Citations

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurologic disorder with predictable challenges regarding disease progression and end-of-life care. These include need for respiratory and nutritional support. Little is known about how such choices impact end-of-life health service utilization for these patients. Using OptumLabs Data Warehouse, a large administrative claims database with more than 150 million privately insured, geographically diverse enrollees, we sought to explore outcomes associated with the use of enteral nutrition (EN). Patients were of age ≥18 years, with first ALS diagnosis during calendar years 2006-2012, and 6 months of continuous health plan coverage before first diagnosis. EN use was identified using procedure codes. Data were summarized descriptively. Among 1974 patients with ALS, mean age was 60.0 ± 12.5 years, 41.8% were women, and 9.7% demonstrated use of EN. Median time from ALS diagnosis to evidence of EN was 211 days (interquartile range [IQR]: 70-426). Those receiving EN had greater aggregate comorbidity (47% with Charlson-Deyo Comorbidity Index ≥ 3 vs only 27% in non-EN subset). In total, 38.1% of patients had at least 1 hospitalization, with median time to hospitalization of 162 days. Unfortunately, the EN group ended coverage a median of 155 days after EN started (IQR: 63.5-388), thereby limiting ability to capture outcomes. Although many ALS patients were identified, EN use was lower than expected, due to being earlier in disease trajectory and lost to follow-up with transition from private insurance. As such, databases exclusively including privately insured patients may be suboptimal for detecting late complications of protracted illnesses.

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.

AbstractBackgroundObservational reports suggest that supplementation that increases citric acid cycle intermediates via anaplerosis may have therapeutic advantages over traditional medium‐chain triglyceride (MCT) treatment of long‐chain fatty acid oxidation disorders (LC‐FAODs) but controlled trials have not been reported. The goal of our study was to compare the effects of triheptanoin (C7), an anaplerotic seven‐carbon fatty acid triglyceride, to trioctanoin (C8), an eight‐carbon fatty acid triglyceride, in patients with LC‐FAODs.MethodsA double blinded, randomized controlled trial of 32 subjects with LC‐FAODs (carnitine palmitoyltransferase‐2, very long‐chain acylCoA dehydrogenase, trifunctional protein or long‐chain 3‐hydroxy acylCoA dehydrogenase deficiencies) who were randomly assigned a diet containing 20% of their total daily energy from either C7 or C8 for 4 months was conducted. Primary outcomes included changes in total energy expenditure (TEE), cardiac function by echocardiogram, exercise tolerance, and phosphocreatine recovery following acute exercise. Secondary outcomes included body composition, blood biomarkers, and adverse events, including incidence of rhabdomyolysis.ResultsPatients in the C7 group increased left ventricular (LV) ejection fraction by 7.4% (p = 0.046) while experiencing a 20% (p = 0.041) decrease in LV wall mass on their resting echocardiogram. They also required a lower heart rate for the same amount of work during a moderate‐intensity exercise stress test when compared to patients taking C8. There was no difference in TEE, phosphocreatine recovery, body composition, incidence of rhabdomyolysis, or any secondary outcome measures between the groups.ConclusionsC7 improved LV ejection fraction and reduced LV mass at rest, as well as lowering heart rate during exercise among patients with LC‐FAODs.Clinical Trial Registration: Clinicaltrials.gov NCT01379625.

Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor–positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day. Tumor DNA from serum (circulating cell free [cf); all patients] and biopsies [160 mg/day and expansion]) was sequenced. Results Of 41 enrolled patients, 38 were evaluable for MTD determination. Prior endocrine regimens during which progression occurred included aromatase inhibitor (n = 36), fulvestrant (n = 21), and tamoxifen (n = 15). Patients received endoxifen once daily at seven dose levels (20 to 160 mg). Dose escalation ceased at 160 mg per day given lack of MTD and endoxifen concentrations > 1,900 ng/mL. Endoxifen clearance was unaffected by CYP2D6 genotype. One patient (60 mg) had cycle 1 dose-limiting toxicity (pulmonary embolus). Overall clinical benefit rate (stable > 6 months [n = 7] or partial response by RECIST criteria [n = 3]) was 26.3% (95% CI, 13.4% to 43.1%) including prior tamoxifen progression (n = 3). cfDNA mutations were observed in 13 patients ( PIK3CA [n = 8], ESR1 [n = 5], TP53 [n = 4], and AKT [n = 1]) with shorter progression-free survival ( v those without cfDNA mutations; median, 61 v 132 days; log-rank P = .046). Clinical benefit was observed in those with ESR1 amplification (tumor; 80 mg/day) and ESR1 mutation (cfDNA; 160 mg/day). Comparing tumor biopsies and cfDNA, some mutations ( PIK3CA, TP53, and AKT) were undetected by cfDNA, whereas cfDNA mutations ( ESR1, TP53, and AKT) were undetected by biopsy. Conclusion In endocrine-refractory metastatic breast cancer, Z-endoxifen provides substantial drug exposure unaffected by CYP2D6 metabolism, acceptable toxicity, and promising antitumor activity.

AbstractBackgroundThe extent to which participants act to clinically verify research results is largely unknown. This study examined whether participants who received Lynch syndrome (LS)‐related findings pursued researchers’ recommendation to clinically verify results with testing performed by a CLIA‐certified laboratory.MethodsThe Fred Hutchinson Cancer Research Center site of the multinational Colon Cancer Family Registry offered non‐CLIA individual genetic research results to select registry participants (cases and their enrolled relatives) from 2011 to 2013. Participants who elected to receive results were counseled on the importance of verifying results at a CLIA‐certified laboratory. Twenty‐six (76.5%) of the 34 participants who received genetic results completed 2‐ and 12‐month postdisclosure surveys; 42.3% of these (11/26) participated in a semistructured follow‐up interview.ResultsWithin 12 months of result disclosure, only 4 (15.4%) of 26 participants reported having verified their results in a CLIA‐certified laboratory; of these four cases, all research and clinical results were concordant. Reasons for pursuing clinical verification included acting on the recommendation of the research team and informing future clinical care. Those who did not verify results cited lack of insurance coverage and limited perceived personal benefit of clinical verification as reasons for inaction.ConclusionThese findings suggest researchers will need to address barriers to seeking clinical verification in order to ensure that the intended benefits of returning genetic research results are realized.

The purpose of this prospective study was to determine whether an association exists between foot structure and the development of musculoskeletal overuse injuries. The study group was a well-defined cohort of 449 trainees at the Naval Special Warfare Training Center in Coronado, California. Before beginning training, measurements were made of ankle motion, subtalar motion, and the static (standing) and dynamic (walking) characteristics of the foot arch. The subjects were tracked prospectively for injuries throughout training. We identified risk factors that predispose people to lower extremity overuse injuries. These risk factors include dynamic pes planus, pes cavus, restricted ankle dorsiflexion, and increased hindfoot inversion, all of which are subject to intervention and possible correction.