Estimates from the U.S. Surveillance, Epidemiology, and End Results (SEER) registry suggest that melanoma incidence will reach 70,230 in 2011, of which 8,790 will die. The rising incidence and predilection for young individuals makes this tumor a leading source of lost productive years in the society.High-dose interferon-α2b is the only agent approved for adjuvant therapy of melanoma; the improvement in relapse-free survival has been observed across nearly all published studies and meta-analyses. However toxicity affects compliance and current research is focusing upon biomarkers that may allow selection of patients with greater likelihood of response, and exploring new agents either singly or in combination that may improve upon the benefit of IFN.In this article, we review the data for the adjuvant therapy of malignant melanoma -focusing on the results obtained with various regimens testing the several formulations of interferon-α2, and the adjuvant studies of vaccines and radiotherapy. Recent advances in the treatment of metastatic disease have established a role for CTLA-4 blockade and BRAF-inhibition, and raising hopes that these agents may have a role in the adjuvant setting. At present, several trials investigating combinations of novel agents with existing immunomodulators are underway.

Clostridium difficile infections (CDI) remain the leading cause of infectious diarrhea among hospitalized patients in this country. Patients with hematologic malignancies, especially those who undergo hematopoietic progenitor cell transplants are particularly at risk for developing CDI. One hundred and forty seven consecutive allogeneic hematopoietic progenitor cell transplants were analyzed for peri-transplant Clostridium difficile infections (PT-CDI). Sixteen patients (11%) developed PT-CDI (Median time 5 7 days after transplant). The probability for developing PT-CDI during the peri-transplant period was 12.3%. History of CDI was strongly associated with the development of PT-CDI (P 5 0.008) (OR 5 5.48) (P 5 0.017). These patients also developed PT-CDI much earlier than in those without a history (median 1 day vs. 8 days, P 5 0.03). The probability for developing PT-CDI for those with a history was 39%. There was a trend toward significance (P 5 0.065) between matched related donor grafts and the development of PT-CDI (OR 5 0.245) (P 5 0.08). Age, sex, diagnosis, transplant preparative regimens, Graft-versus-host disease (GVHD) prophylaxis, grade 3/4 acute GVHD, or use of antimicrobials within 8 weeks of transplant were not associated with PT-CDI. Non-CDI-related deaths occurred in one patient in the PT-CDI group and nine in the group without PT-CDI. In the remaining 139 patients, the length of hospital stay for those with PT-CDI was significantly longer than those without (mean 27 days vs. 22 days; P 5 0.02).

end. Proteins destined to be degraded are selectively targeted to the proteasome by the addition of a series of covalently attached ubiquitin molecules. Deubiquitinating enzymes (DUBs) associated with the 19S regulatory subunit remove these ubiquitin chains before proteins can enter the proteolytic subunit. The 20S core contains three major proteolytic activities (β5 chymotrypsin-like, β1 caspase-like, β2 trypsin-like). Inhibitors of the 20S proteasome core particle, such as the prototype proteasome inhibitor bortezomib (Velcade ®), have gained clinical importance for the treatment of multiple myeloma and certain lymphomas 5. Previous studies from our laboratory have shown that targeting the ubiquitin-proteasome machinery with bortezomib is highly effective in GIST cells 6. We could demonstrate that bortezomib-induced apoptosis is mediated by a dual mechanism of action: increased levels of soluble, non-chromatin-bound pro-apoptotic histone H2AX and a dramatic downregulation of KIT expression mediated by inhibition of active gene transcription 6-8. It is known that loss of KIT expression is a strong inducer of apoptosis in GIST cells 7,9. Although bortezomib has not shown significant clinical activity in many solid tumors, including an array of sarcomas 10 , there are recent reports of its clinical activity in GIST. For example, a study evaluating a novel subcutaneous administration regimen of bortezomib in various solid tumors, noted the most significant response in a patient with GIST 11. In another study testing bortezomib in combination with vorinostat, one of the two GIST patients achieved stable disease 12. Nevertheless, bortezomib is associated with marked adverse effects, most importantly irreversible neuropathy, as well as a standard intravenous route of administration warranting the evaluation of second-generation proteasome inhibitors in GIST 11,13. Carfilzomib (Kyprolis ® , PR-171), ixazomib (Ninlaro ® , MLN-9708), and delanzomib (CEP-18770) are inhib

BackgroundMost breast cancer patients die of non-cancer causes. The risk of death from heart disease, a leading cause of death, is unknown. The aim of this study is to characterize the long-term risk of fatal heart disease in breast cancer patients.MethodsThis retrospective study used the Surveillance, Epidemiology, and End Results (SEER) database. Standard mortality ratios (SMR) were calculated for breast cancer patients diagnosed from 1992 to 2014. Patients were stratified by receipt of radiotherapy and/or chemotherapy, disease laterality, and diagnosis era. Hazard ratios (HRs) and odds ratios (ORs) were calculated to compare the risk of death from heart disease among other breast cancer patients.ResultsThere were 1,059,048 patients diagnosed with breast cancer from 1992 to 2014, of which 47,872 (4.6%) died from heart disease. The SMR for death from heart disease at 10+ years for patients who received only radiotherapy was 2.92 (95% CI 2.81–3.04, p < 0.001) and in patients who received only chemotherapy was 5.05 (95% CI 4.57–5.55, p < 0.001). There was no statistically significant difference in SMR for death from heart disease for left-sided vs. right-sided disease. At 10+ years, heart disease made up 28% of deaths from non-primary cancer. HRs and ORs showed that the risk of death from heart disease was highest in patients older than 70 years of age and with longer follow-up.ConclusionThe risk of fatal heart disease was highest in older breast cancer patients with longer follow-up (i.e., >5–10 years) and who received chemotherapy. These patients should be referred to cardio-oncology clinics to mitigate this risk.

The majority of gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, most GISTs develop imatinib resistance through secondary KIT mutations. The type of resistance mutation determines sensitivity to approved second-/third-line TKIs but can show high inter-and intratumoral heterogeneity.Therefore, therapeutic strategies that target KIT independently of the mutational status are intriguing. Inhibiting the ubiquitin-proteasome machinery with bortezomib is effective in GIST cells through a dual mechanism of KIT transcriptional downregulation and upregulation of the pro-apoptotic histone H2AX but clinically problematic due to the drug's adverse effects. We therefore tested second-generation inhibitors of the 20S proteasome (delanzomib, carfilzomib and ixazomib) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination (b-AP15, MLN4924) for their effectiveness and mechanism of action in GIST. All three 20S proteasome inhibitors were highly effective in vitro and in vivo, including in imatinib-resistant models. In contrast, b-AP15 and MLN4924 were only effective at high concentrations or had mostly cytostatic effects, respectively. Our results confirm 20S proteasome inhibitors as promising strategy to overcome TKI resistance in GIST, while highlighting the complexity of the ubiquitinproteasome machinery as therapeutic target.