Laparoscopic Prophylactic Total Gastrectomy for Hereditary Diffuse Gastric Cancer in CDH1 Mutation Carriers.

Background: Patients with hereditary diffuse gastric cancer (HDGC) and germline mutations in the E-cadherin gene, CDH1, have a very high cumulative lifetime risk of developing diffuse gastric cancer. In these patients, it is formally recommended to perform a prophylactic total gastrectomy (PTG). Materials and Methods: We analyzed the course of patients with HDGC who have undergone PTG in our institution. Pedigree analysis, preoperative screening results, operative course, postoperative data, and complete stomach pathologic examination were performed in all patients. Results: Seven patients with confirmed CDH1 mutation underwent PTG, five were women, and average age was 27 years (range 17-42). Signet ring cell carcinoma was found in 1 patient in the preoperative surveillance endoscopic biopsies. Laparoscopic PTG was performed in all patients. There were two complications, an intestinal obstruction that required reintervention and an asymptomatic esophagojejunal anastomosis leak that resolved with conservative treatment. In all gastrectomy specimens, intramucosal signet ring cell carcinoma foci limited to the lamina propria were found (range 1-31), 83.5% were in the body-fundus region. The mean follow-up was 28.5 months (range 8-72). The mean weight loss was 9% (range 2-18). Postoperative symptoms associated with Dumping syndrome were the most frequent. All the patients reported of being very satisfied with the procedure and of having a better quality of life than expected before the procedure. Conclusion: Laparoscopic PTG is an excellent resource to prevent the development of advanced diffuse gastric cancer (DGC) in patients with HDGC with CDH1 mutation. The procedure was well tolerated with a high satisfaction rate and very good functional results. It should be considered in these patients due to the high risk of developing advanced DGC and the lack of effective and reliable surveillance studies.

Prognostic Impact of An Integrative Landscape of Clinical, Immune, and Molecular Features in Non-Metastatic Rectal Cancer.

Rectal Cancer (RC) is a complex disease that involves highly variable treatment responses. Currently, there is a lack of reliable markers beyond TNM to deliver a personalized treatment in a cancer setting where the goal is a curative treatment. Here, we performed an integrated characterization of the predictive and prognostic role of clinical features, mismatch-repair deficiency markers, HER2, CDX2, PD-L1 expression, and CD3-CD8+ tumor-infiltrating lymphocytes (TILs) coupled with targeted DNA sequencing of 76 non-metastatic RC patients assigned to total mesorectal excision upfront (TME; n = 15) or neoadjuvant chemo-radiotherapy treatment (nCRT; n = 61) followed by TME. Eighty-two percent of RC cases displayed mutations affecting cancer driver genes such as TP53, APC, KRAS, ATM, and PIK3CA. Good response to nCRT treatment was observed in approximately 40% of the RC cases, and poor pathological tumor regression was significantly associated with worse disease-free survival (DFS, HR = 3.45; 95%CI = 1.14-10.4; p = 0.028). High neutrophils-platelets score (NPS) (OR = 10.52; 95%CI=1.34-82.6; p = 0.025) and KRAS mutated cases (OR = 5.49; 95%CI = 1.06-28.4; p = 0.042) were identified as independent predictive factors of poor response to nCRT treatment in a multivariate analysis. Furthermore, a Cox proportional-hazard model showed that the KRAS mutational status was an independent prognostic factor associated with higher risk of local recurrence (HR = 9.68; 95%CI = 1.01-93.2; p <0.05) and shorter DFS (HR = 2.55; 95%CI = 1.05-6.21; p <0.05), while high CEA serum levels were associated with poor DFS (HR = 2.63; 95%CI = 1.01-6.85; p <0.05). Integrated clinical and molecular-based unsupervised analysis allowed us to identify two RC prognostic groups (cluster 1 and cluster 2) associated with disease-specific OS (HR = 20.64; 95%CI = 2.63-162.2; p <0.0001), metastasis-free survival (HR = 3.67; 95%CI = 1.22-11; p = 0.012), local recurrence-free survival (HR = 3.34; 95%CI = 0.96-11.6; p = 0.043) and worse DFS (HR = 2.68; 95%CI = 1.18-6.06; p = 0.012). The worst prognosis cluster 2 was enriched by stage III high-risk clinical tumors, poor responders to nCRT, with low TILs density and high frequency of KRAS and TP53 mutated cases compared with the best prognosis cluster 1 (p <0.05). Overall, this study provides a comprehensive and integrated characterization of non-metastatic RC cases as a new insight to deliver a personalized therapeutic approach.

Pre-Existing Tumoral B Cell Infiltration and Impaired Genome Maintenance Correlate with Response to Chemoradiotherapy in Locally Advanced Rectal Cancer.

