article dict | reports listlengths 1 3.97k |
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{
"abstract": "This report describes three cases of posttransplant lymphoproliferative disorder (PTLD) in multivisceral/small bowel transplant patients treated with rituximab (anti-CD20 monoclonal antibodies). In two cases (one of which was a B-cell lymphoma) a good response to therapy was achieved. A third case (with polymorphic PTLD with low CD20 expression) developed a refractory rejection and PTLD was still documented on graftectomy. Rituximab was well tolerated, and a reduction of Epstein-Barr virus (EBV) viral load was documented by quantitive competitive-EBV polymerase chain reaction. Efficacy of therapy needs to be assessed in controlled studies.",
"affiliations": "Department of Internal Medicine and Medical Specialties, Infectious Diseases Clinic, University of Modena and Reggio Emilia, Modena, Italy. codeluppi.mauro@unimo.it",
"authors": "Codeluppi|M|M|;Cocchi|S|S|;Guaraldi|G|G|;Di Benedetto|F|F|;Bagni|A|A|;Pecorari|M|M|;Gennari|W|W|;Pinna|A D|AD|;Gerunda|G E|GE|;Esposito|R|R|",
"chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2005.06.032",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "37(6)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D001706:Biopsy; D001853:Bone Marrow; D017809:Fatal Outcome; D005260:Female; D005736:Gardner Syndrome; D006801:Humans; D007421:Intestine, Small; D008232:Lymphoproliferative Disorders; D008297:Male; D011183:Postoperative Complications; D000069283:Rituximab; D016896:Treatment Outcome; D014781:Viscera",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2634-5",
"pmc": null,
"pmid": "16182770",
"pubdate": "2005",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rituximab as treatment of posttransplant lymphoproliferative disorder in patients who underwent small bowel/multivisceral transplantation: report of three cases.",
"title_normalized": "rituximab as treatment of posttransplant lymphoproliferative disorder in patients who underwent small bowel multivisceral transplantation report of three cases"
} | [
{
"companynumb": "IT-ROCHE-1706356",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GANCICLOVIR"
},
"drugadditional": null,
"dr... |
{
"abstract": "Spontaneous haemoperitoneum is rare. When it occurs it is a life-threatening condition. Common causes of this are gynaecological in nature and rarely due to colonic diverticular perforation. Diverticulitis is a common condition affecting people in western countries. This presentation of spontaneous haemoperitoneum highlights the disproportionate abdominal pain and opioid-induced constipation. Significant bloods on admission included haemoglobin of 148 g/L, C reactive protein (CRP) of 1.1 mg/L, white cell count (WCC) of 12.7×10(9)/L (neutrophils 10.9×10(9)/L). Bloods repeated 10 h later revealed the haemoglobin had dropped to 100 g/L, CRP had increased significantly to 120 mg/L, WCC: 7.4×10(9)/L (neutrophils 5.3×10(9)/L) and a reduced packed cell volume: 0.307 L/L. CT scan revealed free fluid and a possible mass. At laparoscopy, frank haemoperitoneum was seen and a decision was made to open and perform a Hartmann's procedure. The patient did very well postoperatively and was discharged on the ninth postoperative day. He is currently awaiting reversal of the ileostomy.",
"affiliations": "Respiratory Department, Abertawe Bro Morgannwg University Health Board, Swansea, UK.;Department of General Surgical Directorate, Wrexham Maelor Hospital, Wrexham, UK.;Department of Radiology, Wrexham Maelor Hospital, Wrexham, UK.",
"authors": "George|Jayan|J|;Ben-Sassi|Abozed|A|;Dixon|Rebecca|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000006:Abdomen, Acute; D000328:Adult; D012809:Colon, Sigmoid; D004241:Diverticulum, Colon; D004636:Emergency Service, Hospital; D004638:Emergency Treatment; D005500:Follow-Up Studies; D006465:Hemoperitoneum; D006801:Humans; D007416:Intestinal Perforation; D010535:Laparoscopy; D007813:Laparotomy; D008297:Male; D035583:Rare Diseases; D018570:Risk Assessment; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25480140",
"pubdate": "2014-12-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "17235002;14463026;16129236;21850197;16455722;1085269;17342463;10932672",
"title": "Spontaneous haemoperitoneum due to a sigmoid diverticulum.",
"title_normalized": "spontaneous haemoperitoneum due to a sigmoid diverticulum"
} | [
{
"companynumb": "GB-LUPIN PHARMACEUTICALS INC.-2015-00609",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional"... |
{
"abstract": "Heparin-induced thrombocytopenia (HIT) is an immune complication of heparin therapy caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. Pathogenic antibodies to PF4/heparin bind and activate platelets to propagate a hypercoagulable state culminating in life-threatening thrombosis. The serotonin-release assay (SRA) is considered the gold-standard test to diagnose HIT. However, the sensitivity of the SRA was questioned with reported cases of clinical diagnosis of HIT and negative SRA. Herein, we present the utility of platelet factor 4-dependent P-selectin expression assay (PEA) in diagnosing HIT in a patient with thrombocytopenia and recurrent thrombosis who repeatedly tested negative with SRA.",
"affiliations": "Department of Pathology and Laboratory Medicine.;Department of Pathology and Laboratory Medicine.;Division of Hematology and Oncology, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan.;Department of Pathology and Laboratory Medicine.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.;Department of Pathology and Laboratory Medicine.",
"authors": "Arora|Kanika|K|;Rodgers|Shannon|S|;Alkhatib|Yaser|Y|;Onwubiko|Ifeoma N|IN|;Padmanabhan|Anand|A|;Otrock|Zaher K|ZK|",
"chemical_list": "D000925:Anticoagulants; D019007:P-Selectin; C546937:SELP protein, human; D010978:Platelet Factor 4; D006493:Heparin",
"country": "England",
"delete": false,
"doi": "10.1097/MBC.0000000000001062",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0957-5235",
"issue": "32(7)",
"journal": "Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis",
"keywords": null,
"medline_ta": "Blood Coagul Fibrinolysis",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D004797:Enzyme-Linked Immunosorbent Assay; D006403:Hematologic Tests; D006493:Heparin; D006801:Humans; D008297:Male; D019007:P-Selectin; D010978:Platelet Factor 4; D013921:Thrombocytopenia",
"nlm_unique_id": "9102551",
"other_id": null,
"pages": "522-525",
"pmc": null,
"pmid": "34261860",
"pubdate": "2021-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "P-selectin expression assay in a repeatedly serotonin-release assay-negative patient with heparin-induced thrombocytopenia.",
"title_normalized": "p selectin expression assay in a repeatedly serotonin release assay negative patient with heparin induced thrombocytopenia"
} | [
{
"companynumb": "US-DRREDDYS-SPO/USA/21/0139330",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": nul... |
{
"abstract": "A 53-year-old man took his own life while receiving biological therapy with the tumour necrosis factor-α inhibitor adalimumab for severe psoriasis. The patient had a psychiatric history and a 32-year history of variable unstable psoriasis. Reported suicide in patients with psoriasis receiving adalimumab is rare (only one other reported case). It is important, however, to recognize the effects of skin disease on the mental health of vulnerable patients receiving biological agents. Patients will benefit from a more holistic approach that includes both dermatological and psychological assessment and treatment.",
"affiliations": "Department of General Medicine, Whipps Cross Hospital, London, UK.",
"authors": "Ellard|R|R|;Ahmed|A|A|;Shah|R|R|;Bewley|A|A|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D001688:Biological Products; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1111/ced.12351",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0307-6938",
"issue": "39(5)",
"journal": "Clinical and experimental dermatology",
"keywords": null,
"medline_ta": "Clin Exp Dermatol",
"mesh_terms": "D000068879:Adalimumab; D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D001688:Biological Products; D003866:Depressive Disorder; D003880:Dermatology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010819:Physician's Role; D011565:Psoriasis; D012307:Risk Factors; D013405:Suicide",
"nlm_unique_id": "7606847",
"other_id": null,
"pages": "624-7",
"pmc": null,
"pmid": "24934916",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Suicide and depression in a patient with psoriasis receiving adalimumab: the role of the dermatologist.",
"title_normalized": "suicide and depression in a patient with psoriasis receiving adalimumab the role of the dermatologist"
} | [
{
"companynumb": "GB-ABBVIE-14P-167-1256592-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Azathioprine is commonly used in Crohn's disease. It has been administered to many pregnant women over many years without significant side effects. However, pancytopenia and severe combined immune deficiency-like disease have been reported in infants whose mothers received azathioprine throughout pregnancy. Moreover, myelotoxicity has been described in patients being treated with azathioprine and having a low or absent thiopurine S-methyl transferase [TPMT] activity.Here, we describe the case of a newborn girl found to be highly lymphopenic [< 300 CD3+ T cells] after a positive newborn screening for severe combined immuno deficiency. The clinical examination was normal. The mother was treated with azathioprine throughout her pregnancy, without any reduction of the dose. It was shown that the mother was heterozygous for the 3A [TPMT] activity mutation and that the baby was homozygous for the same mutation; 6-thioguanine nucleotides were high (744 pmol/8.108 red blood cells [RBC]) in the mother and detectable in the infant [177 pmol/8.108 RBC].Although rare, this case illustrates the potential grave consequences of unsuspected TPMT homozygosity in a newborn of a mother receiving thiopurines during pregnancy. Because of the severity of the risk for the newborn, consideration should be given to performing maternal genetic testing and newborn routine blood count in cases of thiopurine treatment during pregnancy.",
"affiliations": "Service d'hématologie et d'immunologie pédiatrique, Hôpital Mère-Enfants, CHU de Nantes, Nantes, France.;Service de pharmacologie Clinique, CHU de Nantes, Nantes, France.;Laboratoire ANDEMEGEN, Nantes Cédex 1, France.;Service d'immunologie, CHU de Nantes, Nantes, France.;Direction de la recherche, cellule Innovation, CHU de Nantes, Nantes, France.;Service d'hématologie et d'immunologie pédiatrique, Hôpital Mère-Enfants, CHU de Nantes, Nantes, France.;Service de pharmacologie Clinique, CHU de Nantes, Nantes, France.;Service de pédiatrie, Hôpital Mère-Enfants, CHU de NANTES, Nantes, France.;Service d'immunologie, CHU de Nantes, Nantes, France.",
"authors": "Thomas|Caroline|C|;Monteil-Ganiere|Catherine|C|;Mirallié|Sophie|S|;Hémont|Caroline|C|;Dert|Cecile|C|;Léger|Alexandra|A|;Joyau|Caroline|C|;Caldari|Dominique|D|;Audrain|Marie|M|",
"chemical_list": "D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1093/ecco-jcc/jjx123",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1873-9946",
"issue": "12(2)",
"journal": "Journal of Crohn's & colitis",
"keywords": "Azathioprine; Crohn’s disease; SCID; TRECs; pregnancy",
"medline_ta": "J Crohns Colitis",
"mesh_terms": "D001379:Azathioprine; D003424:Crohn Disease; D005260:Female; D006720:Homozygote; D006801:Humans; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D008231:Lymphopenia; D008780:Methyltransferases; D009154:Mutation; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects",
"nlm_unique_id": "101318676",
"other_id": null,
"pages": "258-261",
"pmc": null,
"pmid": "28961694",
"pubdate": "2018-01-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Severe Neonatal Lymphopenia Associated With Administration of Azathioprine to the Mother in a Context of Crohn's Disease.",
"title_normalized": "a severe neonatal lymphopenia associated with administration of azathioprine to the mother in a context of crohn s disease"
} | [
{
"companynumb": "FR-ALKEM LABORATORIES LIMITED-FR-ALKEM-2021-01082",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"dru... |
{
"abstract": "Vancomycin is a prevalent cause of the severe hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which leads to significant morbidity and mortality and commonly occurs in the setting of combination antibiotic therapy, affecting future treatment choices. Variations in HLA class I in particular have been associated with serious T cell-mediated adverse drug reactions, which has led to preventive screening strategies for some drugs.\n\n\n\nWe sought to determine whether variation in the HLA region is associated with vancomycin-induced DRESS.\n\n\n\nProbable vancomycin-induced DRESS cases were matched 1:2 with tolerant control subjects based on sex, race, and age by using BioVU, Vanderbilt's deidentified electronic health record database. Associations between DRESS and carriage of HLA class I and II alleles were assessed by means of conditional logistic regression. An extended sample set from BioVU was used to conduct a time-to-event analysis of those exposed to vancomycin with and without the identified HLA risk allele.\n\n\n\nTwenty-three subjects met the inclusion criteria for vancomycin-associated DRESS. Nineteen (82.6%) of 23 cases carried HLA-A*32:01 compared with 0 (0%) of 46 of the matched vancomycin-tolerant control subjects (P = 1 × 10-8) and 6.3% of the BioVU population (n = 54,249, P = 2 × 10-16). Time-to-event analysis of DRESS development during vancomycin treatment among the HLA-A*32:01-positive group indicated that 19.2% had DRESS and did so within 4 weeks.\n\n\n\nHLA-A*32:01 is strongly associated with vancomycin-induced DRESS in a population of predominantly European ancestry. HLA-A*32:01 testing could improve antibiotic safety, help implicate vancomycin as the causal drug, and preserve future treatment options with coadministered antibiotics.",
"affiliations": "Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tenn.;Department of Infectious Diseases, Austin Health, Heidelberg, Australia; National Centre for Infections in Cancer, Department of Infectious Diseases, Peter MacCallum Cancer Centre, Parkville, Australia; Department of Medicine, University of Melbourne, Parkville, Australia.;Telethon Kids Institute, University of Western Australia, Nedlands, Australia.;Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia.;Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.;Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tenn.;Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Fla.;Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Fla.;Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.;Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pa.;Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tenn.;Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.;Department of Clinical Immunology, Fiona Stanley Hospital, Murdoch, Australia.;Department of Clinical Immunology, Fiona Stanley Hospital, Murdoch, Australia; Department of Clinical Immunology, Royal Perth Hospital, Perth, Australia; Division of Pathology and Laboratory Medicine, School of Medicine, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Crawley, Australia.;Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia.;Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia.;Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia.;Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia.;Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.;Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tenn; Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia; Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn.;Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tenn; Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia; Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tenn. Electronic address: elizabeth.j.phillips@vumc.org.",
"authors": "Konvinse|Katherine C|KC|;Trubiano|Jason A|JA|;Pavlos|Rebecca|R|;James|Ian|I|;Shaffer|Christian M|CM|;Bejan|Cosmin A|CA|;Schutte|Ryan J|RJ|;Ostrov|David A|DA|;Pilkinton|Mark A|MA|;Rosenbach|Misha|M|;Zwerner|Jeffrey P|JP|;Williams|Kristina B|KB|;Bourke|Jack|J|;Martinez|Patricia|P|;Rwandamuriye|Francois|F|;Chopra|Abha|A|;Watson|Mark|M|;Redwood|Alec J|AJ|;White|Katie D|KD|;Mallal|Simon A|SA|;Phillips|Elizabeth J|EJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D015234:HLA-A Antigens; C531148:HLA-A*32 antigen; D014640:Vancomycin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaci.2019.01.045",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-6749",
"issue": "144(1)",
"journal": "The Journal of allergy and clinical immunology",
"keywords": "T-cell hypersensitivity; Vancomycin; antibiotic allergy; delayed hypersensitivity; drug reaction with eosinophilia and systemic symptoms; human leukocyte antigen",
"medline_ta": "J Allergy Clin Immunol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D015234:HLA-A Antigens; D006801:Humans; D008297:Male; D008875:Middle Aged; D062105:Molecular Docking Simulation; D014640:Vancomycin; D055815:Young Adult",
"nlm_unique_id": "1275002",
"other_id": null,
"pages": "183-192",
"pmc": null,
"pmid": "30776417",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "11888582;11943262;12165215;13679828;15024131;15057820;18256392;18766337;19131951;19239928;19499576;20124702;20383002;21577229;22645359;22722860;22920398;23806270;23855313;24599767;24635062;24911354;25414323;27156746;28207879;29100867;3041915;7249508",
"title": "HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms.",
"title_normalized": "hla a 32 01 is strongly associated with vancomycin induced drug reaction with eosinophilia and systemic symptoms"
} | [
{
"companynumb": "US-PENTEC HEALTH-2019PEN00017",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN HYDROCHLORIDE"
},
"drugadditio... |
{
"abstract": "OBJECTIVE\nThese case reports demonstrate that, at the individual level, blood metformin concentrations and metformin effects on lactate do not always correlate.\n\n\nMETHODS\nWe report here on two unusual cases: metformin accumulation in the absence of hyperlactataemia; and metformin-induced hyperlactataemia with no metformin accumulation.\n\n\nRESULTS\nPatient #1 presented with severe kidney failure, severe acidosis (pH: 7.04), normal lactataemia (0.90 mmol/L) and marked metformin accumulation. Patient #2 presented with hyperlactataemia, even after dose reduction, during otherwise well-tolerated metformin treatment. Arterial lactate levels were 8.8, 8.2 and 4.7 mmol/L during metformin therapy with daily doses of 2550, 1700 and 850 mg, respectively. After withdrawal, metformin was reintroduced for 5-day periods at 500 mg/day up to 2000 mg/day with washout intervals. Lactate concentration, normal at baseline, rapidly exceeded 2 mmol/L after metformin administration.\n\n\nCONCLUSIONS\nThese clinical data suggest a new concept for metformin therapy: there may be either resistance or, conversely, hypersensitivity to metformin effects on lactate generation according to the individual patient.",
"affiliations": "Service d'endocrinologie et de nutrition, hôpital Sud, centre hospitalier universitaire, 80054 Amiens cedex 1, France; Unité INSERM 1088, Université de Picardie-Jules-Verne, Amiens, France. Electronic address: lalau.jean-daniel@chu-amiens.fr.;Service d'endocrinologie et de nutrition, hôpital Sud, centre hospitalier universitaire, 80054 Amiens cedex 1, France.;Service d'endocrinologie et de nutrition, hôpital Sud, centre hospitalier universitaire, 80054 Amiens cedex 1, France; Unité INSERM 1088, Université de Picardie-Jules-Verne, Amiens, France.;Service d'endocrinologie et de nutrition, centre hospitalier universitaire du Kremlin-Bicêtre, Paris, France.;Service d'endocrinologie et de nutrition, hôpital Sud, centre hospitalier universitaire, 80054 Amiens cedex 1, France; Unité INSERM 1088, Université de Picardie-Jules-Verne, Amiens, France.",
"authors": "Lalau|J D|JD|;Azzoug|M L|ML|;Kajbaf|F|F|;Briet|C|C|;Desailloud|R|R|",
"chemical_list": "D007004:Hypoglycemic Agents; D019344:Lactic Acid; D008687:Metformin",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1262-3636",
"issue": "40(3)",
"journal": "Diabetes & metabolism",
"keywords": "Hyperlactataemia; Lactate; Lactic acidosis; Metformin; Type 2 diabetes",
"medline_ta": "Diabetes Metab",
"mesh_terms": "D000140:Acidosis, Lactic; D000368:Aged; D003924:Diabetes Mellitus, Type 2; D004334:Drug Administration Schedule; D004342:Drug Hypersensitivity; D004351:Drug Resistance; D005260:Female; D006801:Humans; D065906:Hyperlactatemia; D007004:Hypoglycemic Agents; D019344:Lactic Acid; D008297:Male; D008687:Metformin; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "9607599",
"other_id": null,
"pages": "220-3",
"pmc": null,
"pmid": "24417956",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metformin accumulation without hyperlactataemia and metformin-induced hyperlactataemia without metformin accumulation.",
"title_normalized": "metformin accumulation without hyperlactataemia and metformin induced hyperlactataemia without metformin accumulation"
} | [
{
"companynumb": "FR-WATSON-2014-18392",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": null... |
{
"abstract": "Postmortem redistribution (PMR) leads to challenges in postmortem case interpretation. Particularly antidepressants and neuroleptics are expected to undergo PMR based on their physico-chemical properties. For the current study, time- and site-dependent PMR of 20 antidepressants and neuroleptics were investigated in humans (authentic cases); five of which are discussed in detail (citalopram, mirtazapine, quetiapine, risperidone and venlafaxine) along with two metabolites (9-OH-risperidone and O-desmethylvenlafaxine). Blood [femoral (pB) and heart blood (HB)] and tissue biopsy samples (lung, kidney, liver, spleen, thigh muscle and adipose tissue) were collected upon admission to the institute utilizing a computed tomography-guided sample collection workflow (t1). Approximately 24 h later (t2; mean 23 ± 9.3 h), samples from the same body regions were collected manually. Liquid chromatography-tandem mass spectrometry was used for quantification. Most antidepressants and neuroleptics showed significant time-dependent concentration changes indicating the occurrence of PMR. For the first time, two phases of redistribution in pB for quetiapine were proposed (concentration decreases in the early postmortem phase, followed by concentration increases) and contrasting existing literature, both concentration increases and decreases in pB overtime were observed for risperidone and 9-OH-risperidone. Venlafaxine and its metabolite only showed minimal concentration changes, while citalopram exhibited a trend for concentration increases and mirtazapine for concentration decreases in pB overtime. Based on time-dependent tissue data, passive diffusion processes along the muscle-to-pB, liver-to-HB and lung-to-HB concentration gradients could be proposed along with bacterial degradation. Overall, no case interpretation had to be adjusted, which suggests that PMR changes of antidepressants and neuroleptics do not seem to be relevant for forensic case interpretation within the 24 h period that was investigated. However, limitations of the current study (e.g., temperature-controlled storage of the bodies) could have led to an underestimation of occurring postmortem changes, hence, interpretation of postmortem results should always be conducted with care, considering PMR phenomena and inter-individual variability.",
"affiliations": "Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, Zurich, Switzerland.;Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, Zurich, Switzerland.;Department of Forensic Medicine and Imaging, Zurich Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, 8057 Zurich, Switzerland.;Department of Forensic Medicine and Imaging, Zurich Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, 8057 Zurich, Switzerland.;Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, Zurich, Switzerland.;Department of Forensic Pharmacology and Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse 190/52, Zurich, Switzerland.",
"authors": "Brockbals|Lana|L|;Staeheli|Sandra N|SN|;Gascho|Dominic|D|;Ebert|Lars C|LC|;Kraemer|Thomas|T|;Steuer|Andrea E|AE|",
"chemical_list": "D000928:Antidepressive Agents; D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkaa092",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "45(4)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D001344:Autopsy; D002853:Chromatography, Liquid; D053593:Forensic Toxicology; D006801:Humans; D011180:Postmortem Changes",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "356-367",
"pmc": null,
"pmid": "32856054",
"pubdate": "2021-04-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Time- and Site-Dependent Postmortem Redistribution of Antidepressants and Neuroleptics in Blood and Alternative Matrices.",
"title_normalized": "time and site dependent postmortem redistribution of antidepressants and neuroleptics in blood and alternative matrices"
} | [
{
"companynumb": "CH-OTSUKA-2021_039824",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "4",
... |
{
"abstract": "We document three cases of tuberculosis (TB) in 237 systemic lupus erythematosus (SLE) patients. Their ages at SLE and TB diagnoses were 13/15, 10/25, and 13/24 years. All were female and in all the TB was diagnosed during a period of lupus flare-up when they were receiving prednisolone and other immunosuppressive drugs. All three patients had extrapulmonary TB: Two had miliary TB and one had disseminated TB through the muscles, left knee joint, and lungs. All three patients experienced anti-TB drug-induced hepatotoxicity manifesting as jaundice along with elevated transaminase enzymes from the first-line anti-TB drugs they received, leading to a change to second-line drugs in two of them. In conclusion, although TB in SLE patients is not common, it should be considered when a patient is nonresponsive to the SLE treatment. Higher rates of extrapulmonary TB and anti-TB drug-induced hepatotoxicity in SLE patients with TB were noted.",
"affiliations": "Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Hat Yai, 90110, Thailand.",
"authors": "Ruangnapa|Kanokpan|K|;Dissaneewate|Pornsak|P|;Vachvanichsanong|Prayong|P|",
"chemical_list": "D000995:Antitubercular Agents; D000637:Transaminases",
"country": "Italy",
"delete": false,
"doi": "10.1007/s10238-014-0302-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1591-8890",
"issue": "15(3)",
"journal": "Clinical and experimental medicine",
"keywords": null,
"medline_ta": "Clin Exp Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D005260:Female; D006801:Humans; D007565:Jaundice; D008180:Lupus Erythematosus, Systemic; D000637:Transaminases; D014376:Tuberculosis; D055815:Young Adult",
"nlm_unique_id": "100973405",
"other_id": null,
"pages": "429-32",
"pmc": null,
"pmid": "25099176",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24965809;12794259;19850965;18703174;17804450;15520485;17995946;15176665;19793000;19590444;19080137;19360412;17940720;14699451",
"title": "Tuberculosis in SLE patients: rare diagnosis, risky treatment.",
"title_normalized": "tuberculosis in sle patients rare diagnosis risky treatment"
} | [
{
"companynumb": "TH-LUPIN PHARMACEUTICALS INC.-2015-02563",
"fulfillexpeditecriteria": "2",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional... |
{
"abstract": "Biological therapy with TNF-α inhibitors have been increasingly used in the treatment of inflammatory arthritis. Systemic tuberculosis infections are often known to occur following treatment with these biological agents. However, no case of periprosthetic tuberculous infection of the hip following this therapy has been reported. We report a case of a 45-year-old man who developed periprosthetic tuberculous infection soon after infliximab injection. We also discuss the need of pretreatment awareness, high index of suspicion, early diagnosis and management of such case.",
"affiliations": "Department of Orthopaedics, All India Institute of Medical Sciences, New Delhi, Delhi, India.;Department of Orthopaedics, All India Institute of Medical Sciences, New Delhi, Delhi, India.;Department of Orthopaedics, All India Institute of Medical Sciences, New Delhi, Delhi, India.",
"authors": "Malhotra|Rajesh|R|;Gautam|Deepak|D|;Wahal|Naman|N|",
"chemical_list": "D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-218726",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D018501:Antirheumatic Agents; D019644:Arthroplasty, Replacement, Hip; D006622:Hip Prosthesis; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D016459:Prosthesis-Related Infections; D014057:Tomography, X-Ray Computed; D014394:Tuberculosis, Osteoarticular",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28270399",
"pubdate": "2017-03-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11596589;11964626;12614731;15520485;16573258;16792769;17515245;20304601;22233936;23276761;24932907;26396940;596147;8648322;8676109",
"title": "Tuberculous periprosthetic infection precipitated by infliximab therapy.",
"title_normalized": "tuberculous periprosthetic infection precipitated by infliximab therapy"
} | [
{
"companynumb": "IN-JNJFOC-20170317306",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "There has been a resurgence in the illicit use of 2,4-dinitrophenol by people wishing to achieve rapid weight loss. Despite its availability, the drug is banned for human consumption as it is toxic and can have fatal consequences. We present the case of a 23-year-old man who regularly consumed 2,4-dinitrophenol to generate fat loss without apparent ill effect. He was involved in a high-speed road traffic collision and sustained limb-threatening injuries. The combination of emergency surgery, trauma and 2,4-dinitrophenol consumption culminated in deterioration under anaesthesia, with subsequent death from multiorgan failure in the intensive care unit 48 h later. Previous cases have reported death from 2,4-dinitrophenol toxicity alone. We believe this is the first reported case of 2,4-dinitrophenol toxicity triggered by the additional physiological stress of polytrauma and emergency surgery.",
"affiliations": "Department of Anaesthesia and Intensive Care Leeds General Infirmary Leeds UK.;Department of Anaesthesia and Intensive Care Leeds General Infirmary Leeds UK.;Department of Anaesthesia and Intensive Care Leeds General Infirmary Leeds UK.;Department of Anaesthesia and Intensive Care Leeds General Infirmary Leeds UK.",
"authors": "Freeman|N|N|https://orcid.org/0000-0002-0007-2149;Moir|D|D|;Lowis|E|E|;Tam|E|E|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/anr3.12121",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2637-3726",
"issue": "9(1)",
"journal": "Anaesthesia reports",
"keywords": "addiction: risk factors; hyperkalaemia; ketamine: systemic effects; malignant hyperthermia: signs; postoperative SIRS/sepsis: diagnosis",
"medline_ta": "Anaesth Rep",
"mesh_terms": null,
"nlm_unique_id": "101759073",
"other_id": null,
"pages": "106-109",
"pmc": null,
"pmid": "34027412",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "16803658;23521979;15487646;19286775;21739343",
"title": "2,4-Dinitrophenol: 'diet' drug death following major trauma.",
"title_normalized": "2 4 dinitrophenol diet drug death following major trauma"
} | [
{
"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-340559",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "NOREPINEPHRINE"
},
"... |
{
"abstract": "Progressive liver failure is rarely seen in tuberculosis chemoprophylaxis with isoniazid. We present a case of a 32-year-old woman admitted to our clinic reporting abdominal pain, nausea and vomiting for 2 days. The initial diagnosis was fulminant toxic hepatitis due to isoniazid chemoprophylaxis, which was treated successfully with living donor transplantation. Tuberculosis continues to be a significant public health problem. Isoniazid-related hepatotoxicity is extremely rare in adults. The only treatment in cases of fulminant liver failure is orthotopic liver transplantation from a deceased or living donor. If a deceased donor is not available or the patient refuses this treatment, living donor transplantation is the only choice. Although rare, isoniazid used as protective therapy for pulmonary tuberculosis can lead to fulminant liver failure. When cadaveric liver transplantation is not available, living donor liver transplantation is vital.",
"affiliations": "Antalya Training and Research Hospital, Antalya, Turkey.;Department of General Surgery, Faculty of Medicine, Inonu University, Malatya, Turkey.;Department of General Surgery, Faculty of Medicine, Inonu University, Malatya, Turkey.;Department of General Surgery, Faculty of Medicine, Inonu University, Malatya, Turkey.",
"authors": "Çakır|Tuğrul|T|;Ara|Cengiz|C|;Soyer|Hacı Vural|HV|;Koc|Suleyman|S|",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D005260:Female; D006801:Humans; D007538:Isoniazid; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D019520:Living Donors; D014376:Tuberculosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26106175",
"pubdate": "2015-06-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8053063;17667808;15717216;15100912;7489806;8796249;23769080;7924752;12724633;1824929",
"title": "Successful living donor liver transplantation of fulminant liver failure due to isoniazid prophylaxis.",
"title_normalized": "successful living donor liver transplantation of fulminant liver failure due to isoniazid prophylaxis"
} | [
{
"companynumb": "TR-WATSON-2016-07048",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional": null,
"d... |
{
"abstract": "β-adrenergic antagonists (BAAs) are used to treat cardiovascular disease such as ischemic heart disease, congestive heart failure, dysrhythmias, and hypertension. Poisoning from BAAs can lead to severe morbidity and mortality. We aimed to determine the utility of extracorporeal treatments (ECTRs) in BAAs poisoning.\n\n\n\nWe conducted systematic reviews of the literature, screened studies, extracted data, and summarized findings following published EXTRIP methods.\n\n\n\nA total of 76 studies (4 in vitro and 2 animal experiments, 1 pharmacokinetic simulation study, 37 pharmacokinetic studies on patients with end-stage kidney disease, and 32 case reports or case series) met inclusion criteria. Toxicokinetic or pharmacokinetic data were available on 334 patients (including 73 for atenolol, 54 for propranolol, and 17 for sotalol). For intermittent hemodialysis, atenolol, nadolol, practolol, and sotalol were assessed as dialyzable; acebutolol, bisoprolol, and metipranolol were assessed as moderately dialyzable; metoprolol and talinolol were considered slightly dialyzable; and betaxolol, carvedilol, labetalol, mepindolol, propranolol, and timolol were considered not dialyzable. Data were available for clinical analysis on 37 BAA poisoned patients (including 9 patients for atenolol, 9 for propranolol, and 9 for sotalol), and no reliable comparison between the ECTR cohort and historical controls treated with standard care alone could be performed. The EXTRIP workgroup recommends against using ECTR for patients severely poisoned with propranolol (strong recommendation, very low quality evidence). The workgroup offered no recommendation for ECTR in patients severely poisoned with atenolol or sotalol because of apparent balance of risks and benefits, except for impaired kidney function in which ECTR is suggested (weak recommendation, very low quality of evidence). Indications for ECTR in patients with impaired kidney function include refractory bradycardia and hypotension for atenolol or sotalol poisoning, and recurrent torsade de pointes for sotalol. Although other BAAs were considered dialyzable, clinical data were too limited to develop recommendations.\n\n\n\nBAAs have different properties affecting their removal by ECTR. The EXTRIP workgroup assessed propranolol as non-dialyzable. Atenolol and sotalol were assessed as dialyzable in patients with kidney impairment, and the workgroup suggests ECTR in patients severely poisoned with these drugs when aforementioned indications are present.",
"affiliations": "Research Center, CIUSSS du Nord-de-L'île-de-Montréal, Hôpital du Sacré-Coeur de Montréal, University of Montreal, Montreal, QC, Canada.;Division of Practice Advancement and Clinical Education, UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA.;Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, NYU Grossman School of Medicine, New York, NY, USA.;Centre Intégré de Santé et de Services Sociaux (CISSS) Montérégie-Centre Emergency Department, Hôpital Charles-Lemoyne, Greenfield Park, QC, Canada.;Departments of Renal Medicine and Transplantation and Clinical Pharmacology and Toxicology, St Vincent's Hospital, Sydney, NSW, Australia.;Emergency Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.;Department of Pharmacy and Therapeutics, and Department of Medicine Renal-Electrolyte Division, University of Pittsburgh Schools of Pharmacy and Medicine, Pittsburgh, PA, USA.;Research Center, CIUSSS du Nord-de-L'île-de-Montréal, Hôpital du Sacré-Coeur de Montréal, University of Montreal, Montreal, QC, Canada.;Research Center, CIUSSS du Nord-de-L'île-de-Montréal, Hôpital du Sacré-Coeur de Montréal, University of Montreal, Montreal, QC, Canada. marcghannoum@gmail.com.",
"authors": "Bouchard|Josée|J|0000-0002-6869-7663;Shepherd|Greene|G|;Hoffman|Robert S|RS|;Gosselin|Sophie|S|;Roberts|Darren M|DM|;Li|Yi|Y|;Nolin|Thomas D|TD|;Lavergne|Valéry|V|;Ghannoum|Marc|M|;|||",
"chemical_list": "D000319:Adrenergic beta-Antagonists",
"country": "England",
"delete": false,
"doi": "10.1186/s13054-021-03585-7",
"fulltext": "\n==== Front\nCrit Care\nCritical Care\n1364-8535\n1466-609X\nBioMed Central London\n\n3585\n10.1186/s13054-021-03585-7\nResearch\nExtracorporeal treatment for poisoning to beta-adrenergic antagonists: systematic review and recommendations from the EXTRIP workgroup\nhttp://orcid.org/0000-0002-6869-7663\nBouchard Josée 1\nShepherd Greene 2\nHoffman Robert S. 3\nGosselin Sophie 456\nRoberts Darren M. 78\nLi Yi 9\nNolin Thomas D. 10\nLavergne Valéry 1\nGhannoum Marc marcghannoum@gmail.com\n\n111\nthe EXTRIP workgroupBouchard Josée\nShepherd Greene\nHoffman Robert S.\nGosselin Sophie\nRoberts Darren M.\nLi Yi\nNolin Thomas D.\nLavergne Valéry\nGhannoum Marc\nAlhatali Badria\nAnseeuw Kurt\nBird Steven\nBerling Ingrid\nBunchman Timothy E\nCalello Diane P\nChin Paul K\nDoi Kent\nGalvao Tais\nGoldfarb David S\nHassanian-Moghaddam Hossein\nHoegberg Lotte CG\nKallab Siba\nKebede Sofia\nKielstein Jan T\nLewington Andrew\nMacedo Etienne M\nMacLaren Rob\nMegarbane Bruno\nMowry James B\nNolin Thomas D\nOstermann Marlies E\nPeng Ai\nRoy Jean-Philippe\nVijayan Anitha\nWalsh Steven J\nWong Anselm\nWood David M\nYates Christopher\ninfo@extrip-workgroup.org\n\n1 grid.14848.31 0000 0001 2292 3357 Research Center, CIUSSS du Nord-de-L’île-de-Montréal, Hôpital du Sacré-Coeur de Montréal, University of Montreal, Montreal, QC Canada\n2 grid.10698.36 0000000122483208 Division of Practice Advancement and Clinical Education, UNC Eshelman School of Pharmacy, Chapel Hill, NC USA\n3 grid.137628.9 0000 0004 1936 8753 Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, NYU Grossman School of Medicine, New York, NY USA\n4 grid.420748.d 0000 0000 8994 4657 Centre Intégré de Santé et de Services Sociaux (CISSS) Montérégie-Centre Emergency Department, Hôpital Charles-Lemoyne, Greenfield Park, QC Canada\n5 grid.14709.3b 0000 0004 1936 8649 Department of Emergency Medicine, McGill University, Montreal, QC Canada\n6 Centre Antipoison du Québec, Quebec, QC Canada\n7 grid.437825.f 0000 0000 9119 2677 Departments of Renal Medicine and Transplantation and Clinical Pharmacology and Toxicology, St Vincent’s Hospital, Sydney, NSW Australia\n8 grid.1005.4 0000 0004 4902 0432 St Vincent’s Clinical School, University of New South Wales, Sydney, NSW Australia\n9 grid.506261.6 0000 0001 0706 7839 Emergency Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China\n10 grid.21925.3d 0000 0004 1936 9000 Department of Pharmacy and Therapeutics, and Department of Medicine Renal-Electrolyte Division, University of Pittsburgh Schools of Pharmacy and Medicine, Pittsburgh, PA USA\n11 Verdun Hospital, 4000 Lasalle Boulevard, Verdun, Montreal, QC H4G 2A3 Canada\n10 6 2021\n10 6 2021\n2021\n25 2011 3 2021\n26 4 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nβ-adrenergic antagonists (BAAs) are used to treat cardiovascular disease such as ischemic heart disease, congestive heart failure, dysrhythmias, and hypertension. Poisoning from BAAs can lead to severe morbidity and mortality. We aimed to determine the utility of extracorporeal treatments (ECTRs) in BAAs poisoning.\n\nMethods\n\nWe conducted systematic reviews of the literature, screened studies, extracted data, and summarized findings following published EXTRIP methods.\n\nResults\n\nA total of 76 studies (4 in vitro and 2 animal experiments, 1 pharmacokinetic simulation study, 37 pharmacokinetic studies on patients with end-stage kidney disease, and 32 case reports or case series) met inclusion criteria. Toxicokinetic or pharmacokinetic data were available on 334 patients (including 73 for atenolol, 54 for propranolol, and 17 for sotalol). For intermittent hemodialysis, atenolol, nadolol, practolol, and sotalol were assessed as dialyzable; acebutolol, bisoprolol, and metipranolol were assessed as moderately dialyzable; metoprolol and talinolol were considered slightly dialyzable; and betaxolol, carvedilol, labetalol, mepindolol, propranolol, and timolol were considered not dialyzable. Data were available for clinical analysis on 37 BAA poisoned patients (including 9 patients for atenolol, 9 for propranolol, and 9 for sotalol), and no reliable comparison between the ECTR cohort and historical controls treated with standard care alone could be performed. The EXTRIP workgroup recommends against using ECTR for patients severely poisoned with propranolol (strong recommendation, very low quality evidence). The workgroup offered no recommendation for ECTR in patients severely poisoned with atenolol or sotalol because of apparent balance of risks and benefits, except for impaired kidney function in which ECTR is suggested (weak recommendation, very low quality of evidence). Indications for ECTR in patients with impaired kidney function include refractory bradycardia and hypotension for atenolol or sotalol poisoning, and recurrent torsade de pointes for sotalol. Although other BAAs were considered dialyzable, clinical data were too limited to develop recommendations.\n\nConclusions\n\nBAAs have different properties affecting their removal by ECTR. The EXTRIP workgroup assessed propranolol as non-dialyzable. Atenolol and sotalol were assessed as dialyzable in patients with kidney impairment, and the workgroup suggests ECTR in patients severely poisoned with these drugs when aforementioned indications are present.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s13054-021-03585-7.\n\nKeywords\n\nBeta-blockers\nECLS\nHemodialysis\nHemoperfusion\nOverdose\nIntoxication\nVerdun Research Fundissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nPoisoning from β-adrenergic antagonists (BAAs), also referred as β-blockers, can result in bradycardia, hypotension, dysrhythmias, and cardiogenic shock. Treatment is primarily supportive, but in severe cases high-dose insulin euglycemic therapy, vasopressors, and extracorporeal life support (ECLS) may be required. Extracorporeal treatments (ECTRs) are mentioned as part of the management of BAA poisoning, although their place remains uncertain and controversial [1]. The EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup is composed of international experts representing diverse specialties and professional societies (Additional file 1). Its mission is to provide recommendations on the use of ECTRs in poisoning (http://www.extrip-workgroup.org) [2–5]. We present EXTRIP’s systematic review and recommendations for the use of ECTR in patients with BAA poisoning.\n\nClinical pharmacology and toxicokinetics\n\nBAAs are among the most commonly prescribed drugs for the prevention and treatment of cardiovascular disease [6, 7]. BAAs bind to β-adrenergic receptors, thereby competitively inhibiting the binding of epinephrine and norepinephrine to these receptors, and impairing conduction and contraction. Aside from their relatively small molecular size, BAAs have considerable heterogeneity regarding their physicochemical characteristics and pharmacokinetics (Table 1). For example, labetalol, propranolol, and carvedilol have a large volume of distribution, extensive protein binding, substantial hepatic metabolism, negligible renal clearance, and do not require dose modification in chronic kidney disease (CKD), whereas sotalol, nadolol, and atenolol have opposite characteristics. Additionally, their different properties influence their clinical effect; these include selectivity to the β-1 adrenergic receptors (e.g., metoprolol > propranolol), α-adrenergic antagonist activity (e.g., carvedilol, labetalol), intrinsic sympathomimetic activity (e.g., acebutolol, pindolol), membrane-stabilizing activity (MSA) from sodium channel blockade (e.g., propranolol, acebutolol, and labetalol), central nervous system (CNS) depression (e.g., propranolol), and Class III antidysrhythmic effect because of antagonism of potassium channels (e.g., sotalol). For several commercialized BAAs, intravenous and/or sustained-release forms are available.Table 1 Physicochemical properties and pharmacokinetics of immediate-release β-adrenergic antagonists\n\nDrug\tMW (Da)\tProtein binding (%)\tVD (L/kg)\tF (%)\tTMAX (h)\tEndogenous T1/2 (h)\tEndogenous CL (mL/min)\tRenal CL (mL/min), Normal GFR\tTherapeutic range (mg/L)\tReferences\t\nNormal GFR\tCKD\tNormal GFR\tESKD\tNormal GFR\tESKD\t\nAcebutolol\t336\t10–25\t1.5–2.5\tN/A\t35–50\t2.0–4.0\t4–10&\t600–800\tN/A\t150–300\t0.2–2\t[19, 68, 69, 80, 138–148]\t\nAlprenolol\t249\t80–90\t2.5–3.5\tN/A\t5–15\t1.0–2.0\t2–4\tN/A\t800–1000\tN/A\t50\t0.03–0.15\t[149–152] [153]\t\nAtenolol\t266\t0–5\t1.0–1.2\t50–60\t3.0–3.5\t5–8\t50–100\t140–180\t20\t120–140\t0.1–1.5\t[11, 20, 73, 78, 79, 85, 90, 105, 118, 124, 148, 154–163]\t\nBetaxolol\t344\t50\t4.5–6.0\t5.0–6.5\t75–90\t2.5–4.0\t14–16\t25–35\t220–270\t100–150\t50\t0.005–0.05\t[86, 148, 164–168]\t\nBisoprolol\t325\t30\t2.0–3.0\t90\t1.5–2.5\t9–12\t25–35\t200–250\t50\t120–150\t0.01–0.1\t[93, 98, 148, 169–175]\t\nBopindolol\t381\tN/A\t1.8–2.0\tN/A\t70\t1.0–2.0\t4–6\t8\t350–400\tN/A\tN/A\t0.001–0.015\t[148, 176–180]\t\nCarteolol\t292\t10–30\t4\tN/A\t85\t2.0\t5–7\t30–35\t650\tN/A\t250\t0.01–0.1\t[148, 181–183]\t\nCarvedilol\t405\t98\t1.5–2.5\tN/A\t20–30\t1.0–3.0\t6–7\t600\t5\t0.02–0.2\t[96, 148, 184–190]\t\nCeliprolol\t379\t25\t4–5\tN/A\t30–70\t2.0–4.0\t5–7\tN/A\t900–1000\tN/A\t180–220\t0.05–0.5\t[191–193]7 [148, 194–200]\t\nCetamolol\t310\tN/A\t3.5\t2.5\tN/A\t2.5–3.0\t7\t10–12\t420*\t150\t100–150\t0.01–0.1\t[201–203]\t\nEsmolol\t295\t55\t2.0–3.5\tNot applicable\t0.2\t10,000–15,000\t100–200\t0.15–2\t[95, 148, 204, 205]\t\nLabetalol\t328\t50\t5.0–9.0\t20–30\t0.5–1.5\t3–10\t10–12\t1200–2000\t20\t0.03–0.3\t[92, 206–212] [94, 148, 213]\t\nMedroxalol\t372\tN/A\t10–15\tN/A\t30–50\t2–3\t7–15\tN/A\t1000–1100\tN/A\t80–100\tN/A\t[213–215]\t\nMepindolol\t262\t55\t5.7**\tN/A\tN/A\t1.4\t3–6\t650**\tN/A\t0**\t0.007–0.07\t[88, 148, 216, 217]\t\nMetipranolol\t309\t70\t3–4\tN/A\t40–50\t0.5–2.0\t2.5–3.0\t1100–1300\tN/A\t120–150\t0.02–0.1\t[97, 148, 218–221]\t\nMetoprolol\t267\t10\t3.0–4.0\tN/A\t40–60\t1.5–2.0\t3–5\t800–1200\t100\t0.03–0.5\t[222–225] [9, 73, 82, 106, 148, 226–230]\t\nNadolol\t309\t15–25\t1.5–2.0\tN/A\t30\t2.8\t10–15\t30–45\t120–250\t30\t80–120\t0.01–0.25\t[75, 89, 148, 231–234]\t\nNebivolol\t405\t98\t9–12\tVariable\t1–3\t10–15\t800–1000\t30\t0.001–0.05\t[148, 235–241]\t\nOxprenolol\t265\t80–85\t0.8–1.2\t0.8\t35–50\t0.5–1.5\t1–2\t600–750\t550\t10\t0.05–0.3\t[84, 148, 242–252]\t\nPenbutolol\t291\t90–95\t0.5–1.0\tN/A\t90\t1.0–2.0\t15–20\t30\t300–600\tN/A\t5\t0.01–0.3\t[253] [148, 254–262]\t\nPindolol\t248\t40–55\t1.3–2.3\t1.6–1.8\t50–90\t0.5–1.5\t3–5\t450–550\t180–240\t150–250\t0.02–0.15\t[148, 263–269]\t\nPractolol\t266\t57\t1.5\tN/A\t90–100\t2–5\t10–13\t60–80\t135\t20\t100–120\t1.5–5\t[65, 67, 148, 270–274]\t\nPrenalterol\t225\t5\t2.5–3.5\tN/A\t25–35\t0.5–2.5\t1.5–2.5\tN/A\t800–1400\tN/A\t200–800\t0.01–0.04\t[275–282]\t\nPropranolol\t259\t85–95\t3.0–5.0\t20–50\t1.5–2.0\t3–5\t800–1200\t5\t0.02–0.3\t[20, 66, 70, 74, 154, 230, 283–300] [73, 87, 131, 148, 301, 302]\t\nSotalol\t272\t0\t1.3–1.5\t90\t2.5–3.5\t5–9\t35–60\t120–160\t20–25\t80–120\t0.5–3\t[71, 83, 303–307] [13, 15, 115, 148, 303, 306, 308–310]\t\nTalinolol\t363\t60**\t3.0–3.5\t55\t2.5–3.5\t10–12\t20–25\t320–380\t150–200\t0.04–0.15\t[99, 104, 107, 148, 311–313]\t\nTimolol\t316\t10\t2.0–2.5\tN/A\t60\t1.3–2.0\t3–5\t450–580\tN/A\t100\t0.005–0.1\t[300, 314–317] [72, 148, 315]\t\nTolamolol\t316\t90\t1.2–1.8\tN/A\tN/A\t1–3\t2–3\t1100\tN/A\tN/A\tN/A\t[318–320]\t\nMW: Molecular weight, VD: Volume of distribution, F: bioavailability, TMAX: Time to maximum concentration, T1/2: elimination half-life, CL: Clearance, N/A: Not available\n\n* Not adjusted for bioavailability, ** No reference from primary data (taken from reviews)\n\n& conflicting data, perhaps due to non-sensitive assays which included measurement of metabolites in early reports [68, 69]\n\nTotal body clearance and volume of distribution were obtained from intravenous data. If these data were unavailable but reported for oral data (i.e., as V/F or CL/F), then values were adjusted for bioavailability\n\nThis systematic review has taken the liberty to review all BAAs for which data exist, even if some are not currently commercially available\n\nIn overdose, a prolonged absorption phase, saturation of enzymatic biotransformation, and poison-induced impairment of blood flow to organs may all contribute to a prolonged apparent elimination half-life, which has been described for propranolol [8], metoprolol [9, 10], atenolol [11], and sotalol [12–14] although this finding is inconsistent [15–18]. Protein binding does not appear to be modified in supratherapeutic concentrations [19, 20].\n\nOverview of toxicity\n\nOver the last 5 years, the number of BAA exposures reported to the United States National Poison Data System has increased [21], and is associated with 3.9% of fatal poisonings [21]. In 2019, 11,166 single ingredient BAA exposures were reported in the US including 19 fatalities [21]. Manifestations of BAA poisoning range from asymptomatic bradycardia to cardiogenic shock and death [22–25]. Cardiovascular symptoms usually appear within 2 h of ingestion and are unlikely to occur in an asymptomatic patient after 6 h from ingestion for immediate-release formulations [22, 26, 27], 8 h for sustained-release formulations, and 12 h for sotalol [12, 23, 24, 28]. Decreased consciousness and bronchospasm may occur after these periods, even with normal blood pressure and electrocardiogram [26, 29]. Other manifestations of poisoning from BAAs include hyperkalemia and hypoglycemia [30, 31]. Highly lipophilic drugs, like propranolol, penetrate the blood–brain barrier causing delirium, coma, and seizures [27, 30, 32, 33]. Sotalol, which also possesses potassium efflux channel blocking properties, causes QT interval prolongation and severe ventricular dysrhythmias, including torsade de pointes [12, 32, 34, 35]. In overdose, receptor selectivity is lost, leading to overlapping manifestations among BAAs [36, 37].\n\nSome publications report a linear or threshold relationship between dose and outcome [32, 37]. For specific BAAs, a positive correlation was noted for propranolol [27, 32, 36], sotalol [32], atenolol [32], metoprolol [32, 38], carvedilol [39], and talinolol [36]. Unintentional exposures and inadvertent ingestions in young children rarely cause severe toxicity due to the smaller doses involved, although exceptions are reported [40, 41]. Quantification assays for BAAs are rarely available to guide clinical decisions, and concentrations correlate poorly with the development of symptoms [42–44], except for sotalol [45–48].\n\nFatalities from BAA ingestions are more likely if co-ingested with cardioactive drugs, such as calcium channel blockers [22, 32, 37, 49]. In cohorts of severe BAA poisoning, reported mortality rates range between 0 and 13% [21–23, 25, 32, 50–52].\n\nManagement of BAA poisoning is primarily supportive [1]. Although outside the scope of this review, standard care includes gastrointestinal decontamination, atropine, inotropes and vasopressors, temporary cardiac pacing, glucagon, intravenous calcium, high-dose euglycemic hyperinsulinemia, and extracorporeal life support (ECLS) [1, 53–57].\n\nMethods\n\nThe workgroup developed recommendations following the EXTRIP methodology previously published [3] with modifications, updates, and clarifications. PRISMA statement was followed for reporting items of the presented systematic review of the literature. The full methods are presented in the online Additional file 1.\n\nThe search strategy used was as follows: [(dialysis or hemodialysis or haemodialysis or hemoperfusion or haemoperfusion or plasmapheresis or plasmaphaeresis or hemofiltration or haemofiltration or hemodiafiltration or haemodiafiltration or plasma exchange or CRRT or CVV* or CKRT or exchange transfusion) and (beta blocke* or beta-adrenergic or acebutolol or alprenolol or atenolol or betaxolol or bisoprolol or bopindol or carteolol or carvedilol or celiprolol or cetamolol or esmolol or labetalol or medroxalol or mepindol or metipranolol or metoprolol or nadolol or nebivolol or oxprenolol or penbutolol or pindolol or practolol or prenalterol or propranolol or sotalol or talindolol or talinolol or timolol or tolamolol)].\n\nResults\n\nResults of the literature search are presented in Fig. 1.Fig. 1 Process of selection and inclusion of studies in the review\n\nIn the final analysis, 76 studies were included for qualitative analysis, including 4 in vitro experiments [58–61], 2 animal experiments [62, 63], 1 pharmacokinetic simulation study [64], 37 pharmacokinetic studies [65–101], and 32 case reports/series [13, 15, 35, 102–130]. No comparative studies or randomized controlled trials were identified.\n\nSummary of evidence\n\nDialyzability\n\nBecause of the large heterogeneity in BAAs pharmacokinetics, no a priori overall estimation of dialyzability can be generalized for this entire drug class. Half-lives and clearances of BAAs obtained during ECTR are summarized in Table 2. Pharmacokinetic or toxicokinetic data related to ECTR were available for a total of 334 patients. Ninety percent of the pharmacokinetic articles were published prior to 1992. Although these older reports had robust methods, with several subjects and serial samplings of BAAs concentrations in blood and dialysate, they must be interpreted with caution as they may not reflect current hemodialysis technology. With improved blood and effluent flows and better catheters and filters, these data are expected to be more favorable. For example, atenolol clearance by ECTR has tripled in 30 years [78, 101], bisoprolol clearance has doubled in 20 years [98, 101], and nadolol clearance has increased by 50% in 5 years [75, 89].Table 2 Half-life and clearance of β-adrenergic antagonists during extracorporeal treatments\n\nDrug\tECTR\tT1/2 (Hours)\tClearance (mL/min)\tReferences\t\nDuring ECTR\tEndogenous\tECTR\tEndogenous\t\nMedian\tn\tRange\tNormal GFR\tESKD\tMedian\tn\tRange\tNormal GFR\tESKD\t\nAcebutolol\tHD\t6.1 (Met = 7.2)\t7\t2.2–7\t4–10\t45 (Met = 33.6)\t12\t30.5–55.1\t600–800\tN/A\t[68, 69, 80, 109, 113]\t\nHF-HP\t0.3\t1\t\t151\t1\t\t\nAtenolol\tHD\t4.6\t48\t0.5–17.8\t5–8\t50–100\t119.5\t25\t18–311\t140–180\t20\t[73, 76, 78, 79, 85, 90, 91, 100, 101, 105, 118, 123, 124, 128]\t\nCKRT\t22\t2\t14.5–29.5\t47\t3\t19.9–48\t\nHD-HP\t3.4\t1\t\tN/A\t\nPD\t23\t17\t19.2–34\t2.6\t7\t1.3–3.7\t\nBetaxolol\tHD\tN/A\t14–16\t25–35\t17.5 ± 0.7\t12\t\t220–270\t100–150\t[86]\t\nPD\tN/A\t11.7 ± 1.2\t12\t\t\nBisoprolol\tHD\t7.8\t16\t6.4–9.6\t9–12\t25–35\t41.8\t16\t30.5–70\t200–250\t50\t[93, 98, 101]\t\nPD\t23.6\t3\t20.8–26.4\tN/A\t\nCarvedilol\tHD\t4.6\t8\t4.1–5.3\t6–7\t12.1\t14\t12.1–38.6\t600\t[96, 101]\t\nEsmolol\tHD\t0.12 ± 0.1\t6\t\t0.2\tMet = 76.8 ± 39.1\t6\t\t10,000–15,000\t[95]\t\nPD\t0.13 ± 0.1\t6\t\tMet = 2.7 ± 0.5\t6\t\t\nLabetalol\tHD\t1.8\t7\t0.6–3.8\t3–10\t10–12\t37.4\t14\t25.7–97\t1200–2000\t[92, 94]\t\nPD\t13.1 ± 6.3\t8\t\t1.9 ± 1.7\t8\t\t\nMepindolol\tHD\t3.0\t2\t\t3–6\t31\t2\t\t650\tN/A\t[88]\t\nMetipranolol\tHD\t1.4 ± 0.5\t8\t\t2.5–3.0\tN/A\t1100–1300\tN/A\t[97]\t\nMetoprolol\tHD\t2.9 (Met = 5)\t8\t2.3–3\t3–5\t101\t8\t\t800–1200\t[73, 101, 106]\t\nHP\t2.2\t1\t\t96.1\t1\t\t\nNadolol\tHD\t3.5\t6\t3.0–8.5\t10–15\t30–45\t82\t15\t46.4–102\t120–250\t30\t[75, 89]\t\nOxprenolol\tHD\tMet = 5.6\t3\t\t1–2\tN/A\t600–750\t550\t[84]\t\nPractolol\tHD\t14 (Met = 5)\t14\t8–30\t10–13\t60–80\t > 100*\t6\t\t135\t20\t[65, 67]\t\nPropranolol\tHP\t5.6\t3\t4.9–8.9\t3–5\t189\t2\t188–191\t800–1200\t[66, 70, 73, 74, 87, 102]\t\nHD\t3.4\t23\t1.5–8\t9.4\t11\t3.8–26.5\t\nTPE\t1.2\t1\t\tN/A\t\nSotalol\tHD\t7\t9\t3.5–9.5\t5–9\t35–60\t80\t3\t67–80\t120–160\t20–25\t[13, 15, 71, 83, 108, 115, 122]\t\nHP-HD\t2.8\t1\t\tN/A\t\nCKRT\t18\t1\t\t53.1\t1\t\t\nTalinolol\tHD\tN/A\t10–12\t20–25\t28\t7\t\t320–380\t[99, 104, 107]\t\nHP\t3.3\t2\t2.7–3.8\t109\t2\t96–121\t\nTimolol\tHD\t3.8\t2\t2.3–5.2\t3–5\tN/A\t450–580\tN/A\t[72]\t\nLegend: HD, Hemodialysis; HP, Hemoperfusion; HF, Hemofiltration; TPE, therapeutic plasma exchange; PD, Peritoneal dialysis; CKRT, Continuous kidney replacement therapy; ECTR, Extracorporeal treatment; ESKD, End-stage kidney disease; Met, metabolite; GFR, Glomerular filtration rate; N/A, Not available; n, number\n\nIn order to make data consistent and comparable for analysis, some transformations were performed (if necessary): half-lives were calculated graphically; clearances were calculated from removal data; when both clearance from arterio-venous differences and dialysate collections were provided, these were averaged; in some cases, clearance reported by some authors were calculated by using blood flows and plasma concentrations which may lead to overestimations [13, 98, 109], and so were recalculated\n\n*Reported dialysate flow assumed to be > 300 mL/min\n\nWhen measured from dialysate collection, the amount of BAA removed divided by the reported ingested dose during hemodialysis (when adjusted for a 6-h treatment and bioavailability) was 24% for atenolol [101], 18% for bisoprolol [101], ≈0% for carvedilol [101], 0.5% for labetalol [92], 3.3% for metoprolol [101], 50% for practolol [67], ≈0% for propranolol [70], and 4.6% for talinolol [99].\n\nData for continuous kidney replacement therapy (CKRT) are sparse: in 3 cases of atenolol overdose, CKRT removed between 8 and 25% of total body burden adjusted for a 6-h period [120, 123, 128], with atenolol clearance ranging from 20 to 48 mL/min. In one sotalol overdose, CKRT clearance was estimated as 53 mL/min [122]. These clearances are considerably inferior to those achievable during high-efficiency intermittent hemodialysis (Table 2). There is limited evidence for hemoperfusion and therapeutic plasma exchange (TPE), which can remove BAAs with extensive protein binding. This appears true for propranolol in vitro [59, 61] and in vivo [102, 131], although its high volume of distribution and high hepatic clearance substantially limit its dialyzability. Hemoperfusion in 2 patients with talinolol overdoses yielded clearances of 100–120 mL/min [104, 107] but this represented < 20% of ingested dose, due to its large volume of distribution. As for penbutolol, in vitro data show little to no effect from hemoperfusion and only a minor and slow effect from TPE [60]. For BAAs with limited protein binding, hemoperfusion would not be expected to surpass diffusive or convective techniques as confirmed in one case of metoprolol overdose in which measured clearance [106] was comparable to that obtained during hemodialysis [101]. As expected, dialyzability of BAAs by peritoneal dialysis was consistently poor, with inconsequential impact on pharmacokinetics, i.e., approximately 6% of atenolol was removed in 24 h [90], 0.1% of labetalol in 72 h [92], and the peritoneal clearance of betaxolol only represented 7.5% of total clearance [86].\n\nAn increase in serum/blood concentrations was often observed following ECTR, often referred as “rebound,” in both pharmacokinetic studies [67, 76, 83, 92] and toxicokinetic reports [13, 15, 105, 107, 115, 118, 124]. The median increase in concentration was 15% and occurred independently of volume of distribution.\n\nTable 3 presents grading of dialyzability with the level of evidence, as defined by EXTRIP criteria (Additional file 1). The grading and level of evidence for hemodialysis was assessed as: Dialyzable for atenolol, nadolol, practolol, and sotalol; Moderately dialyzable for acebutolol, bisoprolol, and metipranolol; Slightly dialyzable for metoprolol and talinolol; Not dialyzable for betaxolol, carvedilol, labetalol, mepindolol, propranolol, and timolol. Some publications report that metoprolol may be dialyzable based on achievable clearance of 80–120 mL/min [101]. However, this only represents a small proportion of total body clearance (regardless of genetic polymorphism of clearance pathways), resulting in removal of < 10% of an ingested dose. Because of its high endogenous clearance and volume of distribution, propranolol will not be removed meaningfully by ECTR modalities.Table 3 Final toxicokinetic grading according to EXTRIP criteria\n\nDrug\tPK/TK grading\tNumber of patients\tFinal grading and level of evidence\t\nHD\tPD\tCKRT\tHP\tTPE\tHP-HD\t\nAcebutolol\tDialyzable\t1, MET = 2\t\t\t\t\t\tHD: Moderately dialyzable, D*\n\nHD (MET): Moderately dialyzable, C\n\n\t\nModerately dialyzable\t1, MET = 1\t\t\t\t\t\t\nSlightly dialyzable\t1, MET = 1\t\t\t\t\t\t\nNot dialyzable\t\t\t\t\t\t\t\nAtenolol\tDialyzable\t24\t\t\t\t\t\tHD: Dialyzable, A\n\nCKRT: Slightly dialyzable, C\n\nHD-HP: Moderately dialyzable, D\n\nPD: Not dialyzable, B\n\n\t\nModerately dialyzable\t1\t\t1\t\t\t1\t\nSlightly dialyzable\t\t\t2\t\t\t\t\nNot dialyzable\t\t7\t\t\t\t\t\nBetaxolol\tDialyzable\t\t\t\t\t\t\tHD: Not dialyzable, B\n\nPD: Not dialyzable, C\n\n\t\nModerately dialyzable\t\t\t\t\t\t\t\nSlightly dialyzable\t\t\t\t\t\t\t\nNot dialyzable\t12\t6\t\t\t\t\t\nBisoprolol\tDialyzable\t5\t\t\t\t\t\tHD: Moderately dialyzable, B\t\nModerately dialyzable\t14\t\t\t\t\t\t\nSlightly dialyzable\t\t\t\t\t\t\t\nNot dialyzable\t\t\t\t\t\t\t\nCarvedilol\tDialyzable\t\t\t\t\t\t\tHD: Not dialyzable, B\t\nModerately dialyzable\t\t\t\t\t\t\t\nSlightly dialyzable\t\t\t\t\t\t\t\nNot dialyzable\t8\t\t\t\t\t\t\nLabetalol\tDialyzable\t\t\t\t\t\t\tHD: Not dialyzable, B\n\nPD: Not dialyzable, C\n\n\t\nModerately dialyzable\t\t\t\t\t\t\t\nSlightly dialyzable\t\t\t\t\t\t\t\nNot dialyzable\t17\t8\t\t\t\t\t\nMepindolol\tDialyzable\t\t\t\t\t\t\tHD: Not dialyzable, C\t\nModerately dialyzable\t\t\t\t\t\t\t\nSlightly dialyzable\t1\t\t\t\t\t\t\nNot dialyzable\t1\t\t\t\t\t\t\nMetipranolol\tDialyzable\t\t\t\t\t\t\tHD: Moderately dialyzable, C\t\nModerately dialyzable\t4\t\t\t\t\t\t\nSlightly dialyzable\t\t\t\t\t\t\t\nNot dialyzable\t\t\t\t\t\t\t\nMetoprolol\tDialyzable\tM = 2\t\t\t\t\t\tHD: Slightly dialyzable, B\n\nHD (MET): dialyzable, C\n\nHP: Slightly dialyzable, D (Normal GFR)\n\n\t\nModerately dialyzable\t\t\t\t\t\t\t\nSlightly dialyzable\t8\t\t\t1 (Normal GFR)\t\t\t\nNot dialyzable\t\t\t\t\t\t\t\nNadolol\tDialyzable\t6\t\t\t\t\t\tHD: Dialyzable, B\t\nModerately dialyzable\t\t\t\t\t\t\t\nSlightly dialyzable\t\t\t\t\t\t\t\nNot dialyzable\t\t\t\t\t\t\t\nOxprenolol\tDialyzable\tMET = 3\t\t\t\t\t\tHD (MET): Dialyzable, C\t\nModerately dialyzable\t\t\t\t\t\t\t\nSlightly dialyzable\t\t\t\t\t\t\t\nNot dialyzable\t\t\t\t\t\t\t\nPractolol\tDialyzable\t14\t\t\t\t\t\tHD: Dialyzable, B\t\nModerately dialyzable\t\t\t\t\t\t\t\nSlightly dialyzable\t\t\t\t\t\t\t\nNot dialyzable\t\t\t\t\t\t\t\nPropranolol\tDialyzable\t1, MET = 2\t\t\t\t\t\tHD: Not dialyzable, A\n\nHD (MET): Dialyzable, C\n\nHP: Slightly dialyzable, D (Normal GFR)\n\n\t\nModerately dialyzable\t2\t\t\t\t1**\t\t\nSlightly dialyzable\t\t\t\t2 (Normal GFR)\t\t\t\nNot dialyzable\t13\t\t\t\t\t\t\nSotalol\tDialyzable\t6, 1 (Normal GFR)\t\t\t\t\t\tHD: Dialyzable, B\n\nHD: Dialyzable, D (Normal GFR)\n\nCKRT: Slightly dialyzable, D\n\nHD-HP: Moderately dialyzable, D (Normal GFR)\n\n\t\nModerately dialyzable\t1\t\t\t\t\t1 (Normal GFR)\t\nSlightly dialyzable\t\t\t1\t\t\t\t\nNot dialyzable\t\t\t\t\t\t\t\nTalinolol\tDialyzable\t\t\t\t\t\t\tHD: Slightly dialyzable, B\n\nHP: Slightly dialyzable, C (Normal GFR)\n\n\t\nModerately dialyzable\t\t\t\t\t\t\t\nSlightly dialyzable\t8\t\t\t2 (Normal GFR)\t\t\t\nNot dialyzable\t\t\t\t\t\t\t\nTimolol\tDialyzable\t\t\t\t\t\t\tHD: Not dialyzable, D\t\nModerately dialyzable\t\t\t\t\t\t\t\nSlightly dialyzable\t1\t\t\t\t\t\t\nNot dialyzable\t1\t\t\t\t\t\t\nMET, Metabolites; PK, Pharmacokinetics TK, Toxicokinetics; HD, Hemodialysis; HP, Hemoperfusion; PD, Peritoneal dialysis; CKRT, Continuous kidney replacement therapy; TPE, Therapeutic plasma exchange; HD-HP, hemodialysis and hemoperfusion in series; GFR, Glomerular filtration rate\n\n*6 additional patients would be rated as “dialyzable” but the assay was non-specific and likely measured parent drug and metabolites, so the result is uninterpretable [69]\n\n**Based on half-life comparison, a criterion considered unreliable for poisons with a high Vd like propranolol, so not graded\n\nAlthough extracorporeal clearance of BAAs is independent of kidney function, its relative impact compared to total body clearance will increase for some BAAs as kidney function declines. This can be illustrated graphically (Fig. 2): for example, a hemodialysis clearance of 120 mL/min will represent 46% of total clearance for atenolol in a patient with normal kidney function (endogenous clearance = 140 mL/min) compared to 86% in an anuric patient (endogenous clearance 20 mL/min). Comparatively, ECTR clearance will have very little impact on enhancing total clearance of propranolol, regardless of kidney function. These estimates are considered conservative for several BAAs including sotalol, practolol, nadolol, and betaxolol, as the ECTR data are at least 30 years old [67, 83, 86, 89]. Limited data exist for esmolol but even when assuming an optimal hemodialysis plasmatic clearance of 300 mL/min, this would represent less than 2% of total clearance [95].Fig. 2 Proportion of hemodialysis clearance relative to total clearance. Legend: GFR: Glomerular filtration rate, ESKD: End-stage kidney disease, HD: Hemodialysis. *These are conservative estimations, as ECTR clearances would likely be higher if performed today. **based on endogenous clearance of 12,000 mL/min. For carvedilol, esmolol, propranolol, labetalol, talinolol, metoprolol, and acebutolol, it is assumed the ratio would apply regardless of kidney function\n\nOnly 7 patients that could be assessed for dialyzability grading had normal kidney function, and only two reports were identified for a BAA (sotalol) whose grading may differ depending on kidney function [13, 15]. For these two cases, dialyzability was assessed as “Dialyzable” for one case of hemodialysis and “Moderately dialyzable” for one case of hemoperfusion-hemodialysis in series.\n\nClinical data\n\nAmong case reports and case series, the panel acknowledged variability in methodological quality and lack of reporting of critical information [132]. The evidence for a clinical effect of ECTR in BAA poisoning was available for 37 patients (acebutolol = 4, atenolol = 9, carvedilol = 1, metoprolol = 1, propranolol = 9, sotalol = 9, talinolol = 4), 16 of which had impaired kidney function (Table 4). All included patients were self-poisoned, except 6 dosing errors in end-stage kidney disease (ESKD) (atenolol = 1, sotalol = 5). Bradycardia and hypotension requiring vasopressors and/or inotropes were ubiquitous features for all BAAs except for propranolol and sotalol (predominant features for sotalol were ventricular dysrhythmias).Table 4 Summary of clinical findings of patients receiving extracorporeal treatments for β-adrenergic antagonist removal\n\n\tAcebutolol (n = 4)\tAtenolol\n(n = 9)\tCarvedilol\n(n = 1)\tMetoprolol\n(n = 1)\tPropranolol\n(n = 9)\tSotalol\n(n = 9)\tTalinolol\n(n = 4)\t\nPatient characteristics\t\t\t\t\t\t\t\t\nAge, years\t20 (17–27)\t45 (28–74)\t21\t49\t31 (15–49)\t66 (44–78)\t21 (20–47)\t\nMen, %\t0\t56\t0\t0\t44\t78\t50\t\nESKD, %\t0\t11\t0\t0\t0\t44\t0\t\nPoisoning information\t\t\t\t\t\t\t\t\nIntentional overdose, %\t100\t89\t100\t100\t100\t44\t100\t\nDose if acute ingestion, g\t8.4 (4.8–12)\t4.5 (2.5–10)\t1.8\t0.5\t3.1 (0.6–5.0)\t8.0 (7.2–14.4)\t2.5 (1.5–5.0)\t\nPeak concentration, mg/L\t14 (10–18)\t14 (2.5–70)\t0.6\t2.8\t1.5 (0.04–3)\t17 (2.5–65)\t5.5 (5.0–6.1)\t\nTime from ingestion to admission, hours\t2 (2–2)\t6.5 (2–8)\t\t0.8\t2 (1–8)\t2.5 (1–4)\t6 (2–8)\t\nSigns/ Symptoms / Labs\t\t\t\t\t\t\t\t\nComa, %\t100\t89\t100\t100\t50\t100\t75\t\nAltered consciousness, %\t100\t100\t100\t100\t83\t100\t75\t\nBradycardia, %\t100\t100\t100\t100\t100\t50\t100\t\nSevere dysrhythmia, %\t25\t0\t100\t0\t33\t100\t25\t\nHypotension, %\t100\t100\t100\t100\t75\t89\t100\t\nQRS complex duration, msec\t260\t128 (98–160)\tN/A\tN/A\t104\t120 (104–140)\t420\t\nProlonged QRS complex duration, %\t100\t43\t0\t0\tN/A\t25\t50\t\nQT interval duration, msec\tN/A\t440 (400–448)\tN/A\tN/A\tN/A\t618 (509–880)\t440\t\nProlonged QT interval, %\tN/A\t17\tN/A\tN/A\tN/A\t100\t25\t\nAcute kidney injury, %\t100\t87.5\t100\t0\t0\t38\t0\t\nSerum glucose, mmol/L\t14.7\t7.7 (2.2–19.2)\t8.3\tN/A\t10.7\t4.4 (1.4–7.4)\tN/A\t\nSerum bicarbonate, mmol/L\t16\t19 (10.8–21)\tN/A\tN/A\t20 (15–25)\t17\tN/A\t\nSerum lactate, mmol/L\t1.9\t4.6 (1.8–9.3)\t4.7\tN/A\t7.6 (1.9–13.2)\t1.9\tN/A\t\nSerum potassium, mmol/L\t3.2\t4.3 (< 0.8–8.5)\t5.9\tN/A\t4.2 (3.7–4.7)\t5.1 (3.8–7.1)\tN/A\t\nOther treatments\t\t\t\t\t\t\t\t\nGastric lavage, %\t25\t44\t0\t0\t67\t22\t75\t\nActivated charcoal, %\t75\t56\t0\t100\t50\t11\t25\t\nVasopressors/ inotropes, %\t100\t100\t100\t100\t50\t75\t75\t\nMechanical ventilation, %\t100\t100\t0\t100\t17\t75\t75\t\nAtropine, %\t100\t56\t0\t100\t67\t22\t25\t\nLipid emulsion, %\t0\t11\t0\t0\t16\t0\t0\t\nPacemaker, %\t100\t44\t100\t100\t33\t88\t50\t\nHigh-dose insulin euglycemic therapy, %\t0\t67\t0\t0\t33\t0\t0\t\nGlucagon, %\t75\t100\t100\t100\t83\t33\t25\t\nExtracorporeal life support (ECLS), %\t25\t22\t100\t0\t0\t0\t0\t\nExtracorporeal treatments\t\t\t\t\t\t\t\t\nHemodialysis, n\t1\t3\t0\t0\t0\t6\t0\t\nTPE, n\t0\t0\t1\t0\t2\t0\t0\t\nCKRT, n\t0\t3\t0\t0\t0\t1\t0\t\nMore than 1 ECTR, n\t0\t2\t0\t0\t0\t0\t0\t\nHF-HP, n\t1\t0\t0\t0\t0\t0\t0\t\nHD-HP, n\t1\t1\t0\t0\t3\t1\t1\t\nHP, n\t1\t0\t0\t1\t4\t0\t3\t\nOutcome\t\t\t\t\t\t\t\t\nDeath, %\t0\t11\t0\t0\t11\t11\t50\t\nSequelae, %\t25\t11\t0\t0\tN/A\t11\tN/A\t\nLength of stay, days\t30 (7–49)\t22 (12–32)\t23\tN/A\t6 (5–32)\t20\tN/A\t\nLength of ICU stay, days\t2 (2–2)\t9.5 (1.5–28)\t8\t3\t8.5 (4–13)\t3 (2–6)\tN/A\t\nLength of life-threatening dysrhythmia\tN/A\tN/A\tN/A\tN/A\t56\t16 (12–120)\tN/A\t\nLength of prolonged QT interval, msec\tN/A\tN/A\tN/A\tN/A\tN/A\t37 (30–120)\tN/A\t\nLength of bradycardia/hypotension, hours\t25 (24–26)\t48 (20–168)\t120\t18\t67 (24–70)\t36\t9\t\nResults presented as medians and range. No range is presented when the number of values is one. When specific data was not reported, this was not included in the incidence\n\nESKD, end-stage kidney disease; TPE, therapeutic plasma exchange; CKRT, continuous renal replacement therapy; ECTR, extracorporeal treatment; HF-HP, hemofiltration-hemoperfusion; HD-HP, hemodialysis and hemoperfusion in series; HP, hemoperfusion; ICU, intensive care unit; N/A, Not available\n\nAs reflected by changing trends in the management of BAA poisoning over almost 40 years, treatments were very heterogeneous. In particular, only eight patients received high-dose insulin euglycemic therapy and four patients received ECLS, treatments now considered likely to improve outcome [1]. For these reasons, it was difficult to determine a benefit from ECTR. Three patients died of cardiogenic shock [102, 103, 108], one of irreversible brain injury [107], and one of multiorgan failure after four weeks, despite marked improvement post-ECTR [105]. The overall mortality for the cohort was 13.5%.\n\nFor sotalol, resolution of dysrhythmias/torsade de pointes was rapid with intermittent hemodialysis, often occurring during or just after treatment [13, 15, 35, 115, 116, 121], while this was more protracted with slower techniques like peritoneal dialysis (PD) [114] or CKRT [122]. For atenolol (n = 9), when hemodialysis was used, an increase in blood pressure was noted after the first treatment, with one exception [129]. Again, apparent improvement was slower with CKRT [120, 127, 128]. Dysrhythmias recurred in two patients, within two hours of ECTR cessation, requiring another session [13, 15]. Although nine patients were reported for propranolol, the clinical impact of ECTR could only be analyzed in two patients: one improved slowly after hemoperfusion [125] while the other improved after TPE but had recurrence of hypotension shortly after [130]. For acebutolol, four patients were described, three of which improved during ECTR [109, 113, 117], while this was uncertain in one patient who received hemoperfusion [112]. In all four patients of talinolol poisoning, hemoperfusion was employed alone or in combination with hemodialysis, and two of them died [103, 107]. There was only one patient described for carvedilol [126] and metoprolol [106], which were difficult to interpret because of the co-ingested calcium channel blockers in both cases. No ECTR-associated complications were described in the cohort.\n\nIn summary, clinical improvement from ECTR was generally noted with BAAs considered dialyzable such as atenolol and sotalol when high-efficiency ECTRs were used, whereas this was questionable with other BAAs or when techniques with lower efficiency were used.\n\nTo further measure the effect of ECTR, outcomes of the ECTR cohort were compared to historical controls not receiving ECTRs (Table 5). Unfortunately, this analysis is severely hampered by the small numbers of reported patients, the variability in treatments provided and the heterogeneity of populations compared. For example, historical controls reported to poison control centers are expected to have more benign features than those included in the ECTR cohort. Overall, the mortality of patients receiving ECTRs for BAA poisoning was greater than those reported in historical controls, including one cohort of critically ill patients [23]. Aside from mortality, the only outcome that could be compared to assess the benefit of ECTR was the median duration of QT interval prolongation in sotalol poisoning, which was 37 h [IQR 33.5, 78.5] for the ECTR cohort (median maximal QTc interval = 140% of normal) versus 75 h [IQR 57, 87.5] in one historical cohort (median maximal QTc interval = 172%) [12]. However, this analysis is underpowered. With regard to harms and costs, the use of ECTR is associated with an increased risk of catheter- and ECTR-related complications and added costs which will vary depending on the choice of technique and the geographical location [133]. It is possible that ECTR may exacerbate hypotension in some cases despite the absence of net ultrafiltration, although the incidence of this risk and its magnitude are unknown.Table 5 Extracorporeal treatments + standard care versus standard care in β-adrenergic antagonists poisoning (evidence profile table)\n\nQuality assessment\tSummary of findings\tImportance\t\nDrug\tStudy design\tRisk of bias\tInconsistency\tIndirectness\tImprecision\tOther considerations\tECTR + standard care\tStandard care (controls)\tImpact\tQuality\t\t\nMortality\t\nAll β-adrenergic antagonistsa\n\nn = 10\n\n\tObservational studies\tVery seriousb\tNot serious\tSerious c\tSerious d\tPublication bias strongly suspected e\t13.5% (5/37)\tICU data\n\n8.2% (9/110) admitted in 1 ICU 2002–9 [23]\n\nPCC and hospital data\n\n3.8% (63/1678)\n\n0/858: German PCC 2001–11 single-substance [32]\n\n1/11: children, self-harm [50]\n\n2/73:1 hospital 1993–7 [37]\n\n0/40: 1 hospital 1966–80 [25]\n\n4/280: 2 PCCs 1992–8, [22]\n\n60/416: US PCCs 2017–19, at least major effect [21, 51, 52]\n\n\tComparable mortality between the ECTR group and the control group admitted to ICU (risk difference = 53 more deaths per 1000 patients in the ECTR group (with a 95% CI from 68 less to 175 more deaths per 1000)\t⨁◯◯◯\n\nVERY LOW\n\n\tCRITICAL\t\nPropranololf\n\nn = 5\n\n\tObservational studies\tVery seriousb\tNot serious\tSerious c\tSerious d\tPublication bias strongly suspected e\t11.1% median dose 3.1 g (1/9)\tRanging from 0 to 2.1%\n\n0/41 German PCC 2001–11 single substance median dose 0.4–0.5 g [32]\n\n7/339 UK PCC 2017–18, median dose 0.6 g [321]\n\n0/50: 1 hospital 1993–7 mean dose 1.3 g [37]\n\n0/18 1979–1985 mean dose 1.6 g [36]\n\n\tGroups not comparable\t⨁◯◯◯\n\nVERY LOW\n\n\tCRITICAL\t\nSotalolg\n\nn = 3\n\n\tObservational studies\tVery seriousb\tNot serious\tSerious c\tSerious d\tPublication bias strongly suspected e\t11.1% median 8.0 g (1/9)\tOverall = 0%\n\n0/31: German PCC 2001–11 single substance [32]\n\n0/6: Case in Finland 1977–1980, mean dose 5.7 g [12]\n\n\tGroups not comparable\t⨁◯◯◯\n\nVERY LOW\n\n\tCRITICAL\t\nAtenololh\n\nn = 3\n\n\tObservational studies\tVery seriousb\tNot serious\tSerious c\tSerious d\tPublication bias strongly suspected e\t11.1% median 4.5 g (1/9)\tOverall = 0%\n\n0/48: German PCC 2001–11, single substance, median dose 0.5–0.8 g [32]\n\n0/10: 1 hospital 1993–7 mean dose 2.0 g [37]\n\n\tGroups not comparable\t⨁◯◯◯\n\nVERY LOW\n\n\tCRITICAL\t\nDuration of QT interval prolongation\t\nSotaloli\n\nn = 4\n\n\tObservational studies\tVery seriousb\tNot serious\tSerious c\tSerious d\tPublication bias strongly suspected e\tMedian = 37 h [33.5, 78.5] 3 pts, median 8 g\tMedian = 75 h [57, 87.5] 6 pts median dose 6.2 g 1977–80 [12]\tNo formal comparison possible due to the small sample size of the ECTR group\t⨁◯◯◯\n\nVERY LOW\n\n\tIMPORTANT\t\nSerious complications of catheter insertion j\t\nn = 5 k\tObservational studies\tNot serious\tNot serious l\tNot serious m\tNot serious n\tStrong association o\tRate of serious complications of catheter insertion varies from 0.1% to 2.1%\t≈ 0\tAbsolute effect is estimated to be varying from 1 to 21 more serious complications per 1000 patients in the ECTR group\t⨁⨁⨁◯\n\nMODERATE\n\n\tCRITICAL\t\nSerious complications of ECTR p\t\nn = 4q\tObservational studies\tNot serious\tNot serious\tNot serious\tNot serious\tStrong association r\tRate of serious complications of ECTR varies according to the type of ECTR performed from 0.005% (IHD and CKRT), to 0.6% (TPE) and up to 1.9% (HP)\t≈ 0\tAbsolute effect is estimated to be varying from > 0 to 19 more serious complications per 1000 patients in the ECTR group depending of the type of ECTR performed\t⨁⨁⨁◯\n\nMODERATE\n\n\tCRITICAL\t\nECTR: Extracorporeal treatments, IHD: Intermittent hemodialysis, TPE: Therapeutic plasma exchange, CKRT: Continuous kidney replacement therapy, HP: Hemoperfusion, Pts = patients, PCC: Poison control center\n\n“Requirement for extracorporeal life support,” “Length of requirement of vasopressors,” “Length of hospital stay,” “Length of ICU stay,” and “Sequelae” were outcomes ranked important or critical although no data were reported in the control group, so no comparison with the ECTR group could be performed\n\naIncludes our systematic review of the literature on ECTR (37 patients from 32 case reports or case series) and 9 cohorts on standard care alone in β-adrenergic antagonists. No exclusion was based on the presence of co-ingestants or interventions\n\nbCase reports published on effect of ECTR. Uncontrolled and unadjusted for confounders such as severity of poisoning, co-ingestions, supportive and standard care, and co-interventions. Confounding-by-indication is inevitable since ECTR was often attempted after other therapies had failed\n\ncECTR and standard care performed may not be generalizable to current practice (literature pre-dating 2000)\n\ndFew events in small sample size, optimal information size criteria not met\n\nePublication bias is strongly suspected due to the study design (case reports published in toxicology either report very severe poisoning with/without impressive recovery with treatments attempted)\n\nfIncludes our systematic review of the literature on ECTR (9 case reports) and 4 cohorts on standard care alone in propranolol poisoning\n\ngIncludes our systematic review of the literature on ECTR (9 case reports) and 2 cohorts / case series on standard of care alone in sotalol poisoning\n\nhIncludes our systematic review of the literature on ECTR (9 case reports) and 2 cohorts on standard of care alone in atenolol poisoning\n\niIncludes our systematic review of the literature on ECTR (3 case reports) and 1 case series on standard of care alone in sotalol poisoning\n\njFor venous catheter insertion: serious complications include hemothorax, pneumothorax, hemomediastinum, hydromediastinum, hydrothorax, subcutaneous emphysema retroperitoneal hemorrhage, embolism, nerve injury, arteriovenous fistula, tamponade, and death. Hematoma and arterial puncture were judged not serious and thus excluded from this composite outcome. Deep venous thrombosis and infection complications were not included considering the short duration of catheter use\n\nkBased 5 single-arm observational studies: 2 meta-analyses comparing serious mechanical complications associated with catheterization using or not an ultrasound, which included 6 RCTs in subclavian veins [322] and 11 in internal jugular veins [323]; 2 RCTs comparing major mechanical complications of different sites of catheterization [324, 325]; one large multicenter cohort study reporting all mechanical complications associated with catheterization [326]. Rare events were reported from case series and case reports\n\nlNot rated down for inconsistency since heterogeneity was mainly explained by variation in site of insertion, use of ultrasound, experience of the operator, populations (adults and pediatric), urgency of catheter insertion, practice patterns, and methodological quality of studies\n\nmNot rated down for indirectness since cannulation and catheter insertion was judged similar to the procedure for other indications\n\nnNot rated down for imprecision since wide range reported explained by inconsistency\n\noThe events in the control group are assumed to be zero (since no catheter is installed for ECTR); therefore, the magnitude of effect is at least expected to be large, which increases the confidence in the estimate of effect. Furthermore, none of the studies reported 95%CI which included the null value and all observed complications occurred in a very short timeframe (i.e., few hours)\n\npFor IHD and CKRT: serious complications (air emboli, shock, and death) are exceedingly rare. Minor bleeding from heparin, transient hypotension, and electrolytes imbalance were judged not serious. For HP, serious complications include severe thrombocytopenia, major bleeding, and hemolysis. Transient hypotension, hypoglycemia, hypocalcemia, and thrombocytopenia were judged not serious. For TPE, serious complications include citrate toxicity, severe allergic reaction, arrhythmia, and vasovagal reaction. Hypotension, hypocalcemia, and urticaria were judged as not serious. All non-serious complications were excluded from this composite outcome\n\nqIHD/CKRT: Based on 2 single-arm studies describing severe adverse events per 1000 treatments in large cohorts of patients [327, 328]. TPE: based on the 2 most recent one-arm studies reporting potential life-threatening adverse events [329, 330]. HP: Based on 2 small single-arm studies in poisoned patients [331, 332]. Rare events were reported in case series and case reports\n\nrAssuming that patients in the control group would not receive any form of ECTR, the events in the control group would be zero; therefore, the magnitude of effect is at least expected to be large, which increases the confidence in the estimate of effect. Furthermore, none of the studies reported 95%CI which included the null value and all observed complications occurred in a very short timeframe (i.e., few hours)\n\nDiscussion\n\nRecommendations\n\nAs per EXTRIP methods, the workgroup only voted on BAAs for which the number of patient clinical reports were sufficient. Although there were 4 reports for acebutolol and talinolol, they were not considered to be of sufficient quality to permit elaborations of recommendations.\n\nGeneral statements and indications for ECTR\n\nPropranololIn patients severely poisoned with propranolol, we recommend against performing ECTR in addition to standard care rather than standard care alone (strong recommendation, very low quality evidence).\n\nAtenololIn patients severely poisoned with atenolol and kidney impairment*, we suggest performing ECTR in addition to standard care rather than standard care alone when refractory bradycardia and hypotension is present (weak recommendation, very low quality evidence)\n\nIn patients severely poisoned with atenolol and normal kidney function, we make no recommendation for or against performing ECTR in addition to standard care rather than standard care alone (no recommendation, very low quality evidence)\n\nSotalolIn patients severely poisoned with sotalol and kidney impairment*, we suggest performing ECTR in addition to standard care rather than standard care alone when refractory bradycardia and hypotension and/or recurrent torsade de pointes is present (weak recommendation, very low quality of evidence)\n\nIn patients severely poisoned with sotalol with normal kidney function, we make no recommendation for or against performing ECTR in addition to standard care rather than standard care alone (no recommendation, very low quality evidence).\n\nIn patients severely poisoned with sotalol, we suggest against performing ECTR solely based on the QT interval (weak recommendation, very low quality evidence).\n\n*“Kidney impairment” was defined as stage 3B, 4, or 5 CKD (i.e., eGFR < 45 mL/min/1.73m2) or AKI as KDIGO stage 2 or 3 AKI. In the absence of a baseline serum creatinine concentration, kidney impairment was defined as an eGFR < 45 mL/min/1.73m2 in adults; and in children with no baseline creatinine, the use of KDIGO criteria of AKI stage 2 and 3 after imputing a baseline serum creatinine using the Schwartz 2009 formula assuming 120 mL/min/1.73m2 of \"normal\" eGFR. The presence of oligo/anuria unresponsive to fluid resuscitation should be considered as impaired kidney function, regardless of serum creatinine concentration (See supplemental section)\n\nRationale\n\nSevere BAA poisoning can lead to bradycardia and hypotension refractory to vasopressors and inotropes, occasionally causing death [57]. Assuming all other priority therapeutic measures are in place to mitigate BAA toxicity including involvement of a clinical toxicologist, the workgroup considered the use of ECTR for severe poisoning due to propranolol, atenolol, and sotalol.\n\nPropranolol has a short half-life and a high endogenous clearance independent of kidney function. These attributes added to extensive protein binding make this drug non-dialyzable regardless of the ECTR used. Although the data were limited, ECTR did not appear to accelerate clinical recovery and the mortality from ECTR cases was higher than historical controls. For these reasons, the workgroup recommended against ECTR for propranolol poisoning (Median: 1.0/Upper quartile: 1.0/Disagreement index: 0.0).\n\nAtenolol and sotalol both have endogenous clearances (and elimination half-lives) that are highly dependent on kidney function. The contribution of ECTR in patients with kidney impairment is considerable. The greater the impairment in kidney function, the greater the relative toxicokinetic effect of ECTR. Both are considered to be “Dialyzable” in patients with kidney impairment. Although the number of cases is small, clinical improvement from sotalol and atenolol poisoning appears to coincide with initiation of ECTR, especially when high efficiency techniques are used. It is conceivable that relevant patient-important outcomes (PIOs), such as length of vasopressor requirement, long-term sequelae, and mortality would be reduced with ECTR in this population. In patients who already have vascular access in place, the risk associated with insertion is already taken into account, so the risk-benefit ratio is even lower. The workgroup suggested ECTR in patients with impaired kidney function for both atenolol (Median: 7.0 / Lower quartile: 4.0 / Disagreement index: 0.59) and sotalol (Median: 7.0 / Lower quartile: 4.0 / Disagreement index: 0.59); the workgroup nevertheless acknowledged that the initiation of ECTR, even without net ultrafiltration, might exacerbate hemodynamic instability and may not be possible to perform. The benefit of ECTR is theoretically less for patients poisoned with atenolol or sotalol and normal kidney function, even if the addition of ECTR can approximately double total clearance; the duration of toxicity is expected to be much shorter in this population. For these reasons, the workgroup considered that, at the time of writing, the benefits and harms were balanced with considerable knowledge gaps and made no recommendation for patients poisoned with atenolol or sotalol and normal kidney function.\n\nA major consideration for sotalol is its ability to cause QT prolongation, which is uncommon with other BAAs and can lead to life-endangering torsade de pointes, a poor prognostic indicator in sotalol poisoning. Obviously, the workgroup is not advocating ECTR for the treatment of torsade de pointes, as ECTR would not be technically feasible. However, recurrent torsade de pointes is indicative of severity and of a role for ECTR initiation. For non-recurrent torsades, ECTR is not justified. In the literature, there is no clear QTc duration cut-off which predicts torsade de pointes [134]. The risk of life-threatening cardiac events increases as the QTc gets longer than 500 ms [134, 135] and each 10-ms increase contributes to approximately a 5% to 7% exponential increase in risk. However, QT can be prolonged at therapeutic sotalol concentration. These findings support the recommendation of the workgroup not to perform ECTR solely based on QT prolongation.\n\nAlthough monitoring of poison concentrations is useful in some settings, there remain too many uncertainties in the concentration-effect relationship to provide a threshold concentration for ECTR initiation in BAA poisoning. Hypotension and bradycardia are poorly related to atenolol concentrations [136], QT interval prolongation is correlated with sotalol concentrations but with considerable imprecision [45–48]. Further, only 7 out of 37 panelists had access to atenolol or sotalol assays and only 3 within 12 hours of it being ordered. Very few clinicians outside of large academic centers are likely to have access to BAA assays. The panel did recognize the value of a subtherapeutic concentration in excluding the need for ECTR. The panel emphasized that the indication for ECTR is likely to depend on the availability of ECLS, which should be instituted prior to ECTR assuming both are available in the same center, as it is simple to add a hemodialysis circuit to extracorporeal membrane oxygenation.\n\nResearch gaps\n\nAdditional pharmacokinetic data in ESKD patients are needed, especially during hemodialysis, for acebutolol (because of imprecision about sampling in studies), betaxolol, bopindolol, carteolol, cetamolol, nadolol, oxprenolol, pindolol, sotalol, and timolol. In addition, clinical cases of poisoning with toxicokinetic data of ECTR is required for acebutolol, atenolol, bisoprolol, metoprolol, nadolol and sotalol in patients with normal GFR or slightly impaired GFR.\n\nToxicokinetic/toxicodynamic relationships should better evaluate if serum concentrations can determine the utility of ECTR in clinical decision-making. Better prognostic markers on admission would also be useful to determine which subset of patients are most likely to benefit from ECTR.\n\nThe added value of ECTR to ECLS should be demonstrated. In patients with impaired kidney function, additional studies could help characterize if the transfer of an unstable patient for ECTR with or without ECLS could potentially be beneficial and within which timeframe this could be useful. If ECLS is unavailable in the initial center, studies could compare clinical outcomes associated with transfer for ECLS vs. hemodialysis alone at the initial center.\n\nType of ECTR\n\nIn patients severely poisoned with atenolol or sotalol requiring ECTR: when all modalities are available, we recommend using intermittent hemodialysis rather than any other type of ECTR (strong recommendation, very low quality evidence).\n\nRationale\n\nIf ECTR is used for poison removal, then the most efficient modality at removing atenolol or sotalol should be selected, i.e., intermittent hemodialysis. In the rare circumstance that intermittent hemodialysis is unavailable but other techniques are, then hemoperfusion, CKRT, sustained low-efficiency dialysis (SLED), or prolonged intermittent renal replacement therapy (PIRRT) can be used, preferably the modality providing the best solute clearance and quickest to deliver. Although CKRT and other “slower” techniques such as SLED/PIRRT are often preferred for patients with hemodynamic compromise, this applies specifically to those requiring net ultrafiltration. It is therefore uncertain if CKRT or SLED/PIRRT would be better tolerated than intermittent hemodialysis in patients not requiring net ultrafiltration. It is acknowledged that all techniques may exacerbate hypotension to some extent for various causes including fluid and solute shifts, and electrolyte fluxes.\n\nRegardless of technique, ECTR parameters should be optimized to enhance clearance (higher blood and effluent flows, filter/dialyzer with larger surface area) [137] and to reduce risk of hemodynamic compromise (priming of the ECTR circuit, lowering dialysate temperature, dialysate/replacement fluid without low potassium, calcium and magnesium concentrations, and minimizing net ultrafiltration).\n\nImportantly, if dialysis is performed for sotalol poisoning, the input of a nephrologist is recommended to ensure that the serum magnesium concentration remains above 1 mmol/L and serum potassium concentration within 4.5-5 mmol/L to minimize the risk of dysrhythmias, including torsade de pointes. Magnesium may be added to the dialysate or administered intravenously to offset its elimination during ECTR.\n\nResearch gap\n\nData with hemoperfusion and high-cut off dialysis should be assessed in poisoning from highly protein-bound BAAs with reasonably low volume of distribution and plasma clearance such as penbutolol, oxprenolol, and carvedilol.\n\nCessation of ECTR\n\nIn patients severely poisoned with atenolol or sotalol requiring ECTR, we recommend stopping ECTR based on clinical improvement (strong recommendation, very low quality of evidence)\n\nRationale\n\nThe indication to stop ECTR, once initiated, should be reliant on clinical indicators of improvement. These include appropriate heart rate and blood pressure for adequate end organ perfusion, weaning of ECLS, decreasing inotropic and vasopressor requirements, and sustained cessation of torsade de pointes if applicable. It is recognized that QT interval prolongation may persist even at therapeutic sotalol concentrations so the use of this target for cessation is not recommended. In addition, there is no predefined duration of ECTR to treat BAA poisoning as this will depend on the type and amount of BAA ingested, as well as the underlying kidney function in some cases. The workgroup suggested not to cease ECTR solely based on a target serum concentration, as safe thresholds are not well known, and assays are infrequently available to guide judgement.\n\nOur work has several strengths. This is the first systematic review of the use of extracorporeal therapy in BAA poisoning. This systematic review summarizes the best evidence on the use of extracorporeal therapy in BAA poisoning using the most stringent guideline methodology (GRADE). No articles were rejected based on language or year of publication. It also provides clinical recommendations following a voting process using a two-round modified Delphi procedure from an international collaborative comprising recognized experts from various clinical specialties and resource settings. Limitations of the study are inherently associated with the quality of articles used for the drafting of recommendations. In many cases, details regarding these articles were of poor quality. There were insufficient data to draft recommendations on BAAs other than propranolol, atenolol, and sotalol due to the limited published evidence available; however, the workgroup acknowledged there was little clinical plausibility of a clinical benefit from ECTR for non-dialyzable BAAs such as betaxolol, carvedilol, esmolol, labetalol, mepindolol, and timolol.\n\nConclusion\n\nIn conclusion, poisoning from BAAs can cause serious toxicity and death. β-adrenergic antagonists have different physicochemical properties and pharmacokinetics which will affect their removal by ECTR. The EXTRIP workgroup assessed propranolol as non-dialyzable. Atenolol as well as sotalol were assessed as dialyzable in patients with kidney impairment and the workgroup suggests ECTR in patients severely poisoned with these drugs when aforementioned indications are present.\n\nSupplementary Information\n\nAdditional file 1. Detailed methods and glossary.\n\nAbbreviations\n\nBAA Beta-adrenergic antagonists\n\nCKD Chronic kidney disease\n\nCKRT Continuous kidney replacement therapy\n\nCL Clearance\n\nECLS Extracorporeal life support\n\nECTR Extracorporeal treatments\n\nESKD End-stage kidney disease\n\nEXTRIP The EXtracorporeal TReatments In Poisoning workgroup\n\nF Bioavailability\n\nGFR Glomerular filtration rate\n\nHD Hemodialysis\n\nHF Hemofiltration\n\nHP Hemoperfusion\n\nICU Intensive care unit\n\nIHD Intermittent hemodialysis\n\nIQR Interquartile range\n\nMet Metabolite\n\nMW Molecular weight\n\nN/A Not available\n\nPCC Poison control center\n\nPD Peritoneal dialysis\n\nPIO Patient-important outcomes\n\nPK Pharmacokinetics\n\nPts Patients\n\nT1/2 Elimination half-life\n\nTK Toxicokinetics\n\nTMAX Time to maximum concentration\n\nTPE Therapeutic plasma exchange\n\nVD Volume of distribution\n\nAcknowledgements\n\nWe would like to acknowledge the valuable help of our dedicated translators, librarian, data extractors, and meeting secretary. Official translators were Alexandra Angulo, Alla Abbott, Anant Vipat, Andreas Betz, Angelina Kovaleva, Denise Gemmellaro, Ewa Brodziuk, Helen Johnson, Junzheng Peng, Marcela Covic, Nathalie Eeckhout, Rosie Finnegan, Salih Topal, and Vilma Etchard. The librarian was Elena Guadagno. Data extractors for EXTRIP-2 included Maria Rif, François Filion, Karine Mardini, Maria Rif, Tudor Botnaru, Elizabeth Koo, and Gabrielle Wilson. The meeting secretary was Brenda Gallant.\n\nIn addition to the authors of this manuscript, members of the EXTRIP Group include: Badria Alhatali, Kurt Anseeuw, Steven Bird, Ingrid Berling, Timothy E Bunchman Diane P Calello, Paul K Chin, Kent Doi, Tais Galvao, David S Goldfarb, Hossein Hassanian-Moghaddam, Lotte CG Hoegberg, Siba Kallab, Sofia Kebede, Jan T Kielstein, Andrew Lewington, Etienne M Macedo, Rob MacLaren, Bruno Megarbane, James B Mowry, Thomas D Nolin, Marlies E Ostermann, Ai Peng, Jean-Philippe Roy, Anitha Vijayan, Steven J Walsh, Anselm Wong, David M Wood, Christopher Yates, Josée Bouchard, Greene Shepherd, Robert S. Hoffman, Sophie Gosselin, Darren M. Roberts, Yi Li, Thomas D. Nolin, Valéry Lavergne and Marc Ghannoum.\n\nAuthors' contributions\n\nMG, SG, RSH, VL, TSN, YL, and DMR designed the study; JB, MG, and GS, carried out extractions; all authors participated in analysis and interpretation of data; JB, MG, GS, and VL made the tables and figures; all authors drafted and revised the paper; all authors provided intellectual content of critical importance to the work. All authors read and approved the final manuscript.\n\nFunding\n\nEXTRIP received support consisting of an unrestricted grant of $60,633 Canadian from the Verdun Research Fund (the institution of Marc Ghannoum) solely for the reimbursement of travel expenses for the in-person guideline meeting and payment to dedicated translators for retrieval and translation of foreign language articles. The funding source did not have a role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.\n\nAvailability of data and materials\n\nThe data underlying this article will be shared on reasonable request to the corresponding author.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nNot applicable.\n\nCompeting interests\n\nTDN reports personal fees from MediBeacon, CytoSorbents, and McGraw-Hill Education outside the submitted work. MG is a scholar of the Fonds de Recherche du Québec—Santé. DMR acknowledges support of St. Vincent’s Centre for Applied Medical Research Clinician “Buy-Out” Program. AV reports consulting functions for NxStage, Astute Medical, and Boehringer-Ingelheim and speaker fees from Sanofi-Aventis. MO has received speaker honoraria and research funding from Fresenius Medical and Baxter and has had consulting functions for Nxstage and Baxter. 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Bowman SL Hudson SA Simpson G Munro JF Clements JA A comparison of the pharmacokinetics of propranolol in obese and normal volunteers Br J Clin Pharmacol 1986 21 5 529 532 10.1111/j.1365-2125.1986.tb02837.x 3718810\n299. Cid E Mella F Lucchini L Carcamo M Monasterio J Plasma concentrations and bioavailability of propranolol by oral, rectal, and intravenous administration in man Biopharm Drug Dispos 1986 7 6 559 566 10.1002/bdd.2510070605 3828485\n300. Wilson TW Firor WB Johnson GE Holmes GI Tsianco MC Huber PB Timolol and propranolol: bioavailability, plasma concentrations, and beta blockade Clin Pharmacol Ther 1982 32 6 676 685 10.1038/clpt.1982.223 7140133\n301. Chidsey CA Morselli P Bianchetti G Morganti A Leonetti G Zanchetti A Studies of the absorption and removal of propranolol in hypertensive patients during therapy Circulation 1975 52 2 313 318 10.1161/01.CIR.52.2.313 1149212\n302. Olanoff LS Walle T Cowart TD Walle UK Oexmann MJ Conradi EC Food effects on propranolol systemic and oral clearance: support for a blood flow hypothesis Clin Pharmacol Ther 1986 40 4 408 414 10.1038/clpt.1986.198 3757404\n303. Anttila M Arstila M Pfeffer M Tikkanen R Vallinkoski V Sundquist H Human pharmacokinetics of sotalol Acta Pharmacol Toxicol (Copenh) 1976 39 1 118 128 10.1111/j.1600-0773.1976.tb03162.x 988964\n304. Poirier JM Jaillon P Lecocq B Lecocq V Ferry A Cheymol G The pharmacokinetics of d-sotalol and d, l-sotalol in healthy volunteers Eur J Clin Pharmacol 1990 38 6 579 582 10.1007/BF00278585 2373132\n305. Salazar DE Much DR Nichola PS Seibold JR Shindler D Slugg PH A pharmacokinetic-pharmacodynamic model of d-sotalol Q-Tc prolongation during intravenous administration to healthy subjects J Clin Pharmacol 1997 37 9 799 809 10.1002/j.1552-4604.1997.tb05627.x 9549633\n306. Sundquist H Anttila M Simon A Reich JW Comparative bioavailability and pharmacokinetics of sotalol administered alone and in combination with hydrochlorothiazide J Clin Pharmacol 1979 19 8–9 Pt 2 557 564 10.1002/j.1552-4604.1979.tb02522.x 489773\n307. Uematsu T Kanamaru M Nakashima M Comparative pharmacokinetic and pharmacodynamic properties of oral and intravenous (+)-sotalol in healthy volunteers J Pharm Pharmacol 1994 46 7 600 605 10.1111/j.2042-7158.1994.tb03865.x 7996391\n308. Blair AD Cutler RE Lam FY Pharmacokinetics of sotalol in humans with normal and varying degrees of renal function Clin Res 1980 28 1 68A\n309. Dumas M d'Athis P Besancenot JF Chadoint-Noudeau V Chalopin JM Rifle G Variations of sotalol kinetics in renal insufficiency Int J Clin Pharmacol Ther Toxicol 1989 27 10 486 489 2583875\n310. Sundquist HK Anttila M Forsstrom J Kasanen A Serum levels and half-life of sotalol in chronic renal failure Ann Clin Res 1975 7 6 442 446 1211858\n311. Trausch B Oertel R Richter K Gramatte T Disposition and bioavailability of the beta 1-adrenoceptor antagonist talinolol in man Biopharm Drug Dispos 1995 16 5 403 414 10.1002/bdd.2510160505 8527689\n312. Haustein KO Fritzsche K On the pharmacokinetics of talinolol, a new beta 1-receptor blocking agent Int J Clin Pharmacol Ther Toxicol 1981 19 9 392 395 6117520\n313. Terhaag B Palm U Sahre H Richter K Oertel R Interaction of talinolol and sulfasalazine in the human gastrointestinal tract Eur J Clin Pharmacol 1992 42 4 461 462 1355428\n314. Ishizaki T Tawara K Oyama Y Nakaya H Clinical pharmacologic observations on timolol. I. Disposition and effect in relation to plasma level in normal individuals J Clin Pharmacol. 1978 18 11–12 511 8 10.1002/j.1552-4604.1978.tb01580.x 721948\n315. Else OF Sorenson H Edwards IR Plasma timolol levels after oral and intravenous administration Eur J Clin Pharmacol 1978 14 6 431 434 10.1007/BF00716385 738350\n316. Vedin JA Kristianson JK Wilhelmsson CE Pharmacokinetics of intravenous timolol in patients with acute myocardial infarction and in healthy volunteers Eur J Clin Pharmacol 1982 23 1 43 47 10.1007/BF01061376 7128671\n317. El-Rashidy R Estimation of the systemic bioavailability of timolol in man Biopharm Drug Dispos 1981 2 2 197 202 10.1002/bdd.2510020213 7248483\n318. Faulkner JK Stopher DA Walden R Pharmacokinetic and pharmacological studies with tolamolol in man Br J Clin Pharmacol 1975 2 5 423 428 10.1111/j.1365-2125.1975.tb00551.x 786354\n319. Routledge PA Davies DM Rawlins MD Pharmacokinetics of tolamolol in the treatment of hypertension Eur J Clin Pharmacol 1977 12 3 171 174 10.1007/BF00609855 579342\n320. Balant L, Gorgia A, Marmy A, Tschopp JM. [Clearance concept applied to pharmacokinetics: 2. Experience with tolamolol (beta-blocking agent) in renal insufficiency (author's transl)]. Nephrologie. 1980;1 (4):177–82.\n321. Williams HA Henke D Elamin MEMO Sandilands EA Thomas SHL Thompson JP Can poisons centre data inform safer prescribing? A pilot review of propranolol exposures reported to the UK National Poisons Information Service (NPIS) Clin Toxicol 2019 57 6 453\n322. Brass P, Hellmich M, Kolodziej L, Schick G, Smith AF. Ultrasound guidance versus anatomical landmarks for subclavian or femoral vein catheterization. Cochrane Database Syst Rev. 2015;1:CD011447.\n323. Brass P, Hellmich M, Kolodziej L, Schick G, Smith AF. Ultrasound guidance versus anatomical landmarks for internal jugular vein catheterization. Cochrane Database Syst Rev. 2015;1:CD006962.\n324. Parienti JJ Mongardon N Megarbane B Mira JP Kalfon P Gros A Intravascular complications of central venous catheterization by insertion site N Engl J Med 2015 373 13 1220 1229 10.1056/NEJMoa1500964 26398070\n325. Shin HJ Na HS Koh WU Ro YJ Lee JM Choi YJ Complications in internal jugular vs subclavian ultrasound-guided central venous catheterization: a comparative randomized trial Intensive Care Med 2019 45 7 968 976 10.1007/s00134-019-05651-9 31143996\n326. Bjorkander M Bentzer P Schott U Broman ME Kander T Mechanical complications of central venous catheter insertions: A retrospective multicenter study of incidence and risks Acta Anaesthesiol Scand 2019 63 1 61 68 10.1111/aas.13214 29992634\n327. Wong B Zimmerman D Reintjes F Courtney M Klarenbach S Dowling G Procedure-related serious adverse events among home hemodialysis patients: a quality assurance perspective Am J Kidney Dis 2014 63 2 251 258 10.1053/j.ajkd.2013.07.009 23993152\n328. Tennankore KK d'Gama C Faratro R Fung S Wong E Chan CT Adverse technical events in home hemodialysis Am J Kidney Dis 2015 65 1 116 121 10.1053/j.ajkd.2014.08.013 25441436\n329. Mokrzycki MH Kaplan AA Therapeutic plasma exchange: complications and management Am J Kidney Dis 1994 23 6 817 827 10.1016/S0272-6386(12)80135-1 8203364\n330. Sutton DM Nair RC Rock G Complications of plasma exchange Transfusion 1989 29 2 124 127 10.1046/j.1537-2995.1989.29289146829.x 2919422\n331. Yang X Xin S Zhang Y Li T Early hemoperfusion for emergency treatment of carbamazepine poisoning Am J Emerg Med 2018 36 6 926 930 10.1016/j.ajem.2017.10.048 29066188\n332. Shannon MW Comparative efficacy of hemodialysis and hemoperfusion in severe theophylline intoxication Acad Emerg Med 1997 4 7 674 678 10.1111/j.1553-2712.1997.tb03758.x 9223689\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1364-8535",
"issue": "25(1)",
"journal": "Critical care (London, England)",
"keywords": "Beta-blockers; ECLS; Hemodialysis; Hemoperfusion; Intoxication; Overdose",
"medline_ta": "Crit Care",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D032921:Consensus; D062787:Drug Overdose; D015199:Extracorporeal Membrane Oxygenation; D006801:Humans",
"nlm_unique_id": "9801902",
"other_id": null,
"pages": "201",
"pmc": null,
"pmid": "34112223",
"pubdate": "2021-06-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D000078182:Systematic Review",
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"title": "Extracorporeal treatment for poisoning to beta-adrenergic antagonists: systematic review and recommendations from the EXTRIP workgroup.",
"title_normalized": "extracorporeal treatment for poisoning to beta adrenergic antagonists systematic review and recommendations from the extrip workgroup"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-03934",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METOPROLOL SUCCINATE"
},
... |
{
"abstract": "Skeletal metastases (SM) in advanced pancreatic ductal adenocarcinoma (PDAC) is an infrequent occurrence that has been previously reported in literature to occur in less than 2.5% of the cases. Complications such as pathological fractures can result in intractable pain, immobilization and a significant deterioration in quality of life. The purpose of this study is to improve the understanding of the increasing incidence of SM and the importance of surveillance and adequate management of SM in these patients.\nA retrospective analysis was conducted using a clinical database at a single tertiary care institution for cancer patients; this included 207 patients with advanced PDAC diagnosed between December 2004 and March 2017 receiving palliative chemotherapy. SM were identified by computerized tomography (CT)/fluorodeoxyglucose positron emission tomography (FDG-PET)/magnetic resonance imaging (MRI). Information regarding demographics, clinical course and date of last follow-up/death were collected. After a median follow-up of 11 months, an analysis was conducted, including a Kaplan-Meier survival analysis.\nThe study included 207 patients; 19 out of 207 patients (9.2%) developed SM; the primary tumor was located in the pancreatic body/tail in 12 out of 19 patients (63.2%). The thoracic and lumbar vertebrae were the most common sites of SM. Other common synchronous sites of metastases included the liver and lung. A majority of the lesions were osteolytic (63.2%). The median time of diagnosis from the initial diagnosis was 2 months (range, 0-60 months). Bone pain was observed as the initial symptom in 7 out of 19 patients (36.8%), 2 out of 19 patients (10.5%) had a pathological fracture and 1 out of 19 patients (5.3%) developed a para-spinal mass causing inferior vena cava compression. The median survival period for patients with SM was 11 months (range, 0-62 months) and for those without SM was 12 months (range, 0-147 months) [hazard ratio (HR) 1.24, 95% confidence interval (CI): 0.66-2.30, P=0.51].\nThere has been a challenge with regards to management of the increasing number of patients with SM. Thoracic and lumbar vertebrae are the most common sites and pathological fractures in these sites can be catastrophic. Careful evaluation of skeletal signs and symptoms, early detection and intervention are essential to prevent morbidity and mortality from complications in patients with PDAC and SM.",
"affiliations": "Department of Hematology/Oncology, Houston Methodist, Houston, TX, USA.;Department of Radiology, Banner MD Anderson Cancer Center, Gilbert, AZ, USA.;Banner MD Anderson Cancer Center, Gilbert, AZ, USA.;Banner MD Anderson Cancer Center, Gilbert, AZ, USA.;Banner MD Anderson Cancer Center, Gilbert, AZ, USA.;Division of Cancer Medicine, Banner MD Anderson Cancer Center, Gilbert, AZ, USA.;Division of Cancer Medicine, Banner MD Anderson Cancer Center, Gilbert, AZ, USA.;Division of Cancer Medicine, Banner MD Anderson Cancer Center, Gilbert, AZ, USA.",
"authors": "Puri|Akshjot|A|;Chang|John|J|;Tanner|Natalee|N|;Lucente|Patricia|P|;Desiongco|Janice|J|;Dragovich|Tomislav|T|;Naraev|Boris|B|;Kundranda|Madappa|M|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/jgo-20-361",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2078-6891",
"issue": "12(2)",
"journal": "Journal of gastrointestinal oncology",
"keywords": "Skeletal metastases (SM); advanced pancreatic adenocarcinoma; incidence; intervention; overall survival",
"medline_ta": "J Gastrointest Oncol",
"mesh_terms": null,
"nlm_unique_id": "101557751",
"other_id": null,
"pages": "455-463",
"pmc": null,
"pmid": "34012639",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": "22895395;17452677;624200;15382705;25531049;7848081;23607915;9196156;16248386;15958534;14101850;12548583;19325940;21561347;4695897;2019918;20862374;19708936;24131140;14600620",
"title": "Skeletal metastases in advanced pancreatic ductal adenocarcinoma: a retrospective analysis.",
"title_normalized": "skeletal metastases in advanced pancreatic ductal adenocarcinoma a retrospective analysis"
} | [
{
"companynumb": "US-AMGEN-USASP2021127080",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": null,
... |
{
"abstract": "A 67 year old woman with a 10 year history of rheumatoid arthritis (RA) treated with methotrexate and prednisone, presented with a 2 year history of worsening multiple cutaneous plaques of variable appearance. Two distinct skin lesions were biopsied to reveal a composite cutaneous lymphoma, possibly caused by long term methotrexate therapy. An [18F] fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was performed to stage the malignancy, and was later repeated to evaluate response to chemotherapy, which guided subsequent management. We present the PET/CT imaging findings of this very rare iatrogenic (methotrexate induced) immunodeficiency-associated lymphoproliferative disorder.",
"affiliations": "Department of Diagnostic Imaging, CCI, Diagnostic Imaging, 11560 University Ave NW, Edmonton, Alberta T6G 1Z2 Canada.;MUHC Glen Site, Nuclear Medicine, 1001 Decarie Blvd, Montreal, Quebec H4A 3J1 Canada.;MUHC, Dermatology, 4 Westmount Sq, Suite 100, Westmount, Quebec H3Z 2S6 Canada.;MUHC Glen Site, Pathology, 1001 Decarie Blvd, Montreal, Quebec H4A 3J1 Canada.;MUHC Jewish General Hospital, Nuclear Medicine, 3755 Chemin de la Cote-Sainte-Catherine, Montreal, Quebec H3T 1E2 Canada.",
"authors": "Makis|William|W|;Ciarallo|Anthony|A|;Wang|Beatrice|B|;Gonzalez-Verdecia|Milene|M|;Probst|Stephan|S|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s13139-016-0463-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1869-3474",
"issue": "51(3)",
"journal": "Nuclear medicine and molecular imaging",
"keywords": "Composite lymphoma; Cutaneous lymphoma; Iatrogenic immunodeficiency-associated lymphoproliferative disorder; Methotrexate; PET/CT; Rheumatoid arthritis",
"medline_ta": "Nucl Med Mol Imaging",
"mesh_terms": null,
"nlm_unique_id": "101530478",
"other_id": null,
"pages": "261-265",
"pmc": null,
"pmid": "28878854",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports",
"references": "20631509;9213378;12089729;18509641;15692063;10951162;23560463;8385742;19696197;16882175;20098085;17716987;19620431;15188349;17012914;16921287;17654684",
