Citations

Background The diagnoses of peripheral triangular fibrocartilage complex (TFCC) tears continue to be the subject of numerous investigations. Case Description We describe a novel arthroscopic technique that may be used as an adjunct with other arthroscopic maneuvers to diagnose and confirm repair of peripheral sided TFCC injuries. Literature Review The hook and trampoline tests are intraoperative techniques to diagnose TFCC tears. Clinical Relevance The suction test provides a means to detect peripheral tears and to confirm restoration of its tension post repair.

Abstract Introduction A classification framework for posterior cortical atrophy (PCA) is proposed to improve the uniformity of definition of the syndrome in a variety of research settings. Methods Consensus statements about PCA were developed through a detailed literature review, the formation of an international multidisciplinary working party which convened on four occasions, and a Web‐based quantitative survey regarding symptom frequency and the conceptualization of PCA. Results A three‐level classification framework for PCA is described comprising both syndrome‐ and disease‐level descriptions. Classification level 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico‐radiological syndrome. Classification level 2 (PCA‐pure, PCA‐plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. Classification level 3 (PCA attributable to AD [PCA‐AD], Lewy body disease [PCA‐LBD], corticobasal degeneration [PCA‐CBD], prion disease [PCA‐prion]) provides a more formal determination of the underlying cause of the PCA syndrome, based on available pathophysiological biomarker evidence. The issue of additional syndrome‐level descriptors is discussed in relation to the challenges of defining stages of syndrome severity and characterizing phenotypic heterogeneity within the PCA spectrum. Discussion There was strong agreement regarding the definition of the core clinico‐radiological syndrome, meaning that the current consensus statement should be regarded as a refinement, development, and extension of previous single‐center PCA criteria rather than any wholesale alteration or redescription of the syndrome. The framework and terminology may facilitate the interpretation of research data across studies, be applicable across a broad range of research scenarios (e.g., behavioral interventions, pharmacological trials), and provide a foundation for future collaborative work.

Abstract TGFβ–SMAD signaling exerts a contextual effect that suppresses malignant growth early in epithelial tumorigenesis but promotes metastasis at later stages. Longstanding challenges in resolving this functional dichotomy may uncover new strategies to treat advanced carcinomas. The Krüppel-like transcription factor, KLF10, is a pivotal effector of TGFβ/SMAD signaling that mediates antiproliferative effects of TGFβ. In this study, we show how KLF10 opposes the prometastatic effects of TGFβ by limiting its ability to induce epithelial-to-mesenchymal transition (EMT). KLF10 depletion accentuated induction of EMT as assessed by multiple metrics. KLF10 occupied GC-rich sequences in the promoter region of the EMT-promoting transcription factor SLUG/SNAI2, repressing its transcription by recruiting HDAC1 and licensing the removal of activating histone acetylation marks. In clinical specimens of lung adenocarcinoma, low KLF10 expression associated with decreased patient survival, consistent with a pivotal role for KLF10 in distinguishing the antiproliferative versus prometastatic functions of TGFβ. Our results establish that KLF10 functions to suppress TGFβ-induced EMT, establishing a molecular basis for the dichotomy of TGFβ function during tumor progression. Cancer Res; 77(9); 2387–400. ©2017 AACR.

Objectives: Effective pharmacologic treatments directly targeting lung injury in patients with the acute respiratory distress syndrome are lacking. Early treatment with inhaled corticosteroids and beta agonists may reduce progression to acute respiratory distress syndrome by reducing lung inflammation and enhancing alveolar fluid clearance. Design: Double-blind, randomized clinical trial (ClinicalTrials.gov: NCT01783821). The primary outcome was longitudinal change in oxygen saturation divided by the F io 2 (S/F) through day 5. We also analyzed categorical change in S/F by greater than 20%. Other outcomes included need for mechanical ventilation and development of acute respiratory distress syndrome. Setting: Five academic centers in the United States. Patients: Adult patients admitted through the emergency department at risk for acute respiratory distress syndrome. Interventions: Aerosolized budesonide/formoterol versus placebo bid for up to 5 days. Measurements and Main Results: Sixty-one patients were enrolled from September 3, 2013, to June 9, 2015. Median time from presentation to first study drug was less than 9 hours. More patients in the control group had shock at enrollment (14 vs 3 patients). The longitudinal increase in S/F was greater in the treatment group ( p = 0.02) and independent of shock ( p = 0.04). Categorical change in S/F improved ( p = 0.01) but not after adjustment for shock ( p = 0.15). More patients in the placebo group developed acute respiratory distress syndrome (7 vs 0) and required mechanical ventilation (53% vs 21%). Conclusions: Early treatment with inhaled budesonide/formoterol in patients at risk for acute respiratory distress syndrome is feasible and improved oxygenation as assessed by S/F. These results support further study to test the efficacy of inhaled corticosteroids and beta agonists for prevention of acute respiratory distress syndrome.

243 Background: Cbz/pred extends survival in mCRPC patients (pts) following docetaxel and first-line studies comparing Cbz to docetaxel are ongoing. Mito/pred also has anti-tumor activity in mCRPC and a non-overlapping mechanism of action and toxicity profile with Cbz. A multicenter phase I trial was initiated through the DOD PCCTC to establish the maximally tolerated dose (MTD) of the combination of Cbz, Mito, and Pred. Methods: Chemotherapy (chemo)-naive pts with mCRPC were enrolled in an accelerated titration design. The primary objective was to determine the MTD of CAMP; secondary objectives included assessing PSA and objective response rates and duration of response. Starting dose of Cbz was 25 mg/m2 (the currently approved single-agent dose) and Mito 4 mg/m2, administered on day 1 of a 21-day cycle. Mito was escalated by 2 mg/m2 per dose level. Pred 5 mg BID and pegfilgrastim were administered with each cycle. Results: 9 pts were enrolled (dose level I, N = 1; dose level II, N = 1; dose level III, N = 3; dose level IV N = 4). The median age was 67 (range 55-81) and the median baseline PSA was 82.3 (range 20.4-791.2). There were 2 DLTs observed at dose level IV (Cbz 25 mg/m2 + mito 10 mg/m2), both grade 4 sepsis. The most common grade 3 adverse events were hematologic (neutropenia, n = 5; febrile neutropenia, n = 2, thrombocytopenia, n = 2). 6 of 9 pts remain on study (range 2.2 - 10.5+ months). Maximal PSA declines from baseline > 50% have been observed in 4/7 (57%) evaluable pts to date. 2 of 4 pts with measurable disease have experienced partial responses and a third has had a minor response after 4 cycles of chemo. The median progression-free survival and duration of response have not been reached. Conclusions: The approved single-agent dosage of Mito (12 mg/m2) could not be safely reached in combination with Cbz 25 mg/m2. Pre-planned evaluation of an alternate dosing strategy combining Mito with Cbz 20 mg/m2, which has demonstrated activity in mCRPC and potentially less hematologic toxicity, is underway. Preliminary efficacy data are encouraging but additional follow-up and further study of the treatment combination is required. Clinical trial information: NCT01594918.

25 Background: Women with diabetes are at an increased risk of developing breast cancer, present with later stage disease, and experience higher breast cancer-specific mortality compared to nondiabetic women. Thus, it is imperative that diabetic women undergo routine screening mammography. Previous studies have shown conflicting results with smaller studies showing lower screening mammography rates among diabetics while a study using national self-report data showed that diabetic women were equally likely to be screened compared to nondiabetic women. Given the conflicting data and limitations of previous studies, we aimed to study receipt of mammography in diabetic women using a nationally representative administrative claims database. Methods: This was a retrospective study using a nationally representative administrative claims database from January 1, 2010, through December 31, 2012. We compared rates of receipt of mammography within a 2-year time frame in diabetic and nondiabetic women ages 40 to 64. We used Healthcare Effectiveness Data and Information Set (HEDIS) logic to define women with diabetes. We used CPT and ICD-9 codes to identify mammogram services received. We calculated odds ratios with 95% confidence intervals to compare mammogram rates among diabetics compared to nondiabetics. Results: 1,723,674 nondiabetic women and 133,973 diabetic women were identified. Among women ages 40 to 49, diabetic women had significantly decreased mammography rates compared to nondiabetic women (OR 0.84; 95% CI 0.83, 0.85). Rates were also lower in diabetic women ages 50 to 64 (OR 0.88; 95% CI 0.88, 0.91). Despite lower mammography rates among diabetics, diabetic women had 1.78 times more visits than nondiabetic women. Conclusions: Women with diabetes are less likely to undergo routine screening mammography than women without diabetes, despite having more encounters with health care providers. This study serves as a reminder to provide timely preventive health services to all patients regardless of medical comorbidities.

325 Background: TH-302 is a hypoxia-targeted drug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G+T to standard dose G as first-line therapy of PAC. Methods: An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1,000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G+T arm. The primary efficacy endpoint was a comparison of PFS between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). Overall survival (OS) was a secondary endpoint. Results: 214 pts were treated; 163 (76%) Stage IV and 51 (24%) Stage IIIB. Median age 65 (range 29-86); 126 M/88 F; 38% ECOG 0/62% ECOG 1. Receiving 6 or more cycles: 32% G; 45% G+T240; 55% G+T340. Median PFS was 3.6 mo in G vs 5.6 mo in G+T240 (p=0.06) and 6.0 mo in G+T340 (p=0.01). Median OS was 6.9 mo in G vs 8.7 in G+T240 (p=0.83) vs 9.2 mo in G+T340 (p=0.80). 6-mo OS was 57% in G vs 69% in G+T240 (p=0.12) and 73% in G+340 (p=0.04); 12-mo OS was 26% in G vs 37% in G+T240 (p=0.18) and 38% in G+340 (p=0.13). RECIST best response was 10% in G vs 17% in G+T240 and 26% in G+T340. 14 and 12 pts in G crossed over to T240 and T340, respectively. Median post crossover PFS was 1.8 mo in T240 vs 2.9 mo in T340 (p=0.13). Median post crossover OS was 2.6 mo in T240 vs 13.4 mo in T340 (p=0.01). AEs leading to discontinuation were: 16% G, 17% G+T240 and 12% G+T340. Rash (47% in G+T340) and stomatitis (42% in G+T340) were greater in combination, 3 pts Grd 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G+T240 and 63% G+T340 and Grd 3/4 neutropenia were 31% G, 56% G+T240 and 60% G+T340. Conclusions: The combination of G plus TH-302 improved the PFS of G. Skin and mucosal toxicity and myelosuppression were the most common TH-302 related AEs with no increase in treatment discontinuation. A phase 3 study of TH-302 (340 mg/m2) in combination with G is planned with OS as the primary efficacy endpoint. Clinical trial information: NCT01144455.