Beyond Concurrent Chemoradiation: The Emerging Role of PD-1/PD-L1 Inhibitors in Stage III Lung Cancer.

Concurrent chemoradiation (cCRT) with platinum-based chemotherapy is standard-of-care therapy for patients with stage III unresectable non-small cell lung cancer (NSCLC). Although cCRT is potentially curative, 5-year overall survival has hovered around 20%, despite extensive efforts to improve outcomes with increasing doses of conformal radiation and intensification of systemic therapy with either induction or consolidation chemotherapy. PD-1/PD-L1 immune checkpoint inhibitors have demonstrated unprecedented efficacy in patients with stage IV NSCLC. In addition, preclinical and early clinical evidence suggests that chemotherapy and radiation may work synergistically with anti-PD-1/PD-L1 therapy to promote antitumor immunity, which has led to the initiation of clinical trials testing these drugs in patients with stage III NSCLC. A preliminary report of a randomized phase III trial, the PACIFIC trial, demonstrated an impressive increase in median progression-free survival with consolidative durvalumab, a PD-L1 inhibitor, compared with observation after cCRT. Here, we discuss the clinical and translational implications of integrating PD-1/PD-L1 inhibitors in the management of patients with unresectable stage III NSCLC

Telemedicine Training in Undergraduate Medical Education: Mixed-Methods Review.

BACKGROUND: Telemedicine has grown exponentially in the United States over the past few decades, and contemporary trends in the health care environment are serving to fuel this growth into the future. Therefore, medical schools are learning to incorporate telemedicine competencies into the undergraduate medical education of future physicians so that they can more effectively leverage telemedicine technologies for improving the quality of care, increasing patient access, and reducing health care expense. This review articulates the efforts of allopathic-degree-granting medical schools in the United States to characterize and systematize the learnings that have been generated thus far in the domain of telemedicine training in undergraduate medical education. OBJECTIVE: The aim of this review was to collect and outline the current experiences and learnings that have been generated as medical schools have sought to implement telemedicine capacity-building into undergraduate medical education. METHODS: We performed a mixed-methods review, starting with a literature review via Scopus, tracking with Excel, and an email outreach effort utilizing telemedicine curriculum data gathered by the Liaison Committee on Medical Education. This outreach included 70 institutions and yielded 7 interviews, 4 peer-reviewed research papers, 6 online documents, and 3 completed survey responses. RESULTS: There is an emerging, rich international body of learning being generated in the field of telemedicine training in undergraduate medical education. The integration of telemedicine-based lessons, ethics case-studies, clinical rotations, and even teleassessments are being found to offer great value for medical schools and their students. Most medical students find such training to be a valuable component of their preclinical and clinical education for a variety of reasons, which include fostering greater familiarity with telemedicine and increased comfort with applying telemedical approaches in their future careers. CONCLUSIONS: These competencies are increasingly important in tackling the challenges facing health care in the 21st century, and further implementation of telemedicine curricula into undergraduate medical education is highly merited

From survival to survivorship: late side effects become an issue in high-grade glioma.

“For many patients, controlling neurological symptoms, preventing cognitive dysfunction and maintaining functional independence are just as important as prolonging survival.

Radiation Oncology at Thomas Jefferson University: A Specialty Emerges as a Department Evolves

Jefferson Radiation Oncology has maintained over fifty years of excellence led by only four chairmen. Dr Kramer after receiving his medical training inLondonled the department into the modern megavoltage era while creating the first independent academic radiation oncology department in the country. He was well-respected nationally as a leader and advocate for the specialty and he mastered the execution of progressive ideas that have raised the standard for the profession. The creation of the Radiation Therapy Oncology Group (RTOG) was critical in developing trials to expand the management and treatment of malignancy. The Patterns of Care Study (PCS) educated the masses on providing optimal care to patients by comparing strategies for the management and treatment of carcinoma through surveys across theUnited States. Dr Mansfield expanded his mentor’s vision and together they developed the Bodine Centre for Cancer Treatment, a new state-of-the-art building for cancer treatment. He helped to dispel common misconceptions, thus raising the social consciousness for managing and treating the underserved community. Dr Curran grew the RTOG to new levels in trial development, funding, and respect both domestically and internationally. He helped develop new technology in the department and markedly expanded the Jefferson Cancer Network. Finally, Dr Dicker set a new course for the department with biologically-driven radiation therapy keepingJeffersonat the forefront of new technology for the diagnosis and treatment of malignancy

African American men with low-grade prostate cancer have increased disease recurrence after prostatectomy compared with Caucasian men.

