article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "Vasoplegic syndrome is an unusual cause of refractory hypotension under general anesthesia. It is commonly described in the setting of cardiac surgery, but rarely seen in noncardiac setting. We describe successful management of vasoplegic syndrome during Whipple procedure with vasopressin infusion. A high index of suspicion and prompt treatment with vasopressin can be lifesaving in patients with risk factors for vasoplegic syndrome who present with severe refractory hypotension and who respond poorly to fluid administration and routine vasopressor infusion.",
"affiliations": "Department of Anaesthesiology, MS Ramaiah Medical College and Hospitals, Bangalore, India. Electronic address: drtejeshca@yahoo.com.;Department of Anaesthesiology, MS Ramaiah Medical College and Hospitals, Bangalore, India.;Department of Surgical Oncology, MS Ramaiah Medical College and Hospitals, Bangalore, India.",
"authors": "Anandaswamy|Tejesh C|TC|;Rajappa|Geetha C|GC|;Krishnamachar|Harish|H|",
"chemical_list": "D014662:Vasoconstrictor Agents; D014667:Vasopressins",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jclinane.2016.10.042",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0952-8180",
"issue": "36()",
"journal": "Journal of clinical anesthesia",
"keywords": "Noncardiac surgery; Vasoplegic syndrome; Vasopressin",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000368:Aged; D000768:Anesthesia, General; D006801:Humans; D007022:Hypotension; D008297:Male; D010190:Pancreatic Neoplasms; D016577:Pancreaticoduodenectomy; D011182:Postoperative Care; D014662:Vasoconstrictor Agents; D056987:Vasoplegia; D014667:Vasopressins",
"nlm_unique_id": "8812166",
"other_id": null,
"pages": "151-152",
"pmc": null,
"pmid": "28183555",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vasoplegic syndrome during Whipple procedure.",
"title_normalized": "vasoplegic syndrome during whipple procedure"
} | [
{
"companynumb": "IN-FRESENIUS KABI-FK201702627",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": null,
... |
{
"abstract": "Tuberculosis is one of the most common infectious diseases around the world. With timely diagnosis and treatment, mortality in children is practically zero. It is usually associated with a diverse number of complications that can cause significant morbidity and mortality, such as deep and superficial vein thrombosis. This event has been associated with a procoagulant state caused by the systemic inflammatory response to infection.\nWe report the case of a 14-year-old adolescent with pulmonary tuberculosis under the initial four-drug regimen. She presented two episodes of venous thromboembolism, the first in the kidneys and the second in the lungs. After ruling out diseases such as nephrotic and antiphospholipid antibody syndrome, chest and abdomen tomographies were performed as a fundamental tool for the diagnosis. Thereafter, treatment with low molecular weight heparin was initiated and the symptoms improved. Given the requirement for anticoagulation, further image studies could not be done.\nThromboembolic complications in patients with no other risk factors, associated only with a previous pulmonary tuberculosis diagnosis, offer evidence to consider the procoagulant effect resulting from the systemic inflammatory response that, by itself, could be the cause of a serious complication, often underdiagnosed but also preventable. Therefore, it is recommended to consider the predisposition for venous thromboembolism in these patients and to establish strict surveillance so early anticoagulant therapy can be provided to prevent adverse outcomes.",
"affiliations": "Facultad de Medicina, Universidad CES, Medellín, Colombia. nataosoca@gmail.com.;Facultad de Medicina, Universidad CES, Medellín, Colombia. ireyesmm@gmail.com.",
"authors": "Osorio|Natalia|N|;Reyes|Martha Mónica|MM|",
"chemical_list": "D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight",
"country": "Colombia",
"delete": false,
"doi": "10.7705/biomedica.5195",
"fulltext": "\n==== Front\nBiomedica\nBiomedica\nbio\nBiomédica\n0120-4157 2590-7379 Instituto Nacional de Salud \n\n33275336\n10.7705/biomedica.5195\nPresentación De Casos\nComplicaciones tromboembólicas asociadas con tuberculosis: reporte de un caso pediátrico\nThromboembolic complications associated with tuberculosis: A pediatric case report Osorio Natalia 1 Reyes Martha Mónica 1* \n1 \n Facultad de Medicina, Universidad CES, Medellín, Colombia\nUniversidad CES\nFacultad de Medicina\nUniversidad CES\nMedellín\nColombia\n\n* Correspondencia: Natalia Osorio, Facultad de Medicina, Universidad CES, Calle 10A N° 22-04, Medellín, Colombia Teléfono: (574) 444 0555 ireyesmm@gmail.com\n09 12 2020 \nOct-Dec 2020 \n40 4 587 593\n10 9 2019 03 7 2020 Este es un artículo publicado en acceso abierto bajo una licencia Creative CommonsResumen\nLa tuberculosis es una de las enfermedades infecciosas más comunes en el mundo. Aunque la mortalidad en niños es prácticamente nula cuando el diagnóstico y el tratamiento son oportunos, puede asociarse con complicaciones como la trombosis venosa profunda y la superficial a partir de la respuesta inflamatoria sistémica frente a la infección, lo que propicia la coagulación y ocasiona una significativa morbimortalidad. \n\nSe reporta el caso de una adolescente de 14 años con tuberculosis pulmonar en tratamiento combinado quien, de forma atípica, presentó dos episodios de tromboembolia venosa: el primero en el riñón y el segundo en los pulmones. Tras descartar el síndrome nefrótico y el antifosfolipídico, los estudios de tomografía de tórax y abdomen fueron una herramienta fundamental para su diagnóstico. Se inició tratamiento con heparina de bajo peso molecular con mejoría de los síntomas. Teniendo en cuenta las necesidades de anticoagulación no fue posible realizar estudios adicionales de ampliación. \n\nLas complicaciones tromboembólicas en pacientes con tuberculosis y sin otros factores de riesgo obligan a considerar el efecto coagulante que resulta de la reacción inflamatoria sistémica, la cual podría, por sí sola, ser la causa de una complicación significativa pero prevenible, aunque frecuentemente escapa al diagnóstico. En este sentido, se recomienda considerar la posibilidad de la tromboembolia venosa en estos pacientes y hacer un seguimiento estricto que permita aplicar el tratamiento anticoagulante tempranamente y prevenir, así, resultados adversos.\n\nAbstract\nTuberculosis is one of the most common infectious diseases around the world. With timely diagnosis and treatment, mortality in children is practically zero. It is usually associated with a diverse number of complications that can cause significant morbidity and mortality, such as deep and superficial vein thrombosis. This event has been associated with a procoagulant state caused by the systemic inflammatory response to infection. \n\nWe report the case of a 14-year-old adolescent with pulmonary tuberculosis under the initial four-drug regimen. She presented two episodes of venous thromboembolism, the first in the kidneys and the second in the lungs. After ruling out diseases such as nephrotic and antiphospholipid antibody syndrome, chest and abdomen tomographies were performed as a fundamental tool for the diagnosis. Thereafter, treatment with low molecular weight heparin was initiated and the symptoms improved. Given the requirement for anticoagulation, further image studies could not be done.\n\nThromboembolic complications in patients with no other risk factors, associated only with a previous pulmonary tuberculosis diagnosis, offer evidence to consider the procoagulant effect resulting from the systemic inflammatory response that, by itself, could be the cause of a serious complication, often underdiagnosed but also preventable. Therefore, it is recommended to consider the predisposition for venous thromboembolism in these patients and to establish strict surveillance so early anticoagulant therapy can be provided to prevent adverse outcomes.\n\nPalabras clave:\ntuberculosisembolia pulmonartrombosis de la venaantituberculososanticoagulantesadolescenteKeywords:\nTuberculosispulmonary embolismvenous thrombosisantituberculosis drugsanticoagulantsadolescent\n==== Body\nLa tuberculosis es una de las enfermedades infecciosas más comunes y una de las principales causas de mortalidad globalmente. Afecta a un tercio de la población mundial, de la cual el 11 % corresponde a niños, entre quienes se registra hasta un millón de casos nuevos cada año 1,2. Además, la tuberculosis predomina en poblaciones con barreras de acceso a los servicios de salud y constituye un reto diagnóstico en el caso de los niños ya que, muchas veces, solo tras la búsqueda activa de la fuente de contacto en los adultos, se logra esclarecer el diagnóstico en ellos 1.\n\nAsimismo, la tuberculosis se asocia con diversas complicaciones que implican una morbimortalidad significativa. Entre dichas complicaciones se han descrito la trombosis venosa profunda y la superficial hasta en el 24 % de los diagnósticos post mortem3; se estima que la incidencia fluctúa entre el 3 y el 4 % de los casos de tuberculosis, principalmente en los de la forma miliar, lo que evidencia que el riesgo aumenta según la gravedad de la enfermedad 4-6.\n\nEste tipo de complicación se asocia con estados propiciadores de la inflamación y la coagulación ocasionados por la respuesta inflamatoria sistémica frente a la infección y la presencia de anticuerpos antifosfolípidos, especialmente los anticuerpos antimicroglobulina beta-2 y, más recientemente, los anticuerpos antifosfatidiletanolamina, así como de otras condiciones concomitantes como la compresión extrínseca por adenopatías propia del proceso de tuberculosis, o el reposo prolongado durante la hospitalización 6-8.\n\nPresentación de caso\nSe presenta el caso de una paciente de 14 años con diagnóstico de tuberculosis de origen pulmonar y sin antecedentes patológicos previos. El diagnóstico se confirmó en baciloscopias seriadas positivas y recibió el tratamiento compuesto con isoniacida, rifampicina, pirazinamida y etambutol. Un mes después de iniciar la medicación, consultó por dolor localizado en la fosa renal izquierda, hematuria macroscópica y disuria. En una tomografía de abdomen con contraste se observaron cambios inflamatorios en el riñón izquierdo, y un trombo en la vena renal izquierda con extensión dentro del riñón y la vena cava inferior. Se describieron, asimismo, edema y captación del contraste en el urotelio del costado izquierdo, principalmente el tercio proximal, secundario a ureteritis de probable origen tuberculoso.\n\nAnte los hallazgos descritos, se inició el tratamiento con heparina de bajo peso molecular y se hicieron los estudios en búsqueda de trombofilia; se encontró prolongación del tiempo parcial de tromboplastina y aumento. Sin embargo, dado que la paciente estaba recibiendo anticoagulante y existía el riesgo de falsos negativos, no fue posible hacer otros exámenes paraclínicos. En este punto se decidió darle de alta y continuar con el seguimiento ambulatorio.\n\nCuatro meses después, la paciente consultó de nuevo con disnea, tos no productiva, dolor torácico y aumento de la necesidad de oxígeno. Durante la anamnesis, refirió haber suspendido por decisión propia el tratamiento con heparina de bajo peso molecular. En el examen físico se encontró taquicardia, taquipnea e hipoxemia, por lo que se la hospitalizó.\n\nDurante la hospitalización, se practicaron baciloscopias seriadas de control, las cuales fueron negativas; además, se descartaron enfermedades comúnmente asociadas con la trombosis, como el síndrome nefrótico, pues la concentración de albúmina era normal; el síndrome antifosfolipídico, pues no se demostraron anticuerpos anticardiolipina ni antiglucoproteína beta 2 (cuadro 1), y el lupus eritematoso sistémico, pues los anticuerpos anti-ADN y anti-Smith fueron negativos. No obstante, en otros exámenes de laboratorio se encontraron niveles de dímero D anormalmente elevados, lo cual era indicativo de tromboembolia pulmonar.\n\n\nCuadro 1 Exámenes paraclínicos practicados a la paciente\nLaboratorio\tResultado\tValores de referencia\t\nCardiolipina, anticuerpos IGG (GPL)\t2,63\t<10 negativo\t\nCardiolipina, anticuerpos IGM (MPL)\t5,13\t<7 negativo\t\nTiempo de tromboplastina (s)\t43,3\t23,9-34,9\t\nAnticoagulante lúpico (s)\t47,0\t30,4-45,3\t\nProteína S de coagulación (%)\t64,8\t55-123\t\nProteína S, antígeno total (%)\t122\t70-140\t\nProteína C de coagulación (%)\t105,5\t70-140\t\nDímero D (µg FEU/ml)\t6,75\t0-0,49\t\nGlucoproteína beta 2, anticuerpos IGG (SGU)\t1,45\t0-20\t\nAnticuerpos antinucleares\tPositivo 1:80 patrón moteado\tNegativo\t\nAnticuerpos anti-Ro\t0,1\t0-0,9\t\nAnticuerpos anti-La\t0,17\t0-0,9\t\nAnticuerpos anti-Smith\t0,12\t0-0,9\t\nAnticuerpos anti-Sm/RNP\t0,10\t0-0,9\t\nAnticuerpos anti-ADN\tNegativo\tNegativo\t\nAlbúmina (g/dl)\t3,5\t3,4-5,4\t\n\n\n\nLos estudios se complementaron con tomografías de tórax y de abdomen con contraste, las cuales evidenciaron tromboembolia pulmonar grave (figuras 1 y 2) con múltiples trombos bilaterales, áreas pequeñas de infartos pulmonares, nódulos pulmonares múltiples, y embolia venosa renal bilateral con trombo que comprometía la vena cava superior. Se decidió reiniciar el tratamiento anticoagulante con heparina de bajo peso molecular, con lo cual los síntomas respiratorios mejoraron, lo que permitió dar de alta a la paciente y retomar el seguimiento por consulta externa.\n\n\nFigura 1 Tomografía computarizada de tórax. La flecha blanca señala\n\n\n\n\nFigura 2 Tomografía computarizada de tórax La flecha indica trombosis un gran trombo en la vena pulmonar izquierda. extensa de las venas pulmonares (derecha e izquierda).\n\n\n\nConsideraciones éticas\nSegún el Artículo 11 de la Resolución número 008430 del 4 de octubre de 1993, esta investigación cumple con las condiciones establecidas por el Ministerio de Salud de la República de Colombia para ser clasificada como una investigación sin riesgo, ya que solo implicó la revisión de la historia clínica para el reporte de caso. El estudio fue aprobado por el comité de ética de la institución donde fue atendida la paciente y el guardián legal de la paciente autorizó la publicación mediante un consentimiento informado.\n\nDiscusión\nEl estado propicio para la coagulación secundaria a la tuberculosis se produce principalmente en las fases tempranas de la enfermedad, sin embargo, también se han descrito casos tardíos 9. Es un proceso multifactorial, es decir, la respuesta inflamatoria inherente al proceso infeccioso subyacente compromete los niveles de antitrombina III y proteína C, y produce un importante aumento del fibrinógeno sérico y del dímero D, así como daño directo del endotelio con trombocitosis reactiva, lo que favorece el proceso de agregación plaquetaria y la trombosis 8, y se refleja en la prolongación de los tiempos de coagulación.\n\nPor otro lado, se ha establecido que el tratamiento compuesto de cuatro medicamentos antituberculosos es un factor de riesgo de trombosis, especialmente por la rifampicina. Este fármaco se ha asociado con proliferación del retículo endoplásmico liso en las células hepáticas; además, al ser de metabolismo hepático, causa la inducción de la enzima citocromo P450, lo que compromete la producción de las enzimas anticoagulantes y favorece su rápida depuración, lo cual altera la homeostasis a favor de un estado propicio a la coagulación 10-12.\n\nOtro hallazgo frecuente es la presencia de anticuerpos antifosfolípidos como el anticoagulante lúpico y los anticuerpos antifosfatidiletanolamina. El primero se ha relacionado con la deficiencia parcial de proteína S, un factor anticoagulante conocido que, al disminuir, promueve la tendencia coagulante, en tanto que los segundos aumentan como reacción al proceso infeccioso de la tuberculosis 4,13,14. En el lupus eritematoso sistémico y el síndrome de anticuerpos antifosfolípidos, se ha establecido su papel como factor protrombótico dado que la fosfatidiletanolamina desempeña una función anticoagulante 7.\n\nOtros factores que propician la coagulación son las adenomegalias que, por acción local, pueden ocluir vasos e interrumpir el flujo laminar 15, y aquellos que producen estasis vascular, como el reposo prolongado en pacientes hospitalizados durante periodos extensos, lo cual limita la movilidad y propicia la aparición de la tríada de Virchow 4.\n\nEntre las principales complicaciones tromboembólicas, se ha descrito el compromiso de las venas de miembros inferiores, las hepáticas y los senos venosos cerebrales 13,16. En el presente caso, hubo daño en la vena renal con extensión significativa hasta la vena cava inferior y la superior.\n\nEl tratamiento para las complicaciones trombóticas son los anticoagulantes. En pediatría se utilizan tradicionalmente tres tipos: la heparina no fraccionada, la heparina de bajo peso molecular y los antagonistas de la vitamina K. El primero es un medicamento que, al unirse a la antitrombina III, potencia la actividad inhibitoria de la coagulación, posee una vida media corta, su acción es de inicio rápido y se dispone de antídoto. Se usa sobre todo para la profilaxis en procedimientos y la permeabilidad de accesos vasculares en bolos de 75 a 100 unidades/kg, con dosis de mantenimiento que dependen de la edad: en menores de dos meses, aproximadamente de 28 unidades/kg por hora, y en niños mayores de esta edad, de 18 a 20 unidades/kg por hora 17,18.\n\nPor otra parte, la heparina de bajo peso molecular actúa inhibiendo el factor Xa mediante la activación de la antitrombina III. Entre sus ventajas, resalta la vida media prolongada y el bajo riesgo de interacción farmacológica. El rango terapéutico se infiere de los resultados en población adulta y se basa en el seguimiento de los niveles del antifactor Xa en suero. En neonatos, la dosis media para alcanzar el rango terapéutico varía entre 1,6 y 2 mg/kg dos veces al día y, en niños mayores, entre 1,12 y 1,9 mg/kg dos veces al día 17,18.\n\nPor último, la acción de los antagonistas de la vitamina K, que inhiben factores dependientes de la vitamina como el X, IX, VII, II y las proteínas C y S, varía según la dieta y los medicamentos que ingiera el paciente. Por ejemplo, los niños alimentados con fórmulas infantiles pueden ser resistentes al medicamento porque dichas fórmulas vienen enriquecidas con esta vitamina, por lo que la supervisión es difícil y requiere vigilancia estrecha. La dosis de inicio es de 0,1 a 0,2 mg/kg con rangos terapéuticos del índice internacional normalizado (International Normalized Ratio, INR) entre 2 y 3. En la población pediátrica, especialmente en preescolares y lactantes, la presentación es una limitación, puesto que está disponible únicamente en tabletas y su recomposición en formulación líquida no es segura 17,18.\n\nCabe aclarar que, además de los ya mencionados, los anticoagulantes de nueva generación se han probado en la población pediátrica y están indicados en la trombocitopenia inducida por heparina. Actualmente, se encuentran disponibles los inhibidores de trombina (bivalirudina y argatroban), cuya adecuada seguridad ya ha sido documentada, así como pocos episodios de sangrado y la resolución rápida de los coágulos. El fondaparinux, por su parte, actúa inhibiendo el factor Xa y tiene un perfil de seguridad aceptable, requiere una dosis única al día y se supervisa midiendo los niveles del factor anti-Xa; se recomienda una dosis de 0,1 mg/kg por día y su rango terapéutico es de 0,5 a 1 mg/L 17,18.\n\nEn el presente caso, se llegó a considerar el empleo de warfarina, pero se sabe que los efectos de los cumarínicos se ven atenuados por el uso concomitante de rifampicina y el metabolismo hepático ya descrito 4,10,11, lo que supone una mayor dificultad para mantener el INR aceptado 19. Por ello, la alternativa recomendada fue la heparina de bajo peso molecular, la cual se utilizó tras el diagnóstico de trombosis.\n\nEn algunos estudios se ha propuesto el manejo con heparina de bajo peso molecular como profilaxis 4,10,20, sin embargo, no hay un consenso establecido sobre su inicio. Se plantea que, en casos graves de tuberculosis pulmonar o miliar, se debería iniciar la anticoagulación simultáneamente con el tratamiento compuesto, ya que las alteraciones hematológicas secundarias de la enfermedad usualmente se resuelven tras un mes de tratamiento antituberculoso 4,20.\n\nNo se ha establecido el tiempo mínimo de tratamiento con anticoagulación. En la revisión bibliográfica se encontraron reportes de casos de pacientes tratados durante tres meses que posteriormente hubo que extender hasta seis meses 20. Monagle, et al., publicaron en el 2012 una guía para el tratamiento antitrombótico en neonatos y niños, recomendando el uso de heparina no fraccionada o heparina de bajo peso molecular en quienes presenten trombosis unilateral de la vena renal con extensión a la vena cava superior de una duración aproximada de tres semanas hasta seis meses, como en el presente caso 21. También, se encontraron publicaciones sobre el uso de antagonistas de la vitamina K. Sangani, et al., por ejemplo, reportaron el caso de una paciente de 11 años con tuberculosis y trombosis en la vena cava inferior y en la femoral, tratada con warfarina durante seis meses 22.\n\nEs claro que se debe instaurar de forma temprana el tratamiento compuesto con los cuatro fármacos antituberculosos y mantenerse atento a los signos que sugieran complicaciones secundarias al proceso propiciador de la coagulación para iniciar oportunamente el tratamiento anticoagulante, incluso en aquellos pacientes sin factores de riesgo adicionales.\n\nConclusiones\nLa tuberculosis sigue siendo una causa importante de morbimortalidad en Colombia y es importante documentar las complicaciones secundarias y su frecuencia en la población pediátrica, con el fin de recopilar los datos en cohortes más grandes e informar el comportamiento de las variables hematológicas en este grupo etario. El tratamiento óptimo de las complicaciones tromboembólicas se basa en la vigilancia médica y en la sospecha diagnóstica ante hallazgos clínicos o paraclínicos sugestivos, por lo cual se recomienda un seguimiento estricto de estos pacientes.\n\nCitación: Osorio N, Reyes MM. Complicaciones tromboembólicas asociadas con tuberculosis: reporte de un caso pediátrico. Biomédica. 2020;40:587-93. https://doi.org/10.7705/biomedica.5195\n\n\nContribución de los autores: Las dos autoras analizaron e interpretaron los datos de la paciente, revisaron la bibliografía, y corrigieron y aprobaron el manuscrito final.\n\nFinanciación: No se recibieron recursos.\n\nConflicto de intereses: Las autoras declaran que no tienen intereses en conflicto.\n==== Refs\nReferencias\n1 Holmberg PJ Temesgen Z Banerjee R Tuberculosis in children Pediatr Rev 2019 40 168 178 10.1542/pir.2018-0093 30936398 \n2 Pérez-Vélez CM Marais BJ Tuberculosis in children N Engl J Med 2012 367 348 361 10.1056/NEJMra1008049 22830465 \n3 Posada A Echeverri D Bolaño J Ramírez H García J Embolismo pulmonar masivo en un paciente con tuberculosis pulmonar: una entidad más que una asociación Acta Colombiana de Cuidado Intensivo 2015 15 143 146 10.1016/j.acci.2015.02.003 \n4 Kwas H Habibech S Zendah I Elmjendel I Ghedira H Pulmonary embolism and tuberculosis Asian Cardiovasc Thorac Ann 2014 22 487 490 10.1177/0218492313485071 24771743 \n5 Dentan C Epaulard O Seynaeve D Genty C Bosson J-L Active tuberculosis and venous thromboembolism: Association according to International Classification of Diseases, Ninth Revision Hospital Discharge Diagnosis Codes Clin Infect Dis 2014 58 495 501 10.1093/cid/cit780 24280089 \n6 Park H Cha SI Lim JK Lee SY Kim CH Park JY Clinical characteristics of coexisting pulmonary thromboembolism in patients with respiratory tuberculosis Am J Med Sci 2017 353 166 171 10.1016/j.amjms.2016.11.025 28183418 \n7 Bessis S Bertin D Million M Meddeb L Drancourt M Lagier JC Thromboses in tuberculosis are linked to antiphosphatidylethanolamine antibodies levels: A cross-sectional study J Clin Tuberc Mycobact Dis 2019 15 100092 100092 10.1016/j.jctube.2019.100092 \n8 Kager LM Blok DC Lede IO Rahman W Afroz R Bresser P Pulmonary tuberculosis induces a systemic hypercoagulable state J Infect 2015 70 324 334 10.1016/j.jinf.2014.10.006 25455017 \n9 Shah PA Pulmonary tuberculosis with deep venous thrombosis Webmed Central 2011 2 10.9754/journal.wmc.2011.002093 \n10 Huei TJ Henry TCL Ho CA Mohamad Y A rare case of ileocecal tuberculosis with pulmonary embolism and deep vein thrombosis J Clin Diagn Res 2017 11 PD03 PD04 10.7860/JCDR/2017/27923.10192 \n11 White N Venous thrombosis and rifampicin Lancet 1989 334 434 435 10.1016/s0140-6736(89)90603-x \n12 Naithani R Agrawal N Choudhary VP Deep venous thrombosis associated with tuberculosis Blood Coagul Fibrinolysis 2007 18 377 380 10.1097/MBC.0b013e3280d942b4 \n13 Goncalves IM Alves DC Carvalho A do Ceu Brito M Calvario F Duarte R Tuberculosis and venous thromboembolism: A case series Cases J 2009 2 9333 9333 10.1186/1757-1626-2-9333 20066058 \n14 Suárez S Artilez J Balda I Melado P Arkuch ME Ayala E La tuberculosis como factor de riesgo de trombosis venosa Anales de Medicina Interna 1993 10 398 400 8218787 \n15 Kechaou I Cherif E Ben Hassine L Khalfallah N Deep vein thrombosis and tuberculosis: A causative link? BMJ Case Rep 2014 2014 bcr2013200807 bcr2013200807 10.1136/bcr-2013-200807 \n16 Nkoke C Bain LE Jingi AM Kotta S Mintom P Menanga A Bilateral pulmonary embolism in a patient with pulmonary tuberculosis: A rare association in Yaounde, Cameroon Pan Afr Med J 2014 17 262 262 10.11604/pamj.2014.17.262.4107 25309662 \n17 Ekukwe NC Bain LE Jingi AM Sylvia K Mintom P Menanga A Bilateral pulmonary embolism in a patient with pulmonary tuberculosis: A rare association in Yaounde, Cameroon Pan Afr Med J 2014 17 262 262 10.11604/pamj.2014.17.262.4107 25309662 \n18 Monagle P Newall F. Management of thrombosis in children and neonates: Practical use of anticoagulants in children Hematology 2018 2018 399 404 10.1182/asheducation-2018.L399 30504338 \n19 Kumarihamy KW Ralapanawa DM Jayalath WA A rare complication of pulmonary tuberculosis: A case report BMC Res Notes 2015 8 39 39 10.1186/s13104-015-0990-6 25888831 \n20 Kouismi H Laine M Bourkadi J-E Iraqi G Association of deep venous thrombosis with pulmonary tuberculosis Egypt J Chest Dis Tuberc 2013 62 541 543 10.1016/j.ejcdt.2013.06.001 \n21 Monagle P Chan AKC Goldenberg NA Ichord RN Journeycake JM Nowak-Gottl U Antithrombotic therapy in neonates and children Chest 2012 141 e737S e801S 10.1378/chest.11-2308 22315277 \n22 Sangani J Mukherjee S Biswas S Chaudhuri T Ghosh G Tuberculosis and acute deep vein thrombosis in a paediatric case J Clin Diagn Res 2015 9 SD01 SD02 10.7860/JCDR/2015/11809.6078\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0120-4157",
"issue": "40(4)",
"journal": "Biomedica : revista del Instituto Nacional de Salud",
"keywords": "tuberculosis; pulmonary embolism; venous thrombosis; antituberculosis drugs; anticoagulants; adolescent",
"medline_ta": "Biomedica",
"mesh_terms": "D000293:Adolescent; D000925:Anticoagulants; D005260:Female; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D007668:Kidney; D008168:Lung; D008171:Lung Diseases; D011667:Pulmonary Veins; D014397:Tuberculosis, Pulmonary; D054556:Venous Thromboembolism",
"nlm_unique_id": "8205605",
"other_id": null,
"pages": "587-593",
"pmc": null,
"pmid": "33275336",
"pubdate": "2020-12-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25309662;24771743;25888831;30504338;17473582;22830465;22315277;24859543;8218787;30936398;25455017;26266181;24280089;28183418;31720419;28892968;2569610;20066058",
"title": "Thromboembolic complications associated with tuberculosis: A pediatric case report",
"title_normalized": "thromboembolic complications associated with tuberculosis a pediatric case report"
} | [
{
"companynumb": "CO-LUPIN PHARMACEUTICALS INC.-2021-22363",
"fulfillexpeditecriteria": "1",
"occurcountry": "CO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIFAMPIN"
},
"drugadditional":... |
{
"abstract": "This case illustrates a novel screening protocol for linezolid-induced toxic optic neuropathy.\n\n\n\nTo present a case report and analysis of linezolid-induced optic neuropathies in adult patients to develop screening recommendations.\n\n\n\nA case report of optic neuropathy from extended use of linezolid illustrates its potential effects on vision. We conduct a retrospective analysis of 39 reported cases to derive a recommended screening protocol for linezolid-induced toxic optic neuropathy in adult patients. Of 39 reported adult cases, 32 presented with optic neuropathy within 90 to 365 days of treatment. Within this subset, the duration of linezolid dosage to first symptoms is 235 ± 71 days. Seven outliers either experienced optic neuropathy within the first 28 days or between 600 and 1125 days. Of the 33 cases that quantified visual recovery, 30 reported final binocular visual acuity equivalent to 20/40 or better when the medication was discontinued from 0 to 268 days after symptom onset. Recovery potential was reported over a period of 2 weeks to approximately 6 months after cessation. To evaluate the effect of cumulative dose, the data were separated into patients taking 600 mg twice daily and those at 600 mg once daily. At the higher dosage, a mean of 180 ± 96 days with a mean cumulative dosage of 216 ± 115 g was noted at first symptom, whereas at lower dosage, a mean of 201 ± 102 days was noted with a mean cumulative dose of 138 ± 69 g.\n\n\n\nWe recommend screening adult patients within 1 month after initiating linezolid, followed by a subsequent evaluation every 30 to 60 days beginning 3 months from initiation. Substantial visual recovery is reported when linezolid is discontinued. Toxicity appears to be correlated to duration of treatment, rather than cumulative dose.",
"affiliations": "Salem Veterans Affairs Medical Center, Salem, Virginia.;Salem Veterans Affairs Medical Center, Salem, Virginia.",
"authors": "Dempsey|Sean P|SP|;Sickman|Amy|A|;Slagle|William Scott|WS|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": "10.1097/OPX.0000000000001216",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1040-5488",
"issue": "95(5)",
"journal": "Optometry and vision science : official publication of the American Academy of Optometry",
"keywords": null,
"medline_ta": "Optom Vis Sci",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D019317:Evidence-Based Medicine; D006801:Humans; D000069349:Linezolid; D008297:Male; D009901:Optic Nerve Diseases; D017410:Practice Guidelines as Topic; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence; D014786:Vision Disorders; D058609:Visual Field Tests; D014794:Visual Fields",
"nlm_unique_id": "8904931",
"other_id": null,
"pages": "468-474",
"pmc": null,
"pmid": "29683987",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case Report: Linezolid Optic Neuropathy and Proposed Evidenced-based Screening Recommendation.",
"title_normalized": "case report linezolid optic neuropathy and proposed evidenced based screening recommendation"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-03216",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYANOCOBALAMIN"
},
"... |
{
"abstract": "BACKGROUND\nThe relationship between rhGH treatment and thyroid function has been the subject of numerous studies. Some say that rhGH treatment unmasks central hypothyroidism, other say that rhGH induces subclinical primary hypothyroidism.\n\n\nOBJECTIVE\nTo assess the changes in thyroid function in short stature children in the first year of treatment with rhGH and the impact on growth velocity.\n\n\nMETHODS\nWe evaluated 37 patients treated with rhGH, 5 were excluded because developed side effects during treatment. We measured height, height velocity, and height standard deviation gain during treatment and thyroid function during the first year of treatment.\n\n\nRESULTS\nWe observed a slight increase in the TSH level and no significant change in the f T4 level after the first 3-6 months of treatment in all the groups; in GH deficiency (GHD) patients, we observed a statistically significant decrease of the f T4 level after the first 3-6 months, without a significant increase of the TSH level. After the first year, thyroid function returned to baseline. There were no differences between height velocities in all the groups, except from the GHD patients.\n\n\nCONCLUSIONS\nThe slight increase in the TSH level and the decrease of f T4 level might unmask a transient subclinical primary hypothyroidism but these changes do not influence the growth velocity in first year of rhGH treatment.",
"affiliations": null,
"authors": "Căpraru|Oana-Maria|OM|;Paşcanu|Ionela M|IM|",
"chemical_list": "D015415:Biomarkers; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D013972:Thyrotropin; D013974:Thyroxine",
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0048-7848",
"issue": "118(2)",
"journal": "Revista medico-chirurgicala a Societatii de Medici si Naturalisti din Iasi",
"keywords": null,
"medline_ta": "Rev Med Chir Soc Med Nat Iasi",
"mesh_terms": "D000293:Adolescent; D015415:Biomarkers; D001827:Body Height; D002648:Child; D005260:Female; D006130:Growth Disorders; D019382:Human Growth Hormone; D006801:Humans; D007037:Hypothyroidism; D008297:Male; D011994:Recombinant Proteins; D012189:Retrospective Studies; D013972:Thyrotropin; D013974:Thyroxine",
"nlm_unique_id": "0413735",
"other_id": null,
"pages": "307-14",
"pmc": null,
"pmid": "25076692",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Thyroid function during the first year of recombinant human growth hormone therapy in short stature children.",
"title_normalized": "thyroid function during the first year of recombinant human growth hormone therapy in short stature children"
} | [
{
"companynumb": "RO-ROCHE-1452718",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SOMATROPIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Direct oral anticoagulant (DOAC) agents have become commonly used over the last 9 years for treatment and prophylaxis for thromboembolic conditions, following approvals by the United States Food and Drug Administration. These anticoagulant agents, which include a direct thrombin inhibitor and factor Xa inhibitors, offer potential advantages for patients over warfarin; however, bleeding emergencies with DOACs can present diagnostic and therapeutic challenges because, unlike traditional anticoagulants, their therapeutic effect cannot be easily monitored directly with common clotting assays. This review examines the growing body of evidence on the uses and risks of DOACs in the emergency department, including initiation of therapy and reversal strategies.",
"affiliations": "Assistant Professor, Emergency Medicine and Critical Care, Icahn School of Medicine at Mount Sinai, New York, NY.;Department of Emergency Medicine and Critical Care, Icahn School of Medicine at Mount Sinai, New York, NY.",
"authors": "Maher|Patrick|P|;Taub|Emily|E|",
"chemical_list": "D000925:Anticoagulants; D000991:Antithrombins; D065427:Factor Xa Inhibitors",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-1971",
"issue": "21(8)",
"journal": "Emergency medicine practice",
"keywords": null,
"medline_ta": "Emerg Med Pract",
"mesh_terms": "D000284:Administration, Oral; D000925:Anticoagulants; D000991:Antithrombins; D019468:Disease Management; D004632:Emergency Medical Services; D004636:Emergency Service, Hospital; D065427:Factor Xa Inhibitors; D006801:Humans; D011517:Prothrombin Time; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography",
"nlm_unique_id": "100889097",
"other_id": null,
"pages": "1-28",
"pmc": null,
"pmid": "31339254",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Emergency department management of patients taking direct oral anticoagulant agents.",
"title_normalized": "emergency department management of patients taking direct oral anticoagulant agents"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-032424",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "BACKGROUND\nAlthough esophageal compression due to cardiomegaly may be a risk factor of drug-induced esophageal injuries (DIEIs), the causal relationship between the two conditions has not been fully demonstrated.\nWe present a case of a drug-induced esophageal ulcer caused by left atrial enlargement in a 44-year-old woman with end-stage hypertrophic cardiomyopathy. Upper gastrointestinal endoscopy showed a deep, circumferential ulcer in the middle thoracic esophagus. CT revealed that the esophagus was compressed between the enlarged left atrium (LA) and the vertebral body. In the upper gastrointestinal series, retention of contrast media was observed in the esophagus near the LA.\n\n\nMETHODS\nThe ulcer was a result of potassium chloride retention in the esophagus, which was compressed by the enlarged LA.\n\n\nMETHODS\nAfter cessation of potassium chloride administration for 2 months, the ulcer healed and a stricture developed. Two years after the ulcer development, the patient underwent heart transplantation, and subsequent endoscopic balloon dilation was performed for the esophageal stricture.\n\n\nRESULTS\nThe patient's oral intake recovered completely without any ulcer recurrence.\n\n\nCONCLUSIONS\nThe case demonstrated that esophageal compression by the enlarged LA caused a drug-induced esophageal ulcer. Preventive care and treatment measures for DIEIs, including an anatomical approach, should be considered for patients with LA enlargement.",
"affiliations": "Department of Gastroenterology and Hepatology.;Department of Gastroenterology and Hepatology.;Department of Gastroenterology and Hepatology.;Department of Gastroenterology and Hepatology.;Department of Gastroenterology and Hepatology.;Department of Gastroenterology and Hepatology.;Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Gastroenterology and Hepatology.",
"authors": "Maesaka|Kazuki|K|;Tsujii|Yoshiki|Y|;Shinzaki|Shinichiro|S|;Yoshii|Shunsuke|S|;Hayashi|Yoshito|Y|;Iijima|Hideki|H|;Nakamoto|Kei|K|;Ohtani|Tomohito|T|;Sakata|Yasushi|Y|;Takehara|Tetsuo|T|",
"chemical_list": "D054328:Proton Pump Inhibitors; D011189:Potassium Chloride",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000013380",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30508933MD-D-18-0457510.1097/MD.0000000000013380133804500Research ArticleClinical Case ReportSuccessful treatment of drug-induced esophageal ulcer in a patient with chronic heart failure A case reportMaesaka Kazuki MDaTsujii Yoshiki MD, PhDaShinzaki Shinichiro MD, PhDaYoshii Shunsuke MDaHayashi Yoshito MD, PhDaIijima Hideki MD, PhDaNakamoto Kei MDbOhtani Tomohito MD, PhDbSakata Yasushi MD, PhDbTakehara Tetsuo MD, PhDa∗NA. a Department of Gastroenterology and Hepatologyb Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.∗ Correspondence: Tetsuo Takehara, Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan (e-mail: takehara@gh.med.osaka-u.ac.jp).11 2018 30 11 2018 97 48 e1338023 7 2018 31 10 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nAlthough esophageal compression due to cardiomegaly may be a risk factor of drug-induced esophageal injuries (DIEIs), the causal relationship between the two conditions has not been fully demonstrated.\n\nPatient concerns:\nWe present a case of a drug-induced esophageal ulcer caused by left atrial enlargement in a 44-year-old woman with end-stage hypertrophic cardiomyopathy. Upper gastrointestinal endoscopy showed a deep, circumferential ulcer in the middle thoracic esophagus. CT revealed that the esophagus was compressed between the enlarged left atrium (LA) and the vertebral body. In the upper gastrointestinal series, retention of contrast media was observed in the esophagus near the LA.\n\nDiagnosis:\nThe ulcer was a result of potassium chloride retention in the esophagus, which was compressed by the enlarged LA.\n\nIntervention:\nAfter cessation of potassium chloride administration for 2 months, the ulcer healed and a stricture developed. Two years after the ulcer development, the patient underwent heart transplantation, and subsequent endoscopic balloon dilation was performed for the esophageal stricture.\n\nOutcomes:\nThe patient's oral intake recovered completely without any ulcer recurrence.\n\nLessons:\nThe case demonstrated that esophageal compression by the enlarged LA caused a drug-induced esophageal ulcer. Preventive care and treatment measures for DIEIs, including an anatomical approach, should be considered for patients with LA enlargement.\n\nKeywords\ncardiomegalydrug-induced esophageal injuriesendoscopic dilationesophageal ulcerheart transplantationleft atrial enlargementOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nOver 100 different drugs have thus far been reported to cause drug-induced esophageal injuries (DIEIs).[1] DIEIs occur when caustic drugs dissolve in the esophagus and release their noxious contents.[1,2] The most-important patient-related risk factors for DIEIs are insufficient water consumption and recumbent position while taking medicines, which extend the drug-exposure time in the esophagus.[3] The lesions are frequently located in the middle thoracic esophagus, where the aortic arch and left atrium (LA) physiologically constrict the esophageal lumen and probably delay the transit of medicines.[2,4] In addition, altered esophageal anatomies may be risk factors of DIEIs. Patients with cardiomegaly are particularly susceptible to injury at the site of the esophagus compressed by the LA.[2,4] However, a few studies demonstrated that LA enlargement causes DIEIs and anatomical approaches healed and prevented DIEIs. In this report, we present a case of a potassium chloride-induced esophageal ulcer caused by LA enlargement, which was successfully treated using endoscopic balloon dilation for the stricture after improvement of esophageal compression by heart transplantation.\n\n2 Case report\nA 44-year-old woman with pulmonic valve stenosis and atrial septal defect underwent curative surgery at 4 years of age. At the age of 38 years, she noticed exertional dyspnea and was diagnosed with end-stage hypertrophic cardiomyopathy. At the age of 40 years, she was hospitalized for heart failure due to frequent atrial fibrillation attacks and implanted with a cardiac resynchronization therapy with defibrillator. Nonetheless, she had frequent hospital admissions, and in the current instance, she was hospitalized for heart failure exacerbated by atrial fibrillation attacks. She was administered medication for 1 month of hospitalization, which improved the circulation dynamics, but 3 days after discharge, she was readmitted and referred to our department with complaints of epigastric pain and loss of appetite.\n\nShe underwent upper gastrointestinal endoscopy for odynophagia and dysphagia, which showed a deep circumferential ulcer with white exudates in the esophagus, 28 to 36 cm from the incisors (Fig. 1). Histopathological findings of the biopsy specimens taken from the ulcer showed only infiltration of inflammatory cells, indicating neither infection nor malignancy. There was no retention of food residues in the esophagus, which could cause physical obstacles, nor any history of ingestion of corrosive substances by mistake. Various drugs were administered to control her chronic heart failure, but only potassium chloride was previously reported to cause DIEIs. The potassium chloride dose was increased during the patient's previous hospitalization to prevent atrial fibrillation attacks and most likely induced ulceration. Chest radiography showed cardiomegaly with a cardiothoracic ratio of 56% and scoliosis (Fig. 2). A transthoracic echocardiogram revealed the presence of mild mitral regurgitation and LA enlargement, with a LA dimension of 55 mm. CT showed that the enlarged LA and vertebral body compressed the esophagus, where a high-density area was noted and suspected to retain drugs (Fig. 3). This high-density area likely contained potassium chloride because the drug was orally administered before CT and was radiopaque for several hours after administration. Collectively, these findings indicated that the ulcer was induced by potassium chloride lodged in the esophagus owing to the LA enlargement. In the upper gastrointestinal series, retention of contrast media was observed at the narrowing site of the esophagus, which is close to the LA, suggesting esophageal obstruction due to LA enlargement (Fig. 4).\n\nFigure 1 Upper gastrointestinal endoscopy on admission shows a deep circumferential ulcer with white exudates in the esophagus, 28 to 36 cm from the incisors.\n\nFigure 2 Chest radiography shows cardiomegaly with the cardiothoracic ratio of 56% and scoliosis.\n\nFigure 3 Computed tomography shows that the enlarged left atrium and vertebral body are compressing the esophagus, where a high-density area is seen and suspected to retain drugs (arrowhead). Ao = aorta, LA = left atrium.\n\nFigure 4 Upper gastrointestinal series. (A) Frontal view and (B) lateral view. Retention of contrast media at the narrowing site of the esophagus is observed at the same height as the left atrium (arrowheads). LA = left atrium.\n\nTreatment with a proton-pump inhibitor was initiated, and potassium chloride administration was discontinued. Follow-up endoscopy 2 weeks later showed that the ulcer was healing (Fig. 5), and epigastric distress and odynophagia were alleviated. However, conservative treatment with cardiovascular drugs did not effectively control the patient's heart failure, and therefore, she underwent left ventricular assist device implantation and waited for a heart transplantation. Follow-up endoscopy 2 months later showed that the ulcer had scarred, and an esophageal stricture had developed (Fig. 6). The patient complained of dysphagia and vomiting after ingestion of solid meals, but she managed to maintain nutrition on a soft diet without intravenous nutrition and was observed without endoscopic therapy due to severe cardiac dysfunction.\n\nFigure 5 Follow-up endoscopy 2 weeks after treatment with a proton-pump inhibitor shows the ulcer healing in the esophagus.\n\nFigure 6 Follow-up endoscopy after 2 months from cessation of potassium chloride administration shows the ulcer scar with a stricture formation.\n\nTwo years after the development of the esophageal ulcer, the patient underwent heart transplantation. Surgery was completed without any serious complications. Her general condition improved, but her dysphagia worsened as her medications such as immunosuppressive agents increased. Four months after the heart transplantation, endoscopic balloon dilation was performed for the esophageal stricture. Thereafter, her dysphagia improved during meals and while taking medicines. The patient was discharged 5 months after the heart transplantation. No ulcer recurrence has been observed for 10 months since her discharge.\n\nWe obtained written consent from the patient for publication of this case. Ethics committee approval is not included, as it is accepted in our hospital that case reports do not require such approval. In this work, we did not use patient data that would allow identifying her.\n\n3 Discussion\nIn this report, we present a case of a potassium chloride-induced esophageal ulcer. This case is clinically important because the ulcer was clearly caused by esophageal compression due to LA enlargement. An esophageal stricture developed after the ulcer healed following discontinuation of the drug, but was successfully treated with endoscopic balloon dilation after heart transplantation.\n\nDIEIs are caused by various factors related to drug properties, anatomy, and patient lifestyle.[3] Among them, the chemical structure and pharmaceutical forms of drugs are the most significant factors.[3] Oral administration of tablets or capsules have great advantages in ingestion and transportability compared with liquid preparations. However, these forms have disadvantages of increased local concentration of active pharmaceutical ingredients that injure susceptible tissues, particularly the esophagus, compared with liquid preparations.[1] Capsule forms of medicines such as doxycycline, tetracycline, and clindamycin can adhere to the esophagus and cause more serious injuries than the tablet forms.[3] Large pills such as those for clarithromycin, alendronate, and ibuprofen and sustained-release formulations of drugs such as ferrous sulfate and potassium chloride may be more commonly retained in the esophagus and more injurious than the standard preparations of the same medicines.[1,2]\n\nAlthough LA enlargement may be a risk factor for DIEIs, it has rarely been demonstrated to cause DIEIs thus far. To our knowledge, there was only one report in 1979 about esophageal ulceration due to slow-release potassium in the presence of LA enlargement.[5] In another report, patients with mitral valve disease were found to have delayed esophageal transit of capsules because of the anatomical deformity caused by LA enlargement[6]; in the study, the LA dimensions of the study patients were 22 to 79 mm (mean, 45 mm), while those of the control patients were 21 to 35 mm (mean, 28 mm). In our current case, the LA dimension of the patient was 55 mm, which was large enough to compress the esophagus. However, these previous reports lacked sufficient evidence to demonstrate that the LA enlargement caused the DIEIs. As such, our case is important, because the clinical course verified the causal relationship between the drug-induced esophageal ulcer and anatomical deformities using multiple imaging modalities.\n\nThe efficacy of the anatomical approach to prevent DIEIs has rarely been reported and discussed in detail. Treatments for esophageal stricture without releasing the compression from the dilated heart might be ineffective and result in ulcer recurrence. Partial resection of the inferior and/or superior LA wall at the time of surgery for the mitral valve is a common method for treatment of the giant LA.[7,8] This surgery achieved significant reduction in the LA volume, but is not strongly recommended for patients with poor cardiac function, like our patient, because of the high operative mortality of 8% to 23% caused by low-cardiac-output syndrome and respiratory failure.[8] Furthermore, it was difficult to control end-stage chronic heart failure with partial resection and medication. However, over the last decade, heart transplantation has been increasingly performed worldwide.[9] A previous case of a patient with a giant LA who received heart transplantation was reported in 2014,[10] but the efficacy of the transplantation against esophageal compression after the operation was not assessed. In our case, heart transplantation resolved the cardiomegaly as a fundamental cause of anatomical deformities. Considering that no ulcer recurrence was reported during follow-up, the heart transplantation was also beneficial for preventing DIEIs.\n\nThe important patient-related risk factors of DIEIs are the amount of fluid ingested with medicines and disability of the patient.[3] Pills are more likely to stick to the esophageal walls if swallowed with insufficient water and in the supine position.[2,3] Patients suffering from chronic heart failure are often restricted in terms of water consumption and their activities. Insufficient water consumption, taking drugs in a recumbent position, and bed rest further cause DIEIs. Additionally, patients with ischemic heart disease often take aspirin, which can cause severe esophageal ulceration and is associated with bleeding.[1,2] Therefore, clinicians should pay attention to not only anatomical changes in the esophagus but also other risk factors of DIEIs associated with cardiac disease in order to prevent DIEIs, especially in patients with LA enlargement. As most patients are orally administered medicines without the knowledge of the risk of DIEIs, clinicians should instruct them how to take the medicines, if necessary; restrict their drug dosages; and exchange pharmaceutical forms for safer ones.\n\nThere are some limitations to this case report. First, retained potassium chloride was thought to be responsible for the ulcer formation from upper gastrointestinal series and CT findings, but the component was not actually identified by endoscopy. Next, our diagnosis was based on the improvement of the ulcer by withdrawal of potassium chloride. DIEI is basically a diagnosis of exclusion, and the causality was difficult to prove.\n\nIn summary, we presented a case of a drug-induced esophageal ulcer caused by esophageal compression due to LA enlargement. For patients with LA enlargement, preventive care and treatment measures for DIEIs, including the anatomical approach, should be considered.\n\nAuthor contributions\nData curation: Kazuki Maesaka, Shunsuke Yoshii, Kei Nakamoto.\n\nInvestigation: Kazuki Maesaka.\n\nResources: Shunsuke Yoshii, Kei Nakamoto.\n\nSupervision: Shinichiro Shinzaki, Yasushi Sakata, Tetsuo Takehara.\n\nValidation: Yoshiki Tsujii.\n\nWriting – original draft: Kazuki Maesaka, Yoshiki Tsujii.\n\nWriting – review & editing: Shinichiro Shinzaki, Yoshito Hayashi, Hideki Iijima, Tomohito Ohtani, Yasushi Sakata, Tetsuo Takehara.\n\nAbbreviations: Ao = aorta, DIEIs = drug-induced esophageal injuries, LA = left atrium.\n\nPatient consent: We obtained written consent from the patient for publication of this case.\n\nEthics committee approval is not included, as it is accepted in our hospital that case reports do not require such approval.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Abid S Mumtaz K Jafri W \nPill-induced esophageal injury: endoscopic features and clinical outcomes . Endoscopy \n2005 ;37 :740–4 .16032493 \n[2] Kikendall JW \nPill esophagitis . J Clin Gastroenterol \n1999 ;28 :298–305 .10372925 \n[3] Dağ MS Öztürk ZA Akin I \nDrug-induced esophageal ulcers: case series and the review of the literature . Turk J Gastroenterol \n2014 ;25 :180–4 .25003679 \n[4] Kim SH Jeong JB Kim JW \nClinical and endoscopic characteristics of drug-induced esophagitis . World J Gastroenterol \n2014 ;20 :10994–9 .25152603 \n[5] Lubbe WF Cadogan ES Kannemeyer AH \nOesophageal ulceration due to slow-release potassium in the presence of left atrial enlargement . N Z Med J \n1979 ;90 :377–9 .160516 \n[6] Channer KS Bell J Virjee JP \nEffect of left atrial size on the oesophageal transit of capsules . Br Heart J \n1984 ;52 :223–7 .6234911 \n[7] Flores Umanzor EJ Mimbrero M San Antonio R \nGiant left atrium as a rare cause of dysphagia . Am J Med \n2016 ;129 :e335–6 .27591178 \n[8] Apostolakis E Shuhaiber JH \nThe surgical management of giant left atrium . Eur J Cardiothorac Surg \n2008 ;33 :182–90 .18096399 \n[9] Stehlik J Kobashigawa J Hunt SA \nHonoring 50 years of clinical heart transplantation in circulation: In-depth state-of-the-art review . Circulation \n2018 ;137 :71–87 .29279339 \n[10] Boldyrev SY Lepshokov MK Yakuba II \nA patient with giant left atrium undergoes orthotopic heart transplantation . Tex Heart Inst J \n2014 ;41 :87–90 .24512411\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "97(48)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D015906:Angioplasty, Balloon, Coronary; D004935:Esophageal Diseases; D004940:Esophageal Stenosis; D005260:Female; D006325:Heart Atria; D006333:Heart Failure; D006801:Humans; D017379:Hypertrophy, Left Ventricular; D011189:Potassium Chloride; D054328:Proton Pump Inhibitors; D014057:Tomography, X-Ray Computed; D014456:Ulcer",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e13380",
"pmc": null,
"pmid": "30508933",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of drug-induced esophageal ulcer in a patient with chronic heart failure: A case report.",
"title_normalized": "successful treatment of drug induced esophageal ulcer in a patient with chronic heart failure a case report"
} | [
{
"companynumb": "AU-PFIZER INC-2019013540",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "POTASSIUM CHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nDiuretics are a commonly used for the treatment of acute pulmonary edema. However, inappropriate administration of diuretic drugs can result in clinical treatment failure and cause acute pulmonary edema. This is due to rapid decreases in intravascular volume as a result of diuretic treatment. To date, the clinical phenomenon of inappropriate use of diuretics leading to acute pulmonary edema remains unexplored and unrecognized. Here, we report the first case of this problem-pulmonary edema following diuretic therapy.\nA 71-year-old male patient who was intubated and transferred to the intensive care unit (ICU) due to respiratory failure was initially diagnosed with pneumonia as a complication of acute respiratory distress syndrome (ARDS). After treatments including antibiotics, lung protective ventilation strategies, and restrictive fluid management, his respiratory symptoms improved. However, the patient's dyspnea became more severe after experimental diuretic therapy.\n\n\nMETHODS\nA point-of-care ultrasound (POCUS) examination showed increased extravascular lung water retention during a hypovolemic state. After full examinations and analysis, the diagnosis of acute pulmonary edema was determined.\n\n\nMETHODS\nThe most likely cause of acute pulmonary edema was left ventricular (LV) hyperdynamic status due to a hypovolemic status caused by excessive diuretic therapy. Consequently, we administrated intravenous fluids and a β-receptor blocker to the patient.\n\n\nRESULTS\nFollowing these treatment, the patient's respiratory distress improved remarkably.\n\n\nCONCLUSIONS\nWe report the first case of pulmonary edema following diuretic therapy to stress the need of physicians to follow guidelines of clinical practice. Maintaining an appropriate volume status and treatment of β-receptor blockers is the key to reversing the progress of this adverse effect. In this process, POCUS is a reliable diagnostic tool to identify the cause of acute pulmonary edema and can increase the accuracy of clinical evaluations. It is likely that a wider use of POCUS will help physicians to obtain a faster, and more accurate, diagnosis of the etiology of acute pulmonary edema, thus allowing a more appropriate therapy.",
"affiliations": "Department of Intensive Care Unit (ICU), The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei.;Department of Intensive Care Unit (ICU), The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei.;Department of Intensive Care Unit (ICU), The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei.;Department of Intensive Care Unit (ICU), The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei.;Department of Intensive Care Unit (ICU), The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei.;Department of Intensive Care Unit (ICU), The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei.;Department of Intensive Care Unit (ICU), Peking Union Medical College Hospital.;Department of Intensive Care Unit (ICU), The First Affiliated Hospital of Tsinghua University, Beijing, P.R. China.;Department of Intensive Care Unit (ICU), The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei.",
"authors": "Liu|Lixia|L|;Zhang|Qian|Q|;Zhang|Tao|T|;Wu|Xinhui|X|;Sun|Lixiao|L|;Li|Bin|B|;Wang|Xiaoting|X|;Chao|Yangong|Y|;Hu|Zhenjie|Z|",
"chemical_list": "D004232:Diuretics",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000019180",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\nMD-D-19-03477\n10.1097/MD.0000000000019180\n19180\n3900\nResearch Article\nClinical Case Report\nPulmonary edema following diuretic therapy\nA case reportLiu Lixia MD, PhDa Zhang Qian MDa Zhang Tao MDa Wu Xinhui MD, PhDa Sun Lixiao MDa Li Bin MDa Wang Xiaoting MD, PhDb Chao Yangong MD, PhDc Hu Zhenjie MD, PhDa∗ NA. a Department of Intensive Care Unit (ICU), The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei\nb Department of Intensive Care Unit (ICU), Peking Union Medical College Hospital\nc Department of Intensive Care Unit (ICU), The First Affiliated Hospital of Tsinghua University, Beijing, P.R. China.\n∗ Correspondence: Zhenjie Hu, Department of Intensive Care Unit (ICU), The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, P.R. China (e-mail: huzhenjie0101@sina.com).\n2 2020 \n21 2 2020 \n99 8 e191804 5 2019 4 12 2019 14 1 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Supplemental Digital Content is available in the text\n\nAbstract\nIntroduction:\nDiuretics are a commonly used for the treatment of acute pulmonary edema. However, inappropriate administration of diuretic drugs can result in clinical treatment failure and cause acute pulmonary edema. This is due to rapid decreases in intravascular volume as a result of diuretic treatment. To date, the clinical phenomenon of inappropriate use of diuretics leading to acute pulmonary edema remains unexplored and unrecognized. Here, we report the first case of this problem—pulmonary edema following diuretic therapy.\n\nPatient concerns:\nA 71-year-old male patient who was intubated and transferred to the intensive care unit (ICU) due to respiratory failure was initially diagnosed with pneumonia as a complication of acute respiratory distress syndrome (ARDS). After treatments including antibiotics, lung protective ventilation strategies, and restrictive fluid management, his respiratory symptoms improved. However, the patient's dyspnea became more severe after experimental diuretic therapy.\n\nDiagnosis:\nA point-of-care ultrasound (POCUS) examination showed increased extravascular lung water retention during a hypovolemic state. After full examinations and analysis, the diagnosis of acute pulmonary edema was determined.\n\nInterventions:\nThe most likely cause of acute pulmonary edema was left ventricular (LV) hyperdynamic status due to a hypovolemic status caused by excessive diuretic therapy. Consequently, we administrated intravenous fluids and a β-receptor blocker to the patient.\n\nOutcomes:\nFollowing these treatment, the patient's respiratory distress improved remarkably.\n\nConclusion:\nWe report the first case of pulmonary edema following diuretic therapy to stress the need of physicians to follow guidelines of clinical practice. Maintaining an appropriate volume status and treatment of β-receptor blockers is the key to reversing the progress of this adverse effect. In this process, POCUS is a reliable diagnostic tool to identify the cause of acute pulmonary edema and can increase the accuracy of clinical evaluations. It is likely that a wider use of POCUS will help physicians to obtain a faster, and more accurate, diagnosis of the etiology of acute pulmonary edema, thus allowing a more appropriate therapy.\n\nKeywords\ndiureticpulmonary edemaultrasoundOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAcute pulmonary edema is a common complication in critically ill patients. The first 2 fundamentally different types of pulmonary edema which can occur in humans were reported as cardiogenic or non-cardiogenic pulmonary edema. Although they have distinct causes, it can be difficult to distinguish between the 2 due to their similar clinical manifestations, in particular when they develop simultaneously.[1] Diuresis is the most common method used for treating pulmonary edema. However, inappropriate administration of diuretics can result in clinical treatment failure in acute pulmonary edema when we exactly don’t know its mechanism. We report a case of a special case of pulmonary edema following diuretic therapy. This is a result of rapid intravascular volume depletion secondary to inappropriate diuretic therapy. Pulmonary edema following diuretic therapy can be life-threatening depending on the time taken to diagnose. In this case, point-of-care ultrasound (POCUS) played a critical role in identifying the etiology of acute pulmonary edema.\n\n2 Case presentation\nA 71-year-old man presented with subpleural tubercle on the right inferior lobe. Diagnosed as a non-small cell lung carcinoma, he underwent a lobectomy procedure. On the fifth postoperative day, the patient showed dyspnea. Upon examination, the patient had a heart rate of 122 beats/min, a respiratory rate of 30 breathes/min, and oxygen saturation of 86% to 90% on 10 L of oxygen via face mask. The patient was intubated and transferred to the ICU. He then received analgesia, sedation, and invasive mechanical ventilation. However, the patient remained in respiratory distress and his oxygen saturation sat at 84% while receiving 100% oxygen. A chest auscultation of the patient revealed rales bilaterally. A chest x-ray (CXR) showed bilateral diffuse and heterogeneous opacities (Fig. 1A). Once diagnosed with pneumonia causing the complication of acute respiratory distress syndrome (ARDS), the patient was treated with antibiotics, lung protective ventilation, and restrictive fluid management. His respiratory symptoms improved significantly within 1 week and the chest radiograph showed decreased pulmonary opacities (Fig. 1B). At this time, his cumulative fluid balance was negative 3050 mL.\n\nFigure 1 Imaging studies of chest x-ray and lung ultrasound. Chest x-ray showed bilateral diffuse and heterogeneous opacities on the first day of ICU admission (Panel A). Opacities diminished markedly within 1 week (Panel B) with bilateral A-line on the anterior chest (Panel C, left panel) and multiple B-line on the posterolateral chest wall (Panel C, right panel) evaluated by lung ultrasound examination. One day later, examination showed a marked increase of B lines bilaterally and a disappearance of A lines on the anterior chest (Panel D, left panel: upper point, right panel: lower point). After 24 hours of treatment, a repeated lung ultrasound revealed a marked decreased of B lines and A lines reappeared on the anterior chest. (Panel E, left panel: upper point, right panel: lower point). (The A line: the horizontal lines arising from the pleural line are separated by regular intervals that are equal to the distance between the skin and the pleural line. The A-line indicates air. The B line: multiple vertical comet-tail artifacts arising from the pleural line are spreading to the edge of the screen without fading and moving with lung sliding. It reflects the coexistence of elements with a major acoustic impedance gradient, such as fluid and air. Several B lines indicate increasing pulmonary fluid.). ICU = intensive care unit.\n\nAfter the patient experienced a state of great emotion and restlessness, he became extremely short of breath. Upon examination, his respiratory rate was 28 breathes/min, oxygen saturation had declined to 91% on mechanical ventilation with FiO2 at 50%, and chest auscultation demonstrated bilateral rales as previously. The diagnosis of acute pulmonary edema was determined. The patient was then immediately administered 40 mg of furosemide intravenously. In the ensuing 8 hours, fluid balance was measured at negative 970 mL however, the patient continued display dyspnea and worsening hypoxemia. His respiratory rate was then measured at 34 breathes/min, heart rate at 132 beats/min, and oxygen saturation was at 90% on mechanical ventilation with FiO2 of 70% and positive end-expiratory pressure (PEEP) of 7 cmH2O. POCUS showed an inferior vena cava (IVC) diameter of 0.92 cm with inspiratory collapse (Fig. 2A, video in supplementary file 1). The left ventricular cavity was small (LV end-diastolic dimension = 33 mm) with hyperdynamic left ventricular contraction (LV ejection fraction = 76%). These findings suggested a hypovolemic status and low cardiac preload. Most notably, in systole, an aliasing of color flow doppler images was seen across the left ventricular outflow tract (Fig. 3A left panel, video in supplementary file 3) and the maximal pressure gradient was 29 mmHg, estimated by a continuous-wave doppler flow (Fig. 3B left panel), suggesting an increased resistance of LV ejection. Meanwhile, a paradoxical dynamic obstruction with a jet flow from the apex LV chamber to the basal in diastole was observed (Fig. 3C left panel, video in supplementary file 3), with an early diastolic mitral inflow velocity of 1.1 m/s and an early diastolic mitral annulus velocity at the lateral side of 0.07 m/s (E/e′ratio = 15.7), implying that there was underlying LV diastolic dysfunction.[2] Overall, this showed an elevated LV end-diastolic pressure and impaired LV filling. Accordingly, lung ultrasound evaluation showed increased B lines with a decrease of A lines in both lungs. All of this evidence demonstrated that extra vascular lung water increased despite a hypovolemic status after diuretic treatment (Fig. 1D).\n\nFigure 2 Inferior vena cava (IVC) diameter. IVC diameter was 0.92 cm with inspiratory collapse (Panel A). Video in Supplement 1. At post-treatment examination, IVC diameter increased to 2.1 cm (Panel B). Video in Supplement 2.\n\nFigure 3 Echocardiographic imaging studies before (left panel) and after treatment (right panel). In a small hyperdynamic LV cavity, an aliasing of color flow doppler images was found across LVOT (panel A, left panel) with a maximal pressure gradient of 29 mmHg estimated by a continuous-wave doppler (panel B, left panel) in systole, and a paradoxical dynamic obstruction with a jet flow from the apex LV chamber to the basal was recognized in diastole (panel C, left panel) (video in Supplement 3). At post-treatment, the LV cavity enlarged with a laminar LVOT blood flow in systole (Panel A, right panel) and a laminar LV cavity blood flow from base to apex in diastole (Panel C, right panel) (video in Supplement 4). Meanwhile, the LVOT pressure gradient decreased to 9.0 mmHg (Panel B, right panel) in systole. LV = left ventricular, LVOT = left ventricular outflow tract.\n\nConsidered as the cause of acute pulmonary edema, the left ventricular diastolic dysfunction was due to a hypovolemic state accompanied with hyperdynamic left ventricular contraction. The patient received intravenous fluid therapy (Ringer lactate) for volume expansion, β-receptor blocker (intravenous esmolol) to mitigate increased sympathetic activity, minimize vigorous left ventricular contraction and improve left ventricular diastolic dysfunction and sedation (propofol) to eliminate stress responses and deep spontaneous breath. After 24 hours, the patient's fluid balance was positive 1390 mL. Meanwhile, the patient was stabilized again, respiratory rate was at 20 breathes/min, heart rate at 98 beats/min, and oxygen saturation at 98% on mechanical ventilation on FiO2 of 40% and PS of 12 cmH2O with PEEP of 5 cmH2O. Repeat POCUS evaluation showed the LV cavity had enlarged and the IVC diameter had increased to 2.1 cm (Fig. 2B, video in supplementary file 2), with a laminar left ventricular outflow tract (LVOT) blood flow in systole (Fig. 3A right panel) and a laminar LV cavity blood flow from base to apex in diastole (Fig. 3C right panel, video in supplementary file 4). The LVOT pressure gradient decreased to 9.0 mmHg in systole (Fig. 3B right panel) and the LV E/e′ ratio decreased to 9. These characteristics indicated that the hypovolemic status was corrected and left ventricular systolic and diastolic function had improved. A lung ultrasound examination showed decreased B lines compared with 24 hours beforehand and A lines reappeared in both lungs, implying extravascular lung water had decreased remarkably (Fig. 1E).\n\n3 Discussion\nAcute pulmonary edema is a common complication in critically ill patients. It is caused by increased hydrostatic pressure and increased permeability of vessels.[1] In most cases, a restrictive fluid strategy in conjunction with diuretics remains the first line treatment of acute pulmonary edema. However, aggressive diuresis and rapid volume loss in the systemic circulation can lead to a series of complications.\n\nIn the present case, instead of reducing extravascular lung water then led to further deterioration of acute pulmonary edema. After comprehensive ultrasound examination, we considered that the cause lied in the mechanism that the heart and the lung only can work harder to increase oxygen delivery due to the hypovolemic status. Clinically, this manifests as hyperdynamic status of LV and deep and quick breaths.\n\nThe low cardiac preload due to the rapid volume loss resulted in hyperdynamic LV contraction. This leads to increased resistance of LV ejection during systole and difficulty with LV filling during diastole. The increased LV end-diastolic pressure and left atrial pressure were then transmitted to the pulmonary capillaries to increase pulmonary capillary hydrostatic pressure which pushed fluid out of the vessels and aggravated the hydrostatic pulmonary edema, which ultimately deteriorated the patient's pulmonary edema. Although the pulmonary arterial wedge pressure, estimated from E/e′, was not high enough to induce hydrostatic pulmonary edema, the effect of the hydrostatic pressure on the pulmonary edema may be amplified by high alveolar capillary permeability under certain conditions, such as pneumonia and ARDS. Fifty years ago, ARDS was first described as a form of respiratory failure in infants.[3] This syndrome is characterized by an acute, diffuse, inflammatory lung injury, leading to increased alveolar capillary permeability. Eventually, the patient experienced exacerbated pulmonary edema and respiratory distress which triggered negative pressure pulmonary edema which attributed to the marked negative intrapleural pressure.[4–6]\n\nDeep and quick breaths caused by pulmonary edema result in decreased thoracic pressure even into negative values, which will worsen hydrostatic pulmonary edema by increasing pulmonary capillary hydrostatic pressure. Firstly, the negative thoracic pressure increases right ventricular (RV) output by drawing more venous blood return to the RV[4,6,7] and decreases LV output by elevating LV transmural pressure, contributing to the LV afterload increasing.[8] Together, these 2 elements lead to increased pulmonary capillary hydrostatic pressure. Secondly, the negative thoracic pressure further increases trans-pulmonary capillary pressure. The combination of these elements in this patient resulted in increasing the severity of the hydrostatic pulmonary edema. Negative thoracic pressure also aggravates pulmonary permeability edema by increasing transpulmonary pressure which further exacerbates lung injury.\n\nOverall, pulmonary edema became more severe even in the volume depleted status. The patient improved remarkably after administration of fluids and β-receptor blockers. Although diuretics, vasodilators and inotropic agents are commonly used in clinical practice for the treatment of acute pulmonary edema, preliminary examinations with regard to pulmonary edema following diuretic therapy may guide us to better manage patients and avoid incorrect treatment. Hence, we first identify this type of acute pulmonary edema (Fig. 4). Maintaining an appropriate volume status and treatment with β-receptor blockers is the key to reversing the progress of pulmonary edema following diuretic therapy.\n\nFigure 4 Mechanism of pulmonary edema following diuretic therapy.\n\nIn addition, POCUS is an evolving tool in both emergency and critical care medicine. Using POCUS, clinicians can rapidly evaluate critically ill patients in real time rather than waiting for the availability of advanced imaging or invasive diagnostic procedures. In this context, a rapid bedside method to identify the cause of acute pulmonary edema could speed up the diagnosis, thus favoring early and appropriate therapeutic interventions. POCUS is effective in accurate diagnosis of pulmonary edema following diuretic therapy.\n\n4 Conclusion\nPulmonary edema following diuretic therapy is a potentially life-threatening and under-recognized entity. A clear understanding of the mechanisms causing this may avoid incorrect treatment and help guide clinical practice. POCUS evaluation is invaluable for accurate identification and diagnosis of this type of pulmonary edema.\n\nAuthor contributions\nInvestigation: Xinhui Wu.\n\nSoftware: Tao Zhang, Bin Li.\n\nSupervision: Zhenjie Hu.\n\nVisualization: Lixiao Sun.\n\nWriting – original draft: Lixia Liu, Qian Zhang.\n\nWriting – review & editing: Xiaoting Wang, Yangong Chao.\n\nSupplementary Material\nSupplemental Digital Content\n Supplementary Material\nSupplemental Digital Content\n Supplementary Material\nSupplemental Digital Content\n Supplementary Material\nSupplemental Digital Content\n Abbreviations: ARDS = acute respiratory distress syndrome, CXR = chest x-ray, e′ = early diastolic mitral annulus velocity, E = early diastolic mitral inflow velocity, FiO2 = fraction of inspired oxygen, ICU = intensive care unit, IVC = inferior vena cava, LV = left ventricular, LVOT = left ventricular outflow tract, PEEP = positive end-expiratory pressure, POCUS = point-of-care ultrasound, PS = pressure support, RV = right ventricular.\n\nHow to cite this article: Liu L, Zhang Q, Zhang T, Wu X, Sun L, Li B, Wang X, Chao Y, Hu Z. Pulmonary edema following diuretic therapy: A case report. Medicine. 2020;99:8(e19180).\n\nLL and QZ have contributed equally to the manuscript.\n\nLL, QZ, TZ, XW, and YC are on behalf of Chinese Critical Ultrasound Study Group (CCUSG).\n\nInformed written consent was obtained from the patient for publication of this case report and accompanying images.\n\nEthics approval and consent to participate: not applicable.\n\nFunding: No funding.\n\nThe authors have no conflicts of interest to disclose.\n\nSupplemental Digital Content is available for this article.\n==== Refs\nReferences\n[1] Ware LB Matthay MA \nClinical practice. Acute pulmonary edema\n. N Engl J Med \n2005 ;353 :2788 –96\n.16382065 \n[2] de Gregorio C Andò G Pugliatti P \nProgression rates of apical aneurysm and dynamic obstruction in mid-ventricular hypertrophic cardiomyopathy: can we recognize a ’benign trend’?\n\nInt J Cardiol \n2015 ;182 :491 –3\n.25617607 \n[3] Ashbaugh DG Bigelow DB Petty TL \nAcute respiratory distress in adults\n. Lancet \n1967 ;2 :319 –23\n.4143721 \n[4] Lemyze M Mallat J \nUnderstanding negative pressure pulmonary edema\n. Intensive Care Med \n2014 ;40 :1140 –3\n.24797685 \n[5] Deepika K Kenaan CA Barrocas AM \nNegative pressure pulmonary edema after acute upper airway obstruction\n. J Clin Anesth \n1997 ;9 :403 –8\n.9257208 \n[6] Lang SA Duncan PG Shephard DA \nPulmonary oedema associated with airway obstruction\n. Can J Anaesth \n1990 ;37 :210 –8\n.2178789 \n[7] Guffin TN Har-el G Sanders A \nAcute postobstructive pulmonary edema\n. Otolaryngol Head Neck Surg \n1995 ;112 :235 –7\n.7838544 \n[8] Buda AJ Pinsky MR Ingels NB \nEffect of intrathoracic pressure on left ventricular performance\n. N Engl J Med \n1979 ;301 :453 –9\n.460363\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "99(8)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D004232:Diuretics; D015633:Extravascular Lung Water; D006801:Humans; D008297:Male; D011654:Pulmonary Edema",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e19180",
"pmc": null,
"pmid": "32080100",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pulmonary edema following diuretic therapy: A case report.",
"title_normalized": "pulmonary edema following diuretic therapy a case report"
} | [
{
"companynumb": "CN-VALIDUS PHARMACEUTICALS LLC-CN-2020VAL000208",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadd... |
{
"abstract": "To report the diagnostic and treatment challenges of sighted non-24-hour sleep-wake disorder (N24SWD).\n\n\n\nWe report a series of seven sighted patients with N24SWD clinically evaluated by history and sleep diaries, and when available wrist actigraphy and salivary melatonin levels, and treated with timed melatonin and bright light therapy.\n\n\n\nMost patients had a history of a delayed sleep-wake pattern prior to developing N24SWD. The typical sleep-wake pattern of N24SWD was seen in the sleep diaries (and in actigraphy when available) in all patients with a daily delay in midpoint of sleep ranging 0.8 to 1.8 hours. Salivary dim light melatonin onset (DLMO) was evaluated in four patients but was missed in one. The estimated phase angle from DLMO to sleep onset ranged from 5.25 to 9 hours. All six patients who attempted timed melatonin and bright light therapy were able to entrain their sleep-wake schedules. Entrainment occurred at a late circadian phase, possibly related to the late timing of melatonin administration, though the patients often preferred late sleep times. Most did not continue treatment and continued to have a non-24-hour sleep-wake pattern.\n\n\n\nN24SWD is a chronic debilitating disorder that is often overlooked in sighted people and can be challenging to diagnose and treat. Tools to assess circadian pattern and timing can be effectively applied to aid the diagnosis. The progressive delay of the circadian rhythm poses a challenge for determining the most effective timing for melatonin and bright light therapies. Furthermore, once the circadian sleep-wake rhythm is entrained, long-term effectiveness is limited because of the behavioral and environmental structure that is required to maintain stable entrainment.",
"affiliations": "Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.;Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.;Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.;Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.",
"authors": "Malkani|Roneil G|RG|;Abbott|Sabra M|SM|;Reid|Kathryn J|KJ|;Zee|Phyllis C|PC|",
"chemical_list": "D008550:Melatonin",
"country": "United States",
"delete": false,
"doi": "10.5664/jcsm.7054",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1550-9389",
"issue": "14(4)",
"journal": "Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine",
"keywords": "bright light; circadian rhythm; delayed sleep-wake phase disorder; melatonin; non–24-hour sleep-wake disorder",
"medline_ta": "J Clin Sleep Med",
"mesh_terms": "D056044:Actigraphy; D000293:Adolescent; D000328:Adult; D000078646:Diaries as Topic; D005260:Female; D006801:Humans; D008297:Male; D008550:Melatonin; D008875:Middle Aged; D010789:Phototherapy; D012463:Saliva; D012890:Sleep; D012893:Sleep Wake Disorders; D055815:Young Adult",
"nlm_unique_id": "101231977",
"other_id": null,
"pages": "603-613",
"pmc": null,
"pmid": "29609703",
"pubdate": "2018-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9225375;16687322;10450596;10381883;21188265;18227513;16393710;15649737;11058797;16024905;25477861;28008257;16263827;14582858;12796546;10636163;15749169;10607943;26847016;21594679;21344043;16295212;8059933;24179293;11833864;1537759;22445311;1619000;20410229;26414986;11027741;18006583;5548010;16218077;26973592;9493716;28229310;22846439;8899933;24916394;17684566;17060154;12717008;16120097;3726555;20876818;9141150;12069043",
"title": "Diagnostic and Treatment Challenges of Sighted Non-24-Hour Sleep-Wake Disorder.",
"title_normalized": "diagnostic and treatment challenges of sighted non 24 hour sleep wake disorder"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/18/0101728",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ZOLPIDEM\\ZOLPIDEM TARTRATE"
},
"drugadd... |
{
"abstract": "Kimura disease (KD) is an eosinophilic, granulomatous, benign, chronic inflammatory disease with an unknown etiology. A 33-year-old woman visited our hospital because of a palpable, left subclavian mass, a left scapulo-anterior pseudoaneurysm, and nephrotic syndrome. Her subclavian lymph node biopsy examination result was consistent with KD, and results of a renal biopsy indicated secondary membranous nephropathy. After renal histological examination confirmed nephropathy, treatment with prednisolone and cyclosporine was initiated, which was maintained for over 1 year. However, this therapy only provided a transient improvement in proteinuria. One year after commencing the treatment, both proteinuria and azotemia aggravated as the left axillary mass doubled in size. Finally, the mass was surgically excised, following which the azotemia rapidly normalized and proteinuria resolved within 1 month. This case shows that tumor resection in a patient with KD with secondary nephropathy may resolve secondary renal manifestations. Furthermore, reversible renal dysfunction may be caused by unknown secreted molecules.",
"affiliations": "Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.;Department of Thoracic Surgery, Seoul National University Hospital, Seoul, Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.",
"authors": "Lee|Sunhwa|S|;Yi|Yong Jin|YJ|;Ah Jo|Hyung|H|;Huh|Hyuk|H|;Kim|Kyung-Hwan|KH|;Ki Kim|Dong|D|;Lee|Hajeong|H|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.1016/j.krcp.2014.06.002",
"fulltext": "\n==== Front\nKidney Res Clin PractKidney Res Clin PractKidney Research and Clinical Practice2211-91322211-9140Elsevier S2211-9132(14)00079-510.1016/j.krcp.2014.06.002Case ReportRemission of secondary membranous nephropathy in a patient with Kimura disease after surgical resection Lee Sunhwa 1Yi Yong Jin 1Ah Jo Hyung 1Huh Hyuk 1Kim Kyung-Hwan 2Ki Kim Dong 1Lee Hajeong dewyhj@hanmail.net1⁎1 Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea2 Department of Thoracic Surgery, Seoul National University Hospital, Seoul, Korea⁎ Corresponding author. Division of Nephrology, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110–744, Korea. dewyhj@hanmail.net23 8 2014 9 2014 23 8 2014 33 3 157 160 21 4 2014 16 6 2014 23 6 2014 © 2014. The Korean Society of Nephrology. Published by Elsevier.2014This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Kimura disease (KD) is an eosinophilic, granulomatous, benign, chronic inflammatory disease with an unknown etiology. A 33-year-old woman visited our hospital because of a palpable, left subclavian mass, a left scapulo-anterior pseudoaneurysm, and nephrotic syndrome. Her subclavian lymph node biopsy examination result was consistent with KD, and results of a renal biopsy indicated secondary membranous nephropathy. After renal histological examination confirmed nephropathy, treatment with prednisolone and cyclosporine was initiated, which was maintained for over 1 year. However, this therapy only provided a transient improvement in proteinuria. One year after commencing the treatment, both proteinuria and azotemia aggravated as the left axillary mass doubled in size. Finally, the mass was surgically excised, following which the azotemia rapidly normalized and proteinuria resolved within 1 month. This case shows that tumor resection in a patient with KD with secondary nephropathy may resolve secondary renal manifestations. Furthermore, reversible renal dysfunction may be caused by unknown secreted molecules.\n\nKeywords\nEosinophilic infiltrationKimura diseaseMembranous nephropathyOperative procedures\n==== Body\nIntroduction\nKimura disease (KD) presents as a subcutaneous mass, most frequently occurring in the head and neck regions. The disease is characterized by a benign, angiolymphomatous proliferation with eosinophilic infiltration. The histological characteristics of the disease are hyperplastic lymphoid tissue that contains well-developed lymphoid follicles, marked infiltration of eosinophils, vascular proliferation, and fibrosis. It is also associated with the development of renal disease, especially nephrotic syndrome [1]. Previously, surgical resection was the treatment of choice. However, treatments with steroid and immunosuppressive agents were also reported to produce beneficial effects [2], although discontinuation of steroid often results in recurrence of the masses [3]. In patients with renal manifestations, however, surgical resection is usually not the first-choice treatment. We herein report the case of secondary membranous nephropathy (MN) associated with KD which recovered after surgical resection of the mass.\n\nCase report\nA 33-year-old woman presented with a soft-tissue mass in her left axillary area. A percutaneous biopsy was performed, and histological findings showed atypical lymphoid hyperplasia with many eosinophilic infiltrations, which are consistent with KD (Fig. 1). Neither proteinuria nor hypereosinophilia was noted. One-month treatment with oral prednisolone could not diminish size of the mass. One year after the diagnosis of KD, a 6-cm, left scapulo-anterior pseudoaneurysm was noted (Fig. 1), which required a stent-graft insertion. Following the graft insertion, the size of pseudoaneurysm decreased. Hypereosinophilia (12,450/mm3) was noted during this period. Treatment with prednisolone was continued for 1 year, and eosinophilia gradually improved to<500/mm3 within this period.\n\nOne and half year after the diagnosis of KD, the patient presented with a month-long history of foamy urine and a weight gain of 5 kg; pitting edema of both lower extremities was also observed.\n\nUpon admission, the patient’s blood pressure was 98/61 mmHg, white blood cell (WBC) count was 7,200/mm3 (with 33.8% eosinophils), and hemoglobin and platelet levels were 14.5 g/dL and 287,000/mm3, respectively. Serum blood urea nitrogen and creatinine levels were within the normal range, with a creatinine clearance rate of 120 mL/min/1.73 m2. Other laboratory assessments showed normal electrolyte, low serum albumin (1.3 g/dL), and high cholesterol (521 mg/dL) levels; complement proteins (C3 and C4) and immunoglobulins (Ig) A, G, and M were within normal limits. The patient’s virology profile was negative for hepatitis B and C, and her immunologic status was negative for anti-double-stranded DNA, antistreptococcal antibodies, cryoglobulins, and rheumatoid factor. Urinalysis was 4+ positive for protein, with five to six red blood cells and five to nine WBCs per high-power field. The random, spot urinary protein-to-creatinine ratio (uPCR) was 16.6 g/g, and urine protein electrophoresis showed nonspecific proteinuria.\n\nA light microscopic examination of renal biopsy specimens showed diffuse thickening of the capillary walls, focal, mild hypercellular mesangial cells, and normal-sized glomeruli. An electron microscopic examination revealed electron-dense deposits in some subepithelial areas and diffuse foot process effacement. An immunofluorescence microscopic examination revealed granular deposits of IgM, IgG, C3, and C1q in the mesangium (Fig. 2). Overall, the MN was diagnosed as Ehrenreich and Churg Stage III. Angiotensin receptor blocker or angiotensin-converting enzyme inhibitor was considered the first-choice treatment. However, the patient’s blood pressure was too low to add antihypertensive drugs to the treatment protocol. The proteinuria slowly resolved (from 16.6 g/g/d to 2.0 g/g/d) over a 6-month period upon treatment with cyclosporine (3.5 mg/kg/d) and prednisolone (dose tapered from 0.5 mg/kg/d to 0.17 mg/kg/d within 6 months). However, 1.5 years from the onset of nephrotic syndrome, the patient’s random uPCR and serum creatinine level increased to 31.0 g/g and 2.11 mg/dL, respectively. Fractional sodium excretion was calculated to be 1.23%. Moreover, at the same time, the left subclavian mass had enlarged from an initial 5.8 cm×3.6 cm to 7.2 cm×7.2 cm, causing occlusion of the left axillary artery. Therefore, surgical resection was necessary, and pathological reports of the excised specimen were consistent with KD.\n\nFortunately, after the mass excision, the azotemia normalized from a serum creatinine level of 2.11 mg/dL to 1.11 mg/dL, and proteinuria resolved from a random uPCR of 31.0 g/g to 6.9 g/g within 1 month. After 3 months of follow up, the patient’s serum creatinine level was 0.68 mg/dL, and the random uPCR was 2.78 g/g (Fig. 3).\n\nDiscussion\nKD often follows a benign, chronic course but does not generally resolve spontaneously and shows frequent relapses. Although most patients do not have systemic symptoms, 12–16% of these patients have nephropathy that often presents as nephrotic syndrome [2].\n\nAlthough the pathogenesis of renal involvement and vasculitis in KD is unclear, several immunopathogenetic features have been suggested. Katagiri et al [4] showed that elevated tumor necrosis factor-α, interleukin (IL)-4, IL-5, and IL-13 are found in the peripheral blood cells of KD patients, as well as in the lesion tissue. This observation supports the fact that T-helper 2 (Th2) cytokines play a part in the development of KD [5]. In addition, Lu et al [6] reported a case of KD secondary to chronic renal graft failure. Because chronic graft rejection is considered to be induced by Th2 cell-produced ILs, Th2 cytokines and overgrowth of the CD4+ Th2 may play an important role in KD.\n\nMany treatment methods were proposed for KD, including corticosteroid, cyclosporine, surgical excision, and radiotherapy (RT). Corticosteroids were reported to be effective in controlling KD. This implies that T-cell- mediated pathogenesis maybe involved in KD since corticosteroids are known to regulate T-cell proliferation and lymphokine production. However, recurrence upon termination of steroid therapy was reported in 15–40% of the patients. Recent reports suggest that immunosuppressants such as cyclosporine and vincristine reduce recurrence rate [7], [8]. Katagiri et al [4] reported on the effectiveness of cyclosporine (4 mg/kg/d for 3 months followed by 3.5 mg/kg/d for 6 months) in treating KD. A previous study showed that RT is more effective than local excision and steroid therapy for the treatment of KD. With the 65-month median follow-up duration, local control was achieved in nine (64.3%) of the 14 patients in the RT group and in two (22.2%) of the nine patients in the non-RT group [9].\n\nFor local mass control, surgery is often recommended as the first-choice treatment [10]. However, the role of surgical resection in controlling renal manifestations in patients with KD has not yet been clarified. This case showed that surgical resection resulted in reversal of not only azotemia but also proteinuria. A similar reversal case was reported previously with regard to Castleman’s disease. A patient with a mixed type of localized Castleman’s disease complicated with nephrotic syndrome underwent removal of two mesenteric lymphoid masses. After the surgical resection, the proteinuria gradually decreased and disappeared [11]. In patients with Castleman’s disease having renal complications, immunosuppressants such as prednisolone and azathioprine are often used [12], similar to the treatment for KD. However, surgical resection is helpful to reverse the renal function.\n\nBoth KD and Castleman’s disease cases imply that some unknown circulating mediators secreted by the primary tumor may cause renal dysfunction. It has long been postulated that some circulating humoral factors might cause proteinuria in minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS) [13]. A T-cell-derived humoral factor might induce damages to the glomerular permeability barrier in MCNS. Hemopexin is one of the proposed molecules, which can cause proteinuria and glomerular alterations characteristic of MCNS [14]. In cases with FSGS, post-transplant recurrence of proteinuria and its response to plasmapheresis suggest the role of some plasma factors. Soluble urokinase receptor is detected in the plasma of patients with recurrent FSGS, and this can induce foot process effacement, proteinuria, and FSGS-like glomerulopathy [15].\n\nIn our patient, surgical mass reduction induced reversal of not only proteinuria but also the serum creatinine level. Although the patient’s serum creatinine level gradually increased over a 2-year period, the estimated glomerular filtration rate was fully normalized after surgical mass reduction. This suggests that renal dysfunction in this patient is possibly caused by a reversible mechanism. We can postulate that unknown circulating factors secreted by the angiolymphoid hyperplastic mass persistently restrict glomerular filtration possibly without evident chronic damage. Because proteinuria slowly improved compared with the serum creatinine level, some humoral factors might have induced structural change to the glomerular permeability barrier so that it took more time to recover.\n\nWe described the first official case of secondary MN in a KD patient in Korea. Moreover, renal complications in this patient were nearly normalized after surgical mass reduction. This suggests that surgical resection could be preferentially be considered prior to medical treatment in KD patients with renal complications.\n\nConflict of interest\nAll contributing authors declare no conflict of interest.\n\nFigure 1 Left subclavian mass consistent with Kimura disease. (A) A left scapulo-anterior pseudoaneurysm in the left axillary area (arrow). Light microscopic images of hematoxylin and eosin–stained sections of the subclavian lymph node biopsy specimen show (B) a well-developed lymphoid follicle with eosinophilic infiltration and (C) vascular proliferation (200×).\n\nFigure 2 Renal biopsy specimens diagnosed with membranous nephropathy. (A) Light microscopic image of a biopsy specimen shows hypercellular mesangial cells (Hematoxylin and eosin-stained, 200×). (B) An electron microscopic image of a similar specimen reveals electron-dense deposits in some subepithelial areas and diffuse foot process effacement (20,000×). Using immunofluorescence microscopy, granular deposits of (C) IgG, 3+, (D) IgM, 2+, (E) C3, 3+, and (F) C1q, 1+ were detected in the mesangium (400×). Ig, immunoglobulin.\n\nFigure 3 Serum creatinine and random urinary protein-to-creatinine ratio (uPCR) over time. Initial treatment with cyclosporine and prednisolone (Pd) resulted in transient proteinuria improvement. However, surgical resection of the left subclavian mass was followed by recovery of renal function. The solid line represents serum creatinine levels (mg/dL), whereas the dashed line represents the random uPCR (g/g). KD, Kimura disease.\n==== Refs\nReferences\n1 Chen H Thompson LD Aguilera NS Abbondanzo SL Kimura disease: a clinicopathologic study of 21 cases Am J Surg Pathol 28 2004 505 513 15087670 \n2 Matsuda O Makiguchi K Ishibashi K Chida Y Ida T Matsuda K Tomita K Marumo F Hiruma M Long-term effects of steroid treatment on nephrotic syndrome associated with Kimura’s disease and a review of the literature Clin Nephrol 37 1992 119 123 1563115 \n3 Rajpoot DK Pahl M Clark J Nephrotic syndrome associated with Kimura disease Pediatr Nephrol 14 2000 486 488 10872190 \n4 Katagiri K Itami S Hatano Y Yamaguchi T Takayasu S In vivo expression of IL‐4, IL‐5, IL‐13 and IFN‐γ mRNAs in peripheral blood mononuclear cells and effect of cyclosporin A in a patient with Kimura’s disease Br J Dermatol 137 1997 972 977 9470918 \n5 Enokihara H Koike T Arimura H Aoyagi M Watanabe K Nakamura Y Yamashiro K Tsuruoka N Tsujimoto M Saito K IL-5 mRNA expression in blood lymphocytes from patients with Kimura’s disease and parasite infection Am J Hematol 47 1994 69 73 8092143 \n6 Lu HJ Tsai JD Sheu JC Tzen CY Tsai TC Lin CC Huang FY Kimura disease in a patient with renal allograft failure secondary to chronic rejection Pediatr Nephrol 18 2003 1069 1072 12883971 \n7 Connelly A Powell HR Chan YF Fuller D Taylor RG Vincristine treatment of nephrotic syndrome complicated by Kimura disease Pediatr Nephrol 20 2005 516 518 15690191 \n8 Sato S Kawashima H Kuboshima S Watanabe K Kashiwagi Y Takekuma K Hoshika A Combined treatment of steroids and cyclosporine in Kimura disease Pediatrics 118 2006 e921 e923 16908621 \n9 Chang AR Kim K Kim HJ Kim IH Park CI Jun YK Outcomes of Kimura’s disease after radiotherapy or nonradiotherapeutic treatment modalities Int J Radiat Oncol Biol Phys 65 2006 1233 1239 16750313 \n10 Day TA Abreo F Hoajsoe DK Aarstad RF Stucker FJ Treatment of Kimura’s disease: a therapeutic enigma Otolaryngol Head Neck Surg 112 1995 333 337 7838560 \n11 Keven K Nergizoğlu G Ateş K Erekul S Orhan D Ertürk Ş Tulunay Ö Karatan O Ertuğ AE Remission of nephrotic syndrome after removal of localized Castleman’s disease Am J Kidney Dis 35 2000 1207 1211 10845836 \n12 Chan TM Cheng IK Wong KL Chan KW Resolution of membranoproliferative glomerulonephritis complicating angiofollicular lymph node hyperplasia (Castleman’s disease) Nephron 65 1993 628 632 8302422 \n13 McCarthy ET Sharma M Savin VJ Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis Clin J Am Soc Nephrol 5 2010 2115 2121 20966123 \n14 Lennon R Singh A Welsh GI Coward RJ Satchell S Ni L Mathieson PW Bakker WW Saleem MA Hemopexin induces nephrin-dependent reorganization of the actin cytoskeleton in podocytes J Am Soc Nephrol 19 2008 2140 2149 18753258 \n15 Wei C El Hindi S Li J Fornoni A Goes N Sageshima J Maiguel D Karumanchi SA Yap HK Saleem M Zhang Q Nikolic B Chaudhuri A Daftarian P Salido E Torres A Salifu M Sarwal MM Schaefer F Morath C Schwenger V Zeier M Gupta V Roth D Rastaldi MP Burke G Ruiz P Reiser J Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis Nat Med 17 2011 952 960 21804539\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2211-9132",
"issue": "33(3)",
"journal": "Kidney research and clinical practice",
"keywords": "Eosinophilic infiltration; Kimura disease; Membranous nephropathy; Operative procedures",
"medline_ta": "Kidney Res Clin Pract",
"mesh_terms": null,
"nlm_unique_id": "101586778",
"other_id": null,
"pages": "157-60",
"pmc": null,
"pmid": "26877967",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": "16908621;20966123;7838560;9470918;15087670;18753258;21804539;12883971;8302422;10845836;8092143;10872190;1563115;15690191;16750313",
"title": "Remission of secondary membranous nephropathy in a patient with Kimura disease after surgical resection.",
"title_normalized": "remission of secondary membranous nephropathy in a patient with kimura disease after surgical resection"
} | [
{
"companynumb": "PHHY2014KR141942",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Zolpidem is a hypnotic which acts at the GABAA receptor and is indicated for short-term insomnia. Sleep related disorders including somnambulism, sleep related eating and sleep-driving have been reported with zolpidem. A 51-year-old insomniac who used zolpidem 10 mg nightly starting at 44 years of age is described. A few weeks after starting zolpidem she began walking, eating, and had one episode of driving while asleep. Episodes of sleep related eating, sleepwalking, and sleeptalking occurred 3 nights per week, 1 to 2 h after sleep onset. After her evaluation, the patient's zolpidem was gradually discontinued, and all sleep related activities immediately ceased. An 18F-FDG-PET was obtained 2 months after discontinuation of zolpidem. The following day, FDG was administered 1 h after oral administration of 10 mg zolpidem, and then a second PET was performed. We report the results and a review of the literature regarding other unintended effects seen with zolpidem use.",
"affiliations": "Sleep Disorders Center, Department of Neurology, Louisiana State University School of Medicine, Shreveport, LA, USA. romy.hoque@gmail.com",
"authors": "Hoque|Romy|R|;Chesson|Andrew L|AL|",
"chemical_list": "D006993:Hypnotics and Sedatives; D011725:Pyridines; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D000077334:Zolpidem",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1550-9389",
"issue": "5(5)",
"journal": "Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine",
"keywords": null,
"medline_ta": "J Clin Sleep Med",
"mesh_terms": "D001334:Automobile Driving; D001921:Brain; D001931:Brain Mapping; D001068:Feeding and Eating Disorders; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D006993:Hypnotics and Sedatives; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011725:Pyridines; D011859:Radiography; D019275:Radiopharmaceuticals; D007319:Sleep Initiation and Maintenance Disorders; D013009:Somnambulism; D000077334:Zolpidem",
"nlm_unique_id": "101231977",
"other_id": null,
"pages": "471-6",
"pmc": null,
"pmid": "19961034",
"pubdate": "2009-10-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "10447452;11865155;12398580;12373037;14519043;18226667;11302407;17364638;16720934;11556120;8195460;16268373;9078210;10928588;3992107;18174850;14592194;16331401;11882066;9130951;17993047;2845057;17357126;8873114;15300667;15841201;10721397;15282364;15352681;7966909;10495642;17880558;15553102;15928717;17539703;18468314;11682274;18164949;14985499;8840378;7774760;10804040;12442636;11113332",
"title": "Zolpidem-induced sleepwalking, sleep related eating disorder, and sleep-driving: fluorine-18-flourodeoxyglucose positron emission tomography analysis, and a literature review of other unexpected clinical effects of zolpidem.",
"title_normalized": "zolpidem induced sleepwalking sleep related eating disorder and sleep driving fluorine 18 flourodeoxyglucose positron emission tomography analysis and a literature review of other unexpected clinical effects of zolpidem"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2014-01491",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
"drugadditiona... |
{
"abstract": "Hypochlorhydric states such as atrophic gastritis and partial gastrectomy have long been known to cause iron deficiency anemia. However, studies to date have failed to show a similar association with omeprazole, a proton pump inhibitor that also produces achlorhydria. These studies, however, have primarily involved nonanemic, iron-replete individuals. The effect of the drug has not been studied in patients with established iron deficiency, and to our knowledge the patients presented here are the first of their kind to be reported. Our observations support the probability that the profound hypochlorhydria induced by omeprazole may indeed impair the optimal absorption of orally administered iron in iron-deficient individuals, precluding them from obtaining therapeutically adequate amounts to establish the positive balance necessary for the resolution of anemia and the replenishment of stores. The possible explanations for this phenomenon are also discussed.",
"affiliations": "West Kentucky Hematology and Oncology, Paducah, KY, USA. vrshar01@louisville.edu",
"authors": "Sharma|Vivek R|VR|;Brannon|Mark A|MA|;Carloss|Elizabeth A|EA|",
"chemical_list": "D000897:Anti-Ulcer Agents; D007501:Iron; D009853:Omeprazole",
"country": "United States",
"delete": false,
"doi": "10.1097/01.SMJ.0000110405.63179.69",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0038-4348",
"issue": "97(9)",
"journal": "Southern medical journal",
"keywords": null,
"medline_ta": "South Med J",
"mesh_terms": "D000126:Achlorhydria; D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D018798:Anemia, Iron-Deficiency; D000897:Anti-Ulcer Agents; D005260:Female; D006801:Humans; D007408:Intestinal Absorption; D007501:Iron; D008875:Middle Aged; D009853:Omeprazole",
"nlm_unique_id": "0404522",
"other_id": null,
"pages": "887-9",
"pmc": null,
"pmid": "15455980",
"pubdate": "2004-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Effect of omeprazole on oral iron replacement in patients with iron deficiency anemia.",
"title_normalized": "effect of omeprazole on oral iron replacement in patients with iron deficiency anemia"
} | [
{
"companynumb": "US-APOTEX-2017AP016807",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OMEPRAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nThe incidence of de novo malignancies after organ transplantation is increasing. We herein report a patient who developed gastric cancer after living donor liver transplantation (LDLT) and splenectomy. Intraoperative indocyanine green (ICG) fluorescence angiography immediately after gastrectomy was useful for evaluating the blood supply into the remnant stomach in this patient.\n\n\nMETHODS\nA 69-year-old woman underwent LDLT and splenectomy for end-stage liver disease. Gastric cancer was found by an endoscopic examination eight years after LDLT. Although total gastrectomy was considered due to previous splenectomy, we decided to intraoperatively evaluate the flow of the remnant stomach using ICG fluorescence. After ligation of the left gastric artery and transection of the stomach with a sufficient proximal margin from the tumor, intraoperative ICG fluorescence angiography showed abundant intramural blood flow of the remnant stomach. We were able to preserve the proximal stomach with confidence and she recovered smoothly after the operation without any signs of acute rejection.\n\n\nCONCLUSIONS\nIntraoperative ICG fluorescence angiography may be helpful for evaluating the blood flow in the remnant stomach during surgery for de novo gastric cancer after LDLT.",
"affiliations": "Department of Gastrointestinal Surgery, Jiangxi Provincial Cancer Hospital, No. 519, Beijing East Road, Nanchang 330029, Jiangxi Province, China.;Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. Electronic address: kanetaka@nagasaki-u.ac.jp.;Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.;Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.;Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.;Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.",
"authors": "Zhou|Wei|W|;Kanetaka|Kengo|K|;Yoneda|Akira|A|;Kobayashi|Shinichiro|S|;Hidaka|Masaaki|M|;Eguchi|Susumu|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2020.11.090",
