Citations

Abstract Over the recent years significant knowledge has been accumulated on which drugs can be therapeutically beneficial for a given patient based on mutational profiling of their tumors using selected gene panels. Much less, however, is known under which conditions targeting of genes which are amplified could be beneficial. Apart from successfully targeting HER2-positive cancers, many of which frequently carry amplified ERBB2 gene, no other targeted therapy based on DNA amplifications or gains of the genes is offered to the patients due to lack of clinical response data. Using mate pair sequencing we have profiled 60 high grade serous ovarian tumors to compare genomic rearrangements and copy number changes. The analyses revealed that these tumors carry highly rearranged genome. Copy number changes amplifications, gains and losses were very common and included genes potentially therapeutically targetable. In contrast, only a few of targetable fusion genes were identified in a set of 60 cases. The tumors were propagated in immunocompromised mice (mouse avatars), sequenced and showed identical to original patient tumor landscape of rearrangements. Using these mouse avatar models we tested whether a therapy inhibiting selected based on genomic amplification targets provided a benefit compared to standard chemotherapy. Mice which harbored tumors showing amplifications of CDKs (CDK2, 4 and 9) and ERBB3 were treated with flavopiridol and pertuzumab respectively, and response was compared to that of standard for ovarian cancer chemotherapy (carboplatin and paclitaxel combination). We observed that application of either agent, significantly inhibited tumor growth in treated mice as compared to untreated. However, neither drug alone caused tumor regression. The treatment regimen then was modified to administer chemotherapy and targeted therapy together. A mouse avatars in which genomic analyses revealed amplification at loci involving AKT3 and RICTOR genes was treated with chemotherapy alone and in combination with MK2206 (AKT inhibitor) or MK8669 (mTOR inhibitor). The high level of both target proteins was confirmed by immunoblotting. Significant regression of tumor was observed after 6 weeks of treatment. Addition of either targeted drug provided an extra benefit in killing tumor cells compared to chemotherapy alone. The mice are followed to study tumor recurrence. These data indicated that genomic information obtained using next generation sequencing can aid therapy decisions by tailoring treatments to individual tumor makeup. Avatar models in conjunction with genomic analyses of the original tumors are invaluable for testing specific targeted therapies selected based on amplification/gains of putative genes-targets and for studying mechanisms of tumor recurrence and therapy resistance. Citation Format: Faye R. Harris, Lin Yang, Xiaonan Hou, Konstantinos Leventakos, Saravut J. Weroha, George Vasmatzis, Irina V. Kovtun. Targeting genes which are amplified in ovarian cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A34.

Background: Distal radius malunions lead to functional deficits. This study compares isolated ulnar shortening osteotomy (USO) to distal radius osteotomy (DRO) for the treatment of ulnar impaction syndrome following distal radius malunion. Methods: We retrospectively reviewed 11 patients with extra-articular distal radius malunions treated for ulnar impaction with isolated USO. This group was compared to a 1:1 age- and sex-matched cohort treated with isolated DRO for the same indication. Pain visual analog scale (VAS), wrist motion, grip strength, radiographic parameters, and perioperative complications were analyzed. Mean follow-up was 14.8 months. Results: VAS scores improved. Wrist range of motion improved in both cohorts with the exception of radial deviation, pronation, and supination in the USO cohort, which decreased from a mean of 17°-16°, 67°-57°, and 54°-52°, respectively. There was no significant difference between groups in regard to change in pain or range of motion, with the exception of pronation and ulnar deviation. The mean tourniquet time was shorter in the USO group. The final ulnar variance was 1.8 mm negative in the USO group and 1.1 mm positive in the DRO group. There was 1 reoperation following USO for painful nonunion, while there were 2 reoperations following DRO for persistent ulnar impaction. Conclusions: An improvement in range of motion, grip strength, and VAS with restoration of the radioulnar length relationship was observed in both cohorts. USO is a simpler procedure with a shorter tourniquet time that can be an attractive alternative to DRO for ulnar impaction syndrome after distal radius malunions.

AimsFree vascularised fibular grafting has been used for the treatment of large bony defects for more than 40 years. However, there is little information about the risk factors for failure and whether newer locking techniques of fixation improve the rates of union. The purpose of this study was to compare the rates of union of free fibular grafts fixed with locking and traditional techniques, and to quantify the risk factors for nonunion and failure.Patients and MethodsA retrospective review involved 134 consecutive procedures over a period of 20 years. Of these, 25 were excluded leaving 109 patients in the study. There were 66 men and 43 women, with a mean age of 33 years (5 to 78). Most (62) were performed for oncological indications, and the most common site (52) was the lower limb. Rate of union was estimated using the Kaplan-Meier method and risk factors for nonunion were assessed using Cox regression. All patients were followed up for at least one year.ResultsThe rate of union was 82% at two years and 97% at five years. Union was achieved after the initial procedure in 76 patients (70%) at a mean of ten months (3 to 19), and overall union was achieved in 99 patients (91%). No surgical factor, including the use of locked fixation or supplementary corticocancellous bone grafts increased the rate of union. A history of smoking was significantly associated with a risk of nonunion.DiscussionFree vascularised fibular grafting is a successful form of treatment for large bony defects. These results suggest that the use of modern techniques of fixation does not affect the risk of nonunion when compared with traditional forms of fixation, and smoking increases the risk of nonunion following this procedure. Cite this article: Bone Joint J 2017;99-B:134–8.

