Citations

Abstract Background: CXCL12 is a negative prognostic factor for head & neck (HNSCC) and pancreatic (PDCA) cancers, among others. Its receptor, CXCR4, is a negative prognostic factor in lymphoma/leukemia. CXCR4 signals in part through RAS species, and the expression of CXCL12 and CXCR4 appears to be itself regulated by farnesylated proteins. We provide evidence that targeting the CXCL12/CXCR4 pathway with the farnesyltransferase inhibitor tipifarnib translates to long term clinical benefit. Methods: Next generation sequencing and analyses of gene expression were conducted in tumor samples from squamous cell carcinoma, lymphoma, and acute myeloid leukemia (AML) patients treated in tipifarnib trials (studies KO-TIP-001, KO-TIP-002, CTEP20), and complemented with analyses of related tumor gene expression databases in TCGA and GEO. Results: Activating HRAS mutations in HNSCC and KRAS mutations in PDCA were mutually exclusive with CXCL12 expression, consistent with a role for RAS downstream from CXCR4. Contrary to KRAS and NRAS, HRAS is exclusively farnesylated, and treatment with tipifarnib in patients (pts) with advanced HNSCC tumors with a HRAS mutation variant allele frequency (VAF) >20% resulted in 8 partial responses (PR) in 14 pts. Two complete responses (CR), 3 PRs and 4 disease stabilizations (90% clinical benefit) were observed in 10 pts with relapsed/refractory peripheral T cell lymphoma overexpressing CXCL12. Decreases in plasma CXCL12 levels during treatment were observed. Seven CRs were observed in 11 elderly/unfit AML pts overexpressing CXCL12 in bone marrow (NRAS wt or unknown). Ex vivo treatment of bone marrow stromal cell cultures with tipifarnib decreased secretion of CXCL12. Finally, based on the reported relationship between CXCL12 expression and the suppression of pain in PDCA, we conducted a retrospective analysis of a phase 3 study of gemcitabine plus tipifarnib (GT) in advanced PDCA. Notably, absence of abdominal pain at study entry was associated with higher median survival in the GT arm (no pain, pain): 10.2 vs 5.9 months, HR=0.52, p<0.0001, whereas no significant effect was observed in the control arm: 6.1 vs 6.1 months. PDCA with <7% VAF of KRAS mutation (~30% PDCA pts) overexpressed CXCL12. Conclusions: The mechanism of action of tipifarnib appears to involve targeting the CXCL12/CXCR4 pathway and demonstrates a crucial association with the tumor microenvironment and objective clinical responses. Citation Format: Antonio Gualberto, Catherine Scholz, Vishnu Mishra, Matthew R. Janes, Linda Kessler, Eric Van Cutsem, Alan L. Ho, Thomas Witzig. Mechanism of action of the farnesyltransferase inhibitor, tipifarnib, and its clinical applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT191.

Context Data from the National Collegiate Athletic Association (NCAA) Injury Surveillance Program (ISP) have indicated that ankle injuries are the most common injuries among NCAA soccer players. Objective To review 10 years of NCAA-ISP data for soccer players' ankle injuries to understand how the time period (2004–2005 through 2008–2009 versus 2009–2010 through 2013–2014), anatomical structure injured, and sex of the athlete affected the injury rate, mechanism, and prognosis. Design Descriptive epidemiology study. Setting Online injury surveillance. Main Outcome Measure(s) The NCAA-ISP was queried for men's and women's soccer ankle data from 2004 to 2014. Ankle-injury rates were calculated on the basis of injuries per 1000 athlete-exposures. Rate ratios (RRs) were used to compare injury rates. Injury proportion ratios (IPRs) were used to compare injury characteristics. Results When compared with the 2004–2005 through 2008–2009 seasons, the 2009–2010 through 2013–2014 seasons showed a similar rate of injuries (RR = 0.94, 95% confidence interval [CI] = 0.85, 1.04) but fewer days missed (P < .001) and fewer recurrent injuries (IPR = 0.55, 95% CI = 0.41, 0.74). The 4 most common ankle injuries, which accounted for 95% of ankle injuries, were lateral ligament complex tears (65.67%), tibiofibular ligament (high ankle) sprains (10.3%), contusions (10.1%), and medial (deltoid) ligament tears (9.77%). Of these injuries, high ankle sprains were most likely to cause athletes to miss ≥30 days (IPR = 1.9, 95% CI = 1.24, 2.90). Men and women had similar injury rates (RR = 1.02, 95% CI = 0.94, 1.11). Men had more contact injuries (IPR = 1.28, 95% CI = 1.16, 1.41) and contusion injuries (IPR = 1.34, CI = 1.03, 1.73) but fewer noncontact injuries (IPR = 0.86, 95% CI = 0.78, 0.95) and lateral ligamentous complex injuries (IPR = 0.92, 95% CI = 0.86, 0.98). Conclusions Although the rate of ankle injuries did not change between the 2004–2005 through 2008–2009 seasons and the 2009–2010 through 2013–2014 seasons, the prognoses improved. Among the 4 most common ankle injuries, high ankle sprains resulted in the worst prognosis. Overall, male and female NCAA soccer players injured their ankles at similar rates; however, men were more likely to sustain contact injuries.