"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612 Elsevier \n\nS2210-2612(20)31113-5\n10.1016/j.ijscr.2020.11.090\nCase Report\nThe efficacy of intraoperative indocyanine green fluorescence angiography in gastric cancer operation after living donor liver transplantation: A case report\nZhou Wei a Kanetaka Kengo kanetaka@nagasaki-u.ac.jpb⁎ Yoneda Akira b Kobayashi Shinichiro b Hidaka Masaaki b Eguchi Susumu b a Department of Gastrointestinal Surgery, Jiangxi Provincial Cancer Hospital, No. 519, Beijing East Road, Nanchang 330029, Jiangxi Province, China\nb Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan\n⁎ Corresponding author. kanetaka@nagasaki-u.ac.jp\n24 11 2020 \n2020 \n24 11 2020 \n77 614 617\n29 9 2020 16 11 2020 16 11 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• De novo gastric cancer after living donor liver transplantation.\n\n• Distal gastrectomy after splenectomy.\n\n• ICG is useful for evaluating the blood flow in gastrectomy after LDLT with splenectomy.\n\n\n\nIntroduction\nThe incidence of de novo malignancies after organ transplantation is increasing. We herein report a patient who developed gastric cancer after living donor liver transplantation (LDLT) and splenectomy. Intraoperative indocyanine green (ICG) fluorescence angiography immediately after gastrectomy was useful for evaluating the blood supply into the remnant stomach in this patient.\n\nPresentation of case\nA 69-year-old woman underwent LDLT and splenectomy for end-stage liver disease. Gastric cancer was found by an endoscopic examination eight years after LDLT. Although total gastrectomy was considered due to previous splenectomy, we decided to intraoperatively evaluate the flow of the remnant stomach using ICG fluorescence. After ligation of the left gastric artery and transection of the stomach with a sufficient proximal margin from the tumor, intraoperative ICG fluorescence angiography showed abundant intramural blood flow of the remnant stomach. We were able to preserve the proximal stomach with confidence and she recovered smoothly after the operation without any signs of acute rejection.\n\nConclusion\nIntraoperative ICG fluorescence angiography may be helpful for evaluating the blood flow in the remnant stomach during surgery for de novo gastric cancer after LDLT.\n\nKeywords\nLiving donor liver transplantationSplenectomyGastric cancerIndocyanine greenDe novo malignancy\n==== Body\n1 Introduction\nTransplantation is the only effective method for treating organ failure. The number of organ transplantation has increased rapidly, and advance in immunosuppressant therapy and surgical procedures has markedly improved the long-term survival of patients after transplantation. However, de novo malignancy after organ transplantation has become a major issue affecting the long-term survival of recipients. The recent research has confirmed that de novo malignancy is the second leading cause of death in transplant recipients who survive at least 1-year after transplantation [1].\n\nDe novo gastric cancer is one of these malignancies and there are several reports concerning with its treatment such gastrectomy [[2], [3], [4], [5], [6]]. Although surgery are the mainstay treatments for de novo gastric cancer just as with malignancy that develops in the general population [6,7], there are some issues to be considered when gastrectomy would be attempted especially after liver transplantation: Severe postoperative adhesion and anatomical rearrangement due to vessel reconstruction could lead to vascular injuries. Moreover, if splenectomy was performed with liver transplantation, a dissection between the stomach and splenic hilum might impair a blood supply to the stomach and insufficient blood supply to remnant stomach after gastrectomy is one of risks of anastomotic leakages and gastric necrosis. As these perioperative severe complications could easily place patients at lethal condition because of the perioperative immunocompromised condition due to the administration of immunosuppressive agents, evaluation of blood supply into the remnant stomach is crucial issue.\n\nWe herein report a patient who developed gastric cancer after living donor liver transplantation (LDLT) and splenectomy. Intraoperative indocyanine green (ICG) fluorescence angiography immediately after gastrectomy was useful for evaluating the blood supply both into the remnant stomach.\n\nThis case report has been reported in line with the SCARE 2018 criteria [8].\n\n2 Case report\nA 77-year-old woman was admitted to our hospital for surgical treatment for gastric cancer. She had a history of LDLT and simultaneous splenectomy due to hepatitis C virus (HCV)-related cirrhosis with hepatocellular carcinoma (HCC) and antiviral treatment for eradication of HCV eight years ago. She had no significant family history and psychosocial history. Postoperative immunosuppressive treatment with Mycophenolate Mofetil and Tacrolimus had been continued, and there were no signs of rejection or any problems on routine monitoring of parameters, including the liver function.\n\nThe patient had undergone annual gastroscopy after transplantation, but no pathological findings had been found until gastroscopy performed eight years after transplantation showed ulcerative lesion with an irregular raised margin located in the lower portion of the stomach. A histological examination of the biopsied specimen revealed moderately differentiated adenocarcinoma. Her biochemistry, blood count and tumor markers, including α-fetoprotein (AFP), carcinoembryonic antigen (CEA), and carbohydrate antigen (CA19-9), were within normal ranges.\n\nEndoscopic ultrasonography implied that the depth of cancer invasion was limited to the submucosal layer of the gastric wall. Contrast-enhanced computed tomography (CT) revealed no swollen lymph nodes around the stomach. No distant metastasis and no recurrence of HCC were identified. Three-dimensional CT (3D-CT) demonstrated the left gastric artery and main truncus of the splenic artery, but robust short gastric arteries was absent due to the previous splenectomy procedure. Instead, only small branches divided from the splenic artery were detected in the greater curvature of the stomach. In addition, the right gastroepiploic artery was anastomosed to the right hepatic artery of the transplanted liver as feeding vessels (Fig. 1).Fig. 1 Three-dimensional computed tomography (CT) showing vessels around the stomach. The arrow indicates the left gastric artery (LGA), the right gastroepiploic artery (RGEA) anastomosed to the right hepatic artery in the right lobe of the liver graft (HA of graft). We only found small branches divided from the splenic artery (SpA) due to the history of splenectomy.\n\nFig. 1\n\nUnder the diagnosis of de novo gastric cancer after LDLT, gastrectomy with lymph node dissection was planned, and we preoperatively discussed the ideal procedure for this patient. Distal gastrectomy with lymph node dissection of the left gastric lesion was considered the most curative approach from an oncological perspective. However, there was concern about whether or not the remnant stomach could be safely preserved without the development of ischemia after ligation of the left gastric artery. We therefore decided to intraoperatively evaluate the flow in the remnant stomach using ICG fluorescence, and if an insufficient blood flow was observed, we planned to perform total gastrectomy.\n\nNo peritoneal dissemination was recognized on laparotomy, but severe adhesion between the grafted left lobe of the liver and the stomach was encountered. The grafted liver was enlarged due to regeneration, occupying the left upper part of the abdominal cavity, and the omental stalk, including the right gastroepiploic artery, ran across the dorsal side of the stomach. After careful exfoliation around the right gastroepiploic artery in order to minimize tissue manipulation, the anal side of the stomach was divided 2 cm proximal to the pyloric ring using a linear stapling device. Following ligation of the left gastric artery and vein with lymph node dissection, the stomach was transected with a sufficient proximal margin from the tumor.\n\nThe remnant stomach showed no ischemic manifestation, but whether or not the extragastric arteries, such as the posterior gastric artery, had been preserved was impossible to confirm due to the severe adhesion around the remnant stomach. Intraoperative ICG fluorescence angiography was performed via injection of ICG at a concentration of 2.5 mg/mL to visualize the blood flow and vascular distribution in the remnant stomach. After injecting the ICG solution, abundant intramural blood flow of the remnant stomach was confirmed in about 20 s (Fig. 2).Fig. 2 ICG (3 mL) was administered intravenously at a concentration of 2.5 mg/mL. Intraoperative indocyanine green (ICG) fluorescence angiography showed abundant intramural blood flow of the remnant stomach in about 20 s.\n\nFig. 2\n\nReconstruction was performed with Roux-en-Y gastrojejunostomy via the antecolic route, and an intestinal feeding tube was inserted into the distal bowel. The duration of the operation was 484 min. and blood loss was 6,000 mL.\n\nA histopathological examination of the resected stomach revealed moderately differentiated adenocarcinoma with subserosal invasion. There was no lymph node metastasis, and the tumor was staged as pT3N0M0. Immunosuppressive agents were administered through the nasal feeding tube the day after the operation. The patients recovered smoothly after operation without any signs of acute rejection. She was discharged from the hospital three weeks after the operation. Following the gastric surgery, same dose of immunosuppressive agent prescribed before the surgery was used. One year and three months after gastrectomy, however, multiple liver metastases and local recurrence developed despite her taking one year of adjuvant chemotherapy and she died one year and eight months after gastrectomy.\n\n3 Discussion\nThe incidence of de novo gastric cancer after liver transplantation is reported to range from 0.1% to 1%, with a standard incidence ratio (SIR) of 0.6–11.35 worldwide [[9], [10], [11], [12], [13], [14], [15], [16]]. In Japan, Miyazaki et al. reported 19 cases of de novo gastric cancer among 4226 cases of liver transplantation [16]. The development of de novo gastric cancer is induced by various factors, such as long-lasting immunosuppressive treatment and a pre-transplant condition including complication with metabolic and infectious diseases. Infection with Helicobactor pylori (HP) is a strong etiology underlying the development of gastric cancer in the general population, but from the perspective of geographical characteristics, there seems to be little correlation between the reported prevalence of HP and SIR of de novo gastric cancer after liver transplantation [17]. Thus far, only limited data are available regarding risk factors of de novo gastric cancer after liver transplantation.\n\nCurative treatment should be considered even for gastric cancer after transplantation if the performance status and cardiopulmonary function of each patient are considered medically fit [6,7]. The guideline of the Japanese Research Society for Gastric Cancer recommends distal gastrectomy with dissection of lymph nodes around the stomach and left gastric artery as a radical operation for gastric cancer with submucosal invasion [18]. Special precautions must be taken in cases with anatomical changes resulting from previous transplantation, such as in the hepatic hilum and hepatogastric regions, which contain reconstructive vessels and the bile duct. Therefore, it is important to accurately assess the anatomical information preoperatively in order to avoid iatrogenic injury of these structures. In the present case, 3D-CT was useful for demonstrating the structure of the feeder artery of the right gastroepiploic artery flowing into the grafted liver. However, we were unable to confirm the presence of a potential feeding artery for the remnant stomach after gastrectomy. Theoretically, total gastrectomy should have been selected for this patient, since she had a history of splenectomy.\n\nSplenectomy is performed for splenic malignant lymphoma, hematological disease such as idiopathic thrombocytopenic purpura and hypersplenism. It is also performed simultaneously during LDLT for the improvement of graft outcomes by reducing the portal pressure [19]. Splenectomy also performed for prevention of thrombocytopenia in antiviral treatment for HCV like in our patient. In this procedure, the splenic artery is often ligated. As this artery is essential for maintaining the blood supply to the proximal stomach, in cases of gastrectomy in patients with a history of splenectomy, there is some concern of ischemic necrosis of the remnant stomach or leakage at the anastomosis. These infectious complications are particularly lethal for patients under immunosuppressive treatment, like the present patient.\n\nRecently, the usefulness of intraoperative indocyanine green (ICG) fluorescence angiography has been reported in various situation. Takahashi et al. used ICG fluorescence in visualization of the blood flow in the remnant stomach after the completion of distal pancreatectomy in a patient with prior distal gastrectomy [20]. Yamana et al. also assessed the blood flow of the cancer-bearing gastric tube after clamping the gastroepiploic artery, and they performed subtotal gastrectomy with preservation of these vessels because the flow of gastric tube was insufficient [21].\n\nWe therefore used intraoperative ICG fluorescence angiography in order to evaluate the blood flow in the remnant stomach after distal gastrectomy. Although a preoperative evaluation was unable to detect the robust vessels feeding the upper portion of the stomach, such as the recurrent branches of the left inferior phrenic artery and/or descending branches of the esophageal artery, intraoperative ICG revealed a rich blood flow into the remnant stomach. Potential mechanisms underlying the successful preservation of the blood flow are as follows: The collateral blood flow via small branches of the splenic artery might have played an important role in our patient. There is also the possibility that during a long interval after the previous surgery, small supplemental vessels might be fertilized from adjacent tissues. In addition, the intramural capillary networks in cooperation with the extragastric arterial blood supply may have helped compensate for the loss of blood flow from the left gastric artery.\n\nAdjuvant chemotherapy after curative gastrectomy is recommended in order to prevent postoperative recurrence [22,23]. Our patient has received adjuvant chemotherapy of S1 without any adverse events and no deterioration of the liver function, although multiple liver metastasis and local recurrence nevertheless developed. Park et al. reported that almost all patients with de novo malignancies after liver transplantation in Korea were able to receive aggressive cancer treatment including chemotherapy, suggesting the safety of chemotherapy [10]. However, the results remain controversial, as various drugs, including anticancer agents, may harm the liver and worsen the immunocompromised status.\n\nRecently the safety and curability of endoscopic resection for superficial cancer has been reported provided the tumor invasion is limited to the mucosal layer. This procedure can help avoid gastrectomy, which can diminish the quality of life due to the loss of the reserve function, damage to the antireflux barrier, and dumping syndrome. Furthermore, gastrectomy is known to decrease the surface area for drug absorption, which results in the alteration of the pharmacokinetic profiles of some immunosuppressive agents [24]. Resection of the upper gastrointestinal tract can therefore cause the fluctuation of immunologic activities meant to prevent acute rejection. The early detection of de novo malignancy, especially in the upper gastrointestinal tract, is thus extremely important. Although the appropriate approach to postoperative surveillance for the digestive tract has yet to be clarified, routine endoscopic examinations are recommended after liver transplantation in high-risk recipients. There is a geographic difference in the incidence of gastric cancer, so it is necessary to establish tailored surveillance programs after liver transplantation in each country. Close surveillance through endoscopy is particularly important in countries with a high prevalence of HP, such as Japan,\n\nIn conclusion, with the achievement of a long-term survival after liver transplantation, the incidence of de novo gastric cancer has increased. Surgeons who are not specialized in transplantation may therefore be faced with opportunities to treat malignancy in patients with a history of LDLT, often accompanied by a history of splenectomy. Intraoperative ICG fluorescence angiography may aid in evaluating the blood flow in the remnant stomach in cases of surgery for de novo gastric cancer after LDLT.\n\nDeclaration of Competing Interest\nThe authors report no declarations of interest.\n\nFunding\nThere is no funding.\n\nEthical approval\nThe study is exempt from ethical approval in my institution.\n\nConsent\nWritten informed consent was not obtained from the patient for publication of this case report, because of the patient’s death and provided by next of kin.\n\nRegistration of research studies\nNot applicable.\n\nGuarantor\nKengo Kanetaka.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n\nCRediT authorship contribution statement\nWei Zhou: Conceptualization, Writing - original draft. Kengo Kanetaka: Conceptualization, Writing - review & editing, Supervision. Akira Yoneda: Writing - review & editing. Shinichiro Kobayashi: Writing - review & editing. Masaaki Hidaka: Writing - review & editing. Susumu Eguchi: Supervision.\n==== Refs\nReferences\n1 Rana A. Ackah R.L. Webb G.J. Halazun K.J. Vierling J.M. Liu H. Wu M.F. Yoeli D. Kueht M. Mindikoglu A.L. No gains in long-term survival after liver transplantation over the past three decades Ann. Surg. 269 1 2019 20 27 29303806 \n2 Lee M.S. Kim E.Y. Lee J.H. Jee Y.S. Park D.J. Kim H.H. Kim S.Y. Laparoscopy-assisted distal gastrectomy for gastric cancer after liver transplantation J. Korean Surg. Soc. 80 Suppl. 1 2011 S1 5 22066074 \n3 Shimizu T. Hayashi M. Inoue Y. Komeda K. Asakuma M. Hirokawa F. Miyamoto Y. Tanigawa N. Uchiyama K. A case of gastric cancer after living donor liver transplantation Ann. Transplant. 17 2 2012 122 126 \n4 Xiao H. Bian J. Zhang L. Wang Z. Ding A. Gastric cancer following a liver transplantation for glycogen storage disease type Ia (von Gierke disease): a case report Oncol. Lett. 8 6 2014 2803 2805 25364469 \n5 Na S. Lee G.H. Song J.H. Ahn J.Y. Kim S.O. Park S.J. Park S.E. Kim M.Y. Lee J. Choi K.S. Endoscopic resection of gastric neoplasm in solid-organ transplant recipients Transplantation 97 7 2014 781 787 24406452 \n6 Yang K. Zhu H. Chen C.C. Wen T.F. Zhang W.H. Liu K. Chen X.Z. Guo D.J. Zhou Z.G. Hu J.K. Lessons learned from a case of gastric cancer After liver transplantation for hepatocellular carcinoma: a case report and literatures review Medicine (Baltimore) 95 7 2016 e2666 26886605 \n7 Buell Jf Husted T. Hanaway Mj Peddi Vr Trofe J. Gross Tg Beebe Tm First Mr Woodle Es. Incidental diagnosis of gastric cancer in transplant recipients improves patient survival Surgery 132 4 2002 754 758 discussion 758-760 12407362 \n8 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A.J. Orgill D.P. Group S The SCARE 2018 statement: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279 \n9 Baccarani U. Adani G.L. Serraino D. Lorenzin D. Gambato M. Buda A. Zanus G. Vitale A. Piselli P. De Paoli A. De novo tumors are a major cause of late mortality after orthotopic liver transplantation Transplant. Proc. 41 4 2009 1303 1305 19460546 \n10 Park H.W. Hwang S. Ahn C.S. Kim K.H. Moon D.B. Ha T.Y. Song G.W. Jung D.H. Park G.C. Namgoong J.M. De novo malignancies after liver transplantation: incidence comparison with the Korean cancer registry Transplant. Proc. 44 3 2012 802 805 22483500 \n11 Sampaio M.S. Cho Y.W. Qazi Y. Bunnapradist S. Hutchinson I.V. Shah T. Posttransplant malignancies in solid organ adult recipients: an analysis of the U.S. National Transplant Database Transplantation 94 10 2012 990 998 23085553 \n12 Ettorre G.M. Piselli P. Galatioto L. Rendina M. Nudo F. Sforza D. Miglioresi L. Fantola G. Cimaglia C. Vennarecci G. De novo malignancies following liver transplantation: results from a multicentric study in central and southern Italy, 1990-2008 Transplant. Proc. 45 7 2013 2729 2732 24034034 \n13 Gong C.S. Yoo M.W. Kim B.S. Hwang S. Kim K.H. Yook J.H. Kim B.S. Lee S.G. De novo gastric cancer after liver transplantation Ann. Transplant. 21 2016 386 391 27334929 \n14 Zhou J. Hu Z. Zhang Q. Li Z. Xiang J. Yan S. Wu J. Zhang M. Zheng S. Spectrum of de novo cancers and predictors in liver transplantation: analysis of the scientific registry of transplant recipients database PLoS One 11 5 2016 e0155179 27171501 \n15 Seree O. Altieri M. Guillaume E. De Mil R. Lobbedez T. Robinson P. Segol P. Salame E. Abergel A. Boillot O. Longterm risk of solid organ de novo malignancies after liver transplantation: a French national study on 11,226 patients Liver Transpl. 24 10 2018 1425 1436 30021061 \n16 Miyazaki T. Sato S. Kondo T. Kusaka M. Gotoh M. Saiki Y. Ono M. Kokudo N. Enosawa S. Satoh S. National survey of de novo malignancy after solid organ transplantation in Japan Surg. Today 48 6 2018 618 624 29380136 \n17 Zamani M. Ebrahimtabar F. Zamani V. Miller W.H. Alizadeh-Navaei R. Shokri-Shirvani J. Derakhshan M.H. Systematic review with meta-analysis: the worldwide prevalence of Helicobacter pylori infection Aliment. Pharmacol. Ther. 47 7 2018 868 876 29430669 \n18 Japanese Gastric Cancer A Japanese gastric cancer treatment guidelines 2014 (ver. 4) Gastric Cancer 20 1 2017 1 19 \n19 Yoshizumi T. Mori M. Portal flow modulation in living donor liver transplantation: review with a focus on splenectomy Surg. Today 50 1 2020 21 29 31555908 \n20 Takahashi H. Nara S. Ohigashi H. Sakamoto Y. Gotoh K. Esaki M. Yamada T. Shimada K. Yano M. Kosuge T. Is preservation of the remnant stomach safe during distal pancreatectomy in patients who have undergone distal gastrectomy? World J. Surg. 37 2 2013 430 436 23188537 \n21 Yamana I. Murakami T. Ryu S. Ichikawa J. Shin Y. Koreeda N. Sannomiya H. Sato K. Okamoto T. Sakamoto Y. Subtotal gastrectomy for gastric tube cancer using intraoperative indocyanine green fluorescence method Int. J. Surg. Case Rep. 71 2020 290 293 32480340 \n22 Sakuramoto S. Sasako M. Yamaguchi T. Kinoshita T. Fujii M. Nashimoto A. Furukawa H. Nakajima T. Ohashi Y. Imamura H. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine N. Engl. J. Med. 357 18 2007 1810 1820 17978289 \n23 Noh S.H. Park S.R. Yang H.K. Chung H.C. Chung I.J. Kim S.W. Kim H.H. Choi J.H. Kim H.K. Yu W. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial Lancet Oncol. 15 12 2014 1389 1396 25439693 \n24 Chen L. Liberatore L. Chin T. Walker S. Fanous H. Nash M.M. Rapi L. Huckle J. Zaltzman J.S. Prasad G.V.R. The impact of total gastrectomy on pharmacokinetics in kidney transplant immunosuppressive drug regimes: a case study Transplantation 101 9 2017 2213 2217 27748705\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2210-2612",
"issue": "77()",
"journal": "International journal of surgery case reports",
"keywords": "De novo malignancy; Gastric cancer; Indocyanine green; Living donor liver transplantation; Splenectomy",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "614-617",
"pmc": null,
"pmid": "33395858",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "23188537;27171501;26886605;29380136;24406452;30342279;22066074;19460546;12407362;25364469;24034034;23085553;27748705;31555908;27342689;17978289;27334929;29303806;32480340;30021061;22743730;29430669;25439693;22483500",
"title": "The efficacy of intraoperative indocyanine green fluorescence angiography in gastric cancer operation after living donor liver transplantation: A case report.",
"title_normalized": "the efficacy of intraoperative indocyanine green fluorescence angiography in gastric cancer operation after living donor liver transplantation a case report"
} | [
{
"companynumb": "CN-STRIDES ARCOLAB LIMITED-2021SP004511",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional"... |
{
"abstract": "We present the case of an HIV-seropositive individual with cryptococcal meningitis who was found to have a fluconazole resistant strain of Cryptococcus neoformans. The individual required multiple rounds of amphotericin and fluconazole 800-1200 mg after several episodes of clinical relapse. Cerebrospinal fluid sterilization was achieved and maintained with high doses of fluconazole. This case demonstrates the emerging dilemma of increasing rates of fluconazole resistance in Cryptococcus and the clinical difficulties in meningitis management.",
"affiliations": "Infectious Diseases Institute, Makerere University, Kampala, Uganda.;Infectious Diseases Institute, Makerere University, Kampala, Uganda.;Infectious Diseases Institute, Makerere University, Kampala, Uganda.",
"authors": "Mpoza|Edward|E|;Rhein|Joshua|J|;Abassi|Mahsa|M|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.mmcr.2017.11.004",
"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(17)30062-310.1016/j.mmcr.2017.11.004Case ReportEmerging fluconazole resistance: Implications for the management of cryptococcal meningitis Mpoza Edward aRhein Joshua abAbassi Mahsa abass004@umn.eduab⁎a Infectious Diseases Institute, Makerere University, Kampala, Ugandab University of Minnesota, 420 Delaware Street SE, Minneapolis 55455, USA⁎ Corresponding author at: Infectious Diseases Institute, Makerere University, Kampala, Uganda.Infectious Diseases Institute, Makerere UniversityKampalaUganda abass004@umn.edu26 11 2017 3 2018 26 11 2017 19 30 32 31 10 2017 24 11 2017 © 2017 Published by Elsevier B.V. on behalf of International Society for Human and Animal Mycology.2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We present the case of an HIV-seropositive individual with cryptococcal meningitis who was found to have a fluconazole resistant strain of Cryptococcus neoformans. The individual required multiple rounds of amphotericin and fluconazole 800–1200 mg after several episodes of clinical relapse. Cerebrospinal fluid sterilization was achieved and maintained with high doses of fluconazole. This case demonstrates the emerging dilemma of increasing rates of fluconazole resistance in Cryptococcus and the clinical difficulties in meningitis management.\n\nKeywords\nCryptococcusCryptococcal meningitisAntifungal susceptibilityFluconazole resistanceCryptococcal meningitis relapse\n==== Body\n1 Introduction\nCryptococcus neoformans is an opportunistic pathogen that gives rise to most cases of AIDS-related fungal meningitis worldwide [1]. Initial infection occurs after respiratory inhalation with pulmonary infiltration, followed by subclinical disease with detectable antigenemia by latex agglutination assays for a median of at least 3 weeks, prior to dissemination into the central nervous system (CNS) [1]. The global prevalence of cryptococcal antigenemia, in HIV-seropositive persons with CD4 cell count < 100 cells/μL, is estimated at 6%, with 223,100 (95% CI, 150, 600-282, 400) incident cases of cryptococcal meningitis (CM) occurring annually [2]. Annual deaths from cryptococcal meningitis are estimated at 181,100 (95% CI 119, 400-234, 300), accounting for 10–15% of AIDS-related mortality [2].\n\nThe mainstay therapy for cryptococcal meningitis, presently, begins with induction therapy with amphotericin and flucytosine for 2-weeks [3]. In Sub-Saharan Africa, where most cryptococcal cases occur, flucytosine is not licensed, available, or affordable [4].\n\nTherefore, therapy options are reduced to amphotericin and fluconazole, or when amphotericin is not available, fluconazole monotherapy. At the end of induction therapy, consolidation therapy typically consists of fluconazole 400–800 mg daily for 8 weeks, followed by maintenance therapy with fluconazole 200 mg daily for greater than 1 year [3].\n\nAntifungal susceptibility of Cryptococcus isolates in primary cryptococcal infection is not routinely recommended because antifungal resistance has not yet been a clinically significant problem. However, in cases of either persistent or relapsed cases of cryptococcal meningitis, isolates are recommended to be checked for antifungal susceptibility [3]. Established Cryptococcus breakpoints for fluconazole susceptibility have minimum inhibitory concentrations (MIC) of ≤ 8 μg/mL as susceptible, MIC 16–32 μg/mL as dose-dependent susceptible, and MIC ≥ 64 μg/mL as resistant [5]. We present a case of cryptococcal meningitis in the setting of fluconazole resistance; highlighting factors that give rise to fluconazole resistance as well as difficulties in the management of fluconazole resistant cryptococcal meningitis in settings where alternative antifungals are not available.\n\n2 Case\nA 50 y/o HIV-seropositive man presented to an HIV clinic in Kampala, Uganda on day 0 with persistent headaches, stiff neck, and vomiting. He was diagnosed with cryptococcal meningitis based on symptoms and a positive serum cryptococcal antigen (CrAg+). A lumbar puncture (LP) was not performed and he was given 2-weeks of fluconazole 400 mg/daily as monotherapy for the treatment of cryptococcal meningitis and initiated on antiretroviral therapy (ART) with tenofovir, lamivudine, and nevirapine. He had a temporary resolution of his symptoms.\n\nTwo months later (day 60) he was referred to our HIV clinic with a recurrence of headaches, neck stiffness, and vomiting. At this time, workup revealed a CD4 cell count of 32 cells/μL and a viral load of 34 copies/mL. A LP was performed and opening pressures were elevated to 38 cm H20. Cerebrospinal fluid (CSF) analysis was pertinent for WBC 45 cells/μL, CrAg+, and 80 colony-forming units (CFU) of Cryptococcus/mL CSF. He received 10 days of amphotericin B and fluconazole 800 mg/daily. He had three subsequent therapeutic LPs and CSF sterilization was documented on the 10th day of amphotericin. He continued fluconazole 800 mg/day for one month, followed by 400 mg/day for 10 weeks, and finally 200 mg/day as maintenance therapy.\n\nHe returned to the clinic on day 180 (6 months from his initial encounter) with recurrent symptoms of meningitis reporting poor adherence to fluconazole. A repeat LP was performed and CSF analysis demonstrated WBC 25 cells//μL with CSF culture growing 93,000 Cryptococcus CFU/mL. He received another 14 doses of amphotericin, placed on fluconazole 1200 mg/day, and had 3 therapeutic LPs. At the end of 14 doses of amphotericin, his CSF culture continued to grow 21,000 Cryptococcus CFU/mL. After discharge, he was lost to follow up but returned to the clinic on day 240 (8 months from initial encounter) when his symptoms again recurred. Another LP was performed demonstrating WBC 220 cells/μL with 58,000 Cryptococcus CFU/mL on culture. He refused hospital admission and received only 3 doses of amphotericin as an outpatient prior to again being lost to follow-up. Fluconazole resistance testing performed on the cryptococcal isolates demonstrated a (MIC) > 64 μg/mL with high-level resistance to fluconazole.\n\nHe once again returned to the clinic on day 330 (approximately 1 year from initial encounter) complaining of worsening meningitis symptoms. At this point, his CD4 cell count had dropped to 2 cells/μL with the most recent HIV-1 viral load of 38,605 copies/mL. He received an additional 14 doses of amphotericin and remained on fluconazole 1200 mg/day. At the end of the 14 doses of amphotericin, his CSF cultures continued to grow 110 Cryptococcus CFU/mL. He received another 8 doses of amphotericin and CSF cultures at the end of this had sterilized. He continued high-dose fluconazole as an outpatient, and his ART regimen was switched to abacavir, lamivudine, and ritonavir-boosted atazanavir due to HIV virologic failure. Doses of fluconazole included 1200 mg/day for 10-weeks of consolidation therapy and 800 mg/day thereafter for secondary prophylaxis. On day 480, now 16 months from time of initial diagnosis, he presented with possible paradoxical immune reconstitution inflammatory syndrome vs. severe sepsis secondary to pneumonia. CSF cultures taken at that time were found to be sterile. He passed away 4 days into this hospitalization ( Table 1).Table 1 Clinical summary of events.\n\nTable 1Days\tInitial fungal burden (CFU/mL)\tDoses of amphotericin\tFinal fungal burden (CFU/mL)\tFluconazole dose (mg/day)\tDiagnosis\t\n0\tNot done\t0\tNot done\t400 mg\tPrimary CM\t\n60\t80\t10\tSterile\t800 mg for 2 wks/400 mg for 10wks/200 mg\tUntreated CM\t\n180\t93,000\t14\t21,000\t1200 mg\tCM Relapse\t\n240\t58,000\t3\tNot done\t1200 mg\tPersistent CM\t\n330\tNot done\t14\t110\t1200 mg\tPersistent CM\t\n360\tNot done\t8\tSterile\t1200 mg\tPersistent CM\t\n480\tSterile\t0\tNot done\t800 mg\tIRISa vs. Sepsis\t\na During the last hospitalization a diagnosis of either paradoxical immune reconstitution inflammatory syndrome vs. severe sepsis was made. CSF cultures at this time were sterile and CM relapse was ruled out.\n\n\n\n3 Discussion\nThis case not only highlights the complexity and challenges in managing fluconazole resistant cases of cryptococcal meningitis, but also highlights important factors that facilitate the rise of fluconazole resistance. Without antimicrobial susceptibility testing on initial presentation, it is difficult to determine whether fluconazole resistance, in this case, was intrinsic or acquired. However, several risk factors may have put him at risk for acquired resistance, including: 1) monotherapy with inadequate, FDA-approved doses of fluconazole for cryptococcal meningitis and 2) medication non-adherence and interruptions to fluconazole during both the consolidation and maintenance phases of therapy. The case also raises several important questions. If fluconazole resistance is an emerging threat, does in vitro susceptibility testing translate into clinical outcomes? If so, what are the implications for treatment when fluconazole is the only antifungal therapy option and alternatives are not widely available?\n\nGlobally, there has been an increase in the percentage of Cryptococcus isolates found to have some degree of fluconazole resistance. Over a 10-year period, the ARTEMIS DISK Global Antifungal Surveillance Study found that fluconazole resistance in Cryptococcus has been progressively increasing from 7.3% from 1997 to 2000, to 10.9% from 2001 to 2004, and 11.7% from 2005 to 2007 [6]. In the same surveillance study, fluconazole resistant isolates of Cryptococcus from the United Kingdom and the United States were rare, while isolates from Africa, Cambodia, and Spain demonstrated increasing fluconazole resistance [6]. Individual studies from Taiwan and Uganda have seen similar increases in fluconazole non-susceptibility and increasing MICs among Cryptococcus isolates, all within the last decade [7], [8]. While low rates of fluconazole resistance seen in North America and Europe may be attributed to decreasing rates of cryptococcal disease and fluconazole use with widespread antiretroviral access, increasing rates of fluconazole resistance in Asia, Africa, and Latin America may be attributed to both the increasing uses of fluconazole in clinical setting as well as agricultural settings. The increasing use of triazole fungicides for preventing fungal diseases in crops (e.g. Black Banana Rot Disease) may also be responsible for the rise in fluconazole resistance in Cryptococcus isolates [8].\n\nCryptococcus demonstrates an intrinsic mechanism of survival by adapting to stress caused by stepwise increases in fluconazole concentrations [5]. Prior to the advent and widespread use of azoles, isolates analyzed demonstrated subpopulations of resistant strains able to grow at concentrations of fluconazole between 4 and 64 μg/mL [9]. Fluconazole resistant strains collected from AIDS patients have demonstrated subpopulations of resistant strains that can grow at fluconazole concentrations of 16 and 128 μg/mL [9]. Genetic sequencing has shown that during antifungal therapy, Cryptococcus can undergo mutations that give rise to subpopulations of cells that are drug-resistant [10]. These resistant strains of Cryptococcus can alter their growth rate when exposed to fluconazole, such that fluconazole resistant isolates grow slower than isolates that are susceptible to fluconazole [8]. Therefore, when exposed to fluconazole, susceptible cells are eliminated, while a subpopulation of resistant cells, which exhibit slow growth at higher concentrations of fluconazole, are selected for and can emerge to cause a relapse of clinical disease.\n\nThe clinical significance of the increasing trends of Cryptococcus strains exhibiting fluconazole resistance has not yet been elucidated and studies have had contradictory findings, albeit all with small sample sizes. Nasri et al. found that there was no association between elevated MIC and mortality in 13 out of 35 individuals with Cryptococcus strains with elevated MIC ≥ 16 μg/mL [11]. In Uganda, Smith et al. found a trend towards reduced 2-week culture positivity and lower mortality in individuals who had fluconazole resistant strains of Cryptococcus, although, the sample size was too small to conclude any statistically significant associations [8]. Aller et al. observed better clinical outcomes after maintenance therapy in Cryptococcus strains with fluconazole MIC < 16 μg/mL and a statistically significant association between a MIC ≥ 16 μg/mL and mortality, however, only 5 out of 25 individuals demonstrated elevated fluconazole MIC [12].\n\nThis case represents the emerging clinical dilemma that increasing rates in fluconazole resistant strains of Cryptococcus pose. Widespread use of fluconazole, in addition to inadequate and interruptive uses of fluconazole therapy in the treatment of both cryptococcal antigenemia and cryptococcal meningitis, has lead to an increase in strains of Cryptococcus having elevated MICs. Routine susceptibility testing is not currently recommended in first episodes of cryptococcal meningitis. However, in persons with prior fluconazole use or a history of medication non-adherence with frequent interruptions in therapy leading to relapsed or persistent cases of cryptococcal meningitis, susceptibility testing should be pursued. Although the clinical significance of increased fluconazole MIC is still undetermined, treatment failure and clinical relapse have been documented in cases of elevated fluconazole MIC. As demonstrated in this case, high dose fluconazole can be utilized throughout the consolidation and maintenance phases to maintain CSF sterility, especially in cases when no other antifungals are available. The increasing emergence of fluconazole resistance is becoming a widespread concern. Trends in fluconazole susceptibility should continue to be monitored and emphasis on optimal fluconazole therapy and ongoing advocacy for increasing the availability of alternative antifungals in resource-limited settings should become a priority.\n\nAcknowledgements\nWe would like to thank Drs. Lillian Tugume, Reuben Kiggundu, Kenneth Ssebambulidde, and the ASTRO-CM team for their medical care. We also thank Andrew Akampurira, Tonny Luggya, Kizza Tadeo and the Makerere University Medical School Microbiology Laboratory team. We thank Drs. David Boulware and David Meya for their support in assisting with the drafting of the manuscript, and their input into the intellectual content. Support for this project was received via: the National Institutes of Neurologic Diseases and Stroke and Fogarty International Center (R01NS086312, K01TW010268, R25TW009345).\n\nConflict of interest\nThere are none.\n==== Refs\nReferences\n1 Mitchell T.G. Perfect J.R. Cryptococcosis in the era of AIDS--100 years after the discovery of Cryptococcus neoformans Clin. Microbiol. Rev. 8 4 1995 515 548 8665468 \n2 Rajasingham R. Smith R.M. Park B.J. Jarvis J.N. Govender N.P. Chiller T.M. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis Lancet Infect. Dis. 2017 \n3 Perfect J.R. Dismukes W.E. Dromer F. Goldman D.L. Graybill J.R. Hamill R.J. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america Clin. Infect. Dis.: Off. Publ. Infect. Dis. Soc. Am. 50 3 2010 291 322 \n4 Loyse A. Dromer F. Day J. Lortholary O. Harrison T.S. Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal J. Antimicrob. Chemother. 68 11 2013 2435 2444 23788479 \n5 Cheong J.W. McCormack J. Fluconazole resistance in cryptococcal disease: emerging or intrinsic? Med. Mycol. 51 3 2013 261 269 22989195 \n6 Pfaller M.A. Diekema D.J. Gibbs D.L. Newell V.A. Bijie H. Dzierzanowska D. Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: 10.5-year analysis of susceptibilities of noncandidal yeast species to fluconazole and voriconazole determined by CLSI standardized disk diffusion testing J. Clin. Microbiol. 47 1 2009 117 123 19005141 \n7 Chen Y.C. Chang T.Y. Liu J.W. Chen F.J. Chien C.C. Lee C.H. Increasing trend of fluconazole-non-susceptible Cryptococcus neoformans in patients with invasive cryptococcosis: a 12-year longitudinal study BMC Infect. Dis. 15 2015 277 26194004 \n8 Smith K.D. Achan B. Hullsiek K.H. McDonald T.R. Okagaki L.H. Alhadab A.A. Increased antifungal drug resistance in clinical isolates of cryptococcus neoformans in Uganda Antimicrob. Agents Chemother. 59 12 2015 7197 7204 26324276 \n9 Sionov E. Chang Y.C. Garraffo H.M. Kwon-Chung K.J. Heteroresistance to fluconazole in Cryptococcus neoformans is intrinsic and associated with virulence Antimicrob. Agents Chemother. 53 7 2009 2804 2815 19414582 \n10 Rhodes J. Beale M.A. Vanhove M. Jarvis J.N. Kannambath S. Simpson J.A. A population genomics approach to assessing the genetic basis of within-host microevolution underlying recurrent cryptococcal meningitis infection G3 7 4 2017 1165 1176 28188180 \n11 Nasri H. Kabbani S. Bou Alwan M. Wang Y.F. Rebolledo P.A. Kraft C.S. Retrospective study of cryptococcal meningitis with elevated minimum inhibitory concentration to fluconazole in immunocompromised patients Open Forum Infect. Dis. 3 2 2016 ofw076 27419153 \n12 Aller A.I. Martin-Mazuelos E. Lozano F. Gomez-Mateos J. Steele-Moore L. Holloway W.J. Correlation of fluconazole MICs with clinical outcome in cryptococcal infection Antimicrob. Agents Chemother. 44 6 2000 1544 1548 10817706\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2211-7539",
"issue": "19()",
"journal": "Medical mycology case reports",
"keywords": "Antifungal susceptibility; Cryptococcal meningitis; Cryptococcal meningitis relapse; Cryptococcus; Fluconazole resistance",
"medline_ta": "Med Mycol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101598259",
"other_id": null,
"pages": "30-32",
"pmc": null,
"pmid": "29234588",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": "28188180;22989195;23788479;20047480;8665468;26324276;27419153;28483415;19005141;26194004;10817706;19414582",
"title": "Emerging fluconazole resistance: Implications for the management of cryptococcal meningitis.",
"title_normalized": "emerging fluconazole resistance implications for the management of cryptococcal meningitis"
} | [
{
"companynumb": "UG-GILEAD-2018-0313894",
"fulfillexpeditecriteria": "1",
"occurcountry": "UG",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": null,
... |
{
"abstract": "Acinetobacter baumannii has evolved in recent decades as a major problem in carbapenem-resistant gram-negative nosocomial infections, associated with high mortality rates especially in intensive care units (ICUs). Recent reports highlight the increasing prevalence of resistance to colistin, a last resort therapeutic option for carbapenem-resistant A. baumannii. We retrospectively evaluated the potential efficacy, in terms of clinical and microbiological cure and mortality, of a combination of intravenous colistin and high-dose ampicillin/sulbactam and high-dose tigecycline, concurrently administered with inhaled colistin, in 10 ICU patients with ventilator-associated pneumonia (VAP) caused by carbapenem- and colistin-resistant A. baumannii strains, with high tigecycline MICs > 2μg/mL. Nine patients (90%) exhibited a successful clinical outcome, accompanied by microbiological eradication in seven of them. All clinically cured patients survived at 14 and 28 days. Acute kidney injury (AKI) was observed in one patient. In view of the increasing prevalence of pan-drug resistant A. baumannii infections in ICUs, its associated high rates of mortality and the lack of effective treatment options, we feel that there is an emerging need for our results to be further validated in larger prospective studies.",
"affiliations": "Department of Internal Medicine, Division of Infectious Diseases, University of Patras Medical School, Patras, Greece.;Department of Anaesthesiology and Intensive Care Medicine, University of Patras Medical School, Patras, Greece.;Department of Anaesthesiology and Intensive Care Medicine, University of Patras Medical School, Patras, Greece.;Department of Anaesthesiology and Intensive Care Medicine, University of Patras Medical School, Patras, Greece.;Department of Microbiology, University of Patras Medical School, Patras, Greece.;Department of Microbiology, University of Patras Medical School, Patras, Greece.;Department of Anaesthesiology and Intensive Care Medicine, University of Patras Medical School, Patras, Greece.;Department of Internal Medicine, Division of Infectious Diseases, University of Patras Medical School, Patras, Greece.;Department of Internal Medicine, Division of Infectious Diseases, University of Patras Medical School, Patras, Greece.",
"authors": "Assimakopoulos|Stelios F|SF|;Karamouzos|Vassilis|V|;Lefkaditi|Aikaterini|A|;Sklavou|Christina|C|;Kolonitsiou|Fevronia|F|;Christofidou|Mirto|M|;Fligou|Fotini|F|;Gogos|Charalambos|C|;Marangos|Markos|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D000667:Ampicillin; D013407:Sulbactam; D003091:Colistin",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1124-9390",
"issue": "27(1)",
"journal": "Le infezioni in medicina",
"keywords": null,
"medline_ta": "Infez Med",
"mesh_terms": "D040981:Acinetobacter baumannii; D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000667:Ampicillin; D000900:Anti-Bacterial Agents; D003091:Colistin; D003131:Combined Modality Therapy; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D053717:Pneumonia, Ventilator-Associated; D012189:Retrospective Studies; D013407:Sulbactam; D000078304:Tigecycline",
"nlm_unique_id": "9613961",
"other_id": null,
"pages": "11-16",
"pmc": null,
"pmid": "30882373",
"pubdate": "2019-03-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Triple combination therapy with high-dose ampicillin/sulbactam, high-dose tigecycline and colistin in the treatment of ventilator-associated pneumonia caused by pan-drug resistant Acinetobacter baumannii: a case series study.",
"title_normalized": "triple combination therapy with high dose ampicillin sulbactam high dose tigecycline and colistin in the treatment of ventilator associated pneumonia caused by pan drug resistant acinetobacter baumannii a case series study"
} | [
{
"companynumb": "GR-AXELLIA-002373",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "We report a case of altered consciousness related to hyperammonemia due to FOLFIRI plus bevacizumab therapy in a patient with recurrent colorectal cancer and renal dysfunction.A 76-year-old man received third-line chemotherapy for left mediastinal lymph node metastasis.He complained of diarrhea on the evening of the same day, and mental confusion on day 3 of the first FOLFIRI therapy.He had a JCS of Ⅲ(200).The laboratory results revealed a marked hyperammonemia.5 - fluorouracil(5-FU)-induced hyperammonemia was diagnosed and the patient was ventilated and managed with branchedchain amino acid solutions, lactulose, and hemodialysis in the ICU.After hemodialysis, the blood ammonia level reduced to the normal limits, and the symptoms of encephalopathy resolved on the following day.He was discharged home on the 19th day of hospitalization.5 -FU-containing therapy should be carefully administered in patients with renal dysfunction.Herein, we report a case of 5-FU-induced hyperammonemia with literature considerations.",
"affiliations": "Dept. of Surgery, Yokohama City University.",
"authors": "Sawazaki|Sho|S|;Numata|Masakatsu|M|;Ju|Mihwa|M|;Morita|Junya|J|;Komori|Keisuke|K|;Maezawa|Yukio|Y|;Amano|Shinya|S|;Aoyama|Toru|T|;Tamagawa|Hiroshi|H|;Sato|Tsutomu|T|;Oshima|Takashi|T|;Mushiake|Hiroyuki|H|;Yukawa|Norio|N|;Masuda|Munetaka|M|;Rino|Yasushi|Y|",
"chemical_list": "D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "46(10)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D015179:Colorectal Neoplasms; D003243:Consciousness; D005472:Fluorouracil; D006801:Humans; D022124:Hyperammonemia; D002955:Leucovorin; D008297:Male; D009364:Neoplasm Recurrence, Local",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1632-1634",
"pmc": null,
"pmid": "31631158",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case Altered Consciousness Due to 5-Fluorouracil-Induced Hyperammonemia in a Patient with Recurrent Colorectal Cancer.",
"title_normalized": "a case altered consciousness due to 5 fluorouracil induced hyperammonemia in a patient with recurrent colorectal cancer"
} | [
{
"companynumb": "JP-ACCORD-160891",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "OBJECTIVE\nThis multicenter cooperative study aimed to analyze the adverse events (AEs) associated with tyrosine kinase inhibitors (TKIs) used as initial treatment for chronic-phase chronic myeloid leukemia (CML-CP) and their impact on outcome.\n\n\nMETHODS\nWe retrospectively evaluated 450 patients with CML-CP who received TKIs between 2004 and 2014.\n\n\nRESULTS\nThe 5-year overall survival (OS) and event-free survival (EFS) rates were 95.1% and 89.0%, respectively. Patients with comorbidities (46.4%) and aged ≥60 years (50.4%) at diagnosis had significantly inferior OS to those without comorbidities and aged <60. Patients achieved higher rates of major molecular response (MMR) at 6 and 12 months after initial treatment with dasatinib or nilotinib compared to imatinib, but final MMR rates were almost the same. Sixty-six percent of patients required treatment modifications from first-line TKI therapy; the main reasons were AEs (48.4%) and failure (18%). Grade III-IV AEs in first-line TKI therapy were significantly correlated to inferior OS/EFS compared to grade 0-II AEs.\n\n\nCONCLUSIONS\nAlthough long-term outcomes were similar in CML-CP patients treated with each TKI regardless of first-line TKI selection, severe AEs in first-line TKI therapy decreased their survival rates. Early change in TKIs is recommended, when faced with severe AEs of specific TKIs.",
"affiliations": "Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan.;Department of Hematology, Kushiro Rosai Hospital, Kushiro, Japan.;Department of Hematology, Sapporo City General Hospital, Sapporo, Japan.;Department of Hematology, Hakodate Municipal Hospital, Hakodate, Japan.;Department of Hematology, Asahikawa Medical University, Asahikawa, Japan.;Department of Hematology/Oncology, Asahikawa Kosei Hospital, Asahikawa, Japan.;Faculty of Medicine and Graduate School of Medicine, Department of Hematology, Hokkaido University, Sapporo, Japan.;Department of Hematology, Japanese Red Cross Asahikawa Hospital, Asahikawa, Japan.;Department of Hematology, Teine Keijinkai Hospital, Sapporo, Japan.;Department of Hematology, Aiiku Hospital, Sapporo, Japan.;Department of Hematology, Tenshi Hospital, Sapporo, Japan.;Department of Hematology, Sapporo Medical University, Sapporo, Japan.;Department of Hematology, Steel Memorial Muroran Hospital, Muroran, Japan.;Department of Hematology, Tonan Hospital, Sapporo, Japan.;Department of Pediatrics, Sapporo Medical University, Sapporo, Japan.;Department of Pediatrics, Asahikawa Medical University, Asahikawa, Japan.;Department of Pediatrics, Japanese Red Cross Asahikawa Hospital, Asahikawa, Japan.;Department of Hematology/Oncology for Children and Adolescent, Sapporo Hokuyu Hospital, Sapporo, Japan.;Department of Hematology and Oncology, NTT East Japan Sapporo Hospital, Sapporo, Japan.;Department of Hematology, Kin-ikyo Chuo Hospital, Sapporo, Japan.;Department of Hematology, Higashisapporo Hospital, Sapporo, Japan.;Department of Hematology, Asahikawa City Hospital, Asahikawa, Japan.;Department of Hematology, Obihiro Kosei Hospital, Obihiro, Japan.;Palliative Care Center, Sapporo Kosei Hospital, Sapporo, Japan.;Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan.;Department of Hematology, Hokkaido Cancer Center, Sapporo, Japan.",
"authors": "Ota|Shuichi|S|http://orcid.org/0000-0002-3631-244X;Matsukawa|Toshihiro|T|;Yamamoto|Satoshi|S|;Ito|Shinichi|S|;Shindo|Motohiro|M|;Sato|Kazuya|K|;Kondo|Takeshi|T|;Kohda|Kyuhei|K|;Sakai|Hajime|H|;Mori|Akio|A|;Takahashi|Tohru|T|;Ikeda|Hiroshi|H|;Kuroda|Hiroyuki|H|;Haseyama|Yoshihito|Y|;Yamamoto|Masaki|M|;Sarashina|Takeo|T|;Yoshida|Makoto|M|;Kobayashi|Ryoji|R|;Nishio|Mitsufumi|M|;Ishihara|Toshimichi|T|;Hirayama|Yasuo|Y|;Kakinoki|Yasutaka|Y|;Kobayashi|Hajime|H|;Fukuhara|Takashi|T|;Imamura|Masahiro|M|;Kurosawa|Mitsutoshi|M|",
"chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13081",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "101(1)",
"journal": "European journal of haematology",
"keywords": "adverse events; chronic myeloid leukemia; dasatinib; imatinib; nilotinib; tyrosine kinase inhibitor",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D000069439:Dasatinib; D005260:Female; D016044:Fusion Proteins, bcr-abl; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "95-105",
"pmc": null,
"pmid": "29660177",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Severe adverse events by tyrosine kinase inhibitors decrease survival rates in patients with newly diagnosed chronic-phase chronic myeloid leukemia.",
"title_normalized": "severe adverse events by tyrosine kinase inhibitors decrease survival rates in patients with newly diagnosed chronic phase chronic myeloid leukemia"
} | [
{
"companynumb": "PHHY2018JP011982",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": null,
... |
{
"abstract": "Chronic orofacial pain is a complex multidimensional experience that produces disability and impairment of normal mandibular function. Overall estimations of chronic orofacial pain prevalence are 7 to 11% of the general population. Temporomandibular disorders (TMDs) are one of the most prevalent chronic orofacial pain conditions, with temporomandibular joint (TMJ) arthralgia accounting for 30.1% of TMD patients. Interventional procedures are often used in pain and palliative medicine to achieve reasonable and cost-effective pain relief. The use of intra-articular corticosteroids in relieving arthralgia and improving joint function has been well documented. We present the clinical case of an 84-year-old female patient who presented to the Hospital del Salvador orofacial pain service with preauricular pain, limited range of motion, provoked pain at palpation, and decreased function in the preauricular region. In accordance with the DC/TMD criteria, left TMJ arthralgia and degenerative joint disease was diagnosed and was later corroborated by cone beam computed tomography. An intra-articular injection of 10 mg of methylprednisolone was prescribed, and the patient underwent the procedure in accordance with Hospital del Salvador's intra-articular injection protocol. The patient underwent the intervention without any inconvenience. At the 3-week follow-up visit, the patient presented with a depigmented depression zone adjacent to the site of injection. After echotomography, we concluded that the patient had developed skin depigmentation and subcutaneous lipoatrophy related to the intra-articular injection of methylprednisolone. To the best of our knowledge, this is the first report of this complication secondary to an interventional procedure in the TMJ. Clinicians should be aware of, and patients must be advised of, this rare complication before an intra-articular intervention.",
"affiliations": "Staff, Clinical Coordinator, and Associate Professor, Department of Orofacial Pain and TMDs, Hospital del Salvador, del Servicio Salud Metropolitano Oriente, Santiago, Chile; Private Practitioner, Orofacial Pain, OPH Dental, Santiago, Chile; Private Practitioner, Orofacial Pain, EOC Odontología, Santiago, Chile; and Continuum Dental Education Program in Clinical Occlusion and TMD Diagnostics, Clínica Alemana Santiago, Universidad del Desarrollo, Santiago, Chile. Electronic address: nicolas.skarmeta@gmail.com.;Adjunct Instructor, School of Dental Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago; and Staff, Orofacial Pain, Pain Unit, Hospital Clínico Mutual de Seguridad de la Cámara Chilena de la Construcción, Santiago, Chile.;Head, Dental Service, Hospital del Salvador, del Servicio Salud Metropolitano Oriente, Santiago, Chile.;Head, Department of Maxillofacial Radiology, Hospital del Salvador, del Servicio Salud Metropolitano Oriente, Santiago, Chile; Associate Professor, Department of Maxillofacial Radiology, University Mayor, Santiago, Chile.",
"authors": "Skármeta|Nicolás Patricio|NP|;Hormazábal|Fernando Ariel|FA|;Alvarado|Juan|J|;Rodriguez|Ana Maria|AM|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.joms.2017.07.174",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-2391",
"issue": "75(12)",
"journal": "Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons",
"keywords": null,
"medline_ta": "J Oral Maxillofac Surg",
"mesh_terms": "D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents; D018771:Arthralgia; D001284:Atrophy; D005260:Female; D006801:Humans; D017496:Hypopigmentation; D007270:Injections, Intra-Articular; D008060:Lipodystrophy; D008775:Methylprednisolone; D050151:Subcutaneous Fat; D013705:Temporomandibular Joint Disorders",
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "2540.e1-2540.e5",
"pmc": null,
"pmid": "28866048",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Subcutaneous Lipoatrophy and Skin Depigmentation Secondary to TMJ Intra-Articular Corticosteroid Injection.",
"title_normalized": "subcutaneous lipoatrophy and skin depigmentation secondary to tmj intra articular corticosteroid injection"
} | [
{
"companynumb": "PHHY2017CL191983",
"fulfillexpeditecriteria": "1",
"occurcountry": "CL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "RhD immunoglobulin G (anti-D) administered to pregnant Rh(-) women prevents Rh isoimmunization. Its use has significantly reduced the incidence of haemolytic disease of the foetus and newborn previously responsible for one death in every 2200 births. In pregnancy, acute drug-induced hypersensitivity reactions including anaphylaxis can have serious deleterious effects on the mother and foetus/neonate. Women can be erroneously labelled as drug allergic as the investigation of hypersensitivity reactions in pregnancy is complex and drug challenges are usually contraindicated. We present three cases of suspected anti-D hypersensitivity clinically presenting as anaphylaxis and delayed transfusion-related reaction. We also propose a new algorithm for the investigations of such reaction. It relies on detailed history, cautious interpretation of skin tests, foetal Rh genotyping from maternal blood and, in some cases, anti-D challenges. This is not to deprive women of anti-D which might put their future pregnancies at risk.",
"affiliations": "Allergy Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.",
"authors": "Rutkowski|K|K|;Nasser|S M|SM|",
"chemical_list": "D007518:Isoantibodies; C061961:RHO(D) antibody; D018029:Rho(D) Immune Globulin",
"country": "Denmark",
"delete": false,
"doi": "10.1111/all.12494",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0105-4538",
"issue": "69(11)",
"journal": "Allergy",
"keywords": "anaphylaxis; anti-D; desensitisation; drug allergy; noninvasive Rh foetal genotyping",
"medline_ta": "Allergy",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D019468:Disease Management; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D007518:Isoantibodies; D011247:Pregnancy; D018029:Rho(D) Immune Globulin; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7804028",
"other_id": null,
"pages": "1560-3",
"pmc": null,
"pmid": "25066207",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of hypersensitivity reactions to anti-D immunoglobulin preparations.",
"title_normalized": "management of hypersensitivity reactions to anti d immunoglobulin preparations"
} | [
{
"companynumb": "GB-BEH-2013035075",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HUMAN RHO(D) IMMUNE GLOBULIN"
},
"drugadditional": n... |
{
"abstract": "Refeeding syndrome is a life-threatening condition occurring in severely malnourished patients after initiating feeding. Severe hypophosphatemia with reduced adenosine triphosphate production has been implicated, but little data are available regarding electrolyte abnormalities. In this case, we report electrocardiographic changes consistent with hyperkalemia during potassium replacement after a serum level increase from 1.9 to 2.9 mEq/L. This was reversed by lowering serum potassium back to 2.0 mEq/L. In conclusion, the patient with prolonged malnutrition became adapted to low potassium levels and developed potassium toxicity with replacement.",
"affiliations": "Department of Medicine, Michigan State University, East Lansing, Michigan.;Department of Medicine, Michigan State University, East Lansing, Michigan.;Department of Medicine, Michigan State University, East Lansing, Michigan; Division of Cardiology, Department of Medicine, East Lansing, Michigan.;Transthoracic Cardiovascular Institute/Sparrow Hospital, Lansing, Michigan.;Department of Medicine, Michigan State University, East Lansing, Michigan; Division of Cardiology, Department of Medicine, East Lansing, Michigan. Electronic address: george.abela@ht.msu.edu.",
"authors": "Vemula|Praveen|P|;Abela|Oliver G|OG|;Narisetty|Keerthy|K|;Rhine|David|D|;Abela|George S|GS|",
"chemical_list": "D011188:Potassium",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9149",
"issue": "115(1)",
"journal": "The American journal of cardiology",
"keywords": null,
"medline_ta": "Am J Cardiol",
"mesh_terms": "D004562:Electrocardiography; D002149:Energy Intake; D005260:Female; D006801:Humans; D006947:Hyperkalemia; D008875:Middle Aged; D011188:Potassium; D055677:Refeeding Syndrome; D012720:Severity of Illness Index",
"nlm_unique_id": "0207277",
"other_id": null,
"pages": "147-9",
"pmc": null,
"pmid": "25456880",
"pubdate": "2015-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Potassium toxicity at low serum potassium levels with refeeding syndrome.",
"title_normalized": "potassium toxicity at low serum potassium levels with refeeding syndrome"
} | [
{
"companynumb": "PHHY2014US147745",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "POTASSIUM CHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Influenza A(H1N1)pdm09 viruses carrying a dual neuraminidase (NA) substitution were isolated from immunocompromised patients after administration of one or more NA inhibitors. These mutant viruses possessed an H275Y/I223R, H275Y/I223K, or H275Y/G147R substitution in their NA and showed enhanced cross-resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir compared to single H275Y mutant viruses. Baloxavir could be a treatment option against the multidrug-resistant viruses because these dual H275Y mutant viruses showed susceptibility to this drug. The G147R substitution appears to stabilize the NA structure, with the fitness of the H275Y/G147R mutant virus being similar or somewhat better than that of the wild-type virus. Since the multidrug-resistant viruses may be able to transmit between humans, surveillance of these viruses must continue to improve clinical management and to protect public health.",
"affiliations": "Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.;Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.;Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.;Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.;Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.;Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.;Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.;Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.;Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.;Ibaraki Prefectural Institute of Public Health, Ibaraki 310-0852, Japan.;Tsukuba Memorial Hospital, Ibaraki 300-2622, Japan.;Hiroshima Prefectural Technology Research Institute, Hiroshima 734-0007, Japan.;Hiroshima Prefectural Technology Research Institute, Hiroshima 734-0007, Japan.;National Hospital Organization Hiroshimanishi Medical Center, Hiroshima 739-0696, Japan.;National Hospital Organization Kure Medical Center, Hiroshima 737-0023, Japan.;Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.;Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.",
"authors": "Takashita|Emi|E|0000-0002-9064-4699;Fujisaki|Seiichiro|S|;Yokoyama|Masaru|M|;Shirakura|Masayuki|M|;Morita|Hiroko|H|;Nakamura|Kazuya|K|;Kishida|Noriko|N|;Kuwahara|Tomoko|T|;Sato|Hironori|H|;Doi|Ikuko|I|;Sato|Yuji|Y|;Takao|Shinichi|S|;Shimazu|Yukie|Y|;Shimomura|Takeshi|T|;Ito|Takuo|T|;Watanabe|Shinji|S|;Odagiri|Takato|T|;The Influenza Virus Surveillance Group Of Japan|||",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/pathogens9090725",
"fulltext": "\n==== Front\nPathogens\nPathogens\npathogens\nPathogens\n2076-0817 MDPI \n\n10.3390/pathogens9090725\npathogens-09-00725\nArticle\nIn Vitro Characterization of Multidrug-Resistant Influenza A(H1N1)pdm09 Viruses Carrying a Dual Neuraminidase Mutation Isolated from Immunocompromised Patients\nhttps://orcid.org/0000-0002-9064-4699Takashita Emi 1* Fujisaki Seiichiro 1 https://orcid.org/0000-0003-1641-0365Yokoyama Masaru 2 Shirakura Masayuki 1 Morita Hiroko 1 Nakamura Kazuya 1 Kishida Noriko 1 Kuwahara Tomoko 1 Sato Hironori 2 Doi Ikuko 3 Sato Yuji 4 Takao Shinichi 5 Shimazu Yukie 5 Shimomura Takeshi 6 Ito Takuo 7 Watanabe Shinji 1 Odagiri Takato 1on behalf of The Influenza Virus Surveillance Group of Japan † 1 Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan; seifuji@nih.go.jp (S.F.); masas@nih.go.jp (M.S.); h-morita@nih.go.jp (H.M.); kazuyan@nih.go.jp (K.N.); kishidan@nih.go.jp (N.K.); kuwahara@nih.go.jp (T.K.); sw@nih.go.jp (S.W.); todagiri@nih.go.jp (T.O.)\n2 Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan; yokoyama@nih.go.jp (M.Y.); hirosato@nih.go.jp (H.S.)\n3 Ibaraki Prefectural Institute of Public Health, Ibaraki 310-0852, Japan; i.doi@pref.ibaraki.lg.jp\n4 Tsukuba Memorial Hospital, Ibaraki 300-2622, Japan; satou_yuji@tsukuba-kinen.or.jp\n5 Hiroshima Prefectural Technology Research Institute, Hiroshima 734-0007, Japan; s-takaoe1077@pref.hiroshima.lg.jp (S.T.); y-shimazu89236@pref.hiroshima.lg.jp (Y.S.)\n6 National Hospital Organization Hiroshimanishi Medical Center, Hiroshima 739-0696, Japan; shimomuratakeshi2010@gmail.com\n7 National Hospital Organization Kure Medical Center, Hiroshima 737-0023, Japan; itot@kure-nh.go.jp\n* Correspondence: emitaka@nih.go.jp† The members of the group are listed in the Acknowledgments.\n\n\n02 9 2020 \n9 2020 \n9 9 72512 8 2020 31 8 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Influenza A(H1N1)pdm09 viruses carrying a dual neuraminidase (NA) substitution were isolated from immunocompromised patients after administration of one or more NA inhibitors. These mutant viruses possessed an H275Y/I223R, H275Y/I223K, or H275Y/G147R substitution in their NA and showed enhanced cross-resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir compared to single H275Y mutant viruses. Baloxavir could be a treatment option against the multidrug-resistant viruses because these dual H275Y mutant viruses showed susceptibility to this drug. The G147R substitution appears to stabilize the NA structure, with the fitness of the H275Y/G147R mutant virus being similar or somewhat better than that of the wild-type virus. Since the multidrug-resistant viruses may be able to transmit between humans, surveillance of these viruses must continue to improve clinical management and to protect public health.\n\ninfluenzaneuraminidase inhibitoroseltamivirperamivirzanamivirlaninamivirbaloxavirfavipiravirresistance\n==== Body\n1. Introduction\nIn Japan, four neuraminidase (NA) inhibitors––oseltamivir, peramivir, zanamivir, and laninamivir––and a cap-dependent endonuclease inhibitor, baloxavir marboxil, have been approved for the treatment of influenza [1]. In addition, favipiravir, a viral RNA-dependent RNA polymerase inhibitor, has been approved for influenza pandemic preparedness [2]. Since nationwide monitoring is important for public health planning and clinical management, we have been conducting surveillance of antiviral-resistant viruses.\n\nDuring our surveillance, we detected multidrug-resistant influenza A(H1N1)pdm09 viruses from immunocompromised patients [3,4,5]. These viruses possessed an I223K, an I223R, or a G147R substitution in combination with an H275Y substitution in their NA protein. Several studies have reported the detection of A(H1N1)pdm09 viruses carrying a dual H275Y substitution, such as H275Y/E119D, H275Y/E119G, H275Y/I223K, H275Y/I223R, and H275Y/S247N, from immunocompromised patients [6,7,8,9,10,11]. A few studies have been carried out to understand the impact of the H275Y/E119D and H275Y/I223R substitutions on viral fitness [12,13,14]; however, that of the H275Y/I223K and H275Y/G147R substitutions remains unknown. Here, we report our assessment of the in vitro properties of H275Y/I223K, H275Y/I223R, and H275Y/G147R dual mutant viruses isolated from immunocompromised patients.\n\n2. Materials and Methods\n2.1. Viruses\nThe dual H275Y mutant viruses (H275Y/I223K, H275Y/I223R, and H275Y/G147R) were detected from immunocompromised patients hospitalized in hematology departments after administration of one or more NA inhibitors (Table 1). The representative single H275Y mutant and wild-type viruses detected during the same influenza season are shown in Table 2. These representative viruses are genetically most closely related to the corresponding dual H275Y mutant viruses in the Global Initiative on Sharing All Influenza Data (GISAID) EpiFlu database (http://www.gisaid.org). A/Hiroshima/57/2014, A/Osaka/8/2014, and A/Sakai/23/2013 have hemagglutinin (HA) genes that belong to genetic clade 6B. A/Ibaraki/54/2016, A/Yokohama/94/2016, and A/Yokohama/40/2016 have HA genes that belong to genetic clade 6B.1. A/Hiroshima/13/2016, A/Aichi/83/2016, and A/Yokohama/59/2016 have HA genes that belong to genetic clade 6B.2. All viruses were propagated in MDCK (NBL-2) cells (ATCC CCL-34). The dual substitutions were confirmed in both clinical specimens and isolates by sequencing them.\n\n2.2. Antiviral Compounds\nOseltamivir acid, peramivir trihydrate, and zanamivir hydrate were purchased from Biosynth Carbosynth (Berkshire, UK). Laninamivir was provided by Daiichi Sankyo (Tokyo, Japan). Baloxavir acid was purchased from MedChemExpress (Monmouth Junction, NJ, USA), and favipiravir was purchased from Cayman Chemical (Ann Arbor, MI, USA). Oseltamivir, peramivir, zanamivir, laninamivir, and favipiravir were dissolved in distilled water, and baloxavir was dissolved in dimethyl sulfoxide.\n\n2.3. NA Inhibition Assay\nNA inhibitor susceptibilities were determined by using a fluorescence-based NA inhibition assay with the NA-Fluor influenza neuraminidase assay kit (Applied Biosystems, Foster City, CA, USA) and 4-MU-NANA substrate (Biosynth Carbosynth). Briefly, diluted viruses were mixed with 20-fold serial dilutions of 125,000 nM oseltamivir, peramivir, zanamivir, or laninamivir and incubated for 20 min at 37 °C; 4-MU-NANA substrate was then added, and the mixture was incubated for 30 min at 37 °C. The reaction was stopped by adding 0.12 M Na2CO3 in 40% ethanol. The fluorescence of the solution was measured at an excitation wavelength of 355 nm and an emission wavelength of 460 nm. The results are expressed as 50% inhibitory concentration (IC50) values, which were calculated by using GraphPad Prism (GraphPad Software, San Diego, CA, USA).\n\n2.4. Focus Reduction Assay\nBaloxavir susceptibilities were determined by using a focus reduction assay as previously described [1] in humanized MDCK cells (i.e., hCK cells), which express high levels of α2,6-sialoglycans and very low levels of α2,3-sialoglycans [15]. hCK cells were kindly provided by Dr. Yoshihiro Kawaoka (University of Wisconsin–Madison). hCK cells in 96-well plates were infected with 1000 focus-forming units (FFU)/well of viruses. Virus adsorption was carried out for 1 h at 37 °C and then an equal volume of 1.2% Avicel RC-581 (DuPont Nutrition USA, Wilmington, DE, USA) in culture medium containing serial dilutions (0.025–2500 nM) of baloxavir was added to each well in triplicate. The cells were incubated for 24 h at 34 °C and then fixed with formalin. After the formalin was removed, the cells were immunostained with a mouse monoclonal antibody against influenza A virus nucleoprotein (Merck KGaA, Darmstadt, Germany), followed by a horseradish peroxidase-labeled goat anti-mouse immunoglobulin (SeraCare Life Sciences, Milford, MA, USA). The infected cells were stained with TrueBlue Substrate (SeraCare Life Sciences) and then washed with distilled water. After cell drying, the focus numbers were quantified by using an ImmunoSpot S6 Analyzer, ImmunoCapture software, and BioSpot software (Cellular Technology, Cleveland, OH, USA). The results are expressed as IC50 values.\n\n2.5. Cytopathic Effect Reduction Assay\nFavipiravir susceptibilities were determined by using a cytopathic effect reduction assay as previously described [2] in AX4 cells, which overexpress α2,6-sialoglycans [16]. AX4 cells were kindly provided by Dr. Yoshihiro Kawaoka. AX4 cells in 96-well plates were infected with viruses at a multiplicity of infection (MOI) of 0.01 50% tissue culture infective dose (TCID50)/cell. Virus adsorption was carried out for 1 h at 37 °C and then an equal volume of culture medium containing serial dilutions (0.05–1000 nM) of favipiravir was added to each well in triplicate. The cells were incubated for 3–5 days at 34 °C. To determine the extent of the cytopathic effect, the CellTiter-Glo 2.0 Assay reagent (Promega Corporation, Madison, WI, USA) was added and luminescence was measured. The results are expressed as 50% effective concentration (EC50) values, which were calculated by using GraphPad Prism.\n\n2.6. Plaque Assay\nVirus titrations were conducted by using a plaque assay as previously described [2] in AX4 cells. AX4 cells in 6-well plates were infected with serial dilutions of viruses in triplicate. Virus adsorption was carried out for 1 h at 37 °C. After the inoculum was removed, 0.8% agarose in culture medium was added to each well. The cells were incubated for 3 days at 34°C and the plaque numbers were counted.\n\n2.7. Virus Replication Kinetics In Vitro\nIn vitro replication kinetics of the dual H275Y mutant viruses were determined as previously described [17] in AX4 cells. AX4 cells were infected with viruses at an MOI of 0.001 plaque-forming units (PFU)/cell in triplicate. The cells were incubated at 34°C. The supernatants were harvested at 12, 24, 36, 48, 60, and 72 h post-infection and were subjected to virus titration by using plaque assays.\n\n2.8. Competitive Virus Replication In Vitro\nThe competitive growth capability of each dual H275Y mutant virus with that of the wild-type virus was compared as previously described [18] in AX4 cells. Each dual H275Y mutant virus was coinfected with the corresponding wild-type virus at an MOI of 0.01 PFU/cell in triplicate. The cells were incubated at 34 °C. At 2 days post-infection, the supernatants were subjected to virus titration by using plaque assays and to deep sequencing analysis to determine the relative proportion of each genotype. The viruses were serially passaged 3–4 times at an MOI of 0.01 PFU/cell.\n\n2.9. Deep Sequencing Analysis\nDeep sequencing analysis was performed as previously described [2]. A cDNA library was prepared from viral RNA by using the NEBNext Ultra RNA Library Prep Kit for Illumina and NEBNext Singleplex Oligos for Illumina (New England Biolabs, Ipswich, MA, USA), followed by purification by using Agencourt AMPure XP (Beckman Coulter, Brea, CA, USA). The library was sequenced by using MiSeq Reagent Kits v2 with MiSeq (Illumina, San Diego, CA, USA). Sequence reads were aligned to the reference sequence of A/California/07/2009(H1N1)pdm09 by using CLC Genomics Workbench 8 (CLC bio, Aarhus, Denmark).\n\n2.10. Structural Analysis of the NA Protein\nA structure model of the NA protein of each mutant virus was constructed by use of homology modeling and was refined by using Molecular Operating Environment (MOE) (Chemical Computing Group, Montreal, Canada) as previously described [18]. The crystal structure of the A(H1N1)pdm09 virus NA protein (PDB ID 4B7R; resolution, 1.9 Å) [19] served as the modeling template. Single-point mutations were generated on the NA model. Ensembles of the protein conformations were generated by using the LowMode MD module in MOE. The average stability changes of the ensembles were calculated by using the Boltzmann distribution. The stability scores (∆∆Gs) of the structures were obtained through the stability scoring function of the Protein Design application.\n\n2.11. Statistical Analysis\nStatistical analyses were performed using GraphPad Prism. Statistically significant differences between groups were determined by using an unpaired t-test calculated by fitting a mixed-effects model. p values of <0.05 were considered statistically significant.\n\n3. Results\n3.1. Immunocompromised Patients Infected with Dual H275Y Mutant Viruses\nThe clinical courses of the immunocompromised patients infected with the dual H275Y mutant viruses are shown in Table 1. The first patient, a woman in her late 70s who was infected with the H275Y/I223R mutant virus (A/Hiroshima/57/2014), was treated with peramivir (600 mg) on the day of symptom onset. After four days of peramivir treatment, the patient’s symptoms had not improved, and she was therefore treated with laninamivir (20 mg). She recovered after laninamivir administration. The second patient, a man in his late 70s who was infected with the H275Y/I223K mutant virus (A/Ibaraki/54/2016), was treated with peramivir (300 mg) on the day of symptom onset. His infection persisted for more than two weeks, so he then received combination therapy of peramivir (300 mg) and oseltamivir (75 mg twice daily) for seven days. However, the influenza rapid diagnostic test remained positive. Laninamivir (40 mg) was administered two days after the end of the combination therapy and after six days of laninamivir administration, the rapid diagnostic test was negative. The third patient, a woman in her early 50s who was infected with the H275Y/G147R mutant virus (A/Hiroshima/13/2016), received prophylaxis with laninamivir (40 mg). Three days later, she had onset of illness and was treated with peramivir (600 mg) for five days. Her infection persisted for more than one month and peramivir (600 mg) was administered for three intermittent periods of five days. She developed left lower lobe pneumonia 20 days post-disease onset and alveolar hemorrhage 12 days after. Two days after the end of the third five-day course, she died.\n\n3.2. Antiviral Susceptibilities of the Dual H275Y Mutant Viruses\nWe compared the susceptibility of the dual H275Y mutant viruses (A/Hiroshima/57/2014, A/Ibaraki/54/2016, and A/Hiroshima/13/2016) with that of the corresponding single H275Y mutant (A/Osaka/8/2014, A/Yokohama/94/2016, and A/Aichi/83/2016) and wild-type (A/Sakai/23/2013, A/Yokohama/40/2016, and A/Yokohama/59/2016) viruses to four NA inhibitors (oseltamivir, peramivir, zanamivir, and laninamivir), a cap-dependent endonuclease inhibitor, baloxavir, and a viral RNA-dependent RNA polymerase inhibitor, favipiravir (Table 2). The dual H275Y mutant viruses are genetically most closely related to the corresponding single H275Y mutant and wild-type viruses. The H275Y/I223R, H275Y/I223K, and H275Y/G147R mutant viruses exhibited enhanced cross-resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir compared to the corresponding single H275Y mutant viruses. The H275Y/I223R and H275Y/I223K mutant viruses, but not the H275Y/G147R mutant virus, showed reduced susceptibility to laninamivir. All viruses tested were susceptible to baloxavir and favipiravir.\n\n3.3. In Vitro Replication Kinetics of the Dual H275Y Mutant Viruses\nThe impact of the dual substitution on viral growth was assessed in AX4 cells, which overexpress the human influenza receptor (α2,6-sialoglycans) (Figure 1). Since each of the wild-type viruses has different genetic backgrounds, the virus titers of the wild-type viruses cannot be compared directly with each other. The virus titers of the H275Y/I223R mutant virus were found to be comparable to those of the corresponding wild-type virus as previously described [13]. The replication of the H275Y/I223K mutant virus was significantly reduced compared to that of the corresponding wild-type virus. The H275Y/G147R mutant and the corresponding wild-type viruses had comparable virus titers after 36 h post-infection; however, the dual mutant virus replicated more efficiently than the wild-type virus during the initial cycle of infection. The G147R substitution confers receptor-binding activity to the NA protein of the A(H1N1)pdm09 virus [20]. A higher receptor-binding activity may affect faster virus replication at the early stage of infection. These results indicate that the H275Y/I223K substitution negatively affects viral growth, at least in vitro, but that the H275Y/I223R and H275Y/G147R substitutions do not.\n\n3.4. Competitive Growth Capabilities of the Dual H275Y Mutant Viruses and the Wild-Type Viruses\nTo compare the competitive growth capability of the dual H275Y mutant viruses with that of wild-type viruses, each dual H275Y mutant virus was coinfected with its corresponding wild-type counterpart (Figure 2). The proportion of the H275Y/I223R mutant virus to that of the wild-type virus was similar at passage 1 and then decreased significantly, whereas the proportion of the H275Y/I223K mutant virus to that of the wild-type virus decreased significantly from passage 1. In contrast, the H275Y/G147R mutant virus rapidly became dominant in the mixed virus populations at passages 1 and 2, indicating that this mutant virus continued to replicate efficiently, competing with the wild-type virus during the initial cycle of infection. These results indicate that the growth capability of the H275Y/G147R virus is comparable to, or somewhat better than, that of the wild-type virus at least in vitro.\n\n3.5. Effects of Amino Acid Substitutions on the Stability of the NA Protein\nThe H275Y substitution caused a detrimental effect on viral fitness by decreasing the stability of the NA protein [21]. Additional substitutions, V241I and N369K, were thought to improve the stability of the NA, thereby compensating for the negative effects of the H275Y substitution on the growth and transmissibility of the mutant virus [22,23]. To assess the effect of the I223R, I223K, and G147R substitutions on the stability of the NA protein, we performed an in silico mutagenesis study as previously described [18] (Figure 3). The changes in stability caused by each of the substitutions I223R, I223K, and G147R were 1.32, 3.29, and -2.72 kcal/mol, respectively. These data suggest that the I223R and I223K substitutions may destabilize the NA structure, whereas the G147R substitution likely stabilizes NA, consistent with our previous finding [4].\n\n4. Discussion\nImmunocompromised patients are at great risk for emergence of NA inhibitor-resistant viruses [24,25,26,27]. The high frequency of resistant viruses among immunocompromised patients is associated with the high levels of viral titers and prolonged viral shedding in these patients [28,29,30,31]. A(H1N1)pdm09 viruses carrying the single H275Y substitution rapidly emerge during treatment with oseltamivir and/or peramivir in immunocompromised patients [32,33] and exhibit clinically significant cross-resistance to oseltamivir and peramivir [34]. In the present study, the dual H275Y mutant A(H1N1)pdm09 viruses showed enhanced cross-resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir compared to the single H275Y mutant viruses. Patients infected with the H275Y/I223R or H275Y/I223K mutant virus showed improved clinical and virologic responses after laninamivir treatment, although the laninamivir susceptibilities of these viruses were reduced. The H275Y/G147R mutant virus retained susceptibility to laninamivir, but the patient infected with this mutant virus did not have the opportunity to receive laninamivir treatment before she died. All of the dual H275Y mutant viruses tested were susceptible to baloxavir and favipiravir. Baloxavir was approved for the treatment of influenza A and B virus infections in February 2018 in Japan; favipiravir has been approved and stockpiled for use against novel influenza virus infections for which first-line antivirals are ineffective [1]. Therefore, baloxavir could be a treatment option against these multidrug-resistant viruses.\n\nThe selective pressure from prolonged exposure to NA inhibitors in immunocompromised patients can lead to the emergence of multidrug resistance. The patients infected with the H275Y/I223K or H275Y/G147R mutant virus received prolonged treatment with oseltamivir and/or peramivir, whereas the patient infected with the H275Y/I223R mutant virus was treated with a single dose of peramivir before specimen collection. A pretreatment specimen from this patient was unavailable, but the specimen collected after four days of peramivir treatment contained the dual H275Y/I223R substitution and not a mixture including wild-type 275H and 223I. These observations suggest three possibilities: the patient was infected by another host harboring the single H275Y mutant virus, the patient was infected by another host harboring the single I223R mutant virus, or the patient was infected by another host harboring the dual H275Y/I223R mutant virus. Since the NA inhibitor-resistant viruses transmit well in the immunocompromised patients [35,36], we cannot rule out human-to-human transmission of these mutant viruses.\n\nThe growth capability of the H275Y/I223K mutant virus was significantly reduced compared to that of the wild-type virus, and the H275Y/I223R mutant virus retained growth capability to some extent. Residue 223 is located within the framework of the NA enzymatic active site [37]. Our structural analysis predicted that the I223K and I223R substitutions destabilize the NA structure, but the stability score for I223K was higher than that for I223R. These results suggest that an NA with the I223K substitution is less stable than an NA with the I223R substitution. Therefore, the H275Y/I223K mutant virus showed reduced viral fitness relative to the H275Y/I223R mutant virus.\n\nA large cluster of the H275Y mutant A(H1N1)pdm09 virus occurred in Sapporo, Japan during the 2013–14 season [18]. This mutant virus emerged prior to the main influenza season and spread predominantly in the community. To understand the reason for this large cluster, we examined the in vitro and in vivo properties of the mutant virus. We found that it grew well in vitro and in vivo, with growth similar to, or somewhat better than, the wild-type virus. However, the mutant NA structure was less stable than that of the wild-type virus. Therefore, once the wild-type virus began to circulate in the community, the mutant virus could not compete and faded out. In the present study, we found that the H275Y/G147R mutant virus retained the ability to grow similarly to, or somewhat better than, the wild-type virus. Residue 147 is located in a 150-loop adjacent to the NA enzymatic active site [4,5]. In our structural analysis, the G147R substitution was predicted to stabilize the NA structure. Therefore, the H275Y/G147R mutant virus retained its viral fitness and might be as transmissible among humans as the wild-type virus. In fact, the patient infected with this mutant virus developed pneumonia without the isolation of bacterial pathogens, suggesting viral pneumonia with this mutant virus [4]. The in vivo properties of this mutant virus should be further investigated.\n\nThe H275Y substitution in the A(H1N1)pdm09 virus NA protein compromises viral fitness; however, additional V241I and N369K substitutions in the NA protein were reported to increase the replication and transmission fitness of the H275Y mutant A(H1N1)pdm09 viruses [22,23]. The dual H275Y mutant viruses in the present study possess these permissive substitutions. Furthermore, currently circulating A(H1N1)pdm09 viruses also possess these substitutions, suggesting an increased risk for oseltamivir and peramivir cross-resistant viruses to emerge and spread. The emergence of the multidrug-resistant viruses reduces the antiviral options for treatment. This report highlights the importance of closely monitoring multidrug-resistant viruses in immunocompromised patients to improve clinical management and surveillance of these resistant viruses to protect public health.\n\nAcknowledgments\nWe thank Rie Ogawa, Shiho Nagata, Hideka Miura, Hiromi Sugawara, Miki Akimoto, Aya Sato, and Kayo Watanabe for technical assistance. We also thank Susan Watson for scientific editing. Members of the Influenza Virus Surveillance Group of Japan are Rika Komagome (Hokkaido Institute of Public Health), Asami Ohnishi (Sapporo City Institute of Public Health), Rika Tsutsui (Aomori Prefectural Public Health and Environment Center), Masaki Takahashi (Iwate Prefectural Research Institute for Environmental Sciences and Public Health), Yuko Suzuki (Miyagi Prefectural Institute of Public Health and Environment), Makiko Ushimizu (Sendai City Institute of Public Health), Chihiro Shibata (Akita Prefectural Research Center for Public Health and Environment), Shizuka Tanaka (Yamagata Prefectural Institute of Public Health), Yoshiko Kashiwagi (Fukushima Prefectural Institute of Public Health), Chika Hirokawa (Niigata Prefectural Institute of Public Health and Environmental Sciences), Kazunari Yamamoto (Niigata City Institute of Public Health and Environment), Takako Suzuki (Tochigi Prefectural Institute of Public Health and Environmental Sciences), Shunsuke Kataoka (Utsunomiya City Institute of Public Health and Environment Science), Hiroyuki Tsukagoshi (Gunma Prefectural Institute of Public Health and Environmental Sciences), Noriko Suzuki (Saitama Institute of Public Health), Yuka Uno (Saitama City Institute of Health Science and Research), Noriko Oitate (Chiba Prefectural Institute of Public Health), Wakako Nishikawa (Chiba City Institute of Health and Environment), Sachiko Harada (Tokyo Metropolitan Institute of Public Health), Sumi Watanabe (Kanagawa Prefectural Institute of Public Health), Chiharu Kawakami (Yokohama City Institute of Public Health), Hideaki Shimizu (Kawasaki City Institute of Public Health), Hazime Amano (Yokosuka Institute of Public Health), Sayoko Arakawa (Sagamihara City Institute of Public Health), Masayuki Oonuma (Yamanashi Institute for Public Health), Michiko Takeuchi (Nagano Environmental Conservation Research Institute), Yuichiro Okamura (Nagano City Health Center), Yukiko Sakai (Shizuoka Institute of Environment and Hygiene), Takaharu Maehata (Shizuoka City Institute of Environmental Sciences and Public Health), Toshihiko Furuta (Hamamatsu City Health Environment Research Center), Masatsugu Obuchi (Toyama Institute of Health), Hiroe Kodama (Ishikawa Prefectural Institute of Public Health and Environmental science), Kaori Sato (Fukui Prefectural Institute of Public Health and Environmental Science), Masahiro Nishioka (Gifu Prefectural Research Institute for Health and Environmental Sciences), Yusuke Sato (Gifu Municipal Institute of Public Health), Yoshihiro Yasui (Aichi Prefectural Institute of Public Health), Takuya Yano (Mie Prefecture Health and Environment Research Institute), Hiromi Kodama (Shiga Prefectural Institute of Public Health), Akiko Nagasao (Kyoto City Institute of Health and Environmental Sciences), Satoshi Hiroi and Hideyuki Kubo (Osaka Institute of Public Health), Fumika Okayama (Sakai City Institute of Public Health), Tomohiro Oshibe (Hyogo Prefectural Institute of Public Health and Consumer Sciences), Ai Mori (Kobe Institute of Health), Misako Fujitani (Nara Prefecture Institute of Health), Yuki Matsui (Wakayama Prefectural Research Center of Environment and Public Health), Hidenobu Ekawa (Wakayama City Institute of Public Health), Nobuyuki Kato (Tottori Prefectural Institute of Public Health and Environmental Science), Tetsuo Mita (Shimane Prefectural Institute of Public Health and Environmental Science), Yasuhiro Matsuoka (Okayama Prefectural Institute for Environmental Science and Public Health), Miwako Yamamoto (Hiroshima City Institute of Public Health), Shoichi Toda (Yamaguchi Prefectural Institute of Public Health and Environment), Yumiko Kawakami (Tokushima Prefectural Public Health, Pharmaceutical and Environmental Sciences Center), Yukari Terajima (Kagawa Prefectural Research Institute for Environmental Sciences and Public Health), Akie Ochi (Ehime Prefecture Institute of Public Health and Environmental Science), Noriko Yorimitsu (Kochi Public Health and Sanitation Institute), Yuki Ashizuka (Fukuoka Institute of Health and Environmental Sciences), Shuichi Zaitsu (Fukuoka City Institute of Health and Environment), Takashi Kimura (Kitakyushu City Institute of Health and Environmental Sciences), Katsuyuki Ando (Saga Prefectural Institute of Public Health and Pharmaceutical Research), Kana Miura (Nagasaki Prefectural Institute for Environment Research and Public Health), Kenta Yoshioka (Kumamoto Prefectural Institute of Public-Health and Environmental Science), Kaori Nishizawa (Kumamoto City Environmental Research Center), Miki Kato (Oita Prefectural Institute of Health and Environment), Miho Miura (Miyazaki Prefectural Institute for Public Health and Environment), Yuka Iwamoto (Kagoshima Prefectural Institute for Environmental Research and Public Health), and Yumani Kuba (Okinawa Prefectural Institute of Health and Environment).\n\nAuthor Contributions\nConceptualization, E.T. and T.O.; analysis and investigation, E.T., S.F., M.Y., M.S., H.M., K.N., N.K., T.K., H.S., I.D., Y.S. (Yuji Sato), S.T., Y.S. (Yukie Shimazu), T.S., T.I., The Influenza Virus Surveillance Group of Japan; writing—original draft preparation, E.T.; writing—review and editing, S.W. and T.O. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research was funded by a Grant-in-Aid for Emerging and Reemerging Infectious Diseases from the Ministry of Health, Labour and Welfare, Japan, grant number 10110400 and by Japan Society for the Promotion of Science KAKENHI, grant number JP18K10036.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 In vitro replication kinetics of the dual H275Y mutant influenza A(H1N1)pdm09 viruses. AX4 cells were infected with the H275Y/I223R, H275Y/I223K, or H275Y/G147R mutant virus, or the corresponding wild-type virus at a multiplicity of infection of 0.001 plaque-forming units (PFU)/cell in triplicate. The supernatants were harvested at the indicated time and were subjected to virus titration by using plaque assays. Means and standard deviations are shown. Asterisks indicate statistically significant differences between the dual H275Y mutant and wild-type viruses as determined by using unpaired t-test calculated by fitting a mixed-effects model; ** p < 0.01. Wild-type: (a) A/Sakai/23/2013, (b) A/Yokohama/40/2016, and (c) A/Yokohama/59/2016.\n\nFigure 2 Competitive growth capabilities of the dual H275Y mutant influenza A(H1N1)pdm09 viruses and the wild-type viruses. AX4 cells were coinfected with the H275Y/I223R, H275Y/I223K, or H275Y/G147R mutant virus and with the corresponding wild-type virus at a multiplicity of infection (MOI) of 0.01 plaque-forming units (PFU)/cell in triplicate. At two days post-infection, the supernatants were subjected to virus titration by using plaque assays and to deep sequencing analysis to determine the relative proportion of each genotype. The viruses were serially passaged 3–4 times at an MOI of 0.01 PFU/cell. Means and standard deviations are shown. Asterisks indicate statistically significant differences between the dual H275Y mutant and wild-type viruses as determined by using unpaired t-test calculated by fitting a mixed-effects model; ** p < 0.01. Wild-type: (a) A/Sakai/23/2013, (b) A/Yokohama/40/2016, and (c) A/Yokohama/59/2016.\n\nFigure 3 Structural analysis of the influenza A(H1N1)pdm09 virus neuraminidase (NA) protein. Structure models of the NA proteins were constructed by use of homology modeling. Single-point mutations were generated on the NA model. The average stability changes were calculated by using the Boltzmann distribution. Means and standard deviations of the stability scores (∆∆Gs) of the structures are shown.\n\npathogens-09-00725-t001_Table 1Table 1 Immunocompromised patients infected with the dual H275Y mutant influenza A(H1N1)pdm09 viruses.\n\nIsolate Name\tDate of Symptom Onset\n(Day/Month/Year)\tAntiviral Administration\n(Day/Month/Year)\tDate of Specimen Collection\n(Day/Month/Year)\tNA Substitution\t\nA/Hiroshima/57/2014\t31-03-2014\t31-03-2014: Peramivir\n04-04-2014: Laninamivir\t04-04-2014\tH275Y/I223R\t\nA/Ibaraki/54/2016\t09-02-2016\t09-02-2016: Peramivir\n24-02-2016 to 03-03-2016: Peramivir\n26-02-2016 to 03-03-2016: Oseltamivir\n05-03-2016: Laninamivir\t07-03-2016\tH275Y/I223K\t\nA/Hiroshima/13/2016\t26-02-2016\t23-02-2016: Laninamivir\n26-02-2016 to 01-03-2016: Peramivir\n07-03-2016 to 11-03-2016: Peramivir\n28-03-2016 to 01-04-2016: Peramivir \t11-03-2016\tH275Y/G147R\t\nNA: neuraminidase.\n\npathogens-09-00725-t002_Table 2Table 2 Antiviral susceptibilities of the dual H275Y mutant influenza A(H1N1)pdm09 viruses.\n\nIsolate Name\tGISAID Isolate ID\tNA Substitution\tIC50, nM (Fold-Change 1)\tEC50, µM (Fold-Change 1)\t\nOseltamivir 2\tPeramivir 2\tZanamivir 2\tLaninamivir 2\tBaloxavir 3\tFavipiravir 4\t\nA/Hiroshima/57/2014\tEPI ISL 160499\tH275Y/I223R\t6263.69\n(20,000)\t944.20\n(94,000)\t4.84\n(48)\t4.48\n(20)\t8.34\n(2.1)\t7.99\n(1.2)\t\nA/Osaka/8/2014\tEPI ISL 155839\tH275Y\t173.80\n(560)\t28.25\n(2,800)\t0.03\n(0.3)\t0.14\n(0.6)\t5.10\n(1.3)\t4.76\n(0.7)\t\nA/Sakai/23/2013\tEPI ISL 154461\tNone\n(wild-type)\t0.31\t0.01\t0.10\t0.22\t4.05\t6.64\t\nA/Ibaraki/54/2016\tEPI ISL 221789\tH275Y/I223K\t10161.87\n(16,000)\t501.62\n(7,200)\t2.48\n(12)\t1.94\n(6.9)\t7.24\n(1.2)\t10.20\n(1.0)\t\nA/Yokohama/94/2016\tEPI ISL 218900\tH275Y\t466.79\n(730)\t20.88\n(300)\t0.33\n(1.6)\t0.52\n(1.9)\t3.49\n(0.6)\t21.40\n(2.1)\t\nA/Yokohama/40/2016\tEPI ISL 217919\tNone\n(wild-type)\t0.64\t0.07\t0.21\t0.28\t6.16\t10.01\t\nA/Hiroshima/13/2016\tEPI ISL 220376\tH275Y/G147R\t1324.62\n(1,500)\t114.14\n(1,400)\t1.56\n(4.5)\t0.37\n(0.9)\t10.59\n(1.0)\t15.13\n(1.7)\t\nA/Aichi/83/2016\tEPI ISL 233222\tH275Y\t364.44\n(420)\t31.93\n(400)\t0.77\n(2.2)\t0.77\n(1.9)\t10.18\n(0.9)\t14.83\n(1.7)\t\nA/Yokohama/59/2016\tEPI ISL 217920\tNone\n(wild-type)\t0.86\t0.08\t0.35\t0.40\t11.04\t8.81\t\nGISAID: Global Initiative on Sharing All Influenza Data; NA: neuraminidase; IC50: 50% inhibitory concentration; EC50: 50% effective concentration. 1 Fold-change in IC50 or EC50 values compared with the wild-type viruses. 2 IC50 values were determined by using an NA inhibition assay. 3 IC50 values were determined by using a focus reduction assay. 4 EC50 values were determined by using a cytopathic effect reduction assay.\n==== Refs\nReferences\n1. Takashita E. Morita H. Ogawa R. Nakamura K. Fujisaki S. Shirakura M. Kuwahara T. Kishida N. Watanabe S. Odagiri T. Susceptibility of influenza viruses to the novel cap-dependent endonuclease inhibitor baloxavir marboxil Front. Microbiol. 2018 9 3026 10.3389/fmicb.2018.03026 30574137 \n2. Takashita E. Ejima M. Ogawa R. Fujisaki S. Neumann G. Furuta Y. Kawaoka Y. Tashiro M. Odagiri T. Antiviral susceptibility of influenza viruses isolated from patients pre- and post-administration of favipiravir Antivir. Res. 2016 132 170 177 10.1016/j.antiviral.2016.06.007 27321665 \n3. Takashita E. Meijer A. Lackenby A. Gubareva L. Rebelo-de-Andrade H. Besselaar T. Fry A. Gregory V. Leang S.K. Huang W. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2013–2014 Antivir. Res. 2015 117 27 38 10.1016/j.antiviral.2015.02.003 25721488 \n4. Takashita E. Fujisaki S. Shirakura M. Nakamura K. Kishida N. Kuwahara T. Shimazu Y. Shimomura T. Watanabe S. Odagiri T. Influenza a (H1N1) pdm09 virus exhibiting enhanced cross-resistance to oseltamivir and peramivir due to a dual H275Y/G147R substitution, Japan, March 2016 Euro Surveill. 2016 21 10.2807/1560-7917.ES.2016.21.24.30258 27336226 \n5. Gubareva L.V. Besselaar T.G. Daniels R.S. Fry A. Gregory V. Huang W. Hurt A.C. Jorquera P.A. Lackenby A. Leang S.K. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2015–2016 Antivir. Res. 2017 146 12 20 10.1016/j.antiviral.2017.08.004 28802866 \n6. Nguyen H.T. Fry A.M. Loveless P.A. Klimov A.I. Gubareva L.V. Recovery of a multidrug-resistant strain of pandemic influenza a 2009 (H1N1) virus carrying a dual H275Y/I223R mutation from a child after prolonged treatment with oseltamivir Clin. Infect. Dis. 2010 51 983 984 10.1086/656439 20858074 \n7. Hurt A.C. Lee R.T. Leang S.K. Cui L. Deng Y.M. Phuah S.P. Caldwell N. Freeman K. Komadina N. Smith D. Increased detection in Australia and Singapore of a novel influenza A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation Euro Surveill. 2011 16 19884 10.2807/ese.16.23.19884-en 21679678 \n8. Nguyen H.T. Trujillo A.A. Sheu T.G. Levine M. Mishin V.P. Shaw M. Ades E.W. Klimov A.I. Fry A.M. Gubareva L.V. Analysis of influenza viruses from patients clinically suspected of infection with an oseltamivir resistant virus during the 2009 pandemic in the United States Antivir. Res. 2012 93 381 386 10.1016/j.antiviral.2012.01.006 22330888 \n9. L’Huillier A.G. Abed Y. Petty T.J. Cordey S. Thomas Y. Bouhy X. Schibler M. Simon A. Chalandon Y. van Delden C. E119D neuraminidase mutation conferring pan-resistance to neuraminidase Iinhibitors in an a (H1N1) pdm09 isolate from a stem-cell transplant recipient J. Infect. Dis. 2015 212 1726 1734 10.1093/infdis/jiv288 25985905 \n10. Tamura D. DeBiasi R.L. Okomo-Adhiambo M. Mishin V.P. Campbell A.P. Loechelt B. Wiedermann B.L. Fry A.M. Gubareva L.V. Emergence of multidrug-resistant influenza a (H1N1) pdm09 virus variants in an immunocompromised child treated with oseltamivir and Zanamivir J. Infect. Dis. 2015 212 1209 1213 10.1093/infdis/jiv245 25943200 \n11. Trebbien R. Pedersen S.S. Vorborg K. Franck K.T. Fischer T.K. Development of oseltamivir and zanamivir resistance in influenza a (H1N1) pdm09 virus, Denmark, 2014 Euro Surveill. 2017 22 30445 10.2807/1560-7917.ES.2017.22.3.30445 28128091 \n12. LeGoff J. Rousset D. Abou-Jaoude G. Scemla A. Ribaud P. Mercier-Delarue S. Caro V. Enouf V. Simon F. Molina J.M. I223R mutation in influenza a (H1N1) pdm09 neuraminidase confers reduced susceptibility to oseltamivir and zanamivir and enhanced resistance with H275Y PLoS ONE 2012 7 e37095 10.1371/journal.pone.0037095 22936969 \n13. Pizzorno A. Abed Y. Bouhy X. Beaulieu E. Mallett C. Russell R. Boivin G. Impact of mutations at residue I223 of the neuraminidase protein on the resistance profile, replication level, and virulence of the 2009 pandemic influenza virus Antimicrob Agents Chemother. 2012 56 1208 1214 10.1128/AAC.05994-11 22203589 \n14. Abed Y. Bouhy X. L’Huillier A.G. Rheaume C. Pizzorno A. Retamal M. Fage C. Dube K. Joly M.H. Beaulieu E. The E119D neuraminidase mutation identified in a multidrug-resistant influenza a (H1N1) pdm09 isolate severely alters viral fitness in vitro and in animal models Antivir. Res. 2016 132 6 12 10.1016/j.antiviral.2016.05.006 27185624 \n15. Takada K. Kawakami C. Fan S. Chiba S. Zhong G. Gu C. Shimizu K. Takasaki S. Sakai-Tagawa Y. Lopes T.J.S. A humanized MDCK cell line for the efficient isolation and propagation of human influenza viruses Nat. Microbiol. 2019 4 1268 1273 10.1038/s41564-019-0433-6 31036910 \n16. Hatakeyama S. Sakai-Tagawa Y. Kiso M. Goto H. Kawakami C. Mitamura K. Sugaya N. Suzuki Y. Kawaoka Y. Enhanced expression of an alpha2,6-linked sialic acid on MDCK cells improves isolation of human influenza viruses and evaluation of their sensitivity to a neuraminidase inhibitor J. Clin. Microbiol. 2005 43 4139 4146 10.1128/JCM.43.8.4139-4146.2005 16081961 \n17. Takashita E. Abe T. Morita H. Nagata S. Fujisaki S. Miura H. Shirakura M. Kishida N. Nakamura K. Kuwahara T. Influenza a (H1N1) pdm09 virus exhibiting reduced susceptibility to baloxavir due to a PA E23K substitution detected from a child without baloxavir treatment Antivir. Res. 2020 180 104828 10.1016/j.antiviral.2020.104828 32574689 \n18. Takashita E. Kiso M. Fujisaki S. Yokoyama M. Nakamura K. Shirakura M. Sato H. Odagiri T. Kawaoka Y. Tashiro M. Characterization of a large cluster of influenza a (H1N1) pdm09 viruses cross-resistant to oseltamivir and peramivir during the 2013-2014 influenza season in Japan Antimicrob. Agents Chemother. 2015 59 2607 2617 10.1128/AAC.04836-14 25691635 \n19. Van der Vries E. Collins P.J. Vachieri S.G. Xiong X. Liu J. Walker P.A. Haire L.F. Hay A.J. Schutten M. Osterhaus A.D. H1N1 2009 pandemic influenza virus: Resistance of the I223R neuraminidase mutant explained by kinetic and structural analysis PLoS Pathog. 2012 8 e1002914 10.1371/journal.ppat.1002914 23028314 \n20. Hooper K.A. Crowe J.E. Jr. Bloom J.D. Influenza viruses with receptor-binding N1 neuraminidases occur sporadically in several lineages and show no attenuation in cell culture or mice J. Virol. 2015 89 3737 3745 10.1128/JVI.00012-15 25609803 \n21. Hurt A.C. Hardie K. Wilson N.J. Deng Y.M. Osbourn M. Leang S.K. Lee R.T. Iannello P. Gehrig N. Shaw R. Characteristics of a widespread community cluster of H275Y oseltamivir-resistant a (H1N1) pdm09 influenza in Australia J. Infect. Dis. 2012 206 148 157 10.1093/infdis/jis337 22561367 \n22. Abed Y. Pizzorno A. Bouhy X. Rheaume C. Boivin G. Impact of potential permissive neuraminidase mutations on viral fitness of the H275Y oseltamivir-resistant influenza A(H1N1)pdm09 virus in vitro, in mice and in ferrets J. Virol. 2014 88 1652 1658 10.1128/JVI.02681-13 24257597 \n23. Butler J. Hooper K.A. Petrie S. Lee R. Maurer-Stroh S. Reh L. Guarnaccia T. Baas C. Xue L. Vitesnik S. Estimating the fitness advantage conferred by permissive neuraminidase mutations in recent oseltamivir-resistant A(H1N1)pdm09 influenza viruses PLoS Pathog. 2014 10 e1004065 10.1371/journal.ppat.1004065 24699865 \n24. Harvala H. Gunson R. Simmonds P. Hardie A. Bennett S. Scott F. Roddie H. McKnight J. Walsh T. Rowney D. The emergence of oseltamivir-resistant pandemic influenza a (H1N1) 2009 virus amongst hospitalised immunocompromised patients in Scotland, November–December, 2009 Euro Surveill. 2010 15 19536 10.2807/ese.15.14.19536-en 20394718 \n25. Calatayud L. Lackenby A. Reynolds A. McMenamin J. Phin N.F. Zambon M. Pebody R. Oseltamivir-resistant pandemic (H1N1) 2009 virus infection in England and Scotland, 2009–2010 Emerg. Infect. Dis. 2011 17 1807 1815 10.3201/eid1710.110117 22000349 \n26. Graitcer S.B. Gubareva L. Kamimoto L. Doshi S. Vandermeer M. Louie J. Waters C. Moore Z. Sleeman K. Okomo-Adhiambo M. Characteristics of patients with oseltamivir-resistant pandemic (H1N1) 2009, United States Emerg. Infect. Dis. 2011 17 255 257 10.3201/eid1702.101724 21291599 \n27. Hurt A.C. Chotpitayasunondh T. Cox N.J. Daniels R. Fry A.M. Gubareva L.V. Hayden F.G. Hui D.S. Hungnes O. Lackenby A. Antiviral resistance during the 2009 influenza A H1N1 pandemic: Public health, laboratory, and clinical perspectives Lancet Infect. Dis. 2012 12 240 248 10.1016/S1473-3099(11)70318-8 22186145 \n28. Campanini G. Piralla A. Rovida F. Puzelli S. Facchini M. Locatelli F. Minoli L. Percivalle E. Donatelli I. Baldanti F. First case in Italy of acquired resistance to oseltamivir in an immunocompromised patient with influenza A/H1N1v infection J. Clin. Virol. 2010 48 220 222 10.1016/j.jcv.2010.03.027 20447860 \n29. Tramontana A.R. George B. Hurt A.C. Doyle J.S. Langan K. Reid A.B. Harper J.M. Thursky K. Worth L.J. Dwyer D.E. Oseltamivir resistance in adult oncology and hematology patients infected with pandemic (H1N1) 2009 virus, Australia Emerg. Infect. Dis. 2010 16 1068 1075 10.3201/eid1607.091691 20587176 \n30. Renaud C. Boudreault A.A. Kuypers J. Lofy K.H. Corey L. Boeckh M.J. Englund J.A. H275Y mutant pandemic (H1N1) 2009 virus in immunocompromised patients Emerg. Infect. Dis. 2011 17 653 660 10.3201/eid1704.101429 21470455 \n31. Li T.C. Chan M.C. Lee N. Clinical implications of antiviral resistance in influenza Viruses 2015 7 4929 4944 10.3390/v7092850 26389935 \n32. Gaur A.H. Bagga B. Barman S. Hayden R. Lamptey A. Hoffman J.M. Bhojwani D. Flynn P.M. Tuomanen E. Webby R. Intravenous zanamivir for oseltamivir-resistant 2009 H1N1 influenza N. Engl, J. Med. 2010 362 88 89 10.1056/NEJMc0910893 20032317 \n33. Renaud C. Pergam S.A. Polyak C. Jain R. Kuypers J. Englund J.A. Corey L. Boeckh M.J. Early emergence of an H275Y mutation in a hematopoietic cell transplant recipient treated with intravenous peramivir Transpl. Infect. Dis. 2010 12 513 517 10.1111/j.1399-3062.2010.00582.x 21062390 \n34. Memoli M.J. Hrabal R.J. Hassantoufighi A. Eichelberger M.C. Taubenberger J.K. Rapid selection of oseltamivir- and peramivir-resistant pandemic H1N1 virus during therapy in 2 immunocompromised hosts Clin. Infect. Dis. 2010 50 1252 1255 10.1086/651605 20345239 \n35. Chen L.F. Dailey N.J. Rao A.K. Fleischauer A.T. Greenwald I. Deyde V.M. Moore Z.S. Anderson D.J. Duffy J. Gubareva L.V. Cluster of oseltamivir-resistant 2009 pandemic influenza a (H1N1) virus infections on a hospital ward among immunocompromised patients–North Carolina, 2009 J. Infect. Dis. 2011 203 838 846 10.1093/infdis/jiq124 21343149 \n36. Moore C. Galiano M. Lackenby A. Abdelrahman T. Barnes R. Evans M.R. Fegan C. Froude S. Hastings M. Knapper S. Evidence of person-to-person transmission of oseltamivir-resistant pandemic influenza a (H1N1) 2009 virus in a hematology unit J. Infect. Dis. 2011 203 18 24 10.1093/infdis/jiq007 21148492 \n37. Colman P.M. Hoyne P.A. Lawrence M.C. Sequence and structure alignment of paramyxovirus hemagglutinin-neuraminidase with influenza virus neuraminidase J. Virol. 1993 67 2972 2980 10.1128/JVI.67.6.2972-2980.1993 8497041\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2076-0817",
"issue": "9(9)",
"journal": "Pathogens (Basel, Switzerland)",
"keywords": "baloxavir; favipiravir; influenza; laninamivir; neuraminidase inhibitor; oseltamivir; peramivir; resistance; zanamivir",
"medline_ta": "Pathogens",
"mesh_terms": null,
"nlm_unique_id": "101596317",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32887429",
"pubdate": "2020-09-02",
"publication_types": "D016428:Journal Article",
"references": "25985905;28128091;21148492;24257597;22203589;21470455;25721488;27185624;21343149;20587176;8497041;30574137;22330888;25609803;25691635;22936969;22000349;16081961;20394718;21062390;20858074;20032317;25943200;21679678;22561367;32574689;27321665;26389935;22186145;21291599;20447860;31036910;20345239;23028314;27336226;28802866;24699865",
"title": "In Vitro Characterization of Multidrug-Resistant Influenza A(H1N1)pdm09 Viruses Carrying a Dual Neuraminidase Mutation Isolated from Immunocompromised Patients.",
"title_normalized": "in vitro characterization of multidrug resistant influenza a h1n1 pdm09 viruses carrying a dual neuraminidase mutation isolated from immunocompromised patients"
} | [
{
"companynumb": "JP-BIOCRYST PHARMACEUTICALS, INC.-2020BCR00073",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PERAMIVIR"
},
"drugaddit... |
{
"abstract": "Spontaneous hemothorax is a rare disorder characterized by pleural fluid hematocrit greater than 50% of the peripheral blood hematocrit without natural or iatrogenic trauma to the lungs or pleural space. Since the first case of COVID-19, more than 85 million cases have been confirmed and most patients have sustained symptoms after more than six months of acute infection. This paper reports the case of a 38-year-old woman without signs of endometriosis and a history of COVID-19 infection who developed spontaneous hemothorax after oocyte retrieval. Three months before undergoing assisted reproductive technology (ART) treatment, the patient had a symptomatic COVID-19 infection with a negative PCR test and a positive IgG test four weeks after the onset of symptoms. Controlled ovarian stimulation and oocyte retrieval were conducted uneventfully. Two hours after oocyte retrieval, the patient developed nausea and mild hypogastric pain. Ten hours after the procedure, the patient went to the emergency department with abdominal pain. Chest computed tomography scans revealed moderate right pleural effusion and laminar left pleural effusion. Since the patient had respiratory symptoms, the choice was made to drain the pleural fluid. Fluid analysis confirmed the patient had right hemothorax (400 mL). After drainage, the patient's clinical and imaging signs improved gradually without complications. The patient was asymptomatic one week after the procedure.",
"affiliations": "Conceber Centro de Medicina Reprodutiva, Curitiba, Paraná, Brazil.;Faculdade de Medicina, Pontifícia Universidade Católica, Curitiba, Paraná, Brazil.;Conceber Centro de Medicina Reprodutiva, Curitiba, Paraná, Brazil.;Conceber Centro de Medicina Reprodutiva, Curitiba, Paraná, Brazil.",
"authors": "Rahal|Danilo|D|;Kozlowski|Isadora Ferreira|IF|;Rosa|Vinicius Bonato da|VBD|;Schuffner|Alessandro|A|",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": "10.5935/1518-0557.20210043",