"title": "Composite Cutaneous Lymphoma (Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorder) in a Patient with Rheumatoid Arthritis Treated with Methotrexate: Staging and Evaluation of Response to Therapy with 18F-FDG PET/CT.",
"title_normalized": "composite cutaneous lymphoma iatrogenic immunodeficiency associated lymphoproliferative disorder in a patient with rheumatoid arthritis treated with methotrexate staging and evaluation of response to therapy with 18f fdg pet ct"
} | [
{
"companynumb": "CA-TEVA-816227USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
"dr... |
{
"abstract": "BACKGROUND\nAcute esophageal necrosis (AEN) is a rare condition that has been associated with low volume states, microvascular disease, gastrointestinal (GI) mucosal damage, and impaired GI motility. It has been linked in case reports with diabetic ketoacidosis (DKA) and is commonly associated with GI bleeding (GIB).\n\n\nMETHODS\nWe report a case of endoscopy confirmed AEN as a complication of DKA in a 63-year-old Caucasian male without any overt GIB and a chief complaint of epigastric pain. Interestingly, there was no apparent trigger for DKA other than a newly started ketogenic diet two days prior to symptom onset. A possible potentiating factor for AEN beyond DKA is the recent start of a Glucagon-like peptide-1 receptor agonist (GLP-1 RA), though they have not been previously connected to DKA or AEN. The patient was subsequently treated with high dose proton pump inhibitors, GLP-1 RA was discontinued, and an insulin regimen was instituted. The patient's symptoms improved over the course of several weeks following discharge and repeat endoscopy showed well healing esophageal mucosa.\n\n\nCONCLUSIONS\nThis report highlights AEN in the absence of overt GIB, emphasizing the importance of early consideration of EGD.",
"affiliations": "Department of Internal Medicine, McMaster University, Hamilton L8S 4L8, Ontario, Canada.;Division of Gastroenterology, McMaster University, Hamilton L8S 4L8, Ontario, Canada.;Division of Gastroenterology, McMaster University, Hamilton L8S 4L8, Ontario, Canada. spaziar@mcmaster.ca.",
"authors": "Moss|Kasey|K|;Mahmood|Tahrin|T|;Spaziani|Robert|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v9.i31.9571",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i31.pg9571\n10.12998/wjcc.v9.i31.9571\nCase Report\nAcute esophageal necrosis as a complication of diabetic ketoacidosis: A case report\nMoss K et al. AEN in a DKA patient\nMoss Kasey Department of Internal Medicine, McMaster University, Hamilton L8S 4L8, Ontario, Canada\n\nMahmood Tahrin Division of Gastroenterology, McMaster University, Hamilton L8S 4L8, Ontario, Canada\n\nSpaziani Robert Division of Gastroenterology, McMaster University, Hamilton L8S 4L8, Ontario, Canada. spaziar@mcmaster.ca\n\nAuthor contributions: Moss K was the primary author who wrote and revised the paper; Mahmood T contributed to the writing and revising process heavily; Spaziani R provided his expertise and assistance in editing the paper and was the primary physician involved in the patient encounter; all authors have read and approve the final manuscript.\n\nCorresponding author: Robert Spaziani, FRCP (C), Attending Doctor, Department of Internal Medicine, Division of Gastroenterology, McMaster University, 1280 Main Street West, Hamilton L8S 4L8, Ontario, Canada. spaziar@mcmaster.ca\n\n6 11 2021\n6 11 2021\n9 31 95719576\n27 3 2021\n18 6 2021\n22 9 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.or g/Licenses/by-nc/4.0/\nBACKGROUND\n\nAcute esophageal necrosis (AEN) is a rare condition that has been associated with low volume states, microvascular disease, gastrointestinal (GI) mucosal damage, and impaired GI motility. It has been linked in case reports with diabetic ketoacidosis (DKA) and is commonly associated with GI bleeding (GIB).\n\nCASE SUMMARY\n\nWe report a case of endoscopy confirmed AEN as a complication of DKA in a 63-year-old Caucasian male without any overt GIB and a chief complaint of epigastric pain. Interestingly, there was no apparent trigger for DKA other than a newly started ketogenic diet two days prior to symptom onset. A possible potentiating factor for AEN beyond DKA is the recent start of a Glucagon-like peptide-1 receptor agonist (GLP-1 RA), though they have not been previously connected to DKA or AEN. The patient was subsequently treated with high dose proton pump inhibitors, GLP-1 RA was discontinued, and an insulin regimen was instituted. The patient’s symptoms improved over the course of several weeks following discharge and repeat endoscopy showed well healing esophageal mucosa.\n\nCONCLUSION\n\nThis report highlights AEN in the absence of overt GIB, emphasizing the importance of early consideration of EGD.\n\nAcute esophageal necrosis\nGurvits syndrome\nAcute necrotizing esophagitis\nBlack Esophagus\nDiabetic Ketoacidosis\nGlucagon-like peptide-1 receptor agonists\n==== Body\npmc Core Tip: Acute esophageal necrosis (AEN) is a rare condition with a mortality rate greater than 30%. It has been linked to low volume states including diabetic ketoacidosis in case reports but is usually associated with overt gastrointestinal bleeding (GIB). This report provides an important description of a patient presenting with AEN and no overt GIB. Interestingly, the apparent trigger for ketoacidosis appears to be a ketogenic diet. The case explores Glucagon-like peptide-1 receptor agonists as a possible AEN precipitant, which is not a finding previously described in the existing literature.\n\nINTRODUCTION\n\nAcute esophageal necrosis (AEN), also known as Black Esophagus or Gurvits Syndrome, is a rare entity distinguished by circumferential necrosis of the distal esophageal tissue that does not progress beyond the gastroesophageal junction (GEJ)[1]. The purported mechanisms of injury leading to AEN include ischemic injury, malnutrition, and acute gastric outlet obstruction or slowed peristalsis leading to increased gastric contents[2]. AEN has been linked with disease states that result in hemodynamic compromise, hypoperfusion, low volume states, and corrosive injuries[1]. One such possible disease state is diabetic ketoacidosis (DKA), a condition associated with hypoperfusion and transient hyperglycemic induced gastric dysmotility[3,4]. The treatment is high dose PPI, correction of causative condition, and monitoring for complications that may include esophageal strictures, perforations and abscess formation[2]. AEN is typically associated with gastrointestinal bleeding (GIB)[2], and only one[5] of the previous 13 reported cases, see Table 1 [5-15] of AEN in DKA did not present with overt GIB. We report a case of AEN as a complication of DKA in a patient without any overt GIB.\n\nTable 1 A summary of the presenting symptoms and demographics of both our case and the 13 other patient presentations of diabetic ketoacidosis complicated by acute esophageal necrosis\n\nRef.\tPresenting symptoms\tGI bleeding\tAge\tGender\tDiabetes type 1 or 2\t\nOur case\tNausea, emesis, epigastric pain, dysphagia, odynophagea, anorexia\tNone\t63\tMale\t2\t\nRigolon et al[5]\tNausea, emesis, epigastric pain, polyuria, polydipsia, fever\tNone\t50\tMale\t2\t\nTalebi-Bakhshayesh et al[6]\tAltered mental status, abdominal pain, nausea, emesis, fatigue\tYes\t34\tMale\tUnknown\t\nMccarthy et al[7]\tDeath\tUnknown\t67\tFemale\t2\t\nUhlenhopp et al[8]\tEncephalopathy, hypoxic respiratory failure\tYes\t56\tMale\t2\t\nGhoneim et al[9]\tNausea, emesis, aphasia, gait difficulty\tYes\t67\tFemale\tUnknown\t\nGhoneim et al[9]\tNausea, emesis, right upper quadrant and epigastric abdominal pain\tYes\t78\tFemale\t2\t\nGhoneim et al[9]\tMelena, malaise, chills, cough, anorexia\tYes\t35\tMale\t1\t\nChoksi et al[10]\tAltered mental status\tYes\t65\tMale\tUnknown\t\nVien and Yeung[11]\tLethargy, nausea, emesis, anorexia, odynophagia,\tYes\t37\tFemale\t2\t\nField et al[12]\tNausea, emesis, epigastric pain, anorexia\tYes\t37\tFemale\t1\t\nShah et al[13]\tMelena, sepsis, fever, anorexia, syncope\tYes\t34\tMale\tUnknown\t\nHaghbeyan et al[14]\tEmesis, anorexia\tYes\t55\tFemale\tUnknown\t\nBuckshaw et al[15]\tNausea, emesis, epigastric pain\tYes\t50\tMale\t1\t\n\nCASE PRESENTATION\n\nChief complaints\n\nA 63-year-old retired Caucasian male presented to Emergency with severe epigastric pain and dysphagia and odynophagia to both solids and liquids leading to several days of anorexia. He also complained of nausea and non-bloody, non-bilious emesis. There was no evidence of overt GIB.\n\nHistory of present illness\n\nThe patient noted that due to his hypertension and type 2 diabetes mellitus (T2DM) he was attempting to lose weight. To do this, his primary care provider switched him from his previous liraglutide which he had received for one year, to a trial of semaglutide one week prior to symptom onset. Additionally, he began a ketogenic diet to help with his weight loss goals and 2 d later, when performing manual labour, he became acutely unwell. He did not have a history of reflux disease or dysphagia prior to this episode and attempted to alleviate the discomfort with bed rest and ceasing oral intake. When the pain and nausea peaked 5 d following symptom onset, see Figure 1 for timeline, he presented to the hospital.\n\nFigure 1 Timeline of illness from symptom onset to resolution of esophageal damage in 63 year old Caucasian man with diabetic ketoacidosis and acute esophageal necrosis.\n\nHistory of past illness\n\nThe patient had a several-year history of hypertension, dyslipidemia and T2DM with no known microvascular complications. His glycemic control had been poor with a most recent HbA1c of 8.4%. His medications included metformin 500 mg twice daily, ramipril 5 mg daily, ezetimibe 10 mg daily, duloxetine 60 mg daily, pravastatin 40 mg daily, and semaglutide 0.5 mg weekly.\n\nPersonal and family history\n\nThe patient did not have any pertinent personal or family history. He did not have a significant alcohol intake, nor did he smoke or use recreational drugs.\n\nPhysical examination\n\nThe patient was 94 kg, 1.778 m tall, with a body mass index of 31.14 kg/m². Vital signs on presentation were notable for tachycardia (125 beats per minute), tachypnea (respiratory rate of 40) and blood pressure of 136/81. On physical exam he was noted to be in distress with Kussmaul respirations, lying in lateral decubitus position with voluntary abdominal guarding and frequent painful belching.\n\nLaboratory examinations\n\nAdmission blood work revealed hemoglobin of 165 g/L, leukocytes of 17.9 × 109 /L and an anion gap of 25 with bicarbonate of 5 mmol/L. Venous blood gas showed acidemia (pH = 7.02) and a B-hydroxybutyrate level of 10.2 mmol/L (normal < 0.25 mmol/L). His glucose was initially 17 mmol/L and peaked at 82 mmol/L. Urinalysis was negative for leukocytes or nitrites.\n\nImaging examinations\n\nAn abdominal CT ruled out bowel obstruction or intra-abdominal infection/abscess as the source of his discomfort but demonstrated circumferential wall thickening of the distal esophagus.\n\nFINAL DIAGNOSIS\n\nFollowing investigations, he was admitted to the hospital for first presentation DKA. No triggers were identified except perhaps his recently started ketogenic diet and dehydration. To rule out latent autoimmune diabetes in adults, C-peptides were ordered and were within normal limits, 1087pmol/L (normal 370-1470pmol/L). After the resolution of DKA, he continued to experience out of proportion epigastric pain, reflux symptoms, and dysphagia. To investigate, an esophagogastroduodenoscopy (EGD) was performed. This showed severe class D esophagitis involving the entire esophagus. There were circumferential black, necrotic inflammatory changes in the mid to distal esophagus that stopped abruptly at the GEJ. This was thought to represent AEN which can be seen in Figure 2. Biopsies were not taken of the necrotic tissue. Erosions were seen in the body and antrum of the stomach, and multiple clean based ulcers were seen in the duodenum. Biopsies were taken of the gastric and duodenal mucosa, and histology report showed chronic gastroduodenitis with no sign of H. pylori or infectious organisms as well as no evidence of neoplasia.\n\nFigure 2 Endoscopic images. A: Endoscopic image of the presented patient’s mid-distal esophagus with circumferential black discolouration of the mucosa likely to be necrotic tissue; B: Distal esophagus with circumferential black discolouration of the mucosa with clear demarcation at the gastroesophageal junction in keeping with acute esophageal necrosis.\n\nTREATMENT\n\nFollowing the EGD the patient was given pantoprazole 40 mg intravenously twice daily, sucralfate suspension of 1 g PO four times daily, and instructions to slowly increase from nil per os to clear and then full fluid diet.\n\nOUTCOME AND FOLLOW-UP\n\nHe was discharged home in a stable condition on a liquid diet, sucralfate 2 g with meals and nightly for two weeks, and pantoprazole 40 mg twice daily. At discharge metformin and GLP-1 RA were discontinued and insulin aspart 5 units three times daily and insulin glargine 15 units nightly was prescribed.\n\nA repeat EGD 8 wk post-discharge showed a healed esophagus with one polyp. Biopsies showed healed gastric and duodenal mucosa and mild inflammatory changes to the removed polyp. Follow up was arranged to ensure no return of symptoms and the patient's follow up HbA1c was improved from the previous 8.4 to 7.2.\n\nDISCUSSION\n\nDKA has been previously associated with AEN in several case reports: A rare complication of a common presentation. As mentioned earlier, 13 cases to date have been reported, most of which have been associated with GIB. In fact, AEN, in general, is associated with overt GIB in 88% of presentations, and also often associated with non-specific symptoms such as GI upset, dysphagia, and hypotension[2,16].\n\nIt is critical to recognize AEN as it is associated with a mortality of 32%[2]. This case highlights the importance of considering AEN despite a lack of GIB when other concerning features are present, such as dysphagia. AEN is especially important to consider in patients such as males over 60 or those with increased risk of microvascular disease or hemodynamic compromise[1,16,17].\n\nInterestingly, our case highlights two triggers that may have led to DKA in this patient and put him at greater risk for AEN. First, ketogenic diets, especially in conjunction with other triggers like dehydration or physiologic stress, have been linked to ketoacidosis in multiple case reports in diabetic and non-diabetic patients[18-20]. Ketogenic diets deplete the body’s glucose reserve and shift the metabolism into ketogenesis primarily by hepatic oxidation of fatty acids, making ketones an alternative to glucose[18]. In a patient with type two diabetes mellitus, who already has insulin resistance, the body’s ability to regulate ketogenesis is reduced, making them more prone to ketoacidosis. Moreover, the introduction of GLP-1 RA increases lipolysis and ketogenesis[21]. The combination of these factors may have been sufficient to tip this patient into ketoacidosis.\n\nAfter the development of DKA, the development of AEN is largely thought to be multifactorial. First, DKA is a low volume state that predisposes the esophagus to necrotic injury[22,23]. Second, the hyperglycemia in DKA decreases gastric motility which increases acid reflux to the esophagus and therefore renders the esophagus prone to injury[3,24]. Besides the direct impact of DKA, it is important to consider the risk factors associated with diabetes such as microvascular disease, which may have been underlying, which render the esophagus unable to withstand the hemodynamic changes associated with DKA. Furthermore, semaglutide is associated with adverse GI effects including gastritis, minor delays in gastric emptying, and GERD[23]. The delay in gastric emptying is caused by an inhibition of stomach peristalsis in combination with increased pylorus contraction[25]. A meta-analysis of adverse GI events in patients with T2DM using GLP-1 RAs showed that there is a dose-dependent increase in GI events, and GLP-1 RAs were more likely to cause adverse GI events in comparison to placebo[24] or insulin[25]. Severe GI adverse reactions occurred in 1.7% of patients at our patient’s newly started dose of 0.5 mg[23]. The GERD and gastroparesis associated with GLP-1 RA could cause caustic injury which is a known contributor to AEN.\n\nCONCLUSION\n\nIn conclusion, this case reiterates the association between AEN and DKA. With the evolving era of medicine, where diet and oral hypoglycemics are combined, AEN in the context of DKA may become more prevalent given the various mechanisms of actions involved. This case serves as a reminder for clinicians to keep a low threshold to proceed with EGD even despite a lack of overt GIB.\n\nInformed consent statement: The patient whom the case report was written about provided verbal consent to have their case written and submitted for publication prior to the commencement of the case report being written.\n\nConflict-of-interest statement: None of the authors has any conflicts of interest.\n\nCARE Checklist (2016) statement: The authors have submitted and followed the guidelines within the CARE checklist (2016) statement.\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: March 27, 2021\n\nFirst decision: June 3, 2021\n\nArticle in press: September 22, 2021\n\nSpecialty type: Medicine, research and experimental\n\nCountry/Territory of origin: Canada\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): C, C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Ray S, Shen HN S-Editor: Wang LL L-Editor: A P-Editor: Xing YX\n==== Refs\n1 Gurvits GE Black esophagus: acute esophageal necrosis syndrome World J Gastroenterol 2010 16 3219 3225 20614476\n2 Gurvits GE Shapsis A Lau N Gualtieri N Robilotti JG Acute esophageal necrosis: a rare syndrome J Gastroenterol 2007 42 29 38\n3 Krishnasamy S Abell TL Diabetic Gastroparesis: Principles and Current Trends in Management Diabetes Ther 2018 9 1 42\n4 Ebert EC Gastrointestinal complications of diabetes mellitus Dis Mon 2005 51 620 663 16458726\n5 Rigolon R Fossà I Rodella L Targher G Black esophagus syndrome associated with diabetic ketoacidosis World J Clin Cases 2016 4 56 59 26881192\n6 Talebi-Bakhshayesh M Samiee-Rad F Zohrenia H Zargar A Acute Esophageal Necrosis: A Case of Black Esophagus with DKA Arch Iran Med 2015 18 384 385 26058936\n7 McCarthy S Garland J Hensby-Bennett S Philcox W Kesha K Stables S Tse R Black Esophagus (Acute Necrotizing Esophagitis) and Wischnewsky Lesions in a Death From Diabetic Ketoacidosis: A Possible Underlying Mechanism Am J Forensic Med Pathol 2019 40 192 195 30676335\n8 Uhlenhopp DJ Pagnotta G Sunkara T Acute esophageal necrosis: A rare case of upper gastrointestinal bleeding from diabetic ketoacidosis Clin Pract 2020 10 1254 32670536\n9 Ghoneim S Shah A Dalal S Landsman M Kyprianou A Black Esophagus in the Setting of Diabetic Ketoacidosis: A Rare Finding from Our Institution Case Rep Gastroenterol 2019 13 475 480 31824236\n10 Choksi V Dave K Cantave R Shaharyar S Joseph J Shankar U Kaplan S Feiz H \"Black Esophagus\" or Gurvits Syndrome: A Rare Complication of Diabetic Ketoacidosis Case Rep Gastrointest Med 2017 2017\n11 Vien LP Yeung HM Acute Esophageal Necrosis (Gurvits Syndrome): A Rare Complication of Diabetic Ketoacidosis in a Critically Ill Patient Case Rep Med 2020 2020 5795847 32180810\n12 Field Z Kropf J Lytle M Castaneira G Madruga M Carlan SJ Black Esophagus: A Rare Case of Acute Esophageal Necrosis Induced by Diabetic Ketoacidosis in a Young Adult Female Case Rep Gastrointest Med 2018 2018 7363406 30631610\n13 Shah AR Landsman M Waghray N A Dire Presentation of Diabetic Ketoacidosis with \"Black Esophagus Cureus 2019 11: e4761\n14 Haghbayan H Sarker AK Coomes EA Black esophagus: acute esophageal necrosis complicating diabetic ketoacidosis CMAJ 2018 190 E1049 30181152\n15 Buckshaw R Stern ES Andrews R Stelzer F Esophageal Necrosis: A Rare Complication of Diabetic Ketoacidosis – A Case Report. Poster Presented at: The American College of Physicians- Nationals, Philadelphia, PA\n16 Gurvits GE Cherian K Shami MN Korabathina R El-Nader EM Rayapudi K Gandolfo FJ Alshumrany M Patel H Chowdhury DN Tsiakos A Black esophagus: new insights and multicenter international experience in 2014 Dig Dis Sci 2015 60 444 453 25297468\n17 Day A Sayegh M Acute oesophageal necrosis: a case report and review of the literature Int J Surg 2010 8 6 14 19800431\n18 White-Cotsmire AJ Healy AM Ketogenic Diet as a Trigger for Diabetic Ketoacidosis in a Misdiagnosis of Diabetes: A Case Report Clin Diabetes 2020 38 318 321 32699486\n19 von Geijer L Ekelund M Ketoacidosis associated with low-carbohydrate diet in a non-diabetic lactating woman: a case report J Med Case Rep 2015 9 224 26428083\n20 MacDonald PE El-Kholy W Riedel MJ Salapatek AM Light PE Wheeler MB The multiple actions of GLP-1 on the process of glucose-stimulated insulin secretion Diabetes 2002 51 Suppl 3 S434 S442 12475787\n21 Nakatani Y Maeda M Matsumura M Shimizu R Banba N Aso Y Yasu T Harasawa H Effect of GLP-1 receptor agonist on gastrointestinal tract motility and residue rates as evaluated by capsule endoscopy Diabetes Metab 2017 43 430 437 28648835\n22 Burtally A Gregoire P Acute esophageal necrosis and low-flow state Can J Gastroenterol 2007 21 245 247 17431514\n23 Novo Nordisk Canada Product Monograph Ozempic [Internet]. Mississauga, 2020. [cited 2020 December 21]. Available from: https://www.novonordisk.ca/content/dam/Canada/AFFILIATE/www-novonordisk-ca/OurProducts/PDF/ozempic-product-monograph.pdf\n24 Blanco JC Khatri A Kifayat A Cho R Aronow WS Starvation Ketoacidosis due to the Ketogenic Diet and Prolonged Fasting - A Possibly Dangerous Diet Trend Am J Case Rep 2019 20 1728 1731 31756175\n25 Li WX Gou JF Tian JH Yan X Yang L Glucagon-like peptide-1 receptor agonists versus insulin glargine for type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials Curr Ther Res Clin Exp 2010 71 211 238 24688145\n\n",
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"journal": "World journal of clinical cases",
"keywords": "Acute esophageal necrosis; Acute necrotizing esophagitis; Black Esophagus; Diabetic Ketoacidosis; Glucagon-like peptide-1 receptor agonists; Gurvits syndrome",
"medline_ta": "World J Clin Cases",
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"title": "Acute esophageal necrosis as a complication of diabetic ketoacidosis: A case report.",
"title_normalized": "acute esophageal necrosis as a complication of diabetic ketoacidosis a case report"
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"abstract": "Systemic lupus erythematosus (SLE), a disorder of the immune system, is potentially curable by allogeneic bone marrow transplantation (alloBMT). Until recently, alloBMT was limited by donor availability and toxicity. Reduced intensity conditioning (RIC) combined with post-transplantation cyclophosphamide (PTCy) has improved the availability and safety of alloBMT permitting its exploration in severe-refractory autoimmune illnesses. We report the six-year follow-up of a young female whose refractory SLE-associated nephrosis resolved after RIC alloBMT with PTCy.",
"affiliations": "Johns Hopkins Hospital and Health System, Baltimore, MD, USA.;Johns Hopkins Hospital and Health System, Baltimore, MD, USA.;Johns Hopkins Hospital and Health System, Baltimore, MD, USA.;Johns Hopkins Hospital and Health System, Baltimore, MD, USA.;Johns Hopkins Hospital and Health System, Baltimore, MD, USA.;Johns Hopkins Hospital and Health System, Baltimore, MD, USA.;Johns Hopkins Hospital and Health System, Baltimore, MD, USA.",
"authors": "Gladstone|D E|DE|;Petri|M|M|;Bolaños-Meade|J|J|;Dezern|A E|AE|;Jones|R J|RJ|;Fine|D|D|;Brodsky|R A|RA|",
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"mesh_terms": "D000328:Adult; D016026:Bone Marrow Transplantation; D003520:Cyclophosphamide; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D008180:Lupus Erythematosus, Systemic; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
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"title": "Long-term systemic lupus erythematosus disease control after allogeneic bone marrow transplantation.",
"title_normalized": "long term systemic lupus erythematosus disease control after allogeneic bone marrow transplantation"
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"abstract": "A 50-year-old male UK resident with a history of hypertension and hypercholesterolaemia presented to the emergency department with a 48-hour history of sudden onset bilateral thigh swelling and pain unrelieved by regular analgesia. 3 days prior to presentation, he performed a vigorous workout in the gym. His medications included ramipril 5 mg once daily and atorvastatin 20 mg at night time. He was a non-smoker and did not consume alcohol. He reported no known drug allergies. Physical examination confirmed bilateral swollen thighs, with no overlying skin changes, clinically suggestive of compartment syndrome. His creatine kinase was >50 000 IU with normal renal and liver function tests. Further investigation with MRI-identified prominent swelling of the vastus intermedius and medialis muscles, more marked on the left, with extensive diffuse short tau inversion recovery (STIR) signal hyperintensity and isointensity on T1 sequences, suggestive of rhabdomyolysis. He underwent bilateral fasciotomies of his thighs and aggressive intravenous fluid resuscitation with close monitoring of his electrolytes. Intraoperatively his muscle was healthy, with no evidence of haematoma or necrosis. His medication atorvastatin was stopped due to his rhabdomyolysis. 48 hours later, he returned to theatre and review of his fasciotomy wounds was unremarkable. 4 days later, he was discharged uneventfully. His postoperative recovery was complicated by a serous discharge from his left medial thigh wound. Further investigation with an ultrasound confirmed a 4×1×1cm multiloculated collection within the superficial tissue directly underlying the wound. An aspirate was performed and cultures revealed no growth. He remains under review in the department of plastic surgery. This case report discusses the aetiological spectrum, clinical presentation, pathophysiology, differential diagnosis, investigations, management and complications of rhabdomyolysis.",
"affiliations": "Department of Plastic Surgery, John Radcliffe Hospital, Oxford, UK.;Department of Plastic Surgery, John Radcliffe Hospital, Oxford, UK.;Department of Plastic Surgery, John Radcliffe Hospital, Oxford, UK.",
"authors": "Dunphy|Louise|L|;Morhij|Rossel|R|;Tucker|Sarah|S|",
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"mesh_terms": "D000924:Anticholesteremic Agents; D000959:Antihypertensive Agents; D000069059:Atorvastatin; D003161:Compartment Syndromes; D015444:Exercise; D000071938:Fasciotomy; D006801:Humans; D008297:Male; D008875:Middle Aged; D010146:Pain; D011183:Postoperative Complications; D017257:Ramipril; D012206:Rhabdomyolysis; D013848:Thigh",
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"title": "Rhabdomyolysis-induced compartment syndrome secondary to atorvastatin and strenuous exercise.",
"title_normalized": "rhabdomyolysis induced compartment syndrome secondary to atorvastatin and strenuous exercise"
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"abstract": "Haematological adverse reactions associated with fatal outcome are rare during treatment with ciprofloxacin. A 30-year old Caucasian man reported with abdominal pain and jaundice after 3-day administration of oral ciprofloxacin for a suspect of urinary tract infection. Clinical evaluations suggested an initial diagnosis of severe thrombocytopenia and haemolysis. The patient progressively developed petechiae and purpura on thorax and lower limbs. Despite pharmacological and supportive interventions, laboratory parameters worsened and the patient died 17 hours after admission. An accurate autopsy revealed most organs with diffuse petechial haemorrhages. No signs of bone marrow depression were found. No thrombi or signs of microangiopathies were observed in arterial vessels. Blood and urine cultures did not show any bacterial growth. This case report shows that ciprofloxacin may precipitate life-threatening thrombocytopenia and haemolytic anaemia, even in the early phases of treatment and without apparent previous exposures.",
"affiliations": "Tuscan Regional Centre for Pharmacovigilance, Florence, Italy.",
"authors": "Tuccori|Marco|M|;Guidi|Benedetta|B|;Carulli|Giovanni|G|;Blandizzi|Corrado|C|;Del Tacca|Mario|M|;Di Paolo|Marco|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D016756:Immunoglobulins, Intravenous; D002939:Ciprofloxacin; D014148:Tranexamic Acid",
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"title": "Severe thrombocytopenia and haemolytic anaemia associated with ciprofloxacin: a case report with fatal outcome.",
"title_normalized": "severe thrombocytopenia and haemolytic anaemia associated with ciprofloxacin a case report with fatal outcome"
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"drugadditi... |
{
"abstract": "Coronary vasospasm is an emerging potentially lethal complication of catheter ablation for atrial fibrillation (AF), however, its mechanism in this setting has not been well elucidated. A 55-year-old man with symptomatic paroxysmal AF underwent pulmonary vein isolation under sedation with propofol. The procedure was completed without any complications. Fifteen months later, a repeated session was performed because of AF recurrence. Initially, a high-dose infusion of dexmedetomidine instead of propofol was administered to introduce sedation. Then, an ST-segment elevation developed in the inferior leads and the diagnosis of coronary vasospasm was made by urgent coronary angiography. A comparison of the procedural details between the first and second sessions identified dexmedetomidine, an α-2 adrenergic agonist with a short distribution half-life, as a potential cause of coronary vasospasm seen only in the second session in the same individual. Since it has been shown that α-2 adrenoreceptor-mediated vasoconstriction can involve the coronary circulation, it is thus possible that a stimulation of α-2 adrenergic receptors induced by dexmedetomidine caused a coronary vasospasm. The present case provides new insights into dexmedetomidine-induced vasospasm. Physicians should be aware of this potentially lethal side effect of dexmedetomidine which is increasingly used in the current AF ablation practice. <Learning Objective: Dexmedetomidine has become widely used during catheter ablation for atrial fibrillation since it is generally regarded as a safe drug for sedation and analgesia with fewer respiratory depressant effects compared to other agents. However, it should be noted that dexmedetomidine may cause a coronary vasospasm, especially at the time of an initial high loading-dose infusion. Physicians should be aware of this potentially lethal side effect of dexmedetomidine.>.",
"affiliations": "Department of Cardiology, Ogaki Municipal Hospital, Ogaki, Japan.;Department of Cardiology, Ogaki Municipal Hospital, Ogaki, Japan.;Department of Cardiology, Ogaki Municipal Hospital, Ogaki, Japan.;Department of Cardiology, Ogaki Municipal Hospital, Ogaki, Japan.",
"authors": "Furui|Koichi|K|;Morishima|Itsuro|I|;Kanzaki|Yasunori|Y|;Tsuboi|Hideyuki|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2019.08.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-5409",
"issue": "20(6)",
"journal": "Journal of cardiology cases",
"keywords": "Atrial fibrillation; Catheter ablation; Coronary artery; Dexmedetomidine; Sedation; Vasospasm",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "221-224",
"pmc": null,
"pmid": "31762838",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports",
"references": "29387540;28491725;16191121;29021841;30479946;27412904;29021861;10673263;25516586;24508111",
"title": "Coronary vasospasm caused by intravenous infusion of dexmedetomidine: Unrecognized pitfall of catheter ablation procedures of atrial fibrillation.",
"title_normalized": "coronary vasospasm caused by intravenous infusion of dexmedetomidine unrecognized pitfall of catheter ablation procedures of atrial fibrillation"
} | [
{
"companynumb": "JP-PFIZER INC-2019391988",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
... |
{
"abstract": "Neuromyelitis optica (NMO), also known as Devic's disease, is a classical autoimmune disorder of the central nervous system (CNS). The relapsing-remitting disease course contributes to application of a variety of immunosuppressants to prevent further relapses after high-dose methylprednisolone pulse therapy for acute attacks. Azathioprine is one of the most widely used immunosuppressive drugs during the remission stage of NMO due to its good efficacy and favorable side-effect profile. Even if, enough attention should be paid to some rare but devastating adverse events, such as pellagra. Herein, we reported that a well-nourished patient experienced serious pellagra while receiving oral azathioprine for treating her NMO. Moreover, literature on azathioprine-induced pellagra was reviewed to raise concerns regarding patient safety.",
"affiliations": "Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.;Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.;Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.;Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.;Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.;Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China. Electronic address: guojun_81@163.com.",
"authors": "Zhao|Cong|C|;Liu|Tao|T|;Ma|Chao|C|;Li|Hongzeng|H|;Li|Zhuyi|Z|;Guo|Jun|J|",
"chemical_list": "D007166:Immunosuppressive Agents; D001379:Azathioprine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2018.07.038",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "25()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "Azathioprine; Neuromyelitis optica; Niacin; Pellagra",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D001379:Azathioprine; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D009471:Neuromyelitis Optica; D010383:Pellagra; D012867:Skin",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "104-107",
"pmc": null,
"pmid": "30059893",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Azathioprine-induced pellagra in neuromyelitis optica: A case report and review of literature.",
"title_normalized": "azathioprine induced pellagra in neuromyelitis optica a case report and review of literature"
} | [
{
"companynumb": "CN-SEBELA IRELAND LIMITED-2018SEB00211",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional... |
{
"abstract": "Techniques for haploidentical hematopoietic stem cell transplantation (haplo-HSCT) to treat severe aplastic anemia (SAA) have recently improved, but no protocol has been evaluated in a large number of pediatric patients. Fifty-two children with SAA received haplo-HSCT in our center. The treatment protocol used G-CSF-primed bone marrow with G-CSF-mobilized PBSCs without in vitro T-cell depletion. The conditioning regimen included busulfan/cyclophosphamide and antithymocyte globulin. Fifty-one patients achieved primary engraftment; one child died of regimen-related toxicity on the day +1. Secondary graft failure occurred in three patients. The cumulative incidences of aGVHD grade II-IV and grade III-IV were 39.2±0.5 and 13.7±0.2%, respectively. The cumulative incidence of cGVHD was 34.2±0.5%. The 3-year overall and failure-free survival rates were 84.5±5.0 and 82.7±5.2%, respectively, with a median follow-up time of 744.5 days (100-3294) for surviving patients. The Eastern Cooperative Oncology Group score was the only predictor of overall and failure-free survival rates. Clinical outcomes were similar between the upfront and salvage group. This result suggests that both newly diagnosed and refractory pediatric SAA patients benefit from haplo-HSCT, especially when patients are in good general condition. Therefore, haplo-HSCT might be an alternative therapy for pediatric SAA patients without HLA-matched sibling donors.",
"affiliations": "Hematology Department, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.;Hematology Department, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.;Hematology Department, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.;Hematology Department, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.;Hematology Department, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.;Hematology Department, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.;Hematology Department, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.;Hematology Department, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.;Hematology Department, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.;Hematology Department, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.;Hematology Department, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.;Hematology Department, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.;Hematology Department, Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.",
"authors": "Xu|L P|LP|;Zhang|X H|XH|;Wang|F R|FR|;Mo|X D|XD|;Han|T T|TT|;Han|W|W|;Chen|Y H|YH|;Zhang|Y Y|YY|;Wang|J Z|JZ|;Yan|C H|CH|;Sun|Y Q|YQ|;Zuo|S N|SN|;Huang|X J|XJ|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide; D002066:Busulfan",
"country": "England",
"delete": false,
"doi": "10.1038/bmt.2016.281",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "52(3)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D064591:Allografts; D000741:Anemia, Aplastic; D002066:Busulfan; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D007223:Infant; D008297:Male; D036102:Peripheral Blood Stem Cell Transplantation; D015996:Survival Rate; D014019:Tissue Donors; D019172:Transplantation Conditioning",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "381-387",
"pmc": null,
"pmid": "27941773",
"pubdate": "2017-03",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Haploidentical transplantation for pediatric patients with acquired severe aplastic anemia.",
"title_normalized": "haploidentical transplantation for pediatric patients with acquired severe aplastic anemia"
} | [
{
"companynumb": "CN-SA-2017SA049356",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nIn this case report, we describe a case of epidural hematoma following epidural analgesia in a patient with recent cessation of a direct oral anticoagulant (DOAC).\n\n\nMETHODS\nAn 89-year-old woman requiring upper abdominal surgery presented with multiple comorbidities, including a prior cerebrovascular accident resulting in a left-sided hemiparesis and atrial fibrillation requiring anticoagulation with rivaroxaban. In accordance with our departmental guidelines at the time of procedure, rivaroxaban was discontinued 4 days preoperatively. A thoracic epidural was placed at T8/9 immediately prior to induction. Venous thromboembolism prophylaxis was provided with compression devices, and every-12-hour unfractionated heparin initiated 5.5 hours after epidural placement. On postoperative day 2, the patient was noted to have a bilateral motor block, and imaging demonstrated a thoracic epidural hematoma extending from T6 to T11. Preexisting neurological deficits may have delayed detection. With patient agreement, neurosurgery recommended observation rather than surgical decompression because the patient was a poor surgical candidate and limited neurologic recovery was expected. The patient had modest motor recovery over the next few months.\n\n\nCONCLUSIONS\nGuidelines for cessation of DOACs prior to neuraxial techniques are based on pharmacologic half-lives rather than accumulated experience. This case adds to the experience of neuraxial analgesia complications while following these guidelines. Patient risk may be increased by the combination of recent cessation of a DOAC, as well as the cumulative effect of multiple small risk factors. Continued vigilance and reporting of cases of epidural hematomas will enhance our understanding and ultimately improve patient care. Elderly patients and/or patients with prior neurological deficits may present further challenges for early detection and require frequent assessments with comparison to baseline status.",
"affiliations": "From the Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston, Ontario, Canada.",
"authors": "Burjorjee|Jessica E|JE|;Rooney|Rachel|R|;Jaeger|Melanie|M|",
"chemical_list": "D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban",
"country": "England",
"delete": false,
"doi": "10.1097/AAP.0000000000000738",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1098-7339",
"issue": "43(3)",
"journal": "Regional anesthesia and pain medicine",
"keywords": null,
"medline_ta": "Reg Anesth Pain Med",
"mesh_terms": "D000369:Aged, 80 and over; D015360:Analgesia, Epidural; D004334:Drug Administration Schedule; D065427:Factor Xa Inhibitors; D005260:Female; D046748:Hematoma, Epidural, Spinal; D006801:Humans; D009043:Motor Activity; D000069552:Rivaroxaban",
"nlm_unique_id": "9804508",
"other_id": null,
"pages": "313-316",
"pmc": null,
"pmid": "29369958",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Epidural Hematoma Following Cessation of a Direct Oral Anticoagulant: A Case Report.",
"title_normalized": "epidural hematoma following cessation of a direct oral anticoagulant a case report"
} | [
{
"companynumb": "CA-ACCORD-067392",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "The objective of this study was to evaluate the outcome of the surgical treatment of osteonecrosis of the jaw (ONJ) with the additional use of autologous membranes of platelet-rich fibrin (PRF). The study population consisted of 15 patients with ONJ lesions in the maxilla (n=3), mandible (n=11), or both (n=1). Eight patients had malignant disease and were treated with high-dose anti-resorptive medication; seven were treated with low-dose anti-resorptive drugs for osteoporosis. Thirteen patients had grade 2 ONJ lesions and two had grade 3 lesions. The following standardized surgical technique was applied: resection of necrotic bone, mobilization of mucoperiosteal flaps, and multiple layer coverage of bone with PRF membranes. At follow-up 7-20 months after surgery, complete mucosal healing and an absence of symptoms were found in 14 of the 15 patients (93%). The patient with persistent bone exposure had a grade 3 ONJ lesion before surgery. This study suggests that the use of PRF membranes in the surgical treatment of grade 2 ONJ may be a contributing factor to a successful outcome.",
"affiliations": "Department of Oral and Maxillofacial Surgery, Aarhus University Hospital and Section of Maxillofacial Surgery and Oral Pathology, Aarhus University, Aarhus, Denmark. Electronic address: svenoe@rm.dk.;Department of Oral and Maxillofacial Surgery, Aarhus University Hospital and Section of Maxillofacial Surgery and Oral Pathology, Aarhus University, Aarhus, Denmark.",
"authors": "Nørholt|S E|SE|;Hartlev|J|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "Denmark",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0901-5027",
"issue": "45(10)",
"journal": "International journal of oral and maxillofacial surgery",
"keywords": "Denosumab; anti-resorptive drugs; bisphosphonate-related osteonecrosis of the jaw; membranes; platelet concentrates; platelet-rich fibrin",
"medline_ta": "Int J Oral Maxillofac Surg",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis; D000073183:Platelet-Rich Fibrin; D011446:Prospective Studies",
"nlm_unique_id": "8605826",
"other_id": null,
"pages": "1256-60",
"pmc": null,
"pmid": "27179556",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Surgical treatment of osteonecrosis of the jaw with the use of platelet-rich fibrin: a prospective study of 15 patients.",
"title_normalized": "surgical treatment of osteonecrosis of the jaw with the use of platelet rich fibrin a prospective study of 15 patients"
} | [
{
"companynumb": "PHHY2016DK066932",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "To report a case with myopic traction maculopathy (MTM) that underwent fovea-sparing internal limiting membrane (ILM) peeling and developed a central scotoma with a nasal visual field defect postoperatively.\nA 63-year-old man diagnosed with foveoschisis and a small outer lamellar macular hole underwent 25-gauge, 3-port pars plana vitrectomy and fovea-sparing ILM peeling using indocyanine green (ICG) staining. One year after the vitrectomy, optical coherence tomography (OCT) revealed a resolution of the macular retinoschisis and an intact ellipsoid zone at the fovea. However, macular edema was present over the area of the residual ILM, and the visual acuity had worsened to 20/200. Goldmann perimetry showed a central scotoma and a constriction of the nasal visual field. OCT angiography detected abnormal blood flow in the inner retina corresponding to the area of the residual foveal ILM. The multifocal electroretinograms were reduced in the central area.\nThe findings suggest that functional abnormalities of the fovea induced by ICG toxicity may have been manifested by a central scotoma. Therefore, surgeons need to consider the toxic effects of dyes such as ICG.",
"affiliations": "Department of Ophthalmology, University of Ehime Graduate School of Medicine, Japan.;Department of Ophthalmology, University of Ehime Graduate School of Medicine, Japan.;Department of Ophthalmology, University of Ehime Graduate School of Medicine, Japan.",
"authors": "Mito|Tsuyoshi|T|;Kobayashi|Takeshi|T|;Shiraishi|Atsushi|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2020.100942",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(20)30257-7\n10.1016/j.ajoc.2020.100942\n100942\nCase Report\nCentral scotoma after indocyanine green assisted fovea-sparing internal limiting membrane peeling\nMito Tsuyoshi mito@m.ehime-u.ac.jpab∗ Kobayashi Takeshi a Shiraishi Atsushi a a Department of Ophthalmology, University of Ehime Graduate School of Medicine, Japan\nb Department of Ophthalmology, Kanazawa Medical University, Japan\n∗ Corresponding author. Department of Ophthalmology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan. mito@m.ehime-u.ac.jp\n25 9 2020 \n12 2020 \n25 9 2020 \n20 10094222 1 2020 26 8 2020 20 9 2020 © 2020 Published by Elsevier Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report a case with myopic traction maculopathy (MTM) that underwent fovea-sparing internal limiting membrane (ILM) peeling and developed a central scotoma with a nasal visual field defect postoperatively.\n\nObservations\nA 63-year-old man diagnosed with foveoschisis and a small outer lamellar macular hole underwent 25-gauge, 3-port pars plana vitrectomy and fovea-sparing ILM peeling using indocyanine green (ICG) staining. One year after the vitrectomy, optical coherence tomography (OCT) revealed a resolution of the macular retinoschisis and an intact ellipsoid zone at the fovea. However, macular edema was present over the area of the residual ILM, and the visual acuity had worsened to 20/200. Goldmann perimetry showed a central scotoma and a constriction of the nasal visual field. OCT angiography detected abnormal blood flow in the inner retina corresponding to the area of the residual foveal ILM. The multifocal electroretinograms were reduced in the central area.\n\nConclusion\nThe findings suggest that functional abnormalities of the fovea induced by ICG toxicity may have been manifested by a central scotoma. Therefore, surgeons need to consider the toxic effects of dyes such as ICG.\n\nKeywords\nMyopic traction maculopathyPostoperative visual field defectCentral scotomaIndocyanine greenFovea-sparing internal limiting membrane peeling\n==== Body\n1 Introduction\nIn 2004, Panozzo et al. proposed the name myopic traction maculopathy (MTM) to unify the macular abnormalities, such as foveal retinoschisis, lamellar holes, and foveal detachment, that are caused by vitreous traction in highly myopic eyes.1 To prevent a progression of the lesions associated with MTM, vitrectomy is performed to remove the traction on the retina by an epiretinal membrane (ERM), posterior vitreous cortex, or internal limiting membrane (ILM).2,3 However, there is a risk of intraoperative and postoperative macular hole (MH) formation from the foveal detachments in these eyes with MTM.4,5\n\nRecently, Shimada et al. described a fovea-sparing ILM peeling technique to treat eyes with MTM, and they reported good visual and anatomic outcomes without MH formation.6 To accomplish a complete ILM peeling, a dyeing agent such as indocyanine green (ICG) or Brilliant Blue G (BBG) is used to make the ILM more visible. ICG has been reportedly to be superior to BBG in making the ILM visible,7,8 however there has been some concern that it may be toxic.9 Nevertheless, some surgeons are still using ICG staining in patients with high myopia in which the ILM is difficult to detect.\n\nWe present our findings in an eye with MTM that underwent fovea-sparing ILM peeling with ICG staining and developed a postoperative central scotoma and a constriction of the nasal visual field.\n\n1.1 Case report\nA 63-year-old man was being followed at a local ophthalmic clinic for bilateral MTM since 2011, and his best-corrected visual acuity (BCVA) was 20/20 in both eyes for several years. However, the BCVA of his right eye gradually worsened in the past few years, and it was 20/80 in 2018. He was then referred to the Ehime University Hospital.\n\nAt his initial examination, optical coherence tomography (OCT) revealed a foveal retinoschisis and a small outer lamellar macular hole beneath a focally-thickened area in the right eye (Fig. 1). He underwent 25-gauge 3-port pars plana vitrectomy and lensectomy for a nuclear cataract with an implantation of an intraocular lens. During the vitrectomy, the central vitreous core was removed, and the posterior vitreous cortex was made more visible by triamcinolone acetonide and dissected with an ILM forceps and a vitreous cutter. Then, 0.125% ICG was injected over the macular area to stain the ILM and immediately washed it out. However, we needed to repeat the ICG staining three times during the ILM removal to make ILM more visible. The ILM was peeled from the macular area except over the foveal area. The size of the residual ILM was about one-disc diameter (Fig. 2A–D).Fig. 1 Optical coherence tomographic (OCT) image of the right eye showing retinal schisis extending through the entire macula and a small outer lamellar macular hole which is present beneath the focally-thickened area (asterisk) before the vitrectomy. The OCT image is blurred because patient had moderate cataract.\n\nFig. 1Fig. 2 Intraoperative fundus photographs. A: C: Fundus photographs showing staining of the internal limiting membrane (ILM) by 0.125% indocyanine green. The ILM was peeled toward the fovea (black arrowhead). D: ILM was peeled and trimmed from macular area except over the foveal area. The size of the area of residual ILM was about one-disc diameter. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 2\n\nOne year later, OCT examinations revealed a resolution of the macular retinoschisis, and an intact ellipsoid zone at the fovea. However, the macular area was edematous especially the inner nuclear layer and outer plexiform layer (Fig. 3A), and the BCVA had worsened to 20/200. Goldmann perimetry showed a central scotoma and constriction of the nasal visual field of the right eye (Fig. 4). OCT angiography detected abnormal blood flow, and the en face images had a cystoid pattern in the deep retinal plexus corresponding to the area of the residual foveal ILM (Fig. 3B). The multifocal electroretinograms (mfERGs) were reduced in the central retina of the right eye, and they were smaller than that of the left eye (Fig. 5A and B).Fig. 3 Optical coherence tomographic (OCT) images of the retina one year after the vitrectomy. A: OCT image shows anatomical improvement of the macular schisis. The ellipsoid zone can be seen to be intact but macular edema is present especially in the inner nuclear layer and outer plexiform layer corresponding to the area of residual ILM (white arrow). B: OCT angiography (upper section) showing abnormal blood flow, and en-face image (lower section) shows cystoid pattern in the deep retinal plexus corresponding with the area of residual ILM (white arrowhead).\n\nFig. 3Fig. 4 Postoperative Goldmann visual fields showing central scotoma and nasal visual field defect in the right eye.\n\nFig. 4Fig. 5 Multifocal electroretinograms (mfERGs) and fundus photographs.A. mfERGs showing a reduction in the amplitudes in the central regions of the right eye. B: mfERGs of the left eye. C: Postoperative photograph of fundus of the right eye. D: Fundus photograph of the left eye.\n\nFig. 5\n\n2 Discussion\nFovea-sparing ILM peeling is an important procedure that can prevent MH formation in eyes with MTM. Our patient obtained good postoperative macular morphology without a MH, however his BCVA worsened and a constriction of the nasal visual field was present postoperatively.\n\nEarlier studies have reported that visual field defects can develop after vitrectomy, and it has been suggested that retinal contusion from the high airflow from the infusion port during fluid-air exchange was the cause of the temporal visual field defects.10,11 However, we did not perform fluid-air exchange, and did not observe a rise in the postoperative intraocular pressure that might have caused the visual field abnormalities. In addition, the morphology of the optic disc was not changed after the vitrectomy, and the results of tests for a relative afferent pupillary defect was negative. The reduction in the amplitudes of the mfERGs in the central regions suggests that the central scotoma was not associated with glaucoma which results of damage of only the retinal nerve fiber layer and ganglion cell layer.\n\nAlterations of the physiology of the retina by ILM peeling is another possible reason for the visual field defects, but it is unlikely in this case because the ILM over the foveal area was not peeled.\n\nThere have been two studies that reported that ICG toxicity may be the cause of the visual field defects after vitrectomy.12,13 Most of the cases reported had nasal visual field defects, but the authors did not definitively determine the cause of the visual field defects. There is a possibility that part of the ICG dye had remained on the temporal retina while the ICG on the nasal retina was washed out because of the location of the perfusion port.\n\nThe central scotoma in our cases was located where the ILM remained on the fovea. We suggest that the remaining ILM stained with ICG might be related to the central scotoma. Tognetto et al. reported a case of ICG-related central visual field disorder and observed an extensive, diffuse whitening and thickening of the macular region on the day after the vitrectomy for ERM removal using 0.05% ICG for ILM staining.14 They suggested that the ICG might have come into contact with the ILM-free retina and penetrated into the deeper retinal layers. However, the ILM was not peeied off the macular region in our case, and we did not observe a retinal whitening or intense macular edema in the early period after the vitrectomy.\n\nThere are at least two possible reasons why the central scotoma developed in our case. First, ICG staining was performed several times during surgery because it was difficult to see the ILM in the myopic eye. As a result, a relatively higher amount of ICG may have accumulated on the ILM which was not washed out at the completion of the fovea-sparing ILM peeling. Enaida et al. reported that severely deformed retinal structures and a partial disappearance of the retinal pigment epithelium in light photomicrographs of a rat eye after an intravitreal injection of a high-dose of ICG.9 They reported that the amplitudes of the ERGs were reduced after the intravitreal ICG injection. These morphological and functional alterations of the retina occurred in a dose dependent manner. Second, it is known that ICG is activated by high-power laser lights and by long duration continuous light exposure through optic fibers used for intraocular illumination.15 It is possible that an enhancement of the ICG toxicity may be another reason because it required more time to manipulate the ILM in the myopic fundus.\n\n3 Conclusions\nIn summary, we report a case that developed a central scotoma after fovea-sparing ILM peeling with ICG staining of the ILM. Therefore, surgeons need to consider the toxic effects of ICG even though the frequency of adverse complication is not high.\n\nPatient consent\nWritten informed consent was obtained from the patient to publish and report individual patient data.\n\nFunding\nNo funding was received by any of the authors for writing this manuscript.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for authorship.\n\nDeclaration of competing interest\nAll authors have no financial disclosures.\n\nAcknowledgements\nWe thank Professor Emeritus Duco Hamasaki of the Bascom Palmer Eye Institute for his critical discussion and final manuscript revision.\n==== Refs\nReferences\n1 Panozzo G. Mercanti A. Optical coherence tomography findings in myopic traction maculopathy Arch Ophthalmol 122 10 2004 1455 1460 15477456 \n2 Ikuno Y. Sayanagi K. Ohji M. Vitrectomy and internal limiting membrane peeling for myopic foveoschisis Am J Ophthalmol 137 4 2004 719 724 15059711 \n3 Panozzo G. Mercanti A. Vitrectomy for myopic traction maculopathy Arch Ophthalmol 125 6 2007 767 772 17562987 \n4 Kobayashi H. Kishi S. Vitreous surgery for highly myopic eyes with foveal detachment and retinoschisis Ophthalmology 110 9 2003 1702 1707 13129865 \n5 Gaucher D. Haouchine B. Tadayoni R. Long-term follow-up of high myopic foveoschisis: natural course and surgical outcome Am J Ophthalmol 143 3 2007 455 462 17222382 \n6 Shimada N. Sugamoto Y. Ogawa M. Takase H. Ohno-Matsui K. Fovea-sparing internal limiting membrane peeling for myopic traction maculopathy Am J Ophthalmol 154 4 2012 693 701 22835515 \n7 Henrich P.B. Priglinger S.G. Haritoglou C. Quantification of contrast recognizability during brilliant blue G- and indocyanine green-assisted chromovitrectomy Invest Ophthalmol Vis Sci 52 7 2011 4345 4349 21372008 \n8 Kadonosono K. Arakawa A. Inoue M. Internal limiting membrane contrast after staining with indocyanine green and brilliant blue G during macular surgery Retina 33 4 2013 812 817 23481454 \n9 Enaida H. Sakamoto T. Hisatomi T. Morphological and functional damage of the retina caused by intravitreous indocyanine green in rat eyes Graefes Arch Clin Exp Ophthalmol 240 3 2002 209 213 11935278 \n10 Melberg N.S. Thomas M.A. Visual field loss after pars plana vitrectomy with air/fluid exchange Am J Ophthalmol 120 3 1995 386 388 7661211 \n11 Ohji M. Nao I.N. Saito Y. Hayashi A. Tano Y. Prevention of visual field defect after macular hole surgery by passing air used for fluid-air exchange through water Am J Ophthalmol 127 1 1999 62 66 9933000 \n12 Haritoglou C. Gandorfer A. Gass C.A. Schaumberger M. Ulbig M.W. Kampik A. The effect of indocyanine-green on functional outcome of macular pucker surgery Am J Ophthalmol 135 3 2003 328 337 12614750 \n13 Kanda S. Uemura A. Yamashita T. Kita H. Yamakiri K. Sakamoto T. Visual field defects after intravitreous administration of indocyanine green in macular hole surgery Arch Ophthalmol 122 10 2004 1447 1451 15477455 \n14 Tognetto D. Haritoglou C. Kampik A. Ravalico G. Macular edema and visual loss after macular pucker surgery with ICG-assisted internal limiting membrane peeling Eur J Ophthalmol 15 2 2005 289 291 15812777 \n15 Sippy B.D. Engelbrecht N.E. Hubbard G.B. Indocyanine green effect on cultured human retinal pigment epithelial cells: implication for macular hole surgery Am J Ophthalmol 132 3 2001 433 435 11530072\n\n",
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"keywords": "Central scotoma; Fovea-sparing internal limiting membrane peeling; Indocyanine green; Myopic traction maculopathy; Postoperative visual field defect",
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"title": "Central scotoma after indocyanine green assisted fovea-sparing internal limiting membrane peeling.",
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"abstract": "The RARS2 gene encodes mitochondrial arginine-tRNA synthetase. Patients with variants of the RARS2 gene have pontocerebellar hypoplasia type 6 (PCH6), which is characterized by early onset seizures, progressive microcephaly, and developmental delay. PCH6 is a rare mitochondrial encephalopathy. To the best of our knowledge, the onset seizure type which the ictal video-electroencephalogram (VEEG) was compatible with early myoclonic encephalopathy (EME) has not been reported. Here we reported a term female neonate with EME caused by heterozygous variants of the RARS2 gene [NM_020320: exon10: c.773G>A (p. R258H) Maternal, NM_020320: exon4: c.282_285delAGAG Paternal]. Groan was the first symptom manifested, followed by metabolic disorders, and early marked cerebral atrophy. Metabolic disorders were corrected after feeding with extensively hydrolyzed protein formula. Seizures started at the 19th day of life. Interictal VEEG showed a suppression-burst (SB) pattern and ictal VEEG revealed myoclonic seizures that were compatible with early myoclonic encephalopathy (EME). She had frequent myoclonic seizures resistant to multi-antiepileptic drugs including phenobarbital, levetiracetam and oxcarbazepine, and soon developed into convulsive status epilepticus. At 7 months of age, she had severe developmental delay, and developed infantile spasms. Our case report expands the phenotypic spectrum of the PCH6, meanwhile, RARS2 should be considered be a causative gene in patients with EME.",
"affiliations": "Department of Neurology, Children's Hospital of Fudan University, Shanghai, China.;The Molecular Genetic Diagnosis Center, Shanghai Key Lab of Birth Defects, Pediatrics Research Institute, Children's Hospital of Fudan University, Shanghai, China.;The Molecular Genetic Diagnosis Center, Shanghai Key Lab of Birth Defects, Pediatrics Research Institute, Children's Hospital of Fudan University, Shanghai, China.;Department of Neurology, Children's Hospital of Fudan University, Shanghai, China.;Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.;Department of Neurology, Children's Hospital of Fudan University, Shanghai, China.",
"authors": "Xu|Yan|Y|;Wu|Bing-Bing|BB|;Wang|Hui-Jun|HJ|;Zhou|Shui-Zhen|SZ|;Cheng|Guo-Qiang|GQ|;Zhou|Yuan-Feng|YF|",
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"fulltext": "\n==== Front\nTransl Pediatr\nTransl Pediatr\nTP\nTranslational Pediatrics\n2224-4336\n2224-4344\nAME Publishing Company\n\n33209735\ntp-09-05-707\n10.21037/tp-20-110\nCase Report\nA term neonate with early myoclonic encephalopathy caused by RARS2 gene variants: a case report\nXu Yan 1 #\nWu Bing-Bing 2 #\nWang Hui-Jun 2\nZhou Shui-Zhen 1\nCheng Guo-Qiang 3\nZhou Yuan-Feng 1\n1 Department of Neurology, Children’s Hospital of Fudan University, Shanghai, China;\n2 The Molecular Genetic Diagnosis Center, Shanghai Key Lab of Birth Defects, Pediatrics Research Institute, Children’s Hospital of Fudan University, Shanghai, China;\n3 Department of Neonatology, Children’s Hospital of Fudan University, Shanghai, China\n# These authors contributed equally to this work.\n\nCorrespondence to: Yuan-Feng Zhou; Guo-Qiang Cheng. Department of Neurology, Children’s Hospital of Fudan University, No. 399 Wanyuan road, Minhang District, Shanghai 201102, China. Email: yuanfengzhou99@163.com; gqchengcm@163.com.\n10 2020\n10 2020\n9 5 707712\n25 3 2020\n31 7 2020\n2020 Translational Pediatrics. All rights reserved.\n2020\nTranslational Pediatrics.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.\nThe RARS2 gene encodes mitochondrial arginine-tRNA synthetase. Patients with variants of the RARS2 gene have pontocerebellar hypoplasia type 6 (PCH6), which is characterized by early onset seizures, progressive microcephaly, and developmental delay. PCH6 is a rare mitochondrial encephalopathy. To the best of our knowledge, the onset seizure type which the ictal video-electroencephalogram (VEEG) was compatible with early myoclonic encephalopathy (EME) has not been reported. Here we reported a term female neonate with EME caused by heterozygous variants of the RARS2 gene [NM_020320: exon10: c.773G>A (p. R258H) Maternal, NM_020320: exon4: c.282_285delAGAG Paternal]. Groan was the first symptom manifested, followed by metabolic disorders, and early marked cerebral atrophy. Metabolic disorders were corrected after feeding with extensively hydrolyzed protein formula. Seizures started at the 19th day of life. Interictal VEEG showed a suppression-burst (SB) pattern and ictal VEEG revealed myoclonic seizures that were compatible with early myoclonic encephalopathy (EME). She had frequent myoclonic seizures resistant to multi-antiepileptic drugs including phenobarbital, levetiracetam and oxcarbazepine, and soon developed into convulsive status epilepticus. At 7 months of age, she had severe developmental delay, and developed infantile spasms. Our case report expands the phenotypic spectrum of the PCH6, meanwhile, RARS2 should be considered be a causative gene in patients with EME.\n\nKeywords:\n\nMitochondrial arginyl-tRNA synthetase 2 (RARS2)\nearly myoclonic encephalopathy (EME)\ncase report\n==== Body\npmcIntroduction\n\nThe mitochondrial arginyl-tRNA synthetase 2 (RARS2) gene encodes mitochondrial arginine-tRNA synthetase. Patients with RARS2 gene variants have been classically described in pontocerebellar hypoplasia type 6 (PCH6) that is characterized by early onset seizures, progressive microcephaly, and developmental delay.\n\nEME is a rare early-onset epileptic syndrome, which characterized by frequent intractable seizures and severe developmental impairment. Thus far, EME caused by RARS2 variants has not yet been reported. Here we described a female term neonate with heterozygous variants of the RARS2 gene who was presented with EME. We present the following case in accordance with the CARE reporting checklist (available at http://dx.doi.org/10.21037/tp-20-110).\n\nCase presentation\n\nA female term neonate was the first pregnancy for a nonconsanguineous couple. She was delivered at 39 weeks of gestation via cesarean section for intrauterine fetal distress and premature rupture of fetal membranes with weight of 3,300 g (50%), length of 50 cm (50%) and head circumference of 34 cm (50%) at birth. Her Apgar scores were 8, 10, 10 respectively. Her parents were healthy and denied any family history of genetic disease. Her mother had regular prenatal examinations, and denied any abnormal results, and denied the history of exposure to any harmful substances.\n\nAt day of life 2 (DOL2), groan was manifested, which initially was attributed to respiratory infection. After breast and artificial feeding, hypoglycemia, metabolic acidosis and hyperammonemia were noted repetitively at DOL7 and improved considerably after fasting and parenteral nutrition. Concentrations of plasma ammonia and blood lactic acid remained normal value when she was given extensively hydrolyzed protein formula.\n\nAt DOL19, she manifested partial or fragmentary erratic myoclonus, sometimes massive myoclonus, and muscular hypertonia. Blood tandem mass spectrometry and urine gas chromatography-mass spectrometry were normal. Cerebrospinal fluid (CSF) analyses were unremarkable.\n\nInterictal video-electroencephalogram (VEEG) at DOL24 showed a symmetric and synchronous suppression-burst (SB) pattern during all wakefulness and sleep, which consisted of bursts lasting 2 to 6 seconds followed by almost isoelectric periods lasting 3 to 96 seconds. Ictal VEEG revealed frequent myoclonic seizures often coincided the burst phases (Figure 1).\n\nFigure 1 VEEG at DOL24. International 10–20 system modified for neonates, HHF: 70 Hz, Sensitivity 10 µV/mm. Interictal EEG showed a symmetric and synchronous SB pattern. Ictal EEG revealed frequent myoclonic seizures often coincided the burst phases. Arrow: myoclonic seizures. Electromyogram 1 (EMG1)/EMG2: distal left/right upper extremity muscles. EMG3/EMG4: distal left /right lower extremity muscles.\n\nBrain magnetic resonance imaging (MRI) at DOL27 demonstrated enlarged ventricular system, widened extracerebral space at the frontal, temporal and sylvian fissure but more obviously at left side, significantly small vessels in bilateral temporal region and bilateral symmetric hypomyelination in the posterior limb of internal capsule (Figure 2).\n\nFigure 2 Brain MRI at DOL27 (axial T1-weighted imaging). (A,B) Marked supratentorial atrophy, obviously at the left side; significant small vessels in bilateral temporal region and hypomyelination in the posterior limb of internal capsule.\n\nMulti-antiepileptic drugs therapy including phenobarbital (5 mg/kg/d, used at DOL21, stopped at 5 months of age), levetiracetam (30 mg/kg/d, added at DOL 29, stopped at 5 months of age) and oxcarbazepine (20 mg/kg/d, added at DOL 38, stopped at 5 months of age) were not effective. She soon developed into convulsive status epilepticus. Trio-whole-exome sequencing revealed compound heterozygous variants in RARS2, she carried a pathogenic missense mutation [NM_020320: exon10: c.773G>A (p. R258H) Maternal] (1) in combination with a novel frameshift mutation (NM_020320:exon4:c.282_285delAGAG Paternal), which was confirmed by Sanger sequencing (Figure 3).\n\nFigure 3 Image obtained on Sanger sequencing. A depicts a (G>A) variant in the RARS2 gene from the mother; B depicts a (c.282_285delAGAG) variant in the RARS2 gene from the father.\n\nHer parents discharged automatically with antiepileptic drugs including phenobarbital, levetiracetam and oxcarbazepine when she was 2 months of age. Follow-up revealed that any antiepileptic drugs was withdrawn at 5 months of age because ineffective. She developed infantile spasm at 7 months of age, and had a severe developmental delay (at 7 months of age, she had poor visual fixation without following, had poor head control, was not sitting, grasping and turning over) (Figure 4).\n\nFigure 4 Timeline of this case. AEDs, antiepileptic drugs; MRI, magnetic resonance imaging; VEEG, video-electroencephalogram.\n\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient.\n\nDiscussion\n\nThe RARS2 gene encodes mitochondrial arginine-tRNA synthetase, which was identified by Edvardson et al. in 2007 (2). Variants in RARS2 gene are associated with pontocerebellar hypoplasia type 6 (PCH6; MIM 611523), a rare mitochondrial encephalopathy with phenotype characterized by early onset seizures, profound developmental delay, and progressive pontocerebellar atrophy.\n\nOur patient manifests a series of clinical features common to previously reported (1-6), including early onset of disease, neonatal hypoglycemia, early raised serum and/or CSF lactate and pharmaco-resistant epileptic encephalopathy.\n\nGroan after birth was the first symptom manifested in our patient, while respiratory symptom was seldom described previously. Edvardson et al. (2) have reported one patient had a progression from a single apneic episode at DOL2 to respiratory failure at the age of 3 weeks. The probable causes were supposed to be metabolic acidosis, insufficient mitochondrial energy production or central nervous dysfunction.\n\nFrom the characteristic features of RARS2-PCH6 on neuroimaging perspective, MR imaging of most patients within the first months of life revealed cerebral and/or pontocerebellar atrophy that may be progressive over time (2-6). Other imaging features described in reported patients include subdural effusions and abnormal myelination (1,6). To the best of our knowledge, significant small vessels revealed in bilateral temporal region by MRI have not been reported so far. This phenomenon is unclear and we speculate that the blood vessels may have not decreased accordingly with cerebral atrophy.\n\nThe electroclinical spectrum of Patients with RARS2-PCH manifest multiple different seizure types including generalized tonic-clonic, focal, and myoclonic seizures. Our patient presented with EME, which has not been reported in RARS2-PCH6 previously. EME is a rare early-onset epileptic syndrome that usually begins in neonatal period. It is characterized by frequent myoclonus and partial seizures and by an SB pattern in the EEG (7).\n\nAlthough underlying pathologies of EME are not demonstrated in the majority of cases, the most striking feature of the high incidence of EME in familial cases with metabolic disorders suggests that inborn errors of metabolism and/or genetic factors play a prominent role (7). Metabolic abnormalities such as nonketotic hyperglycinemia and disorders of amino acid metabolism were frequently described in the cases with EME (8-10). Other related genes, including CDKL5 (11), KCNQ2 (12), ErbB4 (13), SCN1A (14), GABRB2 (15), SIK1 (16), AMT (17) and SLC25A22 (18), as well as a 9q33‐q34 deletion including STXBP1 and SPTAN1 (19), have been reported to be associated with EME.\n\nMathew et al. (20) has reported that two siblings with RARS2 variants started myoclonic jerks after birth, however, related MRI and EEG features during the period of neonate were not provided in their report. Nuclear mitochondrial genes, such as AMT encodes an enzyme system for cleavage of glycine which is confined to the mitochondria and SLC25A22 encodes mitochondrial carriers that transport a variety of metabolites across the inner mitochondrial membrane. RARS2 encodes the mitochondrial aminoacyl‐tRNA synthetase enzyme and play an important role in mRNA translation, a key process in maintaining cell integrity, so there may be some correlation in the pathogenesis of EME caused by nuclear mitochondrial gene variants.\n\nIn our case, we diagnosed EME by VEEG and known she had a poor outcome with refractory epilepsy and severe developmental impairment. The main causes of EME were metabolic factors and genetic factors (7). She had no obvious abnormal metabolism. Genetic testing helped us to find the cause in such a complex congenital disease. However, there are no effective treatments at present. The parents also refused to accept any other treatments, such as adrenocorticotropic hormone, ketogenic diet, and vagus nerve stimulation. So we couldn’t obtain the data of following VEEG, MRI and general clinical characteristics.\n\nConclusions\n\nThis case report expands the phenotypic spectrum of the RARS2 variants. Meanwhile, RARS2 should be considered be a causative gene in patients with EME.\n\nSupplementary\n\nThe article’s supplementary files as\n\n10.21037/tp-20-110 10.21037/tp-20-110\n\nAcknowledgments\n\nThe authors are thankful for the doctors and nurses of the Department of Neonatology, Children’s Hospital of Fudan University, Shanghai, China.\n\nFunding: None.\n\nEthical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient. A copy of the written consent is available for review by the Editors-in-Chief of this journal.\n\nReporting Checklist: The authors have completed the CARE reporting checklist. Available at http://dx.doi.org/10.21037/tp-20-110\n\nConflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tp-20-110). The authors have no conflicts of interest to declare.\n==== Refs\nReferences\n\n1 Kastrissianakis K Anand G Quaghebeur G Subdural effusions and lack of early pontocerebellar hypoplasia in siblings with RARS mutations. Arch Dis Child 2013;98 :1004-7. 10.1136/archdischild-2013-304308 24047924\n2 Edvardson S Shaag A Kolesnikova O Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet 2007;81 :857-62. 10.1086/521227 17847012\n3 Cassandrini D Cilio MR Bianchi M Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: Definition of the clinical spectrum and molecular findings in five patients. J Inherit Metab Dis 2013;36 :43-53. 10.1007/s10545-012-9487-9 22569581\n4 Li Z Schonberg R Guidugli L A novel mutation in the promoter of RARS2 causes pontocerebellar hypoplasia in two siblings. J Hum Genet 2015;60 :363-9. 10.1038/jhg.2015.31 25809939\n5 Ngoh A Bras J Guerreiro R RARS2 mutations in a sibship with infantile spasms. Epilepsia 2016;57 :e97-102. 10.1111/epi.13358 27061686\n6 Zhang J Zhang Z Zhang Y Distinct magnetic resonance imaging features in a patient with novel RARS2 mutations: A case report and review of the literature. Exp Ther Med 2018;15 :1099-104.29434700\n7 Ohtahara S Yamatogi Y . Epileptic encephalopathies in early infancy with suppression-burst. J Clin Neurophysiol 2003;20 :398-407. 10.1097/00004691-200311000-00003 14734930\n8 Lombroso CT . Early myoclonic encephalopathy, early infantile epileptic encephalopathy, and benign and severe infantile myoclonic epilepsies: a critical review and personal contributions. J Clin Neurophysiol 1990;7 :380-408. 10.1097/00004691-199007000-00005 2120281\n9 Lee WT . Disorders of amino acid metabolism associated with epilepsy. Brain Dev 2011;33 :745-52. 10.1016/j.braindev.2011.06.014 21803516\n10 Aukett A Bennett MJ Hosking GP . Molybdenum co-factor deficiency: an easily missed inborn error of metabolism. Dev Med Child Neurol 1988;30 :531-5. 10.1111/j.1469-8749.1988.tb04781.x 3169394\n11 Takeda K Miyamoto Y Yamamoto H Clinical features of early myoclonic encephalopathy caused by a CDKL5 mutation. Brain Dev 2020;42 :73-6. 10.1016/j.braindev.2019.08.003 31492455\n12 Kojima K Shirai K Kobayashi M A patient with early myoclonic encephalopathy (EME) with a de novo KCNQ2 mutation. Brain Dev 2018;40 :69-73. 10.1016/j.braindev.2017.06.004 28687180\n13 Backx L Ceulemans B Vermeesch JR Early myoclonic encephalopathy caused by a disruption of the neuregulin-1 receptor ErbB4. Eur J Hum Genet 2009;17 :378-82. 10.1038/ejhg.2008.180 18854870\n14 Ishikawa N Tateishi Y Tani H Successful treatment of intractable life-threatening seizures with perampanel in the first case of early myoclonic encephalopathy with a novel de novo SCN1A mutation. Seizure 2019;71 :20-3. 10.1016/j.seizure.2019.05.024 31176277\n15 Ishii A Kang JQ Schornak CC A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy. J Med Genet 2017;54 :202-11. 10.1136/jmedgenet-2016-104083 27789573\n16 Hansen J Snow C Tuttle E De novo mutations in SIK1 cause a spectrum of developmental epilepsies. Am J Hum Genet 2015;96 :682-90. 10.1016/j.ajhg.2015.02.013 25839329\n17 Belcastro V Barbarini M Barca S A novel AMT gene mutation in a newborn with nonketotic hyperglycinemia and early myoclonic encephalopathy. Eur J Paediatr Neurol 2016;20 :192-5. 10.1016/j.ejpn.2015.08.008 26371980\n18 Cohen R Basel-Vanagaite L Goldberg-Stern H Two siblings with early infantile myoclonic encephalopathy due to mutation in the gene encoding mitochondrial glutamate/H+ symporter SLC25A22. Eur J Paediatr Neurol 2014;18 :801-5. 10.1016/j.ejpn.2014.06.007 25033742\n19 Aravindhan A Shah K Pak J Early-onset epileptic encephalopathy with myoclonic seizures related to 9q33.3-q34.11 deletion involving STXBP1 and SPTAN1 genes. Epileptic Disord 2018;20 :214-8. 10.1684/epd.2018.0969 29897043\n20 Mathew T Avati A D'Souza D Expanding spectrum of RARS2 gene disorders: Myoclonic epilepsy, mental retardation, spasticity, and extrapyramidal features. Epilepsia Open 2018;3 :270-5. 10.1002/epi4.12108 29881806\n\n",
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"abstract": "In a context of asthma, lactic acidosis may occur during beta2-agonist therapy. Several cases have been reported during its administration by intravenous and/or inhaled route. This side-effect seems rather unknown and the mechanism for compensation of metabolic acidosis by hyperventilation may worsen dyspnoea and mislead clinicians. Other causes of lactic acidosis such as a major hypoxemia, a cardiovascular collapse or sepsis may also be experienced in this context and must be ruled out before attributing the lactic acidosis to beta2-agonist treatment. We report the case of a 50-year-old man hospitalized for an acute major asthma, who received a salbutamol continuous infusion associated with inhaled terbutaline. A serum lactate level of 13 mmol/l was noted eight hours after the introduction of the bronchodilator treatment. After reducing doses of beta2-agonists, the evolution was favourable, regarding both respiratory and metabolic aspects, with a rapid decrease of the serum lactate level, which finally returned to normal level after 32 hours of hospitalization.",
"affiliations": "Département d'anesthésie-réanimation, pavillon P réanimation, hôpital Edouard-Herriot, 5, place d'Arsonval, 69003 Lyon, France. kevinchaulier@yahoo.fr",
"authors": "Chaulier|K|K|;Chalumeau|S|S|;Ber|C-E|CE|;Bret|M|M|;Rimmelé|T|T|",
"chemical_list": "D001993:Bronchodilator Agents; D013726:Terbutaline; D000420:Albuterol",
"country": "France",
"delete": false,
"doi": "10.1016/j.annfar.2007.01.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0750-7658",
"issue": "26(4)",
"journal": "Annales francaises d'anesthesie et de reanimation",
"keywords": null,
"medline_ta": "Ann Fr Anesth Reanim",
"mesh_terms": "D000140:Acidosis, Lactic; D000208:Acute Disease; D000420:Albuterol; D001249:Asthma; D001993:Bronchodilator Agents; D005260:Female; D006801:Humans; D008875:Middle Aged; D013726:Terbutaline",
"nlm_unique_id": "8213275",
"other_id": null,
"pages": "352-5",
"pmc": null,
"pmid": "17349773",
"pubdate": "2007-04",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Metabolic acidosis in a context of acute severe asthma.",
"title_normalized": "metabolic acidosis in a context of acute severe asthma"
} | [
{
"companynumb": "FR-BAUSCH-BL-2016-018594",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TERBUTALINE"
},
"drugadditional": "1",
... |
{
"abstract": "Methotrexate (MTX) is the key drug for the treatment of rheumatoid arthritis (RA). MTX-treated RA has been associated with the development of lymphoproliferative disorders (LPDs). Notably, the hyperimmune state of RA itself or the immunosuppressive state induced by MTX administration may contribute to development of LPD. Furthermore, Epstein-Barr virus (EBV) has been indicated to contribute to the development of MTX-LPD. MTX-associated LPD (MTX-LPD) may affect nodal or extranodal sites, including the gastrointestinal tract, skin, lungs, kidneys, and soft tissues, at an almost equal frequency. However, it is rare for MTX-LPD to manifest as multiple bone tumors with a pathological fracture. The present study reported the case of a 46-year-old Japanese woman with RA who had complications of EBV-positive MTX-LPD during an approximate 5-year course of MTX therapy. The present study indicated a rare case in which the LPD had spread to multiple bones in a patient with a pathologic fracture. Notably, the LPD was subclassified as diffuse large B-cell lymphoma (DLBCL).",
"affiliations": "Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Osaka 545-8585, Japan.;Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Osaka 545-8585, Japan.;Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Osaka 545-8585, Japan.;Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Osaka 545-8585, Japan.;Department of Diagnostic Pathology, Osaka City University Graduate School of Medicine, Osaka, Osaka 545-8585, Japan.;Department of Diagnostic Pathology, Osaka City University Graduate School of Medicine, Osaka, Osaka 545-8585, Japan.;Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Osaka 545-8585, Japan.",
"authors": "Oebisu|Naoto|N|;Hoshi|Manabu|M|;Ieguchi|Makoto|M|;Iwai|Tadashi|T|;Tanaka|Sayaka|S|;Osawa|Masahiko|M|;Nakamura|Hiroaki|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2018.1654",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "9(2)",
"journal": "Molecular and clinical oncology",
"keywords": "diffuse large B-cell lymphoma; methotrexate-associated lymphoproliferative disorder; multiple bone tumors; pathological fracture; rheumatoid arthritis",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "187-191",
"pmc": null,
"pmid": "30101019",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": "14504078;18052014;15547182;17117491;2845789;8385742;24515570;11043092;21044442;12010788;15363032;12687538;17654684",
"title": "Lymphoproliferative disorder with pathological fracture of the femur in a patient with rheumatoid arthritis treated with methotrexate: A case report.",
"title_normalized": "lymphoproliferative disorder with pathological fracture of the femur in a patient with rheumatoid arthritis treated with methotrexate a case report"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1051661",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": null,
... |
{
"abstract": "Monoclonal gammopathy of undetermined significance (MGUS) is considered an asymptomatic precursor of malignant lymphoid disorders. This case series and literature review shows that these monoclonal gammopathies can cause significant morbidity. We describe a patient with angioedema due to acquired C1-esterase inhibitor deficiency, a patient with cryoglobulinemia type II causing skin vasculitis and glomerulonephritis, and a patient with glomerulonephritis and nephrotic syndrome - all caused by a monoclonal gammopathy that can be classified as MGUS. Clinicians should be familiar with these consequences of monoclonal gammopathies. The term MGUS should only be used in patients without organ damage caused by monoclonal gammopathies.",
"affiliations": "Department of Nephrology, Jeroen Bosch Hospital, 's-Hertogenbosch, the Netherlands.",
"authors": "Schoot|T S|TS|;van Apeldoorn|M|M|;Sinnige|H A M|HAM|;Beutler|J J|JJ|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "78(4)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D054179:Angioedemas, Hereditary; D003449:Cryoglobulinemia; D005260:Female; D006801:Humans; D007674:Kidney Diseases; D008297:Male; D010265:Paraproteinemias",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "191-195",
"pmc": null,
"pmid": "32641558",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Monoclonal gammopathy with significance: case series and literature review.",
"title_normalized": "monoclonal gammopathy with significance case series and literature review"
} | [
{
"companynumb": "NL-BAUSCH-BL-2020-026328",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "The effect of sex hormones on pyoderma gangrenosum (PG) has not been reported. We report the case of a 34-year-old woman with chronic PG leg ulcers who was found to have recurring, premenstrual flares of PG. Her PG flares were controlled with the use of ethinyl estradiol/drospirenone.",
"affiliations": "Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, U.S.A.;Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, U.S.A.;Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21231, U.S.A.",
"authors": "Jourabchi|N|N|;Rhee|S M|SM|;Lazarus|G S|GS|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bjd.14332",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0963",
"issue": "174(5)",
"journal": "The British journal of dermatology",
"keywords": null,
"medline_ta": "Br J Dermatol",
"mesh_terms": null,
"nlm_unique_id": "0004041",
"other_id": null,
"pages": "1096-1097",
"pmc": null,
"pmid": "26616160",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Premenstrual flares of pyoderma gangrenosum controlled with use of a combined oral contraceptive and antiandrogen (ethinyl estradiol/drospirenone).",
"title_normalized": "premenstrual flares of pyoderma gangrenosum controlled with use of a combined oral contraceptive and antiandrogen ethinyl estradiol drospirenone"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS INC, USA.-2016GMK023417",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DROSPIRENONE\\ETHINYL ESTRADIOL"
... |
{
"abstract": "Hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-negative, antibody to hepatitis B core antigen (anti-HBc)-positive patients after allogeneic hematopoietic stem cell transplantation (HSCT) has not been prospectively studied. HBsAg-negative, anti-HBc-positive patients with undetectable HBV DNA undergoing allogeneic HSCT were prospectively monitored every 4 weeks. The primary endpoint was HBV reactivation, defined as detectable HBV DNA (≥10 IU/mL). Secondary endpoints included overall survival, HBsAg positivity, and changes in liver biochemistry and antibody to HBsAg levels. Among 297 allogeneic HSCT recipients, 85 (28.7%) were HBsAg-negative, anti-HBc-positive, of whom 62 were recruited and monitored for a median of 48 (4-104) weeks. The 2-year cumulative HBV DNA detectability rate was 40.8%, occurring at a median of 44 (8-100) weeks. Multivariate analysis showed that age ≥50 years (P = 0.004, hazard ratio = 8.2) and chronic graft-versus-host disease (P = 0.010, hazard ratio = 5.3) were significantly associated with HBV reactivation. Other clinical parameters, including baseline antibody to HBsAg status, serial changes in antibody to HBsAg levels, and donor serology, were not associated with HBV reactivation. Patients <50 years old and without chronic graft-versus-host disease, compared with the remaining patient cohort, had a significantly lower 2-year cumulative HBV reactivation rate (5.6% versus 65.0%, P = 0.004). Entecavir successfully suppressed HBV DNA to undetectable levels, with no cases developing biochemical hepatitis.\n\n\nCONCLUSIONS\nHBsAg-negative, anti-HBc-positive patients had a high rate of HBV reactivation after allogeneic HSCT, with determinants of HBV reactivation including age ≥50 years and chronic graft-versus-host disease; treatment strategies based on these parameters may prevent HBV reactivation and subsequent complications. (ClinicalTrials.gov identifier NCT01481649.) (Hepatology 2017;65:1451-1461).",
"affiliations": "Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.;School of Public Health, The University of Hong Kong, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.;Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.",
"authors": "Seto|Wai-Kay|WK|http://orcid.org/0000-0002-9012-313X;Chan|Thomas Sau-Yan|TS|;Hwang|Yu-Yan|YY|;Wong|Danny Ka-Ho|DK|;Fung|James|J|;Liu|Kevin Sze-Hang|KS|;Gill|Harinder|H|;Lam|Yuk-Fai|YF|;Lau|Eric H Y|EHY|;Cheung|Ka-Shing|KS|;Lie|Albert K W|AKW|;Lai|Ching-Lung|CL|;Kwong|Yok-Lam|YL|;Yuen|Man-Fung|MF|",
"chemical_list": "D000998:Antiviral Agents; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; C413685:entecavir; D006147:Guanine",
"country": "United States",
"delete": false,
"doi": "10.1002/hep.29022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0270-9139",
"issue": "65(5)",
"journal": "Hepatology (Baltimore, Md.)",
"keywords": null,
"medline_ta": "Hepatology",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000998:Antiviral Agents; D005260:Female; D006086:Graft vs Host Disease; D006147:Guanine; D018380:Hematopoietic Stem Cell Transplantation; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011446:Prospective Studies; D012008:Recurrence; D014775:Virus Activation; D055815:Young Adult",
"nlm_unique_id": "8302946",
"other_id": null,
"pages": "1451-1461",
"pmc": null,
"pmid": "28027590",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Hepatitis B reactivation in occult viral carriers undergoing hematopoietic stem cell transplantation: A prospective study.",
"title_normalized": "hepatitis b reactivation in occult viral carriers undergoing hematopoietic stem cell transplantation a prospective study"
} | [
{
"companynumb": "PHHY2017HK044994",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Lymphocyte-predominant Hodgkin's lymphoma (LPHL) is known to be radiosensitive, and radiotherapy often forms part of the treatment of patients with stage III or IV LPHL. In addition, as LPHL is thought to arise from a germinal centre B-cell, and LPHL cells express the B-cell marker CD20 there is a rationale for using anti-CD20 therapies for the treatment of LPHL. We report a 42-yr-old man with stage III B LPLH who underwent successful treatment of LPHL with (90)Y-ibritumomab tiuxetan. To our knowledge, this is the first report on the use of an anti-CD20 radiolabeled antibody for the treatment of LPHL.",
"affiliations": "First Department of Medicine, Center for Oncology and Hematology, Wilhelminenspital, Vienna, Austria. niklas.zojer@wienkav.at",
"authors": "Zojer|Niklas|N|;Mirzaei|Siroos|S|;Ludwig|Heinz|H|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; C422802:ibritumomab tiuxetan",
"country": "England",
"delete": false,
"doi": "10.1111/j.1600-0609.2008.01107.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "81(4)",
"journal": "European journal of haematology",
"keywords": null,
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D001402:B-Lymphocytes; D018858:Germinal Center; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011859:Radiography; D012074:Remission Induction",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "322-4",
"pmc": null,
"pmid": "18616515",
"pubdate": "2008-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Successful treatment of a patient with lymphocyte-predominant Hodgkin's lymphoma with yttrium-90-ibritumomab tiuxetan.",
"title_normalized": "successful treatment of a patient with lymphocyte predominant hodgkin s lymphoma with yttrium 90 ibritumomab tiuxetan"
} | [
{
"companynumb": "AT-BAXTER-2018BAX004117",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAs reported previously, 140 methamphetamine-dependent participants at eight medical centers in the U.S. were assigned randomly to receive topiramate (N=69) or placebo (N=71) in a 13-week clinical trial. The study found that topiramate did not appear to reduce methamphetamine use significantly for the primary outcome (i.e., weekly abstinence from methamphetamine in weeks 6-12). Given that the treatment responses varied considerably among subjects, the objective of this study was to identify the heterogeneous treatment effect of topiramate and determine whether topiramate could reduce methamphetamine use effectively in a subgroup of subjects.\n\n\nMETHODS\nLatent variable analysis was used for the primary and secondary outcomes during weeks 6-12 and 1-12, adjusting for age, sex, and ethnicity.\n\n\nRESULTS\nOur analysis of the primary outcome identified 30 subjects as responders, who either reduced methamphetamine use consistently over time or achieved abstinence. Moreover, topiramate recipients had a significantly steeper slope in methamphetamine reduction and accelerated to abstinence faster than placebo recipients. For the secondary outcomes in weeks 6-12, we identified 40 subjects as responders (who had significant reductions in methamphetamine use) and 65 as non-responders; topiramate recipients were more than twice as likely as placebo recipients to be responders (odds ratio=2.67; p=0.019). Separate analyses of the outcomes during weeks 1-12 yielded similar results.\n\n\nCONCLUSIONS\nMethamphetamine users appear to respond to topiramate treatment differentially. Our findings show an effect of topiramate on the increasing trend of abstinence from methamphetamine, suggesting that a tailored intervention strategy is needed for treating methamphetamine addiction.",
"affiliations": "Department of Public Health Sciences, University of Virginia, PO Box 800717, Charlottesville, VA 22908, USA. jzm4h@virginia.edu",
"authors": "Ma|Jennie Z|JZ|;Johnson|Bankole A|BA|;Yu|Elmer|E|;Weiss|David|D|;McSherry|Frances|F|;Saadvandi|Jim|J|;Iturriaga|Erin|E|;Ait-Daoud|Nassima|N|;Rawson|Richard A|RA|;Hrymoc|Mark|M|;Campbell|Jan|J|;Gorodetzky|Charles|C|;Haning|William|W|;Carlton|Barry|B|;Mawhinney|Joseph|J|;Weis|Dennis|D|;McCann|Michael|M|;Pham|Tony|T|;Stock|Christopher|C|;Dickinson|Ruth|R|;Elkashef|Ahmed|A|;Li|Ming D|MD|",
"chemical_list": "D000077236:Topiramate; D005632:Fructose; D008694:Methamphetamine",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0376-8716",
"issue": "130(1-3)",
"journal": "Drug and alcohol dependence",
"keywords": null,
"medline_ta": "Drug Alcohol Depend",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D019969:Amphetamine-Related Disorders; D016739:Behavior, Addictive; D005260:Female; D005632:Fructose; D006801:Humans; D008297:Male; D008694:Methamphetamine; D008875:Middle Aged; D013997:Time Factors; D000077236:Topiramate; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7513587",
"other_id": null,
"pages": "45-51",
"pmc": null,
"pmid": "23142494",
"pubdate": "2013-06-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Fine-grain analysis of the treatment effect of topiramate on methamphetamine addiction with latent variable analysis.",
"title_normalized": "fine grain analysis of the treatment effect of topiramate on methamphetamine addiction with latent variable analysis"
} | [
{
"companynumb": "US-JNJFOC-20130808021",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "While chemotherapeutic agents result in an improvement in both disease-free and overall survival in cancer patients, treatment can result in short and long-term complications. One well-known complication is neuropathy which can result from a number of chemotherapeutic agents. However, chemotherapy-induced phrenic neuropathy is an exceedingly rare phenomenon with few cases reported in the literature.\nA 34-year-old male with metastatic testicular cancer presented with progressive dyspnea on exertion after initiation of chemotherapy with bleomycin, cisplatin, and etoposide. Multiple diagnostic studies were performed including pulmonary function testing, chest computed tomography, fluoroscopic sniff evaluation, in addition to phrenic nerve electromyography. Based on results of these tests, the diagnosis of chemotherapy-induced phrenic neuropathy was made.\nChemotherapy-induced phrenic neuropathy, although rare, should be considered as a cause of dyspnea in cancer patients following initiation of chemotherapy.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.;Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.",
"authors": "Norton|Mark|M|;Alkurashi|Adham K|AK|;Hasan Albitar|Hasan Ahmad|HA|;Almodallal|Yahya|Y|;Iyer|Vivek N|VN|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2020.101117",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30271-9\n10.1016/j.rmcr.2020.101117\n101117\nCase Report\nA rare case of chemotherapy induced phrenic neuropathy\nNorton Mark a Alkurashi Adham K. b Hasan Albitar Hasan Ahmad c Almodallal Yahya d Iyer Vivek N. iyer.vivek@mayo.edua∗ a Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA\nb Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA\nc Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA\nd Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA\n∗ Corresponding author. 200 First Street SW, Rochester, MN, 55905, USA. iyer.vivek@mayo.edu\n05 6 2020 \n2020 \n05 6 2020 \n30 10111727 5 2020 4 6 2020 © 2020 Published by Elsevier Ltd.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nWhile chemotherapeutic agents result in an improvement in both disease-free and overall survival in cancer patients, treatment can result in short and long-term complications. One well-known complication is neuropathy which can result from a number of chemotherapeutic agents. However, chemotherapy-induced phrenic neuropathy is an exceedingly rare phenomenon with few cases reported in the literature.\n\nCase\nA 34-year-old male with metastatic testicular cancer presented with progressive dyspnea on exertion after initiation of chemotherapy with bleomycin, cisplatin, and etoposide. Multiple diagnostic studies were performed including pulmonary function testing, chest computed tomography, fluoroscopic sniff evaluation, in addition to phrenic nerve electromyography. Based on results of these tests, the diagnosis of chemotherapy-induced phrenic neuropathy was made.\n\nConclusion\nChemotherapy-induced phrenic neuropathy, although rare, should be considered as a cause of dyspnea in cancer patients following initiation of chemotherapy.\n==== Body\n1 Introduction\nChemotherapy-induced peripheral neuropathy is a well described sequela of several chemotherapeutic agents that can significantly impact the quality of life in affected patients. It can lead to permanent symptoms and disability in up to 40% of cancer survivors [1]. It is a known complication in many chemotherapeutic agents particularly with platinum based agents, taxanes, vinca alkaloids, thalidomide, and bortezomib [1]. Chemotherapeutic agents typically result in sensory neuropathy while motor neuropathy is less common. Moreover, chemotherapy-induced phrenic nerve neuropathy is very rare. We hereby report a case of chemotherapy-induced phrenic nerve neuropathy in a male patient who presented with dyspnea after being treated with bleomycin, cisplatin, and etoposide for metastatic testicular cancer.\n\n2 Case\nA 34-year-old male with a metastatic right testicular cancer presented with a three-month history of progressive dyspnea on exertion. He had undergone right orchiectomy and had received four cycles of chemotherapy with bleomycin, cisplatin, and etoposide. Symptoms were first noted during the final cycle of chemotherapy, and continued to progress over two months. Physical examination was notable for clear lungs on auscultation with no evidence of diaphragmatic paradox.\n\nPulmonary function testing showed a restrictive pattern, with low maximal inspiratory and expiratory pressures (Fig. 1). Chest computed tomography (CT) scan showed bibasilar atelectasis with low lung volumes on scout film when compared to a prior chest x-ray (Fig. 2a, Fig. 2b). Fluoroscopic sniff evaluation demonstrated evidence of right greater than left diaphragmatic weakness. Phrenic nerve electromyography (EMG), while within normal limits, was notable for asymmetric right side predominant nerve conduction discrepancies consistent with possible fascicular phrenic neuropathy. The constellation of temporal onset of clinical symptoms after chemotherapy along with the fluoroscopy and EMG findings were consistent with diaphragmatic weakness secondary to drug-induced phrenic neuropathy.Fig. 1 Pulmonary function test showing a restrictive pattern, with low maximal inspiratory and expiratory pressures.\n\nFig. 1Fig. 2a Scout film of chest CT after chemotherapy demonstrating low lung volumes compared to prior chest x-ray.\n\nFig. 2aFig. 2b Chest CT showing bibasilar atelectasis.\n\nFig. 2b\n\n3 Discussion\nPhrenic nerve neuropathy and diaphragmatic dysfunction can occur from a variety of causes. It most commonly occurs due to direct neoplastic invasion of the phrenic nerve or due to iatrogenic injury during surgery [2]. It can also occur due to infectious neuritis (such as in herpes zoster infections), trauma, in addition to neurologic disorders (such as Guillain-Barré Syndrome), amongst others [2]. Patients with unilateral phrenic nerve paralysis are typically asymptomatic but may present with dyspnea which can worsen in the supine position [2,3]. Those with bilateral phrenic nerve paralysis are typically much more symptomatic and are at risk for developing sleep-disordered breathing [4]. On examination, decreased diaphragmatic excursion may be seen and the presence of abdominal paradox is considered a classic sign of diaphragmatic dysfunction [2].\n\nWhen suspected, a number of tests can help establish the diagnosis. Plain chest radiography can show elevation of the diaphragm, fluoroscopy can be used to demonstrate paradoxical diaphragmatic motion using the sniff test, and pulmonary function testing typically shows a restrictive pattern with further reduction in the vital capacity in the supine position [2,5]. Ultrasonography of the diaphragm can be used to measure the diaphragmatic thickness during breathing with lack of diaphragmatic thickening being an indication of diaphragmatic paralysis [6]. Phrenic nerve EMG is an invasive method to establish the diagnosis, however; this can be technically challenging and is not readily available at all institutions [2]. Finally, measurement of the trans-diaphragmatic pressure is another invasive test that is considered the gold standard for diagnosis but it is not widely used as it can be challenging to perform and interpret [2,7].\n\nWhile sensory neurotoxicity is a common occurrence following exposure to platinum-based agents, motor neuropathy is uncommon. Furthermore, chemotherapy-induced phrenic nerve motor neuropathy is an exceedingly rare phenomenon, with very few cases reported in the literature [[8], [9], [10], [11]]. Of those cases only one case described phrenic neuropathy associated with a regimen that included a platinum-based agent [12]. The exact mechanism of neuropathy induced by platinum-based chemotherapeutics is not yet fully understood. Chemotherapy-induced alternations of mitochondria, membrane ion channels, intracellular signaling, and neurotransmission can ultimately lead to axonal degeneration, DNA damage, and neuroinflammation with resultant neuropathy [13].\n\n4 Conclusion\nIn summary, we present a case of chemotherapy induced phrenic neuropathy leading to diaphragmatic dysfunction and new onset exertional dyspnea. Phrenic nerve neuropathy should be considered as a rare cause of dyspnea in cancer patients following initiation of chemotherapy.\n\nFunding information\nNo funding was received for this study.\n\nSubmission declaration and verification\nThis work has not been published and is not being considered for publication elsewhere.\n\nAuthor contribution\nAll authors have contributed equally to this work.\n\nCRediT authorship contribution statement\nMark Norton: Data curation, Writing - original draft. Adham K. Alkurashi: Data curation, Writing - original draft. Hasan Ahmad Hasan Albitar: Data curation, Writing - original draft. Yahya Almodallal: Data curation, Writing - original draft. Vivek N. Iyer: Data curation, Writing - original draft.\n\nDeclaration of competing interest\nThe authors have no conflicts of interest to report.\n==== Refs\nReferences\n1 Park S.B. Chemotherapy-induced peripheral neurotoxicity: a critical analysis CA Cancer J Clin 63 6 2013 419 437 24590861 \n2 McCool F.D. Tzelepis G.E. Dysfunction of the diaphragm N. Engl. J. Med. 366 10 2012 932 942 22397655 \n3 Kumar N. Folger W.N. Bolton C.F. Dyspnea as the predominant manifestation of bilateral phrenic neuropathy Mayo Clin. Proc. 79 12 2004 1563 1565 15595343 \n4 Qureshi A. Diaphragm paralysis Semin. Respir. Crit. Care Med. 30 3 2009 315 320 19452391 \n5 Mier-Jedrzejowicz A. Assessment of diaphragm weakness Am. Rev. Respir. Dis. 137 4 1988 877 883 3354995 \n6 Cohn D. Diaphragm thickening during inspiration J. Appl. Physiol. 83 1 1997 291 296 9216975 \n7 Steier J. The value of multiple tests of respiratory muscle strength Thorax 62 11 2007 975 980 17557772 \n8 Stevens W.W. Sporn P.H.S. Bilateral diaphragm weakness after chemotherapy for lymphoma Am. J. Respir. Crit. Care Med. 189 7 2014 e12-e12 \n9 Gilliland P. Holguin M. Phrenic nerve paralysis due to vincristine Leuk. Lymphoma 48 12 2007 2452 2453 18067023 \n10 Elghouche A. Unilateral cervical polyneuropathies following concurrent bortezomib, cetuximab, and radiotherapy for head and neck cancer Case Rep Otolaryngol 2016 2016 2313714 \n11 Jinnur P. Lim K.G. Severe acute orthopnea: ipilimumab-induced bilateral phrenic nerve neuropathy Lung 193 4 2015 611 613 25956728 \n12 Yabe N. [A case of phrenic nerve paralysis during adjuvant chemotherapy for rectal cancer] Gan To Kagaku Ryoho 44 12 2017 1916 1918 29394819 \n13 Zajączkowska R. Mechanisms of chemotherapy-induced peripheral neuropathy Int. J. Mol. Sci. 20 6 2019 1451\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "30()",
"journal": "Respiratory medicine case reports",
"keywords": null,
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101117",
"pmc": null,
"pmid": "32547916",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "22397655;19452391;24590861;18067023;27088023;25956728;17557772;3354995;24684366;9216975;15595343;30909387;29394819",
"title": "A rare case of chemotherapy induced phrenic neuropathy.",
"title_normalized": "a rare case of chemotherapy induced phrenic neuropathy"
} | [
{
"companynumb": "US-ACCORD-157979",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "A 49-year-old man had idiopathic epilepsy with recurrent convulsions and history of cleft palate, mental retardation, schizophrenia, and cataract. He had convulsions the day before and on the day of admission. Fosphenytoin was given i.v.; his convulsion stopped, but he lost consciousness 2 h later and was admitted. Glasgow Coma Scale score on arrival was 3. Cerebral computed tomography showed bilateral calcification in the basal ganglia. Laboratory tests showed decreased serum calcium and albumin and increased creatine kinase. He regained consciousness after i.v. calcium gluconate administration. Additionally, he showed decreased parathyroid hormone and 1,25(OH)2 vitamin D. Suspecting hypoparathyroidism, i.v. calcium gluconate was changed to oral vitamin D. His medical history and physical appearance suggested 22q11.2 deletion syndrome, confirmed by chromosomal analysis.\n\n\n\nThe patient was discharged after 29 days and remains convulsion-free.\n\n\n\nHypocalcemia due to hypoparathyroidism should be considered in the differential diagnosis of adult recurrent convulsions.",
"affiliations": "Emergency Medical Center Kagawa University Hospital Miki Kita Kagawa Japan.;Emergency Medical Center Kagawa University Hospital Miki Kita Kagawa Japan.;Department of Endocrinology Kagawa University Hospital Miki Kita Kagawa Japan.;Emergency Medical Center Kagawa University Hospital Miki Kita Kagawa Japan.;Emergency Medical Center Kagawa University Hospital Miki Kita Kagawa Japan.;Department of Endocrinology Kagawa University Hospital Miki Kita Kagawa Japan.;Department of Endocrinology Kagawa University Hospital Miki Kita Kagawa Japan.;Department of Endocrinology Kagawa University Hospital Miki Kita Kagawa Japan.;Emergency Medical Center Kagawa University Hospital Miki Kita Kagawa Japan.;Emergency Medical Center Kagawa University Hospital Miki Kita Kagawa Japan.",
"authors": "Okazaki|Tomoya|T|;Hifumi|Toru|T|;Ibata|Tomohiro|T|;Manabe|Arisa|A|;Hamaya|Hideyuki|H|;Yoshimoto|Takuo|T|;Imachi|Hitomi|H|;Murao|Koji|K|;Kawakita|Kenya|K|;Kuroda|Yasuhiro|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ams2.216",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2052-8817",
"issue": "3(4)",
"journal": "Acute medicine & surgery",
"keywords": "22q11.2 deletion syndrome; Convulsion; hypocalcemia; hypoparathyroidism",
"medline_ta": "Acute Med Surg",
"mesh_terms": null,
"nlm_unique_id": "101635464",
"other_id": null,
"pages": "397-399",
"pmc": null,
"pmid": "29123821",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports",
"references": "25374867;21628941;19829950;21621427;25835143;21293174;25567344;21265963;24648439;2924743",
"title": "Recurrent convulsions, hypocalcemia, and hypoparathyroidism related to delayed diagnosis of 22q11.2 deletion syndrome in a middle-aged man.",
"title_normalized": "recurrent convulsions hypocalcemia and hypoparathyroidism related to delayed diagnosis of 22q11 2 deletion syndrome in a middle aged man"
} | [
{
"companynumb": "JP-ABBVIE-16P-087-1629024-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Wide complex tachycardias are rare in the pediatric population and may be due to ventricular tachycardia, aberrant conduction or antidromic tachycardia each with multiple underlying etiologies. We present a 14 yo female in extremis with syncope at rest witnessed by her mother, found in ventricular tachycardia by EMS who challenged with IVF hydration and amiodarone. Consecutive adequate fluid challenges and antiarrhythmics in the emergency department failed requiring synchronized cardioversion for stabilization. Subsequent viral panels, imaging, genetic testing and cardiac biopsy confirmed a diagnosis of arrhythmogenic right (and left) ventricular dysplasia.",
"affiliations": "Dept of Emergency Medicine, Sarasota Memorial Hospital, 1540 S. Tamiami Trl. Suite 101, Sarasota, FL 34239, United States of America.;Dept of Emergency Medicine, Sarasota Memorial Hospital, 1540 S. Tamiami Trl. Suite 101, Sarasota, FL 34239, United States of America. Electronic address: brett.t.williams@gmail.com.",
"authors": "Lehman|J W|JW|;Williams|B T|BT|",
"chemical_list": "C495337:PKP2 protein, human; D051191:Plakophilins",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2020.11.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "45()",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000293:Adolescent; D004554:Electric Countershock; D004562:Electrocardiography; D005260:Female; D006352:Heart Ventricles; D006801:Humans; D051191:Plakophilins; D013575:Syncope; D017180:Tachycardia, Ventricular",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "677.e5-677.e7",
"pmc": null,
"pmid": "33214017",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Syncope in a 14yo female with ventricular tachycardia; an atypical etiology.",
"title_normalized": "syncope in a 14yo female with ventricular tachycardia an atypical etiology"
} | [
{
"companynumb": "US-AUROBINDO-AUR-APL-2022-006479",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMIODARONE HYDROCHLORIDE"
},
"drugaddi... |
{
"abstract": "A patient with Sjögren's syndrome and seronegative polyarthritis is reported. After piroxicam intake and sun exposure she developed subacute cutaneous lupus erythematosus lesions with Ro antibodies. Despite drug withdrawal, typical cutaneous lesions and serological markers of systemic lupus erythematosus (SLE) progressively appeared. The use of piroxicam and other nonsteroidal anti-inflammatory drugs with photosensitizing potential in patients with Sjögren's syndrome, sicca syndrome or a high suspicion of a collagen disorder should be avoided because these drugs may trigger a latent SLE.",
"affiliations": "Servicio de Dermatologia, Unidad Docente de la UB, Hospital Sagrado Corazón-QSA, Barcelona, España.",
"authors": "Roura|M|M|;Lopez-Gil|F|F|;Umbert|P|P|",
"chemical_list": "D000974:Antibodies, Antinuclear; C035356:SS-A antibodies; D010894:Piroxicam",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000247739",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-9075",
"issue": "182(1)",
"journal": "Dermatologica",
"keywords": null,
"medline_ta": "Dermatologica",
"mesh_terms": "D000328:Adult; D000974:Antibodies, Antinuclear; D001168:Arthritis; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D010787:Photosensitivity Disorders; D010894:Piroxicam; D012859:Sjogren's Syndrome",
"nlm_unique_id": "0211607",
"other_id": null,
"pages": "56-8",
"pmc": null,
"pmid": "2013357",
"pubdate": "1991",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Systemic lupus erythematosus exacerbated by piroxicam.",
"title_normalized": "systemic lupus erythematosus exacerbated by piroxicam"
} | [
{
"companynumb": "ES-PFIZER INC-L-1R391",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PIROXICAM"
},
"drugadditional": null,
"... |
{
"abstract": "OBJECTIVE\nTo determine risk factors for active tuberculosis in patients with inflammatory bowel diseases.\n\n\nMETHODS\nRetrospective, case-control study at 4 referral hospitals in Spain. Cases developed tuberculosis after a diagnosis of inflammatory bowel disease. Controls were inflammatory bowel disease patients who did not develop tuberculosis. For each case, we randomly selected 3 controls matched for sex, age (within 5 years) and time of inflammatory bowel disease diagnosis (within 3 years). Inflammatory bowel disease characteristics, candidate risk factors for tuberculosis and information about the tuberculosis episode were recorded. Multivariate analysis and a Chi-squared automatic interaction detector were used.\n\n\nRESULTS\nThirty-four cases and 102 controls were included. Nine of the 34 cases developed active tuberculosis between 1989 and 1999, and 25 became ill between 2000 and 2012. Multivariate regression showed an association between active tuberculosis and anti-TNF (tumor necrosis factor) therapy in the previous 12 months (OR 7.45; 95% CI, 2.39-23.12; p = .001); hospitalization in the previous 6 months (OR 4.38; 95% CI, 1.18-16.20; p = .027); and albumin levels (OR 0.88; 95% CI, 0.81-0.95; p = .001). The median time between the start of biologic therapy and the onset of active tuberculosis was 13 (interquartile range, 1-58) months. Tuberculosis developed after a year of anti-TNF therapy in 53%, and late reactivation occurred in at least 3 of 8 patients.\n\n\nCONCLUSIONS\nThe main risks factors for developing tuberculosis were anti-TNF therapy and hospitalization. Over half the cases related to anti-TNF treatment occurred after a year.",
