991 29 942 945 10.1016/0006-3223(91)90061-P 1675591 \n22. Yamada Y Takano H Yamada M Satake N Hirabayashi N Okazaki M Pisa syndrome associated with mirtazapine: a case report BMC Pharmacol Toxicol 2018 19 18 20 10.1186/s40360-018-0272-8 29669598 \n23. Perrone V Antoniazzi S Carnovale C Clementi E Radice S Ba G A case of Pisa syndrome during sertraline and Quetiapine treatment J Neuropsychiatry Clin Neurosci 2012 24 31 32 10.1176/appi.neuropsych.11070165 \n24. Kumar N Mendonça DA Jog M Teaching video Neuro images: Lithium-induced reversible Pisa syndrome Neurology. 2017 88 e184 10.1212/WNL.0000000000003892 28461584 \n25. Yohanan M Aulakh JS Weith J Hawkins JW Pisa syndrome in a patient in a wheelchair taking Valproic acid Am J Psychiatry 2006 163 325 10.1176/appi.ajp.163.2.325-a \n26. Duvoisin RC Marsden CD Note on the scoliosis of parkinsonism J Neurol Neurosurg Psychiatry 1975 38 787 793 10.1136/jnnp.38.8.787 1185199 \n27. Tapiola T Alafuzoff I Herukka SK Parkkinen L Hartikainen P Soininen H Cerebrospinal fluid β-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain Arch Neurol 2009 66 382 389 10.1001/archneurol.2008.596 19273758 \n28. Zannas AS Okuno Y Doraiswamy PM Cholinesterase inhibitors and Pisa syndrome: a pharmacovigilance study Pharmacotherapy. 2014 34 272 278 10.1002/phar.1359 24127392 \n29. Inden M Takata K Yanagisawa D Ashihara E Tooyama I Shimohama S Α4 nicotinic acetylcholine receptor modulated by Galantamine on Nigrostriatal terminals regulates dopamine receptor-mediated rotational behavior Neurochem Int 2016 94 74 81 10.1016/j.neuint.2016.02.008 26911419 \n30. Shimizu S Mizuguchi Y Sobue A Fujiwara M Morimoto T Ohno Y Interaction between anti-Alzheimer and antipsychotic drugs in modulating extrapyramidal motor disorders in mice J Pharmacol Sci 2015 127 439 445 10.1016/j.jphs.2015.03.004 25850380 \n31. Ago Y Koda K Ota Y Kita Y Fukada A Takuma K Donepezil, but not galantamine, blocks muscarinic receptor-mediated in vitro and in vivo responses Synapse. 2011 65 1373 1377 10.1002/syn.20969 21780184 \n32. Ohno Y Kunisawa N Shimizu S Antipsychotic treatment of behavioral and psychological symptoms of dementia (BPSD): Management of extrapyramidal side effects Front Pharmacol 2019 10 SEP 1 10 30728774 \n33. Vi tale C, Falco F, Trojano L, Erro R, Moccia M, Allocca R, et al. Neuropsychological correlates of Pisa syndrome in patients with Parkinson’s disease. Acta Neurol Scand. 2016;101–7.\n34. Artusi CA Montanaro E Tuttobene S Romagnolo A Zibetti M Lopiano L Pisa Syndrome in Parkinson’s Disease Is Associated with Specific Cognitive Alterations 2019 1 7 \n35. Wong B Lucente DE Maclean J Padmanabhan J Brandt KD Putcha D Diagnostic evaluation and monitoring of patients with posterior cortical atrophy 2019 \n36. Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 10.1038/clpt.1981.154 7249508\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2377",
"issue": "20(1)",
"journal": "BMC neurology",
"keywords": "Alzheimer’s disease; Choline-esterase inhibitor; Dopamine; Extra-pyramidal symptom; Galantamine; Nicotinic effects; Pisa syndrome",
"medline_ta": "BMC Neurol",
"mesh_terms": "D000544:Alzheimer Disease; D002800:Cholinesterase Inhibitors; D000077265:Donepezil; D005260:Female; D005702:Galantamine; D006801:Humans; D008875:Middle Aged; D000071057:Tardive Dyskinesia",
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"other_id": null,
"pages": "183",
"pmc": null,
"pmid": "32404068",
"pubdate": "2020-05-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28452906;31392920;27927486;23037672;23037668;18986791;10881902;4115928;18506913;12782913;21507139;21780184;7249508;1675591;15389998;25850380;1185199;26427765;16449491;29085106;11488374;19273758;24127392;17767692;31607910;21514890;28461584;29119798;15691290;29783133;31214112;11888337;22362231;30522528;26911419;28104598",
"title": "Pisa syndrome induced by switching of a choline-esterase inhibitor treatment from donepezil to galantamine: a case report.",
"title_normalized": "pisa syndrome induced by switching of a choline esterase inhibitor treatment from donepezil to galantamine a case report"
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"abstract": "Thyroid hormones can directly affect kidney function; elevated levels of thyroid-stimulating hormone (TSH) and chronic kidney disease (CKD) are associated with proteinuria, decreased estimated glomerular filtration rate (eGFR), and progression to end-stage renal disease. Our hypothesis is that in patients with CKD and TSH at levels considered to be in the low subclinical hypothyroidism (SCH) range, lowering TSH with levothyroxine (LVX) improves the clinical parameters of renal function.\nThis was a double-blind, randomized, pilot clinical trial in patients with proteinuric CKD (eGFR <60 ml/min per 1.73 m2 and proteinuria >150 mg/d) performed at the Hospital Civil de Guadalajara, with the intention of lowering TSH (levels of 1.25-2.5 μIU/l) in patients with TSH (levels of 2.6-9.9 μIU/ml with FT4 in the range of 0.7-1.8 ng/dl). Patients were randomized 1:1 to receive LVX or placebo for 12 weeks. The primary objective was to evaluate absolute levels of proteinuria at the beginning compared to the end of the study and, as a secondary objective, the changes in serum creatinine (sCr), eGFR, cholesterol, triglycerides, low-density lipoprotein (LDL), and blood pressure, and to assess the tolerability and safety of LVX.\nBetween March and November 2018, a total of 163 patients were assessed for eligibility; 119 patients did not meet the inclusion criteria or were excluded, and 32 patients were randomized. The demographic and clinical characteristics of the 2 study groups were essentially not different. Subjects were 66.87 (SD 12.19) years of age, 62.5% were female, 75% were diabetes mellitus, eGFR was 23.55 (±12.91) ml/min per 1.73 m2, TSH was 5.37 ± 2.13 μIU/ml, proteinuria in 24-hour urine collection was 1.52 ± 1.12, and all of them were taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs). Proteinuria at 12 weeks in the LVX group was 0.89 SD ± 1.28 g/d, and in the placebo group it was 1.35 SD ± 0.85 g/d; when compared to placebo, LVX showed a significant decrease in proteinuria of 1.1 g/d (P = 0.0011). The eGFR in the LVX group showed an improvement of 4 ml/min/1.73 m2 (P = 0.049); in the placebo group, there was a decrease of 1.98 ml/min per 1.73 m2. The sCr, cholesterol, triglycerides, low-density lipoprotein, systolic blood pressure, and diastolic blood pressure were not different between groups. Adverse events were reported in the LVX group in 7.14% of patients and in 11.11% of patients in the placebo group; none left the study because of adverse effects, and there were no serious adverse events.\nThis single-center, randomized, double-blind, placebo-controlled pilot clinical trial in patients with advanced proteinuric CKD who already used ACEIs or ARBs demonstrated that administering LVX to obtain a TSH range close to 2.5 μIU/ml decreased proteinuria and improved eGFR. Future research is needed to confirm our results and to determine whether our findings generalize to patient groups not explicitly enrolled in this small pilot trial.",
"affiliations": "Service of Nephrology, Civil Hospital of Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico.;Service of Nephrology, Civil Hospital of Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico.;University of Guadalajara, University Center of Health Sciences CUCS, Guadalajara, Jalisco, Mexico.;University of Guadalajara, University Center of Health Sciences CUCS, Guadalajara, Jalisco, Mexico.;Service of Nephrology, Civil Hospital of Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico.;University of Guadalajara, University Center of Health Sciences CUCS, Guadalajara, Jalisco, Mexico.;Service of Nephrology, Civil Hospital of Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico.;Service of Nephrology, Civil Hospital of Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico.;Service of Nephrology, Civil Hospital of Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico.;Service of Nephrology, Civil Hospital of Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico.;Service of Nephrology, Civil Hospital of Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico.;Service of Nephrology, Civil Hospital of Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico.",
"authors": "Blackaller|Guillermo Navarro|GN|;Chávez-Iñiguez|Jonathan S|JS|;Carreón-Bautista|Elsa Edith|EE|;González-Torres|Francisco Javier|FJ|;Villareal-Contreras|Miroslava|M|;Barrientos Avalos|José Roberto|JR|;Aguilera|Pablo Maggiani|PM|;Rosales|Francisco Romo|FR|;José Antonio|Torres Mayorga|TM|;Gómez Fregoso|Juan Alberto|JA|;Michel Gonzalez|Jorge Isaac|JI|;García-García|Guillermo|G|",
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"country": "United States",
"delete": false,
"doi": "10.1016/j.ekir.2020.10.016",
"fulltext": "\n==== Front\nKidney Int Rep\nKidney Int Rep\nKidney International Reports\n2468-0249 Elsevier \n\nS2468-0249(20)31686-7\n10.1016/j.ekir.2020.10.016\nClinical Research\nA Pilot Trial on the Effect of Levothyroxine on Proteinuria in Patients With Advanced CKD\nBlackaller Guillermo Navarro 12 Chávez-Iñiguez Jonathan S. jonarchi_10@hotmail.com12∗ Carreón-Bautista Elsa Edith 2 González-Torres Francisco Javier 2 Villareal-Contreras Miroslava 12 Barrientos Avalos José Roberto 23 Aguilera Pablo Maggiani 12 Rosales Francisco Romo 12 José Antonio Torres Mayorga 12 Gómez Fregoso Juan Alberto 12 Michel Gonzalez Jorge Isaac 12 García-García Guillermo 12 1 Service of Nephrology, Civil Hospital of Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico\n2 University of Guadalajara, University Center of Health Sciences CUCS, Guadalajara, Jalisco, Mexico\n3 Service of Endocrinology, Civil Hospital of Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico\n∗ Correspondence: Jonathan S. Chávez-Íñiguez, Hospital 278, Guadalajara, Jalisco C.P. 44240, México. jonarchi_10@hotmail.com\n03 12 2020 \n1 2021 \n03 12 2020 \n6 1 110 119\n1 5 2020 14 10 2020 20 10 2020 © 2020 International Society of Nephrology. Published by Elsevier Inc.2020International Society of NephrologyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nThyroid hormones can directly affect kidney function; elevated levels of thyroid-stimulating hormone (TSH) and chronic kidney disease (CKD) are associated with proteinuria, decreased estimated glomerular filtration rate (eGFR), and progression to end-stage renal disease. Our hypothesis is that in patients with CKD and TSH at levels considered to be in the low subclinical hypothyroidism (SCH) range, lowering TSH with levothyroxine (LVX) improves the clinical parameters of renal function.\n\nMethods\nThis was a double-blind, randomized, pilot clinical trial in patients with proteinuric CKD (eGFR <60 ml/min per 1.73 m2 and proteinuria >150 mg/d) performed at the Hospital Civil de Guadalajara, with the intention of lowering TSH (levels of 1.25−2.5 μIU/l) in patients with TSH (levels of 2.6−9.9 μIU/ml with FT4 in the range of 0.7−1.8 ng/dl). Patients were randomized 1:1 to receive LVX or placebo for 12 weeks. The primary objective was to evaluate absolute levels of proteinuria at the beginning compared to the end of the study and, as a secondary objective, the changes in serum creatinine (sCr), eGFR, cholesterol, triglycerides, low-density lipoprotein (LDL), and blood pressure, and to assess the tolerability and safety of LVX.\n\nResults\nBetween March and November 2018, a total of 163 patients were assessed for eligibility; 119 patients did not meet the inclusion criteria or were excluded, and 32 patients were randomized. The demographic and clinical characteristics of the 2 study groups were essentially not different. Subjects were 66.87 (SD 12.19) years of age, 62.5% were female, 75% were diabetes mellitus, eGFR was 23.55 (±12.91) ml/min per 1.73 m2, TSH was 5.37 ± 2.13 μIU/ml, proteinuria in 24-hour urine collection was 1.52 ± 1.12, and all of them were taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs). Proteinuria at 12 weeks in the LVX group was 0.89 SD ± 1.28 g/d, and in the placebo group it was 1.35 SD ± 0.85 g/d; when compared to placebo, LVX showed a significant decrease in proteinuria of 1.1 g/d (P = 0.0011). The eGFR in the LVX group showed an improvement of 4 ml/min/1.73 m2 (P = 0.049); in the placebo group, there was a decrease of 1.98 ml/min per 1.73 m2. The sCr, cholesterol, triglycerides, low-density lipoprotein, systolic blood pressure, and diastolic blood pressure were not different between groups. Adverse events were reported in the LVX group in 7.14% of patients and in 11.11% of patients in the placebo group; none left the study because of adverse effects, and there were no serious adverse events.\n\nConclusion\nThis single-center, randomized, double-blind, placebo-controlled pilot clinical trial in patients with advanced proteinuric CKD who already used ACEIs or ARBs demonstrated that administering LVX to obtain a TSH range close to 2.5 μIU/ml decreased proteinuria and improved eGFR. Future research is needed to confirm our results and to determine whether our findings generalize to patient groups not explicitly enrolled in this small pilot trial.\n\nGraphical abstract\nKeywords\nchronic kidney diseaselevothyroxineTSH\n==== Body\nChronic noncommunicable diseases such as obesity, diabetes mellitus, hypertension, and chronic kidney disease (CKD) have become a major public health problem in the Mexican population.1,2 Between 1990 and 2013, the CKD burden rapidly climbed, with age-standardized years of life lost (YLL) and disability-adjusted life-year (DALY) rates increasing more than 130%, the second highest DALY due to CKD in the world.3 The incidence of end-stage renal disease has increased dramatically in parallel with these risk factors.4\n\nThyroid hormones can directly affect kidney function, and impaired renal function can also contribute to thyroid disorders.5, 6, 7, 8, 9 The prevalence of primary overt, subclinical hypothyroidism (SCH) and low T3 syndrome increases with the progression of CKD.10,11\n\nThe prevalence of SCH in patients with an estimated glomerular filtration rate (eGFR) >60 ml/min per 1.73 m2 is 7% and is up to 17.9% in those with an eGFR <60 ml/min per 1.73 m2.11 Thyroid hormone affects the kidney by multiple mechanisms; local hemodynamic changes, decreased renal blood flow, decreased cardiac output, circulating volume, and decreased atrial natriuretic factor contribute to a decrease in renal perfusion with a concomitant reduction in eGFR,5, 6, 7,11, 12, 13 affecting the renin−angiotensin−aldosterone system, glomerular basement membrane, and renal tubular function, and leading to the development of proteinuria through direct effects on megalin and podocytes.8,9\n\nThe frequency of proteinuria in patients with normal thyroid function (euthyroid), SCH, and hypothyroidism is 1.29%, 2.2%, and 2.97%, respectively.14 In addition, it has been reported that the progression to end-stage renal disease is more accelerated in patients with SCH than in euthyroid patients,14,15, 16, 17, 18 and there is evidence that high (>3 μIU/ml) and low (<0.5 μIU/ml) thyroid-stimulating hormone (TSH) are associated with higher mortality rates in patients with CKD.19 There is also an association of mortality in patients with CKD and thyroid functional disease due to increased cardiovascular risk,20 particularly in patients on hemodialysis,21, 22, 23 as well as peritoneal dialysis24 and thyroid function disease.\n\nThe American Thyroid Guidelines, the American Association of Endocrinology,25 and European Guidelines and Clinical Practice Guidelines26 recommend beginning LVX doses of 0.25 μg and not going above 0.50 μg in patients with high cardiovascular risk,27,28 as patients with CKD have been considered.29\n\nLevothyroxine is usually well tolerated in the general population at standard doses (1.6-18.8 μg/kg). In patients with SCH, overdose symptoms were reported in 10% to 21% of cases, and a Cochrane meta-analysis of thyroid hormone replacement for SCH found no significant adverse events.30\n\nHowever, many patients with CKD will experience renal progression, despite antiproteinuric treatment.31,32 These observations led to the examination of alternative pathways to delay CKD, with disappointing results so far. The most commonly used antiproteinuric33,34 drugs are angiotensin-converting enzyme inhibitors,35 angiotensin receptor blockers,36 aldosterone antagonists, 37, 38, 39, 40 and, although they are less effective, statins,41,42 allopurinol,43 and vitamin D activators.43, 44, 45, 46, 47, 48\n\nTreatment of SCH with LVX in the general population improves the lipid profile and cardiac function,49, 50, 51 and patients with CKD show improvement in eGFR and serum creatinine (sCr),14,51 but there are no clinical trials in this field in patients with CKD.\n\nOur hypothesis is that in patients with CKD and TSH at levels considered to be in the SCH range, the normalization of TSH with LVX improves the clinical parameters of renal function.\n\nMaterials and Methods\nWe conducted a pilot randomized, single-center, double-blind, placebo-controlled, parallel group, dose-adjusting trial of levothyroxine (LVX) 25 μg administered orally once daily to patients with proteinuric CKD conducted at the Hospital Civil de Guadalajara from March 2018 to 31 January 2019. The study objectives were to evaluate the efficacy and safety of normalizing TSH levels with LVX and to explore the clinical effect of LVX compared with placebo.\n\nThe measurement of TSH and FT4 was carried out with the UniCel DxI 800 (Beckman Coulter Inc., Indianapolis, IN) access Immunoassay system by chemiluminescence, with the serum FT4 (assay type 2-step competitive) reportable range of 0.25 to 6 ng/dl (3-2-77.2 pmol/l), analytical sensitivity 0.25 ng/dl (3.2 pmol/l), and serum TSH (assay type 1-step sandwich) reportable range of 0.03 to 100 μIU/ml, which incorporates functionality for the lower limit of detection, analytical sensitivity 0.01 μIU/ml, and 0.03 uIU/ml functional, and all samples were analyzed in a single laboratory.\n\nPatients with CKD (eGFR <60 ml/min per 1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) were eligible if they were >18 years of age or if they had proteinuria >150 mg/24 h. With TSH levels between 2.5 and 10.0 μIU/ml, we chose TSH >2.5 μIU/ml, as there is evidence that there was an association of a decrease in eGFR10,52 with proteinuria,10 and TSH <10.0 μIU/ml excludes clinical hypothyroidism. All patients treated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and without renal replacement therapy who attended the Renal Health Clinic were considered for participation in this pilot clinical trial.\n\nWe excluded patients with the following: primary hypothyroidism or preexisting thyroid disease; previous ischemic heart disease within a period of <6 months; arrhythmia; pregnancy; use of drugs that interact with the synthesis of thyroid hormones (Supplementary Table S1); those who did not provide informed consent; those with a serum TSH level <2.5 μIU/ml or >10 μIU/ml; those with a free serum T4 value between 0.6 and 1.8 ng/dl; those with positive anti-thyroid antibodies; and patients weighing <50 kg or >90 kg, because within this weight, all patients will maintain a dosage of 0.3−0.5 μg/kg per day, so it will be easy to prescribe the LVX dose with a narrow error window.\n\nApproval was obtained from the participating site’s Research and Ethics Committee (Hospital CG 034/18 March 2018). Patients provided written informed consent before enrollment in accordance with local and national laws. Conduct and reporting are consistent with the 2010 Consolidated Standards of Reporting Trials (CONSORT) extension for pilot trials.53 The trial was registered in the Clinical Trials Registry (NCT03898622).\n\nMeasures of renal function included the eGFR calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation.54 Proteinuria was measured by means of 24-hour urine collection, expressed in grams per day, at the beginning and end of the study. Serum creatinine, serum electrolytes, hemoglobin, albumin, cholesterol, TSH, FT4, and triglycerides were measured at the beginning of the study and every 4 weeks for 4 months.\n\nUsing a Web-based randomization system, we randomly assigned participants in a 1:1 ratio. Standard care was defined pragmatically; in both the study intervention and the standard care group, the nephrologist determined all aspects of clinical care, based on standard practice and individual patient needs, independent of the study intervention.\n\nThe study consisted of 3 phases. The first phase, with a duration of 8 to 12 weeks, consisted of enrolling patients and collecting demographic and clinical baseline measurements (proteinuria, lipid profile, serum electrolytes, arterial pressure, weight, TSH level, hemoglobin, and serum albumin). The second phase consisted of both groups being treated according to the allocation arm, and the third phase consisted of comparing the variables studied and the data analysis. The dose of LVX has previously been shown to be safe and efficient in adult patients with CKD.14,51\n\nOur primary objective was to evaluate the effect of lowering TSH with the use of LVX or placebo to assess absolute levels at the beginning compared to the end of the study, when proteinuria was measured in urine collected for 24 hours. The secondary objectives were to evaluate the changes in sCr and eGFR and to assess the tolerability and safety of LVX and changes in cholesterol, triglycerides, LDL and blood pressure.\n\nInterventions\nThe treating nephrologist and the patients were blinded to the study intervention.\n\nIf randomized to the intervention arm, the intervention consisted of treatment with oral levothyroxine (LVX) between 0.25 and 0.50 μg according to a dose of 0.3 to 0.5 μg/kg per day during fasting (in the case of taking a drug that interacts with the absorption, use of it was changed according to the hours specified). The dose adjustment was every 4 weeks. Levothyroxine or placebo was adjusted to 25 or 50 μg according to TSH levels (Table 1).Table 1 Dose adjustment of levothyroxine\n\nTSH range\tDose adjustment\t\nTSH < 0.5 μIU/ml\tSuspend the pill\t\nTSH (0.5–1 μIU/ml)\tSuspend the pill if it is at minimum dose\t\nTSH (1.2–2.4 μIU/ml)\tSuspend the pill if it is at minimum dose\t\nTSH (2.5–4.3 μIU/ml)\tDose 25 μg/d\t\nTSH (4.4–6.1 μIU/ml)\tKeep dose if 50 μg/d or increase if taking 25 μg/d\t\nTSH (6.2–8 μIU/ml)\tKeep dose if 50 μg/d or increase if taking 25 μg/d\t\nTSH (8.1–9.9 μIU/ml)\tKeep dose if 50 μg/d or increase if taking 25 μg/d\t\nTSH, thyroid-stimulating hormone.\n\nAll vials (placebo or levothyroxine) presented drugs in one-quarter tablet = 25 μg the first month. In addition, the following months were adjusted according to the TSH range.\n\n\n\nParticipants allocated to placebo took 1 pill per day, with the same bottle characteristics as patients in the intervention arm, for >12 weeks.\n\nThe preparation and packaging of LVX and placebo were carried out by a pharmacist who was not involved in the development of the present study. All patients were followed up every 4 weeks for usual renal health consultation. In addition, the specific aspects of the protocol consisted of monitoring thyroid function for the adjustment of LVX or placebo dose according to the previous dosage adjustment.\n\nTo ascertain compliance and adherence to treatment, a record sheet was created with all drug supplied and returned. During the course of the study, the investigator was responsible for providing additional instructions to retrain any subjects who did not comply with the administration of the study drug or with attendance at the required clinical visits.\n\nAdverse events were recorded during the follow-up, which included thyroid profile control tests every 4 weeks. Previously specified adverse effects were reported and followed up, and were rated in intensity according to the Common Terminology Criteria for Adverse Events (CTC) v. 3.0 (1–5), along with the start date and end date, as well as the treatment received.\n\nThis protocol was not sponsored or financed by any pharmaceutical company, nor are there any conflicts of interest on the part of the authors.\n\nStatistical Analyses\nThe sample calculation was at will. The reason for this pilot trial was to investigate areas of uncertainty regarding future definitive randomized clinical trials on the effects of thyroid hormone reduction with levothyroxine on proteinuria in patients with advanced chronic kidney disease based on eGFR and proteinuria. This was a small-scale study conducted to test the plan and method of a research study; this pilot study addresses treatment safety assessments, determination of dose levels and response, and estimation of the effect of treatment and its variance.\n\nThe methodology for a clinical trial of superiority was carried out. Parametric continuous variables are given as the mean and SD, and nonparametric continuous variables are reported as medians. Comparisons were made using the Student t test or the Mann−Whitney test. Categorical variables are presented as percentages and were compared using the χ2 test or Fisher exact test. The prespecified threshold for significance was a P value <0.05. All statistical analyses were performed using the statistical programs SPSS version 20 (SPSS IBM Corporation, Armonk, NY) and GraphPad 7 (GraphPad Software, San Diego, CA).\n\nResults\nFrom March to November 2018, a total of 163 patients attended the Renal Health Clinic and were considered for participation. Of the patients, 125 were excluded because 64 did not meet the inclusion criteria, 56 patients decided not to participate, and another 5 did not meet the other specifications. Only 38 patients provided consent to participate. Of these, 6 patients were lost during follow-up, leaving a total of 32 patients (77.2%) to be analyzed. Of those, 14 patients (43.75%) were randomized to the placebo group and 18 (56.25%) to the LVX group (Figure 1).Figure 1 Flowchart during the study period.\n\n\n\nBaseline clinical and demographic characteristics are shown in Table 2. Both groups had similar characteristics with respect to sex, age, number of comorbidities, CKD grade, weight, albumin, eGFR, hemoglobin, systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid profile, and proteinuria, except for the statistically higher TSH, sCr and LDL levels in the LVX group. At baseline, the mean (SD) levels of LDL cholesterol were significantly lower in the placebo group than in the LVX group (75.5 ± 19 mg/dl and 102.38 ± 31-42 ng/dl, respectively, P = 0.01). The TSH levels in the placebo group were significantly lower than those in the LVX group (4.46 ± 1.68 μIU/ml and 5.93 ± 2.2 μIU/ml, respectively; P = 0.02). The sCr levels of the placebo group were significantly higher than those of the LVX group (3.05 SD ± 1.65 mg/dl and 2.46 SD ± 1.13 mg/dl, respectively, P = 0.05).Table 2 Demographic and clinical baseline characteristics\n\nBaseline characteristics\tPlacebo (n = 14)\tLevothyroxine (n = 18)\tAll (N = 32)\tP value\t\nSex, n, % female\t10 (71.42)\t10 (55.55)\t20 (62.5)\tNA\t\nAge, yr, SD\t63.85 ± 15\t69.22 ± 8.7\t66.87 ± 12.19\t0.41\t\nDiabetes mellitus\t11 (78.57)\t13 (72.22)\t24 (75)\t1.00\t\nHypertensionn\t12 (85.71)\t16 (88.88)\t28 (87.5)\t1.00\t\nWeight, kg, SD\t67.90 ± 13.83\t67.01 ± 11.32\t67.55 ± 12.13\t0.88\t\nObesity (BMI >30 kg/m2)\t1 (7.14)\t3 (6.6)\t4 (12.5)\t0.61\t\nCKD G3a (45–59 ml/min per 1.73 m2)\t0\t3 (16.6)\t3 (9.37)\t0.23\t\nCKD G3b (30–44 ml/min per 1.73 m2),\t2 (14.28)\t4 (22.22)\t6 (18.75)\t0.67\t\nCKD G4 (15–29 ml/min per 1.73 m2)\t5 (35.71)\t7 (38.88)\t12 (37.5)\t1.00\t\nCKD G5 (<15 ml/min per /1.73 m2)\t7 (50)\t4 (22.22)\t11 (34.37)\t0.14\t\neGFR (ml/min per 1.73 m2)\t18.14 ± 9.96\t27.72 ± 13.38\t23.55 ± 12.91\t0.078\t\nTSH, μIU/ml\t4.46 ± 1.68\t6.08 ± 2.18\t5.37 ± 2.13\t0.02\t\nT4L, ng/dl\t0.93 ± 0.12\t0.99 ± 0.14\t0.96 ± 0.13\t0.65\t\nProteinuria grams/d urine collection\t1.28 ± 1.28\t1.71 ± 1.20\t1.52 ± 1.12\t0.14\t\nsCr, mg/dl\t3.65 ± 1.65\t2.46 ± 1.13\t2.98 ± 1.51\t0.05\t\nAlbumin, mg/dl\t3.99 ± 0.41\t3.8 ± 0.41\t3.88 ± 0.42\t0.24\t\nTriglycerides, mg/dl\t194 ± 75.3\t144.66 ± 91.76\t172.5 ± 87.71\t0.09\t\nCholesterol, mg/dl\t170.57 ± 45.96\t165.5 ± 59.67\t167.71 ± 54.16\t0.67\t\nLDL, mg/dl\t75.5 ± 19\t102.38 ± 31.42\t90.62 ± 29.86\t0.01\t\nHemoglobin, g/dl\t11.37 ± 1.21\t11.95 ± 1.61\t11.72 ± 1.48\t0.17\t\nSBP, mm Hg\t148.14 ± 27.7\t160 ± 19.4\t154.81 ± 24.14\t0.17\t\nDBP, mm Hg\t79 ± 11.72\t81.83 ± 8.2\t80.59 ± 10\t0.60\t\nACEI or ARB\t14 (100)\t18 (100)\t32 (100)\t1.00\t\nAllopurinol\t14 (100)\t18 (100)\t32 (100)\t1.00\t\nStatin\t14 (100)\t18 (100)\t32 (100)\t1.00\t\nACEI, angiotensin converting enzyme inhibitor; ARB, angiotensinogen receptor blockers; BMI, body mass index; DBP, diastolic blood pressure; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; G, grade; kg, kilograms; LDL, low-density cholesterol; NA, not available; SBP, systolic blood pressure; sCr, serum creatinine.\n\nData are n (%) or ±SD, unless otherwise noted.\n\n\n\nThe primary objective, measured at 3 months of randomization, is presented in Table 3 and Figure 2. A total of 32 patients were analyzed, 14 in the placebo group and 18 in the LVX group, whereas 6 were lost during follow-up. The mean (SD) proteinuria at 3 months in the LVX group was 0.89 ± 1.28 g/d, and in the placebo group 1.35 ± 0.85 g/d. When compared to placebo, LVX showed a significant decrease in proteinuria of 1.1 g/d (P = 0.0011).Table 3 Clinical and laboratory variable changes at the end of the study period (12 weeks), according to the placebo or levothyroxine group\n\nPrimary objective\tPlacebo\tLevothyroxine\tP value\t\nProteinuria, g/d\t+0.2 (−0.4 to 2.1)\n(1.35 ± 0.85)\t−1.1 (−4.1 to 0.9)\n(0.89 ± 1.28)\t0.0011\t\nSecondary objectives\t\t\t\t\n Changes in eGFR, ml/min per 1.73 m2\t−1.96 (−5 to 3)\n(16.18 ± 8.37)\t4.04 (9.8 to −2)\n(31.76 ± 11.9)\t0.049\t\n sCr, mg/dl\t0.05 (−0.5 to 1.49)\n(3.71 ± 1.55)\t−0.2 (−0.7 to 0.5)\n(2.36 ± 1.27)\t0.32\t\n Cholesterol, mg/dl\t−28.46 (107 to 26)\n(142.11 ± 44.05)\t−18 (−57 to 37)\n(147.5 ± 30.8)\t0.18\t\n Triglycerides, mg/dl\t−21(−94 to 108)\n(173.2 ± 51.46)\t−14.6 (−286 to 66)\n(130 ± 41.79)\t0.71\t\n SBP, mm Hg\t−2.5 (−57 to 35)\n(145.64 ± 18.58)\t−5.5 (−75 to 57)\n(154.5 ± 26.38)\t0.33\t\n DBP, mm Hg\t−6.43 (−17 to 14)\n(72.57 ± 9.78)\t−9.06 (−20 to 10)\n(72.77 ± 11.51)\t0.33\t\n TSH, μIU/ml\t−0.4 (−3.09 to 1.87)\n(3.97 ± 1.77)\t−3.2 (−6.8 to 1.6)\n(3.2 ± 1.5)\t0.0032\t\n T4L, ng/dl\t−0.1 (−0.18 to 0.12)\n0.92 ± 0.24\t0.05 (−0.38 to 0.4)\n1.04 ± 0.21\t0.77\t\n Weight, kg\t1.63 (−3.5 to 5.5)\n(68.96 ± 14.65)\t−1.05 (−3.5 to 2.1)\n(65.86 ± 11.65)\t0.20\t\nDBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure; sCr, serum creatinine; TSH, thyroid-stimulating hormone.\n\nFigure 2 Proteinuria (in grams per day) at the end of the study period (12 weeks) in the placebo and levothyroxine groups.\n\n\n\nThe comparative secondary objectives are presented in Table 3 and Figure 3. For the eGFR, the LVX group showed an improvement of 4.04 ml/min per 1.73 m2 (P = 0.049); in the placebo group, there was a decrease of 1.96 ml/min per 1.73 m2. The placebo group showed a decrease in TSH of 0.4 μIU/ml, and the LVX group showed a decrease in TSH of 3.2 μIU/ml (P = 0.0032). When comparing the weight reduction, the LVX arm showed a reduction in weight of −1.05 ± 3.72 kg, whereas the placebo group showed an increase in weight of 1.63 SD ± 5.59 kg (P = 0.20). For sCr, cholesterol, triglycerides, LDL, SBP, and DBP, there were no differences between the groups at 3 months (Figure 3). Adverse effects are shown in Table 4. Urinary tract infection presented in 1 patient in the placebo group (7.14%) and nervousness in 2 patients in the LVX group (11.11%) (relative risk 1.55 95% confidence interval 0.15-15.47, P = 1.0). No patients left the study because of adverse effects. Adverse events were not severe according to the severity scale.Figure 3 Clinical and laboratory variable changes at the end of the study period (12 weeks), according to placebo or levothyroxine group. (a) Serum thyroid-stimulating hormone (TSH); (b) serum FT4; (c) serum creatinine (sCr); (d) estimated glomerular filtration rate (eGFR); (e) serum cholesterol; (f) serum triglycerides; (g) systolic blood pressure (SBP); (h) diastolic blood pressure (DBP); (i) Weight loss (in kilograms). CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration.\n\nTable 4 Adverse events during the study period\n\nGroup\tn (%)\tOutcome\t\nLVX group\t1 (7.14)\tUrinary tract infectiona\t\nPlacebo group\t2 (11.11)\tAnxietyb\t\nCI, confidence interval; LVX, levothyroxine; RR, relative risk.\n\nRR = 1.55, 95% CI 0.15–15.47, P = 1.0.\n\na Urinary tract infection: duration of 5 days, without complications.\n\nb Anxiety: duration of 3 days, without complications.\n\n\n\nDiscussion\nThis pilot randomized, single-center, double-blind study in patients with advanced proteinuric CKD demonstrated that administering LVX to obtain a normal TSH range decreased proteinuria and improved eGFR, with few adverse events.\n\nThe management of proteinuria in CKD is mainly due to the effects of blocking the renin−angiotensin−aldosterone system (RAAS), such as with ACEIs and ARBs,35,36 and other drugs to a lesser magnitude, such as allopurinol,55 aldosterone antagonists,37, 38, 39, 40 statins,41,42 and calcitriol44, 45, 46, 47; however, despite these treatments, there is still residual proteinuria that contributes to the deterioration of renal function and cardiovascular risk.2 Proteinuria in hypothyroid human beings and rats has been related to RAAS activity,9 blood pressure, and oxidative stress, although it may be a reflection of glomerular hypertension and decreased glomerular filtration rate,5 changes in the management of tubular proteins, or changes in the structure of the glomerular barrier, specifically at the podocyte and megalin.8,9 In our study, the significant decrease in proteinuria of 1.1 g/d in the LVX group could be explained by the normalization of the TSH range. In addition, the antiproteinuric benefit observed with LVX could be explained by the alteration of glomerular pressure due to the negative inotropic effect on the heart, reduction in the circulating intravascular volume, and increase in peripheral resistance, with renal vasoconstriction adding a counterregulatory effect of RAAS, as well as changes at the level of the glomerular, tubular, and podocyte basal membrane.5,10 Higher baseline ranges were observed for TSH, LDL, and sCr in the LVX group, which could explain why the higher the TSH, the greater the effect on proteinuria.14,50,51 It is very important to consider the administration of LVX in patients with CKD and alterations in TSH for a greater benefit in decreasing proteinuria, thus adding the correlation that thyroid hormone in endothelial damage and in cardiovascular risk could also decrease mortality and decrease eGFR.14,19,50,52\n\nIn our study, eGFR increased in the LVX group by 4 ml/min per 1.73 m2, compared to that in the placebo group, in which eGFR decreased by 2 ml/min per 1.73 m2. Van Welsem et al.9 reported that the normalization of hypothyroidism after treatment with LVX led to a significant improvement in renal function in a patient with CKD.5 In addition, Shin et al. demonstrated that reaching a TSH goal of 1 to 4.5 μIU/ml with LVX at a dose of 25 to 50 μg/d improved the eGFR +4.31 ± 0.5 ml/min per 1.73 m2.51 Chang et al. used a TSH goal of 1.16-2.86 μIU/ml with a dose of LVX 25 μg/d and obtained an improvement in eGFR +5.77 ml/min per 1.73 m2 (P = 0.015).14\n\nAlthough previous studies have shown that LVX improves cardiac function, renal function, and dyslipidemia and delays progression of CKD that is already established in patients with SCH, there is still a lack of consensus in the current guidelines on whether to treat SCH in patients with CKD. In particular, little is known about the effect of thyroid hormone replacement on changes in eGFR.21, 22, 23, 24 Some studies exist comparing CKD and thyroid disorders in which normal TSH ranges were maintained and an improvement in the progression of CKD, decreased proteinuria,5,9,13,17 improved lipid profile,37 and lower cardiovascular risk were observed.20 Rhee et al. found, in more than 220,000 patients, that at TSH levels >3 μIU/ml and TSH <0.5 μIU/ml, there is a higher mortality rate in patients with CKD G3.19\n\nThere are already studies in which the elevation of TSH is associated with the progression of CKD.14,15 In patients already undergoing renal replacement therapy, such as hemodialysis with elevated TSH, it was associated with mortality,21, 22, 23 similar to peritoneal dialysis.24\n\nWe sought to reinforce these benefits of maintaining a range of TSH (<4.5 μIU/ml, considering previous studies in which mortality was associated with TSH >2.5 μIU/ml).19,29 In addition, some authors have reported a greater progression to terminal CKD and mortality in patients with SCH versus euthyroid hypothyroidism.19,20 The American25 and European guidelines27 do not mention the potential benefit of the use of LVX and its impact in patients with CKD and SCH.\n\nAnother possibility of improving proteinuria and eGFR is that by decreasing TSH, an increase in catabolism and weight reduction was achieved, eliminating hyperfiltration and proteinuria. It should be mentioned that at the beginning of the study, only 4 patients had a BMI >30 kg/m2, 1 patient from the placebo group and 3 patients from the LVX group (P = 0.61), and the differences in weight loss (in kilograms) at the end of the study were higher in the LVX group than in the placebo group, with an average of −1.05 SD ± 3.72 kg and 1.63 SD ± 5.59 kg, respectively, but the differences were not significant (P = 0.20). Among the other variables relevant to this study, there were no significant changes in BP or HR.\n\nRegarding tolerance, the use of LVX was safe, there were no severe adverse events, and no patient had to discontinue the study drug. However, more patients in the LVX dose adjustment were required (relative risk = 1.55, 95% confidence interval = 0.15−15.47, P = 1.0). In previous studies, no serious adverse effects have been reported when giving LVX to patients with CKD, considering that they are patients with cardiovascular risk.25,26 This information can be interpreted as showing that LVX is a useful treatment in hypothyroidism and that the risk is minimal.28,29\n\nSeveral limitations need to be acknowledged. This paper presents the results of a small, single-center, randomized controlled pilot clinical trial. As such, estimates of treatment effects may be overoptimistic and/or unique to the population studied. The main analyses did not impute missing data, which, in both the placebo and LVX groups, were assumed to be missing at random. Other limitations of our study include the racial homogeneity of the study population and the short treatment duration (12 weeks). The sustainability of these effects over a longer time period needs to be confirmed in longer-term studies. However, the results demonstrate that the study intervention is feasible and has promising effects on multiple measures of renal function. Another limitation is that TSH levels were different at the time of randomization, although we believe that this had no impact on the final result, as both groups were in ranges of abnormality. Furthermore, there is no objective evidence to suggest that the study population is unique. However, as with all pilot projects, our findings remain exploratory and hypothesis generating.\n\nIn conclusion, this single-center, randomized, double-blind, placebo-controlled pilot clinical study in patients with advanced proteinuric CKD who already used ACEIs or ARBs demonstrated that administering LVX to obtain a TSH range close to 2.5 μIU/ml decreased proteinuria and improved eGFR. These findings could encourage the performance of a clinical trial with sufficient statistical power to demonstrate the benefit of normalizing TSH with LVX in patients with CKD.\n\nDisclosure\nAll the authors declared no competing interests.\n\nSupplementary Material\nSupplementary File (Word)\n \n\nTable S1. Drugs that interact with levothyroxine.\n\nAcknowledgments\nClinical trial registration number: NCT03898622.\n\nSupplementary File (Word)\n\nTable S1. Drugs that interact with levothyroxine.\n==== Refs\nReferences\n1 Hill N.R. Fatima S.T. Oke J.L. Global prevalence of chronic kidney disease: a systematic review and meta-analysis PLoS One 11 2016 e0158765 27383068 \n2 Sarafidis P. Charles J. Morales E. SGLT-2 inhibitors and GLP-1 receptor agonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease. 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Thyroid functional disease and mortality in a national peritoneal dialysis cohort J Clin Endocrinol Metab 101 2016 4054 4061 27525529 \n25 Garber J.R. Cobin R.H. Gharib H. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association Endocr Pract 18 2012 988 1028 23246686 \n26 Biondi B. Bartalena L. Cooper D.S. The 2015 European Thyroid Association guidelines on diagnosis and treatment of endogenous subclinical hyperthyroidism Eur Thyroid J 4 2015 149 163 26558232 \n27 Loon E. The debate on treating subclinical hypothyroidism Singapore Med J 57 2016 539 545 27779276 \n28 Peeter R.P. Subclinical hypothyroidism N Engl J Med 376 2017 26 \n29 Javed Z. Sathyapalan T. Levothyroxine treatment of mild subclinical hypothyroidism: a review of potential risks and benefits Ther Adv Endocrinol Metab 7 2016 12 23 26885359 \n30 Villar H.C.C.E. Saconato H. Valente O. Atallah Á.N. Thyroid hormone replacement for subclinical hypothyroidism (Review) Cochrane Library 3 2007 CD003419 \n31 Sarafidis P.A. Ruilope L.M. Cardiorenal disease development under chronic renin-angiotensin-aldosterone system suppression J Renin Angiotensin Aldosterone Syst 13 2012 217 219 22389391 \n32 Abbate M. Zoja C. Remuzzi G. How does proteinuria cause progressive renal damage? J Am Soc Nephrol 17 2006 2974 2984 17035611 \n33 Palmer B.F. Proteinuria as a therapeutic target in patients with chronic kidney disease Am J Nephrol 27 2007 287 293 17457028 \n34 KDIGO Clinical practice guideline for the evaluation and management of chronic kidney disease Kidney Int Suppl 3 2013 S1 S150 \n35 de Zeeuw D. Remuzzi G. Parving H.-H. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL Kidney Int 65 2004 2309 2320 15149345 \n36 Fernandez Juarez G. Luño J. Barrio V. Effect of dual blockade of the renin-angiotensin system on the progression of type 2 diabetic nephropathy: a randomized trial Am J Kidney Dis 61 2013 211 218 22939518 \n37 Bianchi S. Bigazzi R. Campese V.M. Efectos a largo plazo de la espironolactona sobre la proteinuria y la función renal en pacientes con enfermedad renal crónica Kidney Int. (Edición español) 2 2007 145 153 \n38 Rachmani R. Slavachevsky I. Amit M. The effects of spironolactone, cilazapril and their combination on albuminuria in patients with hypertension and diabetic nephropathy is independent of blood pressure reduction: a randomized controlled study Diabetes Med 21 2004 471 475 \n39 Sato A. Hayashi K. Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy Hypertension 41 2003 64 68 12511531 \n40 Bianchi S. Bigazzi R. Campese V.M. Antagonists of aldosterone and proteinuria in patients with CKD: an uncontrolled pilot study Am J Kidney Dis 46 2005 45 51 15983956 \n41 Goicoechea M. García de Vinuesa S. Lahera V. Papel de las estatinas en la enfermedad renal crónica Clin Invest Arterioscl 22 2010 17 24 \n42 Su X. Zhang L. Lv J. Effect of statins on kidney disease outcomes: a systematic review and meta-analysis Am J Kidney Dis 67 2016 881 892 26905361 \n43 Fishbane S. Chittineni H. Oral paricalcitol in the treatment of patients with CKD and proteinuria: a randomized trial Am J Kidney Dis 54 2009 647 652 19596163 \n44 Pérez-Gómez M.V. Ortiz-Arduán A. Lorenzo-Sellares V. Vitamina D y proteinuria: revisión crítica de las bases moleculares y de la experiencia clínica Nefrologia 33 2013 716 726 24089164 \n45 Alborzi P. Patel N.A. Peterson C. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial Hypertension 52 2008 249 255 18606901 \n46 Zeeuw D. Agarwal R. Amdahl M. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial Lancet 376 2010 1543 1551 21055801 \n47 Sánchez-Niño Bozic M. Córdoba-Lanús E. Beyond proteinuria: VDR activation reduces renal inflammation in experimental diabetic nephropathy Am J Physiol Renal Physiol 302 2012 F647 F657 22169009 \n48 Zhang Z. Sun L. Wang Y. Renoprotective role of the vitamin D receptor in diabetic nephropathy Kidney Int 73 2008 163 171 17928826 \n49 Barovero M. Mereshian P. Geres A. Study on renal function in patients with subclinical hypothyroidism. Response to treatment with levothyroxine Rev Argent Endocrinol Metab 49 2012 115 118 \n50 Huang X. Ding L. Peng K. Thyroid hormones associate with risk of incident chronic kidney disease and rapid decline in renal function: a prospective investigation Transl Med 14 2016 336 \n51 Shin D.H. Lee M.J. Lee H.S. Thyroid hormone replacement therapy attenuates the decline of renal function in chronic kidney disease patients with subclinical hypothyroidism Thyroid 23 2013 654 661 23281965 \n52 Kim S.H. Min H.K. Lee S.W. Relationship between thyroid and kidney function: analysis from the Korea National Health and Nutrition Examination Survey between 2013 and 2015 Kidney Blood Press Res 45 2020 442 454 32369813 \n53 Eldridge S.M. Chan C.L. Campbell M.J. CONSORT 2010 statement: extension to randomised pilot and feasibility trials BMJ 355 2016 i5239 27777223 \n54 Levey A.S. Stevens L.A. Schmid C.H. A new equation to estimate glomerular filtration rate Ann Intern Med 150 2009 604 612 19414839 \n55 Goicoechea M. García de Vinuesa S. Arroyo D. Luño J. Hiperuricemia, gota y enfermedad renal Nefrologia 32 Suppl 3 2012 1 196\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2468-0249",
"issue": "6(1)",
"journal": "Kidney international reports",
"keywords": "TSH; chronic kidney disease; levothyroxine",
"medline_ta": "Kidney Int Rep",
"mesh_terms": null,
"nlm_unique_id": "101684752",
"other_id": null,
"pages": "110-119",
"pmc": null,
"pmid": "33426390",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": "25011453;24089164;22021708;24829799;24315768;26558232;27914474;30197968;22939518;30753708;15807872;22169009;12511531;19095779;25632971;21055801;26905361;19133263;15983956;28403083;22389391;27777223;18606901;15149345;18550654;19075315;27779276;17457028;26885359;23246686;20514116;27383068;28117377;19596163;24211755;15089793;29391480;19414839;32369813;17928826;25246335;17035611;27428519;23281965;27525529;28324018;24574542;29728200",
"title": "A Pilot Trial on the Effect of Levothyroxine on Proteinuria in Patients With Advanced CKD.",
"title_normalized": "a pilot trial on the effect of levothyroxine on proteinuria in patients with advanced ckd"
} | [
{
"companynumb": "MX-MAIA PHARMACEUTICALS, INC.-MAI202101-000003",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE SODIUM"
},
... |
{
"abstract": "Androgen receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted a phase I trial investigating the safety and pharmacokinetics of a potent c-MET inhibitor, crizotinib, with the AR antagonist, enzalutamide, in CRPC.\n\n\n\nEmploying a 3+3 dose-escalation design, we tested three dose levels of crizotinib (250 mg daily, 200 mg twice a day, and 250 mg twice a day) with standard-dose enzalutamide (160 mg daily). The primary endpoint was rate of dose-limiting toxicities (DLTs). Tolerability and pharmacokinetics profile were secondary endpoints.\n\n\n\nTwenty-four patients were enrolled in the dose-escalation (n = 16) and dose-expansion (n = 8) phases. Two DLTs occurred in dose escalation (grade 3 alanine aminotransferase elevation). The MTD of crizotinib was 250 mg twice a day. Most frequent treatment-related adverse events were fatigue (50%), transaminitis (38%), nausea (33%), and vomiting, constipation, and diarrhea (21% each). Grade ≥3 events (25%) included transaminitis (n = 2), fatigue (n = 1), hypertension (n = 1), pulmonary embolism (n = 1), and a cardiac event encompassing QTc prolongation/ventricular arrhythmia/cardiac arrest. Median progression-free survival was 5.5 months (95% confidence interval, 2.8-21.2). Pharmacokinetics analysis at the MTD (n = 12) revealed a mean C max ss of 104 ± 45 ng/mL and AUCτ ss of 1,000 ± 476 ng•h/mL, representing a 74% decrease in crizotinib systemic exposure relative to historical data (C max ss, 315 ng/mL and AUCτ ss, 3,817 ng•h/mL).\n\n\n\nConcurrent administration of enzalutamide and crizotinib resulted in a clinically significant 74% decrease in systemic crizotinib exposure. Further investigation of this combination in CRPC is not planned. Our results highlight the importance of evaluating pharmacokinetics interactions when evaluating novel combination strategies in CRPC.",
"affiliations": "University of Oklahoma Health Science Center, Oklahoma City, Oklahoma.;Massachusetts General Hospital Cancer Center, Boston, Massachusetts.;Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Division of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts.;Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Beckman Research Institute, City of Hope, California.;Stanford University, Stanford, California.;Memorial Sloan Kettering Cancer Center, New York, New York.;Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. lcharshman@gmail.com.",
"authors": "Tripathi|Abhishek|A|;Supko|Jeffrey G|JG|0000-0002-4599-3267;Gray|Kathryn P|KP|0000-0003-3287-3685;Melnick|Zachary J|ZJ|;Regan|Meredith M|MM|0000-0002-2428-6109;Taplin|Mary-Ellen|ME|;Choudhury|Atish D|AD|0000-0001-9344-6631;Pomerantz|Mark M|MM|;Bellmunt|Joaquim|J|0000-0003-2328-3421;Yu|Channing|C|0000-0002-3231-2565;Sun|Zijie|Z|0000-0002-6787-6272;Srinivas|Sandy|S|;Kantoff|Philip W|PW|;Sweeney|Christopher J|CJ|0000-0002-0398-6018;Harshman|Lauren C|LC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-20-2306",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "26(23)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": null,
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "6122-6131",
"pmc": null,
"pmid": "32943461",
"pubdate": "2020-12-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25184629;8743556;8920963;21383285;28578639;25034009;4074823;7639332;22894553;25929560;21975330;23169517;19097774;31157964;10709801;28035616;26858312;26806347;29412780;25917876;12475693;1846706;31727538;24811158;17283128;27400947;25470694;24881730;28192399;24424891;20946682;8628717;18309951;27105539;8755529;29150561;28578607;26381275;19359544;23129213",
"title": "Dual Blockade of c-MET and the Androgen Receptor in Metastatic Castration-resistant Prostate Cancer: A Phase I Study of Concurrent Enzalutamide and Crizotinib.",
"title_normalized": "dual blockade of c met and the androgen receptor in metastatic castration resistant prostate cancer a phase i study of concurrent enzalutamide and crizotinib"
} | [
{
"companynumb": "US-PFIZER INC-2015041839",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ENZALUTAMIDE"
},
"drugadditional": "1",
... |
{
"abstract": "Pregabalin is often used for the treatment of chronic pain syndromes. We here describe two patients with chronic pain and pregabalin-induced myoclonic status epilepticus. Patients treated with pregabalin who experience sudden behavioral changes or mycloni should be investigated for this possible side effect, and pregabalin should be reduced or discontinued if myocloni or status epilepticus occurs.",
"affiliations": "Department of Neurology, Philipps University Marburg, Marburg, Germany. knake@staff.uni-marburg.de",
"authors": "Knake|S|S|;Klein|K M|KM|;Hattemer|K|K|;Wellek|A|A|;Oertel|W H|WH|;Hamer|H M|HM|;Rosenow|F|F|",
"chemical_list": "D000700:Analgesics; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.yebeh.2007.06.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-5050",
"issue": "11(3)",
"journal": "Epilepsy & behavior : E&B",
"keywords": null,
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000369:Aged, 80 and over; D000700:Analgesics; D002908:Chronic Disease; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic; D005260:Female; D006801:Humans; D010146:Pain; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "471-3",
"pmc": null,
"pmid": "17900992",
"pubdate": "2007-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pregabalin-induced generalized myoclonic status epilepticus in patients with chronic pain.",
"title_normalized": "pregabalin induced generalized myoclonic status epilepticus in patients with chronic pain"
} | [
{
"companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2022-03160",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREGABALIN"
},
"druga... |
{
"abstract": "To characterize current treatment practices, we compared the use of atypical antipsychotic drugs among women of childbearing age to men based on electronic medical records of 1073 hospital-based psychiatric outpatients given at least one second-generation antipsychotic drug. One quarter of psychiatric outpatients sampled were prescribed at least one atypical antipsychotic, in more than half of cases for off-label indications. Women were significantly more likely than men to be diagnosed with mood or anxiety disorders than psychotic disorders and to be prescribed quetiapine (60.7 vs. 48.0 %) or aripiprazole (31.2 vs. 23.9 %), but less likely risperidone (15.8 vs. 26.1 %) or ziprasidone (10 vs. 14 %).",
"affiliations": "Department of Psychiatry, Mayo Clinic College of Medicine, Rochester, MN, USA.",
"authors": "Camsarı|Ulas|U|;Viguera|Adele C|AC|;Ralston|Laurel|L|;Baldessarini|Ross J|RJ|;Cohen|Lee S|LS|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D014150:Antipsychotic Agents",
"country": "Austria",
"delete": false,
"doi": "10.1007/s00737-014-0465-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1434-1816",
"issue": "17(6)",
"journal": "Archives of women's mental health",
"keywords": null,
"medline_ta": "Arch Womens Ment Health",
"mesh_terms": "D000328:Adult; D018687:Antidepressive Agents, Second-Generation; D014150:Antipsychotic Agents; D003865:Depressive Disorder, Major; D057286:Electronic Health Records; D005260:Female; D006778:Hospitals, Psychiatric; D006801:Humans; D008297:Male; D056687:Off-Label Use; D010045:Outpatients; D015995:Prevalence; D011618:Psychotic Disorders; D017678:Sex Distribution; D016896:Treatment Outcome",
"nlm_unique_id": "9815663",
"other_id": null,
"pages": "583-6",
"pmc": null,
"pmid": "25253022",
"pubdate": "2014-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Prevalence of atypical antipsychotic use in psychiatric outpatients: comparison of women of childbearing age with men.",
"title_normalized": "prevalence of atypical antipsychotic use in psychiatric outpatients comparison of women of childbearing age with men"
} | [
{
"companynumb": "US-JNJFOC-20141118275",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThis trial evaluated the efficacy of acetaminophen in reducing oxidative injury, as measured by plasma F2-isoprostanes, in adult patients with severe sepsis and detectable plasma cell-free hemoglobin.\n\n\nMETHODS\nSingle-center, randomized, double-blind, placebo-controlled phase II trial.\n\n\nMETHODS\nMedical ICU in a tertiary, academic medical center.\n\n\nMETHODS\nCritically ill patients 18 years old or older with severe sepsis and detectable plasma cell-free hemoglobin.\n\n\nMETHODS\nPatients were randomized 1:1 to enteral acetaminophen 1 g every 6 hours for 3 days (n = 18) or placebo (n = 22) with the same dosing schedule and duration.\n\n\nRESULTS\nF2-Isoprostanes on study day 3, the primary outcome, did not differ between acetaminophen (30 pg/mL; interquartile range, 24-41) and placebo (36 pg/mL; interquartile range, 25-80; p = 0.35). However, F2-isoprostanes were significantly reduced on study day 2 in the acetaminophen group (24 pg/mL; interquartile range, 19-36) when compared with placebo (36 pg/mL; interquartile range, 23-55; p = 0.047). Creatinine on study day 3, a secondary outcome, was significantly lower in the acetaminophen group (1.0 mg/dL; interquartile range, 0.6-1.4) when compared with that in the placebo (1.3 mg/dL; interquartile range, 0.83-2.0; p = 0.039). There was no statistically significant difference in hospital mortality (acetaminophen 5.6% vs placebo 18.2%; p = 0.355) or adverse events (aspartate aminotransferase or alanine aminotransferase > 400; acetaminophen 9.5% vs placebo 4.3%; p = 0.599).\n\n\nCONCLUSIONS\nIn adults with severe sepsis and detectable plasma cell-free hemoglobin, treatment with acetaminophen within 24 hours of ICU admission may reduce oxidative injury and improve renal function. Additional study is needed to confirm these findings and determine the effect of acetaminophen on patient-centered outcomes.",
"affiliations": "1Section of Pulmonary and Critical Care Medicine, Department of Medicine, Louisiana State University School of Medicine, New Orleans, LA. 2Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN. 3Division of Clinical Pharmacology, Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, TN. 4Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN.",
"authors": "Janz|David R|DR|;Bastarache|Julie A|JA|;Rice|Todd W|TW|;Bernard|Gordon R|GR|;Warren|Melissa A|MA|;Wickersham|Nancy|N|;Sills|Gillian|G|;Oates|John A|JA|;Roberts|L Jackson|LJ|;Ware|Lorraine B|LB|;|||",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D028441:F2-Isoprostanes; D006454:Hemoglobins; D000082:Acetaminophen; D003404:Creatinine; D015742:Propofol",
"country": "United States",
"delete": false,
"doi": "10.1097/CCM.0000000000000718",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-3493",
"issue": "43(3)",
"journal": "Critical care medicine",
"keywords": null,
"medline_ta": "Crit Care Med",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D018712:Analgesics, Non-Narcotic; D002474:Cell-Free System; D003404:Creatinine; D016638:Critical Illness; D004311:Double-Blind Method; D028441:F2-Isoprostanes; D005260:Female; D006454:Hemoglobins; D017052:Hospital Mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D015742:Propofol; D012121:Respiration, Artificial; D018805:Sepsis",
"nlm_unique_id": "0355501",
"other_id": null,
"pages": "534-41",
"pmc": null,
"pmid": "25474535",
"pubdate": "2015-03",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "20117459;11053494;20881280;21334433;21372753;21570697;21747051;22446185;23314583;24445744;24601781;22800762;19701085;20133658;11236773;11370851;11445675;12426562;12482927;12700374;1600757;15548893;16294219;16820551;17954231;18443023",
"title": "Randomized, placebo-controlled trial of acetaminophen for the reduction of oxidative injury in severe sepsis: the Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis trial.",
"title_normalized": "randomized placebo controlled trial of acetaminophen for the reduction of oxidative injury in severe sepsis the acetaminophen for the reduction of oxidative injury in severe sepsis trial"
} | [
{
"companynumb": "US-JNJFOC-20151008777",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "COVID-19 patients treated with anti-inflammatory drugs are rarely complicated by candidemia. Since immunosuppressive therapy can blunt inflammatory reactions, clinicians should actively survey latent candidemia during severe COVID-19 treatment.",
"affiliations": "Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.;Center for Graduate Medical Education Okayama University Hospital Okayama Japan.;Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.;Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.",
"authors": "Yamamoto|Koichiro|K|https://orcid.org/0000-0001-9571-1646;Nakamura|Kaoru|K|;Hagiya|Hideharu|H|https://orcid.org/0000-0002-5086-1891;Otsuka|Fumio|F|https://orcid.org/0000-0001-7014-9095",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.4858",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4858\nCCR34858\nClinical Image\nClinical Images\nCandidemia in COVID‐19 treated with corticosteroids and tocilizumab\nYAMAMOTO et al.\nYamamoto Koichiro https://orcid.org/0000-0001-9571-1646\n1 pi291nd8@s.okayama-u.ac.jp\n\nNakamura Kaoru 2\nHagiya Hideharu https://orcid.org/0000-0002-5086-1891\n1\nOtsuka Fumio https://orcid.org/0000-0001-7014-9095\n1\n1 Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan\n2 Center for Graduate Medical Education Okayama University Hospital Okayama Japan\n* Correspondence\nKoichiro Yamamoto, Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2‐5‐1 Shikata‐cho, Kita‐ku, Okayama 700‐8558, Japan.\nEmail: pi291nd8@s.okayama-u.ac.jp\n\n21 9 2021\n9 2021\n9 9 10.1002/ccr3.v9.9 e0485805 9 2021\n29 7 2021\n07 9 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nCOVID‐19 patients treated with anti‐inflammatory drugs are rarely complicated by candidemia. Since immunosuppressive therapy can blunt inflammatory reactions, clinicians should actively survey latent candidemia during severe COVID‐19 treatment.\n\nCOVID‐19 patients treated with anti‐inflammatory drugs are rarely complicated by candidemia. Since immunosuppressive therapy can blunt inflammatory reactions, clinicians should actively survey latent candidemia during severe COVID‐19 treatment.\n\ncandidemia\ncoronavirus disease 2019\ncorticosteroid\nSARS‐CoV‐2\ntocilizumab\nsource-schema-version-number2.0\ncover-dateSeptember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.7 mode:remove_FC converted:22.09.2021\nYamamotoK, NakamuraK, HagiyaH, OtsukaF. Candidemia in COVID‐19 treated with corticosteroids and tocilizumab. Clin Case Rep. 2021;9 :e04858. 10.1002/ccr3.4858\n\nFunding information\n\nNone\n==== Body\npmcA 72‐year‐old man was diagnosed with COVID‐19 on the 10th day (day 10) of its development and was transferred to our hospital. He had a well‐controlled history of dyslipidemia and hypertension. He had obesity (BMI: 21.7 kg/m2), fever (38.6℃), saturation of percutaneous oxygen of 92% (oxygen supply: 4 L/min), and a respiratory rate of 24/min. Chest high‐resolution computed tomography showed bilateral ground‐glass opacities (Figure 1A). We started treatment with dexamethasone (6 mg/day), but he was intubated on Day 13. Since laboratory data indicated a severe cytokine storm, a combination of high‐dose methylprednisolone (125 mg/day for 3 days) and tocilizumab (8 mg/kg once) was administered intravenously. The COVID‐19 pneumonia ameliorated and he was extubated on day 20. However, serum β‐D‐glucan level was elevated (15 pg/ml) and blood culture tests detected Candida albicans (Figure 1B) on the day of extubation. The candidemia was effectively treated by intravenous administration of micafungin (150 mg/day) for 14 days after the confirmation of negative blood culture tests.\n\nFIGURE 1 (A) Chest computed tomography showed bilateral ground‐glass opacities, which were compatible with coronavirus disease 2019. (B) Candida albicans was detected by gram staining in blood culture tests\n\nCandidemia secondary to high‐dose corticosteroid1 and tocilizumab2 administration for COVID‐19 is rarely reported. These agents not only suppress cytokine storm in COVID‐19 but blunt inflammatory reactions. Latent fungal infections should be actively surveyed in similar cases.\n\nCONFLICTS OF INTEREST\n\nThe authors declare no conflicts of interest.\n\nAUTHOR CONTRIBUTIONS\n\nKY wrote the first draft and managed all of the submission process. KN and HH contributed to the clinical management of the patient. FO organized the manuscript.\n\nCONSENT\n\nWritten informed consent was obtained from the patient to publish this case report.\n\nACKNOWLEDGEMENTS\n\nNone.\n\nDATA AVAILABILITY STATEMENT\n\nData sharing not applicable to this article as no datasets were generated or analysed during the current study.\n==== Refs\nREFERENCES\n\n1 Garcia‐VidalC, SanjuanG, Moreno‐GarcíaE, et al. Incidence of co‐infections and superinfections in hospitalized patients with COVID‐19: a retrospective cohort study. Clin Microbiol Infect. 2021;27 :83‐88.32745596\n2 AntinoriS, BonazzettiC, GubertiniG, et al. Tocilizumab for cytokine storm syndrome in COVID‐19 pneumonia: an increased risk for candidemia? Autoimmun Rev. 2020;19 :102564.32376396\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "9(9)",
"journal": "Clinical case reports",
"keywords": "SARS‐CoV‐2; candidemia; coronavirus disease 2019; corticosteroid; tocilizumab",
"medline_ta": "Clin Case Rep",
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"nlm_unique_id": "101620385",
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"pages": "e04858",
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"pmid": "34584718",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": "32376396;32745596",
"title": "Candidemia in COVID-19 treated with corticosteroids and tocilizumab.",
"title_normalized": "candidemia in covid 19 treated with corticosteroids and tocilizumab"
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"abstract": "BACKGROUND\nIn cases of myeloma cast nephropathy in need of haemodialysis (HD), reduction of free light chains using HD with High-Cut-Off filters (HCO-HD), in combination with chemotherapy, may be associated with better renal recovery. The aim of the present study is to evaluate the effectiveness of haemodiafiltration (HDF) in reducing free light chain levels using a less expensive heat sterilized high-flux polyphenylene HF dialyzer (HF-HDF).\n\n\nMETHODS\nIn a single-centre prospective cohort study, 327 dialysis sessions were performed using a 2.2 m2 heat sterilized high-flux polyphenylene HF dialyzer (Phylther HF22SD), a small (1.1m2) or large (2.1 m2) high-cut-off (HCO) dialyzer (HCOS and HCOL) in a cohort of 16 patients presenting with dialysis-dependent acute cast nephropathy and elevated free light chains (10 kappa, 6 lambda). The outcomes of the study were the mean reduction ratio (RR) of kappa and lambda, the proportion of treatments with an RR of at least 0.65, albumin loss and the description of patient outcomes. Statistical analysis was performed using linear and logistic regression through generalized estimating equation analysis so as to take into account repeated observation within subjects and adjust for session duration.\n\n\nRESULTS\nThere were no significant differences in the estimated marginal mean of kappa RR, which were respectively 0.67, 0.69 and 0.70 with HCOL-HD, HCOS-HDF and HF-HDF (P = 0.950). The estimated marginal mean of the proportions of treatments with a kappa RR ≥0.65 were 68%, 63% and 71% with HCOL-HD, HCOS-HDF and HF-HDF, respectively (P = 0.913). The estimated marginal mean of lambda RR were higher with HCOL-HDF (0.78), compared to HCOL-HD and HF-HDF (0.62, and 0.61 respectively). The estimated marginal mean proportion of treatments with a lambda RR ≥0.65 were higher with HCOL-HDF (81%), compared to 57% in HF-HDF (P = 0.042). The median albumin loss were 7, 21 and 63 g/session with HF-HDF, HCOL-HD and HCOL-HDF respectively (P = 0.044). Among survivors, 9 out of 10 episodes of acute kidney injuries became dialysis-independent following a median time of renal replacement therapy of 40 days (range 7-181).\n\n\nCONCLUSIONS\nTherefore, in patients with acute dialysis-dependent myeloma cast nephropathy, in addition to chemotherapy, HDF with a heat sterilized high-flux polyphenylene HF dialyzer could offer an alternative to HCO dialysis for extracorporeal kappa reduction with lower albumin loss.",
