Citations

Context: The fourth edition of the Preparticipation Physical Evaluation recommends functional testing for the musculoskeletal portion of the examination; however, normative data across sex and grade level are limited. Establishing normative data can provide clinicians reference points with which to compare their patients, potentially aiding in the development of future injury-risk assessments and injury-mitigation programs.Objective: To establish normative functional performance and limb-symmetry data for high school-aged male and female athletes in the United States.Design: Cross-sectional study.Setting: Athletic training facilities and gymnasiums across the United States.Patients or Other Participants: A total of 3951 male and female athletes who participated on high school-sponsored basketball, football, lacrosse, or soccer teams enrolled in this nationwide study.Main Outcome Measure(s): Functional performance testing consisted of 3 evaluations. Ankle-joint range of motion, balance, and lower extremity muscular power and landing control were assessed via the weight-bearing ankle-dorsiflexion–lunge, single-legged anterior-reach, and anterior single-legged hop-for-distance (SLHOP) tests, respectively. We used 2-way analyses of variance and χ2 analyses to examine the effects of sex and grade level on ankle-dorsiflexion–lunge, single-legged anterior-reach, and SLHOP test performance and symmetry.Results: The SLHOP performance differed between sexes (males = 187.8% ± 33.1% of limb length, females = 157.5% ± 27.8% of limb length; t = 30.3, P < .001). A Cohen d value of 0.97 indicated a large effect of sex on SLHOP performance. We observed differences for SLHOP and ankle-dorsiflexion–lunge performance among grade levels, but these differences were not clinically meaningful.Conclusions: We demonstrated differences in normative data for lower extremity functional performance during preparticipation physical evaluations across sex and grade levels. The results of this study will allow clinicians to compare sex- and grade-specific functional performances and implement approaches for preventing musculoskeletal injuries in high school-aged athletes.

ABSTRACT We describe results from a multicenter study evaluating the Accelerate Pheno system, a first of its kind diagnostic system that rapidly identifies common bloodstream pathogens from positive blood cultures within 90 min and determines bacterial phenotypic antimicrobial susceptibility testing (AST) results within ∼7 h. A combination of fresh clinical and seeded blood cultures were tested, and results from the Accelerate Pheno system were compared to Vitek 2 results for identification (ID) and broth microdilution or disk diffusion for AST. The Accelerate Pheno system accurately identified 14 common bacterial pathogens and two Candida spp. with sensitivities ranging from 94.6 to 100%. Of fresh positive blood cultures, 89% received a monomicrobial call with a positive predictive value of 97.3%. Six common Gram-positive cocci were evaluated for ID. Five were tested against eight antibiotics, two resistance phenotypes (methicillin-resistant Staphylococcus aureus and Staphylococcus spp. [MRSA/MRS]), and inducible clindamycin resistance (MLSb). From the 4,142 AST results, the overall essential agreement (EA) and categorical agreement (CA) were 97.6% and 97.9%, respectively. Overall very major error (VME), major error (ME), and minor error (mE) rates were 1.0%, 0.7%, and 1.3%, respectively. Eight species of Gram-negative rods were evaluated against 15 antibiotics. From the 6,331 AST results, overall EA and CA were 95.4% and 94.3%, respectively. Overall VME, ME, and mE rates were 0.5%, 0.9%, and 4.8%, respectively. The Accelerate Pheno system has the unique ability to identify and provide phenotypic MIC and categorical AST results in a few hours directly from positive blood culture bottles and support accurate antimicrobial adjustment.

Abstract Electronic medical records (EMRs) have gained widespread use in clinical practice and by default serve as a large patient database with potential for use in clinical research. Although there remains significant interest in leveraging EMRs for research purposes, extraction of data has proven to be complex and with insufficient accuracy. We describe the limitations of an EMR in our attempt to conduct a seemingly simple study aimed at validating variables identified in the PRECiSE 3, a 7-year open label safety and efficacy study of certolizumab pegol in Crohn’s disease that identified clinical factors that predicted both short- and long-term efficacy. A multicenter, retrospective cohort study from 8 academic and large community practices was performed, and data were collected from each respective EMR. Significant challenges with reliable capture of key data elements were encountered, and overall a screen fail rate of 91.8% across all sites was seen. We describe these challenges and potential future directions to work together to advance accuracy and implementation of the use of EMRs in inflammatory bowel disease.

We surveyed multiple apheresis centers represented by the authors for their clinical approach to the management of anticoagulation issues during therapeutic plasma exchange (TPE). We present the results of their practices and a review of the pertinent literature. As plasma is removed during TPE, replacement with all or partial non‐plasma‐containing fluids (eg, 5% albumin) may lead to significant changes in hemostasis. These changes are amplified in patients who are receiving anticoagulation. We discuss various anticoagulants as well as the monitoring and adjustment of anticoagulation before, during, and after TPE. No single guideline can be applied, but rather, patients must be monitored individually, taking into account their often complex clinical conditions and medication profiles.

