Long-Term Risk of Death From Heart Disease Among Breast Cancer Patients.

Background: Most 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. Methods: This 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. Results: There 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. Conclusion: The 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.

Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumor (GIST) cells.

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 shows 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 ubiquitin-proteasome machinery as a therapeutic target.

Adjuvant Therapy for Melanoma.

Systemic adjuvant therapy for surgically resected cutaneous melanoma that is at high risk for disease recurrence and death targets residual micrometastatic disease which is the source of future local or distant relapse. Interferon-alfa (IFNα) has been the most extensively studied in regimens that varied by dosage, route of administration, formulation, and duration of therapy. Most regimens have demonstrated improvements in relapse-free survival (RFS), while the regimen administered at high dosage (HDI) showed improvements in overall survival (OS) in two out of three RCTs. HDI benefits as measured by the hazard ratios (HR) in E1684 (vs. observation), E1690 (vs. observation), and E1694 (vs. vaccine) trials were estimated at 0.61, 0.78, and 0.67 (RFS) and 0.67, 1.0, and 0.72 (OS) when first reported with lesser estimates on later updates. Pegylated IFNα (peg-IFN) as studied in the European Organisation for Research and Treatment of Cancer (EORTC) 18991 trial in patients with stage III melanoma significantly reduced the risk of relapse (HR 0.87) with no impact on OS. More recently (EORTC 18071), ipilimumab at the high dose of 10 mg/kg was shown to significantly improve RFS (HR 0.76) and OS (HR 0.72) of stage III melanoma patients but at a significant cost in terms of immune-related toxicities. Ongoing adjuvant studies are testing ipilimumab at 3 or 10 mg/kg versus HDI (E1609) and the anti-PD-1 antibodies nivolumab (CheckMate 238) and pembrolizumab (KEYNOTE-054 and S1404).

Peri-transplant clostridium difficile infections in patients undergoing allogeneic hematopoietic progenitor cell transplant.

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 = 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 = 0.008) (OR = 5.48) (P = 0.017). These patients also developed PT-CDI much earlier than in those without a history (median 1 day vs. 8 days, P = 0.03). The probability for developing PT-CDI for those with a history was 39%. There was a trend toward significance (P = 0.065) between matched related donor grafts and the development of PT-CDI (OR = 0.245) (P = 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 = 0.02).