"affiliations": "Division of Nephrology, Department of Medicine, CHU de Quebec-Hôtel-Dieu de Québec, Quebec, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Québec, Québec, Canada.;Division of Nephrology, Department of Medicine, CHU de Quebec-Hôtel-Dieu de Québec, Quebec, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Québec, Québec, Canada.;Division of Nephrology, Department of Medicine, CHU de Quebec-Hôtel-Dieu de Québec, Quebec, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Québec, Québec, Canada.;Division of Nephrology, Department of Medicine, CHU de Quebec-Hôtel-Dieu de Québec, Quebec, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Québec, Québec, Canada.",
"authors": "Rousseau-Gagnon|Mathieu|M|;Agharazii|Mohsen|M|;De Serres|Sacha A|SA|;Desmeules|Simon|S|",
"chemical_list": "D015415:Biomarkers; D015314:Dialysis Solutions; D007147:Immunoglobulin Light Chains; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D011108:Polymers; C041325:polyphenylene sulfide",
"country": "United States",
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"doi": "10.1371/journal.pone.0140463",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2646610010.1371/journal.pone.0140463PONE-D-15-10518Research ArticleEffectiveness of Haemodiafiltration with Heat Sterilized High-Flux Polyphenylene HF Dialyzer in Reducing Free Light Chains in Patients with Myeloma Cast Nephropathy Haemofiltration and Free Light Chain ReductionRousseau-Gagnon Mathieu \n1\n\n2\nAgharazii Mohsen \n1\n\n2\n*De Serres Sacha A. \n1\n\n2\nDesmeules Simon \n1\n\n2\n*\n1 \nDivision of Nephrology, Department of Medicine, CHU de Quebec-Hôtel-Dieu de Québec, Quebec, Canada\n\n2 \nDepartment of Medicine, Faculty of Medicine, Université Laval, Québec, Québec, Canada\nBurdmann Emmanuel A Editor\nUniversity of Sao Paulo Medical School, BRAZIL\nCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: SD MRG. Performed the experiments: SD MRG. Analyzed the data: SDS MA. Contributed reagents/materials/analysis tools: SDS MA. Wrote the paper: MRG SD MA SDS.\n\n* E-mail: simon.desmeules@mail.chuq.qc.ca (SD); mohsen.agharazii@crhdq.ulaval.ca (MA)14 10 2015 2015 10 10 e014046311 3 2015 25 9 2015 © 2015 Rousseau-Gagnon et al2015Rousseau-Gagnon et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Introduction\nIn cases of myeloma cast nephropathy in need of haemodialysis (HD), reduction of free light chains using HD with High-Cut-Off filters (HCO-HD), in combination with chemotherapy, may be associated with better renal recovery. The aim of the present study is to evaluate the effectiveness of haemodiafiltration (HDF) in reducing free light chain levels using a less expensive heat sterilized high-flux polyphenylene HF dialyzer (HF-HDF).\n\nMethods\nIn a single-centre prospective cohort study, 327 dialysis sessions were performed using a 2.2 m2 heat sterilized high-flux polyphenylene HF dialyzer (Phylther HF22SD), a small (1.1m2) or large (2.1 m2) high-cut-off (HCO) dialyzer (HCOS and HCOL) in a cohort of 16 patients presenting with dialysis-dependent acute cast nephropathy and elevated free light chains (10 kappa, 6 lambda). The outcomes of the study were the mean reduction ratio (RR) of kappa and lambda, the proportion of treatments with an RR of at least 0.65, albumin loss and the description of patient outcomes. Statistical analysis was performed using linear and logistic regression through generalized estimating equation analysis so as to take into account repeated observation within subjects and adjust for session duration.\n\nResults\nThere were no significant differences in the estimated marginal mean of kappa RR, which were respectively 0.67, 0.69 and 0.70 with HCOL-HD, HCOS-HDF and HF-HDF (P = 0.950). The estimated marginal mean of the proportions of treatments with a kappa RR ≥0.65 were 68%, 63% and 71% with HCOL-HD, HCOS-HDF and HF-HDF, respectively (P = 0.913). The estimated marginal mean of lambda RR were higher with HCOL-HDF (0.78), compared to HCOL-HD and HF-HDF (0.62, and 0.61 respectively). The estimated marginal mean proportion of treatments with a lambda RR ≥0.65 were higher with HCOL-HDF (81%), compared to 57% in HF-HDF (P = 0.042). The median albumin loss were 7, 21 and 63 g/session with HF-HDF, HCOL-HD and HCOL-HDF respectively (P = 0.044). Among survivors, 9 out of 10 episodes of acute kidney injuries became dialysis-independent following a median time of renal replacement therapy of 40 days (range 7–181).\n\nConclusion\nTherefore, in patients with acute dialysis-dependent myeloma cast nephropathy, in addition to chemotherapy, HDF with a heat sterilized high-flux polyphenylene HF dialyzer could offer an alternative to HCO dialysis for extracorporeal kappa reduction with lower albumin loss.\n\nSDS holds a Kidney Research Scientist Core Education and National Training Program (KRESCENT) scholarship supported by Canadian Institute of Health Research, Kidney Foundation of Canada and Canadian Society of Nephrology, and from Fonds de Recherche du Québec—Santé (FRQ-S). MA holds a scholarship from FRQ-S, and a research chair in nephrology from Université Laval. Data AvailabilityAll relevant data is available in the paper and its Supporting Information files.Data Availability\nAll relevant data is available in the paper and its Supporting Information files.\n==== Body\nIntroduction\nMultiple myeloma (MM) is a malignant monoclonal proliferation of plasma cells that usually produces an excess of free light chain (FLC). Myeloma cast nephropathy (CN), the most frequent cause of dialysis-dependent acute kidney injury (AKI), occurs when filtered FLCs precipitate with uromodulin, causing obstruction of the tubules [1]. Among patients with CN, requirement for chronic renal replacement therapy (RRT) is associated with poor clinical outcomes [2]. The single major randomized controlled trial of plasma exchange did not show significant clinical benefits and FLC levels were not measured[3]. More recently, Brunette et al. have reported an 86% renal recovery rate in 14 patients treated with bortezomib and plasma exchange[4]. However, removal of FLC by plasmapheresis has usually been considered inefficient due to the relatively limited volume of plasma as compared to the FLC’s high volume of distribution[3, 5].\n\nConventional haemodialysis (HD) fails to reduce FLC levels significantly given their high molecular weight (monomeric kappa of 22.5 kDa, dimeric lambda of 45 kDa) [6]. Recently, haemodialysis with High-Cut Off dialyzers (HCO-HD), which are highly permeable to low molecular weight proteins of up to 50 kDa, have been shown to achieve a significant reduction in post-dialysis serum FLC levels. Indeed, haemodialysis with a HCO-1100 dialyzer, which has a membrane surface area of 1.1 m2, was effective in reducing both kappa and lambda FLC levels. However, by using 2 HCO-1100 dialyzers in series, and therefore doubling the membrane surface area, there was a greater increase in FLC clearance and FLC reduction ratios [7]. Subsequently, it was shown that patients who received effective chemotherapy regimens and adjunctive HCO-HD had a much better renal recovery rate than historical controls [8–10]. This improvement was achieved by using 2 HCO-1100 dialyzers in series for each dialysis session, and required albumin infusion to compensate for the increased loss of albumin. Consequently, HCO-1100 dialyzers were discontinued by Gambro and were replaced by Theralite, an HCO dialyzer with a membrane surface area of 2.1 m2. Randomized-control trials are ongoing, but even if results are positive, the high cost of HCO filter are likely to limit widespread availability of HCO-HD [11, 12].\n\nEnhancing convective clearance through haemodiafiltration (HDF) has been shown to be more efficient than conventional HD to reduce the levels of middle-size molecules [13]. Indeed, in a recent study where high-efficiency HDF was associated with reduced all-cause mortality compared to conventional haemodialysis, HDF resulted in kappa FLC reduction ratios, which were comparable to those achieved with HCO-HD [14]. Nevertheless, the effectiveness of HDF to improve survival in the general end-stage kidney disease patients still remains controversial [13–17].\n\nTherefore, in a cohort of patients with dialysis-dependant myeloma cast nephropathy and elevated levels of FLC, we sought to determine the comparative effectiveness of HDF in reducing kappa and lambda FLC levels using a heat sterilized high-flux polyphenylene HF dialyzer (HF-HDF), and HCO-HD and HCO-HDF. We also determined the extent of albumin loss and describe the patient outcomes of this cohort.\n\nMaterials and Methods\nStudy design and population\nThis is a single-center longitudinal prospective observational study. Between May 2009 and July 2012, all subjects who started dialysis following a working diagnosis of AKI due to CN were eligible. CN was confirmed by renal biopsy, unless declined or contraindicated due to concurrent antiplatelet therapy (5 patients). The diagnosis of AKI was based on a combination of rising creatinine, non-atrophic kidneys as evaluated by ultrasound, histological examination or subsequent renal recovery. Indication for initiation of dialysis were an eGFR of <10 mL/min/1.73m2 with associated clinical symptoms. Exclusion criteria for extracorporeal reduction of FLC were AKI with elevated FLC not needing replacement therapy, absence of CN on the renal biopsy, and plasma exchange. Serum FLC levels were prospectively measured before and after each session to determine FLC reduction ratio (RR). Clinical data were prospectively collected and no patient was lost to follow-up. The chemotherapy regimen was recorded. The project was evaluated and approved by the Comité d’Éthique de la Recherche du CHU de Québec as a dialysis quality assurance evaluation. All data were anonymized as requested by the ethics committee.\n\nChoice of dialyzer\nIn a preliminary study in patients with myeloma cast nephropathy, we observed a kappa reduction ratio (RR) with various synthetic high flux membranes during HDF were: 0.16 with 2.1 m2 polyarylethersulfone/ polyvinylpyrrolidone/polyamide (Polyflux 210H) (n = 36), 0.27 with 2.5 m2 polysulfone (F250) (n = 2), 0.45 with 2.1 m2 AN-69 ST (Nephral-500) (n = 8) and 0.62 with 2.2 m2 heat sterilized high-flux polyphenylene HF (Phylther HF22SD) (n = 5). For the lambda FLC, HDF with heat sterilized high-flux polyphenylene HF (Phylther HF22SD) achieved a mean RR of 0.35 (n = 3), while an HDF with a 2.1 m2 HCO (Theralite) achieved a mean RR of 0.54 (n = 12).\n\nTherefore, for kappa FLC, we preferentially performed HDF with heat sterilized high-flux polyphenylene HF (HF22SD) over HCO dialyzers (small 1.1 m2 HCO-1100 (HCOS) or large 2.1m2 Theralite (HCOL)). For patients with lambda FLC, because the preliminary analysis suggested a lower lambda RR with HDF with heat sterilized high-flux polyphenylene HF (Phylther HF22SD), we performed a maximum of 35 HDF treatments with large HCO dialyzer. After the initial 35 sessions, because of budgetary constraints, all patients were switched to HDF with the heat sterilized high-flux polyphenylene HF (Phylther HF22SD). In the case of inability to perform HDF, HD was performed with HCO dialyzers. The characteristics and performances of the two dialyzers included in this study are shown in Table 1 [18].\n\n10.1371/journal.pone.0140463.t001Table 1 Dialyzers characteristics and performance.\nDialyzer\tPhylther* HF22SD\tTheralite\t\n\nMaterial\n\tPolyphenylene HF\tPAES/PVP\t\n\nArea (m\n2\n)\n\t2.2\t2.1\t\n\nFlux\n\tHigh-Flux (HF)\tHigh Cut-Off (HCO)\t\n\nMolecular weight cut-off (kDa)\n\t34–36\t170–320\t\n\nMolecular weight retention onset (kDa)\n\t12–14\t15–20\t\n\nPore size (nm)\n\t6–8\t8–12\t\n\nSieving Coefficient\n\t\t\t\n\n β-2 microglobuline (11.8 kDa)\n\t0.93\t0.95\t\n\n Albumin (66.5 kDa)\n\t0.003\t0.2\t\n*Heat sterilized\n\nPAES: polyarylethersulfone; PVP: polyvinylpyrrolidone.\n\nModalities of renal replacement therapy\nFrom 2009 to March 2011, online HDF was performed with a single Gambro’s AK 200 Ultra S dialysis system (Gambro, Lund, Sweden). When water quality standards were not met or machine was unavailable, convective therapy was performed with Gambro’s Integra using Hemosol-BO 5-liter bags as sterile infusion solution. Since March 2011, all online HDF treatments are done with Gambro’s Artis dialysis system.\n\nRenal replacement therapy was performed daily or alternate daily using a single dialyzer. Session length ranged from 210 to 360 minutes. Blood flow (Qb) was between 300 and 400 mL/min and dialysate flow was 700–800 mL/min. As mentioned above and based on clinical availability, HDF was done with 3 different Gambro systems: 1) AK 200 Ultra S performed pre-dilution online HDF with an infusion flow between 125 and 175 mL/min, 2) Integra system allowed post filter infusion of sterile Hemosol-BO at a rate of 50 mL/min and 3) the Artis system maximized post filter infusion using pressure control mode except with HCO dialyzers, where volume controlled post-dilution with an infusion between 70 and 90 mL/min was used. Infusion volumes were recorded at the end of each session. Low volume HDF was defined as an infusion volume per session of less than 15 L while more than 15 L of post filter infusion was qualified as high volume [19]. When heparin anticoagulation was contraindicated, saline flushes or regional citrate anticoagulation were performed. Albumin repletion was performed on clinical basis. Renal replacement was performed until renal recovery as defined below.\n\nOutcome measures\nThe primary outcomes of the study were mean FLC reduction ratios and percentages of treatments with a RR≥0.65 [8]. We examined albumin loss as secondary outcome, and we described patient survival and renal recovery. Recovery of renal function was defined as renal function sufficient to stop dialysis. Dialysis was continued until an estimated glomerular filtration rate (MDRD eGFR) of > 10 mL/min was achieved in combination with a pre-dialysis FLC level of <500–1000 mg/L, depending on the initial levels of FLC at presentation of AKI.\n\nBiological parameters\nSerum FLC, as well as β2-microglobulin and creatinine were measured before and after HDF/HD sessions using the slow-flow/stop-pump technique. Serum FLC was measured by nephelometry using a particle-enhanced, highly specific, homogeneous immunoassay (FREELITE, The Binding Site, San Diego, USA). β2-microglobulin was measured using nephelometry using a specific reactive (BN Prospect, Siemens AG, Munich, Germany). Albumin loss was estimated with a continuous partial collection (20 mL/h) of spent dialysate. Albumin levels in spent dialysate were assessed with a turbidometric immunoassay (Beckman-Coulter DCX600, Mississauga, Canada).\n\nStatistical analysis\nValues are reported as mean (SD) or median (25–75th percentiles) unless specified otherwise. To obtain an estimate of the impact of the dialysis-filter modality on the RR of FLC, a generalized estimating equation (GEE) analysis was used to take into account repeated measures within each individual. To estimate the effect of HDF modality (predilution, low-efficiency post-dilution and high-efficiency post-dilution) on the FLC RR, we used a GEE model to report the estimated marginal means adjusted for the duration of dialysis session. To estimate time adjusted marginal means of the proportion of patients who achieved a FLC RR of ≥0.65, a GEE model was used to take into account repeated measures within each patients. To estimate time adjusted marginal means of the proportion of patients who achieved a FLC RR of ≥0.65, a GEE model was used to take into account repeated measures within each patients. In the examination of the proportion of treatments with lambda RR ≥0.65, it was not possible to estimate the proportions for the HCOL-HD group as all 4 treatments achieved an RR≥0.65 and therefore the convergence criteria were not satisfied. Therefore, the estimates of the proportions of lambda RR ≥0.65 were obtained for HCOL-HDF and HF-HDF by excluding the HCOL-HD group for this analysis. Bonferroni correction method was used to adjust for multiple comparisons. The S1 Dataset that was used for the analysis is available in the Supporting Information files. Data were analysed using SPSS 22. A two-tailed P-value of <0.05 was considered statistically significant.\n\nResults\nClinical characteristics\nExtracorporeal FLC reduction was studied in 16 patients who had 17 episodes of AKI requiring RRT due to probable or confirmed CN. Overall, 8 episodes were due to relapsing MM after at least one course of chemotherapy. At the presentation of AKI, the median age was 67 years and the median initial serum creatinine level was 692 μmol/L (range: 383–1400). Description of the clinical baseline and individual characteristics and outcomes are presented in Table 2. Kappa and lambda monoclonal FLC accounted for 10 and 6 patients respectively.\n\n10.1371/journal.pone.0140463.t002Table 2 Clinical and biochemical characteristics.\n\tn = 16\t\n\nAge (y)\n\t67 (46–79)\t\n\nAKI Episodes (n)\n\t17*\n\t\n\nBaseline serum creatinine (μmol/L)\n\t85 (50–195)\t\n\nSerum creatinine at presentation (μmol/L)\n\t692 (383–1400)\t\n\nKappa MM (n)\n\t10\t\n\n kappa FLC (mg/L)\n\t6 050 (825–35 500)\t\n\nLambda MM (n)\n\t6\t\n\n lambda FLC (mg/L)\n\t11 600 (2 620–14 100)\t\n\nTotal analyzed RRT sessions\n\t324\t\n\nNumber of RRT sessions/subject\n\t18 ± 12\t\n\nNumber of 25% albumin units used\n\t39\t\n\nBaseline serum albumin (g/L)\n\t29±6.8\t\n\nMinimum serum albumin (g/L)\n\t21±6.3\t\n\nClinical outcome\n\t\t\n\n Renal recovery- n (%)\n\t9 (53%)\t\n\n Time to Renal Recovery (d)\n\t40 (7–181)\t\n\n Dialysis dependant\n\t1 (6%)\t\n\n Death–n (%)\n\t7 (41%)\t\n\n Time to Death (d)\n\t36 (6–84)\t\n\nFollow-up Renal Function at 6 Months\n\t\t\n\n Creat (μmol/L)\n\t267 (53–507)\t\n\n Range of eGFR (mL/min/1.73m\n2\n)\n\t10–90\t\n\nBiopsy\n\t\t\n\n CN\n\t9\t\n\n CN+Amyloidosis\n\t1\t\n\n CN+LCDD\n\t1\t\n\n Biopsy declined or contraindicated\n\t5\t\n\nChemotherapy\n*\n\t\t\n\n Bortezomib-Dexamethasone\n\t12\t\n\n Revlimid-Dexamethasone\n\t5\t\n\n Refused chemotherapy\n\t1\t\nCN: Myeloma Cast Nephropathy;LCDD: Light Chain Deposition Disease; MM: Multiple Myeloma; AKI: acute kidney injury. Values are mean ±SD or median (range)\n\n* 1 subject had two distinct episodes of AKI\n\nOne patient received bortezomid- and Revlimid-based regimen. Another patient with two episodes of AKI received Bortezomib and Revlimid respectively for the first and second episode.\n\nReduction ratio of kappa FLC\nOverall, 203 RRT sessions were analysed to determine kappa RR. Table 3 shows the mean kappa RR per patient and treatment protocol.\n\n10.1371/journal.pone.0140463.t003Table 3 Kappa free light chain reduction ratio per patient and treatment protocol.\nPatient\tRRT Modality\tkappa RR\tNumber of RRT\t\n\nk-1\n\tHF-HDF\t0.82±0.08\t26\t\n\nk-2\n\tHCOL-HD\t0.69±0.08\t25\t\n\nk-3\n\tHF-HDF\t0.37±0.10\t13\t\n\nk-4\n\tHF-HDF\t0.78±0.06\t17\t\n\nk-5\n\tHF-HDF\t0.67±0.07\t8\t\n\nk-6\n\tHCOS-HDF\t0.71±0.06\t13\t\n\tHF-HDF\t0.73±0.02\t3\t\n\nk-7\n\tHF-HDF\t0.47±0.11\t26\t\n\nk-8\n\tHF-HDF\t0.78±0.22\t10\t\n\nk-9a\n\tHF-HDF\t0.86±0.02\t6\t\n\nk-9b\n\tHF-HDF\t0.90±0.03\t20\t\n\nk-10\n\tHF-HDF\t0.62±0.12\t36\t\nValues are mean±SD\n\nRRT: Renal replacement therapy;HF-HDF: Haemodiafiltration with heat sterilized Polyphenylene HF of 2.2 m2; HCOs-HDF: Haemodiafiltration with high cut-off small surface area membrane (1.1 m2); HCOL-HD: Hemodialysis with high cut-off large surface area membrane (2.1 m2).\n\n\nFig 1A shows a box-plot graph of the kappa RR according to the RRT modality. Fig 1B shows that the estimates of the kappa RR were similar among the three different modalities taking into account repeated measurements within patients and duration of the session. There were no significant differences in the estimated marginal mean of kappa RR, which were 0.67, 0.69 and 0.70 with HCOL-HD, HCOS-HDF and HF-HDF respectively (P = 0.950). Fig 1C shows the crude percentage of treatment episodes where a kappa RR of more than 0.65 was achieved. Fig 1D shows the adjusted percentages of treatment episodes where a kappa RR of ≥0.65 was achieved, taking into account repeated measurements and duration of the session. The estimated marginal mean of the proportions of treatments with a kappa RR ≥0.65 were 68%, 63% and 71% with HCOL-HD, HCOS-HDF and HF-HDF respectively (P = 0.913). Fig 2A shows that the modality of haemodiafiltration and the volume did not significantly affect the kappa RR in this group of patients.\n\n10.1371/journal.pone.0140463.g001Fig 1 Free light chain reduction ratio by modality of renal replacement therapy.\nThe left panel shows A) the crude reduction ratio (RR) of kappa free light chain by haemodialysis (HD) or haemodiafiltration (HDF) using large (2.1 m2) high cut-off filters (HCOL), small (1.1 m2) high cut-off filters (HCOS), and the 2.2 m2 heat sterilized high-flux polyphenylene HF (HF). Panel B shows the estimated marginal means of kappa reduction ratio taking into account repeated measurements within individuals and session duration using a GEE model. The percentages of the treatments with a kappa reduction ratio of ≥ 0.65 with each modality is shown in panel C. Panel D shows the percentages of the treatments with a kappa reduction ratio of ≥ 0.65 with each modality taking into account repeated measurements within individuals and session duration using a GEE model. The right panel shows the crude RR of lambda free light chain by renal replacement modality (E), and the estimated marginal means of lambda RR (F) taking into account repeated measures within individuals and session duration using GEE model. The crude and adjusted (within subjects and session duration) percentage of treatments with a lambda RR ≥0.65 are respectively shown in panels G and H. All p-values take into account adjustments for multiple comparisons using Bonferroni method.\n\n10.1371/journal.pone.0140463.g002Fig 2 Impact of haemodiafiltration method of free light chain reduction ratio.\nThe impact of haemodiafiltration (HDF) in predilution (Pre), low-efficiency post-dilution (<15L post), and high-efficiency post-dilution (>15L post) are performed using large (2.1 m2) high cut-off filters (HCOL), small (1.1 m2) high cut-off filters (HCOS), and the 2.2 m2 heat sterilized high-flux polyphenylene HF (HF). The estimated marginal means of kappa (A) and lambda (B) light chain reduction ratio taking into account repeated measures and duration of each treatment session. P-values reported are adjusted for multiple comparisons using the Bonferroni correction method.* indicates that values are statistically different from other groups (P<0.01), ** indicates that values are statistically not different compared to other groups.\n\nReduction ratio of lambda FLC\nIn total, 121 RRT sessions were analysed for lambda FLC RR. Table 4 shows the mean lambda RR per patient and treatment protocol.\n\n10.1371/journal.pone.0140463.t004Table 4 Lambda free light chain reduction ratio per patient and treatment protocol.\nPatient\tRRT Modality\tLambda RR\tNumber of RRT\t\n\nl-1\n\tHCOL-HDF\t0.84±0.09\t20\t\n\nl-2\n\tHF-HDF\t0.31±0.15\t4\t\n\tHCOL-HDF\t0.69±0.09\t6\t\n\nl-3\n\tHF-HDF\t0.85±0.03\t10\t\n\tHCOL-HD\t0.83±0.07\t4\t\n\tHCOL-HDF\t0.91±0.05\t5\t\n\nl-4\n\tHF-HDF\t0.47±0.10\t15\t\n\tHCOL-HDF\t0.65±0.11\t35\t\n\nl-5\n\tHCOL-HDF\t0.81±0.02\t3\t\n\nPD\n\tHCOL-HDF\t0.79±0.04\t19\t\nValues are mean±SD\n\nRRT: Renal replacement therapy;HF-HDF: Haemodiafiltration with heat sterilized Polyphenylene HF of 2.2 m2; HCOL-HDF: Haemodiafiltration with high cut-off large surface area membrane (2.1 m2); HCOL-HD: Hemodialysis with high cut-off large surface area membrane (2.1 m2).\n\n\nFig 1E shows a box-plot graph of the lambda RR according to the RRT modality. Fig 1F shows that the estimates of the lambda RR were similar between HF-HDF and HCOL-HD, when taking into account repeated measures within each individual and duration of each session. The estimated marginal mean of lambda RR were higher with HCOL-HDF (0.78) as compared to HCOL-HD and HF-HDF (0.62, and 0.61 respectively). Fig 1G shows the crude percentage of treatment episodes where a lambda RR of more than 0.65 was achieved. Fig 1H shows that a higher proportion of treatments achieved a lambda RR ≥0.65 with HCOL-HDF as compared to HF-HDF, after adjusting for repeated measures and duration of each session. The estimated marginal mean proportion of treatments with a lambda RR ≥0.65 were higher with HCOL-HDF (81%) as compared to 57% in HF-HDF (P = 0.042). Fig 2B shows that high-efficiency post-dilution provided the highest lambda RR.\n\nTaking into account repeated measures and session duration by using generalized estimating equation, Fig 3 shows the reduction ratio of creatinine, β-2 microglobuline, kappa and lambda free light chains, using HF-HDF compared to the pooled data from HCOL-HD and HCOL-HDF.\n\n10.1371/journal.pone.0140463.g003Fig 3 Reduction ratio of molecules of increasing molecular weights.\nThe figure shows the reduction ratio (RR) of creatinine (113 Da), β-2 microglobulin (β2M, 11.8kDa), kappa (22.5 kDa) and lambda (45 kDa) free light chains, using haemodiafiltration with heat sterilized high-flux polyphenylene HF (HF-HDF), compared to haemodialysis or haemodiafiltration with a large (2.1 m2) high-cut-off dialyzer (HCOL). Estimates are obtained by generalized estimating equation taking into account repeated measures and session duration. * indicates a P-value of <0.05.\n\nAlbumin loss\nAlbumin losses were 7 (6–9.6), 21 (12–23), and 63 (48–66) g/session with HF-HDF, HCOL-HD and HCOL-HDF respectively (P = 0.044). Overall, 6 subjects received a total of 39 units of albumin. Patients who received more than 70% of their treatments with an HCO filter received 27 units of albumin.\n\nRenal recovery\nDuring the follow-up, in the 7 patients who died, the causes of death were infection (n = 2), progressive MM (n = 3), treatment refusal (n = 1) and bilateral subdural hematoma (n = 1), with a median time to death of 36 days (range: 6–84 days). Renal function improved sufficiently to wean dialysis in all but one survivor. This patient, in whom both amyloidosis and CN were present on the kidney biopsy remained dialysis-dependent. One patient was treated for two episodes of CN and recovered on both occasions after 7 and 34 days of RRT. Median length of RRT among survivors was 40 d (range 7–181). Two patients were transferred to another facility for follow-up. At 6 months, all surviving patients remained dialysis-free with a median creatinine of 267 μmol/L (range: 53–507).\n\nDiscussion\nThe results of our study suggest that kappa FLC can be reduced effectively with a heat sterilized high-flux polyphenylene HF using haemodiafiltration. Using HF-HDF, kappa FLC RRs with the 2.2 m2 heat sterilized high-flux polyphenylene HF (Phylther HF22SD) compares favourably with the results published in the landmark study of Hutchison and colleagues [8], which showed a median RR for kappa light chains of 0.69 using dual (2 x 1.1 m2) HCO-1100 dialyzers in series for an 8-hour dialysis session. In agreement with the findings from the Hutchison’s study [8], the majority of survivors from our cohort recovered sufficient renal function to be weaned off dialysis.\n\nOur results are in keeping with a recent study showing better FLC RR with HDF when compared to HD [20]. Sieving coefficients of high-flux dialyzers for molecules up to 15 kDa are somewhat similar, suggesting that the ability of the heat sterilized polyphenylene HF to reduce kappa FLC could be due to either adsorptive property specific to the membrane, or a rapid decline in pore size for molecular weights between 15 to 35 kDa. Although the contribution of FLC adsorption to the reduction ratio of kappa FLC with the polyphenylene HF dialyzer was not tested directly in this study, the marked difference in kappa and lambda (22.5 kDa vs 45 kDa) reduction ratios suggest a major role of the pore size hypothesis. However, our results cannot be generalized to other dialyzers made with the same material, as the sterilisation process can affect membrane characteristics [21]. Therefore, heat-sterilised polyphenylene HF may be more porous than gamma sterilised polyphenylene HF, and this distinction should be further studied before further generalization. We also observed good lambda chain removal with heat-sterilised polyphenylene HF using high-volume post-dilution HDF.\n\nNevertheless, because of the heterogeneity in kappa and lambda RR ratio between individuals, it is possible that the existence of free light chains, either as monomers or dimers, affect the molecular weight and therefore affect the sieving coefficient. Indeed, since lambda free light chains are generally present as dimers (45 kDa), we did not expect high-flux dialyzers to clear proteins of this size effectively. Excellent RR of lambda free light chain by HF-HDF in some patients may suggest that lambda free light chain might have been present as monomers. On the other hand, lower kappa FLC RR by HF-HDF may suggest multimerization of the kappa FLC, as described in a recent publication [22]. Thus, irrespective of the method used, monitoring the efficiency of free light chain RR is essential as both types of free light chains can be present as multimers.\n\nThe addition of HDF to large HCO dialyzers numerically improved lambda RR. However, this improvement in lambda RR was associated with a clinically significant three-fold increase in albumin loss (63g/session) [23]. As the proposed benefit of FLC lowering should initially be maintained by daily dialysis, this level of albumin loss seems prohibitive.\n\nWhile a formal pharmacoeconomic analysis is beyond the scope of the present study, our findings suggest that HDF with heat sterilized polyphenylene HF could be cost effective to reduce kappa FLC, considering the very high cost of the HCO dialyzers (CAD $800 vs $9). Solely based on dialyzers costs, using HF-HDF instead of HCO-HD among patients with kappa FLC elevation and a median of 17 sessions before renal recovery could translate into savings of more than CAD$10 000 per patient. Furthermore, systematic albumin replacement is not mandatory, as albumin loss with HF-HDF is at least threefold lower than HCO dialyzers. However, more recently, the use of supra-hemodiafiltration with endogenous reinfusion of the regenerated ultrafiltrate by a sorbent cartridge, has been shown to reduce kappa and lambda free light chains without the need for albumin replacement in 4 patients [24].\n\nOur cohort included a limited number of patients, which limits the conclusion for some modalities. As the renal replacement modality was limited by the availability of filters and haemodiafiltration, individual patients (FLC clones) were not exposed to every treatment modality. However, because of the nature of the outcome measured, the observational design with serial observations on a group of patients offered the opportunity to test the hypothesis adequately using models adjusted for repeated measures. Uromodulin affinity of FLC is variable [25] and our decision to pursue RRT until pre dialysis FLC were less than 500–1000 mg/L might have resulted in unnecessary RRT sessions in some patients. Time to renal recovery may therefore be longer in our cohort since two conditions (GFR and FLC level) had to be fulfilled before stopping dialysis. Furthermore, the small number of patients, the presenting modes (relapse or de novo) and the variability of therapy preclude any conclusion relative to chemotherapy efficacy, analysis of survival and renal recovery. Only one patient presented a second episode of acute renal failure, which occurred 2 years after the first episode. Until we can monitor individual FLC nephrotoxicity thresholds, our approach seems reasonable as, in our cohort, the lowest level of initial FLC in a biopsy proven myeloma cast nephropathy was of 820 mg/L. Finally, our cohort of patients had a high early mortality that was caused by resistance to chemotherapy and chemotherapy-related complications.\n\nIn conclusion, our results suggest that in the setting of acute dialysis-dependent myeloma cast nephropathy due to elevated kappa FLC, HDF with 2.2 m2 heat sterilized high-flux polyphenylene HF could be used as an alternative to HCO-dialysis with a lower albumin loss. The benefits of this renal replacement modality need confirmation with a randomized controlled trial.\n\nSupporting Information\nS1 Dataset Free light chain reduction ratio dataset.\n(XLSX)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \nYing WZ , Allen CE , Curtis LM , Aaron KJ , Sanders PW . Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model . The Journal of clinical investigation . 2012 ;122 (5 ):1777 –85 . 10.1172/JCI46490 \n22484815 \n2 \nTsakiris DJ , Stel VS , Finne P , Fraser E , Heaf J , de Meester J , et al\nIncidence and outcome of patients starting renal replacement therapy for end-stage renal disease due to multiple myeloma or light-chain deposit disease: an ERA-EDTA Registry study . Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association—European Renal Association . 2010 ;25 (4 ):1200 –6 .\n3 \nClark WF , Stewart AK , Rock GA , Sternbach M , Sutton DM , Barrett BJ , et al\nPlasma exchange when myeloma presents as acute renal failure: a randomized, controlled trial . Annals of internal medicine . 2005 ;143 (11 ):777 –84 .\n16330788 \n4 \nBurnette BL , Leung N , Rajkumar SV . Renal improvement in myeloma with bortezomib plus plasma exchange . The New England journal of medicine . 2011 ;364 (24 ):2365 –6 . 10.1056/NEJMc1101834 \n21675906 \n5 \nGupta D , Bachegowda L , Phadke G , Boren S , Johnson D , Misra M . Role of plasmapheresis in the management of myeloma kidney: a systematic review . Hemodialysis international International Symposium on Home Hemodialysis . 2010 ;14 (4 ):355 –63 . 10.1111/j.1542-4758.2010.00481.x \n20955270 \n6 \nBradwell AR , Carr-Smith HD , Mead GP , Tang LX , Showell PJ , Drayson MT , et al\nHighly sensitive, automated immunoassay for immunoglobulin free light chains in serum and urine . Clinical chemistry . 2001 ;47 (4 ):673 –80 .\n11274017 \n7 \nHutchison CA , Harding S , Mead G , Goehl H , Storr M , Bradwell A , et al\nSerum free-light chain removal by high cutoff hemodialysis: optimizing removal and supportive care . Artificial organs . 2008 ;32 (12 ):910 –7 . 10.1111/j.1525-1594.2008.00653.x \n19133018 \n8 \nHutchison CA , Bradwell AR , Cook M , Basnayake K , Basu S , Harding S , et al\nTreatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off hemodialysis . Clinical journal of the American Society of Nephrology: CJASN . 2009 ;4 (4 ):745 –54 . 10.2215/CJN.04590908 \n19339414 \n9 \nHutchison CA , Cockwell P , Stringer S , Bradwell A , Cook M , Gertz MA , et al\nEarly reduction of serum-free light chains associates with renal recovery in myeloma kidney . Journal of the American Society of Nephrology: JASN . 2011 ;22 (6 ):1129 –36 . 10.1681/ASN.2010080857 \n21511832 \n10 \nHutchison CA , Heyne N , Airia P , Schindler R , Zickler D , Cook M , et al\nImmunoglobulin free light chain levels and recovery from myeloma kidney on treatment with chemotherapy and high cut-off haemodialysis . Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association—European Renal Association . 2012 ;27 (10 ):3823 –8 .\n11 \nBridoux F , Fermand J-P . Optimizing Treatment Strategies in Myeloma Cast Nephropathy: Rationale for a Randomized Prospective Trial . Advances in Chronic Kidney Disease . 2012 ;19 (5 ):333 –41 . 10.1053/j.ackd.2012.07.003 \n22920644 \n12 \nGakhar B , Kobrin S , Berns JS . Extracorporeal treatment of cast nephropathy . Seminars in dialysis . 2011 ;24 (1 ):9 –11 . 10.1111/j.1525-139X.2010.00814.x \n21324000 \n13 \nGrooteman MP , van den Dorpel MA , Bots ML , Penne EL , van der Weerd NC , Mazairac AH , et al\nEffect of online hemodiafiltration on all-cause mortality and cardiovascular outcomes . Journal of the American Society of Nephrology: JASN . 2012 ;23 (6 ):1087 –96 . 10.1681/ASN.2011121140 \n22539829 \n14 \nMaduell F , Moreso F , Pons M , Ramos R , Mora-Macia J , Carreras J , et al\nHigh-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients . Journal of the American Society of Nephrology: JASN . 2013 ;24 (3 ):487 –97 . 10.1681/ASN.2012080875 \n23411788 \n15 \nWang AY , Ninomiya T , Al-Kahwa A , Perkovic V , Gallagher MP , Hawley C , et al\nEffect of hemodiafiltration or hemofiltration compared with hemodialysis on mortality and cardiovascular disease in chronic kidney failure: a systematic review and meta-analysis of randomized trials . American journal of kidney diseases: the official journal of the National Kidney Foundation . 2014 ;63 (6 ):968 –78 .24685515 \n16 \nNistor I , Palmer SC , Craig JC , Saglimbene V , Vecchio M , Covic A , et al\nHaemodiafiltration, haemofiltration and haemodialysis for end-stage kidney disease . The Cochrane database of systematic reviews . 2015 ;5 :CD006258 \n10.1002/14651858.CD006258.pub2 \n25993563 \n17 \nOk E , Asci G , Toz H , Ok ES , Kircelli F , Yilmaz M , et al\nMortality and cardiovascular events in online haemodiafiltration (OL-HDF) compared with high-flux dialysis: results from the Turkish OL-HDF Study . Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association—European Renal Association . 2013 ;28 (1 ):192 –202 .\n18 \nBoschetti-de-Fierro A , Voigt M , Storr M , Krause B . Extended characterization of a new class of membranes for blood purification: the high cut-off membranes . The International journal of artificial organs . 2013 ;36 (7 ):455 –63 . 10.5301/ijao.5000220 \n23661558 \n19 \nCanaud B , Bragg-Gresham JL , Marshall MR , Desmeules S , Gillespie BW , Depner T , et al\nMortality risk for patients receiving hemodiafiltration versus hemodialysis: European results from the DOPPS . Kidney international . 2006 ;69 (11 ):2087 –93 .\n16641921 \n20 \nGranger Vallee A , Chenine L , Leray-Moragues H , Patrier L , Cognot C , Cartron G , et al\nOnline high-efficiency haemodiafiltration achieves higher serum free light chain removal than high-flux haemodialysis in multiple myeloma patients: preliminary quantitative study . Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association—European Renal Association . 2011 ;26 (11 ):3627 –33 .\n21 \nKiaii M , Djurdjev O , Farah M , Levin A , Jung B , MacRae J . Use of electron-beam sterilized hemodialysis membranes and risk of thrombocytopenia . JAMA: the journal of the American Medical Association . 2011 ;306 (15 ):1679 –87 . 10.1001/jama.2011.1499 \n22009100 \n22 \nHarding S , Provot F , Beuscart JB , Cook M , Bradwell AR , Stringer S , et al\nAggregated serum free light chains may prevent adequate removal by high cut-off haemodialysis . Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association—European Renal Association . 2011 ;26 (4 ):1438 .\n23 \nSusantitaphong P , Tiranathanagul K , Eiam-Ong S . Extended high cutoff on-line hemodiafiltration is superior to extended high cutoff hemodialysis in removal of free light chain immunoglobulin of myeloma cast nephropathy . Artificial organs . 2012 ;36 (9 ):845 –6 . 10.1111/j.1525-1594.2012.01442.x \n22497276 \n24 \nPasquali S , Iannuzzella F , Corradini M , Mattei S , Bovino A , Stefani A , et al\nA novel option for reducing free light chains in myeloma kidney: supra-hemodiafiltration with endogenous reinfusion (HFR) . Journal of nephrology . 2015 ;28 (2 ):251 –4 . 10.1007/s40620-014-0130-8 \n25149172 \n25 \nLeboulleux M , Lelongt B , Mougenot B , Touchard G , Makdassi R , Rocca A , et al\nProtease resistance and binding of Ig light chains in myeloma-associated tubulopathies . Kidney international . 1995 ;48 (1 ):72 –9 .\n7564094\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "10(10)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D015415:Biomarkers; D015314:Dialysis Solutions; D005260:Female; D017583:Hemodiafiltration; D006801:Humans; D007147:Immunoglobulin Light Chains; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D007677:Kidney Function Tests; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011108:Polymers; D011446:Prospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0140463",
"pmc": null,
"pmid": "26466100",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "16330788;16641921;19133018;19339414;20037169;20955270;21324000;21406545;21511832;21675906;22009100;21508098;22484815;22539829;22920644;22497276;11274017;7564094;22273664;23229932;23411788;23661558;24685515;25149172;25993563",
"title": "Effectiveness of Haemodiafiltration with Heat Sterilized High-Flux Polyphenylene HF Dialyzer in Reducing Free Light Chains in Patients with Myeloma Cast Nephropathy.",
"title_normalized": "effectiveness of haemodiafiltration with heat sterilized high flux polyphenylene hf dialyzer in reducing free light chains in patients with myeloma cast nephropathy"
} | [
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"companynumb": "CA-CELGENE-CAN-2015125123",
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"activesubstancename": "BORTEZOMIB"
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{
"abstract": "Morbihan syndrome is a rare entity causing woody induration of the face. There are numerous case reports of bilateral Morbihan syndrome. We present a case of a 46-year-old man with right infra-orbital cheek swelling and symptoms of rosacea who had histology consistent with granulomatous rosacea following debulking surgery. His clinical presentation and investigation findings support a diagnosis of rosacea causing unilateral Morbihan syndrome.",
"affiliations": "Dermatology, East Kent Hospitals University NHS Foundation Trust, Canterbury, UK s.weeraman@nhs.net.;Dermatology, East Kent Hospitals University NHS Foundation Trust, Canterbury, UK.",
"authors": "Weeraman|Saliya|S|;Birnie|Andrew|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-231074",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(10)",
"journal": "BMJ case reports",
"keywords": "dermatology; skin",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D003937:Diagnosis, Differential; D004487:Edema; D005148:Facial Dermatoses; D006801:Humans; D008297:Male; D008875:Middle Aged; D012393:Rosacea",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31653629",
"pubdate": "2019-10-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23741671;28300928;29364446;9270545",
"title": "Rosacea causing unilateral Morbihan syndrome.",
"title_normalized": "rosacea causing unilateral morbihan syndrome"
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"companynumb": "GB-MYLANLABS-2019M1121866",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
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"activesubstancename": "PIMECROLIMUS"
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"abstract": "In recent years, the incidence of therapy-related myelodysplastic syndrome (t-MDS) and therapy-related acute myeloid leukemia (t-AML) that occur during chemotherapy for ovarian cancer has increased. While alkylating agents and topoisomerase II inhibitors are particularly mutagenic and have strong leukemogenic potential, paclitaxel and combination chemotherapy/radiation therapy also appear to induce t-MDS. The present authors report a case of t-MDS that developed during chemotherapy and radiation therapy for ovarian cancer. The patient was a 75-year-old woman who received six courses of cyclophosphamide/doxorubicin/cisplatin (CAP) therapy after initial surgery for Stage IIIc grade ovarian cancer in 1995. Beginning in February 2005, the patient experienced multiple recurrences due to sternal metastasis. Chemotherapy, including paclitaxel and carboplatin (TC), was administered intermittently and was combined with radiation therapy to a sternal metastatic lesion. Pancytopenia was observed in December 2008, and she was diagnosed with t-MDS (WHO subtype, refractory cytopenias with multilineage dysplasia [RCMD]): the time from first chemotherapy to t-MDS onset was 106 months. Without evidence of blast crisis, the recurrent lesions continued to grow and caused multiple cerebral infarctions, from which she eventually died. The cumulative doses of paclitaxel and carboplatin administered to this patient were 1,968 mg and 6,480 mg, respectively.",
"affiliations": null,
"authors": "Ishikawa|M|M|;Nakayama|K|K|;Rahman|M T|MT|;Rahman|M|M|;Katagiri|H|H|;Katagiri|A|A|;Ishibashi|T|T|;Iida|K|K|;Nakayama|N|N|;Miyazaki|K|K|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel",
"country": "China",
"delete": false,
"doi": null,
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"issn_linking": "0392-2936",
"issue": "35(4)",
"journal": "European journal of gynaecological oncology",
"keywords": null,
"medline_ta": "Eur J Gynaecol Oncol",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D016190:Carboplatin; D002544:Cerebral Infarction; D059248:Chemoradiotherapy; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008113:Liver Neoplasms; D009190:Myelodysplastic Syndromes; D016609:Neoplasms, Second Primary; D009360:Neoplastic Cells, Circulating; D010051:Ovarian Neoplasms; D017239:Paclitaxel",
"nlm_unique_id": "8100357",
"other_id": null,
"pages": "443-8",
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"title": "Therapy-related myelodysplastic syndrome and acute myeloid leukemia following chemotherapy (paclitaxel and carboplatin) and radiation therapy in ovarian cancer: a case report.",
"title_normalized": "therapy related myelodysplastic syndrome and acute myeloid leukemia following chemotherapy paclitaxel and carboplatin and radiation therapy in ovarian cancer a case report"
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"abstract": "The patient was a 77-year-old woman diagnosed as having rheumatoid arthritis (RA) in 1973. She was initiated on infliximab therapy in addition to methotrexate administration in 2009. The therapeutic response decreased after the fifth dose of infliximab, and the patient developed rheumatoid pleuritis due to increased RA disease activity. The therapy was switched from infliximab to tocilizumab, which resulted in amelioration of the arthralgias well as pleuritis. Our results suggest that tocilizumab is an effective treatment alternative for the treatment of rheumatoid pleuritis.",
"affiliations": "Departments of Orthopedics and Rheumatology, Isesaki Fukushima Hospital , Otemachi, Isesakishi, Gumma , Japan , Kiryu-shi, Gumma , Japan.",
"authors": "Ohtsuka|Keiko|K|;Takeuchi|Kimihiko|K|;Matsushita|Masatoshi|M|;Aramaki|Tetsuo|T|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C502936:tocilizumab",
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"issue": "24(6)",
"journal": "Modern rheumatology",
"keywords": "Bilateral pleural effusion; Extra-articular manifestations; Rheumatoid arthritis; Rheumatoid pleuritis; Tocilizumab",
"medline_ta": "Mod Rheumatol",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D010998:Pleurisy; D016896:Treatment Outcome",
"nlm_unique_id": "100959226",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of bilateral rheumatoid pleuritis successfully treated with tocilizumab.",
"title_normalized": "a case of bilateral rheumatoid pleuritis successfully treated with tocilizumab"
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"companynumb": "JP-JNJFOC-20141207027",
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"abstract": "OBJECTIVE\nUremic pruritus is a common problem in hemodialysis patients. Several treatments have been used for decreasing itching in these patients. Gabapentin and ketotifen are two drugs used for treating uremic patients. The aim of this study was to compare gabapentin and ketotifen in treatment of uremic pruritus in hemodialysis patients.\n\n\nMETHODS\nIn this double-blind randomized clinical trial, 52 hemodialysis patients with uremic pruritus referred to 5azarTeaching Hospital in Gorgan in 2013 were studied. Patients were randomly assigned to two groups of 26 subjects (groups G and K). In group G, patients treated with gabapentin capsules 100 mg daily for 2 weeks, and in Group K, patients treated with ketotifen 1 mg twice daily for 2 weeks. Before and at the end of study, pruritus severity was determined based on Shiratori's severity scores. Collected data were analyzed by SPSS-21 statistical software.\n\n\nRESULTS\nThere was no significant different between two groups in the age and sex. After two weeks of treatment, severity of pruritus was significantly reduced in both groups (88.4% in group G vs. 76.9% in group K). Gabapentin compared with ketotifen had a better effect on improving itching in the age group of 30-60 years and in males. 5 patients (19.2%) in both groups suffered from drowsiness and dizziness, but no serious side effects were observed.\n\n\nCONCLUSIONS\nThe results showed that gabapentin and ketotifen significantly improved pruritus in hemodialysis patients, and no significant difference was observed between two groups.",
"affiliations": "Dr. Saeid Amirkhanlou, MD, Assistant Professor, Nephrologist, Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Golestan, Iran.;Dr. Anna Rashedi, MD, Radiologist, Assistant Professor, Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Golestan, Iran.;Dr. Jalal Taherian, MD, General Practitioner, Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Golestan, Iran.;Dr. Ali Akbar Hafezi, MD, General Practitioner, Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Golestan, Iran.;Sahar Parsaei, Medical Student, Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Golestan, Iran.",
"authors": "Amirkhanlou|Saeid|S|;Rashedi|Anna|A|;Taherian|Jalal|J|;Hafezi|Ali Akbar|AA|;Parsaei|Sahar|S|",
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"doi": "10.12669/pjms.321.8547",
"fulltext": "\n==== Front\nPak J Med SciPak J Med SciPJMSPakistan Journal of Medical Sciences1682-024X1681-715XProfessional Medical Publications Pakistan PJMS-32-2210.12669/pjms.321.8547Original ArticleComparison of Gabapentin and Ketotifen in Treatment of Uremic Pruritus in Hemodialysis Patients Amirkhanlou Saeid 1Rashedi Anna 2Taherian Jalal 3Hafezi Ali Akbar 4Parsaei Sahar 51 Dr. Saeid Amirkhanlou, MD, Assistant Professor, Nephrologist, Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Golestan, Iran2 Dr. Anna Rashedi, MD, Radiologist, Assistant Professor, Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Golestan, Iran3 Dr. Jalal Taherian, MD, General Practitioner, Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Golestan, Iran4 Dr. Ali Akbar Hafezi, MD, General Practitioner, Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Golestan, Iran5 Sahar Parsaei, Medical Student, Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Golestan, Iran\nCorrespondence: Dr. Anna Rashedi, MD. E-mail: anna_rashedi@yahoo.comJan-Feb 2016 32 1 22 26 10 7 2015 14 7 2015 28 10 2015 05 11 2015 Copyright: © Pakistan Journal of Medical Sciences2016This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Objectives:\nUremic pruritus is a common problem in hemodialysis patients. Several treatments have been used for decreasing itching in these patients. Gabapentin and ketotifen are two drugs used for treating uremic patients. The aim of this study was to compare gabapentin and ketotifen in treatment of uremic pruritus in hemodialysis patients.\n\nMethods:\nIn this double-blind randomized clinical trial, 52 hemodialysis patients with uremic pruritus referred to 5azarTeaching Hospital in Gorgan in 2013 were studied. Patients were randomly assigned to two groups of 26 subjects (groups G and K). In group G, patients treated with gabapentin capsules 100 mg daily for 2 weeks, and in Group K, patients treated with ketotifen 1 mg twice daily for 2 weeks. Before and at the end of study, pruritus severity was determined based on Shiratori’s severity scores. Collected data were analyzed by SPSS-21 statistical software.\n\nResults:\nThere was no significant different between two groups in the age and sex. After two weeks of treatment, severity of pruritus was significantly reduced in both groups (88.4% in group G vs. 76.9% in group K). Gabapentin compared with ketotifen had a better effect on improving itching in the age group of 30-60 years and in males. 5 patients (19.2%) in both groups suffered from drowsiness and dizziness, but no serious side effects were observed.\n\nConclusions:\nThe results showed that gabapentin and ketotifen significantly improved pruritus in hemodialysis patients, and no significant difference was observed between two groups.\n\nKEY WORDS\nGabapentinKetotifenUremic PruritusHemodialysis\n==== Body\nINTRODUCTION\nPruritus is one of the biggest problems in hemodialysis patients. Unfortunately, approximately 37-90% of the patients with ESRD suffer from itching.1,2 Pathophysiology of pruritus in patients with chronic renal failure (CRF) is unknown.3,4 Uremic pruritus usually appears before starting the treatment with hemodialysis and gradually progresses.5,6\n\nGiven the various causes of pruritus in hemodialysis patients, several treatments have been used and investigated.7,8 Few studies have been done on the effectiveness of gabapentin with antihistamines such ketotifen.9,10 In this study, the effects of gabapentin and ketotifen on improving uremic pruritus were compared.\n\nMETHODS\nThis double-blind randomized clinical trial was conducted after approval from the Research Ethics Committee of Golestan University of Medical Sciences. Of 182 hemodialysis patients referred to 5 azar Teaching Hospital in Gorgan in 2013, 52 eligible patients with uremic pruritus were selected. All patients undergoing hemodialysis were similar in frequency and method (maximum duration and frequency of hemodialysis) and patients suffering from itchy skin condition (non-uremic pruritus) were excluded. Patients were randomly assigned to two groups of 26 subjects (groups G and K). In group G, patients treated with gabapentin capsules (Iran Daroo Pharmaceutical Co., Tehran, Iran) 100 mg daily for 2 weeks, and in Group K, patients treated with ketotifen (Abidi Pharmaceutical Co., Tehran, Iran) 1 mg twice daily for 2 weeks. The patients and drug distributors were not aware of the prescribed medications. For matching two groups, before beginning the study, serum calcium, phosphorus and hemoglobin were reached to above 8 mg/dL, less than 5 mg/dL and about 11 to 12 gr/dL, respectively, and the patient were controlled about anemia and hyperparathyroidism.\n\nBefore and at the end of study, pruritus severity were determined based on Shiratori’s severity scores (0= no itching, 1= minimal, 2= mild, 3= moderate and 4= severe itching).11 Clinical response to treatment was determined as follows: (1) Complete response (no itching or minimal itching after treatment), (2) Partial response (mild or moderate severity of itching after treatment) and (3) No response (severe pruritus after treatment). Two groups of patients were compared in terms of age, gender, response to treatment and medication side effects (dizziness, drowsiness, tachycardia and palpitations). Collected data were analyzed by SPSS-21 statistical software and chi-square (χ2) and t tests, Fisher’s exact test and Mann-Whitney U test.\n\nRESULTS\nA total of 52 hemodialysis patients with uremic pruritus in two groups were treated with gabapentin and ketotifen. The mean age of patients in group G was 60.2±7.4 years, and in group K was 57.6±6.2 years, which was not statistically significant (P=0.127). In group G, 12 patients (46.2%) were males and 14 patients (53.8%) were females, and in group K, 13 patients (50%) were males and 13 patients (50%) were females, which was not significantly different (P=0.098).\n\nThe results showed that of 52 patients, 49 patients (94.2%) reported itching during the day and 47 patients (90.4%) at night. In group G, 3 patients (11.5%) did not respond to treatment, 9 patients (34.6%) had a partial response and 14 patients (53.8%) had a complete response to treatment. In group K, 6 patients (23.1%) did not respond to treatment, 7 patients (26.9%) had a partial response and 13 patients (50.0%) had a complete response to treatment. Hence, there was no significant difference between two groups in terms of the response to treatment (P=0.481) (Fig.1).\n\nFig.1 Comparison of the response to treatment with gabapentin and ketotifen in hemodialysis patients with uremic pruritus. No (no response), P (Partial response), and C (Complete response).\n\nComparing the effects of gabapentin and ketotifen in the treatment of uremic pruritus by age showed that in the age group of 30-60 years, a significant difference was observed between two groups in terms of response to treatment (P= 0.008), but in other age groups, There were no significant differences (P>0.05) (Table-I).\n\nTable-I Comparison of the effects of gabapentin and ketotifen in the treatment of uremic pruritus in hemodialysis patients by age.\n\nAge Groups (year)\t\tResponse to Treatment\tTotal\tP value\t\n\t\n\t\tNo\tPartial\tComplete\t\t\t\n\t\n\t\tFrequency\tPercent\tFrequency\tPercent\tFrequency\tPercent\tFrequency\tPercent\t\t\nUnder 30\tG*\t1\t1.9\t0\t0\t2\t3.8\t3\t5.8\t0.659\t\nK**\t2\t3.8\t1\t1.9\t3\t5.8\t6\t11.5\t\n30-60\tG\t0\t0\t6\t11.5\t6\t11.5\t12\t23.1\t0.008\t\nK\t3\t5.8\t2\t3.8\t6\t11.5\t11\t19.2\t\nUpper 60\tG\t2\t3.8\t3\t5.8\t6\t11.5\t11\t19.2\t0.854\t\nK\t1\t1.9\t4\t7.7\t4\t7.7\t9\t17.3\t\nComparing two treatment groups by sex showed that there was a significant difference in the males between two groups in terms of response to treatment (P= 0.011), but among the females, There was no significant difference (P=0.258) (Table-II).\n\nTable-II Comparison of the effects of gabapentin and ketotifen in the treatment of uremic pruritus in hemodialysis patients by sex.\n\nSex\tResponse to Treatment\tTotal\tP value\t\n\t\n\tNo\tPartial\tComplete\t\t\t\n\t\n\tFrequency\tPercent\tFrequency\tPercent\tFrequency\tPercent\tFrequency\tPercent\t\nMale\tG\t1\t1.9\t4\t7.7\t8\t15.4\t13\t25.0\t0.011\t\nK\t3\t5.8\t3\t5.8\t6\t11.5\t12\t23.1\t\nFemale\tG\t2\t3.8\t5\t9.6\t6\t11.5\t13\t25.0\t0.258\t\nK\t3\t5.8\t4\t7.7\t7\t13.5\t14\t26.9\t\nAssessment of the side effects in both treatment groups showed that in both groups, 4 patients (15.4%) experienced drowsiness and 1 patient (3.8%) had dizziness after taking gabapentin and Ketotifen, that there was no statistically significant difference (P=1.00) (Table-III). Also, no cases with palpitations and tachycardia were observed.\n\nTable-III Comparison of the side effects of gabapentin and ketotifen in hemodialysis patients with uremic pruritus.\n\nSide Effect Drug\tDrowsiness\tDizziness\tNo Side Effect\tTotal\tP value\t\n\t\n\tFrequency\tPercent\tFrequency\tPercent\tFrequency\tPercent\tFrequency\tPercent\t\t\nGabapentin\t4\t7.7\t1\t1.9\t21\t40.4\t26\t50.0\t1.00\t\nKetotifen\t4\t7.7\t1\t1.9\t21\t40.4\t26\t50.0\t\nDISCUSSION\nIn this study, the effects of gabapentin and ketotifen on treating hemodialysis patients with uremic pruritus were studied over a two week period. The results showed that both groups of patients significantly responded to treatment though the response to treatment was greater in gabapentin group (88.4% vs 76.9%), but there was no significant difference between two groups. Also, in the age group of 30-60 years, a significant difference was found between two groups in response to treatment, so that patients of gabapentin group showed a better response to treatment. Moreover, in males, a significant difference was observed between two groups in terms of response to treatment, so that patients treated with gabapentin respond better to treatment. It seems that ketotifen is not superior to gabapentin in the treatment of uremic pruritus and patient response to treatment with gabapentin has been relatively better than ketotifen. But in terms of side effects, a small number of patients in both groups had drowsiness and dizziness and no palpitations and tachycardia were reported. Therefore, the use of these drugs in the treatment of uremic pruritus showed no serious side effects.\n\nThe studies done by other researchers had varying results. Marquez, et al. in their study about comparing the efficacy and safety of desloratidine (an antihistamine) versus gabapentin showed that pruritus was decreased with both treatments but There were no differences when comparing the final pruritus score with both drugs. Excessive sedation was common with gabapentin, while desloratadine was well tolerated.12 In the present study, gabapentin and ketotifen (an antihistamine) were significantly improved pruritus in hemodialysis patients, although the efficacy of gabapentin was slightly better than ketotifen but no significant difference was found between two groups in terms of the side effects. Rayner, et alby compared the effects of gabapentin and pregabalin in reducing pruritus. They concluded that gabapentin relieved itching in 66% of the patients, while pregabalin relieved itching in 81% of the patients. Also, 37% of patients suffered side effects from gabapentin.9 In the present study gabapentin improved pruritus in 88.4% of the patients. Finally, only 5 patients (19.2%) had drowsiness and dizziness, but none of the patients had serious side effects. Razeghi, et al. in their study on uremic pruritus refractory to antihistamines showed that gabapentin is an effective agent in treating uremic pruritus and no significant correlation was found between age and sex with gabapentin effect.13 This study also demonstrated the therapeutic effects of gabapentin in uremic patients, but in the age group of 30-60 years and the males, gabapentin relieved pruritus in hemodialysis patients more significant than ketotifen. Gunal, et alin their study showed that the severity of pruritus in patients treated with gabapentin significantly decreased more than control group. Also, no significant complications were observed. Therefore, gabapentin in the treatment of uremic pruritus appeared to be safe and effective.14 Vila, et al. in their review article showed that gabapentin has demonstrated efficacy in the treatment of multiple types of itch especially in treating patients with uremic patients who are unresponsive to standard therapies. All of the controlled studies consisted of 4 weeks of active treatment, and no patients discontinued gabapentin due to adverse events.15 In the study of Manenti, et al. all patients experienced a rapid subjective improvement in pruritus by gabapentin.16\n\nThere are very few studies on the effects of ketotifen compared gabapentin in ESRD patients, however, a number of studies have shown the beneficial effects of ketotifen in the treatment of uremic pruritus. In the study of Francos, et al. determined all uremic patients treated with ketotifen had significant reductions in pruritus at 8 weeks after treatment.17 Noshad&NazariKhanmiri in a study on comparison of gabapentin and antihistamins (hydroxyzine) in treatment of uremic pruritus showed that reducing the severity of pruritus in gabapentin group (group G) was significantly higher than hydroxyzine group (group A). Itching remained in 10% of the patients in group G versus 80% in group A. The side effects were 35% in group G versus 50% in group A.10 Khalili, et al. in their study about effect of three antihistamines on uremic pruritus in the patients with CRF showed that hydroxyzine (33%) and chlorpheniramine (20%) significantly reduced the severity of itching in uremic patients, but ketotifen (4.5%) was insignificantly decreased pruritus.18 But in the present study, ketotifen relieved itching in 76.9% of patients.\n\nIt is most likely that uraemic pruritus is a mixture of both neuropathic and neurogenic itch. Neuropathic itch can originate from damage of the nervous system located at any point along the afferent pathway. Because its pathophysiology of uremic pruritus is poorly understood, the treatment of uraemic pruritus remains mainly empirical.14 Among the various drugs used in the treatment of uremic pruritus, gabapentin and ketotifen were investigated in this study. Although its mechanism of action is not clear, gabapentin appears to have an effect on voltage-dependent calcium-ion channels. By inhibiting neuronal calcium influx, it may interrupt the series of events that perhaps lead to the pruritic sensation in uraemia.19 On the other hand, it seems that histamine in combination with other factors plays an important role in the pathogenesis of pruritus,20,21 although this finding has not been established in some studies.22,23 Ketotifen is also an antiserotonergic agent and mast cell stabilizer, have been effective in controlling pruritus of some patients.17\n\nCONCLUSION\nThe results of this study showed that gabapentin and ketotifen significantly improved pruritus in hemodialysis patients. Although the effect of gabapentin was better than ketotifen but no significant difference was observed between two groups. Also, in the age group of 30-60 years and in males, gabapentin was significantly more effective than ketotifen. Taking these drugs had few side effects in patients, therefore, this study indicated the efficacy and safety of gabapentin and ketotifen in the treatment of uremic pruritus, although further studies are needed to confirm the results.\n\nACKNOWLEDGMENTS\nThe authors thank Golestan University of Medical Sciences for financial support to undertake the study, and the personnels of dialysis unit in 5th Azar Hospital in Gorgan for their unwavering cooperation in performing this study.\n\nDeclaration of interest: None declared.\n\nGrant Support & Financial Disclosures: Golestan University of Medical Sciences.\n\n\nAuthors’ Contribution\nSA & AR conceived, designed and did statistical analysis & editing of manuscript.\n\nJT, AAH & SP did data collection and manuscript writing.\n\nAAH did review and final approval of manuscript.\n==== Refs\nREFERENCES\n1 Zucker I Yosipovitch G David M Gafter U Prevalence and characterization of uremic pruritus in patients undergoing hemodialysis: uremic pruritus is still a major problem for patients with end-stage renal disease J Am Acad Dermatol 2003 49 842 14576662 \n2 Keithi-Reddy SR Patel TV Armstrong AW Singh AK Uremic pruritus Kidney Int 2007 72 373 377 17429345 \n3 Narita I Iguchi S Omori K Gejyo F Uremic pruritus in chronic hemodialysis patients J Nephrol 2008 21 161 165 18446709 \n4 Robinson-Bostom L DiGiovanna JJ Cutaneous manifestations of end-stage renal disease J Am AcadDermatol 2000 43 6 975 986 quiz 987-990 \n5 Kim KH Lee MS Choi SM Ernst E Acupuncture for treating uremic pruritus in patients with end-stage renal disease: A systematic review J Pain Symptom Manage 2010 40 117 125 21796811 \n6 Shamsaldini S Ebrahimi H Shamsaldini H The effect of ultraviolet beam in itching of patients under hemodialysis and the relationship between itching and elevated PTH Iran J Urol 1996 3 47 51 Persian \n7 Manenti L Tansinda P Vaglio A Uraemic pruritus: clinical characteristics, pathophysiology and treatment Drugs 2009 69 251 263 doi:10.2165/00003495-200969030-00002 19275270 \n8 Lugon JR Uremic pruritus: a review Hemodial Int 2005 9 180 188 16191067 \n9 Rayner H Baharani J Smith S Suresh V Dasgupta I Uraemic pruritus: relief of itching by gabapentin and pregabalin Nephron Clin Pract 2012 122 75 79 doi:10.1159/000349943 23548570 \n10 Noshad H NazariKhanmiri S Comparison of gabapentin and antihistamins in treatment of uremic pruritus and its psychological problems Urmia Med J 2010 21 286 292 Persian \n11 Kumagai H Ebata T Takamori K Miyasato K Muramatsu T Nakamoto H Efficacy and safety of a novel α-agonist for managing intractable pruritus in dialysis patients Am J Nephrol 2012 36 175 183 22868684 \n12 Marquez D Ramonda C Lauxmann JE Romero CA Vukelic VL Martinatto C Uremic pruritus in hemodialysis patients: treatment with desloratidine versus gabapentin J Bras Nefrol 2012 34 148 152 22850916 \n13 Razeghi E Eskandari D Ganji MR Meysamie AP Togha M Khashayar P Gabapentin and uremic pruritus in hemodialysis patients Ren Fail 2009 31 85 90 19212903 \n14 Gunal AI Ozalp G Yoldas TK Gunal SY Kirciman E Celiker H Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial Nephrol Dial Transplant 2004 19 3137 3139 15575002 \n15 Vila T Gommer J Scates AC Role of gabapentin in the treatment of uremic pruritus Ann Pharmacother 2008 42 1080 1084 18492782 \n16 Manenti L Vaglio A Costantino E Danisi D Oliva B Pini S Gabapentin in the treatment of uremic itch: an index case and a pilot evaluation J Nephrol 2005 18 86 91 15772928 \n17 Francos GC Kauh YC Gittlen SD Schulman ES Besarab A Goyal S Elevated plasma histamine in chronic uremia. Effects of ketotifen on pruritus Int J Dermatol 1991 30 884 889 1816135 \n18 Khalili H Dashti S Ahmad Poor P Haji Babaei P Abdollahi F Effect of anti-pruritus drugs in chronic renal failure: a comparative study Tehran Uni Med J 2006 4 36 42 Persian \n19 Rose MA Kam PC Gabapentin: pharmacology and its use in pain management Anaesthesia 2002 57 451 462 11966555 \n20 De Marchi S Cecchin E Villalta D Sepiacci G Santini G Bartoli E Relief of pruritus and decreases in plasma histamine concentrations during erythropoietin therapy in patients with uremia N Engl J Med 1992 326 969 974 1545849 \n21 Gill DS Fonseca VA Barradas MA Balliod R Moorhead JF Dandona P Plasma histamine in patients with chronic renal failure and nephrotic syndrome J Clin Pathol 1991 44 243 245 2013627 \n22 Mettang T Fritz P Weber J Machleidt C Hübel E Kuhlmann U Uremic pruritus in patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). The role of plasma histamine and skin mast cells Clin Nephrol 1990 34 136 141 1699691 \n23 Stockenhuber F Sunder-Plassmann G Balcke P Increased plasma histamine levels in chronic renal failure N Engl J Med 1987 317 86\n\n",
