Spatio-temporal tumor heterogeneity in metastatic CRC tumors: a mutational-based approach

[EN] It is well known that activating mutations in the KRAS and NRAS genes are associated with poor response to anti-EGFR therapies in patients with metastatic colorectal cancer (mCRC). Approximately half of the patients with wild-type (WT) KRAS colorectal carcinoma do not respond to these therapies. This could be because the treatment decision is determined by the mutational profile of the primary tumor, regardless of the presence of small tumor subclones harboring RAS mutations in lymph nodes or liver metastases. We analyzed the mutational profile of the KRAS, NRAS, BRAF and PI3KCA genes using low-density microarray technology in samples of 26 paired primary tumors, 16 lymph nodes and 34 liver metastases from 26 untreated mCRC patients (n=76 samples). The most frequent mutations found in primary tumors were KRAS (15%) and PI3KCA (15%), followed by NRAS (8%) and BRAF (4%). The distribution of the mutations in the 16 lymph node metastases analyzed was as follows: 4 (25%) in KRAS gene, 3 (19%) in NRAS gene and 1 mutation each in PI3KCA and BRAF genes (6%). As expected, the most prevalent mutation in liver metastasis was in the KRAS gene (35%), followed by PI3KCA (9%) and BRAF (6%). Of the 26 cases studied, 15 (58%) displayed an overall concordance in the mutation status detected in the lymph node metastases and liver metastases compared with primary tumor, suggesting no clonal evolution. In contrast, the mutation profiles differed in the primary tumor and lymph node/metastases samples of the remaining 11 patients (48%), suggesting a spatial and temporal clonal evolution. We confirm the presence of different mutational profiles among primary tumors, lymph node metastases and liver metastases. Our results suggest the need to perform mutational analysis in all available tumor samples of patients before deciding to commence anti-EGFR treatment

Coenzyme Q10 deficiency associated with a mitochondrial DNA depletion syndrome: A case report

4 páginas, 1 figura, 1 tabla.-- et al.[Objectives]: To report on a case with a mitochondrial DNA (mtDNA) depletion syndrome. [Design and methods]: Laboratory studies were done in muscle biopsy and fibroblasts to evaluate coenzyme Q10 (CoQ10) status and quantify mitochondrial DNA. [Results]: Decreased CoQ10 values and a 78% of mtDNA depletion were detected in muscle. Mutational studies failed to reveal any pathogenic mutation in nuclear genes related with mtDNA maintenance. [Conclusions]: mtDNA depletion syndrome was associated with CoQ10 deficiency in our patient.This project was supported by grants from the Instituto de Salud Carlos III (FIS:PI04–0009, PI07-0045, PI04-0567 and PI04-1351), Diputación General de Aragón (Grupos Consolidados B33) and European Union contract LSHB-CT-2004-005151. M.D.H-M. is supported by a predoctoral fellowship FIS (FI05/00501). The CIBER de Enfermedades Raras is an initiative of the ISCIII.Peer reviewe

Analysis of Coenzyme Q10 in muscle and fibroblasts for the diagnosis of CoQ10 deficiency syndromes

4 páginas, 2 tablas.OBJECTIVES: To study CoQ(10) concentrations in muscle and fibroblast from 6 patients with a CoQ(10) deficiency syndrome. DESIGN AND METHODS: CoQ(10) was quantified by HPLC with electrochemical detection. RESULTS: Four out of the 6 cases showed muscle CoQ(10) deficiency plus a reduction of mitochondrial respiratory chain enzyme activities. All cases showed decreased CoQ(10) values in fibroblasts when compared with controls. CONCLUSIONS: Biochemical study of CoQ(10) in both muscle and fibroblasts seems advisable to demonstrate the deficiency in all patients.This work was supported by grants PI040567, 041617 and 041351 from the FIS, Ministerio de Sanidad, Spain, and European Union contract LSHB-CT-2004-005151 (UBIGENES).Peer reviewe

Obras clásicas para la historia de Filipinas [Recurso electrónico]

