Microsatellite and RAS/RAF Mutational Status as Prognostic Factors in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

Background

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS.

Methods

Data were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS).

Results

The study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months [95% confidence interval (CI), 33.4–51.2 months], and the median DFS was 13.6 months (95% CI, 12.3–14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4–24.6 months). In addition to the known clinical factors, KRAS mutations (p = 0.005), BRAF mutations (p = 0.01), and MS status (p = 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%; p = 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index [hazard ratio (HR), 1.05 per point], completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS.

Conclusion

For patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients.

     

Nonredundant roles of antibody,cytokines, and perforin in the eradication of established Her-2/neu carcinomas

Since the mechanisms by which specific immunity destroys Her-2/neu carcinoma cells are highly undetermined, these were assessed in BALB/c mice vaccinated with plasmids encoding extracellular and transmembrane domains of the protein product (p185(neu)) of the rat Her-2/neu oncogene shot into the skin by gene gun. Vaccinated mice rejected a lethal challenge of TUBO carcinoma cells expressing p185(neu). Depletion of CD4 T cells during immunization abolished the protection, while depletion of CD8 cells during the effector phase halved it, and depletion of polymorphonuclear granulocytes abolished all protection. By contrast, Ig mu-chain gene KO mice, as well as Fcgamma receptor I/III, beta-2 microglobulin, CD1, monocyte chemoattractant protein 1 (MCP1), IFN-gamma, and perforin gene KO mice were protected. Only mice with both IFN-gamma and perforin gene KOs were not protected. Although immunization also cured all BALB/c mice bearing established TUBO carcinomas, it did not cure any of the perforin KO or perforin and IFN-gamma KO mice. Few mice were cured that had knockouts of the gene for Ig mu-chain, Fcgamma receptor I/III, IFN-gamma, or beta-2 microglobulin. Moreover, vaccination cured half of the CD1 and the majority of the MCP1 KO mice. The eradication of established p185(neu) carcinomas involves distinct mechanisms, each endowed with a different curative potential.     

Absent CNKSR2 causes seizures and intellectual,attention, and language deficits

Synaptic function is central to brain function. Understanding the synapse is aided by studies of patients lacking individual synaptic proteins. Common neurological diseases are genetically complex. Their understanding is likewise simplified by studies of less common monogenic forms. We detail the disease caused by absence of the synaptic protein CNKSR2 in 8 patients ranging from 6 to 62 years old. The disease is characterized by intellectual disability, attention problems, and abrupt lifelong language loss following a brief early childhood epilepsy with continuous spike‐waves in sleep. This study describes the phenotype of CNKSR2 deficiency and its involvement in systems underlying common neurological disorders. Ann Neurol 2014;76:758–764     

Defining High Risk: Cost-Effectiveness of Extended-Duration Thromboprophylaxis Following Major Oncologic Abdominal Surgery

Purpose

Extended-duration thromboprophylaxis (EDTPPX) is the practice of prescribing antithrombotic therapy for 21 days after discharge, commonly used in surgical patients who are at high risk for venothromboembolism (VTE). While guidelines recommend EDTPPX, criteria are vague due to a paucity of data. The criteria can be further informed by cost-effectiveness thresholds. This study sought to determine the VTE incidence threshold for the cost-effectiveness of EDTPPX compared to inpatient prophylaxis.

Methods

A decision tree was used to compare EDTPPX for 21 days after discharge to 7 days of inpatient prophylaxis with base case assumptions based on an abdominal oncologic resection without complications in an otherwise healthy individual. Willingness to pay was set at $50,000/quality-adjusted life year (QALY). Sensitivity analyses were performed to assess uncertainty within the model, with particular interest in the threshold for cost-effectiveness based on VTE incidence.

Results

EDTPPX was the dominant strategy when VTE probability exceeds 2.39 %. Given a willingness to pay threshold of $50,000/QALY, EDTPPX was the preferred strategy when VTE incidence exceeded 1.22 and 0.88 % when using brand name or generic medication costs, respectively.