"affiliations": "Digestivo, Hospital Universitario Central de Asturias, España.;Hospital Universitario Central de Asturias.;Hospital Universitario Central de Asturias.;Hospital de Cabueñes.;Complejo Asistencial Universitario de León.;Hospital San Agustín.;Hospital Universitario Central de Asturias.;Aparato digestivo, Complejo Asistencial Universitario de León., España.;Hospital Universitario Central de Asturias.;Hospital Universitario Central de Asturias.;Hospital Universitario Central de Asturias.;Hospital Universitario Central de Asturias.;Servicio de Vigilancia Epidemiológica, Consejería de Sanidad del Principado de Asturias,.;Hospital Universitario Central de Asturias.",
"authors": "Riestra|Sabino|S|;de Francisco|Ruth|R|;Arias-Guillén|Miguel|M|;Saro|Cristina|C|;García-Alvarado|María|M|;Duque|José María|JM|;Palacios|Juan José|JJ|;Muñoz|Fernando|F|;Blanco|Lorena|L|;Castaño|Olegario|O|;Pérez-Martínez|Isabel|I|;Martínez-Camblor|Pablo|P|;Pérez Hernández|Dolores|D|;Suárez|Adolfo|A|",
"chemical_list": "D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab",
"country": "Spain",
"delete": false,
"doi": "10.17235/reed.2016.4440/2016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1130-0108",
"issue": "108(9)",
"journal": "Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva",
"keywords": null,
"medline_ta": "Rev Esp Enferm Dig",
"mesh_terms": "D000068879:Adalimumab; D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal; D016022:Case-Control Studies; D005260:Female; D006760:Hospitalization; D006801:Humans; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D013030:Spain; D014376:Tuberculosis; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "9007566",
"other_id": null,
"pages": "541-9",
"pmc": null,
"pmid": "27604582",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk factors for tuberculosis in inflammatory bowel disease: anti-tumor necrosis factor and hospitalization.",
"title_normalized": "risk factors for tuberculosis in inflammatory bowel disease anti tumor necrosis factor and hospitalization"
} | [
{
"companynumb": "ES-JNJFOC-20171109423",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "Lung cancer associated with pregnancy is rare but on the increase. The use of tyrosine kinase inhibitor (TKI) therapy for advanced oncogenic-driven non-small cell lung carcinoma (NSCLC) has improved overall survival. Oncological and obstetric outcomes of patients diagnosed with NSCLC and treated by TKIs during pregnancy have been poorly evaluated.\n\n\n\nThree cases of NSCLC treated by TKIs during pregnancy were collected from the prospective database of the Cancer Associé à La Grossesse (CALG) network (France) in addition to eight cases identified by a systematic review performed between 2000 and 2021.\n\n\n\nAmong the eleven reported patients, six received an EGFR- and five an ALK-TKI. All patients were young nonsmokers and four had brain metastases at diagnosis. TKI treatment was initiated during the first trimester for three patients. Premature delivery was induced in 10/11 patients. Anamnios occurred in one patient treated by osimertinib and trastuzumab. Five newborns were hypotrophic. No newborn malformations were observed. Diffusion of the TKIs, confirmed by blood cord sampling, represented about 1/3 (EGFR-TKI) and 1/8 (ALK-TKI) of the maternal concentration. No developmental abnormalities were observed in the children (follow-up 30 months). The anti-tumor efficacy and tolerance of TKIs, when reported, appears similar to that described in the general population.\n\n\n\nOur results support the rationale for using TKIs during pregnancy, both in terms of maternal NSCLC disease control and the relatively mild effects on the fetus. Our data will serve to better inform patients about the risks associated with TKIs used during pregnancy, contributing to shared decision making.",
"affiliations": "Department of Gynaecology and Obstetrics, Tenon Hospital, Sorbonne University, Assistance Publique des Hôpitaux de Paris (AP-HP), France; Cancer Associé à La Grossesse (CALG), French National CALG Network, Sorbonne University, France. Electronic address: annesophie.boudy@aphp.fr.;Department of Gynaecology and Obstetrics, Tenon Hospital, Sorbonne University, Assistance Publique des Hôpitaux de Paris (AP-HP), France.;Department of Gynaecology and Obstetrics, Tenon Hospital, Sorbonne University, Assistance Publique des Hôpitaux de Paris (AP-HP), France; Cancer Associé à La Grossesse (CALG), French National CALG Network, Sorbonne University, France.;Cancer Associé à La Grossesse (CALG), French National CALG Network, Sorbonne University, France; APHP Tenon, INSERM U938, IUC-UPMC, Sorbonne University, Paris, France.;Cancer Associé à La Grossesse (CALG), French National CALG Network, Sorbonne University, France; APHP Tenon, INSERM U938, IUC-UPMC, Sorbonne University, Paris, France; Department of Radiology, Tenon Hospital, Sorbonne University, Assistance Publique des Hôpitaux de Paris (AP-HP), France.;Department of Gynaecology and Obstetrics, Tenon Hospital, Sorbonne University, Assistance Publique des Hôpitaux de Paris (AP-HP), France; Cancer Associé à La Grossesse (CALG), French National CALG Network, Sorbonne University, France; APHP Tenon, INSERM U938, IUC-UPMC, Sorbonne University, Paris, France.;Department of Gynaecology and Obstetrics, Tenon Hospital, Sorbonne University, Assistance Publique des Hôpitaux de Paris (AP-HP), France; Cancer Associé à La Grossesse (CALG), French National CALG Network, Sorbonne University, France; APHP Tenon, INSERM U938, IUC-UPMC, Sorbonne University, Paris, France.;Department of Pulmonology and Thoracic Oncology, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Tenon and GRC 04 Theranoscan, Sorbonne Université, Paris 75970, France. Electronic address: jacques.cadranel@aphp.fr.",
"authors": "Boudy|Anne-Sophie|AS|;Grausz|Noémie|N|;Selleret|Lise|L|;Gligorov|Joseph|J|;Thomassin-Naggara|Isabelle|I|;Touboul|Cyril|C|;Daraï|Emile|E|;Cadranel|Jacques|J|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2021.09.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "161()",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "ALK and EGFR Tyrosine kinase inhibitors; Cancer associated with pregnancy; Lung cancer; Targeted therapy; Teratogenicity",
"medline_ta": "Lung Cancer",
"mesh_terms": "D002289:Carcinoma, Non-Small-Cell Lung; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008175:Lung Neoplasms; D058990:Molecular Targeted Therapy; D009154:Mutation; D011247:Pregnancy; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "68-75",
"pmc": null,
"pmid": "34543940",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Use of tyrosine kinase inhibitors during pregnancy for oncogenic-driven advanced non-small cell lung carcinoma.",
"title_normalized": "use of tyrosine kinase inhibitors during pregnancy for oncogenic driven advanced non small cell lung carcinoma"
} | [
{
"companynumb": "FR-CELLTRION INC.-2021FR014968",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nWe report our findings in a patient who developed central retinal vein occlusion (CRVO) and was a chronic user of olanzapine, an antipsychotic medication.\n\n\nMETHODS\nA 50-year-old Caucasian man, non-smoker, was referred to our clinic with the chief complaint of floater appearance in his left eye for the past 3 days. His past medical history indicated that he had been taking antipsychotic drugs (olanzapine) for about 3 years, with no other systemic disease or risk factors for CRVO. In the examination, his best-corrected visual acuity (BCVA) was 0.7 in the left eye. The fundus showed signs of nonischemic CRVO with subhyaloid hemorrhage and intraretinal hemorrhage in the posterior pole and superior and inferior retina, without macular edema, confirmed by optical coherence tomography (OCT). We ruled out other probable differential diagnoses and risk factors which lead to CRVO through a complete physical exam and blood analysis (complete blood count, glucose, urea, creatinine, lipid profile, erythrocyte sedimentation rate, C-reactive protein, prothrombin time, partial thromboplastin time, Bleeding time (BT), fibrinogen level, proteins, antiphospholipid antibodies, homocysteine blood level, antithrombin III, protein C and S, factor V Leiden, prothrombin mutation, angiotensin-converting enzyme level, other autoantibodies, and human leukocyte antigen [HLA]-B51). Finally, we confirmed the probable side effect of olanzapine in CRVO, which has not been previously reported. A possible pro-thrombogenic mechanism of olanzapine at the molecular level is an affinity for 5-HT2Aserotonin receptors. Blocking these receptors results in increased platelet aggregation and increased blood coagulability.\n\n\nCONCLUSIONS\nThese results indicate that CRVO can be a complication of chronic use of antipsychotic medications such as olanzapine, as shown for the first time in our case report. Clinicians should question patients who develop a sudden CRVO whether they are using antipsychotic medications such as olanzapine.",
"affiliations": "Ophthalmology Department of Hospital universitario SAS Jerez de la Frontera, Jerez de la Frontera, Spain. alinoroozi_co@yahoo.com.;Western University Collage of Dental Medicine, Pamona, California, USA.;Ophthalmology Department of Hospital universitario SAS Jerez de la Frontera, Jerez de la Frontera, Spain.;Ophthalmology Department of Hospital universitario SAS Jerez de la Frontera, Jerez de la Frontera, Spain.;Ophthalmology Department of Hospital universitario SAS Jerez de la Frontera, Jerez de la Frontera, Spain.;Ophthalmology Department of Hospital universitario SAS Jerez de la Frontera, Jerez de la Frontera, Spain.;Ophthalmology Department of Hospital general Universitario de Alicante, Alicante, Spain.",
"authors": "Nowrouzi|Ali|A|http://orcid.org/0000-0001-7326-091X;Kafiabasabadi|Sepideh|S|;Rodriguez-Calzadilla|Mario|M|;Benitez-Del-Castillo|Javier|J|;Soto-Guerrero|Alejandro|A|;Diaz-Ramos|Antonio|A|;Marques-Cavalcante|Kyara Vaneska|KV|",
"chemical_list": "D014150:Antipsychotic Agents; D000077152:Olanzapine",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-02865-8",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2865\n10.1186/s13256-021-02865-8\nCase Report\nCentral retinal vein occlusion in a patient using the antipsychotic drug olanzapine: a case report\nhttp://orcid.org/0000-0001-7326-091X\nNowrouzi Ali alinoroozi_co@yahoo.com\n\n1\nKafiabasabadi Sepideh 2\nRodriguez-Calzadilla Mario 1\nBenitez-del-Castillo Javier 1\nSoto-Guerrero Alejandro 1\nDiaz-Ramos Antonio 1\nMarques-Cavalcante Kyara Vaneska 3\n1 Ophthalmology Department of Hospital universitario SAS Jerez de la Frontera, Jerez de la Frontera, Spain\n2 Western University Collage of Dental Medicine, Pamona, California USA\n3 grid.411086.a 0000 0000 8875 8879 Ophthalmology Department of Hospital general Universitario de Alicante, Alicante, Spain\n29 5 2021\n29 5 2021\n2021\n15 3079 4 2020\n15 4 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nWe report our findings in a patient who developed central retinal vein occlusion (CRVO) and was a chronic user of olanzapine, an antipsychotic medication.\n\nCase presentation\n\nA 50-year-old Caucasian man, non-smoker, was referred to our clinic with the chief complaint of floater appearance in his left eye for the past 3 days. His past medical history indicated that he had been taking antipsychotic drugs (olanzapine) for about 3 years, with no other systemic disease or risk factors for CRVO.\n\nIn the examination, his best-corrected visual acuity (BCVA) was 0.7 in the left eye. The fundus showed signs of nonischemic CRVO with subhyaloid hemorrhage and intraretinal hemorrhage in the posterior pole and superior and inferior retina, without macular edema, confirmed by optical coherence tomography (OCT).\n\nWe ruled out other probable differential diagnoses and risk factors which lead to CRVO through a complete physical exam and blood analysis (complete blood count, glucose, urea, creatinine, lipid profile, erythrocyte sedimentation rate, C-reactive protein, prothrombin time, partial thromboplastin time, Bleeding time (BT), fibrinogen level, proteins, antiphospholipid antibodies, homocysteine blood level, antithrombin III, protein C and S, factor V Leiden, prothrombin mutation, angiotensin-converting enzyme level, other autoantibodies, and human leukocyte antigen [HLA]-B51). Finally, we confirmed the probable side effect of olanzapine in CRVO, which has not been previously reported. A possible pro-thrombogenic mechanism of olanzapine at the molecular level is an affinity for 5-HT2Aserotonin receptors. Blocking these receptors results in increased platelet aggregation and increased blood coagulability.\n\nConclusions\n\nThese results indicate that CRVO can be a complication of chronic use of antipsychotic medications such as olanzapine, as shown for the first time in our case report. Clinicians should question patients who develop a sudden CRVO whether they are using antipsychotic medications such as olanzapine.\n\nKeywords\n\nCentral retinal vein occlusion\nAntipsychotic drug\nVenous thromboembolism\nMacular edema\nOlanzapine\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nIt has been shown that some antipsychotic drugs are risk factors for venous thromboembolic (VTE) diseases such as deep venous thrombosis and pulmonary embolism [1–4]. This has been reported in large primary care populations in previous studies, especially in the Taiwanese population [5, 6]. However, the association between antipsychotic drugs such as quetiapine fumarate, risperidone, and sulpiride (Dogmatyl™) and central retinal vein occlusion (CRVO) has rarely been reported [7].\n\nWe present our findings here, for the first time, of CRVO in a patient who had been taking the antipsychotic drug olanzapine for an extended period, after ruling out other probable causes of CRVO in our case.\n\nCase presentation\n\nA 50-year-old Caucasian man, nonsmoker, was referred to our clinic with the chief complaint of floaters in his left eye for the past 3 days, with no significant family history. He had been diagnosed with bipolar disorder 8 years earlier and was taking olanzapine, fenofibrate, and bisoprolol. He had no other systemic disease or risk factors for CRVO.\n\nUpon examination, his best-corrected visual acuity (BCVA) was 0.7 in the left eye and 1 in the right eye, with normal pupillary reflexes and with no relative afferent pupillary defect (RAPD) in either eye. His intraocular pressure (IOP) was 18 mmHg in his right eye and 20 mmHg in his left eye. Slit-lamp examination of the anterior segment of both eyes was normal, without cataracts. The fundus showed signs of CRVO, with tortuous and dilated retinal veins and hemorrhages, with subhyaloid hemorrhage and intraretinal hemorrhage in the posterior pole and superior and inferior retina, without macular edema (Fig.1), confirmed by optical coherence tomography (OCT) (Fig. 2). In the fundus examination, there was no sign of neovascularization elsewhere (NVE) or at the disc level (NVD).Fig. 1 Fundus photograph, signs of central retinal vein occlusion, with tortuous and dilated retinal veins and hemorrhages, with subhyaloid hemorrhage\n\nFig.2 Optical coherence tomography showing subhyaloid hemorrhage and intraretinal hemorrhage in the posterior pole and superior and inferior retina, without macular edema\n\nIn fluorescein angiography and OCT angiography (Fig. 3), although we could not completely visualize the posterior pole because of the large subhyaloid hemorrhage, there was no significant capillary nonperfusion area or ischemic area, with no posterior segment neovascularization, and we could not detect any leakage to confirm macular edema.Fig.3 Optical coherence tomography angiography showing subhyaloid hemorrhage and intraretinal hemorrhage without any significant zone of ischemia and neovascularization.\n\nAlthough we could not completely exclude the ischemic classification of thrombosis because of subhyaloid hemorrhage, other findings such as visual acuity and the type of thrombosis seemed to be nonischemic (Fig. 4).Fig.4 Fundus photograph: exudation of previous subhyaloid hemorrhage and exudation of previous subretinal hemorrhage in the superior juxtapapillary macular edema\n\nWe ruled out other probable differential diagnoses and risk factors which lead to CRVO through complete physical exam including blood pressure control in 24 hours, chest X-ray and whole-body computed tomography scan to identify any other hemorrhage, and blood analysis including complete blood count (CBC), glucose, urea, creatinine, lipid profile, erythrocyte sedimentation rate (ESR), C-reactive protein, prothrombin time (PT), partial thromboplastin time (PTT), bleeding time (BT), fibrinogen level, proteins, antiphospholipid antibodies (APA), homocysteine blood level, antithrombin III, protein C and S, factor V Leiden, prothrombin mutation, angiotensin-converting enzyme (ACE) level, other autoantibodies, and human leukocyte antigen (HLA)-B51.\n\nFinally, we confirmed the probable side effect of olanzapine as another antipsychotic medication in his recent CRVO which was not previously reported.\n\nWe discontinued olanzapine to prevent any further complications related to this drug, and we added salicylic acid with an anticoagulant dose of 100 µg per day.\n\nIn the second follow-up visit after 2 months, his BCVA was 0.7 in the left eye and 1 in the right eye. His IOP was 16 mmHg in his right eye and 18 mmHg in his left eye.\n\nGonioscopy was performed by Goldmann gonioscopy, and the presence of neovascularization in the angle was ruled out. His fundus showed signs of exudation of previous subhyaloid and subretinal hemorrhage in the superior juxtapapillary zone, without any NVE.\n\nDiscussion\n\nThe pathogenesis of CRVO has not been definitively determined [8]. The most commonly recognized risk factors are age and systemic vascular disorders, although rarely patients under the age of 45 can develop CRVO [9]. Some cases of CRVO are associated with thrombophilia and hematologic disorders [10, 11], and CRVO can occur due to a combination of different systemic disorders, such as hemodynamic changes (venous stasis), degenerative changes in the blood vessel walls, and blood hypercoagulability states. It has also been suggested that hyperviscosity due to high hematocrit levels or other causes may play a role in the development of CRVO. The higher blood viscosity increases the aggregation of erythrocytes and slows the blood flow, thus increasing the risk of clotting [10, 11].\n\nA primary risk factor for the development of CRVO is age, with 90% of patients older than 50 years. Systemic arterial hypertension, open-angle glaucoma, diabetes mellitus, and hyperlipidemia have all been implicated as other primary risk factors for CRVO. Other associated risk factors include smoking, optic disc drusen, optic disc edema, hypercoagulable state (polycythemia, multiple myeloma, cryoglobulinemia, Waldenström macroglobulinemia, antiphospholipid syndrome, Leiden factor V, activated protein C resistance, hyperhomocysteinemia, protein C and S deficiency, antithrombin III mutation, prothrombin mutation), syphilis, sarcoidosis, African American race, sickle cell disease, human immunodeficiency virus (HIV), vasculitis, drugs such as oral contraceptives or diuretics, abnormal platelet function, orbital disease, and rarely migraines [12].\n\nSevere thromboembolic diseases such as pulmonary embolism and VTE have been reported to develop in patients being treated with antipsychotic agents, but the incidence was found to be as low as 0.0091% [2]. Antipsychotic drugs contribute to the development of a hypercoagulable state through several potential mechanisms, including drug-induced sedation, obesity, hyperprolactinemia, increased platelet aggregation, and elevated APA levels [13, 14].\n\nA search of PubMed with the keywords “central retinal vein occlusion and antipsychotic drug” and “branch retinal vein occlusion and antipsychotic drug” yielded only three publications, by Taki et al. [7], Agca et al. [15], and Yong et al. [16].\n\nMetabolic symptoms caused by olanzapine represent an indirect mechanism for VTE development. The pro-thrombogenic metabolic symptoms that often occur during olanzapine treatment include hyperglycemia, hyperleptinemia, dyslipidemia, and weight gain [17]. In our case, we ruled out these indirect effects of olanzapine by the patient’s lab test results showing normoglycemia, no hyperleptinemia, and normal lipid profile. The patient's body mass index (BMI) was 25, classified as overweight, but obesity was not a clear risk factor in our case.\n\nOur case report is the first to report the use of olanzapine associated with CRVO, which we were able to confirm as the probable side effect of this drug. Although olanzapine side effects were previously reported as a precipitating factor for VTE formation [18], CRVO as a probable side effect of this drug has not been published previously.\n\nA possible pro-thrombogenic mechanism of olanzapine at the molecular level is an affinity for 5-HT2Aserotonin receptors. Blocking these receptors results in increased platelet aggregation and increased blood coagulability [19]. Blockade of α1 adrenergic receptors by olanzapine may cause hypotension and therefore venous stasis in the lower limbs. Another mechanism may be olanzapine-induced production of the APAs lupus anticoagulant (LA) and anticardiolipin antibodies (ACLAs) [20]. Increased APA titers is associated with a pro-thrombogenic state [17]. We ruled out increased LA and ACLAs by normal lab test results in our case report. Olanzapine may also induce a temporary increase in prolactin levels early in the course of treatment. Hyperprolactinemia correlates with increased levels of P-selectin, a platelet activation marker [21].\n\nOlanzapine has a high affinity for 5-HT2A, a serotonin receptor. 5-HT2A blockers stimulate 5-HT2A in the platelets and induce platelet aggregation, causing the vascular smooth muscles to contract [22, 23]. Thus, platelet aggregation may have played a role in CRVO in our patient.\n\nThis study does have limitations. The patient took other drugs, and we did not determine which was the real culprit, although there is no other drug in his past medical history that has any kind of confirmed thrombophilia. It would be helpful to measure the retinal venous pressure, particularly in the unaffected contralateral eye [24, 25]. If the retinal venous pressure is dependent on the intake of these antipsychotic drugs, we would have better evidence of a relationship between CRVO and antipsychotic drug use.\n\nConclusions\n\nThese results indicate that CRVO can be a complication of chronic use of antipsychotic medications such as olanzapine, as shown here for the first time in our case report. Clinicians should question patients who develop a sudden CRVO whether they are using antipsychotic medications such as olanzapine.\n\nAbbreviations\n\nCRVO Central retinal vein occlusion\n\nOCT Optical coherence tomography\n\nBCVA Best-corrected visual acuity\n\nVTE Venous thromboembolic\n\nAcknowledgements\n\nWe would like to thank Dr. Ariel Juarez for collaborating with us in editing of this case presentation.\n\nAuthorship\n\nAll authors attest that they meet the current ICMJE criteria for authorship.\n\nAuthors' contributions\n\nSK and MRC performed angiography and did the analysis of the angiographic images. JB-del-C and ASG helped establish and rule out all possible differential diagnoses. ADR and KVMC helped to gather information about the mechanism of olanzapine in thrombotic events in other organs and explain the pathophysiology of this drug in CRVO. All authors read and approved the final manuscript.\n\nFunding\n\nNo funding or grant support.\n\nAvailability of data and materials\n\nAll supporting data are available to be sent to the editorial department when it is necessary.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests and confirm that all relevant data are included in the case presentation.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Curtin F Blum M Antipsychotics and risk of venous thrombosis Br J Psychiatry. 2002 180 85 10.1192/bjp.180.1.85\n2. Liperoti R Pedone C Lapane KL Mor V Bernabei R Gambassi G Venous thromboembolism among elderly patients treated with atypical and conventional antipsychotic agents Arch Intern Med. 2005 165 2677 2682 10.1001/archinte.165.22.2677 16344428\n3. Ray JG Mamdani MM Yeo EL Antipsychotic and antidepressant drug use in the elderly and the risk of venous thromboembolism ThrombHaemost. 2002 88 205 209\n4. Thomassen R Vandenbroucke JP Rosendaal FR Antipsychotic medication and venous thrombosis Br J Psychiatry. 2001 179 63 66 10.1192/bjp.179.1.63 11435271\n5. Parker C Coupland C Hippisley-Cox J Antipsychotic drugs and risk of venous thromboembolism: nested case-control study BMJ 2010 341 c4245 10.1136/bmj.c4245 20858909\n6. Wu CS Lin CC Chang CM Wu KY Liang HY Huang YW Antipsychotic treatment and the occurrence of venous thromboembolism: a 10-year nationwide registry study J Clin Psychiatry. 2013 74 918 924 10.4088/JCP.12m08117 24107765\n7. Taki K Kida T Fukumoto M Sato T Oku H Ikeda T Central retinal vein occlusion in 2 patients using antipsychotic drugs Case Rep Ophthalmol. 2017 8 2 410 415 10.1159/000479219 28924438\n8. Fraenkl SA Mozaffarieh M Flammer J Retinal vein occlusions: the potential impact of a dysregulation of the retinal veins EPMA J. 2010 1 253 261 10.1007/s13167-010-0025-2 21258633\n9. Ehlers JP Fekrat S Retinal vein occlusion: beyond the acute event SurvOphthalmol. 2011 56 281 299\n10. Rehak M Wiedemann P Retinal vein thrombosis: pathogenesis and management J ThrombHaemost. 2010 8 1886 1894 10.1111/j.1538-7836.2010.03909.x\n11. McGrath MA Wechsler F Hunyor AB Penny R Systemic factors contributory to retinal vein occlusion Arch Intern Med. 1978 138 216 220 10.1001/archinte.1978.03630260030012 626551\n12. Lim LL Cheung N Wang JJ Islam FM Mitchell P Saw SM Aung T Wong TY Prevalence and risk factors of retinal vein occlusion in an Asian population Br J Ophthalmol. 2008 92 10 1316 1319 10.1136/bjo.2008.140640 18684751\n13. Masopust J Maly R Andrys C Valis M Bazant J Hosak L Markers of thrombogenesis are activated in unmedicated patients with acute psychosis: a matched case control study BMC Psychiatry 2011 11 2 10.1186/1471-244X-11-2 21199572\n14. Jonsson AK Schill J Olsson H Spigset O Hagg S Venous thromboembolism during treatment with antipsychotics: a review of current evidence CNS Drugs 2018 32 47 64 10.1007/s40263-018-0495-7 29423659\n15. Agca A Bayraktar Z Cakr M Bayraktar S Ekinci O Ylmaz OF Central retinal vein occlusion in a young adult during risperidone therapy Retin Cases Brief Rep. 2008 2 199 201 10.1097/ICB.0b013e3180601196 25390085\n16. Yong KC Kah TA Ghee YT Siang LC Bastion ML Branch retinal vein occlusion associated with quetiapine fumarate BMC Ophthalmol. 2011 11 24 10.1186/1471-2415-11-24 21867521\n17. Borch KH Braekkan SK Mathiesen EB Njolstad I Wilsgaard T Stormer J Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome: the Tromsø study J ThrombHaemost 2009 7 739 745 10.1111/j.1538-7836.2008.03234.x\n18. Masopust J Bazantova V Kuca K Klimova B Valis M Venous Thromboembolism as an Adverse Effect During Treatment With Olanzapine: A Case Series Front Psychiatry. 2019 10 330 10.3389/fpsyt.2019.00330 31156478\n19. Bhanji NH Chouinard G Hoffman L Margolese HC Seizures, coma, and coagulopathy following olanzapine overdose Can J Psychiatry 2005 50 126 127 10.1177/070674370505000214 15807232\n20. Wallaschofski H Eigenthaler M Kiefer M Donne M Hentschel B Gertz HJ Hyperprolactinemia in patients on antipsychotic drugs causes ADP-stimulated platelet activation that might explain the increased risk for venous thromboembolism: pilot study J ClinPsychopharmacol 2003 23 479 483 10.1097/01.jcp.0000088914.24613.51\n21. Christiansen SC Lijfering WM Naess IA Hammerstrom J van Hylckama VA Rosendaal FR The relationship between body mass index, activated protein C resistance and risk of venous thrombosis J ThrombHaemost 2012 10 1761 1767 10.1111/j.1538-7836.2012.04828.x[\n22. Cerrito F Lazzaro MP Gaudio E Arminio P Aloisi G 5HT2-receptors and serotonin release: their role in human platelet aggregation Life Sci. 1993 53 209 215 10.1016/0024-3205(93)90671-O 8321084\n23. Dees C Akhmetshina A Zerr P Reich N Palumbo K Horn A Platelet-derived serotonin links vascular disease and tissue fibrosis J Exp Med. 2011 208 961 972 10.1084/jem.20101629 21518801\n24. Mozaffarieh M Bartschi M Henrich PB Schoetzau A Flammer J Retinal venous pressure in the non-affected eye of patients with retinal vein occlusions Graefes Arch ClinExpOphthalmol. 2014 252 1569 1571 10.1007/s00417-014-2617-3\n25. Flammer J Konieczka K Retinal venous pressure: the role of endothelin EPMA J. 2015 6 21 10.1186/s13167-015-0043-1 26504500\n\n",
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"abstract": "For the last decade, the combination therapy of pegylated interferon (Peg-IFN) plus ribavirin (RBV) has been considered as the standard of care treatment for chronic hepatitis C virus (HCV) infection. However, it has been associated with an increased incidence of many adverse cutaneous reactions and emergence of autoantibodies or even autoimmune diseases. We report a case of irreversible alopecia universalis (AU) with complete hair loss extended to the whole body, which started after discontinuation of Peg-IFN/RBV combination therapy for chronic HCV infection. In conclusion, this case represents an uncommon presentation of a common disease. Physicians must be aware of the potential adverse reactions of an antiviral therapy containing IFN, which might occur even after the discontinuation, and fully inform the patient at the beginning of his treatment course. We hope that interferon-free regimens will utterly supplant interferon-based therapy for most or all HCV patients avoiding the emergence of autoimmune manifestations.",
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"title": "Alopecia universalis after discontinuation of pegylated interferon and ribavirin combination therapy for hepatitis C: a case report.",
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"abstract": "Primary hemophagocytic lymphohistiocytosis is a severe and uncommon disease affecting pediatric patients. Genetic abnormalities have been related to altered apoptosis and exaggerated inflammatory reactions. Chemoimmunotherapy and stem cell transplantation are treatment options, but transplant is the only curative treatment. Here we aim to describe the treatment with hematopoietic stem cell transplantation with a novel strategy and the outcomes.\n\n\n\nAn observational, descriptive, case series study was performed in pediatric patients of two high complexity medical centers in Colombia. Data was collected retrospectively between 2015 and 2020.\n\n\n\nWe describe five pediatric cases with a diagnosis of primary hemophagocytic lymphohistiocytosis. All were treated with replete-cell haploidentical hematopoietic stem transplantation, reduced-intensity conditioning, and post-transplant cyclophosphamide, in two high-complexity centers in Colombia. All patients are alive, and one is receiving management for chronic graft-versus-host disease.\n\n\n\nTo the best of our knowledge, there are few reports in the literature with this strategy, promising a possible alternative when there are no other donor options.",
"affiliations": "Maternal and Child Department, Pediatric Stem Cell Transplant Service, Fundación Valle del Lili, Carrera 98 #18-49, Cali, 760032, Colombia. diego.medina@fvl.org.co.;Maternal and Child Department, Fundación Valle del Lili, Cra 98 No. 18 - 49, Cali, 760032, Colombia.;Centro de Investigaciones Clínicas, Fundación Valle del Lili, Cra 98 No. 18 - 49, Cali, 760032, Colombia.;Pediatric Stem Cell Transplant Unit, Hospital Pablo Tobón Uribe, Cll 78b #69-240, Medellín, 11001, Colombia.;Maternal and Child Department, Pediatric Stem Cell Transplant Service, Fundación Valle del Lili, Carrera 98 #18-49, Cali, 760032, Colombia.;Pediatric Stem Cell Transplant Unit, Hospital Pablo Tobón Uribe, Cll 78b #69-240, Medellín, 11001, Colombia.;School of Medicine, Universidad Icesi, Cali, Colombia.",
"authors": "Medina-Valencia|Diego|D|;Cleves|Daniela|D|0000-0001-7321-2045;Beltran|Estefania|E|0000-0003-2438-8356;Builes|Natalia|N|0000-0002-8918-0065;Franco|Alexis A|AA|0000-0002-3173-6059;Escobar-González|Andrés Felipe|AF|0000-0001-9846-6615;Olaya|Manuela|M|0000-0002-3239-8928",
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"title": "Haploidentical Stem Cell Transplant with Post-Transplant Cyclophosphamide in Pediatric Hemophagocytic Lymphohistiocytosis.",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Treatment with desmopressin diacetate arginine vasopressin (DDAVP) and its withdrawal are associated with side effects. We present a rare case of severe biphasic adverse reactions induced by DDAVP and its withdrawal in a 63-year-old female patient. A lump in the left axillary region was biopsied, and she received DDAVP after surgery. The following day, she lost consciousness, with foaming at the mouth and seizures. Hypotonic encephalopathy was considered. DDAVP was ceased, and she received electrolytes. On day 1, she displayed low blood pressure and increased urine output. She received DDAVP and dopamine as well as electrolytes. The patient was ambulatory on day 7 and was discharged without brain abnormalities on MRI. In conclusion, severe hyponatremia induced by DDAVP and massive polyuria and hypovolemic shock induced by DDAVP withdrawal are life-threatening conditions. This case underlines the need to be vigilant when administering DDAVP and to monitor for any side effects.",
"affiliations": null,
"authors": "Wang|Lijun|L|;Chen|Ruijun|R|;Tian|Fang|F|;Wang|Wei|W|;Wang|Li|L|;Yu|Baojun|B|;Huang|Xianwen|X|;Zhang|Yuehui|Y|;Su|Shengyuan|S|;Ma|Guangnian|G|;Wang|Kaichen|K|",
"chemical_list": "D003894:Deamino Arginine Vasopressin",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP202461",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "54(8)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D003894:Deamino Arginine Vasopressin; D005260:Female; D006801:Humans; D007010:Hyponatremia; D008875:Middle Aged; D011141:Polyuria; D012769:Shock",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "640-4",
"pmc": null,
"pmid": "27142268",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Life threatening biphasic adverse reactions to desmopressin: case report and review of the literature.",
"title_normalized": "life threatening biphasic adverse reactions to desmopressin case report and review of the literature"
} | [
{
"companynumb": "CN-MYLANLABS-2016M1033687",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DESMOPRESSIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMitoxantrone is a chemotherapeutic agent approved for various diseases. The literature has been conflicting in classifying mitoxantrone as a vesicant or irritant.\n\n\nMETHODS\nWe report a patient who had an extravasation of mitoxantrone. Mitoxantrone was administered in 50 ml normal saline. After mitoxantrone was completely infused, the site appeared edematous and the blue color of mitoxantrone developed beneath the skin. The patient reported pain. Management and outcome: The extravasation was treated with dexrazoxane and cold compresses. The pain improved each day. However, blistering developed five weeks later and the patient ultimately required surgical intervention for debridement and grafting.\n\n\nCONCLUSIONS\nExtravasation events are rare and there are few controlled studies. Because of the similarities in chemical structures and mechanism of actions between mitoxantrone and anthracyclines, mitoxantrone extravasation is often treated similar to anthracyclines. Mitoxantrone's classification is unclear, as some literature classifies it as a vesicant and others as an irritant. Our case supports the categorization of mitoxantrone as a vesicant.",
"affiliations": "Pharmacy Department, Stanford Health Care, Stanford, CA, USA.",
"authors": "Chang|Abraham|A|https://orcid.org/0000-0002-1971-7680",
"chemical_list": "D000970:Antineoplastic Agents; D008942:Mitoxantrone",
"country": "England",
"delete": false,
"doi": "10.1177/1078155219893736",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Chemotherapy; extravasation; mitoxantrone",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D017679:Cryotherapy; D005119:Extravasation of Diagnostic and Therapeutic Materials; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008942:Mitoxantrone",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1270-1273",
"pmc": null,
"pmid": "31902285",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of mitoxantrone extravasation.",
"title_normalized": "a case of mitoxantrone extravasation"
} | [
{
"companynumb": "US-TEVA-2020-US-1810039",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": "1",
... |
{
"abstract": "Tigecycline, a recently approved antibiotic, has a broad spectrum of antimicrobial activity. Its unique structure and properties make tigecycline a valuable option for the treatment of infections caused by many multidrug-resistant organisms. We present a case of an 82-year-old patient who developed a significant decrease of fibrinogen levels after the addition of tigecycline to his antibiotic regimen. The patient was treated for a periprosthetic knee joint infection caused by a multidrug-resistant extended-spectrum beta-lactamase-producing Escherichia coli. The reduction of fibrinogen levels, in this case, prompted severe spontaneous hemarthrosis. Tigecycline treatment was discontinued and coagulation disorders were normalized within the next few days. After several days, the joint had to be surgically debrided. Hypofibrinogenemia is a very scarcely reported side effect of tigecycline that can cause spontaneous hemarthrosis.",
"affiliations": "Orthopaedics, General Hospital Hellenic Red Cross Korgialenio Benakio, Athens, GRC.;Orthopaedics, East Surrey Hospital, Surrey and Sussex Healthcare National Health Service Trust, Redhill, GBR.;Orthopaedics, General Hospital Hellenic Red Cross Korgialenio Benakio, Athens, GRC.;Orhopaedics, General Hospital Hellenic Red Cross Korgialenio Benakio, Athens, GRC.;Orthopaedics, General Hospital Hellenic Red Cross Korgialenio Benakio, Athens, GRC.",
"authors": "Balfousias|Theodore|T|;Apostolopoulos|Alexandros P|AP|;Angelis|Stavros|S|;Maris|Spyridon|S|;Papanikolaou|Athanasios|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.5883",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.5883MiscellaneousOrthopedicsInfectious DiseaseSpontaneous Knee Hemarthrosis Due to Hypofibrinogenemia Following Tigecycline Treatment for Periprosthetic Joint Infection Muacevic Alexander Adler John R Balfousias Theodore 1Apostolopoulos Alexandros P 2Angelis Stavros 1Maris Spyridon 3Papanikolaou Athanasios 1\n1 \nOrthopaedics, General Hospital Hellenic Red Cross Korgialenio Benakio, Athens, GRC \n2 \nOrthopaedics, East Surrey Hospital, Surrey and Sussex Healthcare National Health Service Trust, Redhill, GBR \n3 \nOrhopaedics, General Hospital Hellenic Red Cross Korgialenio Benakio, Athens, GRC \nTheodore Balfousias teobalf@gmail.com10 10 2019 10 2019 11 10 e58832 10 2019 10 10 2019 Copyright © 2019, Balfousias et al.2019Balfousias et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/23672-spontaneous-knee-hemarthrosis-due-to-hypofibrinogenemia-following-tigecycline-treatment-for-periprosthetic-joint-infectionTigecycline, a recently approved antibiotic, has a broad spectrum of antimicrobial activity. Its unique structure and properties make tigecycline a valuable option for the treatment of infections caused by many multidrug-resistant organisms. We present a case of an 82-year-old patient who developed a significant decrease of fibrinogen levels after the addition of tigecycline to his antibiotic regimen. The patient was treated for a periprosthetic knee joint infection caused by a multidrug-resistant extended-spectrum beta-lactamase-producing Escherichia coli. The reduction of fibrinogen levels, in this case, prompted severe spontaneous hemarthrosis. Tigecycline treatment was discontinued and coagulation disorders were normalized within the next few days. After several days, the joint had to be surgically debrided. Hypofibrinogenemia is a very scarcely reported side effect of tigecycline that can cause spontaneous hemarthrosis.\n\ntigecyclineperiprosthetic infectionhypofibrinogenemiahemarthrosisadverse effectThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nTigecycline is the first antibiotic in the class of glycylcyclines, a class that has structural similarities with tetracycline. Tigecycline, which was recently approved by the Food and Drug Administration (FDA) in 2005 and in Europe in 2006, has a broad spectrum of antimicrobial activity. Modifications have been made to the tetracycline structure. These modifications make tigecycline active against tetracycline-resistant organisms. In addition to tigecycline’s activity against most gram-positive, gram-negative, and anaerobic bacteria, it is considered effective against many multi-drug resistant organisms (MDROs). Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), Acinetobacter Baumannii, and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are some of the multidrug-resistant bacteria susceptible to tigecycline [1].\n\nVarious adverse events, related to the administration of tigecycline, have been reported in the literature. Gastrointestinal symptoms, including nausea and vomiting, are the most common [2-3]. Acute pancreatitis, liver dysfunction, as well as elevated levels of aminotransferases, bilirubin, and alkaline phosphatase, have also been reported. Coagulation disorders are very uncommon following treatment with tigecycline. Hypofibrinogenemia, caused by tigecycline, is a scarcely reported side effect. We present a patient, who was treated with tigecycline for periprosthetic infection of the knee that developed hypofibrinogenemia and led to severe spontaneous knee hemarthrosis.\n\nCase presentation\nAn 82-year-old male patient was referred to our emergency department due to a neglected periprosthetic knee joint infection of his left knee. He had undergone a primary total knee arthroplasty 11 years ago in another institution because of painful osteoarthritis. Failure of the primary arthroplasty led to revision surgery two years later, at the same institution. The patient reported prolonged mild edema and moderate pain subsequent to the revision surgery and deterioration of symptoms during the past two months.\n\nOn admission, the patient reported severe pain in the left knee. This was the reason for the limitation of his daily activities. The patient was afebrile and no injury in the recent past was referred. Τhe knee joint was excessively swollen, with prominent erythema and warmth. Moreover, imaging by X-ray revealed a constrained revision prosthesis and no signs of fracture (Figure 1). The range of motion was affected, with a major deficit in flexion and a 10 degrees deficit in extension.\n\nFigure 1 Initial X-rays of the patient's knee revealing the revision prosthesis (A): anteroposterior view (B): lateral view\nAn ultrasound of the knee joint was performed in the emergency department and revealed massive fluid accumulation in the joint. Blood samples revealed abnormal inflammatory markers. The C-reactive protein (CRP) was 20.3 mg/L and the erythrocyte sedimentation rate (ESR) was 67 mm/hr, but no leukocytosis was observed. Blood cultures were also obtained. The rest of the standard laboratory evaluation was normal.\n\nAs far as medical history is concerned, the patient reported myelodysplastic syndrome (MDS) and benign prostatic hyperplasia (BPH) under treatment. MDS could possibly be one of the reasons why leucocytosis was absent, even though, in many cases of chronic musculoskeletal infections, the white blood cell count is normal. The platelet count was normal (PLT: 262 X103/μL) and the red blood cell count (RBC) was 4.25 x106/μL with haemoglobin 11.1 g/dL. No known allergic reactions were reported.\n\nSurgical debridement of the joint was decided, and it took place in the operation room on the same day. During the procedure, pus was removed from the joint, several cultures were taken, and the joint was excessively debrided. After the operation, broad-spectrum empiric intravenous antibiotic therapy was initiated, consisting of piperacillin and tazobactam (4 g + 0.5 g) every six hours and vancomycin 1 g every 12 hours. Prophylactic dosage of low molecular weight heparin (LMWH) was also administered subcutaneously (enoxaparin sodium 4,000 IU once daily).\n\nThe cultures from the joint fluid and tissues revealed a multidrug-resistant extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. ESBLs are enzymes that hydrolyze most beta-lactamase antibiotics, including penicillins, cephalosporins, and monobactams. On the other hand, blood cultures turned negative. Seven days after surgical debridement, the antibiotic regimen changed, based on the antibiogram. In collaboration with the department of infectious diseases of the hospital, therapy with intravenous meropenem and high dosage of tigecycline was initiated. The patient received a loading dose of 200 mg tigecycline followed by 100 mg every 12 hours in combination with 2 g meropenem every eight hours.\n\nSix days after the initiation of the therapy with tigecycline, the patient reported complaints of abdominal pain and nausea. No vomiting was referred. Liver function tests, as well as heart function tests and electrocardiogram (ECG), were normal. The abdominal ultrasonography did not reveal any abnormal findings besides the size of the spleen, which was at the upper normal limits. The symptoms subsided with the administration of proton-pump inhibitors (PPIs).\n\nFourteen days after initial tigecycline dosage administration, spontaneous swelling appeared on the left knee. Although systemic inflammatory markers and the patient's general condition were improving, the swelling of the joint progressively worsened within the next two days, despite ice therapy (Figure 2). Simultaneously, a prolongation of the activated partial thromboplastin time (aPTT) and the international normalized ratio (INR) was noted, along with a vast decrease of fibrinogen (FIB) levels. On the other hand, the platelet count slightly decreased but remained in the normal range, over 150 X103/μL. Liver function blood tests were also normal.\n\nFigure 2 Severe hemarthrosis of the left knee after 16 days of tigecycline administration\nJoint aspiration was performed and 120 mL of blood was drained. The aspirate was sent for culture and sensitivity. Administration of low molecular weight heparin (LMWH) was interrupted. Fluid cultures were negative. Lack of platelet consumption, the good general condition of the patient, and an improvement in inflammation markers led us to rule out other causes of hypofibrinogenemia such as disseminated intravascular coagulation (DIC) and sepsis.\n\nHypofibrinogenemia worsened 18 days after the initiation of tigecycline treatment, with fibrinogen (FIB) reaching 158 mg/dL, aPTT 54.3 s, INR 1.78, CRP 11.8 mg/L, platelet count 181 X103/μL, white blood cell count (WBC) 4.3 x103/μL, haemoglobin 9.1 g/dL, and normal liver function tests. The hemarthrosis of the knee worsened, and the patient complained of severe pain of the joint. It was suspected that tigecycline was the causative factor of the hypofibrinogenemia that led to severe hemarthrosis. The antibiotic was discontinued, and the new antibiotic regimen consisted solely of intravenous administration of meropenem. During the next three days, eight fresh frozen plasma units were administered, along with vitamin K and 1 g of intravenous tranexamic acid. Following the discontinuation of tigecycline, the coagulation disorders became normal through the next six days. The fibrinogen levels reversed to the normal range (Table 1).\n\nTable 1 Coagulation parameters and inflammatory markers of the patient on admission, during tigecycline therapy and after drug discontinuation\nINR: International Normalized Ratio; PT: Prothrombin Time; aPTT: Activated Partial Thromboplastin Time; FIB: Fibrinogen; PLT: Platelet Count; CRP: C-Reactive Protein; ESR: Erythrocyte Sedimentation Rate\n\n \tDay of admission\t1st day in tigecycline treatment\t14th day in tigecycline treatment\t18th(final) day of tigecycline\t3 days after tigecycline discontinuation\t6 days after tigecycline discontinuation\t\nINR\t1.12\t1.15\t1.64\t1.78\t1.30\t1.14\t\nPT (s)\t15.2\t14.9\t20.8\t22.1\t17.1\t15.1\t\naPTT (s)\t40.0\t40.0\t48.5\t54.3\t43.2\t39.1\t\nFIB (mg/dL)\t398\t393\t202\t158\t364\t396\t\nPLT (X103/μL)\t262\t197\t226\t181\t146\t149\t\nCRP (mg/L)\t20.3\t16.1\t12.4\t11.8\t14.2\t8.6\t\nESR (mm/hr)\t67\t48\t36\t28\t31\t18\t\nThis improvement was consistent with our initial hypothesis that tigecycline caused the coagulation disfunction. Despite the gradual improvement in hypofibrinogenemia, the severe hemarthrosis had to be surgically treated. The joint had to be debrided in the operation room 10 days after the discontinuation of tigecycline, as blood accumulation could not be aspirated because of blood clots. About 500 mL of clotted blood was obtained after the surgical debridement and no obvious site of hemorrhage was revealed (Figure 3). No recurrence of hemarthrosis during hospitalization was observed.\n\nFigure 3 Surgical debridement of the knee 10 days after the discontinuation of tigecycline, which showed excessive clotted blood accumulation\nDiscussion\nTigecycline is a broad-spectrum, tetracycline analog antibiotic. It blocks protein synthesis, as it binds to the 30S subunit of the ribosome, inhibiting the proliferation of multiple bacteria. It is an active antibiotic against many MDROs, with the exception of Proteus, Providencia, and Pseudomonas aeruginosa [4]. Its use has been approved by the Food and Drugs Administration (FDA) and the European Medicines Agency (EMA) for complicated intra-abdominal infections, community-acquired pneumonia by sensitive bacteria, and complicated skin and soft tissue infections. However, tigecycline has recently been used in the treatment of periprosthetic joint infections [5-6]. Treating periprosthetic joint infections is a challenge because of the presence of a microbial biofilm. Treatment of these kinds of infections requires the surgical removal of all implants and intravenous antibiotic administration.\n\nIn our case, the patient refused to undergo new revision surgery and to replace the prosthesis. Biofilms are complex structures that act as protection of the bacteria from the host defenses and from the antibiotics that are administered. In a recent in vitro study, tigecycline, along with rifampicin, showed superior activity against a Staphylococcus epidermidis biofilm in comparison with ciprofloxacin, vancomycin, cloxacillin, and daptomycin [7]. Additionally, animal studies show that tigecycline is active against foreign body infections, as monotherapy or in combination with other antimicrobial agents [8-9]. Although there is limited experience in the treatment of periprosthetic joint infection because of the biofilm and the MDRO, the use of high dosage tigecycline administration was chosen to maximize the effectiveness of the drug [6,10].\n\nThe poor bioavailability of tigecycline necessitates its intravenous administration. Tigecycline has a relatively long elimination half-life (t 1/2) of 42 hours and reaches steady serum concentration levels after seven days of therapy [3]. It is metabolized mainly by the liver, hence, a reduction in the dosage is recommended in patients with Child-Pugh class C cirrhosis [4]. The recommended dosage is a loading 100 mg (IV, intravenous) the first day of the therapy, followed by 50 mg (IV) every 12 hours the next days. However, there is a debate about the optimal dosage, as there are several publications reporting the better efficiency of tigecycline in high dose administration [10].\n\nSymptoms of the gastrointestinal (GI) tract are the most common side effects of tigecycline. In the clinical trials performed, coagulation disorders, such as the prolongation of INR, aPTT, and prothrombin time (PT), were very infrequently (<2%) reported in patients receiving tigecycline treatment though a reduction in fibrinogen levels was not described [11]. After reviewing the literature for cases of hypofibrinogenemia following the use of tigecycline, six case reports were found published in PubMed after the widespread use of tigecycline worldwide [12-17]. In all cases, hypofibrinogenemia was reversible and the coagulation disorders resolved within days after stopping the administration of the antibiotic. Pieringer et al. were the first to report, in 2009, a case of hypofibrinogenemia that developed after tigecycline was added to the antibiotic regimen of a patient, with no underlying hepatic disease, who was treated for peritonitis. Five days after the discontinuation of tigecycline, the fibrinogen levels returned to normal values [12].\n\nThree small-scale studies are known to assess the effect of tigecycline treatment on fibrinogen levels. Routsi et al. studied the coagulation parameters of 45 patients intensive care unit (ICU) patients and showed that high doses of tigecycline led to a gradual reduction in fibrinogen levels and the prolongation of INR and aPTT, 14 days after the initiation of the treatment. The coagulation parameters returned to normal after the discontinuation of the treatment, although the coagulation parameters could not be assessed in 15 patients, either because of death, non-drug related, or because of discharge from the intensive care unit (ICU) [18]. In another study, Zhang et al. evaluated 20 patients with severe infections, who were treated with tigecycline. Hypofibrinogenemia was described in 80% of the patients, which was proportional to the dose administered. There was no significant difference between age groups. The reduction of FIB levels was reversed after the cessation of treatment [19]. Leng et al. retrospectively studied 50 patients treated with tigecycline and monitored their coagulation parameters. Forty-six of the patients had a reduction of fibrinogen levels and the reduction was more profound in 25 of them. They also found that the alterations in FIB, aPTT, and PT started to appear four days after the initial dosage, and they worsened over the following days of treatment. In this study, the changes in the coagulation parameters gradually reversed four days after the discontinuation of treatment [20].\n\nFibrinogen is a soluble protein, with a half-life of four days; it is produced in hepatocytes. It has a major role in coagulation, as it is converted into insoluble fibrin. It is also one of the acute phase proteins and elevated levels of fibrinogen are expected in systematic inflammation and malignancy. There are rare inherited diseases such as afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia. Moreover, a reduction in fibrinogen levels can be seen in hepatic diseases and malnutrition. Disseminated intravascular coagulation (DIC), transfusions of large amounts of blood, and the administration of drugs (valproic acid, synthetic adrenocorticotropic hormone (ACTH), prednisolone, L-asparaginase, allopurinol, and, recently, tigecycline) can also lead to a reduction in the levels of fibrinogen [14]. The exact mechanism by which tigecycline causes hypofibrinogenemia is ambiguous. It is a member of glycylcyclines with structural similarities to tetracyclines. It can impair the patient’s coagulation either by affecting the vitamin-K-producing flora of the gastrointestinal (GI) tract or by directly provoking alterations on the coagulation cascade [18]. In addition, a possible effect on the hepatic function that leads to impaired fibrinogen levels has also been hypothesized [14].\n\nIn our case, the patient had no history of coagulation disorder or hepatic disease. As the inflammatory markers were improving during the treatment and there was no platelet consumption noted, excluding other causes of reduction of fibrinogen levels, our hypothesis was that hypofibrinogenemia was the result of tigecycline administration. The coagulation parameters, including fibrinogen (FIB) levels, became normal six days after the discontinuation of the antibiotic, confirming our assumption. To our knowledge, this is the first case reported that tigecycline-induced coagulopathy led to an acute, painful hemarthrosis that had to be encountered in the operation room.\n\nConclusions\nHypofibrinogenemia, as an adverse event of tigecycline, should be considered in the event of a spontaneous hematoma. In cases treated with antibiotic regimens, which include tigecycline, we suggest thorough monitoring of the coagulation parameters (aPTT, PT, INR, and fibrinogen). The discontinuation of tigecycline is advised for patients that develop hypofibrinogenemia, especially if there are no other apparent causes present.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Tigecycline: first of a new class of antimicrobial agents Pharmacotherapy Rose WE Rybak MJ 1099 1110 26 2006 16863487 \n2 Pharmacokinetics, pharmacodynamics, safety and tolerability of tigecycline J Chemotherapy Rello J 12 22 17 2005 \n3 Adverse event profile of tigecycline: data mining of the public version of the U.S. Food and Drug Administration adverse event reporting system Biol Pharm Bull Kadoyama K Sakaeda T Tamon A Okuno Y 967 970 35 2012 22687540 \n4 Tigecycline: a new glycylcycline antimicrobial agent Am J Health Syst Pharm Kasbekar N 1235 1243 63 2006 16790575 \n5 Clinical experience with tigecycline in the treatment of prosthetic joint infections Open Forum Infect Dis Lastinger A Dietz M Guilfoose J Sarwari AR 0 4 2017 \n6 Acinetobacter prosthetic joint infection treated with debridement and high-dose tigecycline J Infect Chemother Vila A Pagella H Amadio C Leiva A 324 329 4 2016 \n7 In vitro susceptibility to antibiotics of staphylococci in biofilms isolated from orthopaedic infections Int J Antimicrob Agents Molina-Manso D del Prado G Ortiz-Pérez A Manrubia-Cobo M Gómez-Barrena E Cordero-Ampuero J Esteban J 521 523 41 2013 23611308 \n8 Comparison of tigecycline and vancomycin for treatment of experimental foreign-body infection due to methicillin-resistant Staphylococcus aureus Antimicrob Agents Chemother Vaudaux P Fleury B Gjinovci A Huggler E Tangomo-Bento M Lew DP 3150 3152 53 2009 19364855 \n9 Activities of fosfomycin, tigecycline, colistin, and gentamicin against extended-spectrum-β-lactamase-producing Escherichia coli in a foreign-body infection model Antimicrob Agents Chemother Corvec S Furustrand Tafin U Betrisey B Borens O Trampuz A 1421 1427 57 2013 23295934 \n10 Effectiveness and safety of high-dose tigecycline-containing regimens for the treatment of severe bacterial infections Int J Antimicrob Agents Falagas ME Vardakas KZ Tsiveriotis KP Triarides NA Tansarli GS 1 7 44 2014 24602499 \n11 Tigecycline J Antimicrob Chemother Pankey GA 470 480 3 2005 \n12 Severe coagulation disorder with hypofibrinogenemia associated with the use of tigecycline Ann Hematol Pieringer H Schmekal B Biesenbach G Pohanka E 1063 1064 89 2010 20174923 \n13 Life-threatening coagulopathy and hypofibrinogenaemia induced by tigecycline in a patient with advanced liver cirrhosis Eur J Gastroenterol Hepatol Rossitto G Piano S Rosi S Simioni P Angeli P 681 684 26 2014 24667348 \n14 Hypofibrinogenemia induced by tigecycline: a potentially life-threatening coagulation disorder Infect Dis Sabanis N Paschou E Gavriilaki E Kalaitzoglou A Vasileiou S 743 746 47 2015 \n15 Tigecycline-associated hypofibrinogenemia: a case report and review of the literature IDCases Wu PC Wu CC 56 57 11 2018 29560313 \n16 A case report of patient with severe acute cholangitis with tigecycline treatment causing coagulopathy and hypofibrinogenemia Medicine Wu X Zhao P Dong L Zhang X 0 96 2017 \n17 A lesser known side effect of tigecycline: hypofibrinogenemia Turk J Hematol Yılmaz Duran F Yıldırım H Şen EM 83 84 35 2018 \n18 High-dose tigecycline-associated alterations in coagulation parameters in critically ill patients with severe infections Int J Antimicrob. Agents Routsi C Kokkoris S Douka E Ekonomidou F Karaiskos I Giamarellou H 90 93 45 2015 \n19 Tigecycline treatment causes a decrease in fibrinogen levels Antimicrob Agents Chemother Zhang Q Zhou S Zhou J 1650 1655 59 2015 25547356 \n20 A retrospective analysis of the effect of tigecycline on coagulation function Chem Pharm Bull Leng B Xue YC Zhang W Gao TT Yan GQ Tang H 258 264 67 2019 30828002\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(10)",
"journal": "Cureus",
"keywords": "adverse effect; hemarthrosis; hypofibrinogenemia; periprosthetic infection; tigecycline",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e5883",
"pmc": null,
"pmid": "31772853",
"pubdate": "2019-10-10",
"publication_types": "D002363:Case Reports",
"references": "23295934;29245350;16285354;16790575;29560313;19364855;20174923;25241261;24667348;29212626;27883369;22687540;16040625;24602499;25951751;30828002;23611308;16863487;25547356",
"title": "Spontaneous Knee Hemarthrosis Due to Hypofibrinogenemia Following Tigecycline Treatment for Periprosthetic Joint Infection.",
"title_normalized": "spontaneous knee hemarthrosis due to hypofibrinogenemia following tigecycline treatment for periprosthetic joint infection"
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"companynumb": "GR-PFIZER INC-2019528352",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ENOXAPARIN SODIUM"
},
"drugadditional": null,... |
{
"abstract": "Allergy to steroids is an uncommon and harmful condition that leads to a decrease in treatment options and increase in morbidity due to the suboptimal disease control. It can manifest as an immediate response or a delay manifestation. Worsening of underlying condition and not treatment response can indicate corticosteroids hypersensitivity as well. Despite its low prevalence, all clinicians should be aware of this condition and know the treatment options. This narrative review attempts to update information about corticosteroid allergy and we present a case of a patient with the diagnosis of Vogt Koyanagi Harada Syndrome with a history of steroids allergy, as an example, to integrate this information to the ocular inflammation field.",
"affiliations": "Asociación Para Evitar La Ceguera En México, Hospital Luis Sánchez Bulnes, Ciudad De México, San Lucas, México.;Research Group in Neurosciences NeURos. Escuela De Medicina Y Ciencias De La Salud, Universidad Del Rosario, Bogotá, Colombia.;Research Group in Neurosciences NeURos. Escuela De Medicina Y Ciencias De La Salud, Universidad Del Rosario, Bogotá, Colombia.",
"authors": "Concha-Del Rio|Luz Elena|LE|https://orcid.org/0000-0002-0081-7745;Uribe-Reina|Pilar|P|;De-La-Torre|Alejandra|A|https://orcid.org/0000-0003-0684-1989",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2020.1766511",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": null,
"journal": "Ocular immunology and inflammation",
"keywords": "Corticosteroids; cross reactions; delayed hypersensitivity; hypersensitivity; immediate hypersensitivity",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": null,
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "32643993",
"pubdate": "2020-07-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Allergy against Steroids in Ocular Inflammation.",
"title_normalized": "allergy against steroids in ocular inflammation"
} | [
{
"companynumb": "MX-MYLANLABS-2020M1070248",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nCurrently, there is no validated treatment for fetal cytomegalovirus (CMV). Two studies suggest that high-dose maternal valacyclovir decreases fetal viral load and improves outcomes in moderately-symptomatic fetuses. We offered valacyclovir in cases of fetal infection lacking ultrasound abnormalities or with non-severe infection. Maternal tolerability, fetal outcome and newborn blood viral load were evaluated in pregnancies of mothers receiving valacyclovir.\n\n\nMETHODS\nWe performed a case series including 8 pregnancies with fetal CMV classified as unaffected/mildly-moderately affected. Mothers received valacyclovir (8 g/24h) from fetal infection diagnosis to delivery. Standard newborn evaluation was performed, and viremia was determined in the first 48 h of life and compared according to length of maternal treatment and presence/absence of prenatal anomalies.\n\n\nRESULTS\nValacyclovir was administered at a median gestational age of 26.5 weeks (23.8-33.1) in 3 cases without fetal abnormalities, and 5 with mild/moderate abnormalities. Three were 3 first trimester primary infections, one non-primary infection, and in 4 the type of infection was unknown. Valacyclovir was well-tolerated. Fetal features did not progress. Three newborns were asymptomatic, and one was severely affected (bilateral chorioretinitis). The median newborn viral load (IQR) was 502 IU/mL (231-191781) with lower levels when maternal treatment was administered ≥10 weeks, and in cases without fetal abnormalities [median 234 IU/mL (228-711) vs. 4061 (292-510500) p = .18; and 234 IU/mL (228-379500) vs. 711 IU/mL (292-4061) p = .65, respectively], these differences being non-significant.\n\n\nCONCLUSIONS\nFetal CMV lesions remained stable with high-dose maternal valacyclovir. Newborn viral load was unchanged despite treatment duration and fetal/neonatal abnormalities.\n\n\nCONCLUSIONS\nFetal cytomegalovirus lesions remained stable with high-dose maternal valacyclovir. Newborn viral load was unchanged despite treatment duration and fetal/newborn abnormalities.",
"affiliations": "Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu). Institut Clínic de Ginecología, Obstetricia i Neonatologia, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.;Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu). Institut Clínic de Ginecología, Obstetricia i Neonatologia, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.;Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu). Institut Clínic de Ginecología, Obstetricia i Neonatologia, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.;Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu). Institut Clínic de Ginecología, Obstetricia i Neonatologia, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.;Department of Clinical Microbiology, Hospital Clinic, University of Barcelona; Institute for Global Health (ISGlobal), Barcelona, Spain.;Department of Obstetrics, Prenatal Diagnosis, Miguel Servet University Hospital, Zaragoza, Spain.;Obstetrics Service, Department of Obstetrics, Gynaecology and Reproduction, Institut Universitari Dexeus, Barcelona, Spain.;Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu). Institut Clínic de Ginecología, Obstetricia i Neonatologia, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.;Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu). Institut Clínic de Ginecología, Obstetricia i Neonatologia, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.;Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu). Institut Clínic de Ginecología, Obstetricia i Neonatologia, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.;Department of Pediatric Infectious Diseases, Hospital Sant Joan de Deu, Universitat de Barcelona, Barcelona, Spain.;Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu). Institut Clínic de Ginecología, Obstetricia i Neonatologia, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.",
"authors": "Goncé|Anna|A|;Hawkins-Villarreal|Ameth|A|;Salazar|Laura|L|;Guirado|Laura|L|;Marcos|Maria-Angeles|MA|;Pascual Mancho|Jara|J|;Prats|Pilar|P|;López|Marta|M|;Eixarch|Elisenda|E|;Salvia|Maria-Dolors|MD|;Fortuny|Claudia|C|;Figueras|Francesc|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/14767058.2020.1843016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1476-4954",
"issue": null,
"journal": "The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians",
"keywords": "Fetal cytomegalovirus infection; fetal treatment; high-dose valacyclovir",
"medline_ta": "J Matern Fetal Neonatal Med",
"mesh_terms": null,
"nlm_unique_id": "101136916",
"other_id": null,
"pages": "1-5",
"pmc": null,
"pmid": "33143511",
"pubdate": "2020-11-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Maternal high-dose valacyclovir and its correlation with newborn blood viral load and outcome in congenital cytomegalovirus infection.",
"title_normalized": "maternal high dose valacyclovir and its correlation with newborn blood viral load and outcome in congenital cytomegalovirus infection"
} | [
{
"companynumb": "ES-GLAXOSMITHKLINE-ES2020GSK228840",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VALACYCLOVIR HYDROCHLORIDE"
},
"drug... |
{
"abstract": "METHODS\nWe present a case of a middle-aged man admitted to an inpatient detoxification facility for withdrawal of intranasal heroin, alprazolam, and ethanol. The patient was placed on methadone and chlordiazepoxide tapers. Ondansetron and trazodone were prescribed as needed for symptom control. On the third hospital day, the patient was found unresponsive with blood glucose of 40 mg/dL. He had no history of glucose dysregulation. The patient was pronounced dead shortly thereafter. Methadone overdose was ruled the cause of death.\nThere have been studies linking methadone with glucose dysregulation. Hypoglycemia can induce changes in the electrical system in the heart, including lengthening QT interval, lengthening repolarization, and causing ST wave changes. In addition, there have been studies linking methadone treatment to QT interval prolongation and torsade de pointes. Ondansetron and trazodone have both been associated with cardiac conduction abnormalities.\n\n\nMETHODS\nWe recommend initial blood glucose and cardiac monitoring in patients taking methadone 40 mg daily or higher.",
"affiliations": "Zucker Hillside Hospital, Glen Oaks, NY.;Hofstra Northwell School of Medicine, Hempstead, NY.",
"authors": "Plescia|Christopher J|CJ|;Manu|Peter|P|",
"chemical_list": "D000701:Analgesics, Opioid; D001786:Blood Glucose; D002707:Chlordiazepoxide; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000692",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "25(2)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000701:Analgesics, Opioid; D001786:Blood Glucose; D002707:Chlordiazepoxide; D003645:Death, Sudden; D062787:Drug Overdose; D006801:Humans; D007003:Hypoglycemia; D008297:Male; D008691:Methadone; D008875:Middle Aged; D058850:Opiate Substitution Treatment; D019966:Substance-Related Disorders",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e267-e269",
"pmc": null,
"pmid": "29189312",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypoglycemia and Sudden Death During Treatment With Methadone for Opiate Detoxification.",
"title_normalized": "hypoglycemia and sudden death during treatment with methadone for opiate detoxification"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2017US-158832",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"druga... |
{
"abstract": "A caesarean scar pregnancy is a complex iatrogenic pathology, which represents a consequence of a previous caesarean section. It increased in recent years due to parallel increase of cesarean sections.\nWe present a retrospective study on patients with caesarean scar pregnancy diagnosed in our department from June 2016 to June 2019. Stable women with an embryo (with or without cardiac activity) who accepted our experimental protocol were treated with single dose of methotrexate (50 mg administered locally intracavitary + 50 mg administered intramuscularly) and folinic acid (15 mg/day orally for 30 days). Clinically stable women with embryo (without cardiac activity) who decided to wait, were monitored by serial assays of b-hCG and clinical and ultrasonographic follow up. Women who were clinically unstable with embryo (without cardiac activity), were referred for urgent surgical treatment with dilation and curettage.\nCaesarean scar pregnancy was diagnosed in sixteen women. Among these women, seven were treated according to our experimental protocol with methotrexate and folinic acid and only one had profuse bleeding, which required a laparotomic hysterectomy. Four women were treated urgently with dilatation and curettage. Five women chose to wait: they were monitored and all spontaneously had a miscarriage.\nIn our preliminary study, we highlighted how our experimental protocol gave encouraging results in the first 10 weeks of caesarean scar pregnancy. However, caution is needed in patients with advanced gestational age, a gestational sac with large diameter, higher CRL and presence of embryonic cardiac activity.",
"affiliations": "Department of General Surgery and Medical Surgical Specialties, University of Catania, Catania, Italy.;Department of General Surgery and Medical Surgical Specialties, University of Catania, Catania, Italy.;Department of General Surgery and Medical Surgical Specialties, University of Catania, Catania, Italy.;Department of Obstetrics and Gynecology, \"Filippo Del Ponte\" Hospital, University of Insubria, Varese, Italy.;Department of Obstetrics and Gynaecology, Campus Bio-Medico University, Rome, Italy.;Department of General Surgery and Medical Surgical Specialties, University of Catania, Catania, Italy.",
"authors": "Gulino|Ferdinando Antonio|FA|;Pappalardo|Elisa|E|;Ettore|Carla|C|;Laganà|Antonio Simone|AS|;Capriglione|Stella|S|;Ettore|Giuseppe|G|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5114/pm.2020.97836",
"fulltext": "\n==== Front\nPrz Menopauzalny\nPrz Menopauzalny\nMR\nPrzegla̜d Menopauzalny = Menopause Review\n1643-8876 2299-0038 Termedia Publishing House \n\n97836\n10.5114/pm.2020.97836\nOriginal Paper\nCaesarean scar pregnancy: descriptive paper of three different types of management on a series of clinical cases\nGulino Ferdinando Antonio 1 Pappalardo Elisa 1 Ettore Carla 1 Laganà Antonio Simone 2 Capriglione Stella 3 Ettore Giuseppe 1 1 Department of General Surgery and Medical Surgical Specialties, University of Catania, Catania, Italy\n2 Department of Obstetrics and Gynecology, “Filippo Del Ponte” Hospital, University of Insubria, Varese, Italy\n3 Department of Obstetrics and Gynaecology, Campus Bio-Medico University, Rome, Italy\nCorresponding author: Ferdinando Antonio Gulino MD, Department of General Surgery and Medical Surgical Specialties, University of Catania, 95123 Catania, Italy, e-mail: docferdi@hotmail.it\n13 7 2020 \n7 2020 \n19 2 61 65\n20 3 2020 09 5 2020 Copyright © 2020 Termedia2020This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0). License (http://creativecommons.org/licenses/by-nc-sa/4.0/)Introduction\nA caesarean scar pregnancy is a complex iatrogenic pathology, which represents a consequence of a previous caesarean section. It increased in recent years due to parallel increase of cesarean sections.\n\nMaterial and methods\nWe present a retrospective study on patients with caesarean scar pregnancy diagnosed in our department from June 2016 to June 2019. Stable women with an embryo (with or without cardiac activity) who accepted our experimental protocol were treated with single dose of methotrexate (50 mg administered locally intracavitary + 50 mg administered intramuscularly) and folinic acid (15 mg/day orally for 30 days). Clinically stable women with embryo (without cardiac activity) who decided to wait, were monitored by serial assays of b-hCG and clinical and ultrasonographic follow up. Women who were clinically unstable with embryo (without cardiac activity), were referred for urgent surgical treatment with dilation and curettage.\n\nResults\nCaesarean scar pregnancy was diagnosed in sixteen women. Among these women, seven were treated according to our experimental protocol with methotrexate and folinic acid and only one had profuse bleeding, which required a laparotomic hysterectomy. Four women were treated urgently with dilatation and curettage. Five women chose to wait: they were monitored and all spontaneously had a miscarriage.\n\nConclusions\nIn our preliminary study, we highlighted how our experimental protocol gave encouraging results in the first 10 weeks of caesarean scar pregnancy. However, caution is needed in patients with advanced gestational age, a gestational sac with large diameter, higher CRL and presence of embryonic cardiac activity.\n\ncaesarean scar pregnancymethotrexateexpectant managementdilatation and curettagemiscarriage\n==== Body\nIntroduction\nA caesarean scar pregnancy is a complex iatrogenic pathology, which represents a consequence of a previous caesarean section. It is a condition difficult to treat, and could lead to complications during all three trimesters of pregnancy. It has had an exponential increase in recent years due to parallel increase of the number of cesarean sections.\n\nLate consequences of caesarean sections, such as placenta praevia and placenta accreta spectrum disorders, are well known [1]; the long-term consequences are neither known nor documented. Clinically their expression in the first trimester is represented by the caesarean scar pregnancy. It is defined as a gestational sac, implanted in the scar area of the previous caesarean section.\n\nConsidering the increasing incidence of caesarean sections in recent years, the caesarean scar pregnancy has to be evaluated during the first trimester of pregnancy. The clinical management of a caesarean scar pregnancy is not easy because there are many options of treatment.\n\nFrom an epidemiological point of view, the scientific literature described mainly case reports of caesarean scar pregnancy. Given the limited numbers of patients treated [1], it is difficult to define which is the best clinical practice for the management of this condition.\n\nThe most important scientific works on caesarean scar pregnancy were published in 2012 and 2015 by Timor-Tritsch et al. [1, 2]. However, despite this, no slandered treatment protocol has been universally accepted by the different scientific societies. The Royal College of Obstetricians and Gynaecologists (RCOG) guidelines defined the ultrasonographic criteria for diagnosing caesarean scar pregnancy on transvaginal scan; however, regarding the treatment, they assume that there is insufficient evidence to recommend any one specific intervention over another for caesarean scar pregnancy [3]. Therefore, it is also important to explain to the patient, by an accurate counseling, which are the different types of treatments of this clinical condition.\n\nAim of this study is the evaluation of the efficacy and safety of our experimental treatment protocol, based on the association between intracavitary and intramuscular methotrexate, for patients affected by caesarean scar pregnancy, over a period of 3 years, between June 2016 and June 2019.\n\nMaterial and methods\nThis was a retrospective experimental study conducted in a tertiary referral center of Obstetrics and Gynecology, the “Azienda di Rilievo Nazionale e di Alta Specializzazione” (ARNAS) Garibaldi Nesima of Catania (Italy). All women with a caesarean scar pregnancy, diagnosed in the period between June 2016 and June 2019, were included in the study. This analysis was performed considering the medical records of the first aid department.\n\nThe diagnosis of caesarean scar pregnancy was performed by transvaginal ultrasound with an IC5-9-D endocavitary probe of a GE Voluson E8 Expert BT13 ultrasound, with the ultrasound criteria described by Timor-Tritsch et al. [2]:\n\nempty uterus,\n\nempty endocervical canal,\n\nthin or absent layer of myometrium between gestational sac and urinary bladder,\n\ngestational sac or trophoblast sited anteriorly, at the level of internal os, or lower uterine segment at the site of the previous hysterotomy scar,\n\nevidence of trophoblastic/placental blood flow on Doppler examination.\n\n\n\nCaesarean scar pregnancy was diagnosed in sixteen women between June 2016 and June 2019. Some examples were shown in Figures 1-3.\n\nFig. 1 Color flow of a scar pregnancy\n\nFig. 2 Caesarean scar pregnancy with fetal activity\n\nFig. 3 Caesarean scar pregnancy and crown-rump length\n\nMedical management with high doses of methotrexate and folinic acid (15 mg/day orally for 30 days) as first-line therapy was offered to all clinically stable women and embryo with or without cardiac activity, but without evidence of hemorrhage, or suspected uterine rupture, as assessed ultrasonographically. Liver and kidney function tests, and patient reliability for follow-up was also assessed. There were no exclusion criteria due to gestational age, β-hCG level and diameter of the gestational sac. These women were treated according to our experimental protocol with single dose of methotrexate (50 mg administered locally intracavitary + 50 mg administered intramuscularly) and folinic acid (15 mg/day orally for 30 days). During this treatment, an antibiotic prophylaxis with clarithromycin per os (500 mg × 2 for 5 days) or intramuscular cefazolin (1 g × 2 for 5 days) was administrated.\n\nThe patients who underwent to this type of treatment, according to Italian law, signed an informed consent for abortion according to the law 194/78 art. 5. The patients were not hospitalized because they were clinically stable, but they were advised to come into our hospital if there was abdominal pain or bleeding. The patients were adequately informed about the proposed type of treatment and the risks related to scar pregnancy.\n\nA waiting procedure, with serial assays of β-hCG and clinical and ultrasound monitoring was proposed to all clinically stable patients with embryo devoid of cardiac activity, without evidence of hemorrhage, and no suspicion of uterine rupture, as assessed ultrasonographically, with normal hepatic and renal function and patient reliability for follow-up. The serial assays of b-hCG were performed at the first clinical examination, after 48-72 h, and after 7 days.\n\nWomen who were clinically unstable with embryo devoid of cardiac activity, with evidence of menometrorrhagia, or suspected uterine rupture assessed by ultrasound, were referred for urgent surgical treatment with dilation and curettage, and subsequent close monitoring of vital signs and blood loss.\n\nFollowing data were collected: maternal age, number of previous caesarean sections, gestational age, mean gestational sac diameter, crown-rump length (CRL), presence of embryonic cardiac activity, initial and subsequent β-hCG levels, methotrexate side effects, treatment outcome. The correct therapy with methotrexate was confirmed by subsequent re-evaluations of serum β-hCG level (< 5 IU/l).\n\nData were analyzed using SPSS version 23 (IBM Corp, Armonk, NY). The study was approved by the institutional ethics committee for human research of the ARNAS Garibaldi.\n\nResults\nCaesarean scar pregnancy was diagnosed in sixteen women between June 2016 and June 2019. Among these women, seven were treated according to our experimental protocol with single dose of methotrexate (50 mg administered locally intracavitary + 50 mg administered intramuscularly) and folinic acid (15 mg/day orally for 30 days). Four women, given the presence of high blood loss, were treated urgently with instrumental revision of the uterine cavity (dilation and curettage). Five women, on the other hand, chose to wait; they were monitored and all of them had spontaneous miscarriage (Table 1). Their age ranged from 24 to 47 years, and the number of previous caesarean sections ranged from 1 to 3. Gestational age ranged from 5 + 6 to 11 + 0 weeks based on their last menstrual cycle. The diameter of the gestational sac ranged from 10 mm to 41 mm and the CRL (identified in nine women) ranged from 4 mm to 15 mm. Embryonic cardiac activity was found in five women. The baseline b-hCG level ranged from 3146 to 222123 IU/l.\n\nTable 1 Results of the clinical study\n\nClinical cases\tAge\tNo. of previous CS\tGestational age\tBasal β-hCG\tFetal heart\tSuccess of MTX protocol\t48-72 h β-hCG\t5 days βhcg\tMSD\tCRL\tOther interventions\t\n1\t30\t1\t6 + 1\t26150\t√\t√\t30482\t28654\t18 mm\t5.6\t\t\n2\t37\t3\t8 + 0\t62458\t√\t√\t61966\t37068\t20 mm\t7.2\t\t\n3\t26\t3\t8 + 3\t30355\t×\t√\t29794\t/\t17 mm\t/\t\t\n4\t47\t3\tND\t6557\t×\t√\t1124\t/\t17 mm\t/\t\t\n5\t24\t3\t7 + 3\t222123\t√\t√\t171623\t51506\t14 mm\t7.0\t\t\n6\t38\t1\t7 + 0\t70923\t√\t√\t49441\t/\t19 mm\t9.4\t\t\n7\t35\t2\t11 + 0\t81181\t√\t×\t51418\t42447\t41 mm\t15\tHysterectomy\t\n8\t32\t1\t8 + 1\t47520\t×\t/\t/\t/\t18 mm\t7\tD&C\t\n9\t43\t2\t6 + 2\t13476\t×\t/\t/\t/\t12 mm\t4.7\tD&C\t\n10\t38\t2\t6 + 6\t19836\t×\t/\t/\t/\t16 mm\t/\tD&C\t\n11\t42\t1\t7 + 3\t22941\t×\t/\t/\t/\t16 mm\t/\tD&C\t\n12\t40\t3\t6 + 0\t9250\t×\t/\t/\t/\t14 mm\t4\t\t\n13\t35\t2\t6 + 2\t13654\t×\t/\t/\t/\t16 mm\t5.2\t\t\n14\t36\t2\t5 + 6\t3146\t×\t/\t/\t/\t10 mm\t/\t\t\n15\t43\t2\t6 + 0\t4810\t×\t/\t/\t/\t12 mm\t/\t\t\n16\t42\t1\t6 + 5\t5220\t×\t/\t/\t/\t14 mm\t/\t\t\nMSD – mean sac diameter, CRL – crown-rump lenght, MTX – metotrexate, CS – caesarean section\n\nThere were no adverse effects related to methotrexate, such as bone marrow suppression, lung fibrosis, nonspecific pneumonia, liver cirrhosis, renal failure and gastric ulcer. None of the women under examination complained of nausea. Out of seven women who were treated with methotrexate, only one had profuse bleeding, which required a laparotomic hysterectomy. This patient disappointed our serial follow up and she was in an advanced stage of pregnancy, at 11 weeks of gestational age.\n\nThree women were lost to the serial b-hCG test. However, none of the women who referred to our clinic came back complaining of specific clinical signs or symptoms. Patients who were treated urgently by dilatation and curettage did not have any clinical problem.\n\nThe patients who chose a waiting management had miscarriages, and there were no signs of previous scar pregnancy on ultrasound examination done at the follow up.\n\nDiscussion\nIn our work we have decided to perform an experimental protocol with single dose of methotrexate (50 mg administered locally intracavitary + 50 mg administered intramuscularly) and folinic acid (15 mg/day orally for 30 days) which needs a close monitoring.\n\nIn 2015 a systematic review on the efficacy of systemic methotrexate for caesarean scar pregnancy treatment identified 40 cases from 27 articles, reporting a 55% success rate (22 out of 40) with systemic methotrexate alone, and a 85% success rate (34 of 40 cases) with further minor interventions such as methotrexate locally injected, dilatation and curettage, or dilatation and curettage and embolization of the uterine arteries [4]. In 2017 another systematic review reported a 56% success rate for systemic methotrexate therapy alone [5]. In literature, methotrexate is usually given as a single therapy [6-8] or in multiple-dose regime [9-10]. The single-dose regimen included a dosage of 50 mg/m2 (body surface) [6-8]. Dosage would be 80 mg for an average body surface of 1.6 m2. In multiple doses a regimen of 50 mg/m2 (body surface) [10] or 1.0 mg/kg (weight) [9] of intramuscular methotrexate was administered every other day for about 8-10 doses, so the total amount of methotrexate would be higher, but given over a longer period. Patients were given calcium foliate for detoxication 12 h after the injection [10].\n\nIn the study by Tanaka et al. [11], 24 out of 28 women (85.7%) with high dose intravenous methotrexate therapy alone and 15 mg folinic acid (leucovorin) orally given at 30, 42, 54 and 66 h post commencement of methotrexate, were treated successfully; 3 women (10.7%) required suction evacuation following initial treatment with methotrexate and folinic acid. This study also demonstrated that the efficacy of high dose intravenous methotrexate therapy for caesarean scar pregnancy (85.7%, 24 out of 28 women) is similar to its efficacy for interstitial ectopic pregnancy (93.9%, 31 of 33 women).\n\nSome authors argued instead that systemic methotrexate may not be effective in the treatment of caesarean scar pregnancy due to the surrounding fibrous scar tissue, rather than normally vascular myometrium [12].\n\nIn our scientific work, we have chosen this protocol because some other scientific works [8-11] have demonstrated clinical efficacy of higher doses of methotrexate. We have chosen this higher dose of folinic acid to avoid any toxicity related to the higher single dose of methotrexate.\n\nThe data of our study, although interesting and promising, have to be considered preliminary, related to the smallness of our sample. Further studies with larger sample of patients could give more information about this pathological condition.\n\nConclusions\nIn our preliminary study, we highlighted how the treatment with methotrexate injected in the gestational sac, in association with methotrexate i.m. gave encouraging results in the first 10 weeks of caesarean scar pregnancy.\n\nHowever, caution is needed in patients with advanced gestational age (> 10 weeks), or when the ultrasound shows a gestational sac with large diameter (> 30 mm), higher CRL (> 12 mm) and presence of embryonic cardiac activity. In these cases, additional therapy may be necessary. A primary obstetric objective must therefore be a diagnosis as early as possible to avoid subsequent complications.\n\nDisclosure\nThe authors report no conflict of interest\n==== Refs\n1 Timor-Tritsch IE , Khatib N , Monteagudo A , et al \nCesarean Scar Pregnancies\n. J Ultrasound Med \n2015 ; 34 : 601 -610\n.25792575 \n2 Timor-Tritsch IE , Monteagudo A , Santos R , et al \nThe diagnosis, treatment, and follow-up of cesarean scar pregnancy\n. Am J Obstet Gynecol \n2012 ; 207 : 44e1 -e13\n.22607667 \n3 Elson CJ , Salim R , Potdar N , et al \non behalf of the Royal College of Obstetricians and Gynaecologists. Diagnosis and management of ectopic pregnancy\n. BJOG \n2016 ; 123 : e15 -e55\n.27813249 \n4 Bodur S , Özdamar O , Kiliç S , Gün I \nThe efficacy of the systemic methotrexate treatment in caesarean scar ectopic pregnancy: A quantitative review of English literature\n. J Obstet Gynaecol \n2015 ; 35 : 290 -296\n.25259651 \n5 Maheux-Lacroix S , Li F , Bujold E , et al \nCesarean Scar Pregnancies: A Systematic Review of Treatment Options\n. J Minim Invasive Gynecol \n2017 ; 21 : 915 -925\n.\n6 Lian F , Wang Y , Chen W , et al \nUterine artery embolization combined with local methotrexate and systemic methotrexate for treatment of cesarean scar pregnancy with different ultrasonographic pattern\n. Cardiovasc Intervent Radiol \n2012 ; 35 : 286 -291\n.21271248 \n7 Yang XY , Yu H , Li KM , et al \nUterine artery embolisation combined with local methotrexate for treatment of caesarean scar pregnancy\n. BJOG \n2010 ; 117 : 990 -996\n.20536432 \n8 Peng P , Ggui T , Liu X , et al \nComparative efficacy and safety of local and systemic methotrexate injection in cesarean scar pregnancy\n. Ther Clin Risk Manag \n2015 ; 11 : 137 -142\n.25670903 \n9 Kutuk MS , Uysal G , Dolanbay M , Ozgun MT \nSuccessful medical treatment of cesarean scar ectopic pregnancies with systemic multidose methotrexate: Single-center experience\n. J Obstet Gynaecol Res \n2014 ; 40 : 1700 -1706\n.24888937 \n10 Yang H , Li S , Ma Z , Jia Y \nTherapeutic effects of uterine artery embolisation (UAE) and methotrexate (MTX) conservative therapy used in treatment of cesarean scar pregnancy\n. Arch Gynecol Obstet \n2016 ; 293 : 819 -823\n.26386965 \n11 Tanaka K , Coghill E , Ballard E , et al \nManagement of caesarean scar pregnancy with high dose intravenous methotrexate infusion therapy: 10-year experience at a single tertiary centre\n. Eur J Obstet Gynecol Reprod Biol \n2019 ; 237 : 28 -32\n.30999082 \n12 Ravhon A , Ben-Chetrit A , Rabinowitz R , et al \nSuccessful methotrexate treatment of a viable pregnancy within a thin uterine scar\n. BJOG AnInt J Obstet Gynaecol . 1997 ; 104 : 628 -629\n.\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1643-8876",
"issue": "19(2)",
"journal": "Przeglad menopauzalny = Menopause review",
"keywords": "caesarean scar pregnancy; dilatation and curettage; expectant management; methotrexate; miscarriage",
"medline_ta": "Prz Menopauzalny",
"mesh_terms": null,
"nlm_unique_id": "101263235",
"other_id": null,
"pages": "61-65",
"pmc": null,
"pmid": "32802015",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article",
"references": "30999082;9166212;22607667;25670903;25792575;28599886;24888937;26386965;21271248;25259651;20536432",
"title": "Caesarean scar pregnancy: descriptive paper of three different types of management on a series of clinical cases.",
"title_normalized": "caesarean scar pregnancy descriptive paper of three different types of management on a series of clinical cases"
} | [
{
"companynumb": "IT-ACCORD-198836",
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"actiondrug": "5",
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"activesubstancename": "LEUCOVORIN"
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"drugadditional": "3",
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{
"abstract": "OBJECTIVE\nIsolated deletion (20q) is relatively common in myeloid neoplasms and has been rarely reported in cases of therapy-related myelodysplastic syndrome (MDS). Our aim was to characterize cases of isolated del(20q) in bone marrow biopsy specimens from patients with a history of chemotherapy with morphologic findings insufficient for a diagnosis of MDS.\n\n\nMETHODS\nIn this retrospective study from one institution, we identified 22 patients with isolated del(20q) and no or minimal dysplasia and evaluated clinical and pathologic characteristics.\n\n\nRESULTS\nEleven of the patients had a history of chemotherapy for mostly lymphoproliferative disorders. There were no statistically significant differences in peripheral blood or bone marrow features between patients with a history of chemotherapy and those without. Three patients with a history of chemotherapy had died at last follow-up; cause of death was recurrent nonmyeloid neoplasm. None of the patients with a history of chemotherapy subsequently developed a high-grade myeloid neoplasm, whereas one of the patients who had not received prior chemotherapy developed refractory anemia with excess blasts 2.\n\n\nCONCLUSIONS\nThe presence of del(20q) as an isolated bone marrow cytogenetic abnormality in the absence of morphologic findings sufficient for a diagnosis of acute myeloid leukemia, myeloproliferative neoplasm, or MDS portends an indolent clinical course, regardless of previous exposure to chemotherapy.",
"affiliations": "From the Departments of Laboratory Medicine and Pathology.;From the Departments of Laboratory Medicine and Pathology.;From the Departments of Laboratory Medicine and Pathology.;From the Departments of Laboratory Medicine and Pathology.;From the Departments of Laboratory Medicine and Pathology.;From the Departments of Laboratory Medicine and Pathology.;Medicine, University of Minnesota, Minneapolis.;From the Departments of Laboratory Medicine and Pathology.;From the Departments of Laboratory Medicine and Pathology dolan009@umn.edu.",
"authors": "Courville|Elizabeth L|EL|;Singh|Charanjeet|C|;Yohe|Sophia|S|;Linden|Michael A|MA|;Naemi|Kaveh|K|;Berger|Michael|M|;Ustun|Celalettin|C|;McKenna|Robert W|RW|;Dolan|Michelle|M|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "England",
"delete": false,
"doi": "10.1093/ajcp/aqw024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9173",
"issue": "145(4)",
"journal": "American journal of clinical pathology",
"keywords": "Chemotherapy; Isolated deletion 20q; Myelodysplastic syndrome; Myeloid neoplasm; Therapy related; del(20q)",
"medline_ta": "Am J Clin Pathol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001853:Bone Marrow; D002872:Chromosome Deletion; D002890:Chromosomes, Human, Pair 20; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "0370470",
"other_id": null,
"pages": "459-66",
"pmc": null,
"pmid": "27124938",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Patients With a History of Chemotherapy and Isolated del(20q) With Minimal Myelodysplasia Have an Indolent Course.",
"title_normalized": "patients with a history of chemotherapy and isolated del 20q with minimal myelodysplasia have an indolent course"
} | [
{
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
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... |
{
"abstract": "Kounis syndrome, also known as allergic myocardial infarction or allergic angina syndrome, coincides with chest pain and allergic reactions. It involves the activation of interrelated inflammatory cells following allergic, anaphylactic or anaphylactoid insults. We report a case of Kounis syndrome complicated by an injection of ceftazidime. A 52-year-old man developed shortness of breath and hypotension, leading to immediate unconsciousness, after a ceftazidime injection. Despite intensive care management, he showed no improvement and died approximately 19 h after ceftazidime administration. Autopsy showed massive laryngeal oedema, mucous plugging and collapsed lungs. An ImmunoCAP tryptase assay showed the tryptase level in an autopsy sample to be 118 µg/L (normal < 11.4 µg/L). Microscopy of the myocardium showed cellular infiltration preceding myocardial necrosis. These findings support the pathophysiological theory of Kounis syndrome, with cellular infiltration proposed as the cause of myocardial injury rather than an effect related to the healing process.",
"affiliations": "Department of Forensic Medicine, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.;Department of Forensic Medicine, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.;Department of Forensic Medicine, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.;Department of Forensic Medicine, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.",
"authors": "Kitulwatte|Idg|I|;Gangahawatte|S|S|;Perera|Ulms|U|;Edirisinghe|Pas|P|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002442:Ceftazidime",
"country": "England",
"delete": false,
"doi": "10.1177/0025817217695904",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-8172",
"issue": "85(4)",
"journal": "The Medico-legal journal",
"keywords": "Kounis syndrome; allergy; ceftazidime; myocardial cellular infiltration",
"medline_ta": "Med Leg J",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001344:Autopsy; D002442:Ceftazidime; D006801:Humans; D000074962:Kounis Syndrome; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D011677:Punctures",
"nlm_unique_id": "0412004",
"other_id": null,
"pages": "215-218",
"pmc": null,
"pmid": "29210337",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Death following ceftazidime-induced Kounis syndrome.",
"title_normalized": "death following ceftazidime induced kounis syndrome"
} | [
{
"companynumb": "LK-B. BRAUN MEDICAL INC.-2055586",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFTAZIDIME"
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{
"abstract": "Maraviroc (MVC) is an allosteric inhibitor of human immunodeficiency virus type 1 (HIV-1) entry, and is the only CCR5 antagonist licensed for use as an anti-HIV-1 therapeutic. It acts by altering the conformation of the CCR5 extracellular loops, rendering CCR5 unrecognizable by the HIV-1 envelope (Env) glycoproteins. This study aimed to understand the mechanisms underlying the development of MVC resistance in HIV-1-infected patients. To do this, we obtained longitudinal plasma samples from eight subjects who experienced treatment failure with phenotypically verified, CCR5-tropic MVC resistance. We then cloned and characterized HIV-1 Envs (n = 77) from plasma of pretreatment (n = 36) and treatment failure (n = 41) samples. Our results showed variation in the magnitude of MVC resistance as measured by reductions in maximal percent inhibition of Env-pseudotyped viruses, which was more pronounced in 293-Affinofile cells compared to other cells with similar levels of CCR5 expression. Amino acid determinants of MVC resistance localized to the V3 Env region and were strain specific. We also observed minimal cross-resistance to other CCR5 antagonists by MVC-resistant strains. We conclude that 293-Affinofile cells are highly sensitive for detecting and measuring MVC resistance through a mechanism that is CCR5-dependent yet independent of CCR5 expression levels. The strain-specific nature of resistance mutations suggests that sequence-based diagnostics and prognostics will need to be more sophisticated than simple position scoring to be useful for managing resistance in subjects taking MVC. Finally, the minimal levels of cross-resistance suggests that recognition of the MVC-modified form of CCR5 does not necessarily lead to recognition of other antagonist-modified forms of CCR5.",
"affiliations": "1 School of Health and Biomedical Sciences, College of Science, Engineering and Health, RMIT University , Melbourne, Australia .;1 School of Health and Biomedical Sciences, College of Science, Engineering and Health, RMIT University , Melbourne, Australia .;2 Centre for Biomedical Research, Burnet Institute , Melbourne, Australia .;2 Centre for Biomedical Research, Burnet Institute , Melbourne, Australia .;1 School of Health and Biomedical Sciences, College of Science, Engineering and Health, RMIT University , Melbourne, Australia .;2 Centre for Biomedical Research, Burnet Institute , Melbourne, Australia .;1 School of Health and Biomedical Sciences, College of Science, Engineering and Health, RMIT University , Melbourne, Australia .;2 Centre for Biomedical Research, Burnet Institute , Melbourne, Australia .;2 Centre for Biomedical Research, Burnet Institute , Melbourne, Australia .;5 Pfizer Global Research and Development , Sandwich, United Kingdom .;5 Pfizer Global Research and Development , Sandwich, United Kingdom .;6 Centauri Therapeutics, Ltd. , Sandwich, United Kingdom .;7 Icahn School of Medicine at Mount Sinai , New York, New York.;3 The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital , Melbourne, Australia .;1 School of Health and Biomedical Sciences, College of Science, Engineering and Health, RMIT University , Melbourne, Australia .;1 School of Health and Biomedical Sciences, College of Science, Engineering and Health, RMIT University , Melbourne, Australia .;1 School of Health and Biomedical Sciences, College of Science, Engineering and Health, RMIT University , Melbourne, Australia .",
"authors": "Flynn|Jacqueline K|JK|;Ellenberg|Paula|P|;Duncan|Renee|R|;Ellett|Anne|A|;Zhou|Jingling|J|;Sterjovski|Jasminka|J|;Cashin|Kieran|K|;Borm|Katharina|K|;Gray|Lachlan R|LR|;Lewis|Marilyn|M|;Jubb|Becky|B|;Westby|Mike|M|;Lee|Benhur|B|;Lewin|Sharon R|SR|;Churchill|Melissa|M|;Roche|Michael|M|;Gorry|Paul R|PR|",
"chemical_list": "D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc",
"country": "United States",
"delete": false,
"doi": "10.1089/AID.2017.0097",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0889-2229",
"issue": "33(12)",
"journal": "AIDS research and human retroviruses",
"keywords": "CCR5; HIV-1; Maraviroc; antagonist; envelope; resistance",
"medline_ta": "AIDS Res Hum Retroviruses",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D018791:CD4 Lymphocyte Count; D002460:Cell Line; D003510:Cyclohexanes; D024882:Drug Resistance, Viral; D005260:Female; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D019713:Receptors, CCR5; D017211:Treatment Failure; D014230:Triazoles; D053586:Virus Internalization",
"nlm_unique_id": "8709376",
"other_id": null,
"pages": "1220-1235",
"pmc": null,
"pmid": "28797170",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Analysis of Clinical HIV-1 Strains with Resistance to Maraviroc Reveals Strain-Specific Resistance Mutations, Variable Degrees of Resistance, and Minimal Cross-Resistance to Other CCR5 Antagonists.",
"title_normalized": "analysis of clinical hiv 1 strains with resistance to maraviroc reveals strain specific resistance mutations variable degrees of resistance and minimal cross resistance to other ccr5 antagonists"
} | [
{
"companynumb": "AU-VIIV HEALTHCARE LIMITED-AU2017193250",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MARAVIROC"
},
"drugadditional":... |
{
"abstract": "Although mother-to-child transmission of HIV has dramatically declined, the number of in utero HIV-exposed, uninfected infants is on the increase. HIV-exposed infants are at an increased risk of mortality, morbidity and slower early growth than their non-HIV exposed counterparts. Maternal HIV increases the risk of having preterm deliveries, intrauterine growth restriction and low birth weight babies. However, the mechanism underlying dysregulation of fetal growth in HIV-infected pregnant women is unknown. We sought to determine whether maternal HIV is associated with dysregulation of the insulin-like growth factor (IGF) axis, some angiogenic factors or other related biomarkers that regulate fetal growth. A total of 102 normotensive pregnant women were enrolled in a small cross-sectional study. Amongst these were thirty-one HIV-1 positive women receiving combination antiretroviral therapy (cART) (Mean age: 30.0 ± 5.1 years; % on ART: 83.9%; median plasma viral load: 683 copies/ml; median CD4 count: 350 cells/ul) and 71 HIV uninfected women (mean age: 27.3 ± 5.8) recruited at delivery. A panel of biomarkers including IGF1 and IGF binding proteins (IGFBP1, IGFBP3), angiopoietins (ANG) 1 and 2, matrix metalloproteinases (MMP) 2 and 9, and galectin 13, was measured in plasma collected from the placental intervillous space. The levels of IGF1, IGFBP1, ANG1, ANG2, MMP2, MMP9 and Gal-13 were not affected by maternal HIV, even when adjusted for maternal factors in linear regression models (all p>0.05). It was observed that HIV-infection in pregnancy did not significantly affect key markers of the IGF axis and angiogenic factors. If anything, it did not affect women. These findings highlight the importance of the use of ART during pregnancy, which maintains factors necessary for fetal development closer to those of healthy women. However, decrease in IGF1 levels might be exacerbated in women con-infected with HIV and malaria.",
"affiliations": "The Biotechnology Center, University of Yaoundé I, Yaoundé, Cameroon.;The Biotechnology Center, University of Yaoundé I, Yaoundé, Cameroon.;Biostatistics Core, Department of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii at Manoa, John A. Burns School of Medicine, Honolulu, Hawaii, United States of America.;Department of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii at Manoa, John A. Burns School of Medicine, Honolulu, Hawaii, United States of America.;The Biotechnology Center, University of Yaoundé I, Yaoundé, Cameroon.;The Biotechnology Center, University of Yaoundé I, Yaoundé, Cameroon.;Department of Zoology, College of Natural and Applied Sciences, University of Dar es Salaam, Dar es Salaam, Tanzania.;The Biotechnology Center, University of Yaoundé I, Yaoundé, Cameroon.;Biostatistics Core, Department of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii at Manoa, John A. Burns School of Medicine, Honolulu, Hawaii, United States of America.;Department of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii at Manoa, John A. Burns School of Medicine, Honolulu, Hawaii, United States of America.;The Biotechnology Center, University of Yaoundé I, Yaoundé, Cameroon.;Department of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii at Manoa, John A. Burns School of Medicine, Honolulu, Hawaii, United States of America.;The Biotechnology Center, University of Yaoundé I, Yaoundé, Cameroon.;Department of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii at Manoa, John A. Burns School of Medicine, Honolulu, Hawaii, United States of America.",
"authors": "Esemu|Livo F|LF|0000-0002-0793-2826;Yuosembom|Emile K|EK|;Fang|Rui|R|;Rasay|Shayne|S|;Fodjo|Barriere A Y|BAY|;Nguasong|John T|JT|;Kidima|Winifrida|W|;Ekali|Gabriel L|GL|;Chen|John J|JJ|;Ndhlovu|Lishomwa|L|;Bigoga|Jude D|JD|;Taylor|Diane W|DW|;Leke|Rose G F|RGF|;Babakhanyan|Anna|A|",