Tipo de archivo: TextoPC 486; 8 Mb de memoria RAM; MS-DOS 6.0 y Microsoft Windows 3.1 o superior; Espacio libre en disco duro superior a 10 Mb; Monitor VGA; Lector de CD-ROM.Tít. tomado de la etiquetaAlcázar, José De: Historia de los dominios españoles en Oceanía: Filipinas. Manila: J. Atayde y Comp., 1895. -- Blanco Herrero, Miguel: Política de España en ultramar. Madrid: Sucesores de Ribadeneyra, 1888. -- Buzeta, Manuel; Bravo, FelipeE: Diccionario geográfico, estadístico, histórico de las Islas Filipinas [2 vol.]. Madrid: [s. n.], [1850?]. -- Combés, Francisco:Historia deMindanao y Joló.Madrid:W. E. Retana, 1897. -- Comyn, Tomás De: Estado de las islas Filipinas en 1810. Madrid: Imprenta de Repullés, 1820. -- Fernández De Navarrete, Martín: Colección de los viajes y descubrimientos que hicieron por mar los españoles [2 vol.: IV y V]. Madrid: Imprenta Nacional, 1837. -- Gayo, Fr. Jesús, O. P.: Discurso leído en la solemne apertura del curso académico 1950-1951. Manila: UST. Press, 1950. -- Martín Cerezo, Saturnino: El sitio de Baler: notas y recuerdos. Madrid: Antonio G. Izquierdo, 1911. -- Montero y Vidal, José: Historia general de Filipinas: desde el descubrimiento de dichas islas hasta nuestros días [3 vol.]. Madrid: [s. n.] 1887-1895. -- Moya y Jiménez, Francisco Javier De: Las islas Filipinas en 1882: Estudios históricos, geográficos, estadísticos y descriptivos. Madrid: Imprenta de la Sucesora de M. Minuesa de los Ríos, 1883. -- Navarro, Eduardo: Documentos indispensables para la verdadera historia de Filipinas [2 vol.]. Madrid: Imprenta del asilo de huésfanos, 1908. -- Pigafetta, Antonio: Primer viaje en torno del globo.Madrid: Espasa-Calpe, 1927. -- Retana, W. E.: Archivo del bibliófilo filipino [4 vol.]. Madrid: Imprenta de la viuda de M. Minuesa de los Ríos, 1895. -- Retana, W. E.: Aparato bibliográfico de la historia general de Filipinas [3 vol.]: Volumen 1: (Años 1529-1800); Volumen 2: (Años 1801-1886); Volumen 3: (Años: 1887-1905 — 1811-1905). Madrid: Imprenta de la Sucesora de M. Minuesa de los Ríos, 1906. -- Retana, W. E..: Vida y escritos del Dr. José Rizal. Madrid: Librería general de Victoriano Suárez, 1907. -- Sastrón, Manuel: Insurreción en Filipinas. Madrid: [s. n.], 1901. -- Torres y Lanzas, Pedro: Catálogo de los documentos relativos a las islas Filipinas existentes en el Archivo de Indias de Sevilla: Tomo I: (1493-1572). Barcelona: Compañía de Tabacos General de Filipinas, 1925. -- Vergara, Francisco-Engracio: La masonería en Filipinas: Estudio de actualidad: Apuntes para la historia de la colonización española en el siglo XIX. París: [s. n.], 1896

Guía de Terapéutica Antimicrobiana del Área Aljarafe, 3ª edición

Coordinadora: Rocío Fernández Urrusuno. Co-coordinadora: Carmen Serrano Martino.YesEstas guías son un recurso indispensable en los Programas de Optimización de Antibióticos (PROA). No sólo constituyen una herramienta de ayuda para la toma de decisiones en los principales síndromes infecciosos, proporcionando recomendaciones para el abordaje empírico de dichos procesos, sino que son el patrón/estándar de referencia que permitirá determinar la calidad o adecuación de los tratamientos realizados. Las guías pueden ser utilizadas, además, como herramienta de base para la formación y actualización en antibioterapia, ya que permiten mantener actualizados los conocimientos sobre las nuevas evidencias en el abordaje de las infecciones. Por último, deberían incorporar herramientas que faciliten el proceso de toma de decisiones compartidas con el paciente. El objetivo de esta guía es proporcionar recomendaciones para el abordaje de las enfermedades infecciosas más prevalentes en la comunidad, basadas en las últimas evidencias disponibles y los datos de resistencias de los principales patógenos que contribuyan a mejorar la calidad de la prescripción de antimicrobianos

Novel Benchmark Values for Open Major Anatomic Liver Resection in Non-Cirrhotic Patients. A Multicentric Study of 44 International Expert Centers