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"issue": "32(1)",
"journal": "Pakistan journal of medical sciences",
"keywords": "Gabapentin; Hemodialysis; Ketotifen; Uremic Pruritus",
"medline_ta": "Pak J Med Sci",
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"pages": "22-6",
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"title": "Comparison of Gabapentin and Ketotifen in Treatment of Uremic Pruritus in Hemodialysis Patients.",
"title_normalized": "comparison of gabapentin and ketotifen in treatment of uremic pruritus in hemodialysis patients"
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"abstract": "Primary enteroliths associated with Crohn's disease have been considered to be rare and are most likely caused by severe ileal stenosis. Herein, we report the case of a primary enterolith possibly caused by mild jejunal stenosis in a Crohn's disease patient who received oral administration of ursodeoxycholic acid (UDCA). A 62-year-old woman with a 6-year history of Crohn's disease, currently in clinical remission, was on UDCA prescription for liver dysfunction. Magnetic resonance imaging and double-balloon endoscopy, which were performed to examine epigastric pain, revealed mild jejunal stenosis and an enterolith on the oral side. Since it was difficult to remove or crush the enterolith endoscopically, we decided to remove it surgically with the stenotic jejunum. Component analysis revealed that more than 98% of the enterolith was composed of UDCA; subsequently, oral administration of UDCA was discontinued. This case demonstrated that primary enterolith might develop in Crohn's disease patients with mild intestinal stenosis, and oral administration of UDCA can trigger an enterolith in such patients. Therefore, routine follow-up imaging is necessary for early detection. Oral UDCA should be administered with caution for Crohn's disease patients with stenosis of the proximal small intestine.",
"affiliations": "Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.;Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.",
"authors": "Matsui|Hiroki|H|;Yoshida|Tadashi|T|;Homma|Shigenori|S|;Ichikawa|Nobuki|N|;Emoto|Shin|S|;Miyaoka|Yoichi|Y|;Sakurai|Kensuke|K|;Odagiri|Shinsuke|S|;Katsurada|Takehiko|T|;Taketomi|Akinobu|A|",
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"fulltext": "\n==== Front\nJ Anus Rectum Colon\nJ Anus Rectum Colon\nJournal of the Anus, Rectum and Colon\n2432-3853\nThe Japan Society of Coloproctology\n\n10.23922/jarc.2021-017\nCase Report\nUrsodeoxycholic Acid Triggers Primary Enterolith Growth in a Crohn's Disease Patient with Jejunal Stenosis\nMatsui Hiroki 1\nYoshida Tadashi 1\nHomma Shigenori 1\nIchikawa Nobuki 1\nEmoto Shin 1\nMiyaoka Yoichi 1\nSakurai Kensuke 2\nOdagiri Shinsuke 2\nKatsurada Takehiko 2\nTaketomi Akinobu 1\n1 Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan\n2 Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo, Japan\nCorresponding author: Shigenori Homma, homma.s@nifty.com\n\n2021\n28 10 2021\n5 4 433438\n1 3 2021\n6 5 2021\nCopyright © 2021 by The Japan Society of Coloproctology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ Journal of the Anus, Rectum and Colon is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nPrimary enteroliths associated with Crohn's disease have been considered to be rare and are most likely caused by severe ileal stenosis. Herein, we report the case of a primary enterolith possibly caused by mild jejunal stenosis in a Crohn's disease patient who received oral administration of ursodeoxycholic acid (UDCA). A 62-year-old woman with a 6-year history of Crohn's disease, currently in clinical remission, was on UDCA prescription for liver dysfunction. Magnetic resonance imaging and double-balloon endoscopy, which were performed to examine epigastric pain, revealed mild jejunal stenosis and an enterolith on the oral side. Since it was difficult to remove or crush the enterolith endoscopically, we decided to remove it surgically with the stenotic jejunum. Component analysis revealed that more than 98% of the enterolith was composed of UDCA; subsequently, oral administration of UDCA was discontinued. This case demonstrated that primary enterolith might develop in Crohn's disease patients with mild intestinal stenosis, and oral administration of UDCA can trigger an enterolith in such patients. Therefore, routine follow-up imaging is necessary for early detection. Oral UDCA should be administered with caution for Crohn's disease patients with stenosis of the proximal small intestine.\n\nCrohn's disease\nprimary enterolith\nstenosis of proximal small intestine\nursodeoxycholic acid\n==== Body\npmcIntroduction\n\nStones in the gastrointestinal tract, or enteroliths, can cause intestinal obstruction, erosion, ulcers, bleeding, and perforations and, therefore, require therapeutic interventions, including surgery[1]. Enteroliths are often classified into primary enteroliths that develop in the intestinal tract and secondary enteroliths that originate outside the intestinal tract and move into the intestinal tract through the fistulas[1]. Primary enteroliths develop in areas of intestinal stasis, and one of the causes of intestinal stasis is intestinal stenosis[1]. Crohn's disease, which has been identified as the cause of intestinal stenosis, has been determined to cause primary enteroliths[1,2]. However, reports of primary enteroliths associated with Crohn's disease remain limited, and most reported enteroliths are determined to be caused by severe ileal stenosis after a long period of illness[2-5]. To the best of our knowledge, no studies have so far explored the relationship between primary enteroliths associated with Crohn's disease and the oral administration of ursodeoxycholic acid (UDCA). Herein, we report the case of a patient with primary enterolith possibly caused by mild jejunal stenosis due to Crohn's disease and oral administration of UDCA.\n\nCase Report\n\nA 62-year-old woman with Crohn's disease underwent magnetic resonance imaging (MRI) for transient epigastric pain and was then diagnosed with an enterolith. She had no medical history of biliary tract disease, intestinal diverticulosis, or urinary tract disease. About 6 years ago, she had been examined for upper abdominal pain and was diagnosed with Crohn's disease. She was in remission after receiving prednisolone (PSL), azathioprine (AZA), and infliximab (IFX). After induction of remission, PSL was discontinued, and the administration of AZA and IFX maintained her clinical remission. She was later diagnosed with hepatic dysfunction 5 years ago and received a UDCA prescription (600 mg/day). Double-balloon enteroscopy (DBE) 2 years prior did not show enteroliths or significant intestinal stenosis. An MRI performed 1 month before surgery due to transient epigastric pain examination revealed a 4.5-cm-sized oval structure in the small intestine (Figure 1), which was later diagnosed as an enterolith. The MRI and additional computed tomography (CT) showed stenosis of the small intestine with the thickening of the intestinal wall just on the anal side of the enterolith without any evidence of intestinal obstruction (Figure 1). The imaging did not show any abnormal findings, including in the biliary system or urethral system. Transanal DBE showed a stenotic site in the jejunum, located 250 cm from the terminal ileum (Figure 2a). The jejunal stenosis was mild enough for DBE to pass, with DBE revealing the presence of an enterolith on the oral side of the stenosis (Figure 2b). We failed to remove and crush the enterolith endoscopically (Figure 2b). Therefore, we decided to surgically remove the enterolith. Ports were inserted into the umbilical region, left abdomen, and lower left abdomen to initiate the laparoscopic procedure. The dilated jejunum with the enterolith was found without any adhesions. We then extended the umbilical incision to the cranial and caudal sides and guided the intestinal tract, which was grasped with forceps, to the exterior of the incision. The stenotic site was located in the jejunum, approximately 150 cm from the Treitz ligament, along with the enterolith (Figure 3). No other stenosis or strictures were detected in other parts of the small intestine. Because the enterolith was large and its removal required a large intestinal incision, we were concerned that this intervention would complicate the subsequent procedure. Furthermore, even if we performed a small bowel resection, we thought that the remaining small bowel would be sufficient. Therefore, the jejunum, including the stricture, was resected along with the enterolith. The jejunum was reconstructed using functional end-to-end anastomosis. The surgery duration was 1 hour and 32 minutes, and the amount of bleeding was insignificant. She was later discharged without complications on the 13th day after the surgery. The stenotic site of the resected jejunum showed inflammation and fibrous changes without malignant findings (Figure 4). The enterolith appeared yellowish-brown and oval with a diameter of 4.5 cm (Figure 5a). The cut surface was yellow and had a multilayered structure (Figure 5b). As per the component analysis, it was determined that more than 98% of the enterolith was composed of UDCA. Subsequently, oral administration of UDCA was discontinued after surgery (Figure 5c).\n\nFigure 1. Magnetic resonance imaging (MRI) findings.\n\na) Transverse plane. b) Frontal plane. MRI shows a 4.5-cm oval structure in the small intestine in the pelvis (white star). A stenosis of the small intestine was also detected via MRI with the thickening of the intestinal wall on the anal side of the oval structure (white arrowhead); however, there is no evidence of intestinal obstruction. There are no other abnormal findings on MRI.\n\nFigure 2. Transanal double-balloon enteroscopy (DBE) findings.\n\na) Transanal DBE revealed mild stenosis with an ulcer in the jejunum, approximately 250 cm proximal to the terminal ileum. b) The enteroscope that was inserted through the stenotic site of the jejunum revealed a yellowish-brown oval enterolith on the oral side. Attempts to remove and crush the enterolith using biopsy forceps and snare forceps were unsuccessful. Removal of the enterolith by oral DBE was considered impossible because its large size made it difficult to grasp it securely with snare forceps and to pass it through the pylorus.\n\nFigure 3. Intraoperative findings.\n\nA stenotic site with thickening of the intestinal wall was found in the jejunum, approximately 150 cm distal to the Treitz ligament (black arrowhead). The hard oval enterolith on the oral side is guided to the stenotic site of the jejunum but cannot be moved to the anal side of the stenotic site (white star).\n\nFigure 4. Findings of the resected specimen.\n\na) Inflammatory changes in the intestinal mucosa, scarring, and thickening of the intestinal wall were macroscopically observed at the stenotic site of the jejunum, but no neoplastic lesions were detected. b) Histologically, a partial erosion was observed at the stenotic site of the jejunum, accompanied by the thickening of the mucosa and muscularis mucosae and fibrosis of the submucosa. There were no histological findings indicating malignancy.\n\nFigure 5. Enterolith findings.\n\na) The enterolith, yellowish-brown in color, oval-shaped, and hard, with a maximum diameter of 4.5 cm. b) The cut surface is yellow and has a multilayered structure. c) Component analysis by infrared spectroscopy revealed that more than 98% of the enterolith is composed of ursodeoxycholic acid.\n\nDiscussion\n\nThis case report highlights two important clinical issues. First, this case showed that Crohn's disease patients may develop a primary enterolith due to mild intestinal stenosis. As mentioned earlier, there are two types of enteroliths, that is, primary enteroliths that develop in the intestinal tract and secondary enteroliths that originate outside the intestinal tract and move into the intestinal tract through the fistulas[1]. Most secondary enteroliths develop in the biliary system and the urinary system[1,6]. Our patient was diagnosed with primary enterolith because of the absence of medical history or imaging abnormality in the biliary or urinary systems. Intestinal stenosis can often lead to stasis, which may further cause primary enteroliths[1]. Thus, intestinal stenosis associated with Crohn's disease can be considered as a risk factor for primary enteroliths[1,2]. Mendes et al. reviewed 22 cases of enteroliths caused by Crohn's disease, wherein it was found that enteroliths associated with Crohn's disease developed on average 15.7 years after disease onset, and they were associated with severe intestinal stenosis formed after a long illness period[2]. However, in our case, the enterolith formed shortly after the diagnosis of Crohn's disease, about 6 years after onset, due to mild intestinal stenosis that was penetrable by DBE. Enteroliths that develop under mild intestinal stenosis can be expected to be excreted in stools and are unlikely to cause clinical problems. However, in our patient, the enterolith could not pass through the stenotic site of the intestine even if it was only a case of mild intestinal stenosis. Fortunately, our patient showed only minor symptoms, and the enterolith did not cause any clinical problems, but such enteroliths can cause intestinal obstruction, erosions, ulcers, bleeding, and perforation, and their early detection is important. In this case, the enterolith appears to have developed in less than 2 years, since a DBE performed 2 years prior did not indicate enteroliths or significant intestinal stenosis. Therefore, we propose to follow-up on patients with Crohn's disease every 1-2 years using CT or MRI, which have high detection rates for enteroliths[2,4,7].\n\nSecond, this case showed that the oral administration of UDCA can trigger the formation of enteroliths in Crohn's disease patients with jejunal stenosis. Primary enteroliths include bile acid-based enteroliths that are known to develop under the acidic environment of the proximal small intestine and calcium-based enteroliths that develop under the alkaline environment of the distal small intestine or large intestine[1,8]. Crohn's disease causes intestinal stenosis in all parts of the gastrointestinal tract. Among them, intestinal stenosis frequently occurs in the ileum[2,3]. In addition, Crohn's disease patients are determined to often have a reduced bile acid pool due to impaired bile acid absorption at the terminal ileum[9,10]. Therefore, most enteroliths associated with Crohn's disease are considered to be calcium-based enteroliths in the distal small intestine. Previous reports have shown that enteroliths associated with Crohn's disease are predominantly calcium-based enteroliths in the ileum[2,4,7]. However, in our patient, the enterolith was bile acid-based and developed in the jejunum; it was suspected to be due to jejunal stenosis and oral administration of UDCA (600 mg/day for the past 5 years). We believe that orally administered UDCA might have precipitated to form the enterolith either directly or after enterohepatic circulation in intestinal stasis under the acidic environment caused by the jejunal stenosis. This theory was supported by the results of component analysis, which showed that more than 98% of the enterolith was composed of UDCA.\n\nIn this case, we consider that the enterolith developed when intestinal stasis in an acidic environment due to mild jejunal stenosis was combined with oral administration of UDCA. Oral administration of UDCA was started 5 years ago, but the DBE 2 years ago revealed neither jejunal stenosis nor enteroliths. It is likely that mild jejunal stenosis occurred during the last 2 years and, combined with oral administration of UDCA, caused the enterolith formation.\n\nTo the best of our knowledge, there are no reports of enteroliths caused by the oral administration of UDCA in Crohn's disease patients. However, some case reports have described enteroliths that developed during the oral administration of UDCA in patients who underwent hepaticojejunostomy during living-donor liver transplantation or in those who underwent Billroth II anastomosis when gastrectomy was performed for gastric ulcer. In both cases, the authors consider that the reconstruction caused intestinal stasis under the acidic environment in the elevated jejunum, resulting in the development of enteroliths[11,12]. In another case, four patients had recurring bile duct stones that developed during oral administration of UDCA. One of the four patients underwent choledochoduodenostomy, while one underwent hepaticoduodenostomy. A component analysis of resected samples revealed UDCA as the main component of the stones, and bile duct stones did not develop after discontinuing UDCA[13]. It is possible that, in these patients, the reconstruction caused stasis under the acidic environment in the common bile duct or hepatic duct, resulting in UDCA precipitation leading to the formation of bile duct stones. The oral administration of UDCA can trigger the formation of enteroliths not only in jejunal stenosis patients due to Crohn's disease but also in pathological conditions that can cause stasis under an acidic environment. Oral UDCA should be administered cautiously in such patients.\n\nIn conclusion, this case report has demonstrated that in Crohn's disease patients, a primary enterolith may develop as a result of mild intestinal stenosis after a relatively short period of illness, and oral administration of UDCA could trigger the development of an enterolith in a Crohn's disease patient with jejunal stenosis. Primary enteroliths may develop even in asymptomatic Crohn's disease patients, and follow-up with CT or MRI is necessary for the early detection of enteroliths that may cause complications. In addition, the oral administration of UDCA should be considered with caution not only for Crohn's disease patients with proximal intestinal stenosis but also in cases where intestinal stasis may occur under an acidic environment.\n\nConflicts of Interest\n\nThere are no conflicts of interest.\n\nAuthor Contributions\n\nH.M. and S.H. contributed to the conception of the presented idea. T.Y., S.H., and S.E. performed the operation. H.M. wrote the manuscript with support from T.Y. All authors discussed the text content and contributed to the final manuscript. A.T. gave the final approval for the version to be published.\n\nApproval by Institutional Review Board (IRB)\n\nThis study did not require IRB approval because of case report without medical intervention summarizing not more than nine cases.\n\nInformed Consent\n\nThe patient provided written informed consent for publication of this case report.\n==== Refs\n1. Gurvits GE, Lan G. Enterolithiasis. World J Gastroenterol. 2014 Dec; 20(47): 17819-29.\n2. Ribeiro HKM, Nolan DJ. Enterolithiasis in Crohn's disease. Abdom Imaging. 2000 Oct; 25(5): 526-9.\n3. Perathoner A, Kogler P, Denecke C, et al. Enterolithiasis-associated ileus in Crohn's disease. World J Gastroenterol. 2012 Nov; 18(42): 6160-3.\n4. Tewari A, Weiden J, Johnson JO. Small-bowel obstruction associated with Crohn's enterolith. Emerg Radiol. 2013 Aug; 20(4): 341-4.\n5. Jones MW, Koper B, Weatherhead WF. Crohn's disease with enterolith treated laparoscopically. JSLS. 2005 Jul-Sep; 9(3): 339-41.\n6. Lassandro F, Romano S, Ragozzino A, et al. Role of helical CT in diagnosis of gallstone ileus and related conditions. Am J Roentgenol. 2005 Nov; 185(5): 1159-65.\n7. Wide JM, Loughran CF, Shoker BS. Crohn's disease, calculi and cancer: a report of two cases. Clin Radiol. 1996 Sep; 51(9): 651-3.\n8. Quazi MR, Mukhopadhyay M, Mallick NR, et al. Enterolith containing uric acid: an unusual cause of intestinal obstruction. Indian J Surg. 2011 Aug; 73(4): 295-7.\n9. Vantrappen G, Ghoos Y, Rutgeerts P, et al. Bile acid studies in uncomplicated Crohn's disease. Gut. 1977 Sep; 18(9): 730-5.\n10. Rutgeerts P, Ghoos Y, Vantrappen G. Bile acid studies in patients with Crohn's disease. Gut. 1979 Dec; 20(12): 1072-7.\n11. Mukai S, Onoe T, Tashiro H, et al. Small bowel obstruction due to an unconjugated ursodeoxycholic acid enterolith following living donor liver transplantation: report of a case. Hepatol Res. 2015 Jul; 45(7): 818-22.\n12. Inoguchi K, Yoshioka T, Gomi S, et al. A case of enterolith associated with perforation of jejunal diverticula in the afferent loop. Jpn J Gastroenterol Surg. 2003 Nov; 36(11): 1575-80 (in Japanese).\n13. Akiyama S, Imamura T, Tamura T, et al. Recurrent common bile duct stones composed of ursodeoxycholic acid: a report of four cases. Intern Med. Nov. 2014; 53(21): 2489-92.\n\n",
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"title": "Ursodeoxycholic Acid Triggers Primary Enterolith Growth in a Crohn's Disease Patient with Jejunal Stenosis.",
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"abstract": "Sub-acute neurotoxicity is a well-known complication to high-dose and intrathecal methotrexate (MTX) treatment of children with leukemia. Symptoms can be treated safely by dextromethorphan, a non-competitive antagonist to N-methyl-D-aspartic acid receptor (NMDAR). In a female with subacute MTX neurotoxicity, we observed an electroencephalographic (EEG) with extreme delta brush. Extreme delta brush is an EEG pattern previously described in patients with NMDAR autoimmune encephalitis. The observations suggest that the mechanism of this neurotoxicity may be mediated by the NMDAR. Furthermore, extreme EEG delta brush should suggest a diagnosis of MTX associated subacute neurotoxicity.",
"affiliations": "Department of Pediatrics, University Hospital Herlev, Denmark. Electronic address: samsoe@dadlnet.dk.;Department of Neurophysiology, Zealand University Hospital, Roskilde, Denmark.;Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Denmark and Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Denmark.;Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Denmark.",
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"keywords": "ALL; EEG; Extreme delta brush; Methotrexate; NMDA receptor; Neurotoxicity",
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"abstract": "Parathyroid glands consist primarily of chief cells. In some cases, the proportion of parathyroid oxyphil cells increases in patients with chronic kidney disease. We describe a case of secondary hyperparathyroidism (SHPT) in a patient treated with haemodialysis who initially received large doses of vitamin D and calcium (Ca) supplements, as well as high doses of cinacalcet hydrochloride (C-HCl), but without any effect on parathyroid hormone levels. Following a successful parathyroidectomy, histopathological examination revealed that two of the parathyroid glands consisted of 40% of oxyphil cells. Oxyphil cells have significantly more Ca-sensing receptors (CaSRs) than chief cells, suggesting that CaSRs are involved in the transdifferentiation of chief cells to oxyphil cells. C-HCl treatment leads to a significant increase in parathyroid oxyphil cell content. This case suggests that C-HCl may induce specific phenotypic alterations in hyperplastic parathyroid glands in patients with severe SHPT.",
"affiliations": "Department of Nephrology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.;Department of Endocrine Surgery, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.",
"authors": "Rottembourg|Jacques|J|;Menegaux|Fabrice|F|",
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"fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjClinical Kidney Journal2048-85052048-8513Oxford University Press 10.1093/ckj/sfy062sfy062CKD-MbdAre oxyphil cells responsible for the ineffectiveness of cinacalcet hydrochloride in haemodialysis patients? Rottembourg Jacques 1Menegaux Fabrice 21 Department of Nephrology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France2 Department of Endocrine Surgery, Groupe Hospitalier Pitié-Salpêtrière, Paris, FranceCorrespondence and offprint requests to: Jacques Rottembourg; E-mail: jacques.rottembourg@wanadoo.fr6 2019 23 7 2018 23 7 2018 12 3 433 436 24 2 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nParathyroid glands consist primarily of chief cells. In some cases, the proportion of parathyroid oxyphil cells increases in patients with chronic kidney disease. We describe a case of secondary hyperparathyroidism (SHPT) in a patient treated with haemodialysis who initially received large doses of vitamin D and calcium (Ca) supplements, as well as high doses of cinacalcet hydrochloride (C-HCl), but without any effect on parathyroid hormone levels. Following a successful parathyroidectomy, histopathological examination revealed that two of the parathyroid glands consisted of 40% of oxyphil cells. Oxyphil cells have significantly more Ca-sensing receptors (CaSRs) than chief cells, suggesting that CaSRs are involved in the transdifferentiation of chief cells to oxyphil cells. C-HCl treatment leads to a significant increase in parathyroid oxyphil cell content. This case suggests that C-HCl may induce specific phenotypic alterations in hyperplastic parathyroid glands in patients with severe SHPT.\n\ncalcimimeticcalcium-sensing receptorchronic kidney diseasehaemodialysissecondary hyperparathyroidism\n==== Body\nINTRODUCTION\nSecondary hyperparathyroidism (SHPT) is one of the most important complications in chronic kidney disease-mineral and bone disorder (CKD-MBD). Patients are considered to have severe SHPT when serum phosphate (P), serum calcium (Ca) and intact parathyroid hormone (PTH) levels can no longer be adequately controlled by medical management and when clinical symptoms are associated with a significantly increased risk of cardiovascular morbidity and mortality [1–3]. Cinacalcet hydrochloride (C-HCl) is a calcimimetic agent for SHPT treatment that increases the sensitivity of Ca-sensing receptors (CaSRs) to activation by extracellular Ca and thus suppresses PTH release while simultaneously controlling other mineral biochemical parameters [4, 5]. C-HCl has the potential to control biochemical parameters, even in cases of severe SHPT refractory to conventional treatments with Ca supplements, P binders and active vitamin D analogues. However, in some patients, C-HCl seems to be either only partially effective or ineffective [6, 7], and this case report discusses key points that could explain this, including the presence of severe SHPT and non-compliance to treatment.\n\nCASE REPORT\nA 12-year-old Moroccan female who presented a nephrotic syndrome was treated with corticosteroids, without any effect. A renal biopsy performed 8 years later showed typical focal glomerulosclerosis. Renal insufficiency developed rapidly, with the concomitant development of cardiac failure. Dialysis was required at the age of 22 years. Two years later the patient moved to France and was dialysed in our unit. Dialysis was carried out via an arteriovenous fistula and comprised 4-h sessions three times a week, with a dialysate Ca level consistently maintained at 1.5 mmol/L. When the patient first presented in our unit, our main concern was severe cardiac failure due to uraemic cardiomyopathy, with a left ventricular ejection fraction (LVEF) of 28%. After a few months, following treatment adjustment using diuretics, β-blockers and angiotensin-converting enzyme (ACE) inhibitors, as well as a decrease in body weight, the LVEF improved to 54%. The next important problem was SHPT. The main biological parameters and medications prescribed to the patient are shown in Table 1. Despite an increase in the dosage of C-HCl, the level of PTH did not decrease but paradoxically increased. To ensure that the prescribed doses were effectively taken by the patient, the medication was given at the dialysis unit on the days of dialysis at the end of the dialysis session. However, the level of PTH consistently increased.\n\nIn May 2007, an ultrasound scan of the parathyroid glands revealed normal upper right and upper left parathyroids of ~3 mm in diameter and two enlarged parathyroids, with the right lower gland measuring 8 × 6 × 5.2 mm and the left lower gland measuring 7 × 6 × 4.5 mm. Consequently, a parathyroidectomy was performed in July 2007, at a preoperative PTH level of 2162 pg/mL. The two upper parathyroid glands were slightly hyperplastic but were left intact and controlled with a clip to ensure that they could be easily identified, if necessary. The two lower glands, each ~10 mm in diameter, were resected, with each gland weighing 5.3 and 5.2 g, respectively. The histopathological examination revealed the presence of a benign parathyroid adenoma consisting of chief cells in each resected gland; however, 30–40% of each gland contained oxyphil cells, which was classified as an oxyphil adenoma (Figure 1), and a parathyroid carcinoma was excluded.\n\nTwo hours post-surgery, the serum Ca level dropped to 1.30 mmol/L and the PTH level to 8 pg/mL. The patient was prescribed 12 g/day of intravenous Ca and 6 µg/day of alfacalcidol. Four months later, with a treatment regimen of 4 g/day of Ca and 4 µg/day of alfacalcidol, the Ca level was 2.00 mmol/L, P level 1.20 mmol/L and PTH level 22 pg/mL. In the following year, the patient received a kidney transplant, was pregnant 3 years later and remained well 9 years later, with a creatinine level of 118 µmol/L, Ca level of 2.36 mmol/L and PTH level of 36 pg/ml on a treatment regimen of 2 g/day of Ca and 2 µg/day of alfacalcidol.\n\nFIGURE 1 (A) The chief cells have an amphophilic, vacuolated cytoplasm. (B) The oxyphil cells are composed of large cells with a brightly stained eosinophilic granular cytoplasm. The bar at the bottom represents 1 mm (magnitude ×100).\n\nTable 1. Main biological parameters and medications prescribed to the patient after her arrival in the dialysis unit\n\nParameters\t15 June 2005\t7 December 2005\t07 March 2006\t10 June 2006\t15 September 2006\t6 December 2006\t24 May 2007\tPost- surgery\t6 December 2007\tMarch 2018\t\nBody weight (kg)\t48.5\t43\t42\t43\t42.5\t42\t42\t42\t44\t56\t\nCalcium level (mmol/L)\t2.19\t2.21\t2.10\t2.25\t2.32\t2.28\t2.32\t1.30\t2.00\t2.36\t\nPhosphate level (mmol/L)\t1.56\t2.15\t2.19\t1.80\t1.78\t1.64\t1.62\t1.52\t1.26\t1.06\t\nAlkaline phosphatase (IU/L)\t62\t89\t79\t110\t120\t130\t165\t110\t57\t46\t\nPTH (pg/mL)\t776\t808\t1065\t1347\t1207\t1475\t1869\t8\t15\t36\t\n\nKt/V\t1.78\t1.88\t1.69\t1.73\t1.79\t1.67\t1.72\t–\t1.76\t–\t\nAlfacalcidol (µg/day)\t1\t1\t1\t1\t1\t1\t1\t6\t4\t2\t\nCalcium carbonate (g/day)\t1.5\t1.5\t1.5\t1.5\t1.5\t1.5\t1.5\t12 (IV)\t4.5\t2\t\nSevelamer (mg/day)\t–\t3200\t4800\t7200\t7200\t7200\t7200\t–\t2400\t–\t\nCinacalcet hydrochloride (mg/day)\t–\t–\t30\t60\t90\t120\t150\t–\t–\t–\t\nIV, intravenous.\n\nDISCUSSION\nThis case report raises many important points of discussion: the presence of SHPT, the patient’s compliance with numerous medications, the presence of an oxyphil cell parathyroid adenoma and the role of C-HCl in the histologic type of parathyroid adenoma.\n\nSHPT is a common, serious and progressive complication of CKD-MBD. It is mainly characterized by high serum PTH levels, parathyroid gland hyperplasia and disturbance in mineral metabolism characterized mainly by hypocalcaemia and hyperphosphataemia. Initial treatment of SHPT in haemodialysis (HD) patients usually includes Ca salts, intestinal P binders and vitamin D derivatives. The oral calcimimetic C-HCl is often used later in the course of the disease in patients who fail to respond adequately to the initial treatments. C-HCl has been shown to be effective in reducing circulating PTH levels in HD patients with SHPT in several clinical trials [8–14]. Overall, treatment with C-HCl was associated with significant reductions in the total volume of parathyroid glands, with a corresponding decrease in PTH levels [6]. In another study, Meola et al. [15] found that C-HCl, in combination with conventional treatments, led to an improvement in biochemical and clinical parameters of SHPT and reduced glandular volume in patients with severe SHPT.\n\nThe median number of medications prescribed to HD patients is significant at ~19 pills/day [16]. Prescription of P binders makes up around half of the medications prescribed per day. However, the frequency distribution of adherence to P binders is ~40% [16]. Some patients appear to be insensitive to or exhibit hyporesponsiveness to C-HCl treatment. One explanation could be simply a lack of compliance with treatment and/or inadequate treatment education provided to these patients. In a recent European retrospective observational study [17], it was observed that 23% of the incident patients had their C-HCl treatment discontinued after 1 year. One of the causes of hyporesponsiveness could be the number, size and nodular hyperplastic characteristic of the parathyroid glands, which are known to predict the response to C-HCl. Another possibility of failed treatment with C-HCl could be the development of an oxyphil cell parathyroid adenoma.\n\nOxyphil cell parathyroid adenomas are rare. In 1967 it was postulated by Christie [18] that the development of oxyphil cells may be a defence mechanism in which oxyphil cells may produce a hormone necessary for maintaining ‘a normal biochemical milieu in adverse circumstances in particular in CKD where gross electrolyte imbalance is likely to occur’. Oxyphil cell content is markedly increased in CKD; in general, the proportion of oxyphil cells increases in parallel with the total weight of the parathyroid glands in uraemic patients, suggesting that this cell type is sensitive to stimulation [19]. Recent studies have found an association between treatment of SHPT with calcitriol and/or C-HCl and an even higher oxyphil cell content of the parathyroid glands than in the absence of such treatment [20]. A recent study by Ritter et al. [21] shed new light on the role and function of oxyphil cells. The study analysed patients who underwent parathyroidectomy for SHPT after treatment with paricalcitol and/or C-HCl. The main findings were:\nThe parathyroid tissue in uraemic patients had, on average, five times higher oxyphil cell content than normal parathyroid tissue.\n\nConventional pharmacological treatment of SHPT could have affected the cell population of the parathyroid glands in uraemic patients.\n\nAmong treated patients, the parathyroid tissue in the C-HCl group showed a significantly higher content of oxyphil cells (26.7 ± 14.2%) compared with the paricalcitol group (6.9 ± 5.1%); however, the cubic volume of the parathyroid glands in both groups was similar. In our case, the oxyphil cell content was ~40%.\n\n\n\nThese data indicate that the two conventional treatments for SHPT, i.e. C-HCl and paricalcitol, may have disparate effects on parathyroid tissue composition. However, one of the main questions is the function of parathyroid oxyphil cells in SHPT and the role of C-HCl in the development of these cells. It seems that the oxyphil cells express more CaSRs compared with chief cells, and Ritter et al. [19] postulated that CaSRs and calcimimetics may play a role in the transdifferentiation of chief cells to oxyphil cells. In another paper, Ritter et al. [22] showed that oxyphil cells overexpress parathyroid tissue genes encoding, for example, PTH, calcium-sensing receptor, glial cells missing homolog 2 and parathyroid hormone–related protein.\n\nMoreover, it was reported by the same group that human parathyroid oxyphil cells consistently expressed high levels of 1α-OHase protein compared with parathyroid chief cells [22]. C-HCl directly increased parathyroid 1α-OHase expression in cultured parathyroid cells. The importance of Ca in the regulation of 1α-OHase is also clinically important because calcimimetics are commonly used to treat patients with SHPT. The oxyphil:chief cell ratio was increased by C-HCl treatment [20]. The conversion of chief cells to oxyphil cells may be a compensatory mechanism by which increased local production of calcitriol could act to decrease PTH levels. Because C-HCl directly activates the response of CaSRs to extracellular Ca and calcitriol can activate CaSRs indirectly via its calcaemic effect, these actions may play a role in the transdifferentiation of chief cells to oxyphil cells. The complex balance between chief and oxyphil cells could, at least partly, be determined by an autocrine/paracrine regulation of the activity of chief cells by oxyphil cells [24]. C-HCl could also induce apoptosis and necrosis of parathyroid glands, as demonstrated by Sumida et al. [23], with a significant increase in oxyphil cell area and haemosiderosis score. These results suggest that C-HCl could induce specific qualitative alterations in hyperplastic parathyroid glands in patients with severe SHPT. Lomonte et al. [20] suggested that the change in the oxyphil:chief cell ratio was probably due to a significant decrease in the proportion of chief cells accelerated by C-HCl through an apoptotic mechanism in uraemic rats [24, 25]. It is possible that C-HCl has a qualitative influence on parathyroid cells and induces pathological changes.\n\nClearly further studies are required to determine the role of C-HCl in the chief-to-oxyphil cell transdifferentiation and the consequent influence on parathyroid gland function following treatment of SHPT in CKD patients as well as the possible role of oxyphil cells in attenuating or inactivating the role of C-HCl in the control of SHPT.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n==== Refs\nREFERENCES\n1 \nChertow GM , Plone M , Dillon MA \net al\nHyperparathyroidism and dialysis vintage . Clin Nephrol 2000 ; 54 : 295 –300 11076105 \n2 \nNational Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease . Am J Kidney Dis 2003 ; 42(4 Suppl 3) : S1 –S201 14520607 \n3 \nKetteler M , Block GA , Evenepoel P \net al\nExecutive summary of the 2017 KDIGO chronic kidney disease-mineral and bone disorder (CKD-MBD) guideline update: what’s changed and why it matters . Kidney Int 2017 ; 92 : 26 –36 28646995 \n4 \nUrena P , Frazao JM. \nCalcimimetic agents: review and perspectives . Kidney Int 2003 ; 63(Suppl 85) : S91 –S96 \n5 \nUrena P , Fouque D , Brunet P \net al\nCinacalcet treatment for secondary hyperparathyroidism in dialysis patients in real-world clinical practice – the ECHO observational study: French experience . Nephrol Ther 2012 ; 8 : 527 –533 23018042 \n6 \nKomaba H , Nakanishi S , Fujimori A \net al\nCinacalcet effectively reduces parathyroid hormone secretion and gland volume regardless of pretreatment gland size in patients with secondary hyperparathyroidism . Clin J Am Soc Nephrol 2010 ; 5 : 2305 –2314 20798251 \n7 \nForni Ogna V , Pruijm M , Zweiacker C \net al\nClinical benefits of an adherence monitoring program in the management of secondary hyperparathyroidism with cinacalcet: results of a prospective randomized controlled study . Bio Med Res Int 2013 ; 2013 : 104892 \n8 \nChertow GM , Block GA , Correa-Rotter R \net al\nEffect of cinacalcet on cardiovascular disease in patients undergoing dialysis . N Engl J Med 2012 ; 367 : 2482 –2494 23121374 \n9 \nWetmore JB , Gurevich K , Sprague S \net al\nA randomized trial of cinacalcet versus vitamin D analogs as monotherapy in secondary hyperparathyroidism (PARADIGM) . Clin J Am Soc Nephrol 2015 ; 10 : 1031 –1040 25904755 \n10 \nFishbane S , Shapiro WB , Corry DB \net al\nCinacalcet-HCl and concurrent low-dose vitamin D improves treatment of secondary hyperparathyroidism in dialysis patients compared with vitamin D alone: the ACHIEVE study results . Clin J Am Soc Nephrol 2008 ; 3 : 1718 –1725 18945995 \n11 \nKetteler M , Martin KJ , Wolf M \net al\nParacalcitol versus cinacalcet plus low-dose vitamin D therapy for the treatment of secondary hyperparathyroidism in patients receiving haemodialysis: results of the IMPACT SHPT study . Nephrol Dial Transplant 2012 ; 27 : 3270 –3278 22387567 \n12 \nMessa P , Macario F , Yaqoob M \net al\nThe OPTIMA study: assessing a new cinacalcet (Sensipar/Mimpara) treatment algorithm for secondary hyperparathyroidism . Clin J Am Soc Nephrol 2008 ; 3 : 36 –45 18178780 \n13 \nRaggi P , Chertow GM , Torres PU \net al\nThe ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis . Nephrol Dial Transplant 2011 ; 26 : 1327 –1339 21148030 \n14 \nUrena-Torres P , Bridges I , Christiano C \net al\nEfficacy of cinacalcet with low-dose vitamin D in incident haemodialysis subjects with secondary hyperparathyroidism . Nephrol Dial Transplant 2013 ; 28 : 1241 –1254 23328710 \n15 \nMeola M , Petrucci I , Barsotti G. \nLong-term treatment with Cinacalcet and conventional therapy reduces parathyroid hyperplasia in severe secondary hyperparathyroidism . Nephrol Dial Transplant 2009 ; 24 : 982 –989 19181759 \n16 \nChiu YW , Teitelbaum I , Misra M \net al\nPill burden, adherence, hyperphosphatemia and quality of life in maintenance dialysis patients . Clin J Am Soc Nephrol 2009 ; 4 : 1089 –1096 19423571 \n17 \nde Francisco ALM , Gillespie IA , Gioni I \net al\nAnti-parathyroid treatment effectiveness and persistence in incident haemodialysis patients with secondary hyperparathyroidism . Nefrologia 2016 ; 36 : 164 –175 26654696 \n18 \nChristie AC. \nThe parathyroid oxyphil cells . J Clin Pathol 1967 ; 20 : 591 –602 4880406 \n19 \nRitter CS , Haughey BH , Miller B \net al\nDifferential gene expression by oxyphil cells of human parathyroid glands . J Clin Endocrinol Metab 2012 ; 97 : E1499 –E1505 22585091 \n20 \nLomonte C , Vernaglione L , Chimienti D \net al\nDoes vitamin D receptor and calcium receptor activation therapy play a role in the histopathologic alterations of the parathyroid glands in refractory uremic hyperparthyroidism . Clin J Am Soc Nephrol 2008 ; 3 : 794 –799 18322048 \n21 \nRitter C , Miller B , Coyne DW \net al\nParacalcitol and cinacalcet have disparate actions on parathyroid oxyphil cell content in patients with chronic kidney disease . Kidney Int 2017 ; 92 : 1217 –1222 28750928 \n22 \nRitter CS , Haughey BH , Armbrecht HJ \net al\nDistribution and regulation of the 25-hydroxyvitamin D3 1α-hydroxylase in human parathyroid glands . J Steroid Biochem Mol Biol 2012 ; 130 : 73 –80 22326730 \n23 \nSumida K , Nakamura M , Ubara Y \net al\nHistopathological alterations of the parathyroid glands in haemodialysis patients with secondary hyperparathyroidism refractory to cinacalcet hydrochloride . J Clin Pathol 2011 ; 64 : 756 –760 21565858 \n24 \nMizobuchi M , Ogata H , Hatamura I \net al\nActivation of calcium-sensing receptor accelerates apoptosis in hyperparathyroid cells . Biochem Biophys Res Commun 2007 ; 362 : 11 –16 17706605 \n25 \nWada M , Nagano N. \nControl of parathyroid cell growth by calcimimetics . Nephrol Dial Transplant 2003 ; 18(Suppl 3) : S13 –S17\n\n",
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"journal": "Clinical kidney journal",
"keywords": "calcimimetic; calcium-sensing receptor; chronic kidney disease; haemodialysis; secondary hyperparathyroidism",
"medline_ta": "Clin Kidney J",
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"pages": "433-436",
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"pubdate": "2019-06",
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"title": "Are oxyphil cells responsible for the ineffectiveness of cinacalcet hydrochloride in haemodialysis patients?",
"title_normalized": "are oxyphil cells responsible for the ineffectiveness of cinacalcet hydrochloride in haemodialysis patients"
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"abstract": "OBJECTIVE\nAs the number of intravitreal injections (IVI) increases annually, this study aimed to assess the anatomical and functional outcomes following rhegmatogenous retinal detachment (RRD) surgery for IVI-associated RRD (IVARD).\n\n\nMETHODS\nAll non-vitrectomized eyes developing IVARD since 2007 in two European vitreoretinal centers (Department of Ophthalmology, LMU Munich, Germany, and Eye Clinic Luigi Sacco, University of Milan, Milan, Italy) were included. Main outcomes were primary and secondary retinal attachment rate after surgery, rate of proliferative vitreoretinopathy (PVR), and final functional result. Ten years of incidence rates per injection were calculated for one center.\n\n\nRESULTS\nFifty-two eyes of 52 patients comprised the study. Primary anatomic success rate was 83% (n = 43) and secondary 96% (n = 50). PVR was observed in all uveitic eyes (n = 3), in eyes with postoperative cystoid macular edema (n = 2), and in 8 of 9 eyes that received the dexamethasone implant (DEX). Age, number of prior injections, duration of symptoms, or time between last IVI and RRD did not show any statistically significant differences with regard to presence of PVR or not. Mean BCVA improved in 28 cases, remained stable in 16 cases, and worsened in 8 cases. The RRD incidence rate was statistically significant higher for DEX and ocriplasmin compared with that for anti-VEGF agents.\n\n\nCONCLUSIONS\nThe anatomical result after one surgical intervention seems acceptable, but the final visual outcome remains rather poor, because of the underlying macular disease. In our population, injection with DEX is associated with higher IVARD rate, presence and development of PVR, and recurrent RRD in comparison with anti-VEGF agents.",
"affiliations": "Department of Ophthalmology, University of Ulm, Prittwitzstr 43, D-89075, Ulm, Germany.;Department of Ophthalmology, Ludwig-Maximilians-University Munich, Munich, Germany.;Eye Clinic, Department of Clinical and Biomedical Science Luigi Sacco, Sacco Hospital, University of Milan, Milan, Italy.;Eye Clinic, Department of Clinical and Biomedical Science Luigi Sacco, Sacco Hospital, University of Milan, Milan, Italy.;Department of Ophthalmology, Ludwig-Maximilians-University Munich, Munich, Germany.;Department of Ophthalmology, Ludwig-Maximilians-University Munich, Munich, Germany.;Department of Statistics, University of Ulm, Ulm, Germany.;Department of Ophthalmology, University of Ulm, Prittwitzstr 43, D-89075, Ulm, Germany. wolfarmin@yahoo.com.",
"authors": "Vounotrypidis|Efstathios|E|;Freissinger|Sigrid|S|;Cereda|Matteo|M|;Monteduro|Davide|D|;Kortuem|Karsten|K|;Priglinger|Siegfried|S|;Mayer|Benjamin|B|;Wolf|Armin|A|",
"chemical_list": null,
"country": "Germany",
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"doi": "10.1007/s00417-021-05261-6",
"fulltext": "\n==== Front\nGraefes Arch Clin Exp Ophthalmol\nGraefes Arch Clin Exp Ophthalmol\nGraefe's Archive for Clinical and Experimental Ophthalmology\n0721-832X\n1435-702X\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n34216254\n5261\n10.1007/s00417-021-05261-6\nRetinal Disorders\nIntravitreal injection associated rhegmatogenous retinal detachment: outcomes of a European analysis\nVounotrypidis Efstathios 1\nFreissinger Sigrid 2\nCereda Matteo 3\nMonteduro Davide 3\nKortuem Karsten 2\nPriglinger Siegfried 2\nMayer Benjamin 4\nWolf Armin wolfarmin@yahoo.com\n\n1\n1 grid.6582.9 0000 0004 1936 9748 Department of Ophthalmology, University of Ulm, Prittwitzstr 43, D-89075 Ulm, Germany\n2 grid.5252.0 0000 0004 1936 973X Department of Ophthalmology, Ludwig-Maximilians-University Munich, Munich, Germany\n3 grid.4708.b 0000 0004 1757 2822 Eye Clinic, Department of Clinical and Biomedical Science Luigi Sacco, Sacco Hospital, University of Milan, Milan, Italy\n4 grid.6582.9 0000 0004 1936 9748 Department of Statistics, University of Ulm, Ulm, Germany\n3 7 2021\n3 7 2021\n2021\n259 12 36553664\n12 10 2020\n19 4 2021\n28 5 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/.\nPurpose\n\nAs the number of intravitreal injections (IVI) increases annually, this study aimed to assess the anatomical and functional outcomes following rhegmatogenous retinal detachment (RRD) surgery for IVI-associated RRD (IVARD).\n\nMethods\n\nAll non-vitrectomized eyes developing IVARD since 2007 in two European vitreoretinal centers (Department of Ophthalmology, LMU Munich, Germany, and Eye Clinic Luigi Sacco, University of Milan, Milan, Italy) were included. Main outcomes were primary and secondary retinal attachment rate after surgery, rate of proliferative vitreoretinopathy (PVR), and final functional result. Ten years of incidence rates per injection were calculated for one center.\n\nResults\n\nFifty-two eyes of 52 patients comprised the study. Primary anatomic success rate was 83% (n = 43) and secondary 96% (n = 50). PVR was observed in all uveitic eyes (n = 3), in eyes with postoperative cystoid macular edema (n = 2), and in 8 of 9 eyes that received the dexamethasone implant (DEX). Age, number of prior injections, duration of symptoms, or time between last IVI and RRD did not show any statistically significant differences with regard to presence of PVR or not. Mean BCVA improved in 28 cases, remained stable in 16 cases, and worsened in 8 cases. The RRD incidence rate was statistically significant higher for DEX and ocriplasmin compared with that for anti-VEGF agents.\n\nConclusion\n\nThe anatomical result after one surgical intervention seems acceptable, but the final visual outcome remains rather poor, because of the underlying macular disease. In our population, injection with DEX is associated with higher IVARD rate, presence and development of PVR, and recurrent RRD in comparison with anti-VEGF agents.\n\nKeywords\n\nRhegmatogenous retinal detachment\nIntravitreal injection\nProliferative vitreoretinopathy\nVitrectomy\nVisual outcome\nUniversitätsklinikum Ulm (8941)Open Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2021\n==== Body\npmcIntroduction\n\nIntravitreal injections (IVI) of anti-vascular endothelium growth factors (anti-VEGF), steroid implants (Ozurdex® or Iluvien®), or Ocriplasmin (Jetrea®) have revolutionized the treatment of neovascular age-related degeneration (nAMD) [1–3], retinal vein occlusion (RVO) [4–6], diabetic macular edema (DME) [7–9], uveitis [10], postoperative cystoid macular edema (PCME) [11], vitreomacular traction (VMTS), or full thickness macular hole [12–15]. Whereas fewer than 2000 IVIs were administered annually in the USA in 2000, their number had soared to more than 3.0 million injections in 2016 [16]. Taking into account the increasing prevalence of AMD and diabetic retinopathy, the number of IVIs is expected to rise further globally [17, 18].\n\nAmong the various complications of IVIs [19–21], endophthalmitis and retinal detachment are the most severe and vision threatening, with rates of endophthalmitis ranging from approximately 1 in 2000–3000 injections [22, 23] and rates of rhegmatogenous retinal detachment (RRD) after IVI appearing even lower [1, 20, 24]. However, outcome and complications of RRD repair in these eyes have not yet been reported.\n\nThis retrospective explorative study has been conducted to evaluate the anatomical and visual outcome after surgical repair of IVI-associated RRD (IVARD). To our knowledge, this is the first multicenter case series including steroids and ocriplasmin that tried to figure out any effect of various factors, such as the indication for IVI, number of injections, presence of proliferative vitreoretinopathy (PVR), and duration of symptoms on the final outcome. Furthermore, RRD incidence rates over a period of ten years have been calculated for one center.\n\nMethods\n\nThis retrospective case series enrolled patients from two tertiary vitreoretinal centers (Department of Ophthalmology, LMU Munich, Germany and Eye Clinic, Department of Clinical and Biomedical Science Luigi Sacco, Sacco Hospital, University of Milan, Italy). The study was approved by the institutional review boards of each institution and adhered to the tenets of the Declaration of Helsinki.\n\nA detailed search in the electronic database of each center was performed for identification of patients with a primary diagnosis of RRD that underwent IVI in the same eye in the same center. Exported data included age, gender, localization, indication for IVI, IVI agent, number of prior injections, time period between IVI and RRD, lens status, macular state, presence of proliferative vitreoretinopathy (PVR) at presentation, date and type of intervention, type of injected tamponade, and visual acuity prior to and after surgery. All patients underwent surgery for RRD repair between 15 May 2007 and 06 March 2019, and IVI was performed between 15 December 2006 and 14 October 2018. “Primary PVR” was defined as the presence of clinical signs of PVR such as starfolds before the first surgery; “secondary PVR” was considered a clinical PVR after the first surgical intervention. Overall, PVR was defined as either primary or secondary PVR during the follow-up period.\n\nInclusion and exclusion criteria\n\nNon-vitrectomized phakic or pseudophakic eyes that developed IVARD for any given diagnosis were included. No time limit was set between the time point of last IVI and RRD. A subgroup analysis of eyes having an RRD within 90 days after the last IVI was additionally performed similarly to other large studies.\n\nInjection\n\nAll IVIs were performed in a standard tertiary clinic setting, in a designated procedure room. Eyes were preoperatively prepared with a topical anesthetic and povidone iodine. Injection was performed with a standard 30- or 31-gauge needle in case of anti-VEGF agents (0.05 ml of Bevacizumab, Ranibizumab or Aflibercept), Ocriplasmin (0.1 ml) or recombinant tissue plasminogen activator (rt-PA; 50 µg/0.05 ml) combined with 0.5 ml of SF6 gas. The standard preloaded system was used with a 22-gauge needle for injections of the 0.7 mg slow releasing dexamethasone implant (DEX) and with a 25-gauge needle for the 0.19 mg fluocinolone acetonide implant (Ilu). Injections were performed 3.5 to 4.0 mm from the limbus. Physicians individually determined the use of subconjunctival lidocaine, the use of a bladed lid speculum, a conjunctival displacement before injection, caliper use, and the injection site.\n\nSurgical intervention of RRD\n\nAll eyes that developed IVARD were treated as soon as possible, based on the anatomic features of the RRD and the evaluation of a consultant ophthalmologist. The surgical approach included either scleral buckling with cryopexy or standard small-gauge pars plana vitrectomy (ppV) with laser retinopexy or a combination of both. Silicone oil or gas (C2F6, 15%) was used as primary tamponade. All cases of a recurrence of an RRD were treated with ppV.\n\nOutcomes\n\nPrimary outcome was the primary and secondary retinal attachment rates. Secondary outcomes included the presence and development of primary, secondary, and overall PVR and any association with indication for IVI, IVI agent, number of injections, duration of symptoms, time between IVI and RRD, and macular state. BCVA was chosen not to be the primary outcome as all the patients had functionally affected macula, and thus visual outcome after RRD repair would not be of value for the assessment of surgical results. Snellen visual acuity was converted to the logarithm of the minimum angle of resolution (logMAR) equivalent for statistical tests. Vision levels of counting fingers and hand movements were assigned visual acuity values of 2.0 and 3.0 logMAR according to previous literature [25]. Cases with pre- or postoperative BCVA of light perception were excluded from the visual outcome analysis and were reported separately.\n\nFurthermore, the incidence rate of RRD per number of injections over a 10-year period was calculated for the Department of Ophthalmology, LMU Munich, Germany.\n\nStatistical analysis\n\nSPSS statistics software package version 25 for Windows (IBM, Armonk, NY, USA) was used for statistical analysis. Collected data were tested for normal distribution by the Kolmogorov–Smirnov test. Non-parametrical tests were performed in the absence of normal distributions and t-tests in cases displaying normal distribution. Chi-square or exact Fisher’s test was applied for the evaluation of any associations between categorical variables. Analysis of variance (Kruskal–Wallis ANOVA with Dunn-Bonferroni adjustment) was performed for evaluating the effect of variables with more than three levels on the continuous variables or the final visual outcome. Overall, we followed, due to the retrospective nature of the data and the low number of PVR cases, a purely explorative analysis approach and considered a p ≤ 0.05 statistically significant.\n\nResults\n\nDemographics\n\nA total of 52 eyes (29 right, 23 left) of 52 patients (22 females, 30 males) with a mean age of 66.2 ± 14.5 years presented with IVARD in the studied period of time. The mean duration of RRD symptoms was noted as 6.5 ± 7.8 (range: 1–30) days. At clinical presentation at the time of RRD, the majority of the patients had undergone more than three injections (mean, 4.3 ± 5.0; range, 1–26), with a mean duration between the last IVI and RRD of 11.2 ± 14.3 months (range: 0–60). Moderate to high myopia (> 6 diopters) was observed in 13 patients. The mean follow-up period was 10.7 ± 11.2 months (range: 1–35) after the surgery for IVARD. Detailed demographics are provided as online supplemental material.\n\nThe most common diagnosis for IVI was AMD (n = 13), followed by RVO (n = 12) and myopia (n = 11) with bevacizumab (n = 19), ranibizumab (n = 18), and DEX (n = 9) being the most frequently injected agents in our study population. More patients presented with macular affected RRD (n = 33) and reported symptoms over a mean of 8.7 ± 9.0 days (range: 1–30). Patients with attached macula (n = 19) presented after a shorter duration of symptoms (mean, 2.6 ± 1.5 days; range, 1–6).\n\nSurgery, anatomic success rates, and lens state\n\nFor primary surgery, 45 eyes underwent ppV, and 1 eye was treated with ppV combined with buckle surgery. A combined phacovitrectomy was performed in 17 patients (nine cases with attached macula), representing 74% of all phakic eyes (n = 23). Primary silicone oil fill (as an indicator for the presence of PVR before surgery) was chosen in 14 of 46 eyes undergoing vitrectomy. Buckle surgery alone was performed in 6 phakic cases, one being combined with pneumatic retinopexy. Overall, primary reattachment was achieved in 4 of 6 eyes with non-combined buckling surgery, in 25 of 32 eyes that received gas fill and in 14 of 14 eyes that received primary silicone oil fill, corresponding to a primary anatomic success rate (attachment rate) of 83% (43/52 eyes). Two eyes that have had previous buckle surgery and seven eyes with a prior vitrectomy with gas underwent a second surgery (100% ppV) within the first 3 months after the initial intervention. Silicone oil tamponade was necessary in 1 eye with prior buckling and in 5 eyes with previous vitrectomy; gas tamponade after primary failure was chosen in 1 eye with prior buckling and in 2 eyes with prior vitrectomy. The secondary attachment rate was 96% (50/52 eyes). Two eyes developed a third detachment at 4 and 9 months after the primary surgery, respectively. Both eyes had presented with RD plus macular involvement and signs of PVR at the time of first surgery.\n\nOverall, only four patients of our cohort that underwent buckling surgery remained phakic at the last follow up examination. All other patients underwent concomitant cataract surgery during the first or second vitrectomy.\n\nFrequency of PVR and association with other factors\n\nPrimary PVR occurred in 10 out of 52 cases (19%), all with macular involving RRD. Secondary PVR was observed in 5 eyes at the time of re-detachment (10% of the cases); overall, PVR was present in 15 of 52 cases (29%) during clinical course of RD repair. By observing such low rates of PVR in our cohort, a multivariable analysis including several factors simultaneously was not possible.\n\nInterestingly, primary PVR was observed in all 3 uveitic patients, whereas no myopic eyes showed any primary PVR. Overall, the indication for IVI showed a statistically significant association with presence of primary PVR (p = 0.014, Chi-square test). Secondary PVR occurred in 5 cases, in 3 eyes with retinal vein occlusion, 1 with neovascular AMD, and 1 with PCME.\n\nSurprisingly, PVR, primary or secondary, was observed in eight of the nine eyes that received DEX (4 RVO, 2 Uveitis, 2 PCME), primary PVR in 5 eyes and secondary PVR in 3 eyes. Further eyes that developed primary or secondary PVR had previously received ranibizumab (3 eyes), bevacizumab (3 eyes), or aflibercept (1 eye). Frequency of overall PVR with regard to injected agent is shown in Fig. 1. Overall, all eyes that received IVI for uveitis (n = 3) or PCME (n = 2), five of 12 eyes with RVO, four of 13 with nAMD, and 1 with DME developed PVR during any time of clinical course of retinal detachment repair. Fig. 1 Number of eyes that developed proliferative vitreoretinopathy during the observation period with regard to the injected medication. The numbers in the bars (white boxes) correspond to their percentage. Dexa implant, Ozurdex®; Rani, Ranibizumab®; Beva, Bevacizumab®; Rani + Beva, combination of Ranibizumab® and Bevacizumab®; Rani + Afli, combination of Ranibizumab® and Aflibercept®; rtPA, recombinant tissue plasminogen activator; Ocri, Ocriplasmin®\n\nIVARD involving the macula showed a primary PVR in 10 of 23 cases, whereas no eyes without macular involvement showed any primary PVR indicating the higher association between presence of primary PVR and macular involvement (p = 0.009, Fisher’s exact test).\n\nAge, number of prior injections, duration of symptoms and time between IVI and RRD did not differ statistically significantly between eyes that developed or did not develop PVR (p > 0.05, Mann–Whitney U in all cases). With the exception of one eye with nAMD, all other eyes with primary or secondary PVR were treated with vitrectomy and silicone oil.\n\nVisual acuity\n\nBest corrected visual acuity (BCVA) was equal or better than hand movement throughout the study period in 46 of 52 eyes, whereas in six cases, a visual acuity of light perception was obtained either preoperatively or postoperatively. In particular, four cases presented with a preoperative visual acuity of light perception. In three of them, BCVA improved after surgery, and in one remained unchanged. In two other cases, BCVA worsened after the surgery to light perception. Interestingly, both eyes that developed a worse BCVA after surgery were uveitic eyes that presented with IVARD, primary PVR, and macular involvement and had previously received DEX.\n\nIn the rest of the 46 eyes, mean BCVA changed from 1.19 ± 0.88 (median, 1.00; range, 0.10–3.00) to 0.89 ± 0.76 (median, 0.80; range, 0–3.00) logMAR after surgery (p < 0.0001, Wilcoxon). Four eyes that received buckling surgery only and remained phakic showed an improvement of mean BCVA from 0.43 ± 0.43 (median, 0.30; range, 0.10–1.00) to 0.23 ± 0.19 logMAR (median, 0.15; range, 0.10–0.50). In 42 eyes that underwent vitrectomy, mean BCVA improved from 1.26 ± 0.88 (median, 1.20; range, 0.20–3.00) to 0.95 ± 0.76 (median, 0.85; range, 0.00–3.00). Table 1 shows preoperative and postoperative BCVA of the 42 eyes that underwent vitrectomy with regard to preoperative macular and lens state. Figure 2 shows the individual trajectories of preoperative and postoperative BCVA of all patients that were included in the visual outcome analysis (n = 46). Overall, BCVA worsened in 8 eyes, improved in 28 eyes, and did not change more than 0.1 logMAR in 16 eyes. Table 1 Mean, standard deviation (SD), median, and range of preoperative and postoperative best corrected visual acuity (in logMAR) with regard to preoperative lens and macular state of the 42 eyes that underwent pars plana vitrectomy and were included in the visual acuity outcome analysis. BCVA best corrected visual acuity, On macula preoperatively attached, Off macula preoperatively detached\n\nLens state\tPhakic\tPseudophakic\t\nMacular state\tOn (n = 10)\tOff (n = 9)\tOn (n = 6)\tOff (n = 17)\t\nBCVA\n\npreoperative\n\n(logMAR)\n\n\tMean ± SD\t0.74 ± 0.85\t1.63 ± 0.86\t0.65 ± 0.28\t1.58 ± 0.82\t\nMedian (Range)\t0.4 (0.20–3.00)\t1.30\n\n(0.70–3.00)\n\n\t0.70\n\n(0.2–1.00)\n\n\t1.30\n\n(0.30–3.00)\n\n\t\nBCVA postoperative\n\n(logMAR)\n\n\tMean ± SD\t0.32 ± 0.32\t1.20 ± 0.75\t0.50 ± 0.36\t1.34 ± 0.76\t\nMedian (Range)\t0.30\n\n(0.00–1.00)\n\n\t1.00\n\n(0.50–3.00)\n\n\t0.45\n\n(0.10–1.00)\n\n\t1.30\n\n(0.30–3.00)\n\n\t\n\nFig. 2 Individual trajectories of BCVA (in LogMAR) pre- and postoperatively of all patients included in the final visual outcome analysis (n = 46). The black line corresponds to the mean of all values\n\nFinal postoperative BCVA did not show any significant differences with regard to the indication for IVI, injected medication, and performed surgery (p = 0.165, p = 0.105, and p = 0.133, respectively; Kruskal–Wallis). On the other hand, final postoperative BCVA was significantly lower in cases with presence of PVR or preoperatively detached macula (p = 0.011 and p = 0.0001, respectively; Mann Whitney U).