Locally advanced rectal cancer (LARC) remains a medical challenge. Reliable biomarkers to predict which patients will significantly respond to neoadjuvant chemoradiotherapy (nCRT) have not been identified. We evaluated baseline genomic and transcriptomic features to detect differences that may help predict response to nCRT. Eligible LARC patients received nCRT (3D-LCRT 50.4 Gy plus capecitabine 825 mg/m2/bid), preceded by three cycles of CAPOX in high systemic-relapse risk tumors, and subsequent surgery. Frozen tumor biopsies at diagnosis were sequenced using a colorectal cancer panel. Transcriptomic data was used for pathway and cell deconvolution inferential algorithms, coupled with immunohistochemical validation. Clinical and molecular data were analyzed according to nCRT outcome. Pathways related to DNA repair and proliferation (p < 0.005), and co-occurrence of RAS and TP53 mutations (p = 0.001) were associated with poor response. Enrichment of expression signatures related to enhanced immune response, particularly B cells and interferon signaling (p < 0.005), was detected in good responders. Immunohistochemical analysis of CD20+ cells validated the association of good response with B cell infiltration (p = 0.047). Findings indicate that the presence of B cells is associated with successful tumor regression following nCRT in LARC. The prevalence of simultaneous RAS and TP53 mutations along with a proficient DNA repair system that may counteract chemoradio-induced DNA damage was associated with poor response.

Anemia aguda en la hemorragia digestiva alta. Márgenes de seguridad para su manejo sin transufiones de glóbulos rojo / Acute anemia in high digestive hemorrhage. Margins of securety for their bandling without transfusion of red globules

La transfusión de glóbulos rojos en el paciente con hemorragia aguda, debe siempre ser evaluada en el contexto de una ecuación riesgo beneficio. Las tendencias actuales parecen concluir que resulta inseguro y poco confiable, la utilización de un valor "mágico" de hemotocrito (Hto) para decidir realizar una transfusión de glóbulos rojos. Nosotros hemos realizado un estudio prospectivo, controlado y randomizado, en 60 pacientes con hemorragia digestiva alta aguda, sin deterioro hemodinámico y se los dividió en dos grupos: 1) control: En los que la transfusión se realizaba para mantener el Hito en valores > 28 por ciento. 2) tratamiento: en los que se intensificó hemodilución normovolémica, con soluciones cristaloides y se los montuvo sin transfusión hasta un valor de Hto de 21 por ciento. Todos poseían diagnostico endoscópico de ingreso y fueron evaluados durante el estudio con controles clínicos y de laboratorio. Ambos grupos difirieron significativamente en el valor de el Hto. y Hb. No se observaron diferencias entre los grupos en el número de días de internación requeridos, ni en el número de falla de órganos presentado. Sí hubo diferencia significativa entre los grupos en la cantidad de unidades de glóbulos utilizadas (0.61 + 0.87 vs. 2.14 + 1.10; tratamiento y control respectivamente p < 0.001). El Score APACHE difirió significativamente, siendo mayor en el grupo tratamiento. Ello sugiere que aún los pacientes con mayor edad y probablemente menor reserva fisiológica pueden ser manejados con una conducta transfusional restrictiva, sin complicaciones graves. (AU)

Anemia aguda en la hemorragia digestiva alta. Márgenes de seguridad para su manejo sin transufiones de glóbulos rojo / Acute anemia in high digestive hemorrhage. Margins of securety for their bandling without transfusion of red globules

La transfusión de glóbulos rojos en el paciente con hemorragia aguda, debe siempre ser evaluada en el contexto de una ecuación riesgo beneficio. Las tendencias actuales parecen concluir que resulta inseguro y poco confiable, la utilización de un valor "mágico" de hemotocrito (Hto) para decidir realizar una transfusión de glóbulos rojos. Nosotros hemos realizado un estudio prospectivo, controlado y randomizado, en 60 pacientes con hemorragia digestiva alta aguda, sin deterioro hemodinámico y se los dividió en dos grupos: 1) control: En los que la transfusión se realizaba para mantener el Hito en valores > 28 por ciento. 2) tratamiento: en los que se intensificó hemodilución normovolémica, con soluciones cristaloides y se los montuvo sin transfusión hasta un valor de Hto de 21 por ciento. Todos poseían diagnostico endoscópico de ingreso y fueron evaluados durante el estudio con controles clínicos y de laboratorio. Ambos grupos difirieron significativamente en el valor de el Hto. y Hb. No se observaron diferencias entre los grupos en el número de días de internación requeridos, ni en el número de falla de órganos presentado. Sí hubo diferencia significativa entre los grupos en la cantidad de unidades de glóbulos utilizadas (0.61 + 0.87 vs. 2.14 + 1.10; tratamiento y control respectivamente p < 0.001). El Score APACHE difirió significativamente, siendo mayor en el grupo tratamiento. Ello sugiere que aún los pacientes con mayor edad y probablemente menor reserva fisiológica pueden ser manejados con una conducta transfusional restrictiva, sin complicaciones graves.