OBJECTIVE: This study aims at establishing benchmark values for best achievable outcomes following open major anatomic hepatectomy for liver tumors of all dignities. BACKGROUND: Outcomes after open major hepatectomies vary widely lacking reference values for comparisons among centers, indications, types of resections, and minimally invasive procedures. METHODS: A standard benchmark methodology was used covering consecutive patients, who underwent open major anatomic hepatectomy from 44 high-volume liver centers from 5 continents over a 5-year period (2016-2020). Benchmark cases were low-risk non-cirrhotic patients without significant comorbidities treated in high-volume centers (≥30 major liver resections/year). Benchmark values were set at the 75th percentile of median values of all centers. Minimum follow-up period was 1 year in each patient. RESULTS: Of 8044 patients, 2908 (36%) qualified as benchmark (low-risk) cases. Benchmark cutoffs for all indications include R0 resection ≥78%; liver failure (grade B/C) ≤10%; bile leak (grade B/C) ≤18%; complications ≥grade 3 and CCI ® ≤46% and ≤9 at 3 months, respectively. Benchmark values differed significantly between malignant and benign conditions so that reference values must be adjusted accordingly. Extended right hepatectomy (H1, 4-8 or H4-8) disclosed a higher cutoff for liver failure, while extended left (H1-5,8 or H2-5,8) were associated with higher cutoffs for bile leaks, but had superior oncologic outcomes, when compared to formal left hepatectomy (H1-4 or H2-4). The minimal follow-up for a conclusive outcome evaluation following open anatomic major resection must be 3 months. CONCLUSION: These new benchmark cutoffs for open major hepatectomy provide a powerful tool to convincingly evaluate other approaches including parenchymal-sparing procedures, laparoscopic/robotic approaches, and alternative treatments, such as ablation therapy, irradiation, or novel chemotherapy regimens

Stoma-free survival after anastomotic leak following rectal cancer resection: worldwide cohort of 2470 patients

Background: The optimal treatment of anastomotic leak after rectal cancer resection is unclear. This worldwide cohort study aimed to provide an overview of four treatment strategies applied. Methods: Patients from 216 centres and 45 countries with anastomotic leak after rectal cancer resection between 2014 and 2018 were included. Treatment was categorized as salvage surgery, faecal diversion with passive or active (vacuum) drainage, and no primary/secondary faecal diversion. The primary outcome was 1-year stoma-free survival. In addition, passive and active drainage were compared using propensity score matching (2: 1). Results: Of 2470 evaluable patients, 388 (16.0 per cent) underwent salvage surgery, 1524 (62.0 per cent) passive drainage, 278 (11.0 per cent) active drainage, and 280 (11.0 per cent) had no faecal diversion. One-year stoma-free survival rates were 13.7, 48.3, 48.2, and 65.4 per cent respectively. Propensity score matching resulted in 556 patients with passive and 278 with active drainage. There was no statistically significant difference between these groups in 1-year stoma-free survival (OR 0.95, 95 per cent c.i. 0.66 to 1.33), with a risk difference of -1.1 (95 per cent c.i. -9.0 to 7.0) per cent. After active drainage, more patients required secondary salvage surgery (OR 2.32, 1.49 to 3.59), prolonged hospital admission (an additional 6 (95 per cent c.i. 2 to 10) days), and ICU admission (OR 1.41, 1.02 to 1.94). Mean duration of leak healing did not differ significantly (an additional 12 (-28 to 52) days). Conclusion: Primary salvage surgery or omission of faecal diversion likely correspond to the most severe and least severe leaks respectively. In patients with diverted leaks, stoma-free survival did not differ statistically between passive and active drainage, although the increased risk of secondary salvage surgery and ICU admission suggests residual confounding

Stoma-free Survival After Rectal Cancer Resection With Anastomotic Leakage: Development and Validation of a Prediction Model in a Large International Cohort.

Objective:To develop and validate a prediction model (STOMA score) for 1-year stoma-free survival in patients with rectal cancer (RC) with anastomotic leakage (AL).Background:AL after RC resection often results in a permanent stoma.Methods:This international retrospective cohort study (TENTACLE-Rectum) encompassed 216 participating centres and included patients who developed AL after RC surgery between 2014 and 2018. Clinically relevant predictors for 1-year stoma-free survival were included in uni and multivariable logistic regression models. The STOMA score was developed and internally validated in a cohort of patients operated between 2014 and 2017, with subsequent temporal validation in a 2018 cohort. The discriminative power and calibration of the models' performance were evaluated.Results:This study included 2499 patients with AL, 1954 in the development cohort and 545 in the validation cohort. Baseline characteristics were comparable. One-year stoma-free survival was 45.0% in the development cohort and 43.7% in the validation cohort. The following predictors were included in the STOMA score: sex, age, American Society of Anestesiologist classification, body mass index, clinical M-disease, neoadjuvant therapy, abdominal and transanal approach, primary defunctioning stoma, multivisceral resection, clinical setting in which AL was diagnosed, postoperative day of AL diagnosis, abdominal contamination, anastomotic defect circumference, bowel wall ischemia, anastomotic fistula, retraction, and reactivation leakage. The STOMA score showed good discrimination and calibration (c-index: 0.71, 95% CI: 0.66-0.76).Conclusions:The STOMA score consists of 18 clinically relevant factors and estimates the individual risk for 1-year stoma-free survival in patients with AL after RC surgery, which may improve patient counseling and give guidance when analyzing the efficacy of different treatment strategies in future studies