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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.

BackgroundNonoperative management after neoadjuvant treatment in low rectal cancer enables organ preservation and avoids surgical morbidity. Our aim is to compare oncological outcomes in patients with clinical complete response in watch and wait strategy with those who received neoadjuvant therapy followed by surgery with a pathological complete response.MethodsPatients with non-metastatic rectal cancer after neoadjuvant treatment with clinical complete response in watch and wait approach (group 1,n= 26) and complete pathological responders (ypT0N0) after chemoradiotherapy and surgery (group 2,n= 22), between January 2011 and October 2018, were included retrospectively, and all of them evaluated and followed in a multidisciplinary team. A comparative analysis of local and distant recurrence rates and disease-free and overall survival between both groups was carried out. Statistical analysis was performed using log-rank test, Cox proportional hazards regression model, and Kaplan-Meier curves.ResultsNo differences were found between patient’s demographic characteristics in both groups. Group 1: distance from the anal verge mean 5 cm (r= 1–12), 10 (38%) stage III, and 7 (27%) circumferential resection margin involved. The median follow-up of 47 months (r= 6, a 108). Group 2: distance from the anal verge mean 7 cm (r= 2–12), 16 (72%) stage III, and 13 (59%) circumferential resection margin involved. The median follow-up 49.5 months (r= 3, a 112). Local recurrence: 2 patients in group 1 (8.3%) and 1 in group 2 (4.8%) (p= 0.6235). Distant recurrence: 1 patient in group 1 (3.8%) and 3 in group 2 (19.2%) (p= 0.2237). Disease-free survival: 87.9% in group 1, 80% in group 2 (p= 0.7546). Overall survival: 86% in group 1 and 85% in group 2 (p= 0.5367).ConclusionOncological results in operated patients with pathological complete response were similar to those in patients under a watch and wait strategy mediating a systematic and personalized evaluation. Surgery can safely be deferred in clinical complete responders.

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., Facultad de Ciencias Médicas, Centro de Investigaciones Inmunológicas Básicas y Aplicadas

Neuroendocrine tumors (NET) include a spectrum of malignancies arising from neuroendocrine cells throughout the body. The objective of this clinical investigation of retrospectively and prospectively collected data was to describe the prevalence, demographic data, clinical symptoms and methods of diagnosis of NET and the treatment and long-term follow-up of patients with NET. Data were provided by the participating centers and assessed for consistency by internal reviewers. All the cases were centrally evaluated (when necessary) by the pathologists in our group. The tissue samples were reviewed by hematoxylin and eosin and immunohistochemical staining techniques to confirm the diagnosis of NET. In total, 532 cases were documented: 461 gastroenteropancreatic-NET (GEP-NET) and 71 bronchial NET (BNET). All the tumors were immunohistochemically defined according to the World Health Organization (WHO) and European Neuroendocrine Tumor Society criteria. The most common initial symptoms in GEP-NET were abdominal pain, diarrhea, bowel obstruction, flushing, gastrointestinal bleeding and weight loss. The most common tumor types were carcinoid (58.0%), non-functional pancreatic tumor (23.0%), metastatic NET of unknown primary (16.0%) and functional pancreatic tumor (3.0%). Of the BNET, 89.0% were typical and 11.0% atypical carcinoids. Of the patients with GEP-NET, 59.2% had distant metastasis at diagnosis. The locations of the primary tumors in GEP-NET were the small bowel (26.9%), pancreas (25.2%), colon-rectum (12.4%), appendix (7.6%), stomach (6.9%), esophagus (2.8%), duodenum (2.0%) and unknown primary (16.3%). The histological subtypes based on the WHO classification were well-differentiated NET (20.1%), well-differentiated neuroendocrine carcinomas (66.5%) and poorly differentiated neuroendocrine carcinomas (10.3%). Overall, 67.3% of the patients underwent surgery, 41.2% with curative intent and 26.1% for palliative purposes. The 5-year survival rates were 65.1% (95% confidence interval, 58.0-71.4%) in GEP-NET and 100.0% in typical carcinoid of the lung. This observational, non-interventional, longitudinal study aimed to accumulate relevant information regarding the epidemiology, clinical presentation and current practices in the treatment of NET patients in Argentina, providing insight into regional differences and patterns of care in this heterogeneous disease.

Purpose: Colorectal cancer is the second most frequent cancer and the second and third cause of cancer-related mortality in Argentina for men and women respectively. For locally advanced rectal cancer (LARC), preoperative chemoradiotherapy (CRT) ± induction chemotherapy (iCT) comprises the standard treatment. However, only 15-27% of patients achieve a pathological complete response, while 40-60% respond variably. This scenario poses a strong need for biomarkers able to predict response to CRT and provide guidance towards optimal treatment for each patient. Here we explore LARC gene expression data to identify baseline immune populations and pathways that might be associated with response to CRT. Methods: Using Agilent Human Genome Microarrays, we analyzed gene expression in pre-treatment tumor biopsies of 26 LARC patients as part of an ongoing prospective translational study in Argentina. After treatment with CRT (capecitabine + radiotherapy) ± iCT (capecitabine + oxaliplatin) and surgery, pathological response was assessed according to College of American Pathologists (CAP) guidelines. We grouped CAP scores 0-1 as responders and 2-3 as nonresponders. We estimated cellular heterogeneity of the microenvironment from transcriptomic data by applying two independent computational methods: GSVA and xCell, and inferred patient-specific pathway deregulation with PARADIGM. To elucidate differential features between both patient groups, we performed Two-sample t-Tests for GSVA and xCell, and Rank Product test for PARADIGM. All tests were adjusted for FDR Results: Of 26 analyzed patients, we focused on 16 with currently available response data. T-test yielded 98 differentially expressed genes. From the cell type estimators, among the responder group we observed upmodulation of genes related to B-cells (p-GSVA: 0.0001; p-xCell: 0.004), mast cells (p-GSVA: 0.038; p-xCell: 0.029), activated dendritic cells (p-GSVA: 0.035) and effector memory CD8+cells (p-xCell: 0.034). PARADIGM revealed upmodulated activities in responders such as ‘DNA damage', miR34A (regulation of tumor suppression), and TP73 (apoptotic response to DNA damage). Downmodulated pathways included E2F1/3 (transcriptional/cell cycle activation), PARP1 (DNA repair) and IL8 (tumorigenic/proangiogenic chemokine). For all cases, FDR-adjusted p < 0.0001. Conclusions: Considering the caveats regarding our current sample size, we could detect higher involvement of adaptive immunity cell populations, upmodulation of proapoptotic features, and downmodulation of DNA repair and proliferation activities in baseline biopsies of responders when compared to nonresponders. Overall, a cell cycle-decelerated tumor with poor DNA repair abilities immersed in a proapoptotic environment seems to be the one in which CRT would be more effective. With necessary validation of these analyses underway, we envision this effort as the basis on which we will evaluate genomic biomarkers for response prediction in our LARC population. Citation Format: Juan M. Sendoya, Soledad Iseas, Mariano Golubicki, Juan Robbio, Mariana F. Coraglio, Ubaldo Gualdrini, Ana Cabanne, Mirta Kujaruk, Vanesa Mikolaitis, Mariana Rizzolo, Ruben Salanova, Cecilia Rotondaro, Martin Abba, Osvaldo Podhajcer, Enrique Roca, Andrea Llera. Transcriptome-based inference of immune cell subsets and pathway deregulation in rectal cancer reveals biological processes related to therapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-374.