Conclusions

EDTPPX should be recommended whenever VTE incidence exceeds 2.39 %. When post-discharge estimated VTE risk is 0.88–2.39 %, patient preferences about self-injections and medication costs should be considered.     

Corticotropin-releasing hormone antagonists possess anti-inflammatory effects in the mouse ileum

BACKGROUND & AIMS: Corticotropin-releasing hormone (CRH) released at local sites of inflammation promotes inflammation in the periphery. We investigated its effects in the intestinal responses caused by toxin A from Clostridium difficile, the causative agent of antibiotic-associated colitis. METHODS: Ileal loops were injected with 10 microg of toxin A, and enterotoxic responses were measured at various time points. RESULTS: Pretreatment of mice with 2.5 microg/kg of the CRH receptor antagonist alpha-helical CRH((9-41)) that blocks both CRH receptor subtypes reduced toxin A-mediated ileal secretion, epithelial cell damage, mucosal edema, neutrophil infiltration, and mucosal content of interleukin 1 beta and tumor necrosis factor alpha. Pretreatment with the specific CRH(1) receptor antagonist antalarmin (20 mg/kg, IP) also inhibited toxin A-induced fluid secretion and toxin A-associated histologic changes. CRH messenger RNA and protein were increased in mouse ileum 30 minutes after intraluminal toxin A administration. In situ hybridization and immunohistochemistry demonstrated that toxin A at 1 hour caused a substantial increase in the expression of both CRH receptor subtypes in the ileal mucosa. CONCLUSIONS: Peripheral CRH may play a proinflammatory role in toxin A-induced intestinal secretion and inflammation and that CRH(1) receptor, at least in part, is important in the mediation of these responses.     

Dinámica de la infección por Helicobacter pylori en lactantes durante los primeros 6 meses de vida

Introduction

Mainly due to the high percentage of infection and the ineffectiveness of treatments, Helicobacter pylori is a global health problem. Knowing the age at acquisition is key to preventing the infection.

Assessment of renal flow and flow reserve in humans.

OBJECTIVES: The purpose of this work was to establish the normal range of maximal renal hyperemic response in humans and to identify the ideal renal vasodilatory stimuli. BACKGROUND: Stenotic renovascular atherosclerosis is increasingly treated by percutaneous transluminal renal intervention but with an unpredictable outcome. This may be due to hemodynamically non-significant stenosis or the presence of irreversible damage to the glomerular circulation. We propose that the renovascular hyperemic response may help identify appropriate patients. METHODS: In 28 normotensive patients, quantitative angiographic measurements of the renal artery were obtained, and renal artery pressure and flow velocity were continuously recorded after various hyperemic agents. RESULTS: In a first group of 11 patients, a significant increase in renal artery average peak velocity (APV) was observed after intrarenal (IR) bolus injection of 600 microg isosorbide dinitrate (41 +/- 19%), 30 mg papaverine (50 +/- 34%), 50 microg dopamine (94 +/- 54%), 0.8 microg x kg(-1) fenoldopam (80 +/- 25%), and during IR infusion of 1 microg x kg(-1) x min(-1) fenoldopam (86 +/- 28%). A second group of 17 patients received intravenous infusion of dopamine (3, 5, 10, 20, 30, and 40 microg x kg(-1) x min(-1)). The 3 and 5 microg x kg(-1) x min(-1) of dopamine modestly reduced renal resistance index (RI) (-13 +/- 15% and -25 +/- 20%, respectively). At higher dosages, no further decline in RI was observed. No significant change in vessel diameter was observed before and after the administration of the pharmacological stimuli suggesting that changes in APV corresponded with changes in absolute renal blood flow. CONCLUSIONS: The normal renal flow reserve averages approximately 2 in humans with normal renal function. An IR bolus injection of 50 microg x kg(-1) of dopamine is the most convenient means to elicit maximal renal hyperemia.