"fulltext": "\n==== Front\nJBRA Assist Reprod\nJBRA Assist Reprod\njbra\nJBRA Assisted Reproduction\n1517-5693\n1518-0557\nBrazilian Society of Assisted Reproduction\n\n34415132\n10.5935/1518-0557.20210043\nCase Report\nHemothorax after oocyte retrieval in a patient with a history of COVID-19: a case report\nRahal Danilo 1\nKozlowski Isadora Ferreira 2\nda Rosa Vinicius Bonato 1\nSchuffner Alessandro 1\n1 Conceber Centro de Medicina Reprodutiva, Curitiba, Paraná, Brazil\n2 Faculdade de Medicina, Pontifícia Universidade Católica, Curitiba, Paraná, Brazil\nCorresponding author: Alessandro Schuffner, Conceber Centro de Medicina Reprodutiva Curitiba, Paraná, Brazil. E-mail: alessandro@clinicaconceber.com.br\nOct-Dec 2021\nOct-Dec 2021\n25 4 647649\n27 1 2021\n01 8 2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nSpontaneous hemothorax is a rare disorder characterized by pleural fluid hematocrit greater than 50% of the peripheral blood hematocrit without natural or iatrogenic trauma to the lungs or pleural space. Since the first case of COVID-19, more than 85 million cases have been confirmed and most patients have sustained symptoms after more than six months of acute infection. This paper reports the case of a 38-year-old woman without signs of endometriosis and a history of COVID-19 infection who developed spontaneous hemothorax after oocyte retrieval. Three months before undergoing assisted reproductive technology (ART) treatment, the patient had a symptomatic COVID-19 infection with a negative PCR test and a positive IgG test four weeks after the onset of symptoms. Controlled ovarian stimulation and oocyte retrieval were conducted uneventfully. Two hours after oocyte retrieval, the patient developed nausea and mild hypogastric pain. Ten hours after the procedure, the patient went to the emergency department with abdominal pain. Chest computed tomography scans revealed moderate right pleural effusion and laminar left pleural effusion. Since the patient had respiratory symptoms, the choice was made to drain the pleural fluid. Fluid analysis confirmed the patient had right hemothorax (400 mL). After drainage, the patient's clinical and imaging signs improved gradually without complications. The patient was asymptomatic one week after the procedure.\n\nhemothorax\noocyte retrieval\ncoronavirus infection\n==== Body\npmcINTRODUCTION\n\nInfertility affects about 15% of couples of reproductive age (Alegretti et al., 2013). Spontaneous hemothorax is a rare disorder characterized by pleural fluid hematocrit greater than 50% of the peripheral blood hematocrit without natural or iatrogenic trauma to the lungs or pleural space (Morgan et al., 2015). Spontaneous hemothorax is a rare disorder, with an incidence between 2.0-7.3%, affecting mainly men aged 15-39 years (Long & Grimaldo, 2021).\n\nIn December 2019, the first case of COVID-19 was identified in Wuhan, China, and on March 11, 2020, the disease was declared a pandemic by the World Health Organization (WHO) (Long & Grimaldo, 2021). Since the discovery of COVID-19, more than 85 million cases have been confirmed with more than 1.8 million deaths from the disease (WHO, 2021). A recent study showed that 76% of the evaluated patients sustained symptoms after more than six months of acute infection; women are preferentially affected; and 22% to 56% of the patients had changes in lung diffusion six months after the onset of symptoms (Huang et al., 2021).\n\nThe presence of spontaneous hemothorax in patients with COVID-19 is a very rare presentation (Halvorson et al., 2012; Sopa et al., 2017), and the cases reported occurred during the acute phase of the disease (Long & Grimaldo, 2021). The association of spontaneous hemothorax with in vitro fertilization (IVF) procedures is rare and has been associated with thoracic endometriosis.\n\nThis paper reports the case of a patient without signs of endometriosis and a history of COVID-19 infection who developed spontaneous hemothorax after oocyte retrieval.\n\nCASE DESCRIPTION\n\nThe patient is a 38-year-old nulligravida with a BMI of 21.72 and without comorbidities who had been trying to get pregnant for three years. She had normal hysterosalpingography findings, ultrasound examination showing no signs of deep endometriosis, anti-Müllerian hormone (AMH) levels 11 months before treatment of 2.0 ng/mL, and normal results in other related tests. Her partner had secondary infertility, a spermogram showing increased sperm viscosity, mild left varicocele, and minor bilateral hydrocele.\n\nOne month prior to IVF, the patient's complete blood count showed the following results: Hb 12.6 g/dL; GV 37.7%; 7,260 leukocytes/mm3; and 274,000 platelets/mm3.\n\nThe couple chose to undergo IVF with preimplantation genetic testing for aneuploidy (PGTA) due to the age of the female partner.\n\nThe patient had COVID-19 three months prior to IVF, with symptoms of myalgia, fever, and retro-orbital headache; her PCR test was negative. She was treated for symptoms only. However, since suspicions of infection by SARS-CoV-2 remained, she had an IgG test four weeks later, which confirmed she had COVID-19. The patient progressed well after the acute phase of the disease.\n\nOvulation induction was initiated on the third day of the menstrual cycle with follitropin alfa 225 IU and menotropin 75 IU daily. Serial ultrasound was performed to monitor ovarian follicles. On the seventh day of the cycle, when the largest follicle reached 14mm in average diameter, the patient was started on GnRH antagonist cetrorelix 0.25mg a day. On the tenth day of the cycle, a double trigger was performed, with 250mcg of choriogonadotropin alfa and 0.2mg of triptorelin acetate.\n\nOn the day of trigger, there were 13 follicles above 12mm in average diameter. Oocyte retrieval was performed 35 hours after the trigger. Thirteen mature oocytes, five immature oocytes, and one degenerate oocyte were aspirated. ICSI was performed on all mature oocytes. Twelve fertilized and three evolved into a blastocyst to be biopsied and frozen by vitrification. Of the three biopsied embryos, one had X monosomy, one had mosaic monosomy 4, and the other was normal.\n\nFor the oocyte retrieval procedure, anesthesia was performed with propofol and fentanyl and to manage symptoms (ketoprofen, dexamethasone, dipyrone and ondansetron). The entire standardized technique for follicular aspiration was performed using a single lumen needle with an internal diameter of 17G and 33cm in length, guided by transvaginal ultrasound. The procedure was carried out without complications.\n\nTwo hours after the procedure, the patient developed nausea and mild hypogastric pain, which worsened in an orthostatic position. One hour later the patient improved from the symptoms, became asymptomatic, and was discharged.\n\nTen hours after the procedure, the patient was admitted to the emergency department with complaints of abdominal pain. A complete blood count was performed, showing Hb 10.2g/dL, GV 28.7%, with 11,060 leukocytes/mm3 and 229,000 platelets/mm3. Transvaginal ultrasound (Figure 1) and total abdomen tomography (Figure 2) were performed, showing enlarged ovaries, consistent with a recently performed controlled ovarian stimulation, and a small amount of free intra-abdominal fluid, with no signs of active bleeding. Chest computed tomography scans revealed moderate right pleural and laminar left pleural effusion, and small, elongated non-calcified single bilateral pulmonary nodules of up to 4 mm with benign characteristics, probably lymph nodes.\n\nFigure 1 Pelvic ultrasound 12 hours after oocyte retrieval.\n\nFigure 2 Computed tomography scan showing hemothorax, 10 hours after oocyte retrieval.\n\nOn the following day, since the patient had respiratory symptoms, the choice was made to drain the pleural fluid (performed by a thoracic surgeon). Fluid analysis confirmed the patient had right hemothorax (400mL). Fluid oncotic culture and cytology came back negative. After drainage, the patient's clinical and imaging signs improved gradually without complications. The patient was asymptomatic one week after the procedure.\n\nDISCUSSION\n\nThis report describes the case of a patient with infertility and a history of COVID-19 submitted to IVF who developed spontaneous hemothorax, a development until now not described in the literature.\n\nIn cases of ovarian hyperstimulation syndrome (OHSS), patients may have pleural effusion due to exudate, associated with ascites. The early form occurs 3 to 7 days after the administration of human chorionic gonadotropins (hCG) (Irani et al., 2018), which does not fit the case described.\n\nThere is a report of hemothorax in a patient submitted to IVF, which occurred in association with severe endometriosis with involvement of the diaphragm (Sopa et al., 2017).\n\nSpontaneous hemothorax is rare in patients with acute COVID-19, although it may occur in some cases (Long & Grimaldo, 2021). We were unable to find other publications describing cases of spontaneous hemothorax after late COVID-19.\n\nCould COVID-19 leave pulmonary and/or pleural scars that might cause spontaneous hemothorax after surgical stress or exposure to hormones in ovarian stimulation?\n\nCONFLICT OF INTEREST\n\nThe authors have no conflict of interest to declare.\n==== Refs\nREFERENCES\n\nAlegretti JR Rossi ALS Riboldi M Barros BC Serafini PC Motta ELA Infertility history and age do not change embryonic aneuploidies rates in IVF cycles: 2084 analyzed human blastocysts by Array-CGH JBRA Assist Reprod 2013 17 115 121 10.5935/1518-0557.20130017\nHalvorson SA Ricker MA Barker AF Patton PE Harrison RA Hunter AJ Thoracic endometriosis unmasked by ovarian hyperstimulation for in vitro fertilization J Gen Intern Med 2012 27 603 607 10.1007/s11606-011-1959-3 22234445\nHuang C Huang L Wang Y Li X Ren L Gu X Kang L Guo L Liu M Zhou X Luo J Huang Z Tu S Zhao Y Chen L Xu D Li Y Li C Peng L Li Y 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study Lancet 2021 397 220 232 10.1016/S0140-6736(20)32656-8 33428867\nIrani M Robles A Gunnala V Chung P Rosenwaks Z Unilateral pleural effusion as the sole clinical presentation of severe ovarian hyperstimulation syndrome: a systematic review Gynecol Endocrinol 2018 34 92 99 10.1080/09513590.2017.1390738 29063807\nLong A Grimaldo F Spontaneous hemopneumothorax in a patient with COVID-19 Am J Emerg Med 2021 40 228.e1 2228e2 10.1016/j.ajem.2020.07.065 32800431\nMorgan CK Bashoura L Balachandran D Faiz SA Spontaneous Hemothorax Ann Am Thorac Soc 2015 12 1578 1582 10.1513/AnnalsATS.201505-305CC 26448354\nSopa N Larsen EC Andersen AN A Case with Severe Endometriosis, Ovarian Hyperstimulation Syndrome, and Isolated Unilateral Pleural Effusion after IVF Case Rep Obstet Gynecol 2017 2017 8243204 8243204 10.1155/2017/8243204 28770117\nWorld Health Organization Internet WHO Coronavirus Disease (COVID-19) Dashboard Geneva WHO 2021 2021 Jan 7 Available at: https://covid19.who.int/\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1517-5693",
"issue": "25(4)",
"journal": "JBRA assisted reproduction",
"keywords": "coronavirus infection; hemothorax; oocyte retrieval",
"medline_ta": "JBRA Assist Reprod",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D005260:Female; D006491:Hemothorax; D006801:Humans; D054315:Oocyte Retrieval; D000086402:SARS-CoV-2; D013909:Thorax; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101684552",
"other_id": null,
"pages": "647-649",
"pmc": null,
"pmid": "34415132",
"pubdate": "2021-10-04",
"publication_types": "D002363:Case Reports",
"references": "32800431;28770117;33428867;29063807;26448354;22234445",
"title": "Hemothorax after oocyte retrieval in a patient with a history of COVID-19: a case report.",
"title_normalized": "hemothorax after oocyte retrieval in a patient with a history of covid 19 a case report"
} | [
{
"companynumb": "BR-FERRINGPH-2021FE08161",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MENOTROPINS"
},
"drugadditional": "4",
... |
{
"abstract": "A 59-year-old man with refractory Cronkhite-Canada syndrome (CCS) had poor clinical response to high-dose intravenous steroids, azathioprine, total parenteral nutrition and best supportive care. He remained highly symptomatic with abdominal pain, diarrhoea, recurrent sepsis and profound weight loss. Infliximab induction was given as rescue therapy, with marked clinical improvement observed within 3 weeks. This allowed steroid taper. Within 12 months of infliximab therapy, he achieved complete clinical remission and returned to his baseline weight and a full oral diet. Sequential endoscopies observed significant regression of previous marked gastrointestinal polyposis, including histological remission on colonic biopsies at 3.5 and 5 years of treatment. He currently remains in remission following 6 years of combination therapy with 5 mg/kg 8 weekly infliximab and azathioprine, and there is ongoing discussion with regard to the benefits and risks of therapy de-escalation. This case demonstrates the effectiveness of infliximab in inducing and maintaining remission in refractory CCS.",
"affiliations": "Gastroenterology, Wellington Hospital, Wellington, New Zealand carolinedijiang@gmail.com.;Gastroenterology, Auckland City Hospital, Auckland, New Zealand.;Department of Pathology and Molecular Medicine, University of Otago, Wellington, New Zealand.;Department of Medicine, University of Otago, Wellington, New Zealand.",
"authors": "Jiang|Caroline Di|CD|;Myint|Helen|H|;Tie|Andy|A|;Stace|Nigel H|NH|",
"chemical_list": "D005765:Gastrointestinal Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D000069285:Infliximab; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236990",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(12)",
"journal": "BMJ case reports",
"keywords": "drugs: gastrointestinal system; gastrointestinal system; immunological products and vaccines",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001379:Azathioprine; D003106:Colon; D003113:Colonoscopy; D004351:Drug Resistance; D005765:Gastrointestinal Agents; D005773:Gastroscopy; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D060828:Induction Chemotherapy; D000069285:Infliximab; D007413:Intestinal Mucosa; D044483:Intestinal Polyposis; D008297:Male; D008875:Middle Aged; D011706:Pyloric Antrum; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33370944",
"pubdate": "2020-12-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sustained clinical response to infliximab in refractory Cronkhite-Canada syndrome.",
"title_normalized": "sustained clinical response to infliximab in refractory cronkhite canada syndrome"
} | [
{
"companynumb": "NZ-MYLANLABS-2021M1017636",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRON"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Death from stroke has decreased over the past decade, with stroke now the fifth leading cause of death in the United States. In addition, the incidence of new and recurrent stroke is declining, likely because of the increased use of specific prevention medications, such as statins and antihypertensives. Despite these positive trends in incidence and mortality, many strokes remain preventable. The major modifiable risk factors are hypertension, diabetes mellitus, tobacco smoking, and hyperlipidemia, as well as lifestyle factors, such as obesity, poor diet/nutrition, and physical inactivity. This article reviews the current recommendations for the management of each of these modifiable risk factors.\n\n\n\nIt has been documented that some blood pressure medications may increase variability of blood pressure and ultimately increase the risk for stroke. Stroke prevention typically includes antiplatelet therapy (unless an indication for anticoagulation exists), so the most recent evidence supporting use of these drugs is reviewed. In addition, emerging risk factors, such as obstructive sleep apnea, electronic cigarettes, and elevated lipoprotein (a), are discussed.\n\n\n\nOverall, secondary stroke prevention includes a multifactorial approach. This article incorporates evidence from guidelines and published studies and uses an illustrative case study throughout the article to provide examples of secondary prevention management of stroke risk factors.",
"affiliations": null,
"authors": "Guzik|Amy|A|;Bushnell|Cheryl|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/CON.0000000000000416",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1080-2371",
"issue": "23(1, Cerebrovascular Disease)",
"journal": "Continuum (Minneapolis, Minn.)",
"keywords": null,
"medline_ta": "Continuum (Minneap Minn)",
"mesh_terms": "D066300:Electronic Nicotine Delivery Systems; D006801:Humans; D006973:Hypertension; D012307:Risk Factors; D055502:Secondary Prevention; D020521:Stroke",
"nlm_unique_id": "9509333",
"other_id": null,
"pages": "15-39",
"pmc": null,
"pmid": "28157742",
"pubdate": "2017-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Stroke Epidemiology and Risk Factor Management.",
"title_normalized": "stroke epidemiology and risk factor management"
} | [
{
"companynumb": "US-IPCA LABORATORIES LIMITED-IPC201703-000174",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ATENOLOL"
},
"drugadditio... |
{
"abstract": "Capillary leak syndrome is a critical condition occasionally occurring posttransplant and is characterized by acute endothelial hyperpermeability leading to systemic protein-rich fluid extravasation and consequent hypovolemia, hypoperfusion, and acute kidney injury. Treatment is merely supportive and is based on osmotic drugs, diuretics, continuous renal replacement therapy, and surgical drainage. However, removal of the underlying inflammatory cause is mandatory to achieve stable resolution. Herein, we report the first successful treatment with colchicine in 2 life-threatening pediatric cases of capillary leak syndrome with renal failure occurring after transplant (heart and bone marrow) and unresponsive to any other line of therapy. Both cases were only palliated by supportive therapy and revealed an impressively rapid response to colchicine both in terms of diuresis and clinical condition recovery, allowing for the cessation of renal replacement therapy in a few hours. In both patients, colchicine was temporarily discontinued for transient leukopenia (attributed to an additive effect with mycophenolate mofetil), resulting in extravasation, and renal failure recurrence was restored only after colchicine reintroduction. Although the association of colchicine with an immunosuppressive drug was formerly contraindicated, no other adverse events were noted when using a minimized dose. Both patients are now maintaining a good renal function without recurrence of extravasation after 6 months of follow-up. In conclusion, this strikingly positive experience forces physicians to consider this old and cost-effective drug as a new, powerful rescue tool in such critical cases.",
"affiliations": "University of Turin, Turin, Italy; and.;University of Turin, Turin, Italy; and.;Nephrology, Dialysis and Transplantation Unit.;Pediatric Cardiac Surgery Unit, and.;Pediatric Cardiac Surgery Unit, and.;Pediatric Onco-Hematology Unit, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Turin, Italy.;University of Turin, Turin, Italy; and.",
"authors": "Cocchi|Enrico|E|;Chiale|Federica|F|;Gianoglio|Bruno|B|;Deorsola|Luca|L|;Pace Napoleone|Carlo|C|;Fagioli|Franca|F|;Peruzzi|Licia|L|",
"chemical_list": "D050257:Tubulin Modulators; D003078:Colchicine",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2018-2820",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "143(5)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000293:Adolescent; D019559:Capillary Leak Syndrome; D002648:Child; D003078:Colchicine; D005260:Female; D016027:Heart Transplantation; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D051437:Renal Insufficiency; D050257:Tubulin Modulators",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31000685",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Colchicine: An Impressive Effect on Posttransplant Capillary Leak Syndrome and Renal Failure.",
"title_normalized": "colchicine an impressive effect on posttransplant capillary leak syndrome and renal failure"
} | [
{
"companynumb": "IT-PBT-000020",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "Immune checkpoint inhibitors (ICIs) are associated with a variety of immune-related adverse events (irAEs), but haematological irAEs are rare. We report a case of presumed complement-mediated thrombotic microangiopathy (CM-TMA) in a 78-year-old man with metastatic melanoma following treatment with ICIs. Following two doses of combination nivolumab and ipilimumab therapy, he developed microangiopathic haemolytic anaemia, thrombocytopenia and increased creatinine. ADAMTS13 activity was preserved, CH50 was high, haptoglobin was depleted and a blood film demonstrated fragments. Given this constellation of findings, a diagnosis of CM-TMA was made. Immunotherapy was held and the patient received steroids and supportive care. Six months after his last dose of immunotherapy, he has no evidence of melanoma or CM-TMA. CM-TMA should be suspected in patients on ICI with unexplained anaemia and thrombocytopenia with preserved ADAMTS13 activity. Suspicion of complement dysregulation may have therapeutic implications, such as the necessity of complement pathway inhibition.",
"affiliations": "Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada thiago.muniz@uhn.ca.;Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.;Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.",
"authors": "Muniz|Thiago P|TP|;Patriquin|Christopher J|CJ|;Saibil|Samuel D|SD|",
"chemical_list": "D051056:Complement Inactivating Agents; D000074324:Ipilimumab; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-242075",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "haematology (incl blood transfusion); oncology; skin cancer",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D051056:Complement Inactivating Agents; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma; D000077594:Nivolumab; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34312126",
"pubdate": "2021-07-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Presumed complement-mediated, checkpoint inhibitor-induced, thrombotic microangiopathy in a patient with metastatic melanoma.",
"title_normalized": "presumed complement mediated checkpoint inhibitor induced thrombotic microangiopathy in a patient with metastatic melanoma"
} | [
{
"companynumb": "CA-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-079155",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Drug-induced hepatotoxicity is one of the most challenging hepatic diseases faced nowadays due to a large number of drugs currently used in clinical practice, the enormous dietary supplements which are potentially hepatotoxic, as well as the ability to appear with different clinical symptoms and the absence of specific markers. The current research survey was conducted to investigate drug-induced hepatotoxicity and demographic characteristics of patients with liver damage in the general Maghrebian population between 1992 and 2018. To achieve this goal a questionnaire was adopted to report details on the undesirable effects of drugs and demographic characteristics of affected patients. The results obtained in the current survey showed that 1001 in 25 093 cases of drug-induced toxicity were registered with drug-induced liver damage between 1992 and 2018. Regarding demographic characteristics of affected patients, the most affected age group was 18 to 44-years-old with a percentage of 45.70% followed by the age group 45 to 64-year-old with a percentage of 27.20%. Females were the most frequently affected by the hepatic side effects of drugs vs. males. Paracetamol, isoniazid, rifampicin, and pyrazinamide were the main responsible drugs for liver damage in the study population. Alteration of biological parameters and subclinical phenomena were used as clinical manifestations of liver damage in the study population. The outcome of the present study suggests paying more attention to drugs used for medication and the involvement of rigorous clinical monitoring to prevent or to minimize the side effects of drugs.",
"affiliations": "Faculty of Medicine and Pharmacy, Laboratory of Chemistry-Biochemistry, Environment, Nutrition, and Health, Hassan II University, Casablanca, Morocco.;Department of Pharmacognosy (Medicinal Aromatic and Poisonous Plants Research Center), College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.;Department of Pharmacognosy (Medicinal Aromatic and Poisonous Plants Research Center), College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.;Faculty of Medicine and Pharmacy, Laboratory of Chemistry-Biochemistry, Environment, Nutrition, and Health, Hassan II University, Casablanca, Morocco.",
"authors": "Bourhia|Mohammed|M|;Ullah|Riaz|R|;S Alqahtani|Ali|A|;Ibenmoussa|Samir|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/01480545.2020.1797088",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-0545",
"issue": null,
"journal": "Drug and chemical toxicology",
"keywords": "Drugs; Maghrebian; hepatotoxicity; pharmacological survey; population",
"medline_ta": "Drug Chem Toxicol",
"mesh_terms": null,
"nlm_unique_id": "7801723",
"other_id": null,
"pages": "1-5",
"pmc": null,
"pmid": "32715778",
"pubdate": "2020-07-26",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evidence of drug-induced hepatotoxicity in the Maghrebian population.",
"title_normalized": "evidence of drug induced hepatotoxicity in the maghrebian population"
} | [
{
"companynumb": "SA-JNJFOC-20200809665",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "Tuberculosis (TB) is one of the leading causes of morbidity and mortality worldwide, with ever increasing resistance to commonly used antituberculous drugs. Drug-resistant TB was recognized shortly after the introduction of an effective therapy in the late 1940s, the use of streptomycin, which was the first widely used antituberculosis drug. Patients who received this drug usually had marked and rapid clinical improvement, but treatment failures were common after the first three months of therapy. Most children are infected by household contacts who have TB, particularly parents or other caretakers. Common symptoms of pulmonary TB in children include cough (chronic, without improvement for more than three weeks), fever (higher than 38 °C for more than two weeks), and weight loss or failure to thrive. Findings on a physical exam may suggest the presence of a lower respiratory infection, whereas the clinical presentation of extra pulmonary TB depends on the site of disease. The most common forms of extra pulmonary disease in children are TB of the lymph nodes and of the central nervous system. The role of inadequate treatment and poor compliance in the emergence of resistance highlights the importance of the DOT (Direct Observation Therapy) method in improving treatment outcomes and to control the spread of resistance.",
"affiliations": "Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.;Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.",
"authors": "Al Qurainees|Ghaya Ibrahim|GI|;Tufenkeji|Haysam Taher|HT|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijpam.2015.11.003",
"fulltext": "\n==== Front\nInt J Pediatr Adolesc MedInt J Pediatr Adolesc MedInternational Journal of Pediatrics & Adolescent Medicine2352-6467King Faisal Specialist Hospital and Research Centre S2352-6467(15)00111-810.1016/j.ijpam.2015.11.003Instructive CaseA child with complicated Mycobacterium tuberculosis AL Qurainees Ghaya Ibrahim dr.ghaya83@gmail.com∗Tufenkeji Haysam Taher Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia∗ Corresponding author. Tel.: +966 509410010. dr.ghaya83@gmail.com24 12 2015 3 2016 24 12 2015 3 1 28 33 15 9 2015 18 11 2015 19 11 2015 Copyright © 2016, King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia. Production and hosting by Elsevier B.V.2016King Faisal Specialist Hospital & Research Centre (General Organization), Saudi ArabiaThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Tuberculosis (TB) is one of the leading causes of morbidity and mortality worldwide, with ever increasing resistance to commonly used antituberculous drugs. Drug-resistant TB was recognized shortly after the introduction of an effective therapy in the late 1940s, the use of streptomycin, which was the first widely used antituberculosis drug. Patients who received this drug usually had marked and rapid clinical improvement, but treatment failures were common after the first three months of therapy. Most children are infected by household contacts who have TB, particularly parents or other caretakers. Common symptoms of pulmonary TB in children include cough (chronic, without improvement for more than three weeks), fever (higher than 38 °C for more than two weeks), and weight loss or failure to thrive. Findings on a physical exam may suggest the presence of a lower respiratory infection, whereas the clinical presentation of extra pulmonary TB depends on the site of disease. The most common forms of extra pulmonary disease in children are TB of the lymph nodes and of the central nervous system. The role of inadequate treatment and poor compliance in the emergence of resistance highlights the importance of the DOT (Direct Observation Therapy) method in improving treatment outcomes and to control the spread of resistance.\n\nKeywords\nTuberculosisMultidrug-resistantDirectly observed therapyRifampicinComplianceThrombocytopenia\n==== Body\n1 Introduction\nTB is a disease that is caused by the bacterium Mycobacterium tuberculosis. The bacteria usually attack the lungs, but TB bacteria can attack any part of the body, such as the kidney, spine, or brain. If not treated properly, TB can be fatal. TB was once the leading cause of death.\n\n2 Case presentation\nA 7-year-old Saudi girl presented to the emergency department at this tertiary care hospital with a worsening course of fever, cough, weight loss, and abdominal pain over 3 weeks. She was admitted to a local hospital earlier and was suspected of having lymphoma. There was a history of recent contact with an aunt who was diagnosed as having pulmonary TB 6 months earlier and who was started on treatment with 4 drugs. The results of culture and susceptibility testing are not available. The child's place of residence in AL-Jouf was crowded, with many extended family members, and was poorly ventilated. Her father was 45 years old, and her mother was 35 years old. Both were healthy, but of poor socioeconomic status.\n\nOn examination, the child looked acutely ill, pale, tachypneic, and tachycardic, with a temperature of 39.6 °C, WT 11.7 < 5th centile, and HT 106 cm > 50th centile. There were multiple cautery marks over the chest wall and upper abdomen, and on chest auscultation, there was a marked decrease of air entry on the right side, with bronchial breathing and basal crepitations.\n\n2.1 Laboratory data (Table 1)\nThe chest X-ray (Fig. 1) demonstrated an airspace disease involving the right lower lobe and a cystic change involving the right upper lobe with blunted cardiopulmonary angles. A CT scan of the chest (Fig. 2) demonstrated large airspace consolidation involving the right middle and lower lobes, with a large cavity in the right upper lobe, and bilateral miliary nodules that had a tree-in-bud appearance. There were multiple mediastinal necrotic lymph nodes suggestive of acute on top of chronic TB. The abdominal CT showed small hypo-dense splenic lesions.Table 1 Clinical investigation upon diagnosis and during treatment of DOT.\n\nLaboratory data\tOn diagnosis\tOn DOT\tNormal range\t\nCBC and differential\t\n WBC, 109/L\t19.17\t5.86\t4.30–11.30\t\n RBC, 1012/L\t3.49\t4.34\t4.30–5.50\t\n hemoglobin, g/L\t67\t113\t110–150\t\n Hematocrit, L/L\t0.294\t0.339\t0.350–0.450\t\n MCVfL\t73.7\t78.1\t75–95\t\n MCHCpg\t22.5\t26\t24–30\t\n RDW, %\t19\t12.9\t11–15\t\n Platelet, 109/L\t25\t231\t155–435\t\n Neutrophil absolute, 109/L\t6.20\t1.71\t1.35–7.50\t\n Lymphocyte absolute, 109/L\t1.21\t2.88\t1.90–4.90\t\n ESR, mm/h\t140\t9\t0–15\t\n CRP, mg/L\t103\t0.4\t≤3 mg/L\t\n Albumin, g/L\t17\t42.9\t32–48\t\n AST, U/L\t373\t33.5\t10–45\t\n ALT, U/L\t114\t24.9\t10–35\t\n Bilirubin, total, umol/L\t6.3\t4.9\t0–21\t\n Alkaline phosphate, u/L\t269.5\t246\t100–300\t\n HIV 1–2 antibody screening\tNon reactive\t\t\t\nFigure 1 Airspace disease involving the right middle and lower lobe with a cystic change involving the right upper lobe.\n\nFigure 2 Improvement of the airspace disease in the right middle and lower lobe after starting treatment. Bronchial wall thickening with peribronchial infiltrates in the perihilar region.\n\n\n\nBased on these findings, the patient was diagnosed as having pulmonary TB, iron deficiency anemia, and failure to thrive. Air borne isolation was initiated, and she was admitted to a negative air pressure room and started on INH, Rifampicin, pyrazinamide streptomycin, pyridoxine, and iron therapy. Four days after treatment, her platelet count decreased to 25 x 109/L.\n\nRifampicin-induced thrombocytopenia was suspected, and the drug was therefore discontinued and replaced with ethambutol. Subsequently, the platelet count rebounded to a normal level.\n\nThe Mantoux test was positive. Sputum for the AFB stain was positive, and the rapid DNA amplification test was positive for the M. tuberculosis complex. The culture was later reported to be positive for mycobacterium TB. The isolate was susceptible to streptomycin, isoniazid, rifampin, ethambutol, and pyrazinamide.\n\nThe general condition of the patient improved on treatment, with a normalizing respiratory rate and other vital signs, but she experienced persistent episodes of low-grade fever. Her appetite improved, with good oral intake and increased weight. The baseline eye examination was normal, and follow ups were arranged. After 18 days of inpatient treatment, the patient was discharged, due in part to the insistence of the parents for an early discharge, on ethambutol, INH, Pyrazinamide, a Streptomycin IM injection once daily for 8 weeks (to be given at a local hospital), iron therapy, and pyridoxine with a follow-up OPD appointment.\n\nOn frequent repeated outpatient visits over the ensuing months, the response to treatment was suboptimal, as evidenced clinically and according to the investigation results. Poor compliance was suspected, and her antimicrobial serum levels were found to be undetectable. The local treating physician was contacted, and arrangements were made to initiate direct observation therapy (DOT); however, the family did not agree to have health care personnel in their home. This ultimately resulted in her clinical deterioration and a second admission.\n\nAt this admission, there was a history of fever with chills for one month associated with decreased oral intake and activity. The parents noticed that she developed cervical and sternal ulcers, which were progressively worsening and discharging yellow, milky material.\n\nOn examination, she was conscious, listless, unwell in appearance, pale, and dehydrated. Her vital signs were as follows: temperature: 38.4 °C, heart rate: 147 beats per minute, respiratory rate: 28 per minute, O2 saturation: 100% in room air, and blood pressure: 87/48 mmHg. A chest exam showed clear vesicular breathing, with no added sounds and decreased air entry, mainly on the right side. A cardiovascular exam showed normal S1 and S2, with no murmur. The abdomen was mildly distended with no organomegaly. She had multiple ulcerative skin lesions on the right side of the neck, over the sternum, and chest as well as bilateral axillary lymph nodes, which were ulcerating and discharging milky serous material. Her hemoglobin was 5 g/dl, indicating poor nutrition and poor compliance with all medications, including iron therapy.\n\nShe was admitted with the impression of pulmonary and extra pulmonary (scrofuloderma) TB secondary to poor compliance with medical therapy in addition to social issues. The patient received packed RBCs. A review of the cultures and susceptibility results of the specimens from the sputum and lesions taken earlier showed that the organism had become first resistant to INH, then to ethionamide and streptomycin. The patient was therefore started on ethambutol, pyrazinamide, cycloserine, moxifloxacin, and pyridoxine (vitamin B6) to reduce the risk of the neurotoxicity of cycloserine and iron therapy. A specimen was submitted to a specialized center abroad, and PZA was tested by broth dilution using critical concentrations and CLSI interpretive criteria. All other agents were tested by the microbroth dilution with the (minimal inhibitory concentration) MIC reported and using laboratory developed interpretive criteria. The blood culture was negative. The wound culture was positive for Streptococcus pneumonia and for MRSA, which were treated accordingly. C-reactive protein was 239. A CT chest scan with contrast (Fig. 3) showed an interval increase in the number, size, and necrosis of the previously seen enlarged cervical and axillary lymph nodes, with abscess formation in addition to patchy pneumonic consolidations of the upper, middle, and right lower lobes. A bone scan showed mild increased activity in the left clavicle, likely related to a chronic infectious process. However, according to Pediatric Surgery, there was no role for surgical intervention.Figure 3 Improvement in the miliary nodules as well as the endobronchial tree-in-bud involvement of the right upper lobe and middle lobe after starting treatment.\n\nFigure 4 Chest CT: Large airspace consolidation involving the right middle and lower lobes with cavitary areas, a large cavity in the right upper lobe, bilateral miliary nodules and tree-in-bud appearance, with multiple mediastinal necrotic lymph nodes.\n\n\n\nThe Child Advocacy Committee (CAC) was involved because of obvious parental neglect in the form of poor compliance with medications and refusal to cooperate with local as well as this hospital's medical staff. After several sessions with the parents and in coordination with the local Ministry of Health (MOH) authorities, an arrangement was made for admission to a local hospital where the child would receive her medications as an inpatient and then be followed up later with DOT therapy along with appointments at our hospital for a total of at least 9 months.\n\nOn outpatient follow-up, the patient continued on ethambutol, pyrazinamide, cycloserine, moxifloxacin, pyridoxine, and iron therapy. She has markedly improved, with an absence of fever, weight gain, normal inflammatory markers, and clearing CXR (Fig. 4), Table 1.\n\n3 Discussion\nTB remains a significant global health problem, with nearly 9 million new cases and 1.5 million deaths estimated annually [1], [2]. The estimated incidence of TB in Saudi Arabia is 14/100,000 [3]. Because of increased resistance to commonly used anti-TB drugs, management has become more complex and difficult, requiring the use of second-line drugs and, in some cases, surgical resection. Drug-resistant TB is defined as an infection caused by a strain of M. tuberculosis that is resistant to one of the first-line anti-TB drugs: isoniazid, rifampin, pyrazinamide, ethambutol, or streptomycin. Multidrug-resistant TB (MDR-TB) is defined as an infection caused by a strain of M. tuberculosis that is resistant to at least isoniazid and rifampin. Extensively drug-resistant TB (XDR-TB) is defined as an infection caused by a strain of M. tuberculosis that is resistant to at least isoniazid, rifampin, and fluoroquinolones, as well as either aminoglycosides (amikacin and kanamycin), capreomycin or both [4]. Totally drug-resistant TB (TDR-TB) is defined as an infection caused by a strain of M. tuberculosis that is resistant to all locally tested medications [5], [6]. Primary drug resistance is said to occur in a patient who has never received anti-TB therapy, and secondary drug resistance refers to the development of resistance during or following chemotherapy in patients who had previously had drug-susceptible TB.\n\nThe first representative national survey conducted in Saudi Arabia showed that of 1904 patients, 79.3% had pulmonary and 20% had extra pulmonary TB, with lymph nodes being the most common site of infection (56.2%) [7]. Of the 1609 isolates from new cases of TB, 16.4% were resistant to at least one first-line drug and 1.8% were MDR. Of the 295 isolates from previously treated TB cases, 63.4% were resistant to at least one first-line drug and 15.9% were MDR. The prevalence of resistance to anti-tuberculosis agents was highest for INH followed by streptomycin and rifampicin. Regarding the geographical distribution of MDR-TB in the country, the highest prevalence was detected in the northern and southern provinces, followed by the western and central provinces, and the lowest proportion was reported in the eastern province.\n\nThe treatment of patients with INH monoresistant TB has not been evaluated rigorously in randomized trials, and therefore, approaches are generally based on expert opinion derived from retrospective or single arm studies. In general, most patients with INH monoresistance should be treated with a rifamycin (rifampin or rifabutin), pyrazinamide, and ethambutol.\n\nThe duration of therapy should be six to nine months (or four months after culture conversion) [8], [9], based on trials conducted by the Hong Kong Chest Service/British Medical Research Council, which demonstrated success rates of 95–98% among 107 patients with INH-resistant disease [10]. This finding was also supported by a retrospective study of patients with INH-monoresistant TB treated for six months, which showed comparable rates of failure or relapse among patients with drug-susceptible TB [9].\n\nData supporting the addition of a fluoroquinolone for the treatment of INH-monoresistant TB is inconsistent with one study of 328 patients with smear-positive TB who were randomized to receive either INH or moxifloxacin (in addition to rifampin, pyrazinamide, and ethambutol), in which culture negativity after eight weeks was comparable between the two groups (55 and 60%, respectively) [11]. On the other hand, a retrospective Danish study suggested that the inclusion of a fluoroquinolone in the treatment regimen was associated with a slightly higher success rate [12].\n\nAs per the World Health Organization (WHO) recommendation, the treatment of patients for whom drug susceptibility testing is not available but are known to reside in a region with a background level of INH resistance > 7%, an acceptable approach consists of a standard initial phase (e.g., INH, rifampin, pyrazinamide, and ethambutol), followed by a continuation phase with INH and rifampin as well as the addition of ethambutol (rather than only INH and rifampin). Overall, effective therapy for INH-monoresistant TB is associated with very high bacteriologic, clinical response rates (>95%), and low relapse rates (<5%). National TB treatment guidelines strongly recommend using a patient-cantered case management approach, including directly observed therapy (“DOT”), when treating persons with active TB. DOT is especially critical for patients with drug-resistant TB, HIV-infected patients, and those on intermittent treatment regimens (i.e., 2 or 3 times weekly). DOT means that a trained health care worker or other designated individual (excluding a family member) provides the prescribed TB drugs and watches the patient swallow every dose to ensure that the medications are administered as directed. Because TB treatment entails several drugs taken regularly for several months, people from all social classes, educational backgrounds, ages, genders, and ethnicities may find it difficult to correctly adhere to the instructions. Studies show that 86–90% of patients receiving DOT complete therapy, compared to 61% for those on self-administered therapy. DOT helps patients finish TB therapy as quickly as possible, without unnecessary gaps, prevents TB from spreading to others, decreases the risk of drug-resistance resulting from erratic or incomplete treatment and decreases the chances of treatment failure and relapse [13], [14], [15], [16].\n\nSerious reactions to antituberculosis drugs are uncommon. Rifampicin-induced thrombocytopenia is an uncommon but potentially life-threatening complication of antituberculosis treatment [17]. Rifampicin-induced thrombocytopenia was first reported by Blajchman and co-colleagues [18] in 1970. Most of the described cases were observed with high dose intermittent therapy (1200 mg twice weekly) [19]. Only a few cases of thrombocytopenia have occurred during daily treatment or after the administration of rifampicin following an interruption of therapy [18], [20]. The Tuberculosis Research Centre of Chennai reported only a single case of rifampicin-induced thrombocytopenia among more than over 8000 patients treated for tuberculosis over 30 years [21]. It has been observed that rifampicin-induced thrombocytopenia is caused by the presence of anti-rifampicin antibodies [20]. These antibodies fix a complement on the platelets in the presence of rifampicin, resulting in platelet destruction [21]. It has been found that antibodies against rifampicin are significant in number among patients who have stopped therapy; yet, rifampicin-induced thrombocytopenia is still relatively rare [18], [21]. The low incidence of thrombocytopenia due to daily doses of rifampicin has been attributed to the possible development of neutralizing antibodies formed during continuous treatment or may occur because the antigen–antibody complex is continuously removed without causing an allergic reaction [22]. Thus, daily doses of rifampicin may result in immunologic tolerance, whereas intermittent dosing favors sensitization [23]. It has been recommended that rifampicin-induced thrombocytopenia be an absolute contraindication to further therapy with rifampicin [19]. However, Bhasin and co-colleagues [24] suggested that re-challenges should be performed before withdrawing rifampicin. When it is necessary to re-start rifampicin, one should check the platelets counts frequently, under supervision and with the use of steroids.\n\nWe present this case as an example of a child with complicated TB as illustrated by the initial poor clinical response to therapy caused by the emergence of resistance. On presentation, the organism cultured was sensitive to all first line agents, but because of poor compliance as documented by undetectable drug levels, the patient developed polydrug resistance. The improvement in the intake of medications and the resulting treatment success in this case was undoubtedly achieved by following the DOT method. Moreover, collaboration with the local physician and health care authorities was key in the implementation process. Confirmation of rifampicin-induced thrombocytopenia at the time of initial presentation is not often possible because tests for drug-dependent anti-platelet antibodies are not available in most laboratories. Discontinuation of the suspected drug leading to the resolution of thrombocytopenia provides strong evidence of rifampicin-induced thrombocytopenia. TB is nearly always curable if patients are treated with effective and uninterrupted antituberculous therapy. In children, parental support and an understanding of the importance of adherence to treatment as instructed is critical in bringing about cure, controlling the spread of infection, and minimizing the development of drug resistance. In the U.S.A., a Task Force composed of representatives of many federal agencies has developed a National Action Plan for addressing MDR-TB. The Task Force identified a number of objectives that must be met if MDR-TB is to be successfully combatted. These objectives fall under the categories of a) surveillance and epidemiology to determine the magnitude and nature of the problem; b) laboratory diagnostics to improve the rapidity, sensitivity, and reliability of diagnostic methods for MDR-TB; c) patient management to effectively managing patients who have MDR-TB and to prevent patients with drug-susceptible TB from developing drug-resistant disease; d) screening and preventive therapy to identify persons who are infected with or at risk of developing MDR-TB and to prevent them from developing clinically active TB; e) infection control to minimize the risk of transmission of MDR-TB to patients, workers, and others in institutional settings; f) outbreak control; g) program evaluation to ensure that TB programs are effective in managing patients and preventing MDR-TB; h) information dissemination/training and education; and i) research to provide new more effective tools with which to combat MDR-TB [25].\n\nConflict of interest\nAuthors declare no competing interests.\n\nPeer review under responsibility of King Faisal Specialist Hospital & Research Centre (General Organization), Saudi Arabia.\n==== Refs\nReferences\n1 Raviglione M.C. Marais B. Floyd K. Lonnroth K. Getahun H. Migliori G.B. Scaling up interventions to achieve global tuberculosis control: progress and new developments Lancet 379 2012 1902 1913 22608339 \n2 World Health Organization Global tuberculosis control report 2011 2011 World Health Organization Geneva, Switzerland \n3 World Health Organization (WHO) estimates of tuberculosis incidence by country 2013 http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1195733758290 \n4 World Health Organization (WHO) Laboratory XDR-TB definitions 2006 Meeting of the Global XDR TB Task Force Geneva \n5 Velayati Ali Akbar Masjedi Mohammad Reza Farnia Parissa Tabarsi Payam Ghanavi Jalladein ZiaZarifi Abol Hassan Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran Chest 136 2009 420 19349380 \n6 Udwadia Z.F. Amale R.A. Ajbani K.K. Rodrigues C. Totally drug-resistant tuberculosis in India Clin Infect Dis 54 2012 579 22190562 \n7 Sahal Al-Hajoj, Bright Varghese, Mohammed M. Shoukri, Ruba Al-Omari, Mais Al-Herbwai, Fahad AlRabiah, et al. Epidemiology of antituberculosis drug resistance in Saudi Arabia: findings of the first national survey.\n8 Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. Centers for Disease Control and Prevention MMWR Recomm Rep 47 1998 1 \n9 Cattamanchi Adithya Dantes Raymund B. Metcalfe John Z. Jarlsberg Leah G. Grinsdale Jennifer Kawamura L. Masae Clinical characteristics and treatment outcomes of patients with isoniazid-monoresistant tuberculosis Clin Infect Dis 48 2009 179 19086909 \n10 Five-year follow-up of a controlled trial of five 6-month regimens of chemotherapy for pulmonary tuberculosis. Hong Kong Chest Service/British Medical Research Council Am Rev Respir Dis 136 1987 1339 2891333 \n11 Dorman Susan E. Johnson John L. Goldberg Stefan Muzanye Grace Padayatchi Nesri Bozeman Lorna Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary tuberculosis Am J Respir Crit Care Med 180 2009 273 19406981 \n12 Bang D. Andersen P.H. Andersen A.B. Thomsen V.Ø. Isoniazid-resistant tuberculosis in Denmark: mutations, transmission and treatment outcome J Infect 60 2010 452 20347869 \n13 Treatment of tuberculosis, American Thoracic Society, CDC and Infectious Diseases Society of America Am J Respir Crit Care Med 167 2003 on line at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm \n14 Interactive core curriculum on tuberculosis (web-based) 2004 CDC www.cdc.gov/tb/webcourses/corecurr/index.htm \n15 DOT essentials: a training curriculum for TB control programs 2003 Francis J. Curry National Tuberculosis Center \n16 Management: directly observed therapy 2001 New York City Department of Health \n17 Garg R. Gupta V. Mehra S. Singh R. Prasad R. Rifampicin induced thrombocytopenia Indian J Tuberc 54 2007 94 96 17575681 \n18 Blajchman M.A. Lowry R.C. Pettit J.E. Stradling P. Rifampicin-induced immune thrombocytopenia Br Med J 3 1970 24 26 5427483 \n19 Poole G. Stradling P. Worrledge S. Potentially serious side effects of high-dose twice-weekly rifampicin Br Med J 3 1971 343 347 5314737 \n20 Mehta Y.S. Jijina F.F. Badakere S.S. Pathare A.V. Mohanty D. Rifampicin induced immune thrombocytopenia Tuberc Lung Dis 77 1996 558 562 \n21 Banu Rekha V.V. Adhilakshmi A.R. Jawahar M.S. Rifampicin-induced acute thrombocytopenia Lung India 22 2005 122 124 \n22 Bassi L. di Berardino L. Perna G. Silvestre L.G. Antibodies against rifampicin in patients with tuberculosis after discontinuation of daily treatment (note) Am Rev Respir Dis 114 1976 1189 1190 1008352 \n23 Girling D.J. Adverse effect of anti mycobacterial drugs Drugs 23 1982 56 74 6459920 \n24 Bhasin D.K. Sarode R. Puri S. Marwaha N. Singh K. Can rifampicin be restarted in patients with rifampicin- induced thrombocytopenia? Tubercle 72 1991 306 371 1811365 \n25 National action plan to combat multidrug-resistant tuberculosis MMWR Recomm Rep 41 RR-11 1992 Jun 19 5 48\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-6467",
"issue": "3(1)",
"journal": "International journal of pediatrics & adolescent medicine",
"keywords": "Compliance; Directly observed therapy; Multidrug-resistant; Rifampicin; Thrombocytopenia; Tuberculosis",
"medline_ta": "Int J Pediatr Adolesc Med",
"mesh_terms": null,
"nlm_unique_id": "101670718",
"other_id": null,
"pages": "28-33",
"pmc": null,
"pmid": "30805464",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports",
"references": "1008352;1640920;17575681;1811365;19086909;19349380;19406981;20347869;22190562;22608339;23459478;2891333;5314737;5427483;6459920;9039451;9809743",
"title": "A child with complicated Mycobacterium tuberculosis.",
"title_normalized": "a child with complicated mycobacterium tuberculosis"
} | [
{
"companynumb": "SA-LUPIN PHARMACEUTICALS INC.-2016-03128",
"fulfillexpeditecriteria": "2",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional... |
{
"abstract": "OBJECTIVE\nThe aims of this study are to describe two patients whose manic symptoms persisted for several months after the cessation of corticosteroids, to review the literature and to suggest treatment.\n\n\nMETHODS\nThe presentation of two elderly patients with persistent manic symptoms following cessation of corticosteroids several months previously afforded the author the opportunity to examine them carefully, investigate and treat them.\n\n\nRESULTS\nThe patients were investigated to rule out other causes and were treated with sodium valproate and quetiapine (in the second patient). When well, the medications were slowly decreased and stopped. Both patients were well at one-year follow-up.\n\n\nCONCLUSIONS\nManic symptoms may persist for many months after stopping corticosteroids and active treatment is needed to control them.",
"affiliations": "Asssociate Professor of Psychiatry, Sydney Adventist Medical School, University of Sydney, Sydney, NSW, Australia.",
"authors": "Roxanas|Milton G|MG|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D018692:Antimanic Agents",
"country": "England",
"delete": false,
"doi": "10.1177/1039856218758566",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1039-8562",
"issue": "26(5)",
"journal": "Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists",
"keywords": "corticosteroid-induced mania; prolonged steroid mania; steroid psychosis; treatment of steroid-induced mania",
"medline_ta": "Australas Psychiatry",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D018692:Antimanic Agents; D001714:Bipolar Disorder; D005260:Female; D006801:Humans; D008297:Male",
"nlm_unique_id": "9613603",
"other_id": null,
"pages": "520-523",
"pmc": null,
"pmid": "29446641",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Persistent mania following cessation of corticosteroids.",
"title_normalized": "persistent mania following cessation of corticosteroids"
} | [
{
"companynumb": "AU-MYLANLABS-2018M1081280",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nDose intensification with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) every 2 weeks improves outcomes in patients older than 60 years with diffuse large B-cell lymphoma compared with CHOP every 3 weeks. We investigated whether this survival benefit from dose intensification persists in the presence of rituximab (R-CHOP) in all age groups.\n\n\nMETHODS\nPatients (aged ≥18 years) with previously untreated bulky stage IA to stage IV diffuse large B-cell lymphoma in 119 centres in the UK were randomly assigned centrally in a one-to-one ratio, using minimisation, to receive six cycles of R-CHOP every 14 days plus two cycles of rituximab (R-CHOP-14) or eight cycles of R-CHOP every 21 days (R-CHOP-21). R-CHOP-21 was intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1·4 mg/m(2) (maximum dose 2 mg), and rituximab 375 mg/m(2) on day 1, and oral prednisolone 40 mg/m(2) on days 1-5, administered every 21 days for a total of eight cycles. R-CHOP-14 was intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 2 mg, rituximab 375 mg/m(2) on day 1, and oral prednisolone 100 mg on days 1-5, administered every 14 days for six cycles, followed by two further infusions of rituximab 375 mg/m(2) on day 1 every 14 days. The trial was not masked. The primary outcome was overall survival (OS). This study is registered, number ISRCTN 16017947.\n\n\nRESULTS\n1080 patients were assigned to R-CHOP-21 (n=540) and R-CHOP-14 (n=540). With a median follow-up of 46 months (IQR 35-57), 2-year OS was 82·7% (79·5-85·9) in the R-CHOP-14 group and 80·8% (77·5-84·2) in the R-CHOP-21 (standard) group (hazard ratio 0·90, 95% CI 0·70-1·15; p=0·3763). No significant improvement was noted in 2-year progression-free survival (R-CHOP-14 75·4%, 71·8-79·1, and R-CHOP-21 74·8%, 71·0-78·4; 0·94, 0·76-1·17; p=0·5907). High international prognostic index, poor-prognosis molecular characteristics, and cell of origin were not predictive for benefit from either schedule. Grade 3 or 4 neutropenia was higher in the R-CHOP-21 group (318 [60%] of 534 vs 167 [31%] of 534), with no prophylactic use of recombinant human granulocyte-colony stimulating factor mandated in this group, whereas grade 3 or 4 thrombocytopenia was higher with R-CHOP-14 (50 [9%] vs 28 [5%]); other frequent grade 3 or 4 adverse events were febrile neutropenia (58 [11%] vs 28 [5%]) and infection (125 [23%] vs 96 [18%]). Frequencies of non-haematological adverse events were similar in the R-CHOP-21 and R-CHOP-14 groups.\n\n\nCONCLUSIONS\nR-CHOP-14 is not superior to R-CHOP-21 chemotherapy for previously untreated diffuse large B-cell lymphoma; therefore, R-CHOP-21 remains the standard first-line treatment in patients with this haematological malignancy. No molecular or clinical subgroup benefited from dose intensification in this study.\n\n\nBACKGROUND\nChugai Pharmaceutical, Cancer Research UK, National Institute for Health Research Biomedical Research Centres scheme at both University College London and the Royal Marsden NHS Foundation Trust, and Institute of Cancer Research.",
"affiliations": "Royal Marsden NHS Foundation Trust, London and Surrey, UK. david.cunningham@rmh.nhs.uk",
"authors": "Cunningham|David|D|;Hawkes|Eliza A|EA|;Jack|Andrew|A|;Qian|Wendi|W|;Smith|Paul|P|;Mouncey|Paul|P|;Pocock|Christopher|C|;Ardeshna|Kirit M|KM|;Radford|John A|JA|;McMillan|Andrew|A|;Davies|John|J|;Turner|Deborah|D|;Kruger|Anton|A|;Johnson|Peter|P|;Gambell|Joanna|J|;Linch|David|D|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "381(9880)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "1817-26",
"pmc": null,
"pmid": "23615461",
"pubdate": "2013-05-25",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles.",
"title_normalized": "rituximab plus cyclophosphamide doxorubicin vincristine and prednisolone in patients with newly diagnosed diffuse large b cell non hodgkin lymphoma a phase 3 comparison of dose intensification with 14 day versus 21 day cycles"
} | [
{
"companynumb": "PHHY2018GB049519",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCross-reactive immunological material-negative (CRIM-negative) infantile Pompe disease (IPD) patients develop an immune response against enzyme replacement therapy (ERT) with alglucosidase alfa that nullifies ERT efficacy. Prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and IVIG successfully prevents development of deleterious rhGAA IgG antibodies; however, safety, likelihood of success, and long-term efficacy of ITI in a larger cohort remain unknown.\n\n\nMETHODS\nClinical data were analyzed for 19 CRIM-negative IPD patients who received ITI with rituximab, methotrexate, and IVIG in the ERT-naive setting (ERT+ITI) and compared to a historical cohort of 10 CRIM-negative IPD patients on ERT monotherapy.\n\n\nRESULTS\nITI was safely tolerated, although infections were reported in 4 patients. Fourteen (74%) ERT+ITI patients were alive, with a median age of 44.2 months at their final assessment. The eldest survivor was 103.9 months old, with 100.2 months of follow-up after initiation of ERT+ITI. Death (n = 5) occurred at a median age of 29.2 months and was unrelated to the administration of ITI. Fifteen patients either did not seroconvert (n = 8) or maintained low titers (n = 7; defined as titers of ≤6,400 throughout the course of ERT) following ERT+ITI. Only one patient developed high and sustained antibody titers (defined as titers of ≥51,200 at or beyond 6 months on ERT). Left ventricular mass index (LVMI) decreased from a median of 248.5 g/m2 at baseline to 76.8 g/m2 at a median time from ERT+ITI initiation to 59 weeks. ERT+ITI significantly improved overall survival (P = 0.001), eliminated/reduced antibodies at values of ≤6,400 at week 52 on ERT (P = 0.0004), and improved LVMI at week 52 on ERT (P = 0.02) when compared with ERT monotherapy.\n\n\nCONCLUSIONS\nEvidence from this international cohort of CRIM-negative IPD patients further supports the safety, feasibility, and efficacy of ITI in the prevention of immune responses to ERT.\n\n\nBACKGROUND\nClinicaltrials.gov NCT01665326.\n\n\nBACKGROUND\nThis research was supported in part by the Lysosomal Disease Network, a part of NIH Rare Diseases Clinical Research Network, and by a grant from Genzyme, a Sanofi company.",
"affiliations": "Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.;Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.;Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.;University of Alabama at Birmingham, Birmingham, Alabama, USA.;Division of Metabolic Disorders, Children's Hospital of Orange County, Orange, California, USA.;Division of Medical Genetics, Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi, USA.;Division of Genetics and Metabolism, Children's National Health System, Washington, DC, USA.;Genomics Medicine Program, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA.;Pediatric Endocrinology and Metabolism Unit, Soroka Medical Center, Beer Sheva, Israel.;Department of Pediatrics, New York Medical College, Valhalla, New York, USA.;Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.;Division of Medical Genetics, Akron Children's Hospital, Akron, Ohio, USA.;Division of Medical Genetics, Akron Children's Hospital, Akron, Ohio, USA.;Division of Medical Genetics, Department of Pediatrics, St. Joseph's Regional Medical Center Genetics, Paterson, New Jersey, USA.;Division of Therapeutic Proteins, Office of Biotechnology Products, Center for Drug Evaluation and Research, US FDA, Bethesda, Maryland, USA.;Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.",
"authors": "Kazi|Zoheb B|ZB|;Desai|Ankit K|AK|;Berrier|Kathryn L|KL|;Troxler|R Bradley|RB|;Wang|Raymond Y|RY|;Abdul-Rahman|Omar A|OA|;Tanpaiboon|Pranoot|P|;Mendelsohn|Nancy J|NJ|;Herskovitz|Eli|E|;Kronn|David|D|;Inbar-Feigenberg|Michal|M|;Ward-Melver|Catherine|C|;Polan|Michelle|M|;Gupta|Punita|P|;Rosenberg|Amy S|AS|;Kishnani|Priya S|PS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2379-3708",
"issue": "2(16)",
"journal": "JCI insight",
"keywords": "Genetics; Immunology",
"medline_ta": "JCI Insight",
"mesh_terms": null,
"nlm_unique_id": "101676073",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28814660",
"pubdate": "2017-08-17",
"publication_types": "D016428:Journal Article",
"references": "21637107;22252923;25741864;16737883;23601496;10389919;27493997;12584368;23411799;25842186;24715333;17151339;22871665;26597321;23430560;19775921;23060045;15167056;23825616;11286229;26167453;25210119;23887636;19521244;1876513;27896120;19287243;22528067;21658619;11064373;19542901;19129538;11350880;16860134;20882352;26497565;22237443",
"title": "Sustained immune tolerance induction in enzyme replacement therapy-treated CRIM-negative patients with infantile Pompe disease.",
"title_normalized": "sustained immune tolerance induction in enzyme replacement therapy treated crim negative patients with infantile pompe disease"
} | [
{
"companynumb": "US-SA-2016SA062036",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALGLUCOSIDASE ALFA"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nInjection of botulinum toxin into the internal anal sphincter is a well-documented intervention to reduce anal hypertonia in the treatment of anal fissures. In patients receiving chemotherapy, painful anal conditions are frequent, secondary to change in bowel habits and reduced immunity. However, injection of botulinum toxin is often not offered due to fear of complications.\n\n\nMETHODS\nIn this retrospective longitudinal observational study, performed in a tertiary hospital setting, we analysed patient characteristics, outcome and complication rates of botulinum toxin injection in patients actively receiving chemotherapy.\n\n\nRESULTS\nTwenty-six patients were treated with 20-50 IU botulinum toxin while actively receiving chemotherapy because of intractable pain and hypertonia. The fissure was located dorsally in 69% (n = 18) and ventrally in 19% (n = 5), while in 3 patients (12%), no fissure was documented. The majority of the patients (88%, n = 23) had complete (54%, n = 14) or partial (35%, n = 9) relief of pain. In three patients, additional anal pathology developed in the weeks following botulinum toxin injection: thrombosis of grade IV haemorrhoids, perianal haematoma and an intersphincteric abscess.\n\n\nCONCLUSIONS\nInjection of botulinum toxin in the anal sphincters is a safe and effective analgesic option in patients with anal fissure while actively receiving chemotherapy.",
"affiliations": "Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium. philip.roelandt@uzleuven.be.;Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium.;Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium.",
"authors": "Roelandt|Philip|P|https://orcid.org/0000-0003-4475-9089;Coremans|Georges|G|;Wyndaele|Jan|J|",
"chemical_list": "D000700:Analgesics; D009465:Neuromuscular Agents; D019274:Botulinum Toxins, Type A",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-020-05641-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "28(11)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "Anal fissure; Analgesia; Botulinum toxin; Chemotherapy; Safety",
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D001003:Anal Canal; D000700:Analgesics; D019274:Botulinum Toxins, Type A; D002908:Chronic Disease; D005260:Female; D005401:Fissure in Ano; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009122:Muscle Hypertonia; D009369:Neoplasms; D009465:Neuromuscular Agents; D010146:Pain; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "5053-5054",
"pmc": null,
"pmid": "32712827",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Analgesic injection of botulinum toxin in anal fissures is efficient and can be performed safely in patients actively receiving chemotherapy.",
"title_normalized": "analgesic injection of botulinum toxin in anal fissures is efficient and can be performed safely in patients actively receiving chemotherapy"
} | [
{
"companynumb": "BE-ALLERGAN-2030040US",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BOTULINUM TOXIN TYPE A"
},
"drugadditional": null... |
{
"abstract": "We report on 4 children who presented with aseptic panniculitis associated with inherited immunodeficiency. Three patients had a B-cell immunodeficiency resulting from mutations in the TRNT1 and NF-κb2 genes (no mutation was found in the third patient), and 1 had a T-cell deficiency (mutation in the LCK gene). Panniculitis occurred before the age of 2 years in the 4 patients and preceded the onset of recurrent infections because of immunodeficiency in 2. It presented either as nodules, which resolved spontaneously within 1 to 2 weeks (3 patients), or chronic ulcerative lesions (1 patient) associated with unexplained fever and elevated acute phase reactants, without evidence of infection or high-titer autoantibodies. Febrile nodules relapsed in 2 patients, and recurrent attacks of unexplained fever (without relapse of panniculitis) occurred in the third. Skin biopsy revealed predominantly lympho-histiocytic or septal neutrophilic panniculitis in 1 and 3 patients, respectively. Panniculitis was associated with dermal involvement in the 4 patients. Patients with B-cell deficiency received monthly intravenous immunoglobulin replacement. Two patients who underwent bone marrow transplant died of bone marrow transplant-related complications. The 2 remaining patients had persistent, mild autoinflammatory disease, which did not require specific treatment. In these cases, the need for careful immunologic evaluation of patients who present with unexplained panniculitis, especially early-onset panniculitis before the age of 2 years, is highlighted.",
"affiliations": "Départements d'Immunologie, Hématologie, et Rhumatologie Pédiatrique, brigitte.bader-meunier@aphp.fr.;Institut Imagine, INSERM U1163.;Département d'Immunologie et Rhumatologie Pédiatrique, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Quebec, Canada.;Départements d'Immunologie, Hématologie, et Rhumatologie Pédiatrique.;Institut Imagine, INSERM U1163.;d'Anatomie Pathologique, and.;Institut Imagine, INSERM U1163.",
"authors": "Bader-Meunier|Brigitte|B|;Rieux-Laucat|Frédéric|F|;Touzot|Fabien|F|;Frémond|Marie-Louise|ML|;André-Schmutz|Isabelle|I|;Fraitag|Sylvie|S|;Bodemer|Christine|C|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D052003:NF-kappa B p52 Subunit; C498206:NFKB2 protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D009713:Nucleotidyltransferases; C000610948:TRNT1 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2017-0213",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "141(Suppl 5)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D001402:B-Lymphocytes; D016026:Bone Marrow Transplantation; D002675:Child, Preschool; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007153:Immunologic Deficiency Syndromes; D007223:Infant; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008297:Male; D009154:Mutation; D052003:NF-kappa B p52 Subunit; D009713:Nucleotidyltransferases; D015434:Panniculitis; D011183:Postoperative Complications; D013601:T-Lymphocytes",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "S496-S500",
"pmc": null,
"pmid": "29610179",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Inherited Immunodeficiency: A New Association With Early-Onset Childhood Panniculitis.",
"title_normalized": "inherited immunodeficiency a new association with early onset childhood panniculitis"
} | [
{
"companynumb": "FR-SAMSUNG BIOEPIS-SB-2019-03959",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,... |
{
"abstract": "Eumycetomas are chronic suppurative granulomas caused by fungi characterised by invasive tumefactive lesions, sinuses and discharging grains. Herein, we describe a case of pedal eumycetoma due to Fusarium solani sensu stricto in a person with diabetes mellitus. A 45-year-old gentleman presented with an insidious onset swelling over his right foot with nodules and discharging grains. He had received itraconazole and anti-tuberculous therapy elsewhere, without response. Re-evaluation included a biopsy which confirmed eumycetoma and newly diagnosed diabetes. Surgical excision followed by histopathological, microbiological and multigene sequencing analyses [translation elongation factor, calmodulin and internal transcribed spacer region of rDNA] of the mould on culture were performed. Histopathology revealed septate fungal hyphae amidst a dense inflammatory infiltrate (Splendore-Hoeppli) reaction. Oral voriconazole was started and good glycemic control attained. Tissue growth sequences showed > 99% similarity with Fusarium solani sensu stricto. Antifungal susceptibility testing showed lowest MIC to voriconazole (0.5 mg/L). The patient showed excellent response to combined therapeutic modality with a near-complete resolution in size of lesion and obliteration of sinuses following 4 months of therapy and is planned for prolonged voriconazole therapy till complete radiological resolution. Diabetes predisposes to fungal infections of foot but eumycetomas are uncommon. Combined surgery and antifungals can improve morbidity and avoid amputations.",
"affiliations": "Department of Endocrinology, PGIMER, 1012, Nehru Hospital Extension Block, Chandigarh, 160012, India.;Department of General Surgery, PGIMER, Chandigarh, India.;Department of Histopathology, PGIMER, Chandigarh, India.;Department of Radiology, PGIMER, Chandigarh, India.;Department of Endocrinology, PGIMER, 1012, Nehru Hospital Extension Block, Chandigarh, 160012, India.;Department of Endocrinology, PGIMER, 1012, Nehru Hospital Extension Block, Chandigarh, 160012, India.;Department of Medical Microbiology, PGIMER, Nehru Hospital, Research Block A, Chandigarh, India.;Department of Medical Microbiology, PGIMER, Nehru Hospital, Research Block A, Chandigarh, India. mrshivprakash@yahoo.com.;Department of Endocrinology, PGIMER, 1012, Nehru Hospital Extension Block, Chandigarh, 160012, India. pinaki_dutta@hotmail.com.",
"authors": "Das|Liza|L|http://orcid.org/0000-0002-9701-9554;Dahiya|Divya|D|;Gupta|Kirti|K|;Prakash|Mahesh|M|;Malhotra|Bhanu|B|;Rastogi|Ashu|A|;Choudhary|Hansraj|H|;Rudramurthy|Shivaprakash M|SM|;Dutta|Pinaki|P|http://orcid.org/0000-0001-5415-1611",
"chemical_list": "D000935:Antifungal Agents; D065819:Voriconazole",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11046-020-00524-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-486X",
"issue": "186(2)",
"journal": "Mycopathologia",
"keywords": "Diabetes; Eumycetoma; Fusarium solani complex; Voriconazole",
"medline_ta": "Mycopathologia",
"mesh_terms": "D000935:Antifungal Agents; D003920:Diabetes Mellitus; D005670:Fusarium; D006801:Humans; D008297:Male; D008875:Middle Aged; D008271:Mycetoma; D065819:Voriconazole",
"nlm_unique_id": "7505689",
"other_id": null,
"pages": "277-288",
"pmc": null,
"pmid": "33687638",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "25726758;27928841;11913759;31076497;27054821;24244780;14748803;3842114;12605286;15336224;12682194;23813152;28774696;25941632;24266687;26135866;26497138;25267555;23189544;22382571;20577905;26900232;17097407;16966172;11283807;28794542;32352976;26738840;17350499;22981317;29719823;18976399;28657120;29746460;29557534;24244780;27055573;10946914;29931660",
"title": "Eumycetoma of the Foot due to Fusarium solani in a Person with Diabetes Mellitus: Report of a Case and Review of Literature.",
"title_normalized": "eumycetoma of the foot due to fusarium solani in a person with diabetes mellitus report of a case and review of literature"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2022-00465",
"fulfillexpeditecriteria": "2",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"d... |
{
"abstract": "We report a combination of BK virus-specific T cells and pembrolizumab as a treatment option in progressive multifocal leukoencephalopathy (PML).\n\n\n\nA 57-year-old male patient diagnosed with PML presented a fast-progressing right hemiparesis, aphasia, and cognitive deficits. Brain MRI showed a severe leukoencephalopathy with diffusion restriction. The patient was treated with 10 doses of pembrolizumab (2 mg/kg body weight) in differing intervals and 2 partially human leukocyte antigen-matched allogenic BK virus-specific T cell transfusions after the fifth pembrolizumab treatment. Although pembrolizumab alone decreased the viral load but failed to control the virus, BK-specific T cell transfer further enhanced the decline of JC virus copies in the CSF. Moreover, the regression of leukoencephalopathy and disappearance of diffusion restriction in subsequent brain MRI were observed. The combined treatment resulted in a clinical stabilization with improvements of the cognitive and speech deficits.\n\n\n\nThis case supports the hypothesis that pembrolizumab is more efficient in the presence of an appropriate number of functional antigen-specific T cells. Thus, the combined treatment of pembrolizumab and virus-specific T cells should be further evaluated as a treatment option for PML in future clinical trials.",
"affiliations": "From the Department of Neurology (R.W., T.K., B.H., M.D.), Klinikum rechts der Isar, Technical University Munich; Medical Department III for Hematology and Oncology (S.H., M.V.), Klinikum rechts der Isar, Technical University Munich; Institute for Transfusion Medicine (B.E.-V.), Hannover Medical School; Department of Pediatric Hematology and Oncology (B.M.-K.), Hannover Medical School; Department of Neuroradiology (J.S.K.), Klinikum Rechts der Isar, Technical University Munich; Unilabs A/S (A.P.), Copenhagen, Denmark; Institute of Experimental Neuroimmunology (T.K.), Klinikum rechts der Isar, Technical University of Munich; and Munich Cluster for Systems Neurology (SyNergy) (T.K., B.H.), Germany. rebecca.wicklein@tum.de.;From the Department of Neurology (R.W., T.K., B.H., M.D.), Klinikum rechts der Isar, Technical University Munich; Medical Department III for Hematology and Oncology (S.H., M.V.), Klinikum rechts der Isar, Technical University Munich; Institute for Transfusion Medicine (B.E.-V.), Hannover Medical School; Department of Pediatric Hematology and Oncology (B.M.-K.), Hannover Medical School; Department of Neuroradiology (J.S.K.), Klinikum Rechts der Isar, Technical University Munich; Unilabs A/S (A.P.), Copenhagen, Denmark; Institute of Experimental Neuroimmunology (T.K.), Klinikum rechts der Isar, Technical University of Munich; and Munich Cluster for Systems Neurology (SyNergy) (T.K., B.H.), Germany.;From the Department of Neurology (R.W., T.K., B.H., M.D.), Klinikum rechts der Isar, Technical University Munich; Medical Department III for Hematology and Oncology (S.H., M.V.), Klinikum rechts der Isar, Technical University Munich; Institute for Transfusion Medicine (B.E.-V.), Hannover Medical School; Department of Pediatric Hematology and Oncology (B.M.-K.), Hannover Medical School; Department of Neuroradiology (J.S.K.), Klinikum Rechts der Isar, Technical University Munich; Unilabs A/S (A.P.), Copenhagen, Denmark; Institute of Experimental Neuroimmunology (T.K.), Klinikum rechts der Isar, Technical University of Munich; and Munich Cluster for Systems Neurology (SyNergy) (T.K., B.H.), Germany.;From the Department of Neurology (R.W., T.K., B.H., M.D.), Klinikum rechts der Isar, Technical University Munich; Medical Department III for Hematology and Oncology (S.H., M.V.), Klinikum rechts der Isar, Technical University Munich; Institute for Transfusion Medicine (B.E.-V.), Hannover Medical School; Department of Pediatric Hematology and Oncology (B.M.-K.), Hannover Medical School; Department of Neuroradiology (J.S.K.), Klinikum Rechts der Isar, Technical University Munich; Unilabs A/S (A.P.), Copenhagen, Denmark; Institute of Experimental Neuroimmunology (T.K.), Klinikum rechts der Isar, Technical University of Munich; and Munich Cluster for Systems Neurology (SyNergy) (T.K., B.H.), Germany.;From the Department of Neurology (R.W., T.K., B.H., M.D.), Klinikum rechts der Isar, Technical University Munich; Medical Department III for Hematology and Oncology (S.H., M.V.), Klinikum rechts der Isar, Technical University Munich; Institute for Transfusion Medicine (B.E.-V.), Hannover Medical School; Department of Pediatric Hematology and Oncology (B.M.-K.), Hannover Medical School; Department of Neuroradiology (J.S.K.), Klinikum Rechts der Isar, Technical University Munich; Unilabs A/S (A.P.), Copenhagen, Denmark; Institute of Experimental Neuroimmunology (T.K.), Klinikum rechts der Isar, Technical University of Munich; and Munich Cluster for Systems Neurology (SyNergy) (T.K., B.H.), Germany.;From the Department of Neurology (R.W., T.K., B.H., M.D.), Klinikum rechts der Isar, Technical University Munich; Medical Department III for Hematology and Oncology (S.H., M.V.), Klinikum rechts der Isar, Technical University Munich; Institute for Transfusion Medicine (B.E.-V.), Hannover Medical School; Department of Pediatric Hematology and Oncology (B.M.-K.), Hannover Medical School; Department of Neuroradiology (J.S.K.), Klinikum Rechts der Isar, Technical University Munich; Unilabs A/S (A.P.), Copenhagen, Denmark; Institute of Experimental Neuroimmunology (T.K.), Klinikum rechts der Isar, Technical University of Munich; and Munich Cluster for Systems Neurology (SyNergy) (T.K., B.H.), Germany.;From the Department of Neurology (R.W., T.K., B.H., M.D.), Klinikum rechts der Isar, Technical University Munich; Medical Department III for Hematology and Oncology (S.H., M.V.), Klinikum rechts der Isar, Technical University Munich; Institute for Transfusion Medicine (B.E.-V.), Hannover Medical School; Department of Pediatric Hematology and Oncology (B.M.-K.), Hannover Medical School; Department of Neuroradiology (J.S.K.), Klinikum Rechts der Isar, Technical University Munich; Unilabs A/S (A.P.), Copenhagen, Denmark; Institute of Experimental Neuroimmunology (T.K.), Klinikum rechts der Isar, Technical University of Munich; and Munich Cluster for Systems Neurology (SyNergy) (T.K., B.H.), Germany.;From the Department of Neurology (R.W., T.K., B.H., M.D.), Klinikum rechts der Isar, Technical University Munich; Medical Department III for Hematology and Oncology (S.H., M.V.), Klinikum rechts der Isar, Technical University Munich; Institute for Transfusion Medicine (B.E.-V.), Hannover Medical School; Department of Pediatric Hematology and Oncology (B.M.-K.), Hannover Medical School; Department of Neuroradiology (J.S.K.), Klinikum Rechts der Isar, Technical University Munich; Unilabs A/S (A.P.), Copenhagen, Denmark; Institute of Experimental Neuroimmunology (T.K.), Klinikum rechts der Isar, Technical University of Munich; and Munich Cluster for Systems Neurology (SyNergy) (T.K., B.H.), Germany.;From the Department of Neurology (R.W., T.K., B.H., M.D.), Klinikum rechts der Isar, Technical University Munich; Medical Department III for Hematology and Oncology (S.H., M.V.), Klinikum rechts der Isar, Technical University Munich; Institute for Transfusion Medicine (B.E.-V.), Hannover Medical School; Department of Pediatric Hematology and Oncology (B.M.-K.), Hannover Medical School; Department of Neuroradiology (J.S.K.), Klinikum Rechts der Isar, Technical University Munich; Unilabs A/S (A.P.), Copenhagen, Denmark; Institute of Experimental Neuroimmunology (T.K.), Klinikum rechts der Isar, Technical University of Munich; and Munich Cluster for Systems Neurology (SyNergy) (T.K., B.H.), Germany.;From the Department of Neurology (R.W., T.K., B.H., M.D.), Klinikum rechts der Isar, Technical University Munich; Medical Department III for Hematology and Oncology (S.H., M.V.), Klinikum rechts der Isar, Technical University Munich; Institute for Transfusion Medicine (B.E.-V.), Hannover Medical School; Department of Pediatric Hematology and Oncology (B.M.-K.), Hannover Medical School; Department of Neuroradiology (J.S.K.), Klinikum Rechts der Isar, Technical University Munich; Unilabs A/S (A.P.), Copenhagen, Denmark; Institute of Experimental Neuroimmunology (T.K.), Klinikum rechts der Isar, Technical University of Munich; and Munich Cluster for Systems Neurology (SyNergy) (T.K., B.H.), Germany.",
"authors": "Wicklein|Rebecca|R|;Heidegger|Simon|S|;Verbeek|Mareike|M|;Eiz-Vesper|Britta|B|;Maecker-Kolhoff|Britta|B|;Kirschke|Jan Stefan|JS|;Page|Agata|A|;Korn|Thomas|T|;Hemmer|Bernhard|B|;Deschauer|Marcus|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/NXI.0000000000001042",
"fulltext": "\n==== Front\nNeurol Neuroimmunol Neuroinflamm\nNeurol Neuroimmunol Neuroinflamm\nnnn\nNEURIMMINFL\nNeurology® Neuroimmunology & Neuroinflammation\n2332-7812\nLippincott Williams & Wilkins Hagerstown, MD\n\n34285093\nNEURIMMINFL2021039091\n10.1212/NXI.0000000000001042\n3\n120\n142\nClinical/Scientific Notes\nCombined Treatment With Pembrolizumab and Allogenic BK Virus-Specific T Cells in Progressive Multifocal Leukoencephalopathy\nA Case Report\nWicklein Rebecca\nHeidegger Simon MD simon.heidegger@tum.de\n\nVerbeek Mareike MD mareike.verbeek@tum.de\n\nEiz-Vesper Britta MD eiz-vesper.britta@mh-hannover.de\n\nMaecker-Kolhoff Britta MD maecker.britta@mh-hannover.de\n\nKirschke Jan Stefan MD jan.kirschke@mri.tum.de\n\nPage Agata PhD agata.page@unilabs.com\n\nKorn Thomas MD thomas.korn@tum.de\n\nHemmer Bernhard MD hemmer@tum.de\n\nDeschauer Marcus MD marcus.deschauer@mri.tum.de\n\nFrom the Department of Neurology (R.W., T.K., B.H., M.D.), Klinikum rechts der Isar, Technical University Munich; Medical Department III for Hematology and Oncology (S.H., M.V.), Klinikum rechts der Isar, Technical University Munich; Institute for Transfusion Medicine (B.E.-V.), Hannover Medical School; Department of Pediatric Hematology and Oncology (B.M.-K.), Hannover Medical School; Department of Neuroradiology (J.S.K.), Klinikum Rechts der Isar, Technical University Munich; Unilabs A/S (A.P.), Copenhagen, Denmark; Institute of Experimental Neuroimmunology (T.K.), Klinikum rechts der Isar, Technical University of Munich; and Munich Cluster for Systems Neurology (SyNergy) (T.K., B.H.), Germany.\nCorrespondence R. Wicklein rebecca.wicklein@tum.de\nThe Article Processing Charge was funded by TUM Open Access Publishing Fund.\n\nGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.\n\n9 2021\n20 7 2021\n20 7 2021\n8 5 e104210 5 2021\n10 6 2021\nCopyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.\n2021\nAmerican Academy of Neurology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nObjective\n\nWe report a combination of BK virus-specific T cells and pembrolizumab as a treatment option in progressive multifocal leukoencephalopathy (PML).\n\nResults\n\nA 57-year-old male patient diagnosed with PML presented a fast-progressing right hemiparesis, aphasia, and cognitive deficits. Brain MRI showed a severe leukoencephalopathy with diffusion restriction. The patient was treated with 10 doses of pembrolizumab (2 mg/kg body weight) in differing intervals and 2 partially human leukocyte antigen-matched allogenic BK virus-specific T cell transfusions after the fifth pembrolizumab treatment. Although pembrolizumab alone decreased the viral load but failed to control the virus, BK-specific T cell transfer further enhanced the decline of JC virus copies in the CSF. Moreover, the regression of leukoencephalopathy and disappearance of diffusion restriction in subsequent brain MRI were observed. The combined treatment resulted in a clinical stabilization with improvements of the cognitive and speech deficits.\n\nDiscussion\n\nThis case supports the hypothesis that pembrolizumab is more efficient in the presence of an appropriate number of functional antigen-specific T cells. Thus, the combined treatment of pembrolizumab and virus-specific T cells should be further evaluated as a treatment option for PML in future clinical trials.\n\nOPEN-ACCESSTRUE\n==== Body\npmcProgressive multifocal leukoencephalopathy (PML) is a rare disease caused by the reactivation of JC virus in immunocompromised patients, often with poor outcome. There is no standard therapy, but case series showed promising results regarding 2 treatment options: In 2019, treatment with the anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab resulted in clinical stabilization, decrease in virus load, and no further progression in brain MRI in 5 of 8 patients with PML.1 PD-1 is an inducible surface receptor and negative regulator of T cell lytic function. In chronic viral infections, persistent exposure to viral antigens can result in permanent PD-1 expression and T cell exhaustion.2 It was hypothesized that pembrolizumab boosts antiviral activity by blocking the PD-1 pathway in otherwise dysfunctional T cells, suggesting that pembrolizumab treatment relies on pre-existing virus-specific T cells.3 In 2018, a small case series reported a favorable ouotcome in 2 of 3 patients with PML after treatment with allogenic BK virus-specific T cells from healthy donors.4 BK virus has a high sequence homology with JC virus, and consequently, these T cells expanded with a pool of BK peptides showed cross-reactivity with JC virus-derived peptides. In this case study, according to CARE guidelines,5 we report the results of the combined treatment with pembrolizumab and BK virus-specific T cells in a patient with PML.\n\nResults\n\nThe 57-year-old male patient was in complete remission of stage IV nodal marginal zone lymphoma (nMZL; R-CHOP-21 treatment) diagnosed 4 years before PML onset. He presented with a mild right hemiparesis lasting 1 week. A brain MRI revealed multiple, diffusion impaired, hyperintense T2-weighted fluid-attenuated inversion-recovery (FLAIR) lesions, mainly in the left hemisphere. There was no gadolinium enhancement arguing against a cerebral manifestation of the original lymphoma occurring rarely in patients with nMZL. After rapid clinical progression reflected by an increase of leukoencephalopathy in the subsequent brain MRI 4 days later, the diagnosis of PML was confirmed by the detection of JC virus DNA in the CSF (40 copies/mL, high sensitivity PCR; Unilabs A/S, Copenhagen, Denmark). Apart from signs of increased blood-brain barrier permeability, CSF analysis remained normal. CT scans and a bone marrow biopsy showed no signs of recurrent or novel B cell lymphoma.\n\nFour weeks after onset, we initiated treatment with pembrolizumab (2 mg/kg body weight) with a dosage interval of 4 to 6 weeks.1 Three weeks after the initial dose (week 7), the patient was readmitted to hospital because of progressive hemiparalysis with a plegic right arm, cognitive deficits, and nonfluent aphasia. We intensified treatment with pembrolizumab by reducing the interval to 2 weeks, in accordance with another pembrolizumab protocol of a PML case.6 After 5 treatment courses (week 14), the patient achieved a stable clinical condition, but JC viral load in CSF increased to 10,000 copies/mL and further progression of leukoencephalopathy was evident by MRI. At week 23, cranial MRI showed no further progression, but brain atrophy was observed in affected areas. Viral load in CSF was still high (2,262 copies/mL). To enhance virus elimination, we initiated a 5/10 partially human leukocyte antigen (HLA)-matched allogenic BK virus-specific T cell transfusion.4 T cells from a HLA-matched healthy donor from alloCELL registry (20,000 CD3+ cells/kg bodyweight) were administered twice 7 weeks apart (week 24, 31), followed by 5 infusions of pembrolizumab (Figure). Both treatments were tolerated very well. In particular, we did not observe any signs of graft vs host disease. Viral load in CSF dropped to 495 copies/mL (week 46). Brain MRI revealed a slight reduction of FLAIR lesions with a progressive atrophy of affected regions in the left hemisphere and no more diffusion restriction. The patient's clinical condition, particularly aphasia and cognitive deficits, further improved after administration of the virus-specific T cells. However, the right arm remained plegic.\n\nFigure Treatment (Pembrolizumab, BK Virus-Specific T Cells), MRI Monitoring, JC Viral Load, and Clinical Course (NIHSS)\n\nClinical and MRI stability in particular concerning FLAIR lesions were achieved after the fourth and fifth infusion of pembrolizumab, respectively (11 and 14 weeks after onset). The initial prominent marginal diffusion impairment as a sign of viral activity was no longer detectable 32 weeks after onset. The peak of JC virus load in the cerebral fluid was 10,000 copies/mL 15 weeks after onset. FLAIR = T2-weighted fluid-attenuated inversion-recovery (scoring: hyperintensity); Gd+ = gadolinium enhancement; DWI = diffusion-weighted imaging (scoring: hyperintensity); MRI scoring = - nonexistent, + mild, ++ moderate, +++ profound, and ++++ severe; NIHSS = NIH Stroke Scale.\n\nDiscussion\n\nWe report a combination of BK virus-specific T cells and pembrolizumab as a treatment option for patients with PML. Although pembrolizumab alone decreased the viral load but failed to control the virus, BK-specific T cell transfer further enhanced the decline of JC virus copies in the CSF. This case supports the hypothesis that pembrolizumab is more efficient in the presence of an appropriate number of functional antigen-specific T cells. We did not observe any signs of immune reconstitution inflammatory syndrome. The treatment resulted in clinical improvement and regression of leukoencephalopathy in MRI. Case-control series (and ideally controlled clinical trials) might shed more light on the potential benefit of a sequential or combined treatment with checkpoint inhibitors and allogeneic antigen-specific T cell transfer in PML.\n\nStudy Funding\n\nThe authors report no targeted funding.\n\nDisclosure\n\nThe authors report no disclosures relevant to the manuscript. Go to Neurology.org/NN for full disclosures.\n\nAppendix Authors\n==== Refs\nReferences\n\n1. CorteseI, MuranskiP, Enose-AkahataY, et al . Pembrolizumab treatment for progressive multifocal leukoencephalopathy. N Engl J Med. 2019;380 (17 ):1597-1605. 10.1056/NEJMoa1815039.30969503\n2. JubelJM, BarbatiZR, BurgerC, WirtzDC, SchildbergFA. The role of PD-1 in acute and chronic infection. Front Immunol. 2020;11 :487. 10.3389/fimmu.2020.00487.32265932\n3. PawlitzkiM, Schneider-HohendorfT, RolfesL, et al . Ineffective treatment of PML with pembrolizumab: exhausted memory T-cell subsets as a clue? Neurol Neuroimmunol Neuroinflamm. 2019;6 (6 ):e627. doi:10.1212/NXI.0000000000000627.31597692\n4. MuftuogluM, OlsonA, MarinD, et al . Allogeneic BK virus-specific T cells for progressive multifocal leukoencephalopathy. N Engl J Med. 2018;379 (15 ):1443-1451. 10.1056/NEJMoa1801540.30304652\n5. GagnierJJ, KienleG, AltmanDG, MoherD, SoxH, RileyD. The CARE guidelines: consensus-based clinical case reporting guideline development. BMJ Case Rep. 2013;2013 :201554. 10.1136/bcr-2013-201554.\n6. RauerS, MarksR, UrbachH, et al . Treatment of progressive multifocal leukoencephalopathy with pembrolizumab. N Engl J Med. 2019;380 (17 ):1676-1677. 10.1056/NEJMc1817193.30969507\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2332-7812",
"issue": "8(5)",
"journal": "Neurology(R) neuroimmunology & neuroinflammation",
"keywords": null,
"medline_ta": "Neurol Neuroimmunol Neuroinflamm",
"mesh_terms": null,
"nlm_unique_id": "101636388",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34285093",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": "24155002;30969507;30304652;31597692;32265932;30969503",
"title": "Combined Treatment With Pembrolizumab and Allogenic BK Virus-Specific T Cells in Progressive Multifocal Leukoencephalopathy: A Case Report.",
"title_normalized": "combined treatment with pembrolizumab and allogenic bk virus specific t cells in progressive multifocal leukoencephalopathy a case report"
} | [
{
"companynumb": "DE-009507513-2108DEU004869",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Allogenic hematopoietic stem cell transplant is the only curative option for symptomatic sickle cell disease (SCD). HLA haploidentical related donor transplants are associated with high graft failure rates. We conceptualized a novel protocol (APOLLO protocol) using pre-transplant immune and myelosuppression (PTIS) using fludarabine, cyclophosphamide, and dexamethasone followed by augmented John Hopkins protocol by adding thiotepa to conditioning. Twenty-five consecutive patients suffering from symptomatic SCD were enrolled into the study. We added upfront plerixafor to granulocyte colony stimulating factor (GCSF) for mobilization of healthy donors. Graft versus host disease (GvHD) prophylaxis was done using post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil. Graft failure was not seen in any of our patients. Five patients developed acute grade II/IV GvHD (4 classical acute, 1 late onset), 3 had limited chronic GvHD. Out of 25 evaluable patients, 22 are alive and disease free, making an overall survival (OS) and disease-free survival (DFS) of 88% with a median follow up of 485 days (range 198-802). T-cell-replete haploidentical transplant with PTIS, augmented John Hopkins conditioning and plerixafor based mobilization is a safe and effective way of treating patients suffering from SCD with minimal or no risk of graft failure and acceptable GvHD rates.",
"affiliations": "Center for Bone Marrow Transplant and Cellular Therapy, Indraprastha Apollo Hospital, New Delhi, India. gaurav.kharya@gmail.com.;Center for Bone Marrow Transplant and Cellular Therapy, Indraprastha Apollo Hospital, New Delhi, India.;Center for Bone Marrow Transplant and Cellular Therapy, Indraprastha Apollo Hospital, New Delhi, India.;Center for Bone Marrow Transplant and Cellular Therapy, Indraprastha Apollo Hospital, New Delhi, India.",
"authors": "Kharya|Gaurav|G|http://orcid.org/0000-0003-2181-1825;Bakane|Atish|A|;Agarwal|Shirali|S|;Rauthan|Archana|A|",
"chemical_list": "D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D003520:Cyclophosphamide; C088327:plerixafor",
"country": "England",
"delete": false,
"doi": "10.1038/s41409-020-01054-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "56(2)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000755:Anemia, Sickle Cell; D001596:Benzylamines; D000080027:Cyclams; D003520:Cyclophosphamide; D006086:Graft vs Host Disease; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006571:Heterocyclic Compounds; D006801:Humans; D019172:Transplantation Conditioning",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "492-504",
"pmc": null,
"pmid": "32929175",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": "22544533;8663884",
"title": "Pre-transplant myeloid and immune suppression, upfront plerixafor mobilization and post-transplant cyclophosphamide: novel strategy for haploidentical transplant in sickle cell disease.",
"title_normalized": "pre transplant myeloid and immune suppression upfront plerixafor mobilization and post transplant cyclophosphamide novel strategy for haploidentical transplant in sickle cell disease"
} | [
{
"companynumb": "NVSC2021IN087593",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drug... |
{
"abstract": "A 78-year-old woman was admitted with benign biliary stenosis. A plastic stent was placed at the left branch to prevent obstructive cholangitis. Two weeks after the procedure, the patient was readmitted with cholangitis caused by hemobilia. However, computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), peroral cholangioscopy, and abdominal angiography failed to establish the bleeding source. At the seventh bleeding, CT revealed a hepatic artery pseudoaneurysm for which coil embolization was successfully performed. Hemobilia after plastic stent placement is extremely rare. We urge clinicians to consider the possibility of a pseudoaneurysm near the stent when trying to identify the bleeding source.",
"affiliations": "Departments of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.;Departments of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.;Departments of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.;Departments of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.",
"authors": "Yamauchi|Kenji|K|;Uchida|Daisuke|D|;Kato|Hironari|H|;Okada|Hiroyuki|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.8983-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2903342310.2169/internalmedicine.8983-17Case ReportRecurrent Bleeding from a Hepatic Artery Pseudoaneurysm after Biliary Stent Placement Yamauchi Kenji 1Uchida Daisuke 1Kato Hironari 1Okada Hiroyuki 1\n1 Departments of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, JapanCorrespondence to Dr. Kenji Yamauchi, yamauchi.kenji@hotmail.com\n\n16 10 2017 1 1 2018 57 1 49 52 5 2 2017 10 5 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 78-year-old woman was admitted with benign biliary stenosis. A plastic stent was placed at the left branch to prevent obstructive cholangitis. Two weeks after the procedure, the patient was readmitted with cholangitis caused by hemobilia. However, computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), peroral cholangioscopy, and abdominal angiography failed to establish the bleeding source. At the seventh bleeding, CT revealed a hepatic artery pseudoaneurysm for which coil embolization was successfully performed. Hemobilia after plastic stent placement is extremely rare. We urge clinicians to consider the possibility of a pseudoaneurysm near the stent when trying to identify the bleeding source. \n\nhemobiliahepatic artery pseudoaneurysmplastic stent\n==== Body\nIntroduction\nHemobilia causes symptoms such as upper abdominal pain, upper gastrointestinal bleeding, and jaundice, the combination of which is known as Quincke's triad due to bleeding in the bile duct. The main causes of hemobilia are iatrogenic and include liver biopsy or percutaneous biliary drainage. Hemobilia as a complication of plastic stent placement is exceedingly rare. To the best of our knowledge, there have only been five previously reported cases. In the present case, 2 weeks after the first plastic stent placement, the patient needed to be admitted 7 times for recurrent intermittent biliary bleeding. Several factors are associated with hemobilia after plastic stent placement. It was recently reported that endoscopic retrograde cholangiopancreatography (ERCP)-related bile duct injury, malignant tumor invasion, cholangitis, and liver abscess may contribute to hemobilia. In the present case, benign biliary stricture, recurrent cholangitis, and long-term steroid use are presumed to be the cause of hemobilia.\n\nCase Report\nA 78-year-old woman was admitted for biliary stenosis and protracted cholangitis after undergoing endoscopic sphincterotomy (EST) for the treatment of biliary calculi. The patient had taken oral prednisolone for the treatment of autoimmune hepatitis for over a decade. She took oral psednisolone 30 mg/day as the initial treatment. After the usual tapering of the prednisolone to a maintenance dose of 10 mg, she received maintenance therapy for 10 years.\n\nHer abdomen was soft and flat and no mass was palpable on physical examination. Laboratory findings revealed an elevated level of lactate dehydrogenase [253 IU/L (normal range, 124-222 IU/L)] and decreased level of albumin [3.4 g/dL (normal range, 3.8-5.2 g/dL)] (Table 1). ERCP and brush cytology revealed benign biliary stricture caused by recurrent cholangitis due to duodenal content reflux after EST (Fig. 1, arrow). A plastic stent was placed at the left branch (B3) to prevent obstructive cholangitis without causing any injury to the bile duct.\n\nTable 1. Laboratory Data at Presentation.\n\n\tUnit\t\tUnit\t\tUnit\t\nWBC\t6,340\t/µL\tTotal bilirubin\t1\tg/dL\tNa\t146\tmEq/L\t\nRBC\t391\t×104/µL\tDirect bilirubin\t0.2\tg/dL\tK\t4.1\tmEq/L\t\nHemoglobin\t12.7\tg/dL\tAST\t22\tIU/L\tCl\t106\tmEq/L\t\nHematocrit\t38.2\t%\tALT\t15\tIU/L\tCRP\t0.16\tmg/dL\t\nPlatelets\t22.3\t×104/µL\tLDH\t\n253\n\tIU/L\tCA19-9\t21\tU/mL\t\nPT\t113\t%\tALP\t184\tIU/L\tCEA\t4.6\tng/mL\t\nAPTT\t\n25.6\n\tsec\tγ-GTP\t30\tIU/L\tDUPAN-2\t\n164\n\tU/mL\t\nTotal protein\t25.6\tg/dL\tBUN\t14\tmg/dL\t\t\t\t\nAlbumin\t\n3.4\n\tg/dL\tCreatinine\t0.7\tmg/dL\t\t\t\t\nUnderlines show the values outside the reference ranges.\n\nWBC: white blood cells, RBC: red blood cells, PT: prothrombin time, APTT: activated partial thromboplastin time, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: gamma-glutamyl transferase, BUN: blood urea nitrogen, CRP: C-reactive protein, CA19-9: carbohydrate antigen 19-9, CEA: carcinoembryonic antigen, DUPAN-2: duke pancreatic monoclonal antigen type 2\n\nTwo weeks after the procedure, the patient was readmitted with cholangitis caused by hemobilia. ERCP revealed pulsating bleeding from the bile duct. The bleeding was arrested by replacing the plastic stent (Fig. 2), but the bleeding source could not be identified on subsequent angiography.\n\nAfter the first bleeding, the patient needed to be admitted six times over 6 months for recurrent intermittent bleeding. However, CT, ERCP, and peroral cholangioscopy failed to establish the bleeding source. At the seventh bleeding, computed tomography (CT) revealed the extravasation of contrast dye to the bile duct (Fig. 3A, arrow) and the presence of a hepatic artery aneurysm (Fig. 3B, arrow). Three-dimensional CT angiography also revealed an aneurysm that developed at the side of the stent (Fig. 4, arrow). The aneurysn measured about 3 mm in diameter. Angiography revealed an aneurysm at the bifurcation of segment 2 and 3 branches of the left hepatic artery (Fig. 5, arrow). Successful coil embolization of the left hepatic artery pseudoaneurysm was performed. No recurrent bleeding occurred over the following days (Fig. 6).\n\nFigure 1. Endoscopic retrograde cholangiopancreatography image showing biliary stricture. A plastic stent was placed to prevent obstructive cholangitis.\n\nFigure 2. Endoscopic scan showing active bleeding from the duodenal papilla.\n\nFigure 3. (A) Computed tomography scan during the arterial phase showing extravasation of the contrast dye to the main bile duct (white arrow) and distention of the common bile duct with hematoma formation (black arrow). (B) A hepatic artery aneurysm near the plastic stent (white arrow).\n\nFigure 4. Three-dimensional computed tomography angiography image showing an aneurysm that developed adjacent to the stent.\n\nFigure 5. Angiography image showing an aneurysm at the bifurcation of branches 2 and 3 of the left hepatic artery. Coil embolization of the left hepatic artery pseudoaneurysm was successfully performed.\n\nFigure 6. Clinical course.\n\nDiscussion\nHemobilia causes symptoms, such as upper abdominal pain, upper gastrointestinal bleeding, and jaundice, the combination of which is known as Quincke's triad due to bleeding in the bile duct (1). The main causes of hemobilia are iatrogenic and include liver biopsy or percutaneous biliary drainage (2). Apart from iatrogenic bleeding, malignant tumor is the main cause (3). In this case, a hepatic artery pseudoaneurysm after plastic stent placement for benign biliary stricture caused the hemobilia.\n\nHepatic artery pseudoaneurysm as a complication of plastic stent placement for benign biliary stricture is rare. Pseudoaneurysm formation by metal stent placement for malignant biliary obstruction is reported to occur in 1.2% of cases (4). In contrast to metal stents, plastic stents seem to very rarely cause pseudoaneurysm. However, the exact prevalence remains uncertain. To the best of our knowledge, there have only been five previously reported cases of hemobilia caused by plastic stent placement (5-9). The characteristics of these five cases in addition to the case described herein are presented in Table 2. These cases included five women and one man 59-78 years of age. The symptoms of hemobilia appeared several weeks to several months before presentation. In almost all cases, the bleeding source was identified on CT.\n\nTable 2. Review of Case Reports on Hemobilia Caused by Plastic Stent Placement.\n\nNo.\tReference\tAge\tSex\tUnderlying disease\tBleeding source\tTime to hemobilia\t\n1\t5\t59\tfemale\tmetastasis of ovarian carcinoma\tunspecified\tunspecified\t\n2\t6\t75\tmale\tpancreatic pseudocysts\tarteriobiliary fistula after bile duct injury\t3 weeks\t\n3\t7\t62\tfemale\tKlatskin’s tumor\thepatic artery pseudoaneurysm\t2 months\t\n4\t8\t68\tfemale\tKlatskin’s tumor\thepatic artery pseudoaneurysm\t3 weeks\t\n5\t9\t75\tfemale\tcholangitis\tarteriobiliary fistula after perforation of the bile duct\t5 weeks\t\n6\tpresent case\t78\tfemale\tbenign biliary stricture\thepatic artery pseudoaneurysm\t2 weeks\t\nSeveral factors are associated with hemobilia after plastic stent placement. ERCP-related bile duct injury (6, 9), malignant tumor invasion (5, 8), cholangitis (7, 8), and liver abscess (7) may also contribute to hemobilia. In this case, we suspect that the stent was the primary cause of the aneurysm because it developed at the same location as the stent.\n\nHowever, this may not be the only cause. Recurrent cholangitis with increased intrabiliary pressure and inflammation may affect the formation of aneurysms (7). Of the 222 cases of hemobilia reported between January 1996 and December 1999, 11 cases (5%) demonstrated an etiology associated with cholangitis (10). Moreover, long-term steroid use might have also contributed to the weakness of the bile ducts. Chronic steroid use has been reported to make the arterial walls fragile (11). CT finally revealed the bleeding source after the seventh episode of hemobilia due to a slowly expanding pseudoaneurysm.\n\nIn summary, we herein reported a rare case of hepatic artery pseudoaneurysm associated with a plastic stent insertion and long-term steroid use. The aneurysm was initially difficult to detect. However, it developed after repeated bleeding. We believe that to identify the source of hemobilia, attention should be given to the possible development of a pseudoaneurysm near the plastic stent.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nChin MW , Enns R \nHemobilia . Curr Gastroenterol Rep \n12 : 121 -129 , 2010 .20424984 \n2. \nGreen MH , Duell RM , Johnson CD , Jamieson NV \nHaemobilia . Br J Surg \n88 : 773 -786 , 2001 .11412246 \n3. \nKim KH , Kim TN \nEtiology, clinical features, and endoscopic management of hemobilia: a retrospective analysis of 37 cases . Korean J Gastroenterol \n59 : 296 -302 , 2012 .22544027 \n4. \nNezu Y , Nakaji S , Fujii H , Ishii E , Hirata N \nPseudoaneurysm caused by a self-expandable metal stent: a report of three cases . Endoscopy \n46 : 248 -251 , 2014 .24573734 \n5. \nConio M , Caroli-Bosc FX , Buckley M , Chiaramondia M , D'Addazio G , Munizzi F \nMassive hematobilia after extraction of plastic biliary endoprosthesis . J Clin Gastroenterol \n25 : 706 , 1997 .\n6. \nWolters F , Ryan B , Beets-Tan R , Dejong C \nDelayed massive hemobilia after biliary stenting . Endoscopy \n35 : 976 -977 , 2003 .14606026 \n7. \nPark JY , Ryu H , Bang S , Song SY , Chung JB \nHepatic artery pseudoaneurysm associated with plastic biliary stent . Yonsei Med J \n48 : 546 -548 , 2007 .17594167 \n8. \nInoue H , Tano S , Takayama R , et al \nRight hepatic artery pseudoaneurysm: rare complication of plastic biliary stent insertion . Endoscopy \n43 (Suppl 2 UCTN ): E396 , 2011 .22275018 \n9. \nLee SH , Hong SG , Lee KY , et al \nDelayed severe hemobilia after endoscopic biliary plastic stent insertion . Clin Endosc \n49 : 303 -307 , 2016 .27012288 \n10. \nGreen MH , Duell RM , Johnson CD , Jamieson NV \nHaemobilia . Br J Surg \n88 : 773 -786 , 2001 .11412246 \n11. \nMizukami H , Hara S , Kobayashi M , et al \nRupture of abdominal aortic aneurysm associated with long-term steroid therapy-a case report . Legal Med (Tokyo) \n16 : 33 -35 , 2014 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(1)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "hemobilia; hepatic artery pseudoaneurysm; plastic stent",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D017541:Aneurysm, False; D001662:Biliary Tract Surgical Procedures; D002761:Cholangitis; D003251:Constriction, Pathologic; D004621:Embolization, Therapeutic; D005260:Female; D006431:Hemobilia; D006499:Hepatic Artery; D006801:Humans; D015607:Stents; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "49-52",
"pmc": null,
"pmid": "29033423",
"pubdate": "2018-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24156880;11412246;17594167;27012288;9451700;24573734;22544027;22275018;14606026;20424984",
"title": "Recurrent Bleeding from a Hepatic Artery Pseudoaneurysm after Biliary Stent Placement.",
"title_normalized": "recurrent bleeding from a hepatic artery pseudoaneurysm after biliary stent placement"
} | [
{
"companynumb": "JP-BAUSCH-BL-2018-002712",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Uteroplacental vascular dysfunction, characterized by diminished uterine artery (UtA) blood flow in the second trimester is a clinically useful predictor of the further development of preeclampsia, fetal growth restriction and stillbirth. Efforts to develop effective treatments to protect pregnancies with abnormal UtA Dopplers would be of significant clinical benefit for mothers and their fetuses.\n\n\n\nThe aim of this pilot non randomized control study was to use pravastatin +L-arginine to improve uteroplacental haemodynamics and prevent adverse maternal and neonatal outcomes in women with abnormal Dopplers and high risk for developing adverse pregnancy outcomes.\n\n\n\nThis study was performed between 2015 and 2018. All women received primary care at OB/GYN Polyclinic Jurisic and Narodni Front University Hospital, University of Belgrade Medical School, Serbia. Approval for investigational drug use was obtained and all women gave informed consent. 10 pregnant women with a poor obstetric history that developed uteroplacental dysfunction (UtA pulsatility index (PI) above the 95th percentile and notching) at 20.5 weeks IQR [17.7-22] gave consent to be treated daily with pravastatin (40 mg) and L-arginine (1.5 g) to improve placental blood flow and pregnancy outcomes. 5 women remained untreated after diagnosis at 21 weeks [20-22] (control group). Due to presence of risk factors for pregnancy complications, close maternal and fetal monitoring was undertaken in all patients. Doppler examinations were performed to monitor changes in placental vascular resistance and fetal well-being and growth.\n\n\n\nPRAV+L-arginine improved uteroplacental haemodynamics, increased fetal growth and prevented early onset preeclampsia leading to delivery close to term (delivery date: median 38 weeks, IQR[36.5-39]) and appropriate weight for gestational age compared to controls, in which placental blood flow did not improve and 2 women developed severe early onset preeclampsia. Neonates from the control group were born preterm (25 weeks IQR[23.5-25]), growth restricted and spent several months at NICU. Two neonates died due to prematurity-associated complications. PRAV+L-arginine treatment prolonged pregnancies for 4.1 months, compared to 26 days in the untreated group, preventing neonatal complications associated with prematurity. The infants are now 1-3 years old and show normal growth and development.\n\n\n\nThis study describes the successful management with pravastatin+L-arginine of 10 pregnant patients with uteroplacental vascular dysfunction and high risk of adverse maternal and fetal outcomes. A larger study is being organized to confirm these observations.",
"affiliations": "University of Belgrade Medical School, Narodni Front University Hospital, Belgrade, Serbia; OB/GYN Polyclinic Jurisic, Belgrade, Serbia.;OB/GYN Polyclinic Jurisic, Belgrade, Serbia.;Perigenesis, Institute of Obstetric Haematology, Thessaloniki, Greece.;College of Medicine, QU Health, Qatar University, Qatar. Electronic address: guillerminagirardi@gmail.com.",
