Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience.

CARD11-associated diseases are monogenic inborn errors of immunity involving immunodeficiency, predisposition to malignancy and immune dysregulation such as lymphoproliferation, inflammation, atopic and autoimmune manifestations. Defects in CARD11 can present as mutations that confer a complete or a partial loss of function (LOF) or contrarily, a gain of function (GOF) of the affected gene product. We report clinical characteristics, immunophenotypes and genotypes of 15 patients from our center presenting with CARD11-associated diseases. Index cases are pediatric patients followed in our immunology division who had access to next generation sequencing studies. Variant significance was defined by functional analysis in cultured cells transfected with a wild type and/or with mutated hCARD11 constructs. Cytoplasmic aggregation of CARD11 products was evaluated by immunofluorescence. Nine index patients with 9 unique heterozygous CARD11 variants were identified. At the time of the identification, 7 variants previously unreported required functional validation. Altogether, four variants showed a GOF effect as well a spontaneous aggregation in the cytoplasm, leading to B cell expansion with NF-κB and T cell anergy (BENTA) diagnosis. Additional four variants showing a LOF activity were considered as causative of CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS). The remaining variant exhibited a neutral functional assay excluding its carrier from further analysis. Family segregation studies expanded to 15 individuals the number of patients presenting CARD11-associated disease. A thorough clinical, immunophenotypical, and therapeutic management evaluation was performed on these patients (5 BENTA and 10 CADINS). A remarkable variability of disease expression was clearly noted among BENTA as well as in CADINS patients, even within multiplex families. Identification of novel CARD11 variants required functional studies to validate their pathogenic activity. In our cohort BENTA phenotype exhibited a more severe and expanded clinical spectrum than previously reported, e.g., severe hematological and extra hematological autoimmunity and 3 fatal outcomes. The growing number of patients with dysmorphic facial features strengthen the inclusion of extra-immune characteristics as part of the CADINS spectrum. CARD11-associated diseases represent a challenging group of disorders from the diagnostic and therapeutic standpoint, especially BENTA cases that can undergo a more severe progression than previously described.

Limitation of life support techniques at admission to the intensive care unit: a multicenter prospective cohort study.

PURPOSE: To determine the frequency of limitations on life support techniques (LLSTs) on admission to intensive care units (ICU), factors associated, and 30-day survival in patients with LLST on ICU admission. METHODS: This prospective observational study included all patients admitted to 39 ICUs in a 45-day period in 2011. We recorded hospitals' characteristics (availability of intermediate care units, usual availability of ICU beds, and financial model) and patients' characteristics (demographics, reason for admission, functional status, risk of death, and LLST on ICU admission (withholding/withdrawing; specific techniques affected)). The primary outcome was 30-day survival for patients with LLST on ICU admission. Statistical analysis included multilevel logistic regression models. RESULTS: We recruited 3042 patients (age 62.5 ± 16.1 years). Most ICUs (94.8%) admitted patients with LLST, but only 238 (7.8% [95% CI 7.0-8.8]) patients had LLST on ICU admission; this group had higher ICU mortality (44.5 vs. 9.4% in patients without LLST; p < 0.001). Multilevel logistic regression showed a contextual effect of the hospital in LLST on ICU admission (median OR = 2.30 [95% CI 1.59-2.96]) and identified the following patient-related variables as independent factors associated with LLST on ICU admission: age, reason for admission, risk of death, and functional status. In patients with LLST on ICU admission, 30-day survival was 38% (95% CI 31.7-44.5). Factors associated with survival were age, reason for admission, risk of death, and number of reasons for LLST on ICU admission. CONCLUSIONS: The frequency of ICU admission with LLST is low but probably increasing; nearly one third of these patients survive for ≥ 30 days.

Cirugía laparoscópica en el cáncer gástrico / Laparoscopic surgery in gastric cancer

Introducción. Aportamos nuestra experiencia en el tratamiento del cáncer gástrico mediante cirugía laparoscópica. Pacientes y método. Entre enero de 2003 y de 2004 hemos sustituido, en casos seleccionados, la laparotomía por la laparoscopia en la cirugía del cáncer gástrico. Aportamos nuestra experiencia con 8 pacientes de un total de 23 gastrectomías realizadas. En 6 hemos efectuado una gastrectomía total con reconstrucción esofagoyeyunal en "Y" de Roux a la que hemos asociado una pequeña laparotomía transversa subxifoidea para extraer la pieza y realizar la anastomosis esofagoyeyunal. En otros 2 casos hemos realizado una gastrectomía subtotal con reconstrucción en "Y" de Roux. La pequeña laparotomía transversa sólo se utiliza aquí para extraer la pieza. La linfadenectomía es la misma que en cirugía abierta: D2 completa en los tumores de tercio inferior y D1 más los grupos ganglionares 7, 8 y 9 del segundo nivel en los de cuerpo y fondo gástrico. Resultados. Los resultados aún son poco valorables debido al reducido número de pacientes operados. La mortalidad fue nula y la morbilidad del 12 por ciento. La duración media de las intervenciones fue de 230 min. Se redujeron los requerimientos de analgesia postoperatoria y la estancia hospitalaria media se situó en 8,3 días. Se reconvirtió a cirugía abierta a otros 3 pacientes. Conclusiones. La resección gástrica y la linfadenectomía asociada pueden realizarse perfectamente por laparoscopia de manera segura. Su mayor complejidad exige una mejor preparación en la técnica laparoscópica. En los escasos trabajos sobre el tema no se aprecian inconvenientes oncológicos para su realización (magnitud de la resección, linfadenectomía, recidivas) (AU)