Citations

Abstract Background: Besides revealing cancer predisposition variants or the absence of any changes, genetic testing for cancer predisposition genes can also identify variants of uncertain clinical significance (VUS). Classifying VUSs is a pressing problem, as ever more patients seek genetic testing for disease syndromes and receive noninformative results from those tests. In cases such as the breast and ovarian cancer syndrome in which prophylactic options can be severe and life changing, having information on the disease relevance of the VUS that a patient harbors can be critical. Methods: We describe a computational approach for inferring the disease relevance of VUSs in disease genes from data derived from an in vitro functional assay. It is based on a Bayesian hierarchical model that accounts for sources of experimental heterogeneity. Results: The functional data correlate well with the pathogenicity of BRCA1 BRCT VUSs, thus providing evidence regarding pathogenicity when family and genetic data are absent or uninformative. Conclusions: We show the utility of the model by using it to classify 76 VUSs located in the BRCT region of BRCA1. The approach is both sensitive and specific when evaluated on variants previously classified using independent sources of data. Although the functional data are very informative, they will need to be combined with other forms of data to meet the more stringent requirements of clinical application. Impact: Our work will lead to improved classification of VUSs and will aid in the clinical decision making of their carriers. Cancer Epidemiol Biomarkers Prev; 20(6); 1078–88. ©2011 AACR.

Abstract Introduction: CX-4945 is a first-in-class, orally administered small molecule that potently and selectively inhibits protein kinase CK2, a previously unexploited molecular target with well documented roles in many cancers. In vitro, CX-4945 selectively kills cancer cells by modulating key survival pathways, resulting in cell cycle arrest, inhibition of cell proliferation, and promotion of apoptosis. CK2 hyperactivation of the PI3K/Akt pathway promotes the phosphorylation of several proteins which we have exploited as biomarkers for CX-4945 activity. A validated laser scanning cytometry method has been developed to quantify the phosphorylation of p21 and Akt in cells, and this has been employed to characterize these substrates in circulating blood cells collected from patients in the phase I clinical trial of CX-4945. Procedures: Eligible patients with advanced solid tumors with progressive disease, or for whom there are no available standard therapies, were administered CX-4945 in successive dose cohorts using a standard 3×3 design at: 90, 160, 300, 460, and 700 mg per dose. Oral doses were administered twice daily for twenty-one consecutive days of a four week cycle. Serial plasma samples were collected for pharmacokinetic analysis on the first and final dosing days of Cycle 1 (i.e., Day 1 and Day 21). In addition, whole blood samples were collected at pre-treatment, 4 hours and 8 hours following the first dose of CX-4945 on Day 1 and Day 21, and peripheral blood mononuclear cells (PBMCs) were isolated for pharmacodynamic biomarker evaluations (specifically, total and phosphorylated forms of p21 and Akt). Plasma samples were also collected at these time points for quantification of plasma IL-6. Results: Seventeen patients with advanced solid tumors from five separate dose cohorts have received oral doses of CX-4945 to date, and all patients in the study participated in the collection of PBMCs. Biomarkers from patients in Cohorts 3 and 4 demonstrated changes in their profile consistent with the inhibition of CK2. CX-4945 displays general linearity in PK parameters between the dose cohorts, with a terminal half life of approximately 25 hours at steady state. Conclusions: To date, no DLTs have yet been observed, and the MTD remains to be defined in this Phase I study. Early signals suggest a modulation of the biomarker profile consistent with CK2 inhibition. Patient enrollment will continue, to further characterize CX-4945's safety, tolerance, pharmacokinetics and pharmacodynamic effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2763.

Pneumatosis intestinalis (PI), defined as gas within the bowel wall, is an uncommon radiographic sign which can represent a wide spectrum of diseases and a variety of underlying diagnoses. Because its etiology can vary greatly, management of PI ranges from surgical intervention to outpatient observation (see, Greenstein et al. (2007), Morris et al. (2008), and Peter et al. (2003)). Since PI is infrequently encountered, clinicians may be unfamiliar with its diagnosis and management; this unfamiliarity, combined with the potential necessity for urgent intervention, may place the clinician confronted with PI in a precarious medical scenario. We present a case of pneumatosis intestinalis in a patient who posed a particularly challenging diagnostic dilemma for the primary team. Furthermore, we explore the differential diagnosis prior to revealing the intervention offered to our patient; our concise yet inclusive differential and thought process for rapid evaluation may be of benefit to clinicians presented with similar clinical scenarios.