"authors": "Jurisic|Aleksandar|A|;Jurisic|Zaklina|Z|;Lefkou|Eleftheria|E|;Girardi|Guillermina|G|",
"chemical_list": "D001120:Arginine; D017035:Pravastatin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.vph.2020.106824",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1537-1891",
"issue": "137()",
"journal": "Vascular pharmacology",
"keywords": "Doppler studies; Intrauterine growth restriction; L-arginine; Neonatal complications; Placenta; Pravastatin; Preeclampsia; Preterm birth; Pulsatility index; Uterine arteries",
"medline_ta": "Vascul Pharmacol",
"mesh_terms": "D000328:Adult; D001120:Arginine; D004359:Drug Therapy, Combination; D005260:Female; D005317:Fetal Growth Retardation; D006439:Hemodynamics; D006801:Humans; D050498:Live Birth; D010865:Pilot Projects; D021041:Placental Circulation; D010927:Placental Insufficiency; D017035:Pravastatin; D011225:Pre-Eclampsia; D011247:Pregnancy; D013997:Time Factors; D016896:Treatment Outcome; D018608:Ultrasonography, Doppler; D016216:Ultrasonography, Prenatal",
"nlm_unique_id": "101130615",
"other_id": null,
"pages": "106824",
"pmc": null,
"pmid": "33249273",
"pubdate": "2021-04",
"publication_types": "D000068397:Clinical Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pravastatin plus L-arginine prevents adverse pregnancy outcomes in women with uteroplacental vascular dysfunction.",
"title_normalized": "pravastatin plus l arginine prevents adverse pregnancy outcomes in women with uteroplacental vascular dysfunction"
} | [
{
"companynumb": "RS-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-110781",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PRAVASTATIN SODIUM"
},
... |
{
"abstract": "IgM flare is a transient, treatment-induced, increase of monoclonal IgM levels in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) patients. Until recently this phenomenon was observed in patients treated with Cladribine and Rituximab. Here we report a case of a heavily pretreated chronic lymphocytic leukemia patient with an atypically high immunoglobulin production who developed clinically significant immunoglobulin flare following Idelalisib treatment.",
"affiliations": "a Department of Internal Medicine and Haematology, 3rd Faculty of Medicine , Charles University in Prague, University Hospital Kralovske Vinohrady Prague , Praha , Czech Republic.;c 1st Department of Internal Medicine, 3rd Faculty of Medicine , Charles University in Prague, University Hospital Kralovske Vinohrady Prague , Praha , Czech Republic.;a Department of Internal Medicine and Haematology, 3rd Faculty of Medicine , Charles University in Prague, University Hospital Kralovske Vinohrady Prague , Praha , Czech Republic.;d Department of Laboratory Medicine, 3rd Faculty of Medicine , Charles University in Prague, University Hospital Kralovske Vinohrady Prague , Praha , Czech Republic.;a Department of Internal Medicine and Haematology, 3rd Faculty of Medicine , Charles University in Prague, University Hospital Kralovske Vinohrady Prague , Praha , Czech Republic.",
"authors": "Novak|Jan|J|;Havrda|Martin|M|;Gaherova|Lubica|L|;Spicka|Jan|J|;Kozak|Tomas|T|",
"chemical_list": "D007075:Immunoglobulin M; D011687:Purines; D052999:Quinazolinones; D017338:Cladribine; D000069283:Rituximab; C552946:idelalisib",
"country": "England",
"delete": false,
"doi": "10.1080/08923973.2017.1318912",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0892-3973",
"issue": "39(4)",
"journal": "Immunopharmacology and immunotoxicology",
"keywords": "Idelalisib; chronic lymphocytic leukemia; complication; immunoglobulin flare; treatment",
"medline_ta": "Immunopharmacol Immunotoxicol",
"mesh_terms": "D000368:Aged; D017338:Cladribine; D005260:Female; D006801:Humans; D007075:Immunoglobulin M; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D011687:Purines; D052999:Quinazolinones; D000069283:Rituximab; D008258:Waldenstrom Macroglobulinemia",
"nlm_unique_id": "8800150",
"other_id": null,
"pages": "251-252",
"pmc": null,
"pmid": "28523957",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clinical case: idelalisib-induced immunoglobulin flare.",
"title_normalized": "clinical case idelalisib induced immunoglobulin flare"
} | [
{
"companynumb": "CZ-GILEAD-2017-0276594",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IDELALISIB"
},
"drugadditional": "3",
... |
{
"abstract": "A 62-year-old Japanese woman developed numbness of the extremities and megaloblastic anemia. She had undergone total abdominal hysterectomy, whole-pelvis radiation therapy and chemotherapy for gynecological cancer 10 years before. Chronic abdominal pain, diarrhea and intermittent small-bowel obstruction had afflicted her for a long time. We diagnosed her with vitamin B12 deficiency anemia and polyneuropathy due to chronic radiation enteritis causing malabsorption. Vitamin B12 injections improved her numbness and anemia. The early diagnosis and treatment of deficiency of vitamin B12 are important. Physicians should regularly measure vitamin B12 levels and supplement vitamin B12 as needed in patients with chronic radiation enteritis.",
"affiliations": "Division of Neurology, Shizuoka Cancer Center, Japan.;Division of Gynecology, Shizuoka Cancer Center, Japan.;Division of Gynecology, Shizuoka Cancer Center, Japan.",
"authors": "Fukuda|Hiroyuki|H|;Takekuma|Munetaka|M|;Hirashima|Yasuyuki|Y|",
"chemical_list": "D014805:Vitamin B 12",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.3695-19",
"fulltext": "\n==== Front\nIntern Med\nIntern. Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n31735792\n10.2169/internalmedicine.3695-19\nCase Report\nVitamin B12 Deficiency Anemia and Polyneuropathy Due to Chronic Radiation Enteritis\nFukuda Hiroyuki 1 Takekuma Munetaka 2 Hirashima Yasuyuki 2 \n1 Division of Neurology, Shizuoka Cancer Center, Japan\n\n2 Division of Gynecology, Shizuoka Cancer Center, Japan\nCorrespondence to Dr. Hiroyuki Fukuda, h.fukuda@scchr.jp\n\n\n18 11 2019 \n15 3 2020 \n59 6 859 861\n22 7 2019 3 10 2019 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 62-year-old Japanese woman developed numbness of the extremities and megaloblastic anemia. She had undergone total abdominal hysterectomy, whole-pelvis radiation therapy and chemotherapy for gynecological cancer 10 years before. Chronic abdominal pain, diarrhea and intermittent small-bowel obstruction had afflicted her for a long time. We diagnosed her with vitamin B12 deficiency anemia and polyneuropathy due to chronic radiation enteritis causing malabsorption. Vitamin B12 injections improved her numbness and anemia. The early diagnosis and treatment of deficiency of vitamin B12 are important. Physicians should regularly measure vitamin B12 levels and supplement vitamin B12 as needed in patients with chronic radiation enteritis. \n\ngynecological cancermegaloblastic anemiapolyneuropathyradiation enteritisvitamin B12 deficiency\n==== Body\nIntroduction\nRadiation enteritis is an injury of the small intestine and colon secondary to radiotherapy and divided into acute and chronic forms. The acute type has been recognized to cause diarrhea, and the chronic type has been reported to cause perforation, ileus, chronic diarrhea and nutritional deficiency (1). Malfunction of the terminal ileum due to the chronic form can cause vitamin B12 deficiency, as vitamin B12 is absorbed in the form of a conjugate with the intrinsic factor in the terminal ileum.\n\nWe herein report a case of vitamin B12 deficiency anemia and polyneuropathy due to chronic radiation enteritis.\n\nCase Report\nA 62-year-old Japanese woman who had a history of tuberculosis was admitted because of numbness of the extremities and anemia. She had undergone total abdominal hysterectomy, whole-pelvis radiation therapy (50.4 Gy, 1.80 Gy ×25 fractions of extended field and anterior/posterior opposed fields with low dose in multiple fractions) and chemotherapy (5- fluorouracil and cisplatin) for cervical cancer (stage IIb, pT2N1M0) 10 years before. Her body mass index (BMI) was 17.0. Chronic abdominal pain and diarrhea had afflicted her for a long time after chemoradiotherapy. She also had often developed intermittent small-bowel obstruction (Fig. 1) despite medical treatments and been clinically diagnosed with chronic radiation enteritis. She had noticed numbness in both hands and legs six months before the admission but did not report any difficulty in using her hands or walking. She also had developed anemia, but her general condition had been good.\n\nFigure 1. Computed tomography scan showing dilation and fluid retention of the small intestine.\n\nA physical examination on admission revealed a normal mental function and normal cranial nerves. The motor and sensory functions, including superficial and deep sensations, were normal. There was no ataxia or gait disturbance. The tendon reflexes except for the Achilles tendons were depressed. Laboratory data revealed pancytopenia (megaloblastic anemia), hypoproteinemia and hypocalcemia: WBC 3,700 μL, RBC 157×104 μL, Hb 6.8 g/dL, Ht 19.8%, mean corpuscular volume (MCV) 126.1 fL, mean corpuscular hemoglobin (MCH) 43.3 pg, mean corpuscular hemoglobin concentration (MCHC) 34.3%, platelet 9.2×104 μL, total protein 5.5 g/dL, albumin 3.3 g/dL, glutamic oxaloacetic transaminase (GOT) 33 U/L, glutamic pyruvate transaminase (GPT) 17 U/L, lactate dehydrogenase (LDH) 106 IU/L, γ-GTP 130 U/L, blood urea nitrogen (BUN) 15.7 mg/dL, creatinine (Cr) 0.4 mg/dL, Ca 6.6 mg/dL, Fe 117 μg/dL, TIBC 203 μg/dL, glucose 90 mg/dL, F-T3 2.36 pg/mL, F-T4 1.30 ng/mL, thyroid-stimulating hormone (TSH) 2.18 IU/L. vitamin B1 24 ng/mL, vitamin B12<50 pg/mL, folic acid 13.6 ng/mL and negative anti-gastric parietal cell antibody. Gastroscopy and colonoscopy revealed no abnormalities. Capsule endoscopy was deemed dangerous due to the history of repeated bowel obstructions and so was not performed. A nerve conduction study demonstrated no response of the sural nerve and slightly slow conduction of the other sensory nerves (Table, Fig. 2). These results indicated that she had vitamin B12 deficiency anemia and polyneuropathy. The neurological findings of the normal motor and sensory functions appeared to indicate that there was no subacute combined degeneration of the spinal cord. She was given multiple vitamin B12 injections (hydroxocobalamin 1,000 μg three times a week), and her numbness and anemia had improved (Hb 12.7 g/dL) by 2 months later. A nerve conduction study 16 months after the initiation of vitamin B12 treatment showed a marked improvement (Table, Fig. 2).\n\nTable. The Results of Nerve Conduction Studies before Vitamin B12 Treatment (white Frames) and 16 Months after the Initiation of the Treatment (gray Frames).\n\n\tMCV (m/s) \nDL (ms)\tCMAP (mV)\tSCV (m/s) \nDL (ms)\tSNAP (μV)\t\nright median nerve\t56.7\t58.7\t14.2\t15.3\t48.0\t65.1\t19.9\t17.5\t\n\t3.1\t2.5\t\t\t2.5\t1.9\t\t\t\nright ulnar nerve\t56.7\t67.9\t14.3\t17.2\t41.7\t61.8\t8.4\t18.5\t\n\t2.7\t2.5\t\t\t2.4\t1.7\t\t\t\nright tibial nerve\t45.2\t52.8\t23.8\t35.9\t\t\t\t\t\n\t3.5\t3.4\t\t\t\t\t\t\t\nright sural nerve\t\t\t\t\tNR\t46.6\tNR\t1.8\t\n\t\t\t\t\t\t3.2\t\t\t\nThe right sural nerve showed no response before the treatment but a normal conduction velocity with a small amplitude after the treatment. The conduction velocities became faster, distal latencies were shortened, and the amplitudes grew larger in other nerves after the treatment, except for the SNAP of the right median nerve. MCV: motor nerve conduction velocity, DL: distal latency, CMAP: compound muscle action potential, SCV: sensory nerve conduction velocity, SNAP: sensory nerve action potential, NR: no response\n\nFigure 2. The wave forms of orthodromic sensory nerve conduction studies of the right ulnar and sural nerves before (top traces) and 16 months after the initiation of vitamin B12 treatment (bottom traces).\n\nDiscussion\nWe encountered a patient with megaloblastic anemia and polyneuropathy due to vitamin B12 deficiency during the course of chronic enteritis.\n\nChronic radiation enteritis develops months to years after exposure to radiotherapy and usually presents with diarrhea and malabsorption (1). Factors on the patient side that increase the risk of developing radiation enteritis have been reported to be a history of intestinal surgery, low BMI, hypertension, diabetes mellitus, inflammatory bowel disease and smoking. The volume of the small bowel in the radiotherapy field, radiotherapy dose and fractionation, radiotherapy technique and concomitant chemotherapy use have been presented as factors related to treatment (2). The present patient had no history of hypertension, diabetes mellitus, inflammatory bowel disease or a smoking habit. However, she had undergone surgery and chemotherapy associated with radiation, and her BMI had been low at that time. The total radiation therapy dose received was 50.40 Gy, and the incidence of serious injury is reported to increase when the dose exceeds 50 Gy (3). The amount of radiation received and the fields of her radiation therapy were suggested to be strong factors that increased her risk of radiation enteritis. We suspected that the radiation therapy had been the main factor causing her chronic enteritis, with her history of chemotherapy and low BMI also influencing the occurrence to some extent.\n\nCauses of malabsorption of vitamin B12 can be divided into gastric and ileal disorders, as the key components of the normal pathway for vitamin B12 absorption require a functioning stomach for the production of the protein intrinsic factor and an intact cubilin receptor in the terminal ileum. We considered that the main cause of vitamin B12 deficiency in our case was malabsorption in the terminal ileum, which had been damaged by radiation therapy, as the findings on gastroscopy were normal and she was negative for anti-gastric parietal cell antibody. Her development of vitamin B12 deficiency may also have been influenced by the fact that she had reduced her daily food intake in order to avoid constipation and diarrhea.\n\nPrevious studies have reported cases of vitamin B12 deficiency due to malabsorption after radiotherapy in gynecologic cancer patients (4-10). A significant vitamin B12 deficiency was reported in 20% of 55 patients at 6-12 years after pelvic radiation (11). Various causes of vitamin B12 deficiency have been recognized, but disease or resection of the ileum as the cause of absorption disturbance has been described in recent reviews (12-14). To our knowledge, no other reports have described a case of vitamin B12 deficiency associated with chronic radiation enteritis in Japan, and chronic radiation enteritis does not seem to be well recognized as a potential cause of vitamin B12 deficiency. Keeping in mind that vitamin B12 deficiency is likely to occur in patients with chronic radiation enteritis, physicians should regularly measure the vitamin B12 levels and supplement vitamin B12 as needed in such patients.\n\nPeripheral nerves affected by vitamin B12 deficiency are reported to show myelin sheath fragmentation and axon degeneration (15). The relatively early and good recovery of the neuropathy in our case suggest that myelin sheath fragmentation was the main factor in her neuropathy.\n\nIn conclusion, we encountered the first case of vitamin B12 deficiency anemia and polyneuropathy due to chronic radiation enteritis in Japan. The serum levels of vitamin B12 should be regularly measured in patients with chronic radiation enteritis.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nWebb GJ , Brooke R , De Silva AN \nChronic radiation enteritis and malnutrition\n. J Dig Dis \n14 : 350 -357\n, 2013 .23560564 \n2. \nTheis VS , Sripadam R , Ramani V , Lal S \nChronic radiation enteritis\n. Clin Oncol \n22 : 70 -83\n, 2010 .\n3. \nBismar MM , Sinicrope FA \nRadiation enteritis\n. Curr Gastroenterol Rep \n4 : 361 -365\n, 2002 .12228037 \n4. \nGreenberger NJ , Isselbacher KJ \nMalabsorption following radiation injury to the gastrointestinal tract\n. Am J Med \n36 : 450 -456\n, 1964 .\n5. \nDuncan W , Leonard JC \nThe malabsorption syndrome following radiotherapy\n. Q J Med \n34 : 319 -329\n, 1965 .4953805 \n6. \nTankel HI , Clark DH , Lee FD \nRadiation enteritis with malabsorption\n. Gut \n6 : 560 -569\n, 1965 .5857892 \n7. \nWellwood JM , Jackson BT \nThe intestinal complications of radiotherapy\n. Br J Surg \n60 : 814 -818\n, 1973 .4748388 \n8. \nAnderson CG , Walton KR , Chanarin I \nMegaloblastic anaemia after pelvic radiotherapy for carcinoma of the cervix\n. J Clin Pathol \n34 : 151 -152\n, 1981 .6785319 \n9. \nBandy LC , Clarke-Pearson DL , Creasman WT \nVitamin-B12 deficiency following therapy in gynecologic oncology\n. Gynecol Oncol \n17 : 370 -374\n, 1984 .6706235 \n10. \nSnijders-Keilholz A , Griffioen G , Davelaar J , et al \nVitamin B12 malabsorption after irradiation for gynaecological tumours\n. Anticancer Res \n13 : 1877 -1881\n, 1993 .8267396 \n11. \nVistad I , Kristensen GB , Fosså SD , Dahl AA , Mørkrid L \nIntestinal malabsorption in long-term survivors of cervical cancer treated with radiotherapy\n. Int J Radiat Oncol Biol Phys \n73 : 1141 -1147\n, 2009 .18760883 \n12. \nStabler SP \nClinical practice. Vitamin B12 deficiency\n. N Engl J Med \n368 : 149 -160\n, 2013 .23301732 \n13. \nGreen R \nVitamin B12 deficiency from the perspective of a practicing hematologist\n. Blood \n129 : 2603 -2611\n, 2017 .28360040 \n14. \nWolffenbuttel BHR , Wouters HJCM , Heiner-Fokkema MR , et al \nThe many faces of cobalamin (Vitamin B12) deficiency\n. Mayo Clin Proc Innov Qual Outcomes \n3 : 200 -214\n, 2019 .31193945 \n15. \nKosik KS , Mullins TF , Bradley WG , Tempelis LD , Cretella AJ \nComa and axonal degeneration in vitamin B12 deficiency\n. Arch Neurol \n37 : 590 -592\n, 1980 .7417063\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "59(6)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "gynecological cancer; megaloblastic anemia; polyneuropathy; radiation enteritis; vitamin B12 deficiency",
"medline_ta": "Intern Med",
"mesh_terms": "D000749:Anemia, Megaloblastic; D004751:Enteritis; D005260:Female; D005767:Gastrointestinal Diseases; D005833:Genital Neoplasms, Female; D006801:Humans; D006987:Hypesthesia; D008286:Malabsorption Syndromes; D008875:Middle Aged; D011115:Polyneuropathies; D011832:Radiation Injuries; D014805:Vitamin B 12; D014806:Vitamin B 12 Deficiency",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "859-861",
"pmc": null,
"pmid": "31735792",
"pubdate": "2020-03-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18760883;4953805;28360040;6706235;12228037;7417063;8267396;23560564;4748388;6785319;23301732;19897345;31193945;5857892",
"title": "Vitamin B12 Deficiency Anemia and Polyneuropathy Due to Chronic Radiation Enteritis.",
"title_normalized": "vitamin b12 deficiency anemia and polyneuropathy due to chronic radiation enteritis"
} | [
{
"companynumb": "JP-ACCORD-163268",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"dr... |
{
"abstract": "Bisphosphonates (BPs) are currently used in the treatment of diverse bone diseases including fibrous dysplasia of bone (FD). In pediatric patients, a radiographic consequence of cyclical administration of BPs is the development of apo-, epi-, and meta-physeal sclerotic bands, otherwise known as zebra lines, which result from the temporary inhibition of osteoclastic activity at the time of drug treatment. We report here on a child with McCune-Albright syndrome (FD in addition to hyperfunctioning endocrinopathies and skin hyperpigmentation) treated with cyclical intravenous infusions of pamidronate in which conventional radiography, contact microradiography, histology, and backscattered electron image analysis demonstrated that zebra lines formed only where bone was normal, were arrested at the boundary between FD-unaffected and FD-affected bone where bone is sclerotic, and were absent within the undermineralized FD bone. Moreover, in spite of the treatment, the FD lesions continued to expand. This case report is unique because no previously published studies correlated the radiographic and the histologic features of BP-induced zebra lines in the metaphysis of an FD-affected long bone of the limbs.",
"affiliations": "Department of Molecular Medicine, Sapienza University, Policlinico Umberto I, Viale Regina 324, 00161, Rome, Italy. alessandro.corsi@uniroma1.it.;Department of Orthopaedic Surgery, University of Rome Tor Vergata, Rome, Italy.;Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.;Department of Molecular Medicine, Sapienza University, Policlinico Umberto I, Viale Regina 324, 00161, Rome, Italy. mara.riminucci@uniroma1.it.;Dental Physical Sciences, Queen Mary University of London, London, E1 4NS, UK.",
"authors": "Corsi|Alessandro|A|;Ippolito|Ernesto|E|;Robey|Pamela G|PG|;Riminucci|Mara|M|;Boyde|Alan|A|",
"chemical_list": "D004164:Diphosphonates; D000077268:Pamidronate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00256-017-2698-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0364-2348",
"issue": "46(10)",
"journal": "Skeletal radiology",
"keywords": "BSE-SEM image analysis; Bisphosphonates; Contact microradiography; Fibrous dysplasia; McCune–Albright syndrome; Zebra lines",
"medline_ta": "Skeletal Radiol",
"mesh_terms": "D000293:Adolescent; D004164:Diphosphonates; D018450:Disease Progression; D005260:Female; D005269:Femur; D005359:Fibrous Dysplasia, Polyostotic; D006801:Humans; D000077268:Pamidronate",
"nlm_unique_id": "7701953",
"other_id": null,
"pages": "1435-1439",
"pmc": null,
"pmid": "28660402",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17606790;11154006;10024373;12709749;24390518;14729043;1594625;13678786;15207763;17414005;27826699;15177003;27649526;1944469;17340165;1609087;9333137;4707191;17228998;10709889;10646121;9258763;14557424;15846396;8077356;25033066;17228999;24423331;12854833;12199352;21774705;9868289;12703030;10969268;7909013;16509531",
"title": "Bisphosphonate-induced zebra lines in fibrous dysplasia of bone: histo-radiographic correlation in a case of McCune-Albright syndrome.",
"title_normalized": "bisphosphonate induced zebra lines in fibrous dysplasia of bone histo radiographic correlation in a case of mccune albright syndrome"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-145522",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PAMIDRONATE DISODIUM"
},
... |
{
"abstract": "BACKGROUND\nThe optimal treatment for tuberculosis (TB) in human immunodeficiency virus (HIV) infected patients in resource-poor settings receiving lopinavir-ritonavir (LPV/r) based second-line antiretroviral therapy (ART) has yet to be determined. In South Africa, clinicians are advised to use 'double-dose' LPV/r dosed at 800 mg/200 mg twice daily during anti-tuberculosis treatment.\n\n\nRESULTS\nWe conducted a retrospective study of HIV-infected patients who received ≥2 months of double-dose LPV/r-based ART during concomitant rifampicin-containing anti-tuberculosis treatment. We used standard definitions for TB and HIV outcomes; virological failure was defined as a viral load >1000 copies/ml. During co-administration, gastro-intestinal toxicity occurred in 9/25 (36%) patients, a symptomatic rise in aspartate aminotransferase or alanine aminotransferase of any grade was noted in 3 (12%), with two Grade 3 events, and 3 (12%) patients required treatment discontinuation. Outcomes were favourable, with 20/25 (80%) patients achieving TB treatment success and virological failure observed among 3 (12%) patients during co-administration.\n\n\nCONCLUSIONS\nWe found the use of double-dose LPV/r during simultaneous standard anti-tuberculosis treatment to be an effective and reasonably well tolerated interim strategy.",
"affiliations": "McCord Hospital, Durban, South Africa.;St. Vincent Hospital, Indianapolis, Indiana, USA.;Department of Medicine New York University School of Medicine, New York, New York, USA.;University of Edinburgh, Edinburgh, Scotland, UK.;McCord Hospital, Durban, South Africa.;Massachusetts General Hospital, Boston, Massachusetts, USA;;Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard, Boston, Massachusetts, USA.;Albert Einstein College of Medicine, New York, New York, USA.",
"authors": "Sunpath|H|H|;Winternheimer|P|P|;Cohen|S|S|;Tennant|I|I|;Chelin|N|N|;Gandhi|R T|RT|;Murphy|R A|RA|",
"chemical_list": "D000904:Antibiotics, Antitubercular; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; D019438:Ritonavir; D012293:Rifampin",
"country": "France",
"delete": false,
"doi": "10.5588/ijtld.13.0492",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1027-3719",
"issue": "18(6)",
"journal": "The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease",
"keywords": null,
"medline_ta": "Int J Tuberc Lung Dis",
"mesh_terms": "D000328:Adult; D000904:Antibiotics, Antitubercular; D060085:Coinfection; D004338:Drug Combinations; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D006801:Humans; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012293:Rifampin; D019438:Ritonavir; D013019:South Africa; D016896:Treatment Outcome; D014376:Tuberculosis; D019562:Viral Load; D055815:Young Adult",
"nlm_unique_id": "9706389",
"other_id": null,
"pages": "689-93",
"pmc": null,
"pmid": "24903940",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Double-dose lopinavir-ritonavir in combination with rifampicin-based anti-tuberculosis treatment in South Africa.",
"title_normalized": "double dose lopinavir ritonavir in combination with rifampicin based anti tuberculosis treatment in south africa"
} | [
{
"companynumb": "ZA-RANBAXY-2014RR-88410",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of massive suicidal overdose of meprobamate leading to cardiovascular collapse, respiratory failure, and severe central nervous system depression. We observed first-order elimination kinetics despite significant overdose, and demonstrated effectiveness of continuous venovenous hemodiafiltration (CVVHDF) for extracorporeal removal of meprobamate in this patient. Total body clearance was calculated to be 87 mL/minute, with 64 mL/minute (74%) due to CVVHDF. CVVHDF was stopped after 36 hours, and the patient made an uneventful recovery.",
"affiliations": "Swiss Toxicological Information Centre, Associated Institute of the University of Zurich, Zurich, Switzerland.",
"authors": "Ceschi|Alessandro|A|;Berger|David|D|;Dickenmann|Michael|M|;Bodmer|Michael|M|",
"chemical_list": "D008620:Meprobamate",
"country": "Canada",
"delete": false,
"doi": "10.1111/hdi.12047",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1492-7535",
"issue": "17(4)",
"journal": "Hemodialysis international. International Symposium on Home Hemodialysis",
"keywords": "CVVHDF; Poisoning; hemodiafiltration; meprobamate",
"medline_ta": "Hemodial Int",
"mesh_terms": "D058186:Acute Kidney Injury; D062787:Drug Overdose; D005260:Female; D017583:Hemodiafiltration; D006801:Humans; D008620:Meprobamate; D008875:Middle Aged; D013406:Suicide, Attempted",
"nlm_unique_id": "101093910",
"other_id": null,
"pages": "656-9",
"pmc": null,
"pmid": "23615322",
"pubdate": "2013-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pharmacokinetics of meprobamate in overdose treated with continuous venovenous hemodiafiltration (CVVHDF).",
"title_normalized": "pharmacokinetics of meprobamate in overdose treated with continuous venovenous hemodiafiltration cvvhdf"
} | [
{
"companynumb": "CH-WATSON-2014-16078",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PRAZEPAM"
},
"drugadditional": null,
"d... |
{
"abstract": "Antidepressants, especially amitriptyline, are among the most frequent drug classes involved in intoxications. Despite its small molecular weight, amitriptyline is not considered to be eliminated by extracorporeal treatment methods due to its high protein binding and large volume of distribution. New high cut-off dialysers have so far not been used for removal of amitriptyline. We report two cases of amitriptyline poisoning in which we measured the amitriptyline elimination using extended high cut-off (HCO) dialysis. Despite dialyser clearances of 33 and 58 mL/min, resulting in the reduction of initial serum concentrations by ∼30%, only 211 and 920 µg of amitryptilin, respectively, (<3% of the ingested amount) could be recovered in the total collected dialysate. Hence, due to the high volume of distribution of amitriptyline, even HCO dialysis does not contribute substantially to the extracorporeal removal of amitryptilin.",
"affiliations": "Department of Nephrology , Hannover Medical School , Hannover , Germany.;Department of Nephrology , Hannover Medical School , Hannover , Germany.;Medical Laboratory of Bremen , Bremen , Germany.;Department of Pneumology , Hannover Medical School , Hannover , Germany.;Department of Pneumology , Hannover Medical School , Hannover , Germany.;Department of Gastroenterology, Hepatology and Endocrinology , Hannover Medical School , Hannover , Germany.;Department of Nephrology , Hannover Medical School , Hannover , Germany.",
"authors": "Schmidt|Julius J|JJ|;Bertram|Anna|A|;Kühn-Velten|W Nikolaus|WN|;Suhling|Hendrik|H|;Wiesner|Olaf|O|;Schneider|Andrea|A|;Kielstein|Jan T|JT|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ckj/sfv094",
"fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjndtplusClinical Kidney Journal2048-85052048-8513Oxford University Press 10.1093/ckj/sfv094sfv094ContentsDialysisTreatment of amitriptyline intoxications by extended high cut-off dialysis Schmidt Julius J. 1Bertram Anna 1Kühn-Velten W. Nikolaus 2Suhling Hendrik 3Wiesner Olaf 3Schneider Andrea 4Kielstein Jan T. 11 Department of Nephrology, Hannover Medical School, Hannover, Germany2 Medical Laboratory of Bremen, Bremen, Germany3 Department of Pneumology, Hannover Medical School, Hannover, Germany4 Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, GermanyCorrespondence to: Julius J. Schmidt; E-mail: schmidt.julius_j@yahoo.de12 2015 29 9 2015 29 9 2015 8 6 796 799 13 6 2015 31 8 2015 © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.2015This 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.comAntidepressants, especially amitriptyline, are among the most frequent drug classes involved in intoxications. Despite its small molecular weight, amitriptyline is not considered to be eliminated by extracorporeal treatment methods due to its high protein binding and large volume of distribution. New high cut-off dialysers have so far not been used for removal of amitriptyline. We report two cases of amitriptyline poisoning in which we measured the amitriptyline elimination using extended high cut-off (HCO) dialysis. Despite dialyser clearances of 33 and 58 mL/min, resulting in the reduction of initial serum concentrations by ∼30%, only 211 and 920 µg of amitryptilin, respectively, (<3% of the ingested amount) could be recovered in the total collected dialysate. Hence, due to the high volume of distribution of amitriptyline, even HCO dialysis does not contribute substantially to the extracorporeal removal of amitryptilin.\n\nacute interstitial nephritisantidepressantsproton pump inhibitors\n==== Body\nBackground\nAntidepressants represent the sixth leading substance category causing intoxication in the USA, with tricyclic antidepressants (TCAs) being the most important category in that group. TCA intoxications led to 69 fatalities in 2012. With 6305 exposures in 2012, amitriptyline was the single most important TCA involved in intoxication [1]. Similar findings are reported all over the world: amitriptyline is the second most responsible drug for death in antidepressant poisoning in the UK, where antidepressant self-poisoning is used in 20% of all poisoning suicides [2]. TCAs were the most common suicide poison used in New Zealand between 2001 and 2005 [3]. In Tehran, Iran, amitriptyline is the most used TCA in drug intoxication, where TCAs are responsible for 16% of all admissions due to intoxication [4]. In adult out-patients, amitriptyline is normally dosed between 75 and 150 mg/day, which provides therapeutic concentrations between 80 and 250 µg/L [5]. In cases of overdose, amitriptyline may cause an alteration of consciousness, hypernatraemia, convulsive seizure, arrhythmia and respiratory depression. First-line treatment focuses on general measures as well as correction of electrolyte disorders and arrhythmia [6]. Activated charcoal is frequently administered. Extracorporeal means of toxin removal consist of charcoal haemoperfusion [7] and plasma exchange, which decreased amitriptyline blood concentrations in a few cases [8]. Due to its high plasma protein binding and volume of distribution (VOD), amitriptyline is considered to be non-dialyzable. The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup therefore recommends not to use extracorporeal removal of TCA, as this approach is not likely to offer a clinical benefit [9]. We report two cases of amitriptyline poisoning in which we measured the amitriptyline elimination using a high cut-off (HCO) dialyzer.\n\nEssential information on both patients as recommended by the EXTRIP workgroup [10] is summarized in Table 1.\nTable 1. Relevant case report characteristics recommended by the EXTRIP workgroup [10]\n\n\tCase 1\tCase 2\t\nGeneral information\t\n Age (years)\t54\t53\t\n Weight (kg)\t54\t75\t\n Height (cm)\t168\t157\t\n Gender\t♀\t♀\t\n Concurrent diseases\tBreast cancer, chronic pain syndrome, depression\tMGUS, depression, chronic pain syndrome\t\n Source providing the history of the poisoning\tParamedics\tParamedics\t\n Time from ingestion to hospital admission (h)\t7.5\t8.5\t\n Known co-medication\tLorazepam\tPantoprazole, citalopram, mirtazapine\t\n Other toxins\tTilidine, ethanol\tIbuprofen, β-blockers, alcohol\t\n Activated charcoal given\tNo\tYes\t\n ICU stay (days)\t3\t5\t\n Discharge from hospital (days)\t3\t20\t\nLaboratory values\t\n Albumin (g/L)\t34.8\t42\t\n Creatinine at baseline (µmol/L)/eGFR CKD-EPI\t36/115.3\t643/6 (AKIN III)\t\n Serum amitriptyline peak concentration (µg/L)\t458\t412\t\n Serum nortipytilin peak concentrations (µg/L)\t283\t259\t\n Serum tilidine/nortilidin peak concentrations (µg/L)\t56/849\tNA\t\n Urine excretion (mL/days)\t3100\tanuria\t\n Urine amitriptyline concentration (µg/L)\t623\tNA\t\n Haematocrit (%)\t40\t36.5\t\nECTR characteristics\t\n Modality of ECTR\tIntermitted haemodialysis\tIntermitted haemodialysis\t\n Indication for ECTR\tDetoxification\tAKI, rhabdomyolysis, detoxification\t\n ECTR start after admission (h)\t2.5\t1.5\t\n Dialyser (material/surface)a\tHCO dialyser (polysulfone, 1.8 m2)\tHigh-flux dialyser (polysulfone, 1.3 m2)\nHCO dialyser (polysulfone, 1.8 m2)\t\n Dialysis time (min)\t295 (first treatment)\n220 (second treatment)\t320 (first treatment)\n775 (second treatment)/350 (HCO)\t\n Blood flow (mL/min)\t300 (first treatment)\n110 (second treatment)\t240 (high-flux)\n240 (high-flux)\t\n Dialysate flow (mL/min)\t300 (first treatment)\n55 (second treatment)\t240 (high-flux)\n240 (high-flux)\t\n Ultrafiltration rate (mL/h)\t50\t50 (first treatment)/50 (second treatment)/200 (HCO)\t\n Anticoagulation\tHeparin\tHeparin\t\n Amitriptyline reduction ratio (%)b\t27\t28 (HCO)\t\n ECTR amitriptyline clearance (mL/min)c\t58\t7 (high-flux)\n33 (HCO)\t\n Total amount of amitriptyline in the collected dialysate (µg)\t211\t920 (high-flux)\nNA (HCO)\t\nAKI, acute kidney injury; AKIN, acute kidney injury network; CKD-EPI, chronic kidney disease epidemiology collaboration; eGFR, estimated glomerular filtration rate; HPLC, high-performance liquid chromatography; MS/MS, tandem mass spectrometry.\n\nAmitriptyline and nortriptyline were quantified (detection limit 5 µg/L) by HPLC followed by electrospray ionization and mass spectrometric detection and quantification of selected ion fragments (triple quadrupole MS/MS, API2000, PE Sciex) after simple deproteinization with acetonitrile/methanol. Tilidine and its metabolites were similarly quantified (detection limit 5 µg/L) by HPLC-MS (Waters Micromass, Quattro Micro) after fluid extraction with cyclohexane.\n\naAdditional membrane characteristics are reported elsewhere [11].\n\nbCalculations of reduction ratios were executed according to equation (1): (1) RR=(Cpost−Cpre)/Cpre×100 \n\n\ncDialyser clearance was measured according to equation (2), using the patients’ hematocrit concentration (Hct) at the time of clearance sampling: (2) Kplasma=QB×(1−Hct/100)×((Cart−Cven)/Cart) \n\n\n\n\nCase 1\nA 54-year-old Caucasian woman, who ingested an unknown amount of amitriptyline and tilidine in a suicide attempt, was admitted to our hospital deeply unconscious with a Glasgow Coma Scale score of 5. Naloxone had no effect. Blood pressure was 140/80 mmHg and heart rate was 94 bpm. Electrocardiography showed a broad QRS complex (134 ms) and prolonged QTc (517 ms), representing increased risk for ventricular arrhythmias. Based on the clinical condition, we started a 5 h dialysis using an HCO EMiC2 dialyser (polysulfone; 1.8 m2) with a dialysate and blood flow of 300 mL/min to eliminate tilidine and other potentially ingested drugs. The treatment was well tolerated, and immediately afterwards a dialysis with low dialysate and blood flow was started with the aim of performing an extended dialysis. Due to clotting of the extracorporeal circuit, this dialysis prematurely ended after 220 min. Plasma concentrations of both substances were drawn at different time points (Figure 1a). Plasma dialyser clearances for amitriptyline and tilidine were 58 and 67 mL/min, respectively, at the beginning and decreased towards the end of the first dialysis session (Supplementary Table S1). For comparison, dialyser clearances for creatinine and urea were 115 and 132 mL/min, respectively. Dialyser reduction ratios, dialyser clearance and total loss into the collected spent dialysate are listed in Supplementary Table S1.\nFig. 1. (a) Time course of plasma concentrations for amitriptyline and tilidine. (b) Time course of amitriptyline and myoglobin concentrations during HCO dialysis treatment. Open triangles denote myoglobin values at the upper laboratory detection range. *Amitriptyline concentration measured in different laboratories.\n\n\n\nInto the sixth hour of treatment, the patient regained consciousness and was transferred to psychiatric care after 3 days in the intensive care unit (ICU).\n\nCase 2\nA 53-year-old Caucasian female who ingested ∼1750 mg of amitriptyline and 12 g of ibuprofen in a suicide attempt was admitted to our hospital. The patient was found with a Glasgow Coma Scale score of 5. Blood pressure was 119/72 mmHg and heart rate was 96 bpm. An electrocardiogram showed a regular sinus rhythm. Serum creatinine was 634 µmol/L, sodium 137 mmol/L and creatine kinase 27 308 U/L. Amitriptyline serum concentration was 412 µg/L. The unconscious patient was transferred to our ICU, intubated and mechanically ventilated. Gastroscopy revealed unabsorbed pills in the stomach, and activated charcoal was administered after they were removed. Haemodialysis was started 2 h after admission due to anuric acute kidney injury caused by rhabdomyolysis. Dialysis using an FX60S polysulfone dialyser (Fresenius Medical Care; 1.3 m2) was performed with a blood and dialysate flow of 240 mL/min. After a quick decrease of amitriptyline to 205 µg/L at the start of the second dialysis treatment, amitriptyline concentrations did not show any remarkable decline in the following hours of treatment (Figure 1b). To enhance extracorporeal removal, we employed the HCO EMiC2 dialyser (Fresenius Medical Care, polysulfone; 1.8 m2) with a dialysate and blood flow of 240 mL/min, decreasing amitriptyline to 163 µg/L. The reduction ratio for amitryptilin was 28%. The increased removal was also confirmed by a plasma dialyser clearance of 33 mL/min for amitriptyline and 124 mL/min for myoglobin. Myoglobin serum concentrations decreased from >60 000 µg/L (upper detection limit) to 11 642 µg/L.\n\nFive days after admission, the patient was transferred to the nephrology ward, and renal replacement therapy was stopped after 14 days of intermittent haemodialysis. On renal biopsy, eosinophil interstitial nephritis was identified as the cause of acute kidney injury. Twenty days after initial admission, the patient was transferred to a psychiatric hospital. Of note, therapy with proton pump inhibitors, a therapy the patient had been prescribed for years, can cause both rhabdomyolysis and interstitial nephritis [12].\n\nDiscussion\nVery recently, the EXTIRP workgroup recommended not performing any extracorporeal treatments (ECTRs) for intoxication with TCAs [9]. This recommendation is based on the fact that conventional haemodialysis is ineffective due to the high protein binding (>90%) and large VOD (14–17 L/kg) and the lipophilic properties of TCA [13]. However, most of the haemodialysis data the workgroup based the recommendation on are from the 1960s and 1970s. Hence, data about the performance of modern membranes in TCA intoxication are limited. The potential benefit of modern means of renal replacement therapy was suggested in a report on haemodiafiltration after acute amitriptyline intoxication in which the patient showed an improved vigilance during treatment. As no amitriptyline blood concentrations were reported, establishing causality for clinical improvement is difficult [14]. Recently, extended dialysis using an HCO dialyser has been introduced to remove large quantities of free light chains in patients with multiple myeloma [11]. These dialysers are characterized by a larger pore size, which allows enhanced middle molecule removal without substantial elimination of albumin [15]. Myoglobin, accumulated in rhabdomyolysis as in one of our cases, is also dialysed by highly permeable membranes [16]. So far, there are only anecdotal reports on the use of HCO dialysers for the removal of toxins [17]. We could show that even with an increase of the amitriptyline dialyser clearance using HCO instead of high-flux dialysis, the estimated total eliminated amount of amitriptyline by HCO dialysis remains low (<0.1% of the ingested dose) and therefore may not exceed 3% of the ingested dose per HCO dialysis session, which is considered to be the lower threshold for dialysability according to EXTRIP criteria [9]. Therefore, amitriptyline can be defined as ‘non-dialysable’, even under HCO dialysis.\n\nAn additional factor influencing amitryptilin concentrations is concomitantly ingested drugs, especially those that are metabolized mainly via CYP2D6. Although these drugs, especially pantoprazole in our cases, might have an effect on metabolization, these mechanisms will most likely not affect extracorporeal removal. Notwithstanding, the inherent limitation of only two reported patients, is an important shortcoming of this article. In summary, even the elevated amitriptyline clearance by HCO membranes in the context of extended dialysis is unlikely to confer a clinical benefit, supporting a recent recommendation of EXTRIP to refrain from any ECTR in intoxication with TCAs. As a finding unrelated to the topic of extracorporeal toxin removal, we could show that HCO extended dialysis is very effective in lowering elevated myoglobin in rhabdomyolysis.\n\nSupplementary data\nSupplementary data are available online at http://ckj.oxfordjournals.org.\n\nConflicts of interest statement\nNone declared.\n\nSupplementary Material\nSupplementary Data\n==== Refs\nReferences\n1 Mowry JB Spyker DA Cantilena LR Jr \n2012 annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 30th annual report . Clin Toxicol (Phila) \n2013 ; 51 : 949 –1229 24359283 \n2 Hawton K Bergen H Simkin S \nToxicity of antidepressants: rates of suicide relative to prescribing and non-fatal overdose . Br J Psychiatry \n2010 ; 196 : 354 –358 20435959 \n3 Gallagher LM Kappatos D Tisch C \nSuicide by poisoning in New Zealand—a toxicological analysis . N Z Med J \n2012 ; 125 : 15 –25 23178601 \n4 Dianat S Zarei MR Hassanian-Moghaddam H \nTricyclic antidepressants intoxication in Tehran, Iran: epidemiology and associated factors . Hum Exp Toxicol \n2011 ; 30 : 283 –288 20488849 \n5 Hiemke C Baumann P Bergemann N \nAGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011 . Pharmacopsychiatry \n2011 ; 44 : 195 –235 \n6 Kerr GW McGuffie AC Wilkie S \nTricyclic antidepressant overdose: a review . Emerg Med J \n2001 ; 18 : 236 –241 11435353 \n7 Ash SR Levy H Akmal M \nTreatment of severe tricyclic antidepressant overdose with extracorporeal sorbent detoxification . Adv Ren Replace Ther \n2002 ; 9 : 31 –41 11927905 \n8 Sari I Turkcuer I Erurker T \nTherapeutic plasma exchange in amitriptyline intoxication: case report and review of the literature . Transfus Apher Sci \n2011 ; 45 : 183 –185 21872530 \n9 Yates C Galvao T Sowinski KM \nExtracorporeal treatment for tricyclic antidepressant poisoning: recommendations from the EXTRIP Workgroup . Semin Dial \n2014 ; 27 : 381 –389 24712820 \n10 Lavergne V Ouellet G Bouchard J \nGuidelines for reporting case studies on extracorporeal treatments in poisonings: methodology . Semin Dial \n2014 ; 27 : 407 –414 24890576 \n11 Hutchison CA Cockwell P Reid S \nEfficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies . J Am Soc Nephrol \n2007 ; 18 : 886 –895 17229909 \n12 Wilhelm SM Rjater RG Kale-Pradhan PB \nPerils and pitfalls of long-term effects of proton pump inhibitors . Expert Rev Clin Pharmacol \n2013 ; 6 : 443 –451 23927671 \n13 Dargan PI Colbridge MG Jones AL \nThe management of tricyclic antidepressant poisoning: the role of gut decontamination, extracorporeal procedures and fab antibody fragments . Toxicol Rev \n2005 ; 24 : 187 –194 16390220 \n14 Ozayar E Degerli S Gulec H \nHemodiafiltration: a novel approach for treating severe amitriptyline intoxication . Toxicol Int \n2012 ; 19 : 319 –321 23293473 \n15 Schmidt JJ Hafer C Clajus C \nNew high-cutoff dialyzer allows improved middle molecule clearance without an increase in albumin loss: a clinical crossover comparison in extended dialysis . Blood Purif \n2012 ; 34 : 246 –252 23171639 \n16 Sorrentino SA Kielstein JT Lukasz A \nHigh permeability dialysis membrane allows effective removal of myoglobin in acute kidney injury resulting from rhabdomyolysis . Crit Care Med \n2011 ; 39 : 184 –186 21057310 \n17 Baroke E Schmidt JJ Strunk AK \nSaving two lives with one dialysis treatment . Clin Nephrol \n2015 ; 84 : 104 –107 25600858\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2048-8505",
"issue": "8(6)",
"journal": "Clinical kidney journal",
"keywords": "acute interstitial nephritis; antidepressants; proton pump inhibitors",
"medline_ta": "Clin Kidney J",
"mesh_terms": null,
"nlm_unique_id": "101579321",
"other_id": null,
"pages": "796-9",
"pmc": null,
"pmid": "26613042",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": "23171639;17229909;20435959;11927905;23178601;16390220;24890576;23927671;25600858;21872530;21969060;20488849;24359283;23293473;21057310;24712820;11435353",
"title": "Treatment of amitriptyline intoxications by extended high cut-off dialysis.",
"title_normalized": "treatment of amitriptyline intoxications by extended high cut off dialysis"
} | [
{
"companynumb": "DE-PFIZER INC-2016161980",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional":... |
{
"abstract": "Presentation of pooled analysis of safety data for fremanezumab in patients with chronic (CM) or episodic migraine (EM) from 4 placebo-controlled phase 2b and phase 3 studies.\n\n\n\nThere is a need for an effective, safe, and well-tolerated preventive therapy that specifically targets the pathophysiology of migraine to reduce the frequency and severity of migraine attacks in patients with CM or EM who experience 4 or more migraine days per month. Fremanezumab is a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, a neuropeptide involved in the pathophysiology of migraine.\n\n\n\nThe 4 placebo-controlled phases 2b and 3 studies included in this analysis were 16-week, multicenter, randomized, double-blind, placebo-controlled, and parallel-group studies consisting of a screening visit, a 28-day pretreatment baseline period, and a 12-week treatment period with a final evaluation 4 weeks after the final dose of the study drug. Safety endpoints included adverse events (AEs) and immunogenicity.\n\n\n\nA total of 2566 patients were randomized across all studies (fremanezumab, n = 1704; placebo, n = 862), and 2563 patients were treated. Common reasons for study discontinuation were withdrawal by patient (n = 78), patient lost to follow-up (n = 60), and AE (n = 50). The mean (standard deviation) duration of exposure was 83.8 (13.6) days for the patients who received fremanezumab, with a total exposure of 390.4 patient years and maximum exposure of 181 days. AEs were mostly mild to moderate in severity and were reported among 48-69% of patients in all treatment groups, and most were injection site reactions (pain, induration, and erythema). Two deaths occurred (chronic obstructive pulmonary disease and intentional overdose of diphenhydramine), both of which were deemed unrelated to study drug by the investigators and sponsor. Cardiovascular adverse events, abnormal liver function tests, and hypersensitivity were uncommon and occurred at similar rates between the placebo and fremanezumab groups.\n\n\n\nFremanezumab is a generally safe and well-tolerated preventive therapy for migraine in adults.",
"affiliations": "Jefferson Headache Center, Thomas Jefferson University, Philadelphia, PA, USA.;New England Institute for Neurology and Headache, Stamford, CT, USA.;Teva Pharmaceuticals, Frazer, PA, USA.;Ratiopharm GmbH, Ulm, Germany.;Ratiopharm GmbH, Ulm, Germany.;Teva Pharmaceuticals, Frazer, PA, USA.;Teva Pharmaceuticals, Frazer, PA, USA.;Teva Pharmaceuticals, Frazer, PA, USA.;Teva Pharmaceuticals, Frazer, PA, USA.;Teva Pharmaceuticals, Frazer, PA, USA.;Teva Pharmaceuticals, Frazer, PA, USA.",
"authors": "Silberstein|Stephen D|SD|;McAllister|Peter|P|;Ning|Xiaoping|X|;Faulhaber|Nicola|N|;Lang|Nicole|N|;Yeung|Paul|P|;Schiemann|Jimmy|J|;Aycardi|Ernesto|E|;Cohen|Joshua M|JM|;Janka|Lindsay|L|;Yang|Ronghua|R|",
"chemical_list": "D000911:Antibodies, Monoclonal; C000604315:fremanezumab; D015740:Calcitonin Gene-Related Peptide",
"country": "United States",
"delete": false,
"doi": "10.1111/head.13534",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-8748",
"issue": "59(6)",
"journal": "Headache",
"keywords": "headache; migraine; safety and tolerability",
"medline_ta": "Headache",
"mesh_terms": "D000818:Animals; D000911:Antibodies, Monoclonal; D015740:Calcitonin Gene-Related Peptide; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D006801:Humans; D008881:Migraine Disorders; D015337:Multicenter Studies as Topic; D016032:Randomized Controlled Trials as Topic",
"nlm_unique_id": "2985091R",
"other_id": null,
"pages": "880-890",
"pmc": null,
"pmid": "30977520",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety and Tolerability of Fremanezumab for the Prevention of Migraine: A Pooled Analysis of Phases 2b and 3 Clinical Trials.",
"title_normalized": "safety and tolerability of fremanezumab for the prevention of migraine a pooled analysis of phases 2b and 3 clinical trials"
} | [
{
"companynumb": "US-PFIZER INC-2019166961",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE HYDROCHLORIDE"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nThis randomised, open-label, multicenter phase II study compared progression-free survival (PFS) of S-1 plus oxaliplatin (SOX) with that of S-1 alone in patients with gemcitabine-refractory pancreatic cancer.\n\n\nMETHODS\nPatients with confirmed progressive disease following the first-line treatment with a gemcitabine-based regimen were randomised to receive either S-1 (80/100/120 mg day(-1) based on body surface area (BSA), orally, days 1-28, every 6 weeks) or SOX (S-1 80/100/120 mg day(-1) based on BSA, orally, days 1-14, plus oxaliplatin 100 mg m(-2), intravenously, day 1, every 3 weeks). The primary end point was PFS.\n\n\nRESULTS\nBetween January 2009 and July 2010, 271 patients were randomly allocated to either S-1 (n=135) or SOX (n=136). Median PFS for S-1 and SOX were 2.8 and 3.0 months, respectively (hazard ratio (HR)=0.84; 95% confidence interval (CI), 0.65-1.08; stratified log-rank test P=0.18). Median overall survival (OS) was 6.9 vs 7.4 months (HR=1.03; 95% CI, 0.79-1.34; stratified log-rank test P=0.82). The response rate (RR) was 11.5% vs 20.9% (P=0.04). The major grade 3/4 toxicities (S-1 and SOX) were neutropenia (11.4% and 8.1%), thrombocytopenia (4.5% and 10.3%) and anorexia (12.9% and 14.7%).\n\n\nCONCLUSIONS\nAlthough SOX showed an advantage in RR, it provided no significant improvement in PFS or OS compared with S-1 alone.",
"affiliations": "Department of Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, 2-3-2, Nakao, Asahi-ku, Yokohama, Kanagawa 241-8515, Japan.;Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.;Department of Gastroenterology, Graduate School of Medicine, University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.;Department of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho Sunto-gun, Shizuoka 411-8777, Japan.;Department of Gastroenterology, Saitama Cancer Center, 780, Komuro, Inamachi, Kitaadachi-gun, Saitama 362-0806, Japan.;Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.;Department of Gastroenterology, National Hospital Organization Kyushu Cancer Center, 3-1-1, Notame, Minami-ku, Fukuoka 811-1395, Japan.;Department of Chemotherapy, Japanese Red Cross Nagoya Daiichi Hospital, 15-1, Michishita-cho, Nakamura-ku, Nagoya, Aichi 453-8511, Japan.;Department of Internal Medicine, Keio University Hospital, 35, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.;Department of Hepatobiliary-Pancreatic Surgery, Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka 540-0006, Japan.;Department of Surgery, Niigata Cancer Center, 2-15-3, Kawagishi-cho, Chuo-ku, Niigata 951-8566, Japan.;Department of Digestive Surgery, Kumamoto University Hospital, 1-1-1, Honjo, Chuo-ku, Kumamoto 860-8556, Japan.;Department of Gastroenterology, Cancer Institute Hospital of JFCR, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan.;Department of Chemotherapy, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan.;Department of Surgery, Nara Medical University Hospital, 840, Shijo-cho, Kashihara, Nara 634-8522, Japan.;Department of Clinical Oncology, Kyoto University Hospital, 54, Kawahara-cho, Shogoin, Sakyo-ku Kyoto 606-8507, Japan.;Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3, Asahimachi, Abeno-ku, Osaka 545-8585, Japan.;Department of Surgery, Kansai Medical University Hirakata Hospital, 2-3-1, Shinmachi, Hirakata, Osaka 573-1191, Japan.;Department of Hepatobiliary-Pancreatic Surgery, Tohoku University Hospital, 1-1, Seiryomachi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.;Department of Gastroenterological Surgery, Yokohama City University Hospital, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.;Department of Clinical Oncology, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.;Department of Digestive Surgery, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo 105-8470, Japan.;Department of Surgery, Iwate Medical University Hospital, 19-1, Uchimaru, Morioka, Iwate 020-8505, Japan.;Department of Internal Medicine, Tokyo Metropolitan Matsuzawa Hospital, 2-1-1, Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan.;Department of Gastroenterological Oncology, Hyogo Cancer Center, 13-70, Kitaoji-cho, Akashi, Hyogo, 673-8558, Japan.;Department of Surgery, Kobe City Medical Center General Hospital, 2-1-1, Minatojimanakamachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.;Department of Management Science, Tokyo University of Science, 1-3, Kagurazaka, Shinjuku-ku, Tokyo, 162-8601, Japan.;Department of Gastroenterology, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8577, Japan.",
"authors": "Ohkawa|S|S|;Okusaka|T|T|;Isayama|H|H|;Fukutomi|A|A|;Yamaguchi|K|K|;Ikeda|M|M|;Funakoshi|A|A|;Nagase|M|M|;Hamamoto|Y|Y|;Nakamori|S|S|;Tsuchiya|Y|Y|;Baba|H|H|;Ishii|H|H|;Omuro|Y|Y|;Sho|M|M|;Matsumoto|S|S|;Yamada|N|N|;Yanagimoto|H|H|;Unno|M|M|;Ichikawa|Y|Y|;Takahashi|S|S|;Watanabe|G|G|;Wakabayashi|G|G|;Egawa|N|N|;Tsuda|M|M|;Hosotani|R|R|;Hamada|C|C|;Hyodo|I|I|",
"chemical_list": "D004338:Drug Combinations; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; C056507:gemcitabine",
"country": "England",
"delete": false,
"doi": "10.1038/bjc.2015.103",
"fulltext": "\n==== Front\nBr J CancerBr. J. CancerBritish Journal of Cancer0007-09201532-1827Nature Publishing Group bjc201510310.1038/bjc.2015.10325880004Clinical StudyRandomised phase II trial of S-1 plus oxaliplatin vs S-1 in patients with gemcitabine-refractory pancreatic cancer SOX vs S-1 in GEM refractory pancreatic cancerOhkawa S 1*Okusaka T 2Isayama H 3Fukutomi A 4Yamaguchi K 5Ikeda M 6Funakoshi A 7Nagase M 8Hamamoto Y 9Nakamori S 10Tsuchiya Y 11Baba H 12Ishii H 13Omuro Y 14Sho M 15Matsumoto S 16Yamada N 17Yanagimoto H 18Unno M 19Ichikawa Y 20Takahashi S 21Watanabe G 22Wakabayashi G 23Egawa N 24Tsuda M 25Hosotani R 26Hamada C 27Hyodo I 281 Department of Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, 2-3-2, Nakao, Asahi-ku, Yokohama, Kanagawa 241-8515, Japan2 Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan3 Department of Gastroenterology, Graduate School of Medicine, University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan4 Department of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho Sunto-gun, Shizuoka 411-8777, Japan5 Department of Gastroenterology, Saitama Cancer Center, 780, Komuro, Inamachi, Kitaadachi-gun, Saitama 362-0806, Japan6 Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan7 Department of Gastroenterology, National Hospital Organization Kyushu Cancer Center, 3-1-1, Notame, Minami-ku, Fukuoka 811-1395, Japan8 Department of Chemotherapy, Japanese Red Cross Nagoya Daiichi Hospital, 15-1, Michishita-cho, Nakamura-ku, Nagoya, Aichi 453-8511, Japan9 Department of Internal Medicine, Keio University Hospital, 35, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan10 Department of Hepatobiliary-Pancreatic Surgery, Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka 540-0006, Japan11 Department of Surgery, Niigata Cancer Center, 2-15-3, Kawagishi-cho, Chuo-ku, Niigata 951-8566, Japan12 Department of Digestive Surgery, Kumamoto University Hospital, 1-1-1, Honjo, Chuo-ku, Kumamoto 860-8556, Japan13 Department of Gastroenterology, Cancer Institute Hospital of JFCR, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan14 Department of Chemotherapy, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan15 Department of Surgery, Nara Medical University Hospital, 840, Shijo-cho, Kashihara, Nara 634-8522, Japan16 Department of Clinical Oncology, Kyoto University Hospital, 54, Kawahara-cho, Shogoin, Sakyo-ku Kyoto 606-8507, Japan17 Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3, Asahimachi, Abeno-ku, Osaka 545-8585, Japan18 Department of Surgery, Kansai Medical University Hirakata Hospital, 2-3-1, Shinmachi, Hirakata, Osaka 573-1191, Japan19 Department of Hepatobiliary-Pancreatic Surgery, Tohoku University Hospital, 1-1, Seiryomachi, Aoba-ku, Sendai, Miyagi 980-8574, Japan20 Department of Gastroenterological Surgery, Yokohama City University Hospital, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan21 Department of Clinical Oncology, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan22 Department of Digestive Surgery, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo 105-8470, Japan23 Department of Surgery, Iwate Medical University Hospital, 19-1, Uchimaru, Morioka, Iwate 020-8505, Japan24 Department of Internal Medicine, Tokyo Metropolitan Matsuzawa Hospital, 2-1-1, Kamikitazawa, Setagaya-ku, Tokyo 156-0057, Japan25 Department of Gastroenterological Oncology, Hyogo Cancer Center, 13-70, Kitaoji-cho, Akashi, Hyogo, 673-8558, Japan26 Department of Surgery, Kobe City Medical Center General Hospital, 2-1-1, Minatojimanakamachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan27 Department of Management Science, Tokyo University of Science, 1-3, Kagurazaka, Shinjuku-ku, Tokyo, 162-8601, Japan28 Department of Gastroenterology, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8577, Japan* E-mail: s-ohk@kcch.jp28 04 2015 16 04 2015 28 4 2015 112 9 1428 1434 09 12 2014 07 02 2015 23 02 2015 Copyright © 2015 Cancer Research UK2015Cancer Research UKThis work is licensed under the Creative Commons Attribution-Non-Commercial-Share Alike 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/Background:\nThis randomised, open-label, multicenter phase II study compared progression-free survival (PFS) of S-1 plus oxaliplatin (SOX) with that of S-1 alone in patients with gemcitabine-refractory pancreatic cancer.\n\nMethods:\nPatients with confirmed progressive disease following the first-line treatment with a gemcitabine-based regimen were randomised to receive either S-1 (80/100/120 mg day−1 based on body surface area (BSA), orally, days 1–28, every 6 weeks) or SOX (S-1 80/100/120 mg day−1 based on BSA, orally, days 1–14, plus oxaliplatin 100 mg m−2, intravenously, day 1, every 3 weeks). The primary end point was PFS.\n\nResults:\nBetween January 2009 and July 2010, 271 patients were randomly allocated to either S-1 (n=135) or SOX (n=136). Median PFS for S-1 and SOX were 2.8 and 3.0 months, respectively (hazard ratio (HR)=0.84; 95% confidence interval (CI), 0.65–1.08; stratified log-rank test P=0.18). Median overall survival (OS) was 6.9 vs 7.4 months (HR=1.03; 95% CI, 0.79–1.34; stratified log-rank test P=0.82). The response rate (RR) was 11.5% vs 20.9% (P=0.04). The major grade 3/4 toxicities (S-1 and SOX) were neutropenia (11.4% and 8.1%), thrombocytopenia (4.5% and 10.3%) and anorexia (12.9% and 14.7%).\n\nConclusions:\nAlthough SOX showed an advantage in RR, it provided no significant improvement in PFS or OS compared with S-1 alone.\n\nchemotherapyoxaliplatinpancreatic cancerS-1SOX\n==== Body\nPancreatic cancer is associated with an extremely poor prognosis and the eighth leading cause of cancer-related deaths worldwide (Jemal et al, 2011).\n\nGemcitabine (GEM) has been the standard first-line therapy in patients with advanced pancreatic cancer for a long time. In order to improve the prognosis of such patients, there is an urgent need to establish an effective second-line therapy. Although various second-line therapies have been studied, any phase III data do not support a particular regimen (Petrelli et al, 2010). In Japan, S-1 is commonly used for the treatment of pancreatic cancer patients who failed GEM-based treatment. In the phase II study of S-1 for pancreatic cancer resistant to GEM, the median progression-free survival (PFS) and overall survival (OS) were only 2.0 months and 4.5 months, respectively (Morizane et al, 2009). More effective regimens had been eagerly awaited.\n\nIn 2008, the addition of oxaliplatin to 5-FU and leucovorin (5-FU/LV (OFF)) was reported to show significant improvements in OS and PFS in a second-line setting in the CONKO 003 trial (Oettle et al, 2014). The good efficacy of oxaliplatin plus S-1 (SOX) had been previously demonstrated in colorectal and gastric cancer (Yamada et al, 2008; Koizumi et al, 2010), and was, therefore, expected to provide similar efficacy to the OFF treatment. Here, we conducted a randomised phase II trial to evaluate the efficacy and safety of SOX compared with S-1 alone in patients with GEM-refractory pancreatic cancer as a second-line setting.\n\nMaterials and methods\nPatients\nThe inclusion criteria were as follows: refractory to GEM, histologically or cytologically confirmed pancreatic adenocarcinoma or adenosquamous carcinoma, a measurable metastatic lesion based on Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.0, age of ⩾20 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1, adequate bone marrow function (haemoglobin level of ⩾9.0 g dl−1, white blood cell count of ⩽12 000 per mm3, neutrophil count of ⩾1500 per mm3, and platelet count of ⩾100 000 per mm3), adequate liver function (total bilirubin ⩽2.0 mg dl−1, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ⩽150 IU l−1), and adequate renal function (serum creatinine (CRE) level of ⩽1.2 mg dl−1). GEM-refractory was defined as follows: (i) patients who developed progression confirmed by the image in the first-line therapy including GEM or (ii) patients who relapsed during the GEM-adjuvant treatment or within 24 weeks after the last GEM administration.\n\nPatients were excluded if they had received previous chemotherapy containing platinum or fluoropyrimidine drugs, previous radiotherapy except for intraoperative radiation therapy, or either blood transfusion, blood products, or hematopoietic growth factor preparations such as granulocyte-colony stimulating factor within 14 days prior to enrolment; if they were receiving treatment with phenytoin, potassium warfarin, or flucytosine at the time of the study; or if they had grade 2 or higher peripheral sensory neuropathy, more than moderate coelomic fluid (pleural effusion, ascites, or pericardial fluid), watery stools, a synchronous cancer with the exception of an early stage tumour (stage I), poorly controlled diabetes, or other serious concomitant diseases.\n\nThis study was conducted in accordance with the Declaration of Helsinki principals and Good Clinical Practice (GCP) guidelines. The protocol was approved by the ethics committees of all participating institutions and informed consent was obtained from all patients before their enrolment into the study.\n\nThe study is registered with JAPIC Clinical Trial Information (Japic CTI-090685).\n\nStudy design\nThis multicenter, randomised, open-label phase II trial was conducted at 24 centres. Patients were randomly allocated to receive either treatment with SOX or S-1 alone. Randomisation was performed centrally in a 1 : 1 ratio with stratification according to center, PS (0 or 1), and duration of previous GEM treatment (<90 days, 90 to <180 days, or ⩾180 days) using the minimisation method (Pocock and Simon, 1975) independently processed by the Contract Research Organization (AC Medical). The study treatments were started within 8 days from the randomisation and within 29 days from disease progression of the first-line GEM treatment. An Independent Data Monitoring Committee (IDMC) supervised the assessment of efficacy and safety.\n\nThe primary end point was PFS and secondary end points were OS, time-to-treatment failure (TTF), response rate (RR), disease control rate (DCR), and safety.\n\nTreatments\nPatients allocated to the S-1 arm received S-1 orally twice daily at a dose according to the body surface area (<1.25 m2, 80 mg day−1; 1.25 m2 to 1.5 m2, 100 mg day−1; ⩾1.5 m2, 120 mg day−1) on days 1–28 of every 6-week period. Patients allocated to the SOX arm received oxaliplatin at a dose of 100 mg m−2 as a 2-hour intravenous infusion on day 1 plus S-1 at the same daily-dose of the S-1 alone arm on days 1–14 of every 3-week period. The treatment was continued until disease progression, unacceptable toxicity, or patient refusal.\n\nIn both treatment arms, chemotherapy was delayed until recovery from toxicities (neutrophil count of <1500 per mm3, platelet count of <75 000 per mm3, AST or ALT >150 IU l−1, CRE >1.2 mg dl−1, grade 2 or higher diarrhoea or stomatitis, fever suspicious of infection, and grade 3 or higher peripheral sensory neuropathy (only for the SOX arm)). During the administration of S-1, patients who developed neutrophil count of <1000 per mm3, platelet count of <50 000 per mm3, CRE >1.5 mg dl−1, grade 2 or higher diarrhoea or stomatitis, grade 3 rash, or fever suspicious of infection had to withdraw S-1 until they recovered from the toxicities. The doses of oxaliplatin and S-1 could be reduced by 25 mg m−2 and 10–30 mg day−1, respectively, up to two times, but the treatment was discontinued if subsequent reduction was required. In both arms, the dose of each drug was reduced by one level if grade 4 neutropenia, febrile neutropenia, grade 4 thrombocytopenia, thrombocytopenia requiring platelet transfusion, or grade 3 or higher diarrhoea or stomatitis occurred. In the SOX arm, if grade 2, 3, or 4 sensory neuropathy occurred and did not recover before the next administration, oxaliplatin was reduced by one dose level, skipped, or discontinued.\n\nAssessments\nComplete blood counts, blood chemical tests, and physical examinations were performed at least once a week for 12 weeks, and every 3 weeks thereafter. Computed tomography scans were performed and tumour markers (CEA and CA19-9) were measured every 4 weeks. Tumour responses were extramurally reviewed by Independent Review Committee in accordance with the RECIST version 1.0 guidelines. Safety was assessed using the Common Terminology Criteria for Adverse Events version 3.0.\n\nStatistical analysis\nThe safety analysis set included the patients who received at least one dose of study drugs and had no major GCP violations. The full analysis set (FAS) included the patients who met the eligibility criteria in the safety analysis set. Efficacy was evaluated in the FAS population. PFS was defined as the time from randomisation to the first event of progressive disease or death because of any cause. If no such event occurred in a patient, data for that patient was censored on the day of the last imaging confirmation. OS was defined as the time from randomisation to death from any cause. In the absence of the event, data was censored on the last day of survival confirmation. TTF was the time from enrolment to the first event of discontinuation of treatment, progressive disease, or death because of any cause.\n\nThis trial was designed to detect an hazard ratio (HR) of 0.667 with an increase in median PFS from 2 to 3 months. In order to detect the assumed differences with a power of 85% and a two-sided 5% type 1 error, a minimum of 220 events were required for primary analysis. Considering patients' dropout, the sample size was set at 240.\n\nRegarding patient background, imbalances among the groups were examined using the χ2 test or Fisher's exact test for categorical variables. The stratified log-rank test was used to assess the differences between groups in PFS and OS. The stratification factors were PS (0 or 1), and duration of previous GEM treatment (<90 days, 90 to <180 days or ⩾180 days). The stratified Cox proportional hazards model was used to estimate HRs and corresponding 95% confidence intervals (CI) for PFS, OS, and TTF. The point estimate of the median PFS, OS, and TTF and the 95% CI were calculated using the Kaplan–Meier method. The exploratory subgroup analysis was performed with stratified Cox proportional hazards model. All analyses were done with SAS (version 9.1.3).\n\nResults\nPatient characteristics\nFrom January 2009 to July 2010, a total of 271 patients from 24 Japanese centres were enroled, and 135 patients were allocated to the S-1 arm and 136 patients allocated to the SOX arm. The cut-off date for analysis was 31 March 2011.\n\nIn the S-1 arm, three patients were excluded from the safety analysis set; two patients did not receive S-1 treatment and one patient received commercial S-1 instead of the provided study drug. Two patients were excluded from the FAS because they were ineligible; one patient was not proven to have adenocarcinoma or adenosquamous carcinoma, and another patient had massive fluid retention. In the SOX arm, two patients were also excluded from the FAS because of the same reasons mentioned above (Figure 1). As a result, a total of 268 patients (S-1 arm: 132 patients, SOX arm: 136 patients) were assessed for safety and 264 patients (S-1 arm: 130 patients, SOX arm: 134 patients) were assessed for efficacy. Both arms were well balanced in patients' characteristics (Table 1). Approximately 70% of patients had PS 0 or liver metastasis in both arms. Patients whose primary tumour was resected accounted for about 20% in both arms.\n\nEfficacy\nThe analysis of PFS was based on 256 events among 264 patients (97.0%) with a median follow-up time of 12.6 months. Median PFS was 2.8 months (95% CI, 1.9–3.5) in the S-1 arm and 3.0 months (95% CI, 2.8–3.7) in the SOX arm (Figure 2), and there was no significant difference between the arms (HR=0.84; 95% CI, 0.65–1.08, stratified log-rank test P=0.18). The analysis of OS was based on 232 deaths among the 264 patients (87.9%). Median OS was 6.9 months (95% CI, 5.8–9.0) in the S-1 arm and 7.4 months (95% CI, 6.2–8.6) in the SOX arm (Figure 3), and there was no significant difference between the arms (HR=1.03, 95% CI, 0.79–1.34, stratified log-rank test P=0.82). The RR was 11.5% (95% CI, 6.6–18.3) in the S-1 arm and 20.9% (95% CI, 14.4–28.8) in the SOX arm (P=0.04). The DCR was 53.8% (95% CI, 44.9–62.6) in the S-1 arm and 60.4% (95% CI, 51.6–68.8) in the SOX arm (P=0.28). With respect to tumour markers, serum CRE levels decreased in 31% of patients in the S-1 arm and in 24% of patients in the SOX arm. Serum CRE 19-9 levels decreased in 54% of patient of the S-1 arm and in 55% of patients in the SOX arm. There was no obvious difference in tumour marker decrease between the S-1 arm and the SOX arm. No clear correlation was also seen between tumour response and tumour maker decrease. After the study treatment, 75 patients in the S-1 arm and 72 patients in the SOX arm received the third-line therapies, and those contents were similar in the two arms.\n\nIn the subgroup analysis, the SOX arm showed longer PFS in patients with age <65 years (HR, 0.68; 95% CI, 0.47–0.99; Figure 4). The SOX arm also showed longer OS in patients with age <65 years (HR, 0.68; 95% CI, 0.46–1.00), whereas the S-1 arm showed longer OS in patients with age >65 years (HR, 1.58; 95% CI, 1.06–2.36) (Figure 5).\n\nSafety\nThe major toxicities are summarised in Table 2. Anorexia, decreased serum sodium, lymphopenia, and neutropenia were the most common events in both arms. The incidence of anaemia, stomatitis, and pigmentation were 10% or higher in the S-1 arm than in the SOX arm. The incidence of thrombocytopenia, peripheral sensory neuropathy, anorexia and vomiting were 10% or higher in the SOX arm than in the S-1 arm. There was no difference between the arms in grade 3 or worse adverse events. One treatment-related death owing to bacterial peritonitis was observed in the SOX arm.\n\nTreatment\nThe median treatment duration was 73 days (range 4–840 days) in the S-1 arm and 78 days (range 3–455 days) in the SOX arm. The major reasons for discontinuation of the treatment were disease progression (S-1 arm: 113 patients, SOX arm: 96 patients), adverse events (S-1 arm: 14 patients, SOX arm: 22 patients), and consent withdrawal (S-1 arm: 1 patient, SOX arm: 10 patients). As for the treatment discontinuation relating to adverse events, neutropenia, and thrombocytopenia were more frequently seen in the SOX arm than the S-1 arm. The major causes for consent withdrawal in the SOX arm were non-haematological toxicities such as fatigue and vomiting. There was no patient who withdrew consent owing to neurotoxicity. The median relative dose intensity (RDI) and the median total dose of S-1 were 89.7% and 6000 mg m−2 in the S-1 arm and 84.3% and 5010 mg m−2 in the SOX arm, respectively. The median RDI of oxaliplatin was 95.4% and the median total dose was 400 mg m−2 in the SOX arm.\n\nDose reduction of S-1 was observed in 16 patients (12.1%) in the S-1 arm and 24 patients (17.6%) in the SOX arm. Dose reduction of oxaliplatin was observed in 28 patients (20.6%). Dose reduction of both drugs was observed in 14 patients (10.3%). Postponement of drug administration was observed in 58 patients (43.9%) in the S-1 arm and 76 patients (55.9%) in the SOX arm. Dose interruption of S-1 was observed in 59 patients (44.7%) in the S-1 arm and 38 patients (27.9%) in the SOX arm.\n\nDiscussion\nThis phase II study could not demonstrate the relevant benefit by adding oxaliplatin to S-1 in PFS and OS, although some increased response was gained. In the first-line therapy, GEM alone treatment is considered for the majority of patients. Recently, two regimens, FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin combination) and GEM plus nab-paclitaxel, have become the new standard options for advanced pancreatic cancer (Conroy et al, 2011; Von Hoff et al, 2013). Fluoropyrimidine-based regimens could be used as the second-line chemotherapy in patients who failed in GEM alone or GEM plus nab-paclitaxel treatment, although their benefit has not been proven yet (Boeck et al, 2007; Gebbia et al, 2007; Kulke et al, 2007; Xiong et al, 2008; Morizane et al, 2009; Novarino et al, 2009). In the second line setting for pancreatic cancer, patients with poor PS were enroled in some studies (Gebbia et al, 2007; Xiong et al, 2008). However, we are not sure if SOX therapy fits such patients because only patients with good PS were enroled in this study.\n\nIn this trial, the primary end point was PFS, and we assessed response every 4 weeks to detect small difference between the two arms (expected median PFS; S-1 2.0 months vs SOX 3.0 months). However, the primary end point was not met owing to unexpectedly good PFS in the S-1 arm. The subgroup analysis showed that SOX improved both OS and PFS in the group of patients <65 years. In the SOX arm, the RDI of S-1 was 87.6% for the group of patients <65 years and 79.0% for the group ⩾65 years. One possible explanation is that anorexia or fatigue requiring a dose reduction of S-1 was more frequently observed in the group of aged ⩾65 years than that of aged <65 years. The SOX regimen might be an effective therapy for particularly non-elderly patients with GEM-refractory pancreatic cancer.\n\nMany trials with 5-fluorouracil and platinum combination have been reported in the second-line treatment for advanced pancreatic cancer. Recently, a comprehensive analysis of published 12 trials data (n=450) for that combination was performed (Rahma et al, 2013). It provided a median PFS of 2.9 months and OS of 5.7 months for the combination of 5-fluorouracil and platinum agents. These are similar to those reported in the OFF arm of CONKO-003 trial (median PFS 2.9 month and median OS 5.9 months) and in the SOX arm of our study (median PFS 3.0 month and median OS 7.4 months). There was no big difference between the median total dose of oxaliplatin reported in the OFF arm (340 mg m−2) and that obtained in the SOX arm of this study (400 mg m−2). Although cross-trial comparison should be carefully interpreted because of the different inclusion/exclusion criteria, different drugs (oral and intravenous), and schedules, these data indicate that the benefit by this kind of combination was limited.\n\nToxicities were generally mild-to-moderate in both arms, and similar to those reported in the previous trials using 5-fluorouracil and oxaliplatin. Grade 3 peripheral sensory neuropathy, the most critical toxicity of oxaliplatin, was low (2.9%). In the treatment for metastatic colorectal cancer, oxaliplatin-induced grade 3 neuropathy was reported to occur in around 30% of the patients treated with cumulative doses of oxaliplatin ranging from 765 mg m−2 to 1020 mg m−2 (Kalofonos et al, 2005; Van Cutsem et al, 2006; Argyriou et al, 2007; Land et al, 2007; Otsu et al, 2014). In this trial, the median cumulative dose of oxaliplatin was 400 mg m−2, and the less cumulative dose of oxaliplatin would lead to less frequency of grade 3 neuropathy.\n\nIn conclusion, SOX showed no significant improvement in PFS and OS as compared with S-1 in the second-line chemotherapy for patients with GEM-refractory pancreatic cancer.\n\nThis study was supported by Yakult Honsha Co., Ltd. We thank all patients, clinicians, and support staff who participated in this study. We are grateful to Yuh Sakata, Fumitaka Nagamura, and Satoshi Morita for their helpful advice as members of the IDMC, and Atsushi Sato, Kunihisa Miyakawa and Kouki Yoshikawa as members of the Independent Review Committee. We also thank Yuki Tanaka for his helpful advice.\n\nHiroyuki Isayama received honoraria from Yakult Honsha Co., Ltd. and Taiho Pharmaceutical; Chikuma Hamada has received consulting fees from Yakult Honsha Co., Ltd.. The remaining authors declare no conflict of interest.\n\nFigure 1 CONSORT diagram.\n\nFigure 2 Kaplan–Meier estimates of progression-free survival (PFS). The median PFS was 2.8 months (95% CI, 1.9–3.5) in the S-1 arm and 3.0 months (95% CI, 2.8–3.7) in the SOX arm.\n\nFigure 3 Kaplan–Meier estimates of overall survival (OS). The median OS was 6.9 months (95% CI, 5.8–9.0) in the S-1 arm and 7.4 months (95% CI, 6.2–8.6) in the SOX arm.\n\nFigure 4 Subgroup analyses of progression-free survival. *Some patients had overlapped locations.\n\nFigure 5 Subgroup analyses of overall survival. *Some patients had overlapped locations.\n\nTable 1 Patient characteristics\n \tS-1\nn=130 (%)\tSOX\nn=134 (%)\t\nSex\t\nMale\t80 (61.5)\t82 (61.2)\t\nFemale\t50 (38.5)\t52 (38.8)\t\nAge (years)\t\nMedian\t63.5\t65\t\nRange\t43–80\t27–83\t\n<65\t73 (56.2)\t66 (49.3)\t\n⩾65\t57 (43.8)\t68 (50.7)\t\nECOG performance status\t\n0\t92 (70.8)\t93 (69.4)\t\n1\t38 (29.2)\t41 (30.6)\t\nTreatment duration of 1st-line GEM\t\n<90 days\t43 (33.1)\t46 (34.3)\t\n⩾90 to <180 days\t50 (38.5)\t52 (38.8)\t\n⩾180 days\t37 (28.5)\t36 (26.9)\t\nBody surface area\t\n<1.25\t6 (4.6)\t8 (6.0)\t\n⩾1.25 to <1.5\t51 (39.2)\t53 (39.4)\t\n⩾1.5\t73 (56.2)\t74 (54.5)\t\nDiagnosis\t\nAdenocarcinoma\t128 (98.5)\t132 (98.5)\t\nAdenosquamous carcinoma\t2 (1.5)\t2 (1.5)\t\nPancreatic tumour locationa\t\nHead\t34 (26.2)\t38 (28.4)\t\nBody\t41 (31.5)\t40 (29.9)\t\nTail\t30 (23.1)\t27 (20.1)\t\nNone\t38 (29.2)\t38 (28.4)\t\nMetastatic sitesa\t\nLiver\t86 (66.2)\t98 (73.1)\t\nLung\t32 (24.6)\t37 (27.6)\t\nLymph node\t67 (51.5)\t64 (47.8)\t\nPeripheral\t18 (13.8)\t23 (17.2)\t\nBone\t3 (2.3)\t3 (2.2)\t\nOther\t7 (5.4)\t3 (2.2)\t\nFluid retension (ascites, pleural effusion)\t\nNo\t84 (64.6)\t82 (61.2)\t\nYes\t46 (35.4)\t52 (38.8)\t\nAdjuvant chemotherapy\t\nNo\t102 (78.5)\t108 (80.6)\t\nYes\t28 (21.5)\t26 (19.4)\t\nAbbreviations: ECOG=eastern cooperative oncology group; GEM=gemcitabine; SOX=S-1 plus oxaliplatin.\n\na Some patients had overlapped locations.\n\nTable 2 Toxicities\n \tS-1 (n=132)\tSOX (n=136)\t\n \tAll grades (%)\t⩾Grade 3 (%)\tAll grades (%)\t⩾Grade 3 (%)\t\nHaematological toxicities\t\nThrombocytopenia\t76 (57.6)\t6 (4.5)\t102 (75.0)\t14 (10.3)\t\nLeucopenia\t59 (44.7)\t3 (2.3)\t61 (44.9)\t6 (4.4)\t\nLymphopenia\t63 (47.7)\t29 (22.0)\t59 (43.4)\t23 (16.9)\t\nAnaemia\t78 (59.1)\t18 (13.6)\t58 (42.6)\t11 (8.1)\t\nNeutropenia\t45 (34.1)\t15 (11.4)\t55 (40.4)\t11 (8.1)\t\nNon-haematological toxicities\t\nPeripheral sensory neuropathy\t6 (4.5)\t1 (0.8)\t103 (75.7)\t4 (2.9)\t\nAnorexia\t78 (59.1)\t17 (12.9)\t94 (69.1)\t20 (14.7)\t\nAlbumin decreased\t77 (58.3)\t7 (5.3)\t86 (63.2)\t9 (6.6)\t\nAST increased\t70 (53.0)\t6 (4.5)\t83 (61.0)\t9 (6.6)\t\nNausea\t71 (53.8)\t4 (3.0)\t80 (58.8)\t9 (6.6)\t\nWeight decreased\t70 (53.0)\t4 (3.0)\t71 (52.2)\t6 (4.4)\t\nBilirubin increased\t58 (43.9)\t10 (7.6)\t65 (47.8)\t16 (11.8)\t\nHyponatremia\t58 (43.9)\t21 (15.9)\t65 (47.8)\t19 (14.0)\t\nDiarrhoea\t68 (51.5)\t8 (6.1)\t64 (47.1)\t7 (5.1)\t\nALT increased\t55 (41.7)\t6 (4.5)\t63 (46.3)\t4 (2.9)\t\nVomiting\t45 (34.1)\t1 (0.8)\t60 (44.1)\t4 (2.9)\t\nALP increased\t53 (40.2)\t7 (5.3)\t58 (42.6)\t8 (5.9)\t\nFatigue\t42 (31.8)\t5 (3.8)\t46 (33.8)\t4 (2.9)\t\nPigmentation\t62 (47.0)\t0 (0)\t40 (29.4)\t0 (0)\t\nFever\t41 (31.1)\t3 (2.3)\t39 (28.7)\t0 (0)\t\nHyperkalemia\t45 (34.1)\t2 (1.5)\t39 (28.7)\t3 (2.2)\t\nStomatitis\t53 (40.2)\t3 (2.3)\t36 (26.5)\t2 (1.5)\t\nDeep vein thrombosis\t1 (0.8)\t0 (0)\t0 (0)\t0 (0)\t\nAbbreviations: ALT=alanine aminotransferase; ALP=alkaline phosphatase; AST=aspartate aminotransferase; SOX=S-1 plus oxaliplatin.\n==== Refs\nArgyriou AA Polychronopoulos P Iconomou G Koutras A Makatsoris T Gerolymos MK Gourzis P Assimakopoulos K Kalofonos HP Chroni E 2007 Incidence and characteristics of peripheral neuropathy during oxaliplatin-based chemotherapy for metastatic colon cancer Acta Oncol 46 1131 1137 17851880 \nBoeck S Wilkowski R Bruns CJ Issels RD Schulz C Moosmann N Laessig D Haas M Golf A Heinemann V 2007 Oral capecitabine in gemcitabine-pretreated patients with advanced pancreatic cancer Oncology 73 221 227 18424886 \nConroy T Desseigne F Ychou M Bouche O Guimbaud R Becouarn Y Adenis A Raoul J-L Gourgou-Bourgade S Fouchardiere C Bennouna J Bachet J-B Khemissa-Akouz F Pere-Verge D Delbaldo C Assenat E Chauffert B Michel P Montoto-Grillot C Chem M Ducreux M 2011 FOLFIRINOX versus gemcitabine for metastatic pancreas cancer N Engl J Med 364 1817 1825 21561347 \nGebbia V Maiello E Giuliani F Borsellino N Caruso M Di Maggio G Ferraù F Bordonaro R Verderame F Tralongo P Di Cristina L Agueli R Russo P Colucci G 2007 Second-line chemotherapy in advanced pancreatic carcinoma: a multicenter survey of the Gruppo Oncologico Italia Meridionale on the activity and safety of the FOLFOX4 regimen in clinical practice Ann Oncol 6 vi124 vi127 17591805 \nJemal A Bray F Center MM Ferlay J Ward E Forman D 2011 Global cancer statistics CA Cancer J Clin 61 69 90 21296855 \nKalofonos HP Aravantinos G Kosmidis P Papakostas P Economopoulos T Dimopoulos M Skarlos D Bamias A Pectasides D Chalkidou S Karina M Koutras A Samantas E Bacoyiannis C Samelis GF Basdanis G Kalfarentzos F Fountzilas G 2005 Irinotecan or oxaliplatin combined with leucovorin and 5-fluorouracil as first-line treatment in advanced colorectal cancer: a multicenter, randomized, phase II study Ann Oncol 16 869 877 15855226 \nKoizumi W Takiuchi H Yamada Y Boku N Fuse N Muro K Komatsu Y Tsuburaya A 2010 Phase II study of oxaliplatin plus S-1 as first-line treatment for advanced gastric cancer (G-SOX study) Ann Oncol 21 1001 1005 19875759 \nKulke MH Blaszkowsky LS Ryan DP Clark JW Meyerhardt JA Zhu AX Enzinger PC Kwak EL Muzikansky A Lawrence C Fuchs CS 2007 Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer J Clin Oncol 25 4787 4792 17947726 \nLand SR Kopec JA Cecchini RS Ganz PA Wieand HS Colangelo LH Murphy K Kuebler JP Seay TE Needles BM Bearden JD 3rdColman LK Lanier KS Pajon ER JrCella D Smith RE O'Connell MJ Costantino JP Wolmark N 2007 Neurotoxicity from oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: NSABP C-07 J Clin Oncol 25 2205 2211 17470850 \nMorizane C Okusaka T Furuse J Ishii H Ueno H Ikeda M Nakachi K Najima M Ogura T Suzuki E 2009 A phase II study of S-1 in gemcitabine-refractory metastatic pancreatic cancer Cancer Chemother Pharmacol 63 313 319 18398614 \nNovarino A Satolli MA Chiappino I Giacobino A Bellone G Rahimi F Milanesi E Bertetto O Ciuffreda L 2009 Oxaliplatin, 5-fluorouracil, and leucovorin as second-line treatment for advanced pancreatic cancer Am J Clin Oncol 32 44 48 19194124 \nOettle H Riess H Stieler JM Heil G Schwaner I Seraphin J Görner M Mölle M Greten TF Lakner V Bischoff S Sinn M Dörken B Pelzer U 2014 Second-line oxaliplatin, folnic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from CONKO-003 trial J Clin Oncol 32 2423 2429 24982456 \nOtsu S Hirashima Y Nishikawa K Sakashita H Morinaga R Watanabe K Shirao K 2014 Neurological toxicity in metastatic colorectal cancer patients treated with modified FOLFOX6 plus bevacizumab Jpn Clin Med 5 19 23 25210489 \nPetrelli F Borgonovo K Ghilardi M Cabiddu M Barni S 2010 What else in gemcitabine-pretreated advanced pancreatic cancer? An update of second line therapies Rev Recent Clin Trials 5 43 56 20205687 \nPocock SJ Simon R 1975 Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial Biometrics 31 103 115 1100130 \nRahma OE Duffy A Liewehr DJ Steinberg SM Greten TF 2013 Second-line treatment in advanced pancreatic cancer: a comprehensive analysis of published clinical trials Ann Oncol 24 1972 1979 23670093 \nVan Cutsem E Nordlinger B Adam R Köhne CH Pozzo C Poston G Ychou M Rougier P 2006 Towards a pan-European consensus on the treatment of patients with colorectal liver metastases Eur J Cancer 42 2212 2221 16904315 \nVon Hoff DD Ervin T Arena FP Chiorean EG Infante J Moore M Seay T Tjulandin SA Ma WW Saleh MN Harris M Reni M Dowden S Laheru D Bahary N Ramanathan RK Tabernero J Hidalgo M Goldstein D Cutsem EV Wei X Iglesias J Renschler MF 2013 Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine N Engl J Med 369 1691 1703 24131140 \nXiong HQ Varadhachary GR Blais JC Hess KR Abbruzzese JL Wolff RA 2008 Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer Cancer 113 2046 2052 18756532 \nYamada Y Tahara M Miya T Satoh T Shirao K Shimada Y Ohtsu A Sasaki Y Tanigawara Y 2008 Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer Br J Cancer 98 1034 1038 18319719\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0007-0920",
"issue": "112(9)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D018196:Carcinoma, Adenosquamous; D003841:Deoxycytidine; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010094:Oxonic Acid; D010190:Pancreatic Neoplasms; D011379:Prognosis; D015996:Survival Rate; D005641:Tegafur",
"nlm_unique_id": "0370635",
"other_id": null,
"pages": "1428-34",
"pmc": null,
"pmid": "25880004",
"pubdate": "2015-04-28",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "19875759;19194124;16904315;21561347;24131140;25210489;17851880;17947726;15855226;24982456;18424886;18756532;17470850;18398614;20205687;18319719;1100130;23670093;21296855;17591805",
"title": "Randomised phase II trial of S-1 plus oxaliplatin vs S-1 in patients with gemcitabine-refractory pancreatic cancer.",
"title_normalized": "randomised phase ii trial of s 1 plus oxaliplatin vs s 1 in patients with gemcitabine refractory pancreatic cancer"
} | [
{
"companynumb": "JP-CIPLA LTD.-2015JP03340",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"d... |
{
"abstract": "Intravascular papillary endothelial hyperplasia (IPEH), commonly known as Masson's tumor, is a benign lesion that manifests as an excessive proliferation of endothelial cells within a vessel wall. IPEH is extremely rare in the brain, with only 36 intracranial cases previously described in the literature. It is commonly mistaken for more malignant pathologies, such as angiosarcoma. Careful histopathological examination is required for diagnosis, as no clinical or radiographic features are characteristic of this lesion. In this first published case of intracranial IPEH presenting during pregnancy, the authors describe a 32-year-old female with a left frontal intraparenchymal hemorrhage resulting in complete expressive aphasia at 28 weeks 6 days' gestation. An MRI scan obtained at a local hospital demonstrated an area of enhancement within the hemorrhage. The patient underwent a left frontoparietal craniotomy for hematoma evacuation and gross-total resection (GTR) of an underlying hemorrhagic mass at 29 weeks' gestation. This case illustrates the importance of multidisciplinary patient care and the feasibility of intervention in the early third trimester with subsequent term delivery. While GTR of IPEH is typically curative, the decision to proceed with surgical treatment of any intracranial lesion in pregnancy must balance maternal stability, gestational age, and suspected pathology.",
"affiliations": "Departments of1Neurosurgery.;2Obstetrics and Gynecology.;Departments of1Neurosurgery.;3Pathology, and.;4Radiology, Duke University Medical Center, Durham, North Carolina.;2Obstetrics and Gynecology.;2Obstetrics and Gynecology.;Departments of1Neurosurgery.",
"authors": "Sankey|Eric W|EW|;Hynes|Jenna S|JS|;Komisarow|Jordan M|JM|;Maule|Jake|J|;Griffin|Andrew S|AS|;Dotters-Katz|Sarah K|SK|;Mitchell|Courtney J|CJ|;Friedman|Allan H|AH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3085",
"issue": null,
"journal": "Journal of neurosurgery",
"keywords": "GTR = gross-total resection; IPEH; IPEH = intravascular papillary endothelial hyperplasia; Masson’s tumor; STR = subtotal resection; intraparenchymal hemorrhage; intravascular papillary endothelial hyperplasia; neurooncology; oncology; pregnancy; β-hCG = beta–human chorionic gonadotropin",
"medline_ta": "J Neurosurg",
"mesh_terms": null,
"nlm_unique_id": "0253357",
"other_id": null,
"pages": "1-8",
"pmc": null,
"pmid": "31675720",
"pubdate": "2019-11-01",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Masson's tumor presenting as a left frontal intraparenchymal hemorrhage resulting in severe expressive aphasia during pregnancy: case report.",
"title_normalized": "masson s tumor presenting as a left frontal intraparenchymal hemorrhage resulting in severe expressive aphasia during pregnancy case report"
} | [
{
"companynumb": "US-ORGANON-O2103USA002403",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "Chemotherapy-induced peripheral neuropathy (CIPN) frequently occurs in lymphoma patients receiving R-CHOP, a drug combination therapy. Although severe CIPN may lead to reduction and/or discontinuation of the medication, predictive factors of CIPN have not been investigated sufficiently to date. We performed a retrospective exploratory research to determine associations between prevalence of severe CIPN and sociodemographic data, health characteristics, and medical conditions such as anemia at initial diagnosis. Forty patients (indolent lymphoma, n = 9; diffuse large B-cell lymphoma; n = 31) received R-CHOP therapy from September 2009 to July 2014. The median age of patients was 58 years (range = 27-76 years). Statistical analyses were applied to the patients, who were divided into two groups: mild CIPN (no symptoms or grade 1 according to the CTCAE version 3.0 program) and severe CIPN patients (grade 2 or higher). Forward stepwise logistic regression analyses were performed using the following variables: sex, BMI, BSA, hyperglycemia, malnutrition, and anemia. Severe CIPN occurred in seven patients (17.5%). Gender and anemia remained following the stepwise procedure, and anemia predicted severe CIPN significantly (OR = 19.45, 95% confidence interval = 1.52-171.12). Our study suggests that anemia at initial diagnosis could be a predictive factor of R-CHOP-induced CIPN.",
"affiliations": "Department of Community Health Sciences, Kobe University Graduate School of Health Sciences, Kobe, Japan.;Department of Medical Oncology and Hematology, Kakogawa Central City Hospital, Kakogawa, Japan.;Division of Rehabilitation Medicine, Kobe University Hospital, Kobe, Japan.;Division of Rehabilitation Medicine, Kobe University Hospital, Kobe, Japan.;Division of Nursing, Kobe University Hospital, Kobe, Japan.;Division of Medical Oncology and Hematology, Kobe University, Kobe, Japan.;Division of Medical Oncology and Hematology, Kobe University, Kobe, Japan.;Division of Rehabilitation Medicine, Kobe University Hospital, Kobe, Japan.;Department of Community Health Sciences, Kobe University Graduate School of Health Sciences, Kobe, Japan.",
"authors": "Saito|Takashi|T|;Okamura|Atsuo|A|;Inoue|Junichiro|J|;Makiura|Daisuke|D|;Doi|Hisayo|H|;Yakushijin|Kimikazu|K|;Matsuoka|Hiroshi|H|;Sakai|Yoshitada|Y|;Ono|Rei|R|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D015415:Biomarkers; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.3727/096504018X15267574931782",
"fulltext": "\n==== Front\nOncol Res\nOncol Res\nOR\nOncology Research\n0965-0407 1555-3906 Cognizant Communication Corporation Elmsford, NY \n\n30126466\nOR1323\n10.3727/096504018X15267574931782\nArticle\nAnemia Is a Novel Predictive Factor for the Onset of Severe Chemotherapy-Induced Peripheral Neuropathy in Lymphoma Patients Receiving Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone Therapy\nANEMIA IS NOVEL PREDICTIVE FACTOR FOR SEVERE CIPNSAITO ET AL.Saito Takashi *† Okamura Atsuo ‡ Inoue Junichiro † Makiura Daisuke † Doi Hisayo § Yakushijin Kimikazu ¶ Matsuoka Hiroshi ¶ Sakai Yoshitada †# Ono Rei * *Department of Community Health Sciences, Kobe University Graduate School of Health Sciences, Kobe, Japan\n\n†Division of Rehabilitation Medicine, Kobe University Hospital, Kobe, Japan\n\n‡Department of Medical Oncology and Hematology, Kakogawa Central City Hospital, Kakogawa, Japan\n\n§Division of Nursing, Kobe University Hospital, Kobe, Japan\n\n¶Division of Medical Oncology and Hematology, Kobe University, Kobe, Japan\n\n#Division of Rehabilitation Medicine, Kobe University Graduate School of Medicine, Kobe, Japan\n\nAddress correspondence to Rei Ono, Department of Community Health Sciences, Kobe University Graduate School of Health Sciences, 7-10-2, Tomogaoka, Suma-ku, Kobe, Hyogo 654-0142, Japan. Tel: +81-78-792-2555; Fax: +81-78-796-4509; E-mail: ono@phoenix.kobe-u.ac.jp\n2019 \n29 3 2019 \n27 4 469 474\nCopyright © 2019 Cognizant, LLC.2019This article is licensed under a Creative Commons Attribution-NonCommercial NoDerivatives 4.0 International License.Chemotherapy-induced peripheral neuropathy (CIPN) frequently occurs in lymphoma patients receiving R-CHOP, a drug combination therapy. Although severe CIPN may lead to reduction and/or discontinuation of the medication, predictive factors of CIPN have not been investigated sufficiently to date. We performed a retrospective exploratory research to determine associations between prevalence of severe CIPN and sociodemographic data, health characteristics, and medical conditions such as anemia at initial diagnosis. Forty patients (indolent lymphoma, n = 9; diffuse large B-cell lymphoma; n = 31) received R-CHOP therapy from September 2009 to July 2014. The median age of patients was 58 years (range = 27–76 years). Statistical analyses were applied to the patients, who were divided into two groups: mild CIPN (no symptoms or grade 1 according to the CTCAE version 3.0 program) and severe CIPN patients (grade 2 or higher). Forward stepwise logistic regression analyses were performed using the following variables: sex, BMI, BSA, hyperglycemia, malnutrition, and anemia. Severe CIPN occurred in seven patients (17.5%). Gender and anemia remained following the stepwise procedure, and anemia predicted severe CIPN significantly (OR = 19.45, 95% confidence interval = 1.52–171.12). Our study suggests that anemia at initial diagnosis could be a predictive factor of R-CHOP-induced CIPN.\n\nKey words\nChemotherapy-induced peripheral neuropathy (CIPN)AnemiaR-CHOPDiffuse large B-cell lymphoma (DLBCL)\n==== Body\nINTRODUCTION\nRituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) is the standard chemotherapy for diffuse large B-cell lymphoma (DLBCL), and this combination drug therapy is also frequently used for indolent lymphoma (IL)1,2. However, R-CHOP therapy induces some significant adverse events such as nausea, alopecia, myelosuppression, and neurological toxicity1. In particular, neurological toxicity, called chemotherapy-induced peripheral neuropathy (CIPN), occurs as an adverse reaction by vincristine (VCR) in approximately 50% of DLBCL patients receiving R-CHOP1. Furthermore, grade 3 CIPN prevents further administration of VCR3. Severe CIPN also affects gait and activities of daily living (ADL) and is followed by worsening performance status (PS). Once severe CIPN occurs, causative medication should be reduced and/or discontinued4. Therefore, these patients cannot obtain further therapeutic benefit from the chemotherapy.\n\nAlthough many studies cover prevention of CIPN and its treatment, predictive factors of severe CIPN have not been sufficiently documented5. To develop treatment and prevention strategies for CIPN so as to continue chemotherapy, we must first accumulate evidence of predictive factors of severe CIPN.\n\nIn the present study, we aimed to identify predictive factors of severe CIPN resulting from R-CHOP treatment. At initial diagnosis, we investigated associations between severe CIPN and sociodemographic data, health characteristics, and medical conditions. Hyperglycemia, renal dysfunction, hepatic dysfunction, anemia, malnutrition, and electrolyte abnormality (defined as “poor medical conditions”) have been reported to be predictive factors of peripheral neuropathy or could influence nerve regeneration and neural transmission6–10. We hypothesize that these preexisting medical conditions contribute to R-CHOP-induced CIPN and hence their presence could predict the onset of severe CIPN.\n\nMATERIALS AND METHODS\nPatients and Study Design\nForty patients, who were diagnosed with DLBCL or IL and received R-CHOP as first-line chemotherapy in Kobe University Hospital from September 2009 to July 2014, were included in this retrospective cohort study. Patients who received other chemotherapy regimens and received blood transfusions were excluded. To find predictive factors of severe CIPN, we evaluated medical conditions such as hyperglycemia, renal dysfunction, hepatic dysfunction, malnutrition, anemia, and electrolyte abnormality using laboratory data at initial diagnosis. This study was approved by the ethics committee of Kobe University Graduate School of Health Sciences. For this type of study, formal consent is not required.\n\nData Collection\nAll data were collected from patient medical records at Kobe University Hospital. We investigated sociodemographic and health characteristics [age, gender, body mass index (BMI)], body surface area (BSA), cancer clinical stage, PS, dose of VCR per cycle, and laboratory data at initial diagnosis.\n\nPoor medical conditions were defined as hyperglycemia with blood glucose (Glu) ≥126 mg/dl according to the World Health Organization (WHO) criteria11; renal dysfunction with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 according to the Kidney Disease: Improving Global Outcomes criteria12; hepatic dysfunction with alanine transaminase (ALT) >30 IU according to the Japan Society of Hepatology Guideline for the Management of Hepatitis C Virus Infection Criteria13; malnutrition with serum albumin (Alb) <3.5 g/dl according to the criteria used in some studies14,15; anemia with hemoglobin (Hb) concentration <12.0 g/dl for females and <13.0 g/dl for males according to the WHO criteria16; and electrolyte abnormality with serum potassium (K) ≥5 or <3.5 mEq/L according to the American Heart Association criteria17. The presence or absence of each condition corresponded to the categorical variables used in this study.\n\nAssessment of CIPN\nInformation on the severity of CIPN was evaluated during each cycle of chemotherapy according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 program, and we adopted the highest grade of CIPN throughout the treatment. We regarded patients with no symptoms or grade 1 CIPN as mild CIPN cases, and patients with grade 2 or higher CIPN as severe CIPN ones.\n\nStatistical Analysis\nTo describe characteristics of the variables, medians for continuous variables and frequencies and percentages for categorical variables were computed. To compare the two groups (mild CIPN vs. severe CIPN patients), Student’s t-test was used for normally distributed continuous variables, the Wilcoxon rank sum test for nonnormally distributed continuous variables, and the chi-square test for categorical variables.\n\nSubsequently, the forward stepwise logistic regression model was performed to find predictive factors of severe CIPN. In this model, factors with ≤0.2 in univariate analysis were used as independent variables. A value of p < 0.05 was defined as statistically significant for all analyses. All statistical analyses were conducted using JMP v11.0 software (SAS Institute, Japan).\n\nRESULTS\nCharacteristics of patient with mild and severe CIPN are shown in Table 1. Thirty-one of 40 patients (77.5%) were diagnosed with DLBCL, and 9 (22.5%) with IL (follicular lymphoma, n = 7; mantle cell lymphoma; n = 2). The median age of the patients was 58 years, and 24 of these patients (60%) were male. During the treatment, seven patients (17.5%) experienced grade 2 or higher CIPN that influenced their ADL in some way. Details of patient symptoms are shown in Table 2. There were no statistically significant differences in all demographic characteristics between mild and severe CIPN patients.\n\nTable 1 Baseline Characteristics of the Patients\n\nVariables\tAll Patients (n = 40)\tMild CIPN Patients (n = 33)\tSevere CIPN Patients (n = 7)\t\np\n\t\nMedian age (years ± SD)\t55.38 ± 11.88\t54.85 ± 2.08\t57.86 ± 4.53\t0.63\t\nGender\t\t\t\t0.06\t\n Male (%)\t24 (60)\t22 (66.7)\t2 (28.6)\t\t\n Female (%)\t16 (40)\t11 (33.3)\t5 (71.4)\t\t\nBMI (kg/m2 ± SD)\t22.88 ± 4.35\t23.21 ± 0.76\t21.28 ± 1.64\t0.17\t\nBSA (m2 ± SD)\t1.67 ± 0.18\t1.69 ± 0.03\t1.56 ± 0.07\t0.10\t\nCancer type\t\t\t\t0.56\t\n DLBCL (%)\t31 (77.5)\t25 (75.8)\t6 (85.7)\t\t\n Indolent lymphoma (%)\t9 (22.5)\t8 (24.2)\t1 (14.3)\t\t\nDisease stage\t\t\t\t0.53\t\n Limited (I–II) (%)\t15 (37.5)\t11 (33.3)\t4 (57.1)\t\t\n Advanced (III–IV) (%)\t21 (52.5)\t18 (54.5)\t3 (42.9)\t\t\n Missing* (%)\t4 (10.0)\t4 (12.2)\t0 (0)\t\t\nLDH ± SD\t295.43 ± 154.45\t303.34 ± 27.5\t259.29 ± 58.78\t0.21\t\nMissing* (%)\t1 (0.03)\t\t\t\t\nECOG PS\t\t\t\t1.00\t\n 0–1 (%)\t24 (60.0)\t20 (60.6)\t4 (57.1)\t\t\n 2–4 (%)\t6 (15.0)\t5 (15.1)\t1 (14.3)\t\t\n Missing (%)\t10 (25.0)\t8 (24.3)\t2 (28.6)\t\t\nDose VCR per cycle (mg)\t1.98 ± 0.10\t1.98 ± 0.01\t1.99 ± 0.04\t0.71\t\nCIPN, chemotherapy-induced peripheral neuropathy; BMI, body mass index; BSA, body surface area; DLBCL, diffuse large B-cell lymphoma; ECOG PS, performance status according to Eastern Collaborative Oncology Group; VCR, dose of vincristine.\n\n* Some data were lacking on the medical records.\n\nTable 2 Details of Severe Chemotherapy-Induced Peripheral Neuropathy (CIPN) Among Seven Patients\n\nPatient\tGrade\tOnset Cycle\tPlace\tADL Restriction\tDuration\t\n1\t3\t2\tLower\tGait\tContinued for 2 months after the end of treatment\t\n2\t3\t2\tLower\tGait: need T-cane\tContinued for 6 months after the end of treatment\t\n3\t2\t3\tUpper\tSkilled movement (i.e., button up)\tRecovery within 1 month after the end of treatment\t\n4\t2\t5\tUpper\tSkilled movement (i.e., button up)\tRecovery within 1 month after the end of treatment\t\n5\t2\t5\tLower\tGait\tContinued for 6 months after the end of treatment\t\n6\t2\t2\tUpper\tSkilled movement (i.e., button up)\tRecovery within 1 month after the end of treatment\t\n7\t2\t2\tUpper\tSkilled movement (i.e., button up)\tRecovery within 1 month after the end of treatment\t\nThe frequency of poor medical conditions at initial diagnosis is shown in Table 3. Seven patients (17.5%) were identified with hyperglycemia, 5 patients (12.5%) with hepatic dysfunction, 12 patients (30%) with malnutrition, 16 patients (40%) with anemia, and only 4 patients (10%) with electrolyte abnormality. The results of the chi-square test showed that there were more patients with anemia in the severe CIPN group than in the mild CIPN group (p < 0.01). The mean values of Hb concentrations at baseline were 13.13 ± 1.66 and 11.64 ± 0.96 g/dl in the mild CIPN group and the severe CIPN group, respectively. The prevalence of other medical conditions was not significantly different between the mild and severe CIPN groups. Regarding hyperglycemia, there were four patients with diabetes mellitus in this study. Two of them were included in the normal blood glucose group, in accordance with the results of the chi-square test, because their disease was medically well managed. Therefore, we included them in the hyperglycemia group and performed reanalysis. As a result, the prevalence of hyperglycemia increased to 14.29% in the severe CIPN group; however, this change did not affect the association of CIPN and hyperglycemia (p = 0.32). All variables, such as gender, BMI, BSA, hyperglycemia, malnutrition, and anemia, satisfied the criteria of entry into the forward stepwise logistic regression model. Gender and anemia remained in the regression model following the stepwise procedure. The logistic regression analysis showed that anemia predicted severe CIPN in the R-CHOP treatment (odds ratio = 19.45, 95% confidence interval = 1.52–171.12).\n\nTable 3 Frequency of Each Medical Condition at Baseline\n\nVariables\tAll Patients (n = 40)\tMild CIPN Patients (n = 33)\tSevere CIPN Patients (n = 7)\t\np\n\t\nAnemia (%)\t16 (40)\t10 (30.3)\t6 (85.7)\t<0.01\t\nMalnutrition (%)\t12 (30)\t12 (36.7)\t0 (0.0)\t0.06\t\nHepatic dysfunction (%)\t10 (25)\t9 (27.3)\t1 (14.3)\t0.47\t\nHyperglycemia (%)\t7 (17.5)\t7 (21.2)\t0 (0.0)\t0.18\t\nRenal dysfunction (%)\t5 (12.5)\t4 (12.1)\t1 (14.3)\t0.86\t\nElectrolyte abnormality (%)\t4 (10)\t3 (9.1)\t1 (14.3)\t0.68\t\nCIPN, chemotherapy-induced peripheral neuropathy.\n\nDISCUSSION\nDose reduction of anticancer drugs due to symptoms of severe CIPN indicates that patients could not complete the planned chemotherapy regimen and receive enough therapeutic value. Therefore, it is necessary to predict and establish an effective management strategy for CIPN. However, few studies show valuable predictors to date18. In this study, we determined that anemia before the treatment was a novel predictive factor of severe CIPN in lymphoma patients receiving R-CHOP therapy, whereas no such relationship was observed for sociodemographic and health characteristics and other medical conditions. Anemia is a good predictor for the development of CIPN, because laboratory data (including blood test) for evaluating medical conditions are commonly examined before chemotherapy.\n\nGlendenning et al. investigated the association between CIPN and age, medical information, and dose of anticancer drugs among testicular cancer patients and reported that age was a significant predictor of peripheral neuropathy19. However, our results differed from those in their study. The reason could be explained by the difference in age groups of participants between two studies. Patients in our study were older and the median age was 58 years, but the median age in their study was 30 years. Aging has been shown to affect the peripheral nervous system, particularly in elderly people (aged over 60 years)20,21. Our patients were generally of such an age that their peripheral nervous system appeared to have degenerated significantly. Therefore, age would be excluded as a predictor in our study.\n\nOur results expand the evidence of CIPN induced by VCR. Kawakami et al. similarly examined whether the baseline laboratory data enabled prediction of severe CIPN among non-small lung cancer patients receiving paclitaxel plus carboplatin therapy (PC therapy)22. They reported that pack-year of smoking and low creatinine clearance level predicted severe CIPN in the treatment. They also argued that renal dysfunction affected metabolism and excretion of paclitaxel, probably followed by developing severe CIPN. However, our results could not support their findings, as VCR has different pharmacokinetics from paclitaxel or carboplatin because the former is metabolized in the liver and excreted with feces. Therefore, renal function does not significantly affect the pharmacokinetics of VCR23.\n\nAlthough anemia is a common medical condition among cancer patients, literature explaining the association between anemia and severe CIPN is not adequate. Penninx et al. showed that anemia was associated with disability and decreased muscle strength24. They also assumed that hypoxia in muscle tissue affected muscle strength, citing the experimental study in vivo by Dodd et al.25. Several publications also reported that anemia affected physical performance and quality of life and suggest that decreased oxygenation of tissues might cause these results26,27. The response to hypoxia varies according to the organ. For example, the brain and the heart can maintain oxygen homeostasis during anemia, but this homeostasis is affected by the peripheral tissues28,29. This peripheral tissue hypoxia is also involved in peripheral nerve system dysfunction and induces a reduction of overall protein synthesis in the cells and production of inflammatory cytokines30,31. Furthermore, protein synthesis disorders may inhibit nerve repair. In addition, sensory nerves are irritated by inflammatory cytokines that occur around the dorsal root ganglion after nerve damage32,33. Therefore, anemia-induced tissue hypoxia might affect the repair of peripheral nerve injured by VCR and subsequently lead to severe CIPN.\n\nThis report has some limitations. First, as this retrospective analysis was performed using a relatively small sample size (40 patients), these results might be influenced by random error. Second, we evaluated CIPN only depending on subjective judgment of the patients using the CTCAE version 3.0 program. Clinical research at the MD Anderson Cancer Center routinely used several objective assessment tools to evaluate CIPN and investigated various sensory disturbances34. More research is required with large sample sizes that include objective assessment tools such as the monofilament test for measuring the touch detection threshold as a superficial sensation35 and the tuning fork test for measuring the vibration detection threshold as a deep sensation36.\n\nIn conclusion, anemia, as a preexisting condition before treatment, was a useful predictive factor of severe CIPN in lymphoma patients receiving R-CHOP therapy. Despite some limitations described above, this result provides a starting point in the management and prevention of CIPN.\n\nACKNOWLEDGMENTS\n\nThe authors are very grateful to the patients who participated in this study and to the staff of the Division of Clinical Oncology and Hematology.\n\n\nThe authors declare no conflicts of interest.\n==== Refs\nREFERENCES\n1 \nCoiffier B , Lepage E , Briere J , Herbrecht R , Tilly H , Bouabdallah R , Morel P , Van Den Neste E , Salles G , Gaulard P , Reyes F , Lederlin P , Gisselbrecht C . CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma\n. N Engl J Med. \n2002 ;346 :235 –42\n.11807147 \n2 \nTomita N , Takasaki H , Fujisawa S , Miyashita K , Ogusa E , Kishimoto K , Matsuura S , Sakai R , Koharazawa H , Yamamoto W , Fujimaki K , Fujita H , Ishii Y , Taguchi J , Kuwabara H , Motomura S , Ishigatsubo Y . Standard R-CHOP therapy in follicular lymphoma and diffuse large B-cell lymphoma\n. J Clin Exp Hematop. \n2013 ;53 :121 –5\n.23995108 \n3 \nMcCune JS , Lindley C . Appropriateness of maximum-dose guidelines for vincristine\n. Am J Health Syst Pharm. \n1997 ;54 :1755 –8\n.9262750 \n4 \nQuasthoff S , Hartung HP . Chemotherapy-induced peripheral neuropathy\n. J Neurol. \n2002 ;249 :9 –17\n.11954874 \n5 \nBeijers AJ , Jongen JL , Vreugdenhil G . Chemotherapy-induced neurotoxicity: The value of neuroprotective strategies\n. Neth J Med. \n2012 ;70 :18 –25\n.22271810 \n6 \nThomas PK , Lascelles RG . Schwann-cell abnormalities in diabetic neuropathy\n. Lancet \n1965 ;1 :1355 –7\n.14306849 \n7 \nNielsen VK . The peripheral nerve function in chronic renal failure. VI. The relationship between sensory and motor nerve conduction and kidney function, azotemia, age, sex, and clinical neuropathy\n. Acta Med Scand. \n1973 ;194 :455 –62\n.4757225 \n8 \nKnill-Jones RP , Goodwill CJ , Dayan AD , Williams R . Peripheral neuropathy in chronic liver disease: Clinical, electrodiagnostic, and nerve biopsy findings\n. J Neurol Neurosurg Psychiatry \n1972 ;35 :22 –30\n.4337271 \n9 \nHattori N , Koike H , Sobue G . [Metabolic and nutritional neuropathy\n]. Rinsho Shinkeigaku. \n2008 ;48 :1026 –7\n.19198152 \n10 \nKabakus N , Ayar A , Yoldas TK , Ulvi H , Dogan Y , Yilmaz B , Kilic N . Reversal of iron deficiency anemia-induced peripheral neuropathy by iron treatment in children with iron deficiency anemia\n. J Trop Pediatr. \n2002 ;48 :204 –9\n.12200980 \n11 \nAlberti KG , Zimmet PZ . Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation\n. Diabet Med. \n1998 ;15 :539 –53\n.9686693 \n12 \nLevey AS , de Jong PE , Coresh J , El Nahas M , Astor BC , Matsushita K , Gansevoort RT , Kasiske BL , Eckardt KU . The definition, classification, and prognosis of chronic kidney disease: A KDIGO Controversies Conference report\n. Kidney Int. \n2011 ;80 :17 –28\n.21150873 \n13 \nDrafting Committee for Hepatitis Management Guidelines, the Japan Society of Hepatology . JSH guidelines for the management of hepatitis C virus infection: A 2014 update for genotype 1\n. Hepatol Res. \n2014 ;44 (Suppl 1 ):59 –70\n.\n14 \nSalive ME , Cornoni-Huntley J , Phillips CL , Guralnik JM , Cohen HJ , Ostfeld AM , Wallace RB . Serum albumin in older persons: Relationship with age and health status\n. J Clin Epidemiol. \n1992 ;45 :213 –21\n.1569418 \n15 \nCorti MC , Guralnik JM , Salive ME , Sorkin JD . Serum albumin level and physical disability as predictors of mortality in older persons\n. JAMA \n1994 ;272 :1036 –42\n.8089886 \n16 \nECC Committee, Subcommittees and Task Forces of the American Heart Association . 2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care\n. Circulation \n2005 ;112 :IV1 –203\n.16314375 \n17 \nWorld Health Organization . Nutritional anaemias. Report of a WHO scientific group\n. World Health Organ Tech Rep Ser. \n1968 ;405 :5 –37\n.4975372 \n18 \nSeretny M , Currie GL , Sena ES , Ramnarine S , Grant R , MacLeod MR , Colvin LA , Fallon M . Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis\n. Pain \n2014 ;155 :2461 –70\n.25261162 \n19 \nGlendenning JL , Barbachano Y , Norman AR , Dearnaley DP , Horwich A , Huddart RA . Long-term neurologic and peripheral vascular toxicity after chemotherapy treatment of testicular cancer\n. Cancer \n2010 ;116 :2322 –31\n.20225230 \n20 \nVerdu E , Ceballos D , Vilches JJ , Navarro X . Influence of aging on peripheral nerve function and regeneration\n. J Peripher Nerv Syst. \n2000 ;5 :191 –208\n.11151980 \n21 \nDorfman LJ , Bosley TM . Age-related changes in peripheral and central nerve conduction in man\n. Neurology \n1979 ;29 :38 –44\n.570675 \n22 \nKawakami K , Tunoda T , Takiguchi T , Shibata K , Ohtani T , Kizu J , Nishio M , Horai T , Hama T , Taguchi K . Factors exacerbating peripheral neuropathy induced by paclitaxel plus carboplatin in non-small cell lung cancer\n. Oncol Res. \n2012 ;20 :179 –85\n.23461065 \n23 \nBender RA , Castle MC , Margileth DA , Oliverio VT . The pharmacokinetics of [3H]-vincristine in man\n. Clin Pharmacol Ther. \n1977 ;22 :430 –5\n.902455 \n24 \nPenninx BW , Pahor M , Cesari M , Corsi AM , Woodman RC , Bandinelli S , Guralnik JM , Ferrucci L . Anemia is associated with disability and decreased physical performance and muscle strength in the elderly\n. J Am Geriatr Soc. \n2004 ;52 :719 –24\n.15086651 \n25 \nDodd SL , Powers SK , Brooks E , Crawford MP . Effects of reduced O2 delivery with anemia, hypoxia, or ischemia on peak VO2 and force in skeletal muscle\n. J Appl Physiol. (1985) \n1993 ;74 :186 –91\n.8444690 \n26 \nPenninx BW , Guralnik JM , Onder G , Ferrucci L , Wallace RB , Pahor M . Anemia and decline in physical performance among older persons\n. Am J Med. \n2003 ;115 :104 –10\n.12893395 \n27 \nLipschitz D . Medical and functional consequences of anemia in the elderly\n. J Am Geriatr Soc. \n2003 ;51 :S10 –13\n.12588566 \n28 \nTsui AK , Marsden PA , Mazer CD , Sled JG , Lee KM , Henkelman RM , Cahill LS , Zhou YQ , Chan N , Liu E , Hare GM . Differential HIF and NOS responses to acute anemia: Defining organ-specific hemoglobin thresholds for tissue hypoxia\n. Am J Physiol Regul Integr Comp Physiol. \n2014 ;307 :R13 –25\n.24760996 \n29 \nLauscher P , Kertscho H , Schmidt O , Zimmermann R , Rosenberger P , Zacharowski K , Meier J . Determination of organ-specific anemia tolerance\n. Crit Care Med. \n2013 ;41 :1037 –45\n.23385097 \n30 \nKoumenis C , Naczki C , Koritzinsky M , Rastani S , Diehl A , Sonenberg N , Koromilas A , Wouters BG . Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha\n. Mol Cell Biol. \n2002 ;22 :7405 –16\n.12370288 \n31 \nEltzschig HK , Carmeliet P . Hypoxia and inflammation\n. N Engl J Med. \n2011 ;364 :656 –65\n.21323543 \n32 \nSegond von Banchet G , Boettger MK , Fischer N , Gajda M , Brauer R , Schaible HG . Experimental arthritis causes tumor necrosis factor-alpha-dependent infiltration of macrophages into rat dorsal root ganglia which correlates with pain-related behavior\n. Pain \n2009 ;145 :151 –9\n.19560272 \n33 \nMassier J , Eitner A , Segond von Banchet G , Schaible HG . Effects of differently activated rodent macrophages on sensory neurons: Implications for arthritis pain\n. Arthritis Rheumatol. \n2015 ;67 :2263 –72\n.25833104 \n34 \nDougherty PM , Cata JP , Cordella JV , Burton A , Weng HR . Taxol-induced sensory disturbance is characterized by preferential impairment of myelinated fiber function in cancer patients\n. Pain \n2004 ;109 :132 –42\n.15082135 \n35 \nBell-Krotoski JA , Fess EE , Figarola JH , Hiltz D . Threshold detection and Semmes-Weinstein monofilaments\n. J Hand Ther. \n1995 ;8 :155 –62\n.7550627 \n36 \nGoldberg JM , Lindblom U . Standardised method of determining vibratory perception thresholds for diagnosis and screening in neurological investigation\n. J Neurol Neurosurg Psychiatry \n1979 ;42 :793 –803\n.501379\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0965-0407",
