Identification of microsatellite unstable (MSI-H) colorectal cancers (CRC) is important not only for the identification of hereditary nonpolyposis colorectal cancer syndrome (HNPCC) but also because MSI-H CRCs have a better prognosis and may respond differently to 5 flourouracil based chemotherapy. We present two nearly equivalent logistic regression models for clinical use that predict microsatellite instability based on the review of 1649 CRCs from patients of all ages collected in a population-based case control study in northern Israel. 198 of these 1649 tumors demonstrated a high degree of microsatellite instability (12%). Multivariate analysis found that >2 TIL cells per high-power field, the lack of dirty necrosis, the presence of a Crohn’s-like reaction, right-sided location, any mucinous differentiation (mucinous or focally mucinous) and well or poor differentiation, and age less than 50 were all independent predictors of MSI-H. We developed two logistic regression models that differ only by the statistical approach used to analyze the number of TIL cells per high-powered field, where the slightly more accurate (and complex) model uses the log of the total number of TIL cells. The simpler clinical model uses a cutoff of 2>TIL cells per high-powered field. The accuracy of both models is high, with an 85.4% vs. 85.0% probability of correctly classifying tumors as MSI-H. By employing the simpler model, pathologists can predict the likelihood of microsatellite instability by compiling the MSI probability score (see Table 4 and figure 1) from simple histologic and clinical data available during sign-out. Our model shows that approximately 43% of CRCs have a MSI probability score of 1 or less and hence have little likelihood (<3%) of being MSI-H. While this model is not perfect in predicting microsatellite instability, its use could improve the efficiency of expensive diagnostic testing.

We describe a family with a novel, inherited AXIN2 mutation (c.1989G>A) segregating in an autosomal dominant pattern with oligodontia and variable other findings including colonic polyposis, gastric polyps, a mild ectodermal dysplasia phenotype with sparse hair and eyebrows, and early onset colorectal and breast cancers. This novel mutation predicts p.Tyr663X, which is a truncated protein that is missing the last three exons, including the DIX (Disheveled and AXIN interacting) domain. This nonsense mutation is predicted to destroy the inhibitory action of AXIN2 on WNT signaling. Previous authors have described an unrelated family with autosomal dominant oligodontia and a variable colorectal phenotype segregating with a nonsense mutation of AXIN2, as well as a frameshift AXIN2 mutation in an unrelated individual with oligodontia. Our report provides additional evidence supporting an autosomal dominant AXIN2-associated ectodermal dysplasia and neoplastic syndrome.

Background Data describing the pharmacokinetics and safety of tenofovir in neonates are lacking. Methods HPTN 057 was a phase 1, open label study of the pharmacokinetics and safety of tenofovir disoproxil fumarate (TDF) in HIV infected women during labor and their infants during the first week of life with 4 dosing cohorts: maternal 600 mg doses/no infant dosing; no maternal dosing/infant 4 mg/kg doses day 0, 3 and 5; maternal 900 mg doses/infant 6 mg/kg doses day 0, 3 and 5; maternal 600 mg doses/infant 6 mg/kg doses daily ×7 doses. Pharmacokinetic sampling was performed on cohort 1 and 3 mothers and all infants. Plasma, amniotic fluid and breast milk tenofovir concentrations were determined by liquid chromatographic – tandem mass spectrometric assay. The pharmacokinetic target was for infant tenofovir concentration throughout the first week of life to exceed 50 ng/mL, the median trough tenofovir concentration in adults receiving standard chronic TDF dosing. Results 122 mother-infant pairs from Malawi and Brazil were studied. Tenofovir exposure in mothers receiving 600 mg and 900 mg exceeded that in non-pregnant adults receiving standard 300 mg doses. Tenofovir elimination in the infants was equivalent to that in older children and adults and trough tenofovir plasma concentrations exceeded 50 ng/mL in 74–97% of infants receiving daily dosing. Conclusion A TDF dosing regimen of 600 mg during labor and daily infant doses of 6 mg/kg maintains infant tenofovir plasma concentration above 50 ng/mL throughout the first week of life and should be used in studies of TDF efficacy for HIV PMTCT and early infant treatment.

Approximately 5% to 15% of all colorectal cancers (CRC) have an activating BRAF somatic mutation, which may be associated with a distinct risk profile compared with tumors without BRAF mutations. Here, we measured the prevalence and epidemiologic correlates of the BRAF V600E somatic mutation in cases collected as a part of a population-based case-control study of CRC in northern Israel. The prevalence of BRAF V600E was 5.0% in this population, and the mutation was more likely to be found in tumors from cases who were of Ashkenazi Jewish descent [odds ratio (OR), 1.87; 95% confidence interval (95% CI), 1.01-3.47], female (OR, 1.97; P = 1.17-3.31), and older (73.8 years versus 70.3 years; P < 0.001). These results were similar when restricting to only tumors with microsatellite instability. Whether smoking was associated with a BRAF somatic mutation depended on gender. Although men were less likely to have a tumor with a BRAF somatic mutation, men who smoked were much more likely to have a tumor with a somatic BRAF mutation (OR interaction , 4.95; 95% CI, 1.18-20.83) than women who never smoked. We note the strong heterogeneity in the reported prevalence of the BRAF V600E mutation in studies of different ethnicities, with a lower prevalence in Israel than other Western populations but a higher prevalence among Jewish than non-Jewish Israeli cases. Epidemiologic studies of CRC should incorporate somatic characteristics to fully appreciate risk factors for this disease. Cancer Epidemiol Biomarkers Prev; 19(3); 838-43. ©2010 AACR.