\n\nSubgroup analysis\n\nWhen we restricted the time period between IVI and RRD to 90 days, we were able to analyze 22 patients. In this group, indication for surgery included 6 RVO, 7 AMD, 2 DME, 3 myopic choroidal neovascularization (CNV), 2 VMTS, and 2 PCME cases; the applied IVIs were 5 dexamethason implants, 5 ranibizumab, 7 bevacizumab, 2 aflibercept, 1 rtPA, and 2 ocriplasmin.\n\nIn two patients, preoperative BCVA was light perception; one showed an improvement to counting finger postoperatively, and the other one showed no change after surgery. In the rest of the 20 patients, mean BCVA improved from 1.40 ± 0.97 (median, 1.3; range, 0.20–3.00) preoperatively to 1.06 ± 0.84 (median, 1.00; range, 0.00–3.00) logMAR at the last follow-up examination. Primary PVR was observed in 3 eyes (2 DEX [1 RVO, 1PCME], 1 ranibizumab [1 nAMD]) and secondary PVR in 4 other eyes (3 DEX [2 RVO, 1PCME], 1 combination of ranibizumab and bevacizumab [1 nAMD]). Interestingly, all 5 eyes that received DEX developed a primary or secondary PVR, regardless of the underlying pathology. Moreover, IVARD after ocriplasmin injection occurred within the first 2 weeks in both cases.\n\nIncidence rate (LMU Munich)\n\nAssuming that all IVARDs were referred to the specific center in which the IVI had previously been performed, we calculated the incidence of RRD in the population of patients with RRD after IVI in one center only.\n\nFollowing this analysis, the yearly incidence rates of RRD after IVI between 2010 and 2019 and the 10-year incidence rates with regard to the injected medication were tabulated (see Table 2). In detail, the 10-year incidence rate for ranibizumab was 0.040% (95%CI: 0.019–0.073), for bevacizumab 0.109% (95%CI: 0.054–0.195), and for the dexamethasone implant 0.214% (95%CI: 0.092 – 0.422). Aflibercept and ocriplasmin were first administered in 2013, and therefore the 7-year rates were calculated: 0.007% (95%CI: 0.000–0.039) and 1.527% (95%CI: 0.185–5.515), respectively. Ocriplasmin showed by far the highest incidence rate of RRD after IVI, and both cases occurred within the first 2 weeks after the injection. Table 2 Number of RRD (in parentheses) and injections per year with regard to injected agent. The three right columns summarize the number of all injections, the number of IVARDs, and the incidence rate of IVARD per year. The bottom rows summarize the number of injections, IVARDs per injected agent between 2010 and 2019 and the incidence IVARD rate and 95%CI per medication. The last two rows demonstrate subgroup analysis data with time between last IVI and IVARD restricted to 90 days\n\nYear\tMedication\tAll\tRRD\tYearly rate\t\nRani\tBeva\tAfli\tOcri\tDex\tIlu\tOther\t\n2010\t642\t2540\t-\t-\t102\t-\t\t3187\t0\t0\t\n2011\t2272\t1311\t-\t-\t344\t-\t\t3912\t0\t0\t\n2012\t2709\t1369\t-\t-\t230\n\n(2)\n\n\t-\t\t4308\t2\t0.0005\t\n2013\t2681\n\n(1)\n\n\t1300\n\n(2)\n\n\t444\t23\n\n(1)\n\n\t235\n\n(1)\n\n\t\t2\t4685\t5\t0.0011\t\n2014\t2446\n\n(4)\n\n\t955\n\n(1)\n\n\t1153\t38\t246\n\n(1)\n\n\t6\t26\t4870\t6\t0.0012\t\n2015\t1776\n\n(2)\n\n\t732\n\n(1)\n\n\t1807\t12\t291\n\n(1)\n\n\t1\t61\t4680\t4\t0.0009\t\n2016\t2258\n\n(2)\n\n\t678\n\n(2)\n\n\t2365\n\n(1)\n\n\t24\t445\n\n(2)\n\n\t5\t79\t5854\t7\t0.0012\t\n2017\t2984\t566\n\n(1)\n\n\t2555\t19\n\n(1)\n\n\t594\t13\t91\t6822\t2\t0.0003\t\n2018\t3462\t350\n\n(1)\n\n\t2867\t9\t610\n\n(1)\n\n\t8\t92\t7398\t2\t0.0003\t\n2019\t3863\n\n(1)\n\n\t302\n\n(2)\n\n\t3266\t6\t639\n\n(1)\n\n\t73\t130\t8279\t4\t0.0005\t\nTotal IVIs\t25,093\n\n(10)\n\n\t10,103\n\n(11)\n\n\t14,457\n\n(1)\n\n\t131\n\n(2)\n\n\t3736\n\n(8)\n\n\t106\t481\t50,808\n\n(32)\n\n\t32\t\t\nIncidence Rate and 95%CI (%)\t0.040\n\n(0.019–0.073)\n\n\t0.109\n\n(0.054–0.195)\n\n\t0.007\n\n(0.000–0.039)\n\n\t1.527\n\n(0.185–5.515)\n\n\t0.214\n\n(0.092–0.422)\n\n\t\t\t0.063\n\n(0.043–0.089)\n\n\t\t\t\nTotal IVARDs (≤ 90 d)\t3\t6\t1\t2\t5\t\t\t17\t\t\t\n90 d incidence rate and 95%CI (%)\t0.012\n\n(0.003–0.035)\n\n\t0.059\n\n(0.022–0.129)\n\n\t0.007\n\n(0.000–0.039)\n\n\t1.527\n\n(0.185–5.515)\n\n\t0.134\n\n(0.044–0.312)\n\n\t\t\t0.033\n\n(0.020–0.054)\n\n\t\t\t\nIVI intravitreal injection, RRD rhegmatogenous retinal detachment, IVARD IVI-associated RRD, d days, CI confidence interval, Rani Ranibizumab®, Beva Bevacizumab®, Afli Aflibercept®, Ocri Ocriplasmin®, Dex Ozurdex®, Ilu Iluvien®\n\nThe observed incidence rates of RRD in the Department of Ophthalmology, LMU Munich, were significantly higher for ocriplasmin (risk difference: + 1.5264%; 95%CI: 0.4192–5.3955) and dexamethason implant (risk difference: + 0.2136; 95%CI: 0.1077–0.4214) in comparison with anti-VEGF agents (p < 0.0001 for ocriplasmin versus all other anti-VEGF agents and p = 0.0001 for dexamethason versus all other anti-VEGF agents; two sample z-test).\n\nIn the subgroup analysis, the incidence rates of RRD after anti-VEGF agents were 0.012% (95%CI: 0.003–0.035) for ranibizumab, 0.007% (95%CI: 0.000–0.039) for aflibercept, and 0.059% (95%CI: 0.022–0.129) for bevacizumab (ranibizumab vs bevacizumab (risk difference, -0.047%; 95%CI: -0.0844 to -0.0105); ranibizumab vs aflibercept (risk difference, + 0.005%; 95%CI: -0.016 to 0.026); aflibercept vs bevacizumab (risk difference, -0.052%; 95%CI: -0.095 to -0.010); p = 0.0118, p = 0.6314, and p = 0.0165, respectively; two sample z-test), whereas the incidence rate of RRD after DEX injection (0.134%, 95%CI: 0.044–0.312) was significantly higher than that of all other anti-VEGF agents (0.02%, 95%CI: 0.010–0.037; risk difference, + 0.114%; 95%CI: 0.058–0.169; p = 0.0001, two sample z-test).\n\nDiscussion\n\nIVIs are nowadays the most common ophthalmological procedure in the daily routine. While complication rates are very low, severe and vision threatening complications such as RRD or endophthalmitis can lead to significant visual deterioration [26, 27]. With regard to anti-VEGF agents, a rate around 0.013% for RRD after IVI has been reported by several large retrospective studies in various parts of the world [24, 26].\n\nThe current bi-center retrospective study was conducted to evaluate the anatomic and visual outcome after RRD repair to treat IVI-related RRD and is the first study to include other agents, such as ocriplasmin and two steroids, namely, the slow releasing 0.7 mg dexamethasone implant and the slow releasing 0.19 mg fluocinolone acetonide implant.\n\nThe primary anatomical success rate after one surgery was 83% (43/52 eyes) and is considered comparable to current attachment rates in complex RRD surgery cases [28, 29]. However, it increased to 96% (50/52) after the second surgery. The unexpectedly high rate of silicone oil fill needed in our cases (with both of the centers encouraging silicone oil fill only in complex cases) can be taken as an indicator for the more than average complexity of these cases.\n\nOverall, mean BCVA improved after surgery in the majority of the eyes with the exception of eyes with uveitis. Myopic eyes achieved the best BCVA after surgery. This might be because of the shorter duration of symptoms in this group (mean of 2.36 days), reflecting the fact that these patients may be more prone to visit an ophthalmologist in case of RRD symptoms. Moreover, eyes with myopic CNV tend to restore a good visual function upon first anti-VEGF treatment as compared with other entities such as nAMD [30]. Additionally, IVI-related RRD after ocriplasmin treatment demonstrates a very good BCVA increase after RRD repair. We consider that these patients were extensively informed about RRD risk after IVI with ocriplasmin and showed a similar short duration of symptoms of 2.5 ± 0.7 days, as in myopic patients. Overall, a short duration of RRD is known to improve the final visual outcome [31].\n\nEyes undergoing silicone oil fill showed a lower increase of BCVA after successful RRD repair. This fact reflects not only the worse preoperative BCVA, but also the higher complexity of these cases, including macular involvement and the presence of PVR.\n\nPVR was observed in all uveitic eyes and eyes with PCME, whereas no PVR was observed in any myopic eyes. A possible explanation is the preexistent inflammation in uveitic eyes and in eyes with PCME, both of which increase the risk of PVR. Interestingly, eight of the nine eyes who developed RRD after the application of DEX showed a primary or secondary PVR and received silicone oil fill. Due to the small number of cases in our population, one can make only assumptions about the possible explanation of this observation. However, two major factors differ between DEX and other injections. One is the larger sclerotomy and the larger needle (22-gauge needle) used for DEX injection, which leads to a higher possibility for vitreous leakage. The second is the different underlying disease spectrum, as more inflammatory eyes (i.e., uveitic, PCME) or eyes with disrupted blood retinal barrier (such as in RVO) are treated with DEX [6, 9, 10]. Since it remains unclear if the dexamethasone implant may impact the development of primary or secondary PVR in these individual cases or if the underlying disease is responsible for this finding, both factors require further investigation for drawing concrete conclusions regarding any association between them and development of PVR. Up to now, the possible adjunct effect of DEX in the treatment of PVR retinal detachment has not been confirmed [32], and the role of DEX in the development of PVR is still not adequately investigated [33]. In our population that had previously received DEX, the implant was removed during primary RRD surgery, and we cannot rule out that this may have resulted in a sudden decrease of steroids leading to a more intense blood retina breakdown that promoted secondary PVR in these eyes.\n\nOverall, the observed incidence rate of RRD after DEX injection or ocriplasmin was significantly higher in comparison to the other anti-VEGF agents. Previous studies have shown varying rates of RRD after DEX [6, 10, 34]. Lowder et al. reported 2 RRD cases in 153 DEX injections in uveitic eyes after a follow-up of 26 weeks [10], Haller et al. 1 case in 2512 DEX injections after a follow-up of 52 weeks in eyes with RVO [6], and Rajesh et al. a rate of 0.03% in 6000 DEX injections with varying indications (52% DME) and a different follow-up [34]. The observed rate in this study lies between the previously reported rates. As for ocriplasmin, prior studies have already indicated RRD as a possible complication [6, 13, 15, 35], because ocriplasmin is associated with vitreous liquefaction, posterior vitreous detachment, and reduced adherence between the retina and RPE as a result of its proteolytic effect [36]. Our study results are in agreement with these findings, as both RRD cases presented within the first 2 weeks after the injection, supporting this causality. With regard to the incidence rate of RRD after anti-VEGF agents, we observed a very low rate for all three anti-VEGF agents. These data are in accordance with those in the literature and, despite some differences, reflect the published rates after each type of injection [24, 26]. The incidence rate of RRD after the 0.19 mg fluocinolone acetonide implant (Iluvien) was zero. However, this fact relies on the very small number of injections in our cohort and does not reflect a long-term incidence rate of RRD after such injections. Therefore, this finding cannot be generalized, and no comparisons with other intravitreal injected agents were performed.\n\nThe retrospective design of the study and the small sample size are the major limitations of our data. Furthermore, while we cannot be sure that all the patients that developed IVARD in each clinic were referred to the same clinic, we think that our data rather underreport the incidence rate of IVARD. Nevertheless, we have enrolled all cases over an extensive period of time in two different centers and included ocriplasmin and cortisone implants in our study. Furthermore, we have conducted a subgroup analysis by reducing the time between IVI and RRD to 90 days to make our results comparable with the largest published study in the USA and calculated the 10-year incidence rates for one large vitreoretinal center in central Europe.\n\nIn conclusion, the anatomical result after one surgical intervention in cases of IVARD is graded as acceptable for such complex cases, but the final visual outcome remains rather poor, most probably because of the underlying macular disease. Furthermore, the presence and development of PVR seem to occur unexpectedly often in these cases. In particular, eyes with IVARD in the need for silicone oil fill remain behind expectations concerning the functional development.\n\nThe RRD rate after IVI with dexamethasone implant seems to be higher compared with that after anti-VEGF agents and is associated with a higher rate of PVR presence and recurrent RRD in our population. The rate of RRD after IVI with fluocinolone implant needs to be further determined in the future in a larger population.\n\nSupplementary Information\n\nBelow is the link to the electronic supplementary material. Supplementary file1 (DOCX 16.0 KB)\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1007/s00417-021-05261-6.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL.\n\nDeclarations\n\nEthics approval\n\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Institutional Review Board from the Department of Ophthalmology, University Hospital, LMU Munich and Eye Clinic Luigi Sacco, University of Milan, Milan, Italy) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.\n\nInformed consent\n\nInformed consent was obtained from all individuals participants included in the study.\n\nConflict of interest\n\nEfstathios Vounotrypidis, Sigrid Freissinger, Cereda Matteo, and Monteduro Davide have nothing to disclose. Karsten Kortüm receives fees for lectures/consulting for Bayer, Novartis, Allergan, and Carl Zeiss Meditec. Siegfried Priglinger receives fees for lectures/consulting for Alcon, Bayer, Carl Zeiss Meditec, Novartis, and Oertli Instrumente. Armin Wolf receives fees for lectures/consulting for Novartis, Bayer, Alimera, and Allergan.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nParts of this work were presented at the XIX Euretina Congress in September 2019 (Paris).\n==== Refs\nReferences\n\n1. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, Group MS Ranibizumab for neovascular age-related macular degeneration N Engl J Med 2006 355 1419 1431 10.1056/NEJMoa054481 17021318\n2. Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, Kirchhof B, Ho A, Ogura Y, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo Y, Anderesi M, Groetzbach G, Sommerauer B, Sandbrink R, Simader C, Schmidt-Erfurth U, View, Groups VS Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration Ophthalmology 2012 119 2537 2548 10.1016/j.ophtha.2012.09.006 23084240\n3. Group CRMartin DF Maguire MG Ying GS Grunwald JE Fine SL Jaffe GJ Ranibizumab and bevacizumab for neovascular age-related macular degeneration N Engl J Med 2011 364 1897 1908 10.1056/NEJMoa1102673 21526923\n4. Heier JS Clark WL Boyer DS Brown DM Vitti R Berliner AJ Kazmi H Ma Y Stemper B Zeitz O Sandbrink R Haller JA Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study Ophthalmology 2014 121 1414–1420 e1411 10.1016/j.ophtha.2014.01.027\n5. Costa RA Jorge R Calucci D Melo LA Jr Cardillo JA Scott IU Intravitreal bevacizumab (avastin) for central and hemicentral retinal vein occlusions: IBeVO study Retina 2007 27 141 149 10.1097/IAE.0b013e31802eff83 17290194\n6. Haller JA Bandello F Belfort R Jr Blumenkranz MS Gillies M Heier J Loewenstein A Yoon YH Jiao J Li XY Whitcup SM Ozurdex GSG Li J Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results Ophthalmology 2011 118 2453 2460 10.1016/j.ophtha.2011.05.014 21764136\n7. Heier JS Korobelnik JF Brown DM Schmidt-Erfurth U Do DV Midena E Boyer DS Terasaki H Kaiser PK Marcus DM Nguyen QD Jaffe GJ Slakter JS Simader C Soo Y Schmelter T Vitti R Berliner AJ Zeitz O Metzig C Holz FG Intravitreal aflibercept for diabetic macular edema: 148-week results from the VISTA and VIVID studies Ophthalmology 2016 123 2376 2385 10.1016/j.ophtha.2016.07.032 27651226\n8. Diabetic Retinopathy Clinical Research NElman MJ Aiello LP Beck RW Bressler NM Bressler SB Edwards AR Ferris FL 3rd Friedman SM Glassman AR Miller KM Scott IU Stockdale CR Sun JK Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema Ophthalmology 2010 117 1064–1077 e1035 10.1016/j.ophtha.2010.02.031\n9. Mastropasqua R Toto L Borrelli E Di Antonio L De Nicola C Mastrocola A Di Nicola M Carpineto P Morphology and function over a one-year follow up period after intravitreal dexamethasone implant (Ozurdex) in patients with diabetic macular edema PLoS ONE 2015 10 e0145663 10.1371/journal.pone.0145663 26720268\n10. Lowder C Belfort R Jr Lightman S Foster CS Robinson MR Schiffman RM Li XY Cui H Whitcup SM Ozurdex HSG Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis Arch Ophthalmol 2011 129 545 553 10.1001/archophthalmol.2010.339 21220619\n11. Mayer WJ Kurz S Wolf A Kook D Kreutzer T Kampik A Priglinger S Haritoglou C Dexamethasone implant as an effective treatment option for macular edema due to Irvine-Gass syndrome J Cataract Refract Surg 2015 41 1954 1961 10.1016/j.jcrs.2015.10.025 26603404\n12. Stalmans P, Benz MS, Gandorfer A, Kampik A, Girach A, Pakola S, Haller JA, Group M-TS Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes N Engl J Med 2012 367 606 615 10.1056/NEJMoa1110823 22894573\n13. Dugel PU Regillo C Eliott D Characterization of anatomic and visual function outcomes in patients with full-thickness macular hole in ocriplasmin phase 3 trials Am J Ophthalmol 2015 160 94–99 e91 10.1016/j.ajo.2015.03.017\n14. Hahn P Chung MM Flynn HW Jr Huang SS Kim JE Mahmoud TH Sadda SR Dugel PU Safety profile of ocriplasmin for symptomatic vitreomacular adhesion: a comprehensive analysis of premarketing and postmarketing experiences Retina 2015 35 1128 1134 10.1097/IAE.0000000000000519 25635575\n15. Haller JA, Stalmans P, Benz MS, Gandorfer A, Pakola SJ, Girach A, Kampik A, Jaffe GJ, Toth CA, Group M-TS Efficacy of intravitreal ocriplasmin for treatment of vitreomacular adhesion: subgroup analyses from two randomized trials Ophthalmology 2015 122 117 122 10.1016/j.ophtha.2014.07.045 25240630\n16. McLaughlin MD Hwang JC Trends in vitreoretinal procedures for Medicare beneficiaries, 2000 to 2014 Ophthalmology 2017 124 667 673 10.1016/j.ophtha.2017.01.001 28283281\n17. Learned D, Pieramici DJ (2018) Epidemiology and natural history of diabetic retinopathy current management of diabetic retinopathy, pp. 1–5.\n18. Wong WL Su X Li X Cheung CMG Klein R Cheng C-Y Wong TY Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis Lancet Global Health 2014 2 e106 e116 10.1016/s2214-109x(13)70145-1 25104651\n19. Reichle ML Complications of intravitreal steroid injections Optometry 2005 76 450 460 10.1016/j.optm.2005.06.013 16150412\n20. Falavarjani KG Nguyen QD Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature Eye (Lond) 2013 27 787 794 10.1038/eye.2013.107 23722722\n21. Frenkel RE Haji SA La M Frenkel MP Reyes A A protocol for the retina surgeon's safe initial intravitreal injections Clin Ophthalmol 2010 4 1279 1285 10.2147/OPTH.S12846 21139676\n22. Rayess N Rahimy E Storey P Shah CP Wolfe JD Chen E DeCroos FC Garg SJ Hsu J Postinjection endophthalmitis rates and characteristics following intravitreal bevacizumab, ranibizumab, and aflibercept Am J Ophthalmol 2016 165 88 93 10.1016/j.ajo.2016.02.028 26944277\n23. Storey PP, Tauqeer Z, Yonekawa Y, Todorich B, Wolfe JD, Shah SP, Shah AR, Koto T, Abbey AM, Morizane Y, Sharma P, Wood EH, Morizane-Hosokawa M, Pendri P, Pancholy M, Harkey S, Jeng-Miller KW, Obeid A, Borkar DS, Chen E, Williams P, Okada AA, Inoue M, Shiraga F, Hirakata A, Shah CP, Prenner J, Garg S, Post-Injection Endophthalmitis Study G The impact of prefilled syringes on endophthalmitis following intravitreal injection of ranibizumab Am J Ophthalmol 2019 199 200 208 10.1016/j.ajo.2018.11.023 30552891\n24. Storey PP Pancholy M Wibbelsman TD Obeid A Su D Borkar D Garg S Gupta O Rhegmatogenous retinal detachment after intravitreal injection of anti-vascular endothelial growth factor Ophthalmology 2019 126 1424 1431 10.1016/j.ophtha.2019.04.037 31042567\n25. Holladay JT Visual acuity measurements J Cataract Refract Surg 2004 30 287 290 10.1016/j.jcrs.2004.01.014 15030802\n26. Meyer CH Michels S Rodrigues EB Hager A Mennel S Schmidt JC Helb HM Farah ME Incidence of rhegmatogenous retinal detachments after intravitreal antivascular endothelial factor injections Acta Ophthalmol 2011 89 70 75 10.1111/j.1755-3768.2010.02064.x 21176118\n27. Shah CP Garg SJ Vander JF Brown GC Kaiser RS Haller JA Post-injection endophthalmitis study T, outcomes and risk factors associated with endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents Ophthalmology 2011 118 2028 2034 10.1016/j.ophtha.2011.02.034 21705087\n28. Deaner JD Aderman CM Bonafede L Regillo CD PPV, Retinectomy, and silicone oil without scleral buckle for recurrent RRD from proliferative vitreoretinopathy Ophthalmic Surg Lasers Imaging Retina 2019 50 e278 e287 10.3928/23258160-20191031-15 31755979\n29. Narala R Nassiri N Kim C Mehregan C Padidam S Abrams GW Outcomes of repeat pars plana vitrectomy after failed surgery for proliferative vitreoretinopathy Retina 2018 38 Suppl 1 S49 S59 10.1097/IAE.0000000000002000 29232332\n30. Wecker T Ehlken C Buhler A Lange C Agostini H Bohringer D Stahl A Five-year visual acuity outcomes and injection patterns in patients with pro-re-nata treatments for AMD, DME, RVO and myopic CNV Br J Ophthalmol 2017 101 353 359 10.1136/bjophthalmol-2016-308668 27215744\n31. Greven MA Leng T Silva RA Leung L-SB Karth PA Moshfeghi DM Sanislo SR Schachar IH Reductions in final visual acuity occur even within the first 3 days after a macula-off retinal detachment Br J Ophthalmol 2019 103 1503 1506 10.1136/bjophthalmol-2018-313191 30504489\n32. Banerjee PJ Quartilho A Bunce C Xing W Zvobgo TM Harris N Charteris DG Slow-release dexamethasone in proliferative vitreoretinopathy: a prospective, randomized controlled clinical trial Ophthalmology 2017 124 757 767 10.1016/j.ophtha.2017.01.021 28237428\n33. Thompson JT Negative results matter: why can't we improve the treatment of proliferative vitreoretinopathy? Ophthalmology 2017 124 753 754 10.1016/j.ophtha.2017.02.020 28528822\n34. Rajesh B, Zarranz-Ventura J, Fung AT, Busch C, Sahoo NK, Rodriguez-Valdes PJ, Sarao V, Mishra SK, Saatci AO, Udaondo Mirete P, Querques G, Farah ME, Lanzetta P, Arevalo JF, Kodjikian L, Chhablani J, for International Ozurdex Study G Safety of 6000 intravitreal dexamethasone implants Br J Ophthalmol 2020 104 39 46 10.1136/bjophthalmol-2019-313991 31040132\n35. Haynes RJ Yorston D Laidlaw DA Keller J Steel DH Real world outcomes of ocriplasmin use by members of the British and Eire Association of Vitreoretinal Surgeons Eye (Lond) 2017 31 107 112 10.1038/eye.2016.195 27589049\n36. Gandorfer A Pharmacologic vitreolysis: rationale, potential indications, and promising agents Retina 2012 32 Suppl 2 S221 224 10.1097/IAE.0b013e31825bc4df 22929325\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0721-832X",
"issue": "259(12)",
"journal": "Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie",
"keywords": "Intravitreal injection; Proliferative vitreoretinopathy; Rhegmatogenous retinal detachment; Visual outcome; Vitrectomy",
"medline_ta": "Graefes Arch Clin Exp Ophthalmol",
"mesh_terms": "D006801:Humans; D058449:Intravitreal Injections; D012163:Retinal Detachment; D012189:Retrospective Studies; D014792:Visual Acuity; D014821:Vitrectomy",
"nlm_unique_id": "8205248",
"other_id": null,
"pages": "3655-3664",
"pmc": null,
"pmid": "34216254",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": "27215744;30504489;31042567;21764136;24679444;26944277;23084240;21176118;17290194;30552891;21220619;25104651;28237428;27589049;23722722;17021318;25635575;25818925;26603404;25240630;26720268;16150412;31040132;22894573;28283281;27651226;29232332;21139676;15030802;22929325;21526923;21705087;31755979;20427088;28528822",
"title": "Intravitreal injection associated rhegmatogenous retinal detachment: outcomes of a European analysis.",
"title_normalized": "intravitreal injection associated rhegmatogenous retinal detachment outcomes of a european analysis"
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"abstract": "•A case report of a 14 year remission of recurrent ovarian cancer with intraperitoneal aldesleukin (IL-2) is presented.•Intraperitoneal IL-2 was given with little toxicity.•Immunotherapy may have the potential for durable remissions in ovarian cancer.",
"affiliations": "California Pacific Medical Center Research Institute, 2200 Webster St. Suite 511, San Francisco, CA 94115, United States.;California Pacific Medical Center Research Institute, 2200 Webster St., San Francisco, CA 94115, United States.;California Pacific Medical Center Research Institute/Palo Alto Medical Foundation, 3838 California St., San Francisco, CA 94118, United States.",
"authors": "Minor|David R|DR|;Moores|Samantha P|SP|;Chan|John K|JK|",
"chemical_list": null,
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"doi": "10.1016/j.gore.2017.09.009",
"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(17)30101-710.1016/j.gore.2017.09.009Case ReportProlonged survival after intraperitoneal interleukin-2 immunotherapy for recurrent ovarian cancer Minor David R. minord@sutterhealth.orga⁎Moores Samantha P. smoores8895@gmail.combChan John K. chanjohn@sutterhealth.orgca California Pacific Medical Center Research Institute, 2200 Webster St. Suite 511, San Francisco, CA 94115, United Statesb California Pacific Medical Center Research Institute, 2200 Webster St., San Francisco, CA 94115, United Statesc California Pacific Medical Center Research Institute/Palo Alto Medical Foundation, 3838 California St., San Francisco, CA 94118, United States⁎ Corresponding author. minord@sutterhealth.org25 9 2017 11 2017 25 9 2017 22 43 44 5 9 2017 19 9 2017 23 9 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• A case report of a 14 year remission of recurrent ovarian cancer with intraperitoneal aldesleukin (IL-2) is presented.\n\n• Intraperitoneal IL-2 was given with little toxicity.\n\n• Immunotherapy may have the potential for durable remissions in ovarian cancer.\n==== Body\n1 Introduction\nIn the last decade, there has been an explosion in the interest and usage of immunotherapy for cancer beginning with the demonstration that checkpoint inhibitors could produce prolonged treatment-free remissions in patients with advanced melanoma (Shadendorf et al., 2015). Immunotherapy with checkpoint inhibitors and as well as an oncolytic virus are now approved and available for the treatment of multiple advanced cancers. Although there is tremendous interest in using immunotherapy for ovarian cancer, success in this field seems limited at present (Drerup et al., 2015). In addition most efforts emphasize systemic immunotherapy, with little attention to the intraperitoneal route for immunotherapeutic agents. The authors felt the report of a patient with recurrent ovarian cancer successfully treated with intra-peritoneal interleukin-2 14 years ago would be of interest. This report was published with the approval of the Sutter Health institutional review board.\n\n2 Case history\nIn 1992 a 62-year-old woman was found to have malignant ascites. The patient had a hysterectomy in 1970 for endometriosis and had also been treated for ductal carcinoma in situ of the breast in 1988. Her serum CA-125 level was elevated at 2002 U/ml (normal < 35 U/ml). She had an abdominal paracentesis that showed malignant cells consistent with adenocarcinoma. Her CT scan showed ascites and the suggestion of a mesenteric or omental mass. She received preoperative chemotherapy with cyclophosphamide and carboplatin for six cycles. The ascites disappeared after two cycles and her CA-125 levels decreased to 11.5 U/ml after four cycles (Fig. 1). She then had an interval cytoreductive surgery with removal of the omentum, ovaries, fallopian tubes, and other visible disease. She was found to have residual cancer in the omentum (10 × 5 × 1 cm) that invaded the colon, pelvic peritoneum, and part of the bladder with diffuse cancer nodules on the liver, right kidney, and diaphragm. Approximately 98% of the cancer-bulk was resected during surgery. The pathology showed adenocarcinoma in the peritoneum in addition to the surface of the left ovary. Following surgery, she received intraperitoneal chemotherapy with etoposide and cisplatin for six cycles and intravenous carboplatin and paclitaxel for three cycles. Her cancer went into remission and she continued to take oral cyclophosphamide for an additional 12 months.Fig. 1 Timeline showing elevation of CA-125 levels 1992–2003.\n\nFig. 1\n\nIn 2001 she relapsed with abdominal pain and was hospitalized for bowel obstruction. Laparotomy showed an obstructed loop of ileum and small implants of carcinoma over the peritoneum and bowel with ascites. Findings from her CT scans showed recurrent ovarian cancer (Fig. 2, where the arrow points at fascial thickening in the paracolic gutter). The cytology of the peritoneal fluid was consistent with adenocarcinoma. Her CA-125 level had risen to 250 U/ml (Fig. 1). Following surgery, she received chemotherapy with paclitaxel and carboplatin for six cycles and carboplatin and docetaxel for three cycles. The CA-125 normalized after the initial chemotherapy cycle.Fig. 2 CT scan showing bowel obstruction and peritoneal thickening due to recurrence.\n\nFig. 2\n\nShe was disease free for another two years but relapsed a second time in 2003. She had an elevated CA-125 level at 83 U/ml, but scans failed to show the site of recurrence. The patient was treated with four doses of docetaxel and carboplatin, and then 16 weekly doses of intraperitoneal aldesleukin (interleukin-2, IL-2) 900,000 units per week administered diluted in one liter D5W as described by Edwards Edwards et al., 1997). She had grade 1 abdominal discomfort and fatigue with therapy but no severe toxicity with this intra-peritoneal immunotherapy. The dosage used for intraperitoneal interleukin-2 is < 1% of the usual intravenous high-dose interleukin-2 dosage. Following the immunotherapeutic treatment with IL-2, the patient has been disease free for 14 years, with repeat clinical exams and CA-125 levels showing no evidence of disease. Subsequent genetic testing has revealed the patient to carry a 2929 deletion in the BRCA2 gene.\n\n3 Discussion\nRecurrent ovarian cancer is traditionally felt to be a universally fatal disease. The authors feel that this patient's prolonged survival after a second relapse of her cancer was almost certainly due to the beneficial effect of the immunotherapy received, not the four additional cycles of chemotherapy in a patient with multiple relapses after previous chemotherapy. Her tumor demonstrated a favorable biology, with both a long remission after her initial chemotherapy and a BRCA2 mutation. The patient's BRCA2 mutation explains the sensitivity of her tumor to platinum chemotherapy but it is unknown whether BRCA mutations increase sensitivity to immunotherapy. In theory the higher mutational load in tumors with BRCA mutations should increase responsiveness to immunotherapy.\n\nAldesleukin (interleukin-2) was approved for the treatment of advanced renal cell cancer in 1992 and melanoma in 1998, but its use has been limited by the toxicity of the high doses required to obtain regressions in patients with advanced cancer when administered intravenously. Interleukin-2 causes activation, proliferation, and trafficking of T-cells and natural killer cells (Wei et al., 2007). When administered locally it may change a non-inflamed tumor into an inflamed tumor, perhaps thereby increasing sensitivity of that tumor to further immune attack. Intraperitoneal administration of interleukin-2 was pioneered by Edwards (Edwards et al., 1997; Vlad et al., 2010; Mantia-Smaldone et al., 2011) in a series of phase 1 and 2 trials that showed this treatment capable of causing regression of advanced ovarian cancer with reasonable toxicity. Phase 3 trials of intraperitoneal aldesleukin were never performed because of lack of funding. Currently over 40 trials of immunotherapy for ovarian cancer are underway using a variety of agents singly or in combination. We hope that this case report, demonstrating prolonged survival after a short course of intraperitoneal interleukin-2, will serve to strengthen interest in the immunotherapy of ovarian cancer in general and the use of local immunotherapy in particular.\n\nAuthor's disclosures of potential conflict of interest\nDr. Minor reports honoraria from Merck and honoraria and other from BMS. Dr. Chan and Ms. Moores have no disclosures.\n==== Refs\nReferences\nDrerup J.M. Liu Y. Padron A.S. Immunotherapy for ovarian cancer Curr. Treat. Options Oncol. 16 1 2015 317 25648541 \nEdwards R.P. Gooding W. Lembersky B.C. Comparison of toxicity and survival following intraperitoneal recombinant interleukin-2 for persistent ovarian cancer after platinum: twenty-four-hour versus 7-day infusion J. Clin. Oncol. 15 1997 3399 3407 9363872 \nMantia-Smaldone G.M. Edwards R.P. Vlad A.M. Targeted treatment of recurrent platinum-resistant ovarian cancer: current and emerging therapies Cancer Manag. Res. 3 2011 25 38 21734812 \nShadendorf D. Hodi F.S. Roberts C. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma J. Clin. Oncol. 33 2015 1889 1894 25667295 \nVlad A.M. Budui R.A. Lenzner D.E. A phase II trial of intraperitoneal interleukin-2 in patients with platinum-resistant or platinum-refractory ovarian cancer Cancer Immunol. Immunother. 59 2010 293 301 19690855 \nWei S. Kryczek I. Edwards R.P. Interleukin-2 administration alters the CD4 + FOXP3 + T-cell pool and tumor trafficking in patients with ovarian carcinoma Cancer Res. 67 2007 7487 7494 17671219\n\n",
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"pubdate": "2017-11",
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"title": "Prolonged survival after intraperitoneal interleukin-2 immunotherapy for recurrent ovarian cancer.",
"title_normalized": "prolonged survival after intraperitoneal interleukin 2 immunotherapy for recurrent ovarian cancer"
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"abstract": "In addition to cutaneous, gastrointestinal, hemodynamic, and respiratory symptoms, allergic reactions can induce an acute coronary syndrome in normal or atheromatous coronary arteries and can cause coronary stent thrombosis. Here, we report a case of coronary stent thrombosis due to allergic acute coronary syndrome during anaphylaxis induced by sugammadex in a female patient undergoing general anesthesia. She was emergently treated with percutaneous transluminal coronary balloon angioplasty with catecholamine, vasodilator, and intraaortic balloon support. Knowledge of perioperative allergy-triggered acute coronary syndrome is crucial for prompt and appropriate treatment.",
"affiliations": "From the Department of Anesthesiology, Hamamatsu Rosai Hospital, Japan Organization of Occupational Health and Safety, Hamamatsu, Japan.;Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, Hamamatsu, Japan.;From the Department of Anesthesiology, Hamamatsu Rosai Hospital, Japan Organization of Occupational Health and Safety, Hamamatsu, Japan.;From the Department of Anesthesiology, Hamamatsu Rosai Hospital, Japan Organization of Occupational Health and Safety, Hamamatsu, Japan.",
"authors": "Kikura|Mutsuhito|M|;Suzuki|Yuji|Y|;Nishino|Junko|J|;Uraoka|Masahiro|M|",
"chemical_list": "D002395:Catecholamines; D000077122:Sugammadex",
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"issue": "13(4)",
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"medline_ta": "A A Pract",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000368:Aged; D000768:Anesthesia, General; D015906:Angioplasty, Balloon, Coronary; D002395:Catecholamines; D003082:Colectomy; D003110:Colonic Neoplasms; D003328:Coronary Thrombosis; D017558:Elective Surgical Procedures; D005260:Female; D006801:Humans; D000077122:Sugammadex; D016896:Treatment Outcome",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "133-136",
"pmc": null,
"pmid": "30985320",
"pubdate": "2019-08-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Allergic Acute Coronary Artery Stent Thrombosis After the Administration of Sugammadex in a Patient Undergoing General Anesthesia: A Case Report.",
"title_normalized": "allergic acute coronary artery stent thrombosis after the administration of sugammadex in a patient undergoing general anesthesia a case report"
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"companynumb": "JP-009507513-1905JPN003425",
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"abstract": "As atypical antipsychotics are increasingly used in the treatment of childhood behavioural disorders either as monotherapy or in combination with other medications, there is a need to know more about their safety, in particular during switching to and from methylphenidate treatment, as antipsychotics and methylphenidate have opposing effects on dopaminergic neurotransmission. This report is about three cases of children who developed severe adverse reactions during switching from risperidone to methylphenidate. The first patient was a 6-year-old boy, diagnosed with attention deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD). He developed severe hyperactivity and agitation on taking methylphenidate after the discontinuation of risperidone treatment. The second patient was a girl of 6, already on risperidone for ADHD and borderline intellectual functioning when referred. She displayed severe hyperactivity, agitation and irritability upon switching to methylphenidate medication. The third patient was a 15-year-old female adolescent with a similar clinical course as the previous patients. In all the cases described here, it is only with the discontinuation of methylphenidate that the adverse reactions resolved and readministration of methylphenidate in two patients did not produce any adverse effect after a drug-free interval. Functional regulation of certain neuroreceptors during risperidone treatment may lead to altered behavioural responses upon switching to methylphenidate. Thus, a drug-free interval is recommended in order to prevent adverse reactions.",
"affiliations": "Department of Child Psychiatry, School of Medicine, Marmara University, Istanbul, Turkey. sabuncuoglu2004@yahoo.com",
"authors": "Sabuncuoglu|Osman|O|",
"chemical_list": "D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.1177/0269881107069466",
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"issue": "21(2)",
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"medline_ta": "J Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D017109:Akathisia, Drug-Induced; D014150:Antipsychotic Agents; D001289:Attention Deficit Disorder with Hyperactivity; D019958:Attention Deficit and Disruptive Behavior Disorders; D000697:Central Nervous System Stimulants; D002648:Child; D002675:Child, Preschool; D019955:Conduct Disorder; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007508:Irritable Mood; D008297:Male; D008774:Methylphenidate; D011595:Psychomotor Agitation; D018967:Risperidone; D011984:Sensory Receptor Cells",
"nlm_unique_id": "8907828",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Risperidone-to-methylphenidate switch reaction in children: three cases.",
"title_normalized": "risperidone to methylphenidate switch reaction in children three cases"
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"activesubstancename": "RISPERIDONE"
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... |
{
"abstract": "Metachronous neoplasms have rarely been reported in patients with neuroblastoma. This report presents the clinical case of a 23-month-old child who was diagnosed with an anaplastic medulloblastoma 5 months after completing treatment for stage IV neuroblastoma. The patient was treated with complete surgical resection and adjuvant chemoradiation followed by maintenance chemotherapy at an outside institution and came to our institution for further management. A pathologic diagnosis and review of both the suprarenal and posterior fossa masses were performed, as well as a genetic analysis of both cerebellar tumor tissue and blood using next-generation gene sequencing. At our institution, the patient was submitted to induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation and remains free of disease 2 years after completion of treatment. Genetic analysis revealed multiple somatic copy number variations with most deleted genes located in 2q37, a region which harbors genes involved in epigenetic regulation and tumor suppression. A homozygous deletion was found in the TSC2 gene, which is a clinically actionable gene, and patients with activating deletions in TSC2 can potentially be eligible for basket clinical trials with mTOR inhibitors. Germline single nucleotide variants were also identified in multiple genes involved in cancer (ALK, FGFR3, FLT3/4, HNF1A, NCOR1, and NOTCH2/3), cancer predisposition (TP53, TSC1, and BRCA1/2), and genes involved in DNA repair (MSH6, PMS2, POLE, and ATM). Metachronous neoplasms are rare and challenging to treat, hence genetic analysis and referral are needed to exclude hereditary cause. DNA sequencing of the tumor and germline can help identify alterations that increase predisposition or can be used to guide treatment decisions on recurrence and when standard options fail.",
"affiliations": null,
"authors": "Eterovic|Agda Karina|AK|;Maher|Ossama M|OM|;Chandra|Joya|J|;Chen|Ken|K|;Huse|Jason|J|;Zaky|Wafik|W|",
"chemical_list": "C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1540-1405",
"issue": "16(6)",
"journal": "Journal of the National Comprehensive Cancer Network : JNCCN",
"keywords": null,
"medline_ta": "J Natl Compr Canc Netw",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002528:Cerebellar Neoplasms; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008527:Medulloblastoma; D016609:Neoplasms, Second Primary; D009447:Neuroblastoma; D017422:Sequence Analysis, DNA; D000077005:Tuberous Sclerosis Complex 2 Protein",
"nlm_unique_id": "101162515",
"other_id": null,
"pages": "683-691",
"pmc": null,
"pmid": "29891519",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Metachronous Medulloblastoma in a Child With Successfully Treated Neuroblastoma: Case Report and Novel Findings of DNA Sequencing.",
"title_normalized": "metachronous medulloblastoma in a child with successfully treated neuroblastoma case report and novel findings of dna sequencing"
} | [
{
"companynumb": "US-BAYER-2018-136694",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"... |
{
"abstract": "Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA) which encompasses hemolytic anemia, thrombocytopenia, and organ impairment. Around 10% of cases are atypical HUS (aHUS), a rare disease with poor outcomes caused by uncontrolled activation of the alternative complement pathway. This case describes a young woman with clinical manifestations compatible with TMA during childhood and adolescence who was formally diagnosed with aHUS at the age of 21. She was managed with intensive plasma exchange and hemodialysis, which failed to improve her severe acute kidney injury and other hematological manifestations of aHUS. This was further compounded by several episodes of flash pulmonary edema and the posterior reversible encephalopathy syndrome (PRES). Treatment with the monoclonal anti-C5 inhibitor, eculizumab, improved all hematological parameters with almost full renal recovery following 3.5 months of dialysis. So far, long-term use of eculizumab (> 11 months) continues to be effective and without complication. Our case illustrates the difficulty but importance of early consideration of aHUS in patients presenting with TMA. More importantly, we highlight that near-normal renal recovery may be attained with eculizumab in adults even after a long dependence on dialysis - an observation that has not been reported in the literature so far.",
"affiliations": null,
"authors": "Povey|Hannah|H|;Vundru|Rahul|R|;Junglee|Naushad|N|;Jibani|Mahdi|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C481642:eculizumab",
"country": "Germany",
"delete": false,
"doi": "10.5414/CN107958",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0430",
"issue": "82(5)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D058186:Acute Kidney Injury; D061067:Antibodies, Monoclonal, Humanized; D065766:Atypical Hemolytic Uremic Syndrome; D003170:Complement Pathway, Alternative; D005260:Female; D006801:Humans; D010951:Plasma Exchange; D054038:Posterior Leukoencephalopathy Syndrome; D006435:Renal Dialysis; D055815:Young Adult",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "326-31",
"pmc": null,
"pmid": "23557793",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Renal recovery with eculizumab in atypical hemolytic uremic syndrome following prolonged dialysis.",
"title_normalized": "renal recovery with eculizumab in atypical hemolytic uremic syndrome following prolonged dialysis"
} | [
{
"companynumb": "GB-MYLANLABS-2014M1013378",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETHINYL ESTRADIOL\\NORELGESTROMIN"
},
"drugad... |
{
"abstract": "Sofosbuvir (SOF)-based regimens achieve excellent efficacy and safety in the treatment of chronic hepatitis C (CHC) with various genotypes. There are few real-world instances of the use of SOF-based regimens to treat genotype 2 CHC. This study determines the effectiveness and safety of SOF/Ribavirn (RBV), SOF/Daclatasvir (DCV) and SOF/DCV/RBV in the treatment of genotype 2 CHC patients in Taiwan.\n\n\n\nPatients with genotype 2 CHC were treated for 12 weeks with SOF/RBV, SOF/DCV or SOF/DCV/RBV under the National Health Insurance reimbursement program in three hospitals in Taiwan. The sustained virological response at 12 weeks (SVR12) was determined. Adverse events were recorded for a safety analysis.\n\n\n\nA total of 467 genotype 2 CHC patients were enrolled from January to October 2018. One hundred and eleven patients (24%) had cirrhosis, including 10 patients (2.1%) with hepatic decompensation. Fifty-five patients (12%) had already experienced interferon-alpha/RBV treatment. Forty-two patients (9%) had a history of hepatocellular carcinoma (HCC) in the baseline. Three hundred and fifty-five patients received SOF/RBV, forty-seven patients received SOF/DCV and sixty-two patients received SOF/DCV/RBV. The SOF/DCV group featured a greater HCV viral load than the SOF/RBV or SOF/DCV/RBV groups. SVR12 was achieved in 94.6% of the SOF/RBV group, 95.7% of the SOF/DCV group and 96.8% of then SOF/DCV/RBV group (P = NS). Thirteen out of 352 patients (3.7%) in the SOF/RBV group, 1 out of 62 patients (1.6%) in the SOF/DCV/RBV group and 1 out of 47 patients (2.1%) in the SOF/DCV group developed virological failure. There are no differences in virological failure between the three groups (P = NS). Multi-variate analysis shows that history of HCC is an independent factor that is associated with the failure of treatment in the SOF/RBV group (odds ratio:4.905, 95% confidence interval (CI): 1.321-18.205, P = 0.017). Hemoglobin levels at 12 weeks are significantly lower in the SOF/RBV and the SOF/RBV/DCV group than in the SOF/DCV group (P<0.05). Serious adverse events (SAE) occurred in six patients (1.6%) in the SOF/RBV group and in one patient (1.6%) in the SOF/RBV/DCV group. No patients in the SOF/DCV group experienced SAE.\n\n\n\nSOF/RBV, SOF/DCV or SOF/DCV/RBV for 12 weeks all achieve very high SVR rates and are equally effective in the treatment of genotype 2 CHC patients in the real world in Taiwan. Patients in the SOF/RBV group who have a history of HCC exhibit a lower SVR rate.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.;Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan.;School of Medicine, National Yang-Ming University, Taipei, Taiwan.",
"authors": "Tsai|Wei-Lun|WL|0000-0001-7557-3370;Wang|Chih-Feng|CF|;Cheng|Jin-Shiung|JS|;Chen|Wen-Chi|WC|;Bair|Ming-Jong|MJ|;Lo|Ching-Chu|CC|",
"chemical_list": "D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0227424",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0227424PONE-D-19-28494Research ArticleBiology and life sciencesOrganismsVirusesRNA virusesFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensFlavivirusesHepacivirusHepatitis C virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesOrganismsVirusesViral pathogensFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensHepatitis virusesHepatitis C virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensHepatitis virusesHepatitis C virusBiology and life sciencesOrganismsVirusesViral pathogensHepatitis virusesHepatitis C virusPeople and PlacesGeographical LocationsAsiaTaiwanMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesCirrhosisResearch and Analysis MethodsResearch DesignClinical Research DesignAdverse EventsMedicine and Health SciencesOncologyCancers and NeoplasmsCarcinomasHepatocellular CarcinomaMedicine and Health SciencesOncologyCancers and NeoplasmsGastrointestinal TumorsHepatocellular CarcinomaMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesHepatocellular CarcinomaBiology and Life SciencesBiochemistryProteinsHemoglobinMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesLiver FibrosisMedicine and Health SciencesHematologyAnemiaSofosbuvir-based regimen for genotype 2 HCV infected patients in Taiwan: A real world experience Sofosbuvir-based regimen for genotype 2 HCVhttp://orcid.org/0000-0001-7557-3370Tsai Wei-Lun ConceptualizationFormal analysisInvestigationMethodologyResourcesWriting – original draft12Wang Chih-Feng Data curationFormal analysisInvestigationResourcesWriting – original draft12Cheng Jin-Shiung Data curationInvestigationResourcesSupervision12Chen Wen-Chi Data curationResources12Bair Ming-Jong ConceptualizationData curationFormal analysisInvestigationMethodologySupervisionWriting – review & editing34*Lo Ching-Chu ConceptualizationData curationFormal analysisInvestigationMethodologySupervisionWriting – review & editing256*1 \nDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan2 \nSchool of Medicine, National Yang-Ming University, Taipei, Taiwan3 \nDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan4 \nMackay Medical College, New Taipei City, Taiwan5 \nDivision of Gastroenterology and Hepatology, Department of Internal Medicine, St. Martin De Porres Hospital, Chiayi, Taiwan6 \nChung-Jen junior College of Nursing, Health Sciences and Management, Chiayi, TaiwanLin Wenyu EditorHarvard Medical School, UNITED STATESCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: locc0320@gmail.com (CCL); a5963@mmh.org.tw (MJB)10 1 2020 2020 15 1 e022742411 10 2019 18 12 2019 © 2020 Tsai et al2020Tsai et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nSofosbuvir (SOF)-based regimens achieve excellent efficacy and safety in the treatment of chronic hepatitis C (CHC) with various genotypes. There are few real-world instances of the use of SOF-based regimens to treat genotype 2 CHC. This study determines the effectiveness and safety of SOF/Ribavirn (RBV), SOF/Daclatasvir (DCV) and SOF/DCV/RBV in the treatment of genotype 2 CHC patients in Taiwan.\n\nMaterial and methods\nPatients with genotype 2 CHC were treated for 12 weeks with SOF/RBV, SOF/DCV or SOF/DCV/RBV under the National Health Insurance reimbursement program in three hospitals in Taiwan. The sustained virological response at 12 weeks (SVR12) was determined. Adverse events were recorded for a safety analysis.\n\nResults\nA total of 467 genotype 2 CHC patients were enrolled from January to October 2018. One hundred and eleven patients (24%) had cirrhosis, including 10 patients (2.1%) with hepatic decompensation. Fifty-five patients (12%) had already experienced interferon-alpha/RBV treatment. Forty-two patients (9%) had a history of hepatocellular carcinoma (HCC) in the baseline. Three hundred and fifty-five patients received SOF/RBV, forty-seven patients received SOF/DCV and sixty-two patients received SOF/DCV/RBV. The SOF/DCV group featured a greater HCV viral load than the SOF/RBV or SOF/DCV/RBV groups. SVR12 was achieved in 94.6% of the SOF/RBV group, 95.7% of the SOF/DCV group and 96.8% of then SOF/DCV/RBV group (P = NS). Thirteen out of 352 patients (3.7%) in the SOF/RBV group, 1 out of 62 patients (1.6%) in the SOF/DCV/RBV group and 1 out of 47 patients (2.1%) in the SOF/DCV group developed virological failure. There are no differences in virological failure between the three groups (P = NS). Multi-variate analysis shows that history of HCC is an independent factor that is associated with the failure of treatment in the SOF/RBV group (odds ratio:4.905, 95% confidence interval (CI): 1.321–18.205, P = 0.017). Hemoglobin levels at 12 weeks are significantly lower in the SOF/RBV and the SOF/RBV/DCV group than in the SOF/DCV group (P<0.05). Serious adverse events (SAE) occurred in six patients (1.6%) in the SOF/RBV group and in one patient (1.6%) in the SOF/RBV/DCV group. No patients in the SOF/DCV group experienced SAE.\n\nConclusions\nSOF/RBV, SOF/DCV or SOF/DCV/RBV for 12 weeks all achieve very high SVR rates and are equally effective in the treatment of genotype 2 CHC patients in the real world in Taiwan. Patients in the SOF/RBV group who have a history of HCC exhibit a lower SVR rate.\n\nhttp://dx.doi.org/10.13039/501100004663Ministry of Science and Technology, Taiwan107-2314-B-075B-002 -MY2http://orcid.org/0000-0001-7557-3370Tsai Wei-Lun This study was supported by Ministry of Science and Technology of Taiwan, 107-2314-B-075B-002 -MY2. Data AvailabilityEthical restrictions prohibit the authors from making the data publicly available in order to protect confidentiality and privacy of patients. Data are available from the St. Martin De Porres Hospital Institutional Data Access / Ethics Committee for researchers who meet the criteria for access to confidential data. Contact information for the St. Martin De Porres Hospital Institutional Ethics Committee: Institutional Review Board of the St. Martin De Porres Hospital; Contact Person: Jiadi Huang; E-mail: H101@stm.org.tw.Data Availability\nEthical restrictions prohibit the authors from making the data publicly available in order to protect confidentiality and privacy of patients. Data are available from the St. Martin De Porres Hospital Institutional Data Access / Ethics Committee for researchers who meet the criteria for access to confidential data. Contact information for the St. Martin De Porres Hospital Institutional Ethics Committee: Institutional Review Board of the St. Martin De Porres Hospital; Contact Person: Jiadi Huang; E-mail: H101@stm.org.tw.\n==== Body\nIntroduction\nIn Taiwan, hepatitis C virus (HCV) infection has a prevalence of around 2–5% and HCV is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) in Taiwan [1]. In patients with acute HCV infection, 60–90% become chronically infected with HCV (CHC) and after 20–30 years of infection, 20–30% develop cirrhosis of the liver or HCC [2,3]. Recent years, there have been significant progress in anti-HCV therapy. The resolution of the three-dimensional structures of several HCV proteins and the development of replicative cell culture systems has led to the identification of a number of potential targets for direct-acting antiviral (DAA) agents [4–5]. DAAs are very effective in the treatment of HCV and are associated with a significant decrease in liver-related morbidity and mortality [6–10]. Sofosbuvir (SOF) is an oral nucleotide analogue inhibitor of the NS5B polymerase of HCV. Phase 3 studies and real world data show that a combination of SOF and ribavirin (RBV) for 12 weeks produces a rate of sustained virological response (SVR) of 83–97% for genotype 2 CHC patients [11–19]. Other real world data show that SVR rates are lower but the independent predictor for the failure of treatment is rarely identified. Daclatasvir (DCV) is an inhibitor of NS5A of HCV. Several recent studies, DCV have added to SOF for the treatment of genotype 2 CHC with a SVR rate of 90–100% [20,21,22]. However, it is not clear that adding DCV to SOF with or without RBV increases SVR rates for the treatment of genotype 2 CHC. This study determines the effectiveness and safety of SOF/RBV, SOF/DCV and SOF/DCV/RBV for the treatment of genotype 2 chronic HCV patients in the real world in Taiwan.\n\nPatients and methods\nStudy design\nSince January 2017, the National Health Insurance Administration (NHIA) of Taiwan provides reimbursement for SOF-based DAAs for patients with advanced fibrosis who are infected with HCV. From January 2018 to October 2018, consecutive patients with genotype 2 chronic HCV who had advanced liver fibrosis and who received SOF/RBV, SOF/DCV or SOF/DCV/RBV were enrolled in a program that was sponsored by the NHIA of Taiwan in three hospitals (Kaohsiung Veterans General Hospital in southern Taiwan, St. Martin De Porres Hospital in central Taiwan and Taitung MacKay Memorial Hospital in eastern Taiwan). This is not a randomized study and in the clinical settings, patients were treated with SOF/RBV, SOF/DCV or SOF/DCV/RBV irrespective of the clinical condition. Advanced fibrosis was at least stage III liver fibrosis and was defined in terms of the presence of any one of the following: transient elastography (TE) with a liver stiffness measurement (LSM) ≥ 9.5Kpa [23], a Fibrosis-4 (FIB-4) score ≥ 3.25 [24], a liver biopsy presenting a METAVIR fibrosis score ≥ 3, [25] or ultrasound-diagnosis of liver cirrhosis with splenomegaly or gastroesophageal varices by endoscopy [26]. Key exclusion criteria included: active HCC before treatment, a Glomerular filtration rate (GFR) of less than 30 ml/min or an absolute contraindication for the use of SOF, DCV or RBV.\n\nAssessment and end-points\nAll enrolled patients received HCV RNA at baseline, 12 weeks on-treatment and 12 weeks end-of-treatment (EOT) and liver function tests, prothrombin time, renal function tests and complete blood counts at baseline and every 4 weeks during treatment and 12 weeks after EOT. Patients in the SOF/RBV group received SOF 400 mg once daily and, weight-based ribavirin (1000 or 1200 mg) twice daily. Patients in the SOF/DCV or SOF/DCV/RBV group received SOF 400 mg once daily and DCV 60 mg once daily with or without weight-based ribavirin (1000 or 1200 mg) twice daily. Anemia that developed during treatment was managed by reducing the RBV dose by 200 mg. Liver decompensation was defined as a Child–Turcotte–Pugh (CTP) classification of B or C. The presence of HCC was confirmed by a histological or image evaluation based on the recommendations of the current guidelines [27–29]. The primary efficacy endpoint was defined as the achievement of SVR12, which was defined as a HCV RNA level of less than the lower limit for quantification (LLOQ, 25 IU/ml) 12 weeks after stopping DAAs. All AEs were recorded and assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) (version4.0).\n\nStatistical analysis\nClinical characteristics and clinical data were described using frequency counts and percentages for categorical variables and means with standard deviations for continuous variables. Group comparisons were performed using a Mann-Whitney Utest and a Pearson chi-square or a Fisher exact test for continuous and categorical variables, respectively. Covariates in the multivariable model were chosen a priori in terms of clinical importance. Each p-value is two-sided and is considered statistically significant if the p-value is less than 0.05. All analyses were performed using SPSS version 18.0.\n\nEthics statement\nThis study was approved by the Institutional Review Boards of Kaohsiung Veterans General Hospital, St. Martin De Porres Hospital and Taitung Mackay Memorial Hospital. This is a retrospective study that does not involve intervention or obtaining clinical specimens and all the data is analyzed anonymously, so the need for informed consent was waived by the Institutional Review Boards of Kaohsiung Veterans General Hospital, St. Martin De Porres Hospital and Taitung Mackay Memorial Hospital. The patients’ medical records were accessed since January 2018 to April 2019.\n\nResults\nCharacteristics of patients\nA total of 341 patients who were chronically infected with genotype 2 CHC were enrolled from January to Aug 2019. 358 patients received SOF/RBV, 62 patients received SOF/RBV/DCV and 47 patients received SOF/DCV treatment. The demographic and baseline characteristics for the SOF/RBV, SOF/DCV/RBV and SOF/DCV groups are shown in Table 1. HCV RNA in the SOF/DCV group is higher than that for the SOF/RBV (P = 0.003) and SOF/RBV/DCV groups (P < 0.001). Total bilirubin level is higher in the SOF/DCV than the SOV/RBV group (P = 0.048). Age, sex, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, hemoglobin, platelet, prothrombin, compensated or decompensated cirrhosis, treatment experienced and history of HCC are comparable for the SOF/RBV, SOF/RBV/DCV and SOF/DCV groups.\n\n10.1371/journal.pone.0227424.t001Table 1 Demographic characteristics of patients by treatment regimen.\n\tSOF+ RBV\nN = 358\tSOF+RBV+DCV\nN = 62\tSOF+DCV\nN = 47\t\nAge (years)\t64+11\t63+13\t65+12\t\nSex (M)\t164 (46%)\t14 (35%)\t21 (47%)\t\nHCV RNA (log10 IU/mL)\t5.7+1**\t5.5+1.0#\t6.2+0.8#**\t\nAlbumin (g/L)\t4.0+0.4\t4+0.5\t4.0+0.4\t\nALT (U/L)\t80+67\t78+79\t63+59\t\nAST (U/L)\t67+48\t64+48\t54+37\t\nTotal Bilirubin (mg/dL)\t0.8+0.4*\t0.9+0.4\t1.0+0.4*\t\nCreatinine (mg/dL)\t0.9+0.9\t1.0+0.4\t0.8+0.2\t\nHemoglobin (g/dL)\t14+1.5\t14+2.2\t14+1.7\t\nPlatelet count (x109/L)\t163+62\t155+63\t160+52\t\nProthrombin time\t11.2+5.6\t11+0.9\t11+0.6\t\nCirrhosis\nCompensated\nDecompensated\t83 (23%)\n74 (21%)\n9 (2.5%)\t18 (29%)\n17 (27%)\n1 (2%)\t10 (21%)\n10 (21%)\n0 (0%)\t\nTreatment experienced\t39 (11%)\t9 (16%)\t7 (15%)\t\nHCC history\t33 (9%)\t5 (8%)\t4 (9%)\t\n# P<0.001\n\n*P = 0.048\n\n** P = 0.003\n\nSOF: sofosbuvir, RBV: ribavirin, DCV: daclatasvir\n\nEfficacy\nA total of 444 of 467 (95.1%) patients achieved SVR12. In the intention to treat (ITT) population analysis, SVR12 was achieved in 339 of 359 (94.6%) patients in the SOF/RBV group and 60 of 62 (96.8%) patients in the SOF/DCV/RBV group and 45 of 47 patients (95.7%) in the SOF/DCV group (P = non-significant (NS). In the per-protocol (PP) population analysis, SVR12 was achieved in 339 of 352 (96.3%) patients in the SOF/RBV group and 60 of 61 (98.3%) patients in the SOF/DCV/RBV group and 45 of 46 patients (97.8%) in the SOF/DCV group (P = non-significant (NS) (Fig 1). Of the 467 patients who were subject to SOF-based regimens, only one patient who received SOF/RBV experienced a virological breakthrough during treatment (Table 2). Thirteen out of 352 patients (3.7%) in the SOF/RBV group, 2 out of 62 patients (3.2%) in the SOF/DCV/RBV group and 1 out of 47 patients (2.1%) in the SOF/DCV group developed virological failure. There are no differences of virological failure between the three groups of patients (P = NS). In the SOF/RBV group, a univariate analysis shows that cirrhosis and history of HCC is associated with treatment failure (P = 0.053 and 0.004 respectively) (Fig 2). Multivariate analysis shows that a history of HCC is associated with treatment failure (odds rati: 4.905, 95% confidence interval (CI): 1.321–18.205, P = 0.017) (Table 3). In the SOF/RBV/DCV and SOF/DCV group, statistical analysis does not determine any independent factors that are associated with treatment failure (Figs 3 and 4). Six patients in the SOF/RBV group and one patient in the SOF/DCV/RBV group can not complete 12 weeks of treatment but they lost follow up and do not have SVR-12 data. Adherence to DAAs as measured by medication event monitoring system or pill counts were not performed in this study. The influence of early stopping or strict adherence of DAA on SVR rate were not known from this study.\n\n10.1371/journal.pone.0227424.g001Fig 1 Sustained virologocal response (SVR) rates in patients who received SOF/RBV, SOF/DCV or SOF/DCV/RBV regimens.\nSOF: sofosbuvir, RBV: ribavirin, DCV: daclatasvir.\n\n10.1371/journal.pone.0227424.g002Fig 2 Subgroup analysis of the sustained virologocal response (SVR) rates in patients who received SOF/RBV regimen.\nSOF: sofosbuvir, RBV: ribavirin.\n\n10.1371/journal.pone.0227424.g003Fig 3 Subgroup analysis of the sustained virologocal response (SVR) rates in patients who received SOF/DCV/RBV regimen.\nSOF: sofosbuvir, RBV: ribavirin, DCV: daclatasvir.\n\n10.1371/journal.pone.0227424.g004Fig 4 Subgroup analysis of the sustained virologocal response (SVR) rates in patients who received SOF/DCV regimen.\nSOF: sofosbuvir, DCV: daclatasvir.\n\n10.1371/journal.pone.0227424.t002Table 2 Virological responses during and after treatment.\nResponse\n(HCV RNA <LLOQ)\tSOF/RBV\nN = 358\tSOF/DCV/RBV\nN = 62\tSOF/DCV\nN = 47\t\nDuring treatment, n/N (%)\t\t\t\t\nAt week 4\t339/353 (96)\t60/61 (98)\t45/47 (96)\t\nAt week 12\t351/352 (99.7)\t61/61 (100)\t47/47 (100)\t\nPost-treatment, n/N (%)\t\t\t\t\nAt week 12 (SVR12)\t339/358 (94.6)\t60/62 (96.8)\t45/47 (96)\t\nVirological failure, n/N (%)\t\t\t\t\nDuring treatment\t1/352 (0.3)\t0\t0\t\nRelapse\nEarly stopping\n(Before 12 wks)\t12/352 (3.4)\n6/358 (1.7)\t1/62 (1.6)\n1/62 (1.6)\t1/47 (2.1)\n0\t\nLost to follow up\t0\t0\t1/47 (2.1)\t\nSOF: sofosbuvir, RBV: ribavirin, DCV: daclatasvir\n\n10.1371/journal.pone.0227424.t003Table 3 Multivariable predictors of DAA treatment failure in genotype 2 chronic hepatitis C patients who received SOF/RBV regimen.\nCovariate\tOdds ratio\t95%CI\tP-value\t\nAge\t0.960\t0.916–1.006\t0.090\t\nMale\t0.525\t0.179–1.543\t0.242\t\nCirrhosis (Yes vs. NO)\t0.658\t0.166–2.616\t0.552\t\nDecompensated (Yes vs. NO)\t1.119\t0.127–9.885\t0.919\t\nBaseline HCC (Yes vs. NO)\t4.905\t1.321–18.205\t0.017\t\nPlatelets (u/L)\t0.990\t0.978–1.001\t0.080\t\nAlbumin (gm/dl)\t0.506\t0.122–2.094\t0.347\t\nAST (u/L)\t0.999\t0.980–1.019\t0.945\t\nALT (u/L)\t1.006\t0.993–1.019\t0.405\t\nBilirubin (gm/dl)\t1.572\t0.451–5.479\t0.477\t\nSafety\nOverall, the SOF based regimen for the treatment of genotype 2 chronic HCV is safe and well tolerated by patients (Table 4). Premature discontinuation of treatment because of adverse events is uncommon for all treatment groups. Six patients in the SOF/RBV group, 6 stopped treatment early, one refused to continue treatment but suffered no adverse effects (AE), 5 stopped treatment due to AE, 1 of whom had progression of ascites, 1 of whom had skin rash, 1 of whom had severe edema in the lower legs and an increase in creatinine level, 1 of whom experienced headache, insomnia and weakness and 1 of whom had severe itching. One patient in the SOF/RBV/DCV group refused to continue treatment but did not have any AE. One patient in the SOF/DCV group completed 12 weeks of treatment but refused to receive follow-up. No patients in the SOF/DCV group developed significant anemia, which is defined as a hemoglobin level of less than 10 mg/dl, but 10% of patients in the SOF/RBV group and 14% of patients in the SOF/RBV/DCV group developed significant anemia (P < 0.05).\n\n10.1371/journal.pone.0227424.t004Table 4 Adverse events.