"issue": "27(4)",
"journal": "Oncology research",
"keywords": null,
"medline_ta": "Oncol Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000740:Anemia; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases; D011241:Prednisone; D000069283:Rituximab; D012720:Severity of Illness Index; D014750:Vincristine",
"nlm_unique_id": "9208097",
"other_id": null,
"pages": "469-474",
"pmc": null,
"pmid": "30126466",
"pubdate": "2019-03-29",
"publication_types": "D016428:Journal Article",
"references": "1569418;23995108;24760996;7550627;22271810;23461065;9686693;501379;11151980;19198152;8444690;14306849;12588566;570675;11954874;8089886;12370288;23385097;15082135;20225230;16314375;12200980;11807147;12893395;4757225;15086651;4975372;24397840;21323543;25833104;25261162;19560272;9262750;902455;21150873;4337271",
"title": "Anemia Is a Novel Predictive Factor for the Onset of Severe Chemotherapy-Induced Peripheral Neuropathy in Lymphoma Patients Receiving Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone Therapy.",
"title_normalized": "anemia is a novel predictive factor for the onset of severe chemotherapy induced peripheral neuropathy in lymphoma patients receiving rituximab plus cyclophosphamide doxorubicin vincristine and prednisolone therapy"
} | [
{
"companynumb": "JP-JNJFOC-20190437671",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Serotonin syndrome (SS) and neuroleptic malignant syndrome (NMS) are life-threatening adverse reactions caused by serotonergic antidepressants and neuroleptics, respectively. SS and NMS have overlapping clinical features, and thus differentially diagnosing the syndromes can be difficult in patients who are taking both types of drugs. Here, the author reports a unique case of a patient who developed SS that overlapped with NMS after taking imipramine and lithium carbonate with the subsequent addition of metoclopramide. This is the first case report of SS that overlapped with NMS. The author also briefly summarizes the clinical symptoms of each syndrome and describes the approaches that were used to differentially diagnose the two syndromes.",
"affiliations": "Department of Psychiatry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan; Nasukohgen Hospital, Tochigi, Japan. Electronic address: midorin@jichi.ac.jp.",
"authors": "Nisijima|Koichi|K|",
"chemical_list": "D000929:Antidepressive Agents, Tricyclic; D009125:Muscle Relaxants, Central; D012702:Serotonin Antagonists; D003533:Cyproheptadine; D003620:Dantrolene; D007099:Imipramine",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-2018",
"issue": "18()",
"journal": "Asian journal of psychiatry",
"keywords": "Imipramine; Lithium carbonate; Metoclopramide; Neuroleptic malignant syndrome; Serotonin syndrome",
"medline_ta": "Asian J Psychiatr",
"mesh_terms": "D000929:Antidepressive Agents, Tricyclic; D000066491:Clinical Decision-Making; D003533:Cyproheptadine; D003620:Dantrolene; D003866:Depressive Disorder; D003937:Diagnosis, Differential; D019468:Disease Management; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007099:Imipramine; D008297:Male; D008875:Middle Aged; D009125:Muscle Relaxants, Central; D009459:Neuroleptic Malignant Syndrome; D012702:Serotonin Antagonists; D020230:Serotonin Syndrome",
"nlm_unique_id": "101517820",
"other_id": null,
"pages": "100-1",
"pmc": null,
"pmid": "26506919",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Serotonin syndrome overlapping with neuroleptic malignant syndrome: A case report and approaches for differentially diagnosing the two syndromes.",
"title_normalized": "serotonin syndrome overlapping with neuroleptic malignant syndrome a case report and approaches for differentially diagnosing the two syndromes"
} | [
{
"companynumb": "JP-TEVA-626364ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMIPRAMINE"
},
"drugadditional": null,
"dru... |
{
"abstract": "Fifty-two-year-old female with high-grade undifferentiated pleomorphic left thigh sarcoma and bilateral metastatic soft tissue lesions to the lungs consistent with metastases, presented with recurrent, anemia, and worsening hemoptysis. Cross-sectional imaging demonstrated erosion of a right lower lobe metastatic mass into an adjacent right inferior lower lobe pulmonary vein with formation of a pseudoaneurysm. We report the successful treatment of this pseudoaneurysm via direct image-guided percutaneous access with subsequent coil embolization.",
"affiliations": "Department of Radiology, Interventional Radiology and Image Guided Intervention Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. rices@mskcc.org.;Department of Radiology, Interventional Radiology and Image Guided Intervention Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.;Department of Radiology, Interventional Radiology and Image Guided Intervention Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.",
"authors": "Rice|Samuel L|SL|;Deipolyi|Amy R|AR|;Martin|Ernesto Santos|ES|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s00270-018-1977-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0174-1551",
"issue": "41(9)",
"journal": "Cardiovascular and interventional radiology",
"keywords": "Embolization; Oncology; Pseudoaneurysm; Pulmonary angiogram",
"medline_ta": "Cardiovasc Intervent Radiol",
"mesh_terms": "D017541:Aneurysm, False; D000072226:Computed Tomography Angiography; D004621:Embolization, Therapeutic; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008875:Middle Aged; D011667:Pulmonary Veins; D012509:Sarcoma",
"nlm_unique_id": "8003538",
"other_id": null,
"pages": "1440-1443",
"pmc": null,
"pmid": "29728719",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Percutaneous Embolization of a Pulmonary Vein Pseudoaneurysm Secondary to Vascular Erosion of a Metastatic Mass.",
"title_normalized": "percutaneous embolization of a pulmonary vein pseudoaneurysm secondary to vascular erosion of a metastatic mass"
} | [
{
"companynumb": "IT-JNJFOC-20180832257",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": null,
... |
{
"abstract": "Allopurinol, a widely prescribed urate lowering agent is responsible for various adverse drug reactions, including erythroderma. A 45-year-old male patient was admitted with the complaints of fever, redness and scaling all over the body after 3-4 weeks of allopurinol treatment for asymptomatic hyperuricemia. Elevated liver enzymes were detected in his blood analysis. Skin biopsy was consistent with drug induced erythroderma. Allopurinol was stopped and steroids were started. Patient improved over a period of 2 weeks.",
"affiliations": "Departments of Dermatology and Dermatology and Venereology, Rama Medical College, Hospital and Research Centre, Mandhana, Kanpur, Uttar Pradesh, India.;Departments of Dermatology and Dermatology and Venereology, Rama Medical College, Hospital and Research Centre, Mandhana, Kanpur, Uttar Pradesh, India.",
"authors": "Sharma|Geeta|G|;Govil|Dinesh Chandra|DC|",
"chemical_list": "D014527:Uric Acid; D000493:Allopurinol",
"country": "India",
"delete": false,
"doi": "10.4103/0253-7613.121381",
"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-45-62710.4103/0253-7613.121381Drug WatchAllopurinol induced erythroderma Sharma Geeta Govil Dinesh Chandra Departments of Dermatology and Dermatology and Venereology, Rama Medical College, Hospital and Research Centre, Mandhana, Kanpur, Uttar Pradesh, IndiaCorrespondence to: Dr. Geeta Sharma, E-mail: docgeetasharma@gmail.comNov-Dec 2013 45 6 627 628 22 6 2013 09 7 2013 15 9 2013 Copyright: © Indian Journal of Pharmacology2013This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Allopurinol, a widely prescribed urate lowering agent is responsible for various adverse drug reactions, including erythroderma. A 45-year-old male patient was admitted with the complaints of fever, redness and scaling all over the body after 3-4 weeks of allopurinol treatment for asymptomatic hyperuricemia. Elevated liver enzymes were detected in his blood analysis. Skin biopsy was consistent with drug induced erythroderma. Allopurinol was stopped and steroids were started. Patient improved over a period of 2 weeks.\n\nKEY WORDS\nAllopurinolerythrodermahyperuricemia\n==== Body\nIntroduction\nAllopurinol, a xanthine oxidase inhibitor is an effective and widely prescribed urate lowering agent. It is safe in most of the patients, but intolerance is estimated to occur in up to 10% of treated patients. Severe or life-threatening allopurinol adverse reactions occur less frequently. Cutaneous adverse reactions to allopurinol are common affecting 2% of patients prescribed.[1] Here, we report a case of erythroderma due to allopurinol.\n\nCase Report\nA 45-years-old male patient was admitted with complains of fever, redness and scaling all over the body for last 20 days. His recent drug history revealed that he was on oral allopurinol 200 mg daily for last 1½ month. He told that allopurinol was given by his general practitioner for increased uric acid level only. However when serum uric acid were repeated at our hospital the levels were normal. On further probing, he gave a history of generalized erythematous maculopapular rash along with a fever after 3 weeks of starting allopurinol, but he continued the medication. Later, there was the development of extensive erythema along with the scaling over the whole body within 4 days.\n\nOn examination, diffuse erythema with fine scaling was observed all over the body. Erythema and scaling were more pronounced over the trunk [Figure 1]. No significant lymphadenopathy or hepatosplenomegaly was observed. A skin biopsy done from back showed epidermal hyperplasia, foci of parakeratosis, spongiosis and a few necrotic keratinocytes. Dermis showed sparse superficial perivascular infiltrates consisting of lymphocytes and a few eosinophils. Laboratory investigations revealed raised liver enzymes (aspartate aminotransferase-114, alanine aminotransferase-112), but bilirubin was normal. Total blood counts including eosinophil count, renal function tests and serum electrolytes were within the normal limits. The causality was assessed using the Naranjo's adverse drug reaction probability scale. The association was “probable” as per the Naranjo's scale; hence, a diagnosis of allopurinol induced erythroderma was made. Allopurinol was stopped. Oral antihistamines and oral prednisolone 40 mg/day were started along with a supportive therapy. Patient improved over a period of 2 weeks [Figure 2 showing improvement after 1week of treatment] and steroids were tapered and eventually stopped.\n\nFigure 1 Erythema and scaling over back\n\nFigure 2 After 1 week of treatment\n\nDiscussion\nErythroderma is the term applied to any inflammatory skin disease that affects more than 90% of the body surface. Clinically, it is characterized by erythema and scaling involving more than 90% of the body surface area. The main causes of erythroderma in adults are preexisting eczema of various types, psoriasis, drugs, lymphoma and leukemia etc. A wide-range of drugs can cause erythroderma. Among the more commonly implicated are pyrazolone derivatives such as phenylbutazone, hydantoin derivatives, carbamazepine, cimetidine, gold salts and lithium. Exposure to the causative drug may last for 2 weeks to several months before the reaction emerges. In the present case, the patient presented after receiving 1½ months of allopurinol treatment with fever, erythema and scaling involving more than 90% of the body surface area alongwith raised liver enzymes. No significant lymphadenopathy or hepatosplenomegaly was observed. Hence, a diagnosis of allopurinol induced erythroderma was made. Prompt resolution of the lesions after withdrawal of the allopurinol and start of oral steroid further supported the diagnosis. Drug induced erythroderma has the best prognosis of all the causes of erythroderma often resolving in 2-6 weeks.\n\nHowever, it is important to remember that the cutaneous manifestations of drug hypersensitivity may be accompanied by involvement of other organs, for example hematological abnormalities, hepatitis or nephritis. An example is the syndrome known as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.[2] Hence drug use must be investigated in patients with the complaints of fever, jaundice, generalized rash, acute renal failure and acute liver failure in order to rule out the possibility of DRESS syndrome.\n\nThe exact pathogenesis of these hypersensitivity events due to allopurinol, whether immune-mediated and/or toxic in nature, is unclear. Accumulation of oxypurinol (principal metabolite of allopurinol) due to renal impairment or co-administration of thiazide diuretics,[3] genetic factors,[4] abnormal T lymphocyte–mediated immune responses to oxypurinol, and to a lesser extent, allopurinol[5] and formation of immune complexes[3] have been implicated. A recent study suggests that in vitro allopurinol-induced release of interferon-γ from peripheral blood T lymphocytes may be a useful test in the diagnosis of Stevens-Johnson syndrome and other sensitivity reactions to allopurinol.[6] Skin testing with either allopurinol or oxypurinol is less specific and has yielded conflicting results.[3]\n\nAllopurinol is the first line drug for serum lowering therapy in gout and is approved by the US Food and Drug Administration. Urate lowering drugs are widely used in people with asymptomatic hyperuricemia. About 5% of the population and a quarter of hospital patients are hyperuricemic. Most are asymptomatic and do not develop gout.[7] Treating asymptomatic hyperuricemia does not have clear benefits and our report shows the potential harm of this practice. Alternative treatments are now emerging for the treatment of gout, including rasburicase[8] and febuxostat.[9]\n\nWith this case report, we aim to create awareness about rare, but potentially fatal drug reaction like erythroderma that can occur with allopurinol, a commonly prescribed urate lowering agent used. A judicious use of allopurinol may decrease the incidence and morbidity caused by the drug reaction.\n\nSource of Support: Nil\n\nConflict of Interest: None declared\n==== Refs\n1 Wortmann RL Gout and hyperuricemia Curr Opin Rheumatol 2002 14 281 6 11981327 \n2 Breathnach SM Burns T Breathnach S Cox N Griffiths C Drug reactions Rook's Textbook of Dermatology 2010 8th ed United Kingdom Wiley-Blackwell 23 46 7 \n3 Arellano F Sacristán JA Allopurinol hypersensitivity syndrome: A review Ann Pharmacother 1993 27 337 43 8453174 \n4 Chan SH Tan T HLA and allopurinol drug eruption Dermatologica 1989 179 32 3 2527769 \n5 Braden GL Warzynski MJ Golightly M Ballow M Cell-mediated immunity in allopurinol-induced hypersensitivity Clin Immunol Immunopathol 1994 70 145 51 8299230 \n6 Halevy S Cohen AD Livni E The diagnostic role of the in vitro drug-induced interferon-gamma release test in Stevens-Johnson syndrome Int J Dermatol 1999 38 835 40 10583616 \n7 Ranu H Jiang J Ming PS A case series of allopurinol-induced toxic epidermal necrolysis Indian J Dermatol 2011 56 74 6 21572797 \n8 Richette P Brière C Hoenen-Clavert V Loeuille D Bardin T Rasburicase for tophaceous gout not treatable with allopurinol: An exploratory study J Rheumatol 2007 34 2093 8 17896799 \n9 Becker MA Schumacher HR Jr Wortmann RL MacDonald PA Eustace D Palo WA Febuxostat compared with allopurinol in patients with hyperuricemia and gout N Engl J Med 2005 353 2450 61 16339094\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7613",
"issue": "45(6)",
"journal": "Indian journal of pharmacology",
"keywords": "Allopurinol; erythroderma; hyperuricemia",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D000493:Allopurinol; D003873:Dermatitis, Exfoliative; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014527:Uric Acid",
"nlm_unique_id": "7902477",
"other_id": null,
"pages": "627-8",
"pmc": null,
"pmid": "24347776",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16339094;8299230;11981327;8453174;2527769;21572797;10583616;17896799",
"title": "Allopurinol induced erythroderma.",
"title_normalized": "allopurinol induced erythroderma"
} | [
{
"companynumb": "IN-WATSON-2014-21174",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALLOPURINOL"
},
"drugadditional": null,
... |
{
"abstract": "HIV-positive patients with hematologic malignancies are frequently not considered for treatment with allogeneic hematopoietic stem cell transplantation (allo-HSCT) because of reported high morbidity and mortality with this procedure and scant published experience. Advances in HIV care and supportive care for allo-HSCT prompted us to review our experience since 2010, after we instituted multidisciplinary management of HIV-infected patients during the peritransplant period.\n\n\n\nWe retrospectively reviewed the records of all HIV-positive patients who received allo-HSCT at our institution since 2010.\n\n\n\nFive patients with various hematologic malignancies received allo-HSCT from matched related (two) or unrelated (three) donors since 2010. All patients received tenofovir (TDF)/emtricitabine in combination with either efavirenz (one) or raltegravir (four) and engrafted a median of 17 days after transplant. The most common infection was cytomegalovirus viremia, with six episodes in four patients, controlled with antivirals. There was no transplant-related mortality. Three patients relapsed 6, 7, and 13 months after transplant, and two were alive and well after 42 and 55 months. HIV viral load remained undetectable and CD4 cell count increased progressively. One patient had acute renal failure and improved with hydration and replacement of TDF with abacavir.\n\n\n\nOur patients received allo-HSCT without transplant-related mortality or major infectious complications. Their HIV viral load remained undetectable without the use of protease inhibitors or need to discontinue antiretroviral therapy. One patient had acute renal failure that resolved after discontinuation of TDF. Our findings support considering selected HIV-infected patients for allo-HSCT when indicated for the management of their hematologic malignancies.",
"affiliations": "aDepartment of Infectious Diseases, Infection Control and Employee Health bDepartment of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas, USA.",
"authors": "Mulanovich|Victor E|VE|;Desai|Parth A|PA|;Popat|Uday R|UR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/QAD.0000000000001240",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-9370",
"issue": "30(17)",
"journal": "AIDS (London, England)",
"keywords": null,
"medline_ta": "AIDS",
"mesh_terms": "D000328:Adult; D015658:HIV Infections; D019337:Hematologic Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "8710219",
"other_id": null,
"pages": "2653-2657",
"pmc": null,
"pmid": "27536985",
"pubdate": "2016-11-13",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "21303358;16355343;26538525;25120135;23385862;19539219;26538524;23800257;11781257;20549392",
"title": "Allogeneic stem cell transplantation for HIV-positive patients with hematologic malignancies.",
"title_normalized": "allogeneic stem cell transplantation for hiv positive patients with hematologic malignancies"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-287359",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RALTEGRAVIR"
},
"dru... |
{
"abstract": "OBJECTIVE\nTo investigate the influence of hydroxyethyl starch solution on exogenous coagulation and active protein C ( APC ) in the patients with septic shock.\n\n\nMETHODS\nA single-center prospective study was conducted. Eighty-four consecutive patients with septic shock admitted to intensive care unit ( ICU ) of Peking University People's Hospital from November 2009 to October 2014 were enrolled. The patients were randomized into two study groups by random digits table: Ringer lactate solution group ( RL group, n = 40 ) and hydroxyethyl starch group ( HES group, n = 44 ), and Ringer lactate solution or hydroxyethl starch 130/0.4 was used for resuscitation respectively. Peripheral blood was collected at four time points: before resuscitation, 6, 12, and 24 hours after resuscitation. The prothrombin time ( PT ), tissue factor ( TF ), tissue factor pathway inhibitor ( TFPI ) and APC were determined, and the length of ICU stay and the mortality were recorded.\n\n\nRESULTS\nThere were no significant differences in PT, TF, TFPI, and APC before and after resuscitation in RL group. No change in PT was found after resuscitation in HES group, and no significant difference was found as compared with RL group. TF after resuscitation in HES group was decreased gradually, and the level at the 24 hours after resuscitation was significantly lower than that before resuscitation ( U/L: 15.80±7.32 vs. 31.40±2.75, P<0.05 ); but there was no significant difference at all time points when compared with that of RL group ( all P>0.05 ). TFPI at 12 hours and 24 hours after resuscitation in HES group was increased when compared with before resuscitation ( μg/L: 1.32±0.22, 1.14±0.09 vs. 0.63±0.54 ). TFPI in HES group was significantly higher than that in RL group ( μg/L: 0.84±0.69, 0.95±0.30 ), but there was no significant differences between two groups ( both P>0.05 ). APC after resuscitation in HES group was decreased gradually, which was significantly lower than that in RL group at 6, 12, 24 hours after resuscitation ( mg/L: 3.38±3.00 vs. 5.98±4.12, 3.31±1.94 vs. 5.33±3.71, 3.42±2.64 vs. 7.53±4.67, P<0.05 or P<0.01 ). The length of ICU stay in HES group was significantly shorter than that in RL group ( days: 12.50±8.83 vs. 17.10±16.60, t = 9.037, P<0.001 ), but there was no significant difference in mortality between HES group and RL group [ 40.9% ( 18/44 ) vs. 60.0% ( 24/40 ), χ (2) = 2.339, P = 0.126 ].\n\n\nCONCLUSIONS\nBoth RL and hydroxyethyl starch fluid resuscitation did not affect the PT of the patients. The use of hydroxyethyl starch probably inhibits excessive activation of the exogenous coagulation and hyper-coagulation in the early stage of sepsis, and inhibits activation of protein C as well.",
"affiliations": "Department of Surgical Intensive Care Unit, Peking University People's Hospital, Beijing 100044, China. Corresponding author: An Youzhong, Email: bjicu@163.com.",
"authors": "Lyu|Jie|J|;Li|Tong|T|;Liu|Fang|F|;An|Youzhong|Y|",
"chemical_list": "D006895:Hydroxyethyl Starch Derivatives; D007552:Isotonic Solutions; D011486:Protein C; D000077325:Ringer's Lactate",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.issn.2095-4352.2015.01.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "27(1)",
"journal": "Zhonghua wei zhong bing ji jiu yi xue",
"keywords": null,
"medline_ta": "Zhonghua Wei Zhong Bing Ji Jiu Yi Xue",
"mesh_terms": "D001777:Blood Coagulation; D001780:Blood Coagulation Tests; D002681:China; D005440:Fluid Therapy; D006801:Humans; D006895:Hydroxyethyl Starch Derivatives; D007362:Intensive Care Units; D007552:Isotonic Solutions; D007902:Length of Stay; D011446:Prospective Studies; D011486:Protein C; D012151:Resuscitation; D000077325:Ringer's Lactate; D018805:Sepsis; D012772:Shock, Septic",
"nlm_unique_id": "101604552",
"other_id": null,
"pages": "28-32",
"pmc": null,
"pmid": "25591433",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The influence of hydroxyethyl starch on exogenous coagulation and active protein C in patients with septic shock.",
"title_normalized": "the influence of hydroxyethyl starch on exogenous coagulation and active protein c in patients with septic shock"
} | [
{
"companynumb": "CN-BAXTER-2015BAX019114",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RINGER^S SOLUTION, LACTATED"
},
"drugadditiona... |
{
"abstract": "BACKGROUND\nOsteoarthritis (OA) is a debilitating condition characterized by chronic pain. Several pain medications are recommended, and patients frequently alternate among these medications.\n\n\nOBJECTIVE\nThe purpose of this study was to examine the use of pain medications in clinical practice with respect to recommended guidelines. This objective was accomplished by evaluating patterns of switching, augmentation, and discontinuation after treatment initiation with select medications in patients with OA.\n\n\nMETHODS\nThe LifeLink Health Plan Claims Database was used to select patients with OA (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 715.XX) who were newly prescribed (index event) nonsteroidal antiinflammatory drugs (NSAIDs), cyclooxygenase (COX)-2 inhibitors, acetaminophen, tramadol, weak opioids, and strong opioids. Descriptive statistics, Kaplan-Meier analyses, and the COX proportional hazards model were used to assess therapy switching, augmentation, and discontinuation during the 12-month postindex period. Patterns of intraarticular injections and joint replacement surgeries among the cohorts were also evaluated.\n\n\nRESULTS\nSubstantial proportions of OA patients switched, augmented, or discontinued therapy during the postindex period. Rates of therapy switching, augmentation, and discontinuation, respectively, were significantly different (all P < 0.0001 for overall effects using log-rank tests) across the evaluated medication cohorts: NSAIDs, 22.3%, 6.7%, 93.2%; COX-2 inhibitors, 27.5%, 10%, 87.4%; acetaminophen, 46.0%, 6.5%, 98.7%; tramadol, 44.5%, 8.4%, 95.6%; weak opioids, 27.2%, 4.1%, 98.3%; and strong opioids, 41.1%, 3.3%, 97%. Therapy switching, augmentation, and discontinuation occurred within 2 months after treatment initiation in two thirds of patients and within 6 months in >90% of patients. The patterns of intraarticular injections were significantly different across treatment cohorts, as were the patterns of joint replacement surgeries (both P < 0.0001 for overall effects using log-rank tests), with average times to surgery that appeared longer with acetaminophen, NSAIDs, and COX-2 inhibitor initiators (416-447 days) than with tramadol and opioids (354-385 days).\n\n\nCONCLUSIONS\nResults indicate that therapy switching and discontinuation were frequent among OA patients initiating treatment with the currently recommended medication classes and might suggest suboptimal pain relief or potentially intolerable therapy-related side effects.",
"affiliations": "Avalon Health Solutions, Inc, Philadelphia, Pennsylvania 19102, USA. mgore@avalonhealthsolutions.com",
"authors": "Gore|Mugdha|M|;Sadosky|Alesia|A|;Leslie|Douglas|D|;Tai|Kei-Sing|KS|;Seleznick|Mitchel|M|",
"chemical_list": "D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clinthera.2011.10.019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0149-2918",
"issue": "33(12)",
"journal": "Clinical therapeutics",
"keywords": null,
"medline_ta": "Clin Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018771:Arthralgia; D019643:Arthroplasty, Replacement; D059350:Chronic Pain; D052246:Cyclooxygenase 2 Inhibitors; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D005260:Female; D019983:Guideline Adherence; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010003:Osteoarthritis; D010147:Pain Measurement; D017410:Practice Guidelines as Topic; D010818:Practice Patterns, Physicians'; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "7706726",
"other_id": null,
"pages": "1914-31",
"pmc": null,
"pmid": "22088416",
"pubdate": "2011-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Patterns of therapy switching, augmentation, and discontinuation after initiation of treatment with select medications in patients with osteoarthritis.",
"title_normalized": "patterns of therapy switching augmentation and discontinuation after initiation of treatment with select medications in patients with osteoarthritis"
} | [
{
"companynumb": "US-JNJFOC-20150218995",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nIncreasing rates of opioid use disorders (OUDs) (abuse and dependence) among patients prescribed opioids are a significant public health concern. We investigated the association between exposure to prescription opioids and incident OUDs among individuals with a new episode of a chronic noncancer pain (CNCP) condition.\n\n\nMETHODS\nWe utilized claims data from the HealthCore Database for 2000 to 2005. The dataset included all individuals aged 18 and over with a new CNCP episode (no diagnosis in the prior 6 mo), and no opioid use or OUD in the prior 6 months (n=568,640). We constructed a single multinomial variable describing prescription on opioid days supply (none, acute, and chronic) and average daily dose (none, low dose, medium dose, and high dose), and examined the association between this variable and an incident OUD diagnosis.\n\n\nRESULTS\nPatients with CNCP prescribed opioids had significantly higher rates of OUDs compared with those not prescribed opioids. Effects varied by average daily dose and days supply: low dose, acute (odds ratio [OR]=3.03; 95% confidence interval [CI], 2.32, 3.95); low dose, chronic (OR=14.92; 95% CI, 10.38, 21.46); medium dose, acute (OR=2.80; 95% CI, 2.12, 3.71); medium dose, chronic (OR=28.69; 95% CI, 20.02, 41.13); high dose, acute (OR=3.10; 95% CI, 1.67, 5.77); and high dose, chronic (OR=122.45; 95% CI, 72.79, 205.99).\n\n\nCONCLUSIONS\nAmong individuals with a new CNCP episode, prescription opioid exposure was a strong risk factor for incident OUDs; magnitudes of effects were large. Duration of opioid therapy was more important than daily dose in determining OUD risk.",
"affiliations": "*RTI International, Behavioral Health Epidemiology, Research Triangle Park, NC †Division of Pharmaceutical Evaluation and Policy, University of Arkansas for Medical Sciences, Little Rock, AR ‡Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA §HealthCore Inc., Wilmington, DE.",
"authors": "Edlund|Mark J|MJ|;Martin|Bradley C|BC|;Russo|Joan E|JE|;DeVries|Andrea|A|;Braden|Jennifer B|JB|;Sullivan|Mark D|MD|",
"chemical_list": "D000701:Analgesics, Opioid; D055553:Prescription Drugs",
"country": "United States",
"delete": false,
"doi": "10.1097/AJP.0000000000000021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-8047",
"issue": "30(7)",
"journal": "The Clinical journal of pain",
"keywords": null,
"medline_ta": "Clin J Pain",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid; D059350:Chronic Pain; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009293:Opioid-Related Disorders; D017063:Outcome Assessment, Health Care; D055553:Prescription Drugs; D055815:Young Adult",
"nlm_unique_id": "8507389",
"other_id": null,
"pages": "557-64",
"pmc": null,
"pmid": "24281273",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "20554392;18547726;20837827;16023304;22048730;19187889;12633908;9926729;17449178;9669787;20579834;16061467;18676205;20049546;20533971;18512264;18063321;18489635;7873954;2873550;20712819;3558716;22766967;20801580;15276196;16862602;20083827;16027761;18178367;17227935;21751058;21067250;19573219;20634006;21562923",
"title": "The role of opioid prescription in incident opioid abuse and dependence among individuals with chronic noncancer pain: the role of opioid prescription.",
"title_normalized": "the role of opioid prescription in incident opioid abuse and dependence among individuals with chronic noncancer pain the role of opioid prescription"
} | [
{
"companynumb": "US-JNJFOC-20140702275",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
},
"drugadditional": null... |
{
"abstract": "Opportunistic fungal pathogens have increased in frequency with the growing immunosuppressed population. New and emerging pathogens, including the rare yeasts, continue to cause significant morbidity and mortality and frequently develop despite prophylaxis with antifungal agents. We report a previously unreported manifestation of disseminated trichosporonosis. Our patient with underlying acute myeloid leukemia presented with as an exophytic toe lesion found secondary to Trichosporon asahii. We highlight the need for a high index of suspicion to diagnose breakthrough infections and the need for aggressive treatment.",
"affiliations": "Department of Internal Medicine, University of California-Davis Health, Sacramento, CA, USA.;Department of Internal Medicine, Division of Infectious Diseases, University of California-Davis Health, 4150 V Street, Suite G500, Sacramento, CA, USA.;Fungus Testing Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center At San Antonio, San Antonio, USA.;Department of Internal Medicine, Division of Infectious Diseases, University of California-Davis Health, 4150 V Street, Suite G500, Sacramento, CA, USA. grthompson@ucdavis.edu.",
"authors": "Salazar|Jorge|J|;Hardin|Kaitlyn A|KA|;Wiederhold|Nathan P|NP|;Thompson|George R|GR|http://orcid.org/0000-0001-8518-5750",
"chemical_list": "D000935:Antifungal Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11046-020-00477-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-486X",
"issue": "185(4)",
"journal": "Mycopathologia",
"keywords": "Rare yeasts; Trichosporon; Voriconazole",
"medline_ta": "Mycopathologia",
"mesh_terms": "D000935:Antifungal Agents; D001487:Basidiomycota; D006801:Humans; D016867:Immunocompromised Host; D014034:Toes; D014250:Trichosporon; D060586:Trichosporonosis",
"nlm_unique_id": "7505689",
"other_id": null,
"pages": "705-708",
"pmc": null,
"pmid": "32705416",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Trichosporonosis Presenting as an Exophytic Cutaneous Mass Lesion.",
"title_normalized": "trichosporonosis presenting as an exophytic cutaneous mass lesion"
} | [
{
"companynumb": "US-MYLANLABS-2021M1079612",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "The authors present the case of en bloc resection of a clival-C2 atypical teratoid/rhabdoid tumor. These aggressive lesions of early childhood generally occur in the cerebellum or cerebral hemispheres. This 7-year-old boy presented with pain on turning his head and was found to have a clival-C2 mass. A metastatic workup was negative for disseminated disease. A transoral biopsy procedure revealed an atypical teratoid/rhabdoid tumor on histological examination. The tumor was resected via a transoral approach, and the patient's spine was stabilized with posterior instrumented fusion from the occiput to C-5. Postoperatively, the patient underwent 16 months of chemotherapy along with 6 weeks of overlapping radiation therapy. Twenty-seven months after the initial surgery he presented with leg pain and was found to have a solitary metastatic lesion at the conus medullaris. There was no local recurrence at the clivus. The conus tumor was resected and found to be consistent with the primary tumor. Several months later the patient presented with disseminated intrathecal disease and ultimately died 42 months after the initial resection.",
"affiliations": "Department of Neurosurgery, Children's Hospital of Philadelphia, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-4399, USA.",
"authors": "Heuer|Gregory G|GG|;Kiefer|Heather|H|;Judkins|Alexander R|AR|;Belasco|Jean|J|;Biegel|Jaclyn A|JA|;Jackson|Eric M|EM|;Cohen|Marc|M|;O'Malley|Bert W|BW|;Storm|Phillip B|PB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3171/2009.8.PEDS08421",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1933-0707",
"issue": "5(1)",
"journal": "Journal of neurosurgery. Pediatrics",
"keywords": null,
"medline_ta": "J Neurosurg Pediatr",
"mesh_terms": "D001707:Biopsy, Needle; D001933:Brain Stem; D002574:Cervical Vertebrae; D002648:Child; D003388:Cranial Fossa, Posterior; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D012086:Reoperation; D018335:Rhabdoid Tumor; D019292:Skull Base Neoplasms; D013116:Spinal Cord; D013117:Spinal Cord Compression; D013123:Spinal Fusion; D013125:Spinal Neoplasms; D013724:Teratoma",
"nlm_unique_id": "101463759",
"other_id": null,
"pages": "75-9",
"pmc": null,
"pmid": "20043739",
"pubdate": "2010-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15735125;19064966;17219838;18401564;9737241;15803379;15105654;2927597;17465367;18976066;12142780;16459991;18076320;9202775;18424980;10088024;7716628;8683283;16319599;15254056;3193195;12494353",
"title": "Surgical treatment of a clival-C2 atypical teratoid/rhabdoid tumor.",
"title_normalized": "surgical treatment of a clival c2 atypical teratoid rhabdoid tumor"
} | [
{
"companynumb": "US-RECORDATI RARE DISEASES INC.-US-R13005-18-00086",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"dr... |
{
"abstract": "BACKGROUND\nPlacebo-controlled trials indicate that cytisine, a partial agonist that binds the nicotinic acetylcholine receptor and is used for smoking cessation, almost doubles the chances of quitting at 6 months. We investigated whether cytisine was at least as effective as nicotine-replacement therapy in helping smokers to quit.\n\n\nMETHODS\nWe conducted a pragmatic, open-label, noninferiority trial in New Zealand in which 1310 adult daily smokers who were motivated to quit and called the national quitline were randomly assigned in a 1:1 ratio to receive cytisine for 25 days or nicotine-replacement therapy for 8 weeks. Cytisine was provided by mail, free of charge, and nicotine-replacement therapy was provided through vouchers for low-cost patches along with gum or lozenges. Low-intensity, telephone-delivered behavioral support was provided to both groups through the quitline. The primary outcome was self-reported continuous abstinence at 1 month.\n\n\nRESULTS\nAt 1 month, continuous abstinence from smoking was reported for 40% of participants receiving cytisine (264 of 655) and 31% of participants receiving nicotine-replacement therapy (203 of 655), for a difference of 9.3 percentage points (95% confidence interval, 4.2 to 14.5). The effectiveness of cytisine for continuous abstinence was superior to that of nicotine-replacement therapy at 1 week, 2 months, and 6 months. In a prespecified subgroup analysis of the primary outcome, cytisine was superior to nicotine-replacement therapy among women and noninferior among men. Self-reported adverse events over 6 months occurred more frequently in the cytisine group (288 events among 204 participants) than in the group receiving nicotine-replacement therapy (174 events among 134 participants); adverse events were primarily nausea and vomiting and sleep disorders.\n\n\nCONCLUSIONS\nWhen combined with brief behavioral support, cytisine was found to be superior to nicotine-replacement therapy in helping smokers quit smoking, but it was associated with a higher frequency of self-reported adverse events. (Funded by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12610000590066.).",
"affiliations": "From the National Institute for Health Innovation (N.W., C.H., V.P., C.B.), the Centre for Tobacco Control Research, Department of Social and Community Health (M.G.), the Department of Pacific Health (V.N.) and the School of Population Health and the School of Pharmacy (J.B.), University of Auckland, Auckland, and the Quit Group, Wellington (B.B.) - all in New Zealand; and Queen Mary University of London, Wolfson Institute of Preventive Medicine, and UK Centre for Tobacco and Alcohol Studies, Barts and the London School of Medicine and Dentistry - all in London (H.M.).",
"authors": "Walker|Natalie|N|;Howe|Colin|C|;Glover|Marewa|M|;McRobbie|Hayden|H|;Barnes|Joanne|J|;Nosa|Vili|V|;Parag|Varsha|V|;Bassett|Bruce|B|;Bullen|Christopher|C|",
"chemical_list": "D000470:Alkaloids; D001392:Azocines; D011807:Quinolizines; C004712:cytisine; D009538:Nicotine",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1407764",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "371(25)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000328:Adult; D000470:Alkaloids; D001392:Azocines; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea; D009538:Nicotine; D011807:Quinolizines; D016540:Smoking Cessation; D061485:Tobacco Use Cessation Devices; D014029:Tobacco Use Disorder; D016896:Treatment Outcome",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "2353-62",
"pmc": null,
"pmid": "25517706",
"pubdate": "2014-12-18",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D065007:Pragmatic Clinical Trial; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cytisine versus nicotine for smoking cessation.",
"title_normalized": "cytisine versus nicotine for smoking cessation"
} | [
{
"companynumb": "NZ-GLAXOSMITHKLINE-NZ2014045382",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "NICOTINE"
},
"drugadditional": null,
... |
{
"abstract": "Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an adverse drug reaction described as the progressive destruction and death of bone tissue of the mandible or maxilla, in the course of bisphosphonate therapy. Orally administered bisphosphonates, widely used for the treatment of osteoporosis, are rarely associated with BRONJ. Instead, the risk greatly increases whether the patient is concomitantly taking steroid and/or immunosuppressant agents. The aims of this paper are to briefly discuss the evidence of the associations between bisphosphonate therapy and BRONJ, and the effects of co-occurring factors such as the presence of rheumatoid arthritis, dental surgery, and concomitant corticosteroid therapy. In particular, we present the case of an elderly woman with BRONJ suffering from rheumatoid arthritis, with a recent dental extraction and with a very unusual complication: a temporal abscess, who was successfully treated.",
"affiliations": "Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Rome, Italy.;Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Rome, Italy.;Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Rome, Italy.;Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Rome, Italy.;Department of Odontology and Maxillofacial Surgery, \"Sapienza\" University, Rome, Italy.;Department of Odontology and Maxillofacial Surgery, \"Sapienza\" University, Rome, Italy.;Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Rome, Italy.;Department of Odontology and Maxillofacial Surgery, \"Sapienza\" University, Rome, Italy.",
"authors": "Manzon|Licia|L|;Ettorre|Evaristo|E|;Viscogliosi|Giovanni|G|;Ippoliti|Stefano|S|;Filiaci|Fabio|F|;Ungari|Claudio|C|;Fratto|Giovanni|G|;Agrillo|Alessandro|A|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "New Zealand",
"delete": false,
"doi": "10.2147/CIA.S67726",
"fulltext": "\n==== Front\nClin Interv AgingClin Interv AgingClinical Interventions in AgingClinical Interventions in Aging1176-90921178-1998Dove Medical Press 10.2147/CIA.S67726cia-9-1409Case ReportBisphosphonate therapy and osteonecrosis of the jaw complicated with a temporal abscess in an elderly woman with rheumatoid arthritis: a case report Manzon Licia 1Ettorre Evaristo 1Viscogliosi Giovanni 1Ippoliti Stefano 1Filiaci Fabio 2Ungari Claudio 2Fratto Giovanni 1Agrillo Alessandro 21 Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Rome, Italy2 Department of Odontology and Maxillofacial Surgery, “Sapienza” University, Rome, ItalyCorrespondence: Giovanni Viscogliosi, Viale del Policlinico 155, Rome, Italy, Tel +39 33 9824 0918, Email giovanni.viscogliosi@libero.it2014 25 8 2014 9 1409 1413 © 2014 Manzon et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an adverse drug reaction described as the progressive destruction and death of bone tissue of the mandible or maxilla, in the course of bisphosphonate therapy. Orally administered bisphosphonates, widely used for the treatment of osteoporosis, are rarely associated with BRONJ. Instead, the risk greatly increases whether the patient is concomitantly taking steroid and/or immunosuppressant agents. The aims of this paper are to briefly discuss the evidence of the associations between bisphosphonate therapy and BRONJ, and the effects of co-occurring factors such as the presence of rheumatoid arthritis, dental surgery, and concomitant corticosteroid therapy. In particular, we present the case of an elderly woman with BRONJ suffering from rheumatoid arthritis, with a recent dental extraction and with a very unusual complication: a temporal abscess, who was successfully treated.\n\nKeywords\nbisphosphonate-related osteonecrosis of the jawBRONJadverse reactionsteroids\n==== Body\nIntroduction\nBisphosphonate-related osteonecrosis of the jaw (BRONJ) is an adverse drug reaction described as the progressive destruction and death of bone that affects the mandible or maxilla of patients exposed to treatment with nitrogen-containing bisphosphonates, in the absence of a previous radiation treatment.1 Currently, bisphosphonates are used in all cases in which it is deemed necessary to prevent bone resorption. They are administered by intravenous injection to treat metastatic osteolytic problems caused by several conditions (ie, multiple myeloma, bone metastasis by solid tumors with or without hypercalcemia, such as breast cancer, prostate cancer, cancer of the kidney or lung, or Paget’s disease).2 They are also used in cases of low mineral bone density such as in post-menopausal osteoporosis or in osteopenia.3\n\nAll bisphosphonates, in particular the amino-bisphosphonates, have high affinity for bone mineral crystals and accumulate in the bone matrix. Bisphosphonates inhibit the enzyme farnesyl-diphosphate-synthase, causing cytoskeletal alterations, inducing apoptosis of the osteoclasts and reducing the bone resorption capacity of these cells.4–6 The half-life into the general circulation is short (from 30 minutes to 2 hours), but the presence of nitrogen in their formulation makes their metabolization difficult, leading to their accumulation in bones. Therefore, once the drugs are incorporated into bone tissue, they can persist for up to 10 years.7,8 Recent studies have shown that bisphosphonates inhibit oral epithelial cell migration, causing a delay of wound healing.9–12\n\nUncertain are the therapeutic possibilities, which up until today appear inadequate. Up until this point, no therapy exists which allows for the complete resolution/healing of lesion at 100%. Osteonecrosis involves only the maxillary bones, because these mostly undergo remodeling with respect to all the other bones in the body and present a higher uptake of bisphosphonates, which here become quickly concentrated and in higher quantities.1 The most affected parts are the mandible and, particularly, the alveolar bone. When in the bone, there has been an accumulation of bisphosphonates sufficient to reach the toxicity threshold for osteoclastic activity and migration inhibition, if surgical or inflammatory damage sets in, the alveolar bone is unable to react.13,14\n\nThere will be difficulty or absence of the healing process, leading to necrosis. The mucosa above begins to lack vascularization from the underlying bone, and bone exposition occurs. The consequence will be bacterial colonization with osteomyelitis. The bacterial strains isolated in the case of BRONJ, are the same that produce periodontal disease or dental abscesses. Actinomyces bacteria is the most frequently isolated strain.15\n\nLocal risk factors include extractions, dental implant placement, periapical surgery, and periodontal surgery involving bone injury. The threshold to inhibit wound bone healing depends on the total quantity of bone mineral in which bisphosphonates are stored: smaller sized patients are more affected than larger sized ones.16\n\nOrally administered bisphosphonates require longer times for the development of BRONJ: 3 years according to Marx et al14 and 1 year in smaller sized patients, according to Sedghizadeh et al.16 The duration of bisphosphonate treatment and the potency of the drug, may also influence the risk of BRONJ. It should be noted that the association of two or more amino-bisphosphonates, and the association with corticosteroids, particularly prednisone taken by subjects affected by rheumatoid arthritis (RA), which mainly affects women, polimyosite, or systemic lupus erythematosus, certainly increases the risk of BRONJ setting in.\n\nRA is considered an important contributing factor for BRONJ, even though the relationship between these diseases has not yet fully been understood. Bone tissue damage and loss are among the typical features of RA.17 The main factors that contribute to cause osteoporosis in patients with RA include glucocorticoid therapy and patient immobility.18,19 Corticosteroid-induced osteoporosis is the most common iatrogenic cause of secondary osteoporosis, and cumulative corticosteroid treatment increases the risk of osteoporosis: in fact 40% of these patients are affected by generalized osteoporosis, mostly after menopause.20 Studies on the effects of bisphosphonate therapy on bone loss due to RA indicate that bisphosphonates are effective in preventing bone loss in patients with RA treated with glucocorticoids. Results from the literature show that BRONJ is triggered by dental surgery procedures (51.7%) or lesions appearing spontaneously (41.38%) in patients affected by RA and treated with oral bisphosphonate.21\n\nCase report\nA 68-year-old woman was referred on January 2014 to the Department of Cranio-Maxillo-Facial Surgery of our hospital with difficulty on mouth opening, trismus, fever, headache, and general malaise. The patient’s past medical history was relevant for RA, treated from 1993 with gold salts, methotrexate, leflunomide, daily oral calcium and vitamin D3, and prednisone. From 2005, after multiple vertebral fractures caused by severe osteoporosis, the patient started a treatment with ibandronic acid, 150 mg, one tablet once a month. In March 2013, following an abscess in 46 zone, her dentist extracted the tooth element.\n\nThe patient showed a noticeable right-sided mandibular abscess and a right-sided soft temporal swelling and redness (Figure 1A), with severe pain on mouth opening.\n\nThe oral examination revealed the presence of an abscess in the posterior mandible, in the area of the recent extraction (Figure 1B), with pus leaking from the empty alveolus. Infection and swelling was extending distally to the back molar 47.\n\nRadiologic exams (orthopantomography and CT [computed tomography] scan) (Figure 2A and B) showed a widespread zone of radiolucency, rarefaction of trabecular bone with a large osteo-necrotic lesion around the extraction site, which extended posteriorly to include the adjacent second molar, persistent extraction socket, and bone sequestra. All these data allowed us to diagnose advanced BRONJ in the right mandibular zone. Magnetic resonance imaging (Figure 3) showed a temporal abscess located lateral to the alveolar crista of the upper jaw and upwards deep into the temporal fascia.\n\nBefore admission to hospital, the patient was treated with amoxicillin and clavulanic acid (875 mg and 125 mg respectively) injection.\n\nAfter 2 days, a surgical toilette of necrotic bone in mandibular angle was performed with extraction of the second molar. The temporal fascia abscess was drained through a temporal incision. Microbiological samples showed an Actinomyces infection, with susceptibility to ampicillin, meropenem, and metronidazole, and with resistance to amoxicillin and clavulanic acid. Surgical incision was not saturated, and daily medication with irrigation on sodium hypochlorite and positioning of gauze of ialuronic acid was made twice a week. After microbiological analyses, which showed a resistance to antibiotic therapy, amoxicillin and clavulanic acid was substituted with meropenem 2 g and metronidazole 500 mg day.\n\nAfter 3 weeks of therapy, the patient was discharged and was followed up monthly in our clinic. Three months after the hospitalization, the patient had complete resolution of infection.\n\nDiscussion and conclusion\nWhile the correlation between use of intravenous injection bisphosphonates and the development of BRONJ is by now widely affirmed in the literature and was reported from 2003 by Marx,4 less clear and predictable is the correlation between BRONJ and orally administered bisphosphonates.22 What remains secure, however, is that dental surgical interventions on patients who take bisphosphonates on a long-term basis orally, present an elevated risk of BRONJ. The concomitant taking of medications containing corticosteroids, as in the case of RA, increases this risk due to the synergistic action of these drugs on the bone.\n\nCorticosteroid medications act directly on the bone by inhibiting the action of osteoblasts, favoring that of the osteoclasts, and indirectly through hormonal pathways.23\n\nThe concomitant inhibitory action of bisphosphonates and corticosteroid drugs on bone and endothelial cells produce a reduction of the bone turnover rate. Following a surgical trauma due to extraction, this triggers BRONJ. In our case, osteonecrosis was already present before extraction of 46, which has highlighted the osteonecrotic zone.\n\nThe peculiarity of this case consisted of the rare localization of the abscess in the temporal position, which has considerably worsened the health status of the patient. This localization is extremely rare and this is the first case documented in the literature. It may happen that a dental abscess extends along muscles and fascia as occurs in the case of a parapharyngeal abscess or Ludwig’s angina; while it is very unusual, it spreads upward.24 This complication is very dangerous because of risk of thrombosis of the cavernous sinus, and it can even compromise the orbit.25\n\nAlthough the extension of infection into the masticatory space has been observed to frequently extend superiorly against gravity, the pathway remains poorly understood.24,26 A submasseteric pathway aided by mastication forces has been proposed.24 This complication is presumably attributable to the declivous position, which the patient frequently used due to her current state of health. The patient, because she was a long-term sufferer of a severe form of RA, was confined to a wheelchair and bed.\n\nAll in all, BRONJ may be a potentially life-threatening condition occurring in patients on bisphosphonate therapy. This case-report emphasizes the importance of screening patients for BRONJ, when they are prescribed with bisphosphonates and concomitantly present further risk factors for BRONJ such as corticosteroid administration or oral surgery.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 (A) Right-sided mandibular abscess and temporal swelling. (B) Abscess of the mandible affecting the extraction area. The pus is leaking from the empty alveolus. The infection and swelling extend to the second molar.\n\nFigure 2 Panoramic (A) and mandibular (B) CT showing a zone of bone rarefaction. There is a large osteo-necrotic lesion around the extraction site adjacent to the second molar, with persistent extraction socket and bone sequestra.\n\nAbbreviation: CT, computed tomography.\n\nFigure 3 Temporal abscess in the right zone.\n==== Refs\nReferences\n1 Campisi G Lo Russo L Agrillo A Vescovi P Fusco V Bedogni A BRONJ expert panel recommendation of the Italian Societies for Maxillofacial Surgery (SICMF) and Oral Pathology and Medicine (SIPMO) on bisphosphonate-related osteonecrosis of the jaws: risk assessment, preventive strategies and dental management Ital J Maxillofac Surg 2011 22 103 124 \n2 Ruggiero SL Dodson TB Assael LA Landesberg R Marx RE Mehrotra B Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw J Oral Maxillofac Surg 2009 35 119 130 \n3 Kanis JA McCloskey EV Johansson H Cooper C Rizzoli R Reginster JY Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF) European guidance for the diagnosis and management of osteoporosis in postmenopausal women Osteoporos Int 2013 24 23 57 23079689 \n4 Marx RE Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic J Oral Maxillofac Surg 2003 61 1115 1117 12966493 \n5 Little DG Peat RA Mcevoy A Williams PR Smith EJ Baldock PA Zoledronic acid treatment results in retention of femoral head structure after traumatic osteonecrosis in young Wistar rats J Bone Miner Res 2003 18 2016 2022 14606515 \n6 Kimachi K Kajiya H Nakayama S Ikebe T Okabe K Zoledronic acid inhibits RANK expression and migration of osteoclast precursors during osteoclastogenesis Naunyn Schmiedebergs Arch Pharmacol 2011 383 297 308 21225243 \n7 Martin TJ Grill V Bisphosphonates – mechanisms of action Aust Prescr 2000 23 130 132 \n8 Roelofs AJ Thompson K Ebetino FH Rogers MJ Coxon FP Bisphoshonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages Curr Pharm Des 2010 16 2950 2960 20722616 \n9 Pabst AM Ziebart T Koch FP Taylor KY Al-Nawas B Walter C The influence of bisphosphonates on viability, migration, and apoptosis of human oral keratinocytes – in vitro study Clin Oral Invest 2012 16 87 93 \n10 Kobayashi Y Hiraga T Ueda A Zoledronic acid delays wound healing of the tooth extraction socket, inhibits oral epithelial cell migration, and promotes proliferation and adhesion to hydroxyapatite of oral bacteria, without causing osteonecrosis of the jaw, in mice J Bone Miner Metab 2010 28 165 175 19882100 \n11 Ziebart T Pabst A Klein MO Bisphosphonates: restrictions for vasculogenesis and angiogenesis: inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro Clin Oral Investig 2011 15 105 111 \n12 Cozin M Pinker BM Solemani K Novel therapy to reverse the cellular effects of bisphosphonates on primary human oral fibroblasts J Oral Maxillofac Surg 2011 69 2564 2578 21807448 \n13 Landesberg R Cozin M Cremers S Inhibition of oral mucosal cell wound healing by bisphosphonates J Oral Maxillofac Surg 2008 66 839 847 18423269 \n14 Marx RE Sawatari Y Fortin M Broumand V Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment J Oral Maxillofac Surg 2005 63 1567 1575 16243172 \n15 Lee CY Pien FD Suzuki JB Identification and treatment of bisphosphonate-associated actinomycotic osteonecrosis of the jaws Implant Dent 2011 20 331 336 21881516 \n16 Sedghizadeh PP Stanley K Caligiuri M Hofkes S Lowry B Shuler CF Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: an institutional inquiry J Am Dent Assoc 2009 140 61 66 19119168 \n17 Breuil V Euller-Ziegler L Bisphosphonate therapy in rheumatoid arthritis Joint Bone Spine 2006 73 349 354 16616575 \n18 Shibuya K Hagino H Morio Y Teshima R Cross-sectional and longitudinal study of osteoporosis in patients with rheumatoid arthritis Clin Rheumatol 2002 21 150 158 12086167 \n19 Haugeberg G Orstavik RE Uhlig T Falch JA Halse JI Kvien TK Bone loss in patients with rheumatoid arthritis: results from a population-based cohort of 366 patients followed up for two years Arthritis Rheum 2002 46 1720 1728 12124854 \n20 Clarke BL Corticosteroid-induced osteoporosis: an update for dermatologists Am J Clin Dermatol 2012 13 167 190 22393910 \n21 Conte-Neto N Bastos AS Marcantonio RA Junior EM Epidemiological aspects of rheumatoid arthritis patients affected by oral bisphosphonate- related osteonecrosis of the jaws Head Face Med 2012 1 5 8 22376948 \n22 Mavrokokki T Cheng A Stein B Goss A Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia J Oral Maxillofac Surg 2007 65 415 423 17307586 \n23 Canalis E Clinical review 83: Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis J Clin Endocrinol Metab 1996 81 3441 3447 8855781 \n24 Schuknecht B Stergiou G Graetz K Masticator space abscess derived from odontogenic infection: imaging manifestation and pathways of extension depicted by CT and MR in 30 patients Eur Radiol 2008 18 1972 1979 18418606 \n25 Kim IK Kim JR Jang KS Moon YS Park SW Orbital abscess from an odontogenic infection Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007 103 e1 e6 17178478 \n26 Jones KC Silver J Millar WS Mandel L Chronic submasseteric abscess: anatomic, radiologic, and pathologic features AJNR Am J Neuroradiol 2003 24 1159 1163 12812946\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-9092",
"issue": "9()",
"journal": "Clinical interventions in aging",
"keywords": "BRONJ; adverse reaction; bisphosphonate-related osteonecrosis of the jaw; steroids",
"medline_ta": "Clin Interv Aging",
"mesh_terms": "D000038:Abscess; D000368:Aged; D000900:Anti-Bacterial Agents; D001172:Arthritis, Rheumatoid; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008336:Mandibular Diseases; D011862:Radiography, Panoramic; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101273480",
"other_id": null,
"pages": "1409-13",
"pmc": null,
"pmid": "25187700",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17178478;19119168;12812946;12966493;16243172;19961450;18423269;22393910;23079689;21225243;18418606;20024592;21225298;19882100;21807448;17307586;20722616;12124854;22376948;8855781;12086167;14606515;16616575;21881516",
"title": "Bisphosphonate therapy and osteonecrosis of the jaw complicated with a temporal abscess in an elderly woman with rheumatoid arthritis: a case report.",
"title_normalized": "bisphosphonate therapy and osteonecrosis of the jaw complicated with a temporal abscess in an elderly woman with rheumatoid arthritis a case report"
} | [
{
"companynumb": "IT-ROXANE LABORATORIES, INC.-2014-RO-01665RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBANDRONIC ACID"
},
"druga... |
{
"abstract": "We retrospectively reviewed 14 children with active blastomycosis. Pulmonary disease occurred in 86% of the cohort and extrapulmonary dissemination was noted in 46%. Urine blastomycosis or histoplasmosis antigens were positive in all tested patients. Acute kidney injury was common in patients who were treated with amphotericin. Mortality tended to be associated with a delay in diagnosis.",
"affiliations": "Departments of Pediatrics and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ilinois.;Greater Roslindale Medical & Dental Center, Roslindale, Massachusetts.;Departments of Pediatrics and.;Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio.;Departments of Pediatrics and.;Departments of Pediatrics and.",
"authors": "Anderson|Evan J|EJ|;Ahn|Paul B|PB|;Yogev|Ram|R|;Jaggi|Preeti|P|;Shippee|Deanna B|DB|;Shulman|Stanford T|ST|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jpids/pis107",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2048-7193",
"issue": "2(4)",
"journal": "Journal of the Pediatric Infectious Diseases Society",
"keywords": "Amphotericin; Blastomycosis; Itraconazole; Pediatric",
"medline_ta": "J Pediatric Infect Dis Soc",
"mesh_terms": null,
"nlm_unique_id": "101586049",
"other_id": null,
"pages": "386-90",
"pmc": null,
"pmid": "26619502",
"pubdate": "2013-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Blastomycosis in Children: A Study of 14 Cases.",
"title_normalized": "blastomycosis in children a study of 14 cases"
} | [
{
"companynumb": "US-JNJFOC-20141207996",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "A patient without clinical symptoms had a mammogram in October 2008. The procedure caused intense persistent pain, swelling and development of a haematoma following mediolateral left breast compression. Three months later, a 9×11 cm mass developed within the same region. Core biopsies showed a necrotizing high-grade ductal carcinoma, with a high mitotic index. Owing to its extensive size, the patient began chemotherapy followed by trastuzumab and later radiotherapy to obtain clear margins for a subsequent mastectomy. The mastectomy in October 2009 revealed an inflammatory carcinoma, with 2 of 3 nodes infiltrated by the tumour. The stage IIIC tumour, oestrogen and progesterone receptor negative, was highly HER2 positive. A recurrence led to further chemotherapy in February 2011. In July 2011, another recurrence was removed from the mastectomy scar. She died of progressive disease in 2012. In this article, we discuss the potential influence of compression on the natural history of the tumour.",
"affiliations": "Department of Biology, University of Victoria, Victoria, British Columbia, Canada.;School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.;Department of Biology, University of Victoria, Victoria, British Columbia, Canada.;Department of Biology, University of Victoria, Victoria, British Columbia, Canada.",
"authors": "van Netten|Johannes Pieter|JP|;Hoption Cann|Stephen|S|;Thornton|Ian|I|;Finegan|Rory|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001940:Breast; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D003131:Combined Modality Therapy; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D006406:Hematoma; D006801:Humans; D008327:Mammography; D008408:Mastectomy; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27581236",
"pubdate": "2016-08-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12565189;21421519;2736178;15230759;9472641;22585698;10767831;3659351;23593347;23789678;18794114;15195650;10188881;2034168;12932384;10604743;9262257",
"title": "Growing concern following compression mammography.",
"title_normalized": "growing concern following compression mammography"
} | [
{
"companynumb": "CA-BAXTER-2017BAX028206",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "The best therapy regimen for refractory obstetrical antiphospholipid syndrome remains to be determined. Additional treatments with steroids, plasma exchanges and immunoglobulins failed to show any beneficial effect. We present a case of a woman who had a better pregnancy outcome after the administration of hydroxychloroquine (HCQ) as additional treatment. Furthermore, we highlighted that HCQ was able to dramatically reduce the antiphospholipid antibodies levels.",
"affiliations": "Department of Obstetrics and Gynecology, Catholic University of Rome, Italy.;Department of Obstetrics and Gynecology, Catholic University of Rome, Italy.;Department of Obstetrics and Gynecology, Catholic University of Rome, Italy.;Department of Obstetrics and Gynecology, Catholic University of Rome, Italy. Electronic address: elviradp1@hotmail.it.;Department of Obstetrics and Gynecology, Catholic University of Rome, Italy.;Department of Obstetrics and Gynecology, Catholic University of Rome, Italy.;Department of Obstetrics and Gynecology, Catholic University of Rome, Italy.;Department of Neonatology, Catholic University of Rome, Italy.",
"authors": "De Carolis|S|S|;Botta|A|A|;Salvi|S|S|;di Pasquo|E|E|;Del Sordo|G|G|;Garufi|C|C|;Lanzone|A|A|;De Carolis|M P|MP|",
"chemical_list": "D017152:Antibodies, Antiphospholipid; D006886:Hydroxychloroquine",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1568-9972",
"issue": "14(9)",
"journal": "Autoimmunity reviews",
"keywords": null,
"medline_ta": "Autoimmun Rev",
"mesh_terms": "D000328:Adult; D017152:Antibodies, Antiphospholipid; D016736:Antiphospholipid Syndrome; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D010641:Phenotype; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome",
"nlm_unique_id": "101128967",
"other_id": null,
"pages": "760-2",
"pmc": null,
"pmid": "25936295",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Is there any role for the hydroxychloroquine (HCQ) in refractory obstetrical antiphospholipid syndrome (APS) treatment?",
"title_normalized": "is there any role for the hydroxychloroquine hcq in refractory obstetrical antiphospholipid syndrome aps treatment"
} | [
{
"companynumb": "IT-BAYER-2015-405971",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nWe report the development of acute lymphoblastic leukemia in a patient in whom temozolomide was used for the treatment of a brain tumor. Unlike that of other alkylating agents, the leukemogenic potential of temozolomide is considered to be very low, and very rarely are such cases reported.\n\n\nMETHODS\nA 26-year-old Pakistani man who was treated for glioblastoma with temozolomide in an adjuvant setting was diagnosed to have acute lymphoblastic leukemia one year after stopping temozolomide.\n\n\nCONCLUSIONS\nTemozolomide is a highly active agent, used in the management of high-grade brain neoplasms. The agent is generally regarded to be safe, with an acceptable safety profile. Very few cases of myelodysplasia associated with temozolomide use have been reported. We report here the first case of acute lymphoblastic leukemia, which developed in a young man about one year after he finished taking temozolomide. This should provide further insight into a possible toxicity profile of this alkylating agent. This finding should be of interest to physicians in general and to medical oncologists in particular.",
"affiliations": "Section of Medical Oncology, The Aga Khan University Hospital, Karachi, Pakistan. asim.jshaikh@hotmail.com.",
"authors": "Shaikh|Asim Jamal|AJ|;Masood|Nehal|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1752-1947-4-274",
"fulltext": "\n==== Front\nJ Med Case ReportsJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-4-2742071895410.1186/1752-1947-4-274Case ReportAcute lymphoblastic leukemia subsequent to temozolomide use in a 26-year-old man: a case report Shaikh Asim Jamal 1asim.jshaikh@hotmail.comMasood Nehal 1nehal.masood@aku.edu1 Section of Medical Oncology, The Aga Khan University Hospital, Karachi, Pakistan2010 18 8 2010 4 274 274 21 11 2009 18 8 2010 Copyright ©2010 Shaikh and Masood; licensee BioMed Central Ltd.2010Shaikh and Masood; 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\nWe report the development of acute lymphoblastic leukemia in a patient in whom temozolomide was used for the treatment of a brain tumor. Unlike that of other alkylating agents, the leukemogenic potential of temozolomide is considered to be very low, and very rarely are such cases reported.\n\nCase Presentation\nA 26-year-old Pakistani man who was treated for glioblastoma with temozolomide in an adjuvant setting was diagnosed to have acute lymphoblastic leukemia one year after stopping temozolomide.\n\nConclusion\nTemozolomide is a highly active agent, used in the management of high-grade brain neoplasms. The agent is generally regarded to be safe, with an acceptable safety profile. Very few cases of myelodysplasia associated with temozolomide use have been reported. We report here the first case of acute lymphoblastic leukemia, which developed in a young man about one year after he finished taking temozolomide. This should provide further insight into a possible toxicity profile of this alkylating agent. This finding should be of interest to physicians in general and to medical oncologists in particular.\n==== Body\nIntroduction\nSurvival rates from aggressive, relapsed, refractory, or high-grade brain tumors are generally poor, with the median survival for some being less than one year [1]. With increased survival, however, the long-term toxicities of the available chemotherapeutic agents used in aggressive brain cancers have become more prominent [2]. Alkylating agents remain the most active agents known for the treatment of aggressive and high-grade brain neoplasms. Treatment-related myelodysplasia (t-MDS) and acute leukemia (t-AL) have remained a concern of prolonged exposure to alkylating agents [3]. Temozolomide (TMZ) is an oral second-generation alkylating agent with activity against recurrent high-grade gliomas and has been considered efficacious and relatively safe [4]. Here we report a case of t-ALL in a patient who received TMZ for the treatment of high-grade mixed glioma.\n\nCase Report\nA 26-year-old Pakistani man presented with history of new-onset seizures. Magnetic resonance imaging (MRI) of the brain revealed a contrast-enhancing lesion in the right frontoparietal region with compressions and a shift of the midline. The mass was resected in August 2007 and confirmed to be a mixed glioma with components of both astrocytoma and oligodendroglioma, WHO grade II. About six weeks after surgery, the patient was brought back with a new history of seizures. An MRI examination revealed a gross local recurrence at the site of the previous surgery, which was infiltrating within the sulci of the brain matter. Based on the clinical behavior and surgical unresectability of the tumor, he was treated with concurrent chemoradiation therapy (radiation: 6000 cGY/temozolomide, 75 mg/m2). He showed an excellent response to concurrent chemoradiotherapy, with a complete disappearance of the recurred lesion. He was given a total of six cycles of TMZ (150 mg/m2, days one to five, every 28 days). He completed chemotherapy in January 2008 and remained well, without evidence of recurrence, on surveillance MRI scans. He recently came in complaining of easy bruisability; blood counts revealed an elevated white blood cell count (total leukocyte count; 20,000 per deciliter; 16% neutrophils; 78% lymphocytes) and thrombocytopenia (platelet count, 16,000 per deciliter). Bone-marrow aspirate revealed diffuse infiltration with blast cells consistent with acute leukemia. Peripheral blood flow cytometry on immunophenotyping with five-color cytomics (fc500 Beckman Coulter flow cytometer) showed this population of cells with bright reactivity with Pan-T-markers (that is, CD5, CD7, and cytoplasm cCD3, along with CD45). Positivity of this population with Tdt was also very prominent, so immunophenotypic results were consistent with precursor-T-acute lymphoblastic leukemia (Pre-T-ALL). Bone marrow cytogenetics revealed a normal karyotype and negative Philadelphia chromosome. He is currently undergoing treatment.\n\nDiscussion\nWe report, to the best of our best knowledge and search of the literature, what appears to be the first reported case of Philadelphia-negative true ALL developing subsequent to the use of TMZ. Some case reports exist of myelodyplasia rapidly transforming in undifferentiated leukemia [3,5] and one report of Ph negative T-ALL in a patient receiving treatment [6].\n\nTMZ is an oral alkylating agent that is now known to be active against a variety of CNS neoplasms. After oral absorption, it spontaneously hydrolyzes to methyltriazen-1-yl imidazole-4-carboxamide (MTIC). MTIC degrades to a highly reactive cation that methylates guanines in DNA at the O6 position, causing base-pair mismatch. Unsuccessful cycles of mismatch repair eventually lead to breaks and permanent nicks in the daughter strand, preventing mitotic division, and the cell undergoes apoptosis [7,8]. The action of TMZ has been shown to be augmented in the concurrent presence of radiation, so the proof of efficacy and superiority of TMZ has led to a paradigm shift in the management of aggressive CNS gliomas [1]. Although the recommended treatment-cycle length is six months after initial treatment, with concurrent chemoradiotherapy, some neuro-oncologists prefer to use it indefinitely [9]. A recent survey of physicians who used TMZ for more than one year, on average, found it to be completely safe, except for grade II and III myelosuppression [10]. All alkylating agents are considered to carry a five to ten percent mutagenic risk potential for development of myeloid leukemia, but not for lymphoblastic leukemia. TMZ is a new alkylating agent; its safety profile and lack of data on any mutagenic potential has led to its incorporation in a large number of studies, for the range from malignant gliomas to malignant melanomas [11]. Little consistent data exist regarding the toxicity of TMZ, so questions have been raised about its mutagenic potential. Some clinical trials have started to include carcinogenic potential as a point of assessment in long-term safety monitoring of the drug [11]. Hartmut Geiger et al. [12] published data that reveal the mutagenic potential of TMZ for bone marrow cells in vivo in the mouse model system.\n\nConclusion\nTMZ has unequivocally shown its therapeutic potential in randomized clinical trials as an effective, relatively safe, and generally well-tolerated therapy for aggressive CNS neoplasms, resulting in better overall survival. Because it is a relatively new and unique alkylating agent, the short-term and long-term data regarding safety, especially leukemogenic potential, must have further time to mature. Although the association is unlikely to be a random finding, the association between TMZ and treatment-related leukemia deserves further study.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nConflict of Interest\nBoth authors declare no conflict of interest with reference to material published.\n\nAuthors' contributions\nAJS wrote the manuscript, searched the literature, and aided in patient coordination. NM wrote the manuscript and searched the literature. Both authors read and approved the final manuscript.\n==== Refs\nStupp R Mason WP van den Bent MJ Weller M Fisher B Taphoorn MJ Belanger K Brandes AA Marosi C Bogdahn U Curschmann J Janzer RC Ludwin SK Gorlia T Allgeier A Lacombe D Cairncross JG Eisenhauer E Mirimanoff RO European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma N Engl J Med 2005 352 987 996 10.1056/NEJMoa043330 15758009 \nSu YW Chang MC Chiang MF Hsieh RK Treatment-related myelodysplastic syndrome after temozolomide for recurrent high-grade glioma J Neuro-oncol 2005 71 315 318 10.1007/s11060-004-2028-0 \nArmitage JO Carbone PP Connors JM Levine A Bennett JM Kroll S Treatment-related myelodysplasia and acute leukemia in non-Hodgkin's lymphoma patients J Clin Oncol 2003 21 897 906 10.1200/JCO.2003.07.113 12610191 \nMacdonald DR Temozolomide for recurrent high-grade glioma Semin Oncol 2001 28 12 \nNoronha V Berliner N Ballen KK Lacy J Kracher J Baehring J Henson JW Treatment-related myelodysplasia/AML in a patient with a history of breast cancer and an oligodendroglioma treated with temozolomide: case study and review of the literature Neuro-oncology 2006 8 280 283 10.1215/15228517-2006-003 16728498 \nDe Vita S De Matteis S Laurenti L Chiusolo P Reddiconto G Fiorini A Leone G Sica S Secondary Ph+ acute lymphoblastic leukemia after temozolomide Ann Hematol 2005 84 760 762 10.1007/s00277-005-1093-6 16044311 \nHegi ME Diserens AC Gorlia T Hamou MF de Tribolet N Weller M Kros JM Hainfellner JA Mason W Mariani L MGMT gene silencing and benefit from temozolomide in glioblastoma N Engl J Med 2005 352 997 1003 10.1056/NEJMoa043331 15758010 \nDarkes MJM Plosker GL Jarvis B Temozolomide a review of its use in the treatment of malignant gliomas Am J Cancer 2002 1 55 80 10.2165/00024669-200201010-00006 \nVillano JL Seery TE Bressler LR Temozolomide in malignant gliomas: current use and future targets Cancer Chemother Pharmacol 2009 64 647 655 10.1007/s00280-009-1050-5 19543728 \nHau P Koch D Hundsberger T Marg E Bauer B Rudolph R Rauch M Brenner A Rieckmann P Schuth J Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma Neurology 2007 68 688 690 10.1212/01.wnl.0000255937.27012.ee 17325277 \nClinical Trials.gov http://clinicaltrials.gov/ct2/results?term=temozolomide\nGeiger H Schleimer D Nattamai KJ Dannenmann SR Davies SM Weiss BD Mutagenic potential of temozolomide in bone marrow cells in vivo Blood 2006 107 3010 3011 10.1182/blood-2005-09-3649 16554488\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "4()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "274",
"pmc": null,
"pmid": "20718954",
"pubdate": "2010-08-18",
"publication_types": "D016428:Journal Article",
"references": "15758010;19543728;12610191;16554488;15735923;15758009;16044311;11550133;16728498;17325277",
"title": "Acute lymphoblastic leukemia subsequent to temozolomide use in a 26-year-old man: a case report.",
"title_normalized": "acute lymphoblastic leukemia subsequent to temozolomide use in a 26 year old man a case report"
} | [
{
"companynumb": "PK-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-165943",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"dr... |
{
"abstract": "Vedolizumab (VDZ) inhibits α4β7 integrins and is used to target intestinal immune responses in patients with inflammatory bowel disease, which is considered to be relatively safe. Here we report on a fatal complication following VDZ administration. A 64-year-old female patient with ulcerative colitis (UC) refractory to tumor necrosis factor inhibitors was treated with VDZ. One week after the second VDZ infusion, she was admitted to hospital with severe diarrhea and systemic inflammatory response syndrome (SIRS). Blood stream infections were ruled out, and endoscopy revealed extensive ulcerations of the small intestine covered with pseudomembranes, reminiscent of invasive candidiasis or mesenteric ischemia. Histology confirmed subtotal destruction of small intestinal epithelia and colonization with Candida. Moreover, small mesenteric vessels were occluded by hyaline thrombi, likely as a result of SIRS, while perfusion of large mesenteric vessels was not compromised. Beta-D-glucan concentrations were highly elevated, and antimycotic therapy was initiated for suspected invasive candidiasis but did not result in any clinical benefit. Given the non-responsiveness to anti-infective therapies, an autoimmune phenomenon was suspected and immunosuppressive therapy was escalated. However, the patient eventually died from multi-organ failure. This case should raise the awareness for rare but severe complications related to immunosuppressive therapy, particularly in high risk patients.",
"affiliations": "Dept. of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.;Institute of Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.;Endopraxis Markgräflerland, Müllheim, Germany.;Helios Klinik Müllheim, Müllheim, Germany.;Center for Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.;Dept. of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.;Dept. of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.;Dept. of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.",
"authors": "Monasterio|Carmen|C|;Schmitt-Gräff|Annette|A|;Pohl|Matthias|M|;Truschel|Thomas|T|;Warnatz|Klaus|K|;Kreisel|Wolfgang|W|;Thimme|Robert|R|;Hasselblatt|Peter|P|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; C543529:vedolizumab",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0043-111805",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0044-2771",
"issue": "55(10)",
"journal": "Zeitschrift fur Gastroenterologie",
"keywords": null,
"medline_ta": "Z Gastroenterol",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D003093:Colitis, Ulcerative; D004751:Enteritis; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D007421:Intestine, Small; D018746:Systemic Inflammatory Response Syndrome",
"nlm_unique_id": "0033370",
"other_id": null,
"pages": "1014-1020",
"pmc": null,
"pmid": "28655067",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal ulcerative enteritis of the small intestine in a patient with ulcerative colitis treated with vedolizumab.",
"title_normalized": "fatal ulcerative enteritis of the small intestine in a patient with ulcerative colitis treated with vedolizumab"
} | [
{
"companynumb": "DE-MYLANLABS-2018M1020573",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BISOPROLOL"
},
"drugadditional": null,
... |
{
"abstract": "Exogenous ochronosis is a cutaneous condition characterized by blue-black pigmentation resulting as a complication of long-term application of skin-lightening creams containing hydroquinone and other substances such as quinine, phenol and mercury derivatives. We report a case of a 55-year-old woman who developed exogenous ochronosis as a result of prolonged use of topical hydroquinone for 5 years, characterized by greyish hyperpigmented patches on the nose and cheeks. The diagnosis was confirmed histologically. Treatment with picosecond laser resulted in marked clinical improvement together with improvement in overall texture and quality of the skin.",
"affiliations": "Clínica Dermatológica Isela Méndez, Ciudad de México, México.;Dermatological Surgery & Laser Unit, St John's Institute of Dermatology, Guys and St Thomas' Hospital, London, UK.;Clínica Dermatológica Isela Méndez, Universidad de Oriente, Anzoátegui, Vzla.;Clínica Dermatológica Isela Méndez, Ciudad de México, México.",
"authors": "Méndez Baca|Isela|I|http://orcid.org/0000-0003-2863-5561;Al-Niaimi|Firas|F|;Colina|Claudia|C|;Anuzita|Alexander|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/jocd.12834",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-2130",
"issue": null,
"journal": "Journal of cosmetic dermatology",
"keywords": "hydroquinone; melasma; ochronosis; picosecond laser",
"medline_ta": "J Cosmet Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101130964",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30556284",
"pubdate": "2018-12-16",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A case of ochronosis successfully treated with the picosecond laser.",
"title_normalized": "a case of ochronosis successfully treated with the picosecond laser"
} | [
{
"companynumb": "MX-BAUSCH-BL-2019-000081",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "KOJIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCongenital cytomegalovirus (CMV) infection is one of the most common during pregnancy. The infection, particularly in the first trimester, is associated with important sequelae in up to half of the children. Valaciclovir and immunoglobulin have been tested separately for the treatment of fetal CMV infection with relative success. Nevertheless, there is no experience with the simultaneous use of both therapies.\n\n\nMETHODS\ncombination therapy (oral valaciclovir 2 g/6h until the end of pregnancy and intravenous hyperimmune gamma globulin 200 UI/kg) was offered to pregnant women with CMV infection acquired during pregnancy and viral load (VL) in amniotic fluid above 105 copies/ml and/or brain injuries in the ultrasonography. Additional immunoglobulin monthly doses were used in case of ultrasonography or MRI evidence of persistent fetal involvement. Neurological and hearing evaluations of infants were performed at birth and every 3 months during follow-up.\n\n\nRESULTS\n15 pregnant women were enrolled: primary infection, 14, non-primary infection, 1; first trimester, 11, second trimester, 4. Mean gestational age at the start of combination treatment were 23.2 weeks and 29.3 weeks, depending on the infection being diagnosed in the first or the second trimester, respectively. Median VL of CMV-DNA in amniotic fluid was 62.5 × 105 copies/ml. Intrauterine progression of fetal brain lesions was only observed in two cases in which the dose of CMV-HIG was repeated, slowing their progression. Although the treatment has failed to reverse ultrasound fetal lesions, only 3 children were born with hearing impairment and their psychomotor development was consistent with chronological age in all patients but one. Combination therapy was not associated with adverse effects in either the mothers or the fetuses.\n\n\nCONCLUSIONS\nCombination therapy with immunoglobulin and valaciclovir may be a useful alternative in CMV fetal infection, particularly if changes in cerebral echography or high VL in the amniotic fluid are present.",
"affiliations": "Department of Obstetrics and Gynaecology, Maternal-Fetal Medicine Unit, La Paz University Hospital, Madrid, Spain.;Department of Pediatric Infectology, La Paz University Hospital, Madrid, Spain.;Department of Pediatric Infectology, La Paz University Hospital, Madrid, Spain.;Department of Obstetrics and Gynaecology, Maternal-Fetal Medicine Unit, La Paz University Hospital, Madrid, Spain.;Department of Neonatology, La Paz University Hospital, Madrid, Spain.;Department of Obstetrics and Gynaecology, Maternal-Fetal Medicine Unit, La Paz University Hospital, Madrid, Spain.;Department of Pediatric Infectology, La Paz University Hospital, Madrid, Spain.;Department of Obstetrics and Gynaecology, Maternal-Fetal Medicine Unit, La Paz University Hospital, Madrid, Spain.",
"authors": "De la Calle|Maria|M|;Baquero-Artigao|Fernando|F|;Rodríguez-Molino|Paula|P|;Cabanes|Maria|M|;Cabrera|Marta|M|;Antolin|Eugenia|E|;Mellado|Maria José|MJ|;Bartha|José Luis|JL|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/14767058.2020.1815188",
"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": "Congenital cytomegalovirus infection; combination therapy; cytomegalovirus-specific immunoglobulins; fetal and placental pathology; fetal therapy; valaciclovir",
"medline_ta": "J Matern Fetal Neonatal Med",
"mesh_terms": null,
"nlm_unique_id": "101136916",
"other_id": null,
"pages": "1-5",
"pmc": null,
"pmid": "32933353",
"pubdate": "2020-09-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Combined treatment with immunoglobulin and valaciclovir in pregnant women with cytomegalovirus infection and high risk of symptomatic fetal disease.",
"title_normalized": "combined treatment with immunoglobulin and valaciclovir in pregnant women with cytomegalovirus infection and high risk of symptomatic fetal disease"
} | [
{
"companynumb": "ES-GLAXOSMITHKLINE-ES2020GSK192356",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VALACYCLOVIR HYDROCHLORIDE"
},
"drug... |
{
"abstract": "A 70-year-old man underwent a laparoscopic radical prostatectomy with preservation of bladder neck for T3aN0R0 prostate cancer in December 2009, (Gleason 4+3, negative surgical margin). His postoperative prostate-specific antigen rose from 0.01 to 0.05 ng/mL over 19 months. He had salvage radiotherapy in May 2012. Following radiotherapy, his urinary control worsened and he needed to wear up to four pads per day. He was being considered for an artificial urinary sphincter placement. He was also taking doxazosin for hypertension, which was discontinued. After stopping the doxazosin, his urinary control improved and he did not require any further intervention. Doctors should be aware of the effect of α-blockers on the internal sphincter and the risk of incontinence in patients post-prostate cancer treatment.",
"affiliations": "Department of MSc Advanced Surgical Practice, Cardiff University, Cardiff, UK Department of Urology, Wirral University Hospital, Wirral, UK.;Department of Urology, Wirral University Hospital, Wirral, UK.",
"authors": "Sarkar|Debashis|D|;Kumar|Manal|M|",
"chemical_list": "D000959:Antihypertensive Agents; D017430:Prostate-Specific Antigen; D017292:Doxazosin",
"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": "D000368:Aged; D000959:Antihypertensive Agents; D017292:Doxazosin; D006801:Humans; D010535:Laparoscopy; D008297:Male; D017430:Prostate-Specific Antigen; D011468:Prostatectomy; D011471:Prostatic Neoplasms; D016879:Salvage Therapy; D001743:Urinary Bladder; D014549:Urinary Incontinence; D016741:Urinary Sphincter, Artificial",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26424824",
"pubdate": "2015-09-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9572189;25017595;23017512;22998904;8904625;25337159",
"title": "An interesting case of an antihypertensive causing post-prostatectomy incontinence.",
"title_normalized": "an interesting case of an antihypertensive causing post prostatectomy incontinence"
} | [
{
"companynumb": "GB-WATSON-2015-25643",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXAZOSIN\\DOXAZOSIN MESYLATE"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nCytotoxic drugs have reduced the mortality in patients with ANCA-associated vasculitis (AASV) but their use carries a substantial risk of toxicity. Efforts are made to switch from cytotoxic drugs to less toxic maintenance regimens. In this study we aimed to assess the efficacy of mycophenolate mofetil (MMF) as maintenance therapy in patients with AASV and renal involvement.\n\n\nMETHODS\n22 patients with newly diagnosed AASV, microscopic polyangiitis (MPA) (n = 16), Wegener's granulomatosis (WG, n = 4), renal limited vasculitis (RLV, n = 1) and Churg-Strauss syndrome (CSS, n = 1) and renal involvement were followed for a median of 42 months (range 24 - 101). After 6 months of standard induction therapy, patients were switched to MMF monotherapy for 18 months. Renal parameters i.e. serum creatinine, proteinuria and urine sediment, BVAS scores and ANCA titers were assessed at baseline, after induction and after 18 months with MMF.\n\n\nRESULTS\nAfter the end of induction, 3 of the 4 patients who were initially hemodialysis (HD) dependent, remained on HD and were withdrawn from further analysis. In the remaining 19 patients, the improvement in renal function (p < 0.001), hematuria (p = 0.011), proteinuria (p = 0.007) and BVAS scores (p < 0.001) after induction was sustained after 18 months maintenance with MMF and no patient relapsing during this period. Until the end of the follow up, 31.58% of patients relapsed, at a median of 21.5 months (range: 18 - 60). Side effects were transient and infrequent.\n\n\nCONCLUSIONS\nIn patients with AASV and renal involvement, MMF seems to be an effective and well tolerated option in sustaining short- and medium-term remission.",
"affiliations": "Center for Nephrology \"G. Papadakis\", General Hospital of Nikea, Nikea, Pireaus, Greece. ciatroug@otenet.gr",
"authors": "Iatrou|C|C|;Zerbala|S|S|;Revela|I|I|;Spanou|E|E|;Marinaki|S|S|;Nakopoulou|L|L|;Boletis|J|J|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D009173:Mycophenolic Acid",
"country": "Germany",
"delete": false,
"doi": "10.5414/cnp72031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0430",
"issue": "72(1)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D019268:Antibodies, Antineutrophil Cytoplasmic; D016009:Chi-Square Distribution; D003520:Cyclophosphamide; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007166:Immunosuppressive Agents; D007674:Kidney Diseases; D007677:Kidney Function Tests; D009173:Mycophenolic Acid; D018709:Statistics, Nonparametric; D016896:Treatment Outcome; D014657:Vasculitis",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "31-7",
"pmc": null,
"pmid": "19640385",
"pubdate": "2009-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Mycophenolate mofetil as maintenance therapy in patients with vasculitis and renal involvement.",
"title_normalized": "mycophenolate mofetil as maintenance therapy in patients with vasculitis and renal involvement"
} | [
{
"companynumb": "NVSC2020GR163034",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report the first case of corneal graft rejection presumably associated with pembrolizumab immunotherapy.\n\n\nMETHODS\nCase report and literature review.\n\n\nRESULTS\nAn asymptomatic 85-year-old woman with a history of bilateral penetrating keratoplasty presented for a follow-up visit with bilateral diffuse keratic precipitates and subepithelial infiltrates. There were no anterior chamber cells. Bilateral subclinical corneal graft rejection was suspected. Three months previously, pembrolizumab immunotherapy was started for a metastatic urothelial cell tumor. Corneal graft rejection was managed with topical dexamethasone drops, which were tapered slowly. Pembrolizumab treatment was continued with careful ophthalmological follow-up. Unfortunately, recurrence of corneal graft rejection was observed 8 weeks after cessation of topical dexamethasone drops. After consulting the treating oncologist, pembrolizumab treatment was stopped to prevent recurrent corneal graft rejection.\n\n\nCONCLUSIONS\nWe report the first case of corneal graft rejection presumably associated with pembrolizumab immunotherapy. Corneal graft rejection may be successfully managed with corticosteroid therapy. However, constant vigilance and follow-up are advised because of the risk of recurrence in case of continued pembrolizumab treatment. Given the subclinical presentation, baseline ophthalmological screening is advised in all corneal graft patients after initiating immune checkpoint inhibitor therapy.",
"affiliations": "Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.;Department of Medical Oncology, General Hospital Lokeren, Lokeren, Belgium; and.;Department of Medical Oncology, General Hospital Lokeren, Lokeren, Belgium; and.;Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium.;Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.",
"authors": "Vanhonsebrouck|Eva|E|;Van De Walle|Mieke|M|;Lybaert|Willem|W|;Kruse|Vibeke|V|;Roels|Dimitri|D|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000002372",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "39(11)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D003316:Corneal Diseases; D004728:Endothelium, Corneal; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D015948:Keratoplasty, Penetrating; D011183:Postoperative Complications; D000072776:Slit Lamp Microscopy; D014571:Urologic Neoplasms",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "1436-1438",
"pmc": null,
"pmid": "32452986",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bilateral Corneal Graft Rejection Associated With Pembrolizumab Treatment.",
"title_normalized": "bilateral corneal graft rejection associated with pembrolizumab treatment"
} | [
{
"companynumb": "BE-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-310443",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"dru... |
{
"abstract": "OBJECTIVE\nTo highlight the intestinal perforation (IP), an uncommon and catastrophic complication after combined liver-kidney transplantation.\n\n\nMETHODS\nCombined liver-kidney transplantation (LKTx) with left kidney excision and a cyst fenestration procedure on the right kidney were performed on a case of 46-year-old female with congenital polycystic disease (CPCD).\n\n\nRESULTS\nTwo sites of IP were noted 40-50 cm proximal to ileocecal area during emergent laparotomy 10 d postoperatively. Despite aggressive surgical and medical management, disease progressed toward a fatal outcome due to sepsis and multiple organ failure 11 d later.\n\n\nCONCLUSIONS\nLong duration of operation without venovenous bypass, overdose of steroid together with postoperative volume excess may all contribute to the risk of idiopathic multiple IPs. Microbiology and pathology inspections suggested that the infected cyst of the fenestrated kidney might be one reason for the fatal intra-peritoneal infection. Thus for the CPCD patients who seem to be very susceptible to infectious complications, any sign of suspected renal-infection found before or during LKTx is indication for the excision of original kidney. And the intensity of immunosuppression therapy should be controlled cautiously.",
"affiliations": "Department of Hepatobiliary Surgery, First Affiliated Hospital, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China. pengpang@hotmail.com",
"authors": "Peng|Tao|T|;Peng|Min-Hao|MH|;Li|Le-Qun|LQ|;Deng|Yao-Liang|YL|;Yang|Ding-Hua|DH|;Lu|Bang-Yu|BY|;Chen|Xi-Gang|XG|;Guo|Ya|Y|;Xiao|Kai-Yin|KY|;Chen|Bin|B|;Zhong|Qin|Q|;Wei|Min-Yi|MY|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v10.i18.2769",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "10(18)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007416:Intestinal Perforation; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008875:Middle Aged; D010538:Peritonitis; D007690:Polycystic Kidney Diseases",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "2769-71",
"pmc": null,
"pmid": "15309740",
"pubdate": "2004-09-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9346534;3079996;1479491;8368937;8499065;2334585;8989302;9498394;1670232;8723195;8035272;9704396;9734499;9113442;7850688",
"title": "Intestinal perforation after combined liver-kidney transplantation for a case of congenital polycystic disease.",
"title_normalized": "intestinal perforation after combined liver kidney transplantation for a case of congenital polycystic disease"
} | [
{
"companynumb": "CN-PFIZER INC-2021294305",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
{
"abstract": "BACKGROUND\nThe aim of this study was to investigate the safety and efficacy of dalteparin during an elective percutaneous coronary intervention (PCI) procedure in a large cohort.\n\n\nMETHODS\nIn this prospective, randomized, open-label design study, 733 patients undergoing elective PCI were divided into an unfractionated heparin group (group 1, 323 patients) or a dalteparin group (group 2, 410 patients). Blood samples were collected before and 18-24 h after the PCI procedure to determine the serum levels of cardiac troponin I (cTnI) and creatine kinase isoenzyme MB. Major adverse cardiac events (MACEs) and bleeding events during hospitalization were also recorded. Patients with an increased level of serum cTnI before PCI were excluded from the study.\n\n\nRESULTS\nAfter PCI, the cTnI values were greater than three times the upper limit of normal in 43 cases (13.3%) in group 1 and 52 cases (12.7%) in group 2, without a statistically significant difference between the two groups (P=0.801). An increased creatine kinase isoenzyme MB level of greater than two times the upper limit of normal was found in 10 cases (3.1%) in group 1 and 12 cases (2.9%) in group 2, without a statistically significant difference between the two groups (P=0.894). Postoperative bleeding was observed in nine patients (2.8%) in group 1 and six patients (1.5%) in group 2. Postoperative MACEs were observed in two patients (0.6%) in group 1 and two patients (0.5%) in group 2. There were no significant differences between the two groups with respect to bleeding events or MACEs.\n\n\nCONCLUSIONS\nOur study showed that dalteparin might be as effective and safe as unfractionated heparin for anticoagulation during elective PCI.",
"affiliations": "aDepartment of Cardiology, The Second Hospital of Hebei Medical University bDepartment of Cardiology, The Third Hospital of Shijiazhuang City cDepartment of Cardiology, People's Hospital of Shijiazhuang City dDepartment of Cardiology, The Third Hospital of Hebei Medical University, Shijiazhuang eDepartment of Cardiology, General Hospital of Huabei Oilfield, Renqiu fDepartment of Cardiology, People's Hospital of Xingtai City, Xingtai gDepartment of Cardiology, 252 Hospital of PLA, Baoding, China.",
"authors": "Zhang|Guangming|G|;Cui|Wei|W|;Li|Yongjun|Y|;Gao|Xiaoli|X|;Wei|Qingmin|Q|;Cao|Xuebin|X|;Xiao|Wenliang|W|;Jiang|Ping|P|;Lyu|Xinhu|X|;Liu|Fan|F|;Gu|Guoqiang|G|;Liu|Jinming|J|",
"chemical_list": "D000925:Anticoagulants; D015415:Biomarkers; D019210:Troponin I; D006493:Heparin; D052279:Creatine Kinase, MB Form; D017985:Dalteparin",
"country": "England",
"delete": false,
"doi": "10.1097/MCA.0000000000000128",
