Citations

AbstractBackground and AimFeedback has been shown to improve performance in colonoscopy including adenoma detection rate (ADR). The frequency at which feedback should be given is unknown. As part of a quality improvement program, we sought to measure the outcome of providing quarterly and monthly feedback on colonoscopy quality measures.MethodsAll screening colonoscopies performed at endoscopy unit at Mayo Clinic Arizona by gastroenterologists between October 2010 and December 2012 were reviewed. Quality indicators, including ADR, were extracted for each individual endoscopist, and feedback was provided. The study period was divided into four distinct groups: pre‐intervention that served as baseline, quarterly feedback, monthly feedback, and post‐intervention. Based on ADR, endoscopists were grouped into “low detectors” (≤ 25%), “average detectors” (26–35%), and “high detectors” (> 35%).ResultsA total of 3420 screening colonoscopies were performed during the study period (555 patients during pre‐intervention, 1209 patients during quarterly feedback, 599 during monthly feedback, and 1057 during the post‐intervention period) by 16 gastroenterologists. The overall ADR for the group improved from 30.5% to 37.7% (P = 0.003). Compared with the pre‐interventional period, all quality indicators measured significantly improved during the monthly feedback and post‐intervention periods but not in the quarterly feedback period.ConclusionsIn our quality improvement program, monthly feedback significantly improved colonoscopy quality measures, including ADR, while quarterly feedback did not. The impact of the intervention was most prominent in the “low detectors” group. Results were durable up to 6 months following the intervention.

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.

Key Clinical MessageHereditary spastic paraplegia is a group of clinically and genetically heterogeneous neurodegenerative disorders, often characterized by weakness and spasticity in the lower limbs. In our study, we describe a spastic paraplegia type 7 patient with an expanded phenotype who was diagnosed after the discovery of pathogenic variants in SPG7.

Abstract Hematopoietic cell transplantation (HCT) is an expensive, resource-intensive, and medically complicated modality for treatment of many hematologic disorders. A well-defined care coordination model through the continuum can help improve health care delivery for this high-cost, high-risk medical technology. In addition to the patients and their families, key stakeholders include not only the transplantation physicians and care teams (including subspecialists), but also hematologists/oncologists in private and academic-affiliated practices. Initial diagnosis and care, education regarding treatment options including HCT, timely referral to the transplantation center, and management of relapse and late medical or psychosocial complications after HCT are areas where the referring hematologists/oncologists play a significant role. Payers and advocacy and community organizations are additional stakeholders in this complex care continuum. In this article, we describe a care coordination framework for patients treated with HCT within the context of coordination issues in care delivery and stakeholders involved. We outline the challenges in implementing such a model and describe a simplified approach at the level of the individual practice or center. This article also highlights ongoing efforts from physicians, medical directors, payer representatives, and patient advocates to help raise awareness of and develop access to adequate tools and resources for the oncology community to deliver well-coordinated care to patients treated with HCT. Lastly, we set the stage for policy changes around appropriate reimbursement to cover all aspects of care coordination and generate successful buy-in from all stakeholders.