Citations

102 Background: Combination irinotecan and cetuximab is approved for irinotecan-refractory mCRC; it is unknown if the addition of bevacizumab would improve outcomes. We studied the efficacy and safety of CBI compared with CI in patients (pts) with RAS wildtype, irinotecan-refractory mCRC. Methods: In this multicenter, randomized, double-blind, placebo-controlled phase II trial, pts with RAS wildtype mCRC and no prior anti-epidermal growth factor receptor therapy who failed at least 1 irinotecan-based chemotherapy regimen and received bevacizumab in at least 1 prior line of therapy were randomized 1:1 to irinotecan 180 mg/m2 (or previously tolerated dose), cetuximab 500 mg/m2, and bevacizumab 5 mg/kg vs CI every 2 wks until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was progression free survival (PFS). Multivariable Cox proportional hazard models stratified by number of prior lines of therapy and bevacizumab receipt in immediate prior line were performed. Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). The study was closed early in January 2018 for reasons related to accrual and funding after enrollment of 36 out of a planned 60 pts. Results: Between July 2015 and December 2017, 36 pts were randomized (19 to CBI, 17 to CI). 34 pts (94%) were treated with 2 or more prior chemotherapy regimens. Baseline characteristics were similar between arms. Median PFS was 9.7 vs 5.5 mo for CBI and CI arms, respectively (log-rank P =0.76; multivariable HR = 0.64; 95% CI, 0.25-1.66). Median OS was 19.7 vs 10.2 mo for CBI and CI (log-rank P= 0.04; multivariable HR = 0.41; 95% CI, 0.15-1.09). ORR was 37% for CBI vs 12% for CI ( P =0.13). Grade 3 or higher AEs occurred in 47% of pts receiving CBI vs 35% for CI ( P =0.46). Conclusions: In this prematurely discontinued trial, there were non-significant increases in PFS and ORR and a statistically significant 9.5 mo increase in median OS in favor of CBI compared to CI. Further investigation of CBI for treatment of irinotecan-refractory mCRC is warranted. Clinical trial information: NCT02292758.

Background: The authors compared long-term health care use and cost in women undergoing immediate autologous breast reconstruction and implant-based breast reconstruction. Methods: This study was conducted using the OptumLabs Data Warehouse, which contains deidentified retrospective administrative claims data, including medical claims and eligibility information from a large U.S. health insurance plan. Women who underwent autologous or implant-based breast reconstruction between January of 2004 and December of 2014 were included. The authors compared 2-year use rates and predicted costs of care. Comparisons were tested using the t test. Results: Overall, 12,296 women with immediate breast reconstruction were identified; 4257 with autologous (35 percent) and 8039 with implant-based (65 percent) breast reconstruction. The proportion of autologous breast reconstruction decreased from 47.2 percent in 2004 to 32.7 percent in 2014. The mean predicted reconstruction cost of autologous reconstruction was higher than that of implant-based reconstruction in both unilateral and bilateral surgery. Similar results for mean predicted 2-year cost of care were seen in bilateral procedures. However, in unilateral procedures, the 2-year total costs were higher for implant-based than for autologous reconstruction. Two-year health care use rates were higher for implant-based reconstruction than for autologous reconstruction for both unilateral and bilateral procedures. Women undergoing unilateral implant-based reconstruction had higher rates of hospital admissions (30.3 versus 23.1 per 100; p < 0.01) and office visits (2445.1 versus 2283.6 per 100; p < 0.01) than those who underwent autologous reconstruction. Emergency room visit rates were similar between the two methods. Bilateral procedures yielded similar results. Conclusion: Although implant-based breast reconstruction is a less expensive index operation than autologous breast reconstruction, it was associated with higher health care use, resulting in similar total cost of care over 2 years.

Background. The ATP-binding cassette, subfamily D, member 1 (ABCD1) protein is a peroxisomal half-transporter that allows for very long chain fatty acid (VLCFA) degradation. Pathogenic variants of ABCD1 cause VLCFAs to build up in various tissues and bodily fluids, resulting in a disorder called X-linked adrenoleukodystrophy (X-ALD). This disorder is most commonly marked by adrenocortical insufficiency and high VLCFA concentration, and has varying levels of neurological involvement depending on phenotype. For example, the Addison-only form of X-ALD has no neurological impact, while the cerebral form of X-ALD often causes severe sensory loss, motor function impairment, cognitive decline, and death. Methods. A newly characterized and suspected pathogenic variant in ABCD1 was analyzed using our protein informatics platform (PIP). Personalized protein-level molecular studies were completed on genetic testing data, complementing the analysis and clinical study. Results. A case of adult onset adrenomyeloneuropathy (AMN) and a novel ABCD1 variant are presented. The unique ABCD1 protein is discussed, and the proband’s case is compared to existing reports of AMN. Conclusions. Data fusion from multiple sources was combined in a comprehensive approach yielding an enriched assessment of the patient’s disease and prognosis. Molecular modeling was performed on the variant to better characterize its clinical significance and confirm pathogenicity.

Background and Aims Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and BTC is currently the leading cause of death in patients with PSC. To open new avenues for management, we aimed to delineate clinically relevant genomic and pathological features of a large panel of PSC‐associated BTC (PSC‐BTC). Approach and Results We analyzed formalin‐fixed, paraffin‐embedded tumor tissue from 186 patients with PSC‐BTC from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations, and copy number variations, along with histomorphological and immunohistochemical characterization. Regardless of the anatomical localization, PSC‐BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, such as TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potentially druggable mutations (e.g., HER2/ERBB2). We found a high frequency of nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%). Conclusions Genomic alterations in PSC‐BTC include a significant number of putative actionable therapeutic targets. Notably, PSC‐BTC shows a distinct extrahepatic morpho‐molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC‐associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome‐based personalized treatment strategies in PSC‐BTC.

Objective: Faulty neuromuscular and biomechanical deficits of the knee are nearly ubiquitous in athletes after anterior cruciate ligament (ACL) reconstruction (ACLR). Knee biomechanical deficits are directly associated with an increased risk of second ACL injury, which typically occurs during a sports-related movement on a single limb. To date, the biomechanical effects of a neuromuscular training (NMT) program on knee biomechanics during a single-leg landing task have not been investigated. Design: Prospective Cohort Study. Setting: Controlled laboratory setting. Participants: Eighteen ACLR and 10 control athletes. Interventions: Neuromuscular training. Main Outcome Measures: Knee kinematics and kinetics. Results: There were no significant interactions of session and limb (P > 0.05) for the athletes with ACLR after training. However, there were several significant main effects of session (P < 0.05) for knee kinematics and kinetics during the single-leg landing task. After training, the athletes with ACLR landed with greater knee flexion angles, decreased knee abduction angles, increased knee flexion range of motion, and decreased knee excursion. Also, the ACLR athletes landed with lower knee flexion moments, greater knee adduction moments, and lower peak vertical ground reaction force. Post-training comparison of the ACLR and control cohorts found no significant interactions of group and limb (P > 0.05) and only a significant main effect of group (P < 0.05) for frontal plane knee angle at initial contact. The athletes with ACLR landed with greater knee adduction angles than the control group. Conclusions: Deficits in knee biomechanics that are associated with an increased risk of ACL injury are attenuated after completion of this NMT program.