Citations

Abstract Background Transcatheter Aortic Valve Implantation (TAVI) is commonly used to deploy new bioprosthetic valves inside degenerated surgically implanted aortic valves in high risk patients. The three scoring systems used to assess risk of postprocedural mortality are: Logistic EuroSCORE (LES), EuroSCORE II (ES II), and Society of Thoracic Surgeons (STS). Objective The purpose of this study is to analyze the accuracy of LES, ES II, and STS in estimating all‐cause mortality after transcatheter aortic valve‐in‐valve (ViV) implantations, which was not assessed before. Methods Using the Valve‐in‐Valve International Data (VIVID) registry, a total of 1,550 patients from 110 centers were included. The study compared the observed 30‐day overall mortality vs. the respective predicted mortalities calculated by risk scores. The accuracy of prediction models was assessed based on calibration and discrimination. Results Observed mortality at 30 days was 5.3%, while average expected mortalities by LES, ES II and STS were 29.49 (± 17.2), 14.59 (± 8.6), and 9.61 (± 8.51), respectively. All three risk scores overestimated 30‐day mortality with ratios of 0.176 (95% CI 0.138–0.214), 0.342 (95% CI 0.264–0.419), and 0.536 (95% CI 0.421–0.651), respectively. 30‐day mortality ROC curves demonstrated that ES II had the largest AUC at 0.722, followed by STS at 0.704, and LES at 0.698. Conclusions All three scores overestimated mortality at 30 days with ES II showing the highest predictability compared to LES and STS; and therefore, should be recommended for ViV procedures. There is a need for a dedicated scoring system for patients undergoing ViV interventions.

AbstractWe aimed to validate the prognostic association of p16 expression in ovarian high‐grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical‐grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis‐associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47–2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30–2.75, p = 0.004), while absence was associated with shorter OS in low‐grade serous carcinomas (HR: 2.95, 95% CI 1.61–5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype‐specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low‐grade serous carcinoma justifies CDK4 inhibition.

Key Points Biomarker scores generated after 1 week of steroid treatment of GVHD are prognostic. Biomarkers reflect prognosis better than early clinical response to GVHD treatment.

238 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 1 trial was initiated through the DOD PCCTC to establish the maximally tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of Cbz, Mito, and Pred (CAMP). Methods: Chemotherapy (chemo)-naïve pts with mCRPC were enrolled in an accelerated titration design. The primary objective was to determine the MTD and RP2D of CAMP; secondary objectives included PSA response rate and duration of response. Cbz 20 and 25 mg/m2 were each evaluated in combination with escalating doses of Mito (starting dose 4 mg/m2), both administered on day 1 of a 21-day cycle. Pred 5 mg BID and pegfilgrastim were given with each cycle. Results: 20 pts were enrolled. The median age was 66 (range 51-78) and the median baseline PSA was 62.5 (range 3.0-791.2). There were 2 DLTs observed at the dose level of Cbz 25 mg/m2 + Mito 10 mg/m2 (sepsis and febrile neutropenia). No DLTs were observed with Cbz 20 mg/m2 (N = 10), establishing Cbz 20 mg/m2 + Mito 12 mg/m2 as the MTD and RP2D. The most common grade ≥ 3 related adverse events were hematologic (neutropenia, n = 8; thrombocytopenia, n = 3; febrile neutropenia, n = 2). No cardiac adverse events were observed. The median number of treatment cycles was 9 (range 2-16), and 5 pts remain on study. Greater than 50% maximal PSA declines from baseline were observed in 8 of 18 evaluable pts (44%). Objective tumor responses have been observed in 2 of 4 pts (50%) with measurable disease, with evaluation ongoing. The median duration of response has not been reached (range 4.9-10.0+ months). Conclusions: The approved single-agent dose of Mito (12 mg/m2) was safely combined with Cbz 20 mg/m2, a dose with demonstrated activity in mCRPC and potentially less hematologic toxicity than 25 mg/m2. Preliminary efficacy data are encouraging with durable responses observed in a subset of pts. Further study of the treatment combination is warranted. Clinical trial information: NCT01594918.

202 Background: Cabazitaxel and prednisone (Cbz/pred) extend 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 1 trial was initiated to establish the maximally tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of Cbz, Mito, and Pred(CAMP). Methods: Chemotherapy (chemo)-naive pts with mCRPC were enrolled in an accelerated titration design. The primary objective was to determine the MTD and RP2D of CAMP; secondary objectives included PSA response rate and duration of response. Cbz 20 and 25 mg/m2 were evaluated in combination with escalating doses of Mito (starting dose 4 mg/m2), both administered on day 1 of a 21-day cycle. Pred 5 mg BID and pegfilgrastim were given with each cycle. Results: 23 pts were enrolled. The median age was 66 (range 51-78) and the median baseline PSA was 62.5 (range 3-791.2). There were 2 DLTs (sepsis and febrile neutropenia) observed at the dose level of Cbz 25 mg/m2 + Mito 10 mg/m2 (n = 4). There was 1 DLT (febrile neutropenia) observed with Cbz 20 mg/m2 (N = 12), establishing Cbz 20 mg/m2 + Mito 12 mg/m2 as the MTD and RP2D. The most common grade ³ 3 related adverse events were hematologic (neutropenia, n = 9; thrombocytopenia, n = 3; febrile neutropenia, n = 3). The median number of treatment cycles was 7.5 (range 2-16), and 2 pts remain on study. Greater than or equal to 50% maximal PSA declines from baseline were observed in 12 of 19 evaluable pts(63%). The median duration of response has not been reached (range 4.9-10.0+ months). Conclusions: The approved single-agent dose of Mito (12 mg/m2) was safely combined with Cbz 20 mg/m2, a dose with demonstrated activity in mCRPC and potentially less hematologic toxicity than 25 mg/m2. Preliminary efficacy data are encouraging with durable control of disease observed in a subset of pts. Further study of the treatment combination is warranted. Clinical trial information: NCT01594918.

BACKGROUND. No laboratory test can predict the risk of nonrelapse mortality (NRM) or severe graft-versus-host disease (GVHD) after hematopoietic cellular transplantation (HCT) prior to the onset of GVHD symptoms. METHODS. Patient blood samples on day 7 after HCT were obtained from a multicenter set of 1,287 patients, and 620 samples were assigned to a training set. We measured the concentrations of 4 GVHD biomarkers (ST2, REG3α, TNFR1, and IL-2Rα) and used them to model 6-month NRM using rigorous cross-validation strategies to identify the best algorithm that defined 2 distinct risk groups. We then applied the final algorithm in an independent test set ( n = 309) and validation set ( n = 358). RESULTS. A 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month NRM of 28% in the high-risk group and 7% in the low-risk group ( P < 0.001). The algorithm performed equally well in the test set (33% vs. 7%, P < 0.001) and the multicenter validation set (26% vs. 10%, P < 0.001). Sixteen percent, 17%, and 20% of patients were at high risk in the training, test, and validation sets, respectively. GVHD-related mortality was greater in high-risk patients (18% vs. 4%, P < 0.001), as was severe gastrointestinal GVHD (17% vs. 8%, P < 0.001). The same algorithm can be successfully adapted to define 3 distinct risk groups at GVHD onset. CONCLUSION. A biomarker algorithm based on a blood sample taken 7 days after HCT can consistently identify a group of patients at high risk for lethal GVHD and NRM. FUNDING. The National Cancer Institute, American Cancer Society, and the Doris Duke Charitable Foundation.