AbstractBackgroundCompelling evidence supports multiple benefits of physical activity (PA) even in small bursts. Less than 50% of Americans achieve recommended PA levels, lower still for individuals living with chronic illness or disease.PurposeThe purpose of this study was to develop and evaluate the feasibility and preliminary effects of 3‐min follow‐along video scenarios to promote brief episodes of low–moderate levels of PA among individuals with chronic diseases.MethodsGuided by our previous studies and self‐efficacy theory, the program (WellMe in 3© for Patients) was modeled after another program developed for healthcare staff. An advisory panel and a health and fitness expert guided the creation of twelve 3‐min video scenarios that included two individuals living with chronic illness and a fitness leader who guided the PA scenarios and how to adapt them based on limitations. The 12 scenarios included 3 min of aerobic activities, stretching, or balance. Preliminary pilot effects were measured among 39 patients living with chronic conditions for one month. Standardized instruments were used to measure PA levels, PA self‐efficacy (SE), and quality of life (QoL); usability and satisfaction were assessed using researcher‐developed tools. Descriptive and inferential statistics were used to evaluate change over time.ResultsTwelve video scenarios were created tailored to persons with chronic illness. Thirty‐nine participants piloted the program, reporting an average of two chronic conditions. Baseline QoL scores were lower than normative data, self‐efficacy scores were low‐to‐moderate, and PA levels were very low. Participants averaged using one video per day. 62% of participants provided complete self‐reported pre‐ and post‐QoL and SE data and 41% provided pre‐ and post‐PA (accelerometer) data. Significant improvements were found for general health and energy scores, and trends were found for self‐efficacy scores. PA levels were highly variable with nonsignificant increases from baseline. Effect sizes were low–moderate for several measures. About 79% of participants rated program “Very good”; all recommended the program.Linking Evidence to ActionPhysical activity has multiple health benefits for all people including those living with chronic conditions. Even short bouts of physical activity have health benefits. A program of 3‐min follow‐along PA videoclips for individuals living with chronic disease holds promise for clinicians and researchers.

Background: The sex- and gender-specific health (SGSH) multimedia case-based learning modules (MCBLMs) were developed to address the absence of validated or peer-reviewed material that incorporates topics of sex and gender differences into medical curricula. This article provides the methodology for development of the modules and reports the results of a field test of the modules in different medical educational settings. Methods: MCBLMs were created by a multidisciplinary committee of scientists, health profession educators, and students. Two modules, osteoporosis and diabetes, were tested in various settings based on the curricular needs at each of the five accredited institutions. Each module consisted of a pretest and three interactive, multimedia stand-alone sections with post-tests. Scores on the tests were compared using a paired-samples t -test. A postmodule survey was used to evaluate the format. Results: Four hundred eighteen students participated in the field testing. For the 194 who completed the osteoporosis module, the post-test scores (M = 13.71, standard deviation [SD] = 2.09) were significantly higher than the pretest scores (M = 10.54, SD = 2.41), p < 0.001. Post-test scores for the 285 who completed the diabetes module (M = 16.55, SD = 2.46) were also significantly higher than the pretest scores (M = 13.71, SD = 2.09), p < 0.001. The postmodule survey showed positive acceptance of the format with an average score of 3.54/4 for osteoporosis and 3.45/4 for diabetes. Conclusion: The SGSH MCBLM field testing results show that the modules have a positive effect on content knowledge in multiple settings and are well accepted by learners.

