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NOTCH1 is recurrently mutated in chronic lymphocytic leukemia (CLL), most commonly as a 2-bp frameshift deletion (c.7541_7542delCT). This mutated allele encodes a truncated form of the receptor (p.P2514Rfs∗4) lacking the C-terminal proline, glutamic acid, serine, and threonine (PEST) degradation domain that increases NOTCH1 signaling duration. NOTCH1 mutation has been associated with poor clinical outcomes in CLL. We validated a highly sensitive and quantitative droplet digital PCR assay for the NOTCH1 delCT mutation, which was anticipated to perform well compared with Sanger sequencing and allele-specific PCR. Performance characteristics of this assay were tested on 126 samples from an unselected CLL cohort and a separate cohort of 85 samples from patients with trisomy 12 CLL. The delCT mutation was detected at allele frequencies as low as 0.024%; 25% of unselected cases and 55% of trisomy 12 cases were positive at the 0.024% detection threshold. Mutational burdens ≥1% were significantly associated with shorter overall survival (OS) in patients with trisomy 12+ disease in multivariate analysis (median OS, 9.1 versus 13 years, with hazard ratio of 2.34; P = 0.031). Mutational burdens1% correlated with shorter OS in univariate, but not multivariate, analyses. These results suggest that droplet digital PCR testing for NOTCH1 delCT mutation may aid in risk stratification and/or disease monitoring in certain subsets of patients with CLL.

Background: Oligometastases refer to a state of disease where cancer has spread beyond the primary site, but is not yet widely metastatic, often defined as 1–3 or 1–5 metastases in number. Stereotactic ablative radiotherapy (SABR) is an emerging radiotherapy technique to treat oligometastases that require further prospective population-based toxicity estimates. Methods: This is a non-randomized phase II trial where all participants will receive experimental SABR treatment to all sites of newly diagnosed or progressing oligometastatic disease. We will accrue 200 patients to assess toxicity associated with this experimental treatment. The study was powered to give a 95% confidence on the risk of late grade 4 toxicity, anticipating a

Metformin exhibits anticancer properties and is currently being explored as a therapeutic option for a variety of cancer types. Epidemiological studies demonstrate associations between metformin use in patients with type 2 diabetes and decreased cancer incidence and cancer-related mortality (Evans et al., 2005). Metformin also exhibits inhibitory effects on cancer cells in vitro and in mouse models (Anisimov et al., 2005; Zakikhani et al., 2006). Its mechanism of action is believed to involve both indirect (insulin-dependent) and direct (insulin-independent) effects.

T-Cell acute lymphoblastic leukemia is considered a largely curable disease in children; however, adult patients and children with refractory or relapsed disease have consistently poor outcomes. On the basis of our prior work highlighting CD44 as a marker of leukemia-initiating cells in animal models and because cancer stem cells are postulated to possess intrinsic resistance to conventional chemotherapy, we examined whether CD44 itself might play a role in mediating chemoresistance. We report here that in both genetically defined mouse models and human cell lines, CD44 expression is associated with chemoresistance, and that this effect is mediated in part through enhanced drug efflux. Interestingly, we also observed increased CD44 expression in residual blasts following standard induction chemotherapy, as compared with blasts from matched, pretherapy samples in a subset of pediatric patients undergoing minimal residual disease monitoring as part of a clinical trial. These findings support a functional role for CD44 in promoting chemotherapy resistance and suggest that targeting it directly or its relevant effector pathways may improve clinical responses in T-cell acute lymphoblastic leukemia.