\nEvents, N (%)\tSOF/RBV\n(N = 358)\tSOF/DCV/RBV\n(N = 62)\tSOF/DCV\n(N = 47)\t\nSAE\t4 (1.1)\t2 (3)\t0 (0)\t\nAE leading to D/C\t5 (1.4)\t0 (0)\t0 (0)\t\nDeath\t0 (0)\t0 (0)\t0 (0)\t\nAST, (> 5x ULN)\t0 (0)\t0 (0)\t0 (0)\t\nALT, (> 5x ULN)\t1 (0.3)\t0 (0)\t0 (0)\t\nBIL, (> 3x ULN)\t0 (0)\t0 (0)\t0 (0)\t\nCr, (> 3x ULN)\t0 (0)\t0 (0)\t0 (0)\t\nDecreased Hb\t\t\t\t\n(< 10 g/dl)\t35 (10)*\t9 (14)#\t0 (0)*#\t\n(< 8 g/dl)\t3 (0.8)\t2 (1.6)\t0 (0)\t\nSOF: sofosbuvir, RBV: ribavirin, DCV: daclatasvir, SAE: serious adverse events, AE: adverse events, AST: aspartate aminotransferase, ALT: Alanine transaminase, BIL: bilirubin, Cr: creatinine\n\nHb: hemoglobin, D/C: discontinue, ULN: upper limit of normal, g/dl: grams per deciliter.\n\n*&#: P<0.05\n\nDiscussion\nSOF/RBV was not recommended by AASLD and EASL. However, in the APASL HCV guideline, for treatment-naive HCV GT-2 patients, daily sofosbuvir plus weight-based ribavirin for 12 weeks is recommended [6,30,31]. The data from three hospitals in Central, Southern and Eastern Taiwan show that the SOF-based regimen achieves an excellent SVR rate and has a good safety profile for genotype 2 CHC patients. Patients who receive SOF/RBV, SOF/DCV or SOF/DCV/RBV for 12 weeks all achieve very high SVR rates and were equally effective in treating genotype 2 CHC patients in the real world in Taiwan.\n\nIn a real world study for North America and Europe, Welzel et al. found that 12 or 16 weeks of SOF/RBV treatment achieves an SVR rate of 88.2% for genotype 2 CHC [17]. Another real world study involving 823 U.S. veterans with genotype-2 CHC showed that the SVR rates for SOF/RBV are 79% [32]. Another European study showed that for 236 patients with genotype 2 CHC who were treated for 12 weeks with SOF/RBV, SVR rates were achieved in only 83% of patients [15]. Several real world studies report similar results and show that SVR rates in real life were lower than those for clinical trials. However, in a phase 3b study in Taiwan, Kao et al. noted that SOF/RBV achieves a SVR rate of 100% in 83 patients with genotype 2 CHC [14]. In a recent real world study in Japan, Akahane et al. noted that treatment with SOF/RBV for 12 weeks results in SVR rates of 96.8% for a group of 914 patients who were infected with genotype II CHC s [16]. This real world study shows that treatment with SOF/RBV for 12 weeks achieves SVR rates of 94.6%, which is comparable with the real world rate for Japan and more than the real world rate for the Western world. Data for the registration clinical trials shows that the SVR rates for a SOF/RBV regimen are lower for patients with cirrhosis, especially for those who do not have previous IFN therapy [33–34]. This study finds that exposure to previous IFN treatment does not affect SVR rates and patients with cirrhosis have lower SVR rates only in a univariate analysis.\n\nSOF/velpatasvir (VEL) combination therapy is recommended for the treatment of genotype 2 CHC patients [6,31]. In a recent study, Belperio et al. found that SVR rates do not differ between DCV + SOF (94.5%) and VEL/SOF (94.4%) or between DCV + SOF + RBV (88.1%) and VEL/SOF + RBV (89.5%) for genotype 2 CHC patients [34]. SOF/DCV with or without RBV remains an important combination regimen for genotype 2 CHC, especially in countries where SOF/VEL is not clinically approved. However, it is unclear whether adding RBV to the combination of SOF/DCV increases the SVR rate. A small Taiwanese study found that SOF/DCV with and without RBV achieves similarly high SVR rates in 32 patients with genotype 2 CHC [35]. Another small Taiwanese study notes that SOF/DCV with or without RBV results in similarly high SVR rates for 50 patients with genotype 2 CHC [36]. This study finds that the SVR rate is achieved for 60 of 62 (96.8%) patients in the SOF/DCV/RBV group and 45 of 47 patients (95.7%) in the SOF/DCV group, and adding RBV to the SOF/DCV regimen does not effect the SVR rate. Few studies compare the efficacy of SOF/RBV and SOF/DCV for the treatment of genotype 2 CHC. A recent study by Sulkowski et al. found that SOF/DCV achieves a SVR rate of 92% for 26 patients with genotype 2 CHC [20]. In a recent study, Belperio et al. found that SOF/DCV results in a SVR rate of 94.5%. [37]. In another recent study, Mangia et al. found that treatment with SOF/DCV for 12 or 24 weeks achieves a 100% SVR rate for 106 patients with genotype 2 CHC [22]. In another recent study, Swallow et al. discovered that for patients who were co-infected with genotype 1–3 CHC and HIV, the SVR12 rate is higher for patients who are treated with SOF/DCV (n = 91) than for those who are treated with SOF/RBV (n = 455) (96.7% vs 84.6%; P = 0.002) [38]. This study finds that SOF/RBV and SOF/DCV achieve similarly high SVR rates (94.6% vs. 95.5%) for the treatment of genotype 2 CHC.\n\nIn a retrospective cohort study, Prenner et al. found that 21% of patients fail to achieve SVR with HCC, compared to 12% of patients without HCC (p = 0.009) [39], but only 5% of patients were genotype 2. A recent study by Beste et al. used a cohort of US veteran patients to show that the overall SVR rate is 91.1% for non-HCC and 74.4% for HCC. The presence of HCC is associated with a lower likelihood of SVR [40]. However almost 80% of patients had genotype 1 CHC. In another recent study of 1021 patients with CHC, Yen et al. discovered that active HCC is associated with non-SVR after DAA treatment [41], but the study was heterogenous and only 32.3% of patients had genotype 2 CHC and up to eight DAA regimens were used in the study. In a recent study from Taiwan, Huang et al. in CHC patients who received DAAs treatment disclosed that a substantially but not significantly lower SVR rate, 92.1% (35/38), was observed in the patients with viable HCC compared with the SVR rate, 97.3% (72/74), in those with curative HCC (p = 0.33) [42]. But only 13% of patients in this study were genotype 2 CHC. For patients in this study who received the SOF/RBV regimens, multivariate analysis shows that a history of HCC is associated with a failure in treatment. This study focuses on patients with genotype 2 CHC who receive a SOF/RBV regimen and identifies the independent factor that is associated with a failure in treatment. Patients with genotype 2 CHC who have a history of HCC have a lower SVR rate so treatment options other than SOF/RBV may be considered.\n\nThe SOF-based regimen for the treatment of genotype 2 chronic HCV is safe and is tolerated by Taiwanese patients. Premature discontinuation of treatment because of adverse events is uncommon for all of the treatment groups but more patients in the SOF/RBV and the SOF/RBV/DCV groups develop significant anemia.\n\nThis real-world data shows that a SOF-based regimen with SOF/RBV, SOF/DCV or SOF/DCV/RB is safe and effective for the treatment of genotype 2 CHC in Taiwan. However, this study has several limitations. It does not determine the efficacy of SOF/VEL for the treatment of genotype 2 CHC because at the time of this study, SOF/VEL had not been approved in Taiwan. Recently, two real-world studies to determine the effectiveness of brand-name or generic SOF/VEL for patients with genotype 2 CHC showed that the SVR12 rates are 94% and 98%, respectively [37,43] and a combination of SOF/VEL does not result in a higher SVR rate than a SOF/DCV regimen. SOF/RBV or SOF/DCV are important regimens for the treatment of genotype 2 CHC.\n\nIn conclusion, SOF/RBV, SOF/DCV or SOF/DCV/RBV for 12 weeks achieve very high SVR rates and are equally effective in the treatment of patients with genotype 2 CHC in Taiwan. A history of HCC results in a lower SVR rate for the SOF/RBV group.\n==== Refs\nReferences\n1 Kao J.H. ; Chen D.S. \nChanging disease burden of hepatocellular carcinoma in the Far East and Southeast Asia . 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APASL consensus statements and recommendation on treatment of hepatitis C.Omata M1,2, Kanda T3, Wei L4, Yu ML5, Chuang WL6, Ibrahim A7, Lesmana CR8, Sollano J910 \nHepatol Int . 2016 \n9 ;10 (5 ):702 –26 . https://www.ncbi.nlm.nih.gov/pubmed/2713047\n10.1007/s12072-016-9717-6 .27130427 \n31 EASL Recommendations on Treatment of Hepatitis C 2018 .European Association for the Study of the Liver . J Hepatol . 2018 \n8 , 69 (2 ), 461 –511 . https://easl.eu/wp-content/uploads/2018/10/HepC-English-report.pdf\n10.1016/j.jhep.2018.03.026 \n29650333 \n32 Backus L.I. ; Belperio P.S. ; Shahoumian T.A. ; Loomis T.P. ; Mole L.A. \nEffectiveness of sofosbuvir-based regimens in genotype 1 and 2 hepatitis C virus infection in 4026 U.S . Veterans. Aliment Pharmacol Ther . 2015 , 42 , 559 –73 . https://www.ncbi.nlm.nih.gov/pubmed/26113432\n10.1111/apt.13300 \n26113432 \n33 Zeuzem S. ; Dusheiko G.M. ; Salupere R. ; Mangia A. ; Flisiak R. ; Hyland R.H. ; et al\nSofosbuvir and ribavirin in HCV genotypes 2 and 3 . N Engl J Med \n2014 , 370 , 1993 –2001 . 10.1056/NEJMoa1316145 \n24795201 \n34 Foster G.R. ; Pianko S. ; Brown A. ; Forton D. ; Nahass R.G. ; George J. ; et al\nEfficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with hepatitis C virus genotype 3 infection and treatment-experienced patients with cirrhosis and hepatitis C virus genotype 2 infection . Gastroenterology . 2015 , 149 , 1462 –70 . https://www.ncbi.nlm.nih.gov/pubmed/26248087\n10.1053/j.gastro.2015.07.043 \n26248087 \n35 Cheng P.N. ; Chiu Y.C ,; Chien S.C .; Chiu H.C . Real-world effectiveness and safety of sofosbuvir plus daclatasvir with or without ribavirin for genotype 2 chronic hepatitis C in Taiwan . J Formos Med Assoc . 2019 \n5 , 118 (5 ), 907 –913 . https://www.ncbi.nlm.nih.gov/pubmed/30316677\n10.1016/j.jfma.2018.09.016 \n30316677 \n36 Wu S.H. ; Chu C.J. ; Su C.W. ; Lin C.C. ; Lee S.D. ; Wang Y.J , et al, Daclatasvir plus sofosbuvir, with or without ribavirin, is highly effective for all kinds of genotype-2 chronic hepatitis-C infection in Taiwan . J Chin Med Assoc . 2019 in press. https://www.ncbi.nlm.nih.gov/pubmed/31356562\n10.1097/JCMA.0000000000000148 \n31356562 \n37 Belperio P.S. ; Shahoumian T.A. ; Loomis T.P. ; Mole L.A. ; Backus L.I. \nReal-world effectiveness of daclatasvir plus sofosbuvir and velpatasvir/sofosbuvir in hepatitis C genotype 2 and 3 . J Hepatol . 2019 \n1 , 70 (1 ), 15 –23 . https://www.ncbi.nlm.nih.gov/pubmed/30266283\n10.1016/j.jhep.2018.09.018 \n30266283 \n38 Swallow E. ; Song J. ; Yuan Y. ; Kalsekar A. ; Kelley C. ; Peeples M , et al,Daclatasvir and Sofosbuvir Versus Sofosbuvir and Ribavirin in Patients with Chronic Hepatitis C Coinfected with HIV: A Matching-adjusted Indirect Comparison . Clin Ther . 2016 \n2 , 38 (2 ), 404 –12 . https://www.ncbi.nlm.nih.gov/pubmed/26839044\n10.1016/j.clinthera.2015.12.017 \n26839044 \n39 Prenner S.B. ; VanWagner L.B. ; Flamm S.L. ; Salem R. ; Lewandowski R.J. ; Kulik L. \nHepatocellular carcinoma decreases the chance of successful hepatitis C virus therapy with direct-acting antivirals . J Hepatol . 2017 \n6 , 66 (6 ), 1173 –1181 . 10.1016/j.jhep.2017.01.020 Epub 2017 Feb 2. https://www.ncbi.nlm.nih.gov/pubmed/28161470\n28161470 \n40 Beste L.A. ; Green P.K. ; Berry K. ; Kogut M.J. ; Allison S.K. ; Ioannou G.N. \nEffectiveness of hepatitis C antiviral treatment in a USA cohort of veteran patients with hepatocellular carcinoma . J Hepatol . 2017 \n7 , 67 (1 ), 32 –39 . https://www.ncbi.nlm.nih.gov/pubmed/28267622\n10.1016/j.jhep.2017.02.027 \n28267622 \n41 Yen Y.H. ; et al\nActive hepatocellular carcinoma is an independent risk factor of direct-acting antiviraltreatment failure: a retrospective study with prospectively collected data . Plos one . 2019 in press. https://www.ncbi.nlm.nih.gov/pubmed/31581209\n10.1371/journal.pone.0222605 \n31581209 \n42 Huang CF , Yeh ML , Huang CI , Liang PC , Lin YH , Hsieh MY , et al, Equal treatment efficacy of direct-acting antivirals in patients with chronic hepatitis C and hepatocellular carcinoma? A prospective cohort study .BMJ Open . 2019 \n5 \n5 ;9 (5 ):e026703 \nhttps://www.ncbi.nlm.nih.gov/pubmed/6501994\n10.1136/bmjopen-2018-026703 \n31061041 \n43 Liu C.H. ; Sun H.Y. ; Liu C.J. ; et al\nGeneric velpatasvir plus sofosbuvir for hepatitis C virus infection in patients with or without human immunodeficiency virus coinfection . Aliment Pharmacol Ther . 2018 , 47 , 1690 –8 . https://www.ncbi.nlm.nih.gov/pubmed/29665069\n10.1111/apt.14647 \n29665069\n\n",
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"title": "Sofosbuvir-based regimen for genotype 2 HCV infected patients in Taiwan: A real world experience.",
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"abstract": "A 63-year-old woman was admitted to our institution for severe pain in her right lower abdomen caused by the perforation of cecal cancer. She underwent emergency surgery, from which she was diagnosed with cecal carcinoma with liver, lung, and lymph node metastases. As she was taking aspirin to prevent cerebral infarction, anti-vascular endothelial growth factor (receptor) antibody and regorafenib therapy were not used. Thus, we started a modified FOLFOX 6+cetuximab regimen. This first-line treatment initially achieved a partial response (PR), but she then developed progressive disease (PD) after 14 months. We changed the regimen to FOLFIRI, followed by trifluridine/tipiracil, but her progression-free survival periods were 2.7 months and 1 month, respectively. Although we cycled through the available array of standard cancer drugs, the patient showed a good performance status, and some benefit from treatment still seemed plausible. We readministered the 5-fluorouracil oral preparation S-1, which maintained stable disease (SD) for 7 months. After PD emerged, we readministered the anti-epidermal growth factor receptor (EGFR) antibody panitumumab for 7.5 months of SD. Finally, 39 months after her diagnosis, she died from rapidly progressing disease. However, her relatively long survival implies that readministering drugs similar to those used in previous regimens might benefit patients with metastatic colorectal cancer.",
"affiliations": "Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School, Japan.;Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School, Japan.;Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School, Japan.;Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School, Japan.;Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School, Japan.;Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School, Japan.",
"authors": "Kawagoe|Tetsuro|T|https://orcid.org/0000-0003-3635-898X;Ikeda|Go|G|;Oshiro|Yu|Y|;Maruki|Yuta|Y|;Kaneko|Keiko|K|;Iwakiri|Katsuhiko|K|",
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"fulltext": "\n==== Front\nCase Rep Oncol Med\nCase Rep Oncol Med\nCRIONM\nCase Reports in Oncological Medicine\n2090-6706 2090-6714 Hindawi \n\n10.1155/2020/2351810\nCase Report\nReadministration of Cancer Drugs in a Patient with Chemorefractory Metastatic Colorectal Cancer\nhttps://orcid.org/0000-0003-3635-898XKawagoe Tetsuro tetsuro@nms.ac.jp Ikeda Go Oshiro Yu Maruki Yuta Kaneko Keiko Iwakiri Katsuhiko Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School, Japan\nAcademic Editor: Ossama W. Tawfik\n\n\n2020 \n23 6 2020 \n2020 235181028 3 2020 3 6 2020 11 6 2020 Copyright © 2020 Tetsuro Kawagoe 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.A 63-year-old woman was admitted to our institution for severe pain in her right lower abdomen caused by the perforation of cecal cancer. She underwent emergency surgery, from which she was diagnosed with cecal carcinoma with liver, lung, and lymph node metastases. As she was taking aspirin to prevent cerebral infarction, anti-vascular endothelial growth factor (receptor) antibody and regorafenib therapy were not used. Thus, we started a modified FOLFOX 6+cetuximab regimen. This first-line treatment initially achieved a partial response (PR), but she then developed progressive disease (PD) after 14 months. We changed the regimen to FOLFIRI, followed by trifluridine/tipiracil, but her progression-free survival periods were 2.7 months and 1 month, respectively. Although we cycled through the available array of standard cancer drugs, the patient showed a good performance status, and some benefit from treatment still seemed plausible. We readministered the 5-fluorouracil oral preparation S-1, which maintained stable disease (SD) for 7 months. After PD emerged, we readministered the anti-epidermal growth factor receptor (EGFR) antibody panitumumab for 7.5 months of SD. Finally, 39 months after her diagnosis, she died from rapidly progressing disease. However, her relatively long survival implies that readministering drugs similar to those used in previous regimens might benefit patients with metastatic colorectal cancer.\n==== Body\n1. Introduction\nChemotherapy is usually the first-choice treatment for metastatic colorectal cancer (mCRC). Relatively new cytotoxic agents (such as irinotecan and oxaliplatin) and molecular targeted agents (such as antibodies against vascular endothelial growth factor (receptor) (VEGF (R)) and epidermal growth factor receptor (EGFR)) have extended the median overall survival of patients with mCRC to more than 20 months [1–3]. Guidelines recommend chemotherapy regimens with standard cancer drugs, such as 5-fluorouracil (FU), irinotecan, oxaliplatin, anti-VEGF (R) or anti-EGFR antibodies, regorafenib, and trifluridine/tipiracil [4–6]. More recently, immunotherapy has become available for a minority of patients with microsatellite instability-high tumors [7]. Although patients who have cycled through these standard chemotherapies are usually only treated palliatively, some selected patients can maintain good performance status (PS) and receive further chemotherapies. For such patients, there are limited further chemotherapeutic options. Here, we report a woman with mCRC who benefitted from the reintroduction of S-1, an oral prodrug of 5-FU, and anti-EGFR antibodies after receiving standard 1st-, 2nd-, and 3rd-line chemotherapies.\n\n2. Case Presentation\nA 63-year-old woman with a medical history of hypertension and cerebral infarction was admitted to our hospital with severe abdominal pain in October 2012.\n\nComputed tomography (CT) scan of the abdomen and pelvis showed inflammation spread, abscess formation, lymphadenopathy around the cecum, and a huge mass with multiple nodules in the liver (Figures 1(a) and 1(b)). A chest CT also revealed multiple pulmonary nodules (Figure 1(c)). She was clinically diagnosed with intestinal perforation owing to cecal cancer and underwent emergency surgery. She was intraoperatively diagnosed with obstruction of the appendicular root owing to cecal cancer, perforation of the vermiform appendix, intraperitoneal abscess, and lymphadenopathy around the cecum and received an ileocecal resection, D1 lymph node dissection, and a peritoneal wash. After surgery, she was finally diagnosed with moderately differentiated wild-type KRAS adenocarcinoma of the cecum (stage: T3N1M1b, per the Union for International Cancer Control criteria). A microsatellite instability (MSI) test was not performed. RAS and BRAF status were also not investigated. We initiated therapy using cetuximab (500 mg/m2; 14-day cycle) and the mFOLFOX6 regimen (5-FU 400 mg/m2 bolus injection; leucovorin (LV) 200 mg/m2, 46 h continuous infusion with 5-FU 2400 mg/m2; and oxaliplatin 85 mg/m2; 14-day cycle) in October 2012. This treatment resulted in 7.75 months of partial response (PR), followed by a stable disease (SD) period of 6.25 months and progressive disease (PD) for a total progression-free survival (PFS) period of 14 months. As a 2nd-line treatment, we started the FOLFIRI regimen (5-FU 400 mg/m2 bolus injection, LV 200 mg/m2, 46 h continuous infusion with 5-FU 2400 mg/m2, and irinotecan 150 mg/m2; 14-day cycle), but she developed PD after 2.7 months. We started trifluridine/tipiracil (35 mg/m2 administered twice daily on Days 1–5 and Days 8–12 of a 28-day cycle) as a 3rd-line treatment, but this led to PD after 1 month. As this patient had a history of cerebral infarction and used antiplatelet drugs, anti-VEGF (R) antibody and regorafenib therapies were contraindicated. Hence, at this stage, no new standard cancer drugs could be tried. However, the patient's general condition was still good, and she requested further chemotherapy. Therefore, we readministered the 5-FU oral preparation S-1 (80 mg/m2, Days 1–28, 42-day cycle), which provided a 7-month SD period (Figure 2). When PD was again confirmed, we administered panitumumab (6 mg/kg once every 2 weeks) as an anti-EGFR antibody rechallenge. The patient achieved SD on this regimen for 7.5 months (Figure 3). Finally, 39 months after her diagnosis, the patient died because of rapid disease progression. While receiving readministered drugs, her PS was well maintained; she suffered no grade ≥ 3 adverse events (per the National Cancer Institute Common Toxicity Criteria, version 4.0; Table 1).\n\n3. Discussion\nAlthough this was a case of unresectable CRC, its treatment can be considered successful because the patient survived for 39 months after diagnosis while maintaining good PS despite being unable to receive anti-VEGF (R) antibody therapy. Because she survived for 14.5 months after cycling through standard cancer regimens, retreatment apparently facilitated her relatively long survival.\n\nSeveral reports on readministering anticancer drugs [8–16] have suggested that after a washout period, earlier-line drugs that were initially effective but then became ineffective might become effective again [11–15]. Santini et al. reported cetuximab rechallenge to be significantly effective after a cetuximab-free interval with cytotoxic chemotherapy [13]. Their hypothesis is as follows. If the anti-EGFR antibody was initially effective, it would have reduced EGFR-sensitive clonal cells and insensitive clones predominate at the PD stage. Subsequent cytotoxic chemotherapy would reduce the number of insensitive clones, and at the time of PD, sensitive clones would grow and become dominant again. As a result, the anti-EGFR antibody would become active again. Their hypothesis appears to be supported by the result of the CRICKET trial [14], in which rechallenge treatment with cetuximab was demonstrated to be effective, especially in patients without RAS mutations in circulating tumor DNA. This hypothesis implies that even if the readministered drug is panitumumab rather than cetuximab, an effect can be expected because both drugs are anti-EGFR antibodies. Panitumumab might also have been effective after cetuximab because panitumumab is a fully human monoclonal antibody (MoAb), whereas cetuximab is a chimeric MoAb consisting of ~30% mouse protein and may have a different sensitivity to cancer. Few reports have investigated the effect of panitumumab after progression on cetuximab in colorectal cancer patients. Marino et al. reported in their retrospective study that treatment with panitumumab after progression on cetuximab was effective because its PR and SD rates were 5% and 25% in 20 patients, respectively, and the median PFS and OS were 5 and 8 months, respectively [15]. In contrast, Wadlow et al. reported no responders to panitumumab treatment after progression on cetuximab and a SD rate of 45% with a median duration of only 1.7 months in their single-arm phase II trial of 20 patients [16]. Because both of these trials were conducted in a small number of patients, and panitumumab treatment after progression on cetuximab was actually effective in our study, it is necessary to identify the type of cases in which panitumumab treatment after progression on cetuximab is effective in the future. S-1 was developed to improve the therapeutic effect of tegafur, an oral fluoropyrimidine, by maintaining high 5-FU concentrations in plasma and tumors with less gastrointestinal toxicity by 5-chloro-4-dihydroxypyridine (CDHP) and potassium oxonate. In this case, the mechanism by which S-1 (as an oral fluoropyrimidine agent) was effective after the 5-FU infusion regimen became ineffective is unclear. Reportedly, the use of the FOLFOX regimen with 5-FU infusion enhances dihydropyrimidine dehydrogenase (DPD) activity in tumors [17]. In the present case, S-1 may have maintained high levels of 5-FU in the tumor by suppressing DPD activity enhanced by pretreatment with CDHP.\n\n4. Conclusion\nIn conclusion, we report a patient with metastatic CRC for whom repeated standard cancer treatments were effective despite prior development of refractory reactions. Why retreatment was effective remains unclear. Further research is needed.\n\nAcknowledgments\nWe thank Marla Brunker, from Edanz Group (https://en-author-services.edanzgroup.com/), for editing a draft of this manuscript.\n\nData Availability\nThe clinical data used to support the findings of this study are included within the article.\n\nConflicts of Interest\nWe report no conflicts of interest. This research was performed as part of the employment of the authors. The employer's name is Nippon Medical School.\n\nFigure 1 Pelvic CT showed inflammation spread and abscess formation around the cecum (a). Abdominal CT showed a huge mass and multiple nodules in the liver (b). Chest CT showed nodules in the lungs (c). Arrows: lesions.\n\nFigure 2 Abdominal and chest CT before the administration of S-1 (a, b). Stable disease after therapy (c, d). Arrows: lesions in the liver.\n\nFigure 3 Abdominal and chest CT before the administration of panitumumab (a, b). Stable disease after therapy (c, d). Pulmonary metastasis was slightly reduced after panitumumab treatment. Arrows: lesions in the liver.\n\nTable 1 Treatment toxicities and performance status.\n\n\tmFOLFOX6+Cetu\tFOLFIRI\tTrifluridine/tipiracil\tS-1\tPanitumumab\t\nGrade 1/2\t\t\t\t\t\t\n Decreased WBCs\t○\t○\t\t\t\t\n Decreased neutrophils\t\t○\t○\t\t\t\n Anemia\t○\t○\t○\t○\t○\t\n Decreased platelets\t○\t\t\t○\t\t\n Fever\t○\t\t○\t○\t○\t\n Anorexia\t○\t\t○\t○\t\t\n Dry skin\t○\t\t\t\t○\t\n Peripheral neuropathy\t○\t○\t\t\t\t\n Insomnia\t○\t\t\t\t\t\n Paronychia\t○\t\t\t\t○\t\n Fatigue\t\t○\t○\t○\t\t\n Mucositis oral\t\t\t\t○\t○\t\n Diarrhea\t\t\t\t○\t\t\n Rash acneiform\t\t\t\t\t○\t\nGrade 3\t\t\t\t\t\t\n Decreased neutrophils\t○\t\t\t\t\t\nPS\t1\t1\t2\t1\t1\t\nCetu: cetuximab; WBC: white blood cells.\n==== Refs\n1 Heinemann V. von Weikersthal L. F. Decker T. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open- label, phase 3 trial The Lancet Oncology 2014 15 10 1065 1075 10.1016/S1470-2045(14)70330-4 2-s2.0-84908573757 25088940 \n2 Loupakis F. Cremolini C. Masi G. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer The New England Journal of Medicine 2014 371 17 1609 1618 10.1056/NEJMoa1403108 2-s2.0-84908139591 25337750 \n3 Baba H. Yamada Y. Takahari D. S-1 and oxaliplatin (SOX) plus bevacizumab versus mFOLFOX6 plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer: updated overall survival analyses of the open-label, non-inferiority, randomised phase III: SOFT study ESMO Open 2017 2 1, article e000135 10.1136/esmoopen-2016-000135 2-s2.0-85052616219 28761727 \n4 Watanabe T. Japanese Society for Cancer of the Colon Rectum K. M. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer International Journal of Clinical Oncology 2018 23 1 1 34 10.1007/s10147-017-1101-6 2-s2.0-85016121993 28349281 \n5 Benson A. B. 3rd Venook A. P. Cederquist L. Colon cancer, version 1.2017, NCCN clinical practice guidelines in oncology Journal of the National Comprehensive Cancer Network 2017 15 3 370 398 10.6004/jnccn.2017.0036 2-s2.0-85016215716 28275037 \n6 Van Cutsem E. Cervantes A. Adam R. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer Annals of Oncology 2016 27 8 1386 1422 10.1093/annonc/mdw235 2-s2.0-84984985398 27380959 \n7 Jeught K. Xu H. C. Li Y. J. Lu X. B. Ji G. Drug resistance and new therapies in colorectal cancer World Journal of Gastroenterology 2018 24 34 3834 3848 10.3748/wjg.v24.i34.3834 2-s2.0-85053307654 30228778 \n8 Tonini G. Imperatori M. Vincenzi B. Frezza A. M. Santini D. Rechallenge therapy and treatment holiday: different strategies in management of metastatic colorectal cancer Journal of Experimental & Clinical Cancer Research 2013 32 1 p. 92 10.1186/1756-9966-32-92 2-s2.0-84887632994 \n9 Hata A. Katakami N. Fujita S. Panitumumab rechallenge in chemorefractory patients with metastatic colorectal cancer Journal of Gastrointestinal Cancer 2013 44 4 456 459 10.1007/s12029-012-9453-7 2-s2.0-84888204094 23212286 \n10 Townsend A. R. Bishnoi S. Broadbridge V. Rechallenge with oxaliplatin and fluoropyrimidine for metastatic colorectal carcinoma after prior therapy American Journal of Clinical Oncology 2013 36 1 49 52 10.1097/COC.0b013e31823fe40e 2-s2.0-84872948810 22270106 \n11 Ozaslan E. Duran A. O. Bozkurt O. Analyses of multiple factors for determination of \"selected patients\" who should receive rechallenge treatment in metastatic colorectal cancer: a retrospective study from Turkey Asian Pacific Journal of Cancer Prevention 2015 16 7 2833 2838 10.7314/APJCP.2015.16.7.2833 2-s2.0-84928637051 25854370 \n12 Yeoh C. Chau I. Cunningham D. Norman A. R. Hill M. Ross P. J. Impact of 5-fluorouracil rechallenge on subsequent response and survival in advanced colorectal cancer: pooled analysis from three consecutive randomized controlled trials Clinical Colorectal Cancer 2003 3 2 102 107 10.3816/CCC.2003.n.016 2-s2.0-0042383055 12952566 \n13 Santini D. Vincenzi B. Addeo R. Cetuximab rechallenge in metastatic colorectal cancer patients: how to come away from acquired resistance? Annals of Oncology 2012 23 9 2313 2318 10.1093/annonc/mdr623 2-s2.0-84865553918 22396447 \n14 Cremolini C. Rossini D. Dell’Aquila E. Rechallenge for patients WithRASandBRAFWild-Type metastatic colorectal cancer with acquired resistance to first-line cetuximab and Irinotecan JAMA Oncology 2019 5 3 343 350 10.1001/jamaoncol.2018.5080 2-s2.0-85057127256 30476968 \n15 Marino A. Caliolo C. Sponziello F. Panitumumab after progression on cetuximab inKRASWild-type metastatic colorectal cancer patients: a single institution experience Tumori 2015 101 5 524 528 10.5301/tj.5000356 2-s2.0-84955748449 26045117 \n16 Wadlow R. C. Hezel A. F. Abrams T. A. Panitumumab in patients with KRASwild-type colorectal cancer after progression on cetuximab The Oncologist 2011 17 1 p. 14 \n17 Baba H. Watanabe M. Okabe H. Upregulation of ERCC1 and DPD expressions after oxaliplatin-based first-line chemotherapy for metastatic colorectal cancer British Journal of Cancer 2012 107 12 1950 1955 10.1038/bjc.2012.502 2-s2.0-84870803143 23169295\n\n",
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"title": "Readministration of Cancer Drugs in a Patient with Chemorefractory Metastatic Colorectal Cancer.",
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"abstract": "This article presented a case of a human leukocyte antigen (HLA)-A2-positive patient with advanced cancer/testis antigen New York esophageal squamous cell carcinoma-1 (NY-ESO-1) expressing lung adenocarcinoma (LADC) who received adoptive cell therapy of T cell receptor engineered-T cells (TCR-T cells) targeting the cancer-testis antigen NY-ESO-1. The appropriate clinical and laboratory assessments were conducted to investigate the safety and efficacy of this therapy for this lung cancer patient. The patient had a clinical response to and was well-tolerated with this therapy in the clinical trial. In addition, a preliminary evaluation of the safety of NY-ESO-1 TCR-T cell therapy was performed in four patients with non-small cell lung cancer (NSCLC) enrolled in a clinical trial. It was well-tolerated and did not observe any serious adverse events post-infusion. Fever, anemia, and a decrease in white blood cell count were common adverse events, which were likely due to the TCR-T cell therapy. Two patients had clinical responses to NY-ESO-1 TCR-T cell therapy, including the 44-year-old female patient with LADC, who achieved a short-term partial response for 4 months, improved in Karnofsky performance status, and had a recovery of drug sensitivity. This suggests that TCR-T cell therapy targeting NY-ESO-1 antigen may be beneficial for HLA-A2-positive late-stage patients with NY-ESO-1-expressing NSCLC.",
"affiliations": "Department of Oncology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China.;Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.;Department of Research and Development, Shenzhen Institute for Innovation and Translational Medicine, Shenzhen, Guangdong 518120, P.R. China.;Department of Research and Development, Shenzhen Institute for Innovation and Translational Medicine, Shenzhen, Guangdong 518120, P.R. China.;Department of Oncology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China.;Department of Oncology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China.;Department of Oncology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China.;Department of Research and Development, Shenzhen Institute for Innovation and Translational Medicine, Shenzhen, Guangdong 518120, P.R. China.;Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.;Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.;Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA.;Department of Oncology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China.;Department of Research and Development, Shenzhen Institute for Innovation and Translational Medicine, Shenzhen, Guangdong 518120, P.R. China.",
"authors": "Xia|Yan|Y|;Tian|Xiaopeng|X|;Wang|Juntao|J|;Qiao|Dongjuan|D|;Liu|Xianhao|X|;Xiao|Liang|L|;Liang|Wenli|W|;Ban|Dongcheng|D|;Chu|Junjun|J|;Yu|Jiaming|J|;Wang|Rongfu|R|;Tian|Geng|G|;Wang|Mingjun|M|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2018.9534",
"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2018.9534OL-0-0-9534ArticlesTreatment of metastatic non-small cell lung cancer with NY-ESO-1 specific TCR engineered-T cells in a phase I clinical trial: A case report Xia Yan 123*Tian Xiaopeng 3*Wang Juntao 2Qiao Dongjuan 2Liu Xianhao 1Xiao Liang 1Liang Wenli 1Ban Dongcheng 2Chu Junjun 3Yu Jiaming 3Wang Rongfu 4Tian Geng 1Wang Mingjun 21 Department of Oncology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518035, P.R. China2 Department of Research and Development, Shenzhen Institute for Innovation and Translational Medicine, Shenzhen, Guangdong 518120, P.R. China3 Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China4 Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USACorrespondence to: Dr Mingjun Wang, Department of Research and Development, Shenzhen Institute for Innovation and Translational Medicine, Building C2, Life Science Industrial Park, Shenzhen International Biological Valley, Kwai Chung, Dapeng, Shenzhen, Guangdong 518120, P.R. China, E-mail: mingjunw429@163.comDr Geng Tian, Department of Oncology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, 3002 Sungang West Road, Shenzhen, Guangdong 518035, P.R. China, E-mail: tiangeng_tg666@163.com* Contributed equally\n\n12 2018 01 10 2018 01 10 2018 16 6 6998 7007 13 2 2018 27 7 2018 Copyright: © Xia et al.2018This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.This article presented a case of a human leukocyte antigen (HLA)-A2-positive patient with advanced cancer/testis antigen New York esophageal squamous cell carcinoma-1 (NY-ESO-1) expressing lung adenocarcinoma (LADC) who received adoptive cell therapy of T cell receptor engineered-T cells (TCR-T cells) targeting the cancer-testis antigen NY-ESO-1. The appropriate clinical and laboratory assessments were conducted to investigate the safety and efficacy of this therapy for this lung cancer patient. The patient had a clinical response to and was well-tolerated with this therapy in the clinical trial. In addition, a preliminary evaluation of the safety of NY-ESO-1 TCR-T cell therapy was performed in four patients with non-small cell lung cancer (NSCLC) enrolled in a clinical trial. It was well-tolerated and did not observe any serious adverse events post-infusion. Fever, anemia, and a decrease in white blood cell count were common adverse events, which were likely due to the TCR-T cell therapy. Two patients had clinical responses to NY-ESO-1 TCR-T cell therapy, including the 44-year-old female patient with LADC, who achieved a short-term partial response for 4 months, improved in Karnofsky performance status, and had a recovery of drug sensitivity. This suggests that TCR-T cell therapy targeting NY-ESO-1 antigen may be beneficial for HLA-A2-positive late-stage patients with NY-ESO-1-expressing NSCLC.\n\nadoptive cell therapynon-small cell lung cancerlung adenocarcinomaNY-ESO-1TCR-engineered T cell\n==== Body\nIntroduction\nLung cancer is a leading cause of cancer deaths worldwide (1), while non-small cell lung cancers (NSCLCs) accounting for >80% of all lung cancer cases (2,3). NSCLC can be categorized into three major histologic subtypes: Lung adenocarcinoma (LADC), lung squamous cell carcinomas (LSCC) and large cell lung cancer (LCLC). Among them, LADC is the most commonly occurring subtype (3). Patients with advanced NSCLC (stage IIIb and IV) have no surgical treatment options available and will be treated with systemic therapeutics, including radiation therapy, chemotherapy, target therapy and immunotherapy (3). However, chemotherapy and radiation therapy have high incidences of severe side effects. The most of therapies targeted lung cancer mutatuion driver genes (such as mutations in EGFR, KRAS, HER2, BRAF, RET, ROS1 and ALK) have eventually failed due to drug resistance (4). Many clinical trials using immune checkpoint blockade therapy have shown impressive and durable clinical benefits in lung cancer, and in other human cancers (5–8). However, the majority of lung cancer patients fail to respond to the checkpoint immunotherapy (9). Therefore, new immunotherapeutic strategies are urgently needed for those who fail to respond to the immune checkpoint therapy. Recently, cancer-specific T cells have been further developed to eradicate cancer cells (10). Adoptive cell therapy (ACT) using cultured autologous tumor-infiltrating lymphocytes (TILs) can induce a clinical response in cancer patients, even in those who have previously experienced treatment failure with other immunotherapies (11,12). However, it remains a challenge to generate tumor-reactive TILs from tumor tissues.\n\nGenetic engineering enables the creation of T cells expressing chimeric antigen receptors (CARs) that recognize tumor membrane antigens, or T cell receptors (TCRs) recognizing tumor membrane and intracellular antigens presented by specific major histocompatibility complex (MHC) molecules (10,13). These approaches redirect the antigen specificity of T cells for in vitro expansion, and thus help overcome practical barriers that limit the widespread use of TILs (14,15). Notably, chimeric antigen receptor-engineered T cells (CAR-T cells) targeting B-cell lineage differentiation antigen CD19 have acheived impressive clinical response rates (16–18). A great effort has been made to use CAR-T immunotherapy to treat patients with solid cancers. However, such a CAR-T therapy has poor clinical response in solid tumor due to the tumor microenvironment and the lack of suitable cell-surface targets that specifically expressed on tumor cells (19).\n\nCancer specific antigens/targets, which are supposed to express in cancer cells but not in normal cells, play a vital role in a successful cancer immunotherapy. Unfortunately, there are few cancer specific antigens available as useful targets for immunotherapy in solid tumor. Cancer-testis antigens are identified as attractive immunotherapy targets in many cancers due to their high expression in a variety of malignant neoplasms, but lack of expression in normal adult tissues with the exception of normal testis. However, male germ cells do not express human leukocyte antigen (HLA) class I molecular, and thus are immunologically protected (20–22). Moreover, expression of some cancer-testis antigens in tumors could induce specific humoral and cellular immune responses in cancer patients (21,23). A recent study shows that TCR-modified CD4+ T cells targeting cancer-testis antigen MAGE-A3 objectively respond to metastatic cancers, including metastatic cervical cancer, esophageal cancer, urothelial cancers and osteosarcoma (19). The cancer-testis antigen NY-ESO-1 is one of the most promising candidate targets for immunotherapy due to the strong associated immunogenicity (24–28). The clinical importance of NY-ESO-1 in T cell therapy has been supported from a case study that a patient with refractory melanoma treated with autologous NY-ESO-1-specific CD4+ T cells stimulated with NY-ESO-1 peptide achieved a long-term complete remission (29). Subsequent studies using ACT with NY-ESO-1 TCR-engineered T cells (TCR-T cells) could effectively mediate tumor regression in melanoma and synovial cell sarcoma, as well as multiple myeloma with well tolerance (13,14,30,31). However, the safety and efficacy of NY-ESO-1 TCR-T cells in lung cancer remain unknown.\n\nNY-ESO-1 antigen is expressed in 11.8–21% of NSCLCs (25,32,33), and serum anti-NY-ESO-1 antibody has been detected in 13–20% patients with lung cancers (34,35) and in 23% patients with NSCLC (35). NY-ESO-1 has already been shown as a promising target for cancer immunotherapy with good safety and efficiency (13,30,31). Therefore, we choose the NY-ESO-1 as an ideal target for TCR-T cells in our study. In the present study, four patients with NSCLC enrolled in the clinical trial (NCT02457650) that aims at preliminarily evaluating the safety and feasibility of NY-ESO-1 TCR-T cell therapy for HLA-A2-positive patients with NY-ESO-1 antigen-expressing malignancies revealed well tolerance. Here, we reported that a female patient with advanced LADC revealed a partial response (PR, 4 months) with NY-ESO-1 TCR-T cell therapy without evident toxicity.\n\nPatients and methods\n\nPatients and clinical trial design\nPatients, aged one year and older, expressing HLA-A2 with NY-ESO-1 antigen-expressing solid tumors refractory to standard treatment, were enrolled into the present clinical trial. We recruited four subjects with NSCLC in our preliminarily study on TCR-T cell therapy. More than 30% of cells in patients' tumor specimen were stained with at least >1+ intensity for NY-ESO-1 antigen expression when immunohistochemical (IHC) staining was performed using anti-NY-ESO-1 monoclonal antibody (Santa Cruz Biotechnology, Inc., Dallas, TX, USA.). Staining intensity was graded as 1+, weak staining; 2+, moderate staining; and 3+, strong staining. A lymphodepleting chemotherapy regimen prior to adoptive T cell infusion has been shown to dramatically enhance the persistence of the transferred cells and improve anticancer effects (36,37). In addition, the lymphodepleting chemotherapy regimen may deplete Treg cells and other suppressive cells in the circulation and the tumor micro environment, thus enabling the survival and amplification of adoptively transferred T cells to achieve effective killing of cancer cells (38). In the current study, a lymphodepleting chemotherapy regimen consisting of cyclophosphamide (CTX; 30 mg/kg/d for 2 days) and fludarabine (Flud; 25 mg/m2/d for 3 days) was purposed to be administrated to patients prior to the NY-ESO-1 TCR-T cell infusion. A previous study reported that the patients receiving a median of 5×1010 T cells transduced with an anti-NY-ESO-1 TCR (range of 1.6 to 130×109) achieved objective clinical responses with good safety in metastatic synovial cell sarcoma and melanoma (14). In the current study, total T cells at a median of 7.16×109 cells (range of 1.67–10.60×109 cells, transfection rate between 36.6% and 96.6%) were intravenously infused in one to three days with interleukin (IL)-2 (Beijing Shuanglu Pharmaceutical Co Lt., Beijing, China) administrated subcutaneously for the following consecutive 14 days (typically, 0.8–2.0 MIU/d) according to patient tolerance. This clinical trial was conducted in Shenzhen Second People's Hospital and approved by the Medical Ethics Committee of the Institutional Review Board of the Shenzhen Second People's Hospital. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and meets the standards of the Declaration of Helsinki in its revised version of 1975 and its amendments of 1983, 1989, and 1996 [JAMA 1997; 277:925-926]. All patients enrolled in the trial provided written informed consent.\n\nT cell transduction and quantitative real-time PCR analyses\nPatient peripheral blood mononuclear cells (PBMCs) were collected via leukopheresis. Then, PBMCs were stimulated using 50 ng/ml anti-CD3 antibody (OKT3; Ortho-Biotech, Bridgewater, NJ, USA) and 300 IU recombinant IL-2 (Peprotech, UK), followed by transduction with retroviral vector carrying nucleic acid sequences encoding an HLA-A2 restricted TCR recognizing NY-ESO-1:157-165 epitope (30,39,40). The transduced cells were then expanded in vitro before being adoptively transferred as previously described (41). Clinical grade retroviral supernatants produced under good manufacturing practice (GMP) conditions were obtained from the Shenzhen Institute for Innovation and Translational Medicine (Shenzhen, China). IFN-γ released by the TCR-T cells was measured based on recognition of tumor cell line Mel 624 (HLA-A2+ and NY-ESO-1+), which had been established in the Surgery Branch, National Cancer Institute from resected tumors (42,43) as described previously (14,40). Co-incubation of TCR-T cells with Mel 586 (HLA-A2− and NY-ESO-1+) was used as a negative control. Mel 624 or Mel 586 cells (5×104 cells/well) were seeded in 96-well cell culture plates with medium, respectively, and incubated overnight. The culture medium was replaced with fresh ones containing TCR-T cells. After co-incubation for 18 h, IFN-γ released in supernatant was measured by enzyme-linked immunosorbent assay (ELISA). The persistence of NY-ESO-1 specific TCR-T cells in vivo was evaluated by quantitative real-time PCR of samples of whole blood at serial time-points before and after cell infusion. Genomic DNA was isolated from whole blood samples using QIAamp DNA blood midi kits (Qiagen, Inc., Valencia, CA, USA) and quantified by spectrophotometer. The qPCR analyses were performed as previously described (31,44–46) using ABI 7900HT Real-Time PCR System (Thermo Fisher Scientific, Inc., Waltham, MA, USA).\n\nT cell tracking and cytokine detection\nThe following antibodies (BD Biosciences, Franklin Lakes, NJ, USA) were used to identify T cells: CD4-PE, CD8-FITC, CD25-FITC, and CD28-PE. Flow cytometry was performed using a BD Accuri™ C6 personal flow cytometer (BD Biosciences) and data were analyzed using FlowJo software (Tree Star, Ashland, OR, USA). Cytokine secretion was evaluated by V-PLEX Human Cytokine 30-Plex kit with measurements by MESO QuickPlex SQ 120 (Meso Scale Discovery, Rockville, MD, USA).\n\nResults\n\nPatients and clinical assessment\nA total of four HLA-A2-positive patients with NY-ESO-1+ metastatic NSCLC received lymphodepleting chemotherapy and then were adoptively transferred with NY-ESO-1 TCR-T cells and coupled with systemic IL-2 administration. Clinical symptoms experienced by the patients and administration of total T cells were listed in Table I. It was revealed that co-incubation of TCR-T cells with Mel 624 cells induced the release of IFN-γ at a median of 3,409 pg/ml, compared to <100 pg/ml in control. All patients with metastatic NSCLC treated with given standard treatments experienced disease progression before being enrolled in the trial. Patients 1 and 2 independently received three and two courses of infusion, respectively, while patients 3 and 4 received just one course of infusion. Patient 1 exhibited stable disease (SD) for nearly 3 months after adoptive transfer of NY-ESO-1 TCR-T cells based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (Table I). Patient 2 experienced a PR lasting 4 months after treatment. Patients (3 and 4) failed to have an observable clinical response after infusion of TCR-T cells. Adverse events probably related to NY-ESO-1 TCR-T cell therapy in four patients with NSCLC were listed in Table II, and toxicities were graded according to NCI CTCAE version 5.0 (November 27, 2017). All patients experienced transient anemia (≤grade 2) and white blood cell decrease (≤grade 3) which were probably induced by the preparative lymphodepleting chemotherapy. These symptoms were relieved after symptomatic treatment, such as granulocyte-colony stimulating factor (G-CSF) infusion and blood transfusion. Three patients exhibited fever (≤grade 3) after administration of IL-2 and recovered upon thermoregulation by themselves or through appropriated treatment. Of note, patient 4 had high fever (40.1°C, grade 3) that was resolved by oral administration of anti-fever medicine acetaminophen and cessation of IL-2 in one hour. In addition, half of the patients exhibited fatigue, rash, nausea, vomiting and abdominal pain. However, it was difficult to draw general conclusions regarding to the clinical efficacy of anit-NY-ESO-1 TCR-T cells in NSCLC due to the small number of patients enrolled in the present study. Therefore, further clinical investigations with a large number of cancer patients are needed in the future to evaluate the safety and efficacy of anit-NY-ESO-1 TCR-T cell therapy for treatment of lung cancer.\n\nCase report of responding patient\nHerein, this study focused on reporting the NY-ESO-1 TCR-T cell treatment in a recruited HLA-A2 positive 44-year-old female patient (patient 2) with metastatic LADC carrying EGFR mutation. Her tumor did not respond to six cycles of combination chemotherapy (docetaxel and carboplatin) in February 2012. In July 2012, she was assessed as having progressive disease (PD) and started to receive treatment with gefitinib for her tumor carrying the EGFR mutation. Computed tomography (CT) scans showed stabilization of her primary lung tumor and liver metastases. However, in January 2015, a surveillance CT scan revealed recurrent disease with new pleural and liver metastases. Treatment was then switched to erlotinib. A follow-up CT scan in September 2015 showed PD in the right pulmonary hilum, mediastinum, right pleura, right hepatic lobe, and liver capsule. There was no central nervous system or skeletal metastases. A bronchoscopic biopsy specimen of the right pulmonary tumor was analyzed by immunohistochemistry and stained strongly for NY-ESO-1 (2+ staining; Fig. 1A). In November 2015, the patient was enrolled in a clinical trial (NCT02457650) assessing autologous T-cell therapy for malignant tumors at the Department of Oncology in Shenzhen Second People's Hospital and the patient provided written informed consent.\n\nA lymphodepleting chemotherapy regimen consisting of CTX (30 mg/kg/d for 2 days) and Flud (25 mg/m2/d for 3 days) was administrated on the patient 2 before the infusion of NY-ESO-1 TCR-T cells. However, before the first infusion of TCR-T cells, a syndrome of pain and hemoptysis aggravated after she received Flud treatment for one day. For the safety of patient 2, Flud treatment was discontinued for the following two days (Fig. 1B). NY-ESO-1 TCR-T cells (3.07×109 total T cells; 2.97×109 TCR-T cells) were then infused over three days (day 0, 1 and 2) (Fig. 1B). Subsequently, IL-2 was administrated according to the patient's physical condition over six consecutive days (Fig. 1B).\n\nA CT scan obtained in day 43 after the first T cell infusion revealed regression of the primary lung tumor and liver metastases, absorption of hydrothorax and pulmonary re-expansion (Fig. 2A). The primary pulmonary lesion size had reduced from 95×86×54 mm to 64×44×54 mm. The metastatic liver lesion had also reduced from 19.8×19.6×20 mm to 10×10×10 mm. The therapeutic effect was assessed as PR according to RECIST 1.1. To further improve treatment efficacy, about one month later, patient 2 received lymphodepleting chemotherapy of CTX (30 mg/kg/d for 2 days) and Flud (25 mg/m2/d for 3 days), a second TCR-T cell infusion (4.54×109 total T cells; 2.87×109 TCR-T cells) within two days (days 74 and 75), and then IL-2 for eight consecutive days (Fig. 1B). However, the patient's disease had progressed when assessed about two months (day 138) after the second infusion (Fig. 1B). CT scans showed the lung tumor (94×88×56 mm) and liver metastases (17.3×16.2×20 mm) had progressed, and the hydrothorax recurred (Fig. 2A). In addition, emission computed tomography (ECT) revealed bone metastases. The efficacy evaluation was PD.\n\nLevels of tumor biomarkers (CEA, CA125, and CA199) were decreased after the initial infusion of TCR-T cells, but later increased. A similar pattern was seen after the second infusion of TCR-T cells targeting NY-ESO-1 (Fig. 2B). The percentage of CD4+ T cells in the peripheral blood of the patient had increased by day 10 after the TCR-T cell infusion, while the percentage of CD8+ T cells was decreased. Furthermore, there was a reduction in the CD8+CD28− subgroup in the blood samples, whereas the percentage of CD4+CD25+ in the peripheral blood had increased by 10 days after the T-cell infusion. However, there were no obvious fluctuations in the proportion of CD8+CD28+cell (Fig. 2C). Of note, the patient had improvement in Karnofsky performance status (KPS) with a score from 50 to 90 post infusion, and resolution of hemoptysis and chest pain. These results indicate that TCR-T cell treatment has improved the patient's clinical symptoms.\n\nLaboratory assays were conducted to track the persistence of TCR-T cells and examine related immunologic response in vivo. As shown in Fig. 3A, after the first infusion (peak value, 6784.48 copies/µg DNA), there was a rapid rise in the quantity of TCR DNA copies in the whole blood samples over 2 weeks after the first infusion. This was followed by a rapid decline. Transduced DNA copies of the NY-ESO-1 specific TCR fluctuated between 330.1 and 166.8 copies per µg DNA at 4 weeks. Similar to the first infusion, the DNA copies of NY-ESO-1-specific TCR reached high levels over the second week (peak value, 2362.02 copies/µg DNA) and then quickly declined over the fourth week after the second TCR-T cell infusion.\n\nFurthermore, patient serum cytokine levels were measured at serial timepoints before and after the cell infusion. IFN-γ levels peaked at the second week after cell infusion (48.92 pg/ml post the first infusion, 47.63 pg/ml post the second infusion) and then gradually degraded to low levels (Fig. 3B). Serum cytokine concentrations of IL-6, IL-10, and granulocyte-macrophage CSF (GM-CSF) displayed little changes (data not shown).\n\nACT of TCR-T cells was well-tolerated by patient 2 and did not induce clinically apparent cytokine release syndrome (CRS). Although patient 2 had a fever (maximum temperature 39.5°C, Grade 2) during and after the infusion, it was successfully resolved within three days. In general, there was no clinical or laboratory evidences revealing SAEs during TCR-T cell therapy for this patient. However, patient 2 suffered a relapse after the TCR-T cell therapy and thus received six cycles of combination chemotherapy (docetaxel and carboplatin). Notably, she kept taking erlotinib before, during and after the clinical trial. As of October 10, 2017, the patient was still alive with SD.\n\nDiscussion\nCancer-testis antigens, such as MAGE-A3 and NY-ESO-1, are promising candidate targets for cell transfer-based immunotherapies due to their specific expression patterns and strong immunogenicity (19,30,31). MAGE-A3 antigen was previously thought to be a preferred target for immunotherapy of cancers, since its expression had been frequently detected in multiple types of tumors but limited in normal somatic cells (47,48). Nevertheless, adoptive transfer of TCR-T cells targeting MAGE-A3 antigen lead to deaths of two patients due to severe neurological toxicity in recent clinical trials (48). This may due to cross-reactivity of TCR-T cells with MAGE-A12, which is expressed at the low level in the brain tissue (48). In addition, engineered T cells expressing affinity-enhanced TCRs targeting MAGE-A3 resulted in deaths of the first two patients in another preliminary clinical trial on melanoma and myeloma due to severe cardiac toxicity, which was confirmed by histopathological analysis of the T cell infiltration (47). The following in-depth investigation in vitro shows that the off-target and off-tumor reactivities maybe due to the cross-reactivity of MAGE-A3 TCR-T cells with the human protein titin, which is highly expressed in cardiac tissue (47,49,50).\n\nNY-ESO-1 is one of the best cancer-testis antigens for immunotherapy due to its strong immunogenicity and specific expression pattern. Early study of adoptive transfer of autologous CD4+ T cells sensitized to NY-ESO-1 peptide in vitro induced tumor regression of metastatic melanoma in 1 of 9 patients (29). Moreover, in a clinical trial conducted by Robbins et al, 11 of 18 HLA-A*0201-positive patients with NY-ESO-1+ synovial cell sarcomas, and 11 of 20 HLA-A*0201-positive patients with NY-ESO-1+ melanoma achieved objective clinical responses following adoptive transfer of NY-ESO-1 TCR-T cells (30). However, one patient with synovial cell sarcomas died three days following the adoptive transfer of NY-ESO-1 TCR-T cells due to septic shock caused by Escherichia coli bacterial infection (30). In another study conducted by Rapoport et al, 16 of 20 patients with myeloma revealed sustained clinical responses following NY-ESO-1 TCR-T cell therapy (31). It was noted that SAEs likely related to treatment, including hypoxia, neutropenia, hyponatremia, hypotension, graft vs. host disease, pancytopenia, and dehydration, were resolved and no treatment related fatalities occurred (31). Meanwhile, no clinically apparent CRS occurred, with the exception of high IL-6 levels (31). By contrast, CRS, which could be potentially life-threatening, was frequently occurred (93%) in 94 patients with refractory large B-Cell lymphoma when treated with CAR-T cells targeting CD19 antigen (51). In the present study, although adverse events likely associated with the TCR-T cell treatment also occurred, including anemia, white blood cell decrease, fever, nausea, fatigue and abdominal pain, they were then resolved by symptomatic treatment. Clinically apparent CRS was not observed, despite transiently high IFN-γ levels. Meanwhile, there were no treatment-related deaths in patients with NSCLC. Taken together, our results show no off-target/off-tumor toxicity and infection. It suggested that NY-ESO-1 TCR-T cell therapy seems to be relatively safe and well-tolerated. Nevertheless, further clinical studies using NY-ESO-1 TCR-T cells in lung cancer and other types of solid tumors are needed in a large number of patients to assess the safety and clinical efficacy of this new treatment.\n\nWe showed that treatment with NY-ESO-1 TCR-T cells mediated tumor regression in a patient (1/4) with metastatic NSCLC. Although patient 2 continued to take erlotinib throughout NY-ESO-1 TCR-T cell treatment for her tumor carrying EGFR mutation, it was unlikely that erlotinib played the main part in tumor size reduction, since the patient did not respond to erlotinib alone prior to infusion. Previous study indicated that lymphodepleting chemotherapy regimen and IL-2 administrated to all of the patients may have contributed to the PR in melanoma and/or synovial cell sarcoma patients (30). Nevertheless, we considered that NY-ESO-1 TCR-T cells played a vital role in tumor regression after the first infusion of the TCR-T cells in this case. Firstly, the expression levels of tumor biomarkers (CEA, CA125, and CA199) showed an inverse association with TCR-T cell persistence in the peripheral blood of the patient. This was indicative of the relationship between the curative effect and NY-ESO-1 TCR-T cells. Secondly, IFN-γ secretion by CD4+ T cells has been shown to be a potential mechanism underlying the therapeutic effect of tumor-specific CD4+ T cells in a mouse model bearing B16 melanoma (52,53). The proportion of CD4+ T cells and levels of IFN-γ in the peripheral blood were increased after TCR-T cell infusion and were positively correlated with NY-ESO-1 TCR-T cells.\n\nAlthough patient 2 initially responded well to the ACT with TCR-T cells and achieved PR for nearly 4 months, tumor relapse eventually occurred after the second infusion of TCR-T cells. According to previous studies, several factors may contribute to tumor recurrence after TCR-T cell therapy. Firstly, a loss of persistence and function of genetically-modified T cells may be associated with tumor relapse (30,31). The persistence of peptide-reactive and tumor-reactive T cells with MART-1- and gp100-recognizing TCRs was positively associated with clinical response (41), while another study showed that relapse was related to the loss of TCR-T cells (31). Therefore, the approaches to sustain the long-term persistence and function of engineered T cells in vivo may benefit the durability of the treatment efficacy (31).\n\nMoreover, the antigen expression pattern, such as expression uniformity at diagnosis, loss of target antigen expression, and/or growth of tumor variants lacking expression of the target antigen post-infusion, was one of principal factors that may influence outcome and tumor relapse following treatment with engineered T cells. Compared to the unsatisfying efficacy of TCR-T cells, clinical trials with CAR-T cells targeting B-cell lineage CD19-differentiation antigen demonstrated remarkable clinical efficacy in the induction of long-term stable remission for B-cell malignancies (17,54,55). Notably, unlike CD19 antigen, which is highly and uniformly expressed on B cells, IHC staining of cancer tissues from the patients in studies revealed heterogeneous expression of cancer-testis antigens, such as NY-ESO-1 in the current study.\n\nFurthermore, tumor cells display very strong plasticity, where therapeutic failure and drug resistance may be due to intratumor heterogeneity, which is featured as dynamic genetic diversity and epigenetic plasticity (56). Patients with metastatic melanoma that underwent adoptive transfer of melanocyte antigen-specific CD8+ T cells displayed post-infusion relapse, where residual nodules revealed selective loss of targeted antigens (gp100, tyrosinase, and MART1) in three of the five patients (57). Other studies have shown antigen escape was associated with PD after treatment with NY-ESO-1 and MAGE-A3 TCR-T cells (19,31). Meanwhile, immunotherapy with antigen-specific T cells has resulted in the outgrowth of antigen-loss tumor variants in some studies (57,58). Suppressive tumor microenvironments expressing inhibitory molecules and receptors, such as PD-1/PD-L1, also contributed to tumor recurrence (59). In the current study, we could not obtain tumor tissue samples for further evaluation after recurrence in the patient 2 due to proximity of the tumor to her right hilus pulmonis. Interestingly, co-treatment with chemotherapy (docetaxel and carboplatin) and erlotinib after treatment with TCR-T cells have controlled disease progression and resulted in SD (as of October 10, 2017).\n\nIn summary, immunotherapy with NY-ESO-1 TCR-T cells in four HLA-A2-positive patients with NSCLC is well tolerated without evident severe toxicities. Among the treated patients, the one with advanced LADC revealed a short-term PR (4 months). Although there are some obstacles that need to be overcome for TCR-T cell therapy in solid tumors, such as identification of suitable target antigens, maintenance of persistence and activity of TCR-T cells, enhancement of TCR-T cell trafficking and function, and improvement of tumor microenvironment with immune suppression (59–61), this and other clinical studies in solid tumors strongly suggest that NY-ESO-1 TCR-T cell immunotherapy is relatively safe and well-tolerated. However, further clinical studies are still warranted in a large number of lung cancer patients.\n\nAcknowledgements\nThe authors would like to thank Dr Wenlan Liu (The First Affiliated Hospital of Shenzhen University) for support with laboratory instruments.\n\nFunding\nThe present study was funded by Shenzhen Peacock Plan (grant no. KQTD20130416114522736); the National Basic Research Program of China (grant no. 2014CB745203), Guangdong Innovative Research Team Program (grant no. 201001Y0104687244), Shenzhen Technology Research Program (grant no. JSGG20160301161836370), Special funds for Dapeng New district industry development (grant nos. KY20150116 and KY20160111) and Natural Science Foundation of Guangdong Province (grant no. 2016A030313238).\n\nAvailability of data and materials\nThe datasets generated and/or analyzed during the current study are not publicly available due to technology secrecy but are available from the corresponding author on reasonable request.\n\nAuthors' contributions\nYX and XT wrote the manuscript, and were responsible for data acquisition, analysis and interpretation; JW, DQ, DB, JC, JY performed TCR-T cell preparation and experimental studies; XL, LX, WL performed clinical studies; MW, GT and RW supervised the entire study, designed the design and approved the protocol. All authors contributed to and approved the final manuscript.\n\nEthics approval and consent to participate\nThe clinical trial (NCT02457650) is registered on ClinicalTrial.gov (https://clinicaltrials.gov/). It was approved by the Medical Ethics Committee of the Institutional Review Board, Shenzhen Second People's Hospital. All procedures performed in studies involving human subjects were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All of the patients enrolled in the trail provided with written informed consent.\n\nPatient consent for publication\nThe patient, or parent, guardian or next of kin provided written informed consent for the publication of any associated data and accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1. NY-ESO-1 TCR-T cell therapy treatment schedule for the patient with LADC. (A) Immunohistochemical analysis revealed 3+ staining for NY-ESO-1. (B) The patient was diagnosed with lung adenocarcinoma in February 2012. Her tumor did not respond to six cycles of combination chemotherapy (docetaxel and carboplatin), gefitinib, or erlotinib by September 2015. The patient was then enrolled in the clinical trial (NCT02457650) and received two separate NY-ESO-1-specific TCR-T cell infusions in November 2015 (days 0, 1, and 2) and January 2016 (Day 74, 75). The patient then received another six cycles of chemotherapy (gemcitabine and cisplatin). In addition, the patient took erlotinib throughout the entire trial period. TCR-T, T cell receptor engineered-T cells; LADC, lung adenocarcinoma; CT, computed tomography; PD, progressive disease; SD, stable disease; IL, interleukin; Flud, fludarabine; CTX, cyclophosphamide; PR, partial response.\n\nFigure 2. Clinical examination. (A) CT scans revealed a primary tumor located in the right pulmonary hilum with metastases to the mediastinum, right pleura, right hepatic lobe, and liver capsule prior to T cell infusions. In January 2016 (day 43), a CT scan obtained 2 months after the first T-cell infusion showed objective regression of the primary lung tumor and liver metastases, as well as hydrothorax absorption and pulmonary re-expansion. In March 2016 (Day 138), a surveillance CT scan detected growth of the primary lung tumor and liver metastases with re-establishment of the hydrothorax. (B) Levels of the tumor biomarkers (CEA, CA125, and CA199) were reduced 2 weeks post infusion, but then increased 4 weeks after the initial infusion of TCR-T cells. A similar pattern was observed after the second infusion of the NY-ESO-1 TCR engineered T-cells. (C) Proportions of T-cell subsets: Percentages of CD4+ and CD8+ T cells in the peripheral blood of the patient were increased and decreased, respectively, by day 10 after the T cell infusion. The CD8+CD28− and CD4+CD25+ T cell subgroups were smaller and larger, respectively, 10 days after the T-cell infusion. There were no obvious changes in the quantity of CD8+CD28+ T cells. CT, computer tomography; TCR-T, T cell receptor engineered-T cells.\n\nFigure 3. Persistence of NY-ESO-1 TCR-T cells and changes in serum IFN-γ. (A) Quantitative real-time PCR was used to assess the persistence of NY-ESO-1 TCR-transduced T-cells in vivo. Results are expressed as the copies of TCR clones per 1 µg DNA. The modified autologous T lymphocytes were undetectable in pre-infusion samples from the patient (sensitivity of detection of 100 copies/µg DNA). The quantity of NY-ESO-1 TCR-T cells had rapidly increased in patient blood samples by 2 weeks. However, there was a rapid decrease in the NY-ESO-1 TCR-T cell population by 4 weeks after the first and second T-cell infusions. (B) Concentration of serum IFN-γ increased 2–14 days post-infusion and then decreased over the following month.\n\nTable I. Clinical symptoms of the patients and administration of anti-NY-ESO-1 TCR-T cells.\n\nPatient\tAge/sex\tDiagnosis\tMetastasis\tPrior treatments\tIntensity of antigen\t% of tumor cells expressing antigen\tTotal cells (×109)\tCD3+/CD4+/CD8+ (% of PBMCs, average)\tAverage IFN-γ (pg/ml)a\tResponse (months)\t\n1\t27/F\tLADC\tLymph nodes, pericardium, pleura, liver, thoracic, ribs, ilium\tChemotherapy, thoracoscope surgery\t2+\t>80\t1.67\t–\t1377.36\tSD (3)\t\n2\t44/F\tLADC\tLymph nodes, liver, pleura\tChemotherapy, target therapy\t2+\t30–40\t7.61\t98.5/2.2/94.8\t1247.08\tPR (4)\t\n3\t59/F\tLADC\tSacral vertebrae\tChemotherapy\t2+\t30\t10.60\t97.88/21/79\t7241.67\tNR\t\n4\t62/M\tLSCC\tLymph nodes\tChemotherapy, radiofrequency ablation\t2+/3+\t40\t8.74\t91.4/11.1/96.3\t3757.10\tNR\t\na IFN-γ released by TCR-T cells in the presence of HLA-A2+ NY-ESO-1+ Mel624 cells was determined by an ELISA assay; LADC, lung adenocarcinoma; LSCC, lung squamous cell carcinoma; SD, stable disease; PR, partial response; NR, non-responder; F, female; M, male; TCR-T, T cell receptor engineered-T cells; PBMC, patient peripheral blood mononuclear cells.\n\nTable II. NY-ESO-1 TCR-T cell therapy-related adverse events in four patients with NSCLC.\n\nEvent\tPatient 1\tPatient 2\tPatient 3\tPatient 4\t\nGeneral disorders and administration site conditions\t\n Chills\t–\t–\t–\t+ (Grade 1)\t\n Fatigue\t+ (Grade 1)\t–\t–\t+ (Grade 1)\t\n Fever\t+ (≤38.6°C, Grade 1)\t+ (≤39.5°C, Grade 2)\t–\t+ (≤40.1°C, Grade 3)\t\n Hyperhidrosis\t+ (Grade 1)\t–\t–\t–\t\nSkin and subcutaneous tissue disorder\t\t\t\t\t\n Rash\t–\t+ (Grade 2)\t+ (Grade 1)\t–\t\nCardiac disorders\t\t\t\t\t\n Palpitations\t–\t–\t+ (Grade 1)\t–\t\nGastrointestinal symptoms\t\t\t\t\t\n Nausea\t+ (Grade 1)\t–\t+ (Grade 2)\t–\t\n Vomiting\t–\t+ (Grade 2)\t+ (Grade 2)\t–\t\n Abdominal pain\t–\t–\t+ (Grade 1)\t+ (Grade 1)\t\nBlood and lymphatic system disorders\t\t\t\t\t\n Anemia\t+ (Grade 2)\t+ (Grade 2)\t+ (Grade 1)\t+ (Grade 1)\t\nInvestigations\t\t\t\t\t\n White blood cell decreased\t+ (Grade 3)\t+ (Grade 3)\t+ (Grade 3)\t+ (Grade 2)\t\nNSCLC, non small cell lung cancer; TCR-T cells, T cell receptor engineered-T cells.\n==== Refs\nReferences\n1 Siegel RL Miller KD Jemal A Cancer statistics, 2017 CA Cancer J Clin 67 7 30 2017 10.3322/caac.21387 28055103 \n2 Zarogoulidis K Zarogoulidis P Darwiche K Boutsikou E Machairiotis N Tsakiridis K Katsikogiannis N Kougioumtzi I Karapantzos I Huang H Spyratos D Treatment of non-small cell lung cancer (NSCLC) J Thorac Dis 5 Suppl 4 S389 S396 2013 24102012 \n3 Ettinger DS Wood DE Aisner DL Akerley W Bauman J Chirieac LR D'Amico TA DeCamp MM Dilling TJ Dobelbower M Non-small cell lung cancer, version 5.2017, NCCN clinical practice guidelines in oncology J Natl Compr Canc Netw 15 504 535 2017 10.6004/jnccn.2017.0050 28404761 \n4 Saito M Suzuki H Kono K Takenoshita S Kohno T Treatment of lung adenocarcinoma by molecular-targeted therapy and immunotherapy Surg Today 48 1 8 2018 10.1007/s00595-017-1497-7 28280984 \n5 Larkin J Chiarion-Sileni V Gonzalez R Grob JJ Cowey CL Lao CD Schadendorf D Dummer R Smylie M Rutkowski P Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma N Engl J Med 373 23 34 2015 10.1056/NEJMoa1504030 26027431 \n6 Robert C Schachter J Long GV Arance A Grob JJ Mortier L Daud A Carlino MS McNeil C Lotem M Pembrolizumab versus Ipilimumab in Advanced Melanoma N Engl J Med 372 2521 2532 2015 10.1056/NEJMoa1503093 25891173 \n7 Kaufman HL Russell J Hamid O Bhatia S Terheyden P D'Angelo SP Shih KC Lebbé C Linette GP Milella M Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: A multicentre, single-group, open-label, phase 2 trial Lancet Oncol 17 1374 1385 2016 10.1016/S1470-2045(16)30364-3 27592805 \n8 Reck M Rodriguez-Abreu D Robinson AG Hui R Csőszi T Fülöp A Gottfried M Peled N Tafreshi A Cuffe S Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer N Engl J Med 375 1823 1833 2016 10.1056/NEJMoa1606774 27718847 \n9 Brahmer JR Immune checkpoint blockade: The hope for immunotherapy as a treatment of lung cancer? 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"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1792-1074",