"fulltext": "\n==== Front\nCoron Artery DisCoron. Artery DisMCACoronary Artery Disease0954-69281473-5830Lippincott Williams & Wilkins 10.1097/MCA.0000000000000128Original ResearchThe effect of dalteparin versus unfractionated heparin on the levels of troponin I and creatine kinase isoenzyme MB in elective percutaneous coronary intervention: a multicenter study Zhang Guangming aCui Wei aLi Yongjun aGao Xiaoli eWei Qingmin fCao Xuebin gXiao Wenliang dJiang Ping bLyu Xinhu cLiu Fan aGu Guoqiang aLiu Jinming aa Department of Cardiology, The Second Hospital of Hebei Medical Universityb Department of Cardiology, The Third Hospital of Shijiazhuang Cityc Department of Cardiology, People’s Hospital of Shijiazhuang Cityd Department of Cardiology, The Third Hospital of Hebei Medical University, Shijiazhuange Department of Cardiology, General Hospital of Huabei Oilfield, Renqiuf Department of Cardiology, People’s Hospital of Xingtai City, Xingtaig Department of Cardiology, 252 Hospital of PLA, Baoding, ChinaCorrespondence to Wei Cui, MD, Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China Tel: +86 311 66002115; fax: +86 311 66002115; e-mail: cuiwei@medmail.com.cn9 2014 06 8 2014 25 6 510 515 24 2 2014 15 4 2014 17 4 2014 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins2014This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.Background\nThe aim of this study was to investigate the safety and efficacy of dalteparin during an elective percutaneous coronary intervention (PCI) procedure in a large cohort.\n\nMaterials and methods\nIn this prospective, randomized, open-label design study, 733 patients undergoing elective PCI were divided into an unfractionated heparin group (group 1, 323 patients) or a dalteparin group (group 2, 410 patients). Blood samples were collected before and 18–24 h after the PCI procedure to determine the serum levels of cardiac troponin I (cTnI) and creatine kinase isoenzyme MB. Major adverse cardiac events (MACEs) and bleeding events during hospitalization were also recorded. Patients with an increased level of serum cTnI before PCI were excluded from the study.\n\nResults\nAfter PCI, the cTnI values were greater than three times the upper limit of normal in 43 cases (13.3%) in group 1 and 52 cases (12.7%) in group 2, without a statistically significant difference between the two groups (P=0.801). An increased creatine kinase isoenzyme MB level of greater than two times the upper limit of normal was found in 10 cases (3.1%) in group 1 and 12 cases (2.9%) in group 2, without a statistically significant difference between the two groups (P=0.894). Postoperative bleeding was observed in nine patients (2.8%) in group 1 and six patients (1.5%) in group 2. Postoperative MACEs were observed in two patients (0.6%) in group 1 and two patients (0.5%) in group 2. There were no significant differences between the two groups with respect to bleeding events or MACEs.\n\nConclusion\nOur study showed that dalteparin might be as effective and safe as unfractionated heparin for anticoagulation during elective PCI.\n\nKeywords:\ncoronary artery diseaseelective percutaneous coronary interventionheparinOPEN-ACCESSTRUE\n==== Body\nIntroduction\nPlaque debris, which impacts blood flow to the capillaries, can result in microvascular mechanical obstruction, platelet activation, and the formation of microthrombi, leading to myocardial injury in patients undergoing a percutaneous coronary intervention (PCI) 1,2. Anticoagulation with effective and safe measures is important during PCI. Currently, unfractionated heparin (UFH) is used widely as an anticoagulant during the PCI procedure. However, because of its undesirable defects in terms of structure and composition, UFH is associated with various problems, such as a short half-life, low bioavailability, nonspecific binding to proteins that leads to unpredictable anticoagulative reactions 3, intrinsic platelet activation, and aggregation 4,5. The intravenous half-life of low-molecular-weight heparin (LMWH) is about 2 h, measured as anti-Xa activity, although somewhat shorter (about 80 min) when measured by anti-IIa assay. The half-life of UFH is dose dependent but, at usual intravenous doses, it is 45–60 min by both assay methods. Unlike subcutaneous UFH, which has a bioavailability of less than 50%, all LMWHs have a bioavailability after a subcutaneous injection of 90–100% 6. Because of the unpredictability of heparin pharmacokinetics, activated clotting time monitoring is needed to adjust the dose of heparin during the PCI procedure. The use of LMWHs, especially enoxaparin, has gradually become more widespread and accepted by guidelines for anticoagulation during PCI, with advantages such as the more predictable anticoagulation and a lower incidence of heparin-induced thrombocytopenia. Our previous work and that of others have shown that elective PCI can be performed safely with dalteparin and other LMWHs instead of UFH 7–11. However, there is a lack of sound evidence on the use of dalteparin as an anticoagulant during PCI. In addition, the changes in myocardial injury markers, such as cardiac troponin I (cTnI) and creatine kinase isoenzyme MB (CK-MB), after PCI have rarely been reported when using dalteparin as an anticoagulant during PCI.\n\nClinically, cTnI and CK-MB are commonly used sensitive and specific markers of myocardial injury. CK-MB, which has high specificity, has served as a classic indicator of myocardial injury in the diagnosis of myocardial injury 12 and also has a good long-term predictive value in patients undergoing PCI 13,14. The sensitivity and specificity of cTnI as a myocardial injury marker are greater than those of CK-MB; in addition, cTnI has a longer diagnostic time window of up to 14 days 15,16.\n\nOur preliminary data have confirmed the feasibility 17 and efficacy of dalteparin during PCI 18. On the basis of these data, we designed this multicenter study to further compare the efficacy and safety of dalteparin as an anticoagulant during elective PCI.\n\nMaterials and methods\nPatient selection\nThis study was a multicenter, randomized, controlled, and open-label design study. In total, 733 patients with coronary artery disease admitted to seven hospitals from February 2010 to April 2011 were enrolled in this study. All of the patients underwent elective PCI 3–5 days after admission. The 733 patients were randomized to the UFH group (group 1: n=323; 232 men and 91 women; mean±SD 59.0±9.9 years) or the dalteparin group (group 2: n=410; 325 men and 85 women; mean±SD 58.1±8.8 years). The exclusion criteria were as follows: increased serum level of cTnI before PCI; side-branch occlusion after PCI; allergy or intolerance to heparin, LMWH, aspirin, or clopidogrel (including heparin-induced thrombocytopenia); a past or present bleeding disorder including a history of bleeding (gastrointestinal bleeding, macroscopic hematuria, or a positive fecal occult blood test) within 3 months before enrollment; systolic blood pressure of at least 180 mmHg and/or diastolic blood pressure of at least 105 mmHg; a history of stroke, other intracranial lesions, or a transient ischemic attack within 1 year; a history of cardiopulmonary resuscitation within 2 weeks; serious body injury within the previous month; major surgery, including coronary artery bypass grafting (CABG), eye surgery, or biopsy within the previous month; a history of arteriovenous malformation, aneurysm, or aortic dissection; an active peptic ulcer within the last 3 months; acute pericarditis; significant retinopathy; platelet count less than 100×109/l; serum creatinine greater than 177 μmol/l; hemodialysis; and a lack of willingness to participate in the study.\n\nAll of the study protocols were approved by the Ethics Committee of the Second Hospital of Hebei Medical University and the six other participating hospitals. Informed consent was obtained from each patient before enrollment.\n\nMethods\nAll of the patients were administered oral treatment with aspirin (75–150 mg, once daily, for ≥3 days), clopidogrel (75 mg, once daily, for ≥3 days), and subcutaneous LMWH (4000–6000 IU) at 12-h intervals for 3–5 consecutive days before the procedure.\n\nThe PCI procedures were performed through either the radial artery or the femoral artery approach, with discontinuation of subcutaneous LMWH 12 h before the procedure. After successful arterial canalization, the patients in group 1 were administered 3000–5000 IU (radial artery, 5000 IU; femoral artery, 3000 IU) UFH (Tianjin Biochemical Pharmaceutical Factory, Tianjin, China), supplemented to a total dose of 120 IU/kg immediately before PCI, with a maximum dose of 10 000 IU. The patients in group 2 were administered 3000–5000 IU anti-Xa (radial artery, 5000 IU; femoral artery, 3000 IU) and dalteparin (provided under the brand name of Fragmin by Pfizer Inc., New York, New York, USA), supplemented to a total dose of 120 IU/kg anti-Xa immediately before PCI, with a maximum dose of 10 000 IU anti-Xa. If the procedure continued for more than 2 h, 2000 IU of UFH or dalteparin was administered for each additional hour.\n\nThe sheath was removed immediately after PCI if the radial artery approach was adopted and it was removed after 2–4 h if the femoral artery approach was used. After PCI, the patients continued to take aspirin (100–300 mg, once daily), clopidogrel (75–150 mg, once daily), and subcutaneous LMWH (4000–6000 IU, twice daily) for 3–5 consecutive days.\n\nRoutine blood, urine, and stool tests; hepatic and renal function tests; prothrombin time; and ECG examinations were performed before the indexed procedure. The levels of cTnI and CK-MB were determined the day before and 18–24 h after the PCI procedure. The serum levels of cTnI and CK-MB were assessed using an ACCESS fully automated microparticle chemiluminescence immunoassay analyzer (Beckman Company, Pasadena, California, USA) and a myoglobin/CK-MB/troponin I triple kit (Beckman Company). Postprocedural myocardial infarction with CK-MB criteria was defined as more than two times the upper limit of normal (ULN). Postprocedural myocardial infarction with cTnI criteria was defined as more than three times the ULN.\n\nThe number of diseased vessels, lesion locations, number of implanted stents, total procedure time, maximum pressure of stent expansion, and other PCI parameters for each patient were recorded. Bleeding events and the incidence of major adverse cardiac events (MACEs) including death, complication of myocardial infarction, target lesion revascularization, and target vessel revascularization during hospitalization were also recorded. Death was defined as all-cause mortality during hospitalization. Complication of myocardial infarction was defined as resuscitated cardiac arrest, recurrent acute coronary syndrome, urgent revascularization, stroke, or peripheral or pulmonary embolism during hospitalization. Non-CABG major bleeding during hospital was defined according to the STEEPLE definition 19 as fatal bleeding, documented retroperitoneal, intracranial, or intraocular bleeding, bleeding resulting in hemodynamic compromise requiring specific treatment, bleeding requiring surgical intervention or decompression of a closed space to control the event, any transfusion, or a decrease in hemoglobin of 30 g/l or more.\n\nSafety evaluation\nBleeding events were classified according to the Thrombin Inhibition in Myocardial Infarction bleeding criteria. Major bleeding was defined as a decrease in hemoglobin of greater than 50 g/l (known or unknown site of bleeding, not associated with CABG), intracranial hemorrhage, or cardiac tamponade. Minor bleeding was defined as a decrease in hemoglobin of greater than 30 g/l but 50 g/l or less (known bleeding site, not associated with CABG), spontaneous macroscopic hematuria, hematemesis, hemoptysis, or puncture-site hematoma.\n\nVascular complications at the access site were recorded as follows: size of the local hematoma (defined as a hematoma with a diameter >5 cm), pseudoaneurysm, and arteriovenous fistula.\n\nStatistical methods\nAll of the statistical analyses were carried out using SPSS 16.0 software (SPSS Inc., Chicago, Illinois, USA). Continuous data were expressed as the mean±SD (±SD) and categorical data were expressed as a percentage (%). Measurements were compared between groups using the independent-sample t-test and categorical data were analyzed using the χ2-test. A difference of P-value less than 0.05 was considered statistically significant.\n\nResults\nBaseline data\nThis study included 733 patients; almost all patients were deployed with drug-eluting stents and only two patients in group 1 and one patient in group 2 were implanted with bare metal stents. The drug-eluting stents were first-generation sirolimus drug-eluting stents, either Cypher or Chinese products (Partner, Lepu Medical, Beijing, China; and Excel, JWMS Medical, Weihai, China).\n\nThere were no significant differences between the two groups with respect to sex, age, hemoglobin, BMI, or other atherosclerotic risk factors (Table 1). In addition, there were no significant differences between the two groups in the number of diseased vessels, stent implant site, number of stents, balloon inflation pressure, expansion time, or size/length of stents (Table 2).\n\nTable 1 Baseline characteristics of the patients\n\nTable 2 Comparison of parameters of stent implantation between the groups\n\nChanges in cardiac injury markers\nBefore the PCI procedure, the serum level of cTnI was within the normal upper limits (<1 μg/l) in both groups. At 18–24 h after PCI, the serum cTnI level increased significantly compared with the baseline values in both groups. The postoperative serum cTnI level was 1.88±4.14 μg/l in group 1 and 1.96±4.68 μg/l in group 2 (t=0.47, P>0.05). Serum cTnI values of greater than1 μg/l, at least 3×ULN, and at least 5×ULN were found in 97 cases (30.0%), 43 cases (13.3%), and 23 cases (7.1%) in group 1, whereas the corresponding values were 127 cases (31.0%), 52 cases (12.7%), and 30 cases (7.3%) in group 2, respectively. There were no significant differences between the two groups with respect to the above measurements (Table 3).\n\nTable 3 Postoperative CK-MB and cTnI values in group 1 and group 2\n\nPreoperatively, the serum CK-MB levels were normal (<25 μg/l) in both groups. Compared with those at baseline, after PCI, the serum CK-MB levels were significantly increased in both groups, with values of 15.67±11.3 μg/l in group 1 and 12.85±11.96 μg/l in group 2, respectively (t=2.00, P<0.05). Serum levels of CK-MB of greater than 25 μg/l, at least 2×ULN, and at least 5×ULN were found in 37 cases (11.5%), 10 cases (3.1%), and zero cases (0.0%) in group 1, whereas the corresponding values were 33 cases (8.1%), 12 cases (2.9%), and one case (0.2%) in group 2, respectively. There was no significant difference in the above measurements between the groups postoperatively (Table 3).\n\nBleeding events\nOne patient in group 1 developed major bleeding in the gastrointestinal tract. Seven hours after PCI, the patient presented with melena and a decrease in hemoglobin of 70 g/l, which suggested the presence of a stress ulcer. The patient’s condition stabilized shortly after a blood transfusion. Two other patients in group 1 experienced minor bleeding presented as a large hematoma at the site of the femoral artery access. No major bleeding episodes occurred in group 2, whereas four patients developed minor bleeding manifested as a hematoma at the puncture site. The overall incidences of bleeding were 2.8% in group 1 and 1.5% in group 2, respectively (P=1.00) (Table 4).\n\nTable 4 Comparison of bleeding episodes between group 1 and group 2\n\nThrombosis within the sheath\nThrombosis within the sheath did not occur in group 1, but was observed in one patient in group 2 (0 vs. 0.2%, P>0.05).\n\nHospital follow-up\nThere were no postoperative deaths in either group. One patient presenting with gastrointestinal bleeding in group 1 developed a subacute stent thrombus 3 days after withdrawal of the antiplatelet agent and therefore underwent another PCI procedure. Myocardial infarction reoccurred in one patient in group 2 at 12 h after PCI and was subsequently confirmed to have acute stent thrombosis by coronary angiography. Accordingly, PCI was performed on this patient. The two patients were finally discharged uneventfully. The MACEs during hospitalization are presented in Table 5.\n\nTable 5 Hospital follow-up of group 1 and group 2 after interventional therapy\n\nDiscussion\nThis study shows that dalteparin as an anticoagulant during elective PCI might be as effective and safe as UFH. There was no significant difference between the two groups with respect to the mean serum levels and incidence of an increase in cTnI and CK-MB levels after PCI (P=0.80 and 0.89). Moreover, the rates of bleeding and MACEs after PCI were also similar in both groups. These results suggest that dalteparin is a safe and effective anticoagulant for use in the context of elective PCI.\n\nIn recent years, researchers have confirmed the safety and effectiveness of using LMWH as an anticoagulant in PCI. Rabah et al.\n20 first found that the use of enoxaparin as an anticoagulant during PCI was both safe and effective in patients vulnerable to bleeding episodes and vascular events compared with UFH. On monitoring the activated clotting time, these two drugs were found to be consistent in terms of the anti-Xa factor activity. After this work was published, more evidence accumulated on the use of LMWH as an adjunctive anticoagulant during PCI. The NICE 1 and NICE 4 studies showed that enoxaparin alone or combined with abciximab provides safe and effective anticoagulation during PCI as shown by a similar MACE rate within 30 days of indexed PCI as UFH 21. The ATOLL study showed that even in the context of primary PCI, enoxaparin could reduce the rate of death, complications of myocardial infarction, and major bleeding compared with UFH in STEMI patients 22. A meta-analysis found that the incidence of serious bleeding was significantly less in patients treated with LMWH compared with those treated with UFH (odds ratio, 0.57; 95% confidence interval, 0.40–0.82, P=0.002), but showed no significant difference in terms of the incidence of other adverse events or anticoagulant effects 23.\n\nIn contrast to relatively sound evidence for using enoxaparin as an anticoagulant during PCI, there are only a few studies on dalteparin as an effective anticoagulant during PCI. Natarajan et al.\n8 found that the anticoagulant effects of dalteparin and UFH are similar. In their patients, angiographic (success rates >90% in both cases) and clinical events (death, myocardial infarction, and revascularization) were also similar in both groups. Li et al.\n24 have reported that dalteparin alone or combined with tirofiban was effective and safe in primary PCI for patients with STEMI compared with UFH. In in-vitro studies, Raaz et al.\n25 confirmed that the modulation of plasma coagulation with LMWH was critical to prevent catheter thrombus formation; thus, these authors favor dalteparin over enoxaparin in the setting of PCI. Our results in this current study further confirmed the conclusions from our preliminary study and the above-mentioned investigations 8,10,17,18,24.\n\nMyocardial injury as measured by the serum cTnI or CK-MB level is not uncommon in patients after PCI, which may result from increased lesion complexity, occluded microcirculation by a thrombus or debris embolization, low perfusion pressure, vascular spasm, insufficient anticoagulation, or vessel dissection 26,27. An increased serum level of cTnI or CK-MB after PCI usually predicts a worse short-term or long-term outcome 28,29. Furthermore, the incidence of adverse cardiac events was positively related to increased levels of myocardial injury markers. Using an appropriate anticoagulant during PCI can reduce the postoperative levels of cTnI and CK-MB, resulting in a decreased rate of myocardial injury following the PCI procedure 1,30–32. In this study, the promising results obtained with the use of dalteparin with a dosage of 120 IU anti-Xa during PCI provide some evidence of adjunctive anticoagulation in such a situation. Our results also further confirmed the feasibility of using dalteparin instead of UFH for anticoagulation during PCI.\n\nNotwithstanding the weaker effect of LMWH against thrombosis induced by foreign objects compared with UFH 9,33, thrombosis within the sheath occurred in only one patient of the dalteparin group, which is not statistically different from that of the UFH group. Therefore, the choice of dalteparin does not mean that more thrombosis was induced by foreign objects.\n\nSome studies indicate that LMWH can reduce the incidence of MACEs and stent thrombosis compared with UFH. Kim et al.\n34 have suggested that tirofiban in combination with dalteparin in patients with acute coronary syndrome can significantly lower the incidence of MACEs compared with UFH plus tirofiban. In our study, no significant differences in the incidence of MACEs or stent thrombosis were found between the two groups (P=0.81 and 0.87).\n\nLimitations of the study\nThe present study had some limitations, including the selection of patients undergoing elective PCI and the limited number of patients treated with a platelet glycoprotein IIb/IIIa receptor antagonist in addition to the anticoagulant. In addition, coronary angiography was necessary to determine whether a patient should undergo PCI. The patients included in the study could therefore not be selected randomly. Furthermore, the dalteparin group enrolled more patients than the UFH group. Finally, considering the relatively small size of the study, the conclusion from this study should be confirmed in the future by a larger, double-blind, and randomized study.\n\nConclusion\nDalteparin is applicable for anticoagulation during elective PCI and is not inferior to UFH in terms of postoperative myocardial injury markers or bleeding complications. Thus, the use of dalteparin might be a feasible alternative to UFH in elective PCI. This study had a small sample size; therefore, the findings may be used to generate hypotheses rather than to provide definite conclusions.\n\nAcknowledgements\nThe authors are indebted to the patients who agreed to participate in this trial, the study contributors, and the investigators who recruited patients. Prof. Wei Cui had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Ricciardi MJ Davidson CJ Gubernikoff G Beohar N Eckman LJ Parker MA Bonow RO Troponin I elevation and cardiac events after percutaneous coronary intervention .Am Heart J 2003 ;145 :522 –528 12660677 \n2 Novis DA Jones BA Dale JC Walsh MK College of American Pathologists Biochemical markers of myocardial injury test turnaround time: a College of American Pathologists Q-Probes study of 7020 troponin and 4368 creatine kinase-MB determinations in 159 institutions .Arch Pathol Lab Med 2004 ;128 :158 –164 14736289 \n3 Antman EM Hirudin in acute myocardial infarction: Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial .Circulation 1996 ;94 :911 –921 8790025 \n4 Hirsh J Levine MN Low molecular weight heparin .Blood 1992 ;79 :1 –17 1309422 \n5 Melandri G Semprini F Cervi V Candiotti N Branzi A Palazzini E Magnani B Comparison of efficacy of low molecular weight heparin (parnaparin) with that of unfractionated heparin in the presence of activated platelets in healthy subjects .Am J Cardiol 1993 ;72 :450 –454 8394644 \n6 Baglin T Barrowcliffe TW Cohen A Greaves M British Committee for Standards in Haematology Guidelines on the use and monitoring of heparin .Br J Haematol 2006 ;133 :19 –34 16512825 \n7 Kereiakes DJ Kleiman NS Fry E Mwawasi G Lengerich R Maresh K Dalteparin in combination with abciximab during percutaneous coronary intervention .Am Heart J 2001 ;141 :348 –352 11231430 \n8 Natarajan MK Velianou JL Turpie AG Mehta SR Raco D Goodhart DM A randomized pilot study of dalteparin versus unfractionated heparin during percutaneous coronary interventions .Am Heart J 2006 ;151 :175 e1–e6 16368313 \n9 Marmur JD Poludasu S Feit A Battala VR Cavusoglu E Activated clotting time (ACT)-guided intravenous dalteparin dosing during percutaneous coronary intervention .J Invasive Cardiol 2008 ;20 :323 –327 18599887 \n10 Wang QY Cui W Lu JC Du J Liu F Xie RQ Effects of dalteparin and unfractionated heparin on plasma anti-Xa activity and activated clotting time during elective percutaneous coronary intervention or coronary angiography .Chin J Interv Cardiol 2009 ;17 :297 –298 \n11 Martin JL Slepian M Use of low-molecular-weight heparins during percutaneous coronary intervention .J Invasive Cardiol 2011 ;23 :1 –8 21183762 \n12 Adgey AA Mathew TP Harbinson MT Periprocedural creatine kinase-MB elevations: long-term impact and clinical implications .Clin Cardiol 1999 ;22 :257 –265 10198735 \n13 Ioannidis JP Karvouni E Katritsis DG Creatine kinase-MB elevation following stent implantation .J Am Coll Cardiol 2005 ;45 :1908 author reply 1908–1909 15936632 \n14 Kini A Kini S Marmur JD Bertea T Dangas G Cocke TP Sharma SK Incidence and mechanism of creatine kinase-MB enzyme elevation after coronary intervention with different devices .Catheter Cardiovasc Interv 1999 ;48 :123 –129 10506764 \n15 Lindbloom EJ Stevermer JJ Cardiac troponin I as a marker for AMI .Am Heart J 1999 ;138 :798 –800 10502333 \n16 Graber MA Cardiac troponin I levels in unstable angina and non-Q wave AMI .J Fam Pract 1997 ;44 :135 –136 9040514 \n17 Zhang K Zhang GM Cui W Liu F Li YJ Yang XH Possible effects of plasma troponin I and creatine kinase MB using dalteparin and unfractionated heparin in elective percutaneous coronary intervention .Clin Focus 2011 ;26 :1480 –1482 \n18 Chen XF Cui W Liu F Gu GQ Yang XH Xie RQ Optimal doses of dalteparin for anticoagulation in patients undergoing elective percutaneous coronary intervention .Clin Focus 2011 ;26 :1667 –1670 \n19 Montalescot G Gallo R White HD Cohen M Steg PG Aylward PE Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention .N Engl J Med 2006 ;355 :1006 –1017 16957147 \n20 Rabah MM Premmereur J Graham M Fareed J Hoppensteadt DA Grines LL Grines CL Usefulness of intravenous enoxaparin for percutaneous coronary intervention instable angina pectoris .Am J Cardiol 1999 ;84 :1391 –1395 10606110 \n21 Kereiakes DJ Grines C Fry E Esente P Hoppensteadt D Midei M Enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention .J Invasive Cardiol 2001 ;13 :272 –278 11287711 \n22 Montalescot G Zeymer U Silvain J Boulanger B Cohen M Goldstein P Intravenous enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomized open-label ATOLL trial .Lancet 2011 ;378 :693 –703 21856483 \n23 Dumaine R Borentain M Bertel O Bode C Gallo R White HD Intravenous low-molecular-weight heparins compared with unfractionated heparin in percutaneous coronary intervention: quantitative review of randomized trials .Arch Intern Med 2007 ;167 :2423 –2430 18071163 \n24 Li WM Yang XC Wang LF Ge YG Wang HS Xu L Comparison of tirofiban combined with dalteparin or unfractionated heparin in primary percutaneous coronary intervention of acute ST-segment elevation myocardial infarction patients .Chin Med J 2011 ;124 :3275 –3280 22088520 \n25 Raaz U Buerke M Busshardt M Maegdefessel L Plehn A Hauroeder B Efficacy of enoxaparin, certoparin and dalteparin in preventing cardiac catheter thrombosis: an in vitro approach .J Thromb Thrombolysis 2010 ;29 :265 –270 19517216 \n26 Saadeddin SM Habbab MA Sobki SH Ferns GA Minor myocardial injury after elective uncomplicated successful PTCA with or without stenting: detection by cardiac troponins .Catheter Cardiovasc Interv 2001 ;53 :188 –192 11387602 \n27 Saadeddin SM Habbab MA Sobki SH Ferns GA Detection of minor myocardial injury after successful percutaneous transluminal coronary angioplasty with or without stenting .Med Sci Monit 2000 ;6 :708 –712 11208396 \n28 Antman EM Tanasijevic MJ Thompson B Schactman M McCabe CH Cannon CP Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes .N Engl J Med 1996 ;335 :1342 –1349 8857017 \n29 Ohman EM Armstrong PW Christenson RH Granger CB Katus HA Hamm CW Cardiac troponin T levels for risk stratification in acute myocardial ischemia .N Engl J Med 1996 ;335 :1333 –1341 8857016 \n30 Fuchs S Kornowski R Mehran R Lansky AJ Satler LF Pichard AD Prognostic value of cardiac troponin-I levels following catheter-based coronary interventions .Am J Cardiol 2000 ;85 :1077 –1082 10781755 \n31 Okmen E Kasikcioglu H Sanli A Uyarel H Cam N Correlations between cardiac troponin I, cardiac troponin T, and creatine phosphokinase MB elevation following successful percutaneous coronary intervention and prognostic value of each marker .J Invasive Cardiol 2005 ;17 :63 –67 15687525 \n32 Saadeddin SM Habbab MA Sobki SH Ferns GA Biochemical detection of minor myocardial injury after elective, uncomplicated, successful percutaneous coronary intervention in patients with stable angina: clinical outcome .Ann Clin Biochem 2002 ;39 :392 –397 12117443 \n33 Fischell TA Attia T Rane S Salman W High-dose, single-bolus eptifibatide: a safe and cost-effective alternative to conventional glycoprotein IIb/IIIa inhibitor use for elective coronary interventions .J Invasive Cardiol 2006 ;18 :487 –491 17042093 \n34 Kim W Jeong MH Hwang SH Kim KH Hong YJ Ahn YK Comparison of abciximab combined with dalteparin or unfractionated heparin in high-risk percutaneous coronary intervention in acute myocardial infarction patients .Int Heart J 2006 ;47 :821 –831 17268117\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0954-6928",
"issue": "25(6)",
"journal": "Coronary artery disease",
"keywords": null,
"medline_ta": "Coron Artery Dis",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D015415:Biomarkers; D002681:China; D052279:Creatine Kinase, MB Form; D017985:Dalteparin; D005260:Female; D006470:Hemorrhage; D006493:Heparin; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D011446:Prospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D019210:Troponin I",
"nlm_unique_id": "9011445",
"other_id": null,
"pages": "510-5",
"pmc": null,
"pmid": "24859356",
"pubdate": "2014-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "10781755;17268117;19517216;11208396;8857016;12117443;11287711;8857017;11231430;15936632;1309422;10198735;14736289;9040514;18599887;10502333;8790025;21183762;16512825;10606110;10506764;15687525;18071163;17042093;22088520;12660677;11387602;16957147;21856483;8394644;16368313",
"title": "The effect of dalteparin versus unfractionated heparin on the levels of troponin I and creatine kinase isoenzyme MB in elective percutaneous coronary intervention: a multicenter study.",
"title_normalized": "the effect of dalteparin versus unfractionated heparin on the levels of troponin i and creatine kinase isoenzyme mb in elective percutaneous coronary intervention a multicenter study"
} | [
{
"companynumb": "CN-PFIZER INC-2016512516",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": n... |
{
"abstract": "A Japanese woman was treated with injectable methylprednisolone and oral prednisolone for dermatomyositis. On admission, her serum was positive for anti-hepatitis C virus (HCV) antibodies, although HCV RNA was undetectable on polymerase chain reaction. Glucocorticoid therapy improved the dermatomyositis; however, the serum alanine aminotransferase levels rapidly increased, with positive serum HCV RNA and a high viral titer. Both parameters decreased in association with prednisolone tapering, whereas dermatomyositis subsequently recurred and the administration of glucocorticoid therapy was repeated. The serum alanine aminotransferase and HCV RNA levels subsequently increased in a similar manner to that observed after the first course of therapy. Liver enzymes and the viral load should be monitored in anti-HCV-positive patients receiving immunosuppressives, even if serum HCV RNA is negative.",
"affiliations": "Department of Gastroenterology/Liver Center, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Japan.",
"authors": "Mori|Nami|N|;Imamura|Michio|M|;Takaki|Shintaro|S|;Araki|Takehisa|T|;Hayes|Nelson C|NC|;Aisaka|Yasuyuki|Y|;Chayama|Kazuaki|K|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D018937:Hepatitis C Antibodies; D012367:RNA, Viral; D011239:Prednisolone; D000410:Alanine Transaminase",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.53.3194",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "53(23)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000410:Alanine Transaminase; D000893:Anti-Inflammatory Agents; D003882:Dermatomyositis; D005260:Female; D016174:Hepacivirus; D006526:Hepatitis C; D018937:Hepatitis C Antibodies; D006801:Humans; D016133:Polymerase Chain Reaction; D011239:Prednisolone; D012367:RNA, Viral; D016896:Treatment Outcome; D014775:Virus Activation; D017735:Virus Latency",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2689-93",
"pmc": null,
"pmid": "25447651",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatitis C virus (HCV) reactivation caused by steroid therapy for dermatomyositis.",
"title_normalized": "hepatitis c virus hcv reactivation caused by steroid therapy for dermatomyositis"
} | [
{
"companynumb": "JP-BAUSCH-BL-2020-011688",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Fatal gas embolism in hospital is usually an iatrogenic complication of invasive diagnostic and therapeutic procedures. Air or gas enters the venous circulation, leading to cardiovascular failure or migrating to the systemic arterial circulation. A 73-year-old man died suddenly in hospital. An allergic reaction was initially suspected because of the presence of soft tissue swelling, but it was noticed that his oxygen tube was attached to the indwelling catheter inserted in the patient's right median cubital vein. Whole-body post-mortem multi-slice computed tomography (pm-MSCT) revealed abundant gas in the subcutaneous fatty tissue, in the heart chambers, in the mediastinum, pericardium, thoracic wall and peritoneum. The external examination revealed massive subcutaneous emphysema with marked palpable cutaneous tension and crepitation on palpation of the entire body's surface. Autopsy found gas bubbles in the heart and throughout the vascular system. Death was attributed to cardiac gas embolism.",
"affiliations": "S.C. Medicina Legale U, A.O.U. Città della Salute e della Scienza di Torino, Corso Bramante 88/90, 10126, Torino, Italy. lucyta1381@gmail.com.;Institute of Legal Medicine and Forensic Sciences, University Medical Centre Charité, University of Berlin, Turmstr. 21, Building N, 10559, Berlin, Germany.;Institute of Legal Medicine and Forensic Sciences, University Medical Centre Charité, University of Berlin, Turmstr. 21, Building N, 10559, Berlin, Germany.",
"authors": "Tattoli|Lucia|L|0000-0002-6299-9900;Gauselmann|Hannah|H|;Oesterhelweg|Lars|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12024-020-00222-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1547-769X",
"issue": "16(3)",
"journal": "Forensic science, medicine, and pathology",
"keywords": "Air embolism; Gas embolism; Hospital; Iatrogenic cause; Postmortem computed tomography",
"medline_ta": "Forensic Sci Med Pathol",
"mesh_terms": "D000059:Accidents; D000368:Aged; D002408:Catheters, Indwelling; D004618:Embolism, Air; D006760:Hospitalization; D006801:Humans; D008297:Male; D061330:Multidetector Computed Tomography; D010102:Oxygen Inhalation Therapy; D051598:Whole Body Imaging",
"nlm_unique_id": "101236111",
"other_id": null,
"pages": "528-530",
"pmc": null,
"pmid": "32107729",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal gas embolism in hospital: accident or suicide?",
"title_normalized": "fatal gas embolism in hospital accident or suicide"
} | [
{
"companynumb": "IT-ALSI-202000153",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYGEN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "Nonconvulsive Status Epilepticus (NCSE) is not uncommon in children, and can be challenging to diagnose and treat. Etiologies vary widely and include infection, trauma and acute withdrawal from medications such as anticonvulsants. We report a child who experienced orofacial dyskinesias concerning for NCSE after withdrawal from high dose benzodiazepines andopiates. Automonic signs typically associated with sedative withdrawal were absent and treatment with benzodiazepines did not improve his symptoms. Diagnostic testing was negative, including electroencephalogram, and resolution was complete within five days. Our case demonstrates the orofacial dyskinesias that may occur during sedative medication withdrawal, and highlights potential confusion with non-convulsive status epilepticus.",
"affiliations": "National Naval Medical Center, Bethesda, MD, USA.",
"authors": "Epstein|David|D|;Difazio|Marc|M|",
"chemical_list": "D000701:Analgesics, Opioid; D006993:Hypnotics and Sedatives; D009020:Morphine; D008874:Midazolam",
"country": "United States",
"delete": false,
"doi": "10.1002/mds.21260",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0885-3185",
"issue": "22(5)",
"journal": "Movement disorders : official journal of the Movement Disorder Society",
"keywords": null,
"medline_ta": "Mov Disord",
"mesh_terms": "D000701:Analgesics, Opioid; D002675:Child, Preschool; D003422:Critical Care; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced; D004569:Electroencephalography; D004826:Epiglottitis; D006801:Humans; D006993:Hypnotics and Sedatives; D007262:Infusions, Intravenous; D008297:Male; D008874:Midazolam; D009020:Morphine; D009460:Neurologic Examination; D012121:Respiration, Artificial; D013226:Status Epilepticus; D013375:Substance Withdrawal Syndrome",
"nlm_unique_id": "8610688",
"other_id": null,
"pages": "712-5",
"pmc": null,
"pmid": "17373722",
"pubdate": "2007-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Orofacial automatisms induced by acute withdrawal from high-dose midazolam mimicking nonconvulsive status epilepticus in a child.",
"title_normalized": "orofacial automatisms induced by acute withdrawal from high dose midazolam mimicking nonconvulsive status epilepticus in a child"
} | [
{
"companynumb": "US-MYLANLABS-V-DE-2007-0458",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "1",
... |
{
"abstract": "A 59-year-old man was referred for CT scan of the abdomen after repair of an eventrated appendectomy wound. The man had a known history of bipolar affective disorder, for which he had been on lithium therapy for many years. As an incidental finding, CT scan showed numerous small hypodense renal lesions. Subsequently a MRI examination was performed to further characterize these renal abnormalities.",
"affiliations": "Department of Radiology, Antwerp University Hospital, University of Antwerp, Edegem.. info@ubiquitypress.com.",
"authors": "Desbuquoit|D|D|;Snoeckx|A|A|;Corthouts|B|B|;Parizel|P M|PM|",
"chemical_list": null,
"country": "Belgium",
"delete": false,
"doi": "10.5334/jbr-btr.790",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0302-7430",
"issue": "98(3)",
"journal": "JBR-BTR : organe de la Societe royale belge de radiologie (SRBR) = orgaan van de Koninklijke Belgische Vereniging voor Radiologie (KBVR)",
"keywords": null,
"medline_ta": "JBR-BTR",
"mesh_terms": null,
"nlm_unique_id": "100888280",
"other_id": null,
"pages": "113-114",
"pmc": null,
"pmid": "30394438",
"pubdate": "2015-06-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Lithium-Induced Nephropathy.",
"title_normalized": "lithium induced nephropathy"
} | [
{
"companynumb": "US-APOTEX-2018AP010285",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LITHIUM CARBONATE"
},
"drugadditional": "1",
... |
{
"abstract": "Limited data exist on safe discontinuation of antiprogrammed cell death protein 1 (PD-1) therapy in responding patients with advanced melanoma. The use of 18fluorodeoxyglucose (18FDG)-PET/CT scan and tumor biopsy for assessment of active disease may be an effective predictive biomarker to guide such treatment decisions.\n\n\n\nA retrospective study of 122 patients with advanced melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anticytotoxic T-lymphocyte-associated protein 4 combination therapy at Georgetown Lombardi Comprehensive Cancer Center was conducted. Uveal melanoma patients and those receiving concurrent experimental therapy were excluded. Baseline characteristics, treatment outcomes, and survival were analyzed. Patients who decided to come off treatment typically after 12 months using CT scan radiographic complete response (CR), 18FDG-PET/CT scan complete metabolic response (CMR) or tumor biopsy of a non-CR/CMR tumor site negative for active disease (possible pathological CR) were identified and compared with patients who discontinued treatment due to toxicity while their disease was in control. Event-free survival (EFS) was assessed from the last dose of anti-PD-1 therapy to progression requiring subsequent treatment (surgery, radiation, and/or systemic therapy) or referral to hospice/death due to melanoma.\n\n\n\n24 (20%) patients discontinued treatment by choice with no active disease and 28 (23%) patients discontinued treatment due to toxicity with disease control after 12-month and 4-month median treatment durations, respectively. Similar baseline characteristics were observed between cohorts except higher prior receipt of ipilimumab (29% vs 7%; p=0.036) and fewer BRAF mutant positive disease (17% vs 41%; p=0.064) in patients off treatment by choice. Three-year EFS rates were 95% and 71%, respectively. No significant associations between EFS and sex, disease stage, lactate dehydrogenase elevation, BRAF status, prior systemic therapy, ECOG performance status, presence of brain metastases, or combination versus monotherapy were observed. Tumor biopsies led to alternative management in 3/10 patients due to active metastatic melanoma or second malignancy.\n\n\n\nAnti-PD-1 therapy discontinuation after 12 months when no active disease is observed on CT scan, PET/CT scan or tumor biopsy may have low rates of disease relapse in patients with advanced melanoma. Biopsy of residual disease may frequently lead to a change in management. These findings are undergoing validation in the EA6192 trial.",
"affiliations": "Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, District of Columbia, USA geoffrey.t.gibney@gunet.georgetown.edu.;Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.;Charleston Oncology, Charleston, South Carolina, USA.;Memorial Sloan Kettering Cancer Center, New York, New York, USA.;Moffitt Cancer Center, Tampa, Florida, USA.;MedStar Georgetown University Hospital, Washington, District of Columbia, USA.;Inform Diagnostics, Irving, Texas, USA.;Georgetown University Medical Center, Washington, District of Columbia, USA.;MedStar Georgetown University Hospital, Washington, District of Columbia, USA.;MedStar Georgetown University Hospital, Washington, District of Columbia, USA.;Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.;Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, District of Columbia, USA.",
"authors": "Gibney|Geoffrey T|GT|0000-0002-5401-8498;Zaemes|Jacob|J|;Shand|Shelly|S|;Shah|Neil J|NJ|;Swoboda|David|D|;Gardner|Kellie|K|;Radfar|Arash|A|;Petronic-Rosic|Vesna|V|;Reilly|Michael J|MJ|;Al-Refaie|Waddah B|WB|;Rapisuwon|Suthee|S|0000-0002-1389-925X;Atkins|Michael B|MB|0000-0003-3901-9924",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/jitc-2021-002955",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n34599027\njitc-2021-002955\n10.1136/jitc-2021-002955\nImmunotherapy Biomarkers\n1506\n2437\nOriginal researchPET/CT scan and biopsy-driven approach for safe anti-PD-1 therapy discontinuation in patients with advanced melanoma\nhttp://orcid.org/0000-0002-5401-8498\nGibney Geoffrey T. 1\nZaemes Jacob 1\nShand Shelly 2\nShah Neil J. 3\nSwoboda David 4\nGardner Kellie 5\nRadfar Arash 6\nPetronic-Rosic Vesna 7\nReilly Michael J. 5\nAl-Refaie Waddah B. 5\nhttp://orcid.org/0000-0002-1389-925X\nRapisuwon Suthee 18\nhttp://orcid.org/0000-0003-3901-9924\nAtkins Michael B. 19\n1 Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, District of Columbia, USA\n2 Charleston Oncology, Charleston, South Carolina, USA\n3 Memorial Sloan Kettering Cancer Center, New York, New York, USA\n4 Moffitt Cancer Center, Tampa, Florida, USA\n5 MedStar Georgetown University Hospital, Washington, District of Columbia, USA\n6 Inform Diagnostics, Irving, Texas, USA\n7 Georgetown University Medical Center, Washington, District of Columbia, USA\n8 MedStar Washington Hospital Center, Washington, District of Columbia, USA\n9 Department of Oncology, Georgetown University, Washington, District of Columbia, USA\nCorrespondence to Dr Geoffrey T. Gibney; geoffrey.t.gibney@gunet.georgetown.edu\n2021\n1 10 2021\n9 10 e00295513 7 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.\n\nBackground\n\nLimited data exist on safe discontinuation of antiprogrammed cell death protein 1 (PD-1) therapy in responding patients with advanced melanoma. The use of 18fluorodeoxyglucose (18FDG)-PET/CT scan and tumor biopsy for assessment of active disease may be an effective predictive biomarker to guide such treatment decisions.\n\nMethods\n\nA retrospective study of 122 patients with advanced melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anticytotoxic T-lymphocyte-associated protein 4 combination therapy at Georgetown Lombardi Comprehensive Cancer Center was conducted. Uveal melanoma patients and those receiving concurrent experimental therapy were excluded. Baseline characteristics, treatment outcomes, and survival were analyzed. Patients who decided to come off treatment typically after 12 months using CT scan radiographic complete response (CR), 18FDG-PET/CT scan complete metabolic response (CMR) or tumor biopsy of a non-CR/CMR tumor site negative for active disease (possible pathological CR) were identified and compared with patients who discontinued treatment due to toxicity while their disease was in control. Event-free survival (EFS) was assessed from the last dose of anti-PD-1 therapy to progression requiring subsequent treatment (surgery, radiation, and/or systemic therapy) or referral to hospice/death due to melanoma.\n\nResults\n\n24 (20%) patients discontinued treatment by choice with no active disease and 28 (23%) patients discontinued treatment due to toxicity with disease control after 12-month and 4-month median treatment durations, respectively. Similar baseline characteristics were observed between cohorts except higher prior receipt of ipilimumab (29% vs 7%; p=0.036) and fewer BRAF mutant positive disease (17% vs 41%; p=0.064) in patients off treatment by choice. Three-year EFS rates were 95% and 71%, respectively. No significant associations between EFS and sex, disease stage, lactate dehydrogenase elevation, BRAF status, prior systemic therapy, ECOG performance status, presence of brain metastases, or combination versus monotherapy were observed. Tumor biopsies led to alternative management in 3/10 patients due to active metastatic melanoma or second malignancy.\n\nConclusions\n\nAnti-PD-1 therapy discontinuation after 12 months when no active disease is observed on CT scan, PET/CT scan or tumor biopsy may have low rates of disease relapse in patients with advanced melanoma. Biopsy of residual disease may frequently lead to a change in management. These findings are undergoing validation in the EA6192 trial.\n\nimmunotherapy\nmelanoma\ntumor biomarkers\nprogrammed cell death 1 receptor\nspecial-featureunlocked\n==== Body\npmcBackground\n\nImmune checkpoint inhibitor therapies targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have become standard therapy options for patients with advanced unresectable stage III and IV melanoma. Anti-PD-1 monotherapy (nivolumab, pembrolizumab) and combination anti-PD-1/anti-CTLA-4 therapy (nivolumab plus ipilimumab, pembrolizumab plus ipilimumab) have demonstrated objective response rates of 45%–61% in the front-line setting, along with improved progression-free survival (PFS) and overall survival (OS) compared with ipilimumab monotherapy and historical data.1–4 Long-term follow-up has demonstrated 5-year OS rates of 41%–52%. However, the optimal duration of therapy in responding patients without toxicity issues is unknown.\n\nOn the Keynote 001 study, where patients with complete response (CR) on two serial scans with pembrolizumab were permitted to discontinue treatment and follow by observation alone, the estimated 24-month disease-free survival rate was 90% (median duration of treatment was 23 months).3 On the Keynote 006 study, there was a preplanned discontinuation of therapy after 2 years of pembrolizumab in patients with maintained disease control (CR, partial response (PR), or stable disease (SD)) and no dose limiting toxicities.4 A total of 103 patients met these criteria and the estimated 24-month PFS rate after pembrolizumab discontinuation was 78%. The estimated PFS rates off treatment for patients with CR or PR were 85% and 82%, respectively, and 40% in those with SD suggesting that many patients with radiographic PR and SD had no residual active tumor. It remains unclear if shorter durations of anti-PD-1 therapy in selected patients with metastatic melanoma can be equally effective and which patients with prolonged PR or SD can safely discontinue therapy. Of note, in a second-line nivolumab study in patients with advanced non-small-cell lung cancer (NSCLC) (Checkmate 153), patients with disease control randomized to continue treatment beyond 1 year had superior PFS compared with those who were assigned to discontinue therapy at the one-year time point (HR=0.42),5 suggesting that at least in patients with NSCLC discontinuation of treatment without further justification may be detrimental.\n\nDurable responses with short durations of anti-PD-1 therapy have been seen in patients with advanced melanoma who stop immunotherapy early due to toxicity. On the Checkmate 067 and 069 studies, 56/96 (58%) of patients who discontinued nivolumab plus ipilimumab in the first 12 weeks (median treatment duration 1.4 months) due to toxicity achieved an objective response and ongoing responses were observed in 64% of these responding patients.6 Of note, there is a known association of immune toxicities and clinical benefit with anti-PD-1 therapy,7 suggesting that patients with melanoma and a strong antitumor immune response with treatment may only need a brief course of therapy in order to eliminate their viable tumor cells. This is supported by neoadjuvant studies with pembrolizumab, nivolumab and nivolumab plus ipilimumab, which have demonstrated complete pathological responses in 19%–57% of patients with advanced locoregional melanoma after 1–3 cycles of treatment even though the actual radiologic response rate was considerably less.8\n\nThe current standard, conventional computed tomography (CT) scan, for assessing benefit likely under-represents the number of patients with complete therapeutic response with anti-PD-1 therapies in advanced melanoma given that pathological responses occur before radiographic responses and many patients with radiographic PR and SD have durable disease control after treatment is discontinued. The use of 18fluorodeoxyglucose (18FDG)-positron emission tomography/CT (PET/CT) scan and/or biopsy of residual tumors may serve as a better biomarker for assessing residual active disease and thus need for further therapy. In a study conducted by the Melanoma Institute of Australia, complete metabolic response (CMR) in tumor sites by 18FDG-PET/CT scan after 1 year of anti-PD-1/programmed cell death-ligand 1 (PD-L1) therapy was associated with superior survival compared with patients with a non-CMR.9 The subgroup of patients with a radiographic PR but with a CMR, the PFS rate was 100% at 12 months and 93% at 24 months post-18FDG-PET/CT. Further, of those patients with PR or SD but non-CMR, the PFS rate was 49% after 24 months. This implies complete pathological response may have been achieved despite the residual radiographic and/or metabolic findings. Data from neoadjuvant anti-PD-1 studies reinforce the long-term clinical impact of complete pathological response to immunotherapy, where recurrence-free survival has been reported to be 100% at 24 months in high-risk patients.8\n\nGiven the lack of a standard of care for anti-PD-1 treatment duration and the frequency of pathological CR in patients without CR on CT scans, patients at Georgetown Lombardi Comprehensive Cancer Center have been offered a PET/CT scan after approximately 12 months of therapy to determine if tumor sites are metabolically active and if so, they are offered to undergo a biopsy of a representative site for evaluation of active residual disease. If patients are negative for active disease, they have been offered the option of being observed off active anti-PD-1 therapy. Here, we present our experience in patients with advanced melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy to determine the frequency of residual active disease by 18FDG-PET/CT scan metabolic response and/or tumor biopsy and the durability of response in patients who come off treatment by choice without evidence of active disease in comparison to patients with disease control who needed to come off treatment due to toxicity.\n\nMethods\n\nPatients and data collection\n\nUnder an Institutional Review Board (IRB)-approved protocol at Georgetown University, clinical outcome data were collected retrospectively on patients with advanced, unresectable stage III and IV melanoma treated with anti-PD-1 monotherapy (pembrolizumab or nivolumab) and combination anti-PD-1/anti-CTLA-4 therapy (nivolumab plus ipilimumab or pembrolizumab plus ipilimumab) at the MedStar Georgetown University Hospital Lombardi Comprehensive Cancer Center from 2013 to 2019. Patients with uveal melanoma were excluded as well as those with prior anti-PD-1 treatment in the adjuvant setting or receipt of concurrent experimental therapy. If patients received more than one line of anti-PD-1-based therapy, only the first line of therapy was included in the analyses. Baseline characteristics, therapeutic regimens, best overall radiographic response (provider assessed), treatment duration, the reason for treatment discontinuation, PFS, and OS were captured. Patients with disease control (CR, PR, or SD) who discontinued therapy due toxicity and by choice after a CR by CT scan or no active disease by 18FDG-PET/CT scan and/or tumor biopsy were analyzed. The elective treatment discontinuation was typically after 12 months of active therapy based on practice patterns at our cancer center, but patients receiving shorter and longer durations of treatment were included, such as where a CR or a negative tumor biopsy was observed prior to 12 months or patients’ preference to remain on treatment longer than 12 months. Criteria for no active disease by 18FDG-PET/CT scan were concluded when no suspicious hypermetabolic lesions were identified, that is, CMR as determined by 18FDG-uptake by standard uptake value (SUV) in responding tumor lesions was <SUV of the liver. Tumor biopsy was performed in patients not achieving CMR and considered negative when no viable tumor cells were identified by H&E or melanoma immunohistochemistry (IHC) markers (eg, S100, melan-A, or HMB-45). The finding of melanin laden or IHC positive macrophages (melanophages) in the absence of viable tumor cells was considered to be negative for residual tumor.\n\nStatistical methods\n\nDescriptive statistics were summarized for age, gender, primary melanoma type, BRAF status, Eastern Cooperative Oncology Group performance status (ECOG PS), American Joint Committee on Cancer (AJCC) eighth edition stage at the time of anti-PD-1 therapy, lactate dehydrogenase (LDH), presence of brain metastases, receipt of prior therapies, and type of anti-PD-1 therapy received. For continuous variables, a Student’s t-test was used for determination of statistical differences. For proportion, differences between the populations, χ2 tests (Pearson correlation) were used for categorical variables. Best overall response was based on provider assessment following Response Evaluation Criteria in Solid Tumours (RECIST) guidelines.10 Patients with SD on the first restaging scan but either clinical or radiographic disease progression by the next scan time point were considered progressive disease (PD) overall. Patients with unconfirmed PR were considered SD. Patients assessed to have clinical deterioration/progression without restaging scans were assigned PD. OS was defined as the duration from the date of first anti-PD-1 dose to the date of death/hospice referral related to melanoma. Event-free survival (EFS) was defined as the duration from the date of the last anti-PD-1 dose to date of progression requiring treatment (systemic therapy, surgery, or radiation) or death/hospice referral related to melanoma. Survival was evaluated using the Kaplan-Meier (KM) method and Cox regression. Survival differences between populations were determined using a log-rank test for KM. All statistical analyses were performed using IBM SPSS (V.24) and GraphPad Prism (V.6.0). A two-sided p≤0.05 was considered statistically significant.\n\nResults\n\nPatient characteristics\n\nA total of 122 patients with advanced melanoma receiving standard anti-PD-1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy were included in the study (online supplemental table 1). There were 46 subjects who received anti-PD-1 monotherapy and 76 who received an anti-PD-1/anti-CTLA-4 combination therapy. Most subjects had cutaneous or unknown primary (84%), stage IV M1c/M1d disease (61%), and ECOG PS 0–1 (94%). Prior systemic therapy had been administered in 36% of patients. Provider assessed best overall response was 52% (CR 12%; PR 40%; SD 11%; PD 38%). Five-year landmark OS was estimated to be 58% (53% for the monotherapy cohort and 62% for the combination therapy cohort, p=0.052; online supplemental figure 1).\n\n10.1136/jitc-2021-002955.supp1 Supplementary data\n\nOf the 28 patients considered for monitoring off treatment by choice, 22 subjects underwent PET/CT scan to evaluate for metabolic response (figure 1). Fourteen (64%) patients had CMR. All eight non-CMR patients underwent tumor biopsy: six patients demonstrated no viable tumor cells, one patient demonstrated a new primary NSCLC (residual hypermetabolic lung mass on PET/CT scan), and one patient demonstrated a new primary colorectal cancer (residual hypermetabolic bowel lesion on PET/CT scan). Two patients with PR without a PET/CT scan underwent biopsy of a representative tumor site to evaluate for active disease—one patient demonstrated no viable tumor cells while the second patient demonstrated viable melanoma tumor cells and subsequently had treatment changed to talimogene laherparepvec (TVEC) plus anti-PD-1 therapy. In total, 3 out of 10 patients who underwent a biopsy to evaluate for active residual disease demonstrated active melanoma or another malignancy leading to a change in management.\n\nFigure 1 Outcomes for patients with advanced melanoma treated with anti-PD-1 therapy. Of 122, 24 (20%) of patients came off treatment by choice based on no evidence of active disease by imaging and/or biopsy. Of 122, 28 (23%) of patients came off treatment due to toxicity with disease control. CTLA-4, cytotoxic T-lymphocyte-associated protein 4; NSCLC, non-small-cell lung cancer; PD-1, programmed cell death protein 1; TVEC, talimogene laherparepvec; CRC, colorectal cancer; PR, partial response.\n\nTwenty-four patients (20%) came off active treatment by choice after no evidence of active disease by CR on CT scan, CMR on PET/CT scan or negative tumor biopsy (figure 1). Twenty-eight patients (23%) came off active treatment due to toxicity with disease control. These two groups were further analyzed for EFS as individual cohorts and then combined to examine EFS by baseline patient and disease characteristics. Table 1 shows the baseline characteristics for these two patient cohorts included in the EFS analyses. Overall, similar characteristics were observed between patients who came off treatment by choice with no active disease and those who came off treatment for toxicity. This included age (median 67 and 63 years, respectively), elevated LDH (29% in each), M1c/M1d disease (54% and 75%, respectively), brain metastases (42% and 25%, respectively), prior systemic therapy (33% and 25%) and receipt of anti-PD-1/anti-CTLA-4 combination therapy (58% and 75%, respectively). Exceptions include fewer patients with BRAF mutant melanoma (17% vs 41%, p=0.064) and more patients with prior ipilimumab (29% vs 7%, p=0.036) in patients off treatment by choice than patients off treatment for toxicity.\n\nTable 1 Baseline Patient characteristics\n\nCharacteristics\tChoice (n=24)\tToxicity (n=28)\tStatistics\t\nMedian age\t67 years\t63 years\tP=0.311 (two-sided t-test)\t\nMale gender\t17 (71%)\t17 (61%)\tP=0.444 (Pearson χ2)\t\nECOG PS 0–1\t24 (100%)\t27 (96%)\t-\t\nLDH elevated\t7 (29%)\t8 (29%)\tP=0.971 (Pearson χ2)\t\nPrimary tumor type\t\t\tP=0.468 (Pearson χ2)\t\n Cutaneous\t12 (50%)\t19 (68%)\t\n Acral\t1 (4%)\t0\t\n Mucosal\t2 (8%)\t2 (7%)\t\n Unknown\t9 (38%)\t7 (25%)\t\nDisease stage at tx\t\t\tP=0.115 (Pearson χ2)\t\n III–IV M1b\t11 (46%)\t7 (25%)\t\n IV M1c/M1d\t13 (54%)\t21 (75%)\t\nBRAF mut (%)\t4 (17%)*\t12 (41%)†\tP=0.064 (Pearson χ2)\t\nBrain mets (%)\t10 (42%)\t7 (25%)\tP=0.202 (Pearson χ2)\t\nPrior systemic tx\t8 (33%)\t7 (25%)\tP=0.508 (Pearson χ2)\t\nIpilimumab\t7 (29%)\t2 (7%)\tP=0.036 (Pearson χ2)\t\nBRAFi/MEKi\t1 (4%)\t4 (14%)\tP=0.217 (Pearson χ2)\t\nTherapy received\t\t\tP=0.202 (Pearson χ2)\t\n Anti-PD1/Anti-CTLA4\t14 (58%)\t21 (75%)\t\n Anti-PD-1\t10 (42%)\t7 (25%)\t\n*N=3 (13%) unknown BRAF status.\n\n†N=5 (18%) unknown BRAF status.\n\nCTLA4, cytotoxic T-lymphocyte-associated protein 4; LDH, lactate dehydrogenase; PD-1, programmed cell death protein 1; PS, performance status.\n\nBest overall response, treatment duration, and determination of no active disease\n\nIn the cohort of patients off treatment by choice, the best overall response by CT scan was CR in 8/24 patients (33%), PR in 15/24 patients (63%) and SD 1 patient (4%). Median duration of treatment was 12.1 months (range 2.3–24.1 months). The patients came off treatment after demonstrating CR on CT scan alone (n=3/24; 13%), CMR on PET/CT scan (n=14/24, 58%), and non-CMR on PET/CT scan but biopsy negative (n=6/24; 25%). Note five of the patients with CMR on PET/CT scan also had a CR on CT scan. One additional patient had initial increase in nodal disease and biopsy was negative for active disease; patient elected to discontinue treatment after 2.3 months and subsequent CT scans demonstrated PR (n=1/24; 4%). Of the patients with CMR on PET/CT scan, five had CR, eight had PR, and one had SD on diagnostic CT scan. No patient with a CR on CT scan had a non-CMR PET/CT scan. For the six patients with non-CMR and negative biopsy, all demonstrated PR by diagnostic CT scan. Figure 2 illustrates a patient with a PR on CT scan and non-CMR by PET/CT scan where a biopsy was negative for viable tumor cells. Of note, the presence of melanophages was observed.\n\nFigure 2 Example of a patient with a non-CMR on PET/CT scan but negative biopsy for viable tumor. The patient achieved a partial response to anti-PD-1 therapy. (A, B) shows a hypermetabolic subcutaneous metastasis at the left calf pretreatment and 1-year post-treatment with anti-PD-1 therapy. The patient underwent excisional biopsy of the residual left calf lesion. (C) shows pathology findings of excised lesion on H&E stain. Fibrosis, brown pigmented cells considered melanophages and no viable tumor cells identified. (D) shows higher power view of fibrosis and melanophages. (E) shows brown stain with anti-CD68, highlighting melanophages. Additional stains showed melanophages positive for melan-A and fontana mason, but negative for iron (data not shown). CMR, complete metabolic response; PD-1, programmed cell death protein 1.\n\nIn the cohort of patients off treatment due to toxicity, the best overall response was CR in 5/28 patients (18%), PR in 22/28 patients (79%), and SD in 1/28 patients (4%). Median treatment duration in this cohort of patients was 3.7 months (range 0.7–14.0 months).\n\nEvent-free survival\n\nEFS was evaluated in patients who came off treatment by choice and who came off treatment due to toxicity with disease control. No significant EFS difference was observed between the two cohorts, although fewer events occurred in the cohort off treatment by choice (p=0.160, figure 3). In the patient cohort off treatment by choice, estimated 1-year, 2-year, and 3-year EFS rates were 100%, 95%, and 95%, respectively (online supplemental table 2). Only 2 out of 24 patients had an event in this cohort. One patient had surgical resection of an isolated lymph node recurrence rendering him free of active disease and continues to be followed off treatment without recurrence for 3+ years; one patient with progression after a 3-year EFS is deceased after receiving subsequent rechallenge with nivolumab plus ipilimumab (online supplemental table 3). In the patient cohort off treatment due to toxicity, the estimated 1-year, 2-year, and 3-year EFS rates were 87%, 83%, and 71%, respectively (online supplemental table 2). There were six events in this cohort. Two patients had surgery to render them free of active disease; one is currently followed off active treatment and the second developed a progressive brain metastasis and is lost to follow-up (online supplemental table 3). Four patients received subsequent systemic therapy for melanoma. One patient was rechallenged with ipilimumab and developed recurrent immune colitis after four cycles. She demonstrated disease regression but then was started on dabrafenib/trametinib for clinical progression and had a CR. Dabrafenib/trametinib was discontinued due to toxicity, and she has been followed off active treatment for over 2.5 years. Three other patients with disease progression received pembrolizumab, none of whom responded to therapy. One patient is alive after CR to BRAF/MEK inhibitors, and two patients are deceased.\n\nFigure 3 Event-free survival (EFS) in patients treated with anti-PD-1 therapy. Patients who discontinued treatment by choice after no evidence of active disease by CT scan, 18FDG-PET/CT scan or tumor biopsy are represented by the green survival curve (n=24). Patients who discontinue treatment due to toxicity with initial disease control are represented by the purple survival curve (n=28). Two events were observed in the cohort off treatment by choice and six events were observed in the cohort off treatment due to toxicity. Log-rank p=0.160. 18FDG, 18fluorodeoxyglucose; PD-1, programmed cell death protein 1.\n\nEFS associations with baseline patient characteristics and treatment were evaluated by KM and Cox regression analyses (refer to figure 4 and online supplemental table 4). Both cohorts of patients were combined for these analyses. A trend for association between primary tumor type and EFS was observed by KM with lower survival in patients with mucosal melanoma compared with other subgroups (figure 4A). However, the mucosal subgroup size was low (N=4) and EFS association was only statistically significant on Cox proportion analyses when the mucosal and unknown primary subgroups were compared (p=0.026). There were no significant associations between EFS and sex, stage of disease, presence of brain metastases, ECOG PS, or prior systemic therapy (a separate EFS association analysis for the off treatment by choice cohort alone was performed and showed similar findings with the exception that the mucosal-unknown primary subgroup analysis was no longer significant as only two patients had mucosal melanoma in this cohort). None of the patients with baseline ECOG PS 2–4 (6% of all patients) achieved EFS status. EFS was numerically lower in patients treated with combination anti-PD-1/anti-CTLA-4 therapy compared with anti-PD-1 monotherapy, but this was not statistically significant (figure 4B; online online supplemental table 4). Of note, there was a higher representation of combination anti-PD-1/anti-CTLA-4 therapy in the total EFS data set, particularly in the toxicity cohort (75%; table 1).\n\nFigure 4 EFS associations with primary tumor site (A, p=0.064), and receipt of anti-PD-1 monotherapy versus combination therapy (B, p=0.195). EFS data for patients off treatment by choice and due to toxicity were combined for these analyses. CTLA-4, cytotoxic T-lymphocyte-associated protein 4; EFS, event-free survival; PD-1, programmed cell death protein 1.\n\nDiscussion/conclusion\n\nIn this retrospective study, patients with advanced melanoma receiving anti-PD-1 alone and in combination with anti-CTLA-4 demonstrated efficacy similar to what has been previously reported in prospective randomized studies.1 4 Of note, a higher 5-year OS was observed in patients who were treated with combination anti-PD-1/anti-CTLA-4 therapy consistent with the Checkmate 067 study. Almost half of all patients had treatment cessation in the absence of disease progression, with 23% of patients off treatment for toxicity with disease control and 20% of patients off treatment by choice without evidence of active disease. Similar high rates of EFS were seen in both cohorts with numerically greater survival rates in patients off treatment by choice. While the majority of patients received combination anti-PD-1/anti-CTLA-4 therapy in both cohorts, the radiographic CR rate was lower, and treatment duration was shorter in the patients who came off treatment due to toxicity. These factors, along with the use of immunosuppressive agents and lack of selection for absence of residual by PET/CT or biopsy, may account for the slightly lower EFS rate in the off treatment due to toxicity cohort.\n\nSeveral retrospective studies of patients with advanced melanoma have also shown that elective discontinuation of anti-PD-1 therapy after treatment durations shorter than 24 months can be associated with durable off treatment survival.11–13 In one study where patients with CR, PR, or SD electively discontinued anti-PD-1 therapy after a median of 12 months, the 1-year and 2-year PFS rates after discontinuation were 90% and 71%, respectively.12 Patients with CR had a significantly lower risk of disease progression compared with patients with PR or SD. Also, patients with CR who received less than 6 months of therapy had shorter PFS compared with patients with CR who received anti-PD-1 therapy for 6 months or longer. In another study of patients with CR who came off treatment after a median of 9.4 months, the 3-year PFS rate after discontinuation was 72%.11 The PFS rates in this second study may have been impacted by the inclusion of patients who came off treatment due to toxicity (24%). This assumption is supported by the higher number of progression events observed in the toxicity cohort of our study as well as in the combined Checkmate 067/069 toxicity outcome dataset.6 The more favorable PFS rate after anti-PD-1 discontinuation (EFS) in our cohort of patients off treatment by choice (2-year and 3-year EFS of 95%) may be due to selection of patients with CMR on 18FDG-PET/CT scan and tumor biopsy showing no active disease.\n\nThe CMR rate on 18FDG-PET/CT scan in patients with PR/SD after a median of 1 year from the start of treatment in our study (53%; n=9/17) was similar to the CMR rate reported in the Melanoma Institute of Australia study (65%).9 The small difference in rates may be to the smaller sample size (random variation) and higher use of anti-PD-1/anti-CTLA-4 combination therapy with resultant increased potential for false positives due to inflammation in our study. Interestingly, 3 of 10 patients undergoing biopsy to clarify disease status had residual active melanoma or a new second malignancy. In the one patient with active residual melanoma, he was able to transition to an effective alternative immunotherapy strategy. The use of biopsy to clarify disease status in non-CMR patients appears to provide valuable management guidance. This is supported by the high rate of progression in non-CMR patients on the Melanoma Institute of Australia study despite 1 year of disease control with anti-PD-1 therapy. Additional biomarkers may be important to predict survival outcomes in patients with PR/SD and non-CMR after 1 year of anti-PD-1 therapy, particularly when discontinuing therapy. For example, the presence of circulating tumor DNA after initiation of anti-PD-1 therapy in patients with advanced melanoma has demonstrated worse survival outcomes14 15 and could potentially be used as a biomarker for residual active disease.\n\nPatient selection based on baseline characteristics may also play a role in off treatment survival. For example, patients with advanced uveal melanoma were excluded from our study based on the lower response rate and survival with anti-PD-1 therapies compared with other tumor melanoma subtypes.16 17 In our subgroup analyses, patients with mucosal melanoma had worse EFS, although the sample size was small. This is supported by data showing lower response rates and shorter PFS with nivolumab monotherapy and in combination with ipilimumab in patients with advanced mucosal melanoma versus cutaneous melanoma.18 Other subgroups previously shown to have worse survival outcomes with anti-PD-1 therapy, such as those with elevated LDH and M1c disease,1 were not statistically significant in our study for associations with EFS. This suggests that once patients show no residual disease on PET/CT or biopsy after anti-PD-1 therapy, baseline (pretreatment) poor prognostic factors may no longer be applicable. The additional comparison for receipt of anti-PD-1 monotherapy versus anti-PD-1/anti-CLTA-4 combination therapy showed no negative impact on the EFS outcomes with anti-PD-1 monotherapy. In fact, there was only one event after stopping therapy observed in patients treated with anti-PD-1 monotherapy compared with the seven events observed in patients treated with nivolumab plus ipilimumab. The higher rate of events in patients receiving combination anti-PD-1/anti-CTLA-4 therapy may have been due to the higher representation (75%) in the treatment discontinuation due to toxicity cohort where treatment duration was shorter and patients may not have been free of active disease at time of discontinuation. However, this warrants further investigation.\n\nWhile the probability of progression off treatment after discontinuation by choice or due to toxicity was low in our study, no patients had responses to rechallenge with anti-PD-1 therapy (0/4 patients). Only one of these relapsed patients was in the treatment discontinuation by choice cohort. In other studies, response rates to rechallenge with anti-PD-1 based therapies have ranged from 15% to 54%.4 11 12 It remains unclear if long-term outcomes would be different if these patients remained on continuous anti-PD-1 therapy (ie, beyond 12 or 24 months). Other prospective studies have demonstrated progression events occurring after 12 months despite continuous anti-PD-1 therapy.1 4 This suggests that a subset of responding patients likely develop areas of subclinical resistant disease in the first 12 months of anti-PD-1 therapy and will eventually exhibit disease progression requiring alternative treatment options perhaps irrespective of whether they remain on therapy or not.\n\nEarly safe discontinuation of anti-PD-1 therapy has potential safety and cost benefits to patients. Late onset adverse events (AEs) are observed in patients, particularly when remaining on long-term anti-PD-1 therapy. In a retrospective study of 110 patients with advanced melanoma treated with at least 2 years of nivolumab or pembrolizumab, 43% of patients experienced late onset AEs, including 4% of all patients requiring hospitalization.19 Increased number of doses and duration of treatment were associated with occurrence of late-onset AEs, most frequently cutaneous, gastrointestinal and neuromuscular AEs. In addition, the financial burden on patients and the healthcare system increases with prolonged courses of anti-PD-1 therapy. This includes the cost of the anti-PD-1 agent and its administration, along with AE management. For example, the average monthly cost of each nivolumab and pembrolizumab treatment (drug plus administration) has been previously estimated to be US$13, 736 and US$13, 387, respectively.20 The cost for an additional year of nivolumab would be US$164, 832 and US$160,644, respectively. Similar costs would be incurred with the larger doses with more extended dosing intervals for these two agents currently being used (current wholesale acquisition list price for nivolumab 480 mg every 4weeks is US$13, 358 and pembrolizumab 400 mg every 6 weeks is US$20, 135).21 22 Such expenses dwarf the costs of a single 18FDG-PET/CT scan at 12 months and biopsy in non-CMR patients (typically under US$10, 000 total) that would occur in 10%–20% of patients receiving anti-PD-1 therapies using the strategy examined here for safe discontinuation. Stopping treatment also untethers patients from frequent physician visits and often allows more freedom and confidence to return to their normal precancer lives and activities.\n\nBased on these data and the potential benefit to patients of shorter anti-PD-1 therapy durations and longer time free from treatment, validation for the use of 18FDG-PET/CT scan and tumor biopsy for assessing residual disease after 12 months of anti-PD-1 therapy and identifying patients at low relapse risk with treatment discontinuation is warranted. This approach for safe discontinuation of anti-PD-1 therapy is currently under investigation with the ongoing ECOG-ACRIN study, EA6192 (ClinicalTrials.gov Identifier: NCT04462406; figure 5).\n\nFigure 5 Study design for the ongoing EA6192 trial validating 18FDG-PET/CT scan and tumor biopsy as predictive biomarkers for safe anti-PD-1 therapy discontinuation in patients with advanced melanoma. ClinicalTrials.gov Identifier: NCT04462406. CR, complete response; 18FDG, 18fluorodeoxyglucose; PD-1, programmed cell death protein 1; PR, partial respons; SD, stable disease.\n\nData availability statement\n\nData are available on reasonable request. Data and materials used in this study are available by communication with the corresponding author.\n\nEthics statements\n\nPatient consent for publication\n\nNot required.\n\nEthics approval\n\nThis retrospective study was conducted under an Institutional Review Board (IRB) approved protocol at Georgetown University. Waiver for consent was granted by the IRB.\n\nTwitter: @Mdswoboda\n\nContributors: GTG contributed in development of the research project, data collection, analyses, interpretation of the data, and manuscript writing. JZ and SS contributed in data collection, analyses, interpretation of the data, and manuscript writing. NJS and AR contributed in data collection, interpretation of the data, and manuscript writing. DS contributed in data collection interpretation of the data, and manuscript writing. KG contributed in data collection and manuscript writing. VP-R, MJR and WBA-R contributed in interpretation of the data and manuscript writing. SR contributed in development of the research project, interpretation of the data and manuscript writing. MBA contributed in development of the research project, data analyses, interpretation of the data, and manuscript writing. All authors support the submission of the manuscript for publication.\n\nFunding: Funding support for the article processing charge provided by the Sher Grant to the Georgetown-Lombardi Comprehensive Cancer Center.\n\nCompeting interests: GTG has served as a consultant for Novartis, Bristol Myers Squibb, Array Biopharma, Merck, Regeneron, Exicure and Sapience Therapeutics, and has received institutional research support from Exelixis and Lucerno Dynamics. MBA has served as an advisor for Arrowhead, Aveo, Bristol Myers Squibb, Eisai, Elpis, Genetech/Roche, Leads, Merck, Novartis, Pfizer, Pneuma, Pyxis Oncology, Werewolf and as a consultant to Adagene, Agenus, Apexigen, Exelixis, Idera, ImmunoCore, Iovance, and Neoleuken.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nSupplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.\n==== Refs\nReferences\n\n1 LarkinJ, Chiarion-SileniV, GonzalezR, et al . Five-Year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2019;381 :1535–46. 10.1056/NEJMoa1910836 31562797\n2 LongGV, AtkinsonV, CebonJS. Long-term follow-up of standard-dose pembrolizumab plus Reduced-Dose ipilimumab in 153 patients with advanced melanoma: KEYNOTE-029 1B. Pigment Cell & Melanoma Res 2018.\n3 RobertC, RibasA, HamidO, et al . Durable complete response after discontinuation of pembrolizumab in patients with metastatic melanoma. J Clin Oncol 2018;36 :1668–74. 10.1200/JCO.2017.75.6270 29283791\n4 RobertC, RibasA, SchachterJ, et al . Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol 2019;20 :1239–51. 10.1016/S1470-2045(19)30388-2 31345627\n5 SpigelDR, McCleodM, HusseinMA. CheckMate153: randomized results of continuous vs 1-year Fixed-Duration nivolumab in patients with advanced non-small cell lung cancer. Ann Oncol 2017;28 :3182.\n6 SchadendorfD, WolchokJD, HodiFS, et al . Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol 2017;35 :3807–14. 10.1200/JCO.2017.73.2289 28841387\n7 Freeman-KellerM, KimY, CroninH, et al . Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 2016;22 :886–94. 10.1158/1078-0432.CCR-15-1136 26446948\n8 MenziesAM, RozemanEA, AmariaRN, et al . Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International neoadjuvant melanoma Consortium (INMC). JCO 2019;37 :9503. 10.1200/JCO.2019.37.15_suppl.9503\n9 TanAC, EmmettL, LoS, et al . FDG-PET response and outcome from anti-PD-1 therapy in metastatic melanoma. Ann Oncol 2018;29 :2115–20. 10.1093/annonc/mdy330 30137228\n10 EisenhauerEA, TherasseP, BogaertsJ, et al . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45 :228–47. 10.1016/j.ejca.2008.10.026 19097774\n11 Betof WarnerA, PalmerJS, ShoushtariAN, et al . Long-Term outcomes and responses to retreatment in patients with melanoma treated with PD-1 blockade. J Clin Oncol 2020;38 :1655–63. 10.1200/JCO.19.01464 32053428\n12 JansenYJL, RozemanEA, MasonR, et al . Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma. Ann Oncol 2019;30 :1154–61. 10.1093/annonc/mdz110 30923820\n13 PokomyR, McPhersonJP, GrossmanKF. Clinical outcomes with early-elective discontinuation of PD-1 inhibitors at one year in patients with metastatic melanoma. J Clin Oncol 2020;38 :10048.\n14 LeeJH, LongGV, BoydS, et al . Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic melanoma. Ann Oncol 2017;28 :1130–6. 10.1093/annonc/mdx026 28327969\n15 SeremetT, JansenY, PlankenS, et al . Undetectable circulating tumor DNA (ctDNA) levels correlate with favorable outcome in metastatic melanoma patients treated with anti-PD1 therapy. J Transl Med 2019;17 :303. 10.1186/s12967-019-2051-8 31488153\n16 AlgaziAP, TsaiKK, ShoushtariAN, et al . Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer 2016;122 :3344–53. 10.1002/cncr.30258 27533448\n17 RossiE, PagliaraMM, OrteschiD, et al . Pembrolizumab as first-line treatment for metastatic uveal melanoma. Cancer Immunol Immunother 2019;68 :1179–85. 10.1007/s00262-019-02352-6 31175402\n18 D'AngeloSP, LarkinJ, SosmanJA, et al . Efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis. J Clin Oncol 2017;35 :226–35. 10.1200/JCO.2016.67.9258 28056206\n19 NardinC, DalleS, LecciaMT, et al . Long-term immune-related adverse events under PD-1 inhibitors: a multicenter prospective cohort study (MELBASE). J Clin Oncol 2020;38 :10057. 10.1200/JCO.2020.38.15_suppl.10057\n20 TarhiniA, McDermottD, AmbavaneA, et al . Clinical and economic outcomes associated with treatment sequences in patients with BRAF-mutant advanced melanoma. Immunotherapy 2019;11 :283–95. 10.2217/imt-2018-0168 30563395\n21 keytruda. Available: https://www.keytruda.com/financial-support/ [Accessed 7 Oct 2021].\n22 Bristol-Myers Squibb pricing information. Available: https://www.bmspricinginformation.com/opdivo [Accessed 7 Oct 2021].\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2051-1426",
"issue": "9(10)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "immunotherapy; melanoma; programmed cell death 1 receptor; tumor biomarkers",
"medline_ta": "J Immunother Cancer",
"mesh_terms": null,
"nlm_unique_id": "101620585",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34599027",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19097774;27533448;31345627;28327969;31488153;28056206;28841387;31562797;26446948;33558722;30563395;30137228;32605909;32053428;31175402;30923820;29283791",
"title": "PET/CT scan and biopsy-driven approach for safe anti-PD-1 therapy discontinuation in patients with advanced melanoma.",
"title_normalized": "pet ct scan and biopsy driven approach for safe anti pd 1 therapy discontinuation in patients with advanced melanoma"
} | [
{
"companynumb": "US-009507513-2111USA001698",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "An 85-year-old man was being treated for advanced squamous cell lung carcinoma with nivolumab as a second-line treatment. From the beginning of the third course, erythema appeared on his trunk and gradually progressed. Around the start of the fifth course, erythema spread to the proximal part of all limbs in addition to the trunk and was accompanied by a strong itching sensation. He was diagnosed as having contact dermatitis by a dermatologist because his rash was observed only where the moisture-absorbing fiber material of his underwear made contact with the skin surface. After suspending treatment of nivolumab, changing his underwear to a cotton material, and using moisturizers and steroid ointments, his rash disappeared in about a month and the size of his lung tumors remained reduced. The patient developed contact dermatitis despite the use of similar underwear without any skin problems for several years. We speculated that nivolumab-induced T-cell activation may have occurred in his skin, making him more likely to develop contact dermatitis, whose onset is thought to involve T-cell activation. No cases of contact dermatitis have been reported previously although the frequency of eruption as an immune-related adverse event is relatively high. When using immune checkpoint inhibitors including nivolumab, clinicians need to pay attention to the occurrence of skin disorders related to T-cell activation.",
"affiliations": "Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.;Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan.",
"authors": "Sato|Shintaro|S|;Oba|Tomohiro|T|;Ohta|Hiroki|H|;Tsukahara|Yuta|Y|;Kida|Gen|G|;Tsumiyama|Emiri|E|;Kusano|Kenji|K|;Nishizawa|Tomotaka|T|;Kawabe|Rie|R|;Yamakawa|Hideaki|H|;Akasaka|Keiichi|K|;Amano|Masako|M|;Matsushima|Hidekazu|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2020.101134",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30045-9\n10.1016/j.rmcr.2020.101134\n101134\nCase Report\nNivolumab-induced contact dermatitis in a patient with advanced lung cancer\nSato Shintaro smallerss@hotmail.com∗ Oba Tomohiro Ohta Hiroki Tsukahara Yuta Kida Gen Tsumiyama Emiri Kusano Kenji Nishizawa Tomotaka Kawabe Rie Yamakawa Hideaki Akasaka Keiichi Amano Masako Matsushima Hidekazu Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan\n∗ Corresponding author. Department of Respiratory Medicine, Saitama Red Cross Hospital, 1-5 Shintoshin, Chuo-ku, Saitama, 330-8553, Japan. smallerss@hotmail.com\n15 6 2020 \n2020 \n15 6 2020 \n30 1011347 2 2020 14 6 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).An 85-year-old man was being treated for advanced squamous cell lung carcinoma with nivolumab as a second-line treatment. From the beginning of the third course, erythema appeared on his trunk and gradually progressed. Around the start of the fifth course, erythema spread to the proximal part of all limbs in addition to the trunk and was accompanied by a strong itching sensation. He was diagnosed as having contact dermatitis by a dermatologist because his rash was observed only where the moisture-absorbing fiber material of his underwear made contact with the skin surface. After suspending treatment of nivolumab, changing his underwear to a cotton material, and using moisturizers and steroid ointments, his rash disappeared in about a month and the size of his lung tumors remained reduced. The patient developed contact dermatitis despite the use of similar underwear without any skin problems for several years. We speculated that nivolumab-induced T-cell activation may have occurred in his skin, making him more likely to develop contact dermatitis, whose onset is thought to involve T-cell activation. No cases of contact dermatitis have been reported previously although the frequency of eruption as an immune-related adverse event is relatively high. When using immune checkpoint inhibitors including nivolumab, clinicians need to pay attention to the occurrence of skin disorders related to T-cell activation.\n\nKeywords\nNivolumabContact dermatitisLung cancerImmune-related adverse eventAbbreviations\nALK, anaplastic lymphoma kinaseCTCAE, Common Terminology Criteria for Adverse EventsEGFR, epidermal growth factor receptorICI, immune checkpoint inhibitorirAE, immune-related adverse eventPD-L1, programmed death-ligand 1\n==== Body\n1 Introduction\nThe recent development of immune checkpoint inhibitors (ICIs) has led to promising progress in the treatment of patients with various advanced or metastatic malignancies. In the lung cancer area, the anti-programmed cell death 1 antibodies nivolumab and pembrolizumab or the anti-programmed cell death ligand 1 (PD-L1) antibodies atezolizumab and durvalumab are used as standard therapies for advanced or relapsed lung cancer [1]. However, ICIs may cause immune-related adverse events (irAEs) such as thyroiditis, hypophysitis, interstitial pneumonia, type I diabetes mellitus, adrenal failure, myasthenia gravis, or skin disorders [2]. Despite the relatively high frequency of skin disorders, there has been no report of contact dermatitis to our knowledge. We report a case of contact dermatitis after nivolumab use was begun and caution that ICIs could cause such skin disorders.\n\n2 Case report\nAn 85-year-old Japanese man was referred to our hospital by nearby general hospital for detailed examination of chest X-ray abnormalities. The patient had a history of aortic aneurysm, hyperthyroidism, and was undergoing hormone therapy for prostate cancer. He had been smoking 10 cigarettes a day from the age of 20 until first visit. He had no special history of allergies. On computed tomography, a tumor 36 mm in diameter was found in the right lower lobe S6 and was diagnosed as squamous cell carcinoma with no EGFR (epidermal growth factor receptor) mutations or the ALK (anaplastic lymphoma kinase) fusion oncogene by bronchoscopic examination (Fig. 1A). The PD-L1 expression was found to be <1%. Stage diagnosis was cT2aN0M1c stage IVB (bone and liver metastasis), and performance status was 0.Fig. 1 Chest computed tomography scan images and photographs of the skin rash. At the time of the lung cancer diagnosis, a tumor was found in the right lower lobe (A), and a new central metastasis to the lung was discovered after first-line chemotherapy (B). After the subsequent use of nivolumab, the tumor began to shrink (C), but pruritic eruptions appeared on the patient's extremities and trunk (D, E).\n\nFig. 1\n\nHe started first-line treatment with carboplatin and nab-paclitaxel, after which he was determined to have progressive disease due to the appearance of an intrapulmonary metastasis after four courses of treatment (Fig. 1B). Subsequently, administration of nivolumab as a second-line treatment was started at 240 mg/body every two weeks, and there were no obvious adverse events or changes in X-ray findings through the two courses of treatment. From the beginning of the third course, however, erythema accompanied by itching appeared on his trunk that gradually progressed with repeated exacerbations. Around the start of the fifth course, the erythema spread to the proximal part of his limbs in addition to the trunk and was accompanied by a strong itching sensation, but pustules, blisters, erosion, and epidermal necrosis were not consistently observed (Fig. 1D and E).\n\nA dermatologist was consulted because of no improvement despite the use of antihistamines. As a result, a skin rash was observed only where the moisture-absorbing fiber material of his underwear contacted his skin, leading to a diagnosis of contact dermatitis for this material (CTCAE grade 3). The patient had worn the same moisture-absorbing fiber underwear for the last five years, but this was the first time that a rash had ever appeared. He also had been wearing this underwear since the start of the third course of nivolumab. After suspending treatment with nivolumab, changing his underwear to cotton, and using moisturizers and steroid ointments, the rash disappeared over a month. In addition, his lung tumors have been shrinking and maintaining partial response at 4 months after the last dose of nivolumab (Fig. 1C).\n\n3 Discussion\nWe experienced a case of contact dermatitis that developed during the use of nivolumab for advanced lung cancer. Skin toxicities appear to be one of the most frequent irAEs that occur during the use of ICIs [3]. Their frequency has been reported to range between 35 and 50% [4], and the types of skin rash reported include maculopapular rash, pruritus, lichenoid reactions, psoriasis, acneiform rashes, vitiligo-like lesions, and autoimmune skin diseases [3]. However, there has been no report of a skin eruption diagnosed as contact dermatitis so far, and to our knowledge, this is the first report of contact dermatitis whose suspected cause was nivolumab treatment.\n\nAs a treatment method when skin rash appears during ICIs treatment, for CTCAE grade 1–2 eruptions, topical steroids should be used instead of discontinuing ICIs. However, for moderate to severe grade 3–4 rashes including Stevens-Johnson syndrome and toxic epidermal necrolysis, ICIs should be discontinued and consultation with a dermatologist for the indication of systemic steroid administration is required [5]. Antigen avoidance is required when the rash is presumed to be contact dermatitis. Therefore, accurate diagnosis of the etiology of the rash is clinically important in the treatment of irAEs.\n\nICIs exerts an antitumor effect by blocking the negative regulators of T-cell function. However, it has been pointed out that enhanced T-cell activity may be involved in the development of irAEs, and there have been several reports of patients with irAEs exhibiting robust infiltration of T cells [6]. It is noteworthy that T cells have been reported to be critical regulators in the pathophysiology of contact dermatitis in recent years [7].\n\nThe pathophysiology of contact dermatitis is divided into three phases: sensitization, elicitation, and resolution [8]. In the sensitization phase, haptens are collected by resident dendric cells of the skin. Dendric cells migrate to the lymph nodes and present an antigen to naive cells. In the elicitation phase, presentation of an antigen and costimulation activate antigen-specific CD4+ and CD8+ T cells. Reexposure to the hapten initiates transmigration of the effector memory T cells to the dermis and epidermis, resulting in the clinical manifestations of contact dermatitis. In the resolution phase, inflammation tends to converge by prevention of extravasation of circulating effector T cells. As mentioned above, different populations of T cells are deeply involved in various stages of the development of contact dermatitis.\n\nOur patient developed contact dermatitis despite wearing similar underwear without any skin problems for several years, suggesting that nivolumab-induced T-cell activation may have occurred in the skin, thus making the development of contact dermatitis more likely. The use of nivolumab has reduced the size of the tumor to date in our patient, but it is controversial whether it should be re-administered if the tumors grow in the future. Although it is reported that retreatment with anti-PD-L1 therapy resulted in the recurrence of irAEs in 52% of patients with non-small-cell lung carcinoma [9], we consider re-administration to be reasonable in this patient because avoiding underwear made of moisture-absorbing fiber material may reduce the recurrence rate of this irAE.\n\nIn conclusion, we reported the first case of nivolumab-induced contact dermatitis in a patient with lung cancer. We speculated that the activation of T cells by nivolumab triggered the development of the contact dermatitis. Although the incidence of skin disorders during ICIs treatment is relatively high, clinicians should consider contact dermatitis to be one of the differential diagnoses because it is important to avoid causative antigens in this disorder. As well, it is crucial to cooperate with dermatologists in the practice of lung cancer to obtain an appropriate diagnosis.\n\nDeclaration of competing interest\nThe authors declare no Conflicts of Interest (COI) in association with this article.\n==== Refs\nReferences\n1 Jain P. Jain C. Velcheti V. Role of immune-checkpoint inhibitors in lung cancer Ther. Adv. Respir. Dis. 12 2018 1753465817750075 10.1177/1753465817750075 \n2 Connolly C. Bambhania K. Naidoo J. Immune-related adverse events: a case-based approach Front. Oncol. 9 2019 530 10.3389/fonc.2019.00530 31293970 \n3 Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy Am. J. Clin. Dermatol. 19 3 2018 345 361 29256113 \n4 Patel A.B. Pacha O. Skin reactions to immune checkpoint inhibitors Adv. Exp. Med. Biol. 995 2018 117 129 30539508 \n5 Brahmer J.R. Lacchetti C. Schneider B.J. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline J. Clin. Oncol. 36 17 2018 1714 1768 29442540 \n6 Johnson D.B. McDonnell W.J. Ericsson-Gonzalez P.I. A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis Nat. Med. 25 8 2020 1243 1250 \n7 Smith J.S. Rajagopal S. Atwater A.R. Chemokine signaling in allergic contact dermatitis: toward targeted therapies Dermatitis 29 4 2018 179 186 29939854 \n8 Vocanson M. Hennino A. Rozières A. Effector and regulatory mechanisms in allergic contact dermatitis Allergy 64 12 2009 1699 1714 19839974 \n9 Santini F.C. Rizvi H. Plodkowski A.J. Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC Cancer Immunol. Res. 6 9 2018 1093 1099 29991499\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "30()",
"journal": "Respiratory medicine case reports",
"keywords": "ALK, anaplastic lymphoma kinase; CTCAE, Common Terminology Criteria for Adverse Events; Contact dermatitis; EGFR, epidermal growth factor receptor; ICI, immune checkpoint inhibitor; Immune-related adverse event; Lung cancer; Nivolumab; PD-L1, programmed death-ligand 1; irAE, immune-related adverse event",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101134",
"pmc": null,
"pmid": "32577373",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "29385894;29939854;29442540;31332390;29256113;19839974;29991499;30539508;31293970",
"title": "Nivolumab-induced contact dermatitis in a patient with advanced lung cancer.",
"title_normalized": "nivolumab induced contact dermatitis in a patient with advanced lung cancer"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-254082",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"dru... |
{
"abstract": "Clinical Enterobacteriacae isolates with a colistin minimum inhibitory concentration (MIC) ≥4 mg/L from a United States hospital were screened for the mcr-1 gene using real-time polymerase chain reaction (RT-PCR) and confirmed by whole-genome sequencing. Four colistin-resistant Escherichia coli isolates contained mcr-1. Two isolates belonged to the same sequence type (ST-632). All subjects had prior international travel and antimicrobial exposure.",
"affiliations": "Infectious Diseases Division,Rambam Health Care Campus,Haifa,Israel.;Research Service,Louis Stokes Cleveland Department of Veterans Affairs Medical Center,Cleveland, Ohio.;Department of Pathology,University of Michigan, Medical School,Ann Arbor, Michigan.;Research Service,Louis Stokes Cleveland Department of Veterans Affairs Medical Center,Cleveland, Ohio.;Michigan Department of Health and Human Services (MDHHS)Bureau of Epidemiology and Population Health,Lansing, Michigan.;Michigan Department of Health and Human Service (MDHHS)Bureau of Laboratories,Lansing, Michigan.;Michigan Department of Health and Human Service (MDHHS)Bureau of Laboratories,Lansing, Michigan.;Department of Medicine, Division of Infectious Diseases,University of Michigan, Medical School,Ann Arbor, Michigan.;Department of Infection Prevention and Epidemiology,Michigan Medicine,Ann Arbor, Michigan.;Department of Infection Prevention and Epidemiology,Michigan Medicine,Ann Arbor, Michigan.;Research Service,Louis Stokes Cleveland Department of Veterans Affairs Medical Center,Cleveland, Ohio.;Department of Medicine,Case Western Reserve University,Cleveland, Ohio.;Department of Medicine, Division of Infectious Diseases,University of Michigan, Medical School,Ann Arbor, Michigan.;Infectious Diseases Division,Rambam Health Care Campus,Haifa,Israel.",
"authors": "Henig|Oryan|O|;Rojas|Laura J|LJ|;Bachman|Michael A|MA|;Rudin|Susan D|SD|;Brennan|Brenda M|BM|;Soehnlen|Marty K|MK|;Jones|Kelly L|KL|;Mills|John P|JP|;Dombecki|Carey R|CR|;Valyko|Amanda M|AM|;Marshall|Steven H|SH|;Bonomo|Robert A|RA|;Kaye|Keith S|KS|;Washer|Laraine|L|0000-0002-5699-7706",
"chemical_list": "D029968:Escherichia coli Proteins; C000614037:MCR-1 protein, E coli; D003091:Colistin",
"country": "United States",
"delete": false,
"doi": "10.1017/ice.2019.177",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-823X",
"issue": "40(9)",
"journal": "Infection control and hospital epidemiology",
"keywords": null,
"medline_ta": "Infect Control Hosp Epidemiol",
"mesh_terms": "D000368:Aged; D003091:Colistin; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli; D004927:Escherichia coli Infections; D029968:Escherichia coli Proteins; D005260:Female; D006801:Humans; D008297:Male; D008824:Michigan; D008826:Microbial Sensitivity Tests; D000073336:Whole Genome Sequencing; D055815:Young Adult",
"nlm_unique_id": "8804099",
"other_id": null,
"pages": "1059-1062",
"pmc": null,
"pmid": "31303191",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Identification of four patients with colistin-resistant Escherichia coli containing the mobile colistin resistance mcr-1 gene from a single health system in Michigan.",
"title_normalized": "identification of four patients with colistin resistant escherichia coli containing the mobile colistin resistance mcr 1 gene from a single health system in michigan"
} | [
{
"companynumb": "IL-TEVA-2019-IL-1112055",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null,
... |
{
"abstract": "Gemcitabine and cisplatin are chemotherapeutic agents used for treating multiple cancers, and these agents are sometimes used in combination. Drug-induced thrombotic microangiopathy (TMA) is a rare but potentially fatal complication. It typically presents as a systemic disease with the classical triad of hemolytic anemia, thrombocytopenia, and organ damage. In contrast to systemic TMA, cases of renal-limited TMA, defined as biopsy-proven renal TMA without the classical triad, have been reported with relatively good prognosis. Most cases of renal-limited TMA are associated with calcineurin inhibitors, and cases of drug-induced renal-limited TMA due to gemcitabine-dexamethasone-cisplatin therapy have been rarely reported.\n\n\n\nA 43-year-old woman with lymphoma developed acute kidney injury with marked proteinuria, microhematuria, and abnormal urinary casts after receiving one cycle of gemcitabine-dexamethasone-cisplatin therapy. Although she did not show hemolytic anemia and thrombocytopenia, renal biopsy showed diffuse injury to the glomerular endothelial cells, supporting the diagnosis of renal-limited TMA. Her condition improved only with the cessation of gemcitabine and cisplatin treatment. She received another chemotherapy without gemcitabine and platinum agents, and no recurrence of renal-limited TMA was observed.\n\n\n\nDrug-induced TMA occurs early after gemcitabine and cisplatin use in renal-limited form and is reversible when detected and managed in a timely manner. Urinalysis, which is simple and inexpensive and can be easily performed, is a beneficial screening tool for early-onset drug-induced TMA among patients who receive gemcitabine-dexamethasone-cisplatin therapy.",
"affiliations": "Department of Hematology, Kobe City Medical Center General Hospital, 2-1-1 Minami-machi, Minatojima, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. mnishi90@yahoo.co.jp.;Department of Hematology, Kobe City Medical Center General Hospital, 2-1-1 Minami-machi, Minatojima, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.;Department of Hematology, Kobe City Medical Center General Hospital, 2-1-1 Minami-machi, Minatojima, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.;Department of Nephrology, Kobe City Medical Center General Hospital, Kobe, Hyogo, 650-0047, Japan.;Department of Pathology, Kobe City Medical Center General Hospital, Kobe, Hyogo, 650-0047, Japan.;Department of Pathology, Kobe City Medical Center General Hospital, Kobe, Hyogo, 650-0047, Japan.;Department of Hematology, Kobe City Medical Center General Hospital, 2-1-1 Minami-machi, Minatojima, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.",
"authors": "Nishikubo|Masashi|M|0000-0002-6183-8910;Shimomura|Yoshimitsu|Y|;Hiramoto|Nobuhiro|N|;Sawamura|Naohiko|N|;Yamaguchi|Takako|T|;Hara|Shigeo|S|;Ishikawa|Takayuki|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12882-021-02386-y",
