Anshu K. Jain

Centromere and kinetochore gene misexpression predicts cancer patient survival and response to radiotherapy and chemotherapy

Chromosomal instability (CIN) is a hallmark of cancer that contributes to tumour heterogeneity and other malignant properties. Aberrant centromere and kinetochore function causes CIN through chromosome missegregation, leading to aneuploidy, rearrangements and micronucleus formation. Here we develop a Centromere and kinetochore gene Expression Score (CES) signature that quantifies the centromere and kinetochore gene misexpression in cancers. High CES values correlate with increased levels of genomic instability and several specific adverse tumour properties, and prognosticate poor patient survival for breast and lung cancers, especially early-stage tumours. They also signify high levels of genomic instability that sensitize cancer cells to additional genotoxicity. Thus, the CES signature forecasts patient response to adjuvant chemotherapy or radiotherapy. Our results demonstrate the prognostic and predictive power of the CES, suggest a role for centromere misregulation in cancer progression, and support the idea that tumours with extremely high CIN are less tolerant to specific genotoxic therapies.

Physician leadership: the competencies of change.

he U.S. health-care industry has exploded into 1 of the largest nd fastest growing economies in the world. Currently, it is arger than the Gross National Product of all countries except or the United States, Germany, and Japan. Unfortunately, it is ebatable whether the quality and the delivery of patient care ave kept pace with the economic growth rate of this garganuan entity. As the complexity and the scope of the health-care ndustry have grown, the physician’s role as a leader in the arketplace has been marginalized. Without formal training in eadership skills, many physicians are not equipped to lead in his marketplace. Leadership training in other industries is rounded in the science of behavioral and developmental thery. Currently, an effective leader in the health-care marketlace must possess a working knowledge of this science. Leaders hould cultivate skill sets in finance, self-assessment, behavioral anagement, and personnel analysis, regardless of their clinical eld of expertise. This 2-part series serves to review fundamenal leadership theories and skills (excluding finance) that are ecessary for physicians to lead in the expanding health-care ystem of the future. Theories regarding effective leadership are crucial for undertanding what skills a leader must possess. These theories have volved and are transitioning from theories that emphasize eadership toward strategies that emphasize the necessity of unerstanding and of nurturing workplace culture in which indiiduals can both learn and develop to their fullest potential; this ntity is often termed a “learning culture.” In other words, hen it comes to leadership, facilitation is more effective than harisma; in fact, although the former builds workplace culture, he latter may destroy it. Because a similar evolution has ocurred in education, the educational process is an apropos odel. Current educational strategies emphasize understand-

Intensity-modulated radiotherapy for locally advanced cancers of the larynx and hypopharynx.

Limited data evaluate intensity‐modulated radiotherapy (IMRT) for cancers of the hypopharynx and larynx. We report clinical outcomes and failure patterns for these patients.

A phase II study of concurrent chemoradiation with weekly docetaxel, carboplatin, and radiation therapy followed by consolidation chemotherapy with docetaxel and carboplatin for locally advanced inoperable non-small cell lung cancer (NSCLC).

Introduction: The current standard of care for good performance status patients with locally advanced non-small cell lung carcinoma is concurrent chemoradiation, although a clearly superior regimen has not been identified. Docetaxel has been shown to possess good single-agent activity against non-small cell lung cancer (NSCLC) and radiosensitizing properties, both alone and synergistically with carboplatin. We undertook this phase II study to determine the safety and efficacy of weekly docetaxel-carboplatin and concurrent radiation therapy followed by docetaxel-carboplatin consolidation for the treatment of locally advanced NSCLC. Methods: Sixty-seven patients having previously untreated stage IIIA or IIIB unresectable NSCLC were enrolled, with 61 patients evaluated for endpoints. Docetaxel 20 mg/m2 IV infusion over 30 minutes followed by carboplatin area under the curve = 2 over 30 minutes was administered weekly during concurrent thoracic radiotherapy. After 3 week rest, consolidation docetaxel 75 mg/m2 IV infusion over 60 minutes and carboplatin area under the curve = 6 over 30 minutes was administered every 3 weeks for two cycles. Concurrent thoracic radiation consisted of 45 Gy (1.8 Gy fractions 5 d/wk for first 5 weeks) followed by 18 Gy boost (2.0 Gy fractions 5 d/wk for 2 weeks) for a total dose of 63 Gy. Results: One and 2 years overall survival rates were 45 and 20%, respectively. Progression free survival at 1 year was 27%. Median survival time was 12 months. Median time to progression was 8 months. The primary hematologic toxicity was leukopenia. The primary nonhematologic toxicity was esophagitis. Conclusion: The administered regimen of weekly docetaxel-carboplatin and concurrent radiation therapy followed by docetaxel-carboplatin consolidation has acceptable toxicity profile. However, the overall survivals at 1 and 2 years are somewhat disappointing.