"chemical_list": "D042682:Angiopoietins; D044966:Anti-Retroviral Agents; D015415:Biomarkers; C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D007334:Insulin-Like Growth Factor I; D020780:Matrix Metalloproteinase 9",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0215825",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0215825PONE-D-18-29309Research ArticleBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVHIV-1Medicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVHIV-1Biology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVHIV-1Biology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVHIV-1Biology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVHIV-1Biology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVHIV-1Medicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVHIV-1Biology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVHIV-1Medicine and Health SciencesParasitic DiseasesMalariaMedicine and Health SciencesTropical DiseasesMalariaBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesBiochemistryBiomarkersBiology and Life SciencesAnatomyBody FluidsBloodMedicine and Health SciencesAnatomyBody FluidsBloodBiology and Life SciencesPhysiologyBody FluidsBloodMedicine and Health SciencesPhysiologyBody FluidsBloodMedicine and Health SciencesWomen's HealthMaternal HealthPregnancyMedicine and Health SciencesWomen's HealthObstetrics and GynecologyPregnancyBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyBiology and Life SciencesDevelopmental BiologyEmbryologyPlacentaBiology and Life SciencesAnatomyReproductive SystemPlacentaMedicine and Health SciencesAnatomyReproductive SystemPlacentaImpact of HIV-1 infection on the IGF-1 axis and angiogenic factors in pregnant Cameroonian women receiving antiretroviral therapy HIV-1 does not significantly alter IGF axis and angiogenic factors in pregnancyhttp://orcid.org/0000-0002-0793-2826Esemu Livo F. Data curationFormal analysisInvestigationMethodologyVisualizationWriting – original draftWriting – review & editing123*Yuosembom Emile K. Formal analysisInvestigationMethodologyWriting – review & editing1Fang Rui Data curationSoftwareWriting – review & editing4Rasay Shayne Formal analysisInvestigationWriting – review & editing5Fodjo Barriere A. Y. Formal analysisInvestigationMethodologyWriting – review & editing12Nguasong John T. Formal analysisInvestigationMethodologyWriting – review & editing12Kidima Winifrida MethodologyResourcesSupervisionValidationWriting – review & editing6Ekali Gabriel L. Funding acquisitionMethodologySupervisionValidationWriting – review & editing1Chen John J. Data curationFormal analysisResourcesSoftwareSupervisionValidationWriting – review & editing4Ndhlovu Lishomwa MethodologyResourcesSupervisionValidationWriting – review & editing5Bigoga Jude D. Project administrationResourcesSupervisionValidationWriting – review & editing12Taylor Diane W. ConceptualizationData curationMethodologyProject administrationResourcesSupervisionValidationWriting – review & editing5Leke Rose G. F. Project administrationResourcesSupervisionValidationVisualizationWriting – review & editing13Babakhanyan Anna ConceptualizationFunding acquisitionInvestigationMethodologyResourcesSupervisionValidationVisualizationWriting – original draftWriting – review & editing51 \nThe Biotechnology Center, University of Yaoundé I, Yaoundé, Cameroon2 \nDepartment of Biochemistry, University of Yaoundé I, Yaoundé, Cameroon3 \nCenter for Medical Research, Institute of Medical Research and Medicinal Plant Study, Yaoundé, Cameroon4 \nBiostatistics Core, Department of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii at Manoa, John A. Burns School of Medicine, Honolulu, Hawaii, United States of America5 \nDepartment of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii at Manoa, John A. Burns School of Medicine, Honolulu, Hawaii, United States of America6 \nDepartment of Zoology, College of Natural and Applied Sciences, University of Dar es Salaam, Dar es Salaam, TanzaniaDatiko Daniel Gemechu EditorManagement Sciences for Health, ETHIOPIACompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: esemu_livo@yahoo.com1 5 2019 2019 14 5 e02158259 10 2018 9 4 2019 © 2019 Esemu et al2019Esemu 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.Although mother-to-child transmission of HIV has dramatically declined, the number of in utero HIV-exposed, uninfected infants is on the increase. HIV-exposed infants are at an increased risk of mortality, morbidity and slower early growth than their non-HIV exposed counterparts. Maternal HIV increases the risk of having preterm deliveries, intrauterine growth restriction and low birth weight babies. However, the mechanism underlying dysregulation of fetal growth in HIV-infected pregnant women is unknown. We sought to determine whether maternal HIV is associated with dysregulation of the insulin-like growth factor (IGF) axis, some angiogenic factors or other related biomarkers that regulate fetal growth. A total of 102 normotensive pregnant women were enrolled in a small cross-sectional study. Amongst these were thirty-one HIV-1 positive women receiving combination antiretroviral therapy (cART) (Mean age: 30.0 ± 5.1 years; % on ART: 83.9%; median plasma viral load: 683 copies/ml; median CD4 count: 350 cells/ul) and 71 HIV uninfected women (mean age: 27.3 ± 5.8) recruited at delivery. A panel of biomarkers including IGF1 and IGF binding proteins (IGFBP1, IGFBP3), angiopoietins (ANG) 1 and 2, matrix metalloproteinases (MMP) 2 and 9, and galectin 13, was measured in plasma collected from the placental intervillous space. The levels of IGF1, IGFBP1, ANG1, ANG2, MMP2, MMP9 and Gal-13 were not affected by maternal HIV, even when adjusted for maternal factors in linear regression models (all p>0.05). It was observed that HIV-infection in pregnancy did not significantly affect key markers of the IGF axis and angiogenic factors. If anything, it did not affect women. These findings highlight the importance of the use of ART during pregnancy, which maintains factors necessary for fetal development closer to those of healthy women. However, decrease in IGF1 levels might be exacerbated in women con-infected with HIV and malaria.\n\nNIH Fogarty training grant5D43 TWO1264http://orcid.org/0000-0002-0793-2826Esemu Livo F. NIH Research Training GrantR25 TW009345Babakhanyan Anna Minority Health International Research Training (MHIRT) grantT37MD08636-01Rasay Shayne http://dx.doi.org/10.13039/100000002National Institutes of HealthU54MD007584Chen John http://dx.doi.org/10.13039/100000002National Institutes of HealthU54MD007601Chen John This project was supported by NIH Research Training Grant #R25 TW009345 awarded to the Northern Pacific Global Health Fellows Program by the Fogarty International Center, the University of Hawaii at Mānoa Minority Health International Research Training (MHIRT) grant # T37MD08636-01. LFE was supported by NIH Fogarty training grant 5D43 TWO1264. Data AvailabilityAll relevant data are within the manuscript and its Supporting Information files.Data Availability\nAll relevant data are within the manuscript and its Supporting Information files.\n==== Body\nIntroduction\nIn sub-Saharan Africa, women disproportionately bear the burden of the HIV epidemic [1,2]. Each year, 1.4 million HIV-infected women become pregnant [1], with up to 5.3% of those pregnant being HIV positive in many African countries [3]. In Cameroon, the national HIV prevalence in 2011 was 5.6% in women and 2.9% in men, but the prevalence of HIV among pregnant women was 7.8% [3,4]. Maternal HIV-1 infection increases the risk of pre-term birth (<37 weeks of gestation), small-for-gestational age babies, and fetal intrauterine growth restriction [5–9], resulting in low birth weight (LBW) infants (<2500g) [10–12]. Low birth weight occurs in over 20 million children and 95% of this condition is observed in developing countries [13,14]. Approximately 10% of children born to HIV positive Cameroonian women under prolonged HAART were born with LBW[15]. LBW is a significant cause of infant morbidity and increases the risk of mortality during the first year of life by 40-fold [16].\n\nMechanisms underlying LBW among HIV-exposed infants remains unknown. In term deliveries, HIV-associated LBW is likely to be caused by several factors, but dysregulated vasculogenesis in the placenta is likely to be an important component [17]. Early events such as implantation and development of the placenta are critical for successful pregnancy outcomes[18]. Placental vascular development is tightly regulated by pro-angiogenic angiopoietin 1 (ANG1) and anti-angionetic angiopoietin 2 (ANG2) [19]. During the first trimester, angiogenesis is important for remodeling of uterine spiral arteries into low resistance, high capacity vessels [17,20], which continues until mid-second trimester [19–23]. Dysfunctional remodeling of uterine spiral arteries is associated with complications of pregnancy, such as preeclampsia[24], gestational diabetes mellitus[25], Intra Uterine Growth Restriction[26], and Small for Gestational Age in the neonate [27].\n\nAnother important regulator of placental and fetal growth is the insulin like growth factor (IGF1)[28]. During pregnancy, IGF1 and its regulatory proteins are produced by placental trophoblasts and fetal cells, with the fetal liver being the main source of IGF after birth [29]. IGF1 plays a role in trophoblast migration, invasion, differentiation as well as proliferation. It also functions to influence placental angiogenesis and therefore transplacental transfer of nutrients such as amino acids and glucose. IGF receptors are found on placental cells that mediate IGF activity[30,31]. However, placental bioavailability of IGF1 is modulated by the IGF binding proteins: IGFBP1 and IGFBP3 [32,33]. Changes in IGF1 levels in maternal, placental or fetal compartments during the first trimester have been implicated in fetal growth restriction and LBW and would likely remain altered throughout pregnancy[28,29,34,35].\n\nIn addition, galectins are expressed at the maternal-fetal interface of the placenta and play key roles in placental formation and vascularization[36]. Among the 19 galectins known, placental galectin 13 (or placental protein 13, Gal-13) has been shown to be expressed by the syncytiotrophoblast, endovascular trophoblast and decidual spiral arteries and is important in trophoblast invasion and vascular remodeling during placentation [37]. Gal-13 is also regarded as an endogenous danger/damage signal, as its secretion from the syncytiotrophoblast is dramatically upregulated at the onset of preeclampsia and the hemolysis, elevated liver enzymes and low platelet count syndrome [36]. This lectin likely also plays an important role in feto-maternal tolerance, as it has been shown to promote apoptosis of activated T cells and macrophages[36].\n\nFinally, placental matrix metalloproteinases (MMP) are proteolytic enzymes that have been shown to have a vital role in trophoblast invasion, regulation of vascular endothelial cell functions and placental angiogenesis[38,39]. The MMP function by essentially degrading the extracellular matrix (ECM), releasing growth factors that allow the activation of signals that are important for angiogenesis [40]. For instance, MMP2 and MMP9 are secreted by placental trophoblasts and are critical in trophoblast invasion, vascular endothelial cell migration, attachment, proliferation and survival; therefore, supporting angiogenesis[39,41]. These enzymes have been described as potential candidates in the pathogenesis of preeclampsia [42]. The impact of HIV on levels of angiopoietins, MMPs, IGF1 and Gal-13 has not been investigated. Based on the importance of these factors in the homeostasis of pregnancy, it is plausible that HIV-associated immune activation[43] may dysregulate levels of angiopoietins, MMPs, IGF1 and gal-13. Thus, in this pilot study, the impact of maternal HIV infection on angiopoietins, IGF1 and IGFBPs, MMPs and gal-13 in normotensive pregnant women receiving antiretroviral therapy was examined.\n\nMaterials and methods\nEthical considerations\nThe archival, coded samples used in the current study were exempt from human subject research by the Committee on Human Studies, University of Hawaii, Manoa (CHS 22572). The original study protocol was reviewed and approved by the National Ethics Committee Cameroon (No 2013/11/366/L/CNERSH/SP) and the Institutional Review Board of the University of Hawaii (CHS 21370). Written informed consent was obtained from each woman specifying their sample would be used for further studies, prior to enrollment into the study.\n\nStudy site and population\nIn this pilot cross sectional study, archival plasma samples, obtained from a study carried out between January 2014 and September 2015 at the Yaoundé Central Hospital Maternity, a referral teaching hospital in Yaoundé, Cameroon were used. The prevalence of HIV in the city of Yaoundé is 4.4% [44]. The goal of the mother study was to investigate underlying mechanisms to poorer health observed in children born to HIV-positive women. A total of 102 mother-neonate pairs were recruited in the study at delivery. Women with pre-existing health conditions [e.g. diabetes, preeclampsia and Hemolysis, Elevated Liver enzymes, Low platelet count (HELLP) syndrome] and/or had spontaneous abortions were excluded from the study. Information on each woman’s demographic and clinical history including HIV status, ART intake, use of the intermittent preventive treatment (IPT) with sulphadoxine pyrimethamine (SP) and insecticide treated bednets (ITN) during pregnancy was available. The birth weight, length and APGAR score of newborn were also available. Gestational age was estimated based on date of last menstrual period or ultrasound scan data when available. Women with axillary temperature greater than 37.5°C were considered as having fever. Neonates born between 28 and 37 weeks were classified as premature. Singletons weighing less than 2,500 grams were considered LBW babies. Women were tested for HIV during pregnancy and vaccinated with tetanus vaccine according to national guidelines. All HIV positive women were placed on cART following national guidelines.\n\nSample collection\nMaternal venous blood and cord blood were collected in EDTA and sodium heparin tubes while blood from intervillous space (IVS) was obtained using the pool-biopsy method[45], processed and preserved at -20°C until analyses. In addition, impression smears of placental tissue were prepared and a piece of placental biopsy was stored in 10% buffered formalin for histological studies.\n\nHIV RNA levels\nHIV diagnostic data was available from the medical records at Yaoundé Central Hospital. HIV copy number was determined for all HIV positive women when sufficient amount of plasma was available (n = 14). Testing was conducted at the Chantal Biya International HIV Reference Center, Yaoundé, Cameroon using the using Abbott RealTime PCR HIV-1 kit (Abbott Park, Illinois, USA). Lower detection limit of the assay was less than 150 copies/ml; upper detection limit was 10,000,000 copies/ml.\n\nDiagnosis of peripheral malaria, placental malaria and anemia\nP. falciparum infections in peripheral, IVS and cord blood were detected by microscopy as described previously[46]. Peripheral blood smears were microscopically examined for presence of P. falciparum, P. ovale, P. malariae, P. vivax. Placental biopsies were also fixed in buffered formalin, embedded, stained with hemotoxylin-eosin, and examined for parasites. A woman was considered to have placental malaria (PM) if infected erythrocytes were detected in blood smears of IVS, impression smears of villous tissue, or histological sections of the placenta [47]. Maternal peripheral blood was used to determine the hemoglobin levels (Hb) using HemoCue Hb 201 (HemoCue, Sweden). Anemia was defined as Hb less than 11 g/dl [48].\n\nDetection of fetal blood contamination in placental blood\nIn order to confirm that IVS was collected without fetal blood contamination, the degree of purity of maternal blood was assessed using Fetal Cell Stain Kit (Simmler Inc, High Ridge, MO, United States, SKU: S0412-100) per manufacturer instructions. Positive control cord blood was used as reference.\n\nMeasurement of MMP2, MMP9, ANG1, ANG2, IGFBP1 and IGFBP3 levels in placental intervillous space plasma\nThese biomarkers were measured using Luminex Screening Assay kits (R&D Systems, MN). A four-plex cocktail containing ANG1, ANG2, IGFBP1 and IGFBP3 (R&D Systems, MN, Cat. LXSAHM-04) was used to screen at 1:2 dilution IVS plasma, MMP2 and MMP9 containing 2-plex cocktail (R&D Systems, MN, Cat. LXSAHM-02) was used to screen at 1:50 dilution IVS plasma. The assay was carried out according to the manufacturer’s instructions. Plates were washed using magnetic plate separator (Luminex, Austin, Texas, Cat# CN-0269-01) and a MAGPIX instrument (EMD Millipore, Billerica, MA) was used to read plates. The results were expressed as median fluorescence intensity (MFI). A standard curve was generated for each analyte to convert MFI into corresponding protein concentration. Protein concentrations were adjusted for dilution factors used for each analyte.\n\nMeasurement of IGF1 and Gal-13 levels in placental IVS plasma\nIGF1 levels in IVS plasma were measured using Human IGF-I Immunoassay Quantikine ELISA kit (R&D Systems, MN, Cat. DG100) according to the manufacturer’s instruction. Gal-13 levels in IVS plasma were measured using Human placenta protein13 (PP13) ELISA Kit (My Biosource, CA, Cat. MBS293460). The plates were read using microplate reader (ELISA iMARK BioRad, S#13738, JAPAN) set at 450 nm with wavelength. Results were expressed in optical density (OD) and standard curves were used to calculated protein concentrations. For IGF1, the values were multiplied by 100 (dilution factor from plasma pretreatment step). The detectable concentration range of IGF-I was 0.007 ng/ml—0.056 ng/mL and galectin 13 was 5pg/ml - 2000pg/ml.\n\nStatistical analysis\nBiomarker levels, demographic and clinical variables were summarized using descriptive statistics: means and standard deviations or median and interquartile range (IQR), for continuous variables such as age or parity; and frequencies and percentages for categorical variables, e.g., maternal anemia status (yes or no) and HIV-1 infection status (yes or no). Two-sample t-tests or Mann-Whitney U-tests for continuous variables, and Chi-square tests or Fisher’s exact tests for the categorical variables were used to compare women with and without HIV-1. The biomarker values were log transformed into natural logarithm scales. The effects of maternal HIV-1 infection on levels of each of biomarkers were evaluated through linear regression models, controlling for the selected demographic and clinical variables. All p values less than 0.05 were considered significant. All statistical analysis was performed using SAS 9.4 and GraphPad Prism 7.0.\n\nResults\nParticipant characteristics\nDemographic and clinical characteristics of study participants at delivery are summarized in Table 1 and S1 Table. Overall, 102 women were enrolled in the study, 31 HIV-1 positive and 71 HIV-1 negative. HIV-1 positive and negative women were similar with respect to maternal factors: IPT use, hemoglobin level, temperature, blood pressure, peripheral malaria status, parity and pregnancy outcomes: length of gestation, proportion of singleton deliveries and C-section, neonate sex, neonate weight and prevalence of LBW babies (all p-values>0.05). However, HIV-1 positive women were older compared to their healthy counterparts (p = 0.027) with average age of 30.0 ± 5.1 vs. 27.3 ± 5.8 years, respectively. Majority (83.9%) of the HIV-1 positive pregnant women were receiving ART, and most of the women were on Tenofovir Lamivudine and Efavirenz tritherapy. HIV viral load was available for 14(47%) HIV-1 positive women with median (25th, 75th) of 683 (0, 130,680) copies/μl. CD4 counts were available for 9 (30%) HIV-1 positive women; median (25th, 75th) of 350 (248, 675) cells/μl. Four (13%) HIV-1 positive pregnant women were also infected with placental malaria.\n\n10.1371/journal.pone.0215825.t001Table 1 Demographic and clinical characteristics of mothers.\nCharacteristic\tHIV-1 (-)\tHIV-1 (+)\tp-value\t\nNumber of enrolled participants, n\t71\t31\t-\t\nAge in years, mean ± SDθ\t27.3 ± 5.8\t30.0 ± 5.1\t0.027\t\nMaternal fever, n (%)Φ\t18 (25.4)\t6 (19.4)\t0.35\t\nMaternal weight in kg, mean ± SDθ\t75.7 ± 12.5\t73.9 ± 12.9\t0.64\t\nMaternal BMI in kg/m^2, mean ± SDθ\t29.1 ± 4.3\t28.6 ± 3.7\t0.72\t\nMaternal hemoglobin level in g/dL, mean ± SDθ\t12.1 ± 1.6\t11.7 ± 1.7\t0.41\t\nMaternal anemia, n (%)Φ\t13 (18.3)\t6 (19.4)\t0.73\t\nART use by pregnant women, n (%)\t0\t26 (83.9)\t-\t\nMaternal viral load, median, (25th, 75th)\t0\t683 (0, 130,680)\t-\t\nMaternal CD4 Count median, (25th, 75th)\tN/A\t350 (248,675)\t-\t\nMaternal IPT use, n (%)Φ\t60 (84.5)\t30 (96.8)\t0.18\t\n Number of SP doses pregnant women took, median, (25th, 75th)π\t2 (1, 3)\t2 (2, 2)\t0.92\t\n Maternal bednet use, n (%)Φ\t52 (73.2)\t26 (83.9)\t0.41\t\nMaternal heart rate in beats per minute, mean ± SDθ\t84.7 ± 13.9\t88.5 ± 15.9\t0.39\t\nMaternal blood pressure in mmHg, mean ± SDθ\t\t\t\t\n Systolic\t120.9 ± 17.6\t119.7 ± 8.8\t0.70\t\n Diastolic\t75.2 ± 13.3\t76.1 ± 8.7\t0.74\t\nMaternal peripheral malaria by blood smears, n (%)Φ\t11 (15.5)\t4 (12.9)\t0.75\t\nMaternal parasite density in peripheral blood£ in parasites/uL, median (25th, 75th)π\t1,880 (400, 15,940)\t1,080 (440, 12,490)\t0.61\t\nMalaria by RDT on maternal peripheral bloodθ\t14 (19.7)\t4 (12.9)\t0.44\t\nPlacental malaria, n (%)Φ\t10 (14.1)\t3 (9.7)\t0.33\t\nParasitemia£ in %, median (25th, 75th)π\t5.35 (0.06, 26.0)\t0.23 (0.03, 0.61)\t0.11\t\nParity including current child, median (25th,75th)π\t2 (1, 3)\t3 (1, 4)\t0.40\t\n Primigravidae, n (%)Φ\t12 (16.9)\t4 (12.9)\t0.46\t\n Multigravidae, n (%)Φ\t41 (57.8)\t22 (71.0)\t0.46\t\nLength of gestation in weeks, mean ± SDθ\t39.2 ± 3.0\t38.9 ± 2.6\t0.66\t\nPreterm deliveries, n (%)Φ\t10 (14.1)\t6 (19.4)\t0.59\t\nC-section, n (%)Φ\t6 (8.5)\t5 (16.1)\t0.28\t\nThe data were summarized based on the non-missing values. The total % is not 100 due to missing values or values rounded. £ Calculated for only smear positive individuals. P-values were based on\n\nθ two-sample T-tests\n\nπ Mann Whitney’s tests\n\nΦ Fisher’s exact tests.\n\nValidation of intervillous space blood collection and placental histopathology\nA total of 9 random intervillous blood samples were tested for fetal blood contamination. The average proportion of fetal erythrocytes in intervillous space blood was 1.7 ± 0.3%, which shows that the level of contamination was extremely low (S1 Fig). Thus, the sample collection methodology was validated and the experiment results are reflective of what occurs on the maternal side of the placenta.\n\nPlacental weight was not significantly different between HIV-1 positive and HIV negative women (p = 0.85, Table 2). In placentas from HIV-1 positive mothers, lesions and syncytial knots were occasionally observed; placentas from HIV-1 and PM co-infected women had lesions, fibrinoid tissue (Fig 1). Prevalence of placental malaria was not significantly different between HIV-1 positive (9.7%) and uninfected (14.1%) women (p = 0.33, Table 1). Except in women coinfected with malaria and HIV, women with PM did not have placental inflammation (Fig 1).\n\n10.1371/journal.pone.0215825.g001Fig 1 Placental histology.\n(A) HIV-1 infected woman. Arrow points to a syncytial knot. (B) HIV-1 and placenta malaria co-infected woman. Arrow points to a lesion. (C) HIV-1 and PM co-infected woman. Arrow points to fibrinoid tissue. (D) HIV-1 negative placenta malaria-positive woman. Infected erythrocytes are present in large numbers, no monocytes. 400x magnification.\n\n10.1371/journal.pone.0215825.t002Table 2 Demographic and clinical characteristics of neonates.\nCharacteristic\tHIV-1 (-)\tHIV-1 (+)\tp-value\t\nSingleton deliveries, n (%)Φ\t67 (94.4)\t29 (93.6)\t0.59\t\nMale neonates, n (%)Φ\t38 (53.5)\t20 (64.5)\t0.38\t\nPlacental weight in g, mean ± SDθ\t616 ± 155\t609 ± 177\t0.85\t\nNeonate weight in g, mean ± SDθ\t3169 ± 587\t3127 ± 497\t0.74\t\nLow birth weight, n (%)Φ\t6 (8.5)\t2 (6.5)\t1.00\t\nAPGAR at 1min, mean ± SDθ\t7.9 ± 1.5\t8.4 ± 1.0\t0.17\t\nAPGAR at 5min, mean ± SDθ\t8.8 ± 1.4\t8.9 ± 1.0\t0.81\t\nCord malaria infection by blood smears, n (%)\t0\t0\t-\t\nThe data were summarized based on the non-missing values. The total % is not 100 due to missing values or values rounded. £ Calculated for only smear positive individuals. P-values were based on\n\nθ two-sample T-tests\n\nπ Mann Whitney tests\n\nΦ Fisher’s exact tests.\n\nAngiopoetin 1 and 2 are not dysregulated in HIV-1 positive women on antiretroviral therapy\nThe placental levels of ANG1 and ANG2 biomarkers in natural logarithm scales by HIV-1 status are presented in Table 3. There was no significant difference between HIV-1 positive and HIV-1 negative women in ANG1 (p = 0.68) and ANG2 (p = 0.20) as depicted on Table 3. In general linear regression models adjusted for maternal age and malaria status (Table 4), HIV-1 infection did not have significant impact on ANG1 (p = 0.93) and ANG2 (p = 0.33).\n\n10.1371/journal.pone.0215825.t003Table 3 Placental biomarker levels by HIV-1 status.\n*Biomarker\tHIV-1 (-)\nn = 71\tHIV-1 (+)\nn = 31\tp-value\t\nANG1(pg/ul)\t10.64 ± 0.53\t10.6 ± 0.52\t0.68\t\nANG2(pg/ul)\t9.22 ± 0.42\t9.38 ± 0.54\t0.20\t\nIGF1 (ng/ul)\t4.31 ± 0.19\t4.29 ± 0.24\t0.76\t\nIGFBP1(ug/ul)\t12.02 ± 0.36\t12.01 ± 0.36\t0.92\t\nMMP2(ug/ul)\t12.45 ± 0.30\t12.60 ± 0.36\t0.066\t\nMMP9(ug/ul)\t13.18 ± 1.05\t13.15 ± 0.87\t0.91\t\nGal-13(ug/ul)\t5.70 ± 0.47\t5.45 ± 0.31\t0.06\t\n*Biomarker levels were log transformed and the data were summarized by mean ± SD, based on non-missing values. P-values were based on two-sample T-tests.\n\n10.1371/journal.pone.0215825.t004Table 4 Placental biomarker level reduction due to HIV-1.\n\t\tHIV-1 (+) vs. \nHIV-1 (-)\tMalaria (+) vs. Malaria (-)\tAge\t\nBiomarker\tR2\tEstimate (95% CI)\tp-value\tEstimate (95% CI)\tp-value\tEstimate (95% CI)\tp-value\t\nANG1(pg/ul)\t0.081\t0.012 \n(-0.26, 0.29)\t0.93\t-0.22 \n(-0.55, 0.11)\t0.19\t-0.020 \n(-0.043, 0.004)\t0.11\t\nANG2(pg/ul)\t0.036\t0.14 \n(-0.14, 0.41)\t0.33\t-0.038 \n(-0.37, 0.29)\t0.82\t0.011 \n(-0.015, 0.031)\t0.49\t\nIGF1(ng/ul)\t0.27\t-0.086 \n(-0.19, 0.022)\t0.12\t-0.19 \n(-0.32, -0.067)\t0.0038\t-0.004 \n(-0.014, 0.006)\t0.44\t\nIGFBP1(ug/ul)\t0.0038\t0.10 \n(-0.23, 0.19)\t0.84\t0.12 \n(-0.29, 0.21)\t0.75\t-0.002 \n(-0.019, 0.016)\t0.84\t\nMMP2(ug/ul)\t0.039\t0.12 \n(-0.042, 0.28)\t0.15\t0.092 \n(-0.21, 0.15)\t0.74\t0.007 \n(-0.012, 0.016)\t0.79\t\nMMP9(ug/ul)\t0.029\t0.018 \n(-0.48, 0.52)\t0.95\t0.28 \n(-0.19, 0.93)\t0.20\t0.021 \n(-0.055, 0.028)\t0.53\t\nGal-13(ug/ul)\t0.089\t-0.25 \n(-0.55, 0.042)\t0.090\t0.17 \n(-0.33, 0.30)\t0.82\t0.013 \n(-0.031, 0.023)\t0.79\t\nThe Placental biomarker levels were in natural logarithm scales and the model was adjusted for mat maternal age and malaria status. The malaria status was confirmed by either placental malaria or maternal peripheral blood RDT. P-values were based on linear regression analyses.\n\nIn order to determine whether angiopoetins are dysregulated during HIV-1 infection, ANG1, ANG2, as well as ANG2/ANG1 ratio were measured in placental intervillous space plasma from HIV-1 positive PM-negative and HIV-1 negative PM-negative women. No significant differences in ANG1 or ANG2 (all p>0.05) were observed between women with HIV-1 and their healthy counterparts (Fig 2). No significant differences between HIV-1 negative PM-positive women and their healthy counterparts were observed for either ANG1 or ANG2 (all p>0.05, Fig 2). ANG1 was lower in 3 co-infected pregnant women compared to healthy women, but the difference was not statistically significant (p = 0.08, Fig 2).\n\n10.1371/journal.pone.0215825.g002Fig 2 Angiopoietin levels in placental intervillous space.\nANG1 and ANG2 levels, as well as ANG2/ANG1 ratio was measured in placental intervillous space in healthy (HIV-&PM-, n = 30), HIV-infected (HIV+&PM-, n = 21), PM-positive (HIV&PM+, n = 8) and co-infected (HIV+&PM+, n = 3) women. Median and interquartile ranges (IQR) are plotted; differences between the healthy and infected women were assessed using Mann-Whitney test. HIV: Human Immunodeficiency Virus; ANG1: Angiopoetin 1; ANG2: Angiopoetin 2; PM: Placenta Malaria positive mothers.\n\nIGF axis is not dysregulated in HIV-1 infected women receiving antiretroviral therapy\nThe placental biomarkers levels of IGF axis in natural logarithm scales by HIV-1 status are presented in Table 3. There was no significant difference between HIV-1 positive and HIV-1 negative women in IGF1 (p = 0.76) and IFGBP1 (p = 0.92). In linear regression models adjusted for maternal age and malaria status (Table 4), IGF-1 was not significantly reduced as a result of HIV-1 (p = 0.12) but due to malaria status (p = 0.0038), while no effect of HIV-1 on IFGBP1 was identified (p = 0.84).\n\nThe impact of HIV-1 on IGF axis was evaluated by probing placental intervillous space plasma obtained from HIV-1 positive PM-negative, HIV-1 negative PM-negative and HIV-1 negative PM-positive women for IGF-1 and IGFBP1 and IGFBP3. Lower but not significant levels (p = 0.3) of IGF-1 were observed in HIV-1 positive PM-negative women compared to healthy women (Fig 3). No significant differences in IGFBP1 were observed between HIV-1 infected and healthy women. In linear regression models adjusted for maternal age and anemia status no significant effect of HIV-1 on IGFBP1 was identified (Table 4). IGFBP3 was not detected in any of the samples and thus excluded from analysis.\n\n10.1371/journal.pone.0215825.g003Fig 3 IGF1 and IGFBP1 levels in placental intervillous space.\nIGF1 levels were measured in placental intervillous space plasma of healthy (HIV-&PM-, n = 15), HIV-infected (HIV+&PM-, n = 16), PM-positive (HIV-&PM+, n = 6) and co-infected (HIV+&PM+, n = 3) women. IGFBP1 and IGFBP3 levels were also measured in healthy (HIV-&PM-, n = 30), HIV-infected (HIV+&PM-, n = 21), PM-positive (HIV-&PM+, n = 8) and co-infected (HIV+&PM+, n = 3) women. Median and interquartile ranges (IQR) are plotted; differences between the healthy and infected women were assessed using Mann-Whitney test. HIV: Human Immunodeficiency Virus; IGF1: Insulin Growth Factor 1; IGFBP1: IGF Binding Protein 1; PM: Placenta Malaria positive mothers.\n\nHIV-1 is not associated with decreased levels of MMP2, MMP9 and Gal-13\nThe placental levels of MMP2, MMP9 and Gal-13 biomarkers in natural logarithm scales by HIV-1 status are also presented in Table 3. There was no significant difference between HIV-1 positive and HIV-1 negative women in MMP9 (p = 0.91), but marginally significant in MMP2 (p = 0.066) and Gal-13 (p = 0.060). After adjusting for maternal age and malaria status, HIV-1 status had no significant impact on MMP2, MMP9 and Gal-13 (all p>0.05, Table 4).\n\nThe impact of HIV-1 on additional biomarkers of placental formation and vascularization were also explored, including MMP2, MMP9 and Gal-13. No significant differences were observed between HIV-1 positive PM-negative and healthy women for MMP2 and MMP9 levels in intervillous space plasma (all p>0.05, Fig 4 and Table 3). No significant differences in MMP2 and MMP9 levels were observed between HIV-1 negative PM-positive women and their healthy counterparts (all p>0.05, Fig 4). Intervillous space plasma Gal-13 levels were not significantly different between HIV-1 positive and healthy women (Fig 4), and linear regression model showed HIV-1 had no significant impact on Gal-13 levels (Table 4).\n\n10.1371/journal.pone.0215825.g004Fig 4 MMP and Gal 13 levels in plasma from placental intervillous space plasma.\nMMP2 and MMP9 levels were measured in placental intervillous space in uninfected (HIV-&PM-, n = 40), HIV-infected (HIV+&PM-, n = 24), PM-positive (HIV-&PM+, n = 12) women and co-infected (HIV+&PM+, n = 4) women. Gal-13 were measured in intervillous space plasma of healthy (HIV-&PM-, n = 17), HIV-infected (HIV+&PM-, n = 16), PM-positive (HIV-&PM+, n = 6) and co-infected (HIV+&PM+, n = 3) women. Median and interquartile ranges (IQR) are plotted; differences between the healthy and infected women were assessed using Mann-Whitney test. HIV: Human Immunodeficiency Virus; MMP: Matrix Metalloproteinase; Gal-13: Galectin-13; PM: Placenta Malaria positive mothers.\n\nDiscussion\nThe goal of our study was to determine whether maternal HIV is associated with the dysregulation of insulin-like growth factor (IGF) axis, angiogenic factors—or other related biomarkers that regulate fetal growth. In this pilot study, a panel of biomarkers implicated in placental homeostasis and fetal growth were assessed in intervillous space plasma of HIV-1 positive normotensive women on antiretroviral therapy and their HIV-1 negative counterparts. This panel of biomarkers included those involved in angiogenesis, IGF axis, as well as profile of MMPs and Gal-13. Angiogenic factors were not affected by maternal HIV-1 in our cohort of pregnant women receiving antiretroviral therapy. Angiopoetins 1 and 2 levels were not significantly different between HIV-1 positive and healthy women, even after adjusting for maternal factors.\n\nStudies have shown that persistent HIV infection contributes to the development of chronic arterial injury and subsequent endothelial damage, atherosclerosis and thrombosis [49]. In addition, HIV-infected children have arterial stiffness and endothelial dysfunction in the absence of cardiovascular risk factors [50]. Since most of the women in our study were on ART, it is likely that combination antiretroviral therapy (cART) prevents angiopoietin dysregulation. Graham et al. reported that in non-pregnant Kenyan HIV-1 positive women with advanced HIV infection, initiation of cART significantly lowered ANG2 levels, while ANG1 was increased [51]. In agreement with previous studies, we confirmed that HIV-1 negative women with PM had significantly lower ANG1 levels compared to uninfected pregnant women [52,53]. The reason for this observation may stem from malaria parasite level in blood of PM+ women. Silver et al, (2010) found an inverse association between parasitemia and ANG1 levels [54]. With very low parasitemia in malaria positive women (0.13%) in this study, there is possibly no major alteration on the levels ANG1. This might explain the minimal changes observed between PM positive women when compared to HIV-1 negative, PM negative women.\n\nMMP2 and MMP9 levels in intervillous space plasma were not significantly different between HIV-1 positive and healthy pregnant women. MMPs are involved in vascular remodeling and vasculogenesis, especially in new blood vessel formation and angiogenesis [39]. In line with findings for angiopoietins, these data support the fact that in HIV-1 infected pregnant women on antiretroviral therapy, angiopoietin pathway is not dysregulated. Placental malaria did not have any significant effect on MMP2 or MMP9 in this study. This is in line with a previous study, in which no significant changes in plasma levels of MMP9 were observed in children with malaria infection compared to malaria negative children[55].\n\nIn linear regression models, maternal HIV-1 did not significantly associate with lower IGF1 in placental intervillous space plasma. Lower IGF1 levels were observed in HIV-infected Ugandan children [56]. In non-pregnant adults, however, serum IGF1 has been shown to depend on level of immunodeficiency in HIV-infection and it was significantly higher in patients treated with protease inhibitors-based regimen compared to non-nucleoside reverse transcriptase inhibitors and healthy subjects [57]. Similar findings were also reported by Matarazzo et al, who found an association between decreased IGF1 levels and diseases progression in HIV-1 positive individuals [58]. In this study, IGF1 was significantly higher in HIV-1 negative PM- positive women when compared to their healthy counterparts as previously described [59]. Further, in a small subset of HIV-1 positive/PM+ co-infected Cameroonian pregnant women in this study, IGF1 levels were significantly lower compared to healthy pregnant women, indicating that HIV-1 further exacerbates PM- associated dysregulation of IGF axis.\n\nGal-13 is critical in trophoblast invasion during placentation and has also been reported to have angiogenic effects in the placenta [60]. Studies in animal model show that the expression of Gal-13 increases vasodilation [60] and therefore placental perfusion. In addition, lack of expression of Gal-13 has been shown to impair syncytialization [61] and hence subsequent placental hormone production by syncytiotrophoblast, which is vital in the development of the placenta. Gal-13 levels have not been studied in HIV-1 positive pregnant women, but they have been described for other pathological pregnancy conditions. No significant difference was found in Gal-13 intervillous space plasma levels between HIV-1 women under cART and their uninfected counterparts. Studies by Than et al. showed that Gal-13 placental expression was lower in preterm preeclamptic placentas compared to preterm control placentas [62], while maternal peripheral serum Gal-13 concentration was higher in preterm preeclamtic women compared to preterm controls. In contrast, Sammar et al. did not observe any significant differences in maternal peripheral plasma Gal-13 levels in HIV-1 uninfected pregnant women with preeclampsia or hemolysis, elevated liver enzymes and low platelet count syndrome compared to HIV uninfected [63]. Also, there was no difference in placental Gal-13 levels between HIV-1 negative PM-positive pregnant Cameroonian women and healthy pregnant women.\n\nThis study has a number of limitations, including limited number of LBW neonates in both HIV-positive and HIV-negative groups, inability to differentiate effects of HIV from those of ART because ART is standard of care. Of course, an ideal study design would be to investigate these biomarkers with and without cART in a case-control study, it is not ethical to withhold cART from women. However, we observed that even though women have HIV, cART therapy was effective in maintaining their ANG levels close to that of HIV-negative women. A few women were not on cART or had high viral load for some reason beyond our grasp. It is worth mentioning we did not have viral load for all samples and thus could not perfectly do the analysis. Moreover, the findings from this pilot study will need to be confirmed in a larger study due to small samples size. Within the sphere of our study, Cameroon was transitioning from PMTCT Option A to Option B+. Most studies have associated infant growth with Protease Inhibitors [64,65] and very few studies have associated dysregulated fetal growth with prolonged cART. However, our sample size was a limiting factor in the assessment of this hypothesis [64,65]. The cross-sectional study design did not allow monitoring of fetal growth rate and concomitant biomarker levels over time during pregnancy. Given that many of the aforementioned factors are important for placentation, vasculogenesis and placental perfusion and fetal growth, a longitudinal study design would be more effective. At the same time, it is well established that maternal peripheral plasma levels and placental plasma levels may not be the same [53].\n\nWhile a limitation of the study were the small number of cases, the study demonstrates that maternal HIV-1 infection might not have a dramatic influence on placental IGF1, IGFBP1, MMP2, MMP9, ANG1, ANG2 and Gal-13 levels in Cameroonian pregnant normotensive women with majority receiving cART. It is not clear whether inflammatory cytokines in the placental environment of HIV-1 infected mothers [66–69] or direct effect of HIV infection on syncytial trophoblasts lead to subtle dysregulation of IGF1, IGFBP1, MMP2, MMP9, ANG1, ANG2 and Gal-13 expression in the placenta [70]. Larger prospective longitudinal studies are required to determine, whether there is significant maternal HIV-associated dysregulation in the IGF1 axis and angiogenic factors during pregnancy, especially in women with low CD4 counts, and its effects on the neonate birth weight.\n\nSupporting information\nS1 Fig Fetal blood contamination of intervillous space blood.\nNine randomly selected maternal intervillous blood samples were screened for presence of fetal erythrocytes (experimental). In addition, known amount of cord blood was mixed with corresponding maternal intervillous space blood as a positive control. Percentage of fetal erythrocytes in each intervillous blood sample was determined; mean and standard deviation for the samples are presented in the figure.\n\n(TIF)\n\nClick here for additional data file.\n\n S1 Table Other demographic and clinical characteristics of mothers.\nThe data were summarized based on the non-missing values. The total % is not 100 due to missing values or values rounded. £ Calculated for only smear positive individuals. P-values were based on θ two-sample T-tests, Φ Fisher’s exact tests.\n\n(DOCX)\n\nClick here for additional data file.\n\n S1 Database Database of IDCPC_Rui_Livo v3.\n(XLSX)\n\nClick here for additional data file.\n\n We would like to thank all the mothers and their neonates who have participated in our study. We are grateful to Dr. Robert Leke, doctors and nurses at the maternity ward of the Yaoundé Central Hospital for their assistance with this study. We are grateful to Dr. Claude Djontu, Mrs. Grace Sama, Mrs. Philomina Gwamensia, Mr. Joshua Manjo Sahfe, Prof. Wilfred Mbacham, Dr. Olivia Achonduh at the Biotechnology Center, Univ. of Yaounde I; Nicole Hobbs, Drs. Vivek Nerurkar and Joe Zunt from the Northern Pacific Global Health Fellows Program. We are thankful to SIMMLER Inc, High Ridge, MO, USA for providing fetal stain kit for the study. 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"mesh_terms": "D000328:Adult; D042682:Angiopoietins; D044966:Anti-Retroviral Agents; D015415:Biomarkers; D002163:Cameroon; D003430:Cross-Sectional Studies; D005260:Female; D015658:HIV Infections; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1; D007334:Insulin-Like Growth Factor I; D008288:Malaria; D020780:Matrix Metalloproteinase 9; D010920:Placenta; D011247:Pregnancy; D055815:Young Adult",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0215825",
"pmc": null,
"pmid": "31042729",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "14972443;25030058;18700258;1034483;7841697;18400990;10329354;10405861;25302305;25050734;19010537;16165387;29020282;7476305;12634661;15096807;11994360;11687497;20208992;10438439;25107626;21257080;12093439;22187472;11531954;23953090;23406577;27682438;25191322;6634666;17678629;22378334;11722965;26090803;23734875;10833363;18791734;10630142;3790464;9841821;18219215;10930154;19176632;9094636;18647287;9240855;29334919;19915445;23483768;10703779;21216864;25258707;15772313;21713302;14740871;28819030;25266889;22331427;23316964;23840100;23941777",
"title": "Impact of HIV-1 infection on the IGF-1 axis and angiogenic factors in pregnant Cameroonian women receiving antiretroviral therapy.",
"title_normalized": "impact of hiv 1 infection on the igf 1 axis and angiogenic factors in pregnant cameroonian women receiving antiretroviral therapy"
} | [
{
"companynumb": "CM-VIIV HEALTHCARE LIMITED-CM2019GSK097768",
"fulfillexpeditecriteria": "1",
"occurcountry": "CM",
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"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
},
"drugaddition... |
{
"abstract": "Catatonia is a syndrome that can present in different forms and can occur in multiple psychiatric and somatic conditions. This case report describes lethal catatonia caused by delayed toxic leukoencephalopathy after excessive use of cocaine and methadone. The characteristic radiographic imaging and biphasic course are discussed.\n\n\n\nA 54-year-old woman was presented unconsciously at the emergency department after intoxication with methadone and cocaine. After initial recovery, her condition deteriorated unexpectedly, resulting in lethal catatonia. Magnetic resonance imaging (MRI) showed hyperintense white matter abnormalities and diffusion restriction, evident for leukoencephalopathy.\n\n\n\nCatatonia can develop in multiple psychiatric and somatic diseases, including toxic leukoencephalopathy. A biphasic course and specific MRI findings are characteristics for delayed toxic leukoencephalopathy, due to intoxication with drugs.",
"affiliations": "Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands (AMJvE, AF, JGEJ, AFAS); Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands (BSH, RAJE); and Department of Radiology, Radboud University Medical Center, Nijmegen, the Netherlands (SCAS).",
"authors": "van Esch|Anouk M J|AMJ|;Fest|Antine|A|;Hoffland|Britt S|BS|;Janzing|Joost G E|JGE|;Steens|Stefan C A|SCA|;Esselink|Rianne A J|RAJ|;Schellekens|Arnt F A|AFA|",
"chemical_list": "D003042:Cocaine; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000470",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1932-0620",
"issue": "13(3)",
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": "D002389:Catatonia; D003042:Cocaine; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D056784:Leukoencephalopathies; D008279:Magnetic Resonance Imaging; D008691:Methadone; D008875:Middle Aged; D066127:White Matter",
"nlm_unique_id": "101306759",
"other_id": null,
"pages": "241-244",
"pmc": null,
"pmid": "30394993",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Toxic Leukoencephalopathy Presenting as Lethal Catatonia.",
"title_normalized": "toxic leukoencephalopathy presenting as lethal catatonia"
} | [
{
"companynumb": "NL-VISTAPHARM, INC.-VER201907-000544",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"druga... |
{
"abstract": "An 80-year-old female patient arrived with a pronounced lymphadenopathy and weight loss. 6 years ago she had been diagnosed with rheumatoid arthritis. At the time of arrival, she was administered Methotrexate (MTX) 10 mg/week.\n\n\n\nBy lymph node biopsy, a clonal population of both EBV-positive B and T cells was seen. Newly occurring anemia (Hb 10 g/dl), monoclonal gammopathy of the Ig M isotype and detection of 40 % EBV-positive plasma cells in the bone marrow were consistent with the diagnosis of Ig M myeloma. We interpret these findings as a biclonal Epstein Barr Virus-positive Methotrexate-associated lymphoproliferative disorder (MTX-LPD).\n\n\n\nThe clinical condition improved immediately after MTX discontinuation. In the follow-up after 4 months, the gamma globulin concentration in serum was significantly reduced (from 51.1 to 34.7 %) and a renewed immune electrophoresis of the serum was without evidence of monoclonal gammopathy.\n\n\n\nBased on this case, the association of RA with lymphoproliferative disorders can be confirmed - here as an association of RA with biclonal MTX-LPD or multiple myeloma. Therapy with MTX and reactivation of EBV infection are important influencing factors.",
"affiliations": "Klinik für Innere Medizin, Schönklinik Hamburg-Eilbek.;Klinik für Diagnostische und Interventionelle Radiologie, Schönklinik Hamburg-Eilbek.;Onkologie-Lerchenfeld, Hamburg.;Hämatopathologie Lübeck, Lübeck.;Klinik für Innere Medizin, Schönklinik Hamburg-Eilbek.",
"authors": "Wernecke|Marie|M|;Frieling|David|D|;Brandl|Ulrike|U|;Feller|Alfred|A|;von Wichert|Götz|G|",
"chemical_list": "D018501:Antirheumatic Agents; D008727:Methotrexate",
"country": "Germany",
"delete": false,
"doi": "10.1055/a-1328-8468",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-0472",
"issue": "146(4)",
"journal": "Deutsche medizinische Wochenschrift (1946)",
"keywords": null,
"medline_ta": "Dtsch Med Wochenschr",
"mesh_terms": "D000369:Aged, 80 and over; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D008198:Lymph Nodes; D008232:Lymphoproliferative Disorders; D008727:Methotrexate; D010265:Paraproteinemias",
"nlm_unique_id": "0006723",
"other_id": null,
"pages": "262-265",
"pmc": null,
"pmid": "33592662",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "EBV-positive MTX-associated lymphoproliferative disorder and Ig M myeloma in rheumatoid arthritis.",
"title_normalized": "ebv positive mtx associated lymphoproliferative disorder and ig m myeloma in rheumatoid arthritis"
} | [
{
"companynumb": "DE-MYLANLABS-2021M1016242",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "1",
... |
{
"abstract": "One hundred two patients with evolving myocardial infarction of 6 hours' duration were given aspirin and intravenous heparin and randomly allocated to intravenous front-loaded, weight-adjusted rTPA administration over a 90-minute period (52 patients) or to two 15 mg doses of recombinant staphylokinase, 30 minutes apart (50 patients). Thrombolysis in Myocardial infarction (TIMI) perfusion grade 3 at 90 minutes was achieved in 68% (95% confidence interval, 55% to 81%) of patients treated with staphylokinase versus 57% (95% confidence interval, 43% to 72%) of patients treated with rTPA (p = not significant). Double-bolus staphylokinase was significantly more fibrin-specific than accelerated rTPA with residual fibrinogen at 90 minutes of 105% +/- 4.1% and 68% +/- 7.5%, respectively (p < 0.0001). Thirteen patients in each study group underwent angioplasty of the culprit coronary artery within the first 24 hours because of suboptimal recanalization (TIMI < 3). In the patients without prior coronary intervention, TIMI 3 at 24 hours was 100% after staphylokinase administration (n = 35) versus 79% after rTPA (n = 34) (p = 0.005). The distribution of inhospital events did not significantly differ between both groups. One patient receiving rTPA died in the hospital from ischemic stroke. Staphylokinase administration did not induce allergic reactions, but significant staphylokinase-neutralizing activity (> 5 micrograms/ml) and specific anti-staphylokinase IgG developed in 73% of patients after 2 weeks. Thus two 15 mg doses of staphylokinase induce early, complete, and sustained coronary artery patency at least as frequently as accelerated rTPA without associated fibrinogen degradation but with subsequent induction of circulating neutralizing antibodies.",
"affiliations": "Center for Molecular and Vascular Biology, University of Lauven, Belgium.",
"authors": "Vanderschueren|S|S|;Dens|J|J|;Kerdsinchai|P|P|;Desmet|W|W|;Vrolix|M|M|;De Man|F|F|;Van den Heuvel|P|P|;Hermans|L|L|;Collen|D|D|;Van de Werf|F|F|",
"chemical_list": "D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D005340:Fibrinogen; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D008666:Metalloendopeptidases; C022653:auR protein, Staphylococcus aureus",
"country": "United States",
"delete": false,
"doi": "10.1016/s0002-8703(97)70127-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-8703",
"issue": "134(2 Pt 1)",
"journal": "American heart journal",
"keywords": null,
"medline_ta": "Am Heart J",
"mesh_terms": "D005260:Female; D005340:Fibrinogen; D005343:Fibrinolytic Agents; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008666:Metalloendopeptidases; D008875:Middle Aged; D009203:Myocardial Infarction; D010960:Plasminogen Activators; D011446:Prospective Studies; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D014654:Vascular Patency",
"nlm_unique_id": "0370465",
"other_id": null,
"pages": "213-9",
"pmc": null,
"pmid": "9313600",
"pubdate": "1997-08",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Randomized coronary patency trial of double-bolus recombinant staphylokinase versus front-loaded alteplase in acute myocardial infarction.",
"title_normalized": "randomized coronary patency trial of double bolus recombinant staphylokinase versus front loaded alteplase in acute myocardial infarction"
} | [
{
"companynumb": "BE-ROCHE-2350038",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "OBJECTIVE\nThe objective of this study was to describe the incidence of grade 3/4 neutropenia, patterns of chemotherapy treatment, and granulocyte colony-stimulating factor (G-CSF) use patterns among patients with non-Hodgkin's lymphoma (NHL)<65 and ≥65 years.\n\n\nMETHODS\nThis retrospective, observational study included adult patients with NHL who received cyclophosphamide, doxorubicin, vincristine, and prednisone±rituximab (CHOP±R) from January 2006 to June 2010.\n\n\nRESULTS\nA total of 1,579 patients were included, with 54.1%<65 years and 45.9%≥65 years. Most received CHOP-R on a Q3W schedule. Among patients<65 years, the incidence of grade 3/4 neutropenia was 52.3%, the mean relative dose intensity (RDI) was 80.4%, and the incidences of dose delays and reductions were 26.5 and 9.6%, respectively. Among patients≥65 years, the incidence of grade 3/4 neutropenia was 63.2%, the mean RDI was 73.9%, and the incidences of dose delays and reductions were 24.6 and 24.9%, respectively. Most patients (86.9%) received G-CSF. Among patients<65 years, 71.9, 17.4, and 10.7% first received G-CSF as primary prophylaxis, secondary prophylaxis, or treatment, respectively. Among patients≥65 years, 80.1, 11.6, and 8.3% first received G-CSF as primary prophylaxis, secondary prophylaxis, or treatment, respectively.\n\n\nCONCLUSIONS\nChemotherapy regimens and schedules were similar among age groups. Grade 3/4 neutropenia, reduced RDI, and dose delays were common in both age groups, though patients≥65 years had a higher incidence of dose reductions. In spite of these similarities, patients<65 years were less likely to receive primary prophylactic G-CSF. Thus, careful assessment of neutropenia risk factors is needed across age groups to determine appropriate G-CSF use and support planned chemotherapy.",
"affiliations": "The West Clinic, 100 N Humphreys Blvd, Memphis, TN, 38120, USA, lschwartzberg@westclinic.com.",
"authors": "Schwartzberg|Lee S|LS|;Saleh|Mansoor|M|;Whittaker|Sadie|S|;Abella|Esteban|E|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D016179:Granulocyte Colony-Stimulating Factor; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-014-2157-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "22(7)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": null,
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D011241:Prednisone; D012189:Retrospective Studies; D012307:Risk Factors; D000069283:Rituximab; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "1833-41",
"pmc": null,
"pmid": "24535242",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "15751024;5216294;14716755;11529466;19055662;15967836;16575919;14959849;16682719;912645;12488289;7691119;11707832;1381626;1711156;15016643;18165618;3060443;11807147;16162551;23452298;19110415;11707870;9166835;18632435;15381684;17952688;11904116;2348230;14613340;11821454;16736985;9704731;9168439",
"title": "Severe neutropenia and relative dose intensity among patients<65 and ≥65 years with non-Hodgkin's lymphoma receiving CHOP-based chemotherapy.",
"title_normalized": "severe neutropenia and relative dose intensity among patients 65 and 65 years with non hodgkin s lymphoma receiving chop based chemotherapy"
} | [
{
"companynumb": "US-JNJFOC-20140702600",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "Rickettsia is the pathogen of Q fever, Brucella ovis is the pathogen of brucellosis, and both of them are Gram-negative bacteria which are parasitic in cells. The mixed infection of rickettsia and Brucella ovis is rarely reported in clinic. Early diagnosis and treatment are of great significance to the treatment and prognosis of brucellosis and Q fever. Here, we report a case of co-infection Rickettsia burneti and Brucella melitensis. The patient is a 49-year-old sheepherder, who was hospitalized with left forearm trauma. Three days after admission, the patient developed fever of 39.0°C, accompanied by sweating, fatigue, poor appetite and headache. Indirect immunofluorescence (IFA) was used to detect Rickettsia burneti IgM. After 72 hours of blood culture incubation, bacterial growth was detected in aerobic bottles, Gram-negative bacilli were found in culture medium smear, the colony was identified as Brucella melitensis by mass spectrometry. Patients were treated with doxycycline (100 mg bid, po) and rifampicin (600 mg qd, po) for 4 weeks. After treatment, the symptoms disappeared quickly, and there was no sign of recurrence or chronic infection. Q fever and Brucella may exist in high-risk practitioners, so we should routinely detect these two pathogens to prevent missed diagnosis.",
"affiliations": "Laboratory Department, the First People's Hospital of Tianmen City, Tianmen, 431700, Hubei, China.;Laboratory Department, the First People's Hospital of Tianmen City, Tianmen, 431700, Hubei, China.;Laboratory Department, the First People's Hospital of Tianmen City, Tianmen, 431700, Hubei, China.;Gastrology department, the First People's Hospital of Tianmen City, Tianmen, 431700, Hubei, China.;General surgery department, the First People's Hospital of Tianmen City, Tianmen, 431700, Hubei, China.;Department of science and education, the First People's Hospital of Tianmen City, Tianmen, 431700, Hubei, China.;Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, Hubei, China. 421085646@qq.com.;Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. 1466041119@qq.com.",
"authors": "Song|Jiangqin|J|;Hu|Xiaorong|X|;Li|Xiaolong|X|;Chen|Youping|Y|;Yan|Xiangyuan|X|;Zhu|Weifang|W|;Ding|Yan|Y|;Zhou|Junyang|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12866-021-02323-x",
"fulltext": "\n==== Front\nBMC Microbiol\nBMC Microbiol\nBMC Microbiology\n1471-2180\nBioMed Central London\n\n2323\n10.1186/s12866-021-02323-x\nResearch\nRickettsia burneti and Brucella melitensis co-infection: a case report and literature review\nSong Jiangqin 1\nHu Xiaorong 1\nLi Xiaolong 1\nChen Youping 2\nYan Xiangyuan 3\nZhu Weifang 4\nDing Yan 421085646@qq.com\n\n5\nZhou Junyang 1466041119@qq.com\n\n6\n1 grid.508000.d Laboratory Department, the First People’s Hospital of Tianmen City, Tianmen, 431700 Hubei China\n2 grid.508000.d Gastrology department, the First People’s Hospital of Tianmen City, Tianmen, 431700 Hubei China\n3 grid.508000.d General surgery department, the First People’s Hospital of Tianmen City, Tianmen, 431700 Hubei China\n4 grid.508000.d Department of science and education, the First People’s Hospital of Tianmen City, Tianmen, 431700 Hubei China\n5 grid.443573.2 0000 0004 1799 2448 Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000 Hubei China\n6 grid.417303.2 0000 0000 9927 0537 Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004 Jiangsu China\n5 10 2021\n5 10 2021\n2021\n21 27023 7 2021\n17 9 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nRickettsia is the pathogen of Q fever, Brucella ovis is the pathogen of brucellosis, and both of them are Gram-negative bacteria which are parasitic in cells. The mixed infection of rickettsia and Brucella ovis is rarely reported in clinic. Early diagnosis and treatment are of great significance to the treatment and prognosis of brucellosis and Q fever. Here, we report a case of co-infection Rickettsia burneti and Brucella melitensis. The patient is a 49-year-old sheepherder, who was hospitalized with left forearm trauma. Three days after admission, the patient developed fever of 39.0°C, accompanied by sweating, fatigue, poor appetite and headache. Indirect immunofluorescence (IFA) was used to detect Rickettsia burneti IgM. After 72 hours of blood culture incubation, bacterial growth was detected in aerobic bottles, Gram-negative bacilli were found in culture medium smear, the colony was identified as Brucella melitensis by mass spectrometry. Patients were treated with doxycycline (100 mg bid, po) and rifampicin (600 mg qd, po) for 4 weeks. After treatment, the symptoms disappeared quickly, and there was no sign of recurrence or chronic infection. Q fever and Brucella may exist in high-risk practitioners, so we should routinely detect these two pathogens to prevent missed diagnosis.\n\nKeywords\n\nRickettsia burneti\nBrucella melitensis\nbrucellosis\nQ-fever\ncoinfection\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nBrucella melitensis is the pathogen of brucellosis, and Rickettsia burneti is the causative agent of Q fever, both of which are intracellular parasitic Gram-negative bacteria. Studies have shown that brucellosis and Q fever have roughly the same source of infection and route of transmission. Brucella can be transmitted from person to person, and vertical transmission is most common between mother and infant [1]. Brucellosis in humans can be severely debilitating, often with longterm adverse consequences for health [2]. Brucellosis in human beings will seriously weaken human body function, which usually causes long-term adverse consequences for health [3]. These two diseases can be prevalent in the same area at the same time, and the same patient (or animal) will be infected with these two diseases at the same time, which poses a great threat to human and animal health and public safety, and also causes great losses to the world economy. Up to now, few cases of mixed infection of Brucella and rickettsia burgdorferi have been reported [4, 5]. In PubMed, we found only one similar case report [6]. Brucellosis and Q fever are probably seriously underestimated and reported as lacking typical clinical symptoms, which are easy to be misdiagnosed and missed.\n\nIn this paper, the pathogenesis, clinical manifestations, laboratory examination results, diagnosis and treatment of a case of complicated infection were introduced in detail, and the related literatures were analyzed, in order to provide experience for the clinical treatment of this kind of disease.\n\nCase presentation\n\nA male aged 49 years was admitted to the First People's Hospital of Tianmen City on May 18 2021 due to left forearm trauma. The patient had no history of surgical trauma, hypertension and diabetes or hepatitis. The patient is a shepherd. In the past three months, he has delivered sheep several times. He lives in Tianmen, Hubei Province, China, where there is no epidemic history of Rickettsia and Brucella.\n\nThe ulnar wound of the patient's left forearm is about 1cm, with severe contusion and slight bleeding. The left forearm is swollen and tender, with limited movement, and the left finger moves. X-ray showed fracture of the left ulna. Routine laboratory tests showed that there was no obvious abnormality in white blood cell (WBC), liver and kidney function, or coagulation function. Chest computed tomography (CT) showed some chronic infective lesions in the lungs (Fig. 1A). Emergency doctors gave debridement suture and plaster support for external fixation. On May 21, the patient developed fever, sweating, weakness, loss of appetite and headache, the highest body temperature was about 39.0°c, and the physical examination was normal. There is no obvious abnormality in blood routine (BRE), but procalcitonin (PCT) and C-reactive protein (CRP) are obviously increased (Table 1). After physical cooling treatment, the patient's fever was not significantly ameliorated. Blood culture test was carried out. Considering his direct contact with sheep, respiratory pathogens were detected by IFA, including Legionella pneumophila IgM, Mycoplasma pneumoniae IgM, Rickettsia burgdorferi IgM, Chlamydia pneumoniae IgM, adenovirus IgM, respiratory syncytial virus IgM, influenza A virus IgM, influenza B virus IgM and parainfluenza virus IgM. The IFA test was positive for Rickettsia Burneti IgM (Fig. 1B) and negative for all others. After 72 hours blood incubation, bacterial growth was detected in aerobic bottles, and the culture medium was extracted and inoculated in Columbia blood plate and chocolate plate without vancomycin, and placed in an incubator containing 5% CO 2 at 35°C. Colonies appeared after 24 h of cultured. After 48 hours of culture, small, smooth and non-hemolytic colonies can be seen on the blood plate (Fig. 1C). Gram-negative spherical microbacterium can be seen from the extracted culture medium, with round ends, single chain or paired, short chain arrangement and no spores (Fig. 1D). The colony was identified as Brucella melitensis by mass spectrometry. Abdominal ultrasound showed no obvious lesions in liver and kidney. Electrocardiogram was normal.Fig. 1 Chest CT and microbiological examination results during hospitalization. A. Chest CT showed a few chronic infective lesions in the lung. B. Rickettsia Burneti IgM was positive by IFA test. The positive bacteria emitted green fluorescence(200X). C. Images of pure bacteria after 48 hours of culture. Small, smooth and non-hemolytic colonies can be seen on the blood plate. D. Gram stain of Brucella melitensis. Gram-negative spherical microbacilli can be seen, blunt round at both ends, single or paired, short chain arrangement, no spore (400X)\n\nTable 1 Laboratory tests results of the patient\n\n\tReference range\tMay-19\tMay-23\tMay-28\tJun-4\tJun-11\tJun-28\t\nWBC(×109/L)\t3.5-9.5\t7.23\t5.16\t5.19\t4.00\t4.37\t3.89\t\nMON%(×109/L)\t3-10%\t13.8\t10.5\t5.6\t5.6\t6.2\t6.3\t\nPLT(×109/L )\t125-350\t194\t218\t243\t243\t224\t194\t\nPCT(pg/ml)\t≤0.046\t-\t0.188\t0.087\t0.025\t0.035\t0.022\t\nALT(U/L)\t0-40\t53\t-\t44\t153\t78\t37\t\nAST(U/L)\t0-40\t41\t-\t28\t69\t52\t23\t\nCRP(mg/L)\t<6\t31.12-\t31.62\t23.34\t3.19\t4.37\t1.72\t\nWhite blood cell (WBC), monocyte count (MON#), platelet (PLT), procalcitonin (PCT), alanine aminotransferase (ALT), aspartate aminotransferase(AST), c-reactive protein (CRP), -: none.\n\nAccording to the epidemiological investigation, the patient was a shepherd who raised sheep for more than one year. The patient gave birth to sheep many times in the past three months, but he did not take any anti-infection measures. He did not eat fresh lamb or have goat milk. In view of the clinical feature, laboratory test and epidemiological history (contact with sheep), we suspected the patient had brucellosis and Q-fever. Patient received targeted antimicrobial therapy: doxycycline (100 mg bid, po) and rifampicin (600 mg qd, po). After three days of treatment, the patient's temperature returned to normal, and symptoms such as fatigue were obviously improved. The patient was then discharged from hospital and continued to receive the same treatment at home. However, on June 4th, the patient's liver function indexes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were significantly elevated (Table 1). Considering the side effects caused by taking doxycycline and rifampicin, the patient received additional treatment (Glutathione Buccal Tablets, 0.1g tid, po). During the follow-up, the patient's liver function gradually returned to normal (Table 1). The patient is now in good condition, showing no signs of recurrence or chronic infection.\n\nDiscussion\n\nRickettsia burneti is an intracellular parasitic Gram-negative bacterium, which can cause human acute Q fever. Human infection may occur due to inhalation of dust contaminated by body fluids of infected animals, consumption of unpasteurized dairy products and contact with milk, urine, feces, vaginal mucus or semen of infected animals [7]. The people with the highest risk of this infection are farmers, laboratory workers, sheep and dairy workers and veterinarians [8]. Q fever sufferers may have high fever, chills, severe headache and muscle aches. A few patients may have sore throat, nausea, vomiting, diarrhea, abdominal pain and delirium. The clinical manifestations of Q fever were non-specific and 60% asymptoms, which may cause a large number of misdiagnosis and missed diagnosis. Hepatitis, endocarditis or meningitis are complications observed in rare chronic course disease, with a mortality rate of up to 65%. If left untreated, the mortality rate of acute forms is as high as 1-2 %[9]. Q fever is effective in the early treatment of the disease with antibiotics. If the treatment is delayed, it will easily lead to chronic Q fever, with long treatment period, easy recurrence and high mortality. Therefore, early and accurate diagnosis of Q fever is extremely important. At present, the diagnosis of Q fever mainly relies on serological and molecular biological methods. However, Rickettsia infection is often ignored by people, and the bacteremia period is very short. In addition, Rickettsia is an intracellular parasitic bacterium, and the bacteria content in clinical samples is very low, which makes it difficult to detection. In our case, the patient developed symptoms such as high fever, excessive sweating, weakness, loss of appetite and headache, but no rash was found. WBC, platelet (PLT), ALT, AST showed no obvious changes, but PCT and CRP increased significantly (Table 1). Chest CT showed no obvious abnormality (Fig. 1A). In addition, by IFA test, Rickettsia Burneti IgM was positive in patients' serum (Fig. 1B). Although the patient's clinical symptoms were atypical and there was no obvious abnormality in laboratory examination or CT, it is suspected to be Q fever considering the epidemiological history (contact with sheep).\n\nBrucellosis is a neglected bacterial zoonotic disease, which seriously weakens people's health and usually causes long-term adverse consequences for health [2]. Brucellosis is caused by genus Brucella bacteria. The species considered as important vectors of human disease are B. Melitensis, B. Abortus and B.Sui s[2]. Brucella is more common in cattle, sheep, pigs and other domestic animals. Patients are mainly infected by contacting infected sheep or by drinking infected goat milk. Brucella can also be transmitted from person to person, and the most common is vertical transmission from mother to child [12]. The incubation period is usually 5-60 days [13]. After infection, the symptoms of Brucellosis are atypical and the clinical manifestations are varied, including fever, bone and arthropathy, sweating, fatigue, etc., which can be combined with other diseases. Because of these characteristics, it is easy to cause clinical missed diagnosis and misdiagnosis, delay the disease, and even cause complications such as arthritis, myocarditis and liver and spleen involvement [13]. Many studies have shown that CRP and PCT are sensitive indicators for the diagnosis of Brucellosis [17, 18]. The cure rate of acute brucellosis infection is 90-95%, while the chronic infection caused by brucellosis has not been cured, so early diagnosis and treatment of brucellosis are very important. After 72 hours of blood culture, the culture system reported positive results. Gram-negative spherical bacilli were found in the extracted culture medium (Fig. 1C). After 24 hours of pure bacteria culture, tiny colonies grew on the plate, after 48 hours of culture, typical Brucella colony morphology appeared on the plate (Fig. 1D). The colony was identified as Brucella melitensis by mass spectrometry, so we speculate that the patient was also infected with Brucella. In laboratory tests, we noticed a significantly increase in PCT and CRP (Table 1).\n\nBrucellosis and Q fever are zoonotic infectious diseases that attracted worldwide attention. They have the same infection source, host, transmission route and have similar clinical manifestations. The incidence of interstitial pneumonitis and bronchopneumonia in Brucella infections is low [19, 20] , However, almost half of patients with acute rickettsia burgdorferi infection will develop pneumonia [21]. The incidence of Q fever is lower, but its organ damage is more serious and its mortality is higher. If these two diseases enter the chronic phase, it will be difficult to cure them, so early diagnosis and symptomatic treatment are very important. The mixed infection of Rickettsia burneti and Brucella melitensis is rarely reported in clinical. As far as we know, this is the first case report in China. In PubMed, we only found one similar case report [6]. Although it is rare for patients to be infected with Brucella and Rickettsia at the same time, we should not ignore this situation. For potential infected persons, we should adopt a variety of detection methods to improve the detection rate of the pathogen. Since brucellosis and Q-fever have the same sensitive drugs [22, 23], patients were treated with doxycycline and rifampicin. Three days later, the patient's temperature returned to normal. After the patient was discharged from hospital, the treatment plan continued. Ten days later, the patient's liver function became abnormal (Table 1). Because doxycycline and rifampicin may cause liver damage, so we added liver protection drugs. During the latest follow-up, the patient's liver function returned to normal (Table 1). Therefore, we should pay attention to the detection of changes in liver function when treating co-infection.\n\nIn summary, we report a case of co-infection of Rickettsia burneti and Brucella melitensis. The patient was hospitalized for fracture, and developed high fever three days after admission, with no any other obvious discomfort. Laboratory examination showed that PCT and CRP were elevated, and there was no any other obvious abnormality. Through IFA and mass spectrometry, we confirmed that the patient was infected with Rickettsia burneti and Brucella melitensis. After active treatment with doxycycline and rifampicin, the patient's condition improved significantly. For high-risk practitioners, Q fever and brucellosis may exist in one patient. We should routinely detect these two pathogens through a various tests to prevent missed diagnosis. In the follow-up treatment, we should pay attention to the side effects of drugs, and actively use liver protective drugs to prevent liver function damage.\n\nAbbreviations\n\nIFA indirect immunofluorescence assay\n\nWBC white blood cell\n\nCT computed tomography\n\nBRE Blood routine examination\n\nCRP C-reactive protein\n\nALT alanine aminotransferase\n\nAST aspartate aminotransferase\n\nAuthors’ contributions\n\nJS and JZ contribute to thesis selection and design, data collection; XH and XL participate in data analysis and interpretation; YC, XY and WZ contributes to critical review of the intellectual content of an article; JZ and YD contribute to the manuscript writing.\n\nFunding\n\nThe present study was supported by National Natural Science Foundation of China (81602297), Guangxi Zhuang Autonomous Natural Science Foundation (2018JJB140322)\n\nAvailability of data and materials\n\nAll data y are included in this article\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe study is supported by the patient’s wife and she has signed informed consent.\n\nConsent for publication\n\nNot applicable\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nJiangqin Song and Junyang Zhou contributed equally to this work.\n==== Refs\nReferences\n\n1. Ali S Akhter S Neubauer H Scherag A Kesselmeier M Melzer F Khan I El-Adawy H Azam A Qadeer S Brucellosis in pregnant women from Pakistan: an observational study BMC Infect Dis 2016 16 1 468 10.1186/s12879-016-1799-1 27590009\n2. Corbel MJ Brucellosis: an overview Emerg Infect Dis 1997 3 2 213 221 10.3201/eid0302.970219 9204307\n3. Marrie TJ Raoult D Q fever--a review and issues for the next century Int J Antimicrob Agents 1997 8 3 145 161 10.1016/S0924-8579(96)00369-X 18611796\n4. Günal O Barut S Ayan M Kılıç S Duygu F Investigation of Coxiella burnetii and Brucella seropositivities in patients presenting with acute fever Mikrobiyol Bul 2013 47 2 265 272 10.5578/mb.4659 23621726\n5. Akbarian Z Ziay G Schauwers W Noormal B Saeed I Qanee AH Shahab Z Dennison T Dohoo I Jackson R Brucellosis and Coxiella burnetii Infection in Householders and Their Animals in Secure Villages in Herat Province, Afghanistan: A Cross-Sectional Study PLoS Negl Trop Dis 2015 9 10 e4112 10.1371/journal.pntd.0004112\n6. Peric L Sabadi D Rubil I Bogdan M Guzvinec M Dakovic RO Kaic B Tabain I Vilibic-Cavlek T Imported brucellosis and Q-fever coinfection in Croatia: a case report J Infect Dev Ctries 2018 12 6 499 503 10.3855/jidc.10151 31940303\n7. Dean AS Bonfoh B Kulo AE Boukaya GA Amidou M Hattendorf J Pilo P Schelling E Epidemiology of brucellosis and q Fever in linked human and animal populations in northern togo PLOS ONE 2013 8 8 e71501 10.1371/journal.pone.0071501 23951177\n8. Martinez E Cantet F Bonazzi M Generation and multi-phenotypic high-content screening of Coxiella burnetii transposon mutants J Vis Exp 2015 99 e52851\n9. Tissot-Dupont H Raoult D Q fever Infect Dis Clin North Am 2008 22 3 505 514 10.1016/j.idc.2008.03.002 18755387\n10. Young EJ An overview of human brucellosis Clin Infect Dis 1995 21 2 283 289 10.1093/clinids/21.2.283 8562733\n11. Bosilkovski M Arapović J Keramat F Human brucellosis in pregnancy - an overview Bosn J Basic Med Sci 2020 20 4 415 422 31782698\n12. Khan MY Mah MW Memish ZA Brucellosis in pregnant women Clin Infect Dis 2001 32 8 1172 1177 10.1086/319758 11283806\n13. Marr JS Cathey JT A Century in the Life of the Control of Communicable Diseases Manual: 1917 to 2017 J Public Health Manag Pract 2016 22 6 597 602 10.1097/PHH.0000000000000435 27682728\n14. Abid L Frikha Z Kallel S Chokri Z Ismahen B Amin B Hammami R Abid D Akrout M Hentati M Brucella myocarditis: a rare and life-threatening cardiac complication of brucellosis Intern Med 2012 51 8 901 904 10.2169/internalmedicine.51.6379 22504247\n15. Wallach JC García JL Cardinali PS Seijo AP Benchetrit AG Echazarreta SE Garro SL Deodato B Baldi PC High Incidence of Respiratory Involvement in a Cluster of Brucella suis-Infected Workers from a Pork Processing Plant in Argentina Zoonoses Public Health 2017 64 7 550 553 10.1111/zph.12339 28032696\n16. Yilmaz M Arslan F Başkan O Mert A Splenic abscess due to brucellosis: a case report and a review of the literature Int J Infect Dis 2014 20 68 70 10.1016/j.ijid.2013.11.010 24433982\n17. Liu J Zhao X Clinical features and serum profile of inflammatory biomarkers in patients with brucellosis J Infect Dev Ctries 2017 11 11 840 846 10.3855/jidc.8872 31618182\n18. Okan DH Gökmen Z Seyit B Yuksel K Cevdet Z Deniz A Mean platelet volume in brucellosis: correlation between brucella standard serum agglutination test results, platelet count, and C-reactive protein Afr Health Sci 2014 14 4 797 801 10.4314/ahs.v14i4.4 25834485\n19. Hatipoglu CA Bilgin G Tulek N Kosar U Pulmonary involvement in brucellosis J Infect 2005 51 2 116 119 10.1016/j.jinf.2004.10.004 16038761\n20. Erdem H Inan A Elaldi N Tekin R Gulsun S Ataman-Hatipoglu C Beeching N Deveci Ö Yalci A Bolukcu S Respiratory system involvement in brucellosis: the results of the Kardelen study CHEST 2014 145 1 87 94 10.1378/chest.13-0240 23907372\n21. Panjwani A Shivaprakasha S Karnad D Acute Q Fever Pneumonia J Assoc Physicians India 2015 63 12 83 84 27666914\n22. Shevtsov A Syzdykov M Kuznetsov A Shustov A Shevtsova E Berdimuratova K Mukanov K Ramankulov Y Antimicrobial susceptibility of Brucella melitensis in Kazakhstan Antimicrob Resist Infect Control 2017 6 130 10.1186/s13756-017-0293-x 29299304\n23. Smith CB Evavold C Kersh GJ The Effect of pH on Antibiotic Efficacy against Coxiella burnetii in Axenic Media Sci Rep 2019 9 1 18132 10.1038/s41598-019-54556-6 31792307\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2180",
"issue": "21(1)",
"journal": "BMC microbiology",
"keywords": "Brucella melitensis; Q-fever; Rickettsia burneti; brucellosis; coinfection",
"medline_ta": "BMC Microbiol",
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"references": "28032696;31618182;23907372;9204307;31792307;26485520;25834485;18611796;27590009;8562733;27666914;29299304;31940303;23621726;11283806;27682728;22504247;25992686;31782698;16038761;23951177;18755387;24433982",
"title": "Rickettsia burneti and Brucella melitensis co-infection: a case report and literature review.",
"title_normalized": "rickettsia burneti and brucella melitensis co infection a case report and literature review"
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"abstract": "OBJECTIVE\nResearch regarding the effects of age in patients with schizophrenia taking antipsychotics on the risk of sudden cardiac death is lacking. We determined the effect of patient age on the association between exposure to antipsychotics and the risk of sudden cardiac death in a nationwide schizophrenia cohort.\n\n\nMETHODS\nFrom the Taiwan National Health Insurance Research Database and Department of Health Death Certification System, data of 1836 patients with schizophrenia who had experienced sudden cardiac death between 2000 and 2016 were included. A case-crossover design by using a 14-day window was applied, and subgroup analyses were performed by stratifying patients into three age subgroups (<45, 45-65, and >65 years) to assess the effect of age on the risk of sudden cardiac death in patients taking antipsychotics.\n\n\nRESULTS\nNo association between exposure to antipsychotic agents and sudden cardiac death risk was found in patients aged >65 years who were characterized by a high burden of medical illnesses. However, zotepine significantly increased the risk of sudden cardiac death in patients aged <45 years (adjusted relative risk [RR] = 2.68, P = 0.046). Flupentixol (adjusted RR = 5.30, P = 0.004) and risperidone (adjusted RR = 1.68, P = 0.01) significantly elevated the risk of sudden cardiac death in patients aged 45-65 years.\n\n\nCONCLUSIONS\nThis study suggests that individual antipsychotics pose different risks of sudden cardiac death in patients with schizophrenia across their lifespan. Clinicians should consider patient age when evaluating the risks and benefits of antipsychotic treatment.",
"affiliations": "Department of Psychiatry, Taipei Medical University Hospital, Taipei, Taiwan.;Department of Psychiatry, Taipei Medical University Hospital, Taipei, Taiwan.;Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan.;Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan.;Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan.;Psychiatric Research Center, Taipei Medical University Hospital, Taipei, Taiwan.;Psychiatric Research Center, Taipei Medical University Hospital, Taipei, Taiwan.",
"authors": "Chen|Pao-Huan|PH|https://orcid.org/0000-0001-8454-7414;Tsai|Shang-Ying|SY|https://orcid.org/0000-0001-5662-0055;Pan|Chun-Hung|CH|;Chang|Chi-Kang|CK|;Su|Sheng-Shiang|SS|;Chen|Chiao-Chicy|CC|;Kuo|Chian-Jue|CJ|https://orcid.org/0000-0002-2773-1335",
"chemical_list": "D014150:Antipsychotic Agents; D003988:Dibenzothiepins; D018967:Risperidone; C022172:zotepine",
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"keywords": "age effect; antipsychotics; case-crossover; schizophrenia; sudden cardiac death",
"medline_ta": "Psychiatry Clin Neurosci",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D014150:Antipsychotic Agents; D018592:Cross-Over Studies; D016757:Death, Sudden, Cardiac; D003988:Dibenzothiepins; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012306:Risk; D018967:Risperidone; D012559:Schizophrenia; D013624:Taiwan",
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"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Age effect of antipsychotic medications on the risk of sudden cardiac death in patients with schizophrenia: A nationwide case-crossover study.",
"title_normalized": "age effect of antipsychotic medications on the risk of sudden cardiac death in patients with schizophrenia a nationwide case crossover study"
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"abstract": "We present the case of a woman with bipolar I disorder with severe premenstrual mood instability, confusion, and psychosis resembling the clinical features of postpartum psychosis when estrogen levels are expected to be low, and hypomania when estrogen levels are expected to be elevated. While depressive symptoms across the menstrual cycle have been extensively documented in the literature, there is little information regarding manic and hypomanic symptoms. In addition, we describe the successful treatment of her menstrual-cycle related symptoms. Approaches to the management of menstrual psychosis have not been systematically studied, and clinical guidelines do not exist. Clinical experiences such as the one reported here, in which the clinical formulation of the patient was consistent with known neuroendocrine phenomena and in which the treatment approach was successful, are crucial to developing promising approaches that can be tested in controlled trials.",
"affiliations": "Weill Cornell Medical College, NYP-Westchester Division, 21 Bloomingdale Road, OPD, White Plains, NY, 10605, USA. Lcs7001@med.cornell.edu.;Weill Cornell Medical College, 315 East 62nd St 5th fl, New York, NY, 10065, USA.",
"authors": "Susser|Leah C|LC|;Hermann|Alison D|AD|",
"chemical_list": "D014150:Antipsychotic Agents; D014635:Valproic Acid; D008094:Lithium; D000069056:Lurasidone Hydrochloride",
"country": "Austria",
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"fulltext": null,
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"issue": "20(2)",
"journal": "Archives of women's mental health",
"keywords": "Bipolar disorder; Estrogen; Hormone-related mood symptoms; Menstrual psychosis; Psychosis",
"medline_ta": "Arch Womens Ment Health",
"mesh_terms": "D000339:Affect; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D005260:Female; D006801:Humans; D008094:Lithium; D000069056:Lurasidone Hydrochloride; D008597:Menstrual Cycle; D011293:Premenstrual Syndrome; D011618:Psychotic Disorders; D016896:Treatment Outcome; D014635:Valproic Acid; D055815:Young Adult",
"nlm_unique_id": "9815663",
"other_id": null,
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"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Protection against hormone-mediated mood symptoms.",
"title_normalized": "protection against hormone mediated mood symptoms"
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"abstract": "BACKGROUND\nDrug-eluting coronary stent implantation emerged as a safe and effective therapeutic approach by preventing coronary restenosis and reducing the need for further revascularization. However, in contrast to bare metal stents, recent data suggest a unique underlying pathology, namely late coronary stent thrombosis and delayed endothelial healing.\n\n\nOBJECTIVE\nTo report a case of very late coronary stent thrombosis (834 days after implantation) requiring repeat urgent target-vessel revascularization. Importantly, six days before the acute coronary event, combined nonsteroidal anti-inflammatory drug therapy was initiated.\n\n\nRESULTS\nAlthough a dual antiplatelet regimen was continuously maintained, aggregation measurements indicated only partial antiplatelet effect, which returned to the expected range when nonsteroidal anti-inflammatory drugs were omitted.\n\n\nCONCLUSIONS\nThe observation indicates that, even 834 days after drug-eluting stent implantation, effective combined antiplatelet therapy might be crucial in certain individuals and the possible impact of drug interactions should not be underestimated. Further efforts should focus on the challenging task of identifying patients or medical situations with prolonged, increased risk of stent thrombosis.",
"affiliations": "Heart Center, Semmelweis University, Budapest, Hungary.",
"authors": "Merkely|Bela|B|;Tóth-Zsamboki|Emese|E|;Becker|David|D|;Beres|Bernat Janos|BJ|;Szabó|György|G|;Vargova|Katarina|K|;Fülöp|Gabor|G|;Kerecsen|Gabor|G|;Preda|Istvan|I|;Spaulding|Christian|C|;Kiss|Robert G|RG|",
"chemical_list": "D016861:Cyclooxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D013843:Thiazines; D013844:Thiazoles; D004008:Diclofenac; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin; D000077239:Meloxicam",
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"issue": "25(4)",
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"mesh_terms": "D000328:Adult; D015906:Angioplasty, Balloon, Coronary; D001241:Aspirin; D000077144:Clopidogrel; D003328:Coronary Thrombosis; D016861:Cyclooxygenase Inhibitors; D003925:Diabetic Angiopathies; D004008:Diclofenac; D004347:Drug Interactions; D054855:Drug-Eluting Stents; D004730:Endothelium, Vascular; D006801:Humans; D007405:Intervertebral Disc Displacement; D008297:Male; D000077239:Meloxicam; D009203:Myocardial Infarction; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors; D013843:Thiazines; D013844:Thiazoles; D013988:Ticlopidine; D013997:Time Factors",
"nlm_unique_id": "8510280",
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"pages": "229-32",
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"pubdate": "2009-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "17311117;16488805;17296824;17325255;17148711;16490830;16892439;16485347",
"title": "Very late drug-eluting stent thrombosis after nonsteroidal anti-inflammatory drug treatment despite dual antiplatelet therapy.",
"title_normalized": "very late drug eluting stent thrombosis after nonsteroidal anti inflammatory drug treatment despite dual antiplatelet therapy"
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"activesubstancename": "ASPIRIN"
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"abstract": "OBJECTIVE\nThis retrospective analysis evaluated treatment with trabectedin plus pegylated liposomal doxorubicin (PLD) in 34 heavily pretreated patients (median number of previous lines, 3; range, 2-10) with platinum-sensitive relapsed ovarian cancer (ROC) at a single center in Italy.\n\n\nMETHODS\nTrabectedin/PLD treatment consisted of trabectedin administered every 3 weeks as a 3-hour intravenous (i.v.) infusion at a dose of 1.1 mg/m2, immediately after PLD 30 mg/m2 i.v. infusion. Study objectives were the evaluation of the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS).\n\n\nRESULTS\nThree complete responses and 8 partial responses were observed, with an ORR of 32.4% (95% CI, 17.4-50.5%). Median PFS was 6.1 months (95% CI, 4.4-8.9 months). Median OS was 16.3 months (95% CI, 6.8-23.5). Most responses (9 of 11) were found in patients with partially platinum-sensitive disease (ORR 40.9% in this subset; median PFS 6.8 months and median OS 20.8 months). Grade 3 treatment-related adverse events consisted of nausea/vomiting (n = 5; 14.7%), mucositis (n = 2; 5.9%), alanine aminotransferase increase, anemia and neutropenia (n = 1 each; 2.9%).\n\n\nCONCLUSIONS\nThe overall findings appear consistent with those previously observed in a randomized controlled clinical trial, and support the use of trabectedin/PLD in heavily pretreated patients with platinum-sensitive ROC, especially those with partially platinum-sensitive disease.",
"affiliations": "Medical Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padua - Italy.",
"authors": "Nicoletto|Maria Ornella|MO|;Baldoni|Alessandra|A|;Casarin|Alessandra|A|;Randon|Giovanni|G|;Nardin|Margherita|M|;Baretta|Zora|Z|;Lardelli|Pilar|P|;Nieto|Antonio|A|;Alfaro|Vicente|V|;Rigamonti|Claudia|C|;Conte|Pier Franco|PF|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D017671:Platinum Compounds; D044005:Tetrahydroisoquinolines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D000077606:Trabectedin",
"country": "United States",
"delete": false,
"doi": "10.5301/tj.5000371",
"fulltext": "\n==== Front\nTumoriTumoriTMJsptmjTumori0300-89162038-2529SAGE Publications Sage UK: London, England 10.5301/tj.500037110.5301_tj.5000371Original Research ArticleTrabectedin plus Pegylated Liposomal Doxorubicin: Retrospective\nAnalysis in Heavily Pretreated Platinum-sensitive Ovarian Cancer Nicoletto Maria Ornella Baldoni Alessandra Casarin Alessandra Randon Giovanni Nardin Margherita Baretta Zora Lardelli Pilar Nieto Antonio Alfaro Vicente Rigamonti Claudia Conte Pier Franco 1 Medical Oncology Unit, Istituto Oncológico\nVéneto IOV-IRCCS, Padua - Italy2 Clinical R&D Department, PharmaMar,\nColmenar Viejo, Madrid - Spain3 Medical Affairs Department, PharmaMar Italy,\nMilan - ItalyIstituto Oncologico Veneto IOV-IRCCS Via\nGattamelata 64 35128 Padova, Italy mariaorn@libero.it18 6 2015 9 2015 101 5 506 510 16 5 2015 © 2015 The Authors2015SAGE PublicationsThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial-NoDerivs 4.0 License (http://www.creativecommons.org/licenses/by-nc-nd/4.0/) which\npermits non-commercial use, reproduction and distribution of the work as\npublished without adaptation or alteration, without further permission\nprovided the original work is attributed as specified on the SAGE and Open\nAccess page (https://us.sagepub.com/en-us/nam/open-access-at-sage).Purpose\nThis retrospective analysis evaluated treatment with trabectedin plus\npegylated liposomal doxorubicin (PLD) in 34 heavily pretreated patients\n(median number of previous lines, 3; range, 2-10) with platinum-sensitive\nrelapsed ovarian cancer (ROC) at a single center in Italy.\n\nMethods\nTrabectedin/PLD treatment consisted of trabectedin administered every 3 weeks\nas a 3-hour intravenous (i.v.) infusion at a dose of 1.1 mg/m2,\nimmediately after PLD 30 mg/m2 i.v. infusion. Study objectives\nwere the evaluation of the objective response rate (ORR), progression-free\nsurvival (PFS) and overall survival (OS).\n\nResults\nThree complete responses and 8 partial responses were observed, with an ORR\nof 32.4% (95% CI, 17.450.5%). Median PFS was 6.1 months (95% CI, 4.4-8.9\nmonths). Median OS was 16.3 months (95% CI, 6.8-23.5). Most responses (9 of\n11) were found in patients with partially platinum-sensitive disease (ORR\n40.9% in this subset; median PFS 6.8 months and median OS 20.8 months).\nGrade 3 treatment-related adverse events consisted of nausea/vomiting (n =\n5; 14.7%), mucositis (n = 2; 5.9%), alanine aminotransferase increase,\nanemia and neutropenia (n = 1 each; 2.9%).\n\nConclusions\nThe overall findings appear consistent with those previously observed in a\nrandomized controlled clinical trial, and support the use of trabectedin/PLD\nin heavily pretreated patients with platinum-sensitive ROC, especially those\nwith partially platinum-sensitive disease.\n\nOvarian cancerTrabectedinPLDClinical practicecover-dateSeptember-October 2015\n==== Body\nIntroduction\nTrabectedin (Yondelis®) is a marine-derived antineoplastic agent that was\ninitially isolated from the Caribbean tunicate Ecteinascidia\nturbinata and is currently produced by chemical synthesis. In early\nphase II trials, trabectedin showed encouraging antitumor activity as a single-agent\ntherapy in relapsed ovarian cancer (ROC) (1-4). Trabectedin plus doxorubicin showed synergy\nin vitro (5-7) and, in a phase I trial, trabectedin plus\npegylated liposomal doxorubicin (PLD) was well tolerated and provided clinical\nbenefit in pretreated patients with diverse solid tumor types including epithelial\novarian cancer (8). A randomized\nmulticenter phase III trial (OVA-301) evaluated trabectedin/PLD versus PLD alone in\nROC (9). Trabectedin/PLD\nimproved progression-free survival (PFS) over PLD alone, with a 21% risk reduction\nof disease progression or death (hazard ratio [HR] 0.79; 95% confidence interval\n[CI] 0.65-0.96; p = 0.0190; median 7.3 vs. 5.8 months) and adequate tolerability. In\nthe platinum-sensitive stratum (platinum-free interval [PFI] ≥6 months), the risk\nreduction of PD or death was 27% (HR 0.73; 95% CI 0.56-0.95; p = 0.0170; median PFS\n9.2 vs. 7.5 months). Based on these results, trabectedin/PLD received approval for\nthe treatment of patients with relapsed, platinum-sensitive ovarian cancer in the EU\nin 2009 and in around 70 countries. Further data obtained from the OVA-301 study\nafter a median follow-up of 47.4 months showed a median overall survival (OS) for\nthe trabectedin/PLD and PLD arms of 22.2 and 18.9 months, respectively (HR 0.86; 95%\nCI 0.72-1.02; p = 0.0835) (10).\n\nApart from information obtained in clinical trials, few data are available about the\nuse of trabectedin for ROC in clinical practice. Two retrospective analyses\nevaluated trabectedin as a single agent in patients with ROC (11, 12), but to date little information is available on the use of\ntrabectedin in combination with PLD. This retrospective analysis was conducted on\nheavily pretreated patients with platinum-sensitive ROC receiving trabectedin/PLD\ntreatment at a single center in Italy consecutively from May 2012 to January\n2015.\n\nMethods\nWritten informed consent to treatment and use of clinical data for scientific\npurposes was obtained from all patients at the time of chemotherapy administration.\nGiven the retrospective design of this analysis, approval of local ethics committees\nto retrieve data from clinical charts was not required, but the principles outlined\nin the Declaration of Helsinki were followed.\n\nPatients were adult women with histologically confirmed epithelial ovarian cancer,\npreviously treated with at least 1 platinum-based regimen, and with radiological\nevidence of disease progression, Eastern Cooperative Oncology Group (ECOG)\nperformance status (PS) ≤2 and adequate hematological (hemoglobin ≥9 g/dL; absolute\nneutrophil count ≥1.5 × 109/L; platelets ≥100 × 109/L), renal (serum creatinine ≤1.5 mg/dL) and hepatic function (bilirubin ≤\nupper limit of normal [ULN]; aspartate aminotransferase [AST]/ alanine\naminotransferase [ALT] ≤2.5 × ULN; alkaline phosphatase [AP] ≤2.5 × ULN [if total AP\n>2.5 × ULN, AP liver fraction and/or gamma glutamyltransferase and/or\n5′-nu-cleotidase had to be ≤ULN], and albumin >25 g/L).\n\nTrabectedin/PLD treatment consisted of trabectedin administered every 3 weeks as a\n3-hour intravenous (i.v.) infusion at a dose of 1.1 mg/m2, immediately\nafter i.v. infusion of PLD at a dose of 30 mg/m2. To minimize the risk of\nPLD infusion reactions, the initial dose was administered at a rate no greater than\n1 mg/minute and, if no infusion reaction was observed, subsequent PLD infusions were\nadministered over a 1-hour period. All patients received i.v. prophylactic\nmedication with corticosteroids (dexamethasone 20 mg or equivalent) 30 minutes prior\nto PLD infusion.\n\nTumor response and PFS were assessed according to the Response Evaluation Criteria in\nSolid Tumors, RECIST v. 1.1 (13). Patients were also followed up for OS analysis. PFS and OS were\ncalculated from the first day of trabectedin/PLD treatment to the date of disease\nprogression or death.\n\nThe safety of trabectedin/PLD treatment was evaluated by recording of adverse events\n(AEs), laboratory test results, physical examinations and vital signs. AEs and\nlaboratory abnormalities were graded according to the National Cancer Institute\nCommon Terminology Criteria for Adverse Events (NCI-CTCAE), v.3.0.\n\nDescriptive statistics were used for this retrospective analysis. Noncontiguous\nvariables are described in frequency tables using counts and percentages. Continuous\nvariables are described by median, minimum and maximum. The binomial exact estimator\nand its 95% CI was calculated for the evaluation of categorical efficacy variables\n(e.g., RECIST response). The Kaplan-Meier method was used for time-to-event\nvariables (PFS and OS). Exploratory log-rank tests were utilized to estimate the\nrelationship of time-to-event variables (PFS and OS) with tumor grade, histology,\nBRCA mutation status, number of prior surgical procedures,\nnumber of prior chemotherapy lines or PFI.\n\nResults\nPatient characteristics\nThirty-four patients with ROC were treated with trabect-edin/PLD in the evaluated\nperiod. Their main demographic and baseline characteristics are shown in Table I. Most of them\n(67.6%) had serous adenocarcinoma and differentiation grade 3 tumors (76.5%) at\ntime of diagnosis. All patients had undergone surgery; the initial tumor was\noptimally debulked in 73.5% of cases. BRCA mutation was found\nin 3 of 13 patients with available assessment: 1 in the BRCA1\ngene and 2 in BRCA2.\n\nTable I Demographic and baseline characteristics (n = 34)\n\n\t\tNo.\t%\t\nAge (years)\tMedian (range)\t60 (26-79)\t\nTime from diagnosis (months)\tMedian (range)\t30.0 (11.0-124.9)\t\nHistological type\tSerous\t23\t67.6\t\n\tadenocarcinoma\t\t\t\n\tOthera\t9\t26.5\t\n\tUndetermined\t2\t5.9\t\nTumor grade at diagnosis\t2\t5\t14.7\t\n\t3\t26\t76.5\t\n\t4\t1\t2.9\t\n\tUK\t2\t5.9\t\nResidual tumor\tOptimally debulked <1b\t25\t73.5\t\n\tNon-optimally debulkedc\t9\t26.5\t\n\nBRCA\n\tWild type\t10\t29.4\t\n\tMutated\t3d\t8.8\t\n\tUnknown\t21\t61.8\t\nNumber of previous lines of chemotherapy\tMedian (range)\t3 (2-10)\t\n\t2\t10\t29.4\t\n\t3\t10\t29.4\t\n\t≥4\t14\t41.2\t\nPlatinum-free interval (months)\t6-12\t22\t64.7\t\n\t>12\t12\t35.3\t\nUK = unknown.\n\na Adenocarcinoma not otherwise specified (NOS), clear cell,\nendometrioid (n = 4), mucinous, primitive peritoneal and yolk sac\ntumor.\n\nb Residual tumor <1 cm.\n\nc Residual tumor ≥1 cm (n = 7) or localized peritoneal seeding (n =\n2).\n\nd BRCA1 (n = 1) and BRCA2 (n =\n2).\n\nThe evaluated population had been heavily pretreated; the median number of\nprevious chemotherapy lines was 3 (range, 2-10 lines), and 41.2% of patients had\nreceived 4 or more lines. Most patients (64.7%) had partially platinum-sensitive\ndisease (i.e., PFI was 6-12 months) (Tab. I).\n\nTrabectedin/PLD treatment\nThe median number of trabectedin/PLD cycles received per patient was 5 (range,\n1-16), although those patients less heavily pretreated were able to receive\ntrabectedin/PLD for longer periods: patients with 2 prior chemotherapy lines had\na median of 9 cycles administered.\n\nResponse to treatment\nThirty-one patients were evaluable for response (Tab. II). Three complete responses (CRs) and\n8 partial responses (PRs) were observed, with an objective response rate (ORR)\nof 32.4% (95% CI 17.4-50.5). All but 2 responses were in patients with partially\nplatinum-sensitive disease (ORR was 40.9% in this subset of patients). One CR\nwas found in a patient with partially platinum-sensitive disease and\nBRCA2 mutation. Ten of these 11 tumor responses were\nobserved in patients with serous histology, 9 in patients with grade 3 tumors, 8\nin patients with optimally debulked residual tumor, and 7 in patients with only\n1 previous surgical procedure.\n\nTable II Response rate according to RECIST (n = 34)\n\n\tNo.\t%\t\nComplete response\t3\t8.8\t\nPartial response\t8\t23.5\t\nStable disease\t16\t47.1\t\nProgressive disease\t4\t11.8\t\nNot evaluable\t3\t8.8\t\nObjective response rate, % (95% CI)\t32.4 (17.4-50.5)\t\nRECIST = Response Evaluation Criteria in Solid Tumors; CI =\nconfidence interval.\n\nProgression-free survival\nMedian PFS was 6.1 months (95% CI 4.4-8.9). The PFS rates at 6 and 12 months were\n52.5% and 12.4%, respectively (Tab. III). There was no statistically significant difference\naccording to the number of previous chemotherapy lines, although a trend to a\nbetter outcome was observed in those patients less pretreated (Fig. 1). Median PFS was 6.8\nmonths in patients with partially platinum-sensitive disease. PFS was\nsignificantly longer in patients with serous histology (8.9 vs. 5.2 months in\nthose with other histologies; p = 0.0433).\n\nFig. 1 Kaplan-Meier plot of progression-free survival (PFS) according to the\nnumber of previous chemotherapy lines received. Data shown are medians\n(95% CI). C = censored; CI = confidence interval; N = number of\npatients; n.r. = not reached.\n\nTable III Progression-free survival (n = 30)\n\nProgression-free survival\t\t\nCensored, n (%)\t8 (26.7%)\t\nMedian (95% CI) (months)\t6.1 (4.4-8.9)\t\nPFS at 6 months, % (95% CI)\t52.5% (33.5-71.5)\t\nPFS at 12 months, % (95% CI)\t12.4% (0-27.5)\t\nCI = confidence interval; PFS = progression-free survival.\n\nOverall survival\nThe majority of patients were alive at the time of this retrospective analysis\n(58% of patients censored) and therefore OS data were very immature. Median OS\nwas 16.3 months (95% CI 6.8-23.5). The OS rates at 6 and 12 months were 76.3%\nand 68.9%, respectively. A statistically significant difference (p = 0.0318) was\nfound according to the number of previous chemotherapy lines (Fig. 2).\n\nFig. 2 Kaplan-Meier plot of overall survival (OS) according to the number of\nprevious chemotherapy lines received. Data shown are medians (95% CI). C\n= censored; CI = confidence interval; N = number of patients; n.r. = not\nreached.\n\nSafety\nNo grade 4 treatment-related AEs were reported. Grade 3 treatment-related AEs\nincluded nausea/vomiting (n = 5; 14.7%), mucositis (n = 2; 5.9%), ALT increase,\nanemia and neutropenia (n = 1 each; 2.9%) (Tab. IV).\n\nTable IV Treatment-related adverse events (worst grade per patient; n = 34)\n\n\tNCI-CTCAE grade\t\n1/2\t3\t\nn\t%\tn\t%\t\nAlanine aminotransferase increase\t-\t-\t1\t2.9\t\nAnemia\t1\t2.9\t1\t2.9\t\nAsthenia\t6\t17.6\t-\t-\t\nFever\t1\t2.9\t-\t-\t\nIntolerance to antiemetics\t1\t2.9\t-\t-\t\nMucositis\t3\t8.8\t2\t5.9\t\nMyalgia\t1\t2.9\t-\t-\t\nNausea/vomiting\t12\t35.3\t5\t14.7\t\nNeutropenia\t5\t14.7\t1\t2.9\t\nPancreatitis\t1\t2.9\t-\t-\t\nPhlebitis\t1\t2.9\t-\t-\t\nSensorial peripheral neuropathy\t2\t5.9\t-\t-\t\nThrombocytopenia\t1\t2.9\t-\t-\t\nNCI-CTCAE = National Cancer Institute Common Terminology Criteria for\nAdverse Events.\n\nDiscussion\nThis retrospective analysis evaluated the efficacy and safety outcomes of the\ntrabectedin/PLD combination when used in patients with ROC in daily clinical\npractice. This analysis was conducted in patients with platinum-sensitive disease\n(64.7% had partially platinum-sensitive disease) and showed ORR = 32.4%, median PFS\n= 6.1 months and median OS = 16.3 months. In the pivotal OVA-301 trial, data\nobtained from the platinum-sensitive subset of patients showed ORR = 35.3%, median\nPFS = 9.2 months and median OS = 27.0 months (Tab. V). The ORR obtained in the present study is\nsimilar to that of OVA-301, although in that trial an independent review was\nimplemented. In addition to the difficulties of retrospective comparisons, the\ndifferences in PFS and OS with the pivotal trial may be partially explained by the\nimmaturity of the data in the present study (27% and 58% of patients were censored\nfor PFS and OS, respectively). Nevertheless, the overall data obtained seem to be\nconsistent with those observed in a controlled, randomized clinical trial, and\nsupport that trabectedin/PLD maintains antitumor activity when administered as a\nthird or further chemotherapy line. Trabectedin/PLD activity appears to be unrelated\nto the number of previous chemotherapy lines. A retrospective study on 98 heavily\ntreated ROC patients (median number of previous lines, 4; range, 1-6 lines) who\nreceived single-agent trabectedin as salvage treatment showed an ORR of 27.5%. This\nrate did not vary with the number of previously administered chemotherapy lines\n(14). The present results\nobtained in heavily pretreated patients (median of 3 previous lines, with some\npatients having received up to 10 lines) are similar to those obtained in OVA-301,\nwhere the inclusion criteria allowed only 1 previous line of treatment.\n\nTable V Efficacy outcomes in patients with platinum-sensitive relapsed ovarian cancer\ntreated with trabectedin 1.1 mg/m2 plus PLD 30 mg/m2\n3-hour q3wk infusion.\n\nFirst author (year)\tType of study\tNo.\tNumber of previous lines (median, range)\tPlatinum-sensitive, n (%)\tcycles, median (range)\tORR (%)\tMedian PFS (months)\tMedian OS (months)\t\n\t\t\t\t\t\tPFla\t\n\t\t\t\t\t\t>6\t6-12\t>6\t6-12\t>6\t6-12\t\nMonk (2010, 2012) (9, 10)\tPhase III clinical trial, randomized Independent review\t337\t1b\t278 (64.7%)\t6 (1-21)\t35.3%\tNA\t9.2\t7.4\t27.0\tNA\t\nCurrent study\tSingle-center retrospective analysis\t34\t3 (2-10)\t34 (100.0%)\t5 (1-16)\t32.4%\t40.9%\t6.1\t6.8\t16.3c\t20.8c\t\nORR = objective response rate; OS = overall survival; PFI = platinum-free\ninterval; PFS = progression-free survival; PLD = pegylated liposomal\ndoxorubicin; q3wk = every 3 weeks.\n\na Platinum-sensitive disease (PFI >6 months) and partially\nplatinum-sensitive disease (PFI 6-12 months).\n\nb No data on pretreatment were available, but the inclusion criteria of\nthis study allowed only 1 previous line of treatment.\n\nc The majority of patients were alive at the time of this retrospective\nanalysis (58% of patients censored) and therefore OS data were very\nimmature.\n\nIn the present single-center study, patients with partially platinum-sensitive\ndisease obtained more clinical benefit in terms of ORR, PFS and OS. This is an\nexpected finding as previous studies showed that the efficacy of the trabectedin/PLD\ncombination appears particularly optimized in the partially platinum-sensitive ROC\npopulation (7, 15, 16).\n\nThe safety profile was as expected for trabectedin/PLD treatment; no new safety\nsignals were reported. The median number of cycles received per patient was similar\nto that reported in the pivotal OVA-301 trial in a less heavily pretreated\npopulation (Tab. V).\n\nIn conclusion, this retrospective analysis shows that trabectedin/PLD is an effective\ntreatment for ROC patients in daily clinical practice, especially patients with\npartially platinum-sensitive disease. Our findings were consistent with those of a\nprevious randomized trial and further support that trabectedin/PLD maintains\nantitumor activity when administered as a third or further chemotherapy line.\n\nDisclosures\nFinancial support: PharmaMar provided financial support for statistical analyses\nand manuscript writing.\n\nConflict of interest: Pilar Lardelli, Antonio Nieto, Vicente Alfaro and Claudia\nRigamonti are employees at PharmaMar. Other authors did not declare any conflict\nof interest.\n==== Refs\nReferences\n1. Sessa C. , De Braud F. , Perotti A. \nTrabectedin for women with ovarian carcinoma after treatment with\nplatinum and taxanes fails . J Clin Oncol. \n2005 ; 23 (9 ):\n1867 –1874 .15774779 \n2. Krasner C.N. , McMeekin D.S. , Chan S. \nA Phase II study of trabectedin single agent in patients with\nrecurrent ovarian cancer previously treated with platinum-based\nregimens . Br J Cancer. \n2007 ; 97 (12 ):\n1618 –1624 .18000504 \n3. 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Mascilini F. , Amadio G. , Di Stefano M.G. \nClinical utility of trabectedin for the treatment of ovarian\ncancer: current evidence . Onco Targets\nTher. \n2014 ; 7 :\n1273 –1284 .25050069 \n15. Sehouli J. , Alfaro V. , González-Martín A. \nTrabectedin plus pegylated liposomal doxorubicin in the treatment\nof patients with partially platinum-sensitive ovarian cancer: current\nevidence and future perspectives . Ann\nOncol. \n2012 ; 23 (3 ):\n556 –562 .21734221 \n16. Colombo N. \nOptimizing treatment of the partially platinum-sensitive ovarian\ncancer patient . Future Oncol. \n2013 ; 9 (12 Suppl):\n19 –23 .24195526\n\n",
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"issn_linking": "0300-8916",
"issue": "101(5)",
"journal": "Tumori",
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"medline_ta": "Tumori",
"mesh_terms": "D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D000971:Antineoplastic Combined Chemotherapy Protocols; D004149:Dioxoles; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms; D017671:Platinum Compounds; D011092:Polyethylene Glycols; D012189:Retrospective Studies; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D016896:Treatment Outcome",
"nlm_unique_id": "0111356",
"other_id": null,
"pages": "506-10",
"pmc": null,
"pmid": "26108247",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "18000504;20516432;20643862;23397080;21734221;12783202;19556318;19097774;15774779;24195526;11595721;25050069;18497430;22541893;23774301",
"title": "Trabectedin plus pegylated liposomal doxorubicin: retrospective analysis in heavily pretreated platinum-sensitive ovarian cancer.",
"title_normalized": "trabectedin plus pegylated liposomal doxorubicin retrospective analysis in heavily pretreated platinum sensitive ovarian cancer"
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"abstract": "OBJECTIVE\nConcentration disturbances are frequent in chronic fatigue syndrome (CFS). In a placebo-controlled double-blind crossover study, methylphenidate over 4 weeks was superior to placebo in the relief of fatigue and concentration disturbance. This observational study describes the effect of long-term methylphenidate intake on fatigue, concentration, and daily life activities, as reported by the patients themselves.\n\n\nMETHODS\nA questionnaire was sent to all CFS patients who were prescribed methylphenidate at the general internal medicine department of a university hospital between August 2004 and February 2007, for possible improvement of concentration difficulties and fatigue.\n\n\nRESULTS\nOut of 194 consecutive patients, 149 (76.8%) sent the questionnaire back. At the time of the questionnaire, 65.3% had stopped the intake of methylphenidate, 34.7% still took it daily or occasionally. Among the patients who continued methylphenidate, 48% reported an at least 50% improvement of fatigue, and 62% reported an at least 50% improvement of concentration difficulties. This continued intake of methylphenidate resulted in more working hours in these patients. Side effects (agitation, palpitations, and dry mouth) were reported significantly more in patients who had stopped methylphenidate than in those who still took it.\n\n\nCONCLUSIONS\nThe long-term intake of methylphenidate by CFS patients with concentration difficulties has a positive effect in about one out of three patients.",
"affiliations": "a Department of General Internal Medicine , University Hospital Gasthuisberg , Leuven , Belgium.;b Department of Psychiatry , University Hospital Gasthuisberg , Leuven , Belgium.",
"authors": "Blockmans|Daniel|D|;Persoons|Philippe|P|",
"chemical_list": "D018765:Dopamine Uptake Inhibitors; D008774:Methylphenidate",
"country": "England",
"delete": false,
"doi": "10.1080/17843286.2016.1200816",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "71(6)",
"journal": "Acta clinica Belgica",
"keywords": "Chronic fatigue syndrome; Concentration problems; Methylphenidate",
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000203:Activities of Daily Living; D000328:Adult; D018592:Cross-Over Studies; D018765:Dopamine Uptake Inhibitors; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D015673:Fatigue Syndrome, Chronic; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate; D011788:Quality of Life; D011795:Surveys and Questionnaires; D016896:Treatment Outcome",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "407-414",
"pmc": null,
"pmid": "27351244",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Long-term methylphenidate intake in chronic fatigue syndrome.",
"title_normalized": "long term methylphenidate intake in chronic fatigue syndrome"
} | [
{
"companynumb": "BE-JNJFOC-20161214306",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "OBJECTIVE\nTo compare the pharmacokinetics (PK), safety and efficacy of innovator infliximab (INX) and CT-P13, a biosimilar to INX, in patients with active ankylosing spondylitis (AS).\n\n\nMETHODS\nPhase 1 randomised, double-blind, multicentre, multinational, parallel-group study. Patients were randomised to receive 5 mg/kg of CT-P13 (n=125) or INX (n=125). Primary endpoints were area under the concentration-time curve (AUC) at steady state and observed maximum steady state serum concentration (Cmax,ss) between weeks 22 and 30. Additional PK, efficacy endpoints, including 20% and 40% improvement response according to Assessment in Ankylosing Spondylitis International Working Group criteria (ASAS20 and ASAS40), and safety outcomes were also assessed.\n\n\nRESULTS\nGeometric mean AUC was 32 765.8 μgh/ml for CT-P13 and 31 359.3 μgh/ml for INX. Geometric mean Cmax,ss was 147.0 μg/ml for CT-P13 and 144.8 μg/ml for INX. The ratio of geometric means was 104.5% (90% CI 94% to 116%) for AUC and 101.5% (90% CI 95% to 109%) for Cmax,ss. ASAS20 and ASAS40 responses at week 30 were 70.5% and 51.8% for CT-P13 and 72.4% and 47.4% for INX, respectively. In the CT-P13 and INX groups more than one adverse event occurred in 64.8% and 63.9% of patients, infusion reactions occurred in 3.9% and 4.9%, active tuberculosis occurred in 1.6% and 0.8%, and 27.4% and 22.5% of patients tested positive for anti-drug antibodies, respectively.\n\n\nCONCLUSIONS\nThe PK profiles of CT-P13 and INX were equivalent in patients with active AS. CT-P13 was well tolerated, with an efficacy and safety profile comparable to that of INX up to week 30.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, Inha University Hospital, Incheon, Republic of Korea. parkwon@inha.ac.kr",
"authors": "Park|Won|W|;Hrycaj|Pawel|P|;Jeka|Slawomir|S|;Kovalenko|Volodymyr|V|;Lysenko|Grygorii|G|;Miranda|Pedro|P|;Mikazane|Helena|H|;Gutierrez-Ureña|Sergio|S|;Lim|MieJin|M|;Lee|Yeon-Ah|YA|;Lee|Sang Joon|SJ|;Kim|HoUng|H|;Yoo|Dae Hyun|DH|;Braun|Jürgen|J|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; C000591237:CT-P13; D007074:Immunoglobulin G; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1136/annrheumdis-2012-203091",
