Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer

PURPOSE: Colon tumors with defective DNA mismatch repair (dMMR) have a well-characterized phenotype and accounts for approximately 15% to 20% of sporadic colon cancer as well as those colon cancer patients with Lynch syndrome. Although the presence of dMMR seems to be a favorable prognostic marker, data suggest that these patients do not respond as well to adjuvant chemotherapy. EXPERIMENTAL DESIGN: In this study, we examined the prognostic significance of tumor MMR deficiency and the presence of a specific mutation in BRAF (V600E) in a group of patients (n = 533) who participated in a randomized prospective clinical trial through the North Central Cancer Treatment Group. RESULTS: Tumors with dMMR were found to be associated with higher tumor grade (P = 0.001), proximal location (P < 0.0001), and improved overall and disease-free survival (P = 0.05 and 0.04, respectively). Among all cases examined, evaluation of the BRAF V600E mutation status revealed no statistically significant differences in either disease-free or overall survival. Patients were then grouped into four categories for further analysis: dMMR/BRAF(-), dMMR/BRAF(+), pMMR/BRAF(-), and pMMR/BRAF(+). The dMMR/BRAF(-) group had a significantly improved overall survival (5-year overall survival of 100% versus 73%, P = 0.002) compared with all others. The remaining three groups had very similar survival outcomes. An additional cohort of tumors previously classified as having dMMR were also tested for the BRAF V600E alteration. Results remained significant (P = 0.006) when the two groups were combined for analysis. CONCLUSIONS: Overall, these data suggest that the underlying molecular etiology of those tumors having dMMR may influence the disease outcome in these patients.     

Inhibition of fibroblast growth factor 19 reduces tumor growth by modulating beta-catenin signaling

Fibroblast growth factors (FGF) play important roles in development, angiogenesis, and cancer. FGF19 uniquely binds to FGF receptor 4 (FGFR4). Our previous study has shown that FGF19 transgenic tumors have an activated Wnt-pathway phenotype. Wnt signaling is implicated in initiating or promoting FGF signaling in various cell types and organs. In this study, we examined whether FGF19 or inhibition of FGF19 affects the beta-catenin signaling pathway using human colon cancer cell lines (HCT116, Colo201). Our results show that FGF19 increases tyrosine phosphorylation of beta-catenin and causes loss of beta-catenin-E-cadherin binding. FGF19 increases p-GSK3beta and active beta-catenin levels and anti-FGF19 antibody (1A6) treatment abrogates this effect of FGF19. Anti-FGF19 antibody treatment increases S33/S37/T41 phosphorylation and ubiquitination of beta-catenin. Ion-trap mass spectrometric analysis confirmed that 1A6 increases phosphorylation of beta-catenin in the NH(2) terminus. Using HCT116-paired beta-catenin knockout cells, we show that FGF19 induces TCF/LEF reporter activity in parental (WT/Delta45) and in WT/--but not in mutant (-/Delta45) cells, and that inhibition of endogenous FGF19 reduces this reporter activity, indicating that wild-type beta-catenin is accessible for modulation. FGFR4 knockdown using inducible short hairpin RNA significantly reduces the colony-forming ability in vitro and tumor growth in vivo. Although cleaved caspase-3 immunoreactivity remains unchanged, the number of ki67-positive nuclei is reduced in FGFR4 knockdown tumor xenograft tissues. Consistent with the reduced beta-catenin activation, Taqman analyses show that FGF19/FGFR4 inhibition reduced beta-catenin target gene (cyclin D1, CD44, c-jun, Cox-2, UPAR) expression. These findings highlight that FGF19/FGFR4 cross-talk with beta-catenin and that pathway intervention reduces tumor growth.     

Conformal radiotherapy, reduced boost volume, hyperfractionated radiotherapy, and online quality control in standard-risk medulloblastoma without chemotherapy: results of the French M-SFOP 98 protocol

PURPOSE: Between December 1998 and October 2001, patients <19 years old were treated for standard-risk medulloblastoma according to the Medulloblastome-Société Fran?aise d'Oncologie Pédiatrique 1998 (M-SFOP 98) protocol. Patients received hyperfractionated radiotherapy (36 Gy in 36 fractions) to the craniospinal axis, a boost with conformal therapy restricted to the tumor bed (to a total dose of 68 Gy in 68 fractions), and no chemotherapy. Records of craniospinal irradiation were reviewed before treatment start. RESULTS: A total of 48 patients were considered assessable. With a median follow-up of 45.7 months, the overall survival and progression-free survival rate at 3 years was 89% and 81%, respectively. Fourteen major deviations were detected and eight were corrected. No relapses occurred in the frontal region and none occurred in the posterior fossa outside the boost volume. Nine patients were available for volume calculation without reduction of the volume irradiated. We observed a reduction in the subtentorial volume irradiated to >60 Gy, but a slight increase in the volume irradiated to 40 Gy. No decrease in intelligence was observed in the 22 children tested during the first 2 years. CONCLUSION: This hyperfractionated radiotherapy protocol with a reduced boost volume and without chemotherapy was not associated with early relapses in children. Moreover, intellectual function seemed to be preserved. These results are promising.     

Comparison of ranitidine bismuth citrate plus clarithromycin with omeprazole plus clarithromycin for the eradication of Helicobacter pylori

BACKGROUND: Many dual and triple therapy treatment regimens have been proposed for the eradication of Helicobacter pylori. However, assessing the relative efficacy of these regimens is complicated by differences in study design, and few well-controlled comparative studies have been reported. METHODS: This multicentre, randomized, double-blind study involved 530 duodenal ulcer patients, of whom 520 had confirmed H. pylori infection. Patients received 14 days b.d. dual therapy of either ranitidine bismuth citrate (RBC) 400 mg or omeprazole 20 mg, both with clarithromycin 500 mg to eradicate H. pylori, followed by a further 14 days of treatment with RBC 400 mg b. d. or omeprazole 20 mg o.d. to facilitate ulcer healing. H. pylori eradication and ulcer healing were assessed at least 26 days after the end of treatment. Adverse events were recorded throughout the study. RESULTS: H. pylori was eradicated in 90% of patients who received RBC with clarithromycin and in 66% of patients who received omeprazole with clarithromycin (per protocol; P<0.001). intention-to-treat eradication rates were 77% and 60%, respectively (P<0.001). Ulcer healing rates were 97% in the RBC treatment group and 95% in the omeprazole treatment group. Only 3% and 1% of patients in the RBC and omeprazole treatment groups, respectively, were withdrawn due to adverse events. CONCLUSIONS: RBC with clarithromycin is a simple and highly effective dual therapy regimen for the eradication of H. pylori, and is significantly more effective than omeprazole with clarithromycin. Both treatment regimens are well tolerated and effectively heal duodenal ulcers.     

Evaluation of the potential immunotoxicity of bromodichloromethane in rats and mice

In the past two decades, concern has been expressed over the potential carcinogenicity of disinfection by-products (DBPs) found in chlorinated drinking water. More recently, research efforts have expanded to include noncancer endpoints as well. The objective of the present studies was to evaluate the potential of bromodichloromethane (BDCM), one of the most prevalent DBPs, to adversely affect immune function in mice and rats following drinking water or gavage exposure. Antigen-specific immunity was assessed as the antibody response to sheep erythrocytes; responses to T- and B-cell mitogens were evaluated as a non-antigen-specific measure of the proliferative potential of splenic and mesenteric lymph node lymphocytes. In consideration of an exposure route relevant to humans, C57BL/6 mice received 0.05, 0.25, or 0.5 g BDCM/L and F344 rats received 0.07 or 0.7 g BDCM/L via drinking water. In order to evaluate the effects of higher doses, animals were administered 50, 125, or 250 mg BDCM/kg/d (mice) or 75, 150, or 300 mg BDCM/kg/d (rats) via gavage. Under the conditions of these studies, no significant adverse effects on immune function were observed in mice. Despite some changes that were observed in non-antigen-specific immunity in rats, these experiments suggest that the immune system is not a sensitive target organ for BDCM toxicity.     

Parentification and family responsibility in the family of origin of adult children of alcoholics

The present study examined parentification and family responsibility in the families of origin of 103 female college students who met criteria for being Adult Children of Alcoholics (ACOAs) as compared to 233 women who did not. The gender of the parent with an alcohol problem (mother only, father only, both parents, neither) was also examined in relation to family roles. Participants completed the Parentification Questionnaire-Adult (PQ-A; Sessions, M. W., and Jurkovic, G. J. (1986). Parentification Questionnaire-Adult (PQ-A). Unpublished document. Department of Psychology, Georgia State University, Atlanta, GA), the Filial Responsibility Scale-Adult (FRS-A; Jurkovic, G. J., and Thirkield, A. (1999). Filial Responsibility Scale-Adult (FRS-A). Unpublished document. Department of Psychology, Georgia State University, Atlanta, GA), the Children of Alcoholics Screening Test (CAST; Jones, J. W. (1983). The Children of Alcoholics Screening Test: Test manual. Chicago: Camelot), and indicated whether they suspected their mother/father of a drinking problem. ACOAs reported more parentification, instrumental caregiving, emotional caregiving, and past unfairness in their families of origin as compared to non-ACOAs. However, as compared to ACOAs who indicated that their father was the alcohol-abusing parent or non-ACOAs, respondents who thought their mothers had an alcohol problem reported greater past unfairness. In addition, ACOAs who thought their mothers had a problem with alcohol abuse reported more parentification and emotional caretaking than did non-ACOAs.     

Nutrient intake and ovarian cancer

A case-control study was conducted in Utah between 1984 and 1987 to evaluate the effects of nutrient intake on risk of developing ovarian cancer. Detailed dietary intake information was available from 85 first primary ovarian cancer cases and 492 population-based controls. Calories, fat, protein, fiber, and vitamins A and C did not appreciably alter the risk of developing ovarian cancer. However, high intake of beta-carotene appears to confer protection against ovarian cancer (odds ratio = 0.5, 95% confidence interval 0.3-1.0) after adjusting for age, number of pregnancies, and the body mass index of weight/height.     

A prospective study of outcomes, healthcare resource utilization, and costs associated with postoperative nosocomial infections.

OBJECTIVE: We evaluated 4 important outcomes associated with postoperative nosocomial infection: costs, mortality, excess length of stay, and utilization of healthcare resources. DESIGN: The outcomes for patients who underwent general, cardiothoracic, and neurosurgical operations were recorded during a previous clinical trial. Multivariable analyses including significant covariates were conducted to determine whether nosocomial infection significantly affected the outcomes. SETTING: A large tertiary care medical center and an affiliated Veterans Affairs Medical Center. PATIENTS: A total of 3,864 surgical patients. RESULTS: The overall nosocomial infection rate was 11.3%. Important covariates included age, Karnofsky score, McCabe and Jackson classification of the severity of underlying disease, National Nosocomial Infection Surveillance system risk index, and number of comorbidities. After accounting for covariates, nosocomial infection was associated with increased postoperative length of stay, increased costs, increased hospital readmission rate, and increased use of antimicrobial agents in the outpatient setting. Nosocomial infection was not associated independently with a significantly increased risk of death in this surgical population. CONCLUSION: Postoperative nosocomial infection was associated with increased costs of care and with increased utilization of medical resources. To accurately assess the effects of nosocomial infections, one must take into account important covariates. Surgeons seeking to decrease the cost of care and resource utilization must identify ways to decrease the rate of postoperative nosocomial infection.