PURPOSE: To explore whether disparities in outcomes exist between African American (AA) and Caucasian (CS) men with low-grade prostate cancer and similar cancer of the prostate risk assessment-postsurgery (CAPRA-S) features following prostatectomy (RP). METHODS: The overall cohort consisted of 1,265 men (234 AA and 1,031 CS) who met the National comprehensive cancer network criteria for low- to intermediate-risk prostate cancer and underwent RP between 1990 and 2012. We first evaluated whether clinical factors were associated with adverse pathologic outcomes and freedom from biochemical failure (FFbF) using the entire cohort. Next, we studied a subset of 705 men (112 AA and 593 CS) who had pathologic Gleason score≤6 (low-grade disease). Using this cohort, we determined whether race affected FFbF in men with RP-proven low-grade disease and similar CAPRA-S scores. RESULTS: With a median follow-up time of 27 months, the overall 7-year FFbF rate was 86% vs. 79% in CS and AA men, respectively (P = 0.035). There was no significant difference in one or more adverse pathologic features between CS vs. AA men (27% vs. 31%; P = 0.35) or CAPRA-S score (P = 0.28). In the subset analysis of patients with low-grade disease, AA race was associated with worse FFbF outcomes (P = 0.002). Furthermore, AA race was a significant predictor of FFbF in men with low-grade disease (hazard ratio = 2.01, 95% CI: 1.08-3.72; P = 0.029). CONCLUSIONS: AA race is a predictor of worse FFbF outcomes in men with low-grade disease after RP. These results suggest that a subset of AA men with low-grade disease may benefit from more aggressive treatment

Differential regulation of p53 function by the N-terminal ΔNp53 and Δ113p53 isoforms in zebrafish embryos

<p>Abstract</p> <p>Background</p> <p>The p53 protein family coordinates stress responses of cells and organisms. Alternative promoter usage and/or splicing of p53 mRNA gives rise to at least nine mammalian p53 proteins with distinct N- and C-termini which are differentially expressed in normal and malignant cells. The human N-terminal p53 variants contain either the full-length (FL), or a truncated (ΔN/Δ40) or no transactivation domain (Δ133) altogether. The functional consequences of coexpression of the different p53 isoforms are poorly defined. Here we investigated functional aspects of the zebrafish ΔNp53 ortholog in the context of FLp53 and the zebrafish Δ133p53 ortholog (Δ113p53) coexpressed in the developing embryo.</p> <p>Results</p> <p>We cloned the zebrafish ΔNp53 isoform and determined that ionizing radiation increased expression of steady-state <it>ΔNp53 </it>and <it>Δ113p53 </it>mRNA levels in zebrafish embryos. Ectopic ΔNp53 expression by mRNA injection caused hypoplasia and malformation of the head, eyes and somites, yet partially counteracted lethal effects caused by concomitant expression of FLp53. FLp53 expression was required for developmental aberrations caused by ΔNp53 and for ΔNp53-dependent expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A, p21, Cip1, WAF1). Knockdown of p21 expression markedly reduced the severity of developmental malformations associated with ΔNp53 overexpression. By contrast, forced Δ113p53 expression had little effect on ΔNp53-dependent embryonal phenotypes. These functional attributes were shared between zebrafish and human ΔNp53 orthologs ectopically expressed in zebrafish embryos. All 3 zebrafish isoforms could be coimmunoprecipitated with each other after transfection into Saos2 cells.</p> <p>Conclusions</p> <p>Both alternative N-terminal p53 isoforms were expressed in developing zebrafish in response to cell stress and antagonized lethal effects of FLp53 to different degrees. However, in contrast to Δ113p53, forced ΔNp53 expression itself led to developmental defects which depended, in part, on p21 transactivation. In contrast to FLp53, the developmental abnormalities caused by ΔNp53 were not counteracted by concomitant expression of Δ113p53.</p

Therapeutic Challenge with a CDK 4/6 Inhibitor Induces an RB-Dependent SMAC-Mediated Apoptotic Response in Non-Small Cell Lung Cancer.

Purpose: The retinoblastoma tumor suppressor (RB), a key regulator of cell-cycle progression and proliferation, is functionally suppressed in up to 50% of non-small cell lung cancer (NSCLC). RB function is exquisitely controlled by a series of proteins, including the CyclinD-CDK4/6 complex. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function. Experimental Design and Results: We employed multiple isogenic RB-proficient and -deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo We demonstrate that while short-term exposure to palbociclib induces cellular senescence, prolonged exposure results in inhibition of tumor growth. Mechanistically, CDK 4/6 inhibition induces a proapoptotic transcriptional program through suppression of IAPs FOXM1 and Survivin, while simultaneously augmenting expression of SMAC and caspase-3 in an RB-dependent manner. Conclusions: This study uncovers a novel function of RB activation to induce cellular apoptosis through therapeutic administration of a palbociclib and provides a rationale for the clinical evaluation of CDK 4/6 inhibitors in the treatment of patients with NSCLC