"issue": "16(6)",
"journal": "Oncology letters",
"keywords": "NY-ESO-1; TCR-engineered T cell; adoptive cell therapy; lung adenocarcinoma; non-small cell lung cancer",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "6998-7007",
"pmc": null,
"pmid": "30546433",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": "9547346;23377668;18424733;12574209;12427970;19795170;20156971;12763934;25317870;28404761;25319501;11846609;20479164;26193902;28809608;18565862;28055103;12747765;27592805;27021308;26425336;25538264;22335739;23770775;28110394;28280984;21282551;20430956;21830940;15871677;22896753;23644516;27718847;25906289;17075125;25823737;24103781;25891173;27603913;9438857;15668127;25838374;18354038;16227990;12445278;25154820;28413717;26193344;26027431;10704737;21832238;28421069;2785562;24329797;24565586;19451549;9432985;29226797;24102012;26373276;15992994",
"title": "Treatment of metastatic non-small cell lung cancer with NY-ESO-1 specific TCR engineered-T cells in a phase I clinical trial: A case report.",
"title_normalized": "treatment of metastatic non small cell lung cancer with ny eso 1 specific tcr engineered t cells in a phase i clinical trial a case report"
} | [
{
"companynumb": "CN-MYLANLABS-2018M1086852",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": "... |
{
"abstract": "BACKGROUND\nLower respiratory tract infection with Pseudomonas aeruginosa (PA) is associated with increased morbidity in patients with cystic fibrosis (CF). Current treatment guidelines for inhaled antibiotics are not universally followed due to the perception of decreased efficacy, increasing resistance, drug intolerance, and high treatment burden with current aerosol antibiotics. New treatment options for CF pulmonary infections are needed.\n\n\nOBJECTIVE\nThis study assessed the efficacy and safety of a novel aerosol formulation of levofloxacin (MP-376, Aeroquin) in a heavily treated CF population with PA infection.\n\n\nMETHODS\nThis study randomized 151 patients with CF with chronic PA infection to one of three doses of MP-376 (120 mg every day, 240 mg every day, 240 mg twice a day) or placebo for 28 days. The primary efficacy endpoint was the change in sputum PA density. Secondary endpoints included changes in pulmonary function, the need for other anti-PA antimicrobials, changes in patient-reported symptom scores, and safety monitoring.\n\n\nRESULTS\nAll doses of MP-376 resulted in reduced sputum PA density at Day 28, with MP-376 240 mg twice a day showing a 0.96 log difference compared with placebo (P = 0.001). There was a dose-dependent increase in FEV(1) for MP-376, with a difference of 8.7% in FEV(1) between the 240 mg twice a day group and placebo (P = 0.003). Significant reductions (61-79%) in the need for other anti-PA antimicrobials were observed with all MP-376 treatment groups compared with placebo. MP-376 was generally well tolerated relative to placebo.\n\n\nCONCLUSIONS\nNebulized MP-376was well tolerated and demonstrated significant clinical efficacy in heavily treated patients with CF with PA lung infection. Clinical trial registered with www.clinicaltrials.gov (NCT00677365).",
"affiliations": "Nemours Children's Clinic, Orlando, FL 32801, USA. dgeller@nemours.org",
"authors": "Geller|David E|DE|;Flume|Patrick A|PA|;Staab|Doris|D|;Fischer|Rainald|R|;Loutit|Jeffery S|JS|;Conrad|Douglas J|DJ|;|||",
"chemical_list": "D000900:Anti-Bacterial Agents; D012996:Solutions; D064704:Levofloxacin; D015242:Ofloxacin",
"country": "United States",
"delete": false,
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"journal": "American journal of respiratory and critical care medicine",
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"medline_ta": "Am J Respir Crit Care Med",
"mesh_terms": "D000280:Administration, Inhalation; D000328:Adult; D000900:Anti-Bacterial Agents; D003550:Cystic Fibrosis; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D064704:Levofloxacin; D015242:Ofloxacin; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa; D012129:Respiratory Function Tests; D012996:Solutions; D013183:Sputum; D016896:Treatment Outcome",
"nlm_unique_id": "9421642",
"other_id": null,
"pages": "1510-6",
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"pubdate": "2011-06-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Levofloxacin inhalation solution (MP-376) in patients with cystic fibrosis with Pseudomonas aeruginosa.",
"title_normalized": "levofloxacin inhalation solution mp 376 in patients with cystic fibrosis with pseudomonas aeruginosa"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US10055",
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"abstract": "We report a case of central nervous system myeloma manifesting as cauda equina nodules, successfully treated with triple intrathecal (IT) chemotherapy, lenalidomide and dexamethasone. After presenting with multiple plasmacytomas which led to a diagnosis of non-secretory myeloma at age 56, the patient underwent multiple episodes of treatment for relapsing myeloma over a 7-year period. In March 2017, he presented with declining gait over a month with bilateral hip flexion weakness, absent lower limb reflexes and dorsal column loss. MRI of the spine revealed multiple enhancing cauda equina nodules at L1-L3. Cerebrospinal fluid (CSF) examination confirmed a clonal plasma cell population and disease was not found elsewhere. He was treated with radiotherapy, IT and intravenous methotrexate and cytarabine. However, repeat lumbar puncture revealed persistent disease. Clearance of CSF plasma cells was achieved with two times a week IT cytarabine, methotrexate and dexamethasone. He was started on lenalidomide and dexamethasone with no evidence of disease progression at 12 months.",
"affiliations": "Clinical Haematology Department, ACT Health, Canberra, Australian Capital Territory, Australia.;Clinical Haematology Department, ACT Health, Canberra, Australian Capital Territory, Australia.;Medical Imaging Department, ACT Health, Canberra, Australian Capital Territory, Australia.;Medical Imaging Department, ACT Health, Canberra, Australian Capital Territory, Australia.",
"authors": "Koo|Ray Mun|RM|;Crispin|Philip|P|;Craft|Melissa|M|;Lalloo|Shivendra|S|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D018931:Antineoplastic Agents, Hormonal; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-226146",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "haematology (drugs and medicines); haematology (incl blood transfusion); neuroimaging",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D018931:Antineoplastic Agents, Hormonal; D002420:Cauda Equina; D016543:Central Nervous System Neoplasms; D003907:Dexamethasone; D006801:Humans; D007278:Injections, Spinal; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009364:Neoplasm Recurrence, Local; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30413447",
"pubdate": "2018-11-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17961180;11989585;18757337;22218812;26679866;22109830;795453",
"title": "Successful treatment of central nervous system myeloma manifesting as cauda equina nodules with intrathecal chemotherapy, lenalidomide and dexamethasone.",
"title_normalized": "successful treatment of central nervous system myeloma manifesting as cauda equina nodules with intrathecal chemotherapy lenalidomide and dexamethasone"
} | [
{
"companynumb": "AU-MYLANLABS-2019M1014019",
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{
"abstract": "Multiple studies have shown seemingly unfavorable changes in lipid profiles associated with interleukin-6 receptor (IL-6R) antagonists and some other therapies for rheumatoid arthritis. The aim of this study was to assess the real-world cardiovascular disease (CVD) risk associated with tocilizumab, the first anti-IL-6R medication approved for the treatment of RA.\n\n\n\nWe conducted a cohort study using 2006-2015 Medicare and MarketScan claims for patients with RA in whom treatment with biologic disease-modifying antirheumatic drugs was initiated after January 1, 2010. The primary outcome was a composite of myocardial infarction, stroke, and fatal CVD, assessed using a validated method. The influence of potential confounding due to RA disease activity was assessed in a subgroup analysis (~5-10% of biologic therapy initiations) using the multi-biomarker disease activity (MBDA) score.\n\n\n\nA total of 88,463 patients with RA were included. The crude incidence rate (IR) per 1,000 patient-years for composite CVD events among Medicare patients ranged from 11.8 (95% confidence interval [95% CI] 9.7-14.4) for etanercept users to 17.3 (95% CI 15.2-19.7) for infliximab users. The crude IR for pooled users of a tumor necrosis factor inhibitor was 15.0 (95% CI 13.9-16.3). Compared to tocilizumab, the corresponding adjusted hazard ratios (HRs) were 1.01 (95% CI 0.79-1.28) for abatacept, 1.16 (95% CI 0.89-1.53) for rituximab, 1.10 (95% CI 0.80-1.51) for etanercept, 1.33 (95% CI 0.99-1.80) for adalimumab, and 1.61 (95% CI 1.22-2.12) for infliximab. There were no statistically significant differences in the risk of CVD between tocilizumab and any other biologic when MarketScan data were used. Results were robust in numerous subgroup analyses and after external adjustment to control for RA disease activity in the subgroup of patients with linked MBDA test results (n = 4,156).\n\n\n\nTocilizumab was associated with a CVD risk comparable to that for etanercept as well as a number of other biologics used for the treatment of RA.",
"affiliations": "University of Alabama, Birmingham.;University of Alabama, Birmingham.;University of Alabama, Birmingham.;University of Alabama, Birmingham.;University of Alabama, Birmingham.",
"authors": "Xie|Fenglong|F|;Yun|Huifeng|H|;Levitan|Emily B|EB|;Muntner|Paul|P|;Curtis|Jeffrey R|JR|0000-0002-8907-8976",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C502936:tocilizumab",
"country": "United States",
"delete": false,
"doi": "10.1002/acr.23737",
"fulltext": null,
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"issn_linking": "2151-464X",
"issue": "71(8)",
"journal": "Arthritis care & research",
"keywords": null,
"medline_ta": "Arthritis Care Res (Hoboken)",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D002318:Cardiovascular Diseases; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D014481:United States",
"nlm_unique_id": "101518086",
"other_id": null,
"pages": "1004-1018",
"pmc": null,
"pmid": "30175897",
"pubdate": "2019-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Tocilizumab and the Risk of Cardiovascular Disease: Direct Comparison Among Biologic Disease-Modifying Antirheumatic Drugs for Rheumatoid Arthritis Patients.",
"title_normalized": "tocilizumab and the risk of cardiovascular disease direct comparison among biologic disease modifying antirheumatic drugs for rheumatoid arthritis patients"
} | [
{
"companynumb": "US-JNJFOC-20160914953",
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"activesubstancename": "PREDNISONE"
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"drugadditional": "3",
"... |
{
"abstract": "BACKGROUND\nIrinotecan is commonly used in combination with oxaliplatin as a component of FOLFIRINOX chemotherapy for several gastrointestinal malignancies. The purpose of this case report is to describe a patient who developed acute paralysis and aphasia while receiving her initial infusion of irinotecan.\n\n\nMETHODS\nA 67-year-old woman with newly diagnosed metastatic pancreatic adenocarcinoma presented for her first cycle of FOLFIRINOX chemotherapy. During her infusion of irinotecan, she developed acute onset of generalized weakness, paralysis of all extremities, and nonfluent aphasia with complete inability to communicate. This episode was self-limited and resolved within 2 h. Prior to subsequent infusions she received intravenous repletion of potassium and had no recurrence of symptoms.\n\n\nCONCLUSIONS\nIn selected cases, coadministration of irinotecan and oxaliplatin may result in severe generalized weakness and aphasia, which may be triggered by underlying electrolyte disturbances. Careful monitoring and correction of potassium may help prevent this reaction.",
"affiliations": "University of Chicago (North Shore), North Shore University Health System, Evanston, Ill., USA.;Kellogg Cancer Center, North Shore University Health System, Evanston, Ill., USA.",
"authors": "Chandar|Manisha|M|;de Wilton Marsh|Robert|R|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000380849",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000380849cro-0008-0138Published online: March, 2015Severe Generalized Weakness, Paralysis, and Aphasia following Administration of Irinotecan and Oxaliplatin during FOLFIRINOX Chemotherapy Chandar Manisha a*de Wilton Marsh Robert baUniversity of Chicago (North Shore), North Shore University Health System, Evanston, Ill., USAbKellogg Cancer Center, North Shore University Health System, Evanston, Ill., USA*Manisha Chandar, DO, University of Chicago (North Shore), 2650 Ridge Avenue, Evanston, IL 60201 (USA), E-Mail manisha.chandar@gmail.comJan-Apr 2015 4 3 2015 4 3 2015 8 1 138 141 Copyright © 2015 by S. Karger AG, Basel2015This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Background\nIrinotecan is commonly used in combination with oxaliplatin as a component of FOLFIRINOX chemotherapy for several gastrointestinal malignancies. The purpose of this case report is to describe a patient who developed acute paralysis and aphasia while receiving her initial infusion of irinotecan.\n\nCase Report\nA 67-year-old woman with newly diagnosed metastatic pancreatic adenocarcinoma presented for her first cycle of FOLFIRINOX chemotherapy. During her infusion of irinotecan, she developed acute onset of generalized weakness, paralysis of all extremities, and nonfluent aphasia with complete inability to communicate. This episode was self-limited and resolved within 2 h. Prior to subsequent infusions she received intravenous repletion of potassium and had no recurrence of symptoms.\n\nDiscussion\nIn selected cases, coadministration of irinotecan and oxaliplatin may result in severe generalized weakness and aphasia, which may be triggered by underlying electrolyte disturbances. Careful monitoring and correction of potassium may help prevent this reaction.\n\nKey Words\nIrinotecanOxaliplatinFOLFIRINOXParalysisAphasiaWeaknessDysarthriaNeurologic side effects\n==== Body\nIntroduction\nIrinotecan is a topoisomerase I inhibitor derived from camptothecin, an alkaloid compound extracted from deciduous trees indigenous to Eastern Asia. Its antineoplastic activity is mediated by its inhibition of double-stranded DNA replication through stabilizing the cleavage complexes of topoisomerase I. Its most common use is in the treatment of colorectal cancer. However, since 2010, it has been combined with 5-fluorouracil, leucovorin, and oxaliplatin in the regimen known as FOLFIRINOX, which has been utilized as an effective therapy in patients with metastatic pancreatic cancer as well as other cancers.\n\nThe most commonly cited adverse effects of irinotecan include late-onset diarrhea and bone marrow suppression, with clinically significant neutropenia and thrombocytopenia. A less frequent, acute cholinergic syndrome with resultant symptoms of diaphoresis, hypotension, anxiety, and abdominal cramping with diarrhea may result in severe discomfort and dehydration that can be life-threatening. Atropine is commonly administered with the chemotherapy infusion both for the prevention and treatment of this syndrome.\n\nOxaliplatin is a third-generation platinum derivative that has shown to be an effective therapy in several malignancies, most commonly gastrointestinal cancers. Side effects of oxaliplatin include a dose-limiting severe peripheral sensory neuropathy that is chronic in onset. Less commonly, acute sensory disturbances that may be modulated by cold temperatures may occur. These effects are thought to be mediated by an interaction with voltage-gated sodium channels in peripheral nerves.\n\nHere we report the case of a patient with a rare complication of combination therapy with irinotecan and oxaliplatin, i.e. severe generalized weakness, paralysis, and aphasia, and provide a synopsis of the current literature as well as a proposed therapeutic approach.\n\nCase Report\nA 67-year old Asian woman with a history of poorly controlled diabetes presented with newly diagnosed metastatic pancreatic adenocarcinoma. In November 2013, she received her first cycle of palliative chemotherapy using FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan180 mg/m2, leucovorin 400 mg/m2 IV, and 5-FU 2,400 mg/m2 IV by continuous infusion over 48 h without a bolus, with dexamethasone 10 mg and ondansetron 12 mg IV as premedication). Prior to beginning therapy with FOLFIRINOX, her electrolyte levels were checked, which revealed mild hypokalemia (3.5 mEq/l, normal values 3.5–5.0) with normal serum sodium and calcium (Na 137 mmol/l, Ca 8.7 mg/dl). She completed the oxaliplatin infusion over 2 h without adverse reaction. Following this, she was given 1 mg atropine IVP prior to infusion of irinotecan and leucovorin. Halfway through the irinotecan infusion, she developed acute onset of generalized weakness, paralysis of all extremities, and nonfluent aphasia with complete inability to communicate. Throughout this, she was awake, alert, and aware of her surroundings, with stable vital signs. At this time, the infusion was stopped and she was given a second dose of atropine 1 mg as well as an IV bolus of 1 l normal saline. She was monitored carefully and observed to return close to her baseline status within 1–2 h. Neither the infusion of irinotecan nor the 5-FU infusion was restarted, and she was discharged to her home with appropriate follow-up.\n\nShe returned 2 weeks later for cycle 2 of her FOLFIRINOX therapy and felt completely well. Prior to initiating the infusion, her electrolyte levels were checked, which showed a low-normal potassium level of 3.7 mEq/l with otherwise normal electrolytes. She received 20 mEq IV KCl supplementation leading to an improvement in the potassium level to 4.4 mEq/l immediately preceding the infusion. She was then given her second cycle of FOLFIRINOX with identical doses of the drugs as in the first cycle and was able to complete all of the therapy without recurrence of the symptoms previously experienced at her initial infusion. She was able to continue on therapy without event for a total of 3 cycles before she transferred her care to an institution closer to her home and was lost to follow-up.\n\nDiscussion\nTo date, there have been 9 reported cases of significant central nervous system toxicity during or following the administration of irinotecan, both with and without concurrent oxaliplatin administration. All of these cases involved the development of dysarthria, with 2 of them leading to a complete motor aphasia and 1 case with associated ataxia [1, 2, 3, 4, 5]. In each case, these symptoms developed with the initial infusion of irinotecan and completely resolved with time. The duration of symptoms ranged from as little as 15 min to as long as 8 h. The duration of symptoms appeared to be related to the dose of irinotecan, with doses <200 mg/m2 having a quicker return to baseline (15–45 min) in comparison to larger doses of >200 mg/m2 (2–8 h). The pathophysiology of these adverse reactions remains poorly understood.\n\nIrinotecan and its primary active metabolite, SN-38, bind strongly to plasma proteins and tissues resulting in high plasma distribution. In animal models, irinotecan and its metabolites have been found to cross the blood-brain barrier into the central nervous system [6]. In 2 patients in whom neurologic symptoms developed during irinotecan administration, Hamberg et al. [4] examined the pharmacokinetics of irinotecan and SN-38 and found both of these values to be within the normal range. The acute onset of symptoms shortly after beginning irinotecan infusion also suggests that the manifestation of these symptoms is not dose or duration dependent. Therefore, it is unlikely that altered systemic clearance of irinotecan mediates the presence or absence of neurologic symptoms in these patients.\n\nThe degree of severe generalized weakness seen in our patient following administration of irinotecan has not previously been reported in the literature. Though no imaging of the brain was performed in our patient, CT and MRI performed in prior similar cases have failed to show any evidence of stroke or other acute CNS abnormalities to explain the clinical presentation. Our patient was found to have mild hypokalemia (3.5 mEq/l) prior to chemotherapy (which may have been even lower following hydration and drug administration), which may have contributed to her profound weakness and inability to move and speak while maintaining a normal sensorium. One case of acquired Fanconi syndrome (characterized by proximal tubular dysfunction resulting in electrolyte wasting of potassium, calcium, phosphate, and uric acid) has been reported following combination therapy with capecitabine, irinotecan, and bevacizumab, but a single offending agent was not identified [7]. Correcting our patient's electrolytes prior to the subsequent infusions and ensuring continued stability of these values throughout the infusion was the only change in the treatment plan and resulted in no recurrence of symptoms. We postulate that close monitoring and repletion of potassium was the factor that prevented further neurologic symptoms.\n\nAs irinotecan alone has not previously been implicated in electrolyte-based neurologic complications, we also consider that the findings in our patient were not caused by irinotecan alone, but rather by combination therapy with oxaliplatin as administered in FOLFIRINOX. Two prior case reports have noted the acute onset of severe neurologic deficits (including generalized weakness, limb weakness, dysarthria, ophthalmoparesis, and coma) during and shortly after the administration of oxaliplatin, which our patient received prior to initiation of irinotecan [8, 9]. In both reported cases, the patients were found to have hypokalemia and hypomagnesemia. These electrolyte derangements were mild in the case reported by Krexner et al. [9] (K 3.1 mEq/l, Mg 0.37 mmol/l) and much more severe in the case reported by Basso et al. [8] (K 1.7 mEq/l), which appears to correlate with the severity of symptoms. In these cases, symptoms developed during the oxaliplatin infusion or within 15 min of completion. Our patient tolerated her oxaliplatin therapy without complications during the infusion, but it is possible that the coadministration of oxaliplatin and irinotecan may have increased the risk of developing these reversible neurologic effects. If this is the case, those patients receiving combination FOLFIRINOX therapy may be at significantly higher risk of developing neurologic side effects than those receiving FOLFOX therapy alone.\n\nFrom our experience in this patient, and from our review of the literature, we conclude that in selected cases, the coadministration of irinotecan and oxaliplatin (as is used in FOLFIRINOX) may result in severe generalized weakness and aphasia. It appears that this may be triggered by underlying and unsuspected electrolyte disturbances. We believe that a careful correction of these abnormalities into the upper ranges of normal as needed, both prior to beginning and during the infusion of oxaliplatin/irinotecan, may prevent this reaction. While the symptoms may be transient and self-limited, they may equally be severe. Without knowledge of their etiology and the appropriate therapy, patients may be denied further treatment or may be reexposed to a serious adverse reaction.\n==== Refs\nReferences\n1 Baz DV Bofill JS Nogueira JAM Irinotecan-induced dysarthria J Natl Cancer Inst 2001 93 1419 1420 11562394 \n2 De Marco S Squilloni E Vigna L et al Irinotecan chemotherapy associated with transient dysarthria and aphasia Ann Oncol 2004 15 1147 1148 15205214 \n3 Dressel AJ Van Der Mijn JC Ijke JA et al Irinotecan-Induced Dysarthria Case Rep Oncol 2012 5 47 51 22379477 \n4 Hamberg P De Jong FA Brandsma D et al Irinotecan-induced central nervous system toxicity Report on two cases and review of the literature. Acta Oncol 2008 47 974 978 \n5 Lee KA Kang HW Ahn JH et al Dysarthria Induced by irinotecan in a patient with colorectal cancer Am J Health Syst Pharm 2013 70 1140 1143 23784161 \n6 Van der Bol JM Mathijssen RHJ Loos WJ et al Cigarette smoking and irinotecan treatment: pharmacokinetic interaction and effects on neutropenia J Clin Oncol 2007 25 2719 2726 17563393 \n7 Shaikh A Wiisanen ME Gunderson HD et al Acquired Fanconi syndrome after treatment with capecitabine, irinotecan, and bevacizumab Ann Pharmacother 2009 43 1370 1373 19584382 \n8 Basso M Cassano A Modoni A et al A Reversible Coma after Oxaliplatin Administration Suggests a Pathogenetic Role of Electrolyte Imbalance Eur J Clin Pharmacol 2008 64 739 741 18350285 \n9 Krexner E Stickler A Prainer C et al Acute, generalised but transient muscle cramping and weakness shortly after first oxaliplatin infusion Med Oncol 2012 29 3592 3593 22669568\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "8(1)",
"journal": "Case reports in oncology",
"keywords": "Aphasia; Dysarthria; FOLFIRINOX; Irinotecan; Neurologic side effects; Oxaliplatin; Paralysis; Weakness",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "138-41",
"pmc": null,
"pmid": "25873880",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "22379477;17563393;18350285;11562394;15205214;23784161;22669568;17924208;19584382",
"title": "Severe Generalized Weakness, Paralysis, and Aphasia following Administration of Irinotecan and Oxaliplatin during FOLFIRINOX Chemotherapy.",
"title_normalized": "severe generalized weakness paralysis and aphasia following administration of irinotecan and oxaliplatin during folfirinox chemotherapy"
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"activesubstance": {
"activesubstancename": "IRINOTECAN HYDROCHLORIDE"
},
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{
"abstract": "Noonan syndrome (NS) is a developmental syndrome caused by germline mutations in the Ras signaling pathway. No association has been shown between NS and pediatric colorectal cancer (CRC). We report the case of CRC in a pediatric patient with NS. The patient underwent whole genome sequencing. A germline SOS1 mutation c.1310T>C (p. Ile437Thr) confirmed NS diagnosis. No known hereditary cancer syndromes were identified. Tumor analysis revealed two mutations: a TP53 missense mutation c.481G>A (p. Ala161Tyr) and NCOR1 nonsense mutation c.6052C>T (p. Arg2018*). This report highlights the complexity of Ras signaling and the interplay between developmental syndromes and cancer.",
"affiliations": "Department of Surgery, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.;Mercy St. Vincent Medical Center, Toledo, Ohio.;Mercy St. Vincent Medical Center, Toledo, Ohio.;Mercy St. Vincent Medical Center, Toledo, Ohio.;Section of Pediatric Surgery, Department of Surgery, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.",
"authors": "Prasad|Rahul M|RM|0000-0003-0636-9370;Mody|Rajen J|RJ|0000-0001-5574-1779;Myers|George|G|;Mullins|Melisa|M|;Naji|Zaher|Z|;Geiger|James D|JD|",
"chemical_list": "C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D020837:SOS1 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27362",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "65(11)",
"journal": "Pediatric blood & cancer",
"keywords": "Noonan syndrome; molecular genetics; pediatric hematology/oncology; rare tumors; solid; tumors",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D015179:Colorectal Neoplasms; D005260:Female; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D009634:Noonan Syndrome; D056971:Nuclear Receptor Co-Repressor 1; D020837:SOS1 Protein; D016159:Tumor Suppressor Protein p53",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27362",
"pmc": null,
"pmid": "30039904",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "21500339;26216840;24739573;18064648;17384584;25374920;26086041;24123833;27064257;22810696;25742478;21531565;26729869;23312968;21387466;23539594;26325560;27135926;21407260;27059373",
"title": "A genome-wide analysis of colorectal cancer in a child with Noonan syndrome.",
"title_normalized": "a genome wide analysis of colorectal cancer in a child with noonan syndrome"
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"activesubstancename": "FLUOROURACIL"
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"abstract": "We report the case of a 65-year-old man with COVID-19 (coronavirus disease-2019) post-infectious encephalitis who presented with delirium as an initial manifestation. He had severe COVID-19 pneumonia and recovered with dexamethasone and tocilizumab. One week after discharge, he developed abnormal behavior and delirium without fever and respiratory symptoms. Brain magnetic resonance imaging showed no abnormalities. Cerebrospinal fluid showed pleocytosis and elevated protein concentrations and was negative for severe acute respiratory syndrome-coronavirus-2 RNA. No anti-neuronal autoantibodies against intracellular and neuronal surface proteins were detected. The cerebrospinal fluid inflammatory changes compatible with post-infectious encephalitis, and the patient recovered with intravenous methylprednisolone and intravenous immunoglobulin therapy. Delirium could be an initial symptom of post-infectious encephalitis in older adults with COVID-19, and these patients may require immunosuppressive therapy.",
"affiliations": "Division of Neurology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Neurology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Neurology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Neurology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.;Division of Respiratory Medicine, Department of Medicine, Nihon University School of Medicine.;Division of Respiratory Medicine, Department of Medicine, Nihon University School of Medicine.;Division of Neurology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.",
"authors": "Hara|Makoto|M|;Kouda|Kento|K|;Mizoguchi|Tomotaka|T|;Yokota|Yuki|Y|;Hayashi|Kentaro|K|;Gon|Yasuhiro|Y|;Nakajima|Hideto|H|0000-0002-2154-9196",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096\nSAGE Publications Sage CA: Los Angeles, CA\n\n34229469\n10.1177/23247096211029787\n10.1177_23247096211029787\nCase Report\nCOVID-19 Post-Infectious Encephalitis Presenting With Delirium as an Initial Manifestation\nHara Makoto MD 1\nKouda Kento MD 1\nMizoguchi Tomotaka MD 1\nYokota Yuki MD 1\nHayashi Kentaro MD 2\nGon Yasuhiro MD 2\nhttps://orcid.org/0000-0002-2154-9196\nNakajima Hideto MD 1\n1 Division of Neurology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan\n2 Division of Respiratory Medicine, Department of Medicine, Nihon University School of Medicine\nHideto Nakajima, MD, PhD, Division of Neurology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi, Tokyo 173-8610, Japan. Email: nakajima.hideto@nihon-u.ac.jp\n7 7 2021\nJan-Dec 2021\n9 2324709621102978724 4 2021\n2 6 2021\n12 6 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\nhttps://creativecommons.org/licenses/by-nc/4.0/ 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 page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nWe report the case of a 65-year-old man with COVID-19 (coronavirus disease-2019) post-infectious encephalitis who presented with delirium as an initial manifestation. He had severe COVID-19 pneumonia and recovered with dexamethasone and tocilizumab. One week after discharge, he developed abnormal behavior and delirium without fever and respiratory symptoms. Brain magnetic resonance imaging showed no abnormalities. Cerebrospinal fluid showed pleocytosis and elevated protein concentrations and was negative for severe acute respiratory syndrome-coronavirus-2 RNA. No anti-neuronal autoantibodies against intracellular and neuronal surface proteins were detected. The cerebrospinal fluid inflammatory changes compatible with post-infectious encephalitis, and the patient recovered with intravenous methylprednisolone and intravenous immunoglobulin therapy. Delirium could be an initial symptom of post-infectious encephalitis in older adults with COVID-19, and these patients may require immunosuppressive therapy.\n\nCOVID-19\nSARS-CoV-2\npost-infectious encephalitis\ndelirium\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nThe new coronavirus disease-2019 (COVID-19) caused by the new coronavirus (severe acute respiratory syndrome-coronavirus-2 [SARS-CoV-2]) in Wuhan, China, in 2019 became a global epidemic in 2020. Although SARS-CoV-2 causes acute respiratory infections, it is often accompanied by neurological symptoms such as headache, impaired consciousness, delirium, myopathy, and dysosmia. 1 Also, various neurological complications such as cerebral infarction, encephalitis/encephalopathy, and autoimmune diseases have been reported.2-4 As the pathological condition of the neurological complications of COVID-19, (1) direct invasion of virus into the nervous system, (2) neurological symptoms of COVID-19 as a systemic disease, and (3) para-infectious/post-infectious neurological complications, are assumed. 5 In this article, we present a case of post-infectious encephalitis associated with COVID-19 who presented with delirium as an initial manifestation.\n\nCase Presentation\n\nA 65-year-old man was presented to the emergency department complaining of shortness of breath, fever, cough, and myalgia for 1 week. His history included a 5-year period of diabetes and sleep apnea syndrome, and he had received continuous positive airway pressure therapy. When examined, he was overweight (106 kg body weight, 34.2 kg/m2 body mass index), body temperature of 39.9 °C, blood pressure 142/88 mm Hg, heart rate 120 beats per minute, and respiratory rate 20 breaths per minute. His percutaneous oxygen saturation (SpO2) was 90% and increased to 95% on 2 L/min oxygen supplementation. Both nasopharyngeal rapid antigen test and reverse transcription-polymerase chain reaction (RT-PCR) assay confirmed SARS-CoV-2 infection. Chest radiographs and computed tomography (CT) of the chest showed progressive bilateral patchy interstitial opacities. Laboratory results revealed lymphopenia, elevated C-reactive protein (4.7 mg/dL), and elevated D-dimers (1.2 g/mL). He received azithromycin and favipiravir. In addition, dexamethasone and prophylactic doses of low-molecular-weight heparin were started. Despite these treatments, hypoxemia deteriorated within several days from admission, and his SpO2 decreased to 90% regardless of an oxygen supplementation of 12 L/min. His chest CT revealed extensive bilateral airspace consolidations and ground-glass opacities (Figure 1A), and the interleukin-6 inhibitor tocilizumab at 8 mg/kg (800 mg) was administered as a single infusion on day 7. After tocilizumab infusion, the patient’s state significantly improved, and on day 26, he was discharged from hospital after confirming significant improvement in his CT scan (Figure 1B) and 2 negative SARS-CoV-2 RT-PCR from nasopharyngeal swabs. He did not receive a tracheal intubation during the hospitalization.\n\nFigure 1. The evolution of pulmonary infiltrates in computed tomography (CT). There are extensive bilateral airspace consolidations and ground-glass opacities (A). CT after tocilizumab therapy shows significant improvement (B). CT on second admission reveals further regression of pulmonary changes (C).\n\nHowever, 1 week after the discharge, he developed confusion and verbal communication difficulties, and presented to our department for further evaluation. At presentation, he had no fever, cough, or respiratory symptoms at presentation. Although he showed abnormal behavior and delirious state, his neurologic examination including meningeal irritation sign was normal. Brain magnetic resonance imaging including 3-dimensional volumetric fluid-attenuated inversion recovery and diffusion-weighted imaging revealed no abnormalities in the cerebral cortex/parenchyma, brainstem, and cerebellum. Nasopharyngeal PCR testing was negative for SARS-CoV-2. His SpO2 was 96%, and laboratory results showed normal C-reactive protein (<0.10 mg/dL) and D-dimers (<1.0 g/mL). His chest CT showed further regression of pulmonary changes (Figure 1C). CSF examination revealed pleocytosis (18/mm3), a high protein level of 115 mg/dL, and no oligoclonal immunoglobulin G bands. SARS-CoV-2 RNA, herpes simplex virus DNA, and varicella-zoster virus DNA were negative in CSF. Concerning autoimmune encephalitis, autoantibodies against intracellular (Hu, Yo, CV2, Ri, Ma2/Ta, GAD65, amphiphysin, recoverin, SOX1, titin, zic4, Tr) and surface antigens (NMDAR, LGI-1, AMPAR, Casper 2, GABAR, DPPX, IgLON5) relevant to central nervous system diseases measured by line blots (EUROLINE, Euroimmun) and cell-based assays (BIOCHIP, Euroimmun, performed by Labor Berlin) were all negative. Additionally, tissue-based assay revealed no anti-neuronal autoantibodies in the patient’s CSF.6,7 Serum aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies were also negative. The patient initiated 1 g/day intravenous methylprednisolone immunosuppressant therapy for 6 days, followed by oral prednisolone (60 mg/day). His delirious state did not improve; however, intravenous immunoglobulin (IVIG) was administered additionally on day 9. His symptoms demonstrated significant improvement after IVIG initiation. Oral prednisolone was tapered, and he was discharged without any symptoms or sequelae on day 24 of the second hospitalization.\n\nDiscussion\n\nWe have described the case of post-infectious encephalitis associated with COVID-19 who presented with delirium as an initial manifestation. A wide variety of neurological symptoms has been observed among patients with COVID-19. Recent reports indicated that SARS-CoV-2 can present with neurological features and concomitant encephalitis/encephalopathy in serious cases of COVID-19.2-4 SARS-CoV-2 has rarely been detected in CSF, 8 and there is accumulating evidence that mechanisms other than direct viral invasion in the CNS contribute to neuropathology.9,10 Thus, cytokine storms associated with COVID-19 and the immunoreaction may contribute to brain edema and inflammatory changes, including the pathological condition of acute disseminated encephalomyelitis or acute necrotizing encephalopathy.3,4 Recent reports indicated that COVID-19 patients presenting with neurological symptoms, including myoclonus, oculomotor disturbance, delirium, dystonia, and epileptic seizures showed anti-neuronal autoantibodies in serum or CSF.11,12 In the present patient, no anti-neuronal autoantibodies against intracellular and neuronal surface proteins were detected. However, elevated CSF protein and pleocytosis with negative SARS-CoV-2 RT-PCR revealed inflammatory changes consistent with post-infectious/autoimmune encephalitis. We were unable to recognize evidence of inflammation on his brain magnetic resonance imaging, this is not uncommon in cases of post-COVID-19 autoimmune encephalitis.13,14 Also, this case was remarkable because encephalitis appeared after the regression of COVID-19 pneumonia and the efficacy of immunomodulation with corticosteroid and IVIG supports an immunological mechanism. However, it is unclear whether the combination of steroid and IVIG was effective to his improvement or whether the same outcome could be obtained using steroids alone.\n\nInitially, his delirium was considered to be due to the re-exacerbation of COVID-19 pneumonia, other complications, and metabolic factors by therapeutic agents. However, his laboratory and chest CT results showed no lung injury, and the various examinations results and his clinical course revealed post-infectious encephalitis associated with COVID-19. Among the older adults with COVID-19, delirium was one of the common symptoms at presentation (28%), and was often seen without other typical symptoms. 15 In addition, delirium was associated with poor outcome and hospital death. 15 The cause of delirium is assumed to reduce blood oxygen levels, deterioration of circulation dynamics, or complications for sepsis. Our case suggested that some older adults with COVID-19 presenting delirium should be attributable to post-infectious encephalitis and that those patients may require immunosuppressive therapy.\n\nConclusion\n\nWe reported the case of post-infectious encephalitis associated with COVID-19 who presented with delirium as an initial manifestation. Since delirium can be the initial symptom of post-infectious encephalitis, especially in older adults with COVID-19, an active examination should be required in consideration of immunosuppressive therapy.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient for their anonymized information to be published in this case report.\n\nORCID iD: Hideto Nakajima https://orcid.org/0000-0002-2154-9196\n==== Refs\nReferences\n\n1 Mao L Jin H Wang M , et al . Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77 :683-690.32275288\n2 Helms J Kremer S Merdji H , et al . Neurologic features in severe SARS-CoV-2 infection. N Engl J Med. 2020;382 :2268-2270.32294339\n3 Kremer S Lersy F Anheim M , et al . Neurologic and neuroimaging findings in COVID-19 patients: a retrospective multicenter study. Neurology. 2020;95 :e1868-e1882.32680942\n4 Paterson RW Brown RL Benjamin L , et al . The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain. 2020;143 :3104-3120.32637987\n5 Ellul MA Benjamin L Singh B , et al . Neurological associations of COVID-19. Lancet Neurol. 2020;19 :767-783.32622375\n6 Hara M Nakajima H Kamei S. Practical approach for the diagnosis of disorders associated with antibodies against neuronal surface proteins. Neurol Clin Neurosci. 2021;9 :56-62. doi:10.1111/ncn3.12462\n7 Hara M Ariño H Petit-Pedrol M , et al . DPPX antibody-associated encephalitis: main syndrome and antibody effects. Neurology. 2017;88 :1340-1348.28258082\n8 Neumann B Schmidbauer ML Dimitriadis K , et al . Cerebrospinal fluid findings in COVID-19 patients with neurological symptoms. J Neurol Sci. 2020;418 :117090.32805440\n9 Solomon IH Normandin E Bhattacharyya S , et al . Neuropathological features of covid-19. N Engl J Med. 2020;383 :989-992.32530583\n10 Matschke J Lütgehetmann M Hagel C , et al . Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. 2020;19 :919-929.33031735\n11 Franke C Ferse C Kreye J , et al . High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms. Brain Behav Immun. 2021;93 :415-419.33359380\n12 Hosseini AA Shetty AK Sprigg N , et al . Delirium as a presenting feature in COVID-19: neuroinvasive infection or autoimmune encephalopathy? Brain Behav Immun. 2020;88 :68-70.32531427\n13 Khoo A McLoughlin B Cheema S , et al . Postinfectious brainstem encephalitis associated with SARS-CoV-2. J Neurol Neurosurg Psychiatry. 2020;91 :1013-1014.32636212\n14 Guilmot A Maldonado Slootjes S , et al . Immune-mediated neurological syndromes in SARS-CoV-2-infected patients. J Neurol. 2021;268 :751-757.32734353\n15 Kennedy M Helfand BKI Gou RY , et al . Delirium in older patients with COVID-19 presenting to the emergency department. JAMA Netw Open. 2020;3 :e2029540.\n\n",
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"keywords": "COVID-19; SARS-CoV-2; delirium; post-infectious encephalitis",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000368:Aged; D001921:Brain; D000086382:COVID-19; D003693:Delirium; D018792:Encephalitis, Viral; D006801:Humans; D008168:Lung; D008279:Magnetic Resonance Imaging; D008297:Male; D000086402:SARS-CoV-2; D014057:Tomography, X-Ray Computed",
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"title": "COVID-19 Post-Infectious Encephalitis Presenting With Delirium as an Initial Manifestation.",
"title_normalized": "covid 19 post infectious encephalitis presenting with delirium as an initial manifestation"
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"abstract": "This article employs a paediatric case study, involving a 3-year-old child who had an anaphylactic reaction that occurred as a result of the multidisciplinary team's failure to identify and acknowledge the patient's documented 'known allergy' status. It examines and reconsiders the ongoing healthcare dilemma of medication errors and recommends that known allergy status should be considered the second medication administration 'right' before the prescribing, transcribing, dispensing and administration of any drug. Identifying and documenting drug allergy status is particularly important when caring for paediatric patients, because they cannot speak for themselves and must rely on their parents, guardians or health professionals as patient advocates. The literature states that medication errors can be prevented by employing a 'rights of medication administration' format, whether that be the familiar '5 rights' or a more detailed list. However, none of these formats specify known allergy status as a distinct 'right'. The medication safety literature is also found wanting in respect of the known allergy status of the patient. When health professionals employ a medication administration rights format prior to prescribing, transcribing, dispensing or administering a medication, the 'known allergy status' of the patient should be a transparent inclusion.",
"affiliations": "Associate Professor, Department of Nursing, Faculty of Medicine and Health Sciences, Universiti of Malaysia, UNIMAS, Sarawak, Malaysia.",
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"keywords": "Drug allergy status; Medication administration; Medication error; Patient safety",
"medline_ta": "Br J Nurs",
"mesh_terms": "D002675:Child, Preschool; D004342:Drug Hypersensitivity; D006801:Humans; D008508:Medication Errors; D061214:Patient Safety; D017751:Safety Management",
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"title": "Should known allergy status be included as a medication administration 'right'?",
"title_normalized": "should known allergy status be included as a medication administration right"
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"abstract": "Right-sided infective endocarditis (RIE) is commonly due to Staphylococcus aureus and often involves the tricuspid valve (TV). A 31-year-old man with prior intravenous drug use presented with substernal pain, cough, dyspnoea and fever. Examination revealed a febrile, tachycardic male with peripheral infective endocarditis stigmata and right-heart failure. Laboratory parameters demonstrated leucocytosis, lactic acidosis and methicillin-resistant S. aureus (MRSA) bacteraemia. Echocardiography demonstrated multiple TV echodensities and chest imaging confirmed septic emboli. The MRSA species demonstrated 'vancomycin-creep', necessitating therapy with daptomycin and ceftaroline. Owing to persistent bacteraemia and septic shock, the patient underwent TV surgery, but continued to have a poor postoperative course with subsequent death. Indications for surgical therapy of RIE are limited to the European guidelines and most data are extrapolated from left-heart disease. MRSA exhibiting vancomycin-creep portends a poorer prognosis and requires aggressive therapy. We advocate the use of ceftaroline salvage therapy with daptomycin, pending further trials.",
"affiliations": "Division of Hospital Internal Medicine, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.;Division of Critical Care Medicine, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.;Department of Internal Medicine, Creighton University School of Medicine, Omaha, Nebraska, USA.;Division of Cardiovascular Diseases, Department of Internal Medicine, Creighton University School of Medicine, Omaha, Nebraska, USA.",
"authors": "Sundaragiri|Pranathi Rao|PR|;Vallabhajosyula|Saraschandra|S|;Haddad|Toufik Mahfood|TM|;Esterbrooks|Dennis J|DJ|",
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"nlm_unique_id": "101526291",
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"title": "Tricuspid and mitral endocarditis due to methicillin-resistant Staphylococcus aureus exhibiting vancomycin-creep phenomenon.",
"title_normalized": "tricuspid and mitral endocarditis due to methicillin resistant staphylococcus aureus exhibiting vancomycin creep phenomenon"
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"abstract": "Serum magnesium concentration is determined by the interplay of intestinal absorption and renal excretion. Hypomagnesemia can occur as a result of insufficient magnesium intake, increased gastrointestinal or renal loss, or redistribution from extracellular to intracellular compartments. A number of drugs are known to cause hypomagnesemia, including proton pump inhibitors (PPIs). We report the case of a patient with symptomatic hypomagnesemia due to short bowel syndrome and PPI therapy. Investigations revealed low 24-hour urinary magnesium excretion and secondary hypocalcemia. PPI treatment was withdrawn and the patient was managed with intravenous and oral magnesium and calcium replacement. This teaching case provides an evidence-based discussion of the treatment of hypomagnesemia.",
"affiliations": "Department of Endocrinology, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom.;Department of Endocrinology, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom. Electronic address: neil.gittoes@uhb.nhs.uk.",
"authors": "Ayuk|John|J|;Gittoes|Neil J L|NJ|",
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"keywords": "Hypomagnesemia; intravenous magnesium sulfate; oral magnesium salts; proton pump inhibitor; treatment",
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"mesh_terms": "D058070:Asymptomatic Diseases; D005260:Female; D006801:Humans; D007408:Intestinal Absorption; D008274:Magnesium; D017616:Magnesium Compounds; D008275:Magnesium Deficiency; D008875:Middle Aged; D054328:Proton Pump Inhibitors; D012778:Short Bowel Syndrome",
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"title": "Treatment of hypomagnesemia.",
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"abstract": "Voriconazole, a broad-spectrum antifungal, has been associated with visual and auditory hallucinations. We report the case of patient being treated with voriconazole for pulmonary aspergillosis who developed visual hallucinations and new suicidal ideation with plan. Voriconazole troughs were supratherapeutic (9.0 mcg/mL) and the patient was positive for the CYP2C19*1/*2 allele.",
"affiliations": "PGY2 Infectious Diseases Pharmacy Resident and.;Clinical Pharmacy Specialist, VA St. Louis Health Care System, Missouri; and.;Clinical Pharmacy Specialist, VA St. Louis Health Care System, Missouri; and.",
"authors": "Jansen|Jeffrey W|JW|;Sen|Sumon K|SK|;Moenster|Ryan P|RP|",
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"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n28480228\n10.1093/ofid/ofw215\nofw215\nID Case\nElevated Voriconazole Level Associated With Hallucinations and Suicidal Ideation: A Case Report\nJansen Jeffrey W. 1 Sen Sumon K. 2 Moenster Ryan P. 23 1 \nPGY2 Infectious Diseases Pharmacy Resident and\n2 \nClinical Pharmacy Specialist, VA St. Louis Health Care System, Missouri; and\n3 \nDepartment of Pharmacy Practice, St. Louis College of Pharmacy, Missouri\nCorrespondence: R. P. Moenster, PharmD, FIDSA, Clinical Pharmacy Specialist–Infectious Diseases, VA St. Louis Health Care System, Associate Professor of Pharmacy Practice, St. Louis College of Pharmacy, 4588 Parkview Pl., St. Louis, MO 63110 (ryan.moenster@stlcop.edu).\n\n\nWinter 2017 \n19 1 2017 \n19 1 2017 \n4 1 ofw21511 8 2016 11 1 2017 © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nVoriconazole, a broad-spectrum antifungal, has been associated with visual and auditory hallucinations. We report the case of patient being treated with voriconazole for pulmonary aspergillosis who developed visual hallucinations and new suicidal ideation with plan. Voriconazole troughs were supratherapeutic (9.0 mcg/mL) and the patient was positive for the CYP2C19*1/*2 allele.\n\naspergilosissuicidal ideationsupratherapeuticvoriconazole\n==== Body\nVoriconazole, a broad-spectrum triazole antifungal, is first-line therapy for serious fungal infections, including invasive pulmonary aspergillosis. In clinical trials, and subsequent case reports and retrospective analyses, one of the most common adverse events associated with therapy has been visual and auditory hallucinations, but no reports of suicidal ideation with plan have ever been reported [1, 2]. These central nervous system adverse reactions have been associated with elevated voriconazole levels, which could be the result of incorrect dosing, drug-drug interactions, or genetic variance in the ability to metabolize the drug [2]. In this study, we report the first possible case of suicidal ideation with plan related to elevated voriconazole levels in a patient who was found to be an intermediate voriconazole metabolizer.\n\nPATIENT CASE\nA 67-year-old white male (79.3 kg) with a history of relapsing polychondritis on chronic prednisone therapy, alcoholic hepatitis, chronic pancreatitis, and chronic obstructive pulmonary disorder presented to the emergency department (ED) for evaluation of fatigue, weakness, and fevers (home medications can be found in Table 1). In the ED, the patient was found have an oxygen saturation of 84% on room air and was initiated on vancomycin, cefepime, metronidazole, and treatment doses of sulfamethoxazole/trimethoprim for possible pneumonia. The patient was noted to have diffuse pulmonary infiltrates, and, because of failure to improve on broad-spectrum therapy, the pulmonary service was consulted and decided to perform a bronchoalveolar lavage (BAL). Cultures from the BAL ultimately grew Candida albicans and Aspergillus fumigatus. In addition, a galactomannan serum antigen test was obtained, while on antibiotics, and was found to be positive at 4.57 pg/mL (<0.5 pg/mL). It was determined not to obtain a second galactomannan level because the turnaround time would have been 7 days, but because of the culture and initial galactomannan results, voriconazole was initiated at 400 mg orally every 12 hours for 2 doses, then 200 mg orally every 12 hours.\n\nTable 1. Medications Before Admission\n\nAlbuterol/ipratropium 100/20 micrograms 1 puff inhaled every 6 hours for chronic obstructive pulmonary disease (COPD)\t\nAlbuterol 90 micrograms 2 puffs inhaled every 6 hours as needed for shortness of breath\t\nAzathioprine 150 milligrams by mouth once daily for relapsing polychondritis\t\nBudesonide/formoterol 80/4.5 micrograms 2 puffs inhaled twice daily for COPD\t\nCreon extended release capsules 48000 units 3 times a day with meals for chronic pancreatitis\t\nNifedipine sustained release 30 milligrams once daily for hypertension\t\nPrednisone 40 milligrams once daily for relapsing polychondritis\t\nSennosides 8.6 milligrams twice daily for constipation\t\nSulfamethoxazole/trimethoprim 400/80 milligrams once daily for prevention of infection while on immunosuppressive therapy\t\nTamsulosin 0.4 milligrams once daily for benign prostatic hypertrophy\t\nTramadol 50 milligrams 1–2 tablets every 6 hours as needed for pain\t\nValacyclovir 500 milligrams once daily for prevention of infection while on immunosuppressive therapy\t\nOn day 2 of voriconazole therapy, the patient reported having some visual hallucinations, such as seeing “patterns on ceiling” and “seeing people in his room that weren’t there”; however, the patient’s mental status remained at his baseline. On day 5 of voriconazole therapy, the patient reported having hallucinations and confusion intermittently at night and during the day, which would spontaneously improve. The patient was fully aware of these episodes and knew they were hallucinations. On day 12 of voriconazole therapy, the patient reported new suicidal ideation with a plan of jumping out of his window to his nurse, along with continued mild hallucinations. The patient had previously reported situational depression secondary to his illness but had no formal history of mental disorders and had never previously reported suicidal ideations.\n\nA voriconazole trough level, obtained on day 7, was elevated at 9.0 mcg/mL (therapeutic range, ~2.0–5.0 mcg/mL). Given the supratherapeutic level, visual hallucinations, and new suicidal ideation, which were thought to be secondary to high voriconazole levels, the infectious diseases consult service recommended discontinuing voriconazole; no additional antifungal therapy was initiated due to the belief that Aspergillus sp found on BAL represented non-pathogenic colonization. In addition, material from the first BAL was evaluated by pathology and read as “probable infection with Pneumocystis jiroveci”, and treatment with sulfamethoxazole/trimethoprim was continued for 28 days; the patient’s respiratory status continued to improve and eventually returned to baseline.\n\nBefore being placed on voriconazole therapy, the patient was initiated on omeprazole for stress ulcer prophylaxis and prednisone treatment was continued. To help explain why this patient experienced elevated levels of voriconazole therapy and adverse reactions, a CYP2C19 genotype was ordered and was found to be positive for the *1/*2 allele. This means the patient carries a single nonfunctional CYP2C19 genetic variant that causes reduced metabolism of some drugs; this patient was likely to be an intermediate metabolizer of voriconazole.\n\nDISCUSSION\nAuditory and visual hallucinations secondary to voriconazole toxicity have been widely reported in the literature; however, this is the first report of hallucinations complicated by suicidal ideation with plan in a patient receiving voriconazole [1–3]. Clinical trials of voriconazole report an incidence of visual disturbances of 0% to 9%, whereas smaller analyses report rates of 16.6% or greater [2, 4]. Hallucinations have been described with both intravenous and oral administration of voriconazole [2]. Furthermore, these hallucinations have been correlated with increased drug exposure, as determined by serum trough levels. One analysis showed that hallucinations occurred in 32% of patients with serum concentrations >5 mg/L compared with 1.2% of patients with serum concentrations ≤5 mg/L (P < .01) [5]. Another analysis found that the hazard ratio for neurologic adverse events due to voriconazole was 2.27 (95% confidence interval, 1.45–3.56; P < .001) with every 0.1 µg/mL increase in serum concentration [6]. Because increased voriconazole serum concentrations result in increased incidence of neurologic adverse events, external variables that may have contributed to supratherapeutic voriconazole concentrations in our patient must be explored. These variables include voriconazole metabolism, dose, and drug-drug interactions.\n\nVoriconazole displays nonlinear kinetics due to saturable metabolism. Voriconazole is metabolized through hepatic cytochrome P450 (CYP450) enzymes, primarily CYP2C19, with limited metabolism through CYP3A4 and CYP2C9 [7, 8]. CYP2C19 is known to have genetic polymorphisms that can result in either increased or decreased voriconazole metabolism. Two clinically significant loss of function (LoF) alleles have been described, CYP2C19*2 and CYP2C19*3, with a prevalence in whites of 15% and <1%, respectively [7]. The most common genetic polymorphism observed in CYP2C19 is the gain of function (GoF) allele CYP2C19*17, with a prevalence of 22% in whites [7]. Patients expressing homozygous LoF CYP2C19 alleles have voriconazole exposure 3- to 4-fold higher than wild-type (CYP2C19*1) patients, and patients with heterozygous LoF CYP2C19 alleles have voriconazole exposure 1.5- to 2-fold higher than wild-type patients [1, 9]. In contrast, a single GoF allele results in a 50% decrease in voriconazole exposure, which is further decreased with homozygous GoF alleles [9]. One analysis found a significant increase in serum concentration between patients with CYP2C19*2/*2 and CYP2C19*1/*1 (P = .006); however, the difference in serum concentrations between CYP2C19*1/*2 patients and CYP2C19*1/*1 was not significant [7].\n\nVoriconazole is commonly dosed at 6 milligram per kilogram per dose for 2 doses and then decreased to 3 to 4 milligram per kilogram per dose twice daily [4, 10]. In clinical trials, a standardized oral dose of 200 mg twice daily was used for conversion to oral therapy [4, 11]. The average weight of the population in one clinical trial of voriconazole was 70.4 kg, for which the 200 mg twice daily adheres to the 3 to 4 mg/kg per dose recommendation [4]. An analysis of voriconazole dose and trough levels found that these 2 variables were poorly correlated due interpatient variability [12]. Rather, a relationship between voriconazole dose, CYP2C19 genotype, and voriconazole trough level has been described in a population pharmacokinetic model. The model revealed that patients with a single CYP2C19*17 GoF allele would likely require doses of at least 300 mg twice daily to achieve serum concentrations ≥2 mg/L. Furthermore, the model predicted that 29%–39% of patients receiving 200 mg twice daily with at least 1 CYP2C19*2 allele, like the patient described in the above report, would be at risk of serum concentration ≥5 mg/L [8].\n\nVoriconazole inhibits the fungal CYP450 enzyme 14-α demethylase, which is essential for the conversion of lanosterol to ergosterol. Although voriconazole targets a fungal CYP450 enzyme, cross inhibition of human CYP450 enzymes occurs, resulting in the potential for many drug-drug interactions. Proton pump inhibitors, especially omeprazole, have been previously described to increase voriconazole exposure through competitive inhibition of CYP2C19 [5, 8]. Phenytoin, rifampin, St. John’s wort, and glucocorticoids have all been associated with decreased voriconazole exposure through induction of CYP2C19 and CYP3A4 [5, 8].\n\nCONCLUSIONS\nA case report of a 43-year-old Indian woman shares a similar presentation to the patient reported here, with the exception of suicidal ideation. This woman experienced voriconazole induced hallucinations with a serum concentration of 7.8 mg/L while receiving 200 mg twice daily. The patient was heterozygous for CYP2C19*2 and receiving chronic immunosuppression with prednisone and taking daily esomeprazole, similar to the current patient [13]. Our patient expressed a single CYP2C19*2 allele, received a voriconazole dose of 200 mg twice daily (2.52 mg/kg per dose), and was concurrently receiving omeprazole and prednisone. Despite the large interpatient variability of voriconazole, our patient’s voriconazole trough of 9.0 mg/L was unexpectedly elevated given the relatively low dose and single LoF allele. Furthermore, omeprazole is known to increase voriconazole exposure, but prednisone has been associated with decreased voriconazole exposure [5, 8]. Both patients developed supratherapeutic voriconazole troughs while receiving omeprazole and prednisone therapy concurrently; it seems possible that the CYP2C19 genotype, which was the same for both patients, and the proton pump inhibitor had a greater effect on voriconazole levels than did chronic prednisone therapy. The use of therapeutic drug monitoring and CYP2C19 genotyping in patients with symptoms of voriconazole toxicity is further warranted, and it seems feasible to consider suicidal ideation as a possible manifestation or complication of toxicity.\n\nAcknowledgments\n\nPotential conflicts of interest. All authors: No reported conflicts.\n\nAll authors have submitted the ICMJE Form for Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReference\n1. \nMikulska M Novelli A Aversa F et al. \nVoriconazole in clinical practice\n. J Chemother 2012 ; 24 :311 –27\n.23174096 \n2. \nZonios DI Gea-Banacloche J Childs R Bennett JE \nHallucinations during voriconazole therapy\n. Clin Infect Dis 2008 ; 47 :e7 –10\n.18491963 \n3. \nImataki O Ohnishi H Kitanaka A et al. \nVisual disturbance comorbid with hallucination caused by voriconazole in the Japanese population\n. Int J Hematol 2008 ; 88 :3 –6\n.18574651 \n4. \nHerbrecht R Denning DW Patterson TF et al. \nVoriconazole versus amphotericin B for primary therapy of invasive aspergillosis\n. N Engl J Med 2002 ; 347 :408 –15\n.12167683 \n5. \nDolton MJ Ray JE Chen SC et al. \nMulticenter study of voriconazole pharmacokinetics and therapeutic drug monitoring\n. Antimicrob Agents Chemother 2012 ; 56 :4793 –9\n.22751544 \n6. \nImhof A Schaer DJ Schanz U Schwarz U \nNeurological adverse events to voriconazole: evidence for therapeutic drug monitoring\n. Swiss Med Wkly 2006 ; 136 :739 –42\n.17183438 \n7. \nLamoureux F Duflot T Woillard JB et al. \nImpact of CYP2C19 genetic polymorphisms on voriconazole dosing and exposure in adult patients with invasive fungal infections\n. Int J Antimicrob Agents 2016 ; 47 :124 –31\n.26775563 \n8. \nDolton MJ Mikus G Weiss J et al. \nUnderstanding variability with voriconazole using a population pharmacokinetic approach: implications for optimal dosing\n. J Antimicrob Chemother 2014 ; 69 :1633 –1641\n.24554646 \n9. \nDolton MJ McLachlan AJ \nVoriconazole pharmacokinetics and exposure-response relationships: assessing the links between exposure, efficacy and toxicity\n. Int J Antimicrob Agents 2014 ; 44 :183 –193\n.25106074 \n10. \nVfend (voriconazole) [package insert] . New York, NY : Pfizer ; 2011 .\n11. \nWalsh TJ Pappas P Winston DJ et al. \nVoriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever\n. N Engl J Med 2002 ; 346 :225 –34\n.11807146 \n12. \nZonios D Yamazaki H Muurayama N et al. \nVoriconazole metabolism, toxicity, and the effect of cytochrome P450 2C19 genotype\n. J Infect Dis 2014 ; 209 :1941 –8\n.24403552 \n13. \nSuan D O’Conner K Booth DR et al. \nVoriconazole toxicity related to polymorphisms in CYP2C19\n. Intern Med J 2011 ; 41 :364 –5\n.21507170\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "4(1)",
