Publications

The Stand Up 2 Cancer/Prostate Cancer Foundation-funded West Coast Dream Team project is a prospective multi-institutional study focused on acquiring metastatic castration-resistant prostate cancer (mCRPC) biopsy tissue at the time of resistance to abiraterone or enzalutamide. It is the first large-scale study designed to analyze mCRPC tissue specifically in this patient population. Study accrual is on target, with 261 out of a planned 300 metastatic tumor biopsies performed by August 2016. Paired biopsies have been completed in 42 patients, with paired genomic data before and after therapy obtained in 26 cases. Accrual is expected to be complete by December 2016.

Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC. Patients and Methods Eligible patients had untreated clear cell mRCC and Eastern Cooperative Oncology Group performance status of 0 to 2 and were intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria. Patients were randomly assigned at a one-to-one ratio to cabozantinib (60 mg once per day) or sunitinib (50 mg once per day; 4 weeks on, 2 weeks off). Progression-free survival (PFS) was the primary end point. Objective response rate (ORR), overall survival, and safety were secondary end points. Results From July 2013 to April 2015, 157 patients were randomly assigned (cabozantinib, n = 79; sunitinib, n = 78). Compared with sunitinib, cabozantinib treatment significantly increased median PFS (8.2 v 5.6 months) and was associated with a 34% reduction in rate of progression or death (adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; one-sided P = .012). ORR was 46% (95% CI, 34 to 57) for cabozantinib versus 18% (95% CI, 10 to 28) for sunitinib. All-causality grade 3 or 4 adverse events were 67% for cabozantinib and 68% for sunitinib and included diarrhea (cabozantinib, 10% v sunitinib, 11%), fatigue (6% v 15%), hypertension (28% v 22%), palmar-plantar erythrodysesthesia (8% v 4%), and hematologic adverse events (3% v 22%). Conclusion Cabozantinib demonstrated a significant clinical benefit in PFS and ORR over standard-of-care sunitinib as first-line therapy in patients with intermediate- or poor-risk mRCC.

Multiple myeloma is incurable by standard approaches because of inevitable relapse and development of treatment resistance in all patients. In our prior work, we identified a panel of macropinocytosing human monoclonal antibodies against CD46, a negative regulator of the innate immune system, and constructed antibody-drug conjugates (ADCs). In this report, we show that an anti-CD46 ADC (CD46-ADC) potently inhibited proliferation in myeloma cell lines with little effect on normal cells. CD46-ADC also potently eliminated myeloma growth in orthometastatic xenograft models. In primary myeloma cells derived from bone marrow aspirates, CD46-ADC induced apoptosis and cell death, but did not affect the viability of nontumor mononuclear cells. It is of clinical interest that the CD46 gene resides on chromosome 1q, which undergoes genomic amplification in the majority of relapsed myeloma patients. We found that the cell surface expression level of CD46 was markedly higher in patient myeloma cells with 1q gain than in those with normal 1q copy number. Thus, genomic amplification of CD46 may serve as a surrogate for target amplification that could allow patient stratification for tailored CD46-targeted therapy. Overall, these findings indicate that CD46 is a promising target for antibody-based treatment of multiple myeloma, especially in patients with gain of chromosome 1q.

CONTEXT AND OBJECTIVE

Patient advisory councils (PACs) are a strategy for primary care clinics to engage patients in practice improvement. However, there is scant research on how PACs function. This study aimed to understand how PACs are organized and identify common challenges and perceived benefits of high-functioning PACs.

SETTING AND POPULATION

Key informants identified 8 primary care clinics in California with high-functioning PACs. Leaders from each of the 8 clinics nominated 1 clinic staff member and 1 PAC patient member to be interviewed.

STUDY DESIGN

Semistructured, one-on-one interviews were conducted at each clinic site or by phone. Interviews were dual-coded using modified grounded theory. Common themes were identified that would be pertinent to the development of future best practices for running PACs.

RESULTS

Common characteristics of high-functioning PACs included careful attention to participant recruitment, facilitation strategies guiding diverse personalities toward a common purpose, and assigning accountability for practice improvement projects. Interviewees identified a variety of positive outcomes that ranged from tangible improvements to the waiting area to a more patient-centered staff culture.

CONCLUSIONS

PACs show potential for promoting patient-centered practice improvements in primary care. Lessons learned from high-functioning PACs can inform a common set of strategies to assist practices in creating and sustaining effective advisory councils.

BACKGROUND

In patients with diabetes, the utility of diagnostic screening cardiac tests in subjects without clinical coronary artery disease remains controversial. The aim of this study was to assess the prognostic meaning of dual-imaging stress echocardiography (conventional wall motion analysis and Doppler-derived coronary flow velocity reserve [CFVR] of the left anterior descending coronary artery) in high-risk asymptomatic individuals with diabetes.

METHODS

This was a prospective analysis of 230 asymptomatic patients with diabetes (128 men; mean age, 66 ± 9 years) with no clinical evidence of coronary artery disease, no Q waves or deep negative waves on the electrocardiogram, and no wall motion abnormalities on resting echocardiography. Of these subjects, 147 (64%) had target organ damage and 83 (36%) had two or more associated cardiovascular risk factors. All patients underwent dipyridamole stress echocardiography with CFVR assessment of the left anterior descending coronary artery by transthoracic Doppler, and test results were entered into a database at the time of testing for a clinical and outcome follow-up (mean, 4.6 ± 2.7 years).

RESULTS

Inducible ischemia and reduced CFVR (≤2) were detected in six and 52 patients, respectively. A total of 54 subjects (23%) had abnormal test results (ischemia or reduced CFVR). During follow-up, 39 major adverse cardiac events (MACEs) occurred: 22 hard events (18 deaths and four nonfatal myocardial infarctions) and 17 coronary revascularizations. The yearly incidence rates of hard events and MACEs in the entire study population were 2.1% and 3.6%, respectively. Abnormal test results were the only multivariate indicator of both hard events (hazard ratio, 3.69; 95% CI, 1.54-8.80) and MACEs (hazard ratio, 6.12; 95% CI, 3.22-11.62).

CONCLUSIONS

Abnormal test results were obtained in one of four cases and were a strong and independent predictor of future hard events and MACEs.