Citations

AbstractIntroductionRadiotherapy alone still is the most commonly delivered treatment modality for metastatic spinal cord compression (MSCC). MSCC is an emergency situation, which requires treatment as soon as possible. When radiotherapy is performed with the most commonly used approach 10 × 3 Gy (30 Gy in 10 fractions) over 2 weeks, the question has been asked whether an overall treatment time (OTT) of 14–15 days including two weekends without irradiation leads to worse outcomes than OTT of 12 days (beginning of radiotherapy on a Monday resulting in only one weekend break)?MethodsA total of 412 patients with MSCC were included in this retrospective study. Ninety‐two patients receiving 10 × 3 Gy over 12 days were compared to 320 patients with an OTT of 14–15 days. Ten additional factors were investigated.ResultsOn multivariate analysis, functional outcome was associated with tumour type (P < 0.001), time developing motor deficits (P < 0.001), ambulatory status (P = 0.018) and performance score (P < 0.001); OTT had no significant impact (P = 0.40). On univariate analysis of local control of MSCC (freedom from recurrence in irradiated spinal parts), no factor was significant including OTT (P = 0.66). On multivariate analysis, visceral metastases (P < 0.001), tumour type (P < 0.001), time developing motor deficits (P < 0.001), ambulatory status (P < 0.001) and performance score (P < 0.001) were associated with survival, OTT not even on univariate analysis (P = 0.55).ConclusionsSince an OTT of 14–15 days had no negative impact on outcomes compared to 12 days, compensation in form of an additional radiation fraction or continuation of radiotherapy during weekends is not required, if radiotherapy cannot be started on a Monday.

Abstract B7-H1 (aka PD-L1) blocking antibodies have been tested in the treatment of human cancers through blocking B7-H1 expressed by tumor cells; however, its impact on B7-H1 expressed by tumor-reactive CD8+ T cells is still unknown. Here, we report that tumor-reactive CD8+ T cells expressing B7-H1 were functional effector cells. An agonist antibody to PD-L1 deleted B7-H1+ PD-1+ tumor-reactive CD8+ T cells via activation of p38 MAPK, and failed to suppress tumor growth. As activation of p38 MAPK leads to CD8+ T cell apoptosis upon T cell activation, a PD-L1 antibody that activated p38 MAPK enhanced apoptosis of activated CD8+ T cells. An intracellular molecule, DNA-PKcs, was identified in association with B7-H1 and a DNA-PKcs inhibitor increased p38 MAPK activation in wild type but not in B7-H1 deficient CD8+ T cells. Our results suggest B7-H1 suppresses p38 MAPK activation via DNA-PKcs to prevent CD8+ T cell death. To maximize antitumor function, PD-L1 antibodies should be selected to avoid their collateral activation of p38 MAPK in tumor-reactive CD8+ T cells. Citation Format: Siyu Cao, Xin Liu, Xiaosheng Wu, Aaron Mansfield, Haidong Dong. B7-H1 identifies tumor-reactive effector CD8 T cells susceptible of deletion by agonist PD-L1 antibodies [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A131.

Objectives To investigate the timing (mid‐ vs late life) of physical activity, apolipoprotein ( APO )E ε 4, and risk of incident mild cognitive impairment ( MCI ). Design Prospective cohort study. Setting Mayo Clinic Study of Aging (Olmsted County, MN ). Participants Cognitively normal elderly adults (N = 1,830, median age 78, 50.2% female). Measurements Light, moderate, and vigorous physical activities in mid‐ and late life were assessed using a validated questionnaire. An expert consensus panel measured MCI based on published criteria. Cox proportional hazards models were used to calculate hazard ratios ( HR s) and 95% confidence intervals ( CI s) with age as a time scale after adjusting for sex, education, medical comorbidity, and depression. Results Light ( HR = 0.58, 95% CI = 0.43–0.79) and vigorous ( HR = 0.78, 95% CI = 0.63–0.97) physical activity in midlife were associated with lower risk of incident MCI . The association between moderate activity and incident MCI was not significant ( HR = 0.85, 95% CI = 0.67–1.09). In late life, light ( HR = 0.75, 95% CI = 0.58–0.97) and moderate ( HR = 0.81, 95% CI = 0.66–0.99) but not vigorous physical activity were associated with lower risk of incident MCI . A synergistic interaction was also observed between mid‐ and late‐life activity in reducing risk of incident MCI . Furthermore, APOE ε 4 carriers who did not exercise had a higher risk of incident MCI than noncarriers who reported physical activity. Conclusion Physical activity reduced the risk of incident MCI . Exercising in mid‐ and late life had an additive synergistic interaction in reducing the risk of MCI .

AbstractIntroductionThe objective of this study was to investigate whether 10 phospholipids/metabolites previously identified as prospectively predictive of mild cognitive impairment (MCI) or dementia in whites would also be predictive in a mostly African‐American cohort.MethodsWe repeatedly measured 188 phospholipids/metabolites in plasma samples of 221 participants of the Atherosclerosis Risk in Communities study, 97% African American, who were followed between 2004–2006 and 2011–2013.ResultsAfter a mean follow‐up of 7.3 years, 77 were classified as having MCI and 18 as having dementia. Our study failed to replicate previous findings in this mostly African American cohort, in that the 10 phospholipids/metabolites only achieved a C statistic/AUC of 0.609 in predicting development of MCI or dementia (compared to 0.96) and 0.607 in distinguishing normal from MCI or dementia at the follow‐up visit.ConclusionA panel of 10 phospholipids/metabolites previously associated with incident dementia was not predictive of MCI or dementia in an independent cohort.