RTOG 0017: A Phase I Trial of Concurrent Gemcitabine/Carboplatin or Gemcitabine/Paclitaxel and Radiation Therapy (“Ping-Pong Trial”) Followed By Adjuvant Chemotherapy for Patients with Favorable Prognosis Inoperable Stage IIIA/B Non-small Cell Lung Cancer

Purpose: The optimal dose of gemcitabine that can be used with concurrent radiation therapy for locally advanced non-small cell lung cancer has not been well defined. This trial addresses this question in an alternating sequence “ping-pong” design trial to find the maximum tolerated dose (MTD) for gemcitabine/carboplatin (Sequence A) or gemcitabine/paclitaxel (Sequence B) and thoracic radiation therapy followed by adjuvant gemcitabine/carboplatin chemotherapy. Patients and Methods: Thirty-five patients with histologically confirmed Stage IIIA/B non-small cell lung cancer were entered into two separate sequences, each with multiple cohorts. A dose level was considered acceptable if, of the first six eligible patients on each cohort, fewer than three experienced dose limiting toxicities. Results: Sequence B of this 2 sequence “ping-pong” trial closed early due to toxicity in cohort 2 (gemcitabine 300 mg/m2/wk and paclitaxel 30 mg/m2/wk). On Sequence A, the MTD was the cohort 5 dose: gemcitabine 450 mg/m2/wk and carboplatin 2 area under curve (AUC) concurrently with thoracic radiation. Cohort 7 (gemcitabine 600 mg/m2/wk and carboplatin 2 AUC) showed 4 dose limiting toxicities: 2 grade 3 esophagitis; one grade 3 febrile neutropenia; and one grade 4 neutropenia. Conclusion: Concurrent gemcitabine/paclitaxel chemoradiation regimen followed by adjuvant gemcitabine/carboplatin produced excessive toxicity at the lowest tested dose combination and was not suitable for further study in this trial. Meanwhile, the MTD of concurrent gemcitabine/carboplatin chemoradiation was determined to be gemcitabine 450 mg/m2 and carboplatin AUC-2. This combination was found to be tolerable. Although not a primary end point, survival results are summarized as well.

High-Performance Teams for Current and Future Physician Leaders: An Introduction

The scope of patient management increasingly crosses the defined lines of multiple medical specialties and services to meet patient needs. Concurrently, many hospitals and health-care systems have adapted new multidisciplinary team structures that provide patient-centric care as opposed to the more traditional discipline-centered delivery of care. As health care continues to evolve, the use of teams becomes even more critical in allowing interdependence between multiple disciplines to provide excellent care delivery and ongoing patient management. The use of teams permeates the health-care industry (and has done so for many years), but confusion about the structure, role, and use of teams contributes to limited effectiveness. The health-care industrys underuse of the fundamentals of corporate teamwork has, in part, created ineffective team leadership at the physician level. As the first in a series of documents on teamwork, this article is intended to introduce the reader to the rudiments of team theory and to present an introduction to a model of teamwork. The role of current and future physician leaders in ensuring team effectiveness is emphasized in this discussion. By educating health-care professionals on the foundations of high-performance teamwork, we hope to accomplish two main goals. The first goal is to help create a common and systematic taxonomy that physician leaders and institutional management can agree on and refer to concerning the development of high-performance health-care teams. The second goal is to stimulate the development of future physician leaders who use proven teamwork principles as a powerful modality to achieve efficient and optimal patient care. Most importantly, we wish to emphasize that health care, both philosophically and practically, is delivered best through high-performance teams. For such teams to perform properly, the organizational environment must support the team concept tangibly. In concert, we believe the best manner in which to cultivate knowledge and performance of the health-care organizational mission and goals is by using such teams.

Fundamentals of service lines and the necessity of physician leaders.

In the demanding and unpredictable environment of the health care industry, hospitals and health systems continue to search for ways to improve the efficiency and quality of care provision and, thus, thrive. Service line organization in health care, a concept that was popularized in the past, has recently experienced a resurgence, spanning the gamut from small community hospitals to large academic medical centers. The modern service line has transformed into an organizational tool that provides hospitals and health systems with a novel approach to achieve the goals of efficient and effective care. Physician leaders can play an integral role in the management of service lines, using a combination of management skills and clinical expertise to provide the oversight and direction necessary for assuring excellence in clinical care and value in its delivery. This article presents an overview of service line structure, implementation, implications, and the role of the physician-leader.

High-Performance Teams and the Physician Leader: An Overview

The complexity of health care delivery within the United States continues to escalate in an exponential fashion driven by an explosion of medical technology, an ever-expanding research enterprise, and a growing emphasis on evidence-based practices. The delivery of care occurs on a continuum that spans across multiple disciplines, now requiring complex coordination of care through the use of novel clinical teams. The use of teams permeates the health care industry and has done so for many years, but confusion about the structure and role of teams in many organizations contributes to limited effectiveness and suboptimal outcomes. Teams are an essential component of graduate medical education training programs. The health care industrys relative lack of focus regarding the fundamentals of teamwork theory has contributed to ineffective team leadership at the physician level. As a follow-up to our earlier manuscripts on teamwork, this article clarifies a model of teamwork and discusses its application to high-performance teams in health care organizations. Emphasized in this discussion is the role played by the physician leader in ensuring team effectiveness. By educating health care professionals on the fundamentals of high-performance teamwork, we hope to stimulate the development of future physician leaders who use proven teamwork principles to achieve the goals of trainee education and excellent patient care.

Moving Toward Improved Teamwork in Cancer Care: The Role of Psychological Safety in Team Communication

Effective communication is a requirement in the teamwork necessary for improved coordination to deliver patient-centered, value-based cancer care. Communication is particularly important when care providers are geographically distributed or work across organizations. We review organizational and teams research on communication to highlight psychological safety as a key determinant of high-quality communication within teams. We first present the concept of psychological safety, findings about its communication effects for teamwork, and factors that affect it. We focus on five factors applicable to cancer care delivery: familiarity, clinical hierarchy-related status differences, geographic dispersion, boundary spanning, and leader behavior. To illustrate how these factors facilitate or hinder psychologically safe communication and teamwork in cancer care, we review the case of a patient as she experiences the treatment-planning process for early-stage breast cancer in a community setting. Our analysis is summarized in a key principle: Teamwork in cancer care requires high-quality communication, which depends on psychological safety for all team members, clinicians and patients alike. We conclude with a discussion of the implications of psychological safety in clinical care and suggestions for future research.

The role of stereotactic body radiotherapy and stereotactic radiosurgery in the re-irradiation of metastatic spinal tumors

Stereotactic body radiotherapy (SBRT) and stereotactic radiosurgery (SRS) are advanced radiotherapy delivery techniques that allow for the delivery of high-dose per fraction radiation. Advances in imaging technology and intensity modulation have allowed SRS and SBRT to be used for the treatment of tumors in close proximity to the spinal cord and cauda equina, in particular spinal metastases. While the initial treatment of spinal metastases is often conventional palliative radiotherapy, treatment failure is not uncommon, and conventional re-irradiation may not be feasible due to spinal cord tolerance. SBRT and SRS have emerged as important techniques for the treatment of spinal metastases in the proximity of previously irradiated spinal cord. Here we review the current data on the use of SBRT and SRS spinal re-irradiation, and future directions for these important treatment modalities.