"journal": "Open forum infectious diseases",
"keywords": "aspergilosis; suicidal ideation; supratherapeutic; voriconazole.",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofw215",
"pmc": null,
"pmid": "28480228",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "24554646;26775563;11807146;18491963;18574651;25106074;23174096;22751544;24403552;21507170;12167683;17183438",
"title": "Elevated Voriconazole Level Associated With Hallucinations and Suicidal Ideation: A Case Report.",
"title_normalized": "elevated voriconazole level associated with hallucinations and suicidal ideation a case report"
} | [
{
"companynumb": "US-LANNETT COMPANY, INC.-US-2017LAN000768",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditiona... |
{
"abstract": "Unilateral linear capillaritis (ULC) is a rare variant of pigmented purpuric dermatoses (PPD) that is characterized by a linear or pseudo-dermatomal eruption on a single extremity. Although clinically distinct from the other PPD, it shares histopathologic features with this group. Herein, we present a man in his 50s who presented with asymptomatic macules and scaly papules on the left lower extremity in a linear distribution. The eruption persisted despite treatment with topical triamcinolone 0.1% and oral rutocide.",
"affiliations": "Department of Dermatology, Austin Regional Clinic, Austin, TX Department of Dermatology, Mayo Clinic, Jacksonville, FL. pmhoesly@gmail.com.",
"authors": "Hoesly|Paul M|PM|;Cappel|Mark A|MA|;Sluzevich|Jason C|JC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "25(10)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D002196:Capillaries; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D008875:Middle Aged; D010859:Pigmentation Disorders; D012867:Skin; D017445:Skin Diseases, Vascular",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31735013",
"pubdate": "2019-10-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Persistent dermatomal eruption on a leg.",
"title_normalized": "persistent dermatomal eruption on a leg"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP005007",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RUTOSIDE TRIHYDRATE"
},
"drugad... |
{
"abstract": "A patient being treated for metastatic adenocarcinoma of the pancreas presents to the clinic for a routine appointment. A complete blood count reveals hemoglobin of 6.5 g/dl and a platelet count of 30,000 K/mm3 thought to be from the last of many doses of gemcitabine. On assessment, the only complaint was fatigue with no evidence of bleeding or other abnormal physical findings other than pallor. Past medical history includes hypertension managed with three antihypertensive agents. Additional laboratory tests reveal elevated blood urea nitrogen (69 mg/dl), creatinine (2.76 mg/dl), and lactic dehydrogenase (LDH), was well as indirect bilirubin (2.1 mg/dl). The patient is admitted and transfused with packed red blood cells (pRBCs). The next day, the platelet count drops to 9,000 K/mm3 and the hemoglobin increases, appropriately, to 8.9 g/dl. Urinalysis is positive for hemoglobin (+ 3). The peripheral blood smear is positive for schistocytes (fragmented RBCs). A pheresis catheter is placed after the patient was evaluated by a hematologist and a nephrologist. A presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP) with hemolytic uremic syndrome (HUS) was made.",
"affiliations": "Medical Oncology Nursing, Fox Chase Cancer Center, Philadelphia, PA.",
"authors": "Held-Warmkessel|Jeanne|J|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000959:Antihypertensive Agents; D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069283:Rituximab; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.1188/14.ONF.551-553",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-535X",
"issue": "41(5)",
"journal": "Oncology nursing forum",
"keywords": "HUS; TTP; gemcitabine; renal injury; thrombocytopenia",
"medline_ta": "Oncol Nurs Forum",
"mesh_terms": "D000230:Adenocarcinoma; D058846:Antibodies, Monoclonal, Murine-Derived; D000959:Antihypertensive Agents; D000964:Antimetabolites, Antineoplastic; D016913:Blood Component Transfusion; D003841:Deoxycytidine; D019468:Disease Management; D006463:Hemolytic-Uremic Syndrome; D006801:Humans; D006973:Hypertension; D007676:Kidney Failure, Chronic; D009730:Nursing Assessment; D010190:Pancreatic Neoplasms; D010956:Plasmapheresis; D011697:Purpura, Thrombotic Thrombocytopenic; D006435:Renal Dialysis; D000069283:Rituximab",
"nlm_unique_id": "7809033",
"other_id": null,
"pages": "551-3",
"pmc": null,
"pmid": "25158661",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gemcitabine-associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.",
"title_normalized": "gemcitabine associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome"
} | [
{
"companynumb": "US-TEVA-569559USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugaddit... |
{
"abstract": "Immune checkpoint inhibitors have become the mainstay of treatment for metastatic melanoma. This article presents a new case of acquired generalised lipodystrophy (AGL) during anti-programmed cell death-1 (anti-PD-1) therapy and a systematic review of the literature with an aim to further understand the pathogenesis. A comprehensive search was conducted using PubMed, Embase, MEDLINE and Cochrane Central databases. We identified four cases of lipodystrophy associated with anti-PD-1 immunotherapy, including our own. Of these, three were associated with nivolumab, and one with pembrolizumab. Body composition changes occurred at a median of 7 months after anti-PD-1 initiation. All cases reported AGL, with subcutaneous fat loss affecting majority of the body. There were three reported cases of insulin resistance associated with AGL. AGL should be a recognised adverse event associated with anti-PD-1 therapy.",
"affiliations": "Dermatology Department, The Canberra Hospital.;Dermatology Department, The Canberra Hospital.;Canberra Region Cancer Centre, The Canberra Hospital, Canberra, Australian Capital Territory.;Dermatology Department, The Canberra Hospital.;Dermatology Department, The Canberra Hospital.;Medical School, Australian National University.;Dermatology Department, The Canberra Hospital.",
"authors": "Gnanendran|Subashini S|SS|;Miller|James A|JA|;Archer|Christine A|CA|;Jain|Swaranjali V|SV|;Hwang|Shelley J E|SJE|;Peters|Geoffrey|G|;Miller|Andrew|A|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1097/CMR.0000000000000660",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8931",
"issue": "30(6)",
"journal": "Melanoma research",
"keywords": null,
"medline_ta": "Melanoma Res",
"mesh_terms": "D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008060:Lipodystrophy; D008545:Melanoma; D008875:Middle Aged; D012878:Skin Neoplasms",
"nlm_unique_id": "9109623",
"other_id": null,
"pages": "599-602",
"pmc": null,
"pmid": "32141964",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Acquired lipodystrophy associated with immune checkpoint inhibitors.",
"title_normalized": "acquired lipodystrophy associated with immune checkpoint inhibitors"
} | [
{
"companynumb": "AU-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-026804",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"drug... |
{
"abstract": "We tested dexmedetomidine, an alpha(2) agonist that decreases heart rate, blood pressure, and plasma norepinephrine concentration, for its ability to attenuate stress responses during emergence from anesthesia after major vascular operations. Patients scheduled for vascular surgery received either dexmedetomidine (n = 22) or placebo (n = 19) IV beginning 20 min before the induction of anesthesia and continuing until 48 h after the end of surgery. All patients received standardized anesthesia. Heart rate and arterial blood pressure were kept within predetermined limits by varying anesthetic level and using vasoactive medications. Heart rate, arterial blood pressure, and inhaled anesthetic concentration were monitored continuously; additional measurements included plasma and urine catecholamines. During emergence from anesthesia, heart rate was slower with dexmedetomidine (73 +/- 11 bpm) than placebo (83 +/- 20 bpm) (P = 0.006), and the percentage of time the heart rate was within the predetermined hemodynamic limits was more frequent with dexmedetomidine (P < 0.05). Plasma norepinephrine levels increased only in the placebo group and were significantly lower for the dexmedetomidine group during the immediate postoperative period (P = 0.0002). We conclude that dexmedetomidine attenuates increases in heart rate and plasma norepinephrine concentrations during emergence from anesthesia.\n\n\nCONCLUSIONS\nThe alpha(2) agonist, dexmedetomidine, attenuates increases in heart rate and plasma norepinephrine concentrations during emergence from anesthesia in vascular surgery patients.",
"affiliations": "Departments of Anesthesia, University of California, San Francisco, CA 94143-0648, USA. talkep@anesthesia.ucsf.edu",
"authors": "Talke|P|P|;Chen|R|R|;Thomas|B|B|;Aggarwall|A|A|;Gottlieb|A|A|;Thorborg|P|P|;Heard|S|S|;Cheung|A|A|;Son|S L|SL|;Kallio|A|A|",
"chemical_list": "D000316:Adrenergic alpha-Agonists; D002395:Catecholamines; D020927:Dexmedetomidine; D003000:Clonidine",
"country": "United States",
"delete": false,
"doi": "10.1097/00000539-200004000-00011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2999",
"issue": "90(4)",
"journal": "Anesthesia and analgesia",
"keywords": null,
"medline_ta": "Anesth Analg",
"mesh_terms": "D000316:Adrenergic alpha-Agonists; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure; D002395:Catecholamines; D003000:Clonidine; D020927:Dexmedetomidine; D004311:Double-Blind Method; D005260:Female; D006339:Heart Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D014656:Vascular Surgical Procedures",
"nlm_unique_id": "1310650",
"other_id": null,
"pages": "834-9",
"pmc": null,
"pmid": "10735784",
"pubdate": "2000-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery.",
"title_normalized": "the hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery"
} | [
{
"companynumb": "US-PFIZER INC-2019166939",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXMEDETOMIDINE HYDROCHLORIDE"
},
"drugadditio... |
{
"abstract": "OBJECTIVE\nTo investigate the clinical efficacy of Fu Fan Huang Dai Pian(RIF) and arsenic trioxide (ATO) regimens for treatment of children with acute promyelocytic leukemia (APL) and to explore the risk factors affecting the prognosis of patients.\n\n\nMETHODS\nThe clinical data of 45 newly diagnosed APL children admitted in our hospital from January 2004 to May 2017 were analyzed retrospectively. Among 45 APL children, 25 children were treated by chemotherapetic regimen including RIF (RIF group), another 20 children were treated by chemotherapeutic regimen including ATO (ATO group). The follow-up was performed in all APL children. The prognosis and incidence of side reactions from drugs in 2 groups were compared, and the high risk factors affecting the prognosis of patients were analyzed.\n\n\nRESULTS\nThe median follow-up time was 49.8% months. In RIF group, no early death occured in 25 APL children; 5 cases did not achieve complete remission (CR) after induction therapy, CR rate was 88%. Out of 25 cases 2 caes relapsed, 3 cases died, 20 cases maintained contined CR (CCR), 2 cases failed to be followed-up. In ATO group, 2 cases suffered from early death, 5 cases did not achieve CR after induction therapy, CR rate was 90%, 2 caese relapsed and died, 15 cases maintained CCR, the follow-up failed in 1 caes. The 5 year- OS and EFS rate in all the patients were predicted as (82.2±6.2)% and (76.4±6.6)% respectively. The OS and EFS rate in RIF group were (86.1±7.4)% and (78.4±8.6)% respectively, which were significantly different from OS and EFS rate (76.4%±10.6%) and (74.0%±10.1%) respectively in ATO group (all P>0.05). As for the side reaction from drug, except for the cardiac damage (P<0.05), incidence of other side reactions was not significantly different between 2 groups (P>0.05). In addition, the 5 year-OS and EFS rates in APL children with CNSL were significantly lower than those in APL children without CNSL (all P<0.05), the 5 year OS and EFS rate in APL children did not reache M1 and with high risk were significantly lower than those in APL children reached M1 after induction therapy and with low and standerd risk (P<0.05 and P<0.05); the 5 year-OS and EFS rates did not correlate with age and sex.\n\n\nCONCLUSIONS\nThe Fu Fang Huang Dai Pian shows the therapeutic efficacy on APL children same as ATO, moreover, no obvious enhancement in incidence of side reactions is observed, therefore, the Fu Fang Huang Dai Pian is effective and safe for treatment of APL children. The CNSL, poor respond to treatment, high risk in clinical stratification are high risk factors affecting prognosis of patients.",
"affiliations": "Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China.;Department of Pediatrics, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518017, Guangdong Province, China.;Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China.;Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China.;Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China.;Department of Pediatrics, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518017, Guangdong Province, China.;Department of Pediatrics, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518017, Guangdong Province, China. E-mail: chenchun69@126.com.",
"authors": "Wang|Jian|J|;Huang|Jun-Bin|JB|;Liu|Zu-Lin|ZL|;Zhang|Bi-Hong|BH|;Xu|Hong-Gui|HG|;Xue|Hong-Man|HM|;Chen|Chun|C|",
"chemical_list": "D001152:Arsenicals; D010087:Oxides; D014212:Tretinoin; D000077237:Arsenic Trioxide",
"country": "China",
"delete": false,
"doi": "10.7534/j.issn.1009-2137.2017.06.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1009-2137",
"issue": "25(6)",
"journal": "Zhongguo shi yan xue ye xue za zhi",
"keywords": null,
"medline_ta": "Zhongguo Shi Yan Xue Ye Xue Za Zhi",
"mesh_terms": "D000077237:Arsenic Trioxide; D001152:Arsenicals; D002648:Child; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008516:Medicine, Chinese Traditional; D010087:Oxides; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome; D014212:Tretinoin",
"nlm_unique_id": "101084424",
"other_id": null,
"pages": "1605-1610",
"pmc": null,
"pmid": "29262883",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Comparison of Curative Effect between Fu Fang Huang Dai Pian and Arsenic Trioxide in Treatment of 45 Patients with Acute Promyelocytic Leukaemia.",
"title_normalized": "comparison of curative effect between fu fang huang dai pian and arsenic trioxide in treatment of 45 patients with acute promyelocytic leukaemia"
} | [
{
"companynumb": "CN-CHEPLA-C20180266_02",
"fulfillexpeditecriteria": "2",
"occurcountry": "CN",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRETINOIN"
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"drugadditional": null,
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{
"abstract": "The safety and effectiveness of long-term (10-yr) GH treatment in short Japanese children born small for gestational age (SGA) were evaluated based on interim data analysis from a clinical study, including the findings concerning the influence on the onset of puberty and subjects who achieved near adult height (NAH). Sixty-one subjects were analyzed at baseline in this study. Eleven subjects (6 boys and 5 girls) achieved NAH (mean 157.4 cm and 145.5 cm, respectively), and the Δ height SDS from the start of GH treatment was +1.6 in boys and +1.8 in girls. The median age (yr) at onset of puberty was 11.4 in boys and 9.9 in girls, comparable to healthy children. However, the mean height (cm) at onset of puberty (137.0 in boys; 125.5 in girls) was shorter than that of healthy children. Treatment-related adverse events were generally mild to moderate in severity; however, adenoidal hypertrophy was observed in two subjects as a serious adverse event. One subject had jaw malformation related to GH treatment at a dose of 0.067 mg/kg/d. No notable changes in HbA1c levels were observed, and the levels remained within the reference range. We have confirmed the safety and effectiveness of long-term GH treatment through this ongoing clinical study.",
"affiliations": "Tanaka Growth Clinic, Tokyo, Japan.;National Center for Child Health and Development, Tokyo, Japan.;JCHO Osaka Hospital, Osaka, Japan.;Toho University School of Medicine, Tokyo, Japan.;Sanchikai Medical Corporation, Kanagawa, Japan.;Pfizer Japan Inc., Tokyo, Japan.;Pfizer Japan Inc., Tokyo, Japan.;Pfizer Japan Inc., Tokyo, Japan.",
"authors": "Tanaka|Toshiaki|T|;Yokoya|Susumu|S|;Seino|Yoshiki|Y|;Tada|Hiroshi|H|;Mishina|Jun|J|;Sato|Takahiro|T|;Hiro|Shintaro|S|;Ohki|Nobuhiko|N|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1297/cpe.24.15",
"fulltext": "\n==== Front\nClin Pediatr EndocrinolClin Pediatr EndocrinolCPEClinical Pediatric Endocrinology0918-57391347-7358The Japanese Society for Pediatric Endocrinology 999810.1297/cpe.24.15Original ArticleOnset of puberty and near adult height in short children born small for\ngestational age and treated with GH: Interim analysis of up to 10 years of treatment in\nJapan Tanaka Toshiaki \n1\nYokoya Susumu \n2\nSeino Yoshiki \n3\nTada Hiroshi \n4\nMishina Jun \n5\nSato Takahiro \n6\nHiro Shintaro \n6\nOhki Nobuhiko \n6\n1 Tanaka Growth Clinic, Tokyo, Japan2 National Center for Child Health and Development, Tokyo,\nJapan3 JCHO Osaka Hospital, Osaka, Japan4 Toho University School of Medicine, Tokyo, Japan5 Sanchikai Medical Corporation, Kanagawa, Japan6 Pfizer Japan Inc., Tokyo, JapanCorresponding author : Dr. Toshiaki Tanaka, Tanaka Growth Clinic, 2-36-7, Yohga,\nSetagaya-ku, Tokyo 154-0097, JapanE-mail: toshi_tnk@tanaka-growth-clinic.com10 2 2015 1 2015 24 1 15 25 17 6 2014 18 9 2014 2015©The Japanese Society for Pediatric\nEndocrinology2015This is an open-access article distributed under the terms of the Creative\nCommons Attribution Non-Commercial No Derivatives (by-nc-nd) License. Abstract\nThe safety and effectiveness of long-term (10-yr) GH treatment in short Japanese children\nborn small for gestational age (SGA) were evaluated based on interim data analysis from a\nclinical study, including the findings concerning the influence on the onset of puberty\nand subjects who achieved near adult height (NAH). Sixty-one subjects were analyzed at\nbaseline in this study. Eleven subjects (6 boys and 5 girls) achieved NAH (mean 157.4 cm\nand 145.5 cm, respectively), and the Δ height SDS from the start of GH treatment was +1.6\nin boys and +1.8 in girls. The median age (yr) at onset of puberty was 11.4 in boys and\n9.9 in girls, comparable to healthy children. However, the mean height (cm) at onset of\npuberty (137.0 in boys; 125.5 in girls) was shorter than that of healthy children.\nTreatment-related adverse events were generally mild to moderate in severity; however,\nadenoidal hypertrophy was observed in two subjects as a serious adverse event. One subject\nhad jaw malformation related to GH treatment at a dose of 0.067 mg/kg/d. No notable\nchanges in HbA1c levels were observed, and the levels remained within the reference range.\nWe have confirmed the safety and effectiveness of long-term GH treatment through this\nongoing clinical study.\n\nsmall for gestational age (SGA)short staturelong-term GH treatmentpubertal onsetadult height\n==== Body\nIntroduction\nGH treatment for short children with small for gestational age (SGA) short stature was\napproved in 2008 in Japan. A study of GH (Genotropin®) treatment for SGA short\nstature commenced in 2001 prior to the publication of the Japanese guidelines for GH\ntreatment of SGA short stature (1); we initially used\na height SD score (SDS) ≤ –2.0 as the criterion for initiating GH treatment, which is the\nsame approved criterion used in other disorders causing growth failure. However, the\ncriterion in the Japanese guidelines for GH treatment of SGA short stature is a height SDS\n< –2.5, based on the assumption that short children may possibly achieve a catch-up\nheight of approximately 0.5 SD during puberty (by adulthood) even without GH treatment\n(2).\n\nWe have previously reported the efficacy and safety of GH treatment in this population via\na dose-response study (3) and a follow-up study\nreporting outcomes of long-term GH treatment (4–8 yr) in a subpopulation of Japanese short\nchildren born SGA (4,5,6), who met all criteria for GH treatment\naccording to the Japanese guidelines (1).\n\nHere, we report an interim data analysis from the ongoing study started in 2001 that\nexamined the long-term (10 yr) safety and effectiveness of GH treatment for children with\nSGA short stature, including data from a subpopulation of subjects with a height SDS at\nbaseline of ≥ −2.5 to ≤ −2.0. In addition, we assessed the onset of puberty and adult height\nin these children, which may be influenced by GH treatment. This study is a Pfizer-sponsored\nongoing post-marketing clinical study following the approval of GH treatment for SGA short\nstature in 2008 (clinicaltrials.gov: NCT 01859949).\n\nSubjects and Methods\nSubjects and data source\nSixty-two subjects from 20 sites were enrolled in a subsequent long-term study (study\nnumber: GENASG-0021-007 [hereinafter, referred to as “Study 007”]) of subjects who had\ncompleted a multicenter, open-label, randomized parallel-group comparative study involving\ntwo different dose groups of GH treatment in short children born SGA (study number:\n307-MET-0021-002 [hereinafter, referred to as “Study 002”]).\n\nWe report an interim analysis of data collected as of the cutoff date of June 21,\n2012.\n\nStudy design and statistical methods\nIn Study 002 (3), the subjects were randomly\nassigned to two groups and received different doses of GH (Genotropin®, 0.033 mg/kg/d or\n0.067 mg/kg/d). After treatment for 1 yr, Study 002 was completed, and then the subjects\nwho had completed Study 002 were enrolled in Study 007. In Study 007, the dose was\nincreased to 0.067 mg/kg/d in the group receiving 0.033 mg/kg/d GH (0.033/0.067 mg group),\nwhile the children assigned to the group that received 0.067 mg/kg/d remained on the same\ndose (0.067/0.067 mg group). If any adverse event occurred during Study 002 and the\ninvestigator judged that the dose increase was not appropriate, the 0.033 mg/kg/d dose\ncould be maintained in Study 007, and those subjects were analyzed in the 0.033/0.067 mg\ngroup. Study 007 contains two phases consisting of the period from study start to the date\nof obtaining manufacture and sales approval and the period after the approval date\n(post-marketing phase). The dose can be decreased to 0.033 mg/kg/d during the\npost-marketing phase if it is judged to be appropriate from the viewpoint of age, puberty,\ngrowth rate and safety.\n\nThe treatment termination criteria defined in the protocol are “reaching a height SDS of\n0 SD for chronological age”, “reaching a bone age of 17 yr in boys or 15 yr in girls”,\n“annual height velocity < 2 cm after achieving peak velocity at puberty” and “height\nvelocity for chronological age < 1.0 cm/yr.” When a subject met any of these criteria,\nGH treatment was terminated.\n\nAuxological data, bone age and methodology were collected or calculated as previously\nreported (4). In addition, body mass index (BMI)-SDS\nwas calculated using the formula reported by Kato et al. (7). All adverse events recorded with a Case Report Form\nwere coded with the preferred terms of the World Health Organization-Adverse Reaction\nTerminology (WHO-ART) and categorized by system organ class.\n\nEthical considerations\nThis study was conducted in accordance with the Declaration of Helsinki, Good Clinical\nPractice and Good Post-marketing Study Practice issued by the Ministry of Health, Labour\nand Welfare. The study protocol was approved by the independent ethics committee or\ninstitutional review board for each study site.\n\nAll patients themselves or the patients’ parents/legal guardians provided written\ninformed consent before participation in the study.\n\nResults\nSubject characteristics and disposition\nOf the 62 subjects, one subject did not receive GH during the study period, and the\nremaining 61 subjects were analyzed for effectiveness and safety. In this report, one\nsubject who continuously received the Study 002 dose of 0.033 mg/kg/d throughout this\nstudy was included. The clinical characteristics of the 61 subjects (n = 29,\n0.033/0.067 mg group; n = 32, 0.067/0.067 mg group) at birth and the start of GH treatment\nare shown in Table 1Table 1 Clinical characteristics at birth and start of\nGH treatment\n. Demographic characteristics were\nsimilar between the two treatment groups.\n\nEleven subjects were still participating in this study at the cutoff date for this\nanalysis. Twenty-two subjects completed the study because they met the treatment\ntermination criteria: n = 10, “reaching a height SDS of 0 SD for chronological age”; n =\n9, “reaching a bone age of 17 yr in boys or 15 yr in girls”; n = 2, “annual height\nvelocity < 2 cm after achieving peak velocity at puberty”; n = 1, “height velocity for\nchronological age < 1.0 cm/yr”. Two subjects completed the study on the date of\nmarketing approval (i.e., they did not enter the post-marketing phase). The remaining 26\nsubjects exited the study early (early termination). The most common reason for early\ntermination was withdrawal of consent (n = 19). Other reasons included adverse drug\nreaction (jaw malformation), personal reasons, protocol deviation and modification of the\ntreatment strategy.\n\nEffectiveness\nEleven subjects (6 boys and 5 girls) achieved near adult height (NAH), which was defined\nas an “annual height velocity < 2 cm after achieving peak velocity at puberty” or\n“reaching a bone age of 17 yr in boys or 15 yr in girls.” Among the subjects, the mean NAH\nwas 157.4 cm in boys and 145.5 cm in girls; the change in height SDS from the start of GH\ntherapy was 1.6 in boys and 1.8 in girls. The mean pubertal height gain (from onset of\npuberty to NAH) was 23.8 cm in boys and 21.7 cm in girls (Table 2Table\n2 Achievement of near adult height in\nsubjects\n).\n\nChanges in the height velocity (cm/yr) are shown in Fig. 1Fig. 1. Changes in height\nvelocity.\n\n. In both\ngroups, the mean height velocity increased remarkably 1 yr after the start of GH\ntreatment: from 5.36 cm/yr (n = 29) to 8.09 cm/yr (n = 29) in the 0.033/0.067 mg group and\nfrom 5.45 cm/yr (n = 32) to 9.72 cm/yr (n = 32) in the 0.067/0.067 mg group. In both\ngroups, a gradual decrease in the height velocity was observed after 2 yr of\ntreatment.\n\nImprovements in height SDS were observed throughout the 10-yr study period (Fig. 2Fig. 2. Changes in height\nSDS.\n\n). The mean\nheight SDS in the 0.033/0.067 mg group improved from –3.14 (n = 29) at baseline to –1.76\n(n = 5), and it improved from –3.09 (n = 32) at baseline to –1.25 (n = 6) in the\n0.067/0.067 mg group. The mean change in height SDS (Δ height SDS) from baseline to 10 yr\nof treatment was 1.66 (n = 5) in the 0.033/0.067 mg group and 2.25 (n = 6) in the\n0.067/0.067 mg group.\n\nThe changes in BMI-SDS over the 10-yr period are shown in Fig. 3Fig. 3. Changes in\nBMI-SDS.\n\n. BMI-SDS in\nthe 0.033/0.067 mg group changed from –1.53 (n = 29) at baseline to –0.91 (n = 5), and in\nthe 0.067/0.067 mg group, it changed from –1.67 (n = 32) at baseline to –1.29 (n = 6).\nThere was no difference in BMI-SDS between the 0.033/0.067 mg and 0.067/0.067 mg groups at\nbaseline or in each treatment yr.\n\nOnset of puberty\nThe percentage of subjects who entered puberty is shown in Fig. 4Fig. 4. Cumulative percentage of\nsubjects who entered puberty.\n\n (onset of puberty was defined as secondary sexual characteristics at Tanner\nStage II). In addition, the plot charts of pubertal onset according to age and height in\nthe boys and girls are shown in Fig. 5Fig.\n5. Plot chart of pubertal onset age and\nheight.\n\n. During this\nstudy, pubertal onset was observed in 21 boys at a median age of 11.4 and in 21 girls at a\nmedian age of 9.9. All of the subjects developed puberty within the normal age range for\nJapanese children except for one girl who developed early puberty at the age of 6 yr 2 mo,\nwhich was diagnosed as precocious puberty in 36 mo after the initial dosage. The mean\nheight at onset of puberty (mean ± SD) was 137.0 ± 7.2 cm in boys and 125.5 ± 9.0 cm in\ngirls.\n\nSafety\nThe most common all-cause adverse events in both treatment groups were upper respiratory\ntract infection in 53 subjects (86.9%), influenza-like symptoms in 31 subjects (50.8%),\notitis media in 28 subjects (45.9%), gastroenteritis in 27 subjects (44.3%) and\nconjunctivitis in 20 subjects (32.8%). Treatment-related adverse events are listed in\nTable 3Table\n3 Treatment-related adverse eventsFrequency of adverse drug\nreactions in this long-term study (10 years)\n.\nThroughout the 10-yr treatment period, there were 50 treatment-related adverse events in\n19 (31.1%) of the 61 subjects, with no obvious differences between the groups in the\nincidence and types of adverse events.\n\nSerious adverse events regardless of causality were observed in 15 subjects, and no\ndeaths were reported. Of these subjects, treatment-related serious adverse events were\nreported in two subjects (adenoidal hypertrophy) that were moderate in severity and\nreported to be resolving or to have resolved. Except for these events, a causal\nrelationship with the study drug was ruled out for all serious adverse events.\nTreatment-related adverse events leading to permanent discontinuation were reported in one\ngirl in the 0.067/0.067 mg group (jaw malformation [verbatim term: mandibular\nprotrusion]). However, this event was mild in severity, and her condition was stable,\nalthough the outcome was classified as not resolved.\n\nForty-four abnormal changes in laboratory test results were reported as adverse events in\n22 subjects (36.1%). By the time of this analysis, most of these events had been\nresolved.\n\nNo notable changes in glycated hemoglobin (HbA1c) levels were observed in either group,\nand the levels remained generally within the reference range throughout the 10-yr period\nin all subjects. After 10 yr of GH treatment, the HbA1c (%, Japan Diabetes Society; mean ±\nSD) levels gradually increased from 4.49 ± 0.37 (n = 29) at baseline to 5.10 ± 0.32 (n =\n5) in the 0.033/0.067 mg group and from 4.56 ± 0.32 (n = 31) at baseline to 5.27 ± 0.18 (n\n= 6) in the 0.067/0.067 mg group. Based on an oral glucose tolerance test, one subject\nshowed a diabetic pattern at mo 36 but recovered to a normal pattern at mo 48. At mo 72,\nthe results revealed borderline pattern diabetes.\n\nNo clinically significant changes were observed for bone age. The ratio of the mean bone\nage to chronological age was approximately 0.9 at baseline and remained at that level for\nthe second yr of treatment, after which it increased gradually to approximately 1 and\nremained stable. No trends were observed that indicated excessive bone maturation (Fig. 6Fig. 6. Changes in bone\nage/chronological age.\n\n).\n\nDiscussion\nIn the present study, the mean height SDS improved from –3.14 SD at baseline to –1.48 SD at\nmo 48 in the 0.033/0.067 mg group and from –3.09 SD at baseline to –1.53 SD at mo 36 in the\n0.067/0.067 mg group, but limited further improvement was observed in either group; these\nresults are consistent with previous reports (4,5,6). Therefore,\neven with high-dose GH treatment for SGA short stature, the effective time for catch-up\ngrowth is only approximately 3–4 yr. It is known that the maximum catch-up period is 2–3 yr\nin patients with GH deficiency (GHD). This discrepancy may be largely attributable to the\ndifferences in approved therapeutic doses between indications.\n\nIn a previous report (5) where the therapeutic\neffect, as measured by the mean height SDS and Δ height SDS, was compared between\nsubpopulations stratified by initial height SDS (< −2.5 vs. ≥ −2.5 to ≤\n−2.0), the time course for the Δ height SDS was almost the same in both subpopulations.\nBetween-group analysis (0.033/0.067 mg vs. 0.067/0.067 mg) of the\nsubpopulations by initial height SDS also demonstrated no significant difference in Δ height\nSDS during the period of same-dose treatment (0.067/0.067 mg/kg/d) up to yr 6. Meanwhile,\nthe 17 subjects with a higher initial height SDS (i.e., ≥ −2.5 to ≤ −2.0) reached a normal\nheight (> −2.0 SD) at yr 1.\n\nA stature > −2 SD is academically defined as normal, which results in a height of\n159.2 cm in boys and 147.5 cm in girls as the adult height. Clinically, the minimum adult\nheight that children of short stature and their parents desire is typically 160 cm for boys\n(−1.86 SD) and 150 cm for girls (−1.53 SD), which are higher than the minimum limits of the\nacademically defined normal ranges, especially for girls.\n\nExcellent effects on adult height were observed by van Pareren et al.\n(8), with as many as 85% of subjects achieving a\nnormal adult height (mean adult height SDS: −1.1, 0.033 mg/kg/wk; −0.9, 0.067 mg). In Japan,\ncomplete reports regarding adult height after GH treatment for SGA short stature are\nlacking. In our Study 007, 5 of 6 boys and 3 of 5 girls almost achieved normal stature.\nAlthough it is not conclusive because of the small numbers of subjects, it seems there is no\ndifference in adult height between 0.033/0.067 mg and 0.067/0.067 mg groups. In the present\nanalysis, the mean improvement in height SDS from the start of GH treatment to achievement\nof adult height was ≥ 1.5 SD for both boys and girls; however, the adult height may still be\nunsatisfactory for patients because the height SDS at the start of GH treatment was very\nlow. Owing to the observed intersubject variability, further investigation is important.\n\nWhile a consensus concerning evaluation of GH treatment during puberty has not been reached\nin discussions among expert groups, parameters to be considered were detected in this study:\nage at onset of puberty, height at onset of puberty and height gains during puberty.\n\nThe median age at the onset of puberty was 11.4 in boys and 9.9 in girls, both of which are\nsimilar to those of healthy children (9, 10) and consistent with the findings of Boonstra\net al. (11). Meanwhile, it is\nknown that short-statured children generally experienced delayed onset of puberty,\nsubsequently resulting in a more apparent improvement in adult height SDS compared with the\npre-puberty SD score (12). The age at the onset of\npuberty in untreated short-statured children born SGA is unknown. An improvement in height\nSDS of approximately +0.5 SD between 8 and 18 yr of age with SGA short stature, as that\nreported by Albertsson-Wickland et al. (2), suggests delayed puberty. Therefore, the similarities in age at the onset of\npuberty between the children with SGA short stature in our study and healthy children\nimplies that the high-dose GH treatment may have slightly accelerated the onset of puberty.\nAccording to Kamp et al. (13),\nhigh-dose GH treatment for idiopathic short stature can accelerate the onset of puberty.\nMoreover, precocious puberty is used as a diagnostic criterion for Russell-Silver syndrome.\nFor these reasons, further investigations on the influence of GH on puberty, cases of\nprecocious puberty and the age at the onset of puberty in untreated short children born SGA\nare needed.\n\nGiven the strong positive correlation between height at the onset of puberty and adult\nheight, to achieve the desired adult height, children should have a sufficient height by the\ntime of pubertal onset. The height at the onset of puberty in healthy children is\napproximately 145 cm in boys (9) and 135 cm in girls\n(10), whereas the height at the onset of puberty in\nchildren with SGA short stature is 5–10 cm shorter. Analysis in children with idiopathic\nshort stature has demonstrated that boys and girls who are shorter than 135 and 132.5 cm,\nrespectively, at the onset of puberty will have difficulty achieving adult heights of more\nthan 160 and 150 cm, respectively, and represent a group with a high risk of short adult\nstature resulting from early puberty for height (14).\nAlthough the median age at the onset of puberty was comparable between children with SGA\nshort stature in our study and healthy children, 6 of 21 boys and 16 of 21 girls were\nconsidered to have early puberty for height. As girls reach the age for puberty earlier than\nboys do clinically, they may enter puberty without sufficient catch-up growth and are more\nlikely to have early puberty for height. To achieve a higher height at the onset of puberty,\nGH treatment should be initiated early. Because treatment for SGA short stature is approved\nfor patients older than 3 yr, it is ideal to screen for the disease during the 3-yr\ncheck-up.\n\nA mean pubertal height gain of 25.8 cm in boys and 18.9 cm in girls has been reported among\nchildren with short stature (14). When the pubertal\nheight gain is plotted by age at onset of puberty in idiopathic short stature and GH treated\nSGA short children, the two patient groups are generally considered to be similar,\nindicating that even high-dose GH treatment is not expected to yield a significantly greater\npubertal growth than that in untreated short children. The extent of height gain is\napproximately 1.8 SD over an approximate 4-yr period; therefore, GH treatment may have\nlimited efficacy with a very low height SDS at baseline. Thus, as we have discovered through\nour investigation of GH treatment for SGA short stature, it is important to increase the\nsubject’s height as much as possible before the onset of puberty to improve adult height. In\nSGA children who enter puberty with a short stature, it is necessary to increase pubertal\ngrowth for normalization of their adult height. Combination with gonadotropin-releasing\nhormone analogs has been shown to be effective for GHD and is also expected to be beneficial\nin cases of SGA short stature (15); however, most of\nthese combinations are not covered by the National Health Insurance system in Japan.\n\nThe BMI-SD score, an indicator of body size, slowly increased throughout the GH treatment\nperiod, approaching a normal value. The observed change was consistent with the change in\nthe obesity index, without a tendency toward obesity even after 10 yr of treatment.\n\nMost of the adverse events occurred incidentally owing to infection. One subject\ndiscontinued the GH treatment permanently because of jaw malformation, which was likely\nattributable to the high-dose GH treatment. Regarding glucose tolerance, the HbA1c levels\nremained generally within the reference range; however, 1 subject showed elevated blood\nglucose levels, which then normalized, and this subject was not considered to have overt\ndiabetes.\n\nAcceleration of bone age relative to the chronological age was minimal during the first 1–2\nyr of treatment. In contrast, a clinical study for GHD (16) showed that bone age progressed by approximately 1.3 yr after 1 yr of\ntreatment. This discrepancy might be explained by the difference in age at the start of GH\ntreatment, with the age being approximately 5 yr on average in our study, which was younger\nthan the age (8–9 yr) in the GHD study. Individuals with a younger chronological age at the\nstart of GH treatment may have a different sensitivity to GH in terms of accelerated bone\nage. However, the ratio of bone age to chronological age in the present study approached 1,\nindicating that the bone age caught up to the chronological age before the average height\nwas reached. In GH-treated GHD children, the bone age rarely catches up to the chronological\nage, even at the onset of puberty. Since it has been reported that high-dose GH accelerates\nbone age (13), the possibility that high-dose\ntreatment induced the difference between GHD and SGA short stature cannot be ruled out.\n\nConclusions\nThe growth-promoting effects of GH in short children born SGA were confirmed in this\ninterim analysis of a long-term clinical study, which evaluated data for up to 10 yr of GH\ntreatment.\n\nSince there is a positive correlation between the height at onset of puberty and adult\nheight, our data suggested it is important to achieve a sufficient height before the onset\nof puberty in order to achieve the desired adult height.\n\nThe mean height SDS 10 yr after GH treatment improved to more than +1.5 SDS from the start\nof GH treatment; therefore, normalization of adult height can be expected in SGA\nshort-statured children with a mild level at the start of GH treatment. Although the median\nage at onset of puberty in children with SGA short stature was approximately the same as\nthat of healthy children, the height at the onset of puberty in GH-treated SGA short\nchildren was not normalized. Our data indicated earlier application of GH treatment provides\na benefit, and attempts to increase pubertal growth in GH-treated SGA children who enter\npuberty with a short stature may be also necessary to normalize their adult height.\n\nFurther follow-up investigation is needed in order to evaluate the long-term effects of GH\ntreatment, although no new safety concerns were observed with high-dose GH treatment, such\nas adverse events and influence on glucose tolerance.\n\nAcknowledgments\nWe would like to thank all of the participating patients and their families, as well as the\nfollowing hospitals, investigators, study coordinators and other staff in this clinical\nstudy:\n\nAsahikawa Medical University Hospital (Pediatrics), Hokkaido University Hospital\n(Pediatrics), Obihiro Kyokai Hospital (Pediatrics), Iwate Medical University Hospital\n(Pediatrics), Tohoku University Hospital (Pediatrics), Gunma University Hospital\n(Pediatrics), Toranomon Hospital (Pediatrics), National Center for Child Health and\nDevelopment (Department of Medical Subspecialties), Kitasato University Hospital\n(Pediatrics), University of Yamanashi Hospital (Pediatrics), Seirei Hamamatsu General\nHospital (Pediatrics), Kyoto University Hospital (Pediatrics), JCHO Osaka Hospital\n(Pediatrics), Osaka Medical Center and Research Institute for Maternal and Child Health\n(Department of Pediatric Gastroenterology, Nutrition and Endocrinology), Okayama University\nHospital (Pediatrics), Hiroshima City Hospital (Pediatrics), Tottori University Hospital\n(Pediatrics), University of Occupational and Environmental Health Hospital (Pediatrics) and\nKumamoto University Hospital (Pediatrics, Child Development).\n\nWe are grateful to Dr. Kenji Fujieda for his contribution as Coordinating Investigator and\ncooperation in advancing this study and also to the study team of Pfizer Japan and intellim\nCorporation for their contributions to study management and monitoring. This clinical study\nis sponsored by Pfizer Inc.\n\nConflict of interest: TS, SH and NO are employed by Pfizer Japan. SH is a\nstatistician and was in charge of statistical analysis. TT, SY, YS, HT and JM, who are\nadvisors for this Pfizer-sponsored clinical study, reviewed the statistical analysis,\ndiscussion and conclusion. TT is responsible for this report.\n==== Refs\nReferences\n1 The Japanese Society for\nPediatric Endocrinology, Japan Society for Premature and Newborn\nMedicineGuideline for GH treatment in SGA short children .\nNippon Shonika Gakkai Zasshi 2007 ;111 :\n641 –6 (in\nJapanese) .\n2 Albertsson-Wikland K Karlberg J Natural growth in children born small for gestational age with and\nwithout catch-up growth . Acta Paediatr\nSuppl 1994 ;399 : 64 –70 ,\ndiscussion 71. doi: 10.1111/j.1651-2227.1994.tb13292.x 7949620 \n3 Tanaka T Fujieda K Yokoya S Seino Y Tada H Mishina J Efficacy and safety of growth hormone treatment in children born small\nfor gestational age in Japan . J Pediatr Endocrinol\nMetab 2008 ;21 :\n423 –31 . doi: 10.1515/JPEM.2008.21.5.423 18655523 \n4 Tanaka T Yokoya S Fujieda K Seino Y Tada H Mishina J et\nal Efficacy and safety of up to 8 years of\nlong-term growth hormone treatment in short children born small for gestational age in\nJapan: analysis of the subpopulation according to the Japanese\nguideline . Clin Pediatr\nEndocrinol 2012 ;21 :\n57 –68 . doi: 10.1297/cpe.21.57 23926412 \n5 Tanaka T Yokoya S Fujieda K Seino Y Tada H Mishina J Efficacy and safety of long-term growth hormone treatment up to 7 years\nin children born small for gestational age in Japan: analysis of subpopulation who meet\nwith the criteria for GH treatment initiation of the Japanese guideline .\nHorumon To Rinsho 2010 ;58 :\n341 –52 (in\nJapanese) .\n6 Tanaka T Yokoya S Fujieda K Seino Y Tada H Mishina J Efficacy and safety of growth hormone treatment in children born small\nfor gestational age in Japan: sub-analysis according to the Japanese guidelines for\ninitiation of treatment . Horumon To\nRinsho 2008 ;56 :\n961 –71 (in\nJapanese) .\n7 Kato N Takimoto H Sudo N The cubic functions for spline smoothed L, S and M values for BMI\nreference data of Japanese children . Clin Pediatr\nEndocrinol 2011 ;20 :\n47 –9 . doi: 10.1297/cpe.20.47 23926394 \n8 van\nPareren Y Mulder P Houdijk M Jansen M Reeser M Hokken-Koelega A Effect of discontinuation of growth hormone treatment on risk factors for\ncardiovascular disease in adolescents born small for gestational age .\nJ Clin Endocrinol Metab 2003 ;88 :\n347 –53 . doi: 10.1210/jc.2002-020458 12519875 \n9 Fujieda K Matsuura N Growth and maturation in the male genitalia from birth to adolescence. I.\nChange of testicular volume . Acta Paediatr\nJpn 1987 ;29 : 214 –9 .\ndoi: 10.1111/j.1442-200X.1987.tb00035.x 3150904 \n10 Tanaka T Imai T The standard of breast development in normal girls: Diagnostic criteria\nfor precocious puberty . J Child\nHealth 2005 ;64 :\n33 –8 (in\nJapanese) .\n11 Boonstra V van\nPareren Y Mulder P Hokken-Koelega A Puberty in growth hormone-treated children born small for gestational age\n(SGA) . J Clin Endocrinol\nMetab 2003 ;88 :\n5753 –8 . doi: 10.1210/jc.2003-030512 14671164 \n12 Komatsu K Okamura T Takada G Miyashita M Ohno T Tanaka T Analysis of natural growth of children with short stature at prepuberty\nof at final height I. follow-up of healthy children at Akita prefecture .\nNippon Shonika Gakkai Zasshi 1997 ;101 :\n610 –6 (in\nJapanese) .\n13 Kamp GA Waelkens JJ de Muinck\nKeizer-Schrama SM Delemarre-Van de\nWaal HA Verhoeven-Wind L Zwinderman AH et\nal High dose growth hormone treatment induces\nacceleration of skeletal maturation and an earlier onset of puberty in children with\nidiopathic short stature . Arch Dis\nChild 2002 ;87 :\n215 –20 . doi: 10.1136/adc.87.3.215 12193430 \n14 Tanaka T Naiki Y Horikawa R Clinical factors related to the short adult height: early puberty for\nheight . J Jpn Assoc Hum\nAuxol 2011 ;17 :\n17 –23 .\n15 Tanaka T Sufficiently long-term treatment with combined growth hormone and\ngonadotropin-releasing hormone analog can improve adult height in short children with\nisolated growth hormone deficiency (GHD) and in non-GHD short children .\nPediatr Endocrinol Rev 2007 ;5 :\n471 –81 . 17925788 \n16 Tanaka T Shizume K Hibi I Okuno A Hanew K Nakajima H et\nal Clinical study of authentic recombinant human\ngrowth hormone (JR-8810) for pituitary dwarfism (2nd report) .\nClin Rep 1992 ;26 :\n443 –59 (in\nJapanese) .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-5739",
"issue": "24(1)",
"journal": "Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology",
"keywords": "adult height; long-term GH treatment; pubertal onset; short stature; small for gestational age (SGA)",
"medline_ta": "Clin Pediatr Endocrinol",
"mesh_terms": null,
"nlm_unique_id": "9433330",
"other_id": null,
"pages": "15-25",
"pmc": null,
"pmid": "25678756",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article",
"references": "23926394;12193430;7949620;3150904;14671164;12519875;23926412;17925788;18655523",
"title": "Onset of puberty and near adult height in short children born small for gestational age and treated with GH: Interim analysis of up to 10 years of treatment in Japan.",
"title_normalized": "onset of puberty and near adult height in short children born small for gestational age and treated with gh interim analysis of up to 10 years of treatment in japan"
} | [
{
"companynumb": "JP-PFIZER INC-2003153428JP",
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"patient": {
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{
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"activesubstance": {
"activesubstancename": "SOMATROPIN"
},
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... |
{
"abstract": "We assessed the incidence of febrile neutropenia(FN), infection, and relative dose intensity(RDI)with or without the use of pegfilgrastim in breast cancer patients receiving adjuvant or neoadjuvant chemotherapy. Twenty-five patients received 4 cycles of FEC(5-FU 500mg/m2 plus epirubicin 100 mg/m2 plus cyclophosphamide 100 mg/m2 q3w)followed by 4 cycles of docetaxel(75mg/m2 q3w). Ten patients were administered pegfilgrastim as primary prophylaxis throughout all cycles of chemotherapy, and 15 patients were not. The rate of FN was only 7% in patients not undergoing pegfilgrastim therapy. The infection rate and RDI were not significantly different between the 2 groups, but the incidence of fever was lower in patients treated with pegfilgrastim. In patients with early stage breast cancer, the use of primary pegfilgrastim during all chemotherapy cycles should be considered a safe option.",
"affiliations": "Dept. of Organ Regulatory Surgery, Fukushima Medical University.",
"authors": "Abe|Noriko|N|;Ohtake|Tohru|T|;Abe|Sadahiko|S|;Aoto|Keita|K|;Okano|Maiko|M|;Tachibana|Kazunoshin|K|;Takenoshita|Seiich|S|",
"chemical_list": "D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D016896:Treatment Outcome",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2032-2034",
"pmc": null,
"pmid": "28133212",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Use of Pegfilgrastim in Adjuvant and Neoadjuvant Chemotherapy for Breast Cancer.",
"title_normalized": "use of pegfilgrastim in adjuvant and neoadjuvant chemotherapy for breast cancer"
} | [
{
"companynumb": "JP-ACCORD-048453",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPIRUBICIN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "This paper describes the detection and characterization of unusual metabolite/breakdown products of the anti-psychotic drug risperidone in post-mortem blood and urine as part of a toxicological investigation into an unexpected death of a male suffering from paranoid schizophrenia prescribed risperidone and previously paroxetine. Compounds detected in the post-mortem blood and urine specimens were shown to be benzisoxazole ring scission products of risperidone and a hydroxy metabolite. These compounds are never routinely detected in blood and urine but can be present in mammalian faeces indicating that gut bacteria could be responsible for their formation. In this case, evidence for this process was demonstrated by the controlled in vitro stability study of risperidone spiked into the case blood and urine leading to the hypothesis that the post-mortem blood and urine samples analyzed could have contained bacteria with the ability to breakdown risperidone and its metabolite in this way. This finding is very unusual and has not been encountered before in any previous risperidone cases investigated by the authors, or widely reported in the post-mortem toxicological literature. However, a recently published paper has supported these findings in blood. As a result of this work, it was shown that the deceased had taken risperidone prior to death, even in the absence of any risperidone or its hydroxy metabolite(s) in the blood and urine. Given that risperidone has been reported to interact with paroxetine, the ingestion of risperidone could have been a factor that contributed to the death.",
"affiliations": "Forensics Ltd, Malvern Hills Science Park, Geraldine Road, Malvern, Worcestershire, WR14 3SZ, UK.",
"authors": "Taylor|Kerry|K|;Elliott|Simon|S|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D014150:Antipsychotic Agents; D017374:Paroxetine; D018967:Risperidone",
"country": "England",
"delete": false,
"doi": "10.1002/dta.1503",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1942-7603",
"issue": "5(9-10)",
"journal": "Drug testing and analysis",
"keywords": "benzisoxazole scission; paroxetine; risperidone",
"medline_ta": "Drug Test Anal",
"mesh_terms": "D000328:Adult; D018687:Antidepressive Agents, Second-Generation; D014150:Antipsychotic Agents; D001344:Autopsy; D004355:Drug Stability; D006801:Humans; D008297:Male; D017374:Paroxetine; D018967:Risperidone; D012563:Schizophrenia, Paranoid",
"nlm_unique_id": "101483449",
"other_id": null,
"pages": "748-52",
"pmc": null,
"pmid": "23868704",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An unusual case of risperidone instability in a fatality presenting an analytical and interpretative challenge.",
"title_normalized": "an unusual case of risperidone instability in a fatality presenting an analytical and interpretative challenge"
} | [
{
"companynumb": "GB-JUBILANT CADISTA PHARMACEUTICALS-2021JUB00237",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALCOHOL"
},
"drugaddi... |
{
"abstract": "The role of viruses in children with respiratory tract infections and humoral immunodeficiencies has hardly been studied. We have evaluated these infections in children with humoral immunodeficiencies who required immunoglobulin replacement therapy, considering their relationship with symptoms, lung function, bacterial co-infection, and outcomes.\n\n\n\nWe conducted a prospective case-control study during a 1-year period, including children with humoral immunodeficiencies receiving immunoglobulin replacement therapy. For each patient, at least one healthy family member was included. Respiratory samples for viral detection were taken every 1-3 months, and in case of respiratory tract infections. Symptoms questionnaires were filled biweekly. Spirometry and sputum culture were performed in every episode.\n\n\n\nSixty-six episodes were analyzed in 14 patients (median age 12 years; IQR 7-17), identifying 18 respiratory viruses (27.3%), being rhinovirus the most frequently isolated one (12/18; 66%). Positive viral episodes were associated with clinical symptoms (89% vs 43%), more frequent antibiotic treatment (44% vs 15%) or hospital admission (22% vs 0%) than negative ones. Patients with positive viral detection showed impaired lung function, with lower FEV1 and FVC values.\n\n\n\nIn our experience, viral respiratory tract infections can cause significant respiratory symptoms and impaired lung function, in children with HID, despite immunoglobulin replacement therapy. These patients could benefit from the monitoring of viral infections, as these may be a gateway for ongoing lung damage.",
"affiliations": "Pediatric Infectious Diseases Department, Hospital Universitario La Paz, Madrid, Fundación IdiPaz, Madrid, Spain.;Pediatric Infectious Diseases Department, Hospital Universitario La Paz, Madrid, Fundación IdiPaz, Madrid, Spain.;Pediatric Infectious Diseases Department, Hospital Universitario La Paz, Madrid, Fundación IdiPaz, Madrid, Spain.;Translational Research Network in Pediatric Infectious Diseases (RITIP), Madrid, Spain.;Translational Research Network in Pediatric Infectious Diseases (RITIP), Madrid, Spain.;Translational Research Network in Pediatric Infectious Diseases (RITIP), Madrid, Spain.;Paediatric Pneumology Department, Hospital La Paz, Madrid, Spain.;Immunology Department, Hospital Universitario La Paz, Fundación IdiPaz, Madrid, Spain.;Immunology Department, Hospital Universitario La Paz, Fundación IdiPaz, Madrid, Spain.;Pediatric Infectious Diseases Department, Hospital Universitario La Paz, Madrid, Fundación IdiPaz, Madrid, Spain.",
"authors": "Benavides-Nieto|Marta|M|;Méndez-Echevarría|Ana|A|0000-0002-7455-9080;Del Rosal|Teresa|T|;García-García|María Luz|ML|0000-0003-4906-4227;Casas|Inmaculada|I|;Pozo|Francisco|F|;de la Serna|Olga|O|;Lopez-Granados|Eduardo|E|;Rodriguez-Pena|Rebeca|R|;Calvo|Cristina|C|0000-0002-6503-3423",
"chemical_list": "D007136:Immunoglobulins",
"country": "United States",
"delete": false,
"doi": "10.1002/ppul.24214",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1099-0496",
"issue": "54(2)",
"journal": "Pediatric pulmonology",
"keywords": "humoral immunodeficiency; immunoglobulin replacement therapy; lung function; respiratory tract infection; virus",
"medline_ta": "Pediatr Pulmonol",
"mesh_terms": "D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007136:Immunoglobulins; D007153:Immunologic Deficiency Syndromes; D008297:Male; D012129:Respiratory Function Tests; D012141:Respiratory Tract Infections; D013030:Spain; D014777:Virus Diseases",
"nlm_unique_id": "8510590",
"other_id": null,
"pages": "194-199",
"pmc": null,
"pmid": "30575324",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "30575324;21514636;20163373;20541246;27078120;28734862;29021228;26188881;22295088;23992479;23988764;23490188;25546767;30147696;22751495;16055882;28708268;14748074;16862044;25677249;27555459;29556229;26883540;19900842;12436489;29447988",
"title": "The role of respiratory viruses in children with humoral immunodeficiency on immunoglobulin replacement therapy.",
"title_normalized": "the role of respiratory viruses in children with humoral immunodeficiency on immunoglobulin replacement therapy"
} | [
{
"companynumb": "ES-SHIRE-ES201906011",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "3",
... |
{
"abstract": "Cross-border importation of traditional and prescription medications is common, and many of these drugs are not approved by the Australian Therapeutic Goods Administration. Furthermore, counterfeit versions of prescription medications are also available (eg, weight-loss medications, anabolic steroids, and medications to enhance sexual performance). We describe a 54-year-old man with the first Australian case of severe hypoglycaemia induced by imported, laboratory-confirmed counterfeit Cialis. This serves to remind medical practitioners that counterfeit medication may be the cause of severe hypoglycaemia (or other unexplained illness).",
"affiliations": "Department of Diabetes and Endocrinology, The Townsville Hospital, Townsville, QLD, Australia. drchaubeysk@rediffmail.com",
"authors": "Chaubey|Santosh K|SK|;Sangla|Kunwarjit S|KS|;Suthaharan|Emershia N|EN|;Tan|Yong M|YM|",
"chemical_list": "D007004:Hypoglycemic Agents; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D005905:Glyburide",
"country": "Australia",
"delete": false,
"doi": "10.5694/j.1326-5377.2010.tb03710.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-729X",
"issue": "192(12)",
"journal": "The Medical journal of Australia",
"keywords": null,
"medline_ta": "Med J Aust",
"mesh_terms": "D004340:Drug Contamination; D007172:Erectile Dysfunction; D005905:Glyburide; D006801:Humans; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D011687:Purines; D012651:Self Medication; D000068677:Sildenafil Citrate; D013450:Sulfones; D014665:Vasodilator Agents",
"nlm_unique_id": "0400714",
"other_id": null,
"pages": "716-7",
"pmc": null,
"pmid": "20565353",
"pubdate": "2010-06-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe hypoglycaemia associated with ingesting counterfeit medication.",
"title_normalized": "severe hypoglycaemia associated with ingesting counterfeit medication"
} | [
{
"companynumb": "AU-PFIZER INC-2010123786",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GLYBURIDE"
},
"drugadditional": "3",
... |
{
"abstract": "In the past decade, the resurgence of immunotherapy has changed the landscape of cancer therapy. Checkpoint inhibitors targeting cytotoxic T-lymphocyte antigen-4, programmed death-1 on lymphocytes, and programmed death ligand-1 on tumors cells are currently utilized in the management of several cancers. These agents are double-edged sword with the positive effect being robust antitumor response but on the other side they can throttle up the normal immunologic homeostasis in a negative way, leading to adverse autoimmune toxicities. These adverse toxicities are frequent if patients have active autoimmune disorders. Here, we report a rare case of quiescent bullous pemphigoid which flared after initiation of pembrolizumab, a programmed death ligand-1 inhibitor.",
"affiliations": "Departments of Hematology and Oncology.;Internal Medicine.;Dermatology, University of Iowa Hospitals and Clinics, Iowa City, IA.;Dermatology, University of Iowa Hospitals and Clinics, Iowa City, IA.;Departments of Hematology and Oncology.",
"authors": "Garje|Rohan|R|;Chau|Justin J|JJ|;Chung|Jina|J|;Wanat|Karolyn|K|;Zakharia|Yousef|Y|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1097/CJI.0000000000000191",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-9557",
"issue": "41(1)",
"journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)",
"keywords": null,
"medline_ta": "J Immunother",
"mesh_terms": "D000208:Acute Disease; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D018450:Disease Progression; D005076:Exanthema; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D010392:Pemphigus; D011241:Prednisone; D061026:Programmed Cell Death 1 Receptor; D012872:Skin Diseases, Vesiculobullous; D001743:Urinary Bladder; D001749:Urinary Bladder Neoplasms; D014571:Urologic Neoplasms; D028761:Withholding Treatment",
"nlm_unique_id": "9706083",
"other_id": null,
"pages": "42-44",
"pmc": null,
"pmid": "29111983",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21924997;24424192;25524312;25831416;26371282;26928461;26957557;27043866;27135655;27136138;27367787;27482939;27645330;27687304;363229",
"title": "Acute Flare of Bullous Pemphigus With Pembrolizumab Used for Treatment of Metastatic Urothelial Cancer.",
"title_normalized": "acute flare of bullous pemphigus with pembrolizumab used for treatment of metastatic urothelial cancer"
} | [
{
"companynumb": "US-009507513-1801USA001702",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "Posttransplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases with abnormal proliferation of lymphoid tissue and classical Hodgkin lymphoma (CHL) type PTLD is a very rare subtype. We describe a successfully diagnosed and treated CHL-PTLD stage IV pediatric patient, 8 years after liver transplantation. The patient was treated with standard CHL (Children's Cancer Group 5942 group 3) chemotherapy, rituximab and reduction of immunosuppressant. The patient remains in complete remission after 3 years with stable graft function. To our best knowledge, this is the first pediatric case report of a successfully treated stage IV CHL-PTLD after a liver transplant.",
"affiliations": "Departments of Pediatrics.;Departments of Pediatrics.;Departments of Pediatrics.;Departments of Pediatrics.;Departments of Pediatrics.;Surgery.;Pathology.;Radiology, Seoul National University College of Medicine.;Departments of Pediatrics.;Departments of Pediatrics.",