"fulltext": "\n==== Front\nBMC Nephrol\nBMC Nephrol\nBMC Nephrology\n1471-2369\nBioMed Central London\n\n2386\n10.1186/s12882-021-02386-y\nCase Report\nReversible renal-limited thrombotic microangiopathy due to gemcitabine-dexamethasone-cisplatin therapy: a case report\nhttp://orcid.org/0000-0002-6183-8910\nNishikubo Masashi mnishi90@yahoo.co.jp\n\n1\nShimomura Yoshimitsu 1\nHiramoto Nobuhiro 1\nSawamura Naohiko 2\nYamaguchi Takako 3\nHara Shigeo 3\nIshikawa Takayuki 1\n1 grid.410843.a 0000 0004 0466 8016 Department of Hematology, Kobe City Medical Center General Hospital, 2-1-1 Minami-machi, Minatojima, Chuo-ku, Kobe, Hyogo 650-0047 Japan\n2 grid.410843.a 0000 0004 0466 8016 Department of Nephrology, Kobe City Medical Center General Hospital, Kobe, Hyogo 650-0047 Japan\n3 grid.410843.a 0000 0004 0466 8016 Department of Pathology, Kobe City Medical Center General Hospital, Kobe, Hyogo 650-0047 Japan\n12 5 2021\n12 5 2021\n2021\n22 17510 3 2021\n4 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/. 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\nGemcitabine and cisplatin are chemotherapeutic agents used for treating multiple cancers, and these agents are sometimes used in combination. Drug-induced thrombotic microangiopathy (TMA) is a rare but potentially fatal complication. It typically presents as a systemic disease with the classical triad of hemolytic anemia, thrombocytopenia, and organ damage. In contrast to systemic TMA, cases of renal-limited TMA, defined as biopsy-proven renal TMA without the classical triad, have been reported with relatively good prognosis. Most cases of renal-limited TMA are associated with calcineurin inhibitors, and cases of drug-induced renal-limited TMA due to gemcitabine-dexamethasone-cisplatin therapy have been rarely reported.\n\nCase presentation\n\nA 43-year-old woman with lymphoma developed acute kidney injury with marked proteinuria, microhematuria, and abnormal urinary casts after receiving one cycle of gemcitabine-dexamethasone-cisplatin therapy. Although she did not show hemolytic anemia and thrombocytopenia, renal biopsy showed diffuse injury to the glomerular endothelial cells, supporting the diagnosis of renal-limited TMA. Her condition improved only with the cessation of gemcitabine and cisplatin treatment. She received another chemotherapy without gemcitabine and platinum agents, and no recurrence of renal-limited TMA was observed.\n\nConclusions\n\nDrug-induced TMA occurs early after gemcitabine and cisplatin use in renal-limited form and is reversible when detected and managed in a timely manner. Urinalysis, which is simple and inexpensive and can be easily performed, is a beneficial screening tool for early-onset drug-induced TMA among patients who receive gemcitabine-dexamethasone-cisplatin therapy.\n\nKeywords\n\nThrombotic microangiopathies\nGemcitabine\nCisplatin\nUrinalysis\nLymphoma\nProteinuria\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nDrug-induced thrombotic microangiopathy (TMA) is a rare but significant complication associated with multiple drugs, including chemotherapeutic agents [1]. Gemcitabine, a deoxycytidine analog, and cisplatin, a platinum-containing agent, are widely used as chemotherapeutic agents for malignancy. The combination of gemcitabine and cisplatin is employed in some cases, such as non-small-cell lung carcinoma; hepatobiliary, pancreatic, and urothelial cancer; and relapsed or refractory non-Hodgkin lymphoma [2–7]. Both gemcitabine and cisplatin have been reported to cause drug-induced TMA [8–11]. Regarding drug-induced TMA due to gemcitabine, its incidence has been reported to range from 0.015 to 1.4% [12]. The risk increases with the dose of gemcitabine and with prolonged duration of treatment [12]. Similarly, drug-induced TMA due to cisplatin has been also reported, although it is significantly less frequent than gemcitabine [9, 13]. Drug-induced TMA is a severe complication associated with significant mortality regardless of causative agents [10, 12, 13], and renal damage possibly leading to end-stage renal disease is one of complications observed in drug-induced TMA [12]. Clinically, this condition manifests as a systemic disease, with the classical triad of hemolytic anemia, thrombocytopenia, and organ damage, including renal insufficiency [12, 13]. Apart from the systemic form of TMA, few cases of drug-induced TMA due to gemcitabine and cisplatin, localized in the kidneys, have been reported. Herein, we report a case of a 43-year-old woman with drug-induced renal-limited TMA, which developed after one cycle of gemcitabine-dexamethasone-cisplatin (GDP) therapy. Her condition improved rapidly after cessation of GDP therapy, and urinalysis was beneficial for the early detection of drug-induced TMA.\n\nCase presentation\n\nA 43-year-old Japanese woman was admitted to our hospital for the treatment of angioimmunoblastic T-cell lymphoma. She presented with continuous high fever and a disseminated skin rash. Laboratory data showed elevated lactate dehydrogenase (LDH), C-reactive protein (CRP), and soluble-interleukin-2 receptor levels at hospitalization. She received two cycles of cyclophosphamide, vincristine, doxorubicin, and prednisolone (CHOP) therapy. Her symptoms and abnormal laboratory findings were temporally resolved with chemotherapy initiation, but these worsened after the neutrophil recovery in each course. Positron emission tomography demonstrated residual uptake of fluorodeoxyglucose in the spleen and iliac lymph nodes, suggesting the ineffectiveness of CHOP therapy. Subsequently, she received GDP therapy, which consisted of 1000 mg/m2 of gemcitabine on days 1 and 8, 33 mg/day of dexamethasone from day 1 to day 4, and 75 mg/m2 of cisplatin on day 1 [14]. She received one cycle of GDP therapy as scheduled above with 2800 mg of gemcitabine and 100 mg of cisplatin in total. She developed acute kidney injury (AKI) with a creatinine (Cr) level of 0.35 mg/dL to 0.77 mg/dL, proteinuria (402 mg/gCr), and microhematuria (1–4/high-power field of red blood cell without dysmorphic change) 9 days after the initiation of GDP therapy. Her AKI failed to improve despite hydration and worsened 21 days after the initiation of GDP therapy. Her physical examination at this time revealed a blood pressure of 118/58 mmHg, and the other vital signs were unremarkable. Laboratory findings showed anemia without signs of hemolysis and thrombocytosis and elevated liver enzyme, LDH, and CRP levels (Table 1). There were no coagulopathy and schistocytes in the peripheral blood smear. The abnormal findings of liver enzymes, LDH, and CRP were similar to the previous deteriorations observed after neutrophil recovery of each CHOP therapy and were considered to be mainly due to refractory lymphoma. Regarding the elevated LDH level, based on the absence of findings suggesting hemolysis, such as progressive anemia, elevated indirect bilirubin level, and presence of schistocytes in the peripheral blood smear, it suggested systemic inflammation, not hemolysis. Urinalysis showed marked proteinuria (6549 mg/gCr), microhematuria (30–49/high-power field of red blood cell with dysmorphic change), and hyaline, granular, waxy, and epithelial casts. A 24-h urine specimen showed a protein level of 2464 mg/day. Next, we cancelled the scheduled second GDP therapy and performed a renal biopsy. Moreover, histological findings revealed diffuse and global endothelial swelling, double contours of the glomerular basement membranes, and scattered foamy macrophages. Electron microscopic findings revealed subendothelial edema and new basement membrane formation (Fig. 1). Immune complexes were not found on immunofluorescence. Immunofluorescence staining of complement C3 and C4 was negative. Based on the history of chemotherapy and the absence of the classical triad of systemic TMA, such as hemolytic anemia, thrombocytopenia, and organ damage other than the kidneys, the patient was diagnosed with drug-induced renal-limited TMA due to GDP therapy. She was followed up carefully, and her proteinuria improved gradually. Her AKI also improved to baseline with a Cr level of 0.43 mg/dL and proteinuria of less than 500 mg/gCr 36 days after the initiation of GDP therapy. She received another chemotherapy without gemcitabine and platinating agents, and no recurrence of renal-limited TMA was observed (Fig. 2). Table 1 Laboratory findings at renal-limited thrombotic microangiopathy onset\n\nTest\tResult\tReference range\t\nWBC (white blood cells) (/μL)\t7600\t3900–9800\t\nHemoglobin (g/dL)\t9.0\t11.1–15.1\t\nPLT (platelet count) × 104/μL\t51.4\t13.0–37.0\t\nTP (total protein (g/dL)\t5.9\t6.5–8.5\t\nAlbumin (g/dL)\t3.2\t3.9–4.9\t\nT-Bil (total-bilirubin) (mg/dL)\t0.7\t0.2–1.2\t\nAST (aspartate aminotransferase) (U/L)\t42\t8–40\t\nALT (alanine aminotransferase) (U/L)\t131\t8–40\t\nLDH (lactate dehydrogenase) (U/L)\t573\t124–222\t\nUrea (mg/dL)\t19.2\t8.0–20.0\t\nCreatinine (mg/dL)\t0.78\t0.40–0.80\t\nCRP (C-reactive protein) (mg/dL)\t10.36\t0.00–0.50\t\nPT-INR (prothrombin time-international normalized ratio)\t1.10\t\t\nAPTT (activated partial thromboplastin time (sec)\t26.9\t24.3–38.9\t\nFibrinogen (mg/dL)\t483\t180–320\t\nComplement C3 (mg/dL)\t103\t65–135\t\nComplement C4 (mg/dL)\t31\t13–35\t\n\nFig. 1 Renal biopsy finding. a Periodic acid-Schiff staining (× 400). The glomerulus shows diffuse endothelial swelling (a black arrowhead) and scattered foamy macrophages (black arrows). b Periodic acid-methenamine silver staining (×400). Reduplication of the glomerular basement membrane is observed. c Electron micrograph of a glomerular basement membrane (× 6000). New basement membrane formation (white arrowheads) and subendothelial edema (white arrows) are present\n\nFig. 2 Her clinical course. Day 1 stands for the day when the first dose of gemcitabine-dexamethasone-cisplatin therapy was administered. a LDH levels. The elevation of LDH was observed at the beginning of each chemotherapy. It temporally resolved with chemotherapy initiation, but it worsened after the neutrophil recovery in each course. At the onset of renal-limited TMA, it was observed again probably due to lymphoma itself and inflammation with TMA. It gradually improved with the cessation of GDP therapy and got normalized after the administration of another chemotherapy. b Hemoglobin and platelet levels. The patient already had anemia due to chronic inflammation of refractory lymphoma and myelosuppression due to chemotherapy. However, at the onset of renal-limited TMA, her anemia did not deteriorate; rather, it improved. Also, at the onset of renal-limited TMA, thrombocytosis, not thrombocytopenia, was observed. c Creatinine levels, the amount of urine protein and interventions. The doses of chemotherapy were as follows: 1000 mg/m2 of gemcitabine on days 1 and 8, 33 mg/day of dexamethasone from day 1 to day 4, and 75 mg/m2 of cisplatin on day 1. Abbreviations. GEM: gemcitabine. CDDP: cisplatin. DEX: dexamethasone. RBC: red blood cells\n\nDiscussion and conclusions\n\nThe clinical course of this patient raised two critical issues. First, few doses of gemcitabine and cisplatin can cause renal-limited TMA. Second, renal-limited TMA due to GDP therapy can be alleviated by treatment cessation, and urinalysis may be useful for early detection.\n\nTMA is a pathologic disease entity characterized by generalized microvascular occlusion by platelet emboli, triggered by multiple etiologies, including medications [15]. It presents with the classical triad of thrombocytopenia, microangiopathic hemolytic anemia, and organ injury, including AKI. Apart from the systemic form of TMA, renal-limited TMA cases, defined as biopsy-proven renal TMA without the classical triad, have been reported [13]. Most renal-limited TMA cases are associated with calcineurin inhibitors, which are used for immunosuppression after kidney transplantation [16, 17]. Bevacizumab and quinine can also cause renal-limited TMA [18, 19]. In contrast, although both gemcitabine and cisplatin have been reported as causative agents of drug-induced systemic TMA, alone or in combination, few cases of renal-limited drug-induced TMA with those agents have been reported [16].\n\nThe primary side effects of GDP therapy are myelosuppression, mild liver function abnormalities, gastrointestinal symptoms, infection, thrombosis or embolism, and edema [6, 7]. Regarding gemcitabine, mild proteinuria and hematuria have been commonly reported as side effects of gemcitabine, but these are rarely clinically significant [20]. Although rare, drug-induced TMA due to gemcitabine is a severe complication [12], and the risk of systemic TMA is more significant when the cumulative dose exceeds 12,000 mg/m2 or when the treatment lasts longer than 7 months [12, 21]. However, lower doses of gemcitabine with or without other anticancer drugs including cisplatin can be the cause of systemic TMA [10, 22, 23]. In the present case report, renal-limited TMA developed after the patient was exposed to only 2000 mg/m2 of gemcitabine and 75 mg/m2 of cisplatin, although it is not clear to what extent each drug contributed to the development of TMA. Therefore, clinicians should consider TMA in cases with findings suggestive of TMA, including proteinuria, among patients receiving gemcitabine and cisplatin, even when the cumulative dose is not significant.\n\nRenal-limited TMA usually presents with proteinuria or AKI, and in cases of renal transplant patients, it can be suspected with delayed graft function [16]. Minimization or temporary withdrawal of causative medications is the major therapeutic intervention, and the prognosis is relatively good, with the survival ranging from 75 to 100% [17, 24, 25]. However, once systemic drug-induced TMA associated with gemcitabine and/or cisplatin has developed, treatment cessation alone is rarely curative [12, 13]. Intensive treatment plans, such as plasma exchange, fresh frozen plasma infusion, and steroids and eculizumab administration, are indicated. Although it is still controversial, renal-limited TMA may be a prodromal stage of systemic TMA. Cases wherein TMA initially localizes to the kidney on biopsy, but subsequently progresses to manifest as systemic TMA, have been reported [26, 27]. Therefore, early recognition and prompt intervention are warranted. In the present case report, we detected renal-limited drug-induced TMA by urinalysis. Early detection prompted treatment cessation, which resulted in complete improvement of symptoms. Since urinalysis is simple, inexpensive, and easily performed, routine urinalysis may be useful for early detection and intervention with chemotherapy modification. There are some limitations in our case report. Unfortunately, we did not investigate the Coombs test, haptoglobin value, and ADAMTS-13 activity because we did not consider TMA as a differential diagnosis at the onset of TMA. We did not also perform the genetic analysis of complement genes, which is not available on a commercial basis in Japan.\n\nIn conclusion, GDP therapy caused renal-limited TMA, even when the cumulative dose of gemcitabine or cisplatin was low. With early detection and prompt cessation of causative agents, it was still reversible. Routine screening with urinalysis may be beneficial for patients receiving GDP therapy.\n\nAbbreviations\n\nTMA Thrombotic microangiopathy\n\nCHOP Cyclophosphamide, vincristine, doxorubicin, and prednisolone\n\nGDP Gemcitabine, dexamethasone, and cisplatin\n\nAKI Acute kidney injury\n\nCr Creatinine\n\nNone.\n\nAuthors’ contributions\n\nMN collected the data and wrote the first draft of the manuscript. NS, TY, and SH provided pathological information and comments. YS supervised the manuscript writing, editing, and review. NH and TI coordinated the project and edited the manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nNone.\n\nAvailability of data and materials\n\nNot applicable.\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 of this journal.\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. Al-Nouri ZL Reese JA Terrell DR Vesely SK George JN Drug-induced thrombotic microangiopathy: a systematic review of published reports Blood. 2015 125 4 616 618 10.1182/blood-2014-11-611335 25414441\n2. Scagliotti GV Parikh P von Pawel J Biesma B Vansteenkiste J Manegold C Serwatowski P Gatzemeier U Digumarti R Zukin M Lee JS Mellemgaard A Park K Patil S Rolski J Goksel T de Marinis F Simms L Sugarman KP Gandara D Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer J Clin Oncol 2008 26 21 3543 3551 10.1200/JCO.2007.15.0375 18506025\n3. Valle J Wasan H Palmer DH Cunningham D Anthoney A Maraveyas A Madhusudan S Iveson T Hughes S Pereira SP Roughton M Bridgewater J Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer N Engl J Med 2010 362 14 1273 1281 10.1056/NEJMoa0908721 20375404\n4. Heinemann V Quietzsch D Gieseler F Gonnermann M Schönekäs H Rost A Neuhaus H Haag C Clemens M Heinrich B Vehling-Kaiser U Fuchs M Fleckenstein D Gesierich W Uthgenannt D Einsele H Holstege A Hinke A Schalhorn A Wilkowski R Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer J Clin Oncol 2006 24 24 3946 3952 10.1200/JCO.2005.05.1490 16921047\n5. Bellmunt J von der Maase H Mead GM Skoneczna I De Santis M Daugaard G Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC intergroup study 30987 J Clin Oncol 2012 30 10 1107 1113 10.1200/JCO.2011.38.6979 22370319\n6. Crump M Baetz T Couban S Belch A Marcellus D Howson-Jan K Imrie K Myers R Adams G Ding K Paul N Shepherd L Iglesias J Meyer R Gemcitabine, dexamethasone, and cisplatin in patients with recurrent or refractory aggressive histology B-cell non-Hodgkin lymphoma: a phase II study by the National Cancer Institute of Canada clinical trials group (NCIC-CTG) Cancer. 2004 101 8 1835 1842 10.1002/cncr.20587 15386331\n7. Crump M Kuruvilla J Couban S MacDonald DA Kukreti V Kouroukis CT Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12 J Clin Oncol 2014 32 31 3490 3496 10.1200/JCO.2013.53.9593 25267740\n8. Rabinowits G Herchenhorn D Rabinowits M Weatge D Torres W Fatal pulmonary toxicity in a patient treated with gefitinib for non-small cell lung cancer after previous hemolytic-uremic syndrome due to gemcitabine Anti-Cancer Drugs 2003 14 8 665 668 10.1097/00001813-200309000-00014 14501391\n9. Gilbert RD Stanley LK Fowler DJ Angus EM Hardy SA Goodship TH Cisplatin-induced haemolytic uraemic syndrome associated with a novel intronic mutation of CD46 treated with eculizumab Clin Kidney J 2013 6 4 421 425 10.1093/ckj/sft065 24422172\n10. Zupancic M Shah PC Shah-Khan F Gemcitabine-associated thrombotic thrombocytopenic purpura Lancet Oncol 2007 8 7 634 641 10.1016/S1470-2045(07)70203-6 17613425\n11. Manohar S Leung N Cisplatin nephrotoxicity: a review of the literature J Nephrol 2018 31 1 15 25 10.1007/s40620-017-0392-z 28382507\n12. Daviet F Rouby F Poullin P Moussi-Francès J Sallée M Burtey S Mancini J Duffaud F Sabatier R Pourroy B Grandvuillemin A Grange S Frémeaux-Bacchi V Coppo P Micallef J Jourde-Chiche N Thrombotic microangiopathy associated with gemcitabine use: presentation and outcome in a national French retrospective cohort Br J Clin Pharmacol 2019 85 2 403 412 10.1111/bcp.13808 30394581\n13. van der Heijden M Ackland SP Deveridge S Haemolytic uraemic syndrome associated with bleomycin, epirubicin and cisplatin chemotherapy--a case report and review of the literature Acta Oncol 1998 37 1 107 109 10.1080/028418698423267 9572663\n14. Morschhauser F Depil S Jourdan E Wetterwald M Bouabdallah R Marit G Solal-Céligny P Sebban C Coiffier B Chouaki N Bauters F Dumontet C Phase II study of gemcitabine-dexamethasone with or without cisplatin in relapsed or refractory mantle cell lymphoma Ann Oncol 2007 18 2 370 375 10.1093/annonc/mdl395 17074972\n15. Brocklebank V Wood KM Kavanagh D Thrombotic microangiopathy and the kidney Clin J Am Soc Nephrol 2018 13 2 300 317 10.2215/CJN.00620117 29042465\n16. Schwimmer J Nadasdy TA Spitalnik PF Kaplan KL Zand MS De novo thrombotic microangiopathy in renal transplant recipients: a comparison of hemolytic uremic syndrome with localized renal thrombotic microangiopathy Am J Kidney Dis 2003 41 2 471 479 10.1053/ajkd.2003.50058 12552512\n17. Zarifian A Meleg-Smith S O'donovan R Tesi RJ Batuman V Cyclosporine-associated thrombotic microangiopathy in renal allografts Kidney Int 1999 55 6 2457 2466 10.1046/j.1523-1755.1999.00492.x 10354295\n18. Yamada R Okawa T Matsuo K Suzuki M Mori N Mori K Renal-limited thrombotic microangiopathy after switching from bevacizumab to ramucirumab: a case report BMC Nephrol 2019 20 1 14 10.1186/s12882-018-1194-9 30634936\n19. Anjelo J Rao N David VG Otto S Russ G Renal-limited thrombotic microangiopathy and acute interstitial nephritis with a single dose of quinine Clin Kidney J 2014 7 3 311 313 10.1093/ckj/sfu035 25852897\n20. Aapro MS Martin C Hatty S Gemcitabine--a safety review Anti-Cancer Drugs 1998 9 3 191 201 10.1097/00001813-199803000-00001 9625429\n21. Saif MW Xyla V Makrilia N Bliziotis I Syrigos K Thrombotic microangiopathy associated with gemcitabine: rare but real Expert Opin Drug Saf 2009 8 3 257 260 10.1517/14740330902942299 19505260\n22. De Smet D Jochmans K Neyns B Development of thrombotic thrombocytopenic purpura after a single dose of gemcitabine Ann Hematol 2008 87 6 495 496 10.1007/s00277-007-0429-9 18097666\n23. Willemsen AE van Herpen CM Wesseling P Bult P van Laarhoven HW Fatal thrombotic microangiopathy after a single dose of gemcitabine as fourth-line palliative treatment for metastasized ductal breast carcinoma Acta Oncol 2011 50 3 462 465 10.3109/0284186X.2010.491088 20799915\n24. Young BA Marsh CL Alpers CE Davis CL Cyclosporine-associated thrombotic microangiopathy/hemolytic uremic syndrome following kidney and kidney-pancreas transplantation Am J Kidney Dis 1996 28 4 561 571 10.1016/S0272-6386(96)90468-0 8840947\n25. Hochstetler LA Flanigan MJ Lager DJ Transplant-associated thrombotic microangiopathy: the role of IgG administration as initial therapy Am J Kidney Dis 1994 23 3 444 450 10.1016/S0272-6386(12)81010-9 8128949\n26. Pham PT Peng A Wilkinson AH Gritsch HA Lassman C Pham PC Cyclosporine and tacrolimus-associated thrombotic microangiopathy Am J Kidney Dis 2000 36 4 844 850 10.1053/ajkd.2000.17690 11007689\n27. Trimarchi HM Truong LD Brennan S Gonzalez JM Suki WN FK506-associated thrombotic microangiopathy: report of two cases and review of the literature Transplantation. 1999 67 4 539 544 10.1097/00007890-199902270-00009 10071024\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "22(1)",
"journal": "BMC nephrology",
"keywords": "Cisplatin; Gemcitabine; Lymphoma; Proteinuria; Thrombotic microangiopathies; Urinalysis",
"medline_ta": "BMC Nephrol",
"mesh_terms": null,
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "175",
"pmc": null,
"pmid": "33980166",
"pubdate": "2021-05-12",
"publication_types": "D016428:Journal Article",
"references": "17613425;12552512;30394581;29042465;28382507;25267740;19505260;8128949;16921047;25852897;20375404;8840947;17074972;18506025;10071024;9625429;11007689;10354295;20799915;15386331;9572663;14501391;24422172;18097666;22370319;25414441;30634936",
"title": "Reversible renal-limited thrombotic microangiopathy due to gemcitabine-dexamethasone-cisplatin therapy: a case report.",
"title_normalized": "reversible renal limited thrombotic microangiopathy due to gemcitabine dexamethasone cisplatin therapy a case report"
} | [
{
"companynumb": "JP-PFIZER INC-2021576988",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "1",
... |
{
"abstract": "To analyze the clinical presentation and the treatment process of one case of colchicine poisoning complicated with extra pontine myelinolysis and discuss its pathogenesis. Increasing the attention of hyponatremia caused by colchicine poisoning is of great significance for improving the prognosis and quality of life of patients.",
"affiliations": "Department of Emergency, The First Hospital of Jilin University, Jilin 130021, China.;Department of Emergency, The First Hospital of Jilin University, Jilin 130021, China.;Department of Emergency, The First Hospital of Jilin University, Jilin 130021, China.;Department of Emergency, The First Hospital of Jilin University, Jilin 130021, China.;Department of Emergency, The First Hospital of Jilin University, Jilin 130021, China.",
"authors": "Liu|J L|JL|;Zang|X X|XX|;Pang|L|L|;Li|J M|JM|;Wu|Y|Y|",
"chemical_list": "D003078:Colchicine",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.cn121094-20190918-00384",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1001-9391",
"issue": "38(6)",
"journal": "Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases",
"keywords": "Colchicine; Extra pontine myelinolysis; Hyponatremia; Poisoning",
"medline_ta": "Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi",
"mesh_terms": "D003078:Colchicine; D006801:Humans; D007010:Hyponatremia; D008279:Magnetic Resonance Imaging; D017590:Myelinolysis, Central Pontine; D011149:Pons; D011788:Quality of Life",
"nlm_unique_id": "8410840",
"other_id": null,
"pages": "461-462",
"pmc": null,
"pmid": "32629581",
"pubdate": "2020-06-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of colchicine poisoning complicated with extra pontine myelinolysis.",
"title_normalized": "a case of colchicine poisoning complicated with extra pontine myelinolysis"
} | [
{
"companynumb": "CN-TAKEDA-2020TJP014762",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "COLCHICINE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe integrase inhibitor dolutegravir is now recommended as first-line treatment for HIV. A single case of myocarditis after treatment with dolutegravir was reported in the FLAMINGO trial. We present here 2 cases of severe myocarditis that occurred shortly after the initiation of dolutegravir treatment.\nThe first case is a 45-year-old female who developed severe congestive heart failure and died, weeks after the initiation of dolutegravir treatment (for simplification of her antiretroviral regimen). The second case was a 51-year-old male who presented with effort dyspnea 3 weeks after the initiation of dolutegravir treatment and was later diagnosed as severe congestive heart failure. The treatment was changed and the patient survived, but he still suffers from severe heart failure with functional impairment.\nPatient 1 died, patient 2 suffers from severe heart failure.\n\n\nCONCLUSIONS\nWe discuss here the possible relationship between the initiation of dolutegravir treatment and the development of lymphocytic myocarditis in our patients, and we suggest a possible mechanism.",
"affiliations": "Allergy, Clinical Immunology and AIDS Department, Kaplan Medical Center, Rehovot, Israel.",
"authors": "Mahlab-Guri|Keren|K|;Asher|Ilan|I|;Rosenberg-Bezalel|Shira|S|;Elbirt|Daniel|D|;Burke|Michael|M|;Sthoeger|Zev M|ZM|",
"chemical_list": "D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000005465",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 27893693MD-D-16-0597610.1097/MD.0000000000005465054654850Research ArticleClinical Case ReportTwo case reports of severe myocarditis associated with the initiation of dolutegravir treatment in HIV patients Mahlab-Guri Keren MDAsher Ilan MDRosenberg-Bezalel Shira MDElbirt Daniel MDBurke Michael MDSthoeger Zev M. MD∗Asensi. Victor Allergy, Clinical Immunology and AIDS Department, Kaplan Medical Center, Rehovot, Israel.∗ Correspondence: Professor Zev M. Sthoeger, Allergy, Clinical Immunology and AIDS Department, Kaplan Medical Center, Rehovot 76100, Israel (e-mail: Zev_s@clalit.org.il).11 2016 28 11 2016 95 47 e546527 9 2016 25 10 2016 2 11 2016 Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0Abstract\nRationale:\nThe integrase inhibitor dolutegravir is now recommended as first-line treatment for HIV. A single case of myocarditis after treatment with dolutegravir was reported in the FLAMINGO trial. We present here 2 cases of severe myocarditis that occurred shortly after the initiation of dolutegravir treatment.\n\nPatients concerns:\nThe first case is a 45-year-old female who developed severe congestive heart failure and died, weeks after the initiation of dolutegravir treatment (for simplification of her antiretroviral regimen). The second case was a 51-year-old male who presented with effort dyspnea 3 weeks after the initiation of dolutegravir treatment and was later diagnosed as severe congestive heart failure. The treatment was changed and the patient survived, but he still suffers from severe heart failure with functional impairment.\n\nDiagnosis and Outcome:\nPatient 1 died, patient 2 suffers from severe heart failure.\n\nLessons:\nWe discuss here the possible relationship between the initiation of dolutegravir treatment and the development of lymphocytic myocarditis in our patients, and we suggest a possible mechanism.\n\nKeywords\ndolutegravirHIV treatmentmyocarditisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThe integrase inhibitor dolutegravir (DTG) was approved on August 2013 by the US Food and Drug Administration (FDA) for the treatment of HIV infection.[1] Several studies reported the efficacy of DTG (in combination of abacavir/lamivudine or tenofovir/emtricitabine) in the treatment of naïve and treatment-experienced HIV patients.[2,3] DTG was shown to be safe and well-tolerated by the patients.[2] In addition, DTG has a good lipid profile and limited pharmacological interactions with other drugs.[4] Currently, DTG is recommended as a first-line drug for HIV treatment.[5] We present here 2 cases of severe myocarditis occurred shortly after the initiation of DTG treatment. This report was approved by the ethics committee of Kaplan Medical Center. We discuss the possible relationship between DTG and the development of myocarditis.\n\n1.1 Case 1\nA 45-year-old female was diagnosed with HIV 5 years ago during an investigation for mild thrombocytopenia. She did not smoke, had no hypertension, diabetes mellitus, or hyperlipidemia. There was no family history of any cardiovascular disease. The patient was treated for 10 years with levothyroxine (100 mcg/d) for hypothyroidism. At the time of diagnosis, her CD4 cell count was 49 cells/mL and the viral load (VL) was 1,936,182 copies/mL. Antiretroviral treatment (ART) with efavirenz and emtricitabine/tenofovir was initiated with a good virological (LDL) and immunological (CD4 213 cells/mL) response. Because of depression, her treatment was switched to lopinavir/ritonavir and emtricitabine/tenofovir. The later treatment caused diarrhea and therefore the treatment regimen was changed 3 years ago to raltegravir and emtricitabine/tenofovir. During the past 3 years, the patient felt good without any clinical complication or hospitalizations. Her CD4 cell counts were stable (350–420 cells/mL) with undetectable VL (LDL). The patient wanted to simplify her ART to a single tablet regimen; therefore, after a negative HLA-B5701 test, Triumeq (abacavir/lamivudine and dolutegravir) was initiated. Two weeks later, she was admitted with low-grade fever, severe shortness of breath, and legs edema. Her creatine phosphokinase (CPK) was 345 units/L (normal range 10–190 units/L), aspartate aminotransferase (AST) 92 units/L (normal range 0–35 units/L), and her troponin T levels were 823 ng/L (normal range 0–14 ng/L). She was intubated and mechanically ventilated. Echocardiography revealed severe right and left ventricular systolic dysfunction with an estimated left ventricular ejection fraction of 20% to 25% (normal 60%). Computerized tomography was negative for pulmonary embolism, and cardiac catheterization revealed no coronary artery disease. To confirm the clinical diagnosis of severe myocarditis, an endomyocardial biopsy was done, demonstrating lymphocytic myocarditis with prominent myocyte necrosis. No granulomas, giant cells, or inclusion bodies associated with viral cytopathic effects were found. Immunostaining (CD20, CD3) demonstrated lymphoid aggregates composed of organized B and T-cell populations. Stains for cytomegalovirus (CMV), Herpes simplex virus (HSV), periodic acid–Schiff (PAS), and Grocott-Gomori methenamine silver stain (GMS) were all negative. Triumeq treatment was continued throughout her hospitalization. Despite treatment with antibiotics, dobutamine, and digoxin the patient's condition did not improve. Extracorporeal membrane oxygenation (ECMO) was initiated, but 3 weeks later, the patient had died.\n\n1.2 Case 2\nA 51-year-old male was diagnosed with HIV, acquired by heterosexual contacts, 12 years ago. For the past 5 years the patient had diabetes mellitus and was treated with metformin and aspirin. The patient did not smoke, and had no hypertension, hyperlipidemia, or a family history of cardiovascular disease. At the time of diagnosis, the patient had low CD4 cell counts (70 cells/mL) and a high VL (1,590,000 copies/mL). Treatment with efavirenz, epivir, and didanosine was recommended, but the patient did not take it on a regular basis. Six years ago, he restarted ART with efavirenz and emtricitabine/tenofovir (based on resistance assay) with a good virological response (LDL) and a slight immunological improvement (CD4 cell count was 100 cells/mL). Due to proteinuria, his antiretroviral regimen was changed to efavirenz and abacavir/epivir. The patient was treated with the later regimen for 3 years with a stable clinical, immunological (CD4 110 cells/mL), and virological response (VL-LDL). Due to sleep disturbances, efavirenz was changed to dolutegravir. Three weeks later, he complained of progressive exertional dyspnea. He was referred to cardiological evaluation, but missed his appointment. He continued to suffer from dyspnea, and 2 months later, he was hospitalized because of severe dyspnea and legs edema. Laboratory evaluation revealed elevated troponin T levels (138, normal range 0–14 ng/L), elevated lactate dehydrogenase (LDH) (886, normal range 185–480 units/L), and elevated aspartate aminotransferase (AST) (147, normal range 0–35 units/L). Echocardiography revealed severe left and right ventricular dysfunction (ejection fraction 20%; normal 60%). Computed tomography of the chest was negative for pulmonary emboli. Cardiac catheterization revealed stenosis of the distal left anterior descending (LAD) artery. Technetium (99mTc) scan of the heart showed a small antero-septal subendocardial infarction compatible with his distal LAD stenosis. Since the severity of his ventricular dysfunction was not proportional to the small antero-septal wall infarction, myocarditis was suspected. Indeed, cardiac magnetic resonance imaging (MRI) suggested the diagnosis of myocarditis that was further confirmed by endomyocardial biopsy. The patient was treated with diuretics, the ART was changed to darunavir/ritonavir, epivir, and raltegravir, but he still suffers from severe heart failure.\n\n2 Discussion\nThe 2 patients here developed myocarditis shortly after the initiation of DTG treatment. The first patient was hospitalized with severe congestive heart failure 2 weeks after she was switched (for simplification of her ART) to 1 single tablet regimen of Triumeq (abacavir/lamivudine and DTG). As for the other patient, he started to complain of shortness of breath 3 weeks after the initiation of DTG, but did not attend any medical evaluation. Two months later, he was hospitalized with small antero-septal infarction and severe myocarditis with right and left ventricular failure.\n\nOur first patient did not have any risk factor for heart disease (other than her HIV infection). She presented with clinical symptoms and signs of severe congestive heart failure, elevated levels of cardiac muscle enzymes, evidence of significant systolic ventricular dysfunction, and clear evidence of lymphocytic myocarditis by MRI and endomyocardial biopsy. The second patient had diabetes mellitus, which is a well-known risk factor for atherosclerotic cardiovascular disease. The fact that he was treated with abacavir for 3 years also may contribute to his antero-septal myocardial infarction.[6] Nevertheless, the severity of the ventricular systolic dysfunction and the elevation of his troponin levels were disproportional to his small antero-septal myocardial infarction. Therefore, the patient underwent further evaluation by MRI scan and endomyocardial biopsy, which confirmed the diagnosis of lymphocytic myocarditis.\n\nThe main DTG associated adverse events reported in the DTG trials were diarrhea, nausea, headache, and naso-pharingitis.[1,2] However, the supplementary appendix to the FLAMINGO trial reported 1 case (out of 244 treated patients; 0.4%) of myocarditis in the DTG-treated group.[4] No data are available regarding the backbone treatment of the patients (either tenofovir/emtricitabine or abacavir/lamivudine), the severity of the myocarditis, or the time period between DTG initiation and the development of the myocarditis.\n\nIt should be noted that our 2 patients were also treated by other medications that may be associated with development of heart disease. Thus, the first patient was treated with abacavir which was initiated at the same time of DTG. The second patient was treated for 3 years with abacavir.\n\nThe mechanism involved in the pathogenesis of the severe myocarditis in our 2 patients is not completely clear. Since the patients were, at the time of myocarditis, clinically stable with good virological response (LDL) and stable CD4 cell counts, the possibility of active HIV infection, opportunistic infection, or immune reconstitution inflammatory syndrome (IRIS), as the primary causes for myocarditis, are highly unlikely. The symptoms and signs of myocarditis developed, in both patients, 2 to 3 weeks after the initiation of DTG treatment; thus we cannot rule out the direct effect of DTG on the myocytes. Indeed, muscular toxicity/injury was previously reported in patients receiving raltegravir, which is another integrase inhibitor.[7] Nevertheless, no muscular injury was reported after DTG treatment.[8]\n\nDolutegravir, as an integrase inhibitor, prevents HIV DNA from integrating itself into the human genome,[9] causing accumulation of preintegrating DNA.[10] The accumulation of retroviral elements (caused by DTG) may resemble the effects of the retroviral elements accumulation in the three prime repair exonuclease-1 (Trex-1)-deficient mice, which succumbed due to severe myocarditis. The enzyme Trex-1 is thought to degrade endogenous retroelements.[11] Indeed, integrase inhibitors were shown to exacerbate murine lupus like disease in NZBxW F1 mice,[12] probably by increasing the amounts of retroelements that can stimulate the innate immune syndrome.[11,13] The possibility that our 2 patients had developed kind of Trex-1 pathway mutations (malfunction) cannot be excluded. Interestingly, reverse transcriptase (RT) inhibitors are shown to meliorate the myocarditis in Trex-1-deficient mice.[14] Thus, the role of the other antiretroviral drugs (abacavir, lamivudine) is unlikely. The fact that in both cases the endomyocardial biopsy revealed lymphocytic myocarditis may support an immune mechanism (in response to the accumulation of retroviral elements) for the DTG-associated myocarditis.\n\nAbbreviations: ART = antiretroviral therapy, AST = aspartate aminotransferase, CD4 = cluster of differentiation 4, CMV = cytomegalovirus, CPK = creatinine phosphokinase, DNA = deoxyribonucleic acid, DTG = dolutegravir, ECMO = extracorporeal membrane oxygenation, GMS = Grocott-Gomori methenamine silver stain, HIV = human immunodeficiency virus, HLA = human leukocyte antigen, HSV = Herpes simplex virus, IRIS = immune reconstitution inflammatory syndrome, LAD = left anterior descending, LDH = lactate dehydrogenase, LDL = lower detection limit, MRI = magnetic resonance imaging, NZBXW F1 = first-generation offspring of New Zealand Black and New Zealand White mice, PAS = periodic acid–Schiff, RT = reverse transcriptase, Trex-1 = three prime repair exonuclease-1, VL = viral load.\n\nM-GK and IA contributed equally to this work.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Dow DE Bartlet JA \nDolutegravir, the second-generation of integrase strand transfer inhibitors (INSTIs) for the treatment of HIV . Infect Dis Ther \n2014 ;3 :83 –102 .25134686 \n[2] Van Lunzen J Maggiolo F Arribas JR \nOnce daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial . Lancet Infect Dis \n2012 ;12 :111 –8 .22018760 \n[3] Cahn P Pozniak AL Mingrone H \nDolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study . Lancet \n2013 ;382 :700 –8 .23830355 \n[4] Molina JM Clotet B van Lunzen J \nFLAMINGO Study Team Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study . Lancet HIV \n2015 ;2 :e127 –36 .26424673 \n[5] Günthard HF Aberg JA Eron JJ \nInternational Antiviral Society-USA Panel Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel . JAMA \n2014 ;312 :410 –25 .25038359 \n[6] Behrens GM1 Reiss P \nAbacavir and cardiovascular risk . Curr Opin Infect Dis \n2010 ;23 :9 –14 . 2 .19996748 \n[7] Mededdu G VL De Socio G Ricci E \nMuscle symptoms and creatinine phosphokinase elevations in patients receiving raltegravir in clinical practice: results from SCOLTA project long-term surveillance . Int J Antimicrob Agents \n2015 ;45 :289 –94 .25476452 \n[8] Walmsley SL Antela A Clumeck N \nDolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection . N Engl J Med \n2013 ;19 :1807 –18 . 369 .\n[9] Kulkosky J Jones KS Katz RA \nResidues critical for retroviral integrative recombination in a region that is highly conserved among retroviral/retrotransposon integrases and bacterial insertion sequence transposases . Mol Cell Biol \n1992 ;12 :2331 –8 .1314954 \n[10] Morita M Stamp G Robins P \nGene-targeted mice lacking the Trex1 (DNase III) 3′–>5′ DNA exonuclease develop inflammatory myocarditis . Mol Cell Biol \n2004 ;24 :6719 –27 .15254239 \n[11] Stetson DB Volkman HE \nThe enemy within: endogenous retroelements and autoimmune disease . Nature Immunol \n2014 ;15 :415 –22 .24747712 \n[12] Beck-Engeser GB Eilat D Harrer T \nEarly onset of autoimmune disease by the retroviral integrase inhibitor raltegravir . Proc Natl Acad Sci U S A \n2009 ;106 :20865 –70 .19923437 \n[13] Stetson DB \nEndogenous retroelements and autoimmune disease . Curr Opin Immunol \n2012 ;24 :692 –7 .23062469 \n[14] Beck-Engeser GB Eilat D Wabl M \nAn autoimmune disease prevented by antiretroviral drugs . Retrovirology \n2011 ;8 :91 .22067273\n\n",
"fulltext_license": "CC BY-ND",
"issn_linking": "0025-7974",
"issue": "95(47)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D017809:Fatal Outcome; D005260:Female; D015658:HIV Infections; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008297:Male; D008875:Middle Aged; D009205:Myocarditis; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e5465",
"pmc": null,
"pmid": "27893693",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24747712;23062469;1314954;19996748;25476452;22067273;25134686;23830355;26424673;19923437;25038359;22018760;15254239;24195548",
"title": "Two case reports of severe myocarditis associated with the initiation of dolutegravir treatment in HIV patients.",
"title_normalized": "two case reports of severe myocarditis associated with the initiation of dolutegravir treatment in hiv patients"
} | [
{
"companynumb": "IL-VIIV HEALTHCARE LIMITED-IL2016GSK112581",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EMTRICITABINE\\TENOFOVIR"
},
... |
{
"abstract": "To analyse outcomes and patterns of failure following dose-escalated definitive chemoradiotherapy (CRT) for oesophageal squamous cell carcinoma using fluorodeoxyglucose positron emission tomography for staging and treatment planning.\n\n\n\nA retrospective review of patients with oesophageal squamous cell carcinoma receiving definitive CRT to a dose of ≥56 Gy was conducted. Patient and tumour characteristics, treatment received and first sites of relapse were analysed.\n\n\n\nBetween 2003 and 2014, 72 patients were treated with CRT to a median dose of 60 Gy (range 56-66 Gy). The median age was 63 years; most (61%) were stage III/IVa. The median follow-up was 57 months. Three year in-field control, relapse-free survival and overall survival was 64% (95% confidence interval 50-75%), 38% (95% confidence interval 27-50%) and 42% (95% confidence interval 30-53%), respectively. Of the 41 failures prior to death or at last follow-up date, isolated locoregional relapse occurred in 16 patients (22%) with isolated in-field recurrence in 11 patients (15%). Distant failure as first site of relapse was present in 25 patients (35%). No in-field failures occurred in the 11 patients with cT1-2, N0-1 tumours. The median survival for cT4 tumours was 8 months, with five of eight patients developing local progression within the first 6 months.\n\n\n\nDose-escalated radiotherapy was associated with promising rates of in-field local control, with the exception of cT4 tumours. Distant failure remains a significant competing risk. Our data supports the need for current trials re-examining the role of dose escalation in the modern era.",
"affiliations": "Department of Radiation Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia. Electronic address: rachel.effeney@health.qld.gov.au.;Department of Radiation Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia.;Department of Radiation Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.;Nursing Practice Development Unit, Princess Alexandra Hospital, Brisbane, Queensland, Australia.;Department of Radiation Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.;Department of Radiation Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.;Upper Gastro-intestinal and Soft Tissue Unit, Princess Alexandra Hospital, Brisbane, Queensland, Australia.;Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Upper Gastro-intestinal and Soft Tissue Unit, Princess Alexandra Hospital, Brisbane, Queensland, Australia; Surgical Oncology Group, Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia.;Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia; Upper Gastro-intestinal and Soft Tissue Unit, Princess Alexandra Hospital, Brisbane, Queensland, Australia.;Department of Radiation Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.",
"authors": "Effeney|R|R|;Shaw|T|T|;Burmeister|B H|BH|;Burmeister|E|E|;Harvey|J|J|;Mai|G T|GT|;Thomas|J|J|;Barbour|A P|AP|;Smithers|B M|BM|;Pryor|D I|DI|",
"chemical_list": "D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18",
"country": "England",
"delete": false,
"doi": "10.1016/j.clon.2018.06.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0936-6555",
"issue": "30(10)",
"journal": "Clinical oncology (Royal College of Radiologists (Great Britain))",
"keywords": "Dose escalation; oesophageal cancer; radiotherapy; relapse; squamous cell carcinoma",
"medline_ta": "Clin Oncol (R Coll Radiol)",
"mesh_terms": "D000328:Adult; D000368:Aged; D059248:Chemoradiotherapy; D018450:Disease Progression; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D011879:Radiotherapy Dosage; D012189:Retrospective Studies; D015996:Survival Rate; D017211:Treatment Failure",
"nlm_unique_id": "9002902",
"other_id": null,
"pages": "642-649",
"pmc": null,
"pmid": "30017206",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Patterns of Failure Following Dose-escalated Chemoradiotherapy for Fluorodeoxyglucose Positron Emission Tomography Staged Squamous Cell Carcinoma of the Oesophagus.",
"title_normalized": "patterns of failure following dose escalated chemoradiotherapy for fluorodeoxyglucose positron emission tomography staged squamous cell carcinoma of the oesophagus"
} | [
{
"companynumb": "AU-CORDEN PHARMA LATINA S.P.A.-AU-2018COR000127",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugad... |
{
"abstract": "Lymphomatosis cerebri is a rare form of diffusely infiltrating primary central nervous system (CNS) lymphoma (PCNSL). The neuroradiological findings of lymphomatosis cerebri have not been adequately characterized, as the relevant literature consists only of case reports and small case series. The present study describes an unusual presentation of lymphomatosis cerebri in a 56-year-old immunocompetent woman who presented with diffusely infiltrating lesions with perivascular curvilinear enhancement on initial magnetic resonance imaging (MRI) and multiple nodules on the later follow-up computed tomography (CT) scan. A systematic review of the literature is also performed searching PubMed between January 1996 and December 2016 to collect all pertinent case reports and series written in the English language with pathologically confirmed lymphomatosis cerebri and diffuse infiltrative PCNSL without cohesive masses on initial MRI. A total of 45 cases were identified from 39 articles and the present case report. The patient ages ranged from 28 to 85 years (mean, 57.3 years). Only 3 patients (6.7%) were immunosuppressed (acquired immune deficiency syndrome patients). The most common clinical presentation was cognitive changes or dementia (46.7%). Cerebrospinal fluid analysis in all cases was non-specific. Diffuse and asymmetric abnormal T2-hyperintensity in deep and subcortical white matter was observed in all cases. Gray matter involvement (17.8%), spreading along the corticospinal tract (35.6%) and a slight mass effect (51.1%) also were observed. Contrast-enhanced patterns on MRI could be divided into three forms of non-enhancement (64.4%) and non-mass-like enhancement (35.6%) on initial MRI, as well as nodular or mass-like enhancement on the later follow-up MRI (15.6%). There were non-specific findings on magnetic resonance spectroscopy for 4 patients, on positron emission tomography/CT for 12 patients and on single-photon emission CT for 1 patient. Diagnosis was established by brain biopsy in 35 cases (77.8%) and autopsy in 9 cases (20%), involving B-cell lymphoma in 40 cases (88.9%) and T-cell lymphoma in 4 cases (8.9%). In conclusion, lymphomatosis cerebri, namely diffuse PCNSL or diffuse lymphoma of the CNS, is characterized by rapidly progressive dementia in the elderly, diffusely infiltrated CNS white matter along the corticospinal tract, possible involvement of the gray matter, a slight mass effect and varied contrast-enhancement patterns on MRI. Non-enhancement or non-mass-like enhancement on MRI may be a special form of diffuse PCNL during disease development and progression.",
"affiliations": "Department of Radiology, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, Guangzhou, Guangdong 510507, P.R. China.;Department of Radiology, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, Guangzhou, Guangdong 510507, P.R. China.;Diagnostic Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.",
"authors": "Li|Long|L|;Rong|Jia-Hui|JH|;Feng|Jie|J|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2018.8839",
"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2018.8839OL-0-0-8839ArticlesNeuroradiological features of lymphomatosis cerebri: A systematic review of the English literature with a new case report Li Long 1Rong Jia-Hui 1Feng Jie 21 Department of Radiology, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, Guangzhou, Guangdong 510507, P.R. China2 Diagnostic Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. ChinaCorrespondence to: Professor Long Li, Department of Radiology, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, 268 Yanling Road, Guangzhou, Guangdong 510507, P.R. China, E-mail: radiolilong@hotmail.com8 2018 30 5 2018 30 5 2018 16 2 1463 1474 20 10 2017 04 4 2018 Copyright: © Li et al.2018This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Lymphomatosis cerebri is a rare form of diffusely infiltrating primary central nervous system (CNS) lymphoma (PCNSL). The neuroradiological findings of lymphomatosis cerebri have not been adequately characterized, as the relevant literature consists only of case reports and small case series. The present study describes an unusual presentation of lymphomatosis cerebri in a 56-year-old immunocompetent woman who presented with diffusely infiltrating lesions with perivascular curvilinear enhancement on initial magnetic resonance imaging (MRI) and multiple nodules on the later follow-up computed tomography (CT) scan. A systematic review of the literature is also performed searching PubMed between January 1996 and December 2016 to collect all pertinent case reports and series written in the English language with pathologically confirmed lymphomatosis cerebri and diffuse infiltrative PCNSL without cohesive masses on initial MRI. A total of 45 cases were identified from 39 articles and the present case report. The patient ages ranged from 28 to 85 years (mean, 57.3 years). Only 3 patients (6.7%) were immunosuppressed (acquired immune deficiency syndrome patients). The most common clinical presentation was cognitive changes or dementia (46.7%). Cerebrospinal fluid analysis in all cases was non-specific. Diffuse and asymmetric abnormal T2-hyperintensity in deep and subcortical white matter was observed in all cases. Gray matter involvement (17.8%), spreading along the corticospinal tract (35.6%) and a slight mass effect (51.1%) also were observed. Contrast-enhanced patterns on MRI could be divided into three forms of non-enhancement (64.4%) and non-mass-like enhancement (35.6%) on initial MRI, as well as nodular or mass-like enhancement on the later follow-up MRI (15.6%). There were non-specific findings on magnetic resonance spectroscopy for 4 patients, on positron emission tomography/CT for 12 patients and on single-photon emission CT for 1 patient. Diagnosis was established by brain biopsy in 35 cases (77.8%) and autopsy in 9 cases (20%), involving B-cell lymphoma in 40 cases (88.9%) and T-cell lymphoma in 4 cases (8.9%). In conclusion, lymphomatosis cerebri, namely diffuse PCNSL or diffuse lymphoma of the CNS, is characterized by rapidly progressive dementia in the elderly, diffusely infiltrated CNS white matter along the corticospinal tract, possible involvement of the gray matter, a slight mass effect and varied contrast-enhancement patterns on MRI. Non-enhancement or non-mass-like enhancement on MRI may be a special form of diffuse PCNL during disease development and progression.\n\nlymphomatosis cerebriprimary central nervous system lymphomadiffuse tumorous infiltrationleukoencephalopathyneuroradiologymagnetic resonance imaging\n==== Body\nIntroduction\nNeuroradiology with cranial magnetic resonance imaging (MRI) using fluid-attenuated inversion recovery (FLAIR) and T1-weighted sequences prior to and following contrast injection combined with diffusion-weighted imaging (DWI) is the method of choice for the diagnosis and follow-up of primary central nervous system (CNS) lymphoma (PCNSL) (1). The typical features of PCNSL are intra-axial homogenous single or multiple contrast-enhancing lesions with markedly restricted diffusion that are in contact with a cerebrospinal fluid (CSF) surface (2).\n\nLymphomatosis cerebri is a rare form of PCNSL characterized by diffuse lymphomatous parenchymal infiltration without evidence of cohesive masses or parenchymal architectural distortion (3). The distinguishing neuroradiological features of lymphomatosis cerebri have not yet been established in detail, as the literature contains only case reports and small series reporting imaging findings. In brain MRI studies, lymphomatosis cerebri can be mistaken for a variety of diffuse infiltrative brain tumors or leukoencephalopathy (2).\n\nThe present study first describes a case involving a 56-year-old immunocompetent woman who presented with diffuse infiltrating lesions in the brain parenchyma with perivascular curvilinear enhancement on initial MRI and multiple nodules on the later follow-up computed tomography (CT) scans. The current study also presents the results of a systematic review of the clinical and neuroradiological features of lymphomatosis cerebri. Using strict inclusion criteria, a literature search was performed on the data recorded between January 1996 and December 2016. To the best of our knowledge, this study provides the largest systematic review of neuroradiological features for lymphomatosis cerebri to date, and the present case is the first to be reported with perivascular curvilinear enhancement and subsequent multiple nodules.\n\nMaterials and methods\n\nCase report\nWritten informed consent was obtained from the daughter of the patient for publication of this case report and any accompanying data. A 56-year-old immunocompetent woman presented Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces (Guangzhou, China) with acute onset of headache, confusion and inability to relevantly answer questions on February 25, 2015. Blurred vision had occurred 20 days prior to admission. Personality and behavior changes had appeared 10 days prior to admission. The neurological examination showed fluctuating spatiotemporal disorientation with dyscalculia, a weak voice and moderate bradykinesia. Non-contrast brain CT (LightSpeed VCT XT CT 64-row helical CT scanner; GE Healthcare, Chicago, IL, USA) performed on February 25, 2015, showed abnormal low density results in the right parietal white matter, external capsule and thalamus (Fig. 1). On the initial brain MRI (MAGNETOM SKyra 3T MRI scanner; Siemens Healthineers, Erlangen, Germany) performed following admission on February 26, 2015, the T2-weighted images (T2WI) [repetition time (TR), 6,000 msec; echo time (TE), 99 msec; slice thickness, 5 mm; distance factor, 30%; voxel size, 0.3×0.3×5.0 mm; field of view (FOV), 22×22 cm] and FLAIR images (TR, 9,000 msec; TE, 85 msec; slice thickness, 5 mm; distance. factor, 30%; voxel size, 0.4×0.4×5.0 mm; FOV, 22×22 cm) showed asymmetric and diffuse white-matter hyperintensities involving bilateral paraventricular white matter, bilateral temporal lobes, the left occipital lobe, the medial prefrontal cortex, bilateral basal ganglia, the thalamus and the midbrain, as well as a slight mass effect on the posterior horn of the left lateral ventricle (Fig. 2). DWI (TR, 4,500 msec; TE, 64 msec; slice thickness, 5 mm; dist. factor, 30%; voxel size, 1.4×1.4×5.0 mm; FOV, 22×22 cm; b value, 1,000 sec/mm2) showed mild hyperintense signals, corresponding with T2/FLAIR hyperintensities (Fig. 2). Apparent diffusion coefficient (ADC) maps showed that the areas of increased diffusion signal represented both shine-through artifacts and mild diffusion restriction (Fig. 2C). Subsequent to the bolus intravenous injection of 10 ml gadodiamide (Omniscan®; GE Healthcare), T1-weighted images (T1WI) (TR, 250 msec; TE, 2.49 msec; slice thickness, 5 mm; dist. factor, 30%; voxel size, 0.7×0.7×5.0 mm; FOV, 22×22 cm) showed that asymmetric perivascular curvilinear enhancement perpendicular to the lateral ventricle was present in the bilateral cerebral white matter, and that eppendymal enhancement around the left ventricle and additional more patchy enhancement in the bilateral cerebral white matter were present (Fig. 2). CSF pressure was 160 mmH2O during lumbar puncture. CSF anlysis revealed 0.46 g/l protein (normal range, 0.15–0.45 g/l), 3.8 mmol/l glucose (normal range, 3.3–4.4 mmol/l) and 119.8 mmol/l chloride (normal range, 122–128 mmol/l). No bacteria were detected via gram stain and culture in the CSF. Cytological analysis of the CSF was negative for malignancy, and no oligoclonal bands could be found. Autoimmune and viral serologies were negative.\n\nThe patient was initially diagnosed with acute disseminated encephalomyelitis and treated with 500 mg methylprednisolone via intravenous infusion once a day for 10 days. Following an improved clinical situation, the patient was discharged on March 15, 2015.\n\nThe patient gradually developed gait disturbance, personality changes and dementia beginning on April 10, 2015. On April 22, 2015, a repeat MRI with the aforementioned sequence parameters showed diffuse and asymmetrical pathological signal hyperintensities on T2/FLAIR images, a slightly hyperintense signal on DWI and asymmetric perivascular curvilinear enhancement on T1WI with gadolinium that had expanded compared with that in the initial MRI (Fig. 2). Whole-body fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) scans (Biograph™ mCT PET/CT Scanner; Siemens Healthineers) were also acquired on April 23, 2015 (Fig. 3). No primary FDG-avid malignancy was identified. Brain FDG-PET was markedly abnormal, with increased uptake in the bilateral frontal, parietal, occipital and temporal lobes, basal ganglia, midbrain, cerebellum and cervical cord.\n\nImmunohistochemistry\nA stereotactic brain biopsy of the left frontal lobe was performed on May 8, 2015. The tissue specimens were fixed in 10% neutral buffered formalin solution for 24 h at room temperature, followed by paraffin embedding. Sections with a thickness of 4 ìm were cut and mounted on glass slides for hematoxylin-eosin (H&E) staining performed by a 3 min incubation in hematoxylin followed by a 30 sec incubation in eosin at room temperature. For immunohistological (IHC) staining, 4 ìm paraffin tissue sections were mounted on silanized glass slides using chrome-alum gelatin as adhesive. IHC staining was performed by the Streptavidin-Biotin-Complex (SABC) method according to the Sixth Edition of Dako's Educational Guidebook to IHC Staining Methods (4). Sections were deparaffinized in xylene (2×10 min) and rehydrated through an alcohol gradient: 100% ethanol (2×10 min), 95% ethanol (1×8 min), 80% ethanol (1×5 min), and 70% ethanol (1×5 min) followed by 1×10 min in ddH2O. Then nonspecific background staining was blocked with Background Sniper (BS966M, Biocare Medical, LLC, Paheco, CA, USA), 3% bovine serum albumin (BSA; Sigma-Aldrich; Merck KGaA, Darmstadt, Germay) in phosphate-buffered saline (PBS) and 5% normal goat-serum solution (OriGene Technologies, Inc., Beijing, China) for 30 min at room temperature. Slides were incubated overnight at 4°C with primary antibodies in 3% BSA-PBS. The following antibodies were applied as primary antibodies at a 1:1,000 dilution in Bond primary antibody diluent (cat. no. AR9590; Leica Biosystems, Newcastle, UK), Anti-CK (cat. no. 103228N; Ascend Biotechnology Co., Ltd., Guangzhou, China), anti-CD3 (cat. no. 18379501; OriGene Technologies, Inc.), anti-CD20 (cat. no. 104048N; Ascend Biotechnology Co., Ltd., Guangzhou, China), anti-GFAP (cat. no. 112147N; Ascend Biotechnology Co., Ltd.), anti-S-100 (cat. no. 112117N; Ascend Biotechnology Co., Ltd.), anti-cyclin D1 (cat. no. 17650111; OriGene Technologies, Inc.), anti-CD79a (cat. no. 111027N; Ascend Biotechnology Co., Ltd.), anti-PAX-5 (cat. no. 17600412; OriGene Technologies, Inc.), anti-Bcl-2 (cat. no. 17312610; OriGene Technologies, Inc.), anti-Bcl-6 (cat. no. 18343803; OriGene Technologies, Inc.), anti-CD21 (cat. no. 17660809; OriGene Technologies, Inc.), anti-Ki-67 (cat. no. 111167N; Ascend Biotechnology Co., Ltd.), anti-CD10 (cat. no. 20045299; Dako; Agilent Technologies GmbH, Waldbronn, Germany), and anti-Mum-1 (cat. no. 102288N; Ascend Biotechnology Co., Ltd.). After rinsing 5 times with 0.05% Brij-35 in PBS for 1 min, slides were then incubated with the horseradish peroxidase conjugated Goat anti-Human IgG secondary antibody at 1:1,000 dilution (cat. no. 20047066; Dako; Agilent Technologies GmbH) for 1 h at room temperature. The entire section was systematically examined under high power fields (×400 magnification) in Leica DMLA light microscope (Leica Microsystems, Wetzlar, Germany). The criteria for positive staining was defined as >80% positive staining cells for the Ki-67 and Mum-1 antibodies, and ≥30% for the other antibodies including CD10, CD20, CD79a and Bcl-6 antibodies. The pathological diagnosis was diffuse large B-cell lymphoma of non-germinal center B-cell type (non-GCB), IHC exhibited strong staining for B-cell markers CD-20, CD-79a and Ki-67, as well as negative for CD-10 and Bcl-6; however, was positive for MUM-1 (Fig. 4).\n\nTreatment regimen\nHigh-dose methotrexate and rituximab were administered as follows: 8 g/m2 methotrexate (day 1) and 375 mg/m2 rituximab (day 3), repeated every 14 days. Following three courses of chemotherapy, severe myelosuppression developed. On July 4, 2015, the patient suddenly collapsed and began comatose, and a non-contrast brain CT showed extension of the pathological hypodensities and multiple circular nodules in the white matter lesions of the cerebrum and cerebellum (Fig. 1). The patient succumbed to severe pulmonary infection and serious bleeding resulting from myelosuppression on September 2, 2015.\n\nMethods\nThe PubMed database was searched on December 2016 using the following terms: ‘Lymphomatosis cerebri’, and (‘PCNSL’ or ‘brain lymphoma’) and (‘non-enhancing’ or ‘diffuse’ or ‘diffuse infiltrative’). Cited articles of each relevant study were also reviewed for possible relevant articles. Only articles in the English language literature were evaluated.\n\nThe definition of lymphomatosis cerebri in the present systematic review was that the T2/FLAIR abnormal hyperintensity involved at least three cerebral lobes or three anatomical regions of the CNS in accordance with the description of gliomatosis cerebri in the 2007 World Health Organization classification of tumors of the CNS (5), but also that the non-enhancing lesions or the lesions without nodular or mass enhancement were identified on initial MR images. According to information from full-text articles, the following criteria were used to define inclusion into this systematic literature review: i) The full-text article included at least a T2WI or FLAIR image, and a contrast-enhanced T1WI; ii) the lesions involved at least three cerebral lobes or anatomical regions of the brain; iii) the lesions showed non-enhancement or non-nodular/non-mass-like enhancement on the initial MRI; and iv) the lesions were pathologically confirmed as PCNSL. The exclusion criteria were as follows: i) Concurrent systemic lymphoma; ii) intravascular CNS lymphoma; iii) inconclusive histological data; iv) failure to provide any MR image in the full-text article; v) only providing CT images in the full-text article; vi) prior surgery, radiotherapy, chemotherapy or corticosteroid therapy; and vii) a non-English article. Any case report that did not meet this definition and these criteria was excluded from the present systematic review, even if the author referred to the condition as lymphomatosis cerebri (6–11). The present study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (12).\n\nThe collected data included the clinical data, pathological results and imaging findings. Neuroradiological techniques analyzed included CT, MRI [T1WI, T2WI, FLAIR, T1WI with gadolinium contrast enhancement, DWI, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS)], single-photon emission computed tomography (SPECT) and PET (if any). The lesion location, distribution, morphology, density, contrast enhancement and follow-up imaging were recorded.\n\nResults\n\nSearch results\nThe PRISMA-style flow diagram of identifying literature for this systematic review is outlined in Fig. 5. PubMed database searches and reference articles searched by manual methods identified 73 articles. A total of 34 articles were excluded that did not meet the review inclusion criteria. Furthermore, 5 case reports from 1 case series were excluded due to a lack of any MR image. Thus, 39 relevant publications were included in the present systematic review for a total of 44 previously reported cases (13–51). All publications in this review were case studies without controls, and their publication spanned between January 1996 and December 2016. With the addition of the present new case, the total study cohort was 45 cases of lymphomatosis cerebri. The clinical and neuroradiological features in these 45 cases of lymphomatosis cerebri from the systematic review of the literature are summarized in Tables I and II. A list of detailed clinical data and neuroradiological findings collected from all available case reports are shown as ‘On-line Table I’ and ‘On-line Table II’ in the online repository Baidu Netdisk (https://pan.baidu.com/s/1KeHH0w0aBR6vKO_mLb2lPA).\n\nClinical data\nThe mean age at onset was 57.3 years (range, 28–85 years), including 22 females and 23 males (sex ratio, 1:1.05). A total of 3 patients (6.7%) were immunosuppressed as a result of acquired immunodeficiency syndrome.\n\nThe most common symptoms at onset were progressive dementia and cognitive deficit (44.4%), gait ataxia (37.8%), motor deficit (35.6%), memory loss (24.4%), language deficit (24.4%), changes in consciousness (22.2%), personality changes (17.8%), visual problems (11.1%) and sensory deficit (11.1%). Other clinical features included headaches (8.9%), seizures (8.9%), persistent fever (4.4%), nausea or vomiting (2.2%), anorexia (2.2%), hypersomnia (2.2%), fatigue (2.2%) and vertigo (2.2%).\n\nCSF analysis was mentioned in 35 cases. Abnormal results were observed in 30 of these cases (85.7%), including elevated protein in 22 cases, increased cell counts in 12 cases, decreased glucose in 4 cases, lymphocytosis in 1 case and atypical lymphocytes in 1 case (Table I). None of the 35 CSF cytology reports revealed neoplastic lymphocytes.\n\nNeuroradiology\nThe most common localization of diffuse and asymmetric abnormal T2 hyperintensity involved the cerebral white matter in at least three cerebral lobes or three anatomical regions of the CNS on initial MRI matter (35 cases, 77.8%). The lesions most commonly affected the deep and periventricular white matter, and predominantly involved white matter regions of the frontal, parietal, occipital and temporal lobes. Subcortical white matter hyperintensity and U-fiber involvement were frequently observed (24 cases, 53.3%; including the present case) (13–15,17–19,22,25,26,29,32, 34,36,38,40,42,43,45,48–50). The lesions involved the corpus callosum in 19 cases (42.2%), the basal ganglia in 15 cases (33.3%), the thalamus in 12 cases (26.7%), the midbrain in 21 cases (46.7%), the pons in 20 cases (44.5%), the medulla in 14 cases (31.1%), the cerebellum in 12 cases (26.6%) and the spinal cord in 5 cases (11.1%) (Table II). Lesions were also observed in the cerebral (20,28,41,43,50) and cerebellar (35,41) cortices, and the cerebellar dentate nuclei (30).\n\nThe lesion signals on T2WI/FLAIR MRI were of high intensity in all cases (13–51). Non-enhanced T1WI as used for 13 patients in the systematic review, of which 6 cases were presented as isointensity and 7 cases were hypointensity. DWI results were described for 14 patients in the present systematic review, of which the lesion signals were isointense in 2 cases (34,39), slightly hyperintense in 11 cases (including the present case) (14,20,26,28,29,32,47,48,50) and highly hyperintense in 1 case (24) compared with the normal gray matter.\n\nA slight mass effect could have been caused by abnormal T2 hyperintensities, and consisted of mild compression of the adjacent ventricle or cistern in 18 cases (including the present case) (17,18,20,22,23,28,30–33,40,41,44–48) or mild sulcal effacement in 5 cases (21,36,40,41,49).\n\nFollow-up CT and/or MRI were mentioned or described for 31 patients. Among them, 10 cases reported 3 brain MRI examinations. In the second MRI, 24 cases showed progression (including the present case) (13,14,17,19,20,23,25–27,30,33,35,37,38,41–47,49–51) (Figs. 2 and 3), 5 cases demonstrated reduction of lesions (28,32,36,37,39) and 2 cases showed no change from the initial scan (26,34). In the third MRI, when reported, 6 cases showed the enlargement of lesions (32,35,41,46,49) and 4 cases revealed the reduction of lesions (23,26,30,34,37). In 16 cases, lesion extension was described as spreading along the corticospinal tract down to the basal ganglia, thalamus, midbrain, pons, medulla oblongata and the left cerebellar hemisphere, even into the spinal cord. Lesions extending through the corpus callosum were also observed (23,25,37,39,40).\n\nContrast enhancement patterns on MRI could be divided into three forms: i) Non-enhancing (64.4%)(13–24,26–28,30,32,33,37,38,42,43,45,46,48–51) on initial MRI; ii) non-mass-like enhancement (35.6%) on initial MRI; and iii) nodular or mass-like enhancement on follow-up MRI (15.6%). The non-mass-like enhancements on initial MRI were described as subtle (subtle, faint, slight, little and minimal) in 7 cases (34–36,39,40,44,47), patchy in 5 cases (22,29,32,48) and curvilinear in 4 cases (including the present case) (25,37,41) (Fig. 4). In 8 cases with a non-enhancing pattern on initial MRI, follow-up contrast enhancement MRI revealed patchy enhancement in 5 cases (30,35,42,43,47), single nodular enhancement in 1 case (37) and mass-like enhancement in 2 cases (35,50). In 1 case that presented as a slight enhancement on initial MRI, mass-like enhancement was subsequently found at 4 months post-admission (35). In 4 cases with perivascular curvilinear enhancement on initial MRI, follow-up contrast enhancement MRI revealed patchy enhancement at 5 months post-admission in 1 case, multiple nodular enhancement in 2 cases (including the present case) (25) and multiple mass-like enhancement in 1 case (41).\n\nMRS findings were described for 4 patients. MRS revealed low N-acetylaspartate levels and high choline peaks in 3 cases (28,29,51), with low myo-inositol peaks and high lipid peaks in 1 of these cases (51). The remaining case showed normal concentration patterns of choline, creatine and N-acetyl aspartate (49).\n\n18F-FDG PET/CT findings were mentioned in 12 patients, including 4 cases that revealed high uptake (including the present case) (25,47,50) (Fig. 4), 3 cases with decreased uptake (31,36,47) and 5 cases with normal metabolism (23,26,29,34,43).\n\nSPECT findings were described in only 1case, and revealed hyperperfusion (49).\n\nPathology\nAll the studies confirmed the diagnosis as lymphomatosis cerebri, by pathological analysis of a brain biopsy in 35 cases (including the present case) (13,14,16,17,19–23,25,26,28–30,32,34–38,40–42,44–50) or autopsy in 9 cases (15,17,18,24,27,31,33,39,43). Only 1 case did not describe the method of pathological sampling (44). Tumor cells were distributed throughout the white matter. Single dispersed round neoplastic cells with prominent nuclei were identified under high-power magnification. The typical neoplastic cells were neither cohesive nor formed an ill-defined tumor mass. No necrosis was present. Overall, three patterns of neoplastic cell infiltration were observed in three forms: i) Diffuse scattered infiltration (including the present case) (13,15,17,19,22,36–38,40,41,47,48) (Fig. 5); ii) perivascular distribution (including the present case) (15,16,18,29,33–35,38,39,45,48,49) (Fig. 5); and iii) massive clusters (27,32,42,45).\n\nA total of 40 cases (88.9%) were classified immunohistochemically as B-cell lymphoma and 4 cases (8.9%) were T-cell lymphoma (15,28,29,36), while 1 case (2.2%) was not further classified (18).\n\nDiffuse large B-cell lymphomas were divided into non-GCB in 5 cases (including the present case) (26,30,47,48) (Fig. 4) and GCB in 1 case (31).\n\nTreatment and prognosis\nOverall, 53.3% (24/45) of cases, including the present case, were treated with steroids prior to the diagnosis of lymphomatosis cerebri. Following the stereotactic brain biopsy diagnosing lymphomatosis cerebri, 22.2% (10/45) of cases were treated with radiotherapy. Treatment with chemotherapy occurred in 31.1% (14/45) of cases. Even with aggressive treatment with steroids, radiotherapy and chemotherapy, the median survival time was <24 months.\n\nDiscussion\nAn understanding of the neuroradiological characteristics of lymphomatosis cerebri has yet to be resolved. The histopathological pattern of diffusely infiltrating microgliomatosis (PCNSL) was first described by the case report of Fisher et al (52) in 1969. Gross pathological sections of primary reticulum cell sarcoma of the brain (PCNSL) involved diffusely in the white matter were shown by Schaumburg et al (53) in 1972. The CT finding of a diffuse hypodense lesion without mass effect and contrast enhancement in widely infiltrating PCNSL that was proven pathologically by the brain biopsy was described by the case report of Tadmor et al (54) in 1978. MRI features of primary brain T-lymphoma presenting as progressive leukoencephalopathy were reported by the case report of Provinciali et al (55) in 1988, but it was not included in the present systematic review due to the lack of contrast-enhanced T1WI. The diffusely infiltrating PCNSL without formation of well-defined tumor masses was referred to as ‘lymphomatosis cerebri’ by the case report of Bakshi et al (17) in 1999, on the analogy of the term ‘cerebral gliomas’. For a long time, the literature contained only case reports and small series regarding the clinical and radiological features of lymphomatosis cerebri. Moreover, the term ‘lymphomatosis cerebri’ has not been widely accepted, so the literature has a variety of descriptions for this diffusely infiltrating PCNSL. The recently published systematic review by Izquierdo et al (48) was the most detailed and the largest study on the clinical characteristics of 42 cases with lymphomatosis cerebri; however, the present systematic review focused on neuroradiological features of lymphomatosis cerebri using inclusion and exclusion criteria that differed from those used by Izquierdo et al (48). The present study defined lymphomatosis cerebri as a special entity with abnormal T2 hyperintensities that involved at least three cerebral lobes or three anatomical regions of the CNS, and where the non-enhancing lesions or the lesions without nodular or mass enhancement were identified on initial MR images. By contrast, the study by Izquierdo et al (48) represented lymphomatosis cerebri as the presence of diffuse white-matter disease in the brain MRI without contrast enhancement (although patchy contrast enhancement was also allowed).\n\nThe most common clinical presentation in the present systematic review was cognitive change or dementia (46.7%). Symptoms include persistent headache, seizures, nausea or vomiting, which all occur in other primary brain tumors (56), but appear less commonly in lymphomatosis cerebri. Lymphomatosis cerebri is observed most commonly in the aged adult, and tumor development appears to be unassociated with the immune status of the individuals. Conventional CSF analysis is non-specific. This indicates that lymphomatosis cerebri may rarely involve the leptomeninges. If CSF cytology and flow cytometry have negative results, definitive diagnostic methods should be considered rather than multiple lumbar punctures. With regard to the survival prognostic factors, the most recently published systematic review has suggested that Karnofsky Performance Status scores ≥70 and treatment with methotrexate are independently associated with a favorable outcome, whereas the type of T-cell lymphoma is an independent adverse prognostic factor in patients with lymphomatosis cerebri (48).\n\nDiffuse abnormal T2 hyperintensity is one of the common characteristics of lymphomatosis cerebri. This abnormal T2-hyperintensity can involve the whole CNS, including the brain and spinal cord. A prominent feature of abnormal T2-hyperintensity is the involvement of the deep and periventricular white matter, and involvement of every lobe is reported. Subcortical white matter hyperintensity and U-fiber involvement are frequently observed. Corpus callosum and gray matter involvement are also apparent. The lesion distribution appears to have the propensity for diffuse infiltrative invasion throughout the CNS. It would be more precise if ‘lymphomatosis cerebri’ were renamed ‘diffuse PCNSL’ or ‘diffuse lymphoma of the CNS’.\n\nThe spread of lesions along the corticospinal tract is another common characteristic of diffuse PCNSL based on the results in the present review. In 16 cases reporting follow-up MRI, extensions of lesions were clearly described, spreading along the corticospinal tract down from the cerebral white matter to the spinal cord. The case reported by Samani et al (42) is a representative example. The case reported by Chen and Dong (46) exhibited lesions spreading along the corticospinal tract in upwards and downwards directions at the same time. Lesions extending through the corpus callosum can also be found (30,42,44,46,47). The distribution and spread pattern of this diffuse abnormal signal mimics acute disseminated encephalomyelitis (57).\n\nContrast enhancement patterns of diffuse PCNSL on MR images could be divided into three forms: i) Non-enhancement; ii) various shapes of non-mass-like enhancement on initial MR images; and iii) single or multiple nodular or mass-like enhancement on the later follow-up MRI. Perivascular curvilinear enhancement in the present case appears to be first reported for diffuse infiltrative PCNL. Actually, this perivascular curvilinear enhancement was first described by Alsherbini et al (58) in 2014, in an immune-competent patient who presented with diffusely infiltrating PCNL involving the brainstem. In addition, 5 cases diagnosed definitively as PCNL presented as single or multiple nodular or mass-like enhancement with diffuse leukoencephalopathy on initial MR images, and then became diffusely infiltrating lesions on follow-up (9,55,59–61). Therefore, we speculate that these contrast enhancement patterns could occur at various stages during the development and progression of the disease, and that non-enhancement or non-mass-like enhancement on initial MRI may be only a special pattern of diffuse infiltrative PCNL.\n\nOn the basis of the aforementioned neuroimaging findings, similarly to gliomatosis cerebri (5), we hypothesize that diffuse PCNSL could be divided into primary and secondary subtypes, with primary subtypes exhibiting extensive CNS involvement at the time of initial clinical presentation, and secondary subtypes consisting of progressive infiltration of the brain by a typical locally infiltrative lymphoma observed on clinical follow-up over time. Primary subtypes could then be further divided into type 1 (classical form) and 2, with the classical form presenting as diffuse infiltration without a tumor mass at initial clinical presentation, and type 2 presenting as extensive CNS involvement and a tumor mass.\n\nRadiological-pathological correlation of these contrast enhancement patterns in diffuse PCNSL has not previously been described in detail. It is generally recognized that the patterns and mechanisms of contrast-enhancement depend mostly on the permeability of the blood-brain barrier (BBB) and the extent of vascularity in CNS lesions (62), as well as tumor cellularity (63). The permeability of the BBB is the dominant factor in determining contrast enhancement patterns. The intact BBB will prevent the leakage of contrast material. In the regions with varying degrees of impairment of the BBB, the contrast agent will leak across the vessel wall and begin to accumulate in the perivascular interstitial fluid, which leads to interstitial (extravascular) enhancement (62,63). The non-enhancement pattern is hypothesized to occur when tumor cells are diffusely infiltrative and have not resulted in significant disruption of the BBB (13,14,16,18,20,26,30,31). Another possibility is the vanishing cancer phenomenon caused by corticosteroid-induced apoptosis and lymphoma cell lysis (1,22,40). The present systematic review highlights initial MR images, excluding corticosteroid effects from impacting the findings. Three patterns of neoplastic cell infiltration have been described as diffuse scattered infiltration, perivascular distribution and massive cluster. This could be hypothesized to explain the three contrast-enhancement patterns in diffuse PCNSL. However, in the present systematic review, a corresponding association was not found between contrast-enhancement patterns on neuroimaging and neoplastic cell infiltration patterns on pathology.\n\nCerebral punctate and curvilinear gadolinium enhancements with FLAIR hyperintensities in the corresponding areas indicate small vessel BBB disruption caused by a direct injury of the endothelial cell (64). Recent studies have shown that T1-weighted dynamic contrast-enhanced and dynamic susceptibility-weighted contrast-enhanced MRI could provide further information about intact microvascular integrity and neoangiogenesis, which can be used to improve the preoperative differentiation of PCNSL and other pathological conditions (63,65).\n\nDWI is useful in distinguishing between PCNSL and other tumors and tumor-mimicking lesions (1,2,51,57,66,67). DWI findings in the present systematic review were isointense, slightly hyperintense and high hyperintense compared with normal gray matter. The extension of DWI hyperintensities corresponded with or without abnormal T2-hyperintensity. It is worth noting that almost all of the articles did not provide or describe ADC maps to distinguish between restricted diffusion and T2 shine-through effect on DWI, as well as cytotoxic and vasogenic edema. As for our present case, a combination of DWI and ADC hyperintense signal means vasogenic edema with T2 shine through effect. Therefore, the diagnostic value of DWI for diffuse PCNL should not be determined depending only on this available literature.\n\nPET/CT is a well-established functional imaging method widely used in clinical neurooncology. In a review published by Kawai et al (68), it was concluded that PET/CT is useful in the diagnosis of typical PCNSL and can differentiate PCNSL from other malignant brain tumors. However, the value of PET/CT appears to be limited in the diagnosis of PCNSL with atypical radiological findings, including disseminated or non-enhancing lesions. PET findings in the present systematic review were varied and non-specific. This may be associated with regional cerebral metabolic rates of glucose, cellular differentiation, low cellularity and BBB integrity. The study by Kawai et al (23,69) suggested that the parameters evaluated by FDG kinetic analysis may provide valuable information in the diagnosis of atypical PCNSL. For diffuse PCNSL, the usefulness of whole-body PET scan appears merely for the purposes of excluding systemic lymphoma (2,26,29,36,66).\n\nRapidly progressing dementia in the elderly and diffuse leukoencephalopathy on MRI should prompt the consideration of diffuse PCNSL. Although a substantial number of studies describe how to differentiate between rapidly progressing dementia in the elderly and diffuse leukoencephalopathy (1–3,26,30,33,34,36,49,51,57,62–71), the diagnosis of diffuse PCNSL remains a challenge, and all cases in the present systematic review were misdiagnosed prior to brain biopsy or autopsy. The presumptive diagnosis of diffuse infiltrative brain neoplasia is proposed by the detailed analysis of medical history, clinical presentation, CSF results and serial MRI, including DWI and contrast enhancement. A decision to undertake a brain biopsy as soon as possible may benefit such patients.\n\nThe main limitations of the present systematic review are that only a few cases involved DTI (29), MRS (29,30,49,51) or SPECT (49). The diagnostic values of these imaging methods have yet to be investigated in depth. Furthermore, the treatment and prognosis of lymphomatosis cerebri have not been analyzed in detail, as the present study focuses on describing the neuroradiological features of this condition.\n\nIn conclusion, although all data in the present systematic review are obtained from case reports, neuroradiological features of lymphomatosis cerebri could be characterized by rapidly progressing dementia in the elderly and diffuse leukoencephalopathy that tends to infiltrate the entire CNS along the corticospinal tract, possible involvement of gray matter, and a slight mass effect and varied contrast-enhancement patterns on MRI. It appears more reasonable to rename the so-called ‘lymphomatosis cerebri’ as ‘diffuse PCNSL’ or ‘diffuse lymphoma of the CNS’. Non-enhancement or non-mass-like enhancement on MRI may only be a special form of diffuse PCNL during its development and progression. Early brain biopsy will minimize the duration of misdiagnosis in the setting of a presumptive diagnosis of diffuse infiltrative brain neoplasia.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article. A list of detailed clinical data and neuroradiological findings collected from all available case reports are shown as ‘On-line Table I’ and ‘On-line Table II’ in the online repository Baidu Netdisk (https://pan.baidu.com/s/1KeHH0w0aBR6vKO_mLb2lPA).\n\nAuthors' contributions\nLL designed the study. LL and RJH searched, collected and amalgamated the literature. RJH and FJ gathered the case data. All authors analyzed and interpreted the data. All authors drafted the manuscript. All authors read and approved final manuscript.\n\nEthics approval and consent to participate\nEthical approval for this retrospective study was obtained from the local Institutional Review Board in Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University (Guangzhou, China).\n\nConsent for publication\nWritten informed consent was obtained from the daughter of the patient for publication of this case report and any accompanying data.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAbbreviations\nADCapparent diffusion coefficient\n\nBBBblood-brain barrier\n\nCNScentral nervous system\n\nCSFcerebrospinal fluid\n\nCTcomputed tomography\n\nDTIdiffusion tensor imaging\n\nDWIdiffusion-weighted imaging\n\nFDGfluorodeoxyglucose\n\nFLAIRfluid-attenuated inversion recovery\n\nFOVfield of view\n\nGCBgerminal center B-cell-like\n\nIHCimmunohistochemistry\n\nMRImagnetic resonance imaging\n\nMRSmagnetic resonance spectroscopy\n\nnon-GCBnon-germinal center B-cell type\n\nPCNSLprimary central nervous system lymphoma\n\nPETpositron emission tomography\n\nPRISMApreferred reporting items of systematic reviews and meta-analyses\n\nSPECTsingle-photon emission computed tomography\n\nT1WIT1-weighted image\n\nT2WIT2-weighted image\n\nTEecho time\n\nTRrepetition time\n\nFigure 1. CT findings of lymphomatosis cerebri from the present case report. (A-D) On February 25, 2015, the day of presentation to the neurological clinic, unenhanced CT showed (B) an abnormal low density in the right thalamus, external capsule and (C and D) parietal white matter. (E-H) On July 4, 2015, the follow-up unenhanced CT demonstrated abnormal hyperintensities that extended almost to all cerebral and cerebellar white matter, as well as the thalamus and brainstem. Multiple circular nodules were also observed in (E) the right cerebellar hemisphere, and (F and G) the bilateral occipital white matter and (H) right parietal white matter. CT, computed tomography.\n\nFigure 2. MRI findings of lymphomatosis cerebri from the present case report. (A-J) The initial MRI was performed on February 26, 2015. (A and F) FLAIR and (B and G) DWI showed diffuse multiple asymmetrical hyperintensity in (A) the bilateral basal ganglia and thalamus, (A, B and G) temporal white matter and (F and G) medial prefrontal cortex and periventricular white matter, as well as a slight mass effect on the posterior horn of the left lateral ventricle. (C and H) Apparent diffusion coefficient map showed mild hypotensity with no corresponding T2 hyperintensity, denoting a T2 shine-through effect and slight restricted diffusion. The lesions were (D and I) isointense on Tl-weighted spin-echo images, and (E and J) showed asymmetric perivascular curvilinear enhancement perpendicular to the lateral ventricle following gadolinium administration. (K-O) The follow-up MRI was performed on April 22, 2015. (K) FLAIR and (L) DWI demonstrated broader hyperintensity of the cerebral white matter. (O) The perivascular curvilinear enhancement on T1-weighted imaging with gadolinium expanded markedly. MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery; DWI, diffusion-weighted imaging.\n\nFigure 3. [18F]FDG-PET/CT findings of lymphomatosis cerebri from the present case report. On April 23, 2015, the PET/CT fusion images revealed inhomogeneous and patchy distribution of 18F-FDG uptake, with an SUVmax of 20.5 and SUVave of 15.3 in (A and B) the cerebrum, (C) brainstem, (C) cerebellum and (C and D) cervical cord. (D) No sign of systemic lymphoma was present. FDG, fluorodeoxyglucose; PET/CT, positron emission tomography/computed tomography; SUV, standardized uptake value.\n\nFigure 4. Pathological findings of lymphomatosis cerebri from the current case. On May 12, 2015, a stereotactic brain biopsy of the left frontal lobe revealed (A) prominent diffuse perivascular infiltrates of atypical large B-cells with irregularly shaped nuclei, (B) with strong staining for the B-cell marker CD-20 and for (C) Ki-67, indicative of highly proliferating cells. This case was assigned to the non-germinal center B-cell immunophenotype, as it was negative for (D) CD-10 and (E) Bcl-6, but positive for (F) MUM-1. (A) Hematoxylin and eosin, ×400 magnification; (B) anti-CD20, ×400 magnification; (C) anti-Ki-67, ×200 magnification; (D) anti-CD10, ×400 magnification; (E) anti-Bcl-6, ×400 magnification; and (F) anti-MUM-1, ×400 magnification. CD, cluster of differentiation; Bcl, B-cell lymphoma; MUM-1, multiple myeloma oncogene 1.\n\nFigure 5. Preferred reporting items of systematic reviews and meta-analyses-style flow diagram of the literature search for the systematic review. MRI, magnetic resonance imaging; CNS, central nervous system.\n\nTable I. Summary of demographic and clinical features in 45 cases of lymphomatosis cerebri based on a systematic review.\n\nCharacteristic\tValue\t\nPatients, n\t45\t\nAge, years\t\t\n Mean\t57.3\t\n Range\t28–85\t\nSex, n (%)\t\t\n Male\t23 (51.1)\t\n Female\t22 (48.9)\t\nClinical symptoms, n (%)\t\t\n Cognitive changes/dementia\t20 (44.4)\t\n Gait ataxia\t17 (37.8)\t\n Motor deficit\t16 (35.6)\t\n Sensory deficit\t5 (11.1)\t\n Language deficit\t11 (24.4)\t\n Visual problems\t5 (11.1)\t\n Memory loss\t11 (24.4)\t\n Personality changes\t8 (17.8)\t\n Seizures\t4 (8.9)\t\n Changes in consciousness\t10 (22.2)\t\n Nausea or vomiting\t1 (2.2)\t\n Headache\t4 (8.9)\t\n Persistent fever\t2 (4.4)\t\nImmune status, n (%)\t\t\n Immunocompetent\t42 (93.3)\t\n Immunocompromised (AIDS patients)\t3 (6.7)\t\nCSF examinationa, n (%)\t\t\n Normal\t5 (14.3)\t\n Abnormal\t30 (85.7)\t\n Elevated protein\t22\t\n Increased cell counts\t12\t\n Decreased glucose\t4\t\n Lymphocytosis\t1\t\n Atypical lymphocytes\t1\t\nPathology sampling, n (%)\t\t\n Brain biopsy\t35 (77.8)\t\n Autopsy\t9 (20.0)\t\n Not mentioned\t1 (2.2)\t\nResults\t\t\n B-cell type\t40 (88.9)\t\n T-cell type\t4 (8.9)\t\n Unclassified\t1 (2.2)\t\nOutcome, months after symptom onset\t\t\n Succumbed\t9.8\t\n Alive\t24\t\na n=35. AIDS, acquired immunodeficiency syndrome; CSF, cerebrospinal fluid.\n\nTable II. Summary of neuroimaging features in 45 cases of lymphomatosis cerebri based on a systematic review.\n\nCharacteristic\tValue (%)\t\nMRI (Initial) Localization (n=45)\t\t\nCerebrum\t\t\n Frontal lobe\t35 (77.8): Unilateral 8 (17.8),\t\n\tBilateral 27 (60.0)\t\n Parietal lobe\t32 (73.3): Unilateral 6 (13.3),\t\n\tBilateral 26 (57.8)\t\n Temporal lobe\t33 (73.4): Unilateral 7 (15.6),\t\n\tBilateral 26 (57.8)\t\n Occipital lobe\t29 (64.4): Unilateral 5 (11.1),\t\n\tBilateral 24 (53.3)\t\n Insular lobe\t26 (57.8): Unilateral 4 (8.9),\t\n\tBilateral 22 (48.9)\t\n Periventricular\t10 (22.2): Unilateral 2 (4.4),\t\n white matter\tBilateral 8 (17.8)\t\n Corpus callosum\t19 (42.2)\t\n Basal ganglia\t15 (33.3): Unilateral 1 (2.2),\t\n\tBilateral 14 (31.1)\t\n Thalamus\t12 (26.7): Unilateral 4 (8.9),\t\n\tBilateral 8 (17.8)\t\nBrainstem\t\t\n Midbrain\t21 (46.7): Unilateral 3 (6.7),\t\n\tBilateral 18 (40.0)\t\n Pons\t20 (44.5): Unilateral 3 (6.7),\t\n\tBilateral 17 (37.8)\t\n Medulla\t14 (31.1): Unilateral 3 (6.7),\t\n\tBilateral 11 (24.4)\t\n Cerebellum\t12 (26.6): Unilateral 1 (2.2),\t\n\tBilateral 11 (24.4)\t\n Spinal cord\t5 (11.1)\t\nSignal\t\t\nT1WI (n=13)\t\t\n Isointensity\t6 (46.2)\t\n Hypointensity\t7 (53.8)\t\n T2/FLAIR (n=45),\t45 (100.0)\t\n hyperintensity\t\t\nDWI (n=14)\t\t\n Isointensity\t2 (14.3)\t\n Slightly hyperintensity\t11 (78.6)\t\n High hyperintense\t1 (7.1)\t\nEnhancement (n=45)\t\t\n Absence\t29 (64.4)\t\n Non-mass-like enhancement\t16 (35.6)\t\n Subtle (faint/slight/little/minimal)\t7 (43.8)\t\n Patchy\t5 (31.2)\t\n Perivascular curvilinear\t4 (25.0)\t\n Slight mass effect\t23 (51.1)\t\nMRS (n=4)\t\t\nN-acetylaspartate peak\t\t\n Normal\t1 (25.0)\t\n Decreased\t3 (75.0)\t\nCholine peak\t\t\n Normal\t1 (25.0)\t\n Increased\t3 (75.0)\t\n Myo-inositol peak, increased\t1 (25.0)\t\n Lipid peak, increased\t1 (25.0)\t\n Creatine peak, normal\t1 (25.0)\t\nSPECT (n=1)\t\t\n Increased uptake\t1 (100.0)\t\nPET/CT (n=12)\t\t\n Increased uptake\t4 (33.3)\t\n Decreased uptake\t3 (25.0)\t\n Normal metabolism\t5 (41.7)\t\nMRI, magnetic resonance imaging; T1WI, T1-weighted imaging; FLAIR, fluid-attenuated inversion recovery; DWI, diffusion-weighted imaging; MRS, magnetic resonance spectroscopy; SPECT, single-photon emission computed tomography; PET/CT, positron emission tomography/computed tomography.\n==== Refs\nReferences\n1 Hoang-Xuan K Bessell E Bromberg J Hottinger AF Preusser M Rudà R Schlegel U Siegal T Soussain C Abacioglu U Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: Guidelines from the European Association for Neuro-Oncology Lancet Oncol 16 e322 e332 2015 10.1016/S1470-2045(15)00076-5 26149884 \n2 Bathla G Hegde A Lymphomatous involvement of the central nervous system Clin Radiol 71 602 609 2016 10.1016/j.crad.2016.02.006 27038652 \n3 Deckert M Paulus W Malignant lymphoma WHO Classification of Tumours of the Central Nervous System 4th edition Louis DN Ohgaki H Wiestler OD Cavenee WK IARC Press Lyon 188 196 2007 \n4 Taylor CR Rudbeck L Dako education guide: Immunohistochemical staining methods 6th edition https://www.agilent.com/cs/library/technicaloverviews/public/08002_ihc_staining_methods.pdf 2013 \n5 Fuller GN Kros JM Gliomatosis cerebri Louis DN Ohgaki H Wiestler OD Cavenee WK WHO Classification of Tumours of the Central Nervous System 4th edition Lyon, France IARC Press 50 52 2007 \n6 Weaver JD Vinters HV Koretz B Xiong Z Mischel P Kado D Lymphomatosis cerebri presenting as rapidly progressive dementia Neurologist 13 150 153 2007 10.1097/01.nrl.0000254706.85609.95 17495760 \n7 Pandit L Chickabasaviah Y Raghothaman A Mustafa S Vasudevan A Lymhomatosis cerebri-a rare cause of leukoencephalopathy J Neurol Sci 293 122 124 2010 10.1016/j.jns.2010.02.023 20304432 \n8 Hishikawa N Niwa H Hara T Hara K Ito M Shimada S Yoshida M Hashizume Y Murakami N An autopsy case of lymphomatosis cerebri showing pathological changes of intravascular large B-cell lymphoma in visceral organs Neuropathology 31 612 619 2011 10.1111/j.1440-1789.2011.01203.x 21382094 \n9 Jain TK Sharma P Suman SK Faizi NA Bal C Kumar R Primary central nervous system lymphoma with lymphomatosis cerebri in an immunocompetent child: MRI and 18 F-FDG PET-CT findings Rev Esp Med Nucl Imagen Mol 32 394 396 2013 23743243 \n10 Rivero Sanz E Torralba Cabeza MÁ Sanjuán Portugal F García-Bragado F Lymphomatosis cerebri mimicking iatrogenic Creutzfeldt-Jakob disease BMJ Case Rep 2014 pii bcr2013201246 2014 10.1136/bcr-2013-201246 25199185 \n11 Lee PJ Berrios I Ionete C Smith T Lymphomatosis cerebri: Diagnostic challenges and review of the literature BMJ Case Rep 2016 pii bcr2016216591 2016 10.1136/bcr-2016-216591 27884882 \n12 Stewart LA Clarke M Rovers M Riley RD Simmonds M Stewart G Tierney JF PRISMA-IPD Development Group Preferred reporting items for systematic review and meta-analyses of individual participant data: The PRISMA-IPD statement JAMA 313 1657 1665 2015 10.1001/jama.2015.3656 25919529 \n13 Terae S Ogata A Nonenhancing primary central nervous system lymphoma Neuroradiology 38 34 37 1996 10.1007/BF00593213 8773272 \n14 Carlson BA Rapidly progressive dementia caused by nonenhancing primary lymphoma of the central nervous system AJNR Am J Neuroradiol 17 1695 1697 1996 8896625 \n15 Wanschitz J Hainfellner JA Simonitsch I Schnizer M Deisenhammer E Terunuma H Iwasaki Y Budka H Non-HTLV-I associated pleomorphic T-cell lymphoma of the brain mimicking post-vaccinal acute inflammatory demyelination Neuropathol Appl Neurobiol 23 43 49 1997 10.1111/j.1365-2990.1997.tb01184.x 9061689 \n16 Furusawa T Okamoto K Ito J Kojima N Oyanagi K Tokiguchi S Sakai K Primary central nervous system lymphoma presenting as diffuse cerebral infiltration Radiat Med 16 137 140 1998 9650903 \n17 Bakshi R Mazziotta JC Mischel PS Jahan R Seligson DB Vinters HV Lymphomatosis cerebri presenting as a rapidly progressive dementia: Clinical, neuroimaging and pathologic findings Dement Geriatr Cogn Disord 10 152 157 1999 10.1159/000017116 10026390 \n18 Thurnher MM Rieger A Kleibl-Popov C Settinek U Henk C Haberler C Schindler E Primary central nervous system lymphoma in AIDS: A wider spectrum of CT and MRI findings Neuroradiology 43 29 35 2001 10.1007/s002340000480 11214644 \n19 Ayuso-Peralta L Ortí-Pareja M Zurdo-Hernández M Jiménez-Jiménez FJ Tejeiro-Martínez J Ricoy JR de la Lama A Bernardo AI Cerebral lymphoma presenting as a leukoencephalopathy J Neurol Neurosurg Psychiatry 71 243 246 2001 10.1136/jnnp.71.2.243 11459903 \n20 Giglio P Bakshi R Block S Ostrow P Pullicino PM Primary central nervous system lymphoma masquerading as herpes encephalitis: Clinical, magnetic resonance imaging, and pathologic findings Am J Med Sci 323 59 61 2002 10.1097/00000441-200201000-00011 11814145 \n21 Moulignier A Galicier L Mikol J Masson H Molho M Thiebaut JB Primary cerebral lymphoma presenting as diffuse leukoencephalopathy AIDS 17 1111 1113 2003 10.1097/00002030-200305020-00032 12700473 \n22 Rollins KE Kleinschmidt-DeMasters BK Corboy JR Damek DM Filley CM Lymphomatosis cerebri as a cause of white matter dementia Hum Pathol 36 282 290 2005 10.1016/j.humpath.2005.01.014 15791573 \n23 Kawai N Kawanishi M Tamiya T Nagao S Usefulness of [18 F]FDG-PET kinetic analysis in non-enhancing primary central nervous system lymphoma: Case report Ann Nucl Med 19 415 419 2005 10.1007/BF03027408 16164200 \n24 Vital A Sibon I A 64-year-old woman with progressive dementia and leukoencephalopathy Brain Pathol 17 117 118 121 2007 10.1111/j.1750-3639.2007.00044_2.x 17493046 \n25 Lewerenz J Ding X Matschke J Schnabel C Emami P von Borczyskowski D Buchert R Krieger T de Wit M Münchau A Dementia and leukoencephalopathy due to lymphomatosis cerebri J Neurol Neurosurg Psychiatry 78 777 778 2007 10.1136/jnnp.2006.106385 17210623 \n26 Kanai R Shibuya M Hata T Hori M Hirabayashi K Terada T Fujii K A case of ‘lymphomatosis cerebri’ diagnosed in an early phase and treated by whole brain radiation: Case report and literature review J Neurooncol 86 83 88 2008 10.1007/s11060-007-9437-9 17611716 \n27 Sugie M Ishihara K Kato H Nakano I Kawamura M Primary central nervous system lymphoma initially mimicking lymphomatosis cerebri: An autopsy case report Neuropathology 29 704 707 2009 10.1111/j.1440-1789.2009.01004.x 19389079 \n28 Clark AJ Lee K Broaddus WC Martin MJ Ghatak NR Grossman CE Baker S Jr Baykal A Primary brain T-cell lymphoma of the lymphoblastic type presenting as altered mental status Acta Neurochir (Wien) 152 163 168 2010 10.1007/s00701-009-0433-z 19578806 \n29 Liao MF Toh CH Kuo HC Chu CC Jung SM Huang CC Diffusion tensor images and magnetic resonance spectroscopy in primary central nervous system T-cell lymphoma: A case report Acta Neurol Taiwan 20 59 64 2011 21249594 \n30 Raz E Tinelli E Antonelli M Canevelli M Fiorelli M Bozzao L Di Piero V Caramia F MRI findings in lymphomatosis cerebri: Description of a case and revision of the literature J Neuroimaging 21 e183 e186 2011 10.1111/j.1552-6569.2010.00477.x 20345746 \n31 Leschziner G Rudge P Lucas S Andrews T Lymphomatosis cerebri presenting as a rapidly progressive dementia with a high methylmalonic acid J Neurol 258 1489 1493 2011 10.1007/s00415-011-5965-5 21365456 \n32 Courtois F Gille M Haven F Hantson P Lymphomatosis cerebri presenting as a recurrent leukoencephalopathy Case Rep Neurol 4 181 186 2012 10.1159/000343947 23185172 \n33 Keswani A Bigio E Grimm S Lymphomatosis cerebri presenting with orthostatic hypotension, anorexia, and paraparesis J Neurooncol 109 581 586 2012 10.1007/s11060-012-0931-3 22806340 \n34 Kitai R Hashimoto N Yamate K Ikawa M Yoneda M Nakajima T Arishima H Takeuchi H Sato K Kikuta K Lymphomatosis cerebri: Clinical characteristics, neuroimaging, and pathological findings Brain Tumor Pathol 29 47 53 2012 10.1007/s10014-011-0064-y 21927864 \n35 Yamamoto T Kojima K Koibuchi K Ito S Higuchi Y Iwadate Y Oide T Kuwabara S A case of primary central nervous system lymphoma presenting diffuse infiltrative leukoencephalopathy Intern Med 51 1103 1106 2012 10.2169/internalmedicine.51.6316 22576396 \n36 Sugino T Mikami T Akiyama Y Wanibuchi M Hasegawa T Mikuni N Primary central nervous system anaplastic large-cell lymphoma mimicking lymphomatosis cerebri Brain Tumor Pathol 30 61 65 2013 10.1007/s10014-012-0094-0 22426596 \n37 Sato H Takahashi Y Wada M Shiono Y Suzuki I Kohno K Kato Y Kawanami T Sakurada K Kayama T Kato T Lymphomatosis cerebri with intramedullary spinal cord involvement Intern Med 52 2561 2565 2013 10.2169/internalmedicine.52.0748 24240797 \n38 Choi CY Lee CH Joo M Lymphomatosis cerebri J Korean Neurosurg Soc 54 420 422 2013 10.3340/jkns.2013.54.5.420 24379950 \n39 Miki Y Tomiyama M Kurotaki H Wakabayashi K Baba M Primary central nervous system lymphoma mimicking Bickerstaff's encephalitis Neurol Sci 35 139 141 2014 10.1007/s10072-013-1533-3 24013552 \n40 Giannini C Dogan A Salomão DR CNS lymphoma: A practical diagnostic approach J Neuropathol Exp Neurol 73 478 494 2014 10.1097/NEN.0000000000000076 24806301 \n41 Kawakami T Sakai K Mimura Y Senoo Y Hirabayashi Y Nakazawa H Koshihara H Oguchi K Takei Y Ohara S Development of primary central nervous system lymphoma associated with human immunodeficiency virus and JC virus infection J Clin Exp Hematop 54 211 217 2014 10.3960/jslrt.54.211 25501112 \n42 Samani A Davagnanam I Cockerell OC Ramsay A Patani R Chataway J Lymphomatosis cerebri: A treatable cause of rapidly progressive dementia J Neurol Neurosurg Psychiatry 86 238 240 2015 10.1136/jnnp-2013-307327 24847165 \n43 Imperiale D Taraglio S Atzori C Testi R Diffuse leukoencephalopathy due to lymphomatosis cerebri: A clinicopathological report Neurol Sci 36 1071 1073 2015 10.1007/s10072-014-1974-3 25351342 \n44 Meng H Zhou C Hao Q Gao J Zhang R Wang Z Liu Q Fang S A rare case of Primary Central Nervous System Lymphoma initially diagnosed as demyelinating encephalopathy Neuro Endocrinol Lett 36 124 126 2015 26071579 \n45 Hatanpaa KJ Fuda F Koduru P Young K Lega B Chen W Lymphomatosis cerebri: A diagnostic challenge JAMA Neurol 72 1066 1067 2015 10.1001/jamaneurol.2015.2675 26147788 \n46 Chen H Dong H A rare case of nonenhancing primary central nervous system lymphoma mimic multiple sclerosis Neurosciences (Riyadh) 20 380 384 2015 10.17712/nsj.2015.4.20150125 26492120 \n47 Hashiguchi S Momoo T Murohashi Y Endo M Shimamura M Kawasaki T Kanada S Nozawa A Tada M Koyano S Tanaka F Interleukin 10 level in the cerebrospinal fluid as a possible biomarker for lymphomatosis cerebri Intern Med 54 1547 1552 2015 10.2169/internalmedicine.54.3283 26073248 \n48 Izquierdo C Velasco R Vidal N Sánchez JJ Argyriou AA Besora S Graus F Bruna J Lymphomatosis cerebri: A rare form of primary central nervous system lymphoma. Analysis of 7 cases and systematic review of the literature Neuro Oncol 18 707 715 2016 10.1093/neuonc/nov197 26415875 \n49 Murakami T Yoshida K Segawa M Yoshihara A Hoshi A Nakamura K Ichikawa M Suzuki O Yokoyama Y Toyoshima Y A case of lymphomatosis cerebri mimicking inflammatory diseases BMC Neurol 16 128 2016 10.1186/s12883-016-0655-7 27502482 \n50 Ge J Zuo C Guan Y Zhao G Enhanced MRI and 18 F-FDG PET/CT findings of primary central nervous system lymphoma mimicking encephalitis Clin Nucl Med 41 e436 e438 2016 10.1097/RLU.0000000000001272 27355853 \n51 Brandão LA Castillo M Lymphomas-part 2 Neuroimaging Clin N Am 26 537 565 2016 10.1016/j.nic.2016.06.005 27712793 \n52 Fisher D Mantell BS Urich H The clinical diagnosis and treatment of microgliomatosis: Report of a case J Neurol Neurosurg Psychiatry 32 474 478 1969 10.1136/jnnp.32.5.474 4902523 \n53 Schaumburg HH Plank CR Adams RD The reticulum cell sarcoma-microglioma group of brain tumours A consideration of their clinical features and therapy. Brain 95 199 212 1972 4570086 \n54 Tadmor R Davis KR Roberson GH Kleinman GM Computed tomography in primary malignant lymphoma of the brain J Comput Assist Tomogr 2 135 140 1978 10.1097/00004728-197804000-00002 701497 \n55 Provinciali L Signorino M Ceravolo G Pasquini U Onset of primary brain T-lymphoma simulating a progressive leukoencephalopathy Ital J Neurol Sci 9 377 381 1988 10.1007/BF02334002 3220714 \n56 Chandana SR Movva S Arora M Singh T Primary brain tumors in adults Am Fam Physician 77 1423 1430 2008 18533376 \n57 Sarbu N Shih RY Jones RV Horkayne-Szakaly I Oleaga L Smirniotopoulos JG White matter diseases with radiologic-pathologic correlation Radiographics 36 1426 1447 2016 10.1148/rg.2016160031 27618323 \n58 Alsherbini K Beinlich B Salamat MS Diffusely infiltrating central nervous system lymphoma involving the brainstem in an immune-competent patient JAMA Neurol 71 110 111 2014 10.1001/jamaneurol.2013.1578 24217110 \n59 Matsumoto K Kohmura E Fujita T Tsuruzono K Tsujimura T Kawano K Recurrent primary central nervous system lymphoma mimicking neurodegenerative disease-an autopsy case report Neurol Med Chir (Tokyo) 35 360 363 1995 10.2176/nmc.35.360 7566377 \n60 Brecher K Hochberg FH Louis DN de la Monte S Riskind P Case report of unusual leukoencephalopathy preceding primary CNS lymphoma J Neurol Neurosurg Psychiatry 65 917 920 1998 10.1136/jnnp.65.6.917 9854972 \n61 Nipanal AV Madhumathi R Navya and Angel: CNS lymphoma mimicking a demyelinating lesion J Evol Med Dent Sci 4 11555 11559 2015 10.14260/jemds/2015/1666 \n62 Smirniotopoulos JG Murphy FM Rushing EJ Rees JH Schroeder JW Patterns of contrast enhancement in the brain and meninges Radiographics 27 525 551 2007 10.1148/rg.272065155 17374867 \n63 Kickingereder P Sahm F Wiestler B Roethke M Heiland S Schlemmer HP Wick W von Deimling A Bendszus M Radbruch A Evaluation of microvascular permeability with dynamic contrast-enhanced MRI for the differentiation of primary CNS lymphoma and glioblastoma: Radiologic-pathologic correlation AJNR Am J Neuroradiol 35 1503 1508 2014 10.3174/ajnr.A3915 24722313 \n64 Taieb G Duran-Peña A de Chamfleur NM Moulignier A Thouvenot E Allou T Lacour A Hoang-Xuan K Pelletier J Labauge P Punctate and curvilinear gadolinium enhancing lesions in the brain: A practical approach Neuroradiology 58 221 235 2016 10.1007/s00234-015-1629-y 26700824 \n65 da Rocha AJ Sobreira Guedes BV da Silveira da Rocha TM Maia Junior AC Chiattone CS Modern techniques of magnetic resonance in the evaluation of primary central nervous system lymphoma: Contributions to the diagnosis and differential diagnosis Rev Bras Hematol Hemoter 38 44 54 2016 10.1016/j.bjhh.2015.12.001 26969774 \n66 Patrick LB Mohile NA Advances in primary central nervous system lymphoma Curr Oncol Rep 17 60 2015 10.1007/s11912-015-0483-8 26475775 \n67 Malikova H Koubska E Weichet J Klener J Rulseh A Liscak R Vojtech Z Can morphological MRI differentiate between primary central nervous system lymphoma and glioblastoma? Cancer Imaging 16 40 2016 10.1186/s40644-016-0098-9 27894359 \n68 Kawai N Miyake K Yamamoto Y Nishiyama Y Tamiya T 18 F-FDG PET in the diagnosis and treatment of primary central nervous system lymphoma Biomed Res Int 2013 247152 2013 10.1155/2013/247152 23844359 \n69 Kawai N Okubo S Miyake K Maeda Y Yamamoto Y Nishiyama Y Tamiya T Use of PET in the diagnosis of primary CNS lymphoma in patients with atypical MR findings Ann Nucl Med 24 335 343 2010 10.1007/s12149-010-0356-z 20379859 \n70 Scott BJ Douglas VC Tihan T Rubenstein JL Josephson SA A systematic approach to the diagnosis of suspected central nervous system lymphoma JAMA Neurol 70 311 319 2013 10.1001/jamaneurol.2013.606 23319132 \n71 Deutsch MB Mendez MF Neurocognitive features distinguishing primary central nervous ssystem lymphoma from other possible causes of rapidly progressive sdementia Cogn Behav Neurol 28 1 10 2015 10.1097/WNN.0000000000000048 25812125\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1792-1074",
"issue": "16(2)",
"journal": "Oncology letters",
"keywords": "diffuse tumorous infiltration; leukoencephalopathy; lymphomatosis cerebri; magnetic resonance imaging; neuroradiology; primary central nervous system lymphoma",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "1463-1474",
"pmc": null,
"pmid": "30008825",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": "17493046;25351342;26415875;21927864;26071579;23185172;25501112;26492120;25919529;20345746;16164200;9650903;21382094;27502482;20304432;8896625;25199185;24217110;11459903;24722313;27712793;26969774;15791573;17495760;23743243;9061689;12700473;27618323;21249594;24240797;8773272;24847165;19578806;17611716;22576396;11214644;17374867;17210623;26073248;24806301;4902523;701497;24379950;22426596;3220714;11814145;27355853;4570086;27038652;23844359;22806340;21365456;20379859;26149884;25812125;23319132;26700824;26475775;24013552;19389079;9854972;18533376;27894359;7566377;26147788;27884882;10026390",
"title": "Neuroradiological features of lymphomatosis cerebri: A systematic review of the English literature with a new case report.",
"title_normalized": "neuroradiological features of lymphomatosis cerebri a systematic review of the english literature with a new case report"
} | [
{
"companynumb": "PHHY2018CN071049",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nHypercalcemia in adults has several less common causes. Management in patients with chronic kidney disease (CKD) is challenging because bisphosphonates are contraindicated. This case presents an uncommon cause of hypercalcemia in a subacute rehabilitation patient who was managed with denosumab.\n\n\nMETHODS\nA 79-year-old female with CKD stage 4 was admitted to a skilled nursing facility with a limited-weight-bearing status after right-hip arthroplasty. Four weeks later, she developed hypercalcemia (11.5 mg/dL; normal, 7.9-9.9 mg/dL) with serum albumin of 2.5 g/dL (corrected calcium, 12.7 mg/dL). Despite iv fluids, hypercalcemia worsened (corrected serum calcium, 14.5 mg/dL), and she was rehospitalized. Additional studies eliminated common causes of hypercalcemia, leading to the diagnosis of immobilization hypercalcemia. Due to CKD, a bisphosphonate was not given. She received 10 doses of calcitonin s.c. with mild improvement in her calcium, and she returned to the skilled nursing facility. Because hypercalcemia worsened within days, denosumab 60 mg was administered s.c., and her serum calcium level normalized. Over the next several weeks, her surgical wound worsened. Hip x-ray showed osteolysis of her residual right femoral head. In retrospect, hip x-ray during her hospitalization for hypercalcemia showed osteolysis, likely from osteomyelitis. A contribution of osteomyelitis to hypercalcemia could not be excluded. Despite resolution of hypercalcemia, she succumbed to sepsis.\n\n\nCONCLUSIONS\nImmobilization hypercalcemia is underappreciated in post-acute care older adults. In this patient with CKD, denosumab reversed her hypercalcemia; however, the case highlights potential risks and limitations with this therapy and emphasizes the need for further studies in medically complex older adults.",
"affiliations": "Division of Gerontology, Geriatrics, and Palliative Care, The University of Alabama at Birmingham, Birmingham, Alabama 35294.",
"authors": "Booth|Katrina A|KA|;Hays|Clare I|CI|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D053245:RANK Ligand; D000069448:Denosumab; D002116:Calcitonin",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2013-4205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "99(10)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D002116:Calcitonin; D000069448:Denosumab; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D007103:Immobilization; D053245:RANK Ligand; D012866:Skilled Nursing Facilities",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "3531-5",
"pmc": null,
"pmid": "25033064",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Using denosumab to treat immobilization hypercalcemia in a post-acute care patient.",
"title_normalized": "using denosumab to treat immobilization hypercalcemia in a post acute care patient"
} | [
{
"companynumb": "PHHY2014US139496",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Immune checkpoint inhibitors (ICI) induce improved clinical outcomes associated with numerous cancers, but immune-related adverse events can occur, including neuromuscular complications. We searched for all muscle biopsies from the patient data system of University Hospitals Leuven (UZ Leuven) from January 2014 to July 2018 (n = 686) and collected clinical data of patients with a biopsy-proven ICI-related myositis and expanded the pathological examinations. We identified three cases of ICI-related myositis in patients with malignant melanoma. The clinical phenotype ranged from mild to life threatening. Two patients had a myositis-myasthenia gravis overlap syndrome and one had a co-occurring myocarditis. Pathological examination showed a necrotizing and/or inflammatory myopathy with CD4 + and CD8 + T cells and CD68 + macrophages. IgG staining was positive in all cases. PD-1 and PD-L1 reactions were negative for inhibitors of the PD-1/PD-L1 pathway (nivolumab, atezolizumab) and positive for CTLA-4 inhibitors (ipilimumab). With increasing usage of ICI, clinicians must be aware of rare but potentially serious adverse events such as myositis. Early detection by inquiring about complaints and clinical signs of weakness and monitoring the creatine phosphokinase level in serum are recommended. Our histological findings are in line with other reports. The IgG positivity suggests a local role of the ICI in the pathophysiology of the myositis. Further research must be performed to identify patients at risk and to optimize treatment of the complications.",
"affiliations": "Department of Neurology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. vermeulen_lynn@hotmail.com.;Laboratory for Muscle Diseases and Neuropathies, Department of Neurosciences, KU Leuven, Leuven, Belgium.;Department of Pathology, University Hospitals Leuven, Leuven, Belgium.;Department of Oncology, University Hospitals Leuven, Leuven, Belgium.;Department of Neurology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.;Department of Pathology, University Hospitals Leuven, Leuven, Belgium.;Department of Neurology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.",
"authors": "Vermeulen|Lynn|L|http://orcid.org/0000-0002-3903-8466;Depuydt|Christophe E|CE|;Weckx|Petra|P|;Bechter|Oliver|O|;Van Damme|Philip|P|;Thal|Dietmar R|DR|;Claeys|Kristl G|KG|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000074324:Ipilimumab; D000077594:Nivolumab; C000594389:atezolizumab",
"country": "Italy",
"delete": false,
"doi": "10.1007/s13760-020-01282-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-9009",
"issue": "120(2)",
"journal": "Acta neurologica Belgica",
"keywords": "Immune-related adverse event; Inflammatory myopathy; Myasthenia gravis; Necrotizing autoimmune myopathy",
"medline_ta": "Acta Neurol Belg",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009157:Myasthenia Gravis; D009205:Myocarditis; D009220:Myositis; D000077594:Nivolumab",
"nlm_unique_id": "0247035",
"other_id": null,
"pages": "355-364",
"pmc": null,
"pmid": "31993961",
"pubdate": "2020-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Myositis as a neuromuscular complication of immune checkpoint inhibitors.",
"title_normalized": "myositis as a neuromuscular complication of immune checkpoint inhibitors"
} | [
{
"companynumb": "BE-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-013890",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IPILIMUMAB"
},
"drugadd... |
{
"abstract": "BACKGROUND\nPatients with intracerebral hemorrhage taking anticoagulants are increasingly common in Japan due to the aging population. The clinical benefit of restarting anticoagulants is established, but the optimal timing of resumption is controversial. Risk factors for hemorrhagic and cardioembolic events in the acute phase are also unknown. This study investigated hemorrhagic and cardioembolic events and risk factors in intracerebral hemorrhage patients taking anticoagulants.\n\n\nMETHODS\nThe clinical data of 65 consecutive intracerebral hemorrhage patients taking anticoagulants were retrospectively reviewed. Hemorrhagic and cardioembolic complications and risk factors were analyzed.\n\n\nRESULTS\nLobar hemorrhage was the most frequent (21 of 65 cases, 32.3%). At discharge, 31 patients (47.7%) showed severe disability or had died. Eight (18.6%) of 43 patients who restarted anticoagulants after initial treatment developed hemorrhagic events, including recurrent intracerebral hemorrhage in 3. HAS-BLED score was 2-3 in these 3 patients. Six (15.8%) of 38 patients who took anticoagulants for cardiogenic factors suffered cardioembolism. Systemic inflammatory response syndrome was significantly more common in the cardioembolic group (66.7%) compared with the noncardioembolic group (21.9%, P < .05). CHA2DS2-VASc score was paradoxically high in the noncardioembolic group (3 versus 5, P < .05).\n\n\nCONCLUSIONS\nHAS-BLED score and CHA2DS2-VASc score were not useful for risk assessment for hemorrhagic events, recurrent intracerebral hemorrhage, and cardioembolism in the acute phase. Inflammatory response might be important in the occurrence of cardioembolic events.",
"affiliations": "Department of Neurosurgery, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan. Electronic address: m1620004@gunma-u.ac.jp.;Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan. Electronic address: t-arrow@f8.dion.ne.jp.;Department of Neurosurgery, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan. Electronic address: tadashige07032000@yahoo.co.jp.;Department of Neurosurgery, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan. Electronic address: ryosukeshintoku@yahoo.co.jp.;Department of Neurosurgery, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan. Electronic address: h-fujimaki@maebashi.jrc.or.jp.;Department of Neurosurgery, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan. Electronic address: k-asakura@maebashi.jrc.or.jp.",
"authors": "Osawa|Sho|S|;Shimizu|Tatsuya|T|;Kano|Tadashige|T|;Shintoku|Ryosuke|R|;Fujimaki|Hiroya|H|;Asakura|Ken|K|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2018.09.054",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "28(2)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Cardioembolic complications; Hemorrhagic complications; Intracerebral hemorrhage; anticoagulant; systemic inflammatory response syndrome",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D002543:Cerebral Hemorrhage; D000066491:Clinical Decision-Making; D003661:Decision Support Techniques; D004185:Disability Evaluation; D004334:Drug Administration Schedule; D004617:Embolism; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D007564:Japan; D008297:Male; D011237:Predictive Value of Tests; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "325-329",
"pmc": null,
"pmid": "30415920",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk Factors for Hemorrhagic and Cardioembolic Complications of Intracerebral Hemorrhage Associated with Anticoagulants.",
"title_normalized": "risk factors for hemorrhagic and cardioembolic complications of intracerebral hemorrhage associated with anticoagulants"