PURPOSE Older women with breast cancer remain under-represented in clinical trials. The Cancer and Leukemia Group B 49907 trial focused on women age 65 years and older. We previously reported the primary analysis after a median follow-up of 2.4 years. Standard adjuvant chemotherapy showed significant improvements in recurrence-free survival (RFS) and overall survival compared with capecitabine. We now update results at a median follow-up of 11.4 years. PATIENTS AND METHODS Patients age 65 years or older with early breast cancer were randomly assigned to either standard adjuvant chemotherapy (physician’s choice of either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide and doxorubicin) or capecitabine. An adaptive Bayesian design was used to determine sample size and test noninferiority of capecitabine. The primary end point was RFS. RESULTS The design stopped accrual with 633 patients at its first sample size assessment. RFS remains significantly longer for patients treated with standard chemotherapy. At 10 years, in patients treated with standard chemotherapy versus capecitabine, the RFS rates were 56% and 50%, respectively (hazard ratio [HR], 0.80; P = .03); breast cancer–specific survival rates were 88% and 82%, respectively (HR, 0.62; P = .03); and overall survival rates were 62% and 56%, respectively (HR, 0.84; P = .16). With longer follow-up, standard chemotherapy remains superior to capecitabine among hormone receptor–negative patients (HR, 0.66; P = .02), but not among hormone receptor–positive patients (HR, 0.89; P = .43). Overall, 43.9% of patients have died (13.1% from breast cancer, 16.4% from causes other than breast cancer, and 14.1% from unknown causes). Second nonbreast cancers occurred in 14.1% of patients. CONCLUSION With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease. Competing risks in this older population dilute overall survival benefits.

Purpose The Next Accreditation System requires training programs to demonstrate competence among trainees. Within gastroenterology (GI), there are limited data describing learning curves and structured assessment of competence in esophagogastroduodenoscopy (EGD) and colonoscopy. In this study, the authors aimed to demonstrate the feasibility of a centralized feedback system to assess endoscopy learning curves among GI trainees in EGD and colonoscopy. Method During academic year 2016–2017, the authors performed a prospective multicenter cohort study, inviting participants from multiple GI training programs. Trainee technical and cognitive skills were assessed using a validated competence assessment tool. An integrated, comprehensive data collection and reporting system was created to apply cumulative sum analysis to generate learning curves that were shared with program directors and trainees on a quarterly basis. Results Out of 183 fellowships invited, 129 trainees from 12 GI fellowships participated, with an overall trainee participation rate of 72.1% (93/129); the highest participation level was among first-year trainees (90.9%; 80/88), and the lowest was among third-year trainees (51.2%; 27/53). In all, 1,385 EGDs and 1,293 colonoscopies were assessed. On aggregate learning curve analysis, third-year trainees achieved competence in overall technical and cognitive skills, while first- and second-year trainees demonstrated the need for ongoing supervision and training in the majority of technical and cognitive skills. Conclusions This study demonstrated the feasibility of using a centralized feedback system for the evaluation and documentation of trainee performance in EGD and colonoscopy. Furthermore, third-year trainees achieved competence in both endoscopic procedures, validating the effectiveness of current training programs.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for consequences of cancer and cancer treatment to aid healthcare professionals who work with survivors of adult-onset cancer. Guidance is also provided to help promote physical activity, weight management, and proper immunizations in survivors and to facilitate care coordination to ensure that all needs are addressed. These NCCN Insights summarize some of the topics discussed by the NCCN Survivorship Panel during the 2019 update of the guidelines, including the survivorship population addressed, ways to improve care coordination, and pain management.