Lynch Syndrome from a surgeon perspective: retrospective study of clinical impact of mismatch repair protein expression analysis in colorectal cancer patients less than 50 years old.

BACKGROUND: In clinical practice, unexpected diagnosis of colorectal cancer in young patients requires prompt surgery, thus genetic testing for Lynch Syndrome is frequently missed, and clinical management may result incorrect. METHODS: Patients younger than 50 years old undergoing colorectal resection for cancer in the period 1994-2007 were identified (Group A, 49 cases), and compared to a group of randomly selected patients more than 50 (Group B, 85 cases). In 31 group A patients, immunohistochemical expression analysis of MLH1, MSH2 and MSH6 was performed; personal and familial history of patients with defective MMR proteins expression was further investigated, searching for synchronous and metachronous tumors in probands and their families. RESULTS: Fifty-one percent of patients did not express one or more MMR proteins (MMR-) and should be considered Lynch Syndrome carriers (16 patients, group A1); while only 31.2% of them were positive for Amsterdam criteria, 50% had almost another tumor, 37.5% had another colorectal tumor and 68% had relatives with colorectal tumor. This group of patients, compared with A2 group (< 50 years old, MMR+) and B group, showed typical characteristics of HNPCC, such as proximal location, mucinous histotype, poor differentiation, high stage and shorter survival. CONCLUSIONS: The present study confirms that preoperative knowledge of MMR proteins expression in colorectal cancer patients would allow correct staging, more extended colonic resection, specific follow-up and familial screening

Metachronous hepatic metastases from gastric carcinoma: a multicentric survey

BACKGROUND: The treatment of hepatic metastases from gastric cancer is controversial, due to biologic aggressiveness of the disease. OBJECTIVE: To survey the clinical approach to the subset of atients presenting with metachronous hepatic metastases as sole site of recurrence after curative resection of gastric cancer, focusing on the results achieved by different therapies and to investigate the prognostic factors of major clinical relevance. METHODS: Retrospective multi-center chart review evaluating 73 patients, previously submitted to D >or= 2 gastrectomy for gastric cancer, who developed exclusive hepatic recurrence. Prognostic factors related to the patient, to the gastric malignancy and its treatment, and to the metastatic disease and its therapy were evaluated. RESULTS: Forty-five patients received supportive care, 17 were submitted to chemotherapy, and 11 to hepatic resection. Survival was independently influenced by the variables T (p=0.019), N (p=0.05) and G (p=0.018) of the gastric primary and by the therapeutic approach to the metastases (p<0.005). In particular, T4 gastric cancer, presence of lymph-node metastases and G3 tumor displayed a negative prognostic value. Therapeutic approach to the metastases was the principal prognostic variable: 1, 2, and 3 years survival rates were 22.2%, 4.4% and 2.2%, respectively, for patients without specific treatment; 44.9%, 12.8% and 6.4% after chemotherapy (p=0.08) and 80.8%, 30.3% and 20.2% after surgical resection (p<0.001). CONCLUSIONS: Our data suggest some clinical criteria that may facilitate selection of therapy for patients with hepatic recurrence after primary gastric cancer resection. The best survival rates are associated with surgical treatment, which should be chosen whenever possible

Increased risk of second malignancy in pancreatic intraductal papillary mucinous tumors: Review of the literature.

AIM: To analyze the available evidence about the risk of extrapancreatic malignancies and pancreatic ductal adenocarcinoma associated to pancreatic intraductal papillary mucinous tumors (IPMNs). METHODS: A systematic search of literature was undertaken using MEDLINE, EMBASE, Cochrane and Web-of-Science libraries. No limitations for year of publication were considered; preference was given to English papers. All references in selected articles were further screened for additional publications. Both clinical series and Literature reviews were selected. For all eligible studies, a standard data extraction form was filled in and the following data were extracted: study design, number of patients, prevalence of pancreatic cancer and extrapancreatic malignancies in IPMN patients and control groups, if available. RESULTS: A total of 805 abstracts were selected and read; 25 articles were considered pertinent and 17 were chosen for the present systematic review. Eleven monocentric series, 1 multicentric series, 1 case-control study, 1 population-based study and 3 case report were included. A total of 2881 patients were globally analyzed as study group, and the incidence of pancreatic cancer and/or extrapancreatic malignancies ranged from 5% to 52%, with a mean of 28.71%. When a control group was analyzed (6 papers), the same incidence was as low as 9.4%. CONCLUSION: The available Literature is unanimous in claiming IPMNs to be strongly associated with pancreatic and extrapancreatic malignancies. The consequences in IPMNs management are herein discussed

Association between Serum Interleukin-6 Concentrations and Mortality in Older Adults: The Rancho Bernardo Study

