Precision oncology for patients with advanced cancer: the challenges of malignant snowflakes.

Precision oncology implies customizing treatment to the unique molecular and biologic characteristics of each individual and their cancer. Its implementation is being facilitated by remarkable technological advances in genomic sequencing, as well as the increasing availability of targeted and immunotherapeutic drugs. Yet, next generation sequencing may be a disruptive technology in that its results suggest that classic paradigms for clinical research and practice are a poor fit with the complex reality encountered in metastatic malignancies. Indeed, it is evident that advanced tumors have heterogeneous molecular landscapes that mostly differ between patients. Traditional modes of clinical research/practice are drug centered, with a strategy of finding commonalities between patients so that they can be grouped together and treated similarly. However, if each patient with metastatic cancer has a unique molecular portfolio, a new patient-centered, N-of-one approach that utilizes individually tailored treatment is needed

Application of the Interactional Model of Cultural Diversity to Identify Diversity Climate Factors Associated with Organizational Effectiveness in Accredited U.S. Physical Therapist Education Programs

Accredited U.S. physical therapist education programs are responsible for the preparation of its graduates to provide culturally sensitive care to meet the physical therapy needs of an increasingly diverse population. While the importance of workforce diversity has been articulated, the effect of diversity climate on organizational effectiveness within accredited U.S. physical therapist education programs has not been described. The purpose of this study was to evaluate the effectiveness of the Interactional Model of Cultural Diversity (IMCD, Cox, 1993) as a theoretical framework to identify diversity climate factors associated with organizational effectiveness in accredited U.S. physical therapist education programs. A descriptive, cross-sectional design was used to examine two constructs of the theoretical framework. A total of 151 programs (RR=83.9%) participated in the study. Key informants were academic coordinators/directors of clinical education (N=151). Cronbach\u27s alpha coefficients were .82 for the IAPCC-R (Campinha-Bacote, 2002) and .78 for the perception of diversity climate survey adapted from The Ethnicity Subscale of The Diversity Survey (Brinkman et al, 1992). Some diversity climate factors were associated with organizational effectiveness in accredited U.S. physical therapist education programs in this analysis. Identity structures significantly predicted graduation rate, number of graduates, number of minority graduates and percent minority graduates. Culture and acculturation process significantly predicted licensure rate. Structural integration significantly predicted graduation rate, number of minority graduates and percent minority graduates. Institutional bias in human resource systems significantly predicted number of minority graduates and percent minority graduates. Favorable perceptions of diversity climate were associated with a higher number of minority graduates and higher percent minority graduates. The current diversity climate in accredited U.S. physical therapist education programs is sub-optimal. Unfavorable perceptions of diversity climate were identified in all institutional bias in human resource systems subscales. Future policy directions should explore evidence-based strategies and the effectiveness of studies related to diversity climate to foster the profession\u27s contributions to eliminating health disparities and improving workforce diversity

Targeting autophagy: a novel anticancer strategy with therapeutic implications for imatinib resistance

Autophagy is an ancient, intracellular degradative system which plays important roles in regulating protein homeostasis and which is essential for survival when cells are faced with metabolic stress. Increasing evidence suggests that autophagy also functions as a tumor suppressor mechanism that harnesses the growth and/or survival of cells as they transition towards a rapidly dividing malignant state. However, the impact of autophagy on cancer progression and on the efficacy of cancer therapeutics is controversial. In particular, although the induction of autophagy has been reported after treatment with a number of therapeutic agents, including imatinib, this response has variously been suggested to either impair or contribute to the effects of anticancer agents. More recent studies support the notion that autophagy compromises the efficacy of anticancer agents, where agents such as chloroquine (CQ) that impair autophagy augment the anticancer activity of histone deacetylase (HDAC) inhibitors and alkylating agents. Inhibition of autophagy is a particularly attractive strategy for the treatment of imatinib-refractory chronic myelogenous leukemia (CML) since a combination of CQ with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) compromises the survival of even BCR-ABL-T315I+ imatinib-resistant CML. Additional studies are clearly needed to establish the clinical utility of autophagy inhibitors and to identify patients most likely to benefit from this novel therapeutic approach

Repurposing metformin for cancer treatment: current clinical studies.

