Background Immunotherapy has changed the therapeutic landscape in oncology. Advanced uterine leiomyosarcoma (ULMS) remains an incurable disease in most cases, and despite new drug approvals, improvements in overall survival have been modest at best. The goal of this study was to evaluate programmed-death 1 (PD-1) inhibition with nivolumab in this patient population Methods This single-center phase 2 trial completed enrollment between May and October 2015. Patients received 3 mg/kg of intravenous nivolumab on day 1 of each 2-week cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate. We assessed PD-1, PD-ligand 1 (PD-L1), and PD-L2 expression in archival tumor samples and variations in immune-phenotyping of circulating immune cells during treatment Results Twelve patients were enrolled in the first stage of the 2-stage design. A median of 5 (range, 2-6) 2-week cycles of nivolumab were administered. Of the 12 patients, none responded to treatment. The overall median progression-free survival was 1.8 months (95% confidence interval, 0.8-unknown). The study did not open the second stage due to lack of benefit as defined by the statistical plan. Archival samples were available for 83% of patients. PD-1 (>3% of cells), PD-L1, and PD-L2 (>5% and >10% of tumor cells, respectively) expression were observed in 20%, 20%, and 90% of samples, respectively. No significant differences were observed between pre- and posttreatment cell phenotypes. Conclusion Single-agent nivolumab did not demonstrate a benefit in this cohort of previously treated advanced ULMS patients. Further biomarker-driven approaches and studies evaluating combined immune checkpoint-modulators should be considered.

BACKGROUND: Uterine leiomyosarcoma (ULMS) is identified in 0.1% to 0.2% of hysterectomy specimens of presumed leiomyoma. To date, there is no preoperative technique that reliably differentiates ULMS from uterine leiomyoma. Increasing use of minimally invasive approaches for the management of leiomyomas may result in inadvertently morcellated ULMS with resultant intraperitoneal dissemination of tumor. The objective of this study was to assess the impact of intraperitoneal morcellation on the outcomes of patients with ULMS. METHODS: In this retrospective cohort study, all patients with ULMS who attended the authors' institutions from 2007 to 2012 were reviewed. Demographics and outcomes were compared between those who underwent morcellation or total abdominal hysterectomy (TAH) as their first surgery for uterus-limited ULMS. RESULTS: In total, 58 patients were identified, including 39 who underwent TAH and 19 who underwent intraperitoneal morcellation. Intraperitoneal morcellation was associated with a significantly increased risk of abdominal/pelvic recurrences (P 5.001) and with significantly shorter median recurrence-free survival (10.8 months vs 39.6 months; P 5.002). A multivariate adjusted model demonstrated a >3 times increased risk of recurrence associated with morcellation (hazard ratio, 3.18; 95% confidence interval, 1.5-6.8; P 5.003). CONCLUSIONS: Intraperitoneal morcellation of presumed leiomyoma worsens the outcomes of women with ULMS. Because there are no reliable preoperative techniques to distinguish ULMS from benign leiomyoma, all efforts to minimize intraperitoneal uterine morcellation should be considered. [See editorial on pages 000-000, this issue.] Cancer 2014;120:3154-8.

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Purpose: Polyclonal emergence of KIT secondary mutations is a main mechanism of imatinib progression in gastrointestinal stromal tumor (GIST). Approved KIT inhibitors sunitinib and regorafenib have complementary activity against KIT resistance mutations. Preclinical evidence suggests that rapid alternation of sunitinib and regorafenib broadens the spectrum of imatinib-resistant subclones targeted.Patients and Methods: Phase Ib study investigating continuous treatment with cycles of sunitinib (3 days) followed by regorafenib (4 days) in patients with tyrosine kinase inhibitor (TKI)-refractory GIST. A 3þ3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Plasma samples were analyzed for pharmacokinetics and circulating tumor DNA (ctDNA) studies using targeted error correction sequencing (TEC-seq) and droplet digital PCR (ddPCR).Results: Of the 14 patients enrolled, 2 experienced doselimiting toxicities at dose level 2 (asymptomatic grade 3 hypophosphatemia). Sunitinib 37.5 mg/day and regorafenib 120 mg/day was the RP2D. Treatment was well-tolerated and no unexpected toxicities resulted from the combination. Stable disease was the best response in 4 patients, and median progression-free survival was 1.9 months. Combined assessment of ctDNA with TEC-seq and ddPCR detected plasma mutations in 11 of 12 patients (92%). ctDNA studies showed that KIT secondary mutations remain the main mechanism of resistance in TKI-refractory GIST, revealing effective suppression of KIT-mutant subpopulations in patients benefiting from the combination.Conclusions: Sunitinib and regorafenib combination is feasible and tolerable. Rapid alternation of TKIs with complementary activity might be effective when combining drugs with favorable pharmacokinetics, potentially allowing active doses while minimizing adverse events. Serial monitoring with ctDNA may guide treatment in patients with GIST.

BackgroundThe quality of transitional care is associated with important health outcomes such as rehospitalization and costs. The widely used Care Transitions Measure (CTM‐15) was developed with a classic test theory approach; its short version (CTM‐3) was included in the CAHPS Hospital Survey. We conducted a psychometric evaluation of both measures and explored whether item response theory (IRT) could produce a more precise measure.Methods and ResultsAs part of the Transitions, Risks, and Actions in Coronary Events Center for Outcomes Research and Education, 1545 participants were interviewed during an acute coronary syndrome hospitalization, providing information on general health status (Short Form‐36), CTM‐15, health utilization, and care process questions at 1 month postdischarge. We used classic and IRT analyses and compared the measurement precision of CTM‐15–, CTM‐3–, and CTM‐IRT–based score using relative validity.Participants were 79% non‐Hispanic white and 67% male, with an average age of 62 years. The CTM‐15 had good internal consistency (Cronbach's α=0.95) but demonstrated acquiescence bias (8.7% participants responded “Strongly agree” and 19% responded “Agree” to all items) and limited score variability. These problems were more pronounced for the CTM‐3. The CTM‐15 differentiated between patient groups defined by self‐reported health status, health care utilization, and care transition process indicators. Differences between groups were small (2 to 3 points). There was no gain in measurement precision from IRT scoring. The CTM‐3 was not significantly lower for patients reporting rehospitalization or emergency department visits.ConclusionWe identified psychometric challenges of the CTM, which may limit its value in research and practice. These results are in line with emerging evidence of gaps in the validity of the measure.