"fulltext": "\n==== Front\nAnn Rheum DisAnn. Rheum. DisannrheumdisardAnnals of the Rheumatic Diseases0003-49671468-2060BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR 23687259annrheumdis-2012-20309110.1136/annrheumdis-2012-20309115061507Clinical and Epidemiological ResearchExtended reportA randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study Park Won 1Hrycaj Pawel 2Jeka Slawomir 3Kovalenko Volodymyr 4Lysenko Grygorii 5Miranda Pedro 6Mikazane Helena 7Gutierrez-Ureña Sergio 8Lim MieJin 1Lee Yeon-Ah 9Lee Sang Joon 10Kim HoUng 11Yoo Dae Hyun 12Braun Jürgen 131 Division of Rheumatology, Department of Internal Medicine, Inha University Hospital, Incheon, Republicof Korea2 Department of Rheumatology and Clinical Immunology, Poznan University of Medical Sciences, Poznań, Poland3 Department of Rheumatology and Connective Tissue Diseases, \"NASZ LEKARZ\" Praktyka Grupowa Lekarzy Rodzinnych z Przychodnia, Toruń, Poland4 Section of Non-coronarogenic Myocardial Diseases and Clinical Rheumatology, National Scientific Center, Kiev, Ukraine5 Department of Family Medicine, Kyiv Regional Clinical Hospital, Kiev, Ukraine6 Rheumatology Department, Centro de Estudios Reumatológicos, Santiago, Chile7 Outpatient Clinic ORTO, Riga, Latvia8 Rheumatology Department, Antiguo Hospital Civil de Guadalajara, Guadalajara, Mexico9 Division of Rheumatology, Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Republicof Korea10 Division of Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA11 Clinical Planning and Medical Affairs Department, CELLTRION, Inc, Incheon, Republicof Korea12 Division of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republicof Korea13 Medical Director of Rheumazentrum Ruhrgebiet, a Medical Center specialised for rheumatic diseases, Rheumazentrum Ruhrgebiet, Herne, GermanyHandling editor Tore K Kvien\n\nCorrespondence to Dr W Park, Division of Rheumatology, Department of Internal Medicine, Inha University Hospital, Center for Rheumatism. 27, InhangRo, JungGu, Incheon 400-711, Republic of Korea; parkwon@inha.ac.kr and Professor J Braun, Rheumazentrum Ruhrgebiet, Landgrafenstraße 15, Herne 44652, Germany; j.braun@rheumazentrum-ruhrgebiet.de10 2013 17 5 2013 72 10 1605 1612 19 4 2013 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions2013This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/Objectives\nTo compare the pharmacokinetics (PK), safety and efficacy of innovator infliximab (INX) and CT-P13, a biosimilar to INX, in patients with active ankylosing spondylitis (AS).\n\nMethods\nPhase 1 randomised, double-blind, multicentre, multinational, parallel-group study. Patients were randomised to receive 5 mg/kg of CT-P13 (n=125) or INX (n=125). Primary endpoints were area under the concentration-time curve (AUC) at steady state and observed maximum steady state serum concentration (Cmax,ss) between weeks 22 and 30. Additional PK, efficacy endpoints, including 20% and 40% improvement response according to Assessment in Ankylosing Spondylitis International Working Group criteria (ASAS20 and ASAS40), and safety outcomes were also assessed.\n\nResults\nGeometric mean AUC was 32 765.8 μgh/ml for CT-P13 and 31 359.3 μgh/ml for INX. Geometric mean Cmax,ss was 147.0 μg/ml for CT-P13 and 144.8 μg/ml for INX. The ratio of geometric means was 104.5% (90% CI 94% to 116%) for AUC and 101.5% (90% CI 95% to 109%) for Cmax,ss. ASAS20 and ASAS40 responses at week 30 were 70.5% and 51.8% for CT-P13 and 72.4% and 47.4% for INX, respectively. In the CT-P13 and INX groups more than one adverse event occurred in 64.8% and 63.9% of patients, infusion reactions occurred in 3.9% and 4.9%, active tuberculosis occurred in 1.6% and 0.8%, and 27.4% and 22.5% of patients tested positive for anti-drug antibodies, respectively.\n\nConclusions\nThe PK profiles of CT-P13 and INX were equivalent in patients with active AS. CT-P13 was well tolerated, with an efficacy and safety profile comparable to that of INX up to week 30.\n\nspecial-featureunlockedspecial-featureeditors-choice\n==== Body\nIntroduction\nInnovator infliximab (INX), a chimeric monoclonal antibody (mAb) to tumour necrosis factor-α (TNFα), was the first TNF antagonist shown to be efficacious in ankylosing spondylitis (AS).1 INX significantly improved the signs, symptoms, functional status, and quality of life (QOL) of patients with AS in clinical trials, with clinical improvement seen as early as 2 weeks after initiation of therapy and an acceptable safety profile.2–4 In the Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT) trial, patients receiving INX also showed significant improvement versus placebo in 20% and 40% improvement response according to Assessment in Ankylosing Spondylitis International Working Group criteria (ASAS20/ASAS40), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI), chest expansion and physical component summary score of the SF-36.2 INX and other anti-TNF agents have become important components of the management of patients with active AS.5\n6 With current biologic therapies approaching patent expiration, there has been considerable interest in developing biosimilar products, which are highly similar but not identical and not ‘bioidentical’, to approved ‘reference’ agents.7\n\nCT-P13 is an IgG1 chimeric human-murine mAb biosimilar to INX. CT-P13 is produced in the same type of cell-line (Sp2/0-AG14—purchased from ATCC, Cat. CRL-1581) and has an identical amino acid sequence to INX. CT-P13 and INX have demonstrated comparable in vitro primary pharmacodynamics (PD) in a range of studies (CELLTRION, Inc. Unpublished data (see online supplementary appendix A)). CT-P13 and INX showed comparable binding affinities to monomeric and trimeric forms of human TNFα (hTNFα), transgenic mouse hTNFα (tmhTNFα) expressed by Jurkat cells and to Fcγ receptors and FcRn. Comparable hTNFα neutralising activity against a TNFα-sensitive mouse sarcoma cell-line (WEHI-164) has also been demonstrated. CT-P13 and INX are also comparable in terms of: lack of binding activity to human TNFβ and TNFα from a range of different species known not to bind infliximab; relative binding affinities to complement protein C1q; and complement-dependent cytotoxicity effects and apoptotic effects against a Jurkat T-cell-line expressing tmhTNFα. Comparable cytotoxic activities have been achieved as a result of antibody-dependent cellular cytotoxicity evaluation of human peripheral blood mononuclear cells against tmhTNF α-Jurkat T cells, demonstrating biosimilarity of CT-P13 and INX. Highly comparable human tissue cross-reactivity results have been observed for biotinylated CT-P13 and INX.\n\nAccording to biosimilar guidelines from European Medicines Agency (EMA) and US Food and Drug Administration (FDA), comparative clinical trials for pharmacokinetics (PK) and efficacy are required for demonstration of clinical comparability, preferably double-blind, normally equivalence trials. Programme evaLuating the Autoimmune disease iNvEstigational drug cT-p13 in AS patients (PLANETAS) was conducted with the approval of the regulatory authorities, including the EMA. PLANETAS was not a conventional dose finding Phase 1 clinical trial but a Phase 1 biosimilar study designed to demonstrate PK equivalence and efficacy and safety comparability of CT-P13 and INX in active AS patients. Efficacy equivalence of CT-P13 and INX in a phase 3 study named Programme evaLuating the Autoimmune disease iNvEstigational drug cT-p13 in rheumatoid arthritis (RA) patients (PLANETRA).8 PK and PD endpoints were also assessed, as the indications for the PLANETAS and PLANETRA trials were different.\n\nPatients and methods\nPatients\nPatients with active AS according to the 1984 modified New York classification criteria for ≥3 months prior to screening, with BASDAI score of ≥4 (range 0–10) and a visual analogue scale score for spinal pain of ≥4 (range 0–10) were eligible for PLANETAS study. Patients were permitted to receive both oral glucocorticoids (equivalent to ≤10mg daily prednisolone) and nonsteroidal anti-inflammatory drugs, if they had received a stable dose for ≥4 weeks prior to screening. Additional details of patient eligibility criteria are provided online (see online supplementary appendix B).\n\nStudy design\nThis study (ClinicalTrials.gov NCT01220518) was conducted according to the Declaration of Helsinki and International Committee on Harmonisation good clinical practices. The protocol was reviewed and approved by regulatory authorities and the ethics committees of each study site. Written informed consent was obtained from all patients. The study was conducted at 46 sites across 10 countries in Europe, Asia and Latin America.\n\nPatients were randomly assigned 1:1 to receive either 5 mg/kg of CT-P13 (CELLTRION INC, Incheon, Republic of Korea) or INX (Janssen Biotech Inc, Horsham, Pennsylvania, USA), both administered by 2-h IV infusion, at weeks 0, 2, 6 and then q8 weeks up to week 30. Patients were premedicated with antihistamine (chlorpheniramine 2–4 mg or dose of equivalent antihistamine, eg, 10 mg of cetirizine) 30–60 min prior to the start of infusion at the investigator's discretion.\n\nPatients underwent clinical assessments and blood sampling at baseline, weeks 14 and 30. At each visit, patients were questioned about adverse events (AEs) and concomitant medications and were monitored for any clinical signs and symptoms of tuberculosis (TB). Additional study details are provided in (see online supplementary appendix C).\n\nStudy endpoints\nThe primary endpoint was to demonstrate PK equivalence at steady state (area under the concentration-time curve (AUC] and observed maximum serum concentration (Cmax,ss)) between CT-P13 and INX assessed between weeks 22 and 30 (doses 5 and 6). Serum blood samples for PK analysis were obtained immediately prior to the study treatment infusion, at the end of the infusion and 1 h after the study treatment infusion. For primary PK analysis, a total of 10 serum blood samples were obtained between weeks 22 and 30. All PK analyses were conducted using a flow-through immunoassay platform (GyrolabxP; Gyros AB, Sweden).\n\nIn an equivalence trial, we conclude that two treatments are equivalent if the observable difference (ΔE) between them lies within an established interval for predefined clinical equivalence margin (−d, d). In general, the ‘null hypothesis’ is that the difference (ΔE) is outside of the equivalence margin, that is, either ΔE>d or ΔE<–d. If collected data on the true difference ΔE reject the null hypothesis of ‘non-equivalence’ then we can accept the alternative explanation (−d≤ΔE≤d) that the two treatments work equally well.9 An equivalence margin of 80–125% was selected based on recommendations for bioequivalence trials.10–13 The use of 90% confidence intervals (CIs), lying within the equivalence margin of 80–125%, was therefore considered to be the best available method of determining bioequivalence for PK comparative trials. In our PK analysis, the predetermined difference is defined by its corresponding ratio since we use the ratio of geometric means of PK endpoints.\n\nSecondary endpoints included additional PK, efficacy, immunogenicity and safety parameters. The secondary PK endpoints included assessments of observed maximum serum concentration (Cmax), minimum serum concentration (Cmin), time to reach Cmax (Tmax) up to week 30 and the comparison of the following parameters from week 22 to 30: average concentration at steady state (Cav,ss); minimum concentration at steady state immediately before the next infusion (Cmin,ss); swing ((Cmax,ss−Cmin,ss)/Cmin,ss); degree of fluctuation ((Cmax,ss−Cmin,ss)/Cav,ss); mean residence time (MRT); terminal elimination half-life calculated between doses 5 and 6 (T1/2); total body clearance (CLss) and volume of distribution at steady state (Vss).\n\nEfficacy endpoints were assessed at weeks 14 and 30 and included: proportion of patients achieving ASAS20 or ASAS40 responses; Ankylosing Spondylitis Disease Activity Score (ASDAS) score; change in BASDAI, BASFI and BASMI scores versus baseline; change in chest expansion score versus baseline; and QOL (assessed using the Medical Outcomes Study Short-Form Health Survey (SF-36)).\n\nBlood samples were assessed for anti-drug antibodies (ADA) at weeks 14 and 30. Antibodies against CT-P13 or INX were measured using an electrochemiluminescent immunoassay method utilising the Meso Scale Discovery platform (MSD, Rockville, Maryland, USA).\n\nSafety endpoints included incidence and type of AEs, serious AEs (SAEs) and incidence of infusion-related reactions, infection and changes in clinical laboratory parameters from baseline. AEs were coded using the Medical Dictionary for Regulatory Activities and severity was characterised as mild, moderate or severe. ECGs were recorded at week 30.\n\nAll patients were screened for latent or active TB by an interferon gamma release assay (IGRA) utilising QuantiFERON-TB Gold in tube (Cellestis Ltd, Australia) and chest x-ray. Patients with latent TB received prophylactic medication according to the local guidelines. For countries with an increased incidence of TB, IGRA was used to identify positive conversion from negative results at weeks 14 and 30, in line with the WHO recommendations for sole use of IGRA in non-HIV adults receiving anti-TNF therapy.14\n15\n\nStatistical analysis\nSample size was determined using the following criteria: a coefficient of variation (CV) of 50%, expected ratio of means=1, 2-sided α=0.1, power=90%, and a 2-sided equivalence margin of 80–125% for AUC and Cmax,ss.16\n17 Recruitment of 196 patients were required to demonstrate an effect. Allowing for a drop-out rate of 20%, a minimum of 246 patients were required for randomisation.\n\nThe PK population consisted of all patients who received at least the first five doses of study treatment and provided an end of infusion sample and at least one post-treatment PK sample to facilitate calculation of AUC and Cmax,ss. The PK population included only patients who did not have any major protocol deviations (see online supplementary appendix D).\n\nPrimary endpoints were assessed by statistical comparison of AUC and Cmax,ss. Serum concentrations and PK parameters were summarised using quantitative descriptive statistics (including geometric mean and CV) by actual treatment group and study visit (and by time point for serum concentrations).\n\nEfficacy analysis assessed the proportion of patients achieving clinical response (ASAS20/ASAS40) by logistic regression modelling including all randomised patients, with treatment as a fixed effect and the stratification factors (region, baseline BASDAI score) as covariates. Treatment effect was estimated by calculating the OR and 95% CI. Descriptive statistics for actual result and change from baseline were calculated for the following quantitative parameters: ASDAS, BASDAI, BASFI, BASMI, chest expansion and SF-36.\n\nThe safety population consisted of all patients who received at least one (full or partial) dose of either of the study treatments during any dosing period. In this population, patients were included in the CT-P13 group for safety analyses irrespective of their randomisation if they received at least one (full or partial) dose of CT-P13.\n\nSafety analysis was performed by presenting data on hypersensitivity, ECG results, physical examination, vital sign measurements, clinical laboratory tests (haematology, clinical chemistry and urinalysis), AEs, concomitant medications and immunogenicity.\n\nResults\nPatients\nThe first patient was screened in November 2010; the week 30 evaluation of the last patient was performed in December 2011. Baseline demographics are shown in table 1. Of the 250 randomised patients, 229 completed the 30-week study period and 21 discontinued study treatment prior to week 30, primarily due to AEs (5.2%) and patient withdrawal of consent (2.4%) (figure 1).\n\nTable 1 Baseline demographics*\n\nCharacteristic\tCT-P13\n5 mg/kg (N=125)\tINX\n5 mg/kg (N=125)\tTotal\n(N=250)\t\nAge, years\t38.0 (18–69)\t38.0 (18–66)\t38.0 (18–69)\t\nGender, no. (%)\t\n Male\t99 (79.2)\t103 (82.4)\t202 (80.8)\t\n Female\t26 (20.8)\t22 (17.6)\t48 (19.2)\t\nEthnicity, no. (%)\t\n Caucasian\t97 (77.6)\t92 (73.6)\t189 (75.6)\t\n Asian\t16 (12.8)\t13 (10.4)\t29 (11.6)\t\n Other\t12 (9.6)\t20 (16.0)\t32 (12.8)\t\nHeight, cm\t172.0 (148–198)\t171.0 (147–193)\t172.0 (147–198)\t\nWeight, kg\t72.70 (45.0–120.0)\t76.00 (45.5–122.7)\t73.75 (45.0–122.7)\t\nBody mass index, kg/m2\t24.39 (18.0–38.7)\t25.64 (17.5–42.0)\t25.12 (17.5–42.0)\t\nASDAS, mean (SD)\t3.8 (0.8)\t3.9 (1.1)\t3.9 (1.0)\t\nBASDAI (stratification factor), no. (%)\t\n 4∼≤8\t92 (73.6)\t95 (76.0)\t187 (74.8)\t\n >8–10\t33 (26.4)\t30 (24.0)\t63 (25.2)\t\nBASDAI score, 0–10\t6.8 (3.4–10.0)\t6.6 (1.8–10.0)\t6.7 (1.8–10.0)\t\nBASFI score, 0–10\t6.3 (0.7–9.8)\t6.3 (0.1–10.0)\t6.3 (0.1–10.0)\t\nBASMI score, 0–10\t4.0 (0.0–9.0)\t4.0 (0.0–9.0)\t4.0 (0.0–9.0)\t\nChest expansion, cm\t3.0 (0.5–9.0)\t2.5 (0.0–7.0)\t3.0 (0.0–9.0)\t\nSF-36 summary scores\t\n Physical component\t34.1 (16.2–49.7)\t33.1 (15.3–54.3)\t33.4 (15.3–54.3)\t\n Mental component\t38.2 (15.1–63.7)\t37.2 (12.5–63.6)\t37.8 (12.5–63.7)\t\nCRP level, mg/dl\t1.1 (0.0–13.0)\t1.4 (0.0–17.4)\t1.3 (0.0–17.4)\t\nESR level, mm/h\t33.0 (2.0–110.0)\t34.0 (1.0–119.0)\t34.0 (1.0–119.0)\t\n*Except where indicated otherwise, values are the median (minimum, maximum).\n\nASDAS, Ankylosing Spondylitis Disease Activity Score; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; BASMI, Bath Ankylosing Spondylitis Metrology Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; INX, innovator infliximab; SF-36, quality-of-life questionnaire (Medical Outcomes Study Short-Form Health Survey).\n\nFigure 1 Flowchart of patient disposition. A total of 370 patients were screened for the study, and 250 eligible patients were randomised to the CT-P13 group (N=125), and the innovator infliximab (INX) group (N=125) to receive 5 mg/kg of CT-P13 or INX, respectively. All 250 randomly assigned patients were included in the intent-to-treat population. *Seven patients (three from CT-P13 group, four from INX group) from a potentially fraudulent study site were excluded from analyses.\n\nPK analyses included 223 patients. Efficacy and safety analysis were performed in all 250 patients.\n\nPharmacokinetics\nSteady state PK (AUC and Cmax) was equivalent for CT-P13 (32765.8 μgh/ml and 147.0 μg/ml) and INX (31359.3 μgh/ml and 144.8 μg/ml) in the overall PK population (table 2 and figure 2). The ratio of geometric means was near 100% for AUC and Cmax,ss. In the ADA-negative subset of patients (n=171), geometric means of AUC and Cmax,ss were higher than in the overall PK population, but the ratios of geometric means in this subgroup remained near 100% for both measures. The mean secondary PK endpoints—Cav,ss, Cmin,ss, swing, degree of fluctuation, MRT, T1/2, CLss, Vss, Cmax, Cmin and Tmax—were also highly similar between CT-P13 and INX (table 3).\n\nTable 2 Overall steady state PK between weeks 22 and 30\n\nParameter\tTreatment\tn\tGeometric mean\tRatio (%) of geometric means\t90% CI of ratio (%)\t\nPK population\t\n AUC\tCT-P13\t112\t32765.8\t104.5\t94.3 to 115.8\t\n (μgh/ml)\tINX\t110\t31359.3\t\t\t\n Cmax,ss\tCT-P13\t113\t147.0\t101.5\t94.7 to 108.9\t\n (μg/ml)\tINX\t110\t144.8\t\t\t\nADA-negative subset\t\n AUC\tCT-P13\t84\t37505.2\t103.4\t94.6 to 113.1\t\n (μgh/ml)\tINX\t86\t36266.9\t\t\t\n Cmax,ss\tCT-P13\t85\t153.9\t104.7\t97.2 to 112.9\t\n (μg/ml)\tINX\t86\t146.9\t\t\t\nThe primary PK endpoints of the observed AUC and Cmax,ss in patients treated with CT-P13 and INX at steady state were analysed using an analysis of covariance with treatment as a fixed effect and region and baseline BASDAI score fitted as covariates. Point estimates and 90% CI for differences on the log scale were exponentiated to obtain estimates for ratios of geometric means on the original scale.\n\nADA, anti-drug antibodies; AUC, area under the concentration-time curve; Cmax,ss, observed maximum steady state serum concentration; CI, confidence interval; INX, innovator infliximab; PK, pharmacokinetics.\n\nTable 3 Mean (CV) Serum pharmacokinetic parameters of INX: pharmacokinetic population\n\nParameter\tCT-P13 (N=113)\tINX (N=110)\t\nDose 1 (Week 0)\t\n Cmax (µg/ml)\tn=109\t155.8 (37.2)\tn=107\t145.3 (25.3)\t\n Cmin (µg/ml)\tn=109\t29.1 (40.1)\tn=108\t29.8 (40.8)\t\n Tmax (h)\tn=109\t2.0 (1.9, 3.2)\tn=107\t2.1 (2.0, 3.5)\t\nDose 2 (Week 2)\t\n Cmax (µg/ml)\tn=112\t175.6 (20.9)\tn=108\t181.4 (23.8)\t\n Cmin (µg/ml)\tn=110\t20.1 (56.1)\tn=108\t22.8 (72.0)\t\n Tmax (h)\tn=112\t2.1 (1.8, 3.1)\tn=108\t2.1 (1.8, 3.2)\t\nDose 3 (Week 6)\t\n Cmax (µg/ml)\tn=113\t172.3 (26.8)\tn=110\t166.3 (22.8)\t\n Cmin (µg/ml)\tn=112\t6.9 (80.2)\tn=110\t7.1 (77.6)\t\n Tmax (h)\tn=113\t2.1 (2.0, 3.2)\tn=110\t2.1 (2.0, 3.2)\t\nDose 4 (Week 14)\t\n Cmax (µg/ml)\tn=113\t158.4 (24.0)\tn=110\t153.6 (27.5)\t\n Cmin (µg/ml)\tn=112\t4.5 (83.6)\tn=110\t4.8 (75.2)\t\n Tmax (h)\tn=113\t3.0 (2.0, 3.3)\tn=110\t2.1 (2.0, 4.8)\t\nDose 5 (Week 22)\t\n Cav,ss (µg/ml)\tn=111\t26.0 (34.2)\tn=110\t25.7 (45.7)\t\n Cmin,ss (µg/ml)\tn=108\t4.2 (139.5)\tn=108\t3.6 (88.1)\t\n Swing\tn=108\t102.9 (108.1)\tn=108\t108.8 (100.7)\t\n Degree of fluctuation\tn=108\t6.2 (33.9)\tn=108\t6.8 (50.0)\t\n Mean residence time (h)\tn=103\t353.7 (38.1)\tn=98\t368.2 (37.3)\t\n T1/2 (h)\tn=103\t292.5 (32.2)\tn=98\t298.3 (32.9)\t\n Tmax (h)\tn=113\t3.0 (2.0, 359.1)\tn=110\t3.0 (2.0, 168.0)\t\n CLss(ml/h)\tn=111\t12.7 (73.1)\tn=110\t14.2 (77.7)\t\n Vss (ml)\tn=103\t3830.8 (30.8)\tn=98\t4294.9 (78.3)\t\nDose 6 (Week 30)\t\n Cmax (µg/ml)\tn=108\t152.8 (31.9)\tn=108\t147.8 (26.4)\t\n Tmax (h)\tn=108\t2.1 (1.9, 3.3)\tn=108\t2.2 (2.0, 4.0)\t\nTmax was reported as median (minimum, maximum).\n\nCmax and Tmax were set to missing if the highest concentrations in the profiles occurred at time zero.\n\nCmax was set to missing if the concentration was below the lower limit of quantification or the same as other concentrations.\n\nCmax, maximum serum concentration; Cav,ss, average concentration at steady state; CLss, total clearance at steady state; Cmin, minimum concentration immediately before the next application; Cmin,ss, minimum concentration immediately before the next application at steady state; CV, coefficient of variation; INX, innovator infliximab; MRT, mean residence time; T1/2, terminal elimination half-life; Tmax, time to reach Cmax; Vss, volume of distribution at steady state.\n\nFigure 2 Mean (±SD) serum concentrations of innovator infliximab (INX) and CT-P13 versus time by treatment. Serum concentration of drug was measured using a flow-through immunoassay platform (GyrolabxP). Mean serum drug concentration profiles of CT-P13 and INX were plotted by treatment on scheduled sample times. (A) Mean serum drug concentration following administration of Dose 5 (10 scheduled sample times between weeks 22 and 30) of CT-P13 (5 mg/kg) or INX (5 mg/kg). (B) Mean serum drug concentration of CTP13 and INX following administration of Doses 1–6. Blood samples were obtained 15 min prior to infusion, at the end of the infusion and 1 h postinfusion.\n\nClinical efficacy\nEfficacy was highly similar between the two groups, as measured by all efficacy endpoints. ASAS20 response was achieved in 62.6% and 70.5% for CT-P13 and 64.8% and 72.4% for INX at weeks 14 (OR=0.91, 95% CI 0.53 to 1.54) and 30 (OR=0.91, 95% CI 0.51 to 1.62), respectively. ASAS40 response was achieved in 41.7% and 51.8% for CT-P13 and 45.9% and 47.4% for INX at weeks 14 (OR=0.85, 95% CI 0.51 to 1.42) and 30 (OR=1.19, 95% CI 0.70 to 2.00), respectively (see online supplementary appendix E).\n\nThe mean change from baseline in the ASDAS-CRP score was highly similar for both treatment groups at weeks 14 (−1.8; SD=1.1 vs −1.8; SD=1.1) and 30 (−1.8; SD=1.2 vs −1.7; SD=1.2) for CT-P13 and INX, respectively.\n\nThe median change from baseline to weeks 14 and 30 for CT-P13 and INX was noted in the following secondary endpoints: BASDAI score (week 14: −2.7 vs −2.7 and 30: −3.1 vs −2.5); BASFI score (week 14: −2.2 vs −2.4 and 30: −2.6 vs −2.2); BASMI score (week 14:0.0 vs 0.0 and 30: −1.0 vs −1.0); and chest expansion score (week 14: +0.2 vs +0.5 and 30: +0.5 vs +0.5), respectively. Similarly, SF-36 score increased from baseline to week 14 and 30 similarly at both time points and in both treatment groups. At week 30, a significant improvement from baseline in the physical component score of the SF-36 (median change from baseline 7.6 vs 8.5, respectively) was observed in both treatment groups. A similar effect was observed for the mental component score of the SF-36 (6.5 vs 5.2).\n\nAn ASAS20 response for CT-P13 and INX at week 30, assessed according to baseline C-reactive protein (CRP) levels, was achieved in 75.2% and 77.6% of patients with a baseline CRP of >3 times the upper limit of normal (ULN) (OR=0.76: 95% CI 0.32 to 1.84) and in 68.9% and 67.2% of patients with a baseline CRP ≤3×ULN, respectively (OR=0.99: 95% CI 0.45 to 2.17). The median change from baseline to week 30 in CRP and erythrocyte sedimentation rate was −0.7 mg/dl and −21.0 mm/h for CT-P13 and −0.8 mg/dl and −19.5 mm/h for INX, respectively.\n\nOverall, no statistical significance in clinical response between the treatment groups at weeks 14 and 30 was found.\n\nImmunogenicity\nAntibodies to infliximab with active AS patients were detected in 9.1% (n=11) and 11.0% (n=13) of patients for CT-P13 and INX at week 14 and 27.4% (n=32) and 22.5% (n=25) of patients for CT-P13 and INX, respectively, at week 30.\n\nThe efficacy results were analysed for ADA-positive and ADA-negative patients in a post-hoc analysis, and it was found that ADA-positive patients had a less robust ASAS20 response (see online supplementary appendix F). No statistically significant difference between the CT-P13 and INX treatment groups was observed at week 14 and 30.\n\nSafety\nOverall treatment-emergent AEs (TEAEs) were reported in 83 (64.8%) patients and 78 (63.9%) patients from the CT-P13 and INX treatment arms, respectively (table 4). The majority of TEAEs was mild-to-moderate in intensity. The TEAEs considered by the investigator to be related to the study treatment and most frequently reported for patients were: CT-P13: increased alanine transaminase (ALT) (n=14, 10.9%) and aspartate transaminase (AST) (n=12, 9.4%), latent TB (n=5, 3.9%), urinary tract infection (n=5, 3.9%), serum creatine phosphokinase elevation (n=4, 3.1%) and γ-glutamyltransferase elevation (n=4, 3.1%); INX: increased ALT (n=13, 10.7%) and AST (n=10, 8.2%), γ-glutamyltransferase elevation (n=5, 4.1%) and latent TB (n=4, 3.3%). Infusion-related reactions occurred in five (3.9%) and six (4.9%) patients in CT-P13 and INX groups, respectively. The proportions of infusion-related reactions in CT-P13 and INX groups were 3.1% (n=1) vs 11.1% (n=3) for ADA-positive group and 3.4% (n=3) and 2.2% (n=2) for ADA-negative group, respectively.\n\nTable 4 Related treatment-emergent adverse events reported in at least 1% of patients in either treatment group, no (%)\n\n\tCT-P13 \n5 mg/kg (N=128)\tINX\n5 mg/kg (N=122)\tTotal\n(N=250)\t\nAlanine aminotransferase increased\t14 (10.9)\t13 (10.7)\t27 (10.8)\t\nAspartate aminotransferase increased\t12 (9.4)\t10 (8.2)\t22 (8.8)\t\nγ-glutamyltransferase increased\t4 (3.1)\t5 (4.1)\t9 (3.6)\t\nLatent tuberculosis*\t5 (3.9)\t4 (3.3)\t9 (3.6)\t\nUpper respiratory tract infection\t3 (2.3)\t2 (1.6)\t5 (2.0)\t\nNasopharyngitis\t3 (2.3)\t2 (1.6)\t5 (2.0)\t\nPharyngitis\t2 (1.6)\t3 (2.5)\t5 (2.0)\t\nUrinary tract infection\t5 (3.9)\t0\t5 (2.0)\t\nBacteriuria\t0\t2 (1.6)\t2 (0.8)\t\nTonsillitis\t0\t2 (1.6)\t2 (0.8)\t\nTuberculosis\t2 (1.6)\t1 (0.8)\t3 (1.2)\t\nInfusion-related reaction\t5 (3.9)\t6 (4.9)\t11 (4.4)\t\nSerum creatinine phosphokinase increased\t4 (3.1)\t1 (0.8)\t5 (2.0)\t\nNeutropenia\t2 (1.6)\t2 (1.6)\t4 (1.6)\t\nLeukopenia\t0\t2 (1.6)\t2 (0.8)\t\nPyrexia\t2 (1.6)\t1 (0.8)\t3 (1.2)\t\nHeadache\t3 (2.3)\t1 (0.8)\t4 (1.6)\t\nRash\t0\t3 (2.5)\t3 (1.2)\t\nUrticaria\t0\t2 (1.6)\t2 (0.8)\t\nNausea\t1 (0.8)\t2 (1.6)\t3 (1.2)\t\nThe total number of treatment-emergent adverse events count included all related patient events. At each level of summarisation, a patient was counted once if he or she reported one or more related events. Only the most severe event was counted. Patients who received at least one (full or partial) dose of CT-P13 were included in the CT-P13 group for safety analyses, irrespective of their randomisation.\n\n*Latent tuberculosis (TB) as an AE refers to patients who originally had a negative TB test and became positive subsequently. These cases were considered as an AE as patients were treated for the reasons related to latent TB.\n\nINX, innovator infliximab.\n\nSimilar rates of SAEs were reported between treatment groups, regardless of the relationship with the study drug (see online supplementary appendix G). No deaths were reported during the study.\n\nDiscussion\nThis randomised, double-blind, multicentre and multinational, parallel-group, prospective PLANETAS study assessed the PK equivalence and safety and efficacy comparability of multiple doses of CT-P13 (5 mg/kg) versus INX (5 mg/kg) administered up to week 30 in active AS patients.\n\nThe primary outcome, steady-state PK (AUC and Cmax,ss), was shown to be equivalent for CT-P13 and INX (90% CIs for the mean AUC and Cmax,ss were 94–116% and 95–109%, respectively). These values were within the predefined margins for equivalence (80–125%), thereby satisfying the criteria set for PK equivalence of CT-P13 to INX. This predefined margin is considered appropriate from a clinical perspective because of the broad therapeutic window and high variability of INX.18\n19 AUC and Cmax,ss were higher in the ADA-negative subset of patients in this study, versus values for the overall PK population. Published PK data for the 5mg/kg dose of INX in AS is sparse,20 but the values for AUC and Cmax,ss reported in this study are similar to those reported in previous studies of INX monotherapy using a similar dosing pattern in Crohn's disease.21 The coadministration of methotrexate (MTX) is thought to increase concentrations of INX in patients with rheumatoid arthritis (RA).22–25 Although coadministration of MTX with INX in AS is not recommended,5\n6 the effect of coadministration on CT-P13 should be further studied—especially in patients with peripheral arthritis. In patients with AS, the possible influence of ADA on circulating concentrations of INX, including the potential consequence, an impaired clinical response, has been studied but yielded conflicting results.26–28 Nevertheless, INX monotherapy remains a useful treatment for the majority of patients with AS, for which long-term data are available.29\n30\n\nThe mean secondary PK endpoints were also highly similar between CT-P13 and INX groups. CT-P13 was also equivalent to INX up to week 30 in terms of efficacy as assessed by ASAS20/ASAS40 criteria. The median change from baseline in BASDAI, BASFI, BASMI, chest expansion and SF-36 score was highly similar at weeks 14 and 30, underlining the benefit of CT-P13 and INX in both physician-measured and patient-reported outcomes.\n\nThe efficacy outcomes of this trial were comparable to those reported previously in pivotal randomised controlled trials of INX in AS.1\n2 The ASAS20 and ASAS40 responses at week 30 in this study for INX (72.4% and 47.4%, respectively) are similar to those reported at week 24 in the ASSERT trial (61.2% and 47.0%, respectively). The magnitude of improvements in secondary efficacy endpoints with INX in this trial were also comparable to those reported in ASSERT.2 Improvements from baseline to week 30 of the physical component of the SF-36 in the INX group in this study were comparable to those reported in ASSERT (8.5 vs 10.2, respectively), as were the median baseline scores of the physical component of the SF-36 (28.8 vs 33.1, respectively).2 However, the improvements from baseline to week 30 of the mental component of the SF-36 in this study were not seen in ASSERT (5.2 vs 2.7, respectively), likely reflecting the higher baseline median scores of the mental component of SF-36 in ASSERT (37.2 vs 47.6, respectively).2 ASDAS C was assessed in this study, and values were found to be highly similar between treatment groups at both weeks 14 and 30.31 Comparison of ASAS20 and ASAS40 values for CT-P13 and INX by ADA status showed no statistical significance despite the observational difference in the ADA-positive subset, the latter probably due to the lack of patient numbers.\n\nOverall, CT-P13 and INX were well-tolerated and their safety profiles were comparable. The majority of patients had negative immunogenicity results according to the electrochemiluminescent immunoassay method at weeks 14 and 30. Extra-articular manifestations such as uveitis, psoriasis and inflammatory bowel disease were not assessed in this study, but the single cases of uveitis and psoriasis in the INX group were reported as AEs. The incidence of AEs, SAEs, infections and infusion-related reactions with INX in this trial were comparable to that seen in ASSERT.2\n\nThere were also comparably low rates of TB up to week 30. The incidence of TB in our study (1.2% overall: CT-P13 (n=2), INX group (n=1)) is higher than in ASSERT, a trial of INX in AS, in which no cases were reported during the study period.2 A difference in the study site locations may partly explain this; ASSERT included only centres in North America and Western Europe, whereas our trial included centres in countries known to have higher TB incidence. Interestingly, the incidence of active TB in our study is similar to those of the two major trials of the 3 mg/kg dose of INX in RA, Anti-TNF Trial inRheumatoid Arthritis with Concomitant Therapy (ATTRACT) (0.3%) and Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) (0.5%), which included centres only in North America and Western Europe.18\n32\n\nAccording to the National Institute of Health and Clinical Excellence (NICE) incremental cost-effectiveness ratios (ICERs), INX has not been recommended for treatment of AS because NICE experts did not consider it to be cost-effective. However, this decision should be revisited based on the results of this study of CT-P13 in AS and its lower future price. This may have a potentially positive impact on healthcare costs.\n\nIn this PLANETAS study, PK equivalence for CT-P13 and INX was demonstrated. There was no significant difference in efficacy and safety data. Although only comparable clinical efficacy was shown in this study, clinical bioequivalence was investigated in a Phase 3 study in RA.8\n\nThe positive results of this study provide a rationale for future studies of CT-P13 in the treatment of other TNF-mediated inflammatory diseases.\n\nConclusions\nCT-P13 and INX were shown to be equivalent in terms of AUC and Cmax,ss in patients with active AS. Clinical efficacy endpoints, including ASAS20 and ASAS40 responses, were highly similar between CT-P13 and INX groups. CT-P13 was well-tolerated with an immunogenicity and safety profile comparable to that of INX up to week 30.\n\nSupplementary Material\nWeb appendix A\n Supplementary Material\nWeb appendix B\n Supplementary Material\nWeb appendix C\n Supplementary Material\nWeb appendix D\n Supplementary Material\nWeb appendix E\n Supplementary Material\nWeb appendix F\n Supplementary Material\nWeb appendix G\n The authors wish to thank the patients and study personnel who made this trial possible, and the PLANETAS study investigators: Bulgaria; Kadinov V, Rashkov R; Chile; Aguirre V, Goecke Sariego I, Gutierrez M; Colombia; Otero Escalante WJ; Korea (Republic of); Kang SW, Kim HY, Kim TH, Park YB, Park YE, Song JS, Suh CH; Latvia; Andersone D, Saulite-Kandevica D; Mexico; Abud-Mendoza C, Araiza R, Cons Molina F, Morales-Torres J, Pacheco-Tena C; Poland; Brzezicki J, Brzosko M, Jaworski J, Korkosz M, Krogulec M, Piotrowski M, Ruzga Z, Wiland P; Portugal; Vaz Patto J; Spain; Blanco Garcia F, Díaz-González F; Ukraine; Amosova K, Dyadyk O, Gnylorybov A, Smiyan S, Ter-Vartanian S; USA; Ahn C. Editorial support (writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Vanessa Lane, Peter Hopkins and Rory Elsome (TVF BioLogic, London, UK) and was funded by CELLTRION Inc, Incheon, Republic of Korea.\n\nContributors: WP, SJL and HUK were involved in the conception and design of the study, acquisition of data and/or analysis and interpretation of data; drafting of manuscript and revising it critically for important intellectual content; final approval of the version to be published. DHY and JB were involved in the conception and design of the study; drafting of manuscript and revising it critically for important intellectual content; final approval of the version to be published. PH, SJ, VK, GL, PM, HM, SGU, MJL and YAL were involved in the acquisition of data; drafting of manuscript and revising it critically for important intellectual content; final approval of the version to be published. The project management, clinical and medical monitoring, pharmacovigilance (PVG), data management, analysis of pharmacokinetic (PK) data, biostatistical analysis, and medical writing were performed under contract with PPD, Inc. in collaboration with the CELLTRION, Inc.\n\nFunding: This study was funded by CELLTRION Inc.\n\nCompeting interests: All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: financial support for the submitted work from Celltrion: WP, DHY, PH, VK, PM and YAL received research grants and, or consultancy fees, and logistics support; SJL, SJ, GL, HM, SGU and MJL received research grants and/ or consultancy fees only; HUK is a full-time employee of Celltrion. JB has received payment for consultancy and lectures from Celltrion.\n\nPatient consent: Obtained.\n\nEthics approval: The protocol was reviewed and approved by each site's institutional review board or independent ethics committee.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData sharing statement: All data available for this paper are included in the manuscript and online supplementary appendices.\n==== Refs\nReferences\n1 Braun J Brandt J Listing J \nTreatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial . Lancet \n2002 ;359 :1187 –93 11955536 \n2 van der Heijde D Dijkmans B Geusens P \nEfficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT) . 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Br J Clin Pharmacol \n2012 ;73 :55 –65 21692827 \n21 US Food and Drug Administration \nInfliximab Product Approval Information: Clinical Pharmacology Review , dated 20 July 1998. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm107704.pdf (accessed 29 Nov 2012 ).\n22 US Food and Drug Administration \nInfliximab Product Approval Information: Clinical Pharmacology Review , dated 1 November 1999. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm107725.pdf (accessed 29 Nov 2012 ).\n23 Klotz U Teml A Schwab M \nClinical pharmacokinetics and use of infliximab . Clin Pharmacokinet \n2007 ;46 :645 –60 17655372 \n24 Maini RN Breedveld FC Kalden JR \nTherapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis . Arthritis Rheum \n1998 ;41 :1552 –63 9751087 \n25 Mori S \nA relationship between pharmacokinetics (PK) and the efficacy of infliximab for patients with rheumatoid arthritis: characterization of infliximab-resistant cases and PK-based modified therapy . Mod Rheumatol \n2007 ;17 :83 –91 17437161 \n26 deVries MK Wolbink GJ Stapel SO \nDecreased clinical response to infliximab in ankylosing spondylitis is correlated with anti-infliximab formation . Ann Rheum Dis \n2007 ;66 :1252 –4 17472991 \n27 Ducourau E Mulleman D Paintaud G \nAntibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases . Arthritis Res Ther \n2011 ;\n13 :R105 21708018 \n28 Krzysiek R Breban M Ravaud P \nCirculating concentration of infliximab and response to treatment in ankylosing spondylitis: results from a randomized control study . Arthritis Rheum \n2009 ;61 :569 –76 19405015 \n29 Heldmann F Brandt J van der Horst-Bruinsma IE \nThe European Ankylosing Spondylitis Infliximab Cohort (EASIC): a European multicentre study of long term outcomes in patients with ankylosing spondylitis treated with infliximab . Clin Exp Rheumatol \n2011 ;29 :672 –80 21906431 \n30 Baraliakos X Listing J Fritz C \nPersistent clinical efficacy and safety of infliximab in ankylosing spondylitis after 8 years—early clinical response predicts long-term outcome . Rheumatology (Oxford) \n2011 ;50 :1690 –9 21672969 \n31 Lukas C Landewé R Sieper J \nDevelopment of an ASAS-endorsed disease activity score (ASDAS) in patients with ankylosing spondylitis . Ann Rheum Dis \n2009 ;68 :18 –24 18625618 \n32 St Clair EW van der Heijde DM Smolen JS \nCombination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial . Arthritis Rheum \n2004 ;50 :3432 –43 15529377\n\n",
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"abstract": "BACKGROUND\nAspergillus spp. infections mainly affect patients who are immunocompromised, and are extremely rare in immunocompetent individuals.\n\n\nMETHODS\nAspergillus post-operative mediastinitis is considered to be a devastating infection, usually affecting patients undergoing cardiothoracic surgery with specific predisposing factors. We describe the case of an immunocompetent 68-year-old Caucasian man with severe chronic thromboembolic pulmonary hypertension, who underwent pulmonary thromboendarterectomy and developed post-operative mediastinitis due to Aspergillus flavus. The environmental control did not reveal the source of A. flavus infection and, despite combined antifungal therapy, our patient died as a result of septic shock and multiple organ failure.\n\n\nCONCLUSIONS\nAspergillus mediastinitis mainly affects patients after cardiosurgery operations with predisposing factors, and it is unusual in patients who are immunocompetent. The identification of the Aspergillus spp. source is often difficult, and there are no guidelines for the administration of pre-emptive therapy in this population of at-risk patients.",
"affiliations": "Second Department of Critical Care Medicine, 'ATTIKON' University Hospital, University of Athens Medical School, Athens Greece. dimop@vodafone.net.gr.",
"authors": "Dimopoulos|George|G|;Tsangaris|Iraklis|I|;Poulakou|Garyphalia|G|;Panayiotides|John|J|;Tsaknis|George|G|;Orfanos|Stylianos|S|;Armaganides|Apostolos|A|",
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"fulltext": "\n==== Front\nJ Med Case ReportsJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-4-3122086337810.1186/1752-1947-4-312Case ReportPost-operative Aspergillus mediastinitis in a man who was immunocompetent: a case report Dimopoulos George 1dimop@vodafone.net.grTsangaris Iraklis 1itsangaris@med.uoa.grPoulakou Garyphalia 2poulakoug@med.uoa.grPanayiotides John 3Jpanayotides@med.uoa.grTsaknis George 1gtsaknis@gmail.comOrfanos Stylianos 1sopranos@med.uoa.grArmaganides Apostolos 1aarmag@med.uoa.gr1 Second Department of Critical Care Medicine, 'ATTIKON' University Hospital, University of Athens Medical School, Athens Greece2 Fourth Department of Internal Medicine, 'ATTIKON' University Hospital, University of Athens Medical School, Athens Greece3 Second Department of Pathology, 'ATTIKON' University Hospital, University of Athens Medical School, Athens Greece2010 23 9 2010 4 312 312 19 9 2009 23 9 2010 Copyright ©2010 Dimopoulos et al; licensee BioMed Central Ltd.2010Dimopoulos et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction\nAspergillus spp. infections mainly affect patients who are immunocompromised, and are extremely rare in immunocompetent individuals.\n\nCase presentation\nAspergillus post-operative mediastinitis is considered to be a devastating infection, usually affecting patients undergoing cardiothoracic surgery with specific predisposing factors. We describe the case of an immunocompetent 68-year-old Caucasian man with severe chronic thromboembolic pulmonary hypertension, who underwent pulmonary thromboendarterectomy and developed post-operative mediastinitis due to Aspergillus flavus. The environmental control did not reveal the source of A. flavus infection and, despite combined antifungal therapy, our patient died as a result of septic shock and multiple organ failure.\n\nConclusion\nAspergillus mediastinitis mainly affects patients after cardiosurgery operations with predisposing factors, and it is unusual in patients who are immunocompetent. The identification of the Aspergillus spp. source is often difficult, and there are no guidelines for the administration of pre-emptive therapy in this population of at-risk patients.\n==== Body\nIntroduction\nAspergillus spp. infections mainly affect patients who are immunocompromised, usually being acquired by inhalation of small airborne spores [1,2]. The diagnosis of infection caused by this filamentous fungus poses many difficulties, mainly due to the lack of a laboratory method able to discriminate colonization from infection. Not surprisingly, the diagnosis is often confirmed by autopsy [1-3]. The difficulty in diagnosis may lead to delayed treatment, which could be associated with the extremely high mortality rates. Post-surgical mediastinitis is defined as an infection involving the structures between the sternum and the esophagus, occurring mainly after cardiothoracic surgery [4-6]. The highest risk for the development of this infection is associated with orthotopic heart transplantation (2.5 to 6 instances per 100 procedures), while the species usually involved are Staphylococcus and Enterobacter spp. [7]. Aspergillus spp. infections have been described post-operatively in this patient population, but Aspergillus mediastinitis has been reported in only 11 patients [1]. A recent published study by Jensen et al. reported two cases of mediastinitis among seven cases of post-surgical infection, with a mortality of 100% [8].\n\nWe describe post-operative Aspergillus mediastinitis in our patient, who underwent pulmonary thromboendarterectomy (PEA). We focus on the clinical dilemmas that could be met and cover the early diagnosis, the difficulties associated with detection of the source of Aspergillus spp. and the management of our patient.\n\nCase presentation\nA 68-year-old Caucasian man with severe chronic thromboembolic pulmonary hypertension and progressive decline to New York Heart Association (NYHA) functional class IV was admitted to our intensive care unit (ICU) because of respiratory failure and need for mechanical ventilation. His medical history included repeated episodes of deep vein thrombosis and two episodes of pulmonary embolism despite adequate anticoagulant therapy. Upon completion of the pulmonary hypertension investigation, his pulmonary thromboembolic disease was considered non-operable and was treated with bosentan and inhaled iloprost. Following the initiation of mechanical ventilation he was switched to intravenous iloprost and three months later our patient demonstrated a significant hemodynamic improvement, allowing him to undergo PEA. Details on his hemodynamic status and management are described elsewhere [9].\n\nDuring his hospitalization, our patient had two episodes of ICU-acquired microbial and fungal infections including a catheter related candidaemia due to Candida albicans and Staphylococcus epidermidis (isolated from the catheter tip of a left internal jugular central venous catheter, treated with caspofungin for 15 days and linezolid 600 mg twice a day for 14 days), and an episode of ventilator-associated pneumonia (VAP) due to Acinetobacter baumannii treated according to the detected antimicrobial susceptibilities with imipenem (1 g every six hours) and colistin (3 × 106U every eight hours).\n\nImmediately prior to PEA, our patient was given 1 g of vancomycin as surgical prophylaxis with the induction of anesthesia. During the first post-operative week he was febrile without an apparent site of infection and received antibiotic treatment according to the surveillance cultures. On the eighth post-operative day an exudate drained automatically from the surgical wound; cultures grown in Sabouraud dextrose agar revealed a fast-growing isolate with cottony texture identified as Aspergillus spp. Microscopically, a potassium hydroxide mount confirmed the presence of septate and hyaline, and dichotomously branched hyphae. Conidiophores were uncolored producing spherical to ellipsoidal accessory conidia, covering the entire surface of the biseriate species. Further subcultures in potato flake agar (PFA) were prepared in-house and incubated at 35°C, and identified the presence of Aspergillus flavus. The isolate grew rapidly, producing olive-green colonies. When examined by tape mounts, a slide culture prepared on PFA cultured isolate revealed globose vesicles up to 20 μm in diameter, a biseriate arrangement with metulae and phialides, and globose conidia (3.0 to 6.0 μm in diameter); all features similar to those produced in Sabouraud dextrose agar and characteristic for A. flavus. A computed tomography (CT) scan of his thorax revealed no specific signs of mediastinitis. Serum and bronchoalveolar-lavage galactomannan tests were not performed, as they were not available at the time. No specific signs of mediastinitis were seen either.\n\nA combination of liposomal amphotericin B at a dose of 3 mg/kg daily and voriconazole (6 mg/kg twice a day for the first day followed by 4 mg/kg twice a day thereafter) were added because of the severity of the infection, and surgical debridement of the wound was performed. Despite all the therapeutic measures, the results of culture tests remained positive for A. flavus (surgical wound necrotic tissue test results were positive for hyphae on direct microscopy after the addition of KOH) and our patient died on the 26th post-operative day because of severe septic shock. Our patient underwent a whole body autopsy. Samples from the sternum, lungs and myocardial tissue fixed in a 10% buffered formol solution were embedded in paraffin; sections 4 μm thick stained with hematoxylin and eosin, PAS and Grocott's silver impregnation stains confirmed the presence of hyphae with morphologic characters pertaining to the genus Aspergillus [10] (Figures 1 and 2).\n\nFigure 1 Fragment of lung tissue with an increased number of hyphae obtained on autopsy (PAS stain ×100).\n\nFigure 2 Fragment of myocardium with hyphae obtained on autopsy (Grocott stain ×100).\n\nA detailed investigation of all patients undergoing surgical operation during the same period was performed. A total of 50 environmental samples were collected from various sites in the operating room. Four plates were left open for one hour, one of them on the surgical table and the other at various sites on the floor, focusing on the air conditioning system vents. Various surfaces were also sampled with cotton-tip swabs. The filters of the air conditioning system in the surgical room were replaced and samples culture tested. The central supply rooms that housed equipment used in cardiac surgery operations were all inspected for visible signs of mold contamination or damage that might lead to mold growth. Routine scheduled maintenance and replacement protocols for equipment and air filters were reviewed.\n\nNone of the patients undergoing surgical operation during the same period developed infection of the surgical site due to Aspergillus spp. and the results of environmental samples tested 17 days later were negative. In two of the tested samples hyphomycetes classified as Cladodosporium spp. grew on the 17th day, however these were considered as laboratory contamination. These positive samples derived from a storage area in the surgical room. No further isolation of fungi was noted from the plates, which were kept for one month after the environmental sampling inoculation. Additionally, a subsequent investigation was performed on the ICU staff using nasal cultures for possible nasal colonization with Aspergillus spp., also giving negative culture test results.\n\nDiscussion\nAspergillus mediastinitis has been defined by the US Centers for Disease Control and Prevention as the presence of a positive culture result from a mediastinal sample plus one of the following: (a) fever of over 38°C, or (b) chest pain or sternal instability with purulent effusion in the mediastinum or positive culture results from surgically obtained samples or blood. In a recently published review Pasqualotto et al. summarized cases of Aspergillus mediastinitis reported in the literature, all in patients who had undergone surgery (four with deep sternal wound infections, two with heart transplantation, two with aortitis, one with patch infection after repaired Fallot tetralogy and two patients who were immunocompetent who were affected during an outbreak of aspergillosis related to a contaminated ventilation system in the operating room). The authors considered immunocompromised individuals with defects in alveolar macrophage and neutrophil function as patients at risk (that is, patients undergoing chemotherapy, bone marrow recipients, solid-organ transplants, or patients with congenital or acquired immune disorders). The automatically drained exudate from the surgical wound in our patient, who was feverish, supported the diagnosis of mediastinitis, despite the absence of confirmatory signs from his thorax CT scan. However our patient was low risk for Aspergillus spp. infection development, since he did not fulfill the traditional criteria of immunosuppression (malignancy, chemotherapy or radiotherapy, neutropenia, systematic or immunosuppressive diseases, or systematic steroid treatment). Although our patient had received a short course (7 days) of treatment with steroids (50 mg twice a day) during a septic episode, it is highly unlikely that this resulted in a permanent altered host response. According to Pasqualotto et al. the most important and crucial point for the diagnosis of Aspergillus mediastinitis in patients undergoing cardiac surgery with destructive wound infections and samples that give negative culture test results is a high clinical suspicion [1]. A potential immunomodulatory factor in our case could be the prolonged prostacyclin use. Recent experimental data support an immunosuppressive role for prostacyclin, through impaired regulation of phagocytosis, bacterial killing, and inflammatory mediator production, but the extrapolation of these findings to the clinical setting remains highly speculative [11].\n\nEnvironmental investigations did not reveal the source of contamination in our patient's case. Despite the lack of an air sampler, a thorough investigation was performed without identification an environmental source. This finding argues against an ongoing source of contamination and is in line with the absence of new cases of infections with Aspergillus among patients undergoing surgery within our hospital. Nevertheless, a point source not yet identified cannot be excluded. However, based on previous reports of outbreaks through the ventilation system of the operating theater, the air conditioning filters of the cardiac surgery room were replaced immediately after the identification of the infection [12]. No renovation or construction procedures were being performed at our hospital during this time period. Direct inoculation from our patient's flora could be a possible source, but the common practice of our ICU department consists of testing of bronchial cultures (biweekly) as well as urine and stool cultures (weekly), and this would have revealed such a previous colonization. Pre-existing colonization of bronchial secretions with Aspergillus spp. and chronic lung disease have been demonstrated as risk factors in a case-control study of sternal wound infections, but this was not the case for our patient [13]. To the best of our knowledge, there is no recommendation issued for prophylaxis against Aspergillus infections in immunocompetent hosts [14]. Interestingly, our patient had received a 15-day caspofungin course as pre-emptive treatment for invasive candidiasis based on colonization of urine and bronchial cultures by Candida spp. in conjunction to additional risk factors (prolonged ICU stay, administration of broad spectrum antibiotics, central line placement, mechanical ventilation and total parenteral nutrition administration) [15,16]. The treatment course was terminated 10 days pre-operatively and no selection of fungi resistant to caspofungin was seen on routine surveillance cultures.\n\nConclusion\nAspergillus mediastinitis mainly affects patients undergoing cardiosurgery operations with predisposing factors, and is unusual in patients who are immunocompetent. The identification of the source of Aspergillus spp. is often difficult, and there are no guidelines for the administration of pre-emptive therapy in this population. Our patient could be added to the series of Pasqualotto and Denning as a third immunocompetent patient with post-operative Aspergillus spp. mediastinitis [1].\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nGD, IT, GT and GP analyzed and interpreted data from our patient with regard to ICU admission, surgical procedure and microbiology. JCP performed the histological examination of the myocardium and the lung, and SO and AA were major contributors to the writing of the manuscript. All authors read and approved the final manuscript.\n==== Refs\nPasqualotto AC Denning DW Post-operative aspergillosis Clin Microbiol Infect 2006 12 1060 1076 10.1111/j.1469-0691.2006.01512.x 17002605 \nDimopoulos G Vincent JL Candida and Aspergillus infections in critically ill patients Clin Intens Care 2002 13 1 12 10.1080/714028784 \nDimopoulos G Piagnerelli M Berre J Eddafali B Salmon I Vincent JL Disseminated aspergillosis in intensive care unit patients: an autopsy study J Chemotherapy 2003 15 71 75 \nLevin T Suh B Beltramo D Samuel R Aspergillus mediastinitis following orthotopic heart transplantation: case report and review of the literature Transpl Infect Dis 2004 6 129 131 10.1111/j.1399-3062.2004.00064.x 15569230 \nKing RC Barnes AD Mediastinitis after cardiac surgery Curr Treat Opt Inf Dis 2003 5 377 386 \nKronman MP Baden HP Jeffries HE Heath J Cohen GA Zerr DM An investigation of Aspergillus cardiac surgical site infections in 3 pediatric patients Am J Infect Control 2007 35 332 337 10.1016/j.ajic.2006.10.013 17577481 \nJensen J Guinea J Torres-Narbona M Muñoz P Peláez T Bouza E Post-surgical invasive aspergillosis: an uncommon and under-appreciated entity J Infect 2010 60 162 167 10.1016/j.jinf.2009.11.005 19932132 \nForestier E Remy V Lesens O Martinot M Hansman Y Eisemann B Christmann D A case of Aspergillus mediastinitis after heart transplantation successfully treated with liposomal amphotericin B, caspofungin and voriconazole Eur J Clin Microbiol Infect Dis 2005 24 347 349 10.1007/s10096-005-1327-5 15889298 \nTsangaris H Armaganidis A Argentos S Chamogeorgakis T Rallidis L Lekakis J Orfanos SE Preoperative optimization with prostanoids for severe chronic thromboembolic pulmonary hypertension (CTEPH): a step forward? J Heart Lung Transpl 2007 26 1346 1347 10.1016/j.healun.2007.09.006 \nBinford CH Dooley JR Binford CH, Connor DH Aspergillosis Pathology of Tropical and Extraordinary Diseases 1976 2 Washington, DC: AFTP 562 563 \nAronoff DM Peres CM Serezani CH Ballinger MN Carstens JK Coleman N Moore BB Peebes RS Faccioli LH Peters-Golden M Synthetic prostacyclin analogs differentially regulate macrophage function via distinct analog-receptor binding specificities J Immunol 2007 178 1628 1634 17237412 \nHeinemann S Symoens F Gordts B Jannes H Nolard N Environmental investigations and molecular typing of Aspergillus flavus during an outbreak of postoperative infections J Hosp Infect 2004 57 149 155 10.1016/j.jhin.2004.02.007 15183246 \nRichet HM McNeil MM Davis BJ Duncan E Strickler J Nunley D Jarvis WR Tablan OC Aspergillus fumigatus sternal wound infections in patients undergoing open heart surgery Am J Epidemiol 1992 135 48 58 1736660 \nVonberg RP Gastmeier P Nosocomial aspergillosis in outbreak settings J Hosp Infect 2006 63 246 254 10.1016/j.jhin.2006.02.014 16713019 \nWalsh TJ Anaissie EJ Denning DW Herbrecht R Kontoyiannis DP Marr KA Morrison VA Segal BH Steinbach WJ Stevens DA van Burik JA Wingard JR Patterson TF Infectious Diseases Society of America Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America Clin Infect Dis 2008 46 327 360 10.1086/525258 18177225 \nOstrosky-Zeichner L Sable C Sobel J Alexander BD Donowitz G Kan V Kauffman CA Kett D Larsen RA Morrison V Nucci M Pappas PG Bradley ME Major S Zimmer L Wallace D Dismukes WE Rex JH Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting Eur J Clin Microbiol Infect Dis 2007 26 271 276 10.1007/s10096-007-0270-z 17333081\n\n",
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"abstract": "Epstein-Barr virus-related post-transplant lymphoproliferative disorder (EBV-PTLD) is a rare but life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). T-cell immunodeficiency after transplantation and EBV primary infection/reactivation play major roles in the pathogenesis. Unspecific clinical manifestations make the diagnosis difficult and time consuming. Moreover, this fatal disease usually progresses rapidly, and leads to multiple organ dysfunction or death if not treated promptly. Early diagnosis of EBV-DNAemia or EBV-PTLD generally increases the chances of successful treatment by focusing on regular monitoring of EBV-DNA and detection of symptomatic patients as early as possible. Rituximab ± reduction of immunosuppression (RI) is currently the first-line choice in preemptive intervention and targeted treatment. Unless patients are suffering from severe graft versus host disease (GvHD), it is better to combine rituximab with RI. Once a probable diagnosis is made, the first-line treatment should be initiated rapidly, along with, or ahead of, biopsy, although histopathologic confirmation is requisite. In addition, EBV-specific cytotoxic T lymphocytes (EBV-CTLs) or donor lymphocyte infusion (DLI) has shown promise in cases of suboptimal response. Chemotherapy ± rituximab might lend more opportunities to refractory/relapsed patients, who might also benefit from ongoing clinical trials. Herein, we discuss our clinical experience in detail based on the current literature and our five cases.",
"affiliations": "Hematopoietic Stem Cell Transplantation Center, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.;Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China.;Hematopoietic Stem Cell Transplantation Center, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Via No. 288 Nanjing Road, Tianjin, China.",
"authors": "Liu|Li|L|https://orcid.org/0000-0002-7197-3382;Liu|Qifa|Q|;Feng|Sizhou|S|",
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"fulltext": "\n==== Front\nTher Adv Hematol\nTher Adv Hematol\nTAH\nsptah\nTherapeutic Advances in Hematology\n2040-6207 2040-6215 SAGE Publications Sage UK: London, England \n\n10.1177/2040620720910964\n10.1177_2040620720910964\nReview\nManagement of Epstein–Barr virus-related post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation\nhttps://orcid.org/0000-0002-7197-3382Liu Li Hematopoietic Stem Cell Transplantation Center, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China\n Liu Qifa Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China\n Feng Sizhou Hematopoietic Stem Cell Transplantation Center, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Via No. 288 Nanjing Road, Tianjin, China\n szfeng@ihcams.ac.cn; doctor_szhfeng@163.com\n28 4 2020 \n2020 \n11 20406207209109644 7 2019 21 1 2020 © The Author(s), 20202020SAGE PublicationsThis 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).Epstein–Barr virus-related post-transplant lymphoproliferative disorder (EBV-PTLD) is a rare but life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). T-cell immunodeficiency after transplantation and EBV primary infection/reactivation play major roles in the pathogenesis. Unspecific clinical manifestations make the diagnosis difficult and time consuming. Moreover, this fatal disease usually progresses rapidly, and leads to multiple organ dysfunction or death if not treated promptly. Early diagnosis of EBV-DNAemia or EBV-PTLD generally increases the chances of successful treatment by focusing on regular monitoring of EBV-DNA and detection of symptomatic patients as early as possible. Rituximab ± reduction of immunosuppression (RI) is currently the first-line choice in preemptive intervention and targeted treatment. Unless patients are suffering from severe graft versus host disease (GvHD), it is better to combine rituximab with RI. Once a probable diagnosis is made, the first-line treatment should be initiated rapidly, along with, or ahead of, biopsy, although histopathologic confirmation is requisite. In addition, EBV-specific cytotoxic T lymphocytes (EBV-CTLs) or donor lymphocyte infusion (DLI) has shown promise in cases of suboptimal response. Chemotherapy ± rituximab might lend more opportunities to refractory/relapsed patients, who might also benefit from ongoing clinical trials. Herein, we discuss our clinical experience in detail based on the current literature and our five cases.\n\nallogeneic hematopoietic stem cell transplantationEpstein–Barr virusmanagementpost-transplant lymphoproliferative disorderNational Megaproject on Key Infectious Diseases2017ZX10202102Natural Science Foundation of Tianjin Cityhttps://doi.org/10.13039/50110000660618JCZDJC34400the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences2018PT32034CAMS Initiative for Innovative Medicine2016-I2M-1-017CAMS Initiative for Innovative Medicine2016-I2M-3-023cover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nPost-transplant lymphoproliferative disorder (PTLD), ranging from nondestructive lymphoplasmacytic proliferation to malignant lymphoma, is strongly related to Epstein–Barr virus (called EBV-PTLD) under the status of immunodeficiency that occurs following hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT).1,2 Recipients of allogeneic HSCT (allo-HSCT) are at a particular risk of PTLD due to their profound immunodeficiency. EBV-PTLD develops in fewer than 1% of recipients without risk factors, but in more than 10% of those with several risk factors.3–5 PTLD after allo-HSCT is almost exclusively EBV positive, although rare cases of EBV-negative PTLD are reported.2,6,7 With the growing number of allo-HSCT recipients, post-HSCT EBV-PTLD has attracted increasing attention.2\n\nBoth diagnostic and therapeutic strategies for EBV-PTLD have evolved over time. Although clinical manifestations are unspecific, monitoring the EBV-DNA load in peripheral blood offers an indication for preemptive intervention.2 Preemptive rituximab ± reduction of immunosuppression (RI) is effective in preventing EBV-DNAemia from progressing to EBV-PTLD, but it is hard to define the optimal point of therapy initiation with minimal adverse effects. Histopathologic evidence is vital, but accurate histopathologic classification is not always available due to the overlap of characteristics and coexistence of multiple subtypes, even within a single biopsy sample.1 Rituximab ± RI, adoptive cellular therapy utilizing EBV-specific cytotoxic T lymphocytes (EBV-CTLs) or donor lymphocyte infusion (DLI) and chemotherapy have achieved favorable effects.2,8 However, this disease progresses very rapidly and often leaves limited time for diagnosis and treatment; long-term survival of EBV-PTLD remains unsatisfactory.3,9,10\n\nBased on our five cases (Table 1), we focus mainly on current perspectives and challenges in the management of EBV-PTLD after allo-HSCT.\n\nTable 1. Clinical characteristics of cases.\n\nCase number\tGender\tAge (years)\tUnderlying disease\tPre-transplant risk factors\tPost-transplant risk factors\tTime of EBV-DNA\n⩾1000 copies/ml\tDiagnostic basis\tDiagnosis\tTherapeutic strategies\tClinical outcome\t\nCase 1\tF\t60\tCMML-2 (NR)\t(1) Haplo-HSCT;\n(2) ATG use\t(1) grade III acute GvHD\tday +99\t(1) Abnormal EBV-DNA loads in the peripheral blood\tEBV-DNAemia\t(1) Rituximab\n(2) Donor-derived EBV-CTLs\tAlive\t\nCase 2\tF\t23\tSAA\t(1) ATG use\t–\tday +40\t(1) Fever and Lymphadenopathy;\n(2) Abnormal EBV-DNA loads in the peripheral blood;\n(3) Histopathologic examination with EBER+\tProven EBV-PTLD\t(1) Rituximab + RI\tAlive\t\nCase 3\tM\t36\tAML (CR1)\t(1) Haplo-HSCT\n(2) ATG use\t(1) grade III acute GvHD\tNA\t(1) bloody stools;\n(2) Histopathologic examination with EBER+\tProven EBV-PTLD\t(1) Rituximab\tAlive\t\nCase 4\tM\t21\tAML (CR1)\t(1) Haplo-HSCT;\n(2) ATG use\t–\tday +157\t(1) Abnormal EBV-DNA loads in the peripheral blood and stool;\n(2) Extranodal lesions in the liver and the spleen showed by CT and 18F-FDG-PET/CT;\n(3) Histopathologic examination with EBER+\tProven EBV-PTLD\t(1) Rituximab;\n(2) Donor-derived EBV-CTLs;\n(3) R-COP\tAlive\t\nCase 5\tF\t20\tALL (CR1)\t(1) MUD;\n(2) ATG use\t–\tday +49\t(1) Fever, headache, severe emesis and lymphadenopathy;\n(2) Abnormal EBV-DNA loads in the peripheral blood and CSF;\n(3) Histopathologic evidence of post-transplant DLBCL;\n(4) symmetrical, extensive, supra- and infra-tentorium lesions showed by MRI\tProven EBV-PTLD\tRituximab (intravenously and intrathecally administered)\tAlive\t\nALL, acute lymphocytic leukaemia; AML, acute myelogenous leukaemia; ATG, anti-thymocyte globulin; CMML-2, type 2 chronic myelomonocytic leukemia; CR1, first complete remission; CSF, cerebrospinal fluid; CT, computed tomography; DLBCL, diffuse large B-cell lymphoma; EBER+, EBV-encoded RNA positive; EBV, Epstein–Barr Virus; F, female; 18F-FDG-PET/CT, radionuclide fluorine 18-fluorodeoxyglucose-positron emission tomography/computed tomography; EBV-CTLs, EBV-specific cytotoxic T lymphocytes; GvHD, graft versus host disease; HLA, human leukocyte antigen; M, male; MRI, magnetic resonance imaging; MUD, matched unrelated donor; NA, not available; NR, not remitted; R-COP, rituximab + chemotherapy regimen of cyclophosphamide, vincristine and prednisone; SAA, severe aplastic anaemia.\n\nCase 1\nA 60-year-old woman was diagnosed with type 2 chronic myelomonocytic leukemia (CMML-2). She underwent three cycles of decitabine (DAC) with sorafenib and then haploidentical HSCT (haplo-HSCT) in September 2017, following DAC + busulfan (Bu) + cyclophosphamide (Cy) + fludarabine (Flu) + cytarabine (Ara-C) conditioning. Cyclosporine (CsA) + mycophenolate mofetil (MMF) + methotrexate (MTX) + rabbit anti-thymocyte globulin (r-ATG) (10 mg/kg) was used to prevent graft versus host disease (GvHD). Neutrophils were more than 0.5×109/l on day +13. EBV-DNA in her blood reached 1096 copies/ml on day +99, and kept increasing while she had grade III gastrointestinal acute GvHD (treated with CsA + ruxolitinib + methylprednisolone) and active cytomegalovirus (CMV) infection (treated with intravenous CMV neutralizing immunoglobulin + ganciclovir). Without any symptoms or signs, she received three doses of preemptive rituximab (375 mg/m2, weekly). However, her EBV-DNA loads continued to increase (60,969 copies/ml on day +127). Donor-derived EBV-CTLs were then employed for the management of EBV-DNAemia. Finally, EBV-DNA returned to normal levels after two further courses of rituximab and four doses of EBV-CTL infusion (2.5 × 107, 2 × 107, 3.8 × 107, and 3 × 107) without the exacerbation of GvHD. The patient is currently surviving with normal EBV-DNA levels.\n\nFor EBV-DNAemia after allo-HSCT, rituximab ± RI would eliminate the reactivated viruses for most patients. However, when patients respond poorly to rituximab ± RI, EBV-CTLs or DLI should be considered as early as possible, as in the targeted treatment.\n\nCase 2\nA 23-year-old woman was diagnosed with severe aplastic anemia in March 2008. She under-went matched related allo-HSCT following Bu + Flu + CTX + r-ATG (10 mg/kg) conditioning in March 2016. GvHD prevention comprised CsA and MTX. Neutrophil recovery was achieved on day +12. From day +34, the patient complained of fever that did not respond to cefoperazone-tazobactam and oseltamivir. Physical examination revealed enlarged and tender lymph nodes on both sides of her retroauricular, submandibular, and neck region on day +40. Computed tomography (CT) showed enlarged lymph nodes in the axillae, mediastinum, retroperitoneum, pelvic cavity, and groins. The EBV-DNA load was 117,532 copies/ml on day +40. A diagnosis of probable EBV-PTLD was made, and rituximab (375 mg/m2, weekly) + reduction of CsA was initiated immediately. Subsequent biopsy of the enlarged lymph node indicated polymorphic PTLD [EBV-encoded RNA positive (EBER+)]. After three doses of rituximab, the patient’s EBV-DNA levels returned to normal, with symptoms resolved and lymph nodes shrunken. The patient has subsequently survived free from EBV-PTLD.\n\nThe first-line treatment, rituximab ± RI, should be initiated as soon as the probable diagnosis is made, even though histopathologic confirmation would need more time. During treatment, imaging examinations and biopsy should be completed whenever feasible to confirm the diagnosis.\n\nCase 3\nThe patient was a 36-year-old man diagnosed with acute myelogenous leukemia (AML). He reached complete remission (CR) after one cycle of induction chemotherapy, and accepted two cycles of consolidation chemotherapy. Afterwards, he underwent haplo-HSCT (conditioned with Bu + Flu) in June 2018 and received MTX + CsA + MMF + r-ATG (7.5 mg/kg) for GvHD prevention. Hematopoiesis was reconstituted on day +10. Acute GvHD (grade III) occurred on day +18, involving predominantly the skin and gastrointestinal tract. Diarrhea was alleviated following methylprednisolone, oral budesonide, and ruxolitinib but worsened with bloody stools on day +46 when the patient was on oral budesonide and ruxolitinib. EBV-DNA loads were positive in stools from day +61 but negative in peripheral blood. Enteroscopy revealed erosion and anabrosis involving the ileocaecum and ileocaecal valve, the biopsy results of which turned out to be EBER+ polymorphic PTLD. After four cycles of rituximab, 18F-FDG-PET/CT confirmed the status of CR. The patient has been in continual CR to the latest follow-up.\n\nClinicians must never forget EBV-PTLD in differential diagnosis, especially when patients suffer from changes during the process of improvement. Although it is certainly helpful to monitor EBV-DNA in the peripheral blood of patients after allo-HSCT, there are still a few cases of proven EBV-PTLD without EBV-DNAemia. In that condition, other detection methods, such as exfoliative cytology, imaging examinations, enteroscopy, and biopsy, may provide complementary proof.\n\nCase 4\nA 21-year-old man with AML reached CR after the first cycle of chemotherapy. Then, he received two cycles of consolidation chemotherapy and underwent haplo-HSCT in January 2018 with Ara-C + Bu + Cy + semustine in condition and MTX + CsA + MMF + r-ATG (7.5 mg/kg) for GvHD prevention. Hematopoiesis was reconstituted on day +10. He suffered from acute GvHD (skin, grade II), which faded after CsA and MTX. The regimen was then adjusted into tacrolimus, methylprednisolone, and ruxolitinib due to hemorrhagic cystitis with recurrent fever and cutaneous chronic GvHD. The EBV-DNA load in the blood was 7490 copies/ml on day +157 and continued to increase thereafter. After four cycles of rituximab, EBV-DNA became negative. Accidentally, CT revealed multiple low-density nodules in the patient’s liver on day +191, among which the largest nodule was 3.5 × 3.2 cm. 18F-FDG-PET/CT showed extranodal lesions in the liver [standard uptake value maximum (SUVmax), 17.6] and the spleen (SUVmax, 19.6) (Figure 1, left). Biopsy of the liver revealed an EBER+ post-transplant diffuse large B-cell lymphoma (DLBCL). Donor-derived EBV-CTLs (2 × 107/kg, weekly) and rituximab (R) + cyclophosphamide, vincristine and prednisone (COP) regimen (every 21 days) was applied. After four doses of EBV-CTLs and three courses of R-COP, 18F-FDG-PET/CT showed limited residual hypermetabolic lesions in the liver (SUVmax 3.7) and the spleen (SUVmax 3.4) (Figure 1, right). The patient finally reached CR and has since been free of EBV-PTLD.\n\nFigure 1. 18F-FDG–PET/CT images (maximum-intensity projection).\n\nBaseline images showed extranodal lesions in the liver (SUVmax, 17.6) and the spleen (SUVmax, 19.6) (left, arrows); 18F-FDG–PET/CT after three cycles of R-COP and four doses of EBV-CTLs showed limited residual hypermetabolic lesions in the liver (SUVmax, 3.7) and the spleen (SUVmax, 3.4) (right, arrows).\n\n18F, radionuclide fluorine 18; FDG, fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; R, rituximab; COP, regimen including cyclophosphamide, vincristine and prednisone; EBV-CTLs, Epstein–Barr virus specific cytotoxic T lymphocytes; SUVmax, standard uptake value maximum.\n\nThe patient was not misdiagnosed thanks to the accidental CT scan. It has been stressed that CT or 18F-FDG-PET/CT should play a role in the diagnosis of probable or proven EBV-PTLD. Additionally, clinicians sometimes need to evaluate the necessity of CT or 18F-FDG-PET/CT for asymptomatic patients with positive blood tests for EBV-DNA, since clinical manifestations of EBV-PTLD are heterogeneous and nonspecific. Furthermore, response evaluation should accompany the whole treatment process. Well-timed initiation of second-line treatment would improve the therapeutic outcome when patients respond poorly to rituximab ± RI.\n\nCase 5\nA 20-year-old woman, diagnosed with acute lymphocytic leukemia (ALL), reached CR after one cycle of induction chemotherapy. She underwent matched unrelated HSCT in December 2010 after two cycles of consolidation chemotherapy, and, then, with total body irradiation (TBI) + Cy + etoposide (VP-16) in condition and MTX + CsA + r-ATG (7.5 mg/kg) for GvHD prevention. Hematopoiesis was reconstituted on day +16. On day +49, the patient had fever, headache, severe emesis, and positive EBV-DNA (8.4 × 104 copies/ml) in the blood while on CsA. Cerebrospinal fluid (CSF) was also EBV-DNA positive. The patient also demonstrated lymphadenopathy of the bilateral cervical lymph nodes, and the excisional biopsy confirmed post-transplant DLBCL. Two cycles of intravenous rituximab (375 mg/m2, weekly) attenuated her clinical symptoms. However, the patient later manifested a lack of alertness, cognitive impairment, and gatism, and brain magnetic resonance imaging (MRI) showed symmetrical, extensive, supra- and infra-tentorium lesions (Figure 2, left). Rituximab (10 mg) was thus administered intrathecally with dexamethasone and relieved the neurological symptoms and signs. After two more cycles (20 mg and 30 mg, respectively), EBV-DNA in her CSF was cleared and MRI returned to normalization (Figure 2, right). The patient has been free of PTLD to date.\n\nFigure 2. MRI images. Baseline images showed symmetrical, extensive, supra- and infra-tentorium lesions (left); after three doses of intrathecal rituximab, MRI showed a completely normal image (right).\n\nMRI, magnetic resonance imaging.\n\nThe central nervous system (CNS) is one of the potential sites affected by EBV-PTLD. Measurement of EBV-DNA in the CSF and MRI are conducive to the diagnosis. For these patients, intrathecal administration of rituximab is a successful exploration.\n\nWhat is the pathogenesis of EBV-PTLD?\nEBV, initially described by Michael Anthony Epstein and Yvonne Barr in 1964, is a double-stranded DNA gamma herpesvirus. More than 90% of the world’s adult population have been infected by EBV, usually during childhood through oral transmission via saliva. EBV enters the body via epithelial cells and naïve B cells in the nasopharyngeal tract, and induces a lytic infection with the production of new viral particles.8 EBV then accompanies B cells to migrate, and finally establishes a latent infection by integrating its genome into the host nucleus. In immunocompetent individuals, the T-cell response is directly against EBV-specific epitopes and limits the infection.8,11 In addition, natural killer (NK) cells also play a notable role.8 However, immunodeficiency after allo-HSCT, particularly impaired T-cell immunity, loses control of EBV primary infection or reactivation in recipients’ bodies.8,12 Proteins such as LMP1, LMP2A, LMP2B, EBNA1, EBNA2, and others then mediate suppression or subversion of the host immune response and the immortalization of infected lymphocytes that ultimately progresses to EBV-PTLD.11 EBV-PTLD following allo-HSCT is almost exclusively of donor origin and generally develops during the second to fourth month after transplantation.4,6,13–17 However, no characteristic signature of oncogene expression or mutation in EBV-PTLD has been identified.8 Sporadically, EBV invades T or NK cells and leads to T-/NK- EBV-PTLD.11 EBV-negative PTLD cases are more likely de novo lymphomas in post-transplant recipients.18 Furthermore, studies focusing on gene expression profiling propose EBV-negative cases to be ‘classical’ lymphomas coincidentally occurring in post-transplant recipients rather than real PTLD.19\n\nHow are high-risk recipients identified?\nSeveral factors increase the risk of EBV-PTLD after allo-HSCT by dampening immunity or enhancing EBV primary infection/reactivation. The degree of immunodeficiency, especially T-cell immunodeficiency, is the most important factor in the development of PTLD. T-cell depleting agents (ATG, anti-CD3 monoclonal antibodies, or alemtuzumab) or methods are associated with an increased risk of PTLD.5,20–23 The EBV serostatus of recipients is another important risk factor for the development of EBV-PTLD.2,4 Kalra and colleagues confirmed that EBV seromismatch [recipient (–)/donor (+)] increased the incidence of EBV-PTLD after HSCT with ATG-included conditioning.9 Other risk factors include human leukocyte antigen (HLA)-mismatch, unrelated donor, cord blood transplantation (CBT), use of reduced intensity conditioning (RIC), GvHD, older recipients (age ⩾ 50 years), splenectomy prior to HSCT, second transplantation, and mesenchymal stem cell (MSC) treatment.2–5,23–25 Moreover, with a higher susceptibility of primary EBV infection, pediatric recipients are more likely to develop EBV-PTLD after allo-HSCT.26 The sixth edition guideline published by European Conference on Infections in Leukaemia (ECIL-6) classifies risk factors for EBV-PTLD into existing pre-transplant and developing post-transplant (Figure 3a).2 In individuals without or with one risk factor (ATG included), the cumulative incidence of PTLD was 0.4%, while for those with two, three, four, and five risk factors, the incidence increased to 3.0%, 10.4%, 26.5%, and 40%, respectively.4 In ECIL-6 guidelines, risk stratification includes low risk (i.e. auto-HSCT), standard risk (i.e. MFD allo-HSCT without risk factors; haplo-PTCy-HSCT), and high risk (i.e. MFD allo-HSCT with at least one risk factor; alternative-donor HSCT, including MUD/MMUD allo-HSCT and CBT).2 All of our cases used ATG; Cases 1, 3 and 4 underwent haplo-HSCT without PTCy, and Case 5 accepted matched unrelated HSCT; Cases 1 and 3 experienced acute GvHD (Table 1). According to ECIL-6 guidelines, all of them were at high risk.\n\nFigure 3. (a) Risk factors for EBV-PTLD after HSCT listed in ECIL-6 guidelines. Recipients are defined as a high-risk group for EBV-PTLD if they undergo MFD allo-HSCT with at least one risk factor or alternative-donor HSCT, including MUD/MMUD allo-HSCT and CBT.(b) Proposed management algorithm for high-risk recipients of allo-HSCT.\n\nCBT, cord blood transplantation; CHOP, regimen including cyclophosphamide, doxorubicin, vincristine and prednisone; COP, regimen including cyclophosphamide, vincristine and prednisone; DLI, donor lymphocyte infusion; EBV-CTLs, Epstein–Barr virus-specific cytotoxic T lymphocytes; EBV-PTLD, Epstein–Barr virus-related post-transplant lymphoproliferative disorder; ECIL-6, the sixth edition guideline published by the European Conference on Infections in Leukaemia; FU, follow-up; GvHD, graft-versus-host disease; HLA, human leukocyte antigen; haplo-PTCy-HSCT, haploidentical hematopoietic stem cell transplantation incorporating post-transplant cyclophosphamide; HSCT, hematopoietic stem cell transplantation; MFD, matched family donor; MMUD, mismatched unrelated donor; MUD, matched unrelated donor; MSC, mesenchymal stem cell; RI, reduction of immunosuppression; Tx, transplantation.\n\nAre prophylactic strategies needed?\nProphylaxis may benefit patients at high risk. Depletion of both T and B cells, rather than T cells alone, is accompanied by a relatively lower incidence of EBV-related diseases.5,25 GvHD prevention containing sirolimus or cyclophosphamide is also followed by a lower incidence of EBV-related diseases.27,28 In a large single-center retrospective study, prophylactic rituximab reduced the incidence of EBV-DNAemia and EBV-PTLD, and attenuated grade II–IV acute GvHD (20% versus 38%; p = 0.02).29 However, rituximab apparently delays the reconstitution of B-cell immunity and leads to fatal complications such as cytopenia and infections.9,30,31 Therefore, prophylactic rituximab should be accompanied by immunoglobulin replacement and other supportive methods.2 Adoptive cellular therapy (EBV-CTLs or DLI) has shown efficacy in preventing EBV-PTLD in a multi-center phase I trial,32 but preparation of EBV-CTLs costs money and time, and DLI may exacerbate GvHD. Antiviral drugs (e.g. acyclovir and ganciclovir) are not effective for latent EBV due to the lack of EBV thymidine kinase. Thus, antiviral drugs are not recommended to prevent EBV-PTLD after allo-HSCT.2,28 Given the unavoidable adverse effects, prophylactic strategies should be administered prudently to recipients of allo-HSCT. Instead, close monitoring of EBV-DNA and clinical manifestations was carried out in our cases.\n\nHow should EBV-DNA be monitored and EBV-DNAemia be managed?\nRegular monitoring of EBV-DNA by quantitative polymerase chain reaction (PCR) is recommended for recipients after allo-HSCT. EBV-DNAemia, defined as an abnormal increase in EBV-DNA in the peripheral blood, usually occurs prior to EBV-PTLD, although the data are somewhat conflicting.2,7 Whole blood, plasma and serum are all suitable materials.2 Abnormal EBV-DNA is generally detected earlier in whole blood,33,34 and plasma samples have higher specificity for higher loads.7 It is preferable to start screening EBV-DNA within the first month after HSCT, and to screen weekly for at least 4 months. Longer and more frequent monitoring is considered for those with poor T-cell reconstitution, namely, when receiving treatment for severe GvHD, after haplo-HSCT, with T-cell depletion, or when experiencing an early EBV reactivation (Figure 3b).2 Regarding the cut-off values, the data vary and are related to local experience, but 1000 copies/ml is generally accepted.4,12,20,22,27,29 Notably, discrepant results of EBV-DNA quantification for the same sample may occur in different laboratories.35,36 The continual increase in EBV-DNA quantities in the same laboratory is more informative and valuable.35,36 Quantification of EBV-DNA in the CSF is informative for CNS involvement.16 Quantification of EBV-CTLs, using HLA tetramers, enzyme-linked immune-spot, or flow-cytometry-based intracellular cytokine staining, are also promising methods,37–39 but current assays are costly, complex, time-consuming and nonstandardized.\n\nFurthermore, there is no consensus on the threshold of EBV-DNA load that predicts progression to EBV-PTLD. Rare proven cases have been reported to be EBV-DNAemia negative,17,40 such as Case 3. Recently, Wareham and colleagues proposed a model that improves the identification of recipients at high risk of developing PTLD.41 In addition to EBV-DNA screening, laboratory parameters [hemoglobin, thrombocytes, and C-reactive protein (CRP)] and clinical information (gender, age, year of transplantation, transplant type, number of transplants, and high-risk EBV serostatus) should be taken into consideration. However, this model still needs confirmation by more studies. In our cases, EBV-DNA in the plasma was measured weekly for the first 4 months after transplantation, then once every 2 weeks for the fifth and sixth months, and once per month for the seventh to twelfth months. Once positive, EBV-DNA was measured at least twice a week.\n\nEBV-DNAemia without clinical symptoms/diseases in high-risk recipients is the indication for preemptive therapy.2 The incidence of EBV-DNAemia varies from 18.6% to 81.7% depending on the transplantation type, risk factors, assay sensitivity, cut-off values, and so on.7,10,14,17,30,41 However, it is difficult to define an EBV-DNA load for the initiation of preemptive therapy that produces maximal benefits and limited toxicities. The velocity of rising EBV-DNA seems better for discriminating between recipients who are more likely or unlikely to develop PTLD. EBV-DNA loads indeed increased significantly faster in patients who developed PTLD than those who did not (p < 0.0001) in a large retrospective study, but static EBV-DNAemia appeared to be a better and simpler biomarker for PTLD development.14 Preemptive rituximab was reported to result in a survival advantage for allo-HSCT recipients with higher EBV-DNA loads (50,000 copies/ml) in a single-center retrospective study.42 Consistently, Kalra and colleagues also suggested a threshold between 100,000 and 1,000,000 copies/ml.14 Thus, rapidly increased or higher EBV-DNA loads and local experience can be referenced. In our center, preemptive rituximab will be initiated for high-risk patients when their EBV-DNA loads are higher than 10,000 copies/ml (plasma) or, in a continual rise, as in Case 1 (Figure 3b). EBV-DNAemia in recipients at low or standard risk tends to be self-limited, and more frequent screening is preferred.\n\nRituximab (375 mg/m2, weekly), as preemptive therapy, is documented to have a response rate of >70%.14,15,17,27,30 Preemptive rituximab cleared high EBV-DNAemia (EBV-DNA ⩾20,000 copies/ml) in a single-center retrospective study,21 and reduced the incidence of EBV-PTLD (1.4% versus 21.7%; p = 0.003) compared with that of historical controls in another prospective observation, with a more striking benefit for patients with higher EBV-DNAemia (EBV-DNA ⩾ 40,000 copies/ml) (2.7% versus 62.5%; p < 0.0001).20 However, such treatment did not improve overall survival (OS) or mortality.20,21 Recently, low-dose rituximab (100 mg/m2, weekly) for preemptive treatment has been investigated retrospectively, and resulted a comparative success rate (93.4%, 15/16) but a relatively higher relapse rate (37.5%, 6/16) than the standard dose.43 Of course, prospective, randomized, multicentric trials with larger number of patients are needed to determine the best rituximab dose. RI, the first step for the management of EBV-PTLD after SOT, is defined as a sustained reduction of at least 20% of the daily dose of immunosuppressive drugs, with the exception of low-dose corticosteroids.26,44 However, RI has limitations such as slow response, relatively low efficacy,44 and the possibility of GvHD aggravation. Given that rituximab may reduce the risk of GvHD, RI is applied mostly in combination with rituximab if applicable.2,3 Donor- or third-party-derived EBV-CTLs are highly efficacious but not widely available. If available, EBV-CTLs can be added to obliterate EBV-DNAemia in cases of poor response to rituximab ± RI, as in Case 1. Preemptive therapy is to obtain negative EBV-DNA without progression or relapse.2 Furthermore, clinicians should keep an eye on symptoms or signs of patients.\n\nHow is EBV-PTLD diagnosed?\nClinical manifestations of EBV-PTLD are heterogeneous, nonspecific, and highly variable with localized or disseminated lesions.1 Extranodal involvement is common,45,46 and lesions may invade the liver, gastrointestinal tract, spleen, lung, and others.6,13,24,40 Fever and lymphadenopathy are the most common symptoms and signs.2,3,24,40,47 If not treated promptly, this rapidly progressive disease may soon lead to multiple organ dysfunction and death.2,8\n\nImaging examinations are helpful for providing information on lesions and instructing the subsequent biopsy. 18F-FDG-PET/CT has already shown high sensitivity and specificity in detecting nodal and extranodal involvements in three single-center retrospective studies,45,46,48 as well as occult lesions not identified by other imaging methods.45,48 Generally, more aggressive lesions have a significantly higher SUVmax.45,46 Therefore, 18F-FDG-PET/CT has an excellent ability to differentiate PTLD from nonmalignant diseases.46 Moreover, 18F-FDG-PET/CT is also recommended in treatment evaluation and follow up.1,49 However, it is necessary to exclude false positive results of infection or inflammation and identify false negative results of high background fluorodeoxyglucose (FDG) uptake, CNS involvement, and T-cell PTLD. Additionally, CT or MRI is complementary to 18F-FDG–PET/CT.2 For probable cases with respiratory or gastrointestinal symptoms, endoscopy should also be included.2 In Case 3, enteroscopy played a vital role in the differentiation between EBV-PTLD and GvHD. In Case 4, CT revealed PTLD lesions in the liver by accident, while 18F-FDG–PET/CT helped to show nodal and extranodal involvement and to evaluate the therapeutic response. MRI, with its advantage in showing CNS lesions, was irreplaceable in Case 5.\n\nPatients are diagnosed with probable EBV-PTLD if they have EBV-DNAemia and suspicious symptoms or signs but no histopathologic evidence. Proven EBV-PTLD is defined by the detection of EBV nucleic acids or EBV-encoded proteins in a tissue specimen, together with symptoms and signs. If biopsy cannot be obtained, EBV-DNAemia combined with PET-CT/CT scan can be considered.2 However, clinicians need to exclude other infections, relapse of primary disease, cyclosporine-related encephalopathy, epilepsy, and cerebrovascular diseases. Considering the rapid progression and high fatality, we suggest that targeted rituximab ± RI be initiated immediately once a probable diagnosis of EBV-PTLD is made, and that imaging and histopathologic confirmation be accomplished without delay. In Case 2, we immediately initiated rituximab monotherapy when the patient was diagnosed with probable EBV-PTLD. A biopsy of enlarged lymph nodes followed. Of note, clinicians must be careful if they are to make a diagnosis of PTLD for recipients at low or standard risk. As the staging system specific for PTLD is currently not formed, the Ann Arbor classification and Lugano classification based on PET/CT are usually referenced.2\n\nHistopathologic examination with EBV detection is requisite for the establishment of proven EBV-PTLD.2 An excisional biopsy is usually preferred over a core biopsy, which should be done only if an excisional operation is unfeasible. EBER in situ hybridization is recommended to determine the existence of EBV.50 Immunohistochemistry for EBV proteins (e.g. LMPs and EBNAs) offers information about the infectious stage of the virus.1 WHO revised the classification of PTLD in 2016, with six main types recognized: plasmacytic hyperplasia PTLD, infectious mononucleosis PTLD, florid follicular hyperplasia PTLD, polymorphic PTLD, monomorphic PTLD (B- and T-/NK-cell types), and classical Hodgkin lymphoma PTLD.51 The former three types are nondestructive lymphoplasmacytic proliferations. The wide spectrum of PTLD causes difficulties in pathological diagnosis. Different morphologic subtypes may be present within different locations in the same body or even within a single biopsy sample,1 whereupon a new biopsy should be considered if 18F-FDG-PET-CT suggests a more malignant disease (especially after core needle biopsy).45 Generally, biological behavior is assumed to depend on the most malignant subtype, although well-defined criteria are lacking.1 It is critical to exclude specific and nonspecific lymphoplasmacytic infiltrations associated with infection, GvHD, or recurrence from a known lymphoma.1 Monomorphic PTLD is the most common diagnosis after allo-HSCT, among which DLBCL is the most predominant subtype.6,17 Distinct genetic differences have been explored and have shown promising results between post-transplant DLBCL and DLBCL arising in immunocompetent patients and between EBV-positive and EBV-negative post-transplant DLBCL, which may be useful for more accurate diagnosis and treatment.18,52,53 Exfoliative cytology sometimes provides diagnostic information, especially when it is difficult to perform a biopsy. Specimens can be obtained from CSF, peritoneal fluid, pleural fluid, and bronchoalveolar lavage fluid.54\n\nHow should probable or proven EBV-PTLD be treated?\nTargeted treatment is applied upon the diagnosis of probable or proven EBV-PTLD. Rituximab + RI is recommended as the first-line treatment, if patients are free of severe GvHD. Second-line options include adoptive cellular therapy (EBV-CTLs or DLI) and chemotherapy ± rituximab.2 Clinical trials, for example, novel EBV-CTLs or monoclonal antibodies, small molecule inhibitors, proteasome inhibitors, and new chemotherapy agents, should also be considered.55 The treatment goal is the resolution of all signs and symptoms and negativity of EBV-DNA (Figure 3b).\n\nFirst-line treatment\nRituximab monotherapy (375 mg/m2, weekly), with a positive response rate higher than 60%, is a reliable choice for EBV-PTLD.3,12,13,40,56 Generally, no more than four doses are appropriate due to the downregulation of CD20 expression and subsequent decrease in efficacy of additional doses.2 Combination strategies of rituximab and RI or chemotherapy are also applicable and highly efficient. In a single-center case-control study, rituximab + (RI or chemotherapy) achieved a better CR rate (80.6% versus 44.4%; p = 0.043) and 2-year OS (48.2% versus 13.2%; p = 0.020) than alternative therapies.47 In a multi-center retrospective study from Europe, rituximab-based therapy resulted in a response rate of 69.45%, while rituximab with RI significantly lowered the mortality (16.19% versus 38.71%; p = 0.006), improved the 3-year OS (59.86% versus 40.89%; p = 0.024) and did not exacerbate acute GvHD compared with the corresponding results without reducing immunosuppression.3 Therefore, rituximab should be combined with RI for PTLD patients whenever possible. Histopathologic confirmation is not required for the initiation of first-line treatment, as in Case 2. During rituximab administration, imaging examinations and biopsy should be completed wherever feasible. In Case 2, EBV-PTLD was localized to the lymph nodes and remitted after three doses of rituximab.\n\nRituximab also plays an important role in treating CNS involvement of EBV-PTLD.57 Intrathecal administration is required due to the low penetrance of rituximab across the blood–brain barrier.16 Intrathecal rituximab (on a sequential dose-escalation schedule (10, 20, 30, 40, and 50 mg, weekly), starting from 7–15 days after intravenous rituximab-based treatment) resulted in a good response for CNS involvement after the failure of intravenous rituximab-based treatment.16,56 Intravenous rituximab failed in Case 5, while intrathecal administration finally rescued the patient.\n\nResponse to rituximab is defined as at least one log10 decrease in EBV-DNA load within the first week of treatment.2 Rebound or persistently detectable EBV-DNAemia after rituximab administration is correlated with a poor outcome.3,14 Factors associated with poor response to rituximab include age ⩾30 years, extranodal disease, grade II–IV acute GvHD and without RI, and the mortality in patients with 0/1, 2, and 3 factors were 7%, 37%, and 72%, respectively (p < 0.001).3 Clinicians must carefully evaluate patients’ responses to rituximab ± RI. In cases with the above factors or of poor response to rituximab, it is preferred to combine EBV-CTLs or DLI as early as possible.\n\nSecond-line treatment\nEBV-CTLs or DLI, defined as adoptive cellular therapy, mainly assist the reconstitution of T-cell immunity for the control of EBV primary infection/reactivation, which may still be effective in rituximab ± RI refractory cases. Generally, three methods are in use clinically:58 multimer selection that selects T cells against specific viral peptides in the context of specific HLA class I molecule; IFN-γ capture, in which T cells are selected based on their secretion of IFN-γ under the stimulation of viral antigens;59,60 and faster CTL culture methods, using dendritic cells expressing viral antigens to induce T cells in the presence of cytokines. Of 13 recipients with biopsy-proven or probable EBV-PTLD, 11 achieved sustained CR after infusion of EBV-CTLs.32 In a single-center experiment, DLI achieved rates of durable CR and partial remission (PR) comparable with those of EBV-CTL infusion (73% versus 68%), but the higher risk of reversible acute GvHD (17% versus 0%) in patients using DLI could not be ignored.61 Sequential administration of EBV-CTLs or DLI and rituximab-based treatment may elevate the CR rate and reduce the relapse of PTLD after allo-HSCT. In a multi-center prospective open-label phase II study, EBV-CTLs (1 × 106/kg, biweekly × 8 doses) or DLI (CD3+ T cells, 2 × 107/kg, monthly × 4 doses) following rituximab-based treatment significantly increased the CR rate from 62% to 91% and resulted in a 5-year cumulative incidence of PTLD relapse as low as 4.5% ± 3.3%. The sequential therapeutic strategy achieved a 5-year OS and progression-free survival (PFS) after PTLD of 70.7% ± 5.2% and 68.9% ± 5.3%, respectively.56 Furthermore, the early start of concurrent or sequential strategies might benefit patients with factors of poor response to rituximab. Given the GvHD-inducing potential of DLI, specific cellular therapy is preferred.2,62 However, DLI should be considered when EBV-CTLs are unobtainable. In recent years, various kinds of EBV-CTLs have been reported, such as EBV-CTLs resistant to calcineurin inhibitors or EBNA-1 specific CTLs,59,60 LMP1/LMP2-specific CTLs,63 genetically manipulated EBV-CTLs,64 banked third-party EBV-CTLs,61,65 and multi-virus (BK virus, adenovirus, CMV, and EBV)-specific T cells.66 In a phase II multicenter clinical trial, Haque and colleagues treated 33 EBV-PTLD patients with in vitro stimulated and expanded EBV-CTLs (2 × 106/kg weekly, for 4 weeks-doses) generated from partially HLA-matched unrelated donors, of which the response rate (complete or partial) was 52% at 6 months, and none of the patients developed adverse effects.65 The persistence in vivo and long-term efficacy of third-party T-cells remains to be investigated,62 although related adverse effects such as aggravation of GvHD and cytokine release syndrome (CRS) have been rarely documented. Overall, EBV-CTLs may become widely available and be recognized as another important first-line treatment for EBV-PTLD in the near future.\n\nChemotherapy has shown excellent control of EBV-PTLD in recipients after SOT. It was reported that rituximab (375 mg/m2, weekly) + chemotherapy (CHOP or COP, regimens including cyclophosphamide, doxorubicin, vincristine and prednisone, or cyclophosphamide, vincristine and prednisone, respectively) generated a better PFS (p = 0.005) and OS (p = 0.013) than rituximab monotherapy in allo-HSCT recipients with EBV-PTLD, although with no difference in CR rate (59% versus 66%; p = 0.505).56 However, recipients after allo-HSCT are usually too weak to bear chemotherapeutic regimens such as CHOP or COP; thus, chemotherapy is recommended as second-line therapy.2 It is more suitable for refractory or relapsing EBV-PTLD after allo-HSCT, and appropriate regimens can also be applied to EBV-negative PTLD and T-/NK-PTLD, which are rare and commonly resemble de novo lymphomas rather than PTLD.2 If progression after rituximab ± RI and EBV-CTLs/DLI occurs, it is advisable to proceed to chemotherapy ± rituximab immediately.67 In the treatment of all CD20-positive subtypes, rituximab should be combined.67 In Case 4, rituximab monotherapy failed to remove lesions in the liver and spleen; thereafter, EBV-CTLs and R-COP were applied and turned the situation around at last.\n\nOngoing clinical trials should be considered for patients with PTLD, if feasible. (https://clinicaltrials.gov)\n\nConclusion\nEBV-PTLD is one of the most serious complications after allo-HSCT. It is crucial to identify recipients at high risk of EBV-PTLD and to monitor EBV-DNA loads continuously. Earlier diagnosis and treatment would improve clinical outcomes. Timely initiation of rituximab + RI is the most important step in the treatment of EBV-PTLD, and EBV-CTLs or DLI can complement this when patients response is unsatisfactory. However, further investigations are still warranted to optimize the management strategies.\n\nWe are grateful to Ren Lin for organizing the medical records of cases, and to Ping Zhang for English modification.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work is supported by the National Megaproject on Key Infectious Diseases (2017ZX10202102), the Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (2016-I2M-1-017, 2016-I2M-3-023), the nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018PT32034), and the Natural Science Foundation of Tianjin City (18JCZDJC34400).\n\nConflict of interest statement: The author(s) declare that there is no conflict of interest.\n\nEthics and consent statements: This work has been approved by the Ethics Committee of Blood Diseases Hospital, Chinese Academy of Medical Sciences (Approval No. NI2019010-EC-1). Consent has been waived, as no private patient information was released, and patients were not exposed to any harm.\n\nORCID iD: Li Liu \nhttps://orcid.org/0000-0002-7197-3382\n==== Refs\nReferences\n1 \nDierickx D Tousseyn T Gheysens O \nHow I treat posttransplant lymphoproliferative disorders\n. Blood \n2015 ; 126 : 2274 –2283\n.26384356 \n2 \nStyczynski J van der Velden W Fox CP , et al\nManagement of Epstein–Barr virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: sixth European conference on infections in leukemia (ECIL-6) guidelines\n. 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Bone Marrow Transplant \n2015 ; 50 : 579 –584\n.25581404 \n28 \nKanakry JA Kasamon YL Bolanos-Meade J , et al\nAbsence of post-transplantation lymphoproliferative disorder after allogeneic blood or marrow transplantation using post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis\n. Biol Blood Marrow Transplant \n2013 ; 19 : 1514 –1517\n.23871780 \n29 \nDominietto A Tedone E Soracco M , et al\nIn vivo B-cell depletion with rituximab for alternative donor hemopoietic SCT\n. Bone Marrow Transplant \n2012 ; 47 : 101 –106\n.21460867 \n30 \nLiu Q Xuan L Liu H , et al\nMolecular monitoring and stepwise preemptive therapy for Epstein–Barr virus viremia after allogeneic stem cell transplantation\n. Am J Hematol \n2013 ; 88 : 550 –555\n.23564232 \n31 \nPetropoulou AD Porcher R Peffault de Latour R , et al\nIncreased infection rate after preemptive rituximab treatment for Epstein–Barr virus reactivation after allogeneic hematopoietic stem-cell transplantation\n. Transplantation \n2012 ; 94 : 879 –883\n.23001354 \n32 \nHeslop HE Slobod KS Pule MA , et al\nLong-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients\n. Blood \n2010 ; 115 : 925 –935\n.19880495 \n33 \nGreijer AE Stevens SJ Verkuijlen SA , et al\nVariable EBV DNA load distributions and heterogeneous EBV mRNA expression patterns in the circulation of solid organ versus stem cell transplant recipients\n. Clin Dev Immunol \n2012 ; 2012 : 543085.\n34 \nRuf S Behnke-Hall K Gruhn B , et al\nComparison of six different specimen types for Epstein–Barr viral load quantification in peripheral blood of pediatric patients after heart transplantation or after allogeneic hematopoietic stem cell transplantation\n. J Clin Virol \n2012 ; 53 : 186 –194\n.22182950 \n35 \nPreiksaitis JK Pang XL Fox JD , et al\nInterlaboratory comparison of Epstein–BarrBarr virus viral load assays\n. Am J Transplant \n2009 ; 9 : 269 –279\n.19178414 \n36 \nHayden RT Hokanson KM Pounds SB , et al\nMulticenter comparison of different real-time PCR assays for quantitative detection of Epstein–Barr virus\n. J Clin Microbiol \n2008 ; 46 : 157 –163\n.17989187 \n37 \nD’Aveni M Aissi-Rothe L Venard V , et al\nThe clinical value of concomitant Epstein Barr virus (EBV)-DNA load and specific immune reconstitution monitoring after allogeneic hematopoietic stem cell transplantation\n. Transpl Immunol \n2011 ; 24 : 224 –232\n.21440066 \n38 \nClave E Agbalika F Bajzik V , et al\nEpstein–Barr virus (EBV) reactivation in allogeneic stem-cell transplantation: relationship between viral load, EBV-specific T-cell reconstitution and rituximab therapy\n. Transplantation \n2004 ; 77 : 76 –84\n.14724439 \n39 \nChiereghin A Bertuzzi C Piccirilli G , et al\nSuccessful management of EBV-PTLD in allogeneic bone marrow transplant recipient by virological-immunological monitoring of EBV infection, prompt diagnosis and early treatment\n. Transpl Immunol \n2016 ; 34 : 60 –64\n.26687013 \n40 \nFox CP Burns D Parker AN , et al\nEBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era\n. Bone Marrow Transplant \n2014 ; 49 : 280 –286\n.24212561 \n41 \nWareham NE Mocroft A Sengelov H , et al\nThe value of EBV DNA in early detection of post-transplant lymphoproliferative disorders among solid organ and hematopoietic stem cell transplant recipients\n. J Cancer Res Clin Oncol \n2018 ; 144 : 1569 –1580\n.29804164 \n42 \nRaberahona M Wackenheim C Germi R , et al\nDynamics of Epstein–Barr viral load after hematopoietic stem cell transplantation and effect of preemptive rituximab therapy\n. Transpl Infect Dis \n2016 ; 18 : 889 –895\n.27696681 \n43 \nDelapierre B Reman O Dina J , et al\nLow dose Rituximab for pre-emptive treatment of Epstein Barr virus reactivation after allogenic hematopoietic stem cell transplantation\n. Curr Res Transl Med . Epub ahead of print 16 March 2019. DOI: 10.1016/j.retram.2019.03.001. \n44 \nReshef R Vardhanabhuti S Luskin MR , et al\nReduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder (bigstar)\n. Am J Transplant \n2011 ; 11 : 336 –347\n.21219573 \n45 \nTakehana CS Twist CJ Mosci C , et al\n18F-FDG PET/CT in the management of patients with post-transplant lymphoproliferative disorder\n. Nucl Med Commun \n2014 ; 35 : 276 –281\n.24296883 \n46 \nDierickx D Tousseyn T Requile A , et al\nThe accuracy of positron emission tomography in the detection of posttransplant lymphoproliferative disorder\n. Haematologica \n2013 ; 98 : 771 –775\n.23065524 \n47 \nXu LP Zhang CL Mo XD , et al\nEpstein–Barr virus-related post-transplantation lymphoproliferative disorder after unmanipulated human leukocyte antigen haploidentical hematopoietic stem cell transplantation: incidence, risk factors, treatment, and clinical outcomes\n. Biol Blood Marrow Transplant \n2015 ; 21 : 2185 –2191\n.26253005 \n48 \nPanagiotidis E Quigley AM Pencharz D , et al\n18F-fluorodeoxyglucose positron emission tomography/computed tomography in diagnosis of post-transplant lymphoproliferative disorder\n. Leuk Lymphoma \n2014 ; 55 : 515 –519\n.23772644 \n49 \nZimmermann H Denecke T Dreyling MH , et al\nEnd-of-treatment positron emission tomography after uniform first-line therapy of B-cell posttransplant lymphoproliferative disorder identifies patients at low risk of relapse in the prospective German PTLD registry\n. Transplantation \n2018 ; 102 : 868 –875\n.29189632 \n50 \nStuhlmann-Laeisz C Oschlies I Klapper W \nDetection of EBV in reactive and neoplastic lymphoproliferations in adults-when and how?\n\nJ Hematop \n2014 ; 7 : 165 –170\n.25478033 \n51 \nSwerdlow SH Campo E Pileri SA , et al\nThe 2016 revision of the world health organization classification of lymphoid neoplasms\n. Blood \n2016 ; 127 : 2375 –2390\n.26980727 \n52 \nMenter T Juskevicius D Alikian M , et al\nMutational landscape of B-cell post-transplant lymphoproliferative disorders\n. Br J Haematol \n2017 ; 178 : 48 –56\n.28419429 \n53 \nMorscio J Finalet Ferreiro J Vander Borght S , et al\nIdentification of distinct subgroups of EBV-positive post-transplant diffuse large B-cell lymphoma\n. Mod Pathol \n2017 ; 30 : 370 –381\n.28059091 \n54 \nGibson SE Picarsic J Swerdlow SH , et al\nRole of Epstein–Barr virus status and immunophenotypic studies in the evaluation of exfoliative cytology specimens from patients with post-transplant lymphoproliferative disorders\n. Cancer Cytopathol \n2016 ; 124 : 425 –435\n.26992116 \n55 \nDeStefano CB Desai SH Shenoy AG , et al\nManagement of post-transplant lymphoproliferative disorders\n. Br J Haematol . Epub ahead of print 10 May 2018. DOI: 10.1111/bjh.15263 \n56 \nJiang X Xu L Zhang Y , et al\nRituximab-based treatments followed by adoptive cellular immunotherapy for biopsy-proven EBV-associated post-transplant lymphoproliferative disease in recipients of allogeneic hematopoietic stem cell transplantation\n. Oncoimmunology \n2016 ; 5 : e1139274.\n57 \nHori YS Nagakita K Ebisudani Y , et al\nPrimary central nervous system hodgkin lymphoma-like posttransplant lymphoproliferative disorder\n. World Neurosurg \n2018 ; 114 : 230 –234\n.29609086 \n58 \nAggarwal NR King LS D’Alessio FR \nDiverse macrophage populations mediate acute lung inflammation and resolution\n. Am J Physiol Lung Cell Mol Physiol \n2014 ; 306 : L709–L725.\n59 \nIcheva V Kayser S Wolff D , et al\nAdoptive transfer of Epstein–BarrBarr virus (EBV) nuclear antigen 1-specific t cells as treatment for EBV reactivation and lymphoproliferative disorders after allogeneic stem-cell transplantation\n. J Clin Oncol \n2013 ; 31 : 39 –48\n.23169501 \n60 \nRicciardelli I Brewin J Lugthart G , et al\nRapid generation of EBV-specific cytotoxic T lymphocytes resistant to calcineurin inhibitors for adoptive immunotherapy\n. Am J Transplant \n2013 ; 13 : 3244 –3252\n.24266973 \n61 \nDoubrovina E Oflaz-Sozmen B Prockop SE , et al\nAdoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation\n. Blood \n2012 ; 119 : 2644 –2656\n.22138512 \n62 \nKaeuferle T Krauss R Blaeschke F , et al\nStrategies of adoptive T -cell transfer to treat refractory viral infections post allogeneic stem cell transplantation\n. J Hematol Oncol \n2019 ; 12 : 13 .30728058 \n63 \nKim N Sohn HJ Oh JH , et al\nInfusions of Epstein–Barr virus-specific cytotoxic T lymphocytes as post-remission therapy in high-risk post-transplant lymphoproliferative disorder patients: report of two cases\n. Int J Hematol \n2018 ; 107 : 596 –603\n.29188583 \n64 \nRicciardelli I Blundell MP Brewin J , et al\nTowards gene therapy for EBV-associated posttransplant lymphoma with genetically modified EBV-specific cytotoxic T cells\n. Blood \n2014 ; 124 : 2514 –2522\n.25185261 \n65 \nHaque T Wilkie GM Jones MM , et al\nAllogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial\n. Blood \n2007 ; 110 : 1123 –1131\n.17468341 \n66 \nDave H Luo M Blaney JW , et al\nToward a rapid production of multivirus-specific T cells targeting BKV, adenovirus, CMV, and EBV from umbilical cord blood\n. Mol Ther Methods Clin Dev \n2017 ; 5 : 13 –21\n.28480300 \n67 \nDierickx D Habermann TM \nPost-transplantation lymphoproliferative disorders in adults\n. N Engl J Med \n2018 ; 378 : 549 –562\n.29414277\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2040-6207",
"issue": "11()",
"journal": "Therapeutic advances in hematology",
"keywords": "Epstein–Barr virus; allogeneic hematopoietic stem cell transplantation; management; post-transplant lymphoproliferative disorder",
"medline_ta": "Ther Adv Hematol",
"mesh_terms": null,
"nlm_unique_id": "101549589",
"other_id": null,
"pages": "2040620720910964",
"pmc": null,
"pmid": "32523657",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "22182950;29189632;28581032;26862355;27696681;26744460;24296883;26574232;30871955;19880495;27365460;28831836;29114932;29414277;19264919;17989187;23346186;27189056;24212561;30009980;21440066;21910716;19178414;23405972;28480300;23749107;24292521;29804164;23001354;21219573;25581404;24056821;23489474;29075059;26595071;26901708;27467959;29580864;29741774;28059091;23065524;22138512;23871780;24266973;23772644;26980727;28419429;23564232;26687013;23771985;23169501;25185261;29188583;21460867;24508730;26992116;17468341;26253005;26384356;14724439;28039080;25655616;29966464;30728058;25478033;29609086;26780579",
"title": "Management of Epstein-Barr virus-related post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation.",
"title_normalized": "management of epstein barr virus related post transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation"
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"abstract": "Endovascular revascularization of a chronically occluded internal carotid artery (ICA) is challenging because the occlusive segment can be long and tortuous. A case is presented of a successful recanalization of a chronically occluded ICA by retrograde passing of a guidewire from the intracranial ICA to the cervical ICA via the posterior communicating artery. This case suggests that a retrograde approach for reopening an occluded artery may be useful during neurovascular interventions, similar to percutaneous coronary interventions. In this patient, daily transient ischemic attacks disappeared after successful recanalization of the ICA.",
"affiliations": "Department of Neurosurgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan. unot-tky@umin.ac.jp.;Department of Neurosurgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe-shi, Saitama, Japan.;Department of Neurosurgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan.;Department of Neurosurgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan.;Department of Neurosurgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan.",
"authors": "Uno|Takeshi|T|http://orcid.org/0000-0002-6899-0878;Shojima|Masaaki|M|;Oyama|Yuta|Y|;Yamane|Fumitaka|F|;Matsuno|Akira|A|",