AimsThe purpose of this study was to determine the lifetime risk of revision surgery for patients undergoing Charnley cemented total hip arthroplasty (THA), with 40-year follow up, using death as a competing risk.Materials and MethodsWe retrospectively reviewed 2000 cemented Charnley THAs, with 51 living hips available at 40 years.ResultsThe cumulative risk of revision or removal for any reason was 13% (95% confidence interval (CI) 12 to 15). Patients aged under 50 years at the time of surgery had a 35% (95% CI 28 to 42) risk of revision or removal for any reason (Hazard Ratio (HR) 3.6; 95% CI 2.5 to 5.2; p < 0.001), patients 50 to 59 years old had a 20% risk (95% CI 16 to 24) (HR 2.1; 95% CI 1.5 to 2.8; p < 0.0001), patients aged 60 to 69 years had a 9% risk (95% CI 7 to 11) (reference point), and patients ≥ 70 years old had a 5% risk (95% CI 4 to 7) (HR 0.96; 95% CI 0.6 to 1.5; p = 0.86) during their lifetime. Men had a higher risk of revision or removal for any reason (HR 2.1; 95% CI 1.7 to 2.7; p < 0.001).ConclusionWith almost all the patients in this series followed up till either death or revision, we have been able to develop a ‘rule of thumb’ for lifetime likelihood of revision or implant removal for the Charnley THA: one in three for patients < 50 years, one in five for patients 50 to 59 years, one in ten for patients 60 to 69 years, and one in 20 for patients ≥ 70 years. The results provide a benchmark for comparison of outcomes, for the newer designs of THA. Cite this article: Bone Joint J 2016;98-B:1436–40.

Aims Total hip arthroplasty (THA) has well known subjective benefits, but little is known objectively about the recovery of mobility in the early post-operative period. Patients and Methods A total of 33 patients aged > 60 years who underwent elective primary THA had their activity monitored for 30 days post-operatively using an at-home (Fitbit) ankle accelerometer. Their mean age was 70.7 years (61 to 86); 15 (45.5%) were female. The rate of compliance and the mean level of activity were determined. Comparisons between subgroups based on age, body mass index (BMI), surgical approach, and the destination of the patients when discharged were also performed. Results The mean compliance over the 30 days was 26.7 days (16 to 30; 89%) of use. The mean number of steps increased from 235 (5 to 1152) to 2563 (87 to 7280) (p < 0.001) between the first and the 30th post-operative day. Age < 70 years and an anterior surgical approach were significantly associated with higher levels of activity (1600 to 2400 (p = 0.016 to 0.031) and 1000 to 1800 (p = 0.017 to 0.037) more steps per day, respectively) between the second and the fourth week post-operatively. There was also a trend towards higher levels of activity in those who were discharged to their home rather than to a nursing facility (a mean of 1500 more steps per day, p = 0.02). BMI greater or less than 30 kg/m 2 was not predictive of activity (p = 0.45 to 0.98). Conclusion At-home remote mobility monitoring using existing commercially available technology is feasible in patients who have undergone THA. It showed a clear trend towards increased activity with the passage of time. Additionally, the remote device was able to detect differences in levels of activity clearly between patients in relation to variables of interest including age, BMI, surgical approach, and the destination of the patient at the time of discharge from hospital. Such monitoring may allow for the early identification and targeted intervention in patients who recover slowly. Cite this article: Bone Joint J 2016;98-B:1450–4.

Abstract Purpose: Little is known about the association between myeloid-derived suppressor cell (MDSC) subsets and various chemokines in patients with renal cell carcinoma (RCC) or the factors that draw MDSC into tumor parenchyma. Experimental Design: We analyzed polymorphonuclear MDSC (PMN-MDSC), monocytic MDSC (M-MDSC), and immature MDSC (I-MDSC) from the parenchyma and peripheral blood of 48 patients with RCC, isolated at nephrectomy. We analyzed levels of IL1β, IL8, CXCL5, Mip-1α, MCP-1, and Rantes. Furthermore, we performed experiments in a Renca murine model to assess therapeutic synergy between CXCR2 and anti-PD1 and to elucidate the impact of IL1β blockade on MDSC. Results: Parenchymal PMN-MDSC have a positive correlation with IL1β, IL8, CXCL5, and Mip-1α, and I-MDSC correlate with IL8 and CXCL5. Furthermore, peripheral PMN-MDSC correlate with tumor grade. Given that PMN-MDSC express CXCR2 and parenchymal PMN-MDSC correlated with IL8 and CXCL5, we assessed the response of CXCR2 blockade with or without anti-PD1. Combination therapy reduced tumor weight and enhanced CD4+ and CD8+ T-cell infiltration. In addition, anti-IL1β decreased PMN-MDSC and M-MDSC in the periphery, PMN-MDSC in the tumor, and peripheral CXCL5 and KC. Anti-IL1β also delayed tumor growth. Conclusions: Parenchymal PMN-MDSC have a positive correlation with IL1β, IL8, CXCL5, and Mip-1α, suggesting they may attract PMN-MDSC into the tumor. