In vitro blood cell responsiveness to IFN-α predicts clinical response independently of IL28B in hepatitis C virus genotype 1 infected patients.

BACKGROUND: Treatment with interferon-alpha (IFN-α) and ribavirin successfully clears hepatitis C virus (HCV) infection in 50% of patients infected with genotype 1. Addition of NS3-4A protease inhibitors (PIs) increases response rates but results in additional side effects and significant economic costs. Here, we hypothesised that in vitro responsiveness of peripheral blood mononuclear cells (PBMCs) to IFN-α stimulation would identify patients who achieved sustained virological response (SVR) on dual therapy alone and thus not require addition of PIs. METHODS: PBMCs were isolated from HCV infected patients (n = 42), infected with either HCV genotype 1 or genotype 3, before commencing therapy and stimulated in vitro with IFN-α. Expression of the IFN stimulated genes (ISGs) PKR, OAS and MxA was measured and correlated with subsequent treatment response and IL28B genotype. RESULTS: Genotype 1 infected patients who achieved SVR had significantly higher pre-treatment expression of PKR (p = 0.0148), OAS (p = 0.0019) and MxA (p = 0.0019) in IFN-α stimulated PBMCs, compared to genotype 1 infected patients who did not achieve SVR or patients infected with genotype 3, whose in vitro ISG expression did not correlate with clinical responsiveness. IL28B genotype (rs12979860) did not correlate with endogenous or IFN-α stimulated ISG responsiveness. CONCLUSIONS: In vitro responsiveness of PBMCs to IFN-α from genotype 1 infected patients predicts clinical responsiveness to dual therapy, independently of IL28B genotype. These results indicate that this sub-group of HCV infected patients could be identified pre-treatment and successfully treated without PIs, thus reducing adverse side effects and emergence of PI resistant virus while making significant economic savings.

Proton pump inhibitor therapy use does not predispose to small intestinal bacterial overgrowth.

OBJECTIVES: Small intestinal bacterial overgrowth (SIBO) occurs due to alteration of the microbiota within the upper gastrointestinal tract. Proton pump inhibitor (PPI) therapy has been suggested as a risk factor for SIBO; however, the published reports have yielded conflicting results on the association between PPI therapy and risk of developing SIBO. The aim of this study was to compare the prevalence of SIBO as measured by glucose hydrogen breath testing (GHBT) in patients on PPI therapy compared with those not on PPI therapy. METHODS: A retrospective chart review was completed for all patients who underwent GHBT testing from 2004 to 2010. Breath samples for hydrogen (H2) and methane (CH4) were collected before and every 20 min for 120 min following ingestion of a 50-g oral glucose load. We used the following criteria to define a positive GHBT (a) increase in H2 > 20 parts per million (p.p.m.) over baseline, (b) sustained rise H2 > 10 p.p.m. over baseline, (c) CH4 > 15 p.p.m. over baseline, and (d) either rise H2 > 20 p.p.m. over baseline or CH4 > 15 p.p.m. RESULTS: A total of 1,191 patients (70% female) were included, of whom 566 (48%) were on PPI therapy. GHBT positivity did not differ significantly between PPI users and nonusers by any of the diagnostic criteria used and PPI use was not significantly associated with GHBT positivity using any of these criteria. GHBT positivity was associated with older age (odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01-1.04) and antidiarrheal use (OR 1.99, 95% CI 1.15-3.44) using H2 > 20, older age (OR 1.01, 95% CI 1.00-1.02) and diarrhea (OR 1.53, 95% CI 1.13-2.09) using H2 > 10, and older age (OR 1.01, 95% CI 1.00-1.02) using either H2 > 20 or CH4 > 15. PPI use was not significantly associated with GHBT positivity using any of these criteria. CONCLUSIONS: In this large, adequately powered equivalence study, PPI use was not found to be significantly associated with the presence of SIBO as determined by the GHBT.

Topic update: effects of colorectal cancer treatments on female fertility and potential methods for fertility preservation.

PURPOSE: Preservation of fertility in young females with a diagnosis of colorectal cancer is gaining increasing importance as survival rates of cancer increase. This review examines the effects of pelvic surgery, chemotherapy, and radiotherapy on fecundity. It also discusses the options available to patients including ovarian transposition, gonadotropin-releasing hormone analogs, embryo and ovarian cryopreservation, and ovarian tissue transplantation. METHODS: A search of MEDLINE, EMBASE, and the Cochrane library was performed using keywords and exploded Mesh search headings and the subsequent articles were reviewed. Relevant studies were included. RESULTS: There are no studies that examine the effect of surgery for colorectal cancer on female fertility, in particular, surgery below the peritoneal reflection for rectal cancer. However, patients with familial adenomatous polyposis have a similar fecundity before and after proctocolectomy with ileal pouch-anal anastomosis. These patients did significantly better than patients with ulcerative colitis who underwent the same procedure. There is conflicting evidence regarding the effects of open vs laparoscopic surgery on fertility. Oxaliplatin, an adjuvant therapy, has moderate gonadotoxic effects. Fluorouracil is considered to have almost no effect on human reproductive function. Gonadotropin-releasing hormone agonists are currently used to preserve female fecundity during chemotherapy. A recent update of patients treated for Hodgkin lymphoma showed that significantly fewer women treated with a gonadotropin-releasing hormone agonist during chemotherapy exhibited premature ovarian failure. Ovarian transposition reduces the radiation dose to approximately 5% to 10% of the dose to the ovaries in their normal position. Other options are available to women with cancer who wish to preserve their germ line, including embryo and oocyte cryopreservation and ovarian tissue cryopreservation. CONCLUSION: Significant advances are now allowing females to preserve their fertility after cancer treatment. It is essential that patients receive adequate fertility counseling before any intervention to give them an opportunity to consider fertility alternatives.