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"fulltext": "\n==== Front\nActa Neurochir (Wien)\nActa Neurochir (Wien)\nActa Neurochirurgica\n0001-6268\n0942-0940\nSpringer Vienna Vienna\n\n34014378\n4875\n10.1007/s00701-021-04875-3\nCase Report - Vascular Neurosurgery - Ischemia\nRetrograde endovascular revascularization for chronic total occlusion of the internal carotid artery: a case report\nhttp://orcid.org/0000-0002-6899-0878\nUno Takeshi unot-tky@umin.ac.jp\n\n1\nShojima Masaaki 2\nOyama Yuta 1\nYamane Fumitaka 1\nMatsuno Akira 1\n1 grid.264706.1 0000 0000 9239 9995 Department of Neurosurgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan\n2 grid.410802.f 0000 0001 2216 2631 Department of Neurosurgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe-shi, Saitama, Japan\n20 5 2021\n20 5 2021\n2022\n164 4 10151019\n5 2 2021\n9 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/.\nEndovascular revascularization of a chronically occluded internal carotid artery (ICA) is challenging because the occlusive segment can be long and tortuous. A case is presented of a successful recanalization of a chronically occluded ICA by retrograde passing of a guidewire from the intracranial ICA to the cervical ICA via the posterior communicating artery. This case suggests that a retrograde approach for reopening an occluded artery may be useful during neurovascular interventions, similar to percutaneous coronary interventions. In this patient, daily transient ischemic attacks disappeared after successful recanalization of the ICA.\n\nKeywords\n\nEndovascular revascularization\nRetrograde approach\nICA occlusion\nChronic total occlusion\nTransient ischemic attacks\nissue-copyright-statement© Springer-Verlag GmbH Austria, part of Springer Nature 2022\n==== Body\npmcIntroduction\n\nPatients with chronic internal carotid artery (ICA) occlusion and severe cerebral hypoperfusion have a 20% chance of cerebral ischemic events per year, despite medical treatment [6]. Endovascular procedures for ICA occlusions are sometimes performed, with successful revascularization leading to increased perfusion and improved clinical symptoms, including preserving cognitive function [3, 12, 16]. Nevertheless, these procedures succeed in only about 60 to 80% of patients [19]. For the percutaneous treatment of chronic coronary artery total occlusions, a retrograde approach is useful when an antegrade approach is difficult [14]. For the first time in the neurovascular field, we report a retrograde revascularization technique to treat a chronic total occlusion of the ICA.\n\nClinical presentation\n\nA 52-year-old man with multiple stenting procedures for arteriosclerosis obliterans in bilateral lower extremities history presented with repeated transient left-sided hemiparesis. Magnetic resonance imaging (MRI) and contrast-enhanced computed tomography imaging detected occlusion of the right ICA and hypoperfusion of the right cerebrum. An endovascular revascularization procedure was recommended owing to daily occurrences of transient ischemic attacks (TIAs) despite treatment with acetylsalicylic acid (100 mg) and cilostazol (200 mg). Cerebral angiography revealed complete occlusion of the right ICA (Fig. 1). The closure of the right A1 and formation of collateral circulation through reversed flow in the right ophthalmic artery from the right external carotid artery and the right posterior communicating artery from the posterior circulation. Although the patient refused EC-IC bypass surgery management, he agreed to receive percutaneous revascularization when endovascular treatment was presented as an alternative.Fig. 1 Angiography and perfusion computed tomography before treatment. (a–c) The right common carotid angiography revealed complete right ICA occlusion and formation of collateral circulation through reversed flow in the right ophthalmic artery from the right external carotid artery. (d) The left internal carotid angiography revealed closure of the right A1. (e–f) The right vertebral angiography revealed the right posterior communicating artery from the posterior circulation. (g) Perfusion computed tomography revealed the right cerebral hypoperfusion compared to the left\n\nUnder local anesthesia, the revascularization procedure was performed via a percutaneous transfemoral route. First, an antegrade approach was attempted to pass the guidewire through the occlusive lesion. After an 8-F sheath introducer was placed in the right common femoral artery, heparin was maintained intravenously to keep the activated clotting time > 250 s. An 8-F balloon guiding catheter (FlowGate2; Stryker, Tokyo, Japan) was then positioned in the right common carotid artery to prevent distal embolization. Initially, 0.014- and 0.018-in. hydrophilic guidewires (CHIKAI Black; Asahi intecc, Aichi, Japan) were used to attempt to enter the occlusion site with the support of a microcatheter (Excelsior 1018 straight; Boston Scientific, Natick, MA, USA). The fibrous cap at the occluded vessel's proximal part was too hard to penetrate with these guidewires. Therefore, this cap was breached with a stiff 0.018-in. guidewire (Treasure; Asahi intecc, Aichi, Japan). While carefully rotating, the 0.014-in. guidewire was then advanced in the occluded vessel's lumen, followed by the microcatheter. At around the 90° flexion point of the ICA at the entrance to the skull, the guidewire’s smooth progression ceased, with angiography revealing that the catheter had entered the vascular dissection cavity (Fig. 2). Another guidewire was inserted in parallel [9], and the microcatheter was shaped to change the direction of the wire; however, the true lumen of the blood vessel could not be secured.Fig. 2 Illustration of the retrograde recanalization procedure. (a) In the antegrade procedure, the guidewire broke into the false lumen distal to the carotid canal. (b) The guidewire was then retrogradely advanced from the vertebral artery to the internal carotid artery via the posterior communicating artery. The distal fibrous cap was soft, and the guidewire was easily advanced retrogradely. (c) The tip of the retrograde guidewire was pulled into the guiding catheter in the common carotid artery with a snare catheter. (d) Along the retrograde guidewire, the catheter from the proximal internal carotid artery was passed antegradely across the occluded segment to the distal internal carotid artery. (e) The guidewire was navigated antegradely for the middle cerebral artery, and the occluded segment was dilated with the balloon under proximal protection\n\nAn antegrade approach was then considered inappropriate. Instead, a retrograde approach was attempted from the direction of the catheter access point from the distal to the proximal ICA (Fig. 2). A 6-F sheathless guiding catheter (Medikit, Tokyo, Japan) was placed in the right vertebral artery via the right radial artery. A 0.014-in. hydrophilic guidewire within a microcatheter was then navigated to the right ICA distal to the occlusion site through the collateral route of the posterior communicating artery. The fibrous cap in the distal part of the occluded vessel was not hard; therefore, the guidewire passed through with only slight manipulation. The guidewire and microcatheter were then easily passed through the obstruction to the cervical ICA, and blood return from the common carotid artery was confirmed through the microcatheter. The 0.014-in. guidewire was then exchanged with a 0.010-in. guidewire of 300-cm length (CHIKAI 10; Asahi intecc, Aichi, Japan). The tip of this guidewire was caught by a 4-mm snare device (Amplatz gooseneck; Medtronic, Minnesota, USA) and pulled through the sheath at the right femoral artery, passing from the radial artery through the occluded vessel to the femoral artery. Subsequently, the microcatheter was placed in the proximal to the distal direction of the ICA to carry devices, such as balloons or stents. A microcatheter (Excelsior 1018 straight; Boston Scientific, Natick, MA, USA) was advanced over the 0.010-in. guidewire into the right distal true ICA through the occluded segment, with great care not to move the intracranial vessels. The microcatheter was then passed through the occluded vessel and reached the distal true lumen of the ICA as if it had been guided in an antegrade fashion.\n\nThe subsequent procedure was conducted following the procedure by Shojima et al. [12]. Angiography at the end of the procedure showed antegrade blood flow of the ICA. The patient was discharged 4 days later without neurological deficits. Angiography after 3 months and carotid ultrasonography after 6 months showed antegrade ICA blood flow, without additional TIAs after revascularization (Fig. 3).Fig. 3 Image after treatment. (a–b) The right common carotid angiography revealed patency of the right internal carotid artery after 3 months. (c) Diffusion-weighted magnetic resonance image 1 day after the procedure revealed small ischemic lesions in the ipsilateral cerebral hemisphere\n\nDiscussion\n\nThis report described a successful retrograde revascularization technique through the posterior communicating artery for chronic ICA total occlusions. Endovascular techniques for treating chronic ICA total occlusions are generally beneficial; however, these procedures can be difficult [5], and generally depend on whether the guidewire can successfully be passed through the occluded segment to enter the vessel's true lumen [1, 5]. If a pseudo-vessel lumen is entered, blood vessel perforation can occur, leading to intracranial hemorrhage and death [19]. Until now, such a procedure would generally have been stopped if the true vessel lumen could not be entered using an antegrade approach. However, a retrograde crossing of a chronically occluded segment could be easier than an antegrade crossing because the distal fibrous cap is generally thinner and softer than the proximal cap [4, 8]. In this case, a stiff 0.018-in. guidewire was required to penetrate the proximal fibrous cap, while the distal fibrous cap was penetrated with only a floppy, hydrophilic 0.014-in. guidewire.\n\nRetrograde procedures are becoming more common during coronary interventions, despite no previous report on ICA occlusion [18]. In these cases, the ‘retrograde’ pathway is generally through a grafted blood vessel from previous bypass surgery or a collateral circulation channel, such as septal or epicardial collateral. Guidewires with good torque performance and microcatheters specialized for retrograde approaches have dramatically increased success rates for coronary interventions [17]. Recanalization of chronic total occlusion in coronary intervention improves angina, enhances athletic performance, and reduces mortality and the need for subsequent coronary artery bypass surgery [7, 11, 13]. The success rate of the combined antegrade and retrograde approach has risen to about 90% in recent years from the 70% success rate with antegrade approach alone [2, 10, 15]. This case suggests that a similar retrograde procedure may be useful for recanalizing chronically occluded ICAs as in the coronary intervention area.\n\nGuiding a carotid stent through an intracranial vessel is not always possible owing to the high risk of vascular rupture. Therefore, we entered the true lumen from the occluded vessel's distal end, pulling the stent from the proximal to the distal end with a snare. Pulling up the catheter is likely to move the blood vessel; thus, great care must be taken during this stage. Furthermore, bypass surgeries can also be performed for cerebral revascularization when appropriate.\n\nConclusion\n\nIn this case, the patient’s daily TIAs disappeared completely. His course was good, suggesting that a retrograde technique may be useful not only for percutaneous coronary interventions but also for neurovascular interventions when antegrade revascularization procedures are difficult. Thus, the feasibility and safety of this technique should be assessed through larger-scale studies in the future.\n\nAbbreviations\n\nICA Internal carotid artery\n\nTIA Transient ischemic attacks\n\nMRI Magnetic resonance imaging\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe patient provided written informed consent for publication of the data in this report.\n\nConflict of interest\n\nThe authors declare no competing interests.\n\nThis article is part of the Topical Collection on Vascular Neurosurgery - Ischemia\n\nPublisher's note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Creaney C Walsh SJ Antegrade chronic total occlusion strategies: a technical focus for 2020 Interv Cardiol 2020 15 e08 10.15420/icr.2020.05 32684982\n2. Dash D Retrograde coronary chronic total occlusion intervention Curr Cardiol Rev 2015 11 291 298 10.2174/1573403X11666150909110300 26354513\n3. Fan YL Wan JQ Zhou ZW Chen L Wang Y Yao Q Jiang JY Neurocognitive improvement after carotid artery stenting in patients with chronic internal carotid artery occlusion: a prospective, controlled, single-center study Vasc Endovasc Surg 2014 48 305 310 10.1177/1538574414525863\n4. Fujii K Ochiai M Mintz GS Kan Y Awano K Masutani M Ashida K Ohyanagi M Ichikawa S Ura S Araki H Stone GW Moses JW Leon MB Carlier SG Procedural implications of intravascular ultrasound morphologic features of chronic total coronary occlusions Am J Cardiol 2006 97 1455 1462 10.1016/j.amjcard.2005.11.079 16679083\n5. Gregg W Stone BDR McConahay DR Johnson WL Giorgi LV Ligon RW Hartzler GO Procedural outcome of angioplasty for total coronary artery occlussion: an analysis of 971 lesions in 905 patients J Am Coll Cardiol 1990 15 849 856 10.1016/0735-1097(90)90285-W 2307797\n6. Grubb RL Jr Derdeyn CP Fritsch SM Carpenter DA Yundt KD Videen TO Spitznagel EL Powers WJ Importance of hemodynamic factors in the prognosis of symptomatic carotid occlusion JAMA 1998 280 1055 1060 10.1001/jama.280.12.1055 9757852\n7. Ivanhoe RJ Weintraub WS Douglas JS Jr Lembo NJ Furman M Gershony G Cohen CL King SB 3rd Percutaneous transluminal coronary angioplasty of chronic total occlusions. Primary success, restenosis, and long-term clinical follow-up Circulation 1992 85 106 115 10.1161/01.cir.85.1.106 1728439\n8. Jaffe R Leung G Munce NR Thind AS Leong-Poi H Anderson KJ Qi X Trogadis J Nadler A Shiff D Saperia J Lockwood J Jacobs C Qiang B Teitelbaum A Dick AJ Sparkes JD Butany J Wright GA Strauss BH Natural history of experimental arterial chronic total occlusions J Am Coll Cardiol 2009 53 1148 1158 10.1016/j.jacc.2008.09.064 19324261\n9. Kao HL Lin MS Wang CS Lin YH Lin LC Chao CL Jeng JS Yip PK Chen SC Feasibility of endovascular recanalization for symptomatic cervical internal carotid artery occlusion J Am Coll Cardiol 2007 49 765 771 10.1016/j.jacc.2006.11.029 17306705\n10. Kwon O Lee PH Lee SW Lee JY Kang DY Ahn JM Park DW Kang SJ Kim YH Lee CW Park SW Park SJ Retrograde approach for the percutaneous recanalisation of coronary chronic total occlusions: contribution to clinical practice and long-term outcomes EuroIntervention 2019 15 e354 e361 10.4244/EIJ-D-18-00538 30375334\n11. Ruocco NA Jr Ring ME Holubkov R Jacobs AK Detre KM Faxon DP Results of coronary angioplasty of chronic total occlusions (the National Heart, Lung, and Blood Institute 1985–1986 Percutaneous Transluminal Angioplasty Registry) Am J Cardiol 1992 69 69 76 10.1016/0002-9149(92)90678-r 1729870\n12. Shojima M Nemoto S Morita A Miyata T Namba K Tanaka Y Watanabe E Protected endovascular revascularization of subacute and chronic total occlusion of the internal carotid artery AJNR Am J Neuroradiol 2010 31 481 486 10.3174/ajnr.A1843 19850764\n13. Suero JA Marso SP Jones PG Laster SB Huber KC Giorgi LV Johnson WL Rutherford BD Procedural outcomes and long-term survival among patients undergoing percutaneous coronary intervention of a chronic total occlusion in native coronary arteries: a 20-year experience J Am Coll Cardiol 2001 38 409 414 10.1016/s0735-1097(01)01349-3 11499731\n14. Surmely JFKO Tsuchikane E Nasu K Suzuki T Coronary septal collaterals as an access for the retrograde approach in the percutaneous treatment of coronary chronic total occlusions Catheter Cardiovasc Interv 2007 69 826 832 10.1002/ccd.20816 17253598\n15. Tanaka H Ohya M Kubo S Miura K Otsuru S Habara S Tada T Fuku Y Goto T Kadota K Impact of retrograde approach on long-term clinical outcomes of patients undergoing coronary chronic total occlusion interventions EuroIntervention 2018 14 e1183 e1191 10.4244/EIJ-D-18-00534 30082257\n16. Terada T Okada H Nanto M Shintani A Yoshimura R Kakishita K Masuo O Matsumoto H Itakura T Ohshima K Yamaga H Endovascular recanalization of the completely occluded internal carotid artery using a flow reversal system at the subacute to chronic stage J Neurosurg 2010 112 563 571 10.3171/2009.6.JNS09125 19645534\n17. Tsuchikane E Katoh O Kimura M Nasu K Kinoshita Y Suzuki T The first clinical experience with a novel catheter for collateral channel tracking in retrograde approach for chronic coronary total occlusions JACC Cardiovasc Interv 2010 3 165 171 10.1016/j.jcin.2009.10.026 20170873\n18. Wu EB Tsuchikane E Ge L Harding SA Lo S Lim ST Chen JY Lee SW Qian J Kao HL Yan BPY Retrograde versus antegrade approach for coronary chronic total occlusion in an algorithm-driven contemporary Asia-Pacific Multicentre Registry: comparison of outcomes Heart Lung Circ 2020 29 894 903 10.1016/j.hlc.2019.05.188 31320259\n19. Ying-Hsien Chen W-SL Lin M-S Huang C-C Hung C-S Li H-Y Chan K-K Yeh C-F Chiu M-J Kao H-L Predictors for successful endovascular intervention in chronic carotid artery total occlusion J Am Coll Cardiol Intv 2016 9 1825 1832 10.1016/j.jcin.2016.06.015\n\n",
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"keywords": "Chronic total occlusion; Endovascular revascularization; ICA occlusion; Retrograde approach; Transient ischemic attacks",
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"title": "Retrograde endovascular revascularization for chronic total occlusion of the internal carotid artery: a case report.",
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"abstract": "BACKGROUND\nDual antiplatelet therapy (DAPT) is necessary for stent assisted coiling. However, long term use of DAPT has a potential risk of hemorrhagic events. We aimed to examine the relationship between clopidogrel reactivity and complications.\n\n\nMETHODS\nPatients who underwent stent assisted coiling for unruptured aneurysms or previously treated aneurysms and received periprocedural DAPT in our institution between August 2011 to March 2020 were included. Platelet reactivity for clopidogrel was measured by VerifyNow assay system, and we defined the cut off value of P2Y12 Reaction Units (PRU) at 208 and classified patients as hypo-responders (PRU≧208) or responders (PRU<208). The rates of hemorrhagic and thrombotic events within 30 days (acute phase) and 30 days after the procedure (delayed phase) were compared between the two groups. Furthermore, changes in hemoglobin levels were measured before and after the procedure and at chronic stages (1 to 6 months thereafter).\n\n\nRESULTS\nFrom 61 patients included in this study, 36 patients were hypo-responders and 25 patients were responders. Hemorrhagic events occurred 8.0% only in responders in the acute phase (p = 0.16), and 2.78% in hypo-responders and 20.0% in responders in the delayed phase (p = 0.037). Changes in hemoglobin levels before and after the procedure were 1.22 g/dl in hypo-responders and 1.74 g/dl in responders (p = 0.032) while before the procedure and chronic stages they were 0.39 g/dl in hypo-responders and 1.39 g/dl in responders (p < 0.01). Thrombotic events were not significantly different between the two groups.\n\n\nCONCLUSIONS\nLong term use of DAPT after stent assisted coiling is related to hemorrhagic events in the delayed phase. Preventing for hemorrhagic events, the duration of DAPT should be carefully considered in clopidogrel responders.",
"affiliations": "Department of Neurosurgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu, 501-1194, Japan. sho_ken@gifu-u.ac.jp.;Department of Neurosurgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu, 501-1194, Japan.;Department of Neurosurgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu, 501-1194, Japan.;Department of Neurosurgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu, 501-1194, Japan.;Department of Neurosurgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu, 501-1194, Japan.;Department of Neurosurgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu, 501-1194, Japan.",
"authors": "Shoda|Kenji|K|http://orcid.org/0000-0003-1021-7388;Enomoto|Yukiko|Y|;Egashira|Yusuke|Y|;Kinoshita|Takamasa|T|;Mizutani|Daisuke|D|;Iwama|Toru|T|",
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"fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377\nBioMed Central London\n\n2270\n10.1186/s12883-021-02270-0\nResearch Article\nLong-term complications after stent assist coiling dependent on clopidogrel response\nhttp://orcid.org/0000-0003-1021-7388\nShoda Kenji sho_ken@gifu-u.ac.jp\n\nEnomoto Yukiko\nEgashira Yusuke\nKinoshita Takamasa\nMizutani Daisuke\nIwama Toru\ngrid.256342.4 0000 0004 0370 4927 Department of Neurosurgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu 501-1194 Japan\n28 6 2021\n28 6 2021\n2021\n21 2478 1 2021\n7 6 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nDual antiplatelet therapy (DAPT) is necessary for stent assisted coiling. However, long term use of DAPT has a potential risk of hemorrhagic events. We aimed to examine the relationship between clopidogrel reactivity and complications.\n\nMethods\n\nPatients who underwent stent assisted coiling for unruptured aneurysms or previously treated aneurysms and received periprocedural DAPT in our institution between August 2011 to March 2020 were included. Platelet reactivity for clopidogrel was measured by VerifyNow assay system, and we defined the cut off value of P2Y12 Reaction Units (PRU) at 208 and classified patients as hypo-responders (PRU≧208) or responders (PRU<208). The rates of hemorrhagic and thrombotic events within 30 days (acute phase) and 30 days after the procedure (delayed phase) were compared between the two groups. Furthermore, changes in hemoglobin levels were measured before and after the procedure and at chronic stages (1 to 6 months thereafter).\n\nResults\n\nFrom 61 patients included in this study, 36 patients were hypo-responders and 25 patients were responders. Hemorrhagic events occurred 8.0% only in responders in the acute phase (p = 0.16), and 2.78% in hypo-responders and 20.0% in responders in the delayed phase (p = 0.037). Changes in hemoglobin levels before and after the procedure were 1.22 g/dl in hypo-responders and 1.74 g/dl in responders (p = 0.032) while before the procedure and chronic stages they were 0.39 g/dl in hypo-responders and 1.39 g/dl in responders (p < 0.01). Thrombotic events were not significantly different between the two groups.\n\nConclusion\n\nLong term use of DAPT after stent assisted coiling is related to hemorrhagic events in the delayed phase. Preventing for hemorrhagic events, the duration of DAPT should be carefully considered in clopidogrel responders.\n\nKeywords\n\nDual antiplatelet therapy\nStent assisted coiling\nHemorrhagic events\nChronic phase\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nIn the treatment of intracranial aneurysms, adjunctive techniques such as the balloon assist technique or stent assisted coiling are not only effective for wide-necked aneurysms but also decrease recurrence rates. Periprocedural dual antiplatelet therapy (DAPT) is necessary to reduce increasing thrombotic complications as the procedure complexity augments [1–3]. However, the duration of DAPT varied greatly among previous studies, and an optimal duration remains unknown [4–6], despite long-term DAPT use having a potential risk for hemorrhagic events. Before the procedure, measuring platelet reactivity is recommended, since platelet reactivity shows a high level of interindividual variability, particularly in the case of clopidogrel, which must be converted to a biologically active metabolite by cytochrome P450 enzymes (CYP) [7].\n\nThis study aimed to clarify the relationship between clopidogrel responses and complications. We measured platelet aggregation activity using VerifyNow (Accumetrics, San Diego, CA, USA) and investigated its association to clopidogrel responses and the occurrence of hemorrhagic and thrombotic events within 30 days of stent assisted coiling and 30 days after stent assisted coiling.\n\nMethods\n\nStudy population\n\nThere were 77 aneurysms treated with stent assisted coiling for unruptured intracranial aneurysms (n = 67) and previously treated aneurysms (n = 10) using DAPT from August 2011 to March 2020 at our institution. Whole blood samples were obtained from patients at the time of the initial femoral artery puncture to measure platelet reactivity by VerifyNow. Patients who could not be measured platelet aggregation activity measurements by VerifyNow before the procedure (n = 9), and those who discontinued DAPT at least 1 month after the procedure (n = 7) were excluded. According to American College of Cardiology Foundation (ACCF)/ American Heart Association (AHA) 2011 guidelines [8], we defined the cut off value of P2Y12 Reaction Units (PRU) at 208, and classified patients as hypo-responders (PRU≧208) or responders (PRU<208). We investigated hemorrhagic and thrombotic events within 30 days after the procedure (acute phase) and between one to 6 months after the procedure (delayed phase). Hemorrhagic events were defined as major bleeding events by the International Society of Thrombosis and Hemostasis [9], and thrombotic events were defined as symptomatic hyperintensity lesions on diffusion weighted imaging or transit ischemic attacks. In addition, we tracked changes in hemoglobin (Hb) levels from prior to the procedure to right afterwards and in chronic stages (time of hemorrhagic event or latest visit under DAPT treatment in the delayed phase). Demographic and clinical data collected included age, sex, smoking history, previously treated aneurysms, and the presence of comorbid hypertension, hyperlipidemia, diabetes mellitus, or chronic renal failure. This study was approved by the ethics committee of Gifu University Graduate School of Medicine (No. 2019–184). Due to the retrospective nature of the study, the need for informed written consent was waived by the ethics committee of Gifu University Graduate School of Medicine.\n\nAntiplatelet therapy\n\nAntiplatelet drugs were started 7 days before the procedure, and these usually included clopidogrel 75 mg and aspirin 100 mg. On the morning of the procedure day, we measured platelet reactivity by Light Transmittance Aggregometry. And just before the procedure, final platelet reactivity was measured by VerifyNow. After inserting the sheath, we injected heparin aiming for an activated clotting time of 250–300 s. After the procedure, we initiated continuous intravenous administration of 10,000 units of heparin for 2 days. Six months after the procedure, we moved from DAPT to single antiplatelet therapy. However, if hemorrhagic events occurred, DAPT was discontinued from 1 to 3 months.\n\nStatistical analysis\n\nAll statistical analyses were performed using commercially available software (JUMP 14; SAS Institute, Cary, NC, USA). The student’s t-test was used for comparisons with continuous variables and the Fisher exact test for comparisons with categorical variables. Significant differences were defined as a P value p < 0.05.\n\nResult\n\nSixty-one patients were enrolled in this study. Of those, 36 were hypo-responders (mean PRU 262.4 ± 44.1) while 25 were responders (mean PRU 141.4 ± 42.3). Regarding changes in Hb levels, 14 patients did not have a blood test in our hospital during the chronic phase, therefore 47 patients were evaluated. (hypo-responders: n = 26, responders: n = 21) Demographic and clinical data and are shown in Table 1. There are no significant differences between the two groups. There were 21 Enterprise, 10 Neuroform, and 30 LVIS stents used in this study. The rate of hemorrhagic events in the acute phase was not significantly different between the two groups (p = 0.16) (Fig. 1A, Table 2). Two patients in the responders group suffered from gastrointestinal hemorrhage. Furthermore, hemorrhagic events in the delayed phase were more frequently observed in responders (p = 0.037) (Fig. 1A, Table 3). Thrombotic events occurred in two patients (5.6%) in the hypo-responders group and three patients (12.0%) in the responders group during the acute phase (p = 0.39) (Fig. 1B). Thrombotic events in the delayed phase occurred one patient in the hypo-responders group (Fig. 1B), and one patient in the hypo-responders group showed stent stenosis by follow up angiography 6 months after the procedure. The difference in Hb levels from before to after the procedure was higher in responders than in hypo-responders (1.74 g/dl vs 1.22 g/dl, p = 0.032), as was the change in Hb levels from before the procedure and the chronic stage (1.39 g/dl vs 0.39 g/dl, p < 0.01) (Fig. 1C, Table 4). Patients who were changed earlier to single antiplatelet therapy due to hemorrhagic events did not develop neither hemorrhagic nor thrombotic events in the delayed phase. Table 1 Baseline demographics\n\n\tHypo-responders (n = 36)\tResponders (n = 25)\tp value\t\nAge (years)\t62.4 ± 2.24\t62.6 ± 2.38\t0.97\t\nMale sex (%)\t10 (27.8)\t7 (28.0)\t1\t\nPRU\t262.4 ± 7.36\t142.1 ± 8.59\t< 0.01\t\nARU\t489.1 ± 11.7\t482.5 ± 16.1\t0.73\t\nBody mass index\t22.5 ± 0.61\t22.3 ± 0.61\t0.85\t\nSmoking (%)\t9 (25.0)\t6 (24.0)\t1\t\nPreviously treated aneurysms (%)\t5 (13.9)\t5 (20.0)\t0.73\t\nBlood sample\t\n Hb (mg/dl)\t13.1 ± 0.22\t13.5 ± 0.29\t0.31\t\n Platelet (104/μL)\t21.9 ± 0.99\t24.8 ± 1.27\t0.08\t\n PT-INR\t0.94 ± 0.01\t0.92 ± 0.01\t0.42\t\ncomorbidities\t\n Hypertension (%)\t19 (52.8)\t20 (76.0)\t0.11\t\n Diabetes mellitus (%)\t0\t2 (8.0)\t0.16\t\n Hyperlipidemia (%)\t15 (41.7)\t17 (64.0)\t0.12\t\n Chronic renal failure (%)\t5 (13.89)\t3 (12.0)\t1\t\nContinuous variables are presented as average (mean ± SE). Categorical variables are presented as number of patients (percentage). PRU P2Y12 Reaction Units; ARU Aspirin Reaction Units; Hb Hemoglobin; PT-INR prothrombin time international normalized ratio\n\nFig. 1 A shows the percentage of hemorrhagic events in the acute phase and the delayed phase, and B shows thrombotic events (hypo-responders: n = 36, responders: n = 25). C shows average changes of hemoglobin levels before the procedure to after and before the procedure to the chronic stage (hypo-responders: n = 26, responders: n = 21). Each column and bar represent the mean ± SE. All of them compared hypo-responders and responders. * = p < 0.05 by student’s t-test\n\nTable 2 Complications after stent assist coiling during the acute and delayed phases\n\nEvents\t\tHypo-responders (n = 36)\tResponders (n = 25)\tp value\t\nHemorrhagic events\tAcute phase\t0\t2 (8.0%)\t0.16\t\n\tDelayed phase\t1 (2.8%)\t5 (20.0%)\t0.037\t\nThrombotic events\tAcute phase\t2 (5.6%)\t3 (12.0%)\t0.39\t\n\tDelayed phase\t0\t1 (4.0%)\t0.41\t\n\nTable 3 Hemorrhagic events in the delayed phase\n\nCase\tPRU\tResponse\tHemorrhagic event\tHb change (g/dl)\tAfter the procedure\t\n1\t296\tHypo-responder\tGastrointestinal bleeding\t5\t2 months\t\n2\t94\tResponder\tHematuria\t2.2\t4 months\t\n3\t123\tResponder\tGastrointestinal bleeding\t2.2\t3 months\t\n4\t175\tResponder\tIntracranial hemorrhage\t4.5\t2 months\t\n5\t197\tResponder\tGenital bleeding\t3.5\t1 month\t\n6\t206\tResponder\tHemorrhagic infarction\t2.3\t2 months\t\nPRU P2Y12 Reaction Units; Hb hemoglobin\n\nTable 4 Hb change from before until after the procedure and the chronic stage\n\nHb change\tHypo-responders (n = 26)\tResponders (n = 21)\tp value\t\nBefore to after the procedure (g/dl)\t1.22 ± 0.15\t1.74 ± 0.18\t0.032\t\nBefore to chronic stage (g/dl)\t0.39 ± 0.24\t1.39 ± 0.28\t< 0.01\t\nContinuous variables are presented as average (mean ± SE). Hb hemoglobin.1\n\nDiscussion\n\nIn our study, there was no difference in the incidence of thrombotic events between the two groups, although responders had hemorrhagic events at a significantly higher rate. In interventions for coronary arteries, the AHA/ American Stroke Association (ASA) guideline recommends patients to continue DAPT including P2Y12 inhibitors after stenting [10], and in the neuroendovascular treatment area, antiplatelet drugs are also employed for preventing thrombotic complications. However, the optimal duration of DAPT after stent assist coiling is uncertain. There are some reports on the timing and risk of thrombotic events, for instance, Matsumoto et al. reported that thrombotic events after the procedure are most likely to occur within 40 days after stent assisted coiling even if patients receive DAPT [11]. Furthermore, Song et al. reported that blood vessel tortuosity and large parent vessel size lead to incomplete stent apposition, becoming a risk factor of thrombotic complications [12].\n\nClopidogrel is an antiplatelet drug of widespread application. In Japan, it is administered in approximately 80% of cases in the perioperative period of neurovascular treatments [13]. Clopidogrel is a prodrug which needs to be converted into an active metabolite by CYP. Although CYP2C19 is the major enzyme involved in this process, its genetic variants can affect individual clopidogrel responses. Therefore, measuring platelet reactivity before the procedure is relevant. There are some methods to measure platelet functions, VerifyNow being one of the major points of care platelet reactivity analysis tools and employed on large clinical trials [14, 15]. Some studies have shown an association of hyper-responders to clopidogrel hemorrhagic events while hypo-responders are associated with thrombotic events, although a clear cutoff value has not been defined for neuroendovascular treatments and this value differed among studies [16–22]. A previous report involving the use of the Pipeline indicated that the ideal PRU value for avoiding both hemorrhagic and thrombotic events was between 70 and 150 [22]. Based on the ACCF/AHA 2011 guideline [8], we defined 208 as cutoff value and investigated hemorrhagic and thrombotic events both in the acute and delayed phase. In this study, the occurrence of thrombotic events was not significantly different between the groups, although hemorrhagic events frequently occurred in responders. In addition, Hb levels decreased more from before until after the procedure and during chronic stages in responders than in hypo-responders. Despite not meeting the criteria of International Society of Thrombosis and Hemostasis for major bleeding [9], some patients complained of subcutaneous bleeding, epistaxis, or hematuria, which could be associated with low Hb levels in the chronic stage.\n\nAlthough some studies of stent assisted coiling reported an association of hemorrhagic and thrombotic events with PRU values in the acute phase [17–21], there are few studies of an association between platelet reactivity and these events in the delayed phase after stent assisted coiling. Goh et al. reported that evaluating hemorrhagic events up to 6 weeks after endovascular stenting treatment indicated that patients with > 72% PRU inhibition had more major bleeding than those with PRU < 72% [23]. Song et al. also referred to an association between clopidogrel response and thrombotic events in the delayed phase [21]. These authors reported that thrombotic events, symptomatic and asymptomatic ischemic stroke with positive findings on brain MRI in the territory of the treated aneurysm, or a transient ischemic attack more than 30 days after stent assisted coiling were not significantly correlated with PRU values. In agreement with this finding, our study showed a relationship between PRU values and hemorrhagic events, but not thrombotic events, in the delayed phase. Consequently, PRU appears to be more associated with hemorrhagic events in the delayed phase.\n\nA previous study on DAPT duration in other treatment areas, reported that long-term DAPT use after ischemic stroke or after previous transient ischemic attacks increased the risk of major to life-threatening bleeding [24]. In addition, a recent study showed that, among patients undergoing coronary stents, 1 month of DAPT followed by clopidogrel single antiplatelet therapy resulted in a significantly lower rate of a composite of cardiovascular and bleeding events compared to 12 months of DAPT with clopidogrel and aspirin. Thus, a shorter DAPT duration after stenting may be more beneficial compared to long-term DAPT [25]. Even in cases of hemorrhagic events where DAPT was changed to single antiplatelet therapy 1 to 3 months before usual, there were no thrombotic events. Patients treated for aneurysm with neuro interventions are usually younger and thus, have fewer arteriosclerosis risk factors compared to patients treated with cerebrovascular or coronary revascularization [21], maybe reducing the risk of thrombotic events [23].\n\nIn our study, we found that clopidogrel responders had an increased risk of hemorrhagic events in the delayed phase, and PRU is useful for the prediction of hemorrhagic events. Although DAPT is necessary for thrombotic event prevention, hemorrhagic risk and DAPT duration should be carefully considered in clopidogrel responders. Further studies are needed to determine the ideal duration of DAPT administration.\n\nLimitations\n\nThere are several limitations to this study. First, this study is retrospective in nature, and hence subjected to potential confounding effects and bias. Second, we evaluated only 61 cases for postoperative complications. Therefore, it is quite possible that the statistical power of this study is insufficient to detect small differences. Third, it is known that clopidogrel response may be delayed conversion to clopidogrel hyper response [26]. We measured PRU only during the preoperative period, and thus, our evaluation may not be accurate.\n\nConclusion\n\nOur study demonstrates that long-term DAPT use after stent assisted coiling can lead to hemorrhagic events. Both hemorrhagic events in the delayed phase and decreased hemoglobin levels are associated with clopidogrel responses. Further, we showed that thrombotic events are not associated with PRU. DAPT duration should be carefully considered in clopidogrel responders.\n\nAbbreviations\n\nDAPT Dual antiplatelet therapy\n\nPRU P2Y12 reaction units\n\nCYP Cytochrome P450 enzymes\n\nACCF American College of Cardiology Foundation\n\nAHA American Heart Association\n\nHb Hemoglobin\n\nASA American Stroke Association\n\nARU Aspirin reaction unit\n\nPT-INR Prothrombin time international normalized ratio\n\nAPTT Activated partial thromboplastin time\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [KS], [YE1], [YE2], [TK] [DM] and [TI]. The first draft of the manuscript was written by [KS] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nNot applicable.\n\nAvailability of data and materials\n\nThe datasets during the current study available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthical approval and consent to participate\n\nThis study was approved by the ethics committee of Gifu University Graduate School of Medicine (No. 2019–184). Due to the retrospective nature of the study, the need for informed written consent was waived by the ethics committee of Gifu University Graduate School of Medicine.\n\nConsent for publication\n\nNot applicable.\n\nCompeting interests\n\nThe authors declare that they have no competing interest.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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Rossen JD Chalouhi N Wassef SN Thomas J Abel TJ Jabbour PM Kung DK Hasan DM Incidence of cerebral ischemic events after discontinuation of clopidogrel in patients with intracranial aneurysms treated with stent-assisted techniques J Neurosurg 2012 117 5 929 933 10.3171/2012.8.JNS12185 22957528\n5. Kim T Kim CH Kang SH Relevance of antiplatelet therapy duration after stent-assisted coil embolization for Unruptured intracranial aneurysms World Neurosurg 2018 116 699 708 10.1016/j.wneu.2018.05.071\n6. Hwang G Kim JG Song KS Lee YJ Villavicencio JB Suroto NS Park NM Park SJ Jeong EA Kwon OK Delayed ischemic stroke after stent-assisted coil placement in cerebral aneurysm: characteristics and optimal duration of preventative dual antiplatelet therapy Radiology 2014 273 1 194 201 10.1148/radiol.14140070 24918960\n7. Hulot JS Bura A Villard E Azizi M Remones V Goyenvalle C Aiach M Lechat P Gaussem P P450 2C19 loss-of-function polymorphism is a major determinant of Clopidogrel responsiveness in healthy subjects Blood 2006 108 2244 2247 10.1182/blood-2006-04-013052 16772608\n8. Wright RS Anderson JL Adams CD 2011 ACCF/AHA focused update of the Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons J Am Coll Cardiol 2011 57 19 1920 1959 10.1016/j.jacc.2011.02.009 21450428\n9. Schulman S Kearon C Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients J Thromb Haemost 2005 3 4 692 694 10.1111/j.1538-7836.2005.01204.x 15842354\n10. Levine GN Bates ER Bittl JA 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/ PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery Circulation 2016 134 123 155 10.1161/CIR.0000000000000404\n11. Matsumoto Y Nakai K Tsutsumi M Iko M Nii K Narita S Eto A Mitsutake T Aikawa H Kazekawa K Onset time of ischemic events and antiplatelet therapy after intracranial stent-assisted coil embolization J Stroke Cerebrovasc Dis 2014 23 4 771 777 10.1016/j.jstrokecerebrovasdis.2013.07.008 23954608\n12. Song J Yeon JY Kim JS Hong SC Kim KH Jeon P Delayed thromboembolic events more than 30 days after self-expandable intracranial stent-assisted embolization of unruptured intracranial aneurysms Clin Neurol Neurosurg 2015 135 73 78 10.1016/j.clineuro.2015.05.013 26038280\n13. Enomoto Y Mizutani D Yoshimura S Changing Paradigms of Periprocedural Antithrombotic Therapy in Neuroendovascular Therapy. Analysis of JR-NET 3 Neurol Med Chir (Tokyo) 2019 59 247 256 10.2176/nmc.st.2018-0265 31068546\n14. Stone GW Witzenbichler B Weisz G Rinaldi MJ Neumann FJ Metzger DC Henry TD Cox DA Duffy PL Mazzaferri E Gurbel PA Xu K Parise H Kirtane AJ Brodie BR Mehran R Stuckey TD Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study Lancet. 2013 382 9892 614 623 10.1016/S0140-6736(13)61170-8 23890998\n15. Price MJ Berger PB Teirstein PS Tanguay JF Angiolillo DJ Spriggs D Puri S Robbins M Garratt KN Bertrand OF Stillabower ME Aragon JR Kandzari DE Stinis CT Lee MS Manoukian SV Cannon CP Schork NJ Topol EJ GRAVITAS Investigators Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial JAMA 2011 305 11 1097 1105 10.1001/jama.2011.290 21406646\n16. Fifi JT Brockington C Narang J Clopidogrel resistance is associated with thromboembolic complications in patients undergoing neurovascular stenting AJNR Am J Neuroradiol 2013 34 721 726 10.3174/ajnr.A3405 23275598\n17. Kim HJ Oh JS Park SQ The efficacy of P2Y12 reactive unit to predict the Periprocedural thromboembolic and hemorrhagic complications according to Clopidogrel responsiveness and safety of modification of dual antiplatelet therapy: a meta-analysis J Korean Neurosurg Soc 2019 63 539 549 10.3340/jkns.2019.0082 31661948\n18. Asai T Miyachi S Izumi T Matsubara N Haraguchi K Yamanouchi T Ota K Shintai K Tajima H Wakabayashi T Relationship between low response to clopidogrel and periprocedural ischemic events with coil embolization for intracranial aneurysms J Neurointerv Surg 2016 8 7 752 755 10.1136/neurintsurg-2015-011727 26109688\n19. Kashiwazaki D Kuwayama N Akioka N Hayakawa Y Kuroda S The roles and issues of P2Y12 percent inhibition assessed by VerifyNow assay for patients undergoing Neurointervention: a prospective study J Stroke Cerebrovasc Dis 2014 23 7 1830 1836 10.1016/j.jstrokecerebrovasdis.2014.04.014 24957307\n20. Kim MS Park ES Park JB Lyo IU Sim HB Kwon SC Clopidogrel response variability in Unruptured intracranial aneurysm patients treated with stent-assisted endovascular coil embolization: is follow-up Clopidogrel response test necessary? J Korean Neurosurg Soc. 2018 61 2 201 211 10.3340/jkns.2017.0303.009 29526063\n21. Song J Shin YS Antiplatelet drug resistance did not increase the thromboembolic events after stent-assisted coiling of unruptured intracranial aneurysm: a single center experience of 99 cases Neurol Sci 2017 38 5 879 s885 10.1007/s10072-017-2859-z 28233076\n22. Daou B Starke RM Chalouhi N Barros G Tjoumakaris S Rosenwasser RH Jabbour P P2Y12 reaction units: effect on hemorrhagic and thromboembolic complications in patients with cerebral aneurysms treated with the pipeline embolization device Neurosurgery. 2016 78 1 27 33 10.1227/NEU.0000000000000978 26571145\n23. Goh C Churilov L Mitchell P Dowling R Yan B Clopidogrel hyper-response and bleeding risk in Neurointerventional procedures AJNR Am J Neuroradiol 2013 34 4 721 726 10.3174/ajnr.A3418 23275598\n24. Diener HC Bogousslavsky J Brass LM Cimminiello C Csiba L Kaste M Leys D Matias-Guiu J Rupprecht HJ Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial Lancet. 2004 364 9431 331 337 10.1016/S0140-6736(04)16721-4 15276392\n25. Watanabe H Domei T Morimoto T Natsuaki M Shiomi H Toyota T Ohya M Suwa S Takagi K Nanasato M Hata Y Yagi M Suematsu N Yokomatsu T Takamisawa I Doi M Noda T Okayama H Seino Y Tada T Sakamoto H Hibi K Abe M Kawai K Nakao K Ando K Tanabe K Ikari Y Hanaoka KI Morino Y Kozuma K Kadota K Furukawa Y Nakagawa Y Kimura T for the STOPDAPT-2 Investigators Effect of 1-month dual antiplatelet therapy followed by Clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving PCI. The STOPDAPT-2 randomized clinical trial JAMA 2019 321 24 2414 2427 10.1001/jama.2019.8145 31237644\n26. Delgado Almandoz JE Kadkhodayan Y Crandall BM Scholz JM Fease JL Tubman DE Variability in initial response to standard clopidogrel therapy, delayed conversion to clopidogrel hyper-response, and associated thromboembolic and hemorrhagic complications in patients undergoing endovascular treatment of unruptured cerebral aneurysms J Neurointerv Surg. 2014 6 10 767 773 10.1136/neurintsurg-2013-010976 24353331\n\n",
"fulltext_license": "CC BY",
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"issue": "21(1)",
"journal": "BMC neurology",
"keywords": "Chronic phase; Dual antiplatelet therapy; Hemorrhagic events; Stent assisted coiling",
"medline_ta": "BMC Neurol",
"mesh_terms": "D001792:Blood Platelets; D000077144:Clopidogrel; D006470:Hemorrhage; D006801:Humans; D010975:Platelet Aggregation Inhibitors; D015607:Stents",
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"title": "Long-term complications after stent assist coiling dependent on clopidogrel response.",
"title_normalized": "long term complications after stent assist coiling dependent on clopidogrel response"
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"abstract": "Sinusoidal obstruction syndrome (SOS) is one of the severe complications of hematopoietic stem cell transplantation (HSCT). Systemic management including respiratory and circulatory support is necessary. In addition, abdominal paracentesis is often needed for pain relief and to reduce the pressure of tense ascites. Concentrated ascites reinfusion therapy (CART) involves the filtration, concentration, and reinfusion of drained ascites, which contributes to reuse of autologous proteins. CART has been reported as supportive therapy for patients with liver cirrhosis and cancer. We retrospectively reviewed the efficacy and safety of CART in three patients (two with acute myelogenous leukemia and one with chronic myeloid leukemia) who developed SOS after allo-HSCT. They all had symptomatic, tense, and diuretic-refractory ascites with right costal pain and marked weight gain. Two patients showed immediate improvement after CART. However, one patient experienced four CARTs with slow recovery. All patients are now alive and are being monitored as outpatients over 2 years with remission. No severe adverse event was observed related to CART, and 25.2-98.0 (median 30.2) grams of albumin was collected and reinfused. CART after paracentesis reduces protein loss in ascites by reinfusion of autologous protein instead of exogenous albumin preparations. Although transient fever is reported as a frequent adverse event, no events like severe bleeding or infection were observed. While its safety has not been fully established in patients with hematological disease after HSCT, CART may be a considerable supportive therapy for SOS with tense ascites.",
"affiliations": "Department of Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan.",
"authors": "Takahashi|Hiroyuki|H|;Sakai|Rika|R|;Fujita|Atsuko|A|;Kuwabara|Hideyuki|H|;Hattori|Yukako|Y|;Matsuura|Shiro|S|;Ohshima|Rika|R|;Hagihara|Maki|M|;Tomita|Naoto|N|;Ishigatsubo|Yoshiaki|Y|;Fujisawa|Shin|S|",
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"issue": "37(10)",
"journal": "Artificial organs",
"keywords": "Ascites; Concentrated ascites reinfusion therapy; Hematopoietic stem cell transplantation; Sinusoidal obstruction syndrome",
"medline_ta": "Artif Organs",
"mesh_terms": "D000328:Adult; D001201:Ascites; D005260:Female; D005374:Filtration; D018380:Hematopoietic Stem Cell Transplantation; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D008297:Male; D055815:Young Adult",
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"publication_types": "D016428:Journal Article",
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"title": "Concentrated ascites reinfusion therapy for sinusoidal obstructive syndrome after hematopoietic stem cell transplantation.",
"title_normalized": "concentrated ascites reinfusion therapy for sinusoidal obstructive syndrome after hematopoietic stem cell transplantation"
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"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-339873",
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{
"abstract": "A 75-year-old woman developed a frontal lobe disorder a few days after the diagnostic of an Acute Myeloid Leukemia secondary to a myelodysplastic syndrome. The patterns on the cerebral Magnetic Resonance Imaging and positron emission tomography and the find of antiglutamic acid decarboxylase antibody on cerebral spinal fluid were in favor of a paraneoplastic limbic encephalitis. In cerebral spinal fluid, there were no micro-organisms nor leukemic cells. We found no sign of cancer on full body computerized tomography-scan, on full-body PET and on rectosigmoidoscopy. The patient was treated by corticosteroid and intravenous immunoglobulins with success, but she died before receiving chemotherapy. It's known that anti- glutamic acid decarboxylase antibody is involved in paraneoplastic syndromes. Paraneoplastic limbic encephalitis is frequently associated with carcinoma or Hodgkin's lymphoma, but it was only reported associated with Acute Myeloid Leukemia in one case report. Even if Acute Myeloid Leukemia is not frequently associated with paraneoplastic limbic encephalitis, the clinicians must consider paraneoplastic limbic encephalitis as an etiology of unexplained neurological disorders.",
"affiliations": "La Timone, Internal Medicine Department, University Hospital of Marseille, France. Electronic address: robin.arcani@ap-hm.fr.;La Timone, Internal Medicine Department, University Hospital of Marseille, France.;La Timone, Internal Medicine Department, University Hospital of Marseille, France.;La Timone, Internal Medicine Department, University Hospital of Marseille, France.;La Conception, Hematology and Cellular Therapy Department, University Hospital of Marseille, France.;La Timone, Internal Medicine Department, University Hospital of Marseille, France.",
"authors": "Arcani|Robin|R|;Jean|Estelle|E|;Pozzo Di Borgo|Jacques|J|;Lamarchi|Jean-François|JF|;Venton|Geoffroy|G|;Veit|Véronique|V|",
"chemical_list": "D001323:Autoantibodies; D005968:Glutamate Decarboxylase",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.clineuro.2019.105618",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-8467",
"issue": "189()",
"journal": "Clinical neurology and neurosurgery",
"keywords": "Acute Myeloid Leukemia; Autoantibody; Limbic encephalitis; Paraneoplastic syndrome",
"medline_ta": "Clin Neurol Neurosurg",
"mesh_terms": "D000368:Aged; D001323:Autoantibodies; D005260:Female; D005968:Glutamate Decarboxylase; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D020363:Limbic Encephalitis; D008279:Magnetic Resonance Imaging; D049268:Positron-Emission Tomography",
"nlm_unique_id": "7502039",
"other_id": null,
"pages": "105618",
"pmc": null,
"pmid": "31786428",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Anti-glutamic acid decarboxylase antibody paraneoplastic limbic encephalitis associated with Acute Myeloid Leukemia.",
"title_normalized": "anti glutamic acid decarboxylase antibody paraneoplastic limbic encephalitis associated with acute myeloid leukemia"
} | [
{
"companynumb": "FR-SA-2019SA345960",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": "3",
"dru... |
{
"abstract": "We report 2 cases of refractory reverse amblyopia that developed after instillation of 1-4 drops of atropine. Risk factors appear to include age <4, large-angle esotropia, and lack of adherence to spectacle wear.",
"affiliations": "Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.;Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.;Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.;Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: david.hunter@childrens.harvard.edu.",
"authors": "Elhusseiny|Abdelrahman M|AM|;Wu|Carolyn|C|;MacKinnon|Sarah|S|;Hunter|David G|DG|",
"chemical_list": "D009184:Mydriatics; D001285:Atropine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaapos.2019.12.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1091-8531",
"issue": "24(2)",
"journal": "Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus",
"keywords": null,
"medline_ta": "J AAPOS",
"mesh_terms": "D000550:Amblyopia; D001285:Atropine; D004948:Esotropia; D006801:Humans; D009184:Mydriatics; D014792:Visual Acuity",
"nlm_unique_id": "9710011",
"other_id": null,
"pages": "106-108",
"pmc": null,
"pmid": "31953022",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Severe reverse amblyopia with atropine penalization.",
"title_normalized": "severe reverse amblyopia with atropine penalization"
} | [
{
"companynumb": "US-BAUSCH-BL-2020-028163",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATROPINE"
},
"drugadditional": "1",
... |
{
"abstract": "Severe and enduring eating disorders (EDs) have the highest mortality rate of all psychiatric illnesses (Arch Gen Psychiatry, 2011, 68, 724), especially when comorbid with treatment-resistant depression (TRD) (Psychiatr Res, 2016, 244, 45). We report on four patients with enduring EDs and TRD treated with repeat ketamine over 12 + months, showing improvement in depression with only modest changes in ED symptoms.",
"affiliations": "Department of Psychiatry University of California San Diego San Diego CA USA.;Department of Psychiatry University of California San Diego San Diego CA USA.;Department of Psychiatry University of California San Diego San Diego CA USA.;Department of Psychiatry University of California San Diego San Diego CA USA.;Department of Psychiatry University of California San Diego San Diego CA USA.;Department of Psychiatry University of California San Diego San Diego CA USA.;Department of Psychiatry University of California San Diego San Diego CA USA.",
"authors": "Schwartz|Terry|T|https://orcid.org/0000-0003-0056-7851;Trunko|Mary Ellen|ME|;Feifel|David|D|;Lopez|Emily|E|;Peterson|Danika|D|;Frank|Guido K W|GKW|https://orcid.org/0000-0002-6590-3441;Kaye|Walter|W|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.3869",
"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/ccr3.3869\nCCR33869\nCase Report\nCase Reports\nA longitudinal case series of IM ketamine for patients with severe and enduring eating disorders and comorbid treatment‐resistant depression\nSCHWARTZ et al.\nSchwartz Terry https://orcid.org/0000-0003-0056-7851\n1 taschwartz@ucsd.edu\n\nTrunko Mary Ellen 1\nFeifel David 1\nLopez Emily 1\nPeterson Danika 1\nFrank Guido K. W. https://orcid.org/0000-0002-6590-3441\n1\nKaye Walter 1\n1 Department of Psychiatry University of California San Diego San Diego CA USA\n* Correspondence\nTerry Schwartz, University of California San Diego, 4510 Executive Drive, Suite 315, 92121 San Diego, CA, USA.\nEmail: taschwartz@ucsd.edu\n\n04 4 2021\n5 2021\n9 5 10.1002/ccr3.v9.5 e0386928 9 2020\n04 1 2020\n12 10 2020\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\nSevere and enduring eating disorders (EDs) have the highest mortality rate of all psychiatric illnesses (Arch Gen Psychiatry, 2011, 68, 724), especially when comorbid with treatment‐resistant depression (TRD) (Psychiatr Res, 2016, 244, 45). We report on four patients with enduring EDs and TRD treated with repeat ketamine over 12 + months, showing improvement in depression with only modest changes in ED symptoms.\n\nSevere and enduring eating disorders (EDs) have the highest mortality rate of all psychiatric illnesses, especially when comorbid with treatment‐resistant depression (TRD). We report on four patients with enduring EDs and TRD treated with repeat ketamine over 12 + months, showing improvement in depression with only modest changes in ED symptoms.\n\ndepression\neating disorders\nketamine\ntreatment\nsource-schema-version-number2.0\ncover-dateMay 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:13.05.2021\nSchwartz T , Trunko ME , Feifel D , et al. A longitudinal case series of IM ketamine for patients with severe and enduring eating disorders and comorbid treatment‐resistant depression. Clin Case Rep. 2021;9 :e03869. 10.1002/ccr3.3869\n==== Body\n1 INTRODUCTION\n\nEating disorders (ED) have high comorbidity rates with mood and anxiety disorders. 1 , 2 Such comorbidity adversely impacts engagement in treatment and worsens outcomes for patients with EDs. Specifically, a lifetime diagnosis of major depressive disorder (MDD) is a negative predictor of BMI and recovery in AN. 2\n\nThere is a growing literature, supporting the use of Ketamine for severe treatment‐resistant depression (TRD) 3 and associated suicidality. TRD has varied definitions, but generally refers to patients with MDD who have failed several trials of monotherapy antidepressants (and often failed multiple augmentation strategies). Controlled trials of Ketamine for treatment of TRD have consistently shown rapid and effective response with IV infusion of Ketamine. 4 , 5 Both the robust and the rapid time frame of response (24‐48 hours) have exciting potential for severely depressed patients, at least in the short term. Additionally, case reports of repeat IV Ketamine at variable intervals (weeks to months) for maintenance have preliminary evidence of relative safety and efficacy out to 1 year. 6\n\nIt is not known whether ketamine could be helpful for the treatment of ED symptomatology or whether reduction of depressive symptomatology could mediate improvement of EDs. To our knowledge, there has been only one previous study using ketamine to treat patients with EDs. 7 That case series included underweight and normal‐weight individuals with AN or BN. The effect of ketamine infusion on weight was inconclusive but, in the responders (60%), depression scores improved and measures for compulsive behaviors improved. Therefore, the effectiveness of ketamine in EDs has not been sufficiently studied. We selected patients with EDs who had a very long‐standing TRD as well as severe and enduring ED illness. 8 Our aim was to determine whether ketamine would improve depression in EDs and, also improve ED symptom severity.\n\n2 METHODS\n\nWe selected four female patients who had been chronically ill with an eating disorder for more than 7 years duration. All patients had completed an eating disorder PHP in the previous 6 months, and were having ongoing significant eating disorder and mood symptoms. All patients were in standard outpatient treatment for the bulk of the data collected, with the exception being case 4, who was completing the final few weeks of 3 day IOP program after first ketamine treatment. In addition, subjects met current criterial for treatment‐resistant depression (TRD) without psychotic features. Each had previously failed more than four trials of antidepressant medications of adequate dose and duration. Subjects met DSM‐5 criteria for Major Depressive Episode and an Eating Disorder 9 by clinical interview by 2 senior psychiatrists and moderate or severe level of depression was confirmed by scores on the Beck Depression Inventory‐I ( BDI) 10 being greater than 20. Suicidality was assessed clinically. Additionally, a response of 2 or 3 on question 9 (suicidality question) on BDI was flagged on BDI for immediate follow‐up check in with psychiatrist.\n\nSubjects completed a baseline self‐report assessment and were weighted before the injection of ketamine. These assessments include the BDI, Spielberger state‐trait anxiety inventory (STAI), 11 and Eating Disorder examination questionnaire (EDE‐Q). 12 Depression, anxiety, and ED symptoms were also longitudinally assessed by BDI, STAI, and EDE‐Q preinjection, 24 hours postinjection, 3‐ and 7‐days postinjection. This schedule of measures began after treatment 2 for case 2, and any other missing data points were related to patient not completing measures as requested. Self‐rating scales were used for clinician and patient convenience. Time between follow‐up injections was based (primarily) on individual patient's time frame in which they started to relapse in depression symptoms. Patients were also asked for narrative descriptions of their symptoms and function throughout the treatment course.\n\nAs per previously published guidelines, 4 patients deemed appropriate for a trial of ketamine treatment were provided with relevant information about the treatment, including the fact that the treatment was not currently FDA approved and not reimbursed by insurance. Patients were provided with a written informed consent document for treatment which described potential risks and limitations in detail as well as reasonable expectations of ketamine treatment for depression. Patients were given an opportunity to ask questions which were addressed by the prescribing physicians.\n\nAn experienced Ketamine physician (DF) and RN were in the room, and monitoring patient mental status and vitals signs, per UC San Diego Hospital protocol. Ketamine was administered mainly IM, with the first 2‐3 doses administered IV for cases 3 and 4. IM Ketamine has similar data to support equivalent dosing, efficacy, and safety as with IV Ketamine. 13 IM was used given the convenience of IM over IV dosing. IV dosing requires op room and presence of an anesthesiologist. IM, given slower rates of absorption, can be administered by an MD, without an anesthesiologist present. Of note, in cases 3 and 4, the first several treatments were IV and done with an anesthesiologist present.\n\nThe standard dosing of 0.5 mg/kg was the initial dose. Subsequent doses were titrated to response, side effects, and safety. 14 Some of our cases had an additional injection of 0.3‐0.4 mg/kg to alternate deltoid 24 hours after the first dose, if previous dose of 0.5 mg/kg was well tolerated, but, only partially effective, or ineffective. Patients remained on all their previous medications. Ketamine dose and frequency were determined by clinical status, magnitude, and duration of previous dose response, and safety/side effects. Safety was maintained by monitoring vital signs, side effects, cognitive/psychiatric status, and physical symptoms for approximately 2‐3 hours after injection. The main side effect was the classic ketamine dissociative “trip “that lasted 30‐90 minutes, post‐treatment sleepiness, and occasional mild headache. The patients were then sent home with a preplanned relative or friend driver. There were no vital sign abnormalities.\n\n3 RESULTS\n\n3.1 Case 1: history\n\nA 49‐year‐old single white female with chronic restricting type AN (AN‐R), TRD, and post‐traumatic stress disorder (PTSD). She had been severely depressed for the past 10 years Figure 1, Table 1. She had failed 9 adequate antidepressant trials, including combination therapies with several augmenting agents. She also failed a full course of rTMS (Transcranial Magnetic Stimulation). She had chronic suicidality and was socially isolated. In addition, she failed multiple eating disorder programs including residential, partial hospital, and outpatient levels of care. Her BMI at the time of initial Ketamine treatment was 19. Her medications during Ketamine treatment were as follows: aripiprazole 10 mg and fluoxetine 40 mg. She was in weekly therapy, seeing a dietician monthly, and a psychiatrist monthly for the duration of the trial.\n\nFIGURE 1 Beck depression inventory‐I vs days from initial dose. Cases 1‐4, respectively. Orange dots = ketamine administration day. Blue dots BDI measurement (y‐axis) and day (x‐axis). Days with both Blue and Orange dots depict the preadministration BDI\n\nTABLE 1 Summary of BMI, and qualitative changes in STAI‐state and EDE‐Q eatcon/restraint results\n\nCase\tAge\tED\tOther diagnosis'\tBMI initial\tBMI final\tSTAI‐state\tEDE‐Q control/restraint\t\n1\t49\tAN‐R\tBipolar II‐depressed, PTSD\t19\t22.6\tImproved, partial sustained\tVaried, slight decrease\t\n2\t30\tAN‐R\tMDD\t17.5\t22.2\tImproved, sustained\tImproved, sustained\t\n3\t33\tEDNOS‐BP\tMDD\t25.2\t25.8\tImproved, partial sustained\tImproved, partial sustained\t\n4\t35\tEDNOS‐BP\tMDD, BLPD/O\t37.8\t39.2\tLimited improvement, not sustained\tLimited improved, not sustained\t\nJohn Wiley & Sons, Ltd\n\n3.1.1 Ketamine dose\n\nThe IM injection dosing was adjusted to 0.4 mg/kg right deltoid and 0.4 mg/kg to the left deltoid 24 hours apart, per protocol, this was the minimal dosing to provide adequate benefit, with minimal side effects.\n\n3.1.2 Depression and anxiety\n\nThere were improvements in her mood, energy, and general well‐being within 24 hours. (see Figure 1, panel 1). She continued to get the injections every 3‐5 weeks over the next 18 months. Her BDI was initially 46. She had a rapid decrease in her BDI to the low 20s, increasing to a maximum in the mid‐twenties as time between injections increased, she continued to show a BDI response throughout her course, with no apparent tolerance or reduction in response. Her STAI‐state anxiety symptoms were reduced (from low 70s pretreatment, to low 60s range postinjections). The STAI‐trait anxiety scale remained in low to mid 70s. Her suicidality was significantly clinically reduced from “wanting to be dead” for many years, to only having occasional passive suicidal thoughts.\n\n3.1.3 ED symptoms\n\nEating disorder examination questionnaire weight and shape concern also showed improvement postinjection, with partial rebound to previous level before the next treatment. This correlated clinically with her reports that her food flexibility and obsessionality were reduced, allowing her to be more flexible in her eating. Her BMI increased over the course of treatment from 19 to 22.6.\n\n3.1.4 Impressions\n\nClinically, there was a substantial reduction in hopelessness and suicidal thoughts. She remained stable during a period of a major life stressor/loss for her. Some ED symptoms showed a mild improvement. Her weight increased, and her food variety improved. She also had improved energy, motivation, and drive, allowing her to return to the workforce, and is no longer on disability.\n\n3.2 Case 2: history\n\nA 30‐year‐old female with a chronic course of AN‐R and TRD for over 12 years, with two previous serious suicide attempts culminating in her admission to inpatient psychiatric unit in August of 2014. At the time of her hospitalization, her BMI was 17.5. She was overwhelmed by simultaneously trying to cope with her ED and TRD. She has had 10 + trials of antidepressants, combined with various augmentation strategies, with limited to no response. She was taking escitalopram 20 mg, was in weekly outpatient therapy, and saw psychiatrist every 4‐6 weeks during the trial.\n\n3.2.1 Ketamine dose\n\nInitial dosing was 0.5 mg/kg IM. This was gradually increased at subsequent treatments to two IM ketamine injection 0.5 and 0.4 mg/kg 15 minutes apart (left and right deltoid, respectively) to allow for increased magnitude and duration of mood response and minimizing side effects.\n\n3.2.2 Depression and anxiety\n\nHer BDI preketamine was 43. (Figure 1, panel 2). After 2 IM shots of 0.3 mg/kg and 0.5 mg/kg IM, 24 hours apart, her BDI was reduced to 17. Her subsequent BDIs showed clinically meaningful reduction after each injection, with a lowering of “maximum BDI” between treatments. Over time, her BDIs were frequently below 10. Her response did not diminish over time. After ketamine was stopped, she maintained stability of mood. She did not have any relapse of her ED since starting the Ketamine, nor did her suicidality return. Her ED and anxiety symptoms showed some improvements, mostly coinciding with postinjection times. Clinically, she reported a dramatic improvement in her mood, energy, and hopefulness. She was no longer suicidal, and in fact, was hopeful about her future. Additionally, the patient noted that she experienced a significant reduction in anxiety associated with eating certain foods, including desserts. Her follow‐up outpatient Ketamine IM injections were 0.5, and 0.3 −0.4 mg/kg, to the right and left deltoid, respectively, 15‐20 minutes apart.\n\n3.2.3 ED symptoms\n\nShe has a notable reduction in the EDE‐Q “eating concerns” subscale (2.5‐1). Here, EDE‐Q restraint subscale showed a less robust improvement, though clinically her weight stabilized. Her weight remained stable at 98% of IBW, and, she began to have regular menstrual periods for the first time in 12 years. Her BMI increased from 17.5 when she was first hospitalized to 22.2 over the next year. During this time, she was also treated with Lexapro 10 mg a day.\n\n3.2.4 Impressions\n\nWhile her weight and shape concerns remained unchanged related to ketamine treatments, her “eating concerns” improved, as above. This is consistent with her reports of being more able to eat appropriately, despite the ED thoughts, with less prolonged and intense guilt afterward. Finally, her STAI‐state values also appear to follow her mood improvement. Her STAI‐Trait values remained unchanged.\n\n3.3 Case 3: history\n\nA 33‐year‐old female with Other specified feeding and eating disorders (OSFED) 9 and Major depressive disorder, recurrent as well as having affective dysregulation starting in her teenage years. She had failed 3 prior antidepressant trials. Prior to a trial of ketamine, she has presented to a treatment program with a BMI of 23.2, with AN‐like symptoms including restriction and very rigid, limited food choices. She engaged in compulsive exercise, for 3‐4 hours most mornings, and had no history of binge eating or purging by vomiting. During 4 months of PHP/IOP for her ED, the patient's depression improved significantly but she made minimal progress with ED behaviors and lost insurance coverage for the program. Following discharge, the patient experienced significant weight fluctuations. She began purging by vomiting. During the subsequent 9 months, she gained 30 lbs. (BMI = 27.8), while continuing the excessive exercise, vomiting several times daily, and restricting. The patient denied bingeing and she had begun using alcohol and frequent THC. She continued treatment with sertraline 200 mg and aripiprazole 10 mg, but depression returned. The patient was then referred for ketamine treatment. Her BMI at the time of initial Ketamine treatment was her pre‐Ketamine BMI was 25.2. She was in outpatient care during the trial, seeing a psychiatrist intermittently, and declined individual therapy.\n\n3.3.1 Dose\n\nKetamine 0.5 mg/kg IM to deltoid throughout her treatment.\n\n3.3.2 Depression and anxiety\n\nPatient had consistent reduction in BDI and STAI‐state post‐Ketamine injections. While these measures of depression and anxiety increased between doses, there was a reduction of peak (between doses) BDI and STAI‐state values.\n\n3.3.3 ED symptoms\n\nShe also had consistent reduction in all 4 EDE‐Q subscales after treatments.\n\n3.3.4 Impressions\n\nToward her final treatments, she lost her job and had a relationship break up. Her BDI, scores increased, but, responded well to ketamine. Her narratives during these tougher times reported her ability to stay strong and positive, which surprised her. Clinically, this was correlated with reduced intensity, frequency severity, and duration of eating disorder behaviors. Her BMI was 25.2 pre‐Ketamine, and 25.8 at the end of treatment. What is notable about this, is that her weight stabilized during the 12 months she was getting ketamine.\n\n3.4 Case 4: history\n\nA 35‐year‐old female with widely fluctuating weight history including both AN‐R and obesity, chronic and unremitting MDD, PTSD, somatization, and Borderline personality disorder (BLPD). Patient developed AN and reports a lifetime low BMI = 13.5 in her 20s. She partially weight restored to a BMI of 17.8. She maintained that weight for 4 years, until she was treated for a back injury with steroids for 2 years, which resulted in a serious weight gain, with eventual high BMI of 47.5. Subsequently, she began severely restricting intake, and lost 60 lbs over a couple months, to a BMI = 34.5. After a month‐long fast, she was hospitalized for medical complications, spent 1 month in residential treatment, and then entered an ED partial hospital program (PHP), with step down to intensive outpatient program (IOP). In addition to frequent fasting and excessive exercise she had used diet pills but had never purged by vomiting. Patient had been in and out of PHP/IOP treatment several times and continued to have wide weight fluctuations, with limited change in mood, despite multiple adequate antidepressant trials and augmentation strategies. Even during a 9 + month period with normalized eating patterns and BMI stabilization at 25.5, the patient continued to complain of significant residual depression and PTSD symptoms. Patient was taking venlafaxine XR 150 mg, lamotrigine 200 mg, and topiramate (the latter for migraine headaches). Her mood an anxiety symptoms were unchanged throughout ED treatment, and multiple med trials. She was in her final 3 weeks of a 3 day IOP program at the time of first injection, and otherwise had weekly therapy and every 2‐3 months psychiatry follow‐up per her HMO.\n\n3.4.1 Dose\n\nPatient had initial dose of ketamine IV, 0.5 mg/Kg. She was then converted to IM. Her dose was progressively increased, since lower doses were only partially effective and only lasted <2 weeks. Her max and maintained dose was 0.85 mg/kg weekly injections. She tolerated this dose very well, with mild sedation postinjection.\n\n3.4.2 Depression and anxiety\n\nBoth her mood (BDI) as well as her state anxiety STAI showed clear and repeated response to Ketamine treatment, including times of BDI dropping to under 5, with her pretreatment BDI at 60. She also showed periods of time where her BDI remained lower than her pretreatment baseline. Her responses were more variable after 6 months, and less sustained. During this time, she reported an increase in stress, PTSD symptoms. Her suicidal thoughts varied throughout the treatment period and were more related to interpersonal stressors.\n\n3.4.3 ED symptoms\n\nAll of her EDE subscales showed little to no response to ketamine treatments.\n\n3.4.4 Impressions\n\nWhile this person had initial benefit to her mood and anxiety, the magnitude and consistency of response were limited. This patient was very sensitive to interpersonal stressors, and such events would often limit or eliminate any potential Ketamine benefit. There was no benefit to her eating disorder symptoms.\n\n4 DISCUSSION\n\nKetamine reduced depression in all four cases we reviewed with TRD and severe and enduring EDs—as measured by BDI and clinical assessment. During the trial, none of the patients were hospitalized or admitted to a higher level of care. There were no suicide attempts by any patient for the trial duration. The magnitude of the response did not diminish over time with repeat dosing. BDI response was partially sustained between treatments for Patient 1 and Patient 2 over the 12 + month course. Patients 1 and Patient 2 had significant changes in their course of illness, as measure by functionality, BDI, and clinical assessment. Of note, both patients had been stagnant in their depression and eating disorder treatment.\n\nIn this small sample of patients with severe and enduring EDs complicated by TRD, Ketamine IM (dosing 0.5‐0.80 mg/kg) administered, with repeat dosing at 4‐6 weeks intervals resulted in clinically meaningful changes in depression and to a lesser degree anxiety and eating disorder symptoms. All patients moved at least 1 level down in the classification system used for BDI scores and level of depression (10).\n\nThe improvement in depression was most notable and sustained in Cases 1 and 2 (more classic AN‐R), both of whom had more robust and sustained clinical improvements in depression, anxiety, and 2 clinically relevant EDE‐Q subscales (EDE‐Q eatcon and restraint). Furthermore, both case 1 and case 2 have had remarkable improvements in their previously downward functioning and quality of life trajectories. The longitudinal course of their depression and ED varied, however, for case 2, the patient is in full remission from her 12‐year battle with both AN‐R and TRD. These changes are sustained at 3 years since initiation of Ketamine treatment and 1.5 years out from her last Ketamine dose. For case 1, the patient has continued intranasal Ketamine, continues to work, and is off disability. Patient (case 1) has maintained a BDI in the mild‐moderate range, and, while she is not in full remission from her ED her weight has been in her goal weight range consistently for the past year, which had not been achieved in the past.\n\nTreatment‐resistant depression comorbid with chronic restrictive eating disorders are very difficult patients to treat in terms of response of either disorder. In these few cases, we saw improvement in both disorders, particularly for the 2 classic AN‐R patients. These results, while very preliminary, offer some hope for patients with chronic AN‐R and TRD. Given the combined high morbidity and mortality rate of combined AN‐R and TRD, having a rapid acting effective treatment for 1 or both disorders could help improve outcomes in this patient type, who otherwise have a very poor prognosis.\n\nIn summary, this pilot study found that IM ketamine appeared to efficacious for TRD in this group of patients with severe and enduring EDs. However, the effects of ketamine on ED symptoms were more modest. The 2 patients (cases 1, 2) with AN‐R had the most robust and sustained responses in their ED and TRD. Both these patients also had clinically significant reduction and elimination of suicidality. It remains unknown whether a reduction in mood symptoms contributed to an improvement in ED symptoms, or there was a specific effect on core AN symptoms.\n\n5 LIMITATIONS\n\nThis was an open‐label, naturalistic case series, without a placebo control.\n\nCONFLICT OF INTEREST\n\nThe data that support the findings of this study are available from the corresponding author, [TS], upon reasonable request. The work described in this manuscript was performed as part of routine clinical care and was not funded by any third party. None of the authors have any conflict of interest. However, David Feifel MD PhD now owns a clinic that administers Ketamine for depression. He did not own this company during the treatment and data assessment for these case reports.\n\nAUTHOR CONTRIBUTIONS\n\nTS: involved in psychiatrist providing care 2/4 patients, primary author. MET: involved in psychiatrist working with 2/4 patients. DF: involved in Ketamine Provider and data collection. EL: provided help with graphics. DP: involved in data set management. WK: assisted with data analysis and writing. GKWF: data review and manuscript preparation.\n\nACKNOWLEDGMENTS\n\nPublished with written consent of the patient.\n==== Refs\nREFERENCES\n\n1 Arcelus J , Mitchell A , Wales J , Nielsen S . Mortality rates in patients with anorexia nervosa and other eating disorders. Arch Gen Psychiatry. 2011;68 :724‐731.21727255\n2 Wild B , Friederich H , Zipfel S , et al. Predictors of outcomes in outpatients with anorexia nervosa ‐ results from the ANTOP study. Psychiatr Res. 2016;244 :45‐50.\n3 Han Y , Chen J , Zou D , et al. Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta‐analysis of randomized, double‐blind, placebo‐controlled studies. Neuropsychiatr Dis Treat. 2016;12 :2859‐2867.27843321\n4 Feifel D , Malcolm B , Boggie D , Lee K . Low‐dose ketamine for treatment resistant depression in an academic clinical practice setting. J Affect Disord. 2017;221 :283‐288.28666206\n5 Romeo B , Choucha W , Fossati P , Rotge JY . Meta‐analysis of short‐ and mid‐term efficacy of ketamine in unipolar and bipolar depression. Psychiatr Res. 2015;230 :682‐688.\n6 Szymkowicz S , Finnegan N , Dale R . A 12‐month naturalistic observation of three patients receiving repeat intravenous ketamine infusions for their treatment‐resistant depression. J Affect Disord. 2013;147 :416‐420.23182590\n7 Mills I , Park G , Manara A , Merriman R . Treatment of compulsive behavior in eating disorders with intermittent ketamine infusions. Quarterly J Med. 1998;91 :493‐503.\n8 Hay P , Touyz S . Treatment of patients with severe and enduring eating disorders. Curr Opin Psychiatry. 2015;28 :473‐477.26382154\n9 American Psychiatric Association . Diagnostic and statistical manual of mental disorders (DSM‐V, 5th edn. Washington, DC: American Psychiatric Association; 2013.\n10 Beck A , Steer R , Carbin M . Psychometric properties of the beck depression inventory: twenty‐five years of evaluation. Clin Psychology Rev. 1988;8 :77‐100.\n11 Spielberger CD . Manual for the state‐trait anxiety inventory. Palo Alto, CA: Consulting Psychologists Press Inc; 1983.\n12 Mond J , Hay P , Rodgers B , Owen C . Eating disorder examination questionnaire (EDE‐Q): norms for young adult women. Behav Res Ther. 2006;44 :53‐62.16301014\n13 Chilukuri H , Reddy N , Pathapati R , Manu A , Jollu S , Shaik A . Acute antidepressant effects of intramuscular versus intravenous ketamine. Indian J Psychol Med. 2014;36 :71‐76.24701015\n14 Loo C , Galvez V , O'Keefe E , et al. Placebo‐controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression. Acta Psychiatr Scand. 2016;134 (1 ):48‐56.27028832\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "9(5)",
"journal": "Clinical case reports",
"keywords": "depression; eating disorders; ketamine; treatment",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "e03869",
"pmc": null,
"pmid": "34026123",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports",
"references": "27028832;16301014;24701015;26382154;9797933;28666206;21727255;27467700;26548981;27843321;34026123;23182590",
"title": "A longitudinal case series of IM ketamine for patients with severe and enduring eating disorders and comorbid treatment-resistant depression.",
"title_normalized": "a longitudinal case series of im ketamine for patients with severe and enduring eating disorders and comorbid treatment resistant depression"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-21-02131",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "KETAMINE"
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{
"abstract": "We report a case of delayed respiratory depression due to accidental subcutaneous opioid infusion. A healthy 33-year-old woman underwent orthopedic surgery under general anesthesia. Before the end of the operation, it was noticed that a part of the opioid infusion had been administered subcutaneously. About 15 min after tracheal extubation, the patient developed respiratory depression and loss of consciousness. The patient recovered with the use of jaw lift together with bag-valve-mask ventilation. We believe that accidental subcutaneous opioid accumulation may have caused the respiratory depression.",
"affiliations": "Division of Anesthesiology, Department of Surgery Related, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe City, 650-0017, Japan.;Division of Anesthesiology, Department of Surgery Related, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe City, 650-0017, Japan. moriori@tg8.so-net.ne.jp.;Division of Anesthesiology, Department of Surgery Related, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe City, 650-0017, Japan.;Division of Anesthesiology, Department of Surgery Related, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe City, 650-0017, Japan.;Division of Anesthesiology, Department of Surgery Related, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe City, 650-0017, Japan.;Division of Anesthesiology, Department of Surgery Related, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe City, 650-0017, Japan.;Division of Anesthesiology, Department of Surgery Related, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe City, 650-0017, Japan.",
"authors": "Okada|Takuya|T|;Egi|Moritoki|M|;Sato|Hitoaki|H|;Nomura|Yuki|Y|;Okada|Masako|M|;Izuta|Shinichiro|S|;Mizobuchi|Satoshi|S|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "Japan",
"delete": false,
"doi": "10.1007/s00540-015-2137-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0913-8668",
"issue": "30(3)",
"journal": "Journal of anesthesia",
"keywords": "Delayed respiratory depression; Opioid; Subcutaneous infusion",
"medline_ta": "J Anesth",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D000768:Anesthesia, General; D003243:Consciousness; D005260:Female; D006801:Humans; D012131:Respiratory Insufficiency",
"nlm_unique_id": "8905667",
"other_id": null,
"pages": "489-92",
"pmc": null,
"pmid": "26762999",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17122299;22606400;23772541;9842857",
"title": "A case of delayed respiratory depression caused by accidental subcutaneous opioid infusion.",
"title_normalized": "a case of delayed respiratory depression caused by accidental subcutaneous opioid infusion"
} | [
{
"companynumb": "JP-WATSON-2016-14771",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ROCURONIUM BROMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking.\n\n\n\nWe randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum \"tail\" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety.\n\n\n\nThe median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P=0.04) and early infant death (4.4% vs. 0.6%, P=0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P=0.10 and P=0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART.\n\n\n\nAntenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538 .).",
"affiliations": "From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).;From the Department of Pathology, Johns Hopkins University School of Medicine (M.G.F.), and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health (T.E.T.), Baltimore, and the Division of AIDS, National Institute of Allergy and Infectious Diseases (D.G., K.L.K., R. Browning, L.P.), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (G.K.S.), National Institutes of Health, Bethesda - all in Maryland; the Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston (M.Q., T.F., D.E.S.); the Retrovirology Core Laboratory, University of North Carolina School of Medicine, Chapel Hill (S.A.F., A.J.L.), and FHI 360, Durham (A.S.C.) - both in North Carolina; the UCLA Center for Clinical AIDS Research and Education, Los Angeles (J.S.C.); St. Jude Children's Research Hospital, Memphis, TN (P.M.F.); the Department of Obstetrics and Gynecology, College of Health Sciences, University of Zimbabwe, Harare (T.C.); Anova Health Institute (J.M.), Perinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences (A.V.), and Empilweni Services and Research Unit (R.S.), Johannesburg, School of Public Health and Family Medicine, University of Cape Town (J.M.), and the Department of Obstetrics and Gynaecology, Stellenbosch University (G.B.T.), Cape Town, and the Centre for the AIDS Programme of Research in South Africa-Umlazi Clinical Research Site (D.M.) and Durban Paediatric HIV (R. Bobat), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban - all in South Africa; the University of North Carolina Project, Kamuzu Central Hospital-Tidziwe Center, Lilongwe, Malawi (F.E.M.); Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda (M.O.); the Department of Obstetrics and Gynecology, B.J. Medical College, Pune, India (R. Bhosale); the Centre for Infectious Disease Research in Zambia, Lusaka, Zambia (B.H.C.); Kilimanjaro Christian Medical Center-Duke University Collaboration, Moshi, Tanzania (P.M.); Frontier Science and Technology Research Foundation, Amherst, NY (M.B.); and the Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC (L.M.M.).",
"authors": "Fowler|Mary G|MG|;Qin|Min|M|;Fiscus|Susan A|SA|;Currier|Judith S|JS|;Flynn|Patricia M|PM|;Chipato|Tsungai|T|;McIntyre|James|J|;Gnanashanmugam|Devasena|D|;Siberry|George K|GK|;Coletti|Anne S|AS|;Taha|Taha E|TE|;Klingman|Karin L|KL|;Martinson|Francis E|FE|;Owor|Maxensia|M|;Violari|Avy|A|;Moodley|Dhayendre|D|;Theron|Gerhard B|GB|;Bhosale|Ramesh|R|;Bobat|Raziya|R|;Chi|Benjamin H|BH|;Strehlau|Renate|R|;Mlay|Pendo|P|;Loftis|Amy J|AJ|;Browning|Renee|R|;Fenton|Terence|T|;Purdue|Lynette|L|;Basar|Michael|M|;Shapiro|David E|DE|;Mofenson|Lynne M|LM|;|||",
"chemical_list": "D044966:Anti-Retroviral Agents; D015215:Zidovudine; D019829:Nevirapine; D000068698:Tenofovir",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1511691",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "375(18)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000328:Adult; D001741:African Americans; D044966:Anti-Retroviral Agents; D018791:CD4 Lymphocyte Count; D004359:Drug Therapy, Combination; D005260:Female; D005865:Gestational Age; D015658:HIV Infections; D006801:Humans; D007223:Infant; D007226:Infant Mortality; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007234:Infant, Premature; D018445:Infectious Disease Transmission, Vertical; D019829:Nevirapine; D018743:Perinatal Care; D011247:Pregnancy; D011256:Pregnancy Outcome; D000068698:Tenofovir; D055815:Young Adult; D015215:Zidovudine",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "1726-1737",
"pmc": null,
"pmid": "27806243",
"pubdate": "2016-11-03",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "23066160;22579125;26265780;22692091;25030058;17597712;25030057;26192873;23746775;16988514;22460969;19273671;26379069;21791651;26265779;22904691;18989231;7935654;26740274;17079992;24113254;21791648;23204173",
"title": "Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention.",
"title_normalized": "benefits and risks of antiretroviral therapy for perinatal hiv prevention"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US21383",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
},
"drugadditional": "3",
... |
{
"abstract": "The lamin A/C (LMNA) gene encodes lamins A and C, which have an important role in nuclear cohesion and chromatin organization. Mutations in this gene usually lead to the so-called laminopathies, the primary cardiac manifestations of which are dilated cardiomyopathy and intracardiac conduction defects. Some mutations, associated with lipodystrophy but not cardiomyopathy, have been linked to metabolic abnormalities such as diabetes and severe dyslipidemia. Herein we describe a new phenotype associated with a mutation in exon 11 of the LMNA gene: hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes. A 64-year-old woman with hypertrophic cardiomyopathy and a point mutation in exon 11 of the LMNA gene (c.1718C>T, Ser573Leu) presented with severe symptomatic ventricular hypertrophy and left ventricular outflow tract obstruction. She underwent septal alcohol ablation, followed by Morrow myectomy. The patient was also diagnosed with severe dyslipidemia, diabetes and obesity, and fulfilled diagnostic criteria for metabolic syndrome. No other characteristics of LMNA mutation-related phenotypes were identified. The development of type III atrioventricular block with no apparent cause, and mildly depressed systolic function, prompted referral for cardiac resynchronization therapy. In conclusion, the association between LMNA mutations and different phenotypes is complex and not fully understood, and can present with a broad spectrum of severity.",
"affiliations": "Cardiology Department, Santa Maria University Hospital, CHLN, CAML, CCUL, Faculty of Medicine, University of Lisbon, Lisbon, Portugal. Electronic address: ana.r.francisco@gmail.com.;Cardiology Department, Santa Maria University Hospital, CHLN, CAML, CCUL, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.;Cardiology Department, Santa Maria University Hospital, CHLN, CAML, CCUL, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.;Cardiology Department, Santa Maria University Hospital, CHLN, CAML, CCUL, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.;Cardiology Department, Santa Maria University Hospital, CHLN, CAML, CCUL, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.;Cardiology Department, Santa Maria University Hospital, CHLN, CAML, CCUL, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.",
"authors": "Francisco|Ana Rita G|ARG|;Santos Gonçalves|Inês|I|;Veiga|Fátima|F|;Mendes Pedro|Mónica|M|;Pinto|Fausto J|FJ|;Brito|Dulce|D|",
"chemical_list": "D034904:Lamin Type A",
"country": "Portugal",
"delete": false,
"doi": "10.1016/j.repc.2016.07.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0870-2551",
"issue": "36(9)",
"journal": "Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology",
"keywords": "Atrioventricular block; Bloqueio auriculoventricular; Diabetes; Dislipidemia; Dyslipidemia; Gene LMNA; Hypertrophic cardiomyopathy; LMNA gene; Lamin A/C; Lâmina A/C; Miocardiopatia hipertrófica",
"medline_ta": "Rev Port Cardiol",
"mesh_terms": "D054537:Atrioventricular Block; D002312:Cardiomyopathy, Hypertrophic; D048909:Diabetes Complications; D003920:Diabetes Mellitus; D050171:Dyslipidemias; D005091:Exons; D005260:Female; D006801:Humans; D034904:Lamin Type A; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012720:Severity of Illness Index",
"nlm_unique_id": "8710716",
"other_id": null,
"pages": "669.e1-669.e4",
"pmc": null,
"pmid": "28874324",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Complex phenotype linked to a mutation in exon 11 of the lamin A/C gene: Hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes.",
"title_normalized": "complex phenotype linked to a mutation in exon 11 of the lamin a c gene hypertrophic cardiomyopathy atrioventricular block severe dyslipidemia and diabetes"
} | [
{
"companynumb": "PHHY2017PT134132",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Strongyloidiasis, a neglected tropical disease (NTD), which is caused by Strongyloides stercoralis, can be fatal in immunocompromised patients. In most chronic cases, infections most frequently are asymptomatic, and eosinophilia might be the only clinical characteristic of this disease. The use of corticosteroids in some diseases like chronic obstructive pulmonary disease (COPD) may lead to the development of the life-threatening S. stercoralis hyperinfection syndrome. In the present research, we presented five cases of strongyloidiasis with a history of COPD and receiving corticosteroids from Abadan County, southwestern Iran. By performing the direct smear stool examinations, two cases were identified and the other three cases were diagnosed using the agar plate culture method. Despite reporting eosinophilia in previous patients' hospitalizations, the fecal examination was not performed for parasitic infections. Moreover, pulmonary symptoms were similar, but gastrointestinal symptoms were varied, including nausea, vomiting, abdominal pain, epigastric pain, constipation, and diarrhea. All the included patients were treated with albendazole, which is the second-line drug for S. stercoralis, and relapse of infection was observed in two patients by passing few months from the treatment. The increased blood eosinophil count was shown to play important roles in both the management of COPD and diagnosis of helminthic infections. In COPD patients who are receiving steroids, screening and follow-up for strongyloidiasis should be considered as priorities. In addition, ivermectin, which is the first-line drug for strongyloidiasis, should be available in the region.",
"affiliations": "Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Khuzestan, Iran.;Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Khuzestan, Iran.;Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Khuzestan, Iran.;Abadan School of Medical Sciences, Abadan, Khuzestan, Iran.;Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Khuzestan, Iran.",
"authors": "Ashiri|Alireza|A|;Rafiei|Abdollah|A|;Beiromvand|Molouk|M|;Khanzadeh|Abdollah|A|;Alghasi|Arash|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9637",
"issue": null,
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": null,
"nlm_unique_id": "0370507",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34844210",
"pubdate": "2021-11-29",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Case Report: Challenges for the Diagnosis and Treatment of Strongyloides stercoralis in Chronic Obstructive Pulmonary Disease Patients.",
"title_normalized": "case report challenges for the diagnosis and treatment of strongyloides stercoralis in chronic obstructive pulmonary disease patients"
} | [
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"abstract": "Hypertensive emergency usually appears in older patients with previous recurrent episodes, and is among the most frequent admissions to emergency departments. A 29-year-old woman was referred to our clinic with the diagnosis of hypertensive emergency. The patient complained of severe headache, dyspnea, palpitation, diaphoresis, and confusion due to hypertensive encephalopathy. Her blood pressure was 250/150 mmHg on admission. At the referral hospital, the patient had undergone cranial CT because of her confused state and this excluded acute cerebral hemorrhage. Also at that hospital, thoracoabdominal CT for differential diagnosis depicted an adrenal mass with a necrotic core. After admission to our clinic, initial control of excessive blood pressure was not achieved despite high dose intravenous nitrate therapy. Thereafter intravenous esmolol treatment was initiated simultaneously with oral alpha blocker therapy in order to counterbalance the unopposed alpha adrenergic activity with beta blocker therapy. After 12 hours, sudden onset of hypotension developed and deepened despite IV saline, inotropic and vasopressor agents such as IV dopamine, noradrenaline and adrenaline. The patient died at the 24th hour due to hemodynamic collapse as a result of hyperadrenergic state due to possible pheochromocytoma crisis. This case is an exceptional example of hypertensive emergency secondary to fulminant pheochromocytoma crisis failing to respond to intensive antihypertensive treatment, and in which patient death was unavoidable due to uncontrolled excessive adrenergic activity which led to profound cardiogenic shock.",
"affiliations": "Department of Cardiology, Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital, İstanbul, Turkey. mertilkerh@yahoo.com.;Department of Cardiology, Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital, İstanbul, Turkey.;Department of Cardiology, Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital, İstanbul, Turkey.;Department of Cardiology, Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital, İstanbul, Turkey.;Department of Cardiology, Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital, İstanbul, Turkey.",
"authors": "Hayıroğlu|Mert İlker|Mİ|;Yıldırımtürk|Özlem|Ö|;Bozbay|Mehmet|M|;Eren|Mehmet|M|;Pehlivanoğlu|Seçkin|S|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5543/tkda.2015.77925",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1016-5169",
"issue": "43(8)",
"journal": "Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir",
"keywords": null,
"medline_ta": "Turk Kardiyol Dern Ars",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000328:Adult; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006973:Hypertension; D007022:Hypotension; D010673:Pheochromocytoma; D012770:Shock, Cardiogenic",
"nlm_unique_id": "9426239",
"other_id": null,
"pages": "727-9",
"pmc": null,
"pmid": "26717337",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypertensive emergency due to pheochromocytoma crisis complicated with refractory hemodynamic collapse.",
"title_normalized": "hypertensive emergency due to pheochromocytoma crisis complicated with refractory hemodynamic collapse"
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"activesubstancename": "DOPAMINE\\DOPAMINE HYDROCHLORIDE"
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"abstract": "OBJECTIVE\nDermatopathic reaction is a histopathological finding of lymph nodes that usually occurs in patients with inflammatory pruritic cutaneous lesions. However, it is sometimes seen in patients with cutaneous T cell lymphoma. Adult T cell leukaemia/lymphoma (ATLL) is a T cell malignancy caused by infection with human T cell leukaemia virus type I (HTLV-1), which is frequently accompanied by cutaneous lesions. However, the detailed clinicopathological characteristics of the dermatopathic reaction of lymph nodes in ATLL patients and HTLV-1 carriers, addressed in this study, remains to be clarified.\n\n\nRESULTS\nWe retrospectively analysed 18 nodal lesions with dermatopathic reaction in HTLV-1 carriers. Axillary and inguinal lymph nodes were the primary affected tissues. Three cases with atypical lymphoid cell infiltration were defined as ATLL with dermatopathic reaction (ATLL-D), showing an abnormal T cell immunophenotype and T cell monoclonality. Two of the three ATLL-D patients died 14 and 7 months after diagnosis (the third case had a very short follow-up). The other 15 patients were indistinguishable from reactive lesions and were defined as HTLV-1-associated lymphadenitis with dermatopathic reaction (HAL-D). They showed an indolent clinical course, with only one case eventually transforming to aggressive disease.\n\n\nCONCLUSIONS\nLymph node lesions accompanied by dermatopathic reaction in HTLV1 carriers represent a spectrum that includes reactive and neoplastic conditions. HAL-D should be distinguished from ATLL-D, especially to avoid overtreatment.",
"affiliations": "Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.;Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.;Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.;Department of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.;Department of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.;Department of Pathology, Okinawa Prefectural Nanbu Medical Center and Children's Medical Center, Okinawa, Japan.;Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.;Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.;Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.;Department of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.",
"authors": "Chinen|Shigeki|S|;Miyagi|Takuya|T|;Murakami|Yoshiya|Y|;Takatori|Mitsuyoshi|M|;Sakihama|Shugo|S|;Nakazato|Iwao|I|;Kariya|Yoshiyuki|Y|;Yamaguchi|Sayaka|S|;Takahashi|Kenzo|K|;Karube|Kennosuke|K|https://orcid.org/0000-0002-1205-858X",
"chemical_list": null,
"country": "England",
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"doi": "10.1111/his.14102",
"fulltext": "\n==== Front\nHistopathology\nHistopathology\n10.1111/(ISSN)1365-2559\nHIS\nHistopathology\n0309-0167 1365-2559 John Wiley and Sons Inc. Hoboken \n\n10.1111/his.14102\nHIS14102\nOriginal Article\nOriginal Articles\nDermatopathic reaction of lymph nodes in HTLV‐1 carriers: a spectrum of reactive and neoplastic lesions\nDermatopathic reaction in HTLV‐1 carriersS Chinen et al.Chinen Shigeki \n1\n Miyagi Takuya \n2\n Murakami Yoshiya \n1\n Takatori Mitsuyoshi \n3\n Sakihama Shugo \n3\n Nakazato Iwao \n4\n Kariya Yoshiyuki \n2\n Yamaguchi Sayaka \n2\n Takahashi Kenzo \n2\n Karube Kennosuke https://orcid.org/0000-0002-1205-858X\n3\nkarube@med.u-ryukyu.ac.jp \n1 \nFaculty of Medicine\nUniversity of the Ryukyus\nOkinawa\nJapan\n\n\n2 \nDepartment of Dermatology\nGraduate School of Medicine\nUniversity of the Ryukyus\nOkinawa\nJapan\n\n\n3 \nDepartment of Pathology and Cell Biology\nGraduate School of Medicine\nUniversity of the Ryukyus\nOkinawa\nJapan\n\n\n4 \nDepartment of Pathology\nOkinawa Prefectural Nanbu Medical Center and Children’s Medical Center\nOkinawa\nJapan\n\n* \nAddress for correspondence: K Karube MD, PhD, Department of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara‐cho, Okinawa 903‐0215, Japan. e‐mail karube@med.u-ryukyu.ac.jp\n\n18 6 2020 \n7 2020 \n77 1 10.1111/his.v77.1133 143\n28 10 2019 01 2 2020 07 3 2020 © 2020 The Authors. Histopathology published by John Wiley & Sons Ltd.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.Aims\nDermatopathic reaction is a histopathological finding of lymph nodes that usually occurs in patients with inflammatory pruritic cutaneous lesions. However, it is sometimes seen in patients with cutaneous T cell lymphoma. Adult T cell leukaemia/lymphoma (ATLL) is a T cell malignancy caused by infection with human T cell leukaemia virus type I (HTLV‐1), which is frequently accompanied by cutaneous lesions. However, the detailed clinicopathological characteristics of the dermatopathic reaction of lymph nodes in ATLL patients and HTLV‐1 carriers, addressed in this study, remains to be clarified.\n\nMethods and results\nWe retrospectively analysed 18 nodal lesions with dermatopathic reaction in HTLV‐1 carriers. Axillary and inguinal lymph nodes were the primary affected tissues. Three cases with atypical lymphoid cell infiltration were defined as ATLL with dermatopathic reaction (ATLL‐D), showing an abnormal T cell immunophenotype and T cell monoclonality. Two of the three ATLL‐D patients died 14 and 7 months after diagnosis (the third case had a very short follow‐up). The other 15 patients were indistinguishable from reactive lesions and were defined as HTLV‐1‐associated lymphadenitis with dermatopathic reaction (HAL‐D). They showed an indolent clinical course, with only one case eventually transforming to aggressive disease.\n\nConclusions\nLymph node lesions accompanied by dermatopathic reaction in HTLV1 carriers represent a spectrum that includes reactive and neoplastic conditions. HAL‐D should be distinguished from ATLL‐D, especially to avoid overtreatment.\n\nadult T cell leukaemia/lymphomadermatopathic reactionhuman T cell leukaemia virus type 1immunophenotypeprognosisThe Japanese Society of Hematology Research GrantMinistry of Education, Culture, Sports, Science and Technology of JapanGrants‐in‐aid for Scientific Research (KAKENHI) 1Japan Leukemia Research FundMochida Memorial Foundation for Medical and Pharmaceutical Research 10.13039/501100005865Yasuda Memorial Medical Foundation 10.13039/501100008673Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care 10.13039/501100003837Okinawa Internal Medicine Research Promotion SocietyOkinawa prefecture source-schema-version-number2.0cover-dateJuly 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:27.07.2020\n\n\nChinen \nS \n, \nMiyagi \nT \n, \nMurakami \nY \n, \nTakatori \nM \n, \nSakihama \nS \n, \nNakazato \nI \n, \nKariya \nY \n, \nYamaguchi \nS \n, \nTakahashi \nK \n & \nKarube \nK \n. (2020 ) Histopathology \n77 , 133 –143\n. 10.1111/his.14102 \nDermatopathic reaction of lymph nodes in HTLV‐1 carriers: a spectrum of reactive and neoplastic lesions\n\n32162348\n==== Body\nIntroduction\nDermatopathic reaction is a histopathological finding of the lymph node in which infiltrating Langerhans cells, interdigitating dendritic cells and pigmented macrophages are observed in the expanded paracortex.\n1\n It usually occurs in patients with pruritic cutaneous lesions without malignancy. However, nodal lesions in cases with cutaneous T cell lymphoma (CTCL), such as mycosis fungoides, are sometimes accompanied by tumour cell infiltration, which affects prognosis. Distinguishing lymphoma cell involvement from dermatopathic reaction can be challenging, as dermatopathic reaction is characterised by polymorphous cellular context, including numerous transformed lymphocytes, activated macrophages and dendritic cells.\n1\n, \n2\n, \n3\n\n\n\nAdult T cell leukaemia/lymphoma (ATLL) is a T cell malignancy caused by infection with human T cell leukaemia virus type I (HTLV‐1). ATLL exists as four clinical subtypes: smouldering, chronic, lymphoma and acute.\n4\n, \n5\n The latter two are considered aggressive and generally show a rapid clinical course.\n6\n In contrast, indolent ATLL (smouldering and chronic types) usually progresses slowly and does not require cytotoxic chemotherapy.\n7\n, \n8\n Lymphadenopathy is one of the most frequent manifestations of ATLL. Morphologically, diffuse architectural effacement with proliferation of medium‐sized or large pleomorphic cells is usually seen in the aggressive type. Conversely, HTLV‐1‐associated lymphadenitis (HAL; morphologically reactive lymphadenitis developing in HTLV‐1 carriers) has a good prognosis without treatment.\n9\n Although the morphological distinction between overt lymphoma and HAL is usually not difficult, some pathological features, such as dermatopathic reaction, make it hard to accurately evaluate lymph node lesions in HTLV‐1 carriers.\n\nAlthough skin is one of the most frequently affected organs in ATLL and may be involved in up to 50% of cases,\n10\n the detailed clinicopathological findings of ATLL and HAL cases with dermatopathic reaction remain unclear. To address this issue, we carried out a comparative clinicopathological analysis of lymph nodes with dermatopathic reaction in 18 HTLV‐1‐infected cases with or without ATLL. The majority of these cases were considered to be reactive lesions showing an indolent clinical course, while three cases with definitive involvement by tumour cells showed a relatively poorer prognosis. These findings highlighted the disease spectrum from benign to malignant status in dermatopathic reaction of lymph nodes of HTLV‐1 carriers.\n\nMaterials and methods\nPATIENTS AND SAMPLES\nArchival formalin‐fixed/paraffin‐embedded (FFPE) tissue samples from 15 patients were selected using the search terms ‘dermatopathic’ and ‘lymph node’ from the Ryukyu University Hospital database containing tissue samples of 1134 HTLV‐1 carriers diagnosed between 2010 and 2019,. A further three cases were identified from the archives of the Okinawa Prefectural Nanbu Medical Center and Children's Medical Center. All samples were reviewed and confirmed as showing dermatopathic reaction; namely, an expanded paracortex with increased numbers of Langerhans and interdigitating dendritic cells and scattered pigment. Biopsy of a cutaneous lesion was also performed in 15 of the 18 cases.\n\nThis study was approved by the institutional ethics committees of the Graduate School of Medicine and the School of Health Science at the University of the Ryukyus and Okinawa Prefectural Nanbu Medical Center and Children's Medical Center, Japan. The study protocol adhered to the principles of the Declaration of Helsinki.\n\nHISTOLOGICAL AND IMMUNOHISTOCHEMICAL EVALUATION\nFFPE samples were used for histological and molecular analyses. Tissue histology was examined by haematoxylin and eosin staining. The diagnosis of HAL‐D was made based upon a previous report.\n9\n The diagnosis of ATLL‐D was defined as a lesion with a significant infiltration of atypical lymphocytes. Immunohistochemistry was performed with the Benchmark ULTRA system (Roche, Tokyo, Japan), according to the manufacturer's protocol, using antibodies against CD3 and CD8 (both from Agilent Technologies, Tokyo, Japan); CD4, CD5, CD25 and CD30 (all from Roche); and CD7 (Abcam, Tokyo, Japan). Case 14 was also analysed by in‐situ hybridisation for Epstein–Barr virus (EBV)‐encoded small RNA (EBER‐ISH; Dako, Tokyo, Japan). Immunohistochemistry data provided by cooperating institutions was also included in the analysis.\n\nFLOW CYTOMETRY\nFresh single‐cell suspensions were isolated by flow cytometry on a FACSCanto II instrument (BD Biosciences, Tokyo, Japan) using fluorescein isothiocyanate‐conjugated CD3 and CD4 antibodies and phycoerythrin‐conjugated CD5, CD7, CD25 and CD8 antibodies, all of which were purchased from Beckman Coulter (Tokyo, Japan), apart from anti‐CD25 (BD Biosciences, San Jose, CA, USA).\n\nMOLECULAR ANALYSIS\nGenomic DNA was extracted from FFPE samples. Clonal rearrangement of the T cell receptor gamma (TCR‐γ) gene was analysed by polymerase chain reaction (PCR), according to the BIOMED2 protocol.\n11\n The amplification product was analysed by capillary electrophoresis. Southern blot analysis was performed for cases 6 and 17 using genomic DNA from fresh samples. PstI, EcoRI and HTLV‐1 probes were used, as previously reported.\n12\n\n\n\nResults\nCLINICAL CHARACTERISTICS OF PATIENTS\nThe clinical characteristics of the reported cases are shown in Table 1. The median age was 76 years and 14 of the 18 patients were male. All of the patients were more than 60 years of age, which is older than the cohort in a previous study on lymph nodes with dermatopathic reaction without malignancy.\n13\n Erythema was observed in all cases, and one case showed purpura. Most patients had enlargement of axillary or inguinal lymph nodes. One patient (case 2) was diagnosed as smouldering ATLL based on haematological findings in peripheral blood. Seven cases were considered to be a ‘cutaneous’ variant of the smouldering type based on the pathological findings in skin lesions.\n14\n Another seven cases did not show clear pathological or molecular evidence of lymphoma cell infiltration in either lymph nodes or skin, and were therefore considered as HTLV‐1 carriers. Two patients (cases 16 and 17), classified as ATLL‐D, showed a progressive disease course and died 14 and 7 months respectively after diagnosis despite treatment that included mogamulizumab, an antibody therapy against CCR4. Another case of ATLL‐D (case 18) showed proliferation of atypical lymphocytes in peripheral blood (> 40%) with a slight increase in serum lactate dehydrogenase (LDH) and decreased serum albumin levels (data not shown), indicating a chronic type with an unfavourable prognosis as the clinical subtype.\n8\n The patient with smouldering type (case 2) received oral etoposide (VP‐16) treatment, whereas the remaining 14 cases, including patients regarded as HTLV‐1 carriers or cutaneous‐type ATLL, received topical therapy for their cutaneous lesions. Although a precise comparison of clinical outcome between case 2 and the other HAL‐D patients was difficult, because their treatment regimen was different, case 2 showed an indolent clinical course, similar to the other HAL‐D cases, with no definitive transformation event. Case 12, initially diagnosed as HAL‐D, progressed to aggressive‐type ATLL 30 months after lymph node biopsy and died within 1 month. In the pathological review of the lymph node specimen of case 12, Hodgkin–Reed–Sternberg (HRS)‐like cells, a hallmark finding of incipient ATLL, were not identified. The other HAL‐D cases showed no obvious transformation. Case 5 died 6 years after a diagnosis of HAL‐D, but the cause of death was unknown and no transformation was confirmed. Case 11, diagnosed as cutaneous type, died from Pneumocystis carinii pneumonia 2 months after lymph node biopsy without transformation to aggressive ATLL. Case 14, who exhibited proliferation of EBV‐infected atypical large B cells, was aged 83 years. This patient was seronegative for human immunodeficiency virus and no other immunosuppressive status, including immune suppressive therapy, was noted in the history.\n\nTable 1 Clinical characteristics.\n\nCase no.\tDiagnosis\tAge/sex\tClinical subtype\tProportion of atypical cells in PB\tFollow‐up period (months)**\n\tTreatment\tProgression to aggressive type\tStatus at the last follow‐up\tCause of death\t\n1\tHAL‐D\t69/F\tSmouldering (cutaneous) type\tFew cells*\n\t7\tTopical therapy\t−\tAlive without transformation\t−\t\n2\tHAL‐D\t75/M\tSmouldering type\t6%\t40\tTopical therapy + oral VP‐16\t−\tAlive without transformation\t−\t\n3\tHAL‐D\t64/M\tSmouldering (cutaneous) type\tFew cells*\n\t36\tTopical therapy\t−\tAlive without transformation\t−\t\n4\tHAL‐D\t90/F\tNon‐ATLL (HTLV‐1 carrier)\tFew cells*\n\t21\tTopical therapy\t−\tAlive without transformation\t−\t\n5\tHAL‐D\t74/M\tNon‐ATLL (HTLV‐1 carrier)\tFew cells*\n\t72\tTopical therapy\t−\tDead\tUnknown\t\n6\tHAL‐D\t86/M\tNon‐ATLL (HTLV‐1 carrier)\tFew cells*\n\t2\tTopical therapy\t−\tAlive without transformation\t−\t\n7\tHAL‐D\t85/M\tSmouldering (cutaneous) type\t0%\t2\tTopical therapy\t−\tAlive without transformation\t−\t\n8\tHAL‐D\t80/F\tSmouldering (cutaneous) type\tFew cells*\n\t27\tTopical therapy\t−\tAlive without transformation\t−\t\n9\tHAL‐D\t81/M\tNon‐ATLL (HTLV‐1 carrier)\t2%\t4\tTopical therapy\t−\tAlive without transformation\t−\t\n10\tHAL‐D\t82/M\tSmouldering (cutaneous) type\tFew cells*\n\t1\tTopical therapy\t−\tAlive without transformation\t−\t\n11\tHAL‐D\t76/F\tSmouldering (cutaneous) type\tFew cells*\n\t2\tTopical therapy\t−\tDead\tPneumonia\t\n12\tHAL‐D\t76/M\tNon‐ATLL (HTLV‐1 carrier)\tFew cells*\n\t31\tTopical therapy\t+\tDead\tATLL\t\n13\tHAL‐D\t74/M\tNon‐ATLL (HTLV‐1 carrier)\t0%\t31\tTopical therapy\t−\tAlive without transformation\t−\t\n14\tHAL‐D\t83/M\tSmouldering (cutaneous) type\tFew cells*\n\t15\tTopical therapy\t−\tAlive without transformation\t−\t\n15\tHAL‐D\t68/M\tNon‐ATLL (HTLV‐1 carrier)\tFew cells*\n\t2\tTopical therapy\t−\tAlive without transformation\t−\t\n16\tATLL‐D\t74/M\t\n***\n\tFew cells*\n\t14\tOral VP‐16\t\n***\n\tDead\tATLL\t\n17\tATLL‐D\t79/M\t\n***\n\t0%\t7\tVP‐16 and anti‐CCR4 antibody\t\n***\n\tDead\tATLL\t\n18\tATLL‐D\t64/M\t\n***\n\t41%\t3\tTopical therapy\t\n***\n\tAlive\t‐\t\nF, female; M, male; PB, peripheral blood; HAL‐D, HTLV‐1 associated lymphadenitis with dermatopathic reaction; ATLL‐D, overt adult T cell leukaemia/lymphoma with dermatopathic reaction; CCR4, CC chemokine receptor 4.\n\n* Few atypical cells were observed, but the count was ≤ 1%.\n\n** Follow‐up period is the time (months) from the lymph node biopsy.\n\n*** The clinical subtypes of these cases are discussed in the text.\n\nJohn Wiley & Sons, LtdPATHOLOGICAL CHARACTERISTICS OF PATIENTS\nIn cases with HAL‐D, lymph node tissue architecture was preserved, and proliferation of transformed large lymphoid cells as well as aggregates of interdigitating dendritic cells, Langerhans cells and macrophages forming mottled clear foci was observed in the paracortex (Figure 1A,B). Transformed large lymphocytes with prominent nucleoli were detected in all cases. Numerous CD25‐positive cells distributed in the expanded paracortex were observed in all cases by immunohistochemistry (Figure 1C). The number of CD30‐positive cells varied, and there was no clear correlation between the number of positive cells in neoplastic and reactive lesions (Figure 1D and Table 2). No HRS‐like cells or CD15‐positive large cells were observed in the present series. Although one patient (case 2) showed T cell monoclonality by PCR for TCR‐γ, the definitive atypical tumour cells or phenotypical abnormalities of T cell markers were not identified. No clonal rearrangement was recognised in the other samples (polyclonal pattern in 12 cases and not evaluable in three cases). All lymph node samples of HAL‐D showed a normal T cell phenotype by flow cytometry analysis (Figure 3 and Supporting information, Table S1) and/or immunohistochemistry.\n\nFigure 1 Pathological findings of lymph nodes of human T cell leukaemia virus type I (HTLV‐1)‐associated lymphadenitis with dermatopathic reaction (HAL‐D). Expanded paracortex shows clear foci including dendritic cells and Langerhans cells with abundant clear cytoplasms (A,B, case 3). Large lymphoid cells are also scattered and positive for CD25 (C) or CD30 (D) (C,D, case 3).\n\nTable 2 Pathological characteristics.\n\nCase no.\tDiagnosis\tBiopsied LN\tCD30‐positive cells\tFlow cytometry\tImmunohistochemistry\tClonality (TCR)\t\n1\tHAL‐D\tAxillary\t12\tNo abnormal pattern\tCD3 = CD7 = CD5\tPolyclonal\t\n2\tHAL‐D\tAxillary\t111.75*\n\tND\tCD3 = CD7 = CD5\tMonoclonal\t\n3\tHAL‐D\tInguinal\t90\tNo abnormal pattern\tCD3 = CD7, CD5: ND\tPolyclonal\t\n4\tHAL‐D\tAxillary\t41.75\tND\tCD3 = CD7, CD5: ND\tPolyclonal\t\n5\tHAL‐D\tInguinal\t73.5\tNo abnormal pattern\tCD3 = CD7, CD5: ND\tPolyclonal\t\n6\tHAL‐D\tAxillary\t57\tNo abnormal pattern\tCD3 = CD7 = CD5\tPolyclonal**\n\t\n7\tHAL‐D\tAxillary\t37.5\tND\tCD3 = CD7, CD5: ND\tPolyclonal\t\n8\tHAL‐D\tAxillary\t28\tNo abnormal pattern\tCD3 = CD7, CD5: ND\tPolyclonal\t\n9\tHAL‐D\tAxillary\t5.25\tNo abnormal pattern\tCD3 = CD7, CD5: ND\tPolyclonal\t\n10\tHAL‐D\tInguinal\t6.5*\n\tNo abnormal pattern\tCD3 = CD7 = CD5\tPolyclonal\t\n11\tHAL‐D\tInguinal\t5.25\tNo abnormal pattern\tCD3 = CD7, CD5: ND\tNE\t\n12\tHAL‐D\tInguinal\t64\tNo abnormal pattern\tCD3 = CD7 = CD5\tPolyclonal\t\n13\tHAL‐D\tAxillary\t8.5\tNo abnormal pattern\tCD3 = CD7, CD5: ND\tNE\t\n14\tHAL‐D\tAxillary\t90.75\tND\tCD3 = CD7 = CD5, EBER(+) cells(+)\tPolyclonal\t\n15\tHAL‐D\tAxillary\t62.5\tND\tCD3 = CD7, CD5: ND\tPolyclonal\t\n16\tATLL‐D\tInguinal\t84.75\tCD3 > CD7\tCD3>CD7, CD5: ND\tNE\t\n17\tATLL‐D\tCervical\t20\tCD3 < CD7\tCD3<CD7, CD5: ND\tMonoclonal**\n\t\n18\tATLL‐D\tInguinal\t82\tND\tCD3 = CD5 > CD7\tMonoclonal\t\nNE, not evaluable; ND, not done; HAL‐D, HTLV‐1 associated lymphadenopathy with dermatopathic reaction; ATLL‐D, ATLL with dermatopathic reaction; EBV, Epstein–Barr virus; TCR, T cell receptor; LN, lymph node.\n\n* Average of two samples at the same biopsy.\n\n** These cases were evaluated using Southern blot analysis [the results of polymerase chain reaction (PCR) analysis was not evaluable]. PCR analysis was used for the other cases.\n\nJohn Wiley & Sons, LtdCases 16, 17 and 18, classified as ATLL‐D, also showed a polymorphous inflammatory infiltrate admixed with dendritic cells containing abundant clear cytoplasm that were positive for S‐100 (Figure 2A–F). Although these findings overlap with HAL‐D, a relatively monotonous infiltration of medium‐sized lymphoid cells with mild nuclear atypia in the paracortex was observed (Figure 2E). The majority of atypical lymphoid cells exhibited a T cell phenotype lacking CD3 or CD7 expression (Figure 2G,H). Flow cytometry analysis confirmed an abnormal phenotype, consistent with the results obtained by immunohistochemistry (Figure 3).\n15\n PCR analysis of the TCR rearrangement revealed clonal expansion of T cells in cases 17 and 18 (Table 2).\n\nFigure 2 Pathological findings of adult T cell leukaemia/lymphoma (ATLL) with dermatopathic reaction (ATLL‐D). The lymph node has an expanded paracortex harbouring proliferating dendritic cells with abundant clear cytoplasm [haematoxylin and eosin (H&E); A,B, case 16; C,D, case 17]. Medium‐sized atypical lymphoid cells are admixed with dendritic cells (H&E, E, case 16). Numerous dendritic cells positive for S‐100 are detected by immunohistochemistry (F, case 16). Atypical lymphoid cells express CD3 (G, case 16), but show down‐regulation of CD7 (H, case 16).\n\nFigure 3 Flow cytometry analysis of cases with human T cell leukaemia virus type I‐associated lymphadenitis with dermatopathic reaction (HAL‐D) (case 13, left side) and adult T cell leukaemia/lymphoma dermatopathic reaction (ATLL‐D) (case 17, right side). In HAL‐D, the proportion of CD3‐positive cells is 77.4%, which is similar to those of CD5 (74.9%) and CD7 (75.0%). Conversely, the proportion of CD3‐positive cells in case 13 is 34.0% (arrow), which is much lower than those of CD5 (61.2%) and CD7 (56.3%). Abnormal cells with low CD5 expression were faintly distinguishable from a highly immunopositive population (arrowhead).\n\nSkin samples from 10 patients (cases 1, 2, 3, 7, 8, 10, 11, 14, 17 and 18) showed infiltrating lymphoid cells with nuclear atypia in the dermis and/or epidermis (Figure 4A) that occasionally formed Pautrier's microabscesses (Figure 4B). The atypical lymphoid cells were positive for CD4 (Figure 4C) and CD25 (Figure 4D). Yamaguchi et al. proposed three morphological subtypes in cutaneous lesion of ATLL, i.e. perivascular, nodular and diffuse type.\n10\n All skin lesions analysed in this study were classified as the perivascular type. There was no definite lymphoma cell infiltration in skin samples from five patients (cases 4, 5, 6, 12 and 13) who were regarded as HTLV‐1 carriers and from three other patients (cases 9, 15 and 16) who did not undergo skin biopsy.\n\nFigure 4 Skin lesion diagnosed as smouldering adult T cell leukaemia/lymphoma (ATLL) (cutaneous variant, case 3). Small‐ to medium‐sized lymphoid cells mainly infiltrate the upper dermis (haematoxylin and eosin, A). Although nuclear atypia is not evident, infiltrating lymphoid cells form a Pautrier's microabscess (B) positive for CD4 (C) and CD25 (D).\n\nCase 14 showed a unique histopathological pattern characterised by focal proliferation and aggregation of atypical large lymphoid cells in the lymph node (Figure 5A–E). The cells were uniformly positive for CD20 (Figure 5D), focally positive for CD30 and negative for CD15. These proved to be EBV‐infected B cells (Figure 5E). A distinct neoplastic T cell proliferation was not detected by histological or molecular methods. Based on these findings, Hodgkin‐like incipient ATLL was an unlikely diagnosis.\n\nFigure 5 Human T cell leukaemia virus type I (HTLV‐1)‐associated lymphadenopathy with dermatopathic reaction, with focal proliferation of Epstein–Barr virus (EBV)‐positive transformed B cells (case 14). This lymph node shows an expanded paracortex with increased dendritic cells and pigment deposition (haematoxylin and eosin, arrow in A and C) and monotonous proliferation of atypical large lymphoid cells (arrowheads in A and B). Transformed large lymphoid cells were positive for CD20 (D) and EBV‐encoded small RNA in‐situ hybridisation (E).\n\nDiscussion\nThis is the first study, to our knowledge, to investigate the clinicopathological characteristics of lymph nodes with dermatopathic reaction in patients infected by HTLV‐1. Although HAL‐D cases showed an indolent clinical course for the most part, two of the three patients with ATLL‐D showed a relatively aggressive clinical course. The third ATLL‐D case was accompanied by leukaemic atypical lymphocytes, decreased albumin and elevated LDH, possibly classified as unfavourable chronic type, suggesting a relatively poor prognosis. Our study also showed the usefulness of abnormal T cell immunophenotype to distinguish HAL‐D and ATLL‐D. This method is also used in the evaluation of other T cell type neoplasms, such as Sézary syndrome.\n16\n Kobayashi et al.\n17\n established a method for identifying ATLL tumour cells based on flow cytometric detection of CD3 and CD7 expression. With disease progression, ATLL cells gradually change their immunophenotype from CD3(+)/CD7(+) to CD3(−)/CD7(−). The abnormal T cell immunophenotype seems not only to distinguish neoplastic from inflammatory status, but also predicts aggressiveness of the disease. Conversely, CD25‐positive transformed lymphoid cells proliferated in all cases. The number of CD30‐positive cells varied among cases, but was unrelated to either the distinction of ATLL‐D and HAL‐D or the clinical course. These cells can be regarded as activated/stimulated lymphocytes. Immunohistochemical analysis of lymph nodes with dermatopathic reaction from two cases without HTLV‐1 infection or CTCL revealed that they also harboured proliferating CD25‐ and CD30‐positive cells, suggesting that this is not specific to HTLV‐1‐associated lesions (Supporting information, Supplemental Figure 1). This could complicate diagnosis in cases where infiltration of lymphoid malignancy is suspected, including ATLL.\n\nIn case 14, there was focal proliferation of EBV‐infected large B cells, whereas definitive clonal T cell proliferation or abnormal T cell immunophenotype was not observed. This finding has been described in several lymphomas, including angioimmunoblastic T cell lymphoma, and reflects an immunodeficient local environment created by tumour cells.\n18\n This case was distinguished from the Hodgkin lymphoma‐like variant accompanied by incipient ATLL because the proliferating cells were uniformly positive for CD20 (Figure 5D), focally positive for CD30 and negative for CD15.\n19\n EBV‐positive B cell lymphoproliferative disorders, associated with age‐related immune deficiency and comprising a wide disease spectrum from benign to malignant status, is one possibility.\n20\n, \n21\n However, an immunosuppressive status induced by HTLV‐1 infection could also contribute to the proliferation of EBV‐infected cells, as previously reported.\n22\n, \n23\n ATLL tumour cells and HTLV‐1‐infected cells often exhibit the phenotype of regulatory T cells, including expression of CD4, CD25 and forkhead box P3.\n24\n EBV‐positive cell proliferation combined with dermatopathic reaction mimicking lymphoma‐type ATLL can be a potential pitfall in routine diagnosis.\n\nAlthough ATLL‐D is a form of neoplastic status of ATLL, it is unclear whether these cases should be treated as lymphoma type, which usually have a very aggressive clinical course and dismal prognosis\n8\n. Ohshima et al. described a Hodgkin‐like type as an incipient ATLL.\n19\n Even though the morphological findings of ATLL‐D are different from Hodgkin‐like type, ATLL‐D could be regarded as another variant of incipient ATLL. In fact, one ATLL‐D patient (case 18) was classified clinically as chronic type. However, assessment of the clinicopathological findings in other similar cases is needed to verify this.\n\nIn conclusion, the present study highlighted a spectrum of nodal lesions accompanied by dermatopathic reaction in HTLV‐1 carriers. While HAL‐D and ATLL‐D share several features, careful observation for the detection of atypical lymphoid cell infiltration and abnormal T cell immunophenotype and clonality rearrangement may support the distinction between reactive and neoplastic conditions. Once the possibility of overt lymphoma is excluded, an indolent clinical course can be expected. Cases of HAL‐D should be treated with topical therapy, and overtreatment with cytotoxic chemotherapy should be avoided.\n\nConflicts of interest\nThe authors declare no potential conflicts of interest.\n\nAuthorship contributions\nConception and design: K. Karube, S. Chinen, T. Miyagi, K. Takahashi. Development of methodology: M. Takatori, S. Sakihama. Acquisition of data: S. Chinen, Y. Murakami, I. Nakazato, Y. Kariya, S. Yamaguchi, K. Karube.\n\nSupporting information\n\nFigure S1. Pathological findings of lymph nodes of reactive lymphadenitis with dermatopathic reaction in a HTLV‐1 uninfected patient.\n\nClick here for additional data file.\n\n \nTable S1. Flowcytometric analysis of lymph nodes.\n\nClick here for additional data file.\n\n Acknowledgements\nThe authors thank Chikako Nagamine for technical support and the staff at the Department of Pathology of University of the Ryukyus University Hospital and Okinawa Prefectural Nanbu Medical Center and Children's Medical Center for their assistance. This work was supported by Grants‐in‐aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (no. 15K08371); Okinawa prefecture; Ichiro Kanehara Foundation; Yasuda Medical Foundation; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Japan Leukaemia Research Fund; The Japanese Society of Hematology Research Grant; and Okinawa Internal Medicine Research Promotion Society (all to K.K.).\n==== Refs\nReferences\n1 \n\nBurke \nJS \n, \nColby \nTV \n. Dermatopathic lymphadenopathy. Comparison of cases associated and unassociated with mycosis fungoides\n. Am. J. Surg. Pathol. \n1981 ; 5 ; 343 –352\n.7270782 \n2 \n\nBurke \nJS \n, \nSheibani \nK \n, \nRappaport \nH \n. Dermatopathic lymphadenopathy. An immunophenotypic comparison of cases associated and unassociated with mycosis fungoides\n. Am. J. Pathol. \n1986 ; 123 ; 256 –263\n.3486598 \n3 \n\nWeiss \nLM \n, \nWood \nGS \n, \nWarnke \nRA \n. Immunophenotypic differences between dermatopathic lymphadenopathy and lymph node involvement in mycosis fungoides\n. Am. J. Pathol. \n1985 ; 120 ; 179 –185\n.3161334 \n4 \n\nShimoyama \nM \n. Diagnostic criteria and classification of clinical subtypes of adult T‐cell leukaemia‐lymphoma\n. Br J Haematol \n1991 ; 79 ; 428 –437\n.1751370 \n5 \n\nFukushima \nT \n, \nNomura \nS \n, \nShimoyama \nM \n\net al\nJapan Clinical Oncology Group (JCOG) prognostic index and characterization of long‐term survivors of aggressive adult T‐cell leukaemia–lymphoma (JCOG0902a)\n. Br. J. Haematol. \n2014 ; 166 ; 739 –748\n.24931507 \n6 \n\nKatsuya \nH \n, \nYamanaka \nT \n, \nIshitsuka \nK \n\net al\nPrognostic index for acute‐ and lymphoma‐type adult T‐cell leukaemia/lymphoma\n. J. Clin. Oncol. \n2012 ; 30 ; 1635 –1640\n.22473153 \n7 \n\nYoshida \nN \n, \nKarube \nK \n, \nUtsunomiya \nA \n\net al\nMolecular characterization of chronic‐type adult T‐cell leukaemia/lymphoma\n. Cancer Res. \n2014 ; 74 ; 6129 –6138\n.25320005 \n8 \n\nKatsuya \nH \n, \nIshitsuka \nK \n, \nUtsunomiya \nA \n\net al\nTreatment and survival among 1594 patients with ATL\n. Blood \n2015 ; 126 ; 2570 –2577\n.26361794 \n9 \n\nOhshima \nK \n, \nSuzumiya \nJ \n, \nSato \nK \n\net al\nSurvival of patients with HTLV‐I‐associated lymph node lesions\n. J. Pathol. \n1999 ; 189 ; 539 –545\n.10629555 \n10 \n\nYamaguchi \nT \n, \nOhshima \nK \n, \nKarube \nK \n\net al\nClinicopathological features of cutaneous lesions of adult T‐cell leukaemia/lymphoma\n. Br. J. Dermatol. \n2005 ; 152 ; 76 –81\n.15656804 \n11 \n\nvan Dongen \nJJ \n, \nLangerak \nAW \n, \nBruggemann \nM \n\net al\nDesign and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T‐cell receptor gene recombinations in suspect lymphoproliferations: report of the biomed‐2 concerted action BMH4‐CT98‐3936\n. Leukaemia \n2003 ; 17 ; 2257 –2317\n.\n12 \n\nYoshida \nM \n, \nSeiki \nM \n, \nYamaguchi \nK \n, \nTakatsuki \nK \n. Monoclonal integration of human T‐cell leukaemia provirus in all primary tumors of adult T‐cell leukaemia suggests causative role of human T‐cell leukaemia virus in the disease\n. Proc. Natl. Acad. Sci. USA \n1984 ; 81 ; 2534 –2537\n.6326131 \n13 \n\nKojima \nM \n, \nNakamura \nS \n, \nItoh \nH \n\net al\nClinical implication of dermatopathic lymphadenopathy among Japanese: a report of 19 cases\n. Int. J. Surg. Pathol. \n2004 ; 12 ; 127 –132\n.15173917 \n14 \n\nYagi \nH \n, \nTakigawa \nM \n, \nHashizume \nH \n. Cutaneous type of adult T cell leukaemia/lymphoma: a new entity among cutaneous lymphomas\n. J. Dermatol. \n2003 ; 30 ; 641 –643\n.14578552 \n15 \n\nYokote \nT \n, \nAkioka \nT \n, \nOka \nS \n\net al\nFlow cytometric immunophenotyping of adult T‐cell leukaemia/lymphoma using CD3 gating\n. Am. J. Clin. Pathol. \n2005 ; 124 ; 199 –204\n.16040289 \n16 \n\nBoonk \nSE \n, \nZoutman \nWH \n, \nMarie‐Cardine \nA \n\net al\nEvaluation of immunophenotypic and molecular biomarkers for sezary syndrome using standard operating procedures: a multicenter study of 59 patients\n. J. Invest. Dermatol. \n2016 ; 136 ; 1364 –1372\n.26930587 \n17 \n\nKobayashi \nS \n, \nTian \nY \n, \nOhno \nN \n\net al\nThe CD3 versus CD7 plot in multicolor flow cytometry reflects progression of disease stage in patients infected with HTLV‐I\n. PLoS ONE \n2013 ; 8 ; e53728.23349737 \n18 \n\nHoffmann \nJC \n, \nChisholm \nKM \n, \nCherry \nA \n\net al\nAn analysis of MYC and EBV in diffuse large B‐cell lymphomas associated with angioimmunoblastic T‐cell lymphoma and peripheral T‐cell lymphoma not otherwise specified\n. Hum. Pathol. \n2016 ; 48 ; 9 –17\n.26772393 \n19 \n\nOhshima \nK \n, \nKikuchi \nM \n, \nYoshida \nT \n, \nMasuda \nY \n, \nKimura \nN \n. Lymph nodes in incipient adult T‐cell leukaemia–lymphoma with Hodgkin's disease‐like histologic features\n. Cancer \n1991 ; 67 ; 1622 –1628\n.2001551 \n20 \n\nDojcinov \nSD \n, \nVenkataraman \nG \n, \nPittaluga \nS \n\net al\nAge‐related EBV‐associated lymphoproliferative disorders in the western population: a spectrum of reactive lymphoid hyperplasia and lymphoma\n. Blood \n2011 ; 117 ; 4726 –4735\n.21385849 \n21 \n\nOyama \nT \n, \nIchimura \nK \n, \nSuzuki \nR \n\net al\nSenile EBV+ B‐cell lymphoproliferative disorders: a clinicopathologic study of 22 patients\n. Am. J. Surg. Pathol. \n2003 ; 27 ; 16 –26\n.12502924 \n22 \n\nOhshima \nK \n, \nSuzumiya \nJ \n, \nKato \nA \n, \nTashiro \nK \n, \nKikuchi \nM \n. Clonal HTLV‐I‐infected CD4+ T‐lymphocytes and non‐clonal non‐HTLV‐I‐infected giant cells in incipient ATLL with Hodgkin‐like histologic features\n. Int. J. Cancer \n1997 ; 72 ; 592 –598\n.9259396 \n23 \n\nBeltran \nB \n, \nSalas \nR \n, \nQuinones \nP \n\net al\nEBV‐positive diffuse large B‐cell lymphoma in a human T‐lymphotropic virus type 1 carrier\n. Infect. Agent. Cancer \n2009 ; 4 ; 10 .19580668 \n24 \n\nKarube \nK \n, \nOhshima \nK \n, \nTsuchiya \nT \n\net al\nExpression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T‐cell leukaemia/lymphoma cells\n. Br. J. Haematol. \n2004 ; 126 ; 81 –84\n.15198736\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0309-0167",
