Combined assessment of the TNM stage and BRAF mutational status at diagnosis in sporadic colorectal cancer patients.

The prognostic impact of KRAS mutations and other KRAS-related and non-related genes such as BRAF, NRAS and TP53, on sporadic colorectal cancer (sCRC) remain controversial and/or have not been fully established. Here we investigated the frequency of such mutations in primary sCRC tumors and their impact on patient progression-free survival (PFS) and overall survival (OS). Primary tumor tissues from 87 sCRC patients were analysed using a custom-built next generation sequencing (NGS) panel to assess the hotspot mutated regions of KRAS/NRAS (exons 2, 3 and 4), BRAF (exon 15) and TP53 (all exons). Overall, mutations in these genes were detected in 46/87 sCRC tumors analyzed (53%) with the following frequencies per gene: TP53, 33%; KRAS, 28%; BRAF, 7%; and NRAS, 1%. A significant association was found between KRAS mutations and right side colon tumor location (p=0.05), well-differentiated tumors (p=0.04) and absence of lymphovascular invasion (p=0.05). In turn, BRAF-mutated tumors frequently corresponded to poorly- or moderately-differentiated sCRC (p=0.02) and showed a higher frequency of peritoneal carcinomatosis (p=0.006) and microsatellite instability (p=0.007). From the prognostic point of view, the BRAF mutational status together with the TNM stage were the only variables that showed an independent adverse impact on patient outcome in the multivariate analyses for both PFS and OS. Based on these results a scoring system was built and patients were classified into three prognostic subgroups with different PFS rates at 2 years: 91% vs. 77% vs. 0%, respectively (p<0.0001). Additional prospective studies in larger series of sCRC patients where mutations in genes other than those investigated here are required to validate the utility of the proposed predictive model.

Prognostic impact of a novel gene expression profile classifier for the discrimination between metastatic and non-metastatic primary colorectal cancer tumors.

Despite significant advances have been achieved in the genetic characterization of sporadic colorectal cancer (sCRC), the precise genetic events leading to the development of distant metastasis remain poorly understood. Thus, accurate prediction of metastatic disease in newly-diagnosed sCRC patients remains a challenge. Here, we evaluated the specific genes and molecular pathways associated with the invasive potential of colorectal tumor cells, through the assessment of the gene expression profile (GEP) of coding and non-coding genes in metastatic (MTX) vs. non-metastatic (non-MTX) primary sCRC tumors followed for >5 years. Overall, MTX tumors showed up-regulation of genes associated with tumor progression and metastatic potential while non-MTX cases displayed GEP associated with higher cell proliferation, activation of DNA repair and anti-tumoral immune/inflammatory responses. Based on only 19 genes a specific GEP that classifies sCRC tumors into two MTX-like and non-MTX-like molecular subgroups was defined which shows an independent prognostic impact on patient overall survival, particularly when it is combined with the lymph node status at diagnosis. In summary, we show an association between the global GEP of primary sCRC cells and their metastatic potential and defined a GEP-based classifier that provides the basis for further prognostic stratification of sCRC patients who are at risk of distant metastases.

Genomic characterization of liver metastases from colorectal cancer patients.

Metastatic dissemination is the most frequent cause of death of sporadic colorectal cancer (sCRC) patients. Genomic abnormalities which are potentially characteristic of such advanced stages of the disease are complex and so far, they have been poorly described and only partially understood. We evaluated the molecular heterogeneity of sCRC tumors based on simultaneous assessment of the overall GEP of both coding mRNA and non-coding RNA genes in primary sCRC tumor samples from 23 consecutive patients and their paired liver metastases. Liver metastases from the sCRC patients analyzed, systematically showed deregulated transcripts of those genes identified as also deregulated in their paired primary colorectal carcinomas. However, some transcripts were found to be specifically deregulated in liver metastases (vs. non-tumoral colorectal tissues) while expressed at normal levels in their primary tumors, reflecting either an increased genomic instability of metastatic cells or theiradaption to the liver microenvironment. Newly deregulated metastatic transcripts included overexpression of APOA1, HRG, UGT2B4, RBP4 and ADH4 mRNAS and the miR-3180-3p, miR-3197, miR-3178, miR-4793 and miR-4440 miRNAs, together with decreased expression of the IGKV1-39, IGKC, IGKV1-27, FABP4 and MYLK mRNAS and the miR-363, miR-1, miR-143, miR-27b and miR-28-5p miRNAs. Canonical pathways found to be specifically deregulated in liver metastatic samples included multiple genes related with intercellular adhesion and the metastatic processes (e.g., IGF1R, PIK3CA, PTEN and EGFR), endocytosis (e.g., the PDGFRA, SMAD2, ERBB3, PML and FGFR2), and the cell cycle (e.g., SMAD2, CCND2, E2F5 and MYC). Our results also highlighted the activation of genes associated with the TGFß signaling pathway, -e.g. RHOA, SMAD2, SMAD4, SMAD5, SMAD6, BMPR1A, SMAD7 and MYC-, which thereby emerge as candidate genes to play an important role in CRC tumor metastasis.

Improving the outcome of acute cholecystitis: the non-standardized treatment must no longer be employed.