Purpose Although burnout and low quality of life (QOL) are common among medical students, little remains known about personal fitness habits of medical students that may promote well-being. Method In 2012 the authors conducted a cross-sectional study of U.S. medical students to explore relationships between burnout, QOL, and compliance with Centers for Disease Control and Prevention (CDC) exercise recommendations. Wilcoxon-Mann-Whitney tests, Fisher exact tests, and multivariate logistic regression were performed. Results Among approximately 12,500 medical students invited to participate, 4,402 (35.2%) completed surveys. Most (2,738/4,367; 62.7%) engaged in aerobic exercise in accordance with CDC recommendations, while fewer (1,685/4,376; 38.5%) adhered to muscle strengthening recommendations. Burnout prevalence was lower among students who exercised aerobically consistent with CDC recommendations compared with those who exercised less (53.1% vs. 60.8%, P < .0001). Similarly, rates of burnout were also lower among students who strength trained consistent with CDC recommendations (51.8% vs. 58.6%, P < .0001). Overall QOL scores were higher for medical students adhering to CDC recommendations for aerobic exercise (7.2 vs. 6.6, P < .0001), strength training (7.2 vs. 6.8, P < .0001), or both aerobic and strength training (8.0 vs. 7.0, P < .0001). Compliance with CDC exercise guidelines remained independently associated with lower risk of burnout and higher QOL on multivariate analysis controlling for age, sex, relationship status, children, and year in school. Conclusions Students whose aerobic exercise and/or strength training habits are consistent with CDC guidelines appear less likely to experience burnout and to have higher QOL.

Purpose: To evaluate the safety of single intravitreal 2 mg ziv-aflibercept (0.08 mL) injections for the treatment of choroidal neovascular membranes (CNVM). Methods: Eyes with choroidal neovascular membranes because of several conditions each received single intravitreal injections of 2 mg ziv-aflibercept (0.08 mL). Comprehensive ophthalmic examinations and detailed systemic evaluations were performed at baseline and Days 1, 7, and 30 after injections. Standard electroretinography was performed at baseline and Day 30. Primary outcome measures consisted of safety assessments (signs of clinical toxicity and electroretinographic abnormalities). Secondary outcome measures included changes in best-corrected visual acuity (BCVA) and central subfield thickness (CST) of the macula. Results: Twenty-one eyes of 20 patients (12 males) received injections. Etiologies responsible for the choroidal neovascular membranes included age-related macular degeneration (14), polypoidal choroidal vasculopathy (PCV) (3), myopia (2), and idiopathic juxtafoveal telangiectasia (2). None of the patients complained of worsening vision or pain after the intravitreal injections and no intraocular inflammation was seen. No significant changes in the electroretinographic b/a ratio from baseline to 1 month were measured (scotopic: P = 0.89; photopic: P = 0.13) and mean intraocular pressures were unchanged (14.2 ± 3.6 vs. 13.7 ± 3.0 mmHg; P = 0.62). Mean best-corrected visual acuity did not change significantly from baseline to 1 month (0.66 ± 0.37 logMAR [Snellen equivalent: 20/100] vs. 0.61 ± 0.35 logMAR [Snellen equivalent: 20/80]; P = 0.72) but significant improvements in central subfield thickness were seen (343 ± 177 vs. 210 ± 133 μ m; P = 0.01). Conclusion: Single intravitreal injections of 2 mg ziv-aflibercept (0.08 mL) appear to be safe through 1 month.

Abstract Objective . Automated behavioral state classification can benefit next generation implantable epilepsy devices. In this study we explored the feasibility of automated awake (AW) and slow wave sleep (SWS) classification using wide bandwidth intracranial EEG (iEEG) in patients undergoing evaluation for epilepsy surgery. Approach . Data from seven patients (age 34 ± 12 , 4 women) who underwent intracranial depth electrode implantation for iEEG monitoring were included. Spectral power features (0.1–600 Hz) spanning several frequency bands from a single electrode were used to train and test a support vector machine classifier. Main results . Classification accuracy of 97.8 ± 0.3% (normal tissue) and 89.4 ± 0.8% (epileptic tissue) across seven subjects using multiple spectral power features from a single electrode was achieved. Spectral power features from electrodes placed in normal temporal neocortex were found to be more useful (accuracy 90.8 ± 0.8%) for sleep-wake state classification than electrodes located in normal hippocampus (87.1 ± 1.6%). Spectral power in high frequency band features (Ripple (80–250 Hz), Fast Ripple (250–600 Hz)) showed comparable performance for AW and SWS classification as the best performing Berger bands (Alpha, Beta, low Gamma) with accuracy ⩾90% using a single electrode contact and single spectral feature. Significance . Automated classification of wake and SWS should prove useful for future implantable epilepsy devices with limited computational power, memory, and number of electrodes. Applications include quantifying patient sleep patterns and behavioral state dependent detection, prediction, and electrical stimulation therapies.