} | [
{
"companynumb": "JP-DSJP-DSJ-2019-104247",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CHLORPROMAZINE HYDROCHLORIDE"
},
"drugaddition... |
{
"abstract": "To investigate immune-related ophthalmic side effects of systemic checkpoint inhibitors and compare side effect frequency and requirement for cessation of immunotherapy by checkpoint target.\n\n\n\nPatients taking immune checkpoint inhibitors at a single centre from January 1, 2010 to February 29, 2020 were retrospectively reviewed for clinical characteristics, treatments and concurrent systemic adverse effects.\n\n\n\nOf 996 patients, 28 (2.8%) experienced an ophthalmic side effect that came to the attention of an eye care provider. Mean age at presentation of the side effect was 63 years (median 64, range 25-88). The checkpoint inhibitor most often preceding side effects was pembrolizumab in 12 (43%). The most common side effect was dry eye in 16 (57%), followed by uveitis in 4 (14%) patients, and singular cases of ptosis and binocular diplopia, among others. Ocular surface adverse effects occurred more frequently with programmed death ligand-1 (PD-L1) targeting therapy. There were no significant differences in the frequency of orbit/ocular adnexa and uveitis or retinal side effects based on checkpoint targets. Follow-up was available in 13 (46%) patients, with mean duration of 20 months (median 16, range 2-52 months). Of these patients, the ophthalmic side effects were controlled without discontinuing therapy in 12 (92%). Checkpoint inhibitor cessation was required in one patient with panuveitis.\n\n\n\nOphthalmic immune-related adverse events are rare but could be more common than previously estimated. PD-L1-directed checkpoint inhibitors may have a slight predilection for ocular surface adverse effects. Most ophthalmic events can be treated with targeted therapy without discontinuation of life-prolonging immunotherapy.",
"affiliations": "Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA.;Mayo Clinic School of Medicine - Scottsdale Campus, Scottsdale, Arizona, USA.;Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA dalvin.lauren@mayo.edu.",
"authors": "Fortes|Blake Hugo|BH|0000-0002-3206-0062;Liou|Harris|H|;Dalvin|Lauren A|LA|0000-0001-9710-4284",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000082082:Immune Checkpoint Inhibitors; C582435:pembrolizumab",
"country": "England",
"delete": false,
"doi": "10.1136/bjophthalmol-2020-316970",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1161",
"issue": "105(9)",
"journal": "The British journal of ophthalmology",
"keywords": "Drugs; Immunology; Pharmacology",
"medline_ta": "Br J Ophthalmol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007167:Immunotherapy; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D012189:Retrospective Studies; D012307:Risk Factors; D014481:United States; D014605:Uveitis",
"nlm_unique_id": "0421041",
"other_id": null,
"pages": "1263-1271",
"pmc": null,
"pmid": "32830124",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ophthalmic adverse effects of immune checkpoint inhibitors: the Mayo Clinic experience.",
"title_normalized": "ophthalmic adverse effects of immune checkpoint inhibitors the mayo clinic experience"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-095608",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Pneumocystis jirovecii (P. jirovecii) pneumonia (PJP) is an opportunistic fungal infection after renal transplantation, which is always severe, difficult to diagnose, combined with multiple complications and have poor prognosis. We retrospectively analyzed clinical data, including risk factors, diagnosis, treatment and complications of seven clinical cases suffered with severe PJP after renal transplantation in our department in 2019. All the seven recipients were routinely prescribed with PJP prophylaxis after renal transplantation, and six of them suffered acute graft rejection before the infection. P. jirovecii sequence was identified in blood or broncho-alveolar lavage fluid (BALF) by the metagenomic next-generation sequencing (mNGS) in all patients. All the patients were improved with the therapy trimethoprim-sulfamethoxazole (TMP-SMX) combined with caspofungin for the PJP treatment, but suffered with complications including renal insufficiency, leukopenia, thrombocytopenia, gastrointestinal bleeding, mediastinalemphysema, pulmonary hemorrhage, and hemophagocytic syndrome and other severe infections. Taken together, mNGS is a powerful tool that could be used to diagnose PJP in renal transplantation recipients. And PJP prophylaxis should be prescribed during and after treatment for acute rejection. TMP-SMX is the first-line and effective drug for PJP treatment, but the complications are always life-threatening and lead to poor prognosis. We should pay attention to these life-threatening complications.",
"affiliations": "Department of General Intensive Care Unit, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.;Department of General Intensive Care Unit, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.;Department of General Intensive Care Unit, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.;Department of General Intensive Care Unit, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.;Department of General Intensive Care Unit, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.;Department of General Intensive Care Unit, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.;Department of General Intensive Care Unit, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.;Department of Kidney Transplantation, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.;Department of General Intensive Care Unit, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.",
"authors": "Xie|Dan|D|;Xu|Wen|W|;You|Jingya|J|;Yuan|Xiaofeng|X|;Li|Mingliang|M|;Bi|Xiaogang|X|;Zhang|Kouxing|K|;Li|Heng|H|;Xian|Ying|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/21655979.2021.1911203",
"fulltext": "\n==== Front\nBioengineered\nBioengineered\nBioengineered\n2165-5979\n2165-5987\nTaylor & Francis\n\n33896387\n10.1080/21655979.2021.1911203\n1911203\nVersion of Record\nResearch Article\nResearch Paper\nClinical descriptive analysis of severe Pneumocystis jirovecii pneumonia in renal transplantation recipients\nD. XIE ET AL.\nBIOENGINEERED\nXie Dan a #\nXu Wen a #\nYou Jingya a\nYuan Xiaofeng a\nLi Mingliang a\nBi Xiaogang a\nZhang Kouxing a\nLi Heng b\nXian Ying a\na Department of General Intensive Care Unit, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University , Guangzhou, People’s Republic of China\nb Department of Kidney Transplantation, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University , Guangzhou, People’s Republic of China\nCONTACT Heng Li liheng23@mail.sysu.edu.cn Department of kidney transplantation, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, 2693 Kaichuang Road , Guangzhou, 510530, People’s Republic of China\nHeng Li, Ying Xian xianxian820825@163.com Department of General Intensive Care Unit, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, 2693 Kaichuang Road , Guangzhou, 510530, People’s Republic of China\n# Authors contributed to this article equally.\n\n25 4 2021\n2021\n25 4 2021\n12 1 12641272\nIntegra20 12 2021\nIntegra20 12 2021\n08 2 2021\n26 3 2021\n27 3 2021\n© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.\n2021\nThe Author(s)\nhttps://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nABSTRACT\n\nPneumocystis jirovecii (P. jirovecii) pneumonia (PJP) is an opportunistic fungal infection after renal transplantation, which is always severe, difficult to diagnose, combined with multiple complications and have poor prognosis. We retrospectively analyzed clinical data, including risk factors, diagnosis, treatment and complications of seven clinical cases suffered with severe PJP after renal transplantation in our department in 2019. All the seven recipients were routinely prescribed with PJP prophylaxis after renal transplantation, and six of them suffered acute graft rejection before the infection. P. jirovecii sequence was identified in blood or broncho-alveolar lavage fluid (BALF) by the metagenomic next-generation sequencing (mNGS) in all patients. All the patients were improved with the therapy trimethoprim-sulfamethoxazole (TMP-SMX) combined with caspofungin for the PJP treatment, but suffered with complications including renal insufficiency, leukopenia, thrombocytopenia, gastrointestinal bleeding, mediastinalemphysema, pulmonary hemorrhage, and hemophagocytic syndrome and other severe infections. Taken together, mNGS is a powerful tool that could be used to diagnose PJP in renal transplantation recipients. And PJP prophylaxis should be prescribed during and after treatment for acute rejection. TMP-SMX is the first-line and effective drug for PJP treatment, but the complications are always life-threatening and lead to poor prognosis. We should pay attention to these life-threatening complications.\n\nKEYWORDS\n\nMetagenomic next-generation sequencing (mNGS)\npneumocystis jirovecii pneumonia (pjp)\nrenal transplantation\nopportunistic fungal infection\ntrimethoprim-sulfamethoxazole (tmp-smx)\n==== Body\npmcBackground\n\nAllogeneic renal transplantation (RT) is recognized as the optimal treatment for end-stage renal disease. Pneumocystis jirovecii (P. jirovecii) pneumonia (PJP) is a fatal opportunistic fungal infection after renal transplantation, even with routinely PJP prophylaxis [1,2]. It was associated with high rates of intubation and mortality in RT recipients, which is always severe, difficult to diagnose, combined with multiple complications and have poor prognosis [3,4]. PJP outbreaks have been reported in many countries, such as British [5], North American [6], France [7]. The clinical presentation generally includes fever, dyspnea with hypoxemia, and nonproductive cough. The diagnosis of PJP is based on direct immunofluorescent staining and quantitative nucleic acid amplification of respiratory specimens. At present, trimethoprim–sulfamethoxazole (TMP-SMX) is the first-line agent and drug of choice for therapy of the PJP [8]. However, the positive rate of immunofluorescent staining in the sputum or bronchoalveolar lavage fluid (BALF) is low, and the quantitative nucleic acid amplification of P. jirovecii is not available, resulting in poor therapeutic effect. Therefore, with the limitations of conventional diagnostic approaches, non-targeted metagenomic next generation sequencing (mNGS) has been increasingly applied to diagnosis of infectious diseases [9]. And mNGS can be directly executed on clinical specimens [9].\n\nmNGS allows identification and genomic characterization of bacteria, fungi, parasites and viruses without directly obtaining prior knowledge of specific pathogens from clinical specimens [10]. Wilson et al. [11] used mNGS from 7 meningitis patients to identify parasites, viruses and fungi. In addition, Wang et al. [12] found that the sensitivity of mNGS to diagnose mixed lung infections was significantly higher than that of conventional tests. Even Chen et al. [13] collected BALF from a patient with acute pneumonia after kidney transplantation, and found a large number of P. jirovecii reads using mNGS diagnosis, but no P. jirovecii was found after stained sputum and BALF smears. Confirm the diagnostic value of mNGS for PCP. However, there are still few reports on the use of mNGS after the occurrence of PJP after kidney transplantation.\n\nTherefore, we collected BALF from renal transplant recipients and used mNGS to identify the P. jirovecii. And we retrospectively descriptive analyzed the clinical data of the seven renal transplant recipients who developed PJP after routinely PJP prophylaxis post-transplantation.\n\nMaterials and Methods\n\nPatients\n\nWe retrospectively descriptive analyzed clinical data of seven patients treated for severe PJP in the renal transplant recipients, who transferred to our department from department of kidney transplantation in 2019. The data of demographics, renal transplantation operation time, induction and maintenance of immunosuppressive agents, PJP prophylaxis and cytomegalovirus (CMV) prophylaxis, acute rejection events, anti-rejection therapy, and the blood concentrations of calcineurin inhibitor (CNI) immunosuppressant were collected.\n\nClinical measurements\n\nThe blood routine examination, function of liver and kidney, plasma (1,3)-β- D-glucan test (BDG), plasma loads of CMV-DNA, and the bacterial and fungal cultures of blood, urine, sputum and BALF, chest computed tomography (CT) scan were retrospectively analyzed.\n\nBALF samples were harvested when the patient received mechanical ventilation for the immunofluorescent staining and mNGS detection. The diagnostic test of choice is generally the induced sputum or BALF examination with direct immunofluorescent staining for P. jirovecii.\n\nmNGS and analysis\n\nThe mNGS was performed by Visionmedicals.com (Guangzhou, China). The procedure for BALF samples includes nucleic acid extraction, library construction, sequencing, and information analysis as previously described [14].\n\nTreatment\n\nAnti-thymocyte globulin (ATG) or anti-human T lymphocyte porcine Immunoglobulin (ALG) or basiliximab was given as induction immunosuppressant. All patients received oral maintenance immunosuppressant after RT, including tacrolimus (Tac) or cyclosporine A (CsA), mycophenolic acid (MFA) and prednisone (Pred).\n\nPJP prophylaxis post-transplantation was routinely prescribed with TMP-SMX (twice a week, once a day, two tablets (160/800 mg) each time, each tablet contains 80 mg trimethoprim and 0.4 g sulfamethoxazole) for 3 months, and CMV prophylaxis post-transplantation was routinely prescribed with ganciclovir (one tablet (0.45 g) a day) for 2 months.\n\nThe clinical symptoms, therapeutic regimen for PJP, oxygen therapy, the complications and the outcomes were also analyzed.\n\nResults\n\nBaseline characteristics\n\nAll seven patients received renal transplantation in end-stage renal disease from donation after Cardiac Death. There were two females and five males. The age ranged from 35 to 60 years. All patients were HIV negative. Before the occurrence of PJP infection, six patients suffered acute graft rejection, with the anti-acute rejection treatment of ATG or ALG or methylprednisolone for 3 or 5 days (Table 1). The blood concentrations of maintenance immunosuppressant (Tac, CsA) used in all patients before infection was within the normal reference range at the latest outpatient visit.Table 1. The date of operation, admission and transfer to ICU; the therapy of anti-acute injection and the dosage of TMP-SMX; improvement of the PaO2/FiO2\n\nNo\tGender\tInduction\tMaintenance\tAcute rejection therapy\tOxygen therapy\tTMP-SMX\tPaO2/FiO2\t\nPatient 1\tfemale\tALG\tTac+MPA+Pre\tATG\n50 mg×3d\tMV\t240/1200 mg qid\timproved\t\nPatient 2\tmale\tATG\tTac+MPA+Pre\tATG\n50 mg×2d;\nALG\n0.5 g × 3d\tMV\t320/1600 mg qid\timproved\t\nPatient 3\tfemale\tBasiliximab\tTac+MPA+Pre\tATG\n25 mg×3d;\nATG\n25 mg×5d\tMV\t160/800 mg qid\timproved\t\nPatient 4\tmale\tATG\tCsA+MPA+Pre\tATG\n50 mg×3d;\nATG\n25 mg×5d\tHFNC\t160/800 mg qid\timproved\t\nPatient 5\tmale\tALG\tTac+MPA+Pre\tMP\n0.5 g × 3d\tMV\t240/1200 mg qid\timproved\t\nPatient 6\tmale\tATG\tTac+MPA+Pre\t \tMV\t240/1200 mg qid\timproved\t\nPatient 7\tmale\tATG\tTac+MPA+Pre\tALG\n0.5 g qd×5d;\nMP\n0.5 g × 3d;\n0.25 g × 2d;\tMV\t240/1200 mg qid\timproved\t\nALG: Anti-human T lymphocyte porcine immunoglobulin; ATG: anti-thymocyte globulin; TaC: tacrolimus; MPA: mycophenolic acid; Pre: prednisone; TMP-SMX: trimethoprim–sulfamethoxazole, MP: methylprednisolone; MV, mechanical ventilation; HFNC, high-flow nasal cannula.\n\nOccurrence of PJP\n\nAcute rejection occurred within 1 to 6 months after surgery. Two of them occurred acute rejection within 1 month after surgery. Three of them suffered one episode rejection and the other three had two episodes of acute rejection before PJP infection. Five patients developed infection within one month after latest rejection; the other one patient developed infection within six months after acute rejection. All the seven patients developed PJP infection within 4 to 8 months after kidney transplantation. The detailed information is summarized in Table 1. These patients were admitted with fever, cough, or elevated creatinine. The chest CT scan taken before being transferred to our department showed the presence of diffuse, bilateral interstitial infiltrates (ground-glass opacity) in both lungs (Figure 1a). Based on clinical manifestations and imaging characteristics, PJP is suspected clinically.Figure 1. (a) Chest CT of the patient revealed bilateral ground-glass opacity before transferred to our department. (b) Chest CT of the patient revealed bilateral ground-glass opacity absorbed after treatment\n\nDiagnosis and treatment of PJP\n\nAll patients were transferred to our department for short of breath with hypoxemia. Since patients were transferred to our department, they were treated with oral TMP-SMX (160/800 mg to 320/1600 mg, qid) combined with intravenous carpofungin (loading dosage 70 mg on the first day, 50 mg per day from second day). Meanwhile, all oral immunosuppressive drugs were discontinued. And all patients met criteria of respiratory failure [PaO2 less than 70 mmHg or (A-a) DO2 more than 35 mmHg], methylprednisolone (MP) (40 mg, every 12 hours) was given. The Immunofluorescent staining of P. jirovecii in sputum or BALF of all patients was negative. The BDG was positive in only two patents. P. jirovecii genome (GCF_001477535.1) was detected in all the seven patients (Figure 2 and Table 2).Table 2. The NGS sequences of PJP and CMV in blood and BALF, the complication and other infections of the seven patients\n\nNo\tPJP-BALF\tPJP-Blood\tCMV-BALF\tCMV-Blood\tBDG (pg/ml)\n(reference range 0–10)\tHeart\nfailure\tCRRT\tComplications\tOther infections\t\n1\t1954\t76\t21\t84\t<3.826\t \tyes\tHLH\t \t\n2\t83\tNeg\tNeg\tNeg\t14.798\tyes\tyes\tCerebral infarction\tLung: PDRAB, klebsiella pneumoniae, Candida glabrata\nUTI: PDRAB\t\n3\t1067\tNeg\t2\tNeg\t5.888\t \t \tPulmonary hemorrhage\tLung: aspergillus, Candida glabrata, Candida subglabrata\nUTI: Candida subglabrata\t\n4\tNot detected\t3\tNot detected\t4\t<3.826\tyes\t \tLeukopenia\t \t\n5\t5243\t74\t198\t59\t<3.826\t \tyes\tPneumomediastinu\nsubcutaneous emphysema;\nGastrointestinal bleeding;\nLeukopenia;\nThrombocytopenia\t \t\n6\t5177\tNeg\tNeg\tNeg\t17.782\t \t \tLeukopenia;\nThrombocytopenia;\nIncreasing ALT;\nBilirubinemia\tLung: proteus mirabilis\t\n7\t2311\t24\tNeg\tNeg\t<3.826\t \tyes\tPneumomediastinu\nsubcutaneous emphysema;\nGastrointestinal bleeding;\nLeukopenia;\nThrombocytopenia\tBacterial pneumonia\t\nHLH: Hemophagocytic lymphohistiocytosis; UTI: Urinary tract infection; ALT: Alanine aminotransferase; PDRAB: Pan-drug resistance Acinetobacter baumannii.\n\nFigure 2. Pneumocystis jirovecii genome coverage map of Patient 6\n\nPatient 4 received high-flow nasal cannula (HFNC) oxygen therapy, and only mNGS of blood was performed in this patient and P. jirovecii sequence was detected in the blood. The other six patients were received mechanical ventilation (MV), mNGS both of BALF and blood were performed by mNGS. Among them, P. jirovecii sequence was detected in all the six patients in BALF, but P. jirovecii sequence was detected in blood only three patients (Table 2).\n\nIn terms of co-infection, the PCR method was used to evaluate the plasma loads of CMV-DNA, and a cutoff value of ≥500 copies/ml was considered positive for CMV infection. The copy number of CMV-DNA in all patients was less than 500 copies/ml. Three of the patients did not detect any sequence of CMV both in BALF and blood, and the other four patients only detected few sequences by mNGS (Table 2).\n\nOutcome and complications of PJP\n\nWith the therapy TMP-SMX combined with caspofungin and MF for the PJP treatment, all patients improved their symptoms. And the oxygenation index (PaO2/FiO2) was improved and infiltrations were absorbed (Figure 1b and Table 1). Except patient 4 who received HFNC therapy, the other six patients were treated with MV. Endotracheal tube was successfully removed in five of them (except patient 5 who had not met the standard of weaning from the ventilator), but four of the five patients who successfully removed endotracheal tube received MV again for the complications (patients 1, 2, 3 and 7). Patients 1, 2 and 3 had been transferred back to department of kidney transplantation for a time.\n\nCreatinine levels were elevated in all patients. Acute heart failure occurred in two cases, and four cases received continuous renal replacement therapy (CRRT) (Table 2). Four patients developed bone marrow suppression-leukopenia or thrombocytopenia. After platelet transfusion and drug therapy, they could return to normal without reducing the dosage of TMP-SMX. Patient 6 developed bilirubinemia and elevated alanine aminotransferase. As the dose of TMP-SMX decreased, he gradually returned to normal. Patient 1 developed hemophagocytic lymphohistiocytosis (HLH), patient 2 suffered a cerebral infarction, and patient 3 developed pulmonary hemorrhage with aspergillus pneumonia (Figure 3a and Table 2). Both patients 5 and 7 developed pneumomediastinum, subcutaneous emphysema, and gastrointestinal bleeding (Figure 3b-D and Table 2). Patient 5 received an emergency cervical skin incision by thoracic surgeon for pneumomediastinum and subcutaneous emphysema, but patient 7 received conservative treatment. In patient 5, gastrointestinal bleeding was not cured with proton pump inhibitor, octreotide and transfusion of red blood cells. Patient 7 suffered hypercalcemia with peak level of 3.41 mmol/L and high plasma parathyroid hormone (PTH) with level of 830.78 pg/ml, he received CRRT to treat hypercalcemia, and a neck computed tomography (CT) scan showed one enhancing nodule (10 mm in diameter) in the rear of the right lobe of his thyroid gland.Figure 3. (a) Chest CT scan revealed bilateral diffuse infiltration indicated pulmonary hemorrhage of Patient 3; (b) chest plain radiograph showed pneumomediastinum and subcutaneous emphysema of Patient 5 (red arrow). (c) and (d) Chest CT scan showed pneumomediastinum, subcutaneous emphysema (red arrow) and parenchymal tears of Patient 7 (yellow arrow)\n\nAnd four of them developed other fungal or bacterial infection (Table 2): Patient 2 suffered pneumonia and urinary tract infection (UTI) with pan-drug resistant Acinetobacter baumannii (PDRAB), and other pneumonia with candida glabrata and klebsiella pneumoniae; Patient 3 other fungal infections of the lung with aspergillus, candida glabrata and candida subglabrata, and UTI with candida subglabrata; Patient 6 suffered proteus mirabilis pneumonia; and Patient 7 developed high fever, right lower pneumonia revealed by chest radiograph, he was treated with colistin and TMP-SMX in other hospitals and successfully removed endotracheal tube; at present, he is still being followed up in the outpatient of kidney transplantation department in our hospital.\n\nPatients 4 and 6 were cured and discharged from department of kidney transplantation. The other five patients were discharged from our department for the severe complitations and the economic reasons.\n\nDiscussion\n\nPJP is one of the most common fatal opportunistic pulmonary diseases in renal transplant recipients [15]. The main clinical manifestations were fever, cough, dyspnea, hypoxemia and other nonspecific symptoms. The clinical diagnosis was mainly based on the history, clinical manifestations and chest CT imaging. Microbiology is still the gold standard for diagnosis for PJP, which was based on consensus guidelines, requiring a positive direct immunofluorescence staining on induced sputum or BALF and/or a positive polymerase chain reaction (PCR) assay on a BALF specimen [16]. The positive rate of direct immunofluorescent staining for P. jirovecii in sputum or BAL was low. In this study, seven patients were clinically suspected as PJP, they all had dyspnea, hypoxemia and the chest radiograph showed a diffuse interstitial infiltration. But the immunofluorescence staining on sputum or BALF was all negative. Plasma BDG was the most reliable biomarker for serologic diagnosis of PJP. When cutoff value was 100 pg/mL, sensitivity and specificity of the BDG test for PJP were 89.9% and 71.0%, respectively [17]. Despite being a structural molecule of the P. jirovecii cell wall, BDG is not a species-specific marker, instead presenting a panfungal character. In this paper, only 2 of seven were positive, and the value was below 100 pg/ml. The mNGS is a powerful tool for the detection and identification of pathogens directly from the specimen [18]. And P. jirovecii sequence was detected in all the seven patients. For six of them, both BALF and blood were performed by mNGS, P. jirovecii sequence was detected in all the six patients in BALF, but only in three patients P. jirovecii sequence was detected in blood. The BALF was firstly recommended to detect for the P. jirovecii by mNGS.\n\nCMV infection, allograft rejection, immunosuppressant agents, and a low lymphocyte count have been proposed as risk factors for PJP in kidney transplant recipients (KTRs) after post transplantation prophylaxis [19–21]. Acute rejection and CMV infection were significantly associated with PJP development in KTRs after 6 months of trimethoprim–sulfamethoxazole (TMP-SMX) prophylaxis, two-thirds of patients with PJP presented with a history of rejection or CMV infection, the median time interval between rejection or CMV infection and PJP onset was 6 and 9 months, respectively, it suggests that at least 6 to 9-month chemoprophylaxis may be required for PJP prevention in KTRs with rejection or CMV infection [22]. CMV infection and allograft rejection are independent predictors of PJP, targeted prophylaxis in recipients with CMV infection or allograft rejection may reduce the risk of PJP [23]. The Kidney Disease Improving Global Outcome (KDIGO) and Renal Association (RA)/British Transplantation Society (BTS) clinical practice guidelines (CPGs) were strongly recommended [24]. KDIGO recommends all KTRs receive PJP prophylaxis with TMP-SMX 480 mg daily or 960 mg three times weekly for 3–6 months after transplantation. All KTRs receive PJP prophylaxis with daily TMP-SMX for at least 6 weeks during and after treatment for acute rejection [25]. RA/BTS recommends all patients should receive 3–6 months of treatment with TMP-SMX 480 mg daily for PJP following renal transplantation [26]. The American Society of Transplantation recommends anti-Pneumocystis prophylaxis for all SOT recipients at least 6 − 12 months post-transplant (TMP-SMX: 480 mg daily or 960 mg three times weekly). For patients with a history of prior PJP infection or chronic CMV disease, lifelong prophylaxis may be indicated [27]. Unfortunately, in this paper, considering the renal damage caused by TMP-SMX, PJP prophylaxis was only routinely prescribed for 3 months after RT and PJP prophylaxis was not routinely prescribed after acute rejection. In this series, all patients’ copies of CMV-DNA were less than 500 copies per ml, three of them did not detect the CMV sequence both in BALF and blood by mNGS, and the other four patients only detected few CMV sequences. Acute rejection is more likely to develop PJP compared with CMV infection.\n\nKTRs with PJP recommended to be treated with high-dose intravenous TMP-SMX, corticosteroids, and a reduction in immunosuppressive medication. Treatment with corticosteroids for KTRs with moderate to severe PJP (as defined by PaO2 < 70 mmHg in room air or an alveolar gradient of>35 mm Hg) was recommended [25]. According to the guideline, since the PJP was suspected, immunosuppressive medication was discontinued, and methylprednisolone was given. Oral or nasal feeding of TMP-SMX was prescribed. Caspofungin was also prescribed for combination treatment [28]. The combination therapy with caspofungin, an antifungal agent that acts on the cyst form of p. jirovecii by inhibiting (1, 3) Beta-D-Glucan synthesis, was presented in experimental mouse models [29]. Jin F et al. found high initial plasma BDG concentration may be a predictor of satisfactory caspofungin response to HIV-negative patients with PJP, the choice of combination therapy with caspofungin and TMP/SMX as initial treatment when BDG≥800 pg/ml in moderate to severe HIV negative patients with PJP [30].\n\nWith the combination treatment of TMP-SMX, caspofungin and methylprednisolone, all seven patients’ oxygenation and chest radiographs improved. But some of them had severe and fatal complications that led to a poor prognosis. Patient 1 had hemophagocytic lymphohistiocytosis (HLH). Patient 2 had multi-resistant acinetobacter baumannii in the lung and urinary tract system. Patient 3 had fungal infection in lung and urinary tract system, especially aspergillus pneumoniae infection, which led to pulmonary hemorrhage. Patients 5 and 7 had gastrointestinal bleeding, which may be related to the long-term use of methylprednisolone. In patient 5, he had hypercalcemia. Hypercalcemia develops frequently after renal transplantation and is commonly associated with preexisting secondary hyperparathyroidism. Hypercalcemia in conjunction with PJP is being increasingly reported in renal transplant patients. In all the cases, respiratory symptoms were prominent, hypercalcemia was of mild-to-moderate severity, parathyroid hormone concentration was decreased, and 1,25(OH)(2) D levels were extraordinarily or inappropriately high [31]. But in this patient, the parathyroid hormone was not decreased, but very high, and the neck CT revealed an enhanced parathyroid gland. The hypercalcemia was caused by primary hyperparathyroidism. The gastrointestinal bleeding in patient 7 was not only considering the reason for the use of methylprednisolone, but also should pay attention to the primary hyperparathyroidism [32]. Patients 5 and 7 had spontaneous pneumomediastinum and subcutaneous emphysema. Spontaneous pneumomediastinum with subcutaneous emphysema in PJP is rare [33–35]. In this paper, the chest CT scan of patient 7 showed parenchymal tears which was along the pulmonary veins; this fully confirmed to the mechanism of spontaneous pneumomediastinum.\n\nConclusion\n\nIn conclusion, we use mNGS to diagnose PJP in KTRs. PJP prophylaxis should be prescribed during and after treatment for acute rejection. TMP-SMX is the first-line and effective drug for PJP treatment, but the complications of PJP are always life-threatening and lead to poor prognosis. We should pay attention to these life-threatening complications.\n\nHighlight\n\nP. jirovecii sequence were identified in BALF by the mNGS in renal transplantation recipients.\n\nTMP-SMX combined with caspofungin can improve the infection symptoms of PJP in renal transplantation recipients.\n\nPJP can lead to other complications.\n\nConflict of interest\n\nThe authors declare that they have no conflict of interest.\n\nDisclosure statement\n\nNo potential conflict of interest was reported by the authors.\n==== Refs\nReferences\n\n[1] Yazaki H, Goto N, Uchida K, et al. Outbreak of Pneumocystis jiroveci pneumonia in renal transplant recipients: p. jiroveci is contagious to the susceptible host. Transplantation. 2009;88 (3 ):380–385.19667941\n[2] Gianella S, Haeberli L, Joos B, et al. Molecular evidence of interhuman transmission in an outbreak of Pneumocystis jirovecii pneumonia among renal transplant recipients. Transpl Infect Dis. 2010;12 (1 ):1–10. .19744285\n[3] Iriart X, Challan Belval T, Fillaux J, et al. Risk factors of pneumocystis pneumonia in solid organ recipients in the era of the common use of posttransplantation prophylaxis. Am J Transplant. 2015;15 (1 ):190–199. .25496195\n[4] Goto N, Oka S. Pneumocystis jirovecii pneumonia in kidney transplantation. Transpl Infect Dis. 2011;13 (6 ):551–558.22093172\n[5] Thomas S, Turtle L, Imran M, et al. Outbreak of Pneumocystis Jirovecii Pneumonia in a British Renal Transplant Centre: evidence for human to human transmission, or an environmental source of infection: category: lesson in microbiology & infection control. Journal of Infection. 2011;63 :e25–e26.\n[6] Mulpuru S, Knoll G, Weir C, et al. Pneumocystis pneumonia outbreak among renal transplant recipients at a North American transplant center: risk factors and implications for infection control. Am J Infect Control. 2016;44 (4 ):425–431.26804301\n[7] Le Gal S, Toubas D, Totet A, et al. Pneumocystis infection outbreaks in organ transplantation units in France: a nation-wide survey. Clin Infect Dis. 2020;70 (10 ):2216–2220.31633150\n[8] Fishman JA. Pneumocystis jiroveci. Semin Respir Crit Care Med. 2020;41 (1 ):141–157.32000290\n[9] Gu W, Miller S, Chiu CY. Clinical metagenomic next-generation sequencing for pathogen detection. Annu Rev Pathol. 2019;14 (1 ):319–338.30355154\n[10] Simner PJ, Miller S, Carroll KC. Understanding the promises and hurdles of metagenomic next-generation sequencing as a diagnostic tool for infectious diseases. Clin Infect Dis. 2018;66 (5 ):778–788.29040428\n[11] Wilson MR, O’Donovan BD, Gelfand JM, et al. Chronic meningitis investigated via metagenomic next-generation sequencing. JAMA Neurol. 2018;75 (8 ):947–955.29710329\n[12] Wang J, Han Y, Feng J. Metagenomic next-generation sequencing for mixed pulmonary infection diagnosis. BMC Pulm Med. 2019;19 (1 ):252.31856779\n[13] Chen J, He T, Li X, et al. Metagenomic next-generation sequencing in diagnosis of a case of pneumocystis jirovecii pneumonia in a kidney transplant recipient and literature review. Infect Drug Resist. 2020;13 :2829–2836.32884306\n[14] Miao Q, Ma Y, Wang Q, et al. Microbiological diagnostic performance of metagenomic next-generation sequencing when applied to clinical practice. Clin Infect Dis. 2018;67 (suppl_2 ):S231–s240.30423048\n[15] Kim JE, Han A, Lee H, et al. Impact of Pneumocystis jirovecii pneumonia on kidney transplant outcome. BMC Nephrol. 2019;20 :212.31182046\n[16] Alanio A, Hauser PM, Lagrou K, et al. ECIL guidelines for the diagnosis of Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother. 2016;71 (9 ):2386–2396.27550991\n[17] Esteves F, Calé SS, Badura R, et al. Diagnosis of Pneumocystis pneumonia: evaluation of four serologic biomarkers. Clin Microbiol Infect. 2015;21 (4 ):379.e1-10.\n[18] Camargo JF, Ahmed AA, Lindner MS, et al. Next-generation sequencing of microbial cell-free DNA for rapid noninvasive diagnosis of infectious diseases in immunocompromised hosts. F1000Res. 2019;8 :1194.31814964\n[19] Radisic M, Lattes R, Chapman JF, et al. Risk factors for Pneumocystis carinii pneumonia in kidney transplant recipients: a case-control study. Transpl Infect Dis. 2003;5 (2 ):84–93.12974789\n[20] Garg N, Jorgenson M, Descourouez J, et al. Pneumocystis jiroveci pneumonia in kidney and simultaneous pancreas kidney transplant recipients in the present era of routine post-transplant prophylaxis: risk factors and outcomes. BMC Nephrol. 2018;19 (1 ):332.30463516\n[21] Faure E, Lionet A, Kipnis E, et al. Risk factors for Pneumocystis pneumonia after the first 6 months following renal transplantation. Transpl Infect Dis. 2017;19 (5 ):19.\n[22] Park SY, Jung JH, Kwon H, et al. Epidemiology and risk factors associated with Pneumocystis jirovecii pneumonia in kidney transplant recipients after 6-month trimethoprim-sulfamethoxazole prophylaxis: a case-control study. Transpl Infect Dis. 2020;22 (2 ):e13245.31943590\n[23] Hosseini-Moghaddam SM, Shokoohi M, Singh G, et al. A multicenter case-control study of the effect of acute rejection and cytomegalovirus infection on pneumocystis pneumonia in solid organ transplant recipients. Clin Infect Dis. 2019;68 (8 ):1320–1326.30107568\n[24] Yu Y, Yang H, Yu X, et al. Critical appraisal of the quality and content of clinical practice guidelines for pneumocystis jiroveci pneumonia (PJP) prophylaxis using the AGREE II instrument. J Clin Pharm Ther. 2020;45 (6 ):1325–1333.32710453\n[25] Kasiske BL, Zeier MG, Chapman JR, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int. 2010;77 (4 ):299–311.19847156\n[26] Baker RJ, Mark PB, Patel RK, et al. Renal association clinical practice guideline in post-operative care in the kidney transplant recipient. BMC Nephrol. 2017;18 (1 ):174.28571571\n[27] Martin SI, Fishman JA. Pneumocystis pneumonia in solid organ transplantation. Am J Transplant. 2013;13 (Suppl 4 ):272–279.23465020\n[28] Tu GW, Ju MJ, Xu M, et al. Combination of caspofungin and low-dose trimethoprim/sulfamethoxazole for the treatment of severe Pneumocystis jirovecii pneumonia in renal transplant recipients. Nephrology (Carlton). 2013;18 (11 ):736–742.24571744\n[29] Lobo ML, Esteves F, De Sousa B, et al. Therapeutic potential of caspofungin combined with trimethoprim-sulfamethoxazole for pneumocystis pneumonia: a pilot study in mice. PLoS One. 2013;8 (8 ):e70619.23940606\n[30] Jin F, Liu XH, Chen WC, et al. High initial (1, 3) Beta-d-Glucan concentration may be a predictor of satisfactory response of c aspofungin combined with TMP/SMZ for HIV-negative patients with moderate to severe Pneumocystis jirovecii pneumonia. Int J Infect Dis. 2019;88 :141–148.31442630\n[31] Chatzikyrkou C, Clajus C, Haubitz M, et al. Hypercalcemia and pneumocystis Pneumonia after kidney transplantation: report of an exceptional case and literature review. Transpl Infect Dis. 2011; 13 :496–500.21414118\n[32] Xie D, Hu K, Xian Y, et al. A life-threatening duodenal ulcer hemorrhage due to previously unknown primary hyperparathyroidism. Gastroenterol Rep (Oxf). 2018;6 (3 ):231–233.27616071\n[33] Ali HS, Hassan IF, George S Extra corporeal membrane oxygenation to facilitate lung protective ventilation and prevent ventilator-induced lung injury in severe Pneumocystis pneumonia with pneumomediastinum: a case report and short literature review. BMC Pulm Med. 2016; 16 :52.27080997\n[34] Cheng WL, Ko WC, Lee NY, et al. Pneumomediastinum in patients with AIDS: a case report and literature review. Int J Infect Dis. 2014; 22 :31–34.24589680\n[35] Cho JY, Kim DM, Kwon YE, et al. Newly formed cystic lesions for the development of pneumomediastinum in Pneumocystis jirovecii pneumonia. BMC Infect Dis. 2009;9 (1 ):171.19835635\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2165-5979",
"issue": "12(1)",
"journal": "Bioengineered",
"keywords": "Metagenomic next-generation sequencing (mNGS); opportunistic fungal infection; pneumocystis jirovecii pneumonia (pjp); renal transplantation; trimethoprim-sulfamethoxazole (tmp-smx)",
"medline_ta": "Bioengineered",
"mesh_terms": "D000328:Adult; D000368:Aged; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101581063",
"other_id": null,
"pages": "1264-1272",
"pmc": null,
"pmid": "33896387",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical descriptive analysis of severe Pneumocystis jirovecii pneumonia in renal transplantation recipients.",
"title_normalized": "clinical descriptive analysis of severe pneumocystis jirovecii pneumonia in renal transplantation recipients"
} | [
{
"companynumb": "CN-SA-2021SA161774",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "1",
... |
{
"abstract": "N-Acetylcysteine (NAC) dosing for acetaminophen (APAP) overdose is weight based (150 mg/kg intravenous or 140-mg/kg oral loading dose) and, in the United States, the dosing protocol recommends using a maximum patient weight of 100 and 110 kg, respectively. Little clinical data describe the use of NAC for APAP poisoning in patients weighing >100 kg. The aim of this study was to describe the demographics, outcomes, and adverse event (AE) rates of patients weighing >100 kg treated with oral or IV NAC for APAP poisoning. Patients were identified from a multicenter retrospective NAC safety study for APAP overdose. We included patients with a recorded weight. Trained chart abstractors used a standardized form. Selected data included age, gender, weight, serum alanine transaminase, and aspartate transaminases, coingestants, NAC administration route, ingestion type, AEs, and outcome [hepatotoxicity (alanine transaminase > 1000 U/L), liver transplant, or death]. Descriptive statistics were used. Of 503 study patients, 37 (7.4%) had recorded weights >100 kg. The median (range) weight was 110 kg (101-160). The median (range) dosing for patients treated with oral NAC was 140 mg/kg (127-143 mg/kg) and 150 (108-168) mg/kg for IV NAC. Hepatotoxicity occurred in 12/36 (33.3%) patients. Death occurred in 4/36 (11.1%) patients. Thirteen NAC-related AEs occurred in 8 patients (1.6 per person). All AEs were related to NAC and were rated nonserious by the reviewer. Clinicians use an actual weight-based NAC dose rather than a maximum weight cutoff dose. Hepatotoxicity was common in our cohort. AEs were relatively common but not serious.",
"affiliations": "1Department of Emergency Medicine, Wilford Hall Medical Center, Lackland AFB, TX 2Rocky Mountain Poison and Drug Center, Denver Health and Hospital Authority, Denver, CO 3Department of Emergency Medicine, University of Colorado Denver School of Medicine, Aurora, CO.",
"authors": "Varney|Shawn M|SM|;Buchanan|Jennie A|JA|;Kokko|Jamie|J|;Heard|Kennon|K|",
"chemical_list": "D000931:Antidotes; D000082:Acetaminophen; D000111:Acetylcysteine",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0b013e3182459c40",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "21(3)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D000931:Antidotes; D001835:Body Weight; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "159-63",
"pmc": null,
"pmid": "23011167",
"pubdate": "2014",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Acetylcysteine for acetaminophen overdose in patients who weigh >100 kg.",
"title_normalized": "acetylcysteine for acetaminophen overdose in patients who weigh 100 kg"
} | [
{
"companynumb": "CA-JNJFOC-20160110296",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Abiraterone is an oral inhibitor of cytochrome P450 (17alpha)-hydroxylase/17,20 lyase (CYP17) complex critical to androgen production. Abiraterone in combination with prednisone is currently FDA approved for use in men with metastatic castration-resistant prostate cancer, both in the pre- and post-chemotherapy settings. This article discusses the treatment with abiraterone in a patient with metastatic castration-resistant prostate cancer on hemodialysis.",
"affiliations": "Department of Medical Oncology, Hitit University Education and Research Hospital, Çorum, Turkey.;Department of Medical Oncology, School of Medicine, Necmettin Erbakan University, Konya, Turkey.",
"authors": "Karakurt Eryılmaz|Melek|M|https://orcid.org/0000-0003-2597-5931;Karaağaç|Mustafa|M|",
"chemical_list": "D000736:Androstenes; C089740:abiraterone; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1177/1078155218818250",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(8)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Abiraterone; hemodialysis; metastatic castration-resistant prostate cancer",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000736:Androstenes; D000971:Antineoplastic Combined Chemotherapy Protocols; D006801:Humans; D008297:Male; D011241:Prednisone; D064129:Prostatic Neoplasms, Castration-Resistant; D006435:Renal Dialysis",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "2031-2034",
"pmc": null,
"pmid": "31694496",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Abiraterone experience in a patient with metastatic castration-resistant prostate cancer on hemodialysis.",
"title_normalized": "abiraterone experience in a patient with metastatic castration resistant prostate cancer on hemodialysis"
} | [
{
"companynumb": "TR-SA-2019SA351781",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"dru... |
{
"abstract": "Tumor necrosis factor (TNF)-α inhibitors increase susceptibility to tuberculosis, but the effect of biologics on susceptibility to leprosy has not been described. Moreover, biologics may play a role in treating erythema nodosum leprosum (ENL). The objectives of this systematic review were to determine whether the development of clinical leprosy is increased in patients being treated with biologics and to assess the use of biologics in treating leprosy reactions. A systematic literature review was completed of patients with leprosy who received treatment with biologics either before or after a diagnosis of leprosy was confirmed. All studies and case reports were included for qualitative evaluation. The search yielded 10 cases (including one duplicate publication) of leprosy diagnosed after initiation of TNF-α inhibitors and four case reports of refractory ENL successfully treated with infliximab or etanercept. An unpublished case of persistent ENL responsive to infliximab is also presented. These data demonstrate that the use of TNF-α inhibitors may be a risk factor for developing leprosy or reactivating subclinical infections. Leprosy can present with skin lesions and arthritis, so leprosy should be considered in patients presenting with these signs before starting treatment with these agents. Leprosy should be considered in patients who develop worsening eruptions and neurologic symptoms during treatment with TNF-α inhibitors. Finally, TNF-α inhibitors appear effective in some cases of refractory ENL.",
"affiliations": "Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington.;Department of Dermatopathology, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.;London School of Hygiene and Tropical Medicine, London, United Kingdom.;Division of Dermatology, Department of Medicine, University of Washington, Seattle, Washington.;Department of Dermatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.;London School of Hygiene and Tropical Medicine, London, United Kingdom.;London School of Hygiene and Tropical Medicine, London, United Kingdom.",
"authors": "Cogen|Anna L|AL|;Lebas|Eglantine|E|;De Barros|Barbara|B|;Harnisch|James P|JP|;Faber|William R|WR|;Lockwood|Diana N|DN|;Walker|Stephen L|SL|",
"chemical_list": "D001688:Biological Products; D007917:Leprostatic Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.19-0616",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9637",
"issue": "102(5)",
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": "D000328:Adult; D001688:Biological Products; D006801:Humans; D000069285:Infliximab; D007917:Leprostatic Agents; D007918:Leprosy; D008297:Male; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0370507",
"other_id": null,
"pages": "1131-1136",
"pmc": null,
"pmid": "32157993",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D000078182:Systematic Review",
"references": "19259757;16914716;16779736;23773635;10211535;5950347;28348555;19009974;21125169;22170033;18576299;27847029;15081655;24346871;19289788;26351858;28671966;15127338;21584421;21292656;27242236;29459143;29741821;22542278;21778902;28954119",
"title": "Biologics in Leprosy: A Systematic Review and Case Report.",
"title_normalized": "biologics in leprosy a systematic review and case report"
} | [
{
"companynumb": "US-SAMSUNG BIOEPIS-SB-2020-22643",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo assess efficacy and safety of citalopram compared to quetiapine and olanzapine for the treatment of agitation in patients with Alzheimer disease (AD).\n\n\nMETHODS\nLongitudinal, 6-month study.\n\n\nMETHODS\nNursing home (NH).\n\n\nMETHODS\n75 NH residents with AD and agitation, randomized to citalopram (n = 25), quetiapine (n = 25), or olanzapine (n = 25).\n\n\nMETHODS\nChanges in Neuropsychiatric Inventory (NPI) agitation subscale score and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC) were used to assess treatment efficacy. Participants were surveilled for adverse health outcomes.\n\n\nRESULTS\nCitalopram treatment (30±5.8 mg/d) resulted in similar 6-month efficacy compared to both quetiapine (94.0±40.4 mg/d) and olanzapine (5.2±1.6 mg/d), lower occurrence of falls than olanzapine [odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.68-0.97, P = .012], lower incidence of orthostatic hypotension than both quetiapine (OR = 0.80, 95% CI = 0.66-0.95, P = .032) and olanzapine (OR = 0.75, 95% CI = 0.69-0.91, P = .02), and less all-cause hospitalizations than both quetiapine (OR = 0.92, 95% CI = 0.88-0.95, P = .016) and olanzapine (OR = 0.78, 95% CI = 0.64-0.92, P = .004), after multiple adjustment for potentially confounding variables. No differences were observed for cognitive and functional decline, QTc prolongation, and infections.\n\n\nCONCLUSIONS\nCitalopram resulted in similar efficacy and less adverse outcomes when compared to 2 atypical antipsychotics for treatment of agitation in NH residents with AD. Replication of these findings and assessment of long-term efficacy and safety of citalopram for treatment of neuropsychiatric symptoms in dementia are needed.",
"affiliations": "Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Division of Gerontology, \"Sapienza\" University, Rome, Italy; RSA Longoni, Division of Geriatrics, Rome, Italy; Department of Cardiovascular, Dysmetabolic and Aging-associated Diseases, National Institute of Health, Rome, Italy. Electronic address: giovanni.viscogliosi@libero.it.;RSA Magnolia, Division of Geriatrics, Rome, Italy.;Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Division of Gerontology, \"Sapienza\" University, Rome, Italy.",
"authors": "Viscogliosi|Giovanni|G|;Chiriac|Iulia Maria|IM|;Ettorre|Evaristo|E|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D014150:Antipsychotic Agents; D015283:Citalopram",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jamda.2017.06.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-8610",
"issue": "18(9)",
"journal": "Journal of the American Medical Directors Association",
"keywords": "Citalopram; agitation; atypical antipsychotics; dementia",
"medline_ta": "J Am Med Dir Assoc",
"mesh_terms": "D000368:Aged; D000544:Alzheimer Disease; D018687:Antidepressive Agents, Second-Generation; D014150:Antipsychotic Agents; D015283:Citalopram; D003704:Dementia; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009735:Nursing Homes; D011595:Psychomotor Agitation; D016896:Treatment Outcome",
"nlm_unique_id": "100893243",
"other_id": null,
"pages": "799-802",
"pmc": null,
"pmid": "28739492",
"pubdate": "2017-09-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Efficacy and Safety of Citalopram Compared to Atypical Antipsychotics on Agitation in Nursing Home Residents With Alzheimer Dementia.",
"title_normalized": "efficacy and safety of citalopram compared to atypical antipsychotics on agitation in nursing home residents with alzheimer dementia"
} | [
{
"companynumb": "IT-ALEMBIC PHARMACUETICALS LIMITED-2017SCAL000783",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
... |
{
"abstract": "BACKGROUND\nImmune reconstitution inflammatory syndrome (IRIS) is a constellation of inflammatory disorders that are unmasked after the initiation of anti-retroviral therapy (ART) in Human immunodeficiency virus (HIV) infected patients. Unmasking lymphoma IRIS is a relatively rare manifestation after initiation of anti-retroviral therapy.\n\n\nMETHODS\nWe report a 44-year-old male with HIV on 4 months of ART presenting with pyrexia of unknown origin with a diagnosis of unmasking Hodgkin's lymphoma IRIS stage IV with B symptoms. This case portrays the importance of recognizing the possibility of Hodgkin's lymphoma as a possible manifestation of IRIS within the first 6 months of initiation of ART.\n\n\nCONCLUSIONS\nPatients presenting with pyrexia of unknown origin and lymphadenopathy within the first 6 months of initiation of ART, lymphoma diagnosis should be on the high threshold of suspicion as portrayed by our case.",
"affiliations": "School of Medicine, Wayne State University, Detroit, MI, USA.;Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA. bpmmc24@gmail.com.;Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.;Department of Pathology, Henry Ford Hospital, Detroit, MI, USA.;Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.;Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.",
"authors": "Mahajan|Mansi|M|;Venkatesulu|Bhanu Prasad|BP|http://orcid.org/0000-0003-2541-2055;Sallam|Omar|O|;Taneja|Kanika|K|;Scott|Megan|M|;Brar|Indira|I|",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s43046-020-0019-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1110-0362",
"issue": "32(1)",
"journal": "Journal of the Egyptian National Cancer Institute",
"keywords": "HIV; IRIS; Lymphoma; PUO",
"medline_ta": "J Egypt Natl Canc Inst",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D003937:Diagnosis, Differential; D005334:Fever; D015658:HIV Infections; D006689:Hodgkin Disease; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008198:Lymph Nodes; D008297:Male; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9424566",
"other_id": null,
"pages": "8",
"pmc": null,
"pmid": "32372315",
"pubdate": "2020-01-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unmasking lymphoma immune reconstitution inflammatory syndrome in a patient with pyrexia of unknown origin: a case report.",
"title_normalized": "unmasking lymphoma immune reconstitution inflammatory syndrome in a patient with pyrexia of unknown origin a case report"
} | [
{
"companynumb": "US-HETERO-HET2020US00284",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "COBICISTAT\\DARUNAVIR ETHANOLATE"
},
"drugaddi... |
{
"abstract": "A boy was born with a short sloping forehead, wide metopic suture, persistent metopic fontanelle, telecanthus, ocular hypertelorism, nystagmoid eye movements, bilateral cleft lip and palate, imperforate anus, rectourethral fistula, bifid scrotum and an unusual penis with hypospadias. The neutrophil polymorphs had numerous nuclear projections. The pregnancy was complicated by chronic maternal schizophrenia, severe toxaemia and maternal use of fluphenazine enanthate, dicyclomine hydrochloride, doxylamine succinate, pyridoxine hydrochloride and other drugs. Details of mother's illness, pregnancy and drug usage are presented with the clinical findings and investigations.",
"affiliations": null,
"authors": "Donaldson|G L|GL|;Bury|R G|RG|",
"chemical_list": "D004025:Dicyclomine; D004319:Doxylamine; D011736:Pyridoxine; C017610:fluphenazine enanthate; D005476:Fluphenazine",
"country": "Sweden",
"delete": false,
"doi": "10.1111/j.1651-2227.1982.tb09428.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-656X",
"issue": "71(2)",
"journal": "Acta paediatrica Scandinavica",
"keywords": null,
"medline_ta": "Acta Paediatr Scand",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D002971:Cleft Lip; D002972:Cleft Palate; D004025:Dicyclomine; D004319:Doxylamine; D005260:Female; D005476:Fluphenazine; D006801:Humans; D006972:Hypertelorism; D007231:Infant, Newborn; D008297:Male; D010502:Perineum; D011225:Pre-Eclampsia; D011247:Pregnancy; D011248:Pregnancy Complications; D011736:Pyridoxine; D012562:Schizophrenia, Disorganized",
"nlm_unique_id": "0000211",
"other_id": null,
"pages": "335-8",
"pmc": null,
"pmid": "7136644",
"pubdate": "1982-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple congenital abnormalities in a newborn boy associated with maternal use of fluphenazine enanthate and other drugs during pregnancy.",
"title_normalized": "multiple congenital abnormalities in a newborn boy associated with maternal use of fluphenazine enanthate and other drugs during pregnancy"
} | [
{
"companynumb": "AU-SA-2017SA254196",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUPHENAZINE ENANTHATE"
},
"drugadditional": null,
... |
{
"abstract": "Hepatic involvement in familial Mediterranean fever (FMF) ranges from a nonspecific increase in liver enzymes to cryptogenic cirrhosis, and the liver is mostly involved in patients bearing the M694V MEFV mutation in homozygosis. A 44-year-old Jewish woman with FMF developed nonalcoholic steatohepatitis during colchicine treatment (2,5 mg per day), confirmed by both elastography and liver biopsy. Therefore, combined therapy with the interleukin-1 (IL-1) blocking agent canakinumab (150 mg every four weeks) and colchicine (at a reduced dose of 1.5 mg per day) was started. Three months later, transaminases became normal, and after further six months, there was a marked improvement of liver fibrosis. IL-1 blockade has the power to halt or mitigate liver involvement in FMF patients. However, further experience is required to assess its therapeutic potential in the most severe patients with the hepatic disease who are partially responsive to long-term prophylaxis with colchicine.",
"affiliations": "Division of Internal Medicine, Rare Diseases and Periodic Fevers Research Centre, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy.;Division of Internal Medicine, Rare Diseases and Periodic Fevers Research Centre, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy.;Division of Internal Medicine, Rare Diseases and Periodic Fevers Research Centre, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy.;Division of Internal Medicine, Rare Diseases and Periodic Fevers Research Centre, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy.;Division of Internal Medicine, Rare Diseases and Periodic Fevers Research Centre, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy.;Department of Pathology, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy.;Department of Life Sciences and Public Health, Rare Diseases and Periodic Fevers Research Centre, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy.;Division of Internal Medicine, Rare Diseases and Periodic Fevers Research Centre, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy.",
"authors": "Massaro|Maria Grazia|MG|;Pompili|Maurizio|M|;Sicignano|Luca L|LL|;Pizzolante|Fabrizio|F|;Verrecchia|Elena|E|;Vecchio|Fabio M|FM|;Rigante|Donato|D|;Manna|Raffaele|R|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4084/MJHID.2020.059",
"fulltext": "\n==== Front\nMediterr J Hematol Infect Dis\nMediterr J Hematol Infect Dis\nMediterranean Journal of Hematology and Infectious Diseases\nMediterranean Journal of Hematology and Infectious Diseases\n2035-3006 Università Cattolica del Sacro Cuore \n\n10.4084/MJHID.2020.059\nmjhid-12-1-e2020059\nCase Report\nImprovement of Liver Involvement in Familial Mediterranean Fever After the Introduction of Canakinumab: A Case Report\nMassaro Maria Grazia 1 Pompili Maurizio 14 Sicignano Luca L. 1 Pizzolante Fabrizio 1 Verrecchia Elena 1 Vecchio Fabio M. 34 Rigante Donato 24 Manna Raffaele 14* \n1 Division of Internal Medicine, Rare Diseases and Periodic Fevers Research Centre, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy\n\n2 Department of Life Sciences and Public Health, Rare Diseases and Periodic Fevers Research Centre, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy\n\n3 Department of Pathology, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy\n\n4 Università Cattolica del Sacro Cuore, Rome, Italy\nCorrespondence to: Raffaele Manna, MD, PhD. Institute of Internal Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Sacro Cuore, Rome, Largo A. Gemelli 8, 00168 Rome, Italy. Tel: +39 06 30159433. Fax: +39 06 35502775. E-mail: raffaele.manna@policlinicogemelli.it\n2020 \n01 9 2020 \n12 1 e202005930 5 2020 08 8 2020 2020This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Hepatic involvement in familial Mediterranean fever (FMF) ranges from a nonspecific increase in liver enzymes to cryptogenic cirrhosis, and the liver is mostly involved in patients bearing the M694V MEFV mutation in homozygosis. A 44-year-old Jewish woman with FMF developed nonalcoholic steatohepatitis during colchicine treatment (2,5 mg per day), confirmed by both elastography and liver biopsy. Therefore, combined therapy with the interleukin-1 (IL-1) blocking agent canakinumab (150 mg every four weeks) and colchicine (at a reduced dose of 1.5 mg per day) was started. Three months later, transaminases became normal, and after further six months, there was a marked improvement of liver fibrosis. IL-1 blockade has the power to halt or mitigate liver involvement in FMF patients. However, further experience is required to assess its therapeutic potential in the most severe patients with the hepatic disease who are partially responsive to long-term prophylaxis with colchicine.\n\nFamilial Mediterranean feverAutoinflammationPeriodic feverSteatosisHepatitisColchicineInterleukin-1Innovative biotechnologiesAnakinraCanakinumabPersonalized medicine\n==== Body\nIntroduction\nFamilial Mediterranean fever (FMF) is the oldest and most frequent of all known hereditary periodic fever syndromes:1 its febrile attacks (with peaks over 39–40°C) have a length of about 1–3 days and are characterized by self-limited serositis, joint inflammation and skin manifestations such as erysipelas-like erythema.2–8 Recurrent polyserositis may be a strongly suggestive clue to diagnose FMF.9,10 Secondary renal amyloidosis represents the most ominous complication of FMF, usually found in 8.6% of cases according to a multicenter study performed in Turkey.11 Liver was not considered a district typically involved in FMF, except for liver amyloidosis, which might occur and display an aggressive course.12 To date, FMF has been linked to a spectrum of liver manifestations ranging from a mild-to-moderate increase of liver enzymes to cryptogenic cirrhosis.13 Colchicine is the mainstay of FMF treatment since 1972,14,15 and its efficacy has been largely proved.16 Despite the maximum tolerated colchicine dose, 5–10% of FMF patients experience more than one attack monthly17,18 and are defined as colchicine non-responders. Interleukin-1 (IL-1) blockade is considered the gold-standard treatment in refractory FMF, with several reports having demonstrated both efficacy and safety of anakinra and canakinumab.19–22\n\nWe report a young woman with FMF, undergoing colchicine therapy since the age of 3, who had a frank liver involvement at both laboratory and histological assessment, who progressively improved along with anti-IL-1 treatment.\n\nCase Report\nA 44-year-old Jewish woman was diagnosed to have FMF at the age of 3 years due to recurrent febrile episodes (until 40°C) lasting less than 48 hours and occurring three times/monthly combined with recurrent erysipelas-like erythema on the legs, pericardial effusion, recurrent abdominal pain, and arthromyalgia. The diagnosis was confirmed at a genetic level, finding the M694V mutation (in homozygosis) in the MEFV gene. Colchicine was started and gradually increased during early adulthood, up to an effective dose of 2.5 mg/day, begun at 29 years, and successfully continued non-stop with good tolerance. The patient had endometriosis at the age of 25 so that she underwent laparoscopy with adhesiolysis and removal of multiple endometriotic foci in the peritoneum, uterus, and annexes. Her more recent medical history was also characterized by insulin resistance and mixed anxiety-depressive disorder. For these reasons, she received estrogen-progestin therapy for about ten years and metformin combined with anti-depressive drugs (venlafaxine, reboxetine) plus benzodiazepines for about three years.\n\nIn 2018, after colchicine use for almost 40 years and 15 years after the last increase of colchicine dose (to 2,5 mg/die), the serum level of both transaminases was found abnormal: alanine aminotransferase was repeatedly over 140 IU/l and aspartate aminotransferase over 90 IU/l. The general activity of FMF seemed relatively controlled, as serum amyloid-A (SAA) was 0.74 (n.v. <0.5). Transaminases had been previously within normal limits at the previous patient’s follow-up evaluations, and no changes were noted due to therapies taken by the patient. No viral infections could be detected (serology for hepatitis A-B-C, cytomegalovirus, Epstein-Barr virus, and human immunodeficiency virus was negative). The patient also denied taking toxic substances, such as alcohol or illicit drugs. The autoimmunity panel was completely negative (except for a slight positivity of anti-nuclear antibodies, 1:160). No worsening of FMF typical symptoms was observed during this period.\n\nThe increased level of transaminases was also confirmed by many tests performed with monthly frequency. Liver ultrasound assessment revealed standard dimensions, but inhomogeneous echo-structure as well as moderate steatosis. Neither focal lesions nor intrahepatic biliary tract abnormalities were documented. Furthermore, a liver elastography study carried out utilizing a dedicated convex probe through the “point shear wave” technique (Esaote9 XP) with multiple sampling (10 areas) on the right lobe revealed an increased index of elasticity equal to 10.5 kPa. Given the persistently high transaminases, the patient underwent liver biopsy. Histology showed mild steatosis with widespread hydropic degeneration of hepatocytes and centrilobular balloniform activation of CD68+ Kupffer cells, containing PAS-positive material. This morphological report was compatible with steatohepatitis (Figure 1). However, these results were not consistent with colchicine-induced liver injury, which occurs in cases of drug overdose, characterized by typical histopathological elements, i.e., anisonucleosis with enlarged nuclei, multiple nucleoli and frequent mitotic figures arrested in metaphase23, which were not present.\n\nDespite the increase of transaminases, it was not possible to reduce colchicine dose alone, as the same patient had presented different disease relapses if colchicine was reduced to 2 mg/day. For this reason, we decided to start a combined therapy with canakinumab (150 mg every four weeks) and piecemeal reduced dose of colchicine (until 1.5 mg/day). Three months after starting canakinumab, there was a substantial reduction in the transaminases next to normalization. In addition, liver elastography performed six months from initiating canakinumab revealed a sound improvement in the steatosis framework (6.1 kPa versus 10.5 kPa).\n\nTo date, the patient is still receiving the same therapy based on canakinumab (150 mg every four weeks) and colchicine (1.5 mg/daily), while transaminases have remained in the standard range. There was no exacerbation of FMF typical manifestations, and the disease is currently in remission.\n\nDiscussion\nFMF is an autoinflammatory disease characterized by recurrent self-limiting episodes of fever and polyserositis.1,5–7,10 It is the best-known and most common monogenic fever syndrome, which shows a preferential ethnic distribution in Turks, Armenians, Jews, and Arabs.10,24 This autosomal recessive pathology is caused by mutations in the MEFV gene, which encodes for pyrin. Pyrin has a relevant role in controlling the innate immune system and inflammation activation: its functional abnormality causes aberrant activation of the inflammasome with overproduction of proinflammatory cytokines, in particular IL-1.25 Clinically, the disease is characterized by recurrent inflammation in the serosal membranes, joints, and skin with long-term complications such as renal amyloidosis, which might lead to renal failure, if overlooked.26\n\nUntreated FMF is associated with ongoing persistent inflammation and subsequent accumulation of SAA in different target-organs such as kidney, but also liver.1,5–7,10,27,28 For a long time, the liver was not considered typically involved in FMF, and AA amyloidosis was considered the only possible culprit in the case of hepatic involvement.12 However, an increase of liver enzymes does not occur in the case of amyloidosis,13 as the most frequent signs of liver AA amyloidosis are an increased level of alkaline phosphatase and hepatomegaly.29\n\nTo date, liver involvement in FMF has been widely recognized and reported: both types of MEFV mutation and overproduction of IL-1 are probably involved in the damage progression.30,31 Experiments in mice have shown that an abundant release of IL-1 causes inflammation, pyroptosis, and collagen deposition in the liver with subsequent increase of liver enzymes.13,32 Two conflicting studies have enhanced our knowledge about the connection between FMF and liver involvement, and more between FMF and nonalcoholic fatty liver disease (NAFLD). The survey conducted by Rimar et al. enrolled 27 patients with FMF but without a frank metabolic syndrome and found that 75% of patients had NAFLD. The conclusion of this study hypothesized a correlation between FMF and NAFLD.33 Conversely, the survey conducted by Sarkis et al., which enrolled 52 patients with FMF and 30 healthy controls, showed similar rates of NAFLD in the FMF population compared to the healthy one.34 Indeed, in the study by Rimar et al., FMF patients had fewer risk factors for NAFLD, and NAFLD was demonstrated by biopsy, which is more sensitive than ultrasound.35 A different study conducted by Tweezer-Zaks et al. documented that M694V homozygosity was relatively more frequent among FMF patients with NAFLD and nonalcoholic steatohepatitis.36\n\nFrom a therapeutic point of view, colchicine is the first-choice option for FMF management since 1972.14,15,37 The exact mechanism of action underlying colchicine efficacy is not entirely understood: current evidence suggests that colchicine downregulates multiple inflammatory pathways and modulates innate immunity.38 Colchicine has a narrow therapeutic range, and hepatotoxicity as a possible consequence of long-term administration has been shown.23 In fact, colchicine intoxication with daily doses higher than 5 mg might determine liver toxicity.13,38 Of note, the usual doses used to prevent FMF attacks do not seem to bring about a significant increase in liver enzymes in most cases.40 A potentially life-threatening complication of some autoinflammatory disorders like FMF may be macrophage activation syndrome, characterized by increased hemophagocytic activity in both bone marrow and liver, combined with fever and different signs of liver damage.41,42 Furthermore, various scores have been created to quantify organ damage (including liver) or compare disease outcome in patients with autoinflammatory disorders,43–45 and some of these have been created explicitly for FMF.46\n\nDifferent drugs can come to the rescue for FMF patients who are colchicine-intolerant and non-responders or for those displaying adverse effects to colchicine. Both anakinra, the IL-1 receptor antagonist given subcutaneously daily, and canakinumab, the long-acting specific monoclonal antibody against IL-1β canakinumab, given subcutaneously every four weeks, can be extremely active in the management of another autoinflammatory disorder, which is the cryopyrin-associated periodic syndrome, almost fully mediated by IL-1.47 As an inappropriate production of IL-1 also plays a central role in the pathogenesis of FMF attacks, blocking IL-1 by specific biological anti-IL-1 drugs should be an ideal strategy in colchicine-resistant patients with FMF.48,49 Anakinra and canakinumab have been used in the most difficult-to-treat patients with FMF, though recently it has emerged that canakinumab is better-tolerated for less frequent injection-site reactions.50 It is remarkable that in our patient canakinumab combined with colchicine (at a reduced dose) resulted in normalization of transaminases, in the reduction of fibrosis markers and in a definite improvement of liver steatosis.\n\nConclusions\nClinical studies are needed to confirm the efficacy of anti-IL-1 drugs such as canakinumab in inducing the regression of liver involvement in FMF patients. If so, this drug might represent an excellent therapeutic alternative for all FMF patients with evidence of hepatic disease. Given the pathogenetic mechanism, underlying liver involvement in FMF, and considering the mode of action of anti-IL-1 treatments, a protective effect of IL-1 blockade for the development of liver complications is conceivable.\n\nCompeting interests: The authors declare no conflict of Interest.\n\nFigure 1 Liver biopsy showing mild steatosis with ballooning cells and some glycogenated nuclei (A, B). In the centrilobular zone, the reticulum stain highlights fibrosis (C). Numerous CD68+ and PAS/diastase+ macrophages are also present (D).\n==== Refs\nReferences\n1 Ozdogan H Ugurlu S Familial Mediterranean fever La Presse Med 2019 48 1 Pt 2 e61 e76 10.1016/j.lpm.2018.08.014 30686512 \n2 Livneh A Langevitz P Diagnostic and treatment concerns in familial Mediterranean fever Best Pract Res Clin Rheumatol 2000 14 477 98 10.1053/berh.2000.0089 10985982 \n3 Sohar E Gafni J Pras M Familial Mediterranean fever. A survey of 470 cases and review of the literature Am J Med 1967 43 227 53 5340644 \n4 Tunca M Akar S Onen F Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study Medicine 2005 84 1 11 10.1097/01.md.0000152370.84628.0c 15643295 \n5 Rigante D A systematic approach to autoinflammatory syndromes: a spelling booklet for the beginner Expert Rev Clin Immunol 2017 13 571 97 10.1080/1744666X.2017.1280396 28064547 \n6 Rigante D The broad-ranging panorama of systemic autoinflammatory disorders with specific focus on acute painful symptoms and hematologic manifestations in children Mediterr J Hematol Infect Dis 2018 10 e2018067 10.4084/MJHID.2018.067 30416699 \n7 Manna R Rigante D Familial Mediterranean fever: assessing the overall clinical impact and formulating treatment plans Mediterr J Hematol Infect Dis 2019 11 e2019027 10.4084/MJHID.2019.027 31205631 \n8 Kees S Langevitz P Zemer D Attacks of pericarditis as a manifestation of familial Mediterranean fever Int J Med 1997 90 643 7 10.1093/qjmed/90.10.643 9415347 \n9 Rigante D Cantarini L Imazio M Autoinflammatory diseases and cardiovascular manifestations Ann Med 2011 43 341 6 10.3109/07853890.2010.547212 21284530 \n10 Rigante D Frediani B Galeazzi M From the Mediterranean to the sea of Japan: the transcontinental odyssey of autoinflammatory diseases Biomed Res Int 2013 2013 485103 10.1155/2013/485103 23971037 \n11 Kasifoglu T Bilge SY Sari I Amyloidosis and its related factors in Turkish patients with familial Mediterranean fever: a multi-centre study Rheumatology 2014 53 741 5 10.1093/rheumatology/ket400 24369413 \n12 Ben-Chetrit E Yazici H The liver in familial Mediterranean fever: is it involved? Clin Exp Rheumatol 2017 35 Suppl 108 108 12 28598780 \n13 Fraisse T Savey L Hentgen V Non-amyloid liver involvement in familial Mediterranean fever: a systematic literature review Liver Int 2020 3 20 Epub ahead of print 10.1111/liv.14445 32196885 \n14 Goldfinger SE Colchicine for familial Mediterranean fever N Engl J Med 1972 287 1302 10.1056/NEJM197212212872514 4636899 \n15 Rigante D La Torraca I Avallone L The pharmacological basis of treatment with colchicine in children with familial Mediterranean fever Eur Rev Med Pharmacol Sci 2006 10 173 8 16910346 \n16 Dinarello CA Wolfe SM Goldfinger SE Colchicine therapy for familial Mediterranean fever: a double-blind trial N Engl J Med 1974 291 934 7 10.1056/NEJM197410312911804 4606353 \n17 Ozen S Demirkaya E Erer B EULAR recommendations for the management of familial Mediterranean fever Ann Rheum Dis 2016 75 644 51 10.1136/annrheumdis-2015-208690 26802180 \n18 Ozen S Koné-Paut I Gül A Colchicine resistance and intolerance in familial Mediterranean fever: definition, causes, and alternative treatments Semin Arthritis Rheum 2017 47 115 20 10.1016/j.semarthrit.2017.03.006 28413100 \n19 Laskari K Boura P Dalekos GN Long-term beneficial effect of canakinumab in colchicine-resistant familial Mediterranean fever J Rheumatol 2017 44 102 9 10.3899/jrheum.160518 28042127 \n20 Ben-Zvi I Kukuy O Giat E Anakinra for colchicine-resistant familial Mediterranean fever: a randomized double-blind placebo-controlled trial Arthritis Rheumatol 2017 69 854 62 10.1002/art.39995 27860460 \n21 De Benedetti F Gattorno M Anton J Canakinumab for the treatment of autoinflammatory recurrent fever syndromes N Engl J Med 2018 378 1908 19 10.1056/NEJMoa1706314 29768139 \n22 Kacar M Savic S van der Hilst JCH The efficacy, safety and tolerability of canakinumab in the treatment of familial Mediterranean fever: a systematic review of the literature J Inflamm Res 2020 13 141 9 10.2147/JIR.S206204 32210604 \n23 Abbott CE Xu R Sigal SH Colchicine-induced hepatotoxicity ACG Case Rep J 2017 4 e120 10.14309/crj.2017.120 29201931 \n24 Ben-Chetrit E Touitou I Familial Mediterranean fever in the world Arthritis Rheum 2009 61 1447 53 10.1002/art.24458 19790133 \n25 Rigante D New mosaic tiles in childhood hereditary autoinflammatory disorders Immunol Lett 2018 193 67 76 10.1016/j.imlet.2017.11.013 29198619 \n26 Rigante D A developing portrait of hereditary periodic fevers in childhood Expert Opin Orphan Drugs 2018 6 47 55 10.1080/21678707.2018.1406797 \n27 Lidar M Doron A Barzilai A Erysipelas-like erythema as the presenting feature of familial Mediterranean fever J Eur Acad Dermatol Venereol 2013 27 912 5 10.1111/j.1468-3083.2011.04442.x 22243424 \n28 van der Hilst JC Simon A Drenth JPH Hereditary periodic fever and reactive amyloidosis Clin Exp Med 2005 5 87 98 10.1007/s10238-005-0071-6 16284730 \n29 Ebert EC Nagar M Gastrointestinal manifestations of amyloidosis Am J Gastroenterol 2008 103 776 87 10.1111/j.1572-0241.2007.01669.x 18076735 \n30 Tilg H Wilmer A Vogel W Serum levels of cytokines in chronic liver diseases Gastroenterology 1992 103 264 74 10.1016/0016-5085(92)91122-k 1612333 \n31 Ludwiczek O Vannier E Moschen A Impaired counter-regulation of interleukin-1 by the soluble IL-1 receptor type II in patients with chronic liver disease Scand J Gastroenterol 2008 43 1360 5 10.1080/00365520802179925 18609176 \n32 Wree A Eguchi A McGeough MD NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation and fibrosis in mice Hepatology 2014 59 898 910 10.1002/hep.26592 23813842 \n33 Rimar D Rosner I Rozenbaum M Zuckerman E Familial Mediterranean fever: an association with nonalcoholic fatty liver disease Clin Rheumatol 2011 30 987 91 10.1007/s10067-011-1718-1 21360101 \n34 Sarkis C Caglar E Ugurlu S Nonalcoholic fatty liver disease and familial Mediterranean fever: are they related? Srp Arh Celok Lek 2012 140 589 94 10.2298/sarh1210589s 23289274 \n35 Lee SS Park SH Radiologic evaluation of nonalcoholic fatty liver disease World J Gastroenterol 2014 20 7392 402 10.3748/wjg.v20.i23.7392 24966609 \n36 Tweezer-Zaks N Doron-Libner A Weiss P Familial Mediterranean fever and cryptogenic cirrhosis Medicine (Baltimore) 2007 86 355 62 10.1097/MD.0b013e31815be056 18004180 \n37 La Regina M Ben-Chetrit E Gasparyan AY Current trends in colchicine treatment in familial Mediterranean fever Clin Exp Rheumatol 2013 31 3 Suppl 77 41 6 24064013 \n38 Leung YY Yao Hui LL Kraus VB Colchicine-update on mechanisms of action and therapeutic uses Semin Arthritis Rheum 2015 45 341 50 10.1016/j.semarthrit.2015.06.013 26228647 \n39 Stack J Ryan J McCarthy G Colchicine: new insights to an old drug Am J Ther 2015 22 5 e151 e157 10.1097/01.mjt.0000433937.07244.e1 24100258 \n40 Terkeltaub RA Furst DE Digiacinto JL Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors Arthritis Rheum 2011 63 2226 2237 10.1002/art.30389 21480191 \n41 Rigante D Emmi G Fastiggi M Macrophage activation syndrome in the course of monogenic autoinflammatory disorders Clin Rheumatol 2015 34 1333 9 10.1007/s10067-015-2923-0 25846831 \n42 Stabile A Bertoni B Ansuini V The clinical spectrum and treatment options of macrophage activation syndrome in the pediatric age Eur Rev Med Pharmacol Sci 2006 10 53 9 16705949 \n43 Cantarini L Iacoponi F Lucherini OM Validation of a diagnostic score for the diagnosis of autoinflammatory diseases in adults Int J Immunopathol Pharmacol 2011 24 695 702 10.1177/039463201102400315 21978701 \n44 Ter Haar NM Annink KV Al-Mayouf SM development of the autoinflammatory disease damage index (ADDI) Ann Rheum Dis 2017 76 821 30 10.1136/annrheumdis-2016-210092 27811147 \n45 Ter Haar NM van Delft ALJ Annink KV In silico validation of the Autoinflammatory Disease Damage Index Ann Rheum Dis 2018 77 1599 605 10.1136/annrheumdis-2018-213725 30077992 \n46 Pras E Livneh A Balow JE Jr Clinical differences between North African and Iraqi Jews with familial Mediterranean fever Am J Med Genet 1998 75 2 216 219 10.1002/(sici)1096-8628(19980113)75:2<216::aid-ajmg20>3.0.co;2-r 9450890 \n47 Cantarini L Lucherini OM Frediani B Bridging the gap between the clinician and the patient with cryopyrin-associated periodic syndromes Int J Immunopathol Pharmacol 2011 24 827 36 10.1177/039463201102400402 22230390 \n48 Rigante D Phenotype variability of autoinflammatory disorders in the pediatric patient: a pictorial overview J Evid Based Med 2020 7 6 13 3 Epub ahead of print 10.1111/jebm.12406 32627322 \n49 Vitale A Insalaco A Sfriso P A snapshot on the on-label and off-label use of the interleukin-1 inhibitors in Italy among rheumatologists and pediatric rheumatologists: a nationwide multicenter retrospective observational study Front Pharmacol 2016 7 380 10.3389/fphar.2016.00380 27822185 \n50 van der Hilst JC Moutschen M Messiaen PE efficacy of anti-IL-1 treatment in familial Mediterranean fever: a systematic review of the literature Biologics 2016 10 75 80 10.2147/BTT.S102954 27110096\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2035-3006",
"issue": "12(1)",
"journal": "Mediterranean journal of hematology and infectious diseases",
"keywords": "Anakinra; Autoinflammation; Canakinumab; Colchicine; Familial Mediterranean fever; Hepatitis; Innovative biotechnologies; Interleukin-1; Periodic fever; Personalized medicine; Steatosis",
"medline_ta": "Mediterr J Hematol Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101530512",
"other_id": null,
"pages": "e2020059",
"pmc": null,
"pmid": "32952970",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "29768139;32196885;15643295;24064013;27822185;18609176;1612333;23289274;30686512;10985982;28413100;29198619;4636899;25846831;24100258;9450890;23813842;26228647;9415347;21978701;27811147;30077992;21480191;21360101;16284730;28598780;21284530;31205631;32210604;22243424;28064547;30416699;24369413;32627322;16705949;27860460;24966609;28042127;23971037;18076735;27110096;29201931;5340644;19790133;22230390;4606353;18004180;16910346;26802180",
"title": "Improvement of Liver Involvement in Familial Mediterranean Fever After the Introduction of Canakinumab: A Case Report.",
"title_normalized": "improvement of liver involvement in familial mediterranean fever after the introduction of canakinumab a case report"
} | [
{
"companynumb": "IT-TAKEDA-2020TEU009385",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "COLCHICINE"
},
"drugadditional": "1",
... |
{
"abstract": "The International Society for Peritoneal Dialysis recommends the regular application of topical antibiotic-containing preparations in addition to a routine exit site care to reduce the risk of exit site infection (ESI). Among these prophylactic antimicrobial preparations, topical gentamicin is one of the widely used and effective antibiotics for prevention of ESI and peritonitis in peritoneal dialysis (PD) patients. Overall, topical gentamicin is well tolerated; however, its use can be associated with the development of allergic contact dermatitis (ACD). We describe a first reported case of PD catheter exit site contact ACD due to topical gentamicin mimicking ESI. The patient in this report developed worsening violaceous in color and pruritic rash surrounding the PD catheter exit site that appeared 3 weeks after the initiation of gentamicin cream. The association between development of rash and initiation of topical gentamicin led to a suspicion of local reaction to gentamicin rather than ESI. Skin biopsy confirmed ACD. Discontinuation of the provoking agent and subsequent treatment with topical hydrocortisone application led to a resolution of the exit site rash. Any rash at a PD catheter exit site should be considered infectious until proven otherwise. However, it is important to be aware of noninfectious etiologies of exit site rashes as the treatment of these 2 conditions differs.",
"affiliations": "Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.;Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.;Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.;Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.",
"authors": "Gosmanova|Elvira O|EO|;Ezumba|Ikena|I|;Fisher|Kristopher R|KR|;Cleveland|Kerry O|KO|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/2324709615618222",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961561822210.1177_2324709615618222ArticleA Case Report of Rash at Peritoneal Dialysis Exit Site Gosmanova Elvira O. MD, FASN1Ezumba Ikena MD1Fisher Kristopher R. MD2Cleveland Kerry O. MD11 Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA2 Department of Dermatology, University of Tennessee Health Science Center, Memphis, TN, USAElvira O. Gosmanova, Nephrology Division, Department of Medicine, University of Tennessee Health Science Center, 956 Court Ave, Suite B226, Memphis, TN 38163, USA. Email: egosmano@uthsc.edu27 11 2015 Oct-Dec 2015 3 4 2324709615618222© 2015 American Federation for Medical Research2015American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).The International Society for Peritoneal Dialysis recommends the regular application of topical antibiotic-containing preparations in addition to a routine exit site care to reduce the risk of exit site infection (ESI). Among these prophylactic antimicrobial preparations, topical gentamicin is one of the widely used and effective antibiotics for prevention of ESI and peritonitis in peritoneal dialysis (PD) patients. Overall, topical gentamicin is well tolerated; however, its use can be associated with the development of allergic contact dermatitis (ACD). We describe a first reported case of PD catheter exit site contact ACD due to topical gentamicin mimicking ESI. The patient in this report developed worsening violaceous in color and pruritic rash surrounding the PD catheter exit site that appeared 3 weeks after the initiation of gentamicin cream. The association between development of rash and initiation of topical gentamicin led to a suspicion of local reaction to gentamicin rather than ESI. Skin biopsy confirmed ACD. Discontinuation of the provoking agent and subsequent treatment with topical hydrocortisone application led to a resolution of the exit site rash. Any rash at a PD catheter exit site should be considered infectious until proven otherwise. However, it is important to be aware of noninfectious etiologies of exit site rashes as the treatment of these 2 conditions differs.\n\nperitoneal dialysis catheter exit siteallergic contact dermatitisgentamicincover-dateOctober-December 2015\n==== Body\nBackground\nThe development of rash at the peritoneal dialysis (PD) exit site is never trivial for nephrologists and is always concerning for PD exit site infection (ESI). ESI occurs in up to 20% of PD patients and is associated with a 6-fold increase in incidence of PD-associated peritonitis in the subsequent 60 days even with appropriate treatment of ESI.1 In turn, PD-associated peritonitis poses risks of PD catheter removal, recurrent hospitalizations, and even death.2 Therefore, the International Society for Peritoneal Dialysis (ISPD) recommends using antibiotic-containing preparations, in addition to a routine daily exit site care, to reduce incidence of ESI.3 However, it is important to be aware that antimicrobial preparations do not fully eliminate risk of ESI and, moreover, can be associated with noninfectious complications. We describe for the first time a clinical presentation and diagnostic approach to gentamicin-induced contact dermatitis at the PD catheter exit site that mimicked ESI.\n\nClinical Presentation\nA 54-year-old African American female was undergoing continuous cycling PD for end-stage renal disease due to diabetes. She presented to clinic with 2.5-week history of a worsening pruritic rash around her PD catheter exit site. Three weeks earlier she began topical gentamicin sulfate 0.1% cream for ESI prophylaxis. The patient reported no fever or abdominal pain. On examination, she had normal vital signs. The PD catheter exit site had an 8.5 × 4.5 cm ovoid crusted plaque, violaceous in color with a peripheral rim of erythema and without granulation (Figure 1A). There was no tenderness, swelling, or drainage present at the PD catheter exit site. Abdomen was nontender with normoactive bowel sounds and peritoneal fluid was clear.\n\nFigure 1. Clinical and histological presentation of gentamycin-induced contact dermatitis.\n\n(A) Presenting rash at the peritoneal dialysis catheter exit site. (B) Skin biopsy of the peritoneal dialysis exit site lesion showing spongiotic dermatitis (hematoxylin–eosin, 40×). (C) A higher magnification showing eosinophilic spongiosis; arrows point to eosinophils (hematoxylin–eosin, 200×).\n\nClinical diagnosis of allergic contact dermatitis (ACD) due to gentamicin was made and gentamicin cream was discontinued. Skin biopsy performed the following day demonstrated psoriasiform spongiotic dermatitis with eosinophils, consistent with ACD (Figure 1B and C). The exit site lesion slowly resolved with residual mild hyperpigmentation after stopping gentamicin cream and initiating hydrocortisone 2.5% cream. Mupirocin 2% cream was subsequently added for ESI prophylaxis with no recurrence of exit site rash.\n\nFinal Diagnosis\nACD due to gentamicin cream\n\nDiscussion\nESI should be considered with the development of rash at the PD catheter exit site. ESI is a major risk factor for the development of PD-associated peritonitis; therefore, prompt diagnosis and treatment of ESI are essential.3-5 The most common pathogens causing ESI are Staphylococcus aureus and Pseudomonas aeruginosa. Additional pathogens leading to ESI include Staphylococcus epidermidis, Escherichia coli, diptheroids, streptococci, nontuberculous mycobacteria, and fungi.3,4 The ISPD recommends cleaning of PD catheter exit site with antiseptic agent and application of topical antimicrobials, such as gentamicin or mupirocin, for the prevention of ESI.3 Topical gentamicin has been shown to reduce ESI and peritonitis due to gram-positive and gram-negative organisms;6,7 while, topical mupirocin mainly reduced ESI due to gram-positive organisms.6,8 ESI is typically diagnosed clinically based on the finding of purulent or bloody drainage from PD catheter exit site, surrounding erythema, tenderness, and swelling. However, the presence of skin rash and erythema without drainage at the PD catheter exit site can be also due to early infection, allergic reaction to PD catheter material,9 or to mechanical trauma.4 Additionally, allergic reactions to PD catheter exit site care products such as antibiotic preparations (mupirocin and polysporin)10 and antiseptic agents11,12 can manifest as skin rash around PD catheter exit site.\n\nErythema and rash around the exit site can be mistaken for ESI; however, absence of drainage, tenderness, and swelling may be clues for contact dermatitis. The diagnosis of contact dermatitis is usually established on clinical grounds based on characteristic appearance of rash, negative Gram stain and culture of exit site, and favorable response to withdrawal of suspected agent along with supportive measures such as topical steroid preparations. Skin biopsy can be used to confirm the diagnosis, and in our patient it demonstrated psoriasiform spongiotic dermatitis with eosinophils (Figure 1B and C).\n\nTopical gentamicin (cream, ointment, eye and ear drops) has been previously linked to periocular ACD.13 In a randomized controlled trial comparing effectiveness of topical gentamicin sulfate 0.1% cream and mupirocin 2% cream, only minor exit site irritations developed in 10.5% of patients in both treatment arms with no reported cases requiring discontinuation of antimicrobial preparations.6 ACD is a cell-mediated type 4 delayed hypersensitivity reaction.14 ACD is observed more frequency in patients with atopic eczema, nickel sensitization, stasis dermatitis, and chronic actinic dermatitis.15 Patients who develop ACD from gentamicin are at an increased risk for generalized eczematous eruption following parenteral administration of gentamicin.16 Contact dermatitis from gentamicin can also result in cross-sensitivity to other aminoglycosides like neomycin.17 Of note, allergy to topical neomycin—the most commonly used topical antibiotic in the United States18—has been reported to occur in up to 13.1% of the general population.19\n\nConclusions\nACD due to topical gentamicin is not uncommon and can occur at the PD catheter exit site. It is important to be aware of this association to avoid incorrect diagnosis of PD catheter ESI and inappropriately continued antibiotic use in cases of ACD. In contrast, the routine exit site care, including topical antimicrobials, is continued during PD catheter ESI. The failure to discontinue provoking allergens in ACD can lead to the worsening of exit site rash, incorrect diagnosis of refractory ESI infection, and potentially result in PD catheter removal.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1 \nvan Diepen AT Tomlinson GA Jassal SV. \nThe association between exit site infection and subsequent peritonitis among peritoneal dialysis patients . Clin J Am Soc Nephrol . 2012 ;7 :1266 -1271 .22745277 \n2 \nKofteridis DP Valachis A Perakis K Maraki S Daphnis E Samonis G. \nPeritoneal dialysis-associated peritonitis: clinical features and predictors of outcome . Int J Infect Dis . 2010 ;14 :e489 -493 .19926324 \n3 \nPiraino B Bernardini J Brown E \nISPD position statement on reducing the risks of peritoneal dialysis-related infections . Perit Dial Int . 2011 ;31 :614 -630 .21880990 \n4 \nLi PK Szeto CC Piraino B \nPeritoneal dialysis-related infections recommendations: 2010 update . Perit Dial Int . 2010 ;30 :393 -423 .20628102 \n5 \nPiraino B Bernardini J Sorkin M. \nThe influence of peritoneal catheter exit-site infections on peritonitis, tunnel infections, and catheter loss in patients on continuous ambulatory peritoneal dialysis . Am J Kidney Dis . 1986 ;8 :436 -440 .3812473 \n6 \nBernardini J Bender F Florio T \nRandomized, double-blind trial of antibiotic exit site cream for prevention of exit site infection in peritoneal dialysis patients . J Am Soc Nephrol . 2005 ;16 :539 -545 .15625071 \n7 \nScalamogna A Castelnovo C De Vecchi A Ponticelli C. \nExit-site and tunnel infections in continuous ambulatory peritoneal dialysis patients . Am J Kidney Dis . 1991 ;18 :674 -677 .1962652 \n8 \nWong SS Chu KH Cheuk A \nProphylaxis against gram-positive organisms causing exit-site infection and peritonitis in continuous ambulatory peritoneal dialysis patients by applying mupirocin ointment at the catheter exit site . Perit Dial Int . 2003 ;23 (suppl 2 ):S153 -S158 .17986538 \n9 \nSchmitt R Haller H Hiss M. \nQuiz page September 2012: erythematous rash around peritoneal dialysis catheter exit site . Am J Kidney Dis . 2012 ;60 :A29 -A31 .22901637 \n10 \nMcQuillan RF Chiu E Nessim S \nA randomized controlled trial comparing mupirocin and polysporin triple ointments in peritoneal dialysis patients: the MP3 Study . Clin J Am Soc Nephrol . 2012 ;7 :297 -303 .22134627 \n11 \nPatel UO Fox SR Moy JN Korbet SM. \nPruritic rash and eosinophilia in a patient receiving peritoneal dialysis . Semin Dial . 2011 ;24 :338 -340 .21682774 \n12 \nYavascan O Kara OD Sozen G Aksu N. \nAllergic dermatitis caused by povidone iodine: an uncommon complication of chronic peritoneal dialysis treatment . Adv Perit Dial . 2005 ;21 :131 -133 .16686303 \n13 \nNathawad R Mendez H Ahmad A \nSevere ocular reactions after neonatal ocular prophylaxis with gentamicin ophthalmic ointment . Pediatr Infect Dis J . 2011 ;30 :175 -176 .20885334 \n14 \nSanchez-Borges M Thong B Blanca M \nHypersensitivity reactions to non beta-lactam antimicrobial agents, a statement of the WAO special committee on drug allergy . World Allergy Organ J . 2013 ;6 :18 .24175948 \n15 \nCao LY Taylor JS. \nV Contact dermatitis and related disorders . In: Dale DC Federmann DD , eds. 2 Dermatology. ACP Medicine . Hamilton, Ontario, Canada : BC Decker Inc ; 9 \n2008 .\n16 \nPaniagua MJ García-Ortega P Tella R Gaig P Richart C. \nSystemic contact dermatitis to gentamicin . Allergy . 2002 ;57 :1086 -1087 .12359018 \n17 \nLiippo J Lammintausta K. \nPositive patch test reactions to gentamicin show sensitization to aminoglycosides from topical therapies, bone cements, and from systemic medication . Contact Dermatitis . 2008 ;59 :268 -272 .18976376 \n18 \nMarks JG JrElsner P DeLeo VA \nContact & Occupational Dermatology . St Louis, MO : Mosby ; 2002 :65 -139 .\n19 \nGehrig KA Warshaw EM. \nAllergic contact dermatitis to topical antibiotics: epidemiology, responsible allergens, and management . J Am Acad Dermatol . 2008 ;58 :1 -21 .18158924\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "3(4)",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "allergic contact dermatitis; gentamicin; peritoneal dialysis catheter exit site",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709615618222",
"pmc": null,
"pmid": "26668811",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "22134627;22745277;21880990;12359018;15625071;19926324;20628102;22901637;20885334;24175948;1962652;17986538;21682774;18158924;3812473;16686303;18976376",
"title": "A Case Report of Rash at Peritoneal Dialysis Exit Site.",
"title_normalized": "a case report of rash at peritoneal dialysis exit site"
} | [
{
"companynumb": "PHHY2017US124468",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GENTAMICIN"
},
"drugadditional": "1",
"druga... |
{
"abstract": "OBJECTIVE\nDupilumab is highly effective in treating atopic dermatitis (AD). However, some patients experience difficulties with dupilumab therapy, such as inadequate clinical response, failure to achieve long-term disease control, or adverse events (AEs). Our objective is to assess inadequate response and AEs occurring in children on dupilumab therapy for AD.\n\n\nMETHODS\nThis is a retrospective cohort study of children on dupilumab for AD. Collected variables included patient demographics, medical histories, and dupilumab therapy characteristics. Response analysis was conducted in those with ≥3 months of dupilumab therapy: primary poor responders were defined as those whose EASI scores did not decrease by >50%, and secondary poor responders were those who initially responded but had significant AD flares while on therapy.\n\n\nRESULTS\nWe included 200 patients on dupilumab for AD in our cohort; 192 received ≥3 months of therapy and were included in our response analysis. Twelve children experienced inadequate primary response, and 4 were secondary poor responders. Four of these 16 children discontinued therapy due to inadequate response. The most common dupilumab-associated AEs were facial erythema (n = 24, 12.0%) and injection-site reactions (n = 24, 12.0%). Female sex was significantly associated with experiencing injection-site reactions, and prior hospitalization was significantly associated with HSV infection on dupilumab. Eight patients discontinued therapy due to an AE.\n\n\nCONCLUSIONS\nA small but significant number of patients experienced treatment difficulties while on dupilumab. The risk of inadequate response to dupilumab and dupilumab-associated AEs should be discussed thoroughly with patients and their families prior to initiation.",
"affiliations": "Section of Dermatology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Section of Dermatology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Section of Dermatology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.;Section of Dermatology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.",
"authors": "McKenzie|Paige L|PL|https://orcid.org/0000-0002-5324-8507;Rangu|Sneha|S|;Treat|James R|JR|;Castelo-Soccio|Leslie|L|https://orcid.org/0000-0003-3289-446X",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C582203:dupilumab",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14799",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "38(5)",
"journal": "Pediatric dermatology",
"keywords": "atopic dermatitis; eczema",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D003876:Dermatitis, Atopic; D005260:Female; D006801:Humans; D012189:Retrospective Studies; D012720:Severity of Illness Index; D063128:Tertiary Healthcare; D016896:Treatment Outcome",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "1178-1184",
"pmc": null,
"pmid": "34515353",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Experience using dupilumab for pediatric atopic dermatitis at a tertiary care c enter: Inadequate response and adverse events.",
"title_normalized": "experience using dupilumab for pediatric atopic dermatitis at a tertiary care c enter inadequate response and adverse events"
} | [
{
"companynumb": "US-SA-2021SA309407",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DUPILUMAB"
},
"drugadditional": "1",
"drug... |
{
"abstract": "Lymphocyte-rich classical Hodgkin lymphoma (LRCHL) is a rare subtype of Hodgkin lymphoma with a favorable prognosis, and an aggressive clinical course of LRCHL is uncommon. A 55-year-old man suffering from swelling in the left neck was diagnosed with LRCHL with extranodal lesions in the lung and bone marrow. Initially, he received standard ABVD chemotherapy; however, disease progression, accompanied by hemophagocytic syndrome (HPS), occurred during the second course of ABVD. He received two subsequent courses of intensive chemotherapy containing high-dose steroids, cyclophosphamide, and etoposide. Nevertheless, this therapy was only temporarily effective, and he died of due to an aggressive disease progression accompanied by uncontrollable HPS and severe coagulopathy.",
"affiliations": "Department of Hematology, Osaki Citizen Hospital, Japan.",
"authors": "Ichikawa|Satoshi|S|;Takahashi|Taro|T|;Katsushima|Hiroki|H|;Fukuhara|Noriko|N|;Ichinohasama|Ryo|R|;Harigae|Hideo|H|",
"chemical_list": "D001761:Bleomycin; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.55.5942",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "55(2)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D019046:Bone Marrow Neoplasms; D003606:Dacarbazine; D018450:Disease Progression; D004317:Doxorubicin; D006689:Hodgkin Disease; D006801:Humans; D008207:Lymphatic Metastasis; D008214:Lymphocytes; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D008875:Middle Aged; D014747:Vinblastine",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "191-6",
"pmc": null,
"pmid": "26781022",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Advanced Lymphocyte-rich Classical Hodgkin Lymphoma Complicated with Fatal Hemophagocytic Syndrome.",
"title_normalized": "advanced lymphocyte rich classical hodgkin lymphoma complicated with fatal hemophagocytic syndrome"
} | [
{
"companynumb": "JP-SEATTLE GENETICS-2016SGN00118",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null... |
{
"abstract": "BACKGROUND\nTreatment with escalated BEACOPP achieved a superior time to treatment failure over ABVD in patients with disseminated Hodgkin lymphoma. However, recent clinical trials have failed to confirm BEACOPP overall survival (OS) superiority over ABVD. In addition, the gain in low-risk patients is still a matter of debate.\n\n\nMETHODS\nWe randomly compared ABVD (8 cycles) with BEACOPP (escalated 4 cycles ≥ baseline 4 cycles) in low-risk patients with an International Prognostic Score (IPS) of 0-2. The primary end point was event-free survival (EFS). This parallel group, open-label phase 3 trial was registered under #RECF0219 at French National Cancer Institute.\n\n\nRESULTS\nOne hundred and fifty patients were randomized in this trial (ABVD 80, BEACOPP 70): 28 years was the median age, 50% were male and IPS was 0-1 for 64%. Complete remission rate was 85% for ABVD and 90% for BEACOPP. Progression or relapses were more frequent in the ABVD patients than in the BEACOPP patients (17 versus 5 patients). With a median follow-up period of 5.5 years, seven patients died: six in the ABVD arm and one in the BEACOPP arm (HL 3 and 0, 2nd cancer 2 and 1, accident 1 and 0). The EFS at 5 years was estimated at 62% for ABVD versus 77%, for BEACOPP [hazards ratio (HR) = 0.6, P = 0.07]. The progression-free survival (PFS) at 5 years was 75% versus 93% (HR = 0.3, P = 0.007). The OS at 5 years was 92% versus 99% (HR = 0.18, P = 0.06).\n\n\nCONCLUSIONS\nFewer progressions/relapses were observed with BEACOPP, demonstrating the high efficacy of the more intensive regimen, even in low-risk patients. However, additional considerations, balancing treatment-related toxicity and late morbidity due to salvage may help with decision-making with regard to treatment with ABVD or BEACOPP.",
"affiliations": "Department of Onco-Hematology, Archet Hospital, Nice mounier.n@chu-nice.fr.;Department of Hematology, Saint-Louis Hospital, Paris.;Department of Hematology, Nancy Hospital.;Department of Hematology, Saint-Louis Hospital, Paris.;Department of Hematology, Henri Mondor Hospital, Creteil.;Department of Hematology, Besancon Hospital.;Department of Hematology, la Pitié-Salpétrière Hospital, Paris.;Department of Hematology, CHU de Dijon Hospital, Dijon.;Department of Hematology, St Etienne Hospital, St Etienne.;Department of Hematology, Courlancy Cancer Institute, Reims.;Department of Hematology, Reims Hospital, Reims.;Department of Hematology, Corbeil Hospital, Corbeil Essonnes.;Department of Hematology, Lyon Sud Hospital, Pierre Benite.;Department of Hematology, Leon Berard Cancer Center, Lyon.;Department of Hematology, St Antoine Hospital, Paris.;Department of Hematology, Colmar Hospital, Colmar, France.;Department of Hematology, Mont Godine Hospital, Yvoire, Belgium.;Department of Hematology, Gustave Roussy Institute, Villejuif, France.",
"authors": "Mounier|N|N|;Brice|P|P|;Bologna|S|S|;Briere|J|J|;Gaillard|I|I|;Heczko|M|M|;Gabarre|J|J|;Casasnovas|O|O|;Jaubert|J|J|;Colin|P|P|;Delmer|A|A|;Devidas|A|A|;Bachy|E|E|;Nicolas-Virelizier|E|E|;Aoudjhane|A|A|;Humbrecht|C|C|;Andre|M|M|;Carde|P|P|;|||",
"chemical_list": "D001761:Bleomycin; D011344:Procarbazine; D014750:Vincristine; D014747:Vinblastine; D005047:Etoposide; D003606:Dacarbazine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdu189",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "25(8)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "Hodgkin lymphoma; intensive chemotherapy; phase 3 trial; prognostic factors; secondary malignancy",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D003520:Cyclophosphamide; D003606:Dacarbazine; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011241:Prednisone; D011344:Procarbazine; D016019:Survival Analysis; D016896:Treatment Outcome; D014747:Vinblastine; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "1622-8",
"pmc": null,
"pmid": "24827123",
"pubdate": "2014-08",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "ABVD (8 cycles) versus BEACOPP (4 escalated cycles ≥ 4 baseline): final results in stage III-IV low-risk Hodgkin lymphoma (IPS 0-2) of the LYSA H34 randomized trial.",
"title_normalized": "abvd 8 cycles versus beacopp 4 escalated cycles 4 baseline final results in stage iii iv low risk hodgkin lymphoma ips 0 2 of the lysa h34 randomized trial"
} | [
{
"companynumb": "FR-JNJFOC-20140821400",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "Cancer patients often suffer from pain related problems such as under-treatment of pain, ineffective and persistent opioid administration as well as adverse opioid use outcomes. There is a growing need for non-opioid analgesic alternatives for patients undergoing treatment for obstinate pain. Ketamine is a fast-acting N-methyl-D-aspartate (NMDA) receptor antagonist that has been emerging as an effective medication for pain alleviation. While protocols have been established for the use of Low-Dose Ketamine (LDK) for post-operative pain, there is growing evidence for using LDK as a clinical alternative to opioids in a palliative care setting. This case study involves monitoring the efficacy of LDK treatment in combination with opioid analgesics in a cancer patient in a hospital setting. This is a very selected case of a patient with Metastatic Prostate Cancer (Gleason 9 Adenocarcinoma) where LDK was shown to be efficacious at reducing pain when opioids and standard pain medications were not satisfactory. While the study involved using a relatively novel pharmacological protocol and close patient monitoring, the patient reported a sustained reduction in pain level based on the Numerical Rating Scale for months after the termination of LDK infusions. Moreover, the treatment also resulted in a reduction of total opioid usage after the addition of LDK. Although additional research is needed to ascertain optimal dosing schedules and route of Ketamine, given these promising findings, Ketamine may be a useful option for improving the treatment of refractory pain in patients with cancer and a good tool in palliative medicine for treating neoplastic pain.",
"affiliations": "Department of Physiology, Touro College of Osteopathic Medicine, Middletown, NY, USA.;Department of Physiology, Touro College of Osteopathic Medicine, Middletown, NY, USA.;Rutgers New Jersey Medical School, Newark, NJ, USA.;Pharmacy Department, Garnet Health Medical Center, Middletown, NY, USA.;Palliative Care Medicine, Garnet Health Medical Center, Middletown, NY, USA.;Department of Physiology, Touro College of Osteopathic Medicine, Middletown, NY, USA.",
"authors": "Patel|Sapan|S|;Tatachar|Vivas|V|;Singh|Aditya Bikram|AB|;Galea|Julia|J|;Fattakhov|Emma|E|;Kaur|Gurjinder|G|",
"chemical_list": "D000700:Analgesics; D000701:Analgesics, Opioid; D007649:Ketamine",
"country": "China",
"delete": false,
"doi": "10.21037/apm-20-1685",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2224-5820",
"issue": "10(7)",
"journal": "Annals of palliative medicine",
"keywords": "Low-dose ketamine (LDK); cancer; case report; neoplastic pain; palliative care",
"medline_ta": "Ann Palliat Med",
"mesh_terms": "D000700:Analgesics; D000701:Analgesics, Opioid; D004636:Emergency Service, Hospital; D006801:Humans; D007649:Ketamine; D008297:Male; D009369:Neoplasms; D010148:Pain, Intractable",
"nlm_unique_id": "101585484",
"other_id": null,
"pages": "8328-8333",
"pmc": null,
"pmid": "33615800",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Low-dose ketamine as an adjuvant for pain control in a cancer patient: a case report.",
"title_normalized": "low dose ketamine as an adjuvant for pain control in a cancer patient a case report"
} | [
{
"companynumb": "US-CADILA HEALTHCARE LIMITED-US-ZYDUS-070134",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OXYCODONE HYDROCHLORIDE"
},
... |
{
"abstract": "We present a unique case of a 62-year-old patient with bilateral osteonecrosis of the femoral heads secondary to corticosteroid use. She presented with an occult right femoral neck fracture and was treated with percutaneous pinning of the right femoral neck and a left-sided percutaneous drilling. Despite apparent appropriate technique, the patient sustained a left sub-trochanteric hip fracture while shifting in bed in the postoperative care unit and was taken back for cephalo-medullary nail fixation. Femoral head osteonecrosis may be an under-reported risk factor for development of pathological neck fractures. We present an overview of this topic along with suggestions for joint preservation treatment of similar patients at higher risk for perioperative fracture.",
"affiliations": "Department of Orthopaedic Surgery, Cleveland Clinic, Cleveland, Ohio.;Department of Orthopaedic Surgery, Cleveland Clinic Foundation Cleveland, Ohio.;Department of Orthopaedic Surgery, Cleveland Clinic, Cleveland, Ohio.;Department of Orthopaedic Surgery, Cleveland Clinic, Cleveland, Ohio.;Department of Orthopaedic Surgery, Cleveland Clinic, Cleveland, Ohio.;Department of Orthopaedic Surgery, Cleveland Clinic, Cleveland, Ohio.",
"authors": "Berger|Ryan J|RJ|;Sultan|Assem A|AA|;Cole|Connor|C|;Sodhi|Nipun|N|;Khlopas|Anton|A|;Mont|Michael A|MA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1090-3941",
"issue": "32()",
"journal": "Surgical technology international",
"keywords": null,
"medline_ta": "Surg Technol Int",
"mesh_terms": "D019299:Decompression, Surgical; D005260:Female; D005265:Femoral Neck Fractures; D006620:Hip Fractures; D006801:Humans; D008875:Middle Aged; D010020:Osteonecrosis",
"nlm_unique_id": "9604509",
"other_id": null,
"pages": "361-365",
"pmc": null,
"pmid": "29791709",
"pubdate": "2018-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Sub-Trochanteric Hip Fracture Following Core Decompression for Osteonecrosis in a Patient with a Pre-Existing Contralateral Occult Femoral Neck Fracture.",
"title_normalized": "sub trochanteric hip fracture following core decompression for osteonecrosis in a patient with a pre existing contralateral occult femoral neck fracture"
} | [
{
"companynumb": "US-TEVA-2018-US-977615",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.