Transcriptional subtyping and CD8 immunohistochemistry identifies poor prognosis stage II/III colorectal cancer patients who benefit from adjuvant chemotherapy.

PURPOSE: Transcriptomic profiling of colorectal cancer (CRC) has led to identification of four consensus molecular subtypes (CMS1-4), which have prognostic value in stage II/III disease. More recently, the Colorectal Cancer Intrinsic Subtypes (CRIS) classification system has helped to define the biology specific to the epithelial component of colorectal tumors. However, the clinical value of these classifications in predicting response to standard-of-care adjuvant chemotherapy remains unknown. PATIENTS AND METHODS: Using samples from 4 European sites, we assembled a novel stage II/III CRC patient cohort and performed transcriptomic profiling on 156 samples, targeted sequencing and generated a tissue microarray to enable integrated "multi-omics" analyses. We also accessed data from 2 published stage II/III CRC patient cohorts: GSE39582 and GSE14333 (479 and 185 samples respectively). RESULTS: The epithelial-rich CMS2 subtype of CRC benefitted significantly from adjuvant chemotherapy treatment in both stage II and III disease (p=0.02 and p<0.0001 respectively), while the CMS3 subtype significantly benefitted in stage III only (p=0.00073). Following CRIS sub-stratification of CMS2, we observed that only the CRIS-C subtype significantly benefitted from adjuvant chemotherapy in stage II and III disease (p=0.0081 and p<0.0001 respectively), while CRIS-D significantly benefitted in stage III only (p=0.0034). We also observed that CRIS-C patients with low levels of CD8+ tumor-infiltrating lymphocytes were most at risk of relapse in both stage II and III disease (p=0.0031). CONCLUSION: Patient stratification using a combination of transcriptional subtyping and CD8 immunohistochemistry analyses is capable of identifying poor prognostic stage II/III patients who benefit from adjuvant standard-of-care chemotherapy. These findings are particularly relevant for stage II disease, where the overall benefit of adjuvant chemotherapy is marginal.

Validation of a Metastatic Assay using biopsies to improve risk stratification in patients with prostate cancer treated with radical radiation therapy.

Background: Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however, >30% of patients relapse within 5 years. Clinicopathological parameters currently fail to identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Patients and methods: A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS). Results: Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients [HR = 3.21 (1.35-7.67); P = 0.003]. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases [HR = 2.71 (1.11-6.63); P = 0.030]. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) [HR = 3.23 (1.22-8.59); P = 0.019] whilst CAPRA itself was not significant [HR = 1.88, (0.52-6.77); P = 0.332]. A high concordance [100% (61.5-100)] for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance. Conclusions: The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource.

Advancing women and closing the leadership gap: the Executive Leadership in Academic Medicine (ELAM) program experience.

Women are persistently underrepresented in the higher levels of academic administration despite the fact that they have been entering the medical profession in increasing numbers for at least 20 years and now make up a large proportion of the medical student body and fill a similar proportion of entry level positions in medical schools. Although there are no easy remedies for gender inequities in medical schools, strategies have been proposed and implemented both within academic institutions and more broadly to achieve and sustain the advancement of women faculty to senior level positions. Substantial, sustained efforts to increase programs and activities addressing the major obstacles to advancement of women must be put in place so that the contributions of women can be fully realized and their skills fittingly applied in meeting the medical education and healthcare needs of all people in the 21st century.

Training future leaders of academic medicine: internal programs at three academic health centers.

The authors review the need for internal programs for leadership training at academic health centers and then describe in detail three programs of this type that have operated during the 1990s: (1) the Allegheny Leadership Institute, founded by the Allegheny Health, Education and Research Foundation, Pittsburgh, Pennsylvania; (2) the Physician Executive Management Development Program (PEMDP) of Saint Louis University School of Medicine; and (3) the University of Nebraska Medical Center Leadership Institute. Educational elements common to these programs include having a small class size and participants from many areas of academic medicine and health care, focusing on educational strategies that draw on participants' experiences and training, conducting the training away from the participants' institutions, having short sessions, using faculty from both within and outside the participants' institutions, and creating strategies to reinforce learning. Lessons learned reflect the unique context of each institution; the authors list the major lessons learned by each of the three programs they surveyed (e.g., leaders of the Saint Louis University PEMDP program believe that it is important to help participants implement desired changes in their work areas once they return to work, and are investigating how to do this). The authors conclude with an extensive list of recommendations to optimize the effects of leadership development training carried out in AHCs' internal programs (e.g., "Focus on specific skills that can be learned, and link the learning experiences to real work situations in health care and higher education") and explain why they think internal leadership institutes have at least three distinct advantages over external programs.