"issue": "77(1)",
"journal": "Histopathology",
"keywords": "adult T cell leukaemia/lymphoma; dermatopathic reaction; human T cell leukaemia virus type 1; immunophenotype; prognosis",
"medline_ta": "Histopathology",
"mesh_terms": "D000368:Aged; D005260:Female; D015490:HTLV-I Infections; D015368:Human T-lymphotropic virus 1; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell; D008198:Lymph Nodes; D016410:Lymphoma, T-Cell, Cutaneous; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012867:Skin; D012878:Skin Neoplasms",
"nlm_unique_id": "7704136",
"other_id": null,
"pages": "133-143",
"pmc": null,
"pmid": "32162348",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article",
"references": "1751370;26930587;3161334;15198736;14578552;26772393;26361794;22473153;10629555;15656804;32162348;3486598;2001551;25320005;24931507;12502924;9259396;14671650;16040289;23349737;7270782;6326131;15173917;19580668;21385849",
"title": "Dermatopathic reaction of lymph nodes in HTLV-1 carriers: a spectrum of reactive and neoplastic lesions.",
"title_normalized": "dermatopathic reaction of lymph nodes in htlv 1 carriers a spectrum of reactive and neoplastic lesions"
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"abstract": "Despite the proved safety and efficacy of Woven EndoBridge (WEB) flow disruption in conventional intracranial saccular aneurysms, the literature on its use in partially thrombosed intracranial aneurysms is scarce. We report a series of 4 patients in whom partially thrombosed intracranial aneurysms were treated with the WEB. The 2 patients who received additional intraluminal treatment with conventional stents made a good clinical recovery. Meanwhile, those patients who were treated with the WEB alone had fatal rupture of the aneurysm at short- to medium-term follow-up. This small, select case series demonstrates that WEB placement with adjunctive stent placement may be an effective treatment in the management of partially thrombosed intracranial aneurysms, which merits further validation. However, exclusive intrasaccular flow disruption may have an adverse influence on the natural history of this disease.",
"affiliations": "From the Departments of Neuroradiology (G.A., A.J.P.G., T.P.) Department of Diagnostic Imaging (G.A.), National University Hospital, Singapore. ivyanil10@gmail.com.;From the Departments of Neuroradiology (G.A., A.J.P.G., T.P.).;Neurosurgery (S.M.R., K.D.), Leeds Teaching Hospitals, National Health Service Trust, Leeds, UK.;Neurosurgery (S.M.R., K.D.), Leeds Teaching Hospitals, National Health Service Trust, Leeds, UK.;From the Departments of Neuroradiology (G.A., A.J.P.G., T.P.).",
"authors": "Anil|G|G|0000-0002-8192-1287;Goddard|A J P|AJ|0000-0001-6104-5606;Ross|S M|SM|0000-0002-8006-3137;Deniz|K|K|0000-0003-4612-2401;Patankar|T|T|0000-0003-3460-1528",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3174/ajnr.A4604",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-6108",
"issue": "37(5)",
"journal": "AJNR. American journal of neuroradiology",
"keywords": null,
"medline_ta": "AJNR Am J Neuroradiol",
"mesh_terms": "D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D015607:Stents; D013927:Thrombosis; D016896:Treatment Outcome",
"nlm_unique_id": "8003708",
"other_id": null,
"pages": "892-6",
"pmc": null,
"pmid": "26585255",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20725843;18296545;20566139;20210035;24994823;22678844;19921162;20299431;24694000;3614624;21071538;21881914;21527573;24943909",
"title": "WEB in Partially Thrombosed Intracranial Aneurysms: A Word of Caution.",
"title_normalized": "web in partially thrombosed intracranial aneurysms a word of caution"
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"companynumb": "SG-BAYER-2016-125234",
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"abstract": "Patients chronically infected with the hepatitis B virus (HBV) and receiving long-term treatment with nucleoside or nucleotide analogues are at risk of selecting HBV strains with complex mutational patterns. We herein report two cases of HBV-infected patients with insufficient viral suppression, despite dual antiviral therapy with entecavir (ETV) and tenofovir (TDF). One patient died from aggressive hepatocellular carcinoma (HCC).\n\n\n\nSerum samples from the two patients at different time points were analyzed using ultra-deep pyrosequencing analysis. HBV mutations were identified and transiently transfected into hepatoma cells in vitro using replication-competent HBV vectors, and functionally analyzed. We assessed replication efficacy, resistance to antivirals and potential impact on HBV secretion (viral particles, exosomes).\n\n\n\nSequencing analyses revealed the selection of the rtS78T HBV polymerase mutation in both cases that simultaneously creates a premature stop codon at sC69 and thereby deletes almost the entire small HBV surface protein. One of the patients had an additional 261bp deletion in the preS1/S2 region. Functional analyses of the mutations in vitro revealed that the rtS78T/sC69∗ mutation, but not the preS1/S2 deletion, significantly enhanced viral replication and conferred reduced susceptibility to ETV and TDF. The sC69∗ mutation caused truncation of HBs protein, leading to impaired detection by commercial HBsAg assay, without causing intracellular HBsAg retention or affecting HBV secretion.\n\n\n\nThe rtS78T/sC69∗ HBV mutation, associated with enhanced replication and insufficient response to antiviral treatment, may favor long-term persistence of these isolates. In addition to the increased production of HBV transcripts and the sustained secretion of viral particles in the absence of antigenic domains of S protein, this HBV mutation may predispose patients to carcinogenic effects.\n\n\n\nLong-term treatment with antiviral drugs carries the risk of selecting mutations in the hepatitis B virus (HBV). We herein report two cases of patients with insufficient response to dual tenofovir and entecavir therapy. Molecular analyses identified a distinct mutation, rtS78T/sC69∗, that abolishes HBsAg detection, enhances replication, sustains exosome-mediated virion secretion and decreases susceptibility to antivirals, thereby representing a potentially high-risk mutation for HBV-infected individuals.",
"affiliations": "Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany; Department of Molecular Biology, Princeton University, Princeton, NJ, USA.;Department of Molecular Biology, Princeton University, Princeton, NJ, USA.;Department of Molecular Biology, Princeton University, Princeton, NJ, USA.;Department of Molecular Biology, Princeton University, Princeton, NJ, USA.;Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.;Medical Care Centre, Dr Stein and Colleagues, Mönchengladbach, Germany.;Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.;Roche Diagnostics SL, Sant Cugat del Vallès, Spain.;Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany.;Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany.;Department of Molecular Biology, Princeton University, Princeton, NJ, USA.;Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany. Electronic address: frank.tacke@gmx.net.",
"authors": "Shirvani-Dastgerdi|Elham|E|;Winer|Benjamin Y|BY|;Celià-Terrassa|Toni|T|;Kang|Yibin|Y|;Tabernero|David|D|;Yagmur|Eray|E|;Rodríguez-Frías|Francisco|F|;Gregori|Josep|J|;Luedde|Tom|T|;Trautwein|Christian|C|;Ploss|Alexander|A|;Tacke|Frank|F|",
"chemical_list": "D000998:Antiviral Agents; D015684:Gene Products, pol; C066027:P protein, Hepatitis B virus; C413685:entecavir; D006147:Guanine; D000068698:Tenofovir; D012194:RNA-Directed DNA Polymerase",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jhep.2017.03.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0168-8278",
"issue": "67(2)",
"journal": "Journal of hepatology",
"keywords": "Carcinoma; Drug resistance; Exosomes; Hepatitis B surface antigens; Hepatitis B virus; Hepatocellular; Mutations",
"medline_ta": "J Hepatol",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D024921:Drug Resistance, Multiple, Viral; D004359:Drug Therapy, Combination; D005260:Female; D015684:Gene Products, pol; D005814:Genes, Viral; D006147:Guanine; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012194:RNA-Directed DNA Polymerase; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D000068698:Tenofovir; D014779:Virus Replication",
"nlm_unique_id": "8503886",
"other_id": null,
"pages": "246-254",
"pmc": null,
"pmid": "28392234",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "24587012;17133475;27238466;27394647;19263474;17178796;23286855;23349904;20887378;25759099;17206752;26566064;27650283;18537180;19889778;19586679;27182775;16218172;20049753;22436845;15280461;27504999;22744635;24574711;26433026;27252524;15328117;25532501;24630522;19301976;23796863;25180507;17438047;27084035",
"title": "Selection of the highly replicative and partially multidrug resistant rtS78T HBV polymerase mutation during TDF-ETV combination therapy.",
"title_normalized": "selection of the highly replicative and partially multidrug resistant rts78t hbv polymerase mutation during tdf etv combination therapy"
} | [
{
"companynumb": "DE-MYLANLABS-2017M1049890",
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"occurcountry": "DE",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ENTECAVIR"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAcute toxic leukoencephalopathy following intrathecal methotrexate administration is well documented but intracranial haemorrhage is extremely rare.\n\n\nMETHODS\nA 2-year-6 months old girl with acute lymphoblastic leukemia developed sudden onset neurological deterioration following intrathecal methotrexate.\n\n\nMETHODS\nComputed tomography scan of brain demonstrated intraventricular and subarachnoid hemorrhage.\n\n\nRESULTS\nChild improved gradually on conservative management. Follow-up neuroimaging showed resolution of hemorrhage.\n\n\nCONCLUSIONS\nIntracranial haemorrhage is a rare but serious complication of intrathecal methotrexate.",
"affiliations": "Departments of Pediatric Medicine and *Haematology, NRS Medical College and Hospital, Kolkata, West Bengal, India. Correspondence to: Dr Radheshyam Purkait, Department of Pediatric Medicine, NRS Medical College and Hospital, Kolkata 700 014, West Bengal, India. radheshyampurkait@gmail.com.",
"authors": "Purkait|Radheshyam|R|;Dolai|Tuphan Kanti|TK|;Lath|Chinmoy|C|;Das|Biswajit|B|",
"chemical_list": "D000970:Antineoplastic Agents; D008727:Methotrexate",
"country": "India",
"delete": false,
"doi": "10.1007/s13312-016-0866-4",
"fulltext": null,
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"issn_linking": "0019-6061",
"issue": "53(5)",
"journal": "Indian pediatrics",
"keywords": null,
"medline_ta": "Indian Pediatr",
"mesh_terms": "D000970:Antineoplastic Agents; D001921:Brain; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D020300:Intracranial Hemorrhages; D008727:Methotrexate; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "2985062R",
"other_id": null,
"pages": "423-4",
"pmc": null,
"pmid": "27254055",
"pubdate": "2016-05-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intracranial Hemorrhage Following Intrathecal Methotrexate Therapy for Acute Lymphoblastic Leukaemia.",
"title_normalized": "intracranial hemorrhage following intrathecal methotrexate therapy for acute lymphoblastic leukaemia"
} | [
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"abstract": "A 31-year-old woman at 30 weeks gestation presented to the emergency department following multiple seizures. Her history was significant for extranodal Rosai-Dorfman Disease (RDD) with central nervous system (CNS) lesions. RDD, a rare form of non-Langerhans cell histiocytosis, commonly presents with non-tender cervical lymphadenopathy. CNS involvement accounts for a small number of cases in those with extranodal disease. Patients with CNS RDD can have a variety of neurological symptoms, including seizures. Eclampsia, a relatively rare obstetric hypertensive disorder, is always within the differential diagnosis for patients presenting with late gestation seizures. We present the challenging evaluation and treatment of a patient whose clinical picture did not clearly differentiate eclampsia from new onset seizures related to progression of her RDD. This conundrum perhaps resulted in unnecessary preterm operative delivery of a critically ill patient. Only follow-up of the patient helped clarify the likely antepartum diagnosis.",
"affiliations": "Obstetrics-Gynecology, Wayne State University, Detroit, Michigan, USA kswor@med.wayne.edu.;Neurology, Wayne State University, Detroit, Michigan, USA.;Emergency Medicine, Wayne State University, Detroit, Michigan, USA.;Obstetrics-Gynecology, Wayne State University, Detroit, Michigan, USA.",
"authors": "Swor|Katie|K|;Zutshi|Deepti|D|;Dubey|Elizabeth|E|;Gonik|Bernard|B|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-239427",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(2)",
"journal": "BMJ case reports",
"keywords": "epilepsy and seizures; pregnancy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D003937:Diagnosis, Differential; D018450:Disease Progression; D004461:Eclampsia; D005260:Female; D015618:Histiocytosis, Sinus; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D012640:Seizures",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33602767",
"pubdate": "2021-02-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pregnant patient with extranodal CNS Rosai-Dorfman disease with new-onset seizures: the conundrum of differentiating disease progression from eclampsia.",
"title_normalized": "pregnant patient with extranodal cns rosai dorfman disease with new onset seizures the conundrum of differentiating disease progression from eclampsia"
} | [
{
"companynumb": "US-MLMSERVICE-20210806-3037775-1",
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"activesubstancename": "LEVETIRACETAM"
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"abstract": "Li-Fraumeni syndrome (LFS) is an autosomal dominant condition associated with a high risk of a broad range of childhood- and adult-onset cancers. LFS is related to germline mutations of the tumor-suppressor gene TP53 The most common reported leukemia associated with LFS is hypodiploid acute lymphoblastic leukemia, but myeloid malignancies including acute myeloid leukemia (AML), chronic myeloid leukemia, and myelodysplastic syndrome (MDS) are also reported, often in the setting of therapy-related disease. We reviewed the clinicopathologic characteristics including cytogenetics and molecular analysis for seven adult patients with LFS and hematologic malignancies evaluated at the Hereditary Hematologic Malignancy Clinic (HHMC) at MD Anderson Cancer Center. We present this LFS review series to increase awareness of LFS for the appropriate diagnosis of both patients and potentially affected relatives, as well as provide experience with patient outcomes in this difficult to treat population.",
"affiliations": "Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA.;Department of Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA.;Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA.;Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA.;Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA.",
"authors": "Swaminathan|Mahesh|M|;Bannon|Sarah A|SA|;Routbort|Mark|M|;Naqvi|Kiran|K|;Kadia|Tapan M|TM|;Takahashi|Koichi|K|0000-0002-8027-9659;Alvarado|Yesid|Y|;Ravandi-Kashani|Farhad|F|;Patel|Keyur P|KP|;Champlin|Richard|R|;Kantarjian|Hagop|H|;Strong|Louise|L|;DiNardo|Courtney D|CD|",
"chemical_list": "D016159:Tumor Suppressor Protein p53",
"country": "United States",
"delete": false,
"doi": "10.1101/mcs.a003210",
"fulltext": "\n==== Front\nCold Spring Harb Mol Case StudCold Spring Harb Mol Case StudcshmcscshmcscshmcsCold Spring Harbor Molecular Case Studies2373-2873Cold Spring Harbor Laboratory Press 3070987510.1101/mcs.a003210MCS003210SwaResearch ArticleHematologic malignancies and Li–Fraumeni syndrome Hematologic malignancies and Li–Fraumeni syndromeHematologic malignancies and Li–Fraumeni syndromeSwaminathan Mahesh 1Bannon Sarah A. 2Routbort Mark 3Naqvi Kiran 1Kadia Tapan M. 1http://orcid.org/0000-0002-8027-9659Takahashi Koichi 1Alvarado Yesid 1Ravandi-Kashani Farhad 1Patel Keyur P. 3Champlin Richard 4Kantarjian Hagop 1Strong Louise 5DiNardo Courtney D. 11 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA;2 Department of Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA;3 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA;4 Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USA;5 Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, USACorresponding author: cdinardo@mdanderson.org2 2019 5 1 a0032106 6 2018 4 10 2018 © 2019 Swaminathan et al.; Published by Cold Spring Harbor Laboratory Press2019This 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.Li–Fraumeni syndrome (LFS) is an autosomal dominant condition associated with a high risk of a broad range of childhood- and adult-onset cancers. LFS is related to germline mutations of the tumor-suppressor gene TP53. The most common reported leukemia associated with LFS is hypodiploid acute lymphoblastic leukemia, but myeloid malignancies including acute myeloid leukemia (AML), chronic myeloid leukemia, and myelodysplastic syndrome (MDS) are also reported, often in the setting of therapy-related disease. We reviewed the clinicopathologic characteristics including cytogenetics and molecular analysis for seven adult patients with LFS and hematologic malignancies evaluated at the Hereditary Hematologic Malignancy Clinic (HHMC) at MD Anderson Cancer Center. We present this LFS review series to increase awareness of LFS for the appropriate diagnosis of both patients and potentially affected relatives, as well as provide experience with patient outcomes in this difficult to treat population.\n\nleukemiamultiple lineage myelodysplasia\n==== Body\nINTRODUCTION\nLi–Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome caused by germline TP53 gene mutations, first described in 1969 by Li and Fraumeni (Li and Fraumeni 1969). Patients with this syndrome are at increased risk of developing multiple primary tumors including breast cancer, soft tissue sarcoma, brain tumors, osteosarcoma, and adrenocortical carcinoma (Gonzalez et al. 2009; Ruijs et al. 2010). Other cancers associated with LFS include ovarian, gastrointestinal, pancreatic, genitourinary, skin, renal, thyroid, prostate, and lung, as well as leukemia, lymphoma, and neuroblastoma (McBride et al. 2014). Incidence of leukemias in LFS is ∼4% (Bougeard et al. 2015; World Health Organization 2018), including hypodiploid acute lymphoblastic leukemia (ALL) and therapy-related myeloid disorders including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) (Li et al. 1988; Law et al. 1991; Birch et al. 2001; Talwalkar et al. 2010).\n\nTwo published algorithms are utilized to identify patients at risk of LFS who would benefit from molecular testing, the classical LFS criteria and the Chompret criteria (Tinat et al. 2009; Bougeard et al. 2015), detailed in Table 1. Criteria include a personal history of sarcoma or other LFS spectrum tumors and a family history of cancers at a young age, indicating the importance of obtaining an accurate family history in the evaluation of cancer patients. When used alone, the classical LFS criteria have a lower sensitivity of 40% and the Chompret criteria have a sensitivity of 20% (Sorrell et al. 2013), but when combined, they have a sensitivity of 95% and a specificity of 52% in identifying patients with LFS (Ruijs et al. 2010).\n\nTable 1. Chompret and classical LFS criteria\n\nClassical LFS criteria (one of the following)\tProband with sarcoma diagnosed before age 45 yr\t\nFirst-degree relative with any cancer before age 45 yr\t\nFirst- or second-degree relative with any cancer before age 45 yr or sarcoma at any age\t\nChompret criteria (one of the following)\tProband with LFS tumors (sarcoma, premenopausal breast cancer, brain tumor, adrenocortical carcinoma, leukemia, or bronchoalveolar cancer), before age 46 yr\t\nAt least one first- or second-degree relative with an LFS tumor (except breast cancer if the proband has breast cancer, before age 56 yr or with multiple tumors)\t\nProband with multiple tumors (except multiple breast tumors), two of which belong to LFS tumors and the first of which occurred before age 46 yr\t\nProband diagnosed with adrenocortical carcinoma or choroid plexus tumor, irrespective of family history\t\nAge-related and sex-specific cancer risks with LFS were reported by Chompret et al. (2000). The overall risks of men to develop cancer by ages 16, 45, and 85 yr are 19%, 41%, and 73%, respectively, whereas the risks of women by ages 16, 45, and 85 yr are 12%, 84%, and 100%, respectively (Varley et al. 1997; Chompret et al. 2000). Truncating variants have been suggested to result in decreased penetrance and later age at onset compared to the more common missense mutations (Zerdoumi et al. 2013). Given the dramatic lifetime risk of cancer, individuals with a diagnosis of LFS are followed twice annually by the Li–Fraumeni Education and Early Detection (LEAD) cancer prevention clinic, with biannual physical exam, blood work, and imaging including whole-body magnetic resonance imaging (MRI) for early detection.\n\nDespite the known association of LFS with hematologic malignancies, there is limited awareness of LFS in the adult malignant hematology community. In this case series, we report on the presentation, treatment, and patient outcome of seven adult patients with LFS and hematologic malignancy who were evaluated within the Hereditary Hematologic Malignancy Clinic (HHMC) at the University of Texas MD Anderson Cancer Center. This cohort includes patients who were diagnosed with de novo acute leukemia with a LFS diagnosis established during leukemia therapy, as well as patients with a history of solid tumors and known LFS diagnosis, who developed therapy-related AML or MDS during follow-up within the LEAD prevention clinic.\n\nCLINICAL HISTORIES\nCase 1\nA 34-yr-old woman was referred to clinical cancer genetics because of a history of early-onset breast cancer. She was diagnosed with right breast invasive ductal carcinoma at age 30 and treated with chemotherapy and radiotherapy (Table 2). Her family history was significant for medulloblastoma in her son at age 6 yr, benign adrenal gland tumor in her daughter at age 9 mo, gastric cancer in her mother at age 21 yr, leukemia in her maternal uncle at age 16 yr, gastric cancer in her maternal grandmother when she was in her 40s, and throat cancer in her maternal great-aunt (grandmother's sister), as detailed in the pedigree in Figure 1A. The patient met Chompret criteria for LFS and underwent TP53 genetic testing, which revealed a pathogenic deletion of exons 10–11. After completion of breast cancer therapy, the patient was monitored within the LEAD program. At age 35 yr, she was diagnosed with a right thigh spindle cell sarcoma, which was treated with neoadjuvant chemotherapy + radiotherapy followed by surgical resection. Subsequently, she developed another sarcoma in her right axillary region, which was treated with chemotherapy followed by surgical resection. At age 40 yr, she was diagnosed with therapy-related AML (t-AML) with adverse cytogenetics (monosomal karyotype with extensive chromosomal abnormalities) and IDH2 mutation (Tables 3 and 4). The patient underwent induction chemotherapy with fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG). She attained a complete remission (CR) and after five courses, CR with negative MRD by multiparameter flow cytometry was confirmed and she was further consolidated with a haploidentical stem cell transplantation (SCT) with fludarabine, melphalan, and thiotepa (FMT) conditioning regimen from a tested and LFS-unaffected family member. The SCT was complicated by acute cutaneous graft versus host disease (GVHD), which resolved with topical steroids. Six months after transplantation, her AML relapsed (Table 5). She was then treated on a Phase 1 clinical trial of azacitidine with lirilumab without response, and she then elected to transition to hospice care after sequelae of neutropenic sepsis.\n\nFigure 1. (A) Pedigree charts of (A) case 1, (B) case 2, (C) case 3, (D) case 4, (E) case 5, (F) case 6, and (G) case 7.\n\nTable 2. Treatment of solid tumors preceding hematologic malignancy\n\nCase no.\tAge (years)/sex\tSolid malignant neoplasms\tTreatment received\t\n1\t34/F\tRT breast ductal carcinoma\tDocetaxel + capecitabine × 4 courses (C), 5-fluorouracil, epirubicin, cyclophosphamide × 4 C, RT segmental mastectomy with axillary node dissection, XRT 5000 cGy in 25 fractions and tamoxifen\t\nRT thigh spindle cell cancer\tAdriamycin + ifosfamide × 6 C, XRT 5000 cGy in 25 fractions, and surgical resection\t\nSarcoma of RT axillary region\tGemcitabine + docetaxel × 5 C, and surgical resection\t\n2\t32/F\tLT maxillary sinus osteosarcoma\tDoxorubicin + cisplatin × 4 C, and LT maxillectomy\t\nBilateral papillary thyroid cancer\tThyroidectomy with LT-sided paratracheal neck dissection\t\n3\t42/M\tPleomorphic sarcoma of RT hip and gluteal region\tAdriamycin + ifosfamide × 6 C, XRT 5000 cGy in 25 fractions, and radical resection of sarcoma\t\n4\t28/F\tRT breast pleomorphic spindle cell cancer\tAdriamycin + ifosfamide × 6 C, XRT 5000 cGy in 25 fractions, and bilateral mastectomy\t\nLT breast DCIS\t\n5\t50/F\tRT breast mixed ductal and lobular carcinoma\tModified radical mastectomy, 5-fluorouracil, doxorubicin, cyclophosphamide × 6 C, and prophylactic XRT to LT breast\t\nHigh-grade osteosarcoma of chest wall\tAdriamycin + ifosfamide and docetaxel + gemcitabine × 2 C, RT chest wall resection, and methotrexate × 8 C\t\n6\t34/F\tNone\t\t\n7\t24/M\tAstrocytoma\tSurgical resection\t\n(RT) Right, (LT) left, (DCIS) ductal carcinoma in situ, (XRT) external beam radiation therapy, (C) cycle.\n\nTable 3. Clinicopathologic characteristics of hematologic malignancy\n\nCase no.\tAge (years) /sex\tCytogenetics at diagnosis\tGermline TP53 mutation\tMutations in BM\tBlood malignancy\tTime to hematological malignancy diagnosis (from the treatment of primary cancer) (years)\t\n1\t34/F\t44,X,add(X)(p22.1),−2,del(5)(q15q33),del(11)(p13),−12,−13,−13,−17,−17,+21,add(22)(p11.2),+3mar[6]/45,idem,+mar[9]/45,idem,+8[1]/89,XX,add(X)(p22.1)×2,−2,−2,+3,−4,del(5)(q15q33)×2,−10,del(11)(p13)×2,−12,−12,−13,−13,−13,−13,−14,−17,−17,−17,−17,+21,+21,+22,+22,add(22)(p11.2)×2, +7mar[1]/46,XX[3]\tDel exons 10–11\tIDH2\tt-AML\t10\t\n2\t32/F\t45,X,der(X)t(X;3)(q22;q23),−3,add(5)(q22),der(6)t(3;6)(q13;q23),add(7)(q22),del(12)(p12),add(21)(p11.2),−22,+1∼3mar[cp20]\tc.184G>T (p.E62*) and c.764T>C (p.I255T)\tTP53a\tt-MDS\t2\t\n3\t42/M\t44,XY,del(5)(q13),add(7)(q11.2),−11,−12,−17,−17,+r,+mar[18]/44,XY,del(5)(q13q33),add(7)(q11.2),−11,−12,−17,−17,+1∼2mar[cp2]/10\tc.800G>A (p.R267Q) and c.467G>A (p.R156H)\tTET2, EGFR, TP53a\tt-AML\t2\t\n4\t28/F\t44∼47,X,−X,del(9)(q13q22),−11,+17,der(17)add(17)(p11.2)add(17)(q11.2),der(17)add(17)(p11.2)hsr(11)(q23),+1∼2mar,2∼5dmin[cp20]\tc.586C>T (p.R196*)\tBCORL1, WT1, TP53a\tt-AML\t4\t\n5\t50/F\t55∼58<2n>,XX,+X,+1,+8,+9,+10,+11,+11,+12,der(13;21)(q10;q10),i(13)(q10),+14,+19,+20,+20,+22[cp13]/46,XX,i(11)(p10)[1]/46,XX[6]\tc.734G>A (p.R248Q)\tBCOR, DNMT3A, TP53a\tt-AML\t20\t\n6\t34/F\t62∼66,XX,−X,+1,−3,−4,−5,+6,−7,+8,−9,+12,−13,−13,−15,−16,−17,−17,+18,+18,add(20)(q13.2),+22[cp8]/46,XX[12]\tc.325T>G (p.F109V)\tJAK2, TP53a\tALL\t0\t\n7\t24/M\t41∼45,XY,−1,add(1)(p13),add(1)(p36.1),add(5)(q31),der(6)add(6)(p12)dup(6)(q23q23),+7,−12,−16,del(17)(p11.2),−19,+21,+1∼2mar[cp13]\tc.524G>A (p.R175H)\tNOTCH1, TP53a\tEarly precursor T-ALL\t0\t\n(BM) Bone marrow, (RT) right, (t-AML) therapy-related acute myeloid leukemia, (LT) left, (t-MDS) therapy-related myelodysplastic syndrome, (DCIS) ductal carcinoma in situ, (T-ALL) T-cell acute lymphoblastic leukemia.\n\naGermline mutation.\n\nTable 4. Variants\n\nGene\tChromosome\tHGVS DNA reference\tHGVS protein reference\tVariant type\tPredicted effect (substitution, deletion, etc.)\tdbSNP/dbVar ID\tGenotype (heterozygous/ homozygous)\tClinVar ID\t\nTP53\t17p13.1\tUnknown\tDel exons 10-11\tUnknown\tUnknown\tUnknown\tUnknown\tUnknown\t\nTP53\t17p13.1\tNM_000546.5:c.184G > T\tE62*\tSingle-nucleotide variant\tNonsense variant\tUnknown\tUnknown\tSCV000882434\t\nTP53\t17p13.1\tNM_000546.5:c.800G > A\tR267Q\tSingle-nucleotide variant\tMissense variant\trs587780075\tHeterozygous\t127823\t\nTP53\t17p13.1\tNM_000546.5:c.467G > A\tR156H\tSingle-nucleotide variant\tMissense variant\trs371524413\tHeterozygous\t127811\t\nTP53\t17p13.1\tNM_000546.5:c.586C > T\tR196*\tSingle-nucleotide variant\tNonsense variant\trs397516435\tHeterozygous\t43589\t\nTP53\t17p13.1\tNM_000546.5:c.743G > A\tR248Q\tSingle-nucleotide variant\tMissense variant\trs11540652\tHeterozygous\t12356\t\nTP53\t17p13.1\tNM_000546.5:c.325T > G\tF109V\tSingle-nucleotide variant\tMissense variant\trs1057523496\tHeterozygous\t389644\t\nTP53\t17p13.1\tNM_000546.5:c.524G > A\tR175H\tSingle-nucleotide variant\tMissense variant\trs28934578\tHeterozygous\t12374\t\nTable 5. Treatment outcomes of all seven patients\n\nCase no.\tAge/sex\tHematological malignancy\tChemotherapy\tResponse\tSCT\tStatus\tOverall survivala\t\n1\t34/F\tt-AML\tFLAG\tCR/MRD−\t+\tAlive\t19 mo\t\nAZA + lirilumab\tNR\t\nVenetoclax + LDAC\tNR\t\n2\t32/F\tt-MDS\tDecitabine\tCR/MRD+, followed by NR\t+\tDead\t7 mo\t\n3\t42/M\tt-AML\tCLIA\tCR/MRD\t+\tDead\t9 mo\t\nSGN-CD33A\tNR\t\nDecitabine\tNR\t\n4\t28/F\tt-AML\tDecitabine + fludarabine + cytarabine + venetoclax\tNR\t−\tDead\t5 mo\t\n5\t50/F\tt-AML\tDecitabine\tNR\t−\tAlive\t12 mo\t\nFLAG\tCR/MRD−\t\nDecitabine + venetoclax\tCRi/MRD+\t\n6\t34/F\tALL\tObinutuzumab + hyper-CVAD\tCR/MRD−\t+\tAlive\t23 mo\t\n7\t24/M\tEarly precursor T-ALL\tHyper-CVAD + asparaginase + bortezomib\tCR/MRD−\t+\tDead\t23 mo\t\nNelarabine\tNR\t\nLY3039478 (investigational drug)\tNR\t\nC2V2E\tNR\t\nDecitabine + FIA\tNR\t\n(SCT) Stem cell transplantation, (t-AML) therapy-related acute myeloid leukemia, (FLAG) fludarabine, cytarabine, and granulocyte colony-stimulating factor, (AZA) 5-azacitidine, (LDAC) low-dose ara-cytarabine, (CLIA) cladribine, idarubicin, and ara-cytarabine, (t-MDS) therapy-related myelodysplastic syndrome, (T-ALL) T-cell acute lymphoblastic leukemia, (C2V2E) clofarabine, cyclophosphamide, vincristine, velcade, etoposide, (FIA) fludarabine, idarubicin, and ara-cytarabine, (CVAD) cyclophosphamide, vincristine, doxorubicin (adriamycin), dexamethasone, (CR) complete remission, (NR) no response, (Cri) complete remission with incomplete count recovery, (MRD) minimal residual disease (assessed by multiparameter flow cytometry).\n\naSurvival from the diagnosis of hematological malignancy.\n\nCase 2\nA 32-yr-old healthy woman was referred to clinical cancer genetics to undergo single-site TP53 genetic testing after a TP53 mutation was identified in her sister (proband). She was identified to have the familial TP53 nonsense mutation, c.184G>T (p.E62*). Her family history was significant for bilateral breast and pancreatic cancer in her sister at age 40 yr, sarcoma in another sister at age 3 yr, breast cancer in her mother at age 40 yr, and additional cancers in her maternal relatives (Fig. 1B). The patient was enrolled in the LEAD program for proactive surveillance and screening at age 32 yr. At 35 yr, she underwent bilateral prophylactic mastectomy. Seven months later, she reported painless palate swelling, imaging was performed that demonstrated a left maxillary sinus osteosarcoma, and it was treated with chemotherapy and left maxillectomy. Cancer staging for her osteosarcoma also diagnosed thyroid cancer and at 36 yr; she underwent thyroidectomy with left-sided paratracheal neck dissection for bilateral papillary thyroid cancer. Two years later, she was noted to have pancytopenia and was diagnosed with therapy-related MDS (t-MDS) with complex cytogenetics and dual TP53 mutations c.764T>C (p.I255T) and c.184G>T (p.E62*). She received three courses of decitabine (one 10-d induction cycle followed by two 5-d courses) and subsequently achieved clinical response with count recovery and persistent MRD as assessed by multiparameter flow cytometry. She proceeded to an allogenic matched unrelated donor SCT (MUD-SCT) with busulfan, fludarabine, and cyclophosphamide conditioning. Unfortunately, her disease relapsed 62 d post-SCT and she was restarted on treatment with 10 d of decitabine without regaining clinical response.\n\nCase 3\nA 42-yr-old man was evaluated by the HHMC because of a history of multiple cancers and therapy-related AML at a young age. His history included pleomorphic sarcoma of the right hip and gluteal area at age 40 yr, 2 yr prior to his AML diagnosis, which had been treated with chemotherapy, radiotherapy, and surgery. His family history was significant for a history of unknown cancer in his sister at age 3 yr and in his father at age 42 yr, as shown in Figure 1C. The patient met criteria for LFS evaluation, and TP53 germline analysis was performed on cultured skin fibroblasts, which revealed two alterations, c.800G>A (p.R267Q) and c.467G>A (p.R156H), both clinically classified as variants of uncertain significance (VUS) (Table 4). His AML was characterized by adverse cytogenetics (including deletions in 5q, 7q, and 11q) with mutations in EGFR and TET2 in addition to the two germline TP53 mutations. The patient underwent induction chemotherapy with cladribine, idarubicin, and ara-cytarabine (CLIA) and achieved a complete remission. He was given a course of consolidation chemotherapy with cladribine and cytarabine and remained in complete remission with positive MRD by multiparameter flow cytometry, followed by MUD allogeneic SCT. His disease relapsed 60 d post-SCT. He received salvage treatment with an investigational anti-CD33 monoclonal antibody with no response and then received decitabine for two monthly courses (5 d and then 10 d, respectively) with no evidence of response and overall stable disease. He later opted to transition home with comfort care.\n\nCase 4\nA 28-yr-old woman with LFS presented with therapy-related AML with complex cytogenetics and BCORL1, TP53, and WT1 mutations. She had a medical history of right breast pleomorphic spindle cell sarcoma and contralateral left breast ductal carcinoma in situ (DCIS), diagnosed at age 24 yr, after which genetic testing was performed and demonstrated a germline TP53 mutation c.586C>T (p.R196*) (Table 4). Her family history was significant for glioblastoma in her father at age 25 yr, breast cancer in her paternal grandmother at age 55 yr, and head and neck cancer in a paternal cousin at age 31 yr (Fig. 1D). The patient received induction chemotherapy with decitabine for 10 d followed by fludarabine and cytarabine for 3 d. Venetoclax was added after the initial induction cycle. She then received a second course of decitabine for 10 d with venetoclax. She received a total of three courses of this combination and achieved a partial remission, complicated by neutropenic fever and sepsis.\n\nCase 5\nA 50-yr-old woman was referred to clinical cancer genetics because of a history of multiple cancers: mixed ductal and lobular carcinoma of the right breast diagnosed at age 29 yr followed by postradiation high-grade osteosarcoma of the chest wall diagnosed at 37 yr. Her family history was significant for breast cancer in her mother at age 32 yr, lung cancer in maternal uncle at 58 yr, history of unknown cancer in her maternal grandfather at 73 yr, and breast cancer in her maternal great aunt (at a young age) as shown in Figure 1E. TP53 germline analysis was performed and revealed a c.734G>A (p.R248Q) pathogenic mutation (Table 4), confirming LFS. At the age of 49, she was diagnosed with t-AML with complex karyotype and mutations in BCOR, DNMT3A, and her known TP53 mutation. She was started on decitabine therapy, and she received four courses, two 10-d cycles followed by 5-d cycles. Her disease was persistent, and she then received FLAG re-induction, after which she achieved complete remission with positive MRD by multiparameter flow cytometry. She declined SCT and has received two additional courses of 5-d decitabine with the addition of venetoclax. She achieved complete remission with incomplete count recovery and is currently continued on decitabine with venetoclax treatment.\n\nCase 6\nA 34-yr-old woman with de novo hypodiploid ALL, a TP53 mutation at ∼50% variant allelic frequency, and a strong family history of cancers was referred to the HHMC for LFS evaluation. Her family history was significant for brain cancer in her brother at age 12 yr, gastric and thyroid cancers in her father in his 50s, thyroid cancer in her paternal uncle, and skin cancer (unknown details) in her paternal grandmother at young age (Fig. 1F). Germline TP53 testing on cultured skin fibroblasts identified a TP53 c.325T>G (p.F109V) mutation, initially classified as a VUS (Table 4). Family studies were initiated and the same variant was detected in the patient's father. Segregation data from other families were combined, and this variant was upgraded to a clinically actionable deleterious mutation by the clinical testing laboratory. She received induction chemotherapy with ofatumumab-HCVAD and subsequently achieved complete remission with negative MRD by multiparameter flow cytometry. She received three courses of consolidation with HCVAD, methotrexate, cytarabine, and rituximab followed by further consolidation with an allogeneic SCT with busulfan, fludarabine, and clofarabine conditioning from an HLA-identical and LFS-unaffected sibling. She experienced acute GVHD of the gastrointestinal tract and chronic skin GVHD, treated with systemic steroids. She is currently in remission 555 d post-SCT and continues to be followed in the LEAD clinic.\n\nCase 7\nA 24-yr-old man presented with de novo precursor T-cell ALL (T-ALL). During staging of his T-ALL, he was identified to have a synchronous asymptomatic brain tumor consistent with grade 2 astrocytoma. His family history was significant for rhabdomyosarcoma in his daughter at age 2 yr and lung cancer in his paternal great-grandfather in his 80s, as shown in Figure 1G. His T-ALL characteristics at the time of diagnosis included hypodiploid complex cytogenetics, and sequencing of the bone marrow demonstrated NOTCH1 and TP53 mutations. Based on the high clinical suspicion, evaluation for the germline versus somatic nature of this TP53 mutation was recommended, and he was referred to the HHMC. TP53 germline analysis confirmed the presence of a c.524G>A (p.R175H) mutation (Table 4) in cultured skin fibroblasts, consistent with LFS. He received induction with augmented HCVAD + asparaginase + bortezomib. He achieved complete remission with negative MRD (assessed by multiparameter flow cytometry) and then underwent MUD-SCT with a conditioning regimen of ATG, busulfan, and clofarabine. Unfortunately, his T-ALL relapsed 7 mo post-SCT. He was treated with HCVAD + bortezomib as salvage chemotherapy for two courses without response. He then received nelarabine without response, followed by an investigational Notch inhibitor, also without response. He then received clofarabine + cyclophosphamide + vincristine + bortezomib + etoposide followed by decitabine, fludarabine, idarubicin, and fludarabine (DAC-FIA) without response and ultimately transitioned home on hospice care.\n\nRESULTS\nLFS is a well-known cancer predisposition syndrome; however, the clinical awareness of LFS in adult hematology practices is minimal, and the expected outcomes of patients with LFS with various hematologic malignancies are not well described. We report on seven patients with LFS and hematologic malignancy, specifically two patients with hypodiploid ALL as their first presenting malignancy and five with therapy-related MDS or AML.\n\nOf the patients with therapy-related myeloid malignancy, three patients had breast cancer (cases 1, 4, and 5), two had osteosarcoma (cases 2 and 5), and three had soft tissue sarcoma (cases 1, 3, and 5) preceding their hematologic malignancy. Additionally, one patient had thyroid cancer (case 2) and one had astrocytoma (case 7).\n\nThe treatments and outcomes of patients with hematological malignancies are listed in Table 2. The median time from last chemotherapy or radiation therapy to the development of therapy-related hematological malignancy was 2 yr (range: 0–20 yr).\n\nTwo patients (cases 6 and 7) had hypodiploid ALL; both received hyper-CVAD, achieved complete remission, and proceeded to SCT. Of the five patients with myeloid neoplasms, four patients (cases 1, 3, 4, and 5) had t-AML and one (case 2) had t-MDS. All patients with t-AML received intensive chemotherapy as induction or first salvage. The patient with t-MDS (case 2) received the hypomethylating agent decitabine for t-MDS, achieved complete remission, and proceeded to SCT. At last follow-up, two (cases 1 and 5) patients with myeloid malignancy and one with hypodiploid ALL remain alive.\n\nAll patients, except cases 4 and 5, underwent SCT. Of five patients who had SCT, three patients (cases 2, 3, and 7) received a MUD-SCT, case 1 had haploidentical SCT (donor was her son, tested negative for LFS), and case 6 had matched related donor SCT (donor was her sister, tested negative for LFS). Two patients (cases 2 and 3) with myeloid neoplasms (t-MDS and t-AML, respectively) went to SCT with MRD-positive disease (defined by multiparameter flow cytometry with sensitivity of 0.01%–0.1%) and relapsed on day 62 and 60 post-SCT, respectively. Three patients (cases 1, 6, and 7), including two (cases 6 and 7) with ALL and one (case 1) with t-AML, had MRD-negative disease prior to SCT, and only one patient (case 6) remains in remission. The cytogenetic and molecular characteristics of the hematological malignancies at the time of relapse were similar to the initial presentation in all cases.\n\nGenetic anticipation has been frequently reported with inherited cancer syndromes including LFS (Trkova et al. 2002; Ariffin et al. 2014); we identified the occurrence of genetic anticipation in the pedigrees of all of our patients, with a decrease in the age of onset of cancer in successive generations, as shown in Figure 1A–G.\n\nDISCUSSION\nPatients with LFS have a significant lifetime risk of developing cancer (Hu et al. 2016; Mai et al. 2016; Asdahl et al. 2017). Although there are several published studies on LFS, the outcomes of patients with hematological malignancies remain poorly annotated. In this case series, we provide patient characteristics, including prior cancers and treatments received, leukemia diagnosis and treatments received, and outcomes in the largest case series of patients with LFS and hematologic malignancies to date.\n\nTP53 mutations are frequently inherited, and family history remains a key criterion for the consideration of LFS. However, de novo mutations occur in ∼10%–20% of LFS cases (Chompret et al. 2000; Correa 2016); thus, consideration of LFS should not depend solely on a positive family history. Additionally, the phenotypic variability of cancers even within families that have the same mutation is described (Malkin 2011), and genetic anticipation, often observed in families with LFS, has been hypothesized to be due to telomere shortening (Tabori et al. 2007).\n\nAlthough ALL is a common pediatric cancer, attention should be paid to patients with presumed somatic TP53 mutations identified on NGS panels and/or hypodiploid cytogenetics (defined as fewer than 45 chromosomes [Comeaux and Mullighan 2017]), or the phenomenon of masked hypodiploidy, where hypodiploid genome undergoes reduplication resulting in hyperdiploid karyotype (Carroll et al. 2009). In the setting of hypodiploid cytogenetics, >90% of patients will have a TP53 mutation, and prior work suggests about half of these patients may have germline TP53 mutations. Identification of these patients and timely recognition of potentially affected family members can identify appropriate sibling SCT donors and allow for augmented cancer screening programs.\n\nOverall, although most patients with hematologic malignancy and LFS were able to obtain an initial response to induction therapy (either intensive cytarabine-based treatment or augmented decitabine), clinical responses were short, and outcomes were extremely poor. Somatic TP53 mutations, often associated with complex cytogenetic abnormalities, are well described in hematologic malignancies including MDS, AML, and ALL and are known to confer poor outcomes and treatment resistance (Bowen et al. 2009; Rücker et al. 2012; Kadia et al. 2016; Middeke et al. 2016). Kadia and colleagues identified younger patients with TP53-mutated AML had modestly improved survival with low-intensity chemotherapy compared to intensive chemotherapy (Kadia et al. 2016). Additionally, previous work has demonstrated the TP53-mutated lymphocytes in patients with LFS have an intrinsic resistance to conventional chemotherapeutic drugs (Pepper et al. 2003).\n\nFive patients (cases 1–3, 6, and 7) had SCT, including one patient with ALL who continues in a durable remission more than 1 yr post-SCT. Despite allogeneic SCT in complete remission, including three of the five patients with MRD-negative status by flow cytometry at the time of complete remission, long-term disease control was not achieved with SCT. Future improved SCT regimens and post-SCT maintenance strategies are warranted. Studies have shown that surveillance programs might increase the survival chances in LFS patients (Villani et al. 2011; Etzold et al. 2015; Nandikolla et al. 2017). The National Comprehensive Cancer Network (NCCN) has guidelines for screening TP53 mutation carriers (Daly et al. 2017; Kratz et al. 2017), and whole-body MRI has been shown to be an effective screening tool for early detection of solid tumors (Table 6; Asdahl et al. 2017; Ballinger et al. 2017; Bojadzieva et al. 2017). The effectiveness of early detection of leukemia from screening tests such as biannual complete blood counts is less evident because of the sporadic nature of acute leukemias, and additional clinical research is needed.\n\nTable 6. Screening guidelines of adult patients in LEAD program\n\nCancer\tExams and tests\tFrequency\t\nGeneral cancer prevention\tComplete physical exam with a focus on brain and thyroid\tEvery 6 mo\t\nAdrenocortical tumor\tBasic labs testsa\nWhole-body MRI\tEvery year\t\nBreast (begin screening at age 20–25 or 5–10 yr younger than first diagnosis of breast cancer in the family)\tClinical breast exam by a physician\tEvery 6 mo\t\nMammogram and MRI breast\tEvery year\t\nBrain\tMRI brain\tEvery year\t\nColon (begin at age 25 or 5 yr before the earliest known colon cancer in the family) every 2–5 yr\tColonoscopy\nEsophagogastroduodenoscopy\tEvery 2–5 yr\t\nLeukemia/lymphoma\tBasic laboratory testsa\tEvery year\t\nMelanoma\tSkin exam\tEvery year\t\nOvarian (begin at age 35)\tRefer to a physician specialized in high-risk ovarian cancer screening\t\t\nPancreas\tRefer to a physician specialized in high-risk pancreatic cancer screening\t\t\nSarcoma\tWhole-body MRI\tEvery year\t\naDifferential blood count and metabolic panel.\n\nTherapy-related AML and t-MDS frequently occur in patients with LFS, likely related to their extensive cancer history and myelosuppressive prior treatments. Cytotoxic agents like alkylating agents and topoisomerase inhibitors, as well as radiation therapy, are known to be associated with t-MDS/t-AML (Godley and Larson 2008). Radiation exposure in patients with LFS should be avoided whenever possible because of the high risk of radiation-induced malignancies (Limacher et al. 2001; Cohen et al. 2005; Evans et al. 2006). Although curative therapy must be administered for the patient with LFS and a primary solid tumor, consideration to the augmented lifetime risk of t-MDS/AML is prudent.\n\nAt MD Anderson, the LEAD program enrolls patients with germline TP53 mutations (Lammens et al. 2010; Villani et al. 2016; Ross et al. 2017). Patients and their family members are screened per adult screening guidelines as shown in Table 6. The rationale behind these screening tests and exam is to detect cancer at an early age. For example, Case 2 was referred to LEAD for genetic testing after the patient's sister was found to have a TP53 mutation. She was subsequently diagnosed to have multiple cancers at early stages while being followed by the screening program. This highlights how attention to a strong personal and family history can raise suspicion for LFS and allow evaluation and surveillance programs, like LEAD, to lead to early intervention.\n\nCONCLUSION\nIn this case series, we retrospectively reviewed the characteristics and outcomes of seven adult patients with LFS who developed hematologic malignancies. LFS increases the lifetime risk of cancer in many organ sites, and it is important to consider hypodiploid ALL as a possible presenting malignancy for individuals with LFS. In addition, therapy-related myeloid malignancies including MDS and AML are common in patients with LFS and portend a dismal prognosis with standard therapies and even allogenic SCT. Future TP53-independent leukemia treatment strategies and clinical trial participation are recommended. Screening and surveillance programs for inherited cancer predisposition syndromes like LFS are critical to increase awareness of patients and health-care providers, provide augmented cancer surveillance to improve patient outcomes, and also provide individualized and risk-based treatment decisions at all steps along the cancer pathway continuum.\n\nMETHODS\nPatients with a diagnosis of LFS seen within the HHMC from 2014 to 2018 were included. Germline analysis for evaluation of TP53 status in patients with hematological malignancies included sequencing performed on cultured skin fibroblasts obtained from skin punch biopsy. Clinicopathologic characteristics of the hematologic malignancy including cytogenetics and molecular analysis, treatment, and clinical outcomes were reviewed. Clinical response was assessed using the International Working Group (IWG) criteria for AML and MDS (Cheson et al. 2003, 2006). Minimal residual disease (MRD) was evaluated by multiparameter flow cytometry with a sensitivity of 0.01%–0.1%.\n\nADDITIONAL INFORMATION\nData Deposition and Access\nThe variants have been deposited by external sources in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and can be found under accession numbers: SCV000260755.5, SCV000218877.8, SCV000260299.5, SCV000253851.6, SCV000532251.3, SCV000261917.6, and SCV000882434.\n\nEthics Statement\nInformed consent for all patients was obtained following institutional guidelines and in accordance with the Declaration of Helsinki and MDACC IRB; protocol PA14-0392.\n\nAuthor Contributions\nM.S., C.D.D., and S.A.B. designed the study, collected data, and wrote the manuscript. All the authors reviewed the manuscript and substantially contributed to the conception of the study and acquisition of the data and approved the final version to be published.\n\nFunding\nThis work was supported in part by The University of Texas MD Anderson Cancer Center Support Grant (CA016672), the Charif Souki Cancer Research Fund, The University of Texas MD Anderson Cancer Center Leukemia Specialized Program of Research Excellence (SPORE grant P50 CA100632), and generous philanthropic contributions to MD Anderson's MDS/AML Moon Shot Program.\n\nCompeting Interest Statement\nThe authors have declared no competing interest.\n\nReferees\nAlla Keyzner\n\nAnonymous\n==== Refs\nREFERENCES\nAriffin \nH , Hainaut \nP , Puzio-Kuter \nA , Choong \nSS , Chan \nAS , Tolkunov \nD , Rajagopal \nG , Kang \nW , Lim \nLL , Krishnan \nS , \n2014 \nWhole-genome sequencing analysis of phenotypic heterogeneity and anticipation in Li–Fraumeni cancer predisposition syndrome . 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Arch Pathol Lab Med \n134 : 1010 –1015 .20586629 \nTinat \nJ , Bougeard \nG , Baert-Desurmont \nS , Vasseur \nS , Martin \nC , Bouvignies \nE , Caron \nO , Bressac-de Paillerets \nB , Berthet \nP , Dugast \nC , \n2009 \n2009 version of the Chompret criteria for Li–Fraumeni syndrome . J Clin Oncol \n27 : e108 –e109 ; author reply e110 \n10.1200/JCO.2009.22.7967 19652052 \nTrkova \nM , Hladikova \nM , Kasal \nP , Goetz \nP , Sedlacek \nZ . 2002 \nIs there anticipation in the age at onset of cancer in families with Li–Fraumeni syndrome? \nJ Hum Genet \n47 : 381 –386 . 10.1007/s100380200055 12181637 \nVarley \nJM , Evans \nDG , Birch \nJM . 1997 \nLi–Fraumeni syndrome—a molecular and clinical review . Br J Cancer \n76 : 1 –14 . 10.1038/bjc.1997.328 \nVillani \nA , Tabori \nU , Schiffman \nJ , Shlien \nA , Beyene \nJ , Druker \nH , Novokmet \nA , Finlay \nJ , Malkin \nD . 2011 \nBiochemical and imaging surveillance in germline TP53 mutation carriers with Li–Fraumeni syndrome: a prospective observational study . Lancet Oncol \n12 : 559 –567 . 10.1016/S1470-2045(11)70119-X 21601526 \nVillani \nA , Shore \nA , Wasserman \nJD , Stephens \nD , Kim \nRH , Druker \nH , Gallinger \nB , Naumer \nA , Kohlmann \nW , Novokmet \nA , \n2016 \nBiochemical and imaging surveillance in germline TP53 mutation carriers with Li–Fraumeni syndrome: 11 year follow-up of a prospective observational study . Lancet Oncol \n17 : 1295 –1305 . 10.1016/S1470-2045(16)30249-2 27501770 \nWorld Health Organization . 2018 \nTumors associated with Tp53 germline mutations . IARC \nhttp://p53.iarc.fr/TP53GermlineMutations.aspx \nZerdoumi \nY , Aury-Landas \nJ , Bonaïti-Pellié \nC , Derambure \nC , Sesboüé \nR , Renaux-Petel \nM , Frebourg \nT , Bougeard \nG , Flaman \nJM . 2013 \nDrastic effect of germline TP53 missense mutations in Li–Fraumeni patients . Hum Mutat \n34 : 453 –461 . 10.1002/humu.22254 23172776\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2373-2873",
"issue": "5(1)",
"journal": "Cold Spring Harbor molecular case studies",
"keywords": "leukemia; multiple lineage myelodysplasia",
"medline_ta": "Cold Spring Harb Mol Case Stud",
"mesh_terms": "D000328:Adult; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D019337:Hematologic Neoplasms; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D016864:Li-Fraumeni Syndrome; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D010375:Pedigree; D016159:Tumor Suppressor Protein p53; D055815:Young Adult",
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"pubdate": "2019-02",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "23172776;11498785;1933902;21779515;20522432;26771088;27617148;24642672;26818906;16155191;27496084;12181637;18692692;3409256;28772291;15852362;28040716;17308077;27463065;12695689;25226867;18596741;9218725;27501770;20586629;14673054;19204208;26014290;28301458;28988289;28572266;28356770;19652052;16609072;11474498;20658357;23355100;10864200;25313051;22186996;28003275;5360287;21601526;28772307",
"title": "Hematologic malignancies and Li-Fraumeni syndrome.",
"title_normalized": "hematologic malignancies and li fraumeni syndrome"
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"abstract": "Methotrexate-associated lymphoproliferative disorder is recognized as a lymphoma that occurs following methotrexate administration. The lesion of the spine is extremely rare, and only one case of lesion in the lumbar spine has been reported so far. Here, we present a case of methotrexate-associated lymphoproliferative disorder of the thoracic spine in a 54-year-old woman with rheumatoid arthritis. The lesion formed an extra-skeletal tumor mass from lateral to the vertebral body to the paravertebral muscle extending posterior to the epidural space without bone destruction. Magnetic resonance imaging showed low signal intensities on both T1- and T2-weighted images and high signal intensity with short-tau inversion recovery. These radiological findings were similar to those for primary spinal lymphoma. The lesion rapidly paralyzed the patient, forcing her to be treated with posterior spinal decompression. The lesion could not be resected because it adhered to the dura. Following the histopathological diagnosis as methotrexate-associated lymphoproliferative disorder, methotrexate administration was terminated. The remaining mass lesion showed complete regression within 6 months. Methotrexate-associated lymphoproliferative disorder, which could be cured by the discontinuation of methotrexate, should be considered a differential diagnosis in spinal lesion cases showing lymphoma-like appearance with methotrexate treatment to avoid unnecessary treatments.",
"affiliations": "Department of Orthopaedic Surgery, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan. skamio0024@gmail.com.;Department of Orthopaedic Surgery, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan.;Department of Orthopaedic Surgery, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan.;Department of Pathology and Laboratory Medicine, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan.;Department of Orthopaedic Surgery, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan.",
"authors": "Kamio|Satoshi|S|http://orcid.org/0000-0003-1824-3046;Anazawa|Ukei|U|;Watanabe|Itsuo|I|;Sasaki|Aya|A|;Aoyama|Ryoma|R|",
"chemical_list": "D008727:Methotrexate",
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"doi": "10.1007/s00256-021-03764-1",
"fulltext": "\n==== Front\nSkeletal Radiol\nSkeletal Radiol\nSkeletal Radiology\n0364-2348\n1432-2161\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n33772624\n3764\n10.1007/s00256-021-03764-1\nCase Report\nMethotrexate-associated lymphoproliferative disorder of the thoracic spine in a patient with rheumatoid arthritis receiving methotrexate: a case report\nhttp://orcid.org/0000-0003-1824-3046\nKamio Satoshi skamio0024@gmail.com\n\n1\nAnazawa Ukei 1\nWatanabe Itsuo 1\nSasaki Aya 2\nAoyama Ryoma 1\n1 grid.417073.6 0000 0004 0640 4858 Department of Orthopaedic Surgery, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan\n2 grid.417073.6 0000 0004 0640 4858 Department of Pathology and Laboratory Medicine, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan\n27 3 2021\n27 3 2021\n2021\n50 10 21172123\n13 8 2020\n18 3 2021\n18 3 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nMethotrexate-associated lymphoproliferative disorder is recognized as a lymphoma that occurs following methotrexate administration. The lesion of the spine is extremely rare, and only one case of lesion in the lumbar spine has been reported so far. Here, we present a case of methotrexate-associated lymphoproliferative disorder of the thoracic spine in a 54-year-old woman with rheumatoid arthritis. The lesion formed an extra-skeletal tumor mass from lateral to the vertebral body to the paravertebral muscle extending posterior to the epidural space without bone destruction. Magnetic resonance imaging showed low signal intensities on both T1- and T2-weighted images and high signal intensity with short-tau inversion recovery. These radiological findings were similar to those for primary spinal lymphoma. The lesion rapidly paralyzed the patient, forcing her to be treated with posterior spinal decompression. The lesion could not be resected because it adhered to the dura. Following the histopathological diagnosis as methotrexate-associated lymphoproliferative disorder, methotrexate administration was terminated. The remaining mass lesion showed complete regression within 6 months. Methotrexate-associated lymphoproliferative disorder, which could be cured by the discontinuation of methotrexate, should be considered a differential diagnosis in spinal lesion cases showing lymphoma-like appearance with methotrexate treatment to avoid unnecessary treatments.\n\nKeywords\n\nRheumatoid arthritis\nMethotrexate-associated lymphoproliferative disorder\nSpinal tumor\nissue-copyright-statement© ISS 2021\n==== Body\nIntroduction\n\nMethotrexate (MTX), an antimetabolite and immunosuppressive agent, is used in the treatment of rheumatoid arthritis (RA). As opposed to its effectiveness, its serious adverse effects are widely known, and these include liver disorders, interstitial pneumonia, and myelosuppression. Ellman et al. (1991) first reported lymphoma in a patient with RA treated with low-dose MTX [1]. Since then, MTX-associated lymphoproliferative disorder (MTX-LPD) had been recognized as a lymphoma occurring with MTX administration. Some lymphomas are caused by the Epstein-Barr virus (EBV), a well-known oncogenic virus [2]. Reportedly, the frequency of EBV infections in RA patients with lymphoid neoplasms is significantly higher than that in the general population [3]. In patients with RA, MTX administration results in immunosuppression, which activates the EBV, resulting in LPD development [4]. Furthermore, RA is an active inflammatory condition that could cause lymphoma [5]. Therefore, the pathogenesis of this disorder remains unclear.\n\nIt has been reported that MTX-LPD remission occurs simply by MTX withdrawal [4, 6]. The frequency of MTX-LPD is similar in the nodal and extranodal regions [4, 7]. Extranodal lesions occur in various locations such as the lung, skin, liver, and oropharyngeal region [5, 8]. However, spinal lesions are extremely rare, and to our knowledge, there is just one report on this type of MTX-LPD lesion [9].\n\nHere, we demonstrate that MTX-LPD in the thoracic spine has a radiologically lymphoma-like appearance. Furthermore, this condition cannot be diagnosed with only radiological and pathological findings, without information of the administration history of MTX. In cases of spinal tumors with a history of MTX administration exhibiting lymphoma-like appearance radiologically, it is important to consider MTX-LPD. This is because MTX-LPD and spinal lymphoma not only show similar images but also require different treatments. The former can be treated by discontinuing MTX, whereas the latter requires radiotherapy, chemotherapy, and, in some cases, surgery.\n\nCase report\n\nA 54-year-old woman with RA complained of back pain and numbness in the bilateral lower limbs for the past 3 months. She was on MTX (10 mg/week) for approximately 7 years, followed by adalimumab (40 mg per every other week) and iguratimod (50 mg/day) for approximately 3 years. A radiographical assessment by her previous physician revealed a spinal tumor. Therefore, she was referred to our hospital for further investigation and treatment.\n\nThe initial examination revealed enhanced bilateral patellar and Achilles reflexes, muscle weakness in the bilateral iliopsoas, a manual muscle testing score of 4, and sensory deficit in the bilateral posterior lower legs. The laboratory investigations revealed the following: white blood cell count, 2900/μL; C-reactive protein level, 0.21 (< 0.3) mg/dL; and anti-cyclic citrullinated peptide antibody titer, 148 (> 4.5) U/mL. Although the antibody titers were high, the C-reactive protein level was within the normal range; this indicated that the progression of RA was well controlled by MTX. Tumor markers, namely, carcinoembryonic antigen level, 0.5 (< 5.0) ng/mL; CA19–9 level, 3.1 (< 37) U/mL; and alpha-fetoprotein level, 5.2 (< 20) ng/mL, were within the normal limits.\n\nPlain radiographs and computed tomography (CT) revealed almost imperceptible bone destruction. Thoracic spine radiograph revealed a soft-tissue mass on the left of Th9–10 (Fig. 1), and a differential diagnosis was considered to be mediastinal tumor. Plain CT revealed a soft-tissue density mass lesion on the left of Th10 (Fig. 2a). The partial sclerotic change of the vertebral body was visualized adjacent to the tumor (Fig. 2b). In contrast-enhanced CT, the mass lesion was well enhanced on the left of epidural space and paravertebral muscle (Fig. 2c). Several lymph nodes swelling were detected in the retrocrural space and mediastinum. Differential diagnoses were considered to be malignant lymphoma and spinal metastasis. Fig. 1 Antero–posterior view of the thoracic spine radiograph. Soft tissue density mass is visualized on the left of Th9–10 (white arrow). The mass makes the left transverse process and posterior rib indistinct. This suggests paravertebral lesion\n\nFig. 2 Thoracic spine CT: (a) Soft tissue window. (b) Bone window. (c) Contrast-enhanced CT. Paravertebral mass lesion was observed on the left of the Th10 vertebra. The area adjacent to the tumor-like mass in vertebral body slightly showed bone sclerosis (white arrow). The mass lesion and the left side of epidural space and paravertebral muscle were uniformly enhanced. All enhanced area appeared to be connected (white arrow head)\n\nMagnetic resonance imaging (MRI) showed a low signal intensity in the Th10 vertebral body on both T1- and T2-weighted images and a high signal intensity in the short-tau inversion recovery images, and the signal change covered posterior elements through the pedicle. Paravertebral lesion showed the same signal intensity as the bone lesion in each image. This mass lesion extended to the epidural space, mediastinal area, and paravertebral muscle through intervertebral foramen and intercostal space. The epidural mass lesion compressed the spinal cord, causing spinal canal stenosis from the unilateral dorsal site, and this could lead to spinal paralysis (Fig. 3). MRI findings suggested not only malignant lymphoma and spinal metastasis but also myeloma and inflammatory changes as differential diagnoses. Fig. 3 Magnetic resonance imaging of the thoracic spine. (a–c) Sagittal image of T1- and T2-weighted images, and short-tau inversion recovery images. (d, e) Axial image of T2-weighted images. The lesion on the lateral side of the Th10 vertebral body showed a low signal intensity on the T1- and T2-weighted images and high signal intensity on the short-tau inversion recovery images (white arrow). The signal change extended through the pedicle to the posterior elements, including spinous process. Soft-tissue lesion extended to the epidural space, intervertebral foramen, mediastinal area, intercostal space, and paravertebral muscle, showing the same signal intensity as the bone lesion. The epidural lesion compressed the spinal cord. The nodules reminiscent of lymph nodes were revealed on the dorsal side of the aorta. These findings suggest that the vertebral lesion should extend to the epidural space and paravertebral mediastinum and surrounded the muscle without bone destruction\n\nOn the basis of these imaging findings, the differential diagnosis included malignant lymphoma, metastatic spinal tumor, hematologic tumor, and inflammatory changes. Blood tests showed no prominent elevation in the inflammatory response or abnormal tumor markers. Furthermore, the patient had no history of cancer, and a CT scan of the whole body showed no malignant tumors in the major organs. Thus, we planned a biopsy.\n\nOn day 3 of hospitalization, muscle weakness in the bilateral iliopsoas rapidly progressed, which prevented the patient from walking; it was accompanied by bladder and bowel dysfunctions. Therefore, posterior spinal decompression with laminectomy and posterolateral fixation of the Th9–11 vertebrae were performed as an emergency measure instead of the planned biopsy (Fig. 4). The intraoperative findings confirmed a dark brown neoplastic lesion on the dorsal side of the dura mater at the Th10 vertebral level. The epidural lesion strongly adhered to the dura mater and could not be removed without damaging the dura; therefore, only a pathological specimen was obtained. Consequently, most of the epidural mass lesion was retained. Fig. 4 Lateral view of the postoperative plain radiograph. Vertebral decompression and posterolateral fixation of Th9–11 were performed\n\nThe pathological findings revealed the proliferation of atypical large round cells accompanied by small lymphocytes in a nodular fashion. The nuclei in the atypical large cells were irregularly shaped, and a few cells were multinucleated. The immunostaining results were positive for CD30 and Pax5; partially positive for CD4, CD8, CD15, and CD79a; and negative for CD20, pankeratin, and EMA, indicating histological features similar to those of a classical Hodgkin lymphoma (Fig. 5). The results of EBV-encoded RNA in situ hybridization of pathological specimens were negative. Considering both pathological findings and MTX treatment history, this condition was histopathologically diagnosed as MTX-LPD. Fig. 5 Pathological findings of hematoxylin and eosin staining. (a) 40× magnification, b) 400× magnification. Pathological findings revealed the proliferation of atypical large round cells accompanied by small lymphocytes in a nodular fashion. Atypical large cells had irregularly shaped nucleus, and a few of them appeared multinucleated. Immunohistochemical staining showed tumor cells positive for (c) CD30 and (d) Pax5 and (e) partially positive for CD15, indicating histological features similar to those of classical Hodgkin lymphoma\n\nAn improvement in bilateral iliopsoas muscle weakness and bladder rectal dysfunction was observed postoperatively, and the patient could resume walking. Postoperative investigation demonstrated a high level of anti-EBV capsid antigen-IgG, at 320 times the normal level (normal level, < 10-fold), suggesting a history of infection. After being diagnosed with MTX-LPD, treatment with MTX was terminated. The symptoms of RA did not worsen, and prednisolone 5 mg/day was administered as an alternative to MTX from 1 week after surgery. Three weeks after MTX withdrawal, the MRI findings revealed a partially resected epidural tumor mass with decompressed spinal cord. Moreover, a remnant tumor was noted on the lateral side of the vertebral body. The disappearance of both tumors was confirmed within 6 months after surgery (Fig. 6). Eighteen months after the surgery, the patient could walk independently and did not show tumor recurrence. Fig. 6 Postoperative T2-weighted magnetic resonance images (axial view). (a) One month after surgery. The spinal cord appeared sufficiently decompressed. Partially resected tumor in epidural space and the remaining tumor on the lateral side (white arrows) were confirmed. (b) Six months after surgery. Both epidural and lateral vertebral masses were not observed\n\nDiscussion\n\nFor spinal tumors with progressive symptoms, an accurate diagnosis is essential for determining the appropriate treatment, because chemo- or radio-sensitive tumors can be cured without spinal surgery, which has a complication rate of 21.7–34% [10–12]. However, most of these tumors demonstrate only atypical radiological appearances, and they require biopsy specimens for a definitive diagnosis [13]. Therefore, for tumors that cause rapid paralysis, emergency spinal surgery is performed to obtain the pathological specimen and decompress the spinal cord.\n\nMTX-LPD can show remission after MTX withdrawal without chemotherapy and radiotherapy, and it has a characteristic medical history and condition. Reports of this disorder are more from Japan than from other countries, but it is unclear whether the reason is local perception or racial differences [6]. The World Health Organization classification of hematopoietic and lymphoid tumors classifies MTX-LPD as the “other iatrogenic subgroup of immunodeficiency-associated lymphoproliferative disorders” [14].\n\nHistopathologically, MTX-LPD has several subtypes. MTX-LPD in the present case was similar to classical Hodgkin lymphoma and comprised large round cells and small lymphocytes with multiple nuclear features. The most common subtype of MTX-LPD is diffuse large B cell lymphoma, which accounts for nearly half of all cases. The second most common subtype is Hodgkin lymphoma, which has been reported in approximately 10–20% of patients [4, 6, 15, 16]. Furthermore, complex phenotypes, including atypical peripheral T cell lymphoma, have also been reported [17].\n\nThe clinical characteristics of MTX-LPD include a history of MTX treatment for approximately 30 months or more, previous EBV infection, and the possibility of remission upon MTX discontinuation [18]. The current case demonstrated all features of MTX-LPD: a history of MTX treatment (10 mg/week) for 7 years, a high anti-EBV capsid antigen-IgG level, and complete remission within 6 months post MTX discontinuation.\n\nKameda et al. surveyed 5753 patients with RA in Japan and compared 125 patients without LPD receiving MTX and 28 patients with MTX-LPD. They found that MTX at a concentration of 8 mg/week or more is an independent risk factor for the development of LPD [7]. Furthermore, previous EBV infection may initiate LPD. Hoshida et al. reported that RA patients with LPD have a significantly higher EBV infection rate than those with sporadic LPD [4]. An immunodeficient condition with MTX treatment is considered a basis for the onset of LPD caused by EBV. Furthermore, RA itself could be a cause of lymphoma because of the associated inflammatory condition [5]. It is apparent that an accidental LPD occurred in our patient treated with MTX. Thus, the pathogenesis of this condition is still unknown, including its relationship with MTX.\n\nThe primary treatment option is the discontinuation of MTX. Previous studies have reported that almost half of the MTX-LPD cases show regression with MTX withdrawal alone [4, 17]. A few studies have indicated that EBV-infected patients are likely to show remission [15, 17]. In a few studies, some patients showed a temporary disease regression followed by recurrence, whereas others only showed rapid disease progression post-MTX withdrawal [6, 17]. For these non-responders to MTX withdrawal, conventional chemotherapy for lymphoma should be considered [4]. Rizzi et al. reviewed published data of 26 patients and found that complete remission mostly occurs within 4 weeks after the discontinuation of MTX and other immunosuppressive agents [19]. In contrast, Inui et al. reported the maximum tumor shrinkage only after 8 weeks of MTX termination in 13 of 15 patients [20]. Therefore, follow-up after 8 weeks or more should be favorable to evaluate the response of the tumor.\n\nTo the best of our knowledge, only one case of MTX-LPD arising from the spine has been reported, and it demonstrated an epidural tumor mass and complete remission after MTX discontinuation, as in the current case [9]. The predominant site of this tumor was the nodal region, and it occupied half of the primary site [4, 6]. However, the location of extralymphatic lesions varied, including the lungs, skin, liver, and oropharynx. The occurrence of a bone lesion is particularly rare. Kameda et al. demonstrated a frequency of one out of 28 patients (3.5%) [7]. Moreover, multiple bone lesions and femoral pathological fractures have been reported [21].\n\nIn terms of radiographic appearance, the previous case of spinal MTX-LPD showed findings similar to those observed in the present case, with almost imperceptible bone destruction and low signal intensity on T1- and T2-weighted images of both spinal and epidural lesions [9]. In this case, the tumor extended to the surrounding soft tissue with lymph node swelling, and it had to be differentiated from bone metastasis and infection. However, she did not have a history of cancer, abnormal tumor marker levels, no abnormal lesion in major organs, and no prominent elevation in inflammatory response. In spinal primary lymphoma, most of the bone lesions demonstrated either a permeative pattern, including almost imperceptible bone destruction, or moth-eaten pattern, showing multiple lytic lesions [22]. In the MRI, they demonstrated a low signal intensity on the T1-weighted images and variable signal intensity on the T2-weighted images, and the location of epidural mass in them was often dorsal rather than ventral [23]. The radiological appearance of spinal MTX-LPDs in the previous case and present case included the features of primary spinal lymphoma.\n\nIn conclusion, the MRI of the spinal tumor of a patient with RA receiving MTX demonstrated a primary spinal lymphoma and the histological findings demonstrated classical Hodgkin lymphoma. Only radiological findings and histopathological findings could not distinguish spinal lymphoma from spinal MTX-LPD. In spinal lymphoma-like tumor, the medical history is important to distinguish spinal MTX-LPD from spinal lymphoma. Clinically, MTX-LPD, which could be cured by MTX withdrawal alone, should be considered, when lymphoma-like spinal tumor develops in RA patients with a history of MTX. Further research is required to identify the radiological features and the treatments of this spinal disorder because this type of spinal tumor is very rare.\n\nDeclarations\n\nEthical approval\n\nAll procedures performed in studies involving the human participant 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.\n\nInformed consent\n\nInformed consent was obtained from the participant included in the study.\n\nConflict of interest\n\nThe authors declare that they have no conflict of interest.\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Ellman MH Hurwitz H Thomas C Kozloff M Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate J Rheumatol 1991 18 11 1741 1743 1787499\n2. Young LS Yap LF Murray PG Epstein-Barr virus: more than 50 years old and still providing surprises Nat Rev Cancer 2016 16 789 802 10.1038/nrc.2016.92 27687982\n3. Kamel OW van de Rijn M LeBrun DP Weiss LM Warnke RA Dorfman RF Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: frequency of Epstein-Barr virus and other features associated with immunosuppression Hum Pathol 1994 25 7 638 643 10.1016/0046-8177(94)90295-X 8026822\n4. Hoshida Y Xu JX Fujita S Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication J Rheumatol 2007 34 2 322 331 17117491\n5. Baecklund E Iliadou A Askling J Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis Arthritis Rheum 2006 54 3 692 701 10.1002/art.21675 16508929\n6. Kaneko Y Methotrexate-associated lymphoproliferative disorder Jpn J Clin Immunol Meneki 2017 40 3 174 178 10.2177/jsci.40.174\n7. Salloum E Cooper DL Howe G Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases J Clin Oncol 1996 14 6 1943 1949 10.1200/JCO.1996.14.6.1943 8656264\n8. Kameda T Dobashi H Miyatake N Association of higher methotrexate dose with lymphoproliferative disease onset in rheumatoid arthritis patients Arthritis Care Res 2014 66 9 1302 1309 10.1002/acr.22306\n9. Kikuchi N Uesugi M Koda M Methotrexate-related lymphoproliferative disorder of the lumbar spine origin presenting with severe low-back pain: case report J Neurosurg Spine 2018 29 5 545 548 10.3171/2018.4.SPINE1860 30168781\n10. Lau D Leach MR Than KD Ziewacz J La Marca F Park P Independent predictors of complication following surgery for spinal metastasis Eur Spine J 2013 22 6 1402 1407 10.1007/s00586-013-2706-8 23392558\n11. Arrgio RT Kalanithi P Cheng I Predictors of survival after surgical treatment of spinal metastasis Neurosurgery 2011 68 3 674 681 10.1227/NEU.0b013e318207780c 21311295\n12. Quan GM Vital JM Aurouer N Surgery improves pain, function and quality of life in patients with spinal metastases: a retrospective study on 118 patients Eur Spine J 2011 20 11 1970 1978 10.1007/s00586-011-1867-6 21706361\n13. Scuibba DM Petteys RJ Dekutoski MB Diagnosis and management of metastatic spine disease. A review J Neurosurg Spine 2010 13 1 94 108 10.3171/2010.3.SPINE09202 20594024\n14. Swerdlow SH Campo E Harris NL WHO classification of tumors of haematopoietic and lymphoid tissues 2008 4 Lyon IARC 335 351\n15. Miyazaki T Fujimaki K Shirasugi Y Remission of lymphoma after withdrawal of methotrexate in rheumatoid arthritis: relationship with type of latent Epstein-Barr virus infection Am J Hematol 2007 82 12 1106 1109 10.1002/ajh.21003 17654684\n16. Niitsu N Okamoto M Nakamine H Hirano M Clinicopathologic correlations of diffuse large B-cell lymphoma in rheumatoid arthritis patients treated with methotrexate Cancer Sci 2010 101 5 1309 1313 10.1111/j.1349-7006.2010.01517.x 20210795\n17. Ichikawa A Arakawa F Kiyasu J Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression Eur J Haematol 2013 91 1 20 28 10.1111/ejh.12116 23560463\n18. Minamimoto R Ito K Kubota K Clinical role of FDG PET/CT for methotrexate-related malignant lymphoma Clin Nucl Med 2011 36 7 533 537 10.1097/RLU.0b013e3182177296 21637053\n19. Rizzi R Curci P Delia M Spontaneous remission of “methotrexate-associated lymphoproliferative disorders” after discontinuation of immunosuppressive treatment for autoimmune disease. Review of the literature Med Oncol 2009 26 1 1 9 10.1007/s12032-008-9069-8 18461290\n20. Inui Y Matsuoka H Yakushijin K Methotrexate-associated lymphoproliferative disorders: management by watchful waiting and observation of early lymphocyte recovery after methotrexate withdrawal Leuk Lymphoma 2015 56 11 3045 3051 10.3109/10428194.2015.1022769 25721751\n21. Oebisu N Hoshi M Ieguchi M Lymphoproliferative disorder with pathological fracture of the femur in a patient with rheumatoid arthritis treated with methotrexate: a case report Mol Clin Oncol 2018 9 2 187 191 30101019\n22. Mulligan ME McRae GA Murphey MD Imaging features of primary lymphoma of bone AJR Am J Roentgenol 1999 173 6 1691 1697 10.2214/ajr.173.6.10584821 10584821\n23. Koeller KK Shih RY Extranodal lymphoma of the central nervous system and spine Radiol Clin N Am 2016 54 4 649 671 10.1016/j.rcl.2016.03.003 27265601\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0364-2348",
"issue": "50(10)",
"journal": "Skeletal radiology",
"keywords": "Methotrexate-associated lymphoproliferative disorder; Rheumatoid arthritis; Spinal tumor",
"medline_ta": "Skeletal Radiol",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D008159:Lumbar Vertebrae; D008223:Lymphoma; D008232:Lymphoproliferative Disorders; D008727:Methotrexate; D008875:Middle Aged",
"nlm_unique_id": "7701953",
"other_id": null,
"pages": "2117-2123",
"pmc": null,
"pmid": "33772624",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1787499;17117491;30101019",
"title": "Methotrexate-associated lymphoproliferative disorder of the thoracic spine in a patient with rheumatoid arthritis receiving methotrexate: a case report.",
"title_normalized": "methotrexate associated lymphoproliferative disorder of the thoracic spine in a patient with rheumatoid arthritis receiving methotrexate a case report"
} | [
{
"companynumb": "JP-ACCORD-222175",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "1",
"dru... |
{
"abstract": "Acquired hemophilia A (AHA) is a rare bleeding disorder caused by the autoantibody directed against factor VIII in patients without previous history of a bleeding disorder. We retrospectively analyzed the characteristics and outcomes of 49 patients with AHA diagnosed in our center from February 1994 to October 2012. Twenty-four patients with acute bleeding episodes were treated with prothrombin complex concentrate (PCC) at a relative low dose of 30 to -50 U/kg/d and achieved good outcomes without any adverse reaction. Corticosteroids alone or in combination with cyclophosphamide were used as the first-line therapy to eradicate the inhibitors. In 39 evaluable patients, 35 (89.7%) achieved complete remission (CR). This study demonstrates that when bypassing agents such as recombinant activated factor VII and activated PCCs are not affordable or available, low dose PCC is effective and safe to control acute bleeding in patients with AHA. First-line therapy achieved good outcomes with a CR rate of 89.7%.",
"affiliations": "Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.;Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.;Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.;Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.;Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.;Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.;Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China rcyang65@163.com.",
"authors": "Yang|Yanhui|Y|;Xue|Feng|F|;Shi|Hao|H|;Wang|Hongmei|H|;Zhang|Lei|L|;Ji|Linxiang|L|;Yang|Renchi|R|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D058846:Antibodies, Monoclonal, Murine-Derived; D001323:Autoantibodies; D001779:Blood Coagulation Factors; D007166:Immunosuppressive Agents; C025667:prothrombin complex concentrates; D000069283:Rituximab; D003520:Cyclophosphamide; D005169:Factor VIII",
"country": "United States",
"delete": false,
"doi": "10.1177/1076029613488937",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1076-0296",
"issue": "21(1)",
"journal": "Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis",
"keywords": "PCC; acquired hemophilia A; immunosuppressive therapy; inhibitor",
"medline_ta": "Clin Appl Thromb Hemost",
"mesh_terms": "D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D001323:Autoantibodies; D001779:Blood Coagulation Factors; D002681:China; D003520:Cyclophosphamide; D005169:Factor VIII; D005260:Female; D006467:Hemophilia A; D006470:Hemorrhage; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D012189:Retrospective Studies; D000069283:Rituximab; D055815:Young Adult",
"nlm_unique_id": "9508125",
"other_id": null,
"pages": "35-40",
"pmc": null,
"pmid": "23677912",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Acquired hemophilia a: retrospective analysis of 49 cases from a single Chinese hemophilia center.",
"title_normalized": "acquired hemophilia a retrospective analysis of 49 cases from a single chinese hemophilia center"
} | [
{
"companynumb": "CN-BAXTER-2013BAX045700",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
... |
{
"abstract": "Pregnancy is known to increase the risk of aneurysm formation, likely by a combination of histological changes in vessel walls associated with the hormones of pregnancy and the haemodynamic changes to the circulation. To our knowledge this is the first case of a pregnant woman with a brachial-cephalic arterio-venous fistula (AVF) that had never been needled for haemodialysis, yet became hugely aneurysmal during her pregnancy.",
"affiliations": "Vascular Surgery, King's College Hospital, London, UK.",
"authors": "Stephenson|Matthew A|MA|;Neate|Emily C M|EC|;Mistry|Hiren|H|;Valenti|Domenico|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5301/jva.5000100",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1129-7298",
"issue": "14(1)",
"journal": "The journal of vascular access",
"keywords": null,
"medline_ta": "J Vasc Access",
"mesh_terms": "D000783:Aneurysm; D001132:Arm; D001166:Arteriovenous Shunt, Surgical; D005260:Female; D006801:Humans; D007674:Kidney Diseases; D011247:Pregnancy; D011248:Pregnancy Complications; D006435:Renal Dialysis; D055815:Young Adult",
"nlm_unique_id": "100940729",
"other_id": null,
"pages": "94-5",
"pmc": null,
"pmid": "22865538",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A large aneurysm in an arterio-venous fistula for renal access in a pregnant young woman.",
"title_normalized": "a large aneurysm in an arterio venous fistula for renal access in a pregnant young woman"
} | [
{
"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-338026",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIFEDIPINE"
},
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"abstract": "Limited though promising evidence exists on the efficacy of Deep Brain Stimulation (DBS) of the Medial Forebrain Bundle (MFB) in otherwise intractable patients with Major Depression and Obsessive-Compulsive Disorder (OCD). Herein, we present acute and follow-up results (up to 5 years) of a 42 year old man with a diagnosis of treatment-resistant Bipolar Depression (BD) and comorbid OCD, successfully treated with DBS of the MFB. Regular follow-up visits with psychometric evaluations highlighted a considerable improvement of patient's depressive and OC symptoms at 5 years from implant. According to the limited, reported experience, we support the efficacy and tolerability of DBS of the MFB as a promising intervention in patients with treatment-resistant BD and comorbid OCD, with specific emphasis on the long-term outcome.",
"affiliations": "Department of Psychiatry, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, Milan, Italy.;Dipartimento di Scienze Biomediche e Cliniche \"Luigi Sacco\", University of Milan, ASST Fatebenefratelli-Sacco, Milan, Italy; CRC \"Aldo Ravelli\" for Neuro-technology & Experimental Brain Therapeutics, University of Milan, Milan, Italy. Electronic address: beatrice.benatti@unimi.it.;Dipartimento di Scienze Biomediche e Cliniche \"Luigi Sacco\", University of Milan, ASST Fatebenefratelli-Sacco, Milan, Italy.;IRCCS Orthopedic Institute Galeazzi, Department of Functional Neurosurgery, Tourette Center, Milan, Italy.;IRCCS Orthopedic Institute Galeazzi, Department of Functional Neurosurgery, Tourette Center, Milan, Italy.;IRCCS Orthopedic Institute Galeazzi, Department of Functional Neurosurgery, Tourette Center, Milan, Italy.;Dipartimento di Scienze Biomediche e Cliniche \"Luigi Sacco\", University of Milan, ASST Fatebenefratelli-Sacco, Milan, Italy; Department of Psychiatry and Behavioural Sciences, Bipolar Disorders Clinic, Stanford Medical School, Stanford University, CA, USA; CRC \"Aldo Ravelli\" for Neuro-technology & Experimental Brain Therapeutics, University of Milan, Milan, Italy.",
"authors": "Oldani|Lucio|L|;Benatti|Beatrice|B|;Macellaro|Monica|M|;Porta|Mauro|M|;Servello|Domenico|D|;Zekaj|Edvin|E|;Dell'Osso|Bernardo|B|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2021.04.033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "89()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Deep brain stimulation (DBS); Medial forebrain bundle (MFB); Treatment resistant depression; Treatment resistant obsessive–compulsive disorder",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000328:Adult; D046690:Deep Brain Stimulation; D061218:Depressive Disorder, Treatment-Resistant; D006801:Humans; D008297:Male; D008474:Medial Forebrain Bundle; D009771:Obsessive-Compulsive Disorder",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "103-105",
"pmc": null,
"pmid": "34119251",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A case of treatment-resistant bipolar depression and comorbid OCD treated with deep brain stimulation of the medial forebrain bundle: 5 years follow-up results.",
"title_normalized": "a case of treatment resistant bipolar depression and comorbid ocd treated with deep brain stimulation of the medial forebrain bundle 5 years follow up results"
} | [
{
"companynumb": "IT-PFIZER INC-202101356614",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
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{
"abstract": "The current standard of care is to start antiretroviral therapy in all patients diagnosed with HIV-1, as for HIV-2 current DHHS guideline suggests ART for HIV-2 as soon as diagnosis is established, although this practice is not universal, for instance, in Portugal there are specific criteria to start treatment.\n\n\n\nWe present a case of a man, chronically infected with HIV-1, HIV-2 and hepatitis B virus who developed resistance to HIV-2 while maintaining HIV-1 under control. 6 years after starting antiretroviral therapy he had his first virologic failure. We performed HIV-2 resistance tests that revealed high-grade resistance to all nucleoside reverse-transcriptase inhibitors except tenofovir and to all protease inhibitors except darunavir. After a decade of permanent poor adherence to therapy he developed resistance to both tenofovir and darunavir. We put together a new regiment with tenofovir alafenamide + emtricitabine + dolutegravir + maraviroc and nowadays he is with undetectable HIV-1 and HIV-2 viral loads.\n\n\n\nThis shows the importance of having access to HIV-2 viral load determination and HIV-2 resistance testing.",
"affiliations": "Serviço de Doenças Infeciosas e Medicina Tropical, Hospital De Egas Moniz - Centro Hospitalar Lisboa Ocidental, 1349-019, Lisbon, Portugal. anamargaridacardoso_2@hotmail.com.;Serviço de Doenças Infeciosas e Medicina Tropical, Hospital De Egas Moniz - Centro Hospitalar Lisboa Ocidental, 1349-019, Lisbon, Portugal.;Serviço de Doenças Infeciosas e Medicina Tropical, Hospital De Egas Moniz - Centro Hospitalar Lisboa Ocidental, 1349-019, Lisbon, Portugal.;Laboratório de Biologia Molecular, LMCBM, SPC.HEM - Centro Hospitalar Lisboa Ocidental, 1349-019, Lisbon, Portugal.;Laboratório de Biologia Molecular, LMCBM, SPC.HEM - Centro Hospitalar Lisboa Ocidental, 1349-019, Lisbon, Portugal.;Serviço de Doenças Infeciosas e Medicina Tropical, Hospital De Egas Moniz - Centro Hospitalar Lisboa Ocidental, 1349-019, Lisbon, Portugal.;Laboratório de Biologia Molecular, LMCBM, SPC.HEM - Centro Hospitalar Lisboa Ocidental, 1349-019, Lisbon, Portugal.",
"authors": "Cardoso|Margarida|M|0000-0002-9478-076X;Vasconcelos|Joana|J|;Baptista|Teresa|T|;Diogo|Isabel|I|;Gonçalves|Fátima|F|;Mansinho|Kamal|K|;Gomes|Perpétua|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12981-021-00394-4",
"fulltext": "\n==== Front\nAIDS Res Ther\nAIDS Res Ther\nAIDS Research and Therapy\n1742-6405\nBioMed Central London\n\n394\n10.1186/s12981-021-00394-4\nCase Report\nManagement of HIV-2 resistance to antiretroviral therapy in a HIV-1/HIV-2/HBV co-infected patient\nhttp://orcid.org/0000-0002-9478-076X\nCardoso Margarida anamargaridacardoso_2@hotmail.com\n\n1\nVasconcelos Joana joanapfvasconcelos@hotmail.com\n\n1\nBaptista Teresa teresa.baptista.alberto@gmail.com\n\n1\nDiogo Isabel ifmadeira@chlo.min-saude.pt\n\n2\nGonçalves Fátima mfmgoncalves@chlo.min-saude.pt\n\n2\nMansinho Kamal kmansinho@chlo.min-saude.pt\n\n1\nGomes Perpétua pcrsilva@chlo.min-saude.pt\n\n23\n1 Serviço de Doenças Infeciosas e Medicina Tropical, Hospital De Egas Moniz - Centro Hospitalar Lisboa Ocidental, 1349-019 Lisbon, Portugal\n2 Laboratório de Biologia Molecular, LMCBM, SPC.HEM - Centro Hospitalar Lisboa Ocidental, 1349-019 Lisbon, Portugal\n3 grid.257640.2 0000 0004 0392 4444 Centro de Investigação Interdisciplinar Egas Moniz, CiiEM, ISCSEM, 2829-511 Almada, Portugal\n12 10 2021\n12 10 2021\n2021\n18 6911 12 2020\n23 9 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nThe current standard of care is to start antiretroviral therapy in all patients diagnosed with HIV-1, as for HIV-2 current DHHS guideline suggests ART for HIV-2 as soon as diagnosis is established, although this practice is not universal, for instance, in Portugal there are specific criteria to start treatment.\n\nCase presentation\n\nWe present a case of a man, chronically infected with HIV-1, HIV-2 and hepatitis B virus who developed resistance to HIV-2 while maintaining HIV-1 under control. 6 years after starting antiretroviral therapy he had his first virologic failure. We performed HIV-2 resistance tests that revealed high-grade resistance to all nucleoside reverse-transcriptase inhibitors except tenofovir and to all protease inhibitors except darunavir. After a decade of permanent poor adherence to therapy he developed resistance to both tenofovir and darunavir. We put together a new regiment with tenofovir alafenamide + emtricitabine + dolutegravir + maraviroc and nowadays he is with undetectable HIV-1 and HIV-2 viral loads.\n\nConclusions\n\nThis shows the importance of having access to HIV-2 viral load determination and HIV-2 resistance testing.\n\nKeywords\n\nHIV-2\nHIV-1\nResistance\nMutation\nCoinfection\nAntiretroviral therapy\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nHuman immunodeficiency virus type 1 (HIV-1) infection is responsible for the majority of human immunodeficiency virus cases worldwide. In West Africa human immunodeficiency virus type 2 (HIV-2) is also prevalent with a 0.3–1% estimated coinfection rate [1]. These viruses have different natural history, with HIV-2 usually progressing more slowly than HIV-1 [2].\n\nThe current standard of care is to start antiretroviral therapy (ART) in all patients diagnosed with HIV-1 [3]. In Portugal, the criteria to start treatment in HIV-2 is: TCD4 + count under 350 cells/uL or symptomatic infection or viral load over 100 cp/mL in two sequential measures [4]. HIV-2 is naturally resistant to non-nucleoside reverse-transcriptase inhibitors, susceptible to integrase strand-transfer inhibitors and nucleoside reverse-transcriptase inhibitors and exhibits variable susceptibility to different protease inhibitors [2]. Recently, in 2021, an effort was made by a panel of European HIV-2 experts, to create recommendations for the diagnosis, treatment and follow-up of HIV-2 patients based on the published literature as well as field experience. They recommend to initiate ARV in all symptomatic patients and in asymptomatic with one of the following conditions:TCD4 + count ≤ 500 CD4 + -cells/μL blood,\n\nTCD4 + decrease of more than 30 cells/μL and year, over a period of more than 3 years,\n\nRepeatedly detectable HIV-2 RNA in plasma,\n\nComorbidities, such as chronic HBV infection [5].\n\nCase presentation\n\nWe present a case of a 54 year old Guinean man, chronically infected with human immunodeficiency virus type 1 (HIV-1) subtype B, human immunodeficiency virus type 2 (HIV-2) group A and hepatitis B virus (HBV) with negative HBeAg. Previous medical conditions included hypertensive cardiac insufficiency and a chronic kidney disease.\n\nThe diagnosis of HIV-1 and HIV-2 coinfection was initially made with serological testing, initially a 4th generation assay, followed by positive HIV-1 and HIV-2 Western Blot. HIV-1 viral load was detected using a commercial assay and HIV-2 viral load was detected using an in-house real-time RT-PCR. HIV-2 resistance testing was done with an in house assay. The viral RNA was extracted from plasma using BioMerieux’s Nuclisense® EasyMag® equipment. The integrase and pol genes were amplified using a protocol in house, followed by sequencing by the Sanger method using 8 primers and the BigDye® Terminator v.3.1 Cycle Sequencing Kit. Detection and reading of DNA sequences was performed on the sequencer Automatic ABI Prism ®3100 from Applied Biosystems. Finally the DNA sequences were stored in the RegaDb database, Leuven (Rega Institute; REGA), analyzed using the CromasPro V software. 1.7.6. and interpreted according to the Grade HIV-2 algorithm (https://bit.ly/378Q3tK).\n\nThe patient was diagnosed in 2001 with an initial CD4 245 cells/uL, during pre-surgical screening. According to Centers for Disease Control and Prevention, Atlanta classification, he had category A2 disease. He had not been tested for HIV previously and was probably infected through heterosexual contact. The patient has been followed up twice a year, with viral load monitoring every 6 months in the infectious diseases’ ambulatory clinic since July 2001.\n\nIn 2001 he started ART with atazanavir/lamivudine + nelfinavir (ATV/3TC + nelfinavir). Therapy was switched to ATV/3TC + lopinavir and ritonavir (LPVr) in 2007 due to HIV-2 virologic failure [viral load (VL) = 388 cp/mL] with undetectable HIV-1 VL.\n\nIn 2011 he had another HIV-2 therapeutic failure (VL = 2771 cp/mL), with undetectable HIV-1 VL, high-grade resistance to all nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) except tenofovir disoproxil fumarate (TDF) [Q151M, M184V] and high-grade resistance to all protease inhibitors (PIs) inhibitors except for darunavir (DRV) [V47A, L90M] was shown on further testing. Therefore, ART was switched to TDF/emtricitabine + DRV/r + raltegravir.\n\nIn August 2018 he had undetectable VL to both HIV-1 and HIV-2. However, half a year later he had another virologic failure, this time to both viruses, HIV-1 (VL = 7352 cp/mL) and HIV-2 (VL = 754 cp/mL). We performed both resistance tests and HIV-2 resistance test revealed high grade resistance to all NRTIs [K65R, D67N, Q151M, S215ST] and high-grade resistance to LPV, saquinavir and DRV [V47A, I84V, L90M]. HIV-2 and HIV-1 resistance tests to integrase strand-transfer inhibitors were negative, as well as HIV-1 to PIs and reverse-transcriptase inhibitors.\n\nSince January 2019, he has been taking tenofovir alafenamide fumarate + DTG + maraviroc and at the last evaluation he had undetectable HIV-1 and HIV-2 VL with a CD4 + cells count of 374 cells/uL. (Fig. 1).Fig. 1 Patient HIV-1/HIV-2/HBV viral loads and TCD4 + count over calendar time. This graphic represents the evolution of the HIV-1/HIV-2/HBV viral loads and TCD4 + count between diagnosis in 2001 and last evaluation of the patient in 2019. The curves were represented in a logarithmic scale for better understanding. Additionally we highlighted the moments when ARV was changed (white boxes) and mutations detected (black boxes). The level of detection illustrated is < 20 copies/mL for HIV-1, < 40 copies/mL for HIV-2 and < 20 copies/mL for HBV. Lamivudine (3TC), atazanavir (ATV), darunavir (DRV), dolutegravir (DTG), emtricitabine (FTC) hepatitis B virus (HBV), hepatitis B virus (HBV), human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), lopinavir (LPV), maraviroc (MVC), nelfinavir (NFV), raltegravir (RAL), tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF), viral load (VL)\n\nIt’s relevant to highlight that this is a patient with poor adherence to ART, who stopped ART and follow-up several times in the last years.\n\nHBV VL has remained undetectable through all these years, without HBsAg seroconversion.\n\nDiscussion and conclusions\n\nThis case emphasizes the difficulty of the management of a triple coinfection. We point to the possibility of virologic failure exclusively to HIV-2 with controlled HIV-1 and HBV infections. In fact, it has been reported that HIV-2 may slow down HIV-1 progression [6] and its optimal treatment is challenging considering its different susceptibility to ARV. In our patient it seems that the initial ARV could have been suboptimal for HIV-2, namely nelfinavir [7], leading to the development of mutations.\n\nThis shows the importance of having access to HIV-2 viral load determination and HIV-2 resistance testing and the need to keep updated in clinical practice in order to achieve an efficacious regimen to both HIV (1 and 2) and HBV infections. Taking into account the complexity of HIV-2 infection and less experience in this field we suggest that the management of this infection should be done or guided by experts in the area and if possible in reference centers.\n\nAbbreviations\n\n3TC Lamivudine\n\nART Antiretroviral therapy\n\nATV Atazanavir\n\nDRV Darunavir\n\nHBV Hepatitis B virus\n\nHIV-1 Human immunodeficiency virus type 1\n\nHIV-2 Human immunodeficiency virus type 2\n\nLPV Lopinavir\n\nNRTIs Nucleoside/nucleotide reverse transcriptase inhibitors\n\nPIs Protease inhibitors\n\nr Ritonavir\n\nTDF Tenofovir disoproxil fumarate\n\nVL Viral load\n\nAcknowledgements\n\nWe acknowledge Nuno Taveira for suggestions and revision of this manuscript.\n\nAuthors' contributions\n\nMC, JV, TB and KM were physicians of the patient, all contributed in the discussion, management of patient and writing of the paper. ID, FG and PG work in the laboratory, executing and interpreting the resistance test presented and contributed to the writing of the paper. All authors read and approved the final manuscript.\n\nFunding\n\nThis research received no external funding.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nEthical approval was not required.\n\nConsent for publication\n\nThe patient gave written consent for the publication of the data presented in this clinical case.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Landman R Damond F Gerbe J Brun-Vezinet F Yeni P Matheron S Immunovirological and therapeutic follow up of HIV-1/HIV-2 dually seropositive patients AIDS 2009 23 423 443 10.1097/QAD.0b013e328321305a 19114852\n2. Campbell-Yesufu OT Gandhi RT Update on human immunodeficiency virus (HIV)-2 infection Clin Infect Dis 2011 52 6 780 787 10.1093/cid/ciq248 21367732\n3. European Guidelines for treatment of HIV infected adults in Europe. (version 10.0). European AIDS Clinical Society. 2019.\n4. Recomendações Portuguesas para o tratamento da infeção por VIH-1 e VIH-2. (version 1.0). Programa nacional para a infeção VIH/SIDA–Direção Geral de Saúde. 2016.\n5. Berzow D Descamps D Obermeier M Charpentier C Kaiser R Guertler L Human immunodeficiency virus–2 (HIV-2): a summary of the present standard of care and treatment options for individuals living with HIV-2 in Western Europe Clin Infect Dis 2020 72 3 503 509 10.1093/cid/ciaa275\n6. Esbjörnsson J Månsson F Kvist A Isberg P Nowroozalizadeh S Biague A Inhibition of HIV-1 disease progression by contemporaneous HIV-2 infection N Engl J Med 2012 367 3 224 232 10.1056/NEJMoa1113244 22808957\n7. Rodés B Sheldon J Toro C Jiménez V Álvarez M Soriano V Susceptibility to protease inhibitors in HIV-2 primary isolates from patients failing antiretroviral therapy J Antimicrob Chemother 2006 57 4 709 713 10.1093/jac/dkl034 16464891\n\n",