Objectives Pancreatic ductal adenocarcinoma (PDAC) is often accompanied by weight loss. We sought to characterize factors associated with weight loss and observed nutritional interventions, as well as define the effect of weight loss on survival. Methods Consecutive subjects diagnosed with PDAC (N = 123) were retrospectively evaluated. Univariate analysis was used to compare subjects with and without substantial (>5%) weight loss. Multivariate logistic regression was performed to identify factors associated with weight loss, and survival analyses were performed using Kaplan-Meier curves and Cox survival models. Results Substantial weight loss at diagnosis was present in 71.5% of subjects and was independently associated with higher baseline body mass index, longer symptom duration, and increased tumor size. Recommendations for nutrition consultation and pancreatic enzyme replacement therapy occurred in 27.6% and 36.9% of subjects, respectively. Weight loss (>5%) was not associated with worse survival on multivariate analysis (hazard ratio, 1.32; 95% confidence interval, 0.76–2.30), unless a higher threshold (>10%) was used (hazard ratio, 1.77; 95% confidence interval, 1.09–2.87). Conclusions Despite the high prevalence of weight loss at PDAC diagnosis, there are low observed rates of nutritional interventions. Weight loss based on current criteria for cancer cachexia is not associated with poor survival in PDAC.

Abstract Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2− breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17. Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 23(22); 6823–32. ©2017 AACR.

Background: The reported rate of second anterior cruciate ligament (ACL) injuries (20%-30%), including graft failure and contralateral ACL tears, after ACL reconstruction (ACLR) or nonoperative therapy indicates that multiple factors may predispose patients to subsequent ACL injuries. Purpose: To determine the incidence of second ACL injuries in a population-based cohort over a 10-year observation period (2001-2010) and to identify factors that contribute to the risk of second injuries. Study Design: Descriptive epidemiological study. Methods: International Classification of Diseases, 9th Revision (ICD-9) codes relevant to the diagnosis of an ACL tear and the procedure code for ACLR were utilized to search the Rochester Epidemiology Project, a multidisciplinary county database, between the years of 2001 and 2010. The complete medical records for all cases were reviewed to confirm diagnosis and treatment details. A total of 914 unique patients with 1019 acute, isolated ACL tears were identified. These patients were stratified by primary and secondary tears, sex, age, activity level, side of injury, sex × side of injury, and graft type of reconstruction. Results: Second ACL tears were recorded in 141 (13.8%) of the 914 patients diagnosed with an ACL tear in Olmsted County, Minnesota, USA, from 2001 to 2010; 50.4% of these occurred in the contralateral knee. A noncontact mechanism was responsible for 76.4% of all ACL injuries. A second ACL injury was influenced by factors of sex × age group, treatment type × age group, and treatment type × activity level. Nonparametric analysis of graft disruption × graft type demonstrated that a higher prevalence of second ACL tears occurred with allografts compared with hamstring autografts ( P = .0054) and patellar tendon autografts ( P = .0001). Conclusion: The incidence of second ACL tears in this population-based cohort was 13.8%, and half occurred to the ACL of the contralateral knee. Statistically, second ACL injuries differed by sex, occurring in female patients younger than 25 years and male patients aged 26 to 45 years. Allografts continued to be associated with a greater risk of second ACL injuries compared with hamstring and patellar tendon autografts. Nonoperative treatment carried more risk of contralateral tears than ACLR.

Abstract Introduction: 5-fluorouracil (5-FU)-based chemoradiation (CRT) is a standard neoadjuvant treatment strategy for the treatment of locally-advanced rectal adenocarcinomas (LARC). MEK-1/2 inhibition has been shown to radiosensitize Ras mutant tumors in preclinical models, including colorectal cancer. In this phase 1 trial, we are testing MEK-1/2 inhibition in combination with neoadjuvant CRT for LARC. Methods: This trial is a standard 3+3 design testing 3 dose levels of the MEK-1/2 inhibitor trametinib in combination with CRT: 0.5 mg, 1.0 mg, and 2.0 mg daily, followed by an expansion cohort. All patients first receive a one week lead-in dosing of trametinib monotherapy, and undergo a tumor biopsy at the end of that week to assess pharmacodynamic inhibition by immunohistochemistry (IHC). Then, patients receive standard CRT (5-FU 225 mg/m2 per day by continuous infusion during radiotherapy, and 50.4 Gy in 28 fractions, 5 days/ week) in combination with trametinib (5 days/week). Patients have total mesorectal excision (TME) 6-10 weeks after completion of CRT. Results: 17 patients have been enrolled to date, with current enrollment occurring on the trametinib 2 mg expansion cohort (total 18 patients planned). Of these, 15 patients (10 males, 5 females) have toxicity and surgical response data available. Median age is 53 years (range 35-74 years), and 6 patients have Stage II disease, while 9 patients with Stage III disease. There have been no grade 4-5 toxicities. One dose-limiting toxicity (DLT) of diarrhea occurred in the 2mg dose cohort, attributed mainly to 5FU CRT, but led to trametinib discontinuation. Generalized skin rash led to trametinib discontinuation after 2 weeks of therapy for 1 patient and was held for 3 days for 2 patients. All patients completed TME, and 3 patients had wound infection at 2 weeks after TME, while 2 patients had perineal wound infection at 4 weeks after TME. Three out of 9 (33%) patients at the 2mg dose cohort had a pathologic complete response (pCR), and 2/9 (22%) patients had a near pCR. Adjuvant chemotherapy was given to 10 patients, 4 patients did not receive (3 refused), and 1 patient is pending. Correlative research studies have been performed in the first 12 patients enrolled. Examination of phospho-ERK levels using Vectra quantitative immunohistochemistry in pre-treatment versus post-lead-in trametinib tumor tissue reveals dose-dependent decreases in p-ERK expression in both tumor and stromal tissue as trametinib is increased from 0.5 to 2.0 mg (range 18-46% absolute reduction), with maximal reduction observed in the 2 mg cohort. Additionally, we have performed whole exome sequencing of a custom panel of 279 cancer associated genes (IGNITE platform) in tumor and normal tissue, and have identified high frequency mutations in KRAS, BRAF, and TP53, as well as additional lower frequency mutations in every tumor. One patient was noted to have microsatellite instability. Finally, we will present data correlating degree of change in p-ERK staining, mutational analysis, and mismatch repair status with pathologic response. Conclusions: The combination of trametinib with 5-FU-based CRT for LARC is feasible with promising signs of clinical activity and tolerability. Initial analysis of tumor tissue confirms dose-dependent pharmacodynamic inhibition of ERK-1/2 within 5 days of starting trametinib. Citation Format: Terence M. Williams, Christina Wu, Lai Wei, Emily Chan, Ryan Robb, Sameek Roychowdhury, Amy Webb, Cynthia Timmers, Tanios Bekaii-Saab, Evan Wuthrick. A phase I trial combining MEK-1/2 inhibition in combination with 5-fluorouracil and radiation for locally-advanced rectal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT088. doi:10.1158/1538-7445.AM2017-CT088

