The aborted trial of semagacestat has led some to invoke unanticipated effects of γ‐secretase inhibition on formation of amyloid β. However, the many substrates for γ‐secretases and the varied biological effects of each of the resultant cleavage products make ascribing causality much more complex than that. Ann Neurol 2011

No abstract

Six hundred forty-six women with node-positive breast cancer from two prospective, randomized, adjuvant breast cancer trials were evaluated for changes in weight during and after receiving 60 weeks of chemotherapy, chemohormonal therapy, or observation. The median weight change in the 545 patients remaining on protocol at 60 weeks for observed postmenopausal patients was +1.8 kg, for treated postmenopausal patients +3.6 kg, and for treated premenopausal patients +5.9 kg (P less than .001). After a median follow-up of 6.6 years, premenopausal women who gained more than the median weight at 60 weeks had a risk of relapse 1.5 times greater (covariate P = .17) and a risk of death 1.6 times greater (covariate P = .04) than premenopausal women who had gained less than the median weight. In the postmenopausal patients, the trend for inferior relapse-free and overall survival in those who gained more than the median weight at 60 weeks was not significant (P = .05). We conclude that, relative to observation, adjuvant chemotherapy is associated with greater weight gain in node-positive, postmenopausal breast cancer patients; the amount of weight gain appears greater for premenopausal than postmenopausal women, and in premenopausal women, excessive weight gain may be associated with an increase in relapse and cancer-related deaths in the selected patients who show no evidence of recurrence during 60 weeks of adjuvant chemotherapy. This last point must be interpreted with caution because of the exploratory nature of the analyses.

Castleman's disease (CD) is a rare, poorly understood lymphoproliferative disease. The spectrum of symptoms and course of disease are broad, but there is no large study describing the natural history of this disease. Basic clinic and laboratory data from the records of 113 patients with CD evaluated at the Mayo Clinic and University of Nebraska were abstracted. The impact of these variables on overall survival (OS) from time of diagnosis was evaluated. Sixty patients had multicentric disease. Of the patients with multicentric CD, 32% had criteria sufficient for a diagnosis of POEMS syndrome. For all patients, 2, 5, and 10‐year OS was 92%, 76%, 59%, respectively. Most of the factors identified as risk factors for death on univariate analysis cosegregated with diagnostic criteria for POEMS syndrome, which supported the concept of four categories of CD, which are (along with their 5‐year OS): (1) unicentric CD (91%); (2) multicentric CD associated with the osteosclerotic variant of POEMS syndrome (90%); (3); multicentric CD without POEMS syndrome (65%); and (4) multicentric CD with POEMS syndrome without osteosclerotic lesions (27%). We have demonstrated that CD represents a spectrum of disease that can be differentiated by simple prognostic factors that provide a framework for further study. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.

Synergistic molecular vulnerabilities enhancing hypomethylating agents in myeloid malignancies have remained elusive. RNA-interference drug modifier screens identified antiapoptotic BCL-2 family members as potent 5-Azacytidine-sensitizing targets. In further dissecting BCL-XL, BCL-2 and MCL-1 contribution to 5-Azacytidine activity, siRNA silencing of BCL-XL and MCL-1, but not BCL-2, exhibited variable synergy with 5-Azacytidine in vitro. The BCL-XL, BCL-2 and BCL-w inhibitor ABT-737 sensitized most cell lines more potently compared with the selective BCL-2 inhibitor ABT-199, which synergized with 5-Azacytidine mostly at higher doses. Ex vivo, ABT-737 enhanced 5-Azacytidine activity across primary AML, MDS and MPN specimens. Protein levels of BCL-XL, BCL-2 and MCL-1 in 577 AML patient samples showed overlapping expression across AML FAB subtypes and heterogeneous expression within subtypes, further supporting a concept of dual/multiple BCL-2 family member targeting consistent with RNAi and pharmacologic results. Consequently, silencing of MCL-1 and BCL-XL increased the activity of ABT-199. Functional interrogation of BCL-2 family proteins by BH3 profiling performed on patient samples significantly discriminated clinical response versus resistance to 5-Azacytidine-based therapies. On the basis of these results, we propose a clinical trial of navitoclax (clinical-grade ABT-737) combined with 5-Azacytidine in myeloid malignancies, as well as to prospectively validate BH3 profiling in predicting 5-Azacytidine response.