"authors": "Choi|Sujin|S|;Hong|Kyung Taek|KT|;Choi|Jung Yoon|JY|;Ahn|Hong Yul|HY|;Ko|Jae Sung|JS|;Suh|Kyung-Suk|KS|;Park|Sung-Hye|SH|;Cheon|Jung-Eun|JE|;Shin|Hee Young|HY|;Kang|Hyoung Jin|HJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000002121",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "43(7)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e1015-e1019",
"pmc": null,
"pmid": "33769384",
"pubdate": "2021-10-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Stage IV Classical Hodgkin Lymphoma-type Posttransplant Lymphoproliferative Disorder in a Pediatric Liver Transplant Patient: A Case Report and Review of the Literature.",
"title_normalized": "stage iv classical hodgkin lymphoma type posttransplant lymphoproliferative disorder in a pediatric liver transplant patient a case report and review of the literature"
} | [
{
"companynumb": "KR-MLMSERVICE-20211109-3212218-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "1",
... |
{
"abstract": "Programmed cell death protein 1 (PD-1) inhibitors are a common treatment strategy for metastatic melanoma and other tumour entities. Clinical trials usually exclude patients with preexisting autoimmune diseases, thus experience with PD-1 inhibitor (PD-1i) in this patient population is limited.\n\n\n\nMetastatic melanoma patients with preexisting autoimmune disorders or previous ipilimumab-triggered immune-related adverse events (irAE) undergoing treatment with PD-1i from seven German skin cancer centres were evaluated retrospectively with regard to flare of the preexisting autoimmunity and development of new, not preexisting irAE as well as response to PD-1i therapy.\n\n\n\nIn total, 41 patients had either preexisting autoimmunity (n=19, group A, including two patients with additional ipilimumab-triggered autoimmune colitis) or ipilimumab-triggered irAE (n=22, group B). At PD-1i therapy initiation, six patients in group A and two patients in group B required immunosuppressive therapy. In group A, a flare of preexisting autoimmune disorders was seen in 42% of patients, new irAE in 16%. In group B, 4.5% of patients showed a flare of ipilimumab-triggered irAE and 23% new irAE. All flares of preexisting autoimmune disorders or irAE were managed by immunosuppressive and/or symptomatic therapy and did not require termination of PD-1i therapy. tumour responses (32% in group A and 45% in group B) were unrelated to occurrence of autoimmunity.\n\n\n\nWhile preexisting autoimmunity commonly showed a flare during PD-1i therapy, a flare of ipilimumab-triggered irAE was rare. Response rates were above 30% and unrelated to irAE. PD-1i therapy can be considered in patients with autoimmune disorders depending on severity and activity of autoimmunity.",
"affiliations": "Skin Cancer Center Hannover, Hannover Medical School, Carl Neuberg Str. 1, 30625 Hannover, Germany. Electronic address: Gutzmer.ralf@mh-hannover.de.;Skin Cancer Center Hannover, Hannover Medical School, Carl Neuberg Str. 1, 30625 Hannover, Germany. Electronic address: Koop.anika@mh-hannover.de.;Department of Dermatology and National Center for Tumor Diseases, University Hospital Carl Gustav at the TU Dresden, Fetscherstr. 74, 01307, Dresden, Germany. Electronic address: Friedegund.meier@uniklinikum-dresden.de.;Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany. Electronic address: Jessica.hassel@med.uni-heidelberg.de.;Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23562 Luebeck, Germany. Electronic address: Patrick.terheyden@uksh.de.;Department of Dermatology, University of Duisburg-Essen, Essen, Germany. Electronic address: lisa.zimmer@uk-essen.de.;University Hospital Erlangen, Department of Dermatology, Erlangen, Germany. Electronic address: lucie.heinzerling@uk-erlangen.de.;Department of Dermatology, University of Duisburg-Essen, Essen, Germany. Electronic address: selma.ugurel@uk-essen.de.;Saarland University Medical School, Department of Dermatology, Homburg, Germany. Electronic address: Claudia.pfoehler@uks.eu.;University Hospital Würzburg, Department of Dermatology, Würzburg, Germany. Electronic address: gesierich_a@ukw.de.;Department of Dermatology, University of Duisburg-Essen, Essen, Germany. Electronic address: elisabeth.livingstone@uk.essen.de.;Skin Cancer Center Hannover, Hannover Medical School, Carl Neuberg Str. 1, 30625 Hannover, Germany. Electronic address: Satzger.imke@mh-hannover.de.;Department of Dermatology, Skin Cancer Center, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany. Electronic address: kckaehler@yahoo.de.",
"authors": "Gutzmer|Ralf|R|;Koop|Anika|A|;Meier|Friedegund|F|;Hassel|Jessica C|JC|;Terheyden|Patrick|P|;Zimmer|Lisa|L|;Heinzerling|Lucie|L|;Ugurel|Selma|S|;Pföhler|Claudia|C|;Gesierich|Anja|A|;Livingstone|Elisabeth|E|;Satzger|Imke|I|;Kähler|Katharina C|KC|;|||",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D000074324:Ipilimumab; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C582435:pembrolizumab",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2016.12.038",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "75()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Autoimmunity; Immune-related adverse events; Ipilimumab; Metastatic melanoma; Nivolumab; PD-1 inhibitor; Pembrolizumab",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001327:Autoimmune Diseases; D015551:Autoimmunity; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor; D012008:Recurrence; D012189:Retrospective Studies; D012878:Skin Neoplasms",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "24-32",
"pmc": null,
"pmid": "28214654",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity.",
"title_normalized": "programmed cell death protein 1 pd 1 inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab triggered autoimmunity"
} | [
{
"companynumb": "DE-009507513-2007DEU006961",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Anti-HER2 therapy has greatly improved the long-term prognosis of patients with HER2-positive breast cancer. Meanwhile, by interfering with the protective effects of neuregulin-1/HER2 signaling on stressed cardiomyocytes, anti-HER2 therapy occasionally induces reversible cancer therapeutics-related cardiac dysfunction (CTRCD). Cardiac magnetic resonance (CMR) parametric mapping or myocardial feature-tracking, in combination with late gadolinium enhancement (LGE) imaging, has the potential to detect changes in the myocardium in anti-HER2 therapy-related cardiac dysfunction. Here we report a breast cancer patient who experienced life-threatening CTRCD after treatment with trastuzumab plus pertuzumab. This case showed multiple transmural LGE-positive myocardial lesions in CMR imaging and high native T1 and T2 values in CMR parametric mapping, which was apparently more extensive than those observed in most patients with anti-HER2 therapy-related cardiac dysfunction. Consistent with profound myocardial damage indicated by CMR, her cardiac function was not fully restored despite intensive care and cardioprotective drug therapy. These findings suggest the potential usefulness of LGE imaging and parametric mapping by CMR for the assessment of myocardial injury to determine the clinical severity of anti-HER2 therapy-related cardiac dysfunction.",
"affiliations": "Department of Cardiovascular Medicine, The University of Tokyo.;Department of Cardiovascular Medicine, The University of Tokyo.;Department of Cardiovascular Medicine, The University of Tokyo.;Department of Cardiovascular Medicine, The University of Tokyo.;Department of Cardiovascular Medicine, The University of Tokyo.;Department of Cardiovascular Medicine, The University of Tokyo.;Department of Cardiac Surgery, Graduate School of Medicine, The University of Tokyo.;Department of Cardiac Surgery, Graduate School of Medicine, The University of Tokyo.;Department of Cardiovascular Medicine, The University of Tokyo.;Department of Cardiovascular Medicine, The University of Tokyo.",
"authors": "Kadowaki|Hiroshi|H|;Ishida|Junichi|J|;Uehara|Masae|M|;Ishizuka|Masato|M|;Kiyosue|Arihiro|A|;Hatano|Masaru|M|;Shimada|Shogo|S|;Ono|Minoru|M|;Akazawa|Hiroshi|H|;Komuro|Issei|I|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1536/ihj.21-388",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1349-2365",
"issue": "62(6)",
"journal": "International heart journal",
"keywords": "Anthracycline; Breast cancer; Cancer therapeutics-related cardiac dysfunction; Late gadolinium enhancement; Parametric mapping; Pertuzumab; Trastuzumab",
"medline_ta": "Int Heart J",
"mesh_terms": null,
"nlm_unique_id": "101244240",
"other_id": null,
"pages": "1436-1441",
"pmc": null,
"pmid": "34853231",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Detection of Profound Myocardial Damage by Cardiac MRI in a Patient with Severe Cardiotoxicity Induced by Anti-HER2 Therapy.",
"title_normalized": "detection of profound myocardial damage by cardiac mri in a patient with severe cardiotoxicity induced by anti her2 therapy"
} | [
{
"companynumb": "JP-PFIZER INC-202101741945",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "4",
... |
{
"abstract": "Background: Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of a ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and effective. Methods: We describe our experience, including the challenges of achieving and maintaining ketosis, in an adult with new onset refractory status epilepticus (NORSE). Case Vignette: A previously healthy 29-year-old woman was admitted with cryptogenic NORSE following a febrile illness; course was complicated by prolonged super-refractory SE. A comprehensive work-up was notable only for mild cerebral spinal fluid (CSF) pleocytosis, elevated nonspecific serum inflammatory markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI). Repeat CSF testing was normal and serial MRIs demonstrated resolution of edema and diffusion restriction with progressive hippocampal and diffuse atrophy. She required prolonged therapeutic coma with high anesthetic infusion rates, 16 antiseizure drug (ASD) trials, empiric immunosuppression and partial bilateral oophorectomy. Enteral ketogenic formula was started on hospital day 28. However, sustained beta-hydroxybutyrate levels >2 mmol/L were only achieved 37 days later following a comprehensive adjustment of the care plan. KD was challenging to maintain in the intensive care unit (ICU) and was discontinued due to poor nutritional state and pressure ulcers. KD was restarted again in a non-ICU unit facilitating ASD tapering without re-emergence of SE. Discussion: There are inconspicuous carbohydrates in commonly administered medications for SE including antibiotics, electrolyte repletion formulations, different preparations of the same drug (i.e., parenteral, tablet, or suspension) and even solutions used for oral care-all challenging the use of KD in the hospitalized patient. Tailoring comprehensive care and awareness of possible complications of KD are important for the successful implementation and maintenance of ketosis.",
"affiliations": "Department of Neurology, Neurocritical Care Division, UF Health-Shands Hospital, University of Florida, Gainesville, FL 32611, USA.;Department of Neurology, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT 06520, USA.;Department of Neurology, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT 06520, USA.;Department of Neurology, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT 06520, USA.;Department of Pharmacy Services, Yale New Haven Hospital, New Haven, CT 06510, USA.;Department of Neurology, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT 06520, USA.;Department of Neurology, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT 06520, USA.;Department of Neurology, Epilepsy Division, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.;Department of Neurology, Neurocritical Care Division, UF Health-Shands Hospital, University of Florida, Gainesville, FL 32611, USA.",
"authors": "Katz|Jason B|JB|0000-0002-7786-7839;Owusu|Kent|K|0000-0002-7923-3039;Nussbaum|Ilisa|I|;Beekman|Rachel|R|;DeFilippo|Nicholas A|NA|;Gilmore|Emily J|EJ|;Hirsch|Lawrence J|LJ|;Cervenka|Mackenzie C|MC|0000-0002-4760-857X;Maciel|Carolina B|CB|0000-0002-8763-5839",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jcm10040881",
"fulltext": "\n==== Front\nJ Clin Med\nJ Clin Med\njcm\nJournal of Clinical Medicine\n2077-0383 MDPI \n\n10.3390/jcm10040881\njcm-10-00881\nReview\nPearls and Pitfalls of Introducing Ketogenic Diet in Adult Status Epilepticus: A Practical Guide for the Intensivist\nhttps://orcid.org/0000-0002-7786-7839Katz Jason B. 1 https://orcid.org/0000-0002-7923-3039Owusu Kent 23 Nussbaum Ilisa 2 Beekman Rachel 2 DeFilippo Nicholas A. 45 Gilmore Emily J. 2 Hirsch Lawrence J. 2 https://orcid.org/0000-0002-4760-857XCervenka Mackenzie C. 6 https://orcid.org/0000-0002-8763-5839Maciel Carolina B. 12* Legriel Stephane Academic Editor 1 Department of Neurology, Neurocritical Care Division, UF Health-Shands Hospital, University of Florida, Gainesville, FL 32611, USA; jasonbkatz@ufl.edu\n2 Department of Neurology, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT 06520, USA; kent.owusu@ynhh.org (K.O.); ilisa.nussbaum@ynhh.org (I.N.); rachel.beekman@yale.edu (R.B.); emily.gilmore@yale.edu (E.J.G.); lawrence.hirsch@yale.edu (L.J.H.)\n3 Care Signature, Yale New Haven Health, New Haven, CT 06510, USA\n4 Department of Pharmacy Services, Yale New Haven Hospital, New Haven, CT 06510, USA; nicholas.defilippo@uconn.edu\n5 School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA\n6 Department of Neurology, Epilepsy Division, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; mcerven1@jhmi.edu\n* Correspondence: carolina.maciel@yale.edu or carolina.maciel@neurology.ufl.edu; Tel.: +352-273-5550; Fax: +352-273-5575\n22 2 2021 \n2 2021 \n10 4 88107 1 2021 13 2 2021 © 2021 by the authors.2021Licensee 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/).Background: Status epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of a ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and effective. Methods: We describe our experience, including the challenges of achieving and maintaining ketosis, in an adult with new onset refractory status epilepticus (NORSE). Case Vignette: A previously healthy 29-year-old woman was admitted with cryptogenic NORSE following a febrile illness; course was complicated by prolonged super-refractory SE. A comprehensive work-up was notable only for mild cerebral spinal fluid (CSF) pleocytosis, elevated nonspecific serum inflammatory markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI). Repeat CSF testing was normal and serial MRIs demonstrated resolution of edema and diffusion restriction with progressive hippocampal and diffuse atrophy. She required prolonged therapeutic coma with high anesthetic infusion rates, 16 antiseizure drug (ASD) trials, empiric immunosuppression and partial bilateral oophorectomy. Enteral ketogenic formula was started on hospital day 28. However, sustained beta-hydroxybutyrate levels >2 mmol/L were only achieved 37 days later following a comprehensive adjustment of the care plan. KD was challenging to maintain in the intensive care unit (ICU) and was discontinued due to poor nutritional state and pressure ulcers. KD was restarted again in a non-ICU unit facilitating ASD tapering without re-emergence of SE. Discussion: There are inconspicuous carbohydrates in commonly administered medications for SE including antibiotics, electrolyte repletion formulations, different preparations of the same drug (i.e., parenteral, tablet, or suspension) and even solutions used for oral care―all challenging the use of KD in the hospitalized patient. Tailoring comprehensive care and awareness of possible complications of KD are important for the successful implementation and maintenance of ketosis.\n\nketogenic dietstatus epilepticusnew onset refractory status epilepticusseizurescritical careketosis\n==== Body\n1. Introduction\nStatus epilepticus (SE) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. Recently, the implementation of ketogenic diet (KD) in adults with refractory and super-refractory SE has been shown to be feasible and potentially effective [1,2,3,4,5]. Most often used in childhood epilepsies, KD has emerged as a potential adjunctive treatment for pediatric SE [6,7]. We describe our experience with an adult with new onset refractory status epilepticus (NORSE) focusing on the unexpected challenge of achieving and maintaining ketosis. Practical advice, and a comprehensive review of factors potentially jeopardizing ketosis commonly encountered in the critical care setting and alternatives are provided.\n\n2. Presentation\n\nA previously healthy 29-year-old woman was admitted to another institution with new onset refractory status epilepticus (NORSE) following a febrile illness with a course complicated by prolonged super-refractory SE. Three days prior to presentation she developed fever, headache, emesis and fatigue in the setting of being in contact with her child with an upper respiratory tract infection. On the morning of admission, her friend attempted to awaken her for work and found her unresponsive and convulsing. In the emergency department, she was lethargic and mumbling incoherently. During her initial evaluation she had a witnessed 45-s bilateral tonic-clonic seizure that was aborted with 2 mg lorazepam intravenously. Head computed tomography was unremarkable and initial cerebrospinal fluid (CSF) analysis showed a mononuclear pleocytosis (2 RBC, 41 nucleated cells (57% mononuclear cells), glucose 93, protein 54)). A one-hour electroencephalogram (EEG) showed diffuse delta activity admixed with sleep spindles and K complexes without epileptiform discharges. She was monitored in the step-down unit and treated with levetiracetam and acyclovir. On hospital day two, she was somnolent but arousable to voice; she was able to follow simple midline commands, state her name and the current president, but was disoriented to time. She was noted to have twitching of her face, but no EEG was done at that time. By hospital day three, she began experiencing brief convulsive seizures which were aborted with intravenous lorazepam and always associated with recovery of consciousness. At that point, phenytoin (1 g loading dose, maintenance at 100 mg q8h) was added to her antiseizure drug (ASD) regimen. On hospital day four, she had multiple convulsive seizures without return to baseline, complicated by acute hypoxic respiratory failure requiring intubation. She was transferred to the intensive care unit (ICU) where she was started on propofol, and valproic acid (20 mg/kg loading dose, maintenance at 750 mg Q8H) was added. Routine EEG captured multiple discrete right frontal and centrotemporal onset seizures correlating with episodes of face twitching. She was started on pentobarbital infusion (5 mg/kg bolus, maintenance at 1 mg/kg per hour) and transferred to our center for continuous EEG monitoring.\n\n\n3. Question: How Is Prolonged Seizure Activity Classified and What Are Potential Etiologies to Be Considered?\nAccording to the most recent classification set by The International League Against Epilepsy, SE is a “condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures” [8]. While operational SE definitions based on time-domains vary according to seizure type, it is generally accepted that convulsive seizure activity lasting either greater than 5 min continuously, or two or more seizures during which the individual does not recover to baseline between seizures, represents SE [8]. Inhibitory gamma-aminobutyric acid (GABA) neurons located in the pars reticulata of the substantia nigra are key in seizure termination [9]. During status epilepticus, marked alteration of GABA metabolism occurs in this region and results in disinhibition of excitatory pathways: GABA synthesis slows down [10]. GABA turnover time increases up to three-fold, [10] and GABA receptors (originally located in the surface of the cell membrane) migrate to the intracellular space within minutes of ongoing seizure activity [11,12,13]. Prompt initiation of abortive therapies is key, as the internalization of GABA receptors contributes to refractoriness to treatment.\n\nEmergent administration of parenteral benzodiazepine (e.g., up to 0.1 mg/kg of lorazepam) is considered the first-line therapy for SE [14]. If a patient fails to respond to a benzodiazepine and a second appropriately selected and dosed ASD at adequate doses, they are in refractory status epilepticus (RSE). It has been reported that one in five RSE patients go on to develop super-refractory status epilepticus (SRSE), defined as (1) ongoing seizures lasting 24 h or more after onset of anesthetic therapy (i.e., propofol) or (2) recurrence of SE upon reduction or withdrawal of therapeutic anesthetic coma [15]. The clinical presentation of RSE in patients without overt acute or remote brain injury, prior epilepsy, or acute toxic/metabolic explanation is consistent with New Onset Refractory Status Epilepticus—NORSE [16]. Febrile Infection-Related Epilepsy Syndrome (FIRES) is a subset of NORSE, in which a febrile infectious illness precedes SE onset by 1–14 days [14,15,16]. Thus, our patient qualified as having the syndrome of FIRES as well as NORSE. Further, clinical criteria for unequivocal electroencephalographic status epilepticus in patients without known epileptic encephalopathy has been established in the Salzburg consensus: (1) repeating epileptiform discharges occurring >2.5 Hz, or (2) repeating epileptiform discharges occurring ≤2.5 Hz or rhythmic delta/theta activity >0.5 Hz plus (a) electroclinical response (improvement) following intravenous ASD challenge, (b) subtle clinical correlate associated with pattern, or (c) typical temporal and spatial evolution of pattern [17].\n\nDetermining the underlying etiology of SE may seem a daunting task. However, its importance in achieving seizure cessation cannot be underestimated. Outcome following SE is dependent on the etiology of seizures. Further, appropriately recognizing the electroclinical classification of seizures (i.e., identifying the seizure semiology and its electrographic signature) may not only help selection of therapy but also identify potential etiologies [8]. Among NORSE patients, an etiology is found in up to 50% of cases [16]. Of those with an identifiable cause, the majority (37%) had an autoimmune cause (both nonparaneoplatic and paraneoplastic), while 8% had a probable infectious cause [16]. Thus, if an autoimmune etiology is diagnosed or clinically suspected, immune modulating therapies such as high-dose corticosteroids, intravenous immunoglobulin (IVIg) or plasma exchange therapy, followed by monoclonal antibodies and/or interleukin inhibitors, should be considered early in the course.\n\n\nOur patient underwent a comprehensive work-up to determine the etiology of NORSE, as summarized on Table 1, which was notable only for mild CSF pleocytosis, elevated nonspecific inflammatory serum markers and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (MRI).\n\n\n4. Question: What Are the Initial Steps in the Therapeutic Algorithm for Status Epilepticus?\nBenzodiazepines are the first-line treatment for SE [14,19] with slower-acting, less sedating parenteral ASDs being the second line (e.g., phenytoin, fosphenytoin, valproate and levetiracetam; and possibly lacosamide and phenobarbital). The Established Status Epilepticus Treatment Trial (ESETT) found no difference in efficacy between fosphenytoin (20 mgPE/kg), valproate (40 mg/kg) and levetiracetam (60 mg/kg) in children, adults and older adults; these ASDs were able to abort SE within an hour in nearly 50% of patients [20]. Once the second-line, or a combination of medications, fails to result in seizure cessation, continuous intravenous infusions of anesthetics (i.e., midazolam, pentobarbital, propofol, ketamine) are often recommended [14,19].\n\nIn patients with SE, anesthetic use is associated with longer hospital stay, but not in-hospital or 90-day mortality [21]. Amongst NORSE patients who receive anesthetics, the mortality is high. However, the use of anesthetics is not associated with poor outcome [16]. In 61 patients with RSE, those who underwent deep sedation (defined as either EEG showing burst suppression or isoelectric activity) had both poorer long-term prognosis and increased mortality [22]. Burst suppression on EEG is defined as intermittent alternating periods of low amplitudes (<10 uV for burst suppression; 10–20 uV for burst attenuation) interrupting a background, which may consist of waves of varying frequencies. Earlier attainment of burst suppression may allow for a more rapid anesthetic wean [23], and it is important to frequently monitor the EEG and titrate anesthetic dose as appropriate. The goal of anesthetic use in RSE is the resolution of epileptiform activity in order to avoid physiologic effects while the underlying cause is identified and treated [24,25].\n\nIn our case, 16 antiseizure drug trials in various combinations and high anesthetic infusion rates were attempted. RSE persisted despite 160 mg/h (2.5 mg/kg/h) of midazolam prompting the initiation of ketamine. Despite improved seizure burden following ketamine bolus (1.5 mg/kg), reemergence of SE occurred despite up-titration of ketamine to our maximum infusion rate (7.5 mg/kg/h). Her EEG responded to propofol and pentobarbital with long periods of suppression, although her background remained with abundant generalized periodic discharges (GPD) at 2.5–3 Hz, qualifying as ongoing electrographic SE. [17,26] Burst suppression was eventually achieved with pentobarbital at 3 mg/kg/h and propofol at 40 mcg/kg/min. However, due to re-emergence of 2 Hz GPDs along with breakthrough seizures on attempted wean, she remained in a medically induced coma for over three months.\n\n5. Question: What Are Potential Rescue Therapeutic Approaches to the Management of Super-Refractory Status Epilepticus?\nRefractory and super-refractory SE and their complications are associated with significant morbidity including death, neuronal damage and systemic complications like cardiomyopathy, ischemic bowel, pulmonary edema and renal failure [27]. This highlights the necessity for a prompt and aggressive treatment approach. In the setting of treatment failure, alternative treatment options include inhaled anesthetics, magnesium infusion, pyridoxine, hypothermia, electrical and magnetic stimulation, additional immunotherapy, enteral ASDs and the KD [28].\n\n\nGiven a high suspicion for an autoimmune process, our patient was treated with intravenous methylprednisolone (1 g daily for 5 days), IVIg, plasma exchange and cyclophosphamide. Serial MRIs demonstrated resolution of edema and diffusion restriction with gradually progressive atrophy, predominantly in the hippocampi, and repeat CSF analysis was normal. She underwent empiric bilateral partial oophorectomy for an echogenic focus in her left ovary and concern for possible occult microteratoma, possibly secondary to N-methyl-D-Aspartate (NMDA) encephalitis (NMDA CSF < 1:1 and serum < 1:10) [29].\n\n\n6. Ketogenic Diet\nKetosis is commonly defined as sustained beta-hydroxybutyrate levels > 2 mmol/L [30] or a urinary acetoacetate level of >40 mg/dL [31]. There is evidence supporting the use of KD in children with autoimmune epilepsies, symptomatic epilepsy syndromes, pediatric refractory and super-refractory SE [6,32]. In a study of 10 children (age six months—16 years old) with refractory focal SE, initiation of a KD resulted in lower seizure burden (50% reduction in seizures for 70% of the cohort) and resolution of seizures in 20% [6]. In the minority of patients with less than 50% seizure reduction (n = 3), severe adverse events (pancreatitis or severe vomiting and hypoglycemia) prompted KD discontinuation. In another study of 12 children with fever induced refractory epileptic encephalopathy, KD was able to stop seizures within two days following ketonuria [32]. Nevertheless, the side effects of KD limit its widespread use, and successful ketosis must be attained for seizure control.\n\nMore recently, KD has been evaluated in adult patients; a systematic review of 38 adult patients with RSE or SRSE demonstrated that 82% were able to achieve SE cessation with KD [33]. There are several complex mechanisms for the efficacious effect of KD on reducing seizure activity, which result from reduction in glucose intake, ketone body production and alteration of the gut microbiome. The metabolic changes induced by KD alter the balance of excitatory and inhibitory neurotransmitters, lead to reductions in oxidative stress and systemic as well as neuroinflammation, and have further long-term effects on gene expression [3,34].\n\n\nWe sought KD as a rescue therapy after conventional treatments had failed.\n\n\n7. Question: What Are Some Factors Should the Clinician Consider When Selecting and Initiating KD for Adults with SE?\nInitiating KD Safely\nDetermining the optimal patient for whom to implement KD requires a comprehensive evaluation of the patient’s past medical history, comorbidities and current clinical status. As with all treatment strategies, particularly in the ICU setting, a thoughtful risk-benefit analysis is warranted. Inborn errors of metabolism are a contraindication to KD [35,36]. However, these conditions most often present in early childhood, and rarely in adults, so screening is not routinely obtained prior to KD initiation in adults [1,2]. Other contraindications of KD include unstable metabolic (mitochondrial enzyme deficiencies) conditions, liver failure, acute pancreatitis, pregnancy and an inability to tolerate enteral feeds [5]. Protocols typically avoid starting KD within 24 h of propofol infusions to avoid possibly fatal propofol infusion syndrome, characterized by metabolic acidosis, lipemia, rhabdomyolysis and myocardial failure [37].\n\n8. Question: Should You Fast the Patient to Achieve Ketosis Quickly? If So, How Long and What Are Potential Consequences? If You Decide Not to Fast, Can Ketosis Still Be Achieved?\nVariations in KD Protocols\nHistorically, KD implementation in the setting of childhood epilepsy included an initial fasting period ranging anywhere from 12 [7] to 48 [36,38] hours or more. Once satisfactory ketosis is achieved, ketogenic formulations or meals (typically 4:1 g of fat: carbohydrate + protein ratio) can then be titrated as tolerated until full caloric requirements are met. To avoid potential complications of a fasting period (e.g., dehydration, hypoglycemia), Kim et al. began KD without initial fasting and found equivalency in time to ketosis and seizure reduction in 41 children with intractable epilepsy compared to a retrospective control population of 83 children who fasted prior to KD initiation [39]. While rates of hypoglycemia were similar when compared to controls, there were reduced rates of dehydration and reduced length of hospital stay.\n\nAn alternative, yet equally efficacious approach for childhood epilepsy, does not involve initial fasting or limiting caloric intake. This protocol differs from others in the fact that there is a gradual increase from 1:1 to 2:1 until the goal 4:1 ratio is reached [38]. This gradual induction and establishment of ketosis in children diagnosed with intractable epilepsy showed an equal reduction in seizure activity yet decreased weight loss and episodes of hypoglycemia, acidosis and dehydration. Nevertheless, since time is a major factor in terms of avoiding neurologic and systemic consequences of SE, a more aggressive approach to KD initiation (i.e., fasting and/or more rapidly advancing to full calories as tolerated) may be warranted in this setting.\n\nIndividual patient characteristics including age, illness severity, duration of anesthetic use prior to diet initiation resulting in reduction in gastrointestinal motility, and diet complications, may not allow the luxury of initiating a preferred protocol with certain ketogenic ratio or at a faster rate. This was evident in Cobo’s pediatric SRSE study in which ratios were started as low as 0.75:1 in some instances, and ratios never exceeding 2:1 in some cases [7]. The need for higher protein intake (often in cases of poor wound healing, malnutrition and/or low basal resting energy expenditure) challenges the use of higher fat:protein + carbohydrate ratios, although this is more of a concern with chronic KD use rather than in the acute setting of RSE and SRSE. A possible way to maximize ketosis when using lower ratios (thus, higher protein intake) is the addition of medium-chain triglyceride oils as they yield greater amounts of ketones/kcal of energy than longer chain varieties [36].\n\nWe used these principles, most frequently used in the setting of childhood epilepsy, to initiate KD for our NORSE patient with the goal of achieving ketosis quickly. Our patient was initially started on KD on hospital day 28 (HD 28) with a goal of 5:1 ratio (KetoCal® 4:1 at 55 mL/h plus 33 mL medium-chain triglycerides (MCT) oil to balance carbohydrate intake from medications, documented as 51 g daily on HD 30). At this time, supplemental protein via PROsource® was discontinued to assist with achieving ketosis. On HD 35, beta-hydroxybutyrate (BHB) levels continued to show inadequate ketosis [Figure 1] prompting the increase to 6:1 with additional MCT Oil. Through HD 65, beta-hydroxybutyrate continued to fluctuate below the 2.0 goal. On HD 71, beta-hydroxybutyrate again dropped with the only documented potential carbohydrate source (at that time) being a milk and molasses enema administered by a care team to alleviate constipation. The decision was made to return to a higher carbohydrate-containing formula and refocus nutrition goals on wound healing. At this time, our patient was identified as meeting the criteria for severe malnutrition based on weight loss of >7.5% in three months and limited energy intake for greater than or equal to five days [40].\n\n9. Question: What Factors Can Impede the Success of Achieving Ketosis, and thus Jeopardize the Utility of KD?\nDespite initiating KD with complete enteral feeds on hospital day 28, our patient was only able to reach ketosis a significant 37 days later (Figure 1). After a comprehensive assessment of the care plan, the culprit was found: inconspicuous carbohydrate-containing medications, infusions and oral-care solutions routinely given in the setting of a neurological ICU (Table 2).\n\n10. Hidden Carbohydrates Can Hinder Achievement of Ketosis\nIn our experience, the most likely medication-induced barriers to ketosis include sedatives, antiseizure drugs and antibiotics. Benzodiazepines are not created equally when it comes to hidden/nonobvious carbohydrate content. Diazepam (Valium® 5 mg/mL) and Lorazepam (Ativan® 2 mg/mL) have been shown to have 40% and 80% propylene glycol content, respectively, which equates to an overall carbohydrate content of 0.4 g/mL and 0.8 g/mL [42]. Intake of this carbohydrate content in patients with status epilepticus on KD may hinder achieving ketosis, but can also precipitate propylene glycol toxicity and associated anion-gap, metabolic acidosis [44].\n\nWhile the carbohydrate load of each individual dose may be inconsequential, the cumulative dose given to patients in extended hospital stays may be significant. For example, initial administrations of injectable lorazepam, 2 mg every 6 h yields approximately 3 g of carbohydrate per day [44]. For context, this patient’s energy assessment used an ideal body weight of 64.5 kg, with daily caloric requirements calculated to total 2260 kcal/day (35 kcal/kg). Using KD at a 4:1 ratio (a common target for KD), the macronutrient breakdown is 226 g fat, 51.6 g protein, and 4.9 g carbohydrates. Thus, lorazepam would have contributed over half of the allotted daily carbohydrate load. Figure 1 shows several instances where lorazepam administration was associated with significant troughs in beta-hydroxybutyrate levels. When benzodiazepine infusions are warranted for refractory cases, our recommendation would be to consider midazolam as an alternative; midazolam does not have propylene glycol in its formulation, resulting in lower rates of anion-gap metabolic acidosis [45]. Regarding enteral administration of benzodiazepines, it is worth noting that clobazam (Onfi ®) and clonazepam (Klonopin®) contain 105 mg and 143.5 mg of carbohydrates (i.e., lactose, starch) per 10 mg/0.5 mg tablet, respectively [Table 2]. When selecting benzodiazepines for treatment of SE in patients treated with KD, it is important to evaluate the carbohydrate content for the selected benzodiazepine and the administration method. Generally, solutions and suspensions should be avoided due to high carbohydrate containing excipients.\n\nAnother class of widely used sedatives, often with the potential to inadvertently hinder beta-hydroxybutyrate levels, are the barbiturates, particularly pentobarbital (Nembutal® 50 mg/mL) and phenobarbital (Phenobarb® 130 mg/mL). Barbiturates are commonly used in RSE. However, they have a high propylene glycol content (pentobarbital 414 mg/50 mg vial, phenobarbital 702 mg/130 mg vial [42] amounting to an overall carbohydrate content of 2.9 g/h when pentobarbital is infused at a rate of 5 mg/kg/h for a 70 kg patient) [Table 2]. We suggest that ketamine (and midazolam, as discussed above) be considered as an alternative to pentobarbital in patients with status epilepticus on KD, given their lack of propylene glycol [46], This same concept can be applied for phenytoin (Dilantin® 50 mg/mL), which contains 40% propylene glycol [42] amounting to a carbohydrate content of 414 mg (plus an additional 79 mg of alcohol). These principles can be observed in Figure 1 where beta-hydroxybutyrate levels drop on HD 52, corresponding with a phenobarbital load (a disruption in feeds also occurred to administer phenytoin by mouth). We recommend that fosphenytoin be used instead to avoid propylene glycol excipients (Table 2). Similarly, on HD 56, beta-hydroxybutyrate dropped to 0.63 mmol/L with a medication review showing intravenous phenobarbital administered overnight. Lastly, another note of caution regarding anesthetic infusions: propofol contains 1.1 kcal/mL (mostly from fats), which provides approximately 528 kcal per day (presuming 20 mL/h). While this increased caloric load may aid in ketosis, its 450 mg of glycerol per 20 mL vial may hinder ketosis (Table 2).\n\n11. Noncarbohydrate Related Hindrance of Ketosis\nAmong children with refractory epilepsy, concomitant lamotrigine use decreases KD’s efficacy in seizure reduction [47]. This may be explained by ketosis increasing the metabolism/inactivation of lamotrigine via glucosyltransferases, which ultimately results in increased glutamate release. Lastly, one must not forget that while medication use can influence KD, the inverse is also true. While most serum concentrations of ASD were not found to significantly change upon KD use, valproic acid levels have been shown to decrease [48]. Therefore, it is recommended to monitor valproic acid while using KD therapy.\n\n12. Question: Aside from Sedative Agents, What Other Widely Used Agents in the Neurological ICU Can Hinder Ketosis?\n12.1. Antimicrobials and Respective Diluents as Source of Carbohydrates\nVarious antibiotics that are used frequently in the neurological ICU [49,50] can hinder ketosis. Intravenous trimethoprim-sulfamethoxazole (TMP-SMX, Bactrim®) requires reconstitution with dextrose 5% water and, similarly, vancomycin is often diluted in dextrose 5% water prior to intravenous administration (Table 2). Figure 1 (line graph) shows several instances in which administration of TMP-SMX and vancomycin were associated with troughs in beta-hydroxybutyrate levels.\n\n12.2. Non “Medications” Contain Hidden Carbohydrates\nHidden carbohydrates are found in oral care solutions such as chlorhexidine, dietary supplements and fiber. Chlorhexidine 0.12% oral solution (PeridexTM), reported to be superior to toothbrushing at reducing early ventilator-associated pneumonia [51], contains glycerin and ethyl alcohol (see Appendix A), both carbohydrate-containing substances that can affect KD [52]. Oral fiber supplements, such as psyllium, have a significant carbohydrate load (e.g., 9 g/tablespoon) (Table 2). However, as fiber has a lower glycemic index compared to other carbohydrate-containing sources in the ICU setting, it may still be used in some instances to counteract constipation.\n\n12.3. Comprehensive Approach to Implementing KD in Adult SE\nAdopting a systematic approach is key for the successful implementation and maintenance of a ketotic state. A checklist is provided in Table 3 with a summary of the suggested steps for successful KD initiation [4].\n\n13. Question: What Laboratory Values Should the Intensivist Pay Particular Attention to When Using KD?\nBaseline assessment of certain serum (lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D, and free and total carnitine) [41] and anthropometric (weight, height) parameters [5,33,53] are imperative to effectively see how values trend overtime with KD. This objective data collected longitudinally allows monitoring of metabolic and systemic side effects of KD to allow for cessation if need-be.\n\nAfter deciding that KD is appropriate, the next step is to carefully review all standing orders in the patient’s chart to identify potential sources of hidden carbohydrates and replace with alternatives. Guidance by the dietary/nutrition team as well as an ICU pharmacist are recommended to improve success with achieving and maintaining ketosis. If possible, a nutritionist with knowledge and experience with managing a KD is preferred, which may necessitate involving the pediatric nutrition team.\n\nIn the critical care setting, nutrition is often dictated by the critical care team via administration of formula tube feeding, and patient compliance is not a key factor for achieving ketosis. Route of administration does impact ketosis as suspension or elixir medications, [53] the preferred formulations via percutaneous gastrostomies (PEG) or other enteral routes, must be replaced by alternative formulations with lower carbohydrate content [7]. Additionally, dextrose-free diluents [52] must be used whenever able in intravenous drug formulations. Unavoidable carbohydrates can be balanced with a calculated dose of fat in the form of MCT oil or a commercially available emulsified oil (provided that this addition coincides with caloric and macronutrient percentages discussed later). Additionally, this puts the patient at an increased risk for gastrointestinal complications such as steatorrhea, emesis and reflux.\n\n14. Ketosis Maintenance and Surveillance\nInducing ketosis is only the first step in tackling SE. While a ketotic state is commonly defined as beta-hydroxybutyrate >2 mmol/L [30], similarly to antiseizure drugs, some individuals require higher level of ketosis (or antiseizure drugs) to achieve optimal seizure control. Thus, individual thresholds for optimal ketotic state may vary. In the presented case, the best therapeutic effect was noted with beta-hydroxybutyrate >3.5. Maintaining ketosis above a certain therapeutic level proves to be difficult, particularly when higher targets are required such as >3 mmol/L beta-hydroxybutyrate [7]. For example, Cobo’s case series illustrated that children with SRSE can have sudden, unexplained drops in beta-hydroxybutyrate levels.\n\n\nAfter KD was stopped on HD 73 due to poor nutritional status, KD was reinitiated on HD 106 as the patient was no longer on bolus medications with high carbohydrate content. Ketosis was achieved rapidly over two days, with a beta-hydroxybutyrate of 2.34 mmol/L target once the goal of 6:1 ratio 18 kcal/kg was reached. The rapid achievement of ketotic state likely resulted from several days of fasting prior to its initiation in the setting of percutaneous gastrostomy placement and enterocutaneous fistula repair. The patient remained in ketosis, with beta-hydroxybutyrate levels fluctuating between 1.93–5.32 mmol/L, during which time seizures were best controlled when beta-hydroxybutyrate levels were >3.5 mmol/L.\n\n\nConstant evaluation and re-evaluation of patient intake, including intravenous fluids, must be conducted. It is imperative to remove all common exogenous carbohydrates including glycerin, maltodextrin, propylene glycol, dextrose, fructose, glucose, lactose, sucrose, corn syrup, sugar alcohols and starches [52]. Appropriate alternatives include normal saline, balanced crystalloid or lactated Ringer’s solution.\n\n15. Question: What Natural Physiologic Mechanisms Must Be Accounted for When Attempting to Achieve/Maintain Ketosis?\nIn addition to exogenous carbohydrate management, the intensivist must not overlook endogenous perturbations of glucose homeostasis. Commonly measured anywhere from every four [54] to eight hours after initiation of KD [7], fluctuations are commonly seen in the pediatric population as the clinician attempts to titrate to a glucose target level of 60–79 mg/dL [7]. While the lower limit of 40 mg/dL is referenced in the Academy of Nutrition and Dietetics Practice Paper, the clinicians at Yale New Haven Hospital use a slightly higher limit of 50 mg/dL when evaluating for KD initiation. Ketosis can be threatened by endogenous gluconeogenesis occurring during infection or injury [55]. The topic of glucose perturbations brings up the discussion of whether the use of glucocorticoids concurrently with KD hinders the diet’s efficacy. Among children with epilepsy being treated with KD, there have been reports of glucocorticoid use (even inhaled) being associated with seizure return, elevated glucose and ketosis hindrance [56]. More studies are needed to examine the relationships of KD and glucocorticoid use in the setting of SE/RSE.\n\n16. KD and Supplements\nQuestion: What Supplements may Be Warranted when Starting a Ketogenic Diet?\nThe KD’s inherent shift into fatty acid beta-oxidation predisposes to metabolic acidosis, which can be further compounded if individuals are fasting to achieve ketosis [36]. For these reasons, adequate bicarbonate levels (commonly >17 mmol/L) [7] should be ensured with concomitant sodium bicarbonate [5] and/or potassium citrate supplementation [7].\n\nBeta-oxidation in the mitochondria is reliant on the adequate transport of long-chain fatty acids across the mitochondrial membrane via carnitine [36,53]. Carnitine supplementation is recommended when levels are low (<30 μmol/L) or if the patient is symptomatic, defined by lethargy, weakness and GI symptoms, which are often difficult to assess in a comatose patient [7,36,53]. Carnitine supplementation remains controversial, as levels poorly correlate with tissue stores and symptoms of carnitine deficiency may be difficult to identify in comatose patients [53].\n\nLastly, it is recommended that a low carbohydrate multivitamin, calcium carbonate and Vitamin D be added [34,36] via nasogastric/gastric tube (NG/G-tube). Most commercially available ketogenic formulas have the recommended daily allowance of these substances. Children with epilepsy have hypovitaminosis D (50%) and are at risk for osteoporosis [36,53]. Phosphorous, [53] administered separately to avoid calcium chelation, is a recommended supplement for its role in bone homeostasis. Lastly, it is our recommendation to supplement either lite salt or table salt for patients that have hyponatremia despite administration of sodium containing intravenous fluids.\n\n17. Termination of Ketotic Therapy\nQuestion: Once Anesthetics Have Been Weaned and/or Seizure Activity Has Improved, How Should KD Be Weaned?\nReasons for diet discontinuation include lack of response, development of complications and need for optimization of nutritional status. There are no clear guidelines to define a clear response to KD, as diseases and patient populations are very heterogeneous, and a clear absolute seizure cessation effect may not be seen. In some cases, allowing for anesthetic wean or antiseizure regimen simplification may be considered successful results. It is our recommendation that before considering therapeutic failure, higher ketotic levels should be pursued if the patient is able to tolerate a more aggressive titration of the KD, as patients, such as our patient, may respond to higher beta-hydroxybutyrate levels.\n\nLike any antiseizure therapy, it is generally recommended to wean the KD diet gradually due to the historical thought that abrupt withdrawal of ketosis can precipitate recurrence of seizures or SE. Abrupt withdrawal of KD is recommended for emergencies only. Thus, gradually reducing the ratio of grams of fats:protein + carbohydrates is recommended (i.e., 4:1 to 3:1 to 2:1) [36]. Despite there being a common notion that overzealous weaning of KD can precipitate previously suppressed seizure activity, a study of over 183 children showed no significant difference in the incidence of seizures worsening between discontinuation/weaning rates (i.e., <1 week vs. 1–6 weeks vs. >6 weeks) [57]. However, there was an increase in seizure activity with faster weaning schedules among a particular cohort: children who had higher percentage (55–90%) of seizure reduction while on the KD. Additionally, among children who successfully stopped KD after seizure cessation, 42% of them were unable to achieve symptom improvement with either ASD or reinitiating of KD upon seizure relapse [58].\n\nWe recommend that the clinician use the KD’s treatment success as well as clinical judgement in adopting an individualized weaning schedule. Beginning on HD 194, our patient was weaned from the KD over five days by decreasing the ketogenic formula by 20% every 24 h and replacing it with a traditional critical care formula. Supplemental MCT oil was decreased at the beginning of the weaning process. No complications arose during this transition. Once able to tolerate oral nutrition, the patient will have the autonomy to determine whether to continue KD and contingency plans, such as offering a less strict KD therapy (modified Atkins diet, modified KD), which may be a reasonable alternative.\n\n18. Anticipating and Managing Complications\nQuestion: What Are Some Potential Complications of KD?\nComplications of KD are not uncommon and may result in discontinuation of the diet. In the pediatric literature, 30 [6] to 38% discontinuation rates [59] are described due to inability to tolerate the diet or due to complications. These complications include metabolic derangements like dyslipidemia and hyperuricemia, gastrointestinal symptoms, renal stones, osteopenia and cardiac problems like QT prolongation and cardiomyopathy [36,59]. An uncommon yet reported complication is protein-losing enteropathy [60], and while this can be corrected for by cessation of KD, the likely consequence is an increase in seizures. Like osteoporosis and Vitamin D alterations, which may not be relevant in the setting of acute KD administration for RSE, these complications are less relevant in the setting of short-term KD. Rather, more relevant complications to be aware of include dehydration, hyponatremia, metabolic acidosis, hypoglycemia, gastroparesis and nausea/vomiting [5,59].\n\nAside from poor wound healing and critical illness myopathy, our NORSE patient tolerated KD well and was discharged after 218 days in the hospital. Additional longitudinal studies are needed to examine long-term sequelae of a high fat diet in the context of adults with SE. Future research may focus on complication rates specifically associated with acute administration of KD for adult patients with RSE/SRSE in the neurological ICU setting, as well as cessation upon symptom improvement. Our patient’s neurological examination at discharge was significant for spontaneous eye opening, orientated x 2, minimally talkative with soft but clear speech. She was able to follow simple commands like closing her eyes and wiggle her toes. Strength was 3/5 proximal upper extremity with 2/5 in distal upper and proximal lower extremity. The patient was readmitted three weeks later for cardiac arrest, with subsequent reemergence of status epilepticus. Despite EEG improvement on restarting KD, the patient was eventually transitioned to comfort measures only.\n\n19. Future of KD in Adult SE/RSE/SRSE/NORSE\nWhile the utility of KD in adult populations is certainly promising for the management of RSE and SRSE, there remain several gaps, including a lack of standardized treatment approach, lack of randomized, double-blind controlled studies and hidden carbohydrate sources, which may impair production of ketone bodies. These inconspicuous carbohydrates are found in commonly administered medications for SE including benzodiazepines, antibiotics, electrolyte repletion formulations and even solutions used for oral care. This review offers a brief outline of treatment strategies for KD use in adults and a systematic approach for successfully achieving, maintaining and eliminating ketosis.\n\nAcknowledgments\nJason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor Contributions\nConceptualization, C.B.M., J.B.K., K.O.; Methodology, C.B.M., J.B.K., K.O.; Data Curation, C.B.M., M.C.C., L.J.H., K.O.; Writing—Original Draft Preparation, J.B.K..; Writing—Review & Editing, I.N., R.B., N.A.D., E.J.G., C.B.M.; Visualization, J.B.K., C.B.M., Supervision, C.B.M.; Project Administration, C.B.M.; Software, NA; Validation, NA; Formal analysis, NA; Investigation, NA; Resources, NA; Funding, NA. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nInstitutional Review Board Statement\nThis report is a case study, therefore not meeting the Common Rule definition of research as it is not designed to develop generalizable knowledge and did not required ethical approval.\n\nInformed Consent Statement\nGiven the retrospective nature of this report, the fatal outcome, and the lack of identifiable information, family was not contacted to obtain informed consent.\n\nConflicts of Interest\nThe authors declare no conflict of interest. Jason Katz reports no disclosures. Kent Owusu reports no disclosures. Ilisa Nussbaum reports consultation fees from AjinomotoCambrooke. Rachel Beekman reports no disclosures. Nicholas DeFilippo reports no disclosures. Emily J. Gilmore reports funding from NIH (R01NS117904) and is a speaker for UCB. Lawrence J. Hirsch reports consultation fees from Accure, Aquestive, Ceribell, Marinus, Medtronic, Monteris, Neuropace and UCB; Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, by Hirsch and Brenner; and Honoraria for speaking from Neuropace and Natus. Mackenzie C. Cervenka reports Grant Support from Nutricia, Vitaflo, The William and Ella Owens Medical Research Foundation, BrightFocus Foundation, The Carson Harris Fund, Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation; consulting from Sage Therapeutics, Nutricia, Glut1 Deficiency Foundation; Medical Advisory Board for Glut1 Deficiency Foundation; Honoraria from Nutricia; Royalties from Demos/Springer Publishing Company. Carolina B. Maciel reports no disclosures.\n\nAppendix A\nBriviact (brivaracetam injection) [package insert]. Smyrna, G. and I.R.M. UCB.\n\nCerebyx (fosphenytoin sodium injection) [package insert]. New York, N. and I.R.F. Pfizer.\n\nPropofol injectable emulsion [package insert]. Lake Forest, I. and I.R.M. Hospira.\n\nKetalar (ketamine hydrochloride injection) [package Insert]. Chestnut Ridge, N., P. Pharmaceutical, and R.A. 2020.\n\nVimpat (lacosamide injection) [package insert]. Smyrna, G. and I.R.N. UCB.\n\nMidazolam hydrochloride injection [package insert]. Lake Forest, I. and I.R. Hospira.\n\nThiopental sodium injection [package insert]. Galashiels, U. and L.R.O. Kyowa Kirin.\n\nValproate sodium injection [package insert]. Eatontown, N. and W.-W.P.C.R.M. 2019.\n\nSulfamethoxazole and trimethoprim injection [package insert]. Morgantown, W. and M.I.L.R.D. 2020.\n\nVancomycin hydrochloride for injection [package insert]. Rockford, I. and M.I.L.R.J. 2018.\n\nCarbatrol (carbamazepine extended-release tablet) [package insert]. Lexington, M. and I.R.N. Takeda Pharmaceuticals America.\n\nLevetiracetam immediate-release tablet [package insert]. Chestnut Ridge, N. and P.P.R.S. 2020.\n\nMetamucil (psyllium husk powder) [product information]. Cincinnati, O. and P.G.R.D. 2019.\n\nDivalproex sodium extended-release tablets [package insert]. Bridgewater, N. and A.P.L.R.A. 2020.\n\nPeridex (chlorhexidine gluconate 0.12%) [package insert]. 3M Canada Company Dental Products. 2007.\n\nFigure 1 Drug Interference with achievement of ketosis. Seizure Activity: On HD 14–16, seizure burden was 90% nonconvulsive status epilepticus (NCSE) and decreased to 10–15% by hospital day (HD) 23–24. From HD 30–39, % ictal ranged from 5–20% with HD 40 showing <1% ictal. % Ictal increased briefly during HD 41–47 with an average of 15% ictal but decreased to <1% by HD 48/49. % Ictal remained in the 10–20% range until HD 57 with % ictal < 1. From HD 58–72 % ictal ranged from 5–20% until % ictal <5 by HD 72.\n\njcm-10-00881-t001_Table 1Table 1 Summary work-up for New-Onset Refractory Status Epilepticus (NORSE) patient.\n\nCategories\tSerum\tCSF\tImaging\tPathology\t\nInfectious:\tInfluenza A/B, H1N1, RPR, HIV, cat scratch panel, tick borne panel, Mycoplasma pneumonia, B Henselae, B quintana (all negative)\tWest Nile Virus, Enterovirus, Bacterial culture, HSV, VZV, Lyme disease, fungal culture, HHV6, EBV, Mycoplasma pneumoniae (all negative)\t\n\t\n\t\nInflammatory:\tANA, dsDNA, SSA, SSB, SCL 70, CRP, ESR, TPO antibody, thyroglobulin antibody, complements (C3, C4, CH50), ANCA, B2 glycoprotein, anticardiolipin, Antiribosomal P protein Ab, ACE, smooth muscle antibody, skeletal muscle antibody\tAMPA-R Ab, CASPR2 Ab, DPPX Ab, GABA-B-R Ab, GAD 65, GFAP, LGI1-IgG, mGluR1 Ab, NMDA R Ab\t\n\t\n\t\nParaneoplastic:\tGAD 65, NMDA, voltage gated potassium channel antibody, flow cytometry\tAChR ganglionic neuronal Ab, Amphiphysin Ab, Antiglial nuclear Ab, Antineuronal nuclear Ab, CRMP-5, Neuronal (V-G) K+ channel Ab, N-Type Calcium channel ab, P/Q type calcium channel Ab, Purkinje cell cytoplasmic Ab, Striational Ab (all negative)\t\n\t\n\t\nMetabolic:\tTSH (0.22), Free T4 (1.7 ng/dL), Ammonia (47, 33, 37 µL/dL), serum and urine toxicology (negative)\t\n\t\n\t\n\t\n\n\t\n\t\n\tMRI brain w/wo contrast: restricted diffusion and hyperintense FLAIR signal in the bilateral hippocampi\tBenign ovarian cyst\t\n\n\t\n\t\n\tCT Chest/abdomen/pelvis: no evidence of ovarian teratoma or other malignancy\tNo malignant cells in CSF\t\n\n\t\n\t\n\tUS pelvis: tiny 3–4 mm echogenic focus on the left ovary which may represent a small calcification, however, a tiny teratoma cannot be excluded\t\n\t\n\n\t\n\t\n\tMRI pelvis: no evidence of ovarian teratoma\t\n\t\nWork-up recommendations from Table 1 from Sculier C, Gaspard N. New onset refractory status epilepticus (NORSE). Seizure. 2019 May; 68:72–78. doi: 10.1016/j.seizure.2018.09.018. Epub 2018 Sep 29. PMID: 30482654. [18]. Influenza A/B: negative; H1N1: negative; Smooth and skeletal muscle antibody: negative; RPR: rapid plasma reagent—negative; ANA: antinuclear antibody—1:2560 titer; dsDNA: double-strand DNA—positive, 38.4 IU/mL; SSA: Sjögren’s Syndrome A—greater than 8; SSB: Sjögren’s Syndrome B—negative; SCL 70: Scleroderma (antitopoisomerase)—negative; Antiribosomal P protein—negative; CRP: C-reactive protein—54 mg/L; ESR: erythrocyte sedimentation rate—51 mm/h; C3/C4/CH50: within normal limits; B2 glycoprotein—negative; Anticardiolipin—negative; TPO: thyroperoxidase antibody—negative; thyroglobulin antibody—negative; ANCA: antineutrophil cytoplasmic antibody—negative; ACE: angiotensin converting enzyme—within normal limits; GAD 65: Glutamic acid decarboxylase—negative; NMDA: N-methyl-D-Aspartate receptor antibody—negative; AMPA: α-amino-3-hydroxy-5-methyl-4 -isoxazolepropionic acid receptor- antibody negative; TSH: thyroid stimulating hormone—within normal limits; HIV: Human immunodeficiency virus—negative; Lyme disease—negative; West Nile Virus—negative; Enterovirus- negative; Bacterial and fungal culture—negative; HSV: Herpes Simplex Virus—negative; VZV: Varicella Zoster Virus—negative; HHV6: Human Herpes Virus 6—negative; EBV: Epstein Barr Virus—negative; GFAP: Glial Fibrillary Acidic Protein—negative; LGI1: Leucine-rich glioma-inactivated—negative; CASPR2: Contactin-associated protein-like 2—negative; DPPX: dipeptidyl-peptidase-like protein 6—negative; GABA: gamma-aminobutyric acid—negative; mGlu1: metabotropic glutamate receptor 1—negative; CRMP-5: CV2/collapsin response mediator protein—negative; Voltage gated potassium channel—negative.\n\njcm-10-00881-t002_Table 2Table 2 Common antiseizure medications, medications utilized in hospitalized patients and associated carbohydrate, fat, and alcohol content.\n\n\nIntravenous Product (General Product Concentration)\n\t\nCarbohydrate Excipient and Amount Per Vial\n\t\nCarbohydrate Content at a Common Dose\n\t\nFat Content\n\t\nAlcohol Content\n\t\nBrivaracetam (10 mg/mL)\t–\t–\t–\t–\t\nDiazepam (5 mg/mL) [41]\tPropylene glycol: 414 mg\t828 mg CHO/10 mg\t–\t79 mg\t\nFamotidine (10 mg/mL) [41]\tMannitol: 20 mg\t40 mg CHO/40 mg\t–\t–\t\nFosphenytoin [42] \t–\t–\t–\t–\t\nLorazepam (2 mg/mL) [42] \tPropylene glycol: 753 mg\t–\t–\t–\t\nPentobarbital (50 mg/mL) [41]\tPropylene glycol: 414 mg\t–\t–\t79 mg\t\nPhenobarbital (130 mg/mL) [41]\tPropylene glycol: 702 mg\t–\t–\t79 mg\t\nPhenytoin (50 mg/mL) [41]\tPropylene glycol: 414 mg\t–\t–\t79 mg\t\nPropofol (10 mg/mL) [41]\tGlycerol: 22.5 mg/mL\t450 mg CHO/h\n(20 mL/h)\tSoybean oil: 100 mg/mL\tBenzyl alcohol *\t\nEgg Lecithin: 12 mg/mL\t\nLipid: 100 mg/mL \n(1.1 kcal/mL)\t\nKetamine (multiple) \t–\t–\t–\t–\t\nLacosamide (multiple)\t–\t–\t–\t–\t\nMidazolam (multiple) \t–\t–\t–\tBenzyl alcohol †\t\nThiopental (25 mg/mL) \t–\t–\t–\t–\t\nValproate (20 mg/mL) \t–\t–\t–\t–\t\nTrimethoprim-sulfamethoxazole (Bactrim®) diluted in Dextrose 5% W 100 mL per 80–400 mg TMP-SMX \tDextrose: 5 g/100 ml\tUp to 20 g CHO per dose\t–\t–\t\nVancomycin (Vancocin®) diluted in Dextrose 5% W per 1 g/250 mL solution \tDextrose: 5 g/100 ml\tUp to 2 g CHO per dose\t–\t–\t\n\nEnteral Product § (General Product Strength)\n\t\nCarbohydrate Excipient and Amount Per Unit\n\t\nCarbohydrate Content at a Common Dose\n\t\nFat Content\n\t\nAlcohol Content\n\t\nCarbamazepine (extended-release tablet)\tLactose monohydrate ‡\nMicrocrystalline cellulose ‡\t–\t–\t–\t\nClobazam (10 mg tablet) [43]\t105.3 mg/tablet\t≈100 mg/10 mg\t–\t–\t\nClonazepam (0.5 mg tablet) [43]\t143.5 mg/tablet\t≈2800 mg/10 mg\t–\t–\t\nLevetiracetam (immediate release tablet) \tCroscarmellose sodium ‡\nPolyethylene glycol 3350 ‡\nPolyethylene glycol 6000 ‡\t–\t–\tPolyvinyl alcohol\t\nPsyllium (Metamucil) packet \t9 g CHO/tablespoon\t27 g CHO/day (TID)\t–\t–\t\nDivalproex sodium (extended-release tablet) \tHypromelloses ‡\nLactose monohydrate ‡\nPolyethylene glycol ‡\nPropylene glycol ‡\nMacrogol ‡\nMicrocrystalline cellulose ‡\t–\t–\tn-Butyl alcohol\nIsopropyl alcohol\nPolyvinyl alcohol\t\nSee Appendix A for package inserts. * Present at 1.5 mg/mL in all vial sizes (0.15% w/v). Avoid use in pediatric populations due to benzyl alcohol content. † Present at 10 mg/mL in all vial sizes (1% w/v), except preservative-free formulations. Avoid use in pediatric populations due to benzyl alcohol content. ‡ Unknown amount of relative excipient may affect ketosis but is likely clinically insignificant. § Solution and suspension formulations should be avoided if possible as they usually contain sugars that will affect ketosis.\n\njcm-10-00881-t003_Table 3Table 3 Ketogenic Diet checklist for Status Epilepticus.\n\nPearls to Consider for Starting and Maintaining a Ketogenic Diet (KD)\t\nI. KD initiation\t\n\n○ Check fasting lipid panel, complete metabolic panel, complete blood count, amylase, lipase, Vitamin D serum levels\n\n\n\t\n\n○ Record baseline weight and height\n\n\n\t\n\n○ Continuous video EEG\n\n\n\t\n\n○ Dietitian/nutrition consult (consider pediatric nutritionist)\n\n\n\t\n\n○ Stop current enteral formula\n\n\n\t\n\n○ Reduce carbohydrate content in medications and parenteral fluids with pharmacy input\n\n\n\t\n\n○ Active communication with nursing/pharmacy, EMR warnings, and signs in room are crucial to avoid medication/IV-containing carbohydrates\n\n\n\t\n\n○ Begin KD (e.g., KetoCal/MCT oil)\n\n\n\t\n\n○ Include multivitamin injection, Vit. D and calcium supplementation via nasogastric tube/gastric tube\n\n\n\t\n\n○ Change any oral agents from liquid formulation to crushed tablet formulation\n\n\n\t\nII. KD maintenance\t\n\n○ Remove all common carbohydrate excipients in intravenous fluids, including:\n\n○ Glycerin\n\n○ Maltodextrin\n\n○ Propylene glycol\n\n○ Sugars (dextrose, fructose, glucose, lactose, sucrose, corn syrup)\n\n○ Sugar alcohols (glycerol, mannitol, sorbitol)\n\n○ Starches\n\n○ \nKD can be challenged via coadministration of other meds & IVs!\n\n\n\n\t\nIII. Pitfalls to consider:\t\n\n○ Contraindications: unstable metabolic derangements, hemodynamic instability, coagulopathy/bleeding diathesis, pancreatitis, liver failure, severe hyperlipidemia, ileus, pregnancy, known fatty acid oxidation disorder or pyruvate carboxylase deficiency\n\n○ \nPropofol infusions cannot be given within 24 h before starting a KD!\n\n\n\n\t\nAdapted & modified from Table 3 from Thakur KT, Probasco JC, Hocker SE, et al. Neurology. 2014 Feb 25; 82(8): 665–670. [4].\n==== Refs\nReferences\n1. Cervenka M.C. Wood S. Bagary M. Balabanov A. Bercovici E. Brown M.-G. Devinsky O. Lorenzo C.D. 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Early- and Late-onset Complications of the Ketogenic Diet for Intractable Epilepsy Epilepsia 2004 45 1116 1123 10.1111/j.0013-9580.2004.10004.x 15329077 \n60. Moriyama K. Watanabe M. Yamada Y. Shiihara T. Protein-Losing Enteropathy as a Rare Complication of the Ketogenic Diet Pediatric Neurol. 2015 52 526 528 10.1016/j.pediatrneurol.2015.01.009 25724370\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "10(4)",
"journal": "Journal of clinical medicine",
"keywords": "critical care; ketogenic diet; ketosis; new onset refractory status epilepticus; seizures; status epilepticus",
"medline_ta": "J Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101606588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33671485",
"pubdate": "2021-02-22",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "16162774;11209590;26900382;20813015;30484010;31206357;28626875;26552568;29881797;17910589;31623937;24453083;25454503;26092326;15574625;18823325;25194304;21914716;24464515;8474571;30096755;15286548;26336950;16302862;15329077;19962324;15328567;31420291;32873691;26148985;17262855;15944379;18322097;32614067;21536412;20144378;17241227;19723863;22528274;29399791;29395511;30760973;30482654;32203691;32140640;30214989;27213459;6829359;26296517;29531455;28179470;25724370;19049580",
"title": "Pearls and Pitfalls of Introducing Ketogenic Diet in Adult Status Epilepticus: A Practical Guide for the Intensivist.",
"title_normalized": "pearls and pitfalls of introducing ketogenic diet in adult status epilepticus a practical guide for the intensivist"
} | [
{
"companynumb": "US-UCBSA-2021030732",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PENTOBARBITAL"
},
"drugadditional": "3",
... |
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