Abstract The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) in collaboration with the Colorectal Cancer Family Registry (CCFR) aims to identify genetic variants and environmental risk factors that impact colorectal cancer (CRC). Over 30 studies from North America, Europe, and Australia participate in GECCO. These studies have collected clinical, epidemiological, and survival data, as well as blood and tumor biospecimens, for over 80,000 CRC cases and controls. The current study aims to conduct targeted deep sequencing of tumors and matching normal DNA to identify recurrent and novel somatic and germline variants in 4,200 CRC cases. To achieve this goal, an AmpliSeq targeted sequencing panel of 1.12 Mbp was constructed to sequence the coding regions of 190 significantly mutated genes identified from whole exome sequencing datasets generated by the Nurses’ Health Study and Health Professional’s Follow-up Study, and The Cancer Genome Atlas. The panel also covers coding regions of 15 genes with germline high penetrance mutations in CRC, 54 regions to detect CRC-related copy number alterations (CNAs), and microsatellite and homopolymer repeat regions to identify defective DNA mismatch repair. Primers were also included to detect Fusobacterium nucleatum DNA in tumor biopsies, as F. nucleatum is thought to promote CRC carcinogenesis. Sequencing of the DNA libraries on Illumina HiSeq 2500 produced a mean coverage of greater than 500X for tumor DNA and 100X for normal DNA, with >85% of the bases covered at the target at 50x. So far, targeted sequencing of >1,500 DNA samples from CRC tumors and normal tissues has identified recurrent and novel somatic mutations, germline genetic variants, and hypermutation status of the tumors due to defective DNA mismatch repair or pathogenic mutations in the POLE gene. Targeted sequencing has also allowed quantification of the F. nucleatum DNA in tumor biopsies; the results were validated by a multiplex QPCR assay. At the AACR annual meeting, we will present targeted sequencing results generated from the first two GECCO-participating studies (n=1,300 cases). These data will be valuable for future association testing of somatic mutations, CNAs, hypermutation status, and F. nucleatum with germline genetic variants, lifestyle, and environmental risk factors and survival. This large study will allow development of better strategies for diagnosis, treatment, and prevention of CRC. Citation Format: Syed H. Zaidi, Wei Sun, Jeroen Huyghe, Catherine S. Grasso, Quang Trinh, Charles Connolly, Amy French, Jasmine Mu, Marios Giannakis, Eve Shinbrot, Ivan Borozan, Michael J. Quist, Hermann Brenner, Daniel Buchanan, Peter Campbell, Andrew Chan, Jenny Chang-Claude, Vincent Ferretti, Charles Fuchs, Andrea Gsur, Marc Gunter, Tabitha Harrison, Michael Hoffmeister, Wen-Yi Huang, Paul Krzyzanowski, Stephen Lee, Mathieu Lemire, Jessica Miller, Danielle Pasternack, Cherie Teney, Elaine Mardis, Polly Newcomb, Lincoln Stein, Lee Timms, David Wheeler, Christina Yung, Niha Zubair, Levi Garraway, Shuji Ogino, Li Hsu, Steven Gallinger, Stephen Thibodeau, Thomas Hudson, Ulrike Peters. Targeted deep sequencing of colorectal tumor tissues to study associations of tumor subtypes with germline genetic, lifestyle, and environmental risk factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1286. doi:10.1158/1538-7445.AM2017-1286