Background: Interleukin-6 (IL-6) may have a protective role in acute liver disease but a detrimental effect in chronic liver disease. It is unknown whether IL-6 is associated with risk of liver-related mortality in humans. Aims: To determine if IL-6 is associated with an increased risk of all-cause, cardiovascular disease (CVD), cancer, and liverrelated mortality. Methods: A prospective cohort study included 1843 participants who attended a research visit in 1984–87. Multiple covariates were ascertained including serum IL-6. Multivariable-adjusted Cox proportional hazards regression analyses were used to examine the association between serum IL-6 as a continuous (log transformed) variable with all-cause, CVD, cancer, and liver-related mortality. Patients with prevalent CVD, cancer and liver disease were excluded for cause-specific mortality. Results: The mean (6 standard deviation) age and body-mass-index (BMI) of participants was 68 (610.6) years and 25 (63.7) Kg/m 2, respectively. During the 25,802 person-years of follow-up, the cumulative all-cause, CVD, cancer, and liverrelated mortality were 53.1 % (N = 978), 25.5%, 11.3%, and 1.3%, respectively. The median (6IQR) length of follow-up was 15.3610.6 years. In multivariable analyses, adjusted for age, sex, alcohol, BMI, diabetes, hypertension, total cholesterol, HDL, and smoking, one-SD increment in log-transformed serum IL-6 was associated with increased risk of all-cause, CVD, cancer, and liver-related mortality, with hazard ratios of 1.48 (95 % CI, 1.33–1.64), 1.38 (95 % CI, 1.16–1.65), 1.35 (95 % CI, 1.02–1.79)

Gastric stump cancer after distal gastrectomy for benign disease: clinicopathological features and surgical outcomes.

The purpose of the present study was to analyze clinicopathologic features and long-term prognosis of gastric stump cancer (GSC) arising in the remnant stomach 5 years or later after partial gastrectomy for benign disease. METHODS: We reviewed the results of 176 patients resected with curative intent for GSC at 8 Italian centers belonging to the Italian Research Group for Gastric Cancer (GIRCG). The median (range) follow-up time for surviving patients was 71.2 (6-207) months. RESULTS: One hundred forty-six patients were men, the mean age at the time of diagnosis was 69.2 years, and the great majority (167 cases) underwent Billroth II reconstruction. R0 resection was achieved in 158 (90 %) patients, and in 94 (53 %) lymph node dissection was 65D2. Postoperative mortality and complication rates were 6.2 and 43.2 %, respectively. T1 tumor was diagnosed in 45 (25 %) cases. Lymph node metastases were evident in 86 patients (49 %). Thirteen patients had involvement of the jejunal mesentery nodes (pJN+); five cases were T2-T3 and eight cases were T4. Overall 5-year survival rate was 53.1 %. Five-year survival rates were 68.1, 37.8, and 33.1 % for pT1, pT2-3, and pT4 tumors, respectively (P = 0.001). Five-year survival rate was 56.5 % for node-negative tumors (pN0), 32.3 % for tumors with nodal metastases without involvement of jejunal mesentery nodes (pN+), and 17.1 % for tumors with involvement of jejunal mesentery nodes (pJN+) (P = 0.002). CONCLUSIONS: Our study suggests that an aggressive surgical approach can achieve a satisfactory outcome in GSC

Opposite Effects of HIV-1 p17 Variants on PTEN Activation and Cell Growth in B Cells

The HIV-1 matrix protein p17 is a structural protein that can act in the extracellular environment to deregulate several functions of immune cells, through the interaction of its NH2-terminal region with a cellular surface receptor (p17R). The intracellular events triggered by p17/p17R interaction have been not completely characterized yet. In this study we analyze the signal transduction pathways induced by p17/p17R interaction and show that in Raji cells, a human B cell line stably expressing p17R on its surface, p17 induces a transient activation of the transcriptional factor AP-1. Moreover, it was found to upregulate pERK1/2 and downregulate pAkt, which are the major intracellular signalling components involved in AP-1 activation. These effects are mediated by the COOH-terminal region of p17, which displays the capability of keeping PTEN, a phosphatase that regulates the PI3K/Akt pathway, in an active state through the serin/threonin (Ser/Thr) kinase ROCK. Indeed, the COOH-terminal truncated form of p17 (p17Δ36) induced activation of the PI3K/Akt pathway by maintaining PTEN in an inactive phosphorylated form. Interestingly, we show that among different p17s, a variant derived from a Ugandan HIV-1 strain, named S75X, triggers an activation of PI3K/Akt signalling pathway, and leads to an increased B cell proliferation and malignant transformation. In summary, this study shows the role of the COOH-terminal region in modulating the p17 signalling pathways so highlighting the complexity of p17 binding to and signalling through its receptor(s). Moreover, it provides the first evidence on the presence of a p17 natural variant mimicking the p17Δ36-induced signalling in B cells and displaying the capacity of promoting B cell growth and tumorigenesis