Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma.

BACKGROUND: The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling. METHODS: Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib). RESULTS: Seventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval [CI]: 4.37-6.97) and 9.79 months (95% CI: 7.85-10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment. CONCLUSIONS: Adding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01088815.

Racial disparities in the rate of cardiotoxicity of HER2-targeted therapies among women with early breast cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies are highly effective at preventing breast cancer recurrence but are associated with cardiotoxicity in some patients, and minimal data are available regarding racial disparities in the incidence of this toxicity. The authors conducted a retrospective study to analyze the association of black or white race with treatment-induced cardiotoxicity and incomplete therapy among patients with HER2-positive early breast cancer. METHODS: Women with HER2-positive, stage I through III breast cancer who initiated (neo)adjuvant HER2-targeted therapy (trastuzumab with or without pertuzumab) from January 2005 to March 2015 at the authors' institution were eligible. We analyzed differences in the incidence of cardiotoxicity (a decline in the left ventricular ejection fraction to <50% AND an absolute drop in the left ventricular ejection fraction of ≥10% from baseline) and incomplete therapy (<52 weeks of HER2-targeted therapy) between black and white women in univariate and multivariable analyses. RESULTS: The authors identified 59 black patients and 157 white patients who had a median follow-up 5.2 years. The median patient age was 53 years and was similar for black and white patients. The 1-year cardiotoxicity incidence was 12% overall (95% confidence interval [CI], 7%-16%), 24% in black women (95% CI, 12%-34%), and 7% in white women (95% CI, 3%-11%). Black patients had a significantly greater probability of incomplete therapy compared with white patients (odds ratio, 4.61; 95% CI, 1.70-13.07; P = .002). High correlation was observed between a cardiotoxicity event and incomplete therapy (96% concordance). CONCLUSIONS: Black patients have a higher rate of cardiotoxicity and resultant incomplete adjuvant HER2-targeted therapy than white patients. This patient population may benefit from enhanced cardiac surveillance, cardioprotective strategies, and early referral to cardiology when appropriate. Cancer 2018;124:1904-11. © 2018 American Cancer Society.

Survival Outcomes of Adjuvant Chemotherapy Combined With Radiation Versus Chemotherapy Alone After Pancreatectomy for Distal Pancreatic Adenocarcinoma: A Single-Institution Experience.

OBJECTIVE: We evaluated survival outcomes in patients with distal pancreatic ductal adenocarcinoma (D-PDAC) after distal pancreatectomy (DP) and adjuvant chemotherapy or chemoradiation. METHODS: A retrospective analysis of patients who underwent DP for D-PDAC from 2000 to 2015 at the Johns Hopkins Hospital was performed. Demographics, baseline risk factors, and type of adjuvant treatment were assessed for associations with overall survival (OS) and disease-free survival (DFS). Comparisons were made with log-rank tests and Cox proportional hazards regression models. RESULTS: A total of 294 patients underwent DP for D-PDAC. Of these, 105 patients were followed at the Johns Hopkins Hospital. Forty-five patients received chemotherapy only and 60 patients received chemoradiation. The median OS with chemoradiation was 33.6 months and 27.9 months (P = 0.54) with chemotherapy only. The median DFS was 15.3 months with chemoradiation and 19.8 months with chemotherapy only (P = 0.89). Elevated carbohydrate antigen 19-9, stage II to III disease, splenic vein involvement, and vascular invasion were significant risk factors in multivariate analyses. CONCLUSIONS: In this retrospective analysis, there were no significant differences in OS or DFS with chemoradiation compared with chemotherapy alone after DP in patients with D-PDAC.

Pure erythroid leukemia, presenting with pancytopenia. Images in Hematology.

Pure erythroid leukemia is an aggressive form of acute leukemia, presenting with pancytopenia. It is defined as a neoplasm of erythroid lineage without a significant myeloblastic component, representing >80% of marrow, with 30% or more proerythroblasts. The disease has a rapid clinical course with median survival of only 3 months.

The Molecular and Clinical Landscape of Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors are rare tumors of the pancreas originating from the islets of the Langerhans. These tumors comprise 1% to 3% of all newly diagnosed pancreatic cancers every year and have a unique heterogeneity in clinical presentation. Whole-genome sequencing has led to an increased understanding of the molecular biology of these tumors. In this review, we will summarize the current knowledge of the signaling pathways involved in the tumorigenesis of pancreatic neuroendocrine tumors as well as the major studies targeting these pathways at preclinical and clinical levels.

Venous Thromboembolism Prophylaxis: Inadequate and Overprophylaxis When Comparing Perceived Versus Calculated Risk.

Guidelines for venous thromboembolism (VTE) prophylaxis recommend appropriate risk stratification using risk estimation models as high risk or low risk followed by initiation of chemical or mechanical prophylaxis, respectively. We explored adherence to guidelines on the basis of the documentation of VTE prophylaxis. A retrospective medical record review of 437 consecutive adult patients (≥18 years) admitted to general medical wards under medicine service between January 1, 2015, and March 1, 2015, was performed. The primary outcome was appropriateness of risk stratification using the Padua Prediction Score. Secondary outcomes were appropriateness of type of prophylaxis (chemical vs mechanical) and cost-benefit analysis. We observed appropriate stratification based on the documented risk (compared with the calculated risk) in 54.9% of the patients (40.8% with low risk vs 72.1% with high risk; P<.001). Overall, 182 of 240 low-risk patients received unnecessary chemical prophylaxis, whereas 23 of 197 high-risk patients without contraindications for chemical prophylaxis received mechanical or no prophylaxis. No clinical VTE events were noted in the patients inappropriately assigned to mechanical or no prophylaxis. Also, 67.3% of patients with both low documented and low calculated risk and 74.5% of patients with low documented and high calculated risk received chemical prophylaxis, consistent with a tendency toward overtreatment. A total of 4068 annualized patient-days ($77,652/y) of inappropriate chemical prophylaxis were administered. In conclusion, estimation of the risk of VTE based on clinical impression was not congruent with the risk calculated using risk prediction models and was associated with a tendency toward overtreatment. These data support the inclusion of VTE risk calculators in electronic health record systems.