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"keywords": "Antiretroviral therapy; Coinfection; HIV-1; HIV-2; Mutation; Resistance",
"medline_ta": "AIDS Res Ther",
"mesh_terms": "D060085:Coinfection; D015658:HIV Infections; D015497:HIV-1; D015498:HIV-2; D006515:Hepatitis B virus; D006801:Humans; D008297:Male",
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"pages": "69",
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"title": "Management of HIV-2 resistance to antiretroviral therapy in a HIV-1/HIV-2/HBV co-infected patient.",
"title_normalized": "management of hiv 2 resistance to antiretroviral therapy in a hiv 1 hiv 2 hbv co infected patient"
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"abstract": "Background: Desmoplastic small round cell tumors (DSRCT) are malignant neoplasms of young males arising most commonly in the abdominopelvic cavity, with a subset originating from extra-abdominal soft tissues. As either primary or metastatic lesions, they are rare in intraosseous sites. Case Presentation: We describe the fifth report of primary DSRCT of bone. A healthy 18-year old male presented with a blastic, 17 cm lesion within the left distal femur, suspicious for osteosarcoma or Ewing sarcoma. Subsequent biopsy revealed nests of small round blue cells infiltrating through a desmoplastic stroma. These cells were diffusely positive for epithelial markers, with paranuclear staining for desmin and focal reactivity with NSE. Break-apart FISH revealed a rearrangement in EWSR1, and RNA fusion panel confirmed WT1 as its partner in the pathognomonic t(11;22)(p13;q12) rearrangement. PET/CT showed widespread metastatic disease to visceral and bony sites. Conclusions: Due to their rarity as well as clinicopathologic and immunomorphologic overlap, primary intraosseous DSRCT can create diagnostic challenges with the more frequently encountered tumors of bone.",
"affiliations": "21727University of Chicago Medical Center, Chicago, IL, USA.;21727University of Chicago Medical Center, Chicago, IL, USA.;Advocate Children's Hospital, Park Ridge, IL, USA.;21727University of Chicago Medical Center, Chicago, IL, USA.;21727University of Chicago Medical Center, Chicago, IL, USA.;21727University of Chicago Medical Center, Chicago, IL, USA.;21727University of Chicago Medical Center, Chicago, IL, USA.",
"authors": "Sharma|Aarti E|AE|https://orcid.org/0000-0002-3088-3946;deVries|John A|JA|;Agrawal|Caitlin|C|;Haydon|Rex C|RC|;Krausz|Thomas|T|;Pytel|Peter|P|;Cipriani|Nicole A|NA|https://orcid.org/0000-0003-3092-2746",
"chemical_list": null,
"country": "United States",
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"doi": "10.1177/10668969211046017",
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"issue": null,
"journal": "International journal of surgical pathology",
"keywords": "EWSR1; WT1; desmoplastic small round cell tumor; ewing sarcoma; femur; osteosarcoma",
"medline_ta": "Int J Surg Pathol",
"mesh_terms": null,
"nlm_unique_id": "9314927",
"other_id": null,
"pages": "10668969211046017",
"pmc": null,
"pmid": "34657504",
"pubdate": "2021-10-16",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Primary Desmoplastic Small Round Cell Tumor of the Femur: Case Report and Review of a Rare Intraosseous Malignancy.",
"title_normalized": "primary desmoplastic small round cell tumor of the femur case report and review of a rare intraosseous malignancy"
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"abstract": "BACKGROUND\nICU patients must be kept conscious, calm, and cooperative even during the critical phases of illness. Enteral administration of sedative drugs might avoid over sedation, and would be as adequate as intravenous administration in patients who are awake, with fewer side effects and lower costs. This study compares two sedation strategies, for early achievement and maintenance of the target light sedation.\n\n\nMETHODS\nThis was a multicenter, single-blind, randomized and controlled trial carried out in 12 Italian ICUs, involving patients with expected mechanical ventilation duration > 72 h at ICU admission and predicted mortality > 12% (Simplified Acute Physiology Score II > 32 points) during the first 24 h on ICU. Patients were randomly assigned to receive intravenous (midazolam, propofol) or enteral (hydroxyzine, lorazepam, and melatonin) sedation. The primary outcome was percentage of work shifts with the patient having an observed Richmond Agitation-Sedation Scale (RASS) = target RASS ±1. Secondary outcomes were feasibility, delirium-free and coma-free days, costs of drugs, length of ICU and hospital stay, and ICU, hospital, and one-year mortality.\n\n\nRESULTS\nThere were 348 patients enrolled. There were no differences in the primary outcome: enteral 89.8% (74.1-100), intravenous 94.4% (78-100), p = 0.20. Enteral-treated patients had more protocol violations: n = 81 (46.6%) vs 7 (4.2%), p < 0.01; more self-extubations: n = 14 (8.1%) vs 4 (2.4%), p = 0.03; a lighter sedative target (RASS = 0): 93% (71-100) vs 83% (61-100), p < 0.01; and lower total drug costs: 2.39 (0.75-9.78) vs 4.15 (1.20-20.19) €/day with mechanical ventilation (p = 0.01).\n\n\nCONCLUSIONS\nAlthough enteral sedation of critically ill patients is cheaper and permits a lighter sedation target, it is not superior to intravenous sedation for reaching the RASS target.\n\n\nBACKGROUND\nClinicalTrials.gov, NCT01360346 . Registered on 25 March 2011.",
"affiliations": "Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, A.O. San Paolo - Polo Universitario, Via A. Di Rudinì, 8, 20142, Milano, Italy. giovanni.mistraletti@unimi.it.;SC Anestesia e Rianimazione, ASST Santi Paolo e Carlo, Ospedale San Paolo - Polo Universitario, Milano, Italy.;Dipartimento di Economia, Management e Metodi Quantitativi, Università degli Studi di Milano, Milano, Italy.;Dipartimento Anestesia, Rianimazione ed Emergenza-Urgenza, Fondazione IRCCS Ca'Granda, Ospedale Maggiore Policlinico, Milano, Italy.;SC Anestesia e Rianimazione, ASST Santi Paolo e Carlo, Ospedale San Paolo - Polo Universitario, Milano, Italy.;SC Anestesia e Rianimazione, ASST Santi Paolo e Carlo, Ospedale San Paolo - Polo Universitario, Milano, Italy.;Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, A.O. San Paolo - Polo Universitario, Via A. Di Rudinì, 8, 20142, Milano, Italy.;Dipartimento Anestesia, Rianimazione ed Emergenza-Urgenza, Fondazione IRCCS Ca'Granda, Ospedale Maggiore Policlinico, Milano, Italy.;UOC Anestesia e Rianimazione, ASST Monza, Ospedale di Desio, Monza, Italy.;UO Anestesia e Rianimazione, ASST Ovest Milanese, Ospedale Nuovo di Legnano (MI), Legnano, Italy.;Dipartimento di Medicina e Chirurgia, Università degli Studi Milano Bicocca, A.O. San Gerardo, Monza, Italy.;Dipartimento Medicina Intensiva, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.;UO Anestesia e Rianimazione 2, IRCCS San Matteo, Pavia, Italy.;SC Anestesia Rianimazione B DEA, Ospedale San Giovanni Bosco, Torino, Italy.;SCDU Anestesia e Rianimazione, AOU San Luigi Gonzaga di Orbassano (TO), Torino, Italy.;UO Anestesia e Rianimazione, AO Cardinal Massaia, Asti, Italy.;UO Anestesia e Rianimazione, AO Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.;UO Anestesia e Rianimazione, Nuovo Ospedale Civile Sant'Agostino Estense, Modena, Italy.;Dipartimento di Economia, Management e Metodi Quantitativi, Università degli Studi di Milano, Milano, Italy.;Dipartimento di Economia, Management e Metodi Quantitativi, Università degli Studi di Milano, Milano, Italy.;Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, A.O. San Paolo - Polo Universitario, Via A. Di Rudinì, 8, 20142, Milano, Italy.",
"authors": "Mistraletti|Giovanni|G|http://orcid.org/0000-0001-8322-1623;Umbrello|Michele|M|;Salini|Silvia|S|;Cadringher|Paolo|P|;Formenti|Paolo|P|;Chiumello|Davide|D|;Villa|Cristina|C|;Russo|Riccarda|R|;Francesconi|Silvia|S|;Valdambrini|Federico|F|;Bellani|Giacomo|G|;Palo|Alessandra|A|;Riccardi|Francesca|F|;Ferretti|Enrica|E|;Festa|Maurilio|M|;Gado|Anna Maria|AM|;Taverna|Martina|M|;Pinna|Cristina|C|;Barbiero|Alessandro|A|;Ferrari|Pier Alda|PA|;Iapichino|Gaetano|G|;|||",
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"country": "England",
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"doi": "10.1186/s13054-018-2280-x",
"fulltext": "\n==== Front\nCrit CareCritical Care1364-85351466-609XBioMed Central London 228010.1186/s13054-018-2280-xResearchEnteral versus intravenous approach for the sedation of critically ill patients: a randomized and controlled trial http://orcid.org/0000-0001-8322-1623Mistraletti Giovanni +39.02.50323134giovanni.mistraletti@unimi.it 12Umbrello Michele michele.umbrello@asst-santipaolocarlo.it 2Salini Silvia silvia.salini@unimi.it 3Cadringher Paolo elekton@gmail.com 4Formenti Paolo paolo.formenti@asst-santipaolocarlo.it 2Chiumello Davide davide.chiumello@unimi.it 25Villa Cristina cristina.villa@unimi.it 1Russo Riccarda riccarda.russo@gmail.com 4Francesconi Silvia francesconi.silvia@alice.it 6Valdambrini Federico federico.valdambrini@asst-ovestmi.it 7Bellani Giacomo giacomo.bellani1@unimib.it 8Palo Alessandra a.palo@smatteo.pv.it 9Riccardi Francesca f.riccardi@smatteo.pv.it 10Ferretti Enrica enrica.ferretti@yahoo.it 11Festa Maurilio festa.maurilio@gmail.com 12Gado Anna Maria agado@asl.at.it 13Taverna Martina martinatav@libero.it 14Pinna Cristina c.pinna@ausl.mo.it 15Barbiero Alessandro alessandro.barbiero@unimi.it 3Ferrari Pier Alda pieralda.ferrari@unimi.it 3Iapichino Gaetano g.iapichino@unimi.it 12the SedaEN investigatorsIapichino Gaetano Morabito Alberto alberto.morabito@gmail.com Langer Martin martin.langer@istitutotumori.mi.it Valenza Franco franco.valenza@unimi.it Malacrida Roberto rmalacrida@swissonline.ch Rambaldi Marco Mistraletti Giovanni Chiumello Davide Umbrello Michele Formenti Paolo Spanu Paolo Anania Stefania Andrighi Elisa Di Carlo Alessandra Martinetti Federica Barello Serena Noto Andrea Capello Gianfranco Sabatelli Bruno Brenna Giovanni Astori Morena Placido Pietro Gattinoni Luciano Protti Alessandro Cadringher Paolo Russo Riccarda Pagan Francesca Berto Virna Roselli Paola Ronzoni Giulio Beck Eduardo Francesconi Silvia Gaiotto Maurizio Radrizzani Danilo Ferla Luca Valdambrini Federico Giudici Riccardo Merlini Laura Pesenti Antonio Bellani Giacomo La Bruna Alessia Rezoagli Emanuele Lucchini Alberto Braschi Antonio Palo Alessandra Niebel Thekla Selvini Marina Cortesi Sergio Quaini Attilio Iotti Giorgio Riccardi Francesca Contri Enrico Sacchi Antonella Livigni Sergio Naretto Giuseppe Ferretti Enrica Deprado Alessandro Venturi degli Esposti Virna Caironi Pietro Radeschi Giulio Festa Maurilio Odetto Lorenzo Ferrero Daniele Cognolato Stefano Penso Roberto Vacchelli Roberta Cardellino Silvano Bosco Edda Gado Anna Maria Bresciani Anna Pozzo Ivana Alessio Annachiara Clarindo Rodrigues Vanessa Biase Edna Vivaldi Nicoletta Taverna Martina Nava Antonella Pinna Cristina Ponzetta Francesco Bavutti Lucilla Martina Paola Palacios Beatriz Bergonzini Giancarla mistraletti@gmail.com 1 0000 0004 1757 2822grid.4708.bDipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, A.O. San Paolo - Polo Universitario, Via A. Di Rudinì, 8, 20142 Milano, Italy 2 grid.415093.aSC Anestesia e Rianimazione, ASST Santi Paolo e Carlo, Ospedale San Paolo - Polo Universitario, Milano, Italy 3 0000 0004 1757 2822grid.4708.bDipartimento di Economia, Management e Metodi Quantitativi, Università degli Studi di Milano, Milano, Italy 4 0000 0004 1757 8749grid.414818.0Dipartimento Anestesia, Rianimazione ed Emergenza-Urgenza, Fondazione IRCCS Ca’Granda, Ospedale Maggiore Policlinico, Milano, Italy 5 0000 0004 1757 2822grid.4708.bDipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy 6 0000 0004 1760 8047grid.413643.7UOC Anestesia e Rianimazione, ASST Monza, Ospedale di Desio, Monza, Italy 7 UO Anestesia e Rianimazione, ASST Ovest Milanese, Ospedale Nuovo di Legnano (MI), Legnano, Italy 8 0000 0001 2174 1754grid.7563.7Dipartimento di Medicina e Chirurgia, Università degli Studi Milano Bicocca, A.O. San Gerardo, Monza, Italy 9 Dipartimento Medicina Intensiva, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy 10 0000 0004 1760 3027grid.419425.fUO Anestesia e Rianimazione 2, IRCCS San Matteo, Pavia, Italy 11 0000 0004 1760 7116grid.415044.0SC Anestesia Rianimazione B DEA, Ospedale San Giovanni Bosco, Torino, Italy 12 SCDU Anestesia e Rianimazione, AOU San Luigi Gonzaga di Orbassano (TO), Torino, Italy 13 UO Anestesia e Rianimazione, AO Cardinal Massaia, Asti, Italy 14 UO Anestesia e Rianimazione, AO Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy 15 UO Anestesia e Rianimazione, Nuovo Ospedale Civile Sant’Agostino Estense, Modena, Italy 7 1 2019 7 1 2019 2019 23 316 8 2018 27 11 2018 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nICU patients must be kept conscious, calm, and cooperative even during the critical phases of illness. Enteral administration of sedative drugs might avoid over sedation, and would be as adequate as intravenous administration in patients who are awake, with fewer side effects and lower costs. This study compares two sedation strategies, for early achievement and maintenance of the target light sedation.\n\nMethods\nThis was a multicenter, single-blind, randomized and controlled trial carried out in 12 Italian ICUs, involving patients with expected mechanical ventilation duration > 72 h at ICU admission and predicted mortality > 12% (Simplified Acute Physiology Score II > 32 points) during the first 24 h on ICU. Patients were randomly assigned to receive intravenous (midazolam, propofol) or enteral (hydroxyzine, lorazepam, and melatonin) sedation. The primary outcome was percentage of work shifts with the patient having an observed Richmond Agitation-Sedation Scale (RASS) = target RASS ±1. Secondary outcomes were feasibility, delirium-free and coma-free days, costs of drugs, length of ICU and hospital stay, and ICU, hospital, and one-year mortality.\n\nResults\nThere were 348 patients enrolled. There were no differences in the primary outcome: enteral 89.8% (74.1–100), intravenous 94.4% (78–100), p = 0.20. Enteral-treated patients had more protocol violations: n = 81 (46.6%) vs 7 (4.2%), p < 0.01; more self-extubations: n = 14 (8.1%) vs 4 (2.4%), p = 0.03; a lighter sedative target (RASS = 0): 93% (71–100) vs 83% (61–100), p < 0.01; and lower total drug costs: 2.39 (0.75–9.78) vs 4.15 (1.20–20.19) €/day with mechanical ventilation (p = 0.01).\n\nConclusions\nAlthough enteral sedation of critically ill patients is cheaper and permits a lighter sedation target, it is not superior to intravenous sedation for reaching the RASS target.\n\nTrial registration\nClinicalTrials.gov, NCT01360346. Registered on 25 March 2011.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s13054-018-2280-x) contains supplementary material, which is available to authorized users.\n\nKeywords\nHypnotics and sedativesHydroxyzineMelatoninPatient care planningNursing education researchhttp://dx.doi.org/10.13039/501100009882Regione LombardiaDRL 13465, December 22, 2010Iapichino Gaetano issue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nThe management of pain, agitation, and delirium is a key point in the care of critically ill patients [1]. Once triggering conditions have been dealt with, pharmacological treatment becomes necessary. After adequate analgesia, sedative drugs, usually given by continuous intravenous (IV) infusion, ensure comfort and allow life-saving procedures, constituting an invaluable tool during the ICU stay. However, they have several side effects [2, 3]. International guidelines [4, 5] suggest using the lowest effective doses for early achievement [6, 7] and constant maintenance of a light level of sedation even in the most severe conditions [8, 9]. Several strategies have been proposed to avoid deeper-than-needed [10] levels of sedation, aiming for the goal of keeping ICU patients “calm, conscious, and cooperative” [11–13].\n\nHowever, even if unjustified [8], a large proportion of ICU staff still tend to consider this unfeasible [14] because of the risk of self-removal of invasive devices [15], the fear of greater stress/discomfort among patients, and the increased workload for operators. Despite the widespread use of validated scoring systems for sedation, like the Richmond Agitation and Sedation Scale (RASS) [16], a very large proportion of ICU patients are kept at a sedation level deeper than desired [10, 17], quite likely causing avoidable side effects.\n\nWith continuous intravenous (IV) infusion one can predict the duration of the drug effect using pharmacokinetic calculations. This approach, safe for patients with a short ICU stay, could be useless or dangerous in patients needing mechanical ventilation (MV) for more than 3 days. In these cases, it may cause over-administration [18] even with adequate sedation targets. Moreover, the daily awakening trials [15] could induce non-physiological neurological fluctuations, preventing the formation of factual memories, and becoming a precipitant cause of delirium [19], leading to post-ICU cognitive dysfunction [20].\n\nAnalgesic [21] and sedative [22] drugs are rarely administered enterally (EN) because of their slower onset of effect and unpredictable pharmacokinetics, even when intestinal absorption is adequate from ICU admission [23]. Our “EN sedation” protocol [24] uses hydroxyzine (a first-generation antihistaminic drug, with antiemetic and gastric antisecretory properties) and allows the addition of low doses of lorazepam (a medium-half-life benzodiazepine) if necessary. Melatonin is continuously used [25] as a physiological sleep-inducer, with antioxidant, anti-inflammatory, analgesic, and immune-modulating properties [26, 27].\n\nThe longer onset and offset time of EN administration make this approach difficult. However, at the same time, this route ensures a more stable level of consciousness with less neurological fluctuation and fewer cardiorespiratory side effects. EN drugs cost much less than IV ones [22], are less likely to lead to deep sedation, and are similarly effective as judged by nurses, if an awake target is desired [12].\n\nThe hypothesis of the present study is that an unusual EN sedative drugs administration protocol could reach and maintain light and effective sedation, compared to the more common IV continuous infusion. The main outcome was achievement of the target sedation level in ICU patients needing MV for more than 72 h.\n\nMethods\nStudy design\nThe methods have been described in detail elsewhere [24]. Briefly, the “Enteral versus intravenous sedation trial (SedaEN)” is a randomized, controlled, multicenter, single-blind trial (ClinicalTrials.gov, NCT01360346), to compare two protocols for sedation management, both used after adequate analgesia. In the control group, propofol or midazolam were given by IV infusion. In the intervention group, melatonin, hydroxyzine, and possibly lorazepam were administered enterally, while IV drugs were allowed during the first 48 h on ICU [25].\n\nSetting\nThe 12 Italian participating ICUs were selected on the basis of their availability to use two very different protocols simultaneously; in order to obtain the best generalizability, they were heterogeneous in terms of patient case-mix, central/rural area, previous knowledge about EN sedation, and belonging to academic hospitals. To help in caring for complex cases, three flowcharts were proposed, for pain, agitation, and delirium management [24]. Weaning from MV was not set in the protocol, but was managed according to local guidelines in both groups.\n\nParticipants\nInclusion criteria were age ≥ 18 years, MV duration > 72 h as estimated by the physician in charge at ICU admission, and Simplified Acute Physiology Score II (SAPS II) [28] > 32 points during the first 24 h on ICU, corresponding to expected mortality > 12%. Exclusion criteria are set out in Fig. 1. A study sample of 300 patients was calculated as required in order to detect a clinically relevant difference in the main outcome [24].Fig. 1 The Consolidated Standards of Reporting Trials (CONSORT) diagram for screening and randomization in the “Enteral versus intravenous sedation” (SedaEN) trial. The 339 patients were analyzed using an intention-to-treat approach, without considering treatment interruptions. ICU, intensive care unit; MV, mechanical ventilation; SAPS II, Simplified Acute Physiology Score II; CNS, central nervous system; DNR, do not resuscitate orders; IV, intravenous; EN, enteral\n\n\n\nRandomization and masking\nPatients were randomized through a centralized website [24]. After written informed consent had been obtained from patients or relatives according to the indications of the 12 local ethics committees that approved the study, the group allocation was established with a minimization algorithm balanced within centers. Once a patient was assigned, no change of protocol arm was allowed. Staff members were aware of the group assignment, as it was not possible to blind staff to the sedative drug administration route.\n\nProcedures\nAccording to a patient-centered approach [1, 4, 5], in both groups the attending physicians were invited to state the target sedation level for each work shift, aiming as soon as possible for a conscious, calm, and cooperative target, and to titrate doses of sedatives early with the rule of “timing, adequacy, de-escalation”. Physicians on duty discussed prescriptions at least twice a day during handovers. Nurses assessed the depth of sedation, indicating the prevalent RASS level in their work shift, and stated whether the prescriptions were adequate for the severity of the illness, the invasive procedures, and patients’ surveillance and security. Even though protocol violations were strongly discouraged, they were always allowed and recorded. IV boluses of analgesics (fentanyl or morphine) and/or IV sedatives (propofol or midazolam) were not considered violations in the EN arm when used for extemporary invasive/painful/surgical procedures.\n\nOutcomes\nThe main outcome was the percentage of work shifts in which the desired sedation level was reached or nearly reached (observed RASS = target RASS ±1). The secondary outcomes were feasibility of the sedation protocol (percentage of shifts with assigned protocol violations); delirium-free and coma-free days, assessed by the Confusion Assessment Method for ICU (CAM-ICU) [29] and RASS (coma was defined by RASS levels of − 4 and − 5); ventilation-free days; nursing assessment of the adequacy of sedation (anxiety, cooperation, tolerance of the environment); length of ICU stay; ICU, hospital, and one-year mortality; hospital costs for neuroactive drugs [30]. Adverse events such as self-extubation and removal of other invasive tools, unscheduled diagnostic neurological tests, anxiety, hours of sleep and agitation, and use of anti-psychotics, pharmacological antagonists, or physical restraints were recorded.\n\nStatistical analysis\nAn intention-to-treat statistical approach was planned, because the violation rate was unpredictable a priori. Baseline patient characteristics and single-observation outcomes were analyzed by two-tailed tests: the Wilcoxon rank-sum test for analysis of continuous data and Fisher’s exact test for analysis of categorical data. We performed repeated measures analysis for data recorded during the whole ICU stay; comparisons were made by multilevel mixed-effects Poisson regression. This statistical approach was selected to simultaneously analyze the net effects of group assignment, the effect of time spent in ICU, and the cumulative effect of the sedatives, as calculated by multiplying the group (EN = 1, IV = 0) and the ICU day from group assignment, to highlight the adjunctive effects of the daily EN doses of sedatives.\n\nMortality was analyzed by log-rank test and presented as Kaplan–Meier curves, without adjustment for baseline covariates. There were no missing data on the main outcome, as the centralized website needed these data to be completed before allowing the validation of each patient’s recordings. The Stata 12 statistical package (Stata Corporation, College Station TX, USA) was used for all statistical analyses.\n\nAfter the first 140 patients were enrolled, an interim analysis was planned. The results were discussed in a steering committee meeting (28 May 2012). In the power calculation, a study sample of 141 patients per group (power 80%, alpha 0.05) was calculated as sufficient to observe a 15% difference in the prevalence of sedation adequacy (observed RASS = target RASS ±1) between the two study arms: such a difference was considered clinically relevant and likely to influence medical practice. To allow for missing data, a total of 300 patients was expected to be enrolled, with at least 20 patients per ICU [24].\n\nResults\nParticipants\nThe characteristics of the 12 participating ICUs are described in Additional file 1: Table E1. During the study (24 January 2012 to 31 December 2012), 2914 critically ill patients were admitted and screened; 348 of them were randomized (Fig. 1). The baseline characteristics of patients at ICU admission are presented in Table 1; the two groups were adequately balanced according both the criteria stated a priori and in the other clinical parameters.Table 1 Baseline characteristics\n\n\tGroup IV\n(N = 165)\tGroup EN\n(N = 174)\t\nAge, median [IQR], yearsa\t71 [62–77]\t73 [62–78]\t\nMena\t107 (64.8)\t109 (62.6)\t\nBMI, median [IQR]\t25.9 [23.7–29.4]\t26.1 [23.4–29.4]\t\nSevere sepsis or septic shocka\t48 (29.1)\t64 (36.8)\t\nSAPS II score, median [IQR]a, b\t45 [38–55]\t46 [38–54]\t\nSOFA score, median [IQR] c\t8 [5–10]\t7 [5–10]\t\nType of admissiona, d\t\n Medical\t110 (66.7)\t114 (65.5)\t\n Surgical/traumatic\t55 (33.3)\t60 (34.5)\t\nAdmission from\t\n Emergency room\t55 (33.3)\t61 (37.0)\t\n Ward\t55 (33.3)\t59 (35.8)\t\n Operating theatre\t39 (23.6)\t34 (20.6)\t\n Other ICU\t16 (9.7)\t20 (12.1)\t\nReason for ICU admissione\t\n Respiratory failure\t97 (58.8)\t101 (58.0)\t\n Cardiac failure\t38 (23.0)\t40 (23.0)\t\n Neurologic failure\t11 (6.7)\t12 (6.9)\t\n Monitoring\t6 (3.6)\t9 (5.2)\t\n Other\t13 (7.9)\t12 (6.9)\t\nAcute or chronic kidney failurea\t30 (18.2)\t43 (24.7)\t\nModerate to severe COPDa\t50 (30.3)\t53 (30.5)\t\nAbbreviations: EN enteral, IV intravenous, BMI body mass index, IQR interquartile range, SAPS Simplified Acute Physiology Score, SOFA Sequential Organ Failure Assessment, COPD chronic obstructive pulmonary disease, ICU Intensive Care Units\n\naCharacteristics used by the minimization algorithm for the group assignment\n\nbSAPS II may range from 0 to 163 points, with higher scores indicating more severe diseases\n\ncSOFA score may range from 0 to 24 points, with higher scores indicating more severe diseases\n\ndSurgical/trauma refers to admission from an operating room or postoperative recovery area\n\neMain reasons for admission are mutually exclusive\n\n\n\nInterim analysis\nNo serious adverse events were reported, and there was a significant difference in the RASS target: patients in the EN group were more frequently at a conscious level (RASS = 0) than those randomized to the IV group. Clear recommendations were communicated to all the local investigators during the two planned meetings (24–25 March and 15 September 2012), and during the principal investigator’s visits to each participating center. Even though they progressively decreased, these differences remained statistically significant until the study ended (82.9 vs 93.3%, p < 0.01).\n\nOutcomes\nThe primary outcome of achieving the RASS target (Fig. 2a) was not different in the two groups (94.4 vs 89.8%, p = 0.20) (Table 2). Since the prevalence of RASS target = 0 was higher in the EN group, a multivariate generalized linear model was built to control for all the covariates: the effect of study group on the main outcome was confirmed as not significant (Additional file 1: Table E2).Fig. 2 A Percentage of shifts in total ICU stay. Main outcome means the Richmond Agitation Sedation Scale RASS observed = RASS target ±1. RASS at target means RASS observed = RASS target. Too sedated means RASS observed < RASS target. Too agitated means RASS observed > RASS target. B Absolute number of RASS observations. *P <0.05. ICU, Intensive Care Unit; IV, intravenous; EN, enteral\n\nTable 2 Study outcomes\n\n\tGroup IV\n(N = 165)\tGroup EN\n(N = 174)\tP value\t\nPercentage of shifts at target RASS = 0, median [IQR]\t82.9 [61.3–100]\t93.3 [70.8–100]\t< 0.01\t\nPercentage of shifts at observed RASS = 0/− 1, median [IQR]\t57.9 [33.3–77.8]\t60.1 [33.3–83.7]\t0.53\t\nMain outcome\t\n Percentage of shifts at RASS observed = target ±1, median [IQR]\t94.4 [77.8–100]\t89.8 [74.1–100]\t0.20\t\nSecondary outcomes\t\nPercentage of adequate sedation, as judged by nurses, median [IQR]\t92.4 [80.9–100]\t89.7 [76.2–100]\t0.11\t\nPercentage of shifts with protocol violation, median [IQR]\t0 [0–0]\t0 [0–24.1]\t< 0.01\t\nPatients with protocol violation, n (%)\t7 (4.2)\t81 (46.6)\t< 0.01\t\nComa-free days\t27 [19–28]\t27 [18–28]\t0.80\t\nDelirium-free days\t27 [19–28]\t27 [15–28]\t0.40\t\nComa and delirium-free days\t25 [11–28]\t25 [10–28]\t0.61\t\nVentilator-free days\t21 [3–27]\t22 [2–26]\t0.89\t\nLength of ICU stay\t10 [6–18]\t10 [6–18]\t0.75\t\nMortality\t\n In ICU, n (%)\t41 (24.8)\t45 (25.9)\t0.90\t\n In hospital, n (%)\t54 (32.7)\t62 (35.6)\t0.65\t\n One year, n (%)\t68 (43.9)\t71 (43.0)\t0.82\t\nDaily cost for planned sedatives, €/ventday\t1.64 [0.15–4.78]\t0.38 [0.22–0.60]\t< 0.01\t\nDaily cost for unplanned sedatives, €/ventday\t0 [0–0]\t0.16 [0–2.15]\t< 0.01\t\nDaily cost for all neuroactive drugs, €/ventday\t4.15 [1.20–20.19]\t2.39 [0.75–9.78]\t0.01\t\nSelf-removal of ET tube, n (%)\t4 (2.4)\t14 (8.1)\t0.03\t\nNeed to replace ET tube, n (%)\t3 (1.8)\t10 (5.7)\t0.09\t\nSelf-removal of other invasive tools, n (%)\t21 (12.7)\t29 (16.7)\t0.36\t\nUnscheduled neurological tests, n (%)\t30 (18.2)\t33 (19.0)\t0.89\t\nAbbreviations: IV intravenous, EN enteral, RASS Richmond Agitation Sedation Scale, ICU Intensive Care Unit, ventday day with mechanical ventilation, ET endotracheal\n\n\n\nThe prevalence of adequacy as judged by nurses was not different for the EN and IV groups (89.7% vs 92.4%, p = 0.11), but there were significantly more protocol violations in the EN group. The reported reasons for violations are presented in Additional file 1: Table E3. No differences were evident in coma-free, delirium-free, or ventilator-free days. Mortality did not differ between the groups either in the ICU (Additional file 1: Figure E1) or in hospital, or thereafter until one year after ICU discharge. There were more unplanned self-extubations in the EN group; however, there were no significant differences in the need to replace the endotracheal tube and none of these events were associated with death or other serious complications.\n\nThe drug doses and costs are presented in Additional file 1: Table E4. Daily doses of sedatives were very low overall and were similar to those in other studies [31]. Daily charges for planned sedatives were lower with the EN approach (1.64 vs 0.38 €/day, p < 0.01), but because unplanned sedatives were used more frequently, the sums of all daily charges for sedatives during MV did not differ between the groups (1.64 vs 0.74 €/day, p = 0.16). Considering all the neuroactive drugs used together (sedatives, analgesics, and antipsychotics), the total daily cost was significantly lower in the EN group (4.15 vs 2.39 €/day, p = 0.01).\n\nNeurological observations were gathered during each staff shift, and are presented in Table 3. Patients in the EN group had higher RASS values, both for the target and for the actual value (Fig. 2b); the prevalence of coma was lower in this group, with no difference in the prevalence of delirium.Table 3 Neurological observations\n\n\tGroup IV\nN = 165\tGroup EN\nN = 174\tP values\t\nMaximum number of theoretical observations\t5529\t6663\tgroup\ttime\tgroup*time\t\nPain (VNR ≥ 3 or BPS ≥ 6), n (%)\t663 (12.0)\t734 (11.0)\t0.73\t0.29\t0.12\t\nAnxiety (VNR > 0), n (%)\t511 (33.7)\t574 (32.4)\t0.99\t0.17\t0.14\t\nPhysical restraint use > 1 h, n (%)\t694 (18.0)\t785 (16.2)\t0.62\t< 0.01\t0.42\t\nSleep time > 2 h observed by nurses, n (%)\t571 (86.1)\t649 (86.3)\t0.81\t< 0.01\t0.07\t\nAgitation hours > 1, n (%)\t311 (20.3)\t304 (17.6)\t0.81\t0.46\t0.51\t\nComa- and delirium-free shift, n (%)\t3004 (64.5)\t3552 (64.8)\t0.20\t< 0.01\t< 0.01\t\nDelirium (CAM-ICU ⊕), n (%)\t644 (13.8)\t998 (18.2)\t0.72\t0.02\t0.98\t\nComa (RASS = − 4 or − 5), n (%)\t1009 (21.7)\t933 (17.0)\t0.11\t< 0.01\t< 0.01\t\nSedation adequacy, n (%)\t\n Insufficient\t483 (8.9)\t682 (10.4)\t0.65\t0.28\t0.62\t\n Adequate\t4664 (85.4)\t5324 (81.1)\t\n Excessive\t313 (5.7)\t555 (8.5)\t\nVariables are presented as absolute number (percentage of gathered observations). Comparisons made by multilevel mixed-effects Poisson regressions to simultaneously analyze the net effect of group assignment; the effect of time spent in ICU; the cumulative sedative effect, calculated by multiplying the group (enteral = 1, intravenous = 0) and the number of ICU staff shifts from group assignment, to highlight the adjunctive effects of the repeated sedative administration\n\nAbbreviations: IV intravenous, EN enteral, VNR verbal numeric rating, BPS Behavioral Pain Scale, RASS Richmond Agitation Sedation Scale, CAM-ICU Confusion Assessment Method for Intensive Care Unit\n\n\n\nThere were minor differences between groups in clinical observations, and they arose only after considering the effects of time and group assignment together (Additional file 1: Table E5). The prevalence of sepsis was similar in the two groups, with no differences in the Sequential Organ Failure Assessment (SOFA) scores. Interestingly, even though this was not an outcome of the study, the EN sedation group received a larger amount of EN nutrition, both as planned calories - IV 22.6 (14.2–25) vs EN 23.6 (14.2–28.4) and as delivered calories - IV 22.3 (14.0–25.0) vs EN 22.8 (13.4–28.1) kcal/kg of ideal body weight, p < 0.01 for both comparisons.\n\nDiscussion\nThis study compared two very different approaches for the management of agitation in critically ill patients, using different sedative drugs administered by the unusual EN route compared to the more common IV route. No real differences were found in the most important clinical outcomes.\n\nIn agreement with international guidelines [1, 4, 5], the target was a conscious patient for more than 80% of ICU days. This target was set more frequently in the EN group, but was achieved equally in both groups.\n\nAmong neurological indicators, studied throughout the ICU stay, the EN sedation protocol resulted in a similar incidence of delirium, while the RASS observed was slightly higher (Fig. 2b), which means a lower incidence of coma, but greater psychophysical agitation too. Indeed, the few self-removals of endotracheal tubes - about 5% among all participants - were more prevalent in the EN group. However, none of these caused death or serious complications, and the need to replace the tube was not different between groups, as reported elsewhere [15].\n\nThe feasibility of EN sedation was lower, as this strategy was associated with a higher incidence of protocol violations. It is impossible to say whether these violations were due to higher sedation targets being set by physicians, inadequate drug dosage, or timing of administration. This last point was frequently reported as a problem in centers not used to managing EN sedatives. The raw number of violations has to be considered together with the very different amounts of unplanned drug administered, at times reaching up to one third of the planned amounts for propofol. The absolute difference in the proportions of work shifts with violation was 19.2% in the EN group and 10.7% in the IV group. The EN group had a smaller number of violations in a larger number of patients (46.6% vs 4.2%), meaning that the reasons for violating the protocol were not the same throughout the ICU stay. Perhaps for this reason, nurses judged the EN sedation as being as adequate as IV sedation (89.7 vs 92.4%). From these figures, the separation between EN and IV sedation may seem an academic question and in many cases a combination of both might provide a more rational approach.\n\nIn managing psychophysical agitation, one must consider the pros and cons of physical and pharmacological means of contention (restraints and drugs) [32]. The cultural evolution [33] in the management of conscious critically ill patients involves greater consideration of their surveillance. An updated approach should integrate the MV mode and weaning process, body posture and physiotherapy, nutrition, and communication strategies - also involving relatives at the bedside in ICUs that are open to family visitors.\n\nInterestingly, in the EN group there was a significant tendency to a lower impact on organ function: MV was more assisted than controlled, urinary output was higher, infection signs were weaker, gastrointestinal motility worked better (Additional file 1: Table E5).\n\nThe present study brings to light the need for clinical/cultural change [33] on two key points regarding the management of sedation therapy. First, despite great efforts to recommend aiming for the same RASS target in both arms, this decision was unexpectedly influenced by the group assignment (target RASS = 0 in 93.3% of the EN vs 82.9% of the IV group). Since this study is part of an educational research project, specific online medical education courses [34] were offered. All staff members were invited to increase their knowledge and to use validated tools to evaluate pain, sedation, and delirium. Moreover, since they had to simultaneously manage two different protocols, a phone counseling service from the coordinating center was always available. Despite this, different sedation targets remained, probably because of different knowledge and expertise in the use of the two protocols, requiring the titration of drugs with different pharmacokinetics. The “fear” of a lighter sedation target probably increased when IV drugs with a short half-life were used: since their effect could run out in a few minutes, the patient might become suddenly agitated. On the other side, a “fear of oversedation” due to accumulation of oral drugs could have played a role in targeting lighter sedation in the EN group.\n\nSecond, the habitual use of IV sedation led physicians to plan and administer smaller amounts of enteral nutrition, probably because they know its side effects on gastrointestinal motility. In this context, the challenge to accept less powerful drugs (like hydroxyzine) and to keep patients more awake might serve as a means for introducing good clinical practices.\n\nThe adequacy of nutrition and drugs administered through nasogastric/nasojejunal tubes strongly depends on the ICU staff teamwork and problem-solving attitudes. In order to obtain the best results with such EN drugs with slow onset and offset, we recommended starting with the highest doses in the first 24 h on ICU, to withdraw the IV drugs early. Thereafter, the drugs could be accurately titrated by using validated tools to measure the results, together with a constant effort to decrease/suspend the drugs as early as possible.\n\nHospital charges for the drugs are altogether very low in relation to other ICU costs. The charges for planned sedatives were lower in the EN group and were higher for unplanned drugs. Considering the costs for neuroactive drugs altogether, there was a significant difference (IV 4.15 vs EN 2.39 €/MV day), meaning both that charges for antipsychotics were not increased, and charges for analgesics were slightly lower, probably because of melatonin’s pain-relieving effect [35]. These charges are much lower than those reported in the literature; hospital costs could be significantly higher with respect to new drugs and approaches, like dexmedetomidine or sevoflurane [25].\n\nStudy limitations and strengths\nThe unexpected difference in RASS targets was a significant limitation of this study, which might have favored the IV sedation protocol: as the patients were wanted to be more sedated, reaching such a target was easier. There are also several other limitations, like the single-blind design of the study, the data recording by clinical staff, the lack of anamnestic data on alcohol or substance abuse, the non-protocolized weaning from MV, the lack of a long-term cognitive outcome evaluation, and the sedation assessment over a whole nursing shift (prevalent RASS), which is very subjective. Moreover, some clinical practices were being introduced for the first time (EN protocol, conscious target, use of validated tools for neurological monitoring) in a substantial proportion of centers when the study was started. Data were gathered some years ago, and different skills and habits among intensivists in the use of sedatives could have played some role, particularly in the use of benzodiazepines, which is discouraged nowadays. Last, half the patients in the EN group had protocol violations, meaning the groups were not adequately separated.\n\nThe strengths of the present study are its design coherent with guidelines, always suggesting an early conscious sedation target [1]. Rather than making it different in the two groups [31, 36], two separate strategies were compared in the achievement of the same shared goal: a calm, conscious, and cooperative critically ill patient. Moreover, the lack of homogeneity among participant centers could render the results generalizable. Even with the large number of violations, the two strategies seem to be comparable: non-skilled centers can immediately use the EN strategy too.\n\nConclusions\nThe EN protocol for the management of sedation in high-risk critically ill patients was not associated with any improvement in the rate of achievement of the desired level of sedation. Some hypothesis-generating advantages, like the light sedation target or the lower costs, might reflect a cultural change regarding the EN route. The use of this route for “gentle patient sedation” appeared possible and safe: when aiming at the target of a conscious critically ill patient, this unusual approach - based on drugs with weaker and longer effect - does appear to offer some benefits.\n\nAdditional file\n\nAdditional file 1: Table E1 Description of participating ICUs. Table E2 Multivariate generalized linear model of main outcome. Table E3 Reasons for protocol violation. Table E4 Neuroactive drug doses and hospital charges. Table E5 Daily clinical measurements. Figure E1 Kaplan–Meier plot for ICU survival estimates. (DOC 3129 kb)\n\n \n\n\nAbbreviations\nBMIBody mass index\n\nBPSBehavioral Pain Scale\n\nCAM-ICUConfusion Assessment Method for ICU\n\nCOPDChronic obstructive pulmonary disease\n\nENEnteral\n\nETEndotracheal\n\nICUIntensive care unit\n\nIQRInterquartile range\n\nIVIntravenous\n\nMVMechanical ventilation\n\nRASSRichmond Agitation Sedation Scale\n\nSAPSSimplified Acute Physiology Score\n\nSedaENEnteral versus intravenous sedation trial\n\nSOFASequential Organ Failure Assessment\n\nVNRVerbal numeric rating\n\nAcknowledgements\nThe authors thank all the staff members of the participating ICUs for their essential cooperation. The corresponding author would like to dedicate the present study to the memory of Marco Rambaldi (1954-2014), friend and master, Steering Committee member and head of the Modena center, who was an insightful example of researcher, physician, and man. This publication endorses the “Humanization to Enhance Recovery On Intensive Care bundle” (www.heroicbundle.org). We are grateful to J D Baggott for language editing.\n\nComplete list of SedaEN investigators\n\n\nSteering Committee members\n\n\nGaetano Iapichino (Study Chair), Alberto Morabito (Chair of Statistics, Dipartimento di Scienze cliniche e di comunità, Università degli Studi di Milano), Martin Langer (Dipartimento di Oncologia e Onco-Ematologia, Università degli Studi di Milano and Fondazione IRCCS Istituto Nazionale dei Tumori, Milano), Roberto Malacrida (Fondazione Sasso Corbaro, Bellinzona, Switzerland), Franco Valenza (Dipartimento di Fisiopatologia medico-chirurgica e dei trapianti, Università degli Studi di Milano), Marco Rambaldi (Nuovo Ospedale Civile Sant'Agostino Estense, Modena), Giovanni Mistraletti (Principal Investigator).\n\n\nInvestigators from the 12 participating centers\n\n\nASST Santi Paolo e Carlo, Ospedale San Paolo – Polo Universitario, Milano: Davide Chiumello, Giovanni Mistraletti, Michele Umbrello, Paolo Formenti, Paolo Spanu, Stefania Anania, Elisa Andrighi, Alessandra Di Carlo, Federica Martinetti, Serena Barello, Andrea Noto, Gianfranco Capello, Bruno Sabatelli, Giovanni Brenna, Morena Astori, and Pietro Placido.\n\nIRCCS Ospedale Maggiore Policlinico, Milano: Luciano Gattinoni, Alessandro Protti, Paolo Cadringher, Riccarda Russo, Francesca Pagan, Virna Berto, and Paola Roselli.\n\nASST Monza, Ospedale di Desio (MI): Giulio Ronzoni, Eduardo Beck, Silvia Francesconi, and Maurizio Gaiotto.\n\nASST Ovest Milanese, Ospedale Nuovo di Legnano (MI): Danilo Radrizzani, Luca Ferla, Federico Valdambrini, Riccardo Giudici, and Laura Merlini.\n\nASST Monza, Ospedale San Gerardo, Monza (MB): Antonio Pesenti, Giacomo Bellani, Alessia La Bruna, Emanuele Rezoagli, and Alberto Lucchini.\n\nIRCCS San Matteo, Pavia: AR1 Antonio Braschi, Alessandra Palo, Thekla Niebel, Marina Selvini, Sergio Cortesi, and Attilio Quaini; AR2 Giorgio Iotti, Francesca Riccardi, Enrico Contri, and Antonella Sacchi.\n\nAO San Giovanni Bosco, Torino: Sergio Livigni, Giuseppe Naretto, Enrica Ferretti, Alessandro Deprado, and Virna Venturi degli Esposti.\n\nAOU San Luigi Gonzaga, Orbassano (TO): Pietro Caironi, Giulio Radeschi, Maurilio Festa, Lorenzo Odetto, Daniele Ferrero, Stefano Cognolato, Roberto Penso, and Roberta Vacchelli.\n\nAO Ospedale Cardinal Massaia, Asti: Silvano Cardellino, Edda Bosco, Anna Maria Gado, Anna Bresciani, Ivana Pozzo, Annachiara Alessio, Vanessa Clarindo Rodrigues, and Edna Biase.\n\nAON SS.Antonio e Biagio e Cesare Arrigo, Alessandria: Nicoletta Vivaldi, Martina Taverna, and Antonella Nava.\n\nNuovo Ospedale Civile Sant’Agostino Estense, Modena: Marco Rambaldi, Cristina Pinna, Francesco Ponzetta, Lucilla Bavutti, Paola Martina, Beatriz Palacios, and Giancarla Bergonzini.\n\nTake-home message\n\nIn 348 randomized ICU patients, an unusual enteral sedation protocol (hydroxyzine, lorazepam, and melatonin) gave no differences in clinical outcomes but lower costs than the more common intravenous sedation (propofol, midazolam). Mechanically ventilated patients may require different strategies to manage pharmacological sedation best: “gentle” enteral administration of drugs with longer half-life, accurately titrated to the lowest effective doses, could be an option to aim for, and to maintain them at a light level of sedation.\n\n140-character Tweet\n\nEnteral sedation (hydroxyzine, lorazepam, melatonin) was not superior to intravenous (propofol, midazolam), and cost less in ICU patients.\n\nFunding\nThis study received a grant for independent research provided by the Regione Lombardia (DRL 13465 of December 22, 2010). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing the report. The corresponding author, Giovanni Mistraletti, MD, had full access to all the data in the study and had final responsibility for the decision to submit. He takes responsibility for the integrity of the data and the accuracy of the data analysis.\n\nAvailability of data and materials\nThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nGM is the principal investigator of the study and responsible for the conception, protocol design, and organization of financial support. GI applied for and received financial support from the Regione Lombardia to start this clinical trial. MU, SS, AB, and PAF provided statistical guidance, and were responsible for estimating the sample size and for final statistical analysis. PC was responsible for designing and managing the specific software used for patient allocation. PF, RR, SF, FV, GB, AP, FR, EF, MF, AMG, MT, and CP were responsible for enrollment of patients and data gathering at each study site. GM wrote the first manuscript draft; GI, MU, PF, DC, and PC revised the draft for important intellectual content. All authors have read and approved the final version and submission of the present manuscript to Critical Care.\n\nEthics approval and consent to participate\nAll participating centers obtained local ethics committee approvals to conduct the trial.\n\nThe coordinating center approval was issued by Comitato Etico of A.O. San Paolo - Polo Universitario, Milano: Prot.34/Reg.delibere 2011/CE on 23 February 2011.\n\nThe other ethics committees were:Comitato Etico Interaziendale for the centers A.O.N. SS. Antonio e Biagio e Cesare Arrigo, Alessandria, and A.O. Ospedale Cardinal Massaia, Asti: Prot. 20848 on 16 September 2011\n\nComitato Etico of A.O. Ospedale Civile di Desio (MI): Prot. 17235 on 28 July 2011\n\nComitato Etico of A.O. Ospedale Civile di Legnano (MI): Prot. 15/12 on 18 May 2012\n\n‘Comitato etico’ of N.O.C. Sant’Agostino Estense, Modena: Prot. 3083/CE of September 13, 2011.\n\nComitato Etico of A.O. San Gerardo, Monza (MB): Parere on 17 November 2011\n\nComitato Etico of A.O.U. San Luigi Gonzaga, Orbassano (TO): Prot. 18362 on 23 September 2011\n\nComitato Etico of I.R.C.C.S Ospedale Maggiore Policlinico, Milano: Parere on 13 December 2011\n\nComitato Etico of I.R.C.C.S. San Matteo, Pavia: Prot. 48199 on 3 March 2012\n\nComitato Etico of A.O. San Giovanni Bosco, Torino: Prot. 43718 on 3 August 2011\n\n\n\nWritten informed consent was mandatory for all able patients. When it could not be given, a written declaration of information received was collected from relatives, according to local ethics committee indications. As soon as patients’ neurological conditions improved, all enrolled patients were duly informed of the study and their written consent was obtained, both for the use of previously collected data, and for all prospective treatments and data collection. Patients or their next of kin could request withdrawal from the study at any time.\n\nConsent for publication\nBesides informed consent to participate, specific permission to use anonymized data for scientific purposes was collected from all patients.\n\nCompeting interests\nAll the authors, the Steering Committee members, and the SedaEN investigators declare they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Barr J Fraser GL Puntillo K Ely EW Gelinas C Dasta JF Davidson JE Devlin JW Kress JP Joffe AM Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit Crit Care Med 2013 41 1 263 306 10.1097/CCM.0b013e3182783b72 23269131 \n2. Nseir S Makris D Mathieu D Durocher A Marquette CH Intensive care unit-acquired infection as a side effect of sedation Crit Care 2010 14 2 R30 10.1186/cc8907 20226064 \n3. Vasilevskis EE Ely EW Speroff T Pun BT Boehm L Dittus RS Reducing iatrogenic risks: ICU-acquired delirium and weakness–crossing the quality chasm Chest 2010 138 5 1224 1233 10.1378/chest.10-0466 21051398 \n4. Baron R Binder A Biniek R Braune S Buerkle H Dall P Demirakca S Eckardt R Eggers V Eichler I Evidence and consensus based guideline for the management of delirium, analgesia, and sedation in intensive care medicine. Revision 2015 (DAS-Guideline 2015) - short version Ger Med Sci 2015 13 Doc19 26609286 \n5. Celis-Rodriguez E Birchenall C de la Cal MA Castorena Arellano G Hernandez A Ceraso D Diaz Cortes JC Duenas Castell C Jimenez EJ Meza JC Clinical practice guidelines for evidence-based management of sedoanalgesia in critically ill adult patients Med Int 2013 37 8 519 574 \n6. Shehabi Y Bellomo R Reade MC Bailey M Bass F Howe B McArthur C Seppelt IM Webb S Weisbrodt L Early intensive care sedation predicts long-term mortality in ventilated critically ill patients Am J Respir Crit Care Med 2012 186 8 724 731 10.1164/rccm.201203-0522OC 22859526 \n7. Balzer F Weiss B Kumpf O Treskatsch S Spies C Wernecke KD Krannich A Kastrup M Early deep sedation is associated with decreased in-hospital and two-year follow-up survival Crit Care 2015 19 197 10.1186/s13054-015-0929-2 25928417 \n8. Shah FA Girard TD Yende S Limiting sedation for patients with acute respiratory distress syndrome - time to wake up Curr Opin Crit Care 2017 23 1 45 51 10.1097/MCC.0000000000000382 27898439 \n9. Oddo M Crippa IA Mehta S Menon D Payen JF Taccone FS Citerio G Optimizing sedation in patients with acute brain injury Crit Care 2016 20 1 128 10.1186/s13054-016-1294-5 27145814 \n10. Martin J Franck M Fischer M Spies C Sedation and analgesia in German intensive care units: how is it done in reality? Results of a patient-based survey of analgesia and sedation Intensive Care Med 2006 32 8 1137 1142 10.1007/s00134-006-0214-6 16741692 \n11. Vincent JL Give your patient a fast hug (at least) once a day Crit Care Med 2005 33 6 1225 1229 10.1097/01.CCM.0000165962.16682.46 15942334 \n12. Cigada M Corbella D Mistraletti G Forster CR Tommasino C Morabito A Iapichino G Conscious sedation in the critically ill ventilated patient J Crit Care 2008 23 3 349 353 10.1016/j.jcrc.2007.04.003 18725039 \n13. Vincent JL Shehabi Y Walsh TS Pandharipande PP Ball JA Spronk P Longrois D Strom T Conti G Funk GC Comfort and patient-centred care without excessive sedation: the eCASH concept Intensive Care Med 2016 42 6 962 971 10.1007/s00134-016-4297-4 27075762 \n14. Walsh TS Kydonaki K Antonelli J Stephen J Lee RJ Everingham K Hanley J Phillips EC Uutela K Peltola P Staff education, regular sedation and analgesia quality feedback, and a sedation monitoring technology for improving sedation and analgesia quality for critically ill, mechanically ventilated patients: a cluster randomised trial Lancet Respir Med 2016 4 10 807 817 10.1016/S2213-2600(16)30178-3 27473760 \n15. Girard TD Kress JP Fuchs BD Thomason JW Schweickert WD Pun BT Taichman DB Dunn JG Pohlman AS Kinniry PA Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial Lancet 2008 371 9607 126 134 10.1016/S0140-6736(08)60105-1 18191684 \n16. Sessler CN Gosnell MS Grap MJ Brophy GM O'Neal PV Keane KA Tesoro EP Elswick RK The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients Am J Respir Crit Care Med 2002 166 10 1338 1344 10.1164/rccm.2107138 12421743 \n17. Tanaka LM Azevedo LC Park M Schettino G Nassar AP Rea-Neto A Tannous L de Souza-Dantas VC Torelly A Lisboa T Early sedation and clinical outcomes of mechanically ventilated patients: a prospective multicenter cohort study Crit Care 2014 18 4 R156 10.1186/cc13995 25047960 \n18. Devlin JW The pharmacology of oversedation in mechanically ventilated adults Curr Opin Crit Care 2008 14 4 403 407 10.1097/MCC.0b013e32830280b3 18614903 \n19. Svenningsen H Egerod I Videbech P Christensen D Frydenberg M Tonnesen EK Fluctuations in sedation levels may contribute to delirium in ICU patients Acta Anaesthesiol Scand 2013 57 3 288 293 10.1111/aas.12048 23294103 \n20. Porhomayon J El-Solh AA Adlparvar G Jaoude P Nader ND Impact of sedation on cognitive function in mechanically ventilated patients Lung 2016 194 1 43 52 10.1007/s00408-015-9820-9 26559680 \n21. Wanzuita R Poli-de-Figueiredo LF Pfuetzenreiter F Cavalcanti AB Westphal GA Replacement of fentanyl infusion by enteral methadone decreases the weaning time from mechanical ventilation: a randomized controlled trial Crit Care 2012 16 2 R49 10.1186/cc11250 22420584 \n22. Umbrello M Mistraletti G Corbella D Cigada M Salini S Morabito A Iapichino G Bias reduction in repeated-measures observational studies by the use of propensity score: the case of enteral sedation for critically ill patients J Crit Care 2012 27 6 662 672 10.1016/j.jcrc.2012.06.008 22884533 \n23. Mistraletti G Sabbatini G Taverna M Figini MA Umbrello M Magni P Ruscica M Dozio E Esposti R DeMartini G Pharmacokinetics of orally administered melatonin in critically ill patients J Pineal Res 2010 48 2 142 147 10.1111/j.1600-079X.2009.00737.x 20070489 \n24. Mistraletti G Mantovani ES Cadringher P Cerri B Corbella D Umbrello M Anania S Andrighi E Barello S Di Carlo A Enteral vs. intravenous ICU sedation management: study protocol for a randomized controlled trial Trials 2013 14 92 10.1186/1745-6215-14-92 23551983 \n25. Mistraletti G Umbrello M Sabbatini G Miori S Taverna M Cerri B Mantovani ES Formenti P Spanu P D'Agostino A Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial Minerva Anestesiol 2015 81 12 1298 1310 25969139 \n26. Bourne RS Mills GH Melatonin: possible implications for the postoperative and critically ill patient Intensive Care Med 2006 32 3 371 379 10.1007/s00134-005-0061-x 16477412 \n27. Bellapart J Boots R Potential use of melatonin in sleep and delirium in the critically ill Br J Anaesth 2012 108 4 572 580 10.1093/bja/aes035 22419624 \n28. Le Gall JR Lemeshow S Saulnier F A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study JAMA 1993 270 24 2957 2963 10.1001/jama.1993.03510240069035 8254858 \n29. Ely EW Inouye SK Bernard GR Gordon S Francis J May L Truman B Speroff T Gautam S Margolin R Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU) JAMA 2001 286 21 2703 2710 10.1001/jama.286.21.2703 11730446 \n30. Awissi DK Begin C Moisan J Lachaine J Skrobik Y I-SAVE study: impact of sedation, analgesia, and delirium protocols evaluated in the intensive care unit: an economic evaluation Ann Pharmacother 2012 46 1 21 28 10.1345/aph.1Q284 22202496 \n31. Strom T Martinussen T Toft P A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial Lancet 2010 375 9713 475 480 10.1016/S0140-6736(09)62072-9 20116842 \n32. Maccioli GA Dorman T Brown BR Mazuski JE McLean BA Kuszaj JM Rosenbaum SH Frankel LR Devlin JW Govert JA Clinical practice guidelines for the maintenance of patient physical safety in the intensive care unit: use of restraining therapies--American College of Critical Care Medicine Task Force 2001-2002 Crit Care Med 2003 31 11 2665 2676 10.1097/01.CCM.0000095463.72353.AD 14605540 \n33. Stroem T Toft P Optimizing sedation in critically ill patients: by technology or change of culture? J Thorac Dis 2016 8 12 E1676 E1678 10.21037/jtd.2016.12.87 28149611 \n34. Mistraletti G Umbrello M Anania S Andrighi E DI Carlo A Martinetti F Barello S Sabbatini G Formenti P Maraffi T Neurological assessment with validated tools in general ICU: multicenter, randomized, before and after, pragmatic study to evaluate the effectiveness of an e-learning platform for continuous medical education Minerva Anestesiol 2017 83 2 145 154 27647465 \n35. Wilhelmsen M Amirian I Reiter RJ Rosenberg J Gogenur I Analgesic effects of melatonin: a review of current evidence from experimental and clinical studies J Pineal Res 2011 51 3 270 277 10.1111/j.1600-079X.2011.00895.x 21615490 \n36. Toft P Olsen HT Jorgensen HK Strom T Nibro HL Oxlund J Wian KA Ytrebo LM Kroken BA Chew M Non-sedation versus sedation with a daily wake-up trial in critically ill patients receiving mechanical ventilation (NONSEDA Trial): study protocol for a randomised controlled trial Trials 2014 15 499 10.1186/1745-6215-15-499 25528350\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1364-8535",
"issue": "23(1)",
"journal": "Critical care (London, England)",
"keywords": "Hydroxyzine; Hypnotics and sedatives; Melatonin; Nursing education research; Patient care planning",
"medline_ta": "Crit Care",
"mesh_terms": "D000368:Aged; D000758:Anesthesia; D000982:Antipruritics; D002492:Central Nervous System Depressants; D016638:Critical Illness; D054810:Deep Sedation; D004750:Enteral Nutrition; D005260:Female; D006801:Humans; D006919:Hydroxyzine; D006993:Hypnotics and Sedatives; D007362:Intensive Care Units; D008297:Male; D008550:Melatonin; D008875:Middle Aged; D016012:Poisson Distribution; D000072878:Simplified Acute Physiology Score; D016037:Single-Blind Method",
"nlm_unique_id": "9801902",
"other_id": null,
"pages": "3",
"pmc": null,
"pmid": "30616675",
"pubdate": "2019-01-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "11730446;12421743;14605540;15942334;16477412;16741692;18191684;18614903;18725039;20070489;20116842;20226064;21051398;21615490;22202496;22419624;22420584;22859526;22884533;23269131;23294103;23551983;23773859;25047960;25528350;25928417;25969139;26559680;26609286;27075762;27145814;27473760;27647465;27898439;28149611;8254858",
"title": "Enteral versus intravenous approach for the sedation of critically ill patients: a randomized and controlled trial.",
"title_normalized": "enteral versus intravenous approach for the sedation of critically ill patients a randomized and controlled trial"
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"companynumb": "IT-IMPAX LABORATORIES, LLC-2019-IPXL-00310",
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"abstract": "While the overall survival of patients with castration-resistant prostate cancer (CRPC) has been prolonged by enzalutamide, a considerable number of patients suffer from enzalutamide-induced nausea and fatigue. An 86-year-old male patient who started enzalutamide (160 mg) for CRPC treatment, experienced nausea and vomiting approximately 2 weeks after the start of treatment. Enzalutamide treatment was stopped for two weeks, then restarted enzalutamide at a half-dose (80 mg); the dose was then increased to 120 mg. He remained free from any adverse events and showed good CRPC control for 53 months. We herein report the case of a patient with enzalutamide-induced nausea and vomiting, whose symptoms were overcome and in whom long-term CRPC control was achieved following a temporary drug holiday.",
"affiliations": "Departments of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Japan.;Departments of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Japan.;Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.;Departments of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Japan.",
"authors": "Kawahara|Takashi|T|;Miyoshi|Yasuhide|Y|;Yao|Masahiro|M|;Uemura|Hiroji|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000501849",
"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 10.1159/000501849cro-0012-0568Case ReportThe Achievement of Long-Term CRPC Control in a Patient with Enzalutamide-Induced Nausea and Fatigue after Overcoming the Adverse Events with a Temporary Drug Holiday Kawahara Takashi a*Miyoshi Yasuhide aYao Masahiro bUemura Hiroji aaDepartments of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, JapanbDepartment of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan*Takashi Kawahara, Departments of Urology and Renal Transplantation, Yokohama City University Medical Center, 4–57, Urafune, Minami-ku, Yokohama, Kanagawa 2320024 (Japan), E-Mail takashi_tk2001@yahoo.co.jpMay-Aug 2019 16 7 2019 16 7 2019 12 2 568 572 29 6 2019 2 7 2019 2019 Copyright © 2019 by S. Karger AG, Basel2019This 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.While the overall survival of patients with castration-resistant prostate cancer (CRPC) has been prolonged by enzalutamide, a considerable number of patients suffer from enzalutamide-induced nausea and fatigue. An 86-year-old male patient who started enzalutamide (160 mg) for CRPC treatment, experienced nausea and vomiting approximately 2 weeks after the start of treatment. Enzalutamide treatment was stopped for two weeks, then restarted enzalutamide at a half-dose (80 mg); the dose was then increased to 120 mg. He remained free from any adverse events and showed good CRPC control for 53 months. We herein report the case of a patient with enzalutamide-induced nausea and vomiting, whose symptoms were overcome and in whom long-term CRPC control was achieved following a temporary drug holiday.\n\nKeywords\nEnzalutamidXtandiDrug holiday\n==== Body\nIntroduction\nEnzalutamide is widely used to treat all statuses of castration-resistant prostate cancer (CRPC) including non-metastatic, metastatic chemotherapy naïve, and post-chemotherapy CRPC (PROSPER, PREVAIL, AFFIRM) [1, 2, 3]. Although enzalutamide was shown to be effective in the treatment of CRPC, fatigue are reported as adverse events by 33–36% of enzalutamide-treated patients [2, 3]. In daily clinical practice, drug holidays, changing the timing of drug intake, and Chinese herbal medicine are used to treat fatigue, nausea, decreased appetite, dysgeusia, and other adverse effects induced by enzalutamide [4]. We herein report a case of enzalutamide-induced nausea and vomiting in which the patient's symptoms were overcome by a temporary drug holiday, allowing for the long-term control of CRPC.\n\nCase Presentation\nAn 86-year old man was referred to our hospital due to an elevated serum PSA level (502 ng/mL). A prostate needle biopsy revealed a Gleason Score of 4 + 5 = 9 adnocarcinoma. Bone scintigraphy revealed bone metastasis, without lymph-node or organ metastasis. In April 2016, leuprorelin and bicalutamide were introduced. The patient's serum PSA level decreased to 0.38 ng/mL but gradually re-elevated, leading to the introduction of flutamide. Flutamide significantly reduced his serum PSA level, but was withdrawn due to severe fatigue. In February 2015, two weeks after the initiation of enzalutamide treatment, the patient experienced nausea and vomiting, and presented to our hospital as an emergency case.\n\nAfter stopping enzalutamide for one week, the patient's nausea and fatigue subsided. Enzalutamide was restarted at a half-dose (80 mg), which was gradually increased to 120 mg without any adverse effects. We recommended increasing the dose to 160 mg; however, the patient indicated that he wished to continue treatment at a dose of 120 mg. At the time of writing, the patient's PSA level remains below 0.01 ng/mL without any adverse effects for 53 months (Fig. 1).\n\nDiscussion\nEnzalutamide is widely used as a 2nd generation anti-androgen drug. Its effectiveness has been confirmed by the PROSPER, PREVAIL, and AFFIRM studies [1, 2, 3]. In these studies, vomiting (all grades) was reported in 1.7 and 6.9% in PREVAIL and AFFIRM study respectively. These adverse effects are usually low grade; however, their management is important due to their high incidence and the impact on the daily life of the patient during long-term treatment.\n\nBasch et al. showed that the severity of most patients' symptoms was evaluated as lower by clinicians, underscoring the importance of patient-reported outcomes [5]. Especially in relation to appetite, the difference was higher than the other symptoms who received solid malignant diseases treatment. In the case of decreased appetite, most clinicians rated the severity lower than the patient. Thus clinician should care in mind about these symptoms which related to overall health status.\n\nThe management of enzalutamide-induced adverse events is especially important for patients who have obtained good CRPC control. The reported management strategies include a temporary drug holiday, the prescription of herbal medicine, and changing the timing of enzalutamide intake from morning to before sleep at night [4]. In our case, the patient's nausea and vomiting were overcome with a temporary drug holiday and enzalutamide was restarted. The patient has not experienced any adverse events in the 4 years since enzalutamide was restarted.\n\nIn the present case, the enzalutamide-treated patient showed long-term CRPC control for 53 months after the drug holiday. The median overall survival time of CRPC patients with bone metastasis is reported to be 21.3 months [6]. On the other hand, most urologists experience cases in which long-term control of CRPC can be achieved with one medication added to androgen deprivation therapy. If a prescribed medicine shows good efficacy in the treatment of CRPC, then it is important to manage adverse events with the aim of continuing the medicine is important. In the present case, the patient initially showed enzalutamide-induced fatigue and nausea; however, these adverse events were overcome and the patient is currently free from adverse events at 53 months after restarting enzalutamide.\n\nAvailability of Data and Material\nDue to ethical restrictions, the raw data underlying this paper are available upon request to the corresponding author.\n\nStatement of Ethics\nWritten informed consent to participate and for publication was obtained from the patient for ethics approval. A copy of the written consent form is available for review from the Editor-in-Chief of this journal.\n\nDisclosure Statement\nThe authors declare no conflicts of interest.\n\nFunding Sources\nNone.\n\nFig. 1 Clinical course.\n==== Refs\nReferences\n1 Hussain M Fizazi K Saad F Rathenborg P Shore N Ferreira U Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer N Engl J Med 2018 6 378 (26) 2465 74 29949494 \n2 Scher HI Fizazi K Saad F Taplin ME Sternberg CN Miller K AFFIRM Investigators Increased survival with enzalutamide in prostate cancer after chemotherapy N Engl J Med 2012 9 367 (13) 1187 97 22894553 \n3 Beer TM Armstrong AJ Rathkopf D Loriot Y Sternberg CN Higano CS Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study Eur Urol 2017 2 71 (2) 151 4 27477525 \n4 Tomonori Minagawa TD Toshiro Suzuki, Manabu Ueno, Takashi Nagai, Teruyuki Ogawa, Hideo Kiyokawa, Osamu Ishizuka. EFFECTIVENESS OF HOCHUEKKITO (JAPANESE HARBAL MEDICINE) FOR GENERAL FATIGUE AFTER INTRODUCTION OF ENZALUTAMIDE IN THREE CASES OF CASTRATION-RESISTANT PROSTATE CANCER Jpn J Urol. 2019 110 5 \n5 Basch E The missing voice of patients in drug-safety reporting N Engl J Med 2010 3 362 (10) 865 9 20220181 \n6 Takashi Kawahara SN Yasuhide Miyoshi, Masahiro Yao, Hiroji Uemura. Changing the enzalutamide form from a capsule to a tablet improves the adherence of medicine intake: A case of a significant decrease in the prostate‐specific antigen level and improvement in radiographic findings IJU Case Reports. 2019 2 (3) 143 5\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "12(2)",
"journal": "Case reports in oncology",
"keywords": "Drug holiday; Enzalutamid; Xtandi",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "568-572",
"pmc": null,
"pmid": "31427954",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "20220181;22894553;27477525;29949494",
"title": "The Achievement of Long-Term CRPC Control in a Patient with Enzalutamide-Induced Nausea and Fatigue after Overcoming the Adverse Events with a Temporary Drug Holiday.",
"title_normalized": "the achievement of long term crpc control in a patient with enzalutamide induced nausea and fatigue after overcoming the adverse events with a temporary drug holiday"
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"companynumb": "JP-TOLMAR, INC.-19JP000818",
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{
"abstract": "Osteoporosis (OP) is a common disease in the elderly that causes bone fractures and increases mortality. Denosumab (DMAB) is one of several medications to treat OP. DMAB not only reduces the risk of fractures, but also improves the quality of life. However, an increase in the risk of multiple vertebral fractures has been reported after DMAB discontinuation. We described the rare case of a 71-year-old woman with severe OP who experienced same-side insufficiency fractures of the tibia and femur at 18 months after DMAB discontinuation. Careful monitoring for both vertebral and lower limb fragility fractures is advised after DMAB cessation.",
"affiliations": "Koiwai Orthopedic Clinic, Komoro, Japan.;Center of Osteoporosis and Spinal Disorders, Kamimura Orthopedic Clinic, Matsumoto, Japan.;Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Japan.;Department of Oral and Maxillofacial Radiology, School of Dentistry, Matsumoto Dental University, Hirooka, Japan.",
"authors": "Koiwai|Hidefumi|H|;Kamimura|Mikio|M|;Nakamura|Yukio|Y|;Takahashi|Jun|J|;Taguchi|Akira|A|",
"chemical_list": "D050071:Bone Density Conservation Agents; D000069448:Denosumab",
"country": "England",
"delete": false,
"doi": "10.1080/24725625.2020.1832756",
"fulltext": null,
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"issn_linking": "2472-5625",
"issue": "5(1)",
"journal": "Modern rheumatology case reports",
"keywords": "Osteoporosis; denosumab; discontinuation; insufficiency fracture; lower limb fracture",
"medline_ta": "Mod Rheumatol Case Rep",
"mesh_terms": "D000368:Aged; D015519:Bone Density; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D004334:Drug Administration Schedule; D005260:Female; D005269:Femur; D015775:Fractures, Stress; D006801:Humans; D010024:Osteoporosis; D011859:Radiography; D013977:Tibia; D028761:Withholding Treatment",
"nlm_unique_id": "101761026",
"other_id": null,
"pages": "178-181",
"pmc": null,
"pmid": "33019908",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Same-side insufficiency fractures of the tibia and femur after denosumab discontinuation: a case report.",
"title_normalized": "same side insufficiency fractures of the tibia and femur after denosumab discontinuation a case report"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2020172568",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
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{
"abstract": "Purpose: To analyze the demographic characteristics, clinical features, ocular complications, and visual outcome of pediatric patients with uveitis.Methods: Retrospective evaluation of medical records.Results: The study included 156 eyes of 93 patients. Fifty-three patients were female and 40 were male. Mean age at onset of the uveitis was 9.54 ± 4.29 years. The mean follow-up period was 29.88 ± 28.97 months. Anterior uveitis (49.5%) was the most common anatomic type followed by panuveitis (21.5%), intermediate uveitis (18.3%), and posterior uveitis (10.7%). Juvenile idiopathic arthritis (JIA) was the most common leading systemic disease (18.3%) followed by Behçet disease (11.8%). It was detected at least one complication in 53 (34.0%) eyes at presentation. Mean LogMAR visual acuity was found <0.3 in 136 (87.2%) eyes at final examination.Conclusion: The most common localization was the anterior segment and the most common etiologic relationship was JIA. Visual outcome could be satisfactory with early and appropriate treatment.",
"affiliations": "Department of Ophthalmology, Ondokuz Mayis University, Samsun, Turkey.;Department of Ophthalmology, Ondokuz Mayis University, Samsun, Turkey.",
"authors": "Eser-Ozturk|Hilal|H|https://orcid.org/0000-0002-0050-7894;Sullu|Yuksel|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2020.1758158",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": null,
"journal": "Ocular immunology and inflammation",
"keywords": "Behçet uveitis; childhood uveitis; complications of uveitis; juvenile idiopathic arthritis; pars planitis; pediatric uveitis",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": null,
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "1-5",
"pmc": null,
"pmid": "32463707",
"pubdate": "2020-05-28",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pediatric Uveitis in a Referral Center in North Part of Turkey.",
"title_normalized": "pediatric uveitis in a referral center in north part of turkey"
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"companynumb": "TR-AMGEN-TURSP2022063512",
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"abstract": "OBJECTIVE\nInfantile hemangiomas (IHs) in the airway may be potentially life-threatening during the proliferative phase. Available treatments like oral corticosteroids (OCS) and chemotherapeutic agents usually showed variable responses and serious side effects. Propranolol is a new and promising treatment option.\n\n\nMETHODS\nA case series of five IH patients with airway involvement is presented, supplemented with a review of literature. Propranolol treatment (2.0-3.0mg/kg/day) was initiated between 3 weeks and 6 months of age. Three cases were treated with propranolol monotherapy, 2 cases with OCS primarily and propranolol secondarily, in which treatment with OCS could be reduced rapidly.\n\n\nRESULTS\nIn our case series a dramatic, fast response was observed in all cases, with a permanent effect after discontinuation in four cases. In one patient a relapse of airway problems occurred two months after discontinuation of propranolol at 16 months of age; this resolved after re-start of propranolol. Review of literature together with these five cases showed 81 patients with airway IHs treated with propranolol. Propranolol was effective in 90% of the cases and seven patients were classified as non-responders. Eight IHs relapsed while weaning of propranolol or after discontinuation; dose adjustment or restart was effective in most cases but one patient appeared resistant to therapy.\n\n\nCONCLUSIONS\nPropranolol seems to be a rapidly effective and safe treatment strategy for most IHs obstructing the airway. Because of the fast and important effects of propranolol, randomized controlled trials are hardly justifiable for this specific, relatively rare but, acute treatment indication. Despite the efficacy of propranolol, close monitoring of the patients with an airway IH is required, considering the risk of relapse of symptoms during or after treatment and the reported resistance to propranolol in at least 9% of the published cases. The dose and duration of treatment should be high and long enough to prevent relapse. Further research should focus on the optimal treatment protocol; the actual percentage of non-responders and also the mechanism of resistance to propranolol is unknown and needs to be illuminated.",
"affiliations": "Department of Pediatrics, Deventer Hospital, Deventer, The Netherlands.",
"authors": "Broeks|Ilse Jantine|IJ|;Hermans|Denise Josephina Johanna|DJ|;Dassel|Anne Catherina Maria|AC|;van der Vleuten|Catharina Joanna Maria|CJ|;van Beynum|Ingrid Mathilde|IM|",
"chemical_list": "D011433:Propranolol",
"country": "Ireland",
"delete": false,
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"issn_linking": "0165-5876",
"issue": "77(11)",
"journal": "International journal of pediatric otorhinolaryngology",
"keywords": "Adrenergic beta-antagonist; Airway obstruction; CT; Corticosteroids; ECG; ENT; GLUT1; IHs; Infantile hemangioma; LV; MRI; OCS; PHACES; Propranolol; RAS; RCTs; SPECT; Treatment; VEGF; acronym for posterior fossa brain malformations, hemangiomas of the face, arterial cerebrovascular abnormalities, eye abnormalities and sternal defects; bFGF; basic fibroblast growth factor; computed tomography; ear nose and throat; electrocardiography; glucose transporter protein 1; infantile hemangiomas/hemangiomas of infancy; left ventricle; magnetic resonance imaging; oral corticosteroids; randomized controlled trials; renin–angiotensin system; single photon emission computed tomography; vascular endothelial growth factor",
"medline_ta": "Int J Pediatr Otorhinolaryngol",
"mesh_terms": "D000284:Administration, Oral; D000402:Airway Obstruction; D001707:Biopsy, Needle; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D018324:Hemangioma, Capillary; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D061214:Patient Safety; D011433:Propranolol; D018570:Risk Assessment; D012494:Sampling Studies; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "8003603",
"other_id": null,
"pages": "1791-800",
"pmc": null,
"pmid": "24074695",
"pubdate": "2013-11",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Propranolol treatment in life-threatening airway hemangiomas: a case series and review of literature.",
"title_normalized": "propranolol treatment in life threatening airway hemangiomas a case series and review of literature"
} | [
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"activesubstancename": "PROPRANOLOL\\PROPRANOLOL HYDROCHLORIDE"
... |
{
"abstract": "Twiddler's syndrome is a rare complication after implantation of cardiac pacemakers or cardioverter-defibrillators that usually occurs within the first year after the procedure. However, it has not yet been described following implantation of baroreflex activation therapy (BAT).\nA 61-year-old female patient was referred to the cardiology outpatient clinic due to uncontrolled arterial hypertension despite maximal doses of several established drugs. Therefore, right-sided BAT implantation was successfully performed in February 2017 with good clinical response. Because of sustained neck pain at the site of stimulator, surgical revision was performed in November 2019 including a switch of the lead to the contralateral position. Approximately 1 month later, Twiddler's syndrome was identified on the basis of recurrent pain at the generator site necessitating pocket-revision, however, the lead was only untwisted but not replaced. A few weeks afterwards, unfortunately, lead revision was indispensable due to lead fracture.\nThis case presents the uncommon phenomenon of Twiddler's syndrome after BAT implantation. In addition, the commonly twisted lead should always be replaced as well during surgical pocket-revision in order to ensure proper long-term function.",
"affiliations": "Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.;Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.;Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.;Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.",
"authors": "Dalos|Daniel|D|https://orcid.org/0000-0002-9597-5745;Khazen|Cesar|C|;Schukro|Christoph|C|;Gwechenberger|Marianne|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytab126",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n34124559\n10.1093/ehjcr/ytab126\nytab126\nCase Report\nOther\nAcademicSubjects/MED00200\nTwiddler’s syndrome after implantation of baroreflex activation therapy: a case report\nhttps://orcid.org/0000-0002-9597-5745\nDalos Daniel\nKhazen Cesar\nSchukro Christoph\nGwechenberger Marianne\nDivision of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria\nDuncker David Handling Editor\nAbumuaileq Rami Riziq Yousef Editor\nBettin Markus Editor\nKhan Habib Rehman Editor\nMinguito Carlos Editor\nThomson Ross Editor\nCorresponding author. Tel: +43-1-40400-46140, Fax: +43-1-40400-42160, Email: daniel.dalos@meduniwien.ac.at\n5 2021\n10 5 2021\n10 5 2021\n5 5 ytab12605 11 2020\n30 11 2020\n16 3 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This 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.com\n\nAbstract\n\nBackground\n\nTwiddler’s syndrome is a rare complication after implantation of cardiac pacemakers or cardioverter-defibrillators that usually occurs within the first year after the procedure. However, it has not yet been described following implantation of baroreflex activation therapy (BAT).\n\nCase summary\n\nA 61-year-old female patient was referred to the cardiology outpatient clinic due to uncontrolled arterial hypertension despite maximal doses of several established drugs. Therefore, right-sided BAT implantation was successfully performed in February 2017 with good clinical response. Because of sustained neck pain at the site of stimulator, surgical revision was performed in November 2019 including a switch of the lead to the contralateral position. Approximately 1 month later, Twiddler’s syndrome was identified on the basis of recurrent pain at the generator site necessitating pocket-revision, however, the lead was only untwisted but not replaced. A few weeks afterwards, unfortunately, lead revision was indispensable due to lead fracture.\n\nDiscussion\n\nThis case presents the uncommon phenomenon of Twiddler’s syndrome after BAT implantation. In addition, the commonly twisted lead should always be replaced as well during surgical pocket-revision in order to ensure proper long-term function.\n\nBaroreflex activation therapy\nTwiddler’s syndrome\nLead fracture\nCase report\n==== Body\npmcFor the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast\n\nLearning points\n\nTwiddler’s syndrome may not only occur after implantation of pacemakers or cardioverter-defibrillators but also following implantation of baroreflex activation therapy.\n\nSurgical pocket-revision should always be combined with lead replacement in order to avoid additional procedures due to lead fracture and to ensure proper long-term function.\n\nIntroduction\n\nBaroreflex activation therapy (BAT) is a promising new therapeutic option in patients with hypertension1,2 and heart failure (HF).3 Carotid baroreceptor stimulation activates centrally mediated reduction of sympathic activity while increasing parasympathic activity. The lead is fixed at the carotid bifurcation, subcutaneously tunnelled, and connected with the generator that is usually placed in a pectoral pocket.\n\nTwiddler’s syndrome is described as a malfunction of implanted devices due to manipulation and twisting around its axis within the device pocket with consecutive lead dislodging. It was primarily reported by Bayliss et al.4 in 1968 after implantation of a transvenous pacemaker (PM), and was, in addition, observed after implantation of transvenous implantable cardioverter-defibrillators (ICD),5 or even subcutaneous ICD systems,6 which commonly leads to insufficient pacing or inappropriate ICD therapy delivery.5–8 Furthermore, this rare complication may occur in neurological9 or anaesthesiologic devices10 and was described following implantation of BAT by Galand et al.11 for the first time.\n\nTimeline\n\nFebruary 2017\tBaroreflex activation therapy implantation (sub-pectoral) with a right-sided electrode\t\nNovember 2019\tSurgical revision of the device (subcutaneous) and the lead (left side)\t\nDecember 2019\tTwiddler’s syndrome—pocket-revision and lead untwisting (without revision)\t\nJanuary 2020\tLead revision due to lead fracture\t\n\nCase presentation\n\nA 61-year-old female patient presented with a medical history of herniated discs as well as inherited plaque psoriasis. Essential arterial hypertension was diagnosed several years ago after the exclusion of secondary causes. The patient already received full doses of antihypertensive drugs (olmesartan 40 mg, bisoprolol 10 mg, amlodipine 10 mg, rilmenidine 2 mg, spironolactone 100 mg, torasemide 20 mg, and hydrochlorothiazide 25 mg) and even underwent renal denervation twice until the indication for BAT implantation was made in January 2017 according to the applicable guidelines at that time.12 At this time, there was no evidence of any late complications due to hypertension. Baroreflex activation therapy implantation (CVRx® Neo, Minneapolis, MN, USA) was successfully performed in general anaesthesia in February 2017, where the lead was fixed at the bifurcation of the right carotid artery and the device was placed into a retro-pectoral pocket due to the lean patient constitution [body mass index (BMI) 19.1 kg/m2] (Figure 1A).\n\nFigure 1 Successful baroreflex activation therapy implantation with a right-sided electrode (A). Twiddler’s syndrome and multiple loops of the left-sided electrode (B). Generator and lead position after surgical revision (C). BAT, baroreflex activation therapy.\n\nOutpatient follow-up visits were performed on a regular basis every 3–4 months with a consecutive improvement of systolic and diastolic blood pressure values (Table 1).\n\nTable 1 Blood pressure development\n\n\tPrior to BAT\tRt BAT\tLt BAT\tLead fracture\tAfter revision\t\nBlood pressure, mmHg\t220/124\t152/125\t170/140\t218/136\t171/120\t\nBAT, baroreflex activation therapy; Lt, left-sided; Rt, right-sided.\n\nIn November 2019, the patient presented with progressive pain at the site of the electrode, which was reproducible on palpation and when the patient turned her head in both directions, which finally resulted in a surgical revision procedure. The existing lead was removed from the right side and a new one was placed contralaterally at the bifurcation of the left carotid artery. In addition, the generator was removed from the deep origin below the right major pectoral muscle and the same device was re-implanted subcutaneously because of slightly gained body weight (BMI 20.9 kg/m2). A few weeks later, the patient returned again because of painful sensations at the area of the generator and, although any manipulation has been denied, an immediately performed X-ray revealed a twist of the device of 180° around its transverse axis with multiple loops of the lead (Figure 1B). Therefore, pocket-revision was performed in December 2019, and the existing lead was untwisted, but not replaced due to good technical values, and, finally, re-conducted with the generator without any complications.\n\nAt the time of the next scheduled outpatient visit 1 week after the procedure, stimulation impedance was below an acceptable threshold indicating lead fracture and, therefore, another surgical revision was unavoidable and was performed in January 2020 (Figure 1C). The existing lead was removed, and the novel one was successfully fixed at the same point at the left carotid bifurcation.\n\nFour months later, the patient presented in a stable clinical condition without any pain or signs of infection in relation to the BAT device with inconspicuous technical values.\n\nDiscussion\n\nTwiddler’s syndrome represents a rare complication after PM or ICD implantation that usually occurs within the first year with an incidence of 0.07–7%.13 In 2016, this complication following BAT implantation was described for the first time in a patient with HF.11 In contrast to our case, that patient kept manipulating the device resulting in lead fracture but declined any reintervention.\n\nOver the last years, several risk factors have been identified for the development of Twiddler’s syndrome such as female gender,8,14 older age,14 increased BMI,8,14 mental disorders,15 or a mismatch between the device and the size of the implantation pocket.16 Consecutive device dysfunction may result in life-threatening conditions due to insufficient pacing or inappropriate shock delivery in PM or ICD patients.5–8,16 Although this was not an issue in our case of BAT, suboptimal device positioning at the time of generator and lead relocation might have contributed to early Twiddler’s syndrome only a few weeks afterwards. The generator was placed in a more subcutaneous position despite the fact that the initial position was sub-pectoral due to the patient body constitution. Placing the device under the pectoral muscle has previously shown to prevent Twiddler’s syndrome, and the use of Dacron patches may additionally reduce this risk as tissue growth around the device is accelerated.15,17\n\nTwiddler’s syndrome without lead breakage has been recently described in a deep brain stimulator device.18 Despite several coils lead impedance was still within normal ranges, also after untwisting, but, nevertheless, the surgeons decided to replace the lead to minimize the possibility of acute re-coiling with consecutive lead fracture. Therefore, despite good technical values after untwisting, the lead should always be replaced, also in BAT devices, in order to ensure appropriate device function.\n\nFinally, the following numbers describe the quantity of devices that have been implanted at the Medical University of Vienna in 2018: PM (n = 403), cardiac resynchronization therapy (CRT)-PM (n = 39), ICD (including subcutaneous ICD, n = 162), CRT-ICD (n = 74), and BAT (n = 10).\n\nConclusion\n\nTwiddler’s syndrome may also occur after implantation of BAT devices. Surgical pocket-revision, with an optimized implantation technique, should always be combined with lead replacement in order to avoid additional procedures due to lead fracture.\n\nLead author biography\n\nDr Daniel Dalos graduated from the Medical University of Vienna, recently finished his PhD, works as a specialist in internal medicine at the general hospital in Vienna and is currently in training for cardiology. His scientific interests contain heart failure with preserved ejection fraction, hypertrophic cardiomyopathy as well as implantable cardiac devices.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal—Case Reports online.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.\n\nConflict of interest: None declared.\n\nFunding: None declared.\n\nSupplementary Material\n\nytab126_Supplementary_Data Click here for additional data file.\n\n \n\nFor the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast\n==== Refs\nReferences\n\n1 BisognanoJD, BakrisG, NadimMK, SanchezL, KroonAA, SchaferJ et al Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol 2011;58 :765–773.21816315\n2 de LeeuwPW, BisognanoJD, BakrisGL, NadimMK, HallerH, KroonAA. Sustained reduction of blood pressure with baroreceptor activation therapy: results of the 6-year open follow-up. Hypertension 2017;69 :836–843.28320856\n3 ZileMR, AbrahamWT, WeaverFA, ButterC, DucharmeA, HalbachM et al Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction: safety and efficacy in patients with and without cardiac resynchronization therapy. Eur J Heart Fail 2015;17 :1066–1074.26011593\n4 BaylissCE, BeanlandsDS, BairdRJ. The pacemaker-twiddler's syndrome: a new complication of implantable transvenous pacemakers. Can Med Assoc J 1968;99 :371–373.4952398\n5 JabriA, LaiqZ, NabeelY. Twiddler's syndrome: an unusual cause of repeated shocks by implantable cardioverter-defibrillator in an asymptomatic patient. Heart Views 2019;20 :118–121.31620258\n6 CammCF, RajappanK, CursonM, TillingL. Twiddler's syndrome with a subcutaneous implantable cardioverter-defibrillator presenting with an inappropriate shock: a case report. Eur Heart J Case Rep 2019;3 :1–5.\n7 MoralesJL, NavaS, MarquezMF, GonzalezJ, Gomez-FloresJ, ColinL et al Idiopathic lead migration: concept and variants of an uncommon cause of cardiac implantable electronic device dysfunction. JACC Clin Electrophysiol 2017;3 :1321–1329.29759631\n8 TsengAS, ShipmanJN, LeeJZ, MiL, AminM, KilluAM et al Incidence, patterns, and outcomes after transvenous cardiac device lead macrodislodgment: insights from a population-based study. Heart Rhythm 2019;16 :140–147.30053613\n9 JackowiakE, PatilPG, ChouKL. The deep brain stimulation “Twiddler Syndrome”. JAMA Neurol 2019;76 :620.30985873\n10 ShaoJ, FrizonL, MachadoAG, McKeeK, BethouxF, HartmanJ et al Occlusion of the ascenda catheter in a patient with pump twiddler's syndrome: a case report. Anesth Pain Med 2018;8 :e65312.30027067\n11 GalandV, MartinsRP, LeclercqC. Twiddler’s syndrome with a baroreflex stimulator device. Europace 2016;18 :1433.27582308\n12 ManciaG, FagardR, NarkiewiczK, RedonJ, ZanchettiA, BöhmM et al 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013;34 :2159–2219.23771844\n13 FahraeusT, HoijerCJ. Early pacemaker twiddler syndrome. Europace 2003;5 :279–281.12842644\n14 BoyleNG, AnselmeF, MonahanKM, BeswickP, SchugerCD, ZebedeJ et al Twiddler's syndrome variants in ICD patients. Pacing Clin Electrophysiol 1998;21 :2685–2687.9894663\n15 TahirovicE, Haxhibeqiri-KarabdicI. Twiddler's syndrome: case report and literature review. Heart Views 2018;19 :27–31.29876029\n16 SpenckerS, PoppelbaumA, MullerD. An unusual cause of oversensing leading to inappropriate ICD discharges. Int J Cardiol 2008;129 :e24-6–e26.17669521\n17 FurmanS. Defibrillator twiddler's syndrome. Ann Thorac Surg 1995;59 :544–546.\n18 GhanchiH, TakaTM, BernsteinJE, KashyapS, AnandaAK. The unsuccessful twiddler: a case of twiddler’s syndrome without deep brain stimulator lead breakage. Cureus 2020;12 :e7786.32461858\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "5(5)",
"journal": "European heart journal. Case reports",
"keywords": "Baroreflex activation therapy; Case report; Lead fracture; Twiddler’s syndrome",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "ytab126",
"pmc": null,
"pmid": "34124559",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports",
"references": "21816315;7847991;23771844;30053613;29876029;9894663;29759631;4952398;31620258;12842644;26011593;17669521;30027067;27582308;28320856;32461858;30985873;32123805",
"title": "Twiddler's syndrome after implantation of baroreflex activation therapy: a case report.",
"title_normalized": "twiddler s syndrome after implantation of baroreflex activation therapy a case report"
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"companynumb": "AT-MYLANLABS-2021M1053961",
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{
"abstract": "Background Osimertinib is one of the first-line treatments for advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, the occurrence rate of osimertinib-induced interstitial lung disease (ILD) is particularly high in Japanese patients and little information on subsequent cancer treatment options after recovery from osimertinib-induced ILD is currently available. Thus, this study aims to determine the safety and efficacy of afatinib for the treatment of NSCLC following osimertinib-induced ILD. Methods We retrospectively investigated the clinical courses of all NSCLC patients with EGFR mutations at our facility between August 2018 and September 2019, who received osimertinib as first-line treatment and were subsequently treated with afatinib after developing osimertinib-induced ILD. Results Forty-two patients received osimertinib treatment at our facility during the study period, and four patients received afatinib after developing osimertinib-induced ILD. All events of ILD improved either spontaneously or with steroid therapy before the initiation of afatinib. For the four patients who were retrospectively reviewed, the overall response rate to afatinib therapy was 75%, and the disease control rate was 100%. During the study period, no ILD recurrence was observed in any of the four patients. Conclusions According to our study findings, afatinib treatment after osimertinib-induced ILD is considered safe and effective and it can be used as one of the treatment options for NSCLC following osimertinib-induced ILD.",
"affiliations": "Department of Thoracic Oncology, Osaka Prefectural Hospital Organization, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583- 8588, Japan. hugurahoma@yahoo.co.jp.;Department of Thoracic Oncology, Osaka Prefectural Hospital Organization, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583- 8588, Japan.;Department of Thoracic Oncology, Osaka Prefectural Hospital Organization, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583- 8588, Japan.;Department of Thoracic Oncology, Osaka Prefectural Hospital Organization, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583- 8588, Japan.;Department of Thoracic Oncology, Osaka Prefectural Hospital Organization, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583- 8588, Japan.;Department of Thoracic Oncology, Osaka Prefectural Hospital Organization, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583- 8588, Japan.;Department of Thoracic Oncology, Osaka Prefectural Hospital Organization, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583- 8588, Japan.;Department of Thoracic Oncology, Osaka Prefectural Hospital Organization, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583- 8588, Japan.;Department of Thoracic Oncology, Osaka Prefectural Hospital Organization, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583- 8588, Japan.;Department of Thoracic Oncology, Osaka Prefectural Hospital Organization, Osaka Habikino Medical Center, 3-7-1 Habikino, Habikino City, Osaka, 583- 8588, Japan.",
"authors": "Nasu|Shingo|S|0000-0003-1965-850X;Suzuki|Hidekazu|H|;Shiroyama|Takayuki|T|;Tanaka|Ayako|A|;Samejima|Yumiko|Y|;Kanai|Tomohiro|T|;Noda|Yoshimi|Y|;Morishita|Naoko|N|;Okamoto|Norio|N|;Hirashima|Tomonori|T|",
"chemical_list": "D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C000596361:osimertinib; D000077716:Afatinib",
"country": "United States",
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"doi": "10.1007/s10637-020-00963-w",
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"issue": "38(6)",
"journal": "Investigational new drugs",
"keywords": "Afatinib; Drug-induced interstitial lung disease; Epidermal growth factor receptor mutation; Osimertinib",
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"nlm_unique_id": "8309330",
"other_id": null,
"pages": "1915-1920",
"pmc": null,
"pmid": "32542461",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety and efficacy of afatinib for the treatment of non-small-cell lung cancer following osimertinib-induced interstitial lung disease: A retrospective study.",
"title_normalized": "safety and efficacy of afatinib for the treatment of non small cell lung cancer following osimertinib induced interstitial lung disease a retrospective study"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-269275",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMETREXED"
},
"drug... |
{
"abstract": "Monomorphic posttransplant lymphoproliferative disorders have been defined as lymphoid or plasmacytic proliferations that fulfill criteria for one of the B-cell or T/NK-cell neoplasms recognized in immunocompetent hosts in the current WHO Classification. Low-grade B-cell neoplasms have historically been excluded from this category, although rare reports of marginal zone lymphoma (MZL) have been described. We report 9 cases of posttransplant Epstein-Barr virus-negative MZL, all arising in solid organ transplant recipients (4 renal, 3 liver, 1 cardiac, and 1 liver, pancreas, and small bowel). Seven were extranodal MZL of mucosa-associated lymphoid tissue type, all of which had gastrointestinal involvement (4 colon, 1 duodenum, 1 stomach, and 1 oropharynx/base of tongue). Notably, the preferential involvement of intestine distinguishes posttransplant extranodal MZL from sporadic cases. Immunoglobulin light-chain restriction was seen in all cases, with polymerase chain reaction showing a monoclonal pattern in 7 of 8 cases with successful amplification of polymerase chain reaction products. A clonally unrelated recurrence was seen in one case. Next-generation sequencing identified recurrent mutations previously reported in MZL in 3/5 cases. MZL was diagnosed at least 1 year after solid organ transplant (median time to presentation, 84 mo; range, 13 to 108 mo). The median age was 44 (range, 9 to 73 y); the male: female ratio was 5:4. The mean follow-up was 33.4 months, with an indolent clinical course observed. A subset responded to reduction in immunosuppression and anti-CD20 therapy alone. These data support the designation of Epstein-Barr virus-negative MZL as an uncommon form of monomorphic posttransplant lymphoproliferative disorders.",
"affiliations": "Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD.;Hematopathology Service, Trinity St. James's Cancer Institute, St. James's Hospital and Trinity College.;Department of Pathology, Hematology& Hematopathology, Medical College of Georgia at Augusta University, Augusta, GA.;Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD.;Department of Pathology and Laboratory Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL.;Department of Pathology, University of California San Diego Health System, La Jolla, CA.;Department of Pathology and Laboratory Medicine, St. Vincent's University Hospital, and UCD School of Medicine, Dublin, Ireland.;Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD.;Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD.;Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD.;Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD.",
"authors": "Galera|Pallavi|P|;Flavin|Richard|R|;Savage|Natasha M|NM|;Saksena|Annapurna|A|;Gong|Shunyou|S|;Wang|Huan-You|HY|;Swan|Niall|N|;Xi|Liqiang|L|;Raffeld|Mark|M|;Pittaluga|Stefania|S|;Jaffe|Elaine S|ES|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PAS.0000000000001514",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-5185",
"issue": "44(10)",
"journal": "The American journal of surgical pathology",
"keywords": null,
"medline_ta": "Am J Surg Pathol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D020031:Epstein-Barr Virus Infections; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D018442:Lymphoma, B-Cell, Marginal Zone; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D016377:Organ Transplantation",
"nlm_unique_id": "7707904",
"other_id": null,
"pages": "1340-1352",
"pmc": null,
"pmid": "32554995",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052060:Research Support, N.I.H., Intramural",
"references": null,
"title": "Epstein-Barr Virus-negative Marginal Zone Lymphoma as an Uncommon Form of Monomorphic Posttransplant Lymphoproliferative Disorder.",
"title_normalized": "epstein barr virus negative marginal zone lymphoma as an uncommon form of monomorphic posttransplant lymphoproliferative disorder"
} | [
{
"companynumb": "US-TEVA-2020-US-1863167",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "2",
... |
{
"abstract": "BACKGROUND\nNatalizumab (NAT) is a humanized monoclonal antibody against a4-integrin initially approved for the treatment of multiple sclerosis, and then withdrawn from the market in 2005 due to the risk of progressive multifocal leukoencephalopathy. NAT was approved for the treatment of Crohn's disease in the United States in 2008 under a restricted distribution program. There has been limited data on NAT since then. The purpose of this study was to review the experience with NAT in Crohn's disease patients at a tertiary inflammatory bowel disease center.\n\n\nMETHODS\nA retrospective chart review was performed on all patients who received NAT for treatment of refractory Crohn's disease from January 2008 to August 2010 at Washington University Medical Center in St. Louis.\n\n\nRESULTS\nA total of 20 patients were identified and included in our study. Four patients did not complete induction therapy. Seven patients had a clinical response, with 5 patients continuing treatment up to 2012. Four patients had a partial response, 3 had adverse events, and 2 experienced loss of response. Two patients were pregnant while on NAT, and neither had significant adverse pregnancy outcomes. One patient dependent on total parenteral nutrition developed recurrent line sepsis while on NAT. Of the 5 patients on long-term maintenance therapy, 4 have a positive anti-JC virus antibody. No patients developed progressive multifocal leukoencephalopathy or other neurological complications.\n\n\nCONCLUSIONS\nNAT remains a valuable alternative treatment option for patients with refractory Crohn's disease under a restricted distribution program.",
"affiliations": "Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri (Chien-Huan Chen, Gowri Kularatna, Alexandra M. Gutierrez, Themistocles Dassopoulos), U.S.A.;Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri (Chien-Huan Chen, Gowri Kularatna, Alexandra M. Gutierrez, Themistocles Dassopoulos), U.S.A.;Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri (Chien-Huan Chen, Gowri Kularatna, Alexandra M. Gutierrez, Themistocles Dassopoulos), U.S.A.;Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri (Chien-Huan Chen, Gowri Kularatna, Alexandra M. Gutierrez, Themistocles Dassopoulos), U.S.A.;Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri (Chien-Huan Chen, Gowri Kularatna, Alexandra M. Gutierrez, Themistocles Dassopoulos), U.S.A.",
"authors": "Chen|Chien-Huan|CH|;Kularatna|Gowri|G|;Stone|Christian D|CD|;Gutierrez|Alexandra M|AM|;Dassopoulos|Themistocles|T|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1108-7471",
"issue": "26(3)",
"journal": "Annals of gastroenterology",
"keywords": "Crohn's disease; natalizumab; pregnancy",
"medline_ta": "Ann Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101121847",
"other_id": null,
"pages": "189-190",
"pmc": null,
"pmid": "24714228",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical experience of natalizumab in Crohn's disease patients in a restricted distribution program.",
"title_normalized": "clinical experience of natalizumab in crohn s disease patients in a restricted distribution program"
} | [
{
"companynumb": "US-JNJFOC-20130710759",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nMetformin can be regarded as a first-line treatment in gestational diabetes mellitus (GDM) due to its safety and effectiveness. However, a proportion of women do not achieve adequate glycemic control with metformin alone. We aim to identify predictors of this poor response to metformin.\n\n\nMETHODS\nRetrospective multicentre cohort study of women with GDM who started metformin as first-line treatment. The assessed cohort was divided into a metformin group and metformin plus insulin group. Biometric and demographic characteristics, glycemic control data, obstetric, neonatal and postpartum outcomes were compared between groups and analysed in order to identify predictors of poor response to metformin. Data were analysed using STATA, version 13.1.\n\n\nRESULTS\nOf the 388 women enrolled in the study, 135 (34.8%) required additional insulin therapy to achieve the glycemic targets. Higher age (aOR: 1.08 (1.03-1.13), P = 0.003), higher pre-pregnancy body mass index (BMI) (1.06 (1.02-1.10), P = 0.003) and earlier introduction of metformin (0.89 (0.85-0.94), P < 0.001) were independent predictors for insulin supplementation. Regarding all the analysed outcomes, only cesarean delivery rates and postpartum glucose levels were higher in women requiring insulin supplementation.\n\n\nCONCLUSIONS\nAlthough almost 35% of women did not achieve adequate glycemic control with metformin, insulin supplementation was not associated with poor neonatal outcomes. Higher age, higher pre-pregnancy BMI and earlier introduction of metformin could be used as predictors of poor response to metformin.",
"affiliations": "Department of Obstetrics, Coimbra Hospital and Universitary Centre, Coimbra, Portugal.;Faculty of Medicine, University of Coimbra, Coimbra, Portugal.;Department of Endocrinology, Porto Hospital Centre, Porto, Portugal.;Diabetes and Pregnancy Study Group of the Portuguese Society of Diabetology, Lisbon, Portugal.;Department of Obstetrics, Coimbra Hospital and Universitary Centre, Coimbra, Portugal.",
"authors": "Gante|Inês|I|;Melo|Luís|L|;Dores|Jorge|J|;Ruas|Luísa|L|;Almeida|Maria do Céu|MDC|",
"chemical_list": "D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0804-4643",
"issue": "178(1)",
"journal": "European journal of endocrinology",
"keywords": null,
"medline_ta": "Eur J Endocrinol",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D001786:Blood Glucose; D015992:Body Mass Index; D015331:Cohort Studies; D016640:Diabetes, Gestational; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D011174:Portugal; D049590:Postpartum Period; D011237:Predictive Value of Tests; D011247:Pregnancy; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D017211:Treatment Failure",
"nlm_unique_id": "9423848",
"other_id": null,
"pages": "129-135",
"pmc": null,
"pmid": "29070511",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Metformin in gestational diabetes mellitus: predictors of poor response.",
"title_normalized": "metformin in gestational diabetes mellitus predictors of poor response"
} | [
{
"companynumb": "PT-ALKEM LABORATORIES LIMITED-PT-ALKEM-2017-00804",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "Rituximab (RTX) is currently used in many diseases, but its efficacy and safety in juvenile systemic lupus erythematosus (SLEj) is still unknown. In this chapter we present four case reports of children treated with RTX: three SLE and one immune thrombocytopenic purpura (ITP). Two of the three SLEj patients had class IV lupus nephritis (LN) and hematologic manifestations (pancytopenia), both reaching complete recovery of blood counts and improvement of LN with RTX treatment. Our third SLE patient had a severe onset with generalized microangiopathic manifestations in association with antiphospholipid antibodies and has been in remission for almost 1 year after RTX. However, our fourth case, a patient with ITP and renal failure, was treated with RTX without either hematologic or renal response.",
"affiliations": "Hospital de Santa Maria, Serviço de Reumatologia e Doenças Osseas Metabólicas, Lisboa, Portugal. polidopereira@gmail.com",
"authors": "Polido-Pereira|Joaquim|J|;Ferreira|Daniel|D|;Rodrigues|Ana Maria|AM|;Nascimento|Catarina|C|;Costa|Paula|P|;Almeida|Margarida|M|;da Silva|José Eduardo Esteves|JE|;Simão|Carla|C|;Stone|Rosário|R|;Ramos|Filipa|F|;Neto|Adriano|A|;da Costa|José Carlos Teixeira|JC|;Melo-Gomes|José|J|;Gomes-Pedro|João|J|;Viana-Queiroz|Mário|M|;Canhão|Helena|H|;Fonseca|João Eurico|JE|",
"chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D007155:Immunologic Factors; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1749-6632.2009.04804.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0077-8923",
"issue": "1173()",
"journal": "Annals of the New York Academy of Sciences",
"keywords": null,
"medline_ta": "Ann N Y Acad Sci",
"mesh_terms": "D000293:Adolescent; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D002648:Child; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008180:Lupus Erythematosus, Systemic; D008297:Male; D009393:Nephritis; D010198:Pancytopenia; D016553:Purpura, Thrombocytopenic, Idiopathic; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "7506858",
"other_id": null,
"pages": "712-20",
"pmc": null,
"pmid": "19758220",
"pubdate": "2009-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rituximab use in pediatric autoimmune diseases: four case reports.",
"title_normalized": "rituximab use in pediatric autoimmune diseases four case reports"
} | [
{
"companynumb": "PT-ACCORD-104702",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditional": "3",
"d... |
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