PURPOSE: Therapeutic recommendations of acute cholecystitis are not consistently implemented, which generates greater patient morbidity and higher health care costs. The aim of this article is to evaluate the burden of acute cholecystitis, to detect potentially modifiable variables, and to propose a therapeutic strategy that will allow us to improve the quality of care. METHODS: We carried out a retrospective study of patients who were admitted to the hospital from January 2010 to December 2012 using a univariate analysis of parameters including the admitting department, age, treatment administered, and length of stay. RESULTS: A total of 967 patients were admitted to the hospital with a diagnosis of acute cholecystitis, 692 (72%) to the Surgery Department, 257 (26%) to Internal Medicine-Digestive, and 18 (2%) to other departments. Four hundred ninety-eight (51.5%) were operated on: 107 (21%) on an urgent basis, 111 (22%) at an early stage (<96 h at diagnosis), 152 (30%) at a late stage (>96 h at diagnosis), and 128 (26%) at a delayed date (other admission). Patients who were admitted into the surgery department were five times more likely to be operated on than patients admitted into other departments (p<0.01). Patients operated on at a late stage had a longer length of stay than early stage surgery patients (p<0.05) and than non-operated ones (p<0.05). Patients<74 years old were more frequently operated than older ones (p<0.05). CONCLUSIONS: The non-standardized treatment of acute cholecystitis causes high clinical and surgical variability, long average stay, more readmissions, and high hospital costs. Therefore, patients with a diagnosis of acute cholecystitis should be admitted to the Surgery Department, thereby increasing the probability of receiving definite treatment.

In vitro immunoblockade of VIP inhibits the proliferation of pituitary prolactin cells.

VIP is a peptide synthesised in the pituitary gland and is involved in the stimulation of prolactin secretion. However, to date it has not been determined whether VIP is able to regulate the proliferation of pituitary prolactin-producing cells, like other factors involved in the regulation of prolactin such as estradiol or dopamine. The aim of the present study was to address whether VIP is involved in regulating the proliferation of pituitary prolactin-secreting cells. Thus, we performed an in vitro study on monolayer cultures of rat pituitary cells, neutralising the possible paracrine effect of VIP by immunoblockade of the peptide and later determining the degree of proliferation of prolactin-secreting cells. The effects of immunoblockade were validated by determining the levels of VIP in the culture media, which were decreased (P < 0.01), and modifications in the patterns of the immunohistochemical reaction to prolactin-positive cells. Immunoblockade of VIP decreased the proliferation of pituitary prolactin-positive cells at all antibody concentrations analysed, mainly between 3 and 12 h (P < 0.01). Moreover, immunoblockade decreased the sizes of the cellular and nuclear areas, except at 1 h, at which point it only decreased the nuclear area of prolactin-positive cells. The results obtained suggest that-in the same way as it regulates the secretion of the hormone-VIP could be involved in regulating the proliferation of prolactin cells, like estradiol or dopamine.

Feocromocitoma extraadrenal: actualización de los aspectos más controvertidos. A propósito de dos casos / Extra-adrenal pheochromocytoma: update of the most controversial features. A propos of two cases

Los feocromocitomas son tumores neuroendocrinospoco frecuentes, habitualmente sintomáticos y en la mayoría de los casos esporádicos, que se suelen localizar en la médula suprarrenal. Presentamos 2 casos de feocromocitoma extraadrenal no funcionan-te localizados en el retroperitoneo, aparentemente benignos, esporádicos y no asociados con otras neoplasias endocrinas ni enfermedades hereditarias. Empleamos ecografía, tomografía computarizada y resonancia magnética antes de la escisión completa del tumor por vía abdominal abierta, así como diversas técnicas inmunohistoquímicas para llegar al diagnóstico definitivo. Tras 8 y 14 meses de seguimiento no hay evidencia de recidiva de la enfermedad ni de aparición de otros síndromes. Como consecuencia de estos casos, llevamos a cabo una revisión bibliográfica centrándonos en los puntos más controvertidos (AU)

Pheochromocytomas are uncommon neuroendocrine tumors. They are usually symptomatic and sporadic and are generally located in the adrenal medulla. We present two cases of extra-adrenal nonfunctional pheochromocytomas located in the retro peritoneum. The tumors were apparently benign and sporadic and were not associated with other neoplasms or hereditary diseases. Ultrasonography, computed axial tomography and magnetic resonance imaging were performed before complete excision of the tumors using open abdominal surgery. Several immunohistochemical techniques were performed to reach the definitive diagnosis. After 8 and 14 months of follow-up, there is no evidence of recurrence or other syndromes. As a consequence of these two cases, we performed review of the literature on the topic, focussing on the most controversial areas (AU)

[Extra-adrenal pheochromocytoma: update of the most controversial features. Apropos of two cases]. / Feocromocitoma extraadrenal: actualización de los aspectos más controvertidos. A propósito de dos casos.

Pheochromocytomas are uncommon neuroendocrine tumors. They are usually symptomatic and sporadic and are generally located in the adrenal medulla. We present two cases of extra-adrenal nonfunctional pheochromocytomas located in the retroperitoneum. The tumors were apparently benign and sporadic and were not associated with other neoplasms or hereditary diseases. Ultrasonography, computed axial tomography and magnetic resonance imaging were performed before complete excision of the tumors using open abdominal surgery. Several immunohistochemical techniques were performed to reach the definitive diagnosis. After 8 and 14 months of follow-up, there is no evidence of recurrence or other syndromes. As a consequence of these two cases, we performed a review of the literature on the topic, focussing on the most controversial areas.