In recent years, several studies have presented evidence suggesting a potential role for metformin in anti-cancer therapy. Preclinical studies have demonstrated several anticancer molecular mechanisms of metformin including mTOR inhibition, cytotoxic effects, and immunomodulation. Epidemiologic data have demonstrated decreased cancer incidence and mortality in patients taking metformin. Several clinical trials, focused on evaluation of metformin as an anti-cancer agent are presently underway. Data published from a small number of completed trials has put forth intriguing results. Clinical trials in pre-surgical endometrial cancer patients exhibited a significant decrease in Ki67 with metformin monotherapy. Another interesting observation was made in patients with breast cancer, wherein a trend towards improvement in cancer proliferation markers was noted in patients without insulin resistance. Data on survival outcomes with the use of metformin as an anti-cancer agent is awaited. This manuscript will critically review the role of metformin as a potential cancer treatment

Mutations in DNA repair genes are associated with increased neoantigen burden and a distinct immunophenotype in lung squamous cell carcinoma.

Deficiencies in DNA repair pathways, including mismatch repair (MMR), have been linked to higher tumor mutation burden and improved response to immune checkpoint inhibitors. However, the significance of MMR mutations in lung cancer has not been well characterized, and the relevance of other processes, including homologous recombination (HR) and polymerase epsilon (POLE) activity, remains unclear. Here, we analyzed a dataset of lung squamous cell carcinoma samples from The Cancer Genome Atlas. Variants in DNA repair genes were associated with increased tumor mutation and neoantigen burden, which in turn were linked with greater tumor infiltration by activated T cells. The subset of tumors with DNA repair gene variants but without T cell infiltration exhibited upregulation of TGF-β and Wnt pathway genes, and a combined score incorporating these genes and DNA repair status accurately predicted immune cell infiltration. Finally, high neoantigen burden was positively associated with genes related to cytolytic activity and immune checkpoints. These findings provide evidence that DNA repair pathway defects and immunomodulatory genes together lead to specific immunophenotypes in lung squamous cell carcinoma and could potentially serve as biomarkers for immunotherapy

Farm Management Practices Used by Wheat Producers in the Western Great Plains: Estimating Their Productivity and Profitability

Changes in government farm programs and the introduction of new technology offer wheat producers in the western Great Plains a variety of management practices to alleviate biotic and agronomic constraints inherent in a wheat monoculture. Producers have adopted alternative tillage systems, crop diversification, and insect-resistant varieties in response to the hot, semiarid growing conditions and increased pest pressure. The objective of this study was to determine if those practices generated positive impacts on wheat yield and corresponding net returns. Panel data collected from a group of 141 producers over a four-year period (N = 564) were analyzed using econometric models. The most significant impacts were from crop diversification, which on average more than doubled returns from $29 to$69 per acre compared to a wheat monoculture. Pest-resistant varieties increased returns by 59%, from $32 to$51 per acre. The use of no-till reduced returns by an average of $13 per acre, but when combined with a modest level of crop diversity, returns approached breakeven. Stakeholders should aspire to increase the profitability of no-till to increase its adoption in this environmentally sensitive region

Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure

BACKGROUND. The prognosis of patients with chronic myelogenous leukemia (CML) after failure of imatinib mesylate therapy is not well documented. METHODS. The outcome of 420 patients with CML post-imatinib failure (resistance-recurrence in 374; toxicities in 46) were reviewed in relation to survival, overall, and by different therapies. RESULTS. The estimated 3-year survival rates were 72% in 88 patients who progressed in chronic phase, 30% in 130 patients who progressed in accelerated phase, 7% in 156 patients who progressed in blastic phase, and 75% in 37 patients in chronic phase with imatinib intolerance. Survival in chronic phase was better when subsequent therapy was nilotinib or dasatinib vs allogeneic stem cell transplant vs others (estimated 2-year survival rates 100% vs 72% vs 67%; P = .01), but not in accelerated-blastic phase. CONCLUSIONS. Prognosis post-imatinib failure in chronic phase is reasonable; it is poor if the CML phase post-imatinib failure is accelerated or blastic. Cancer 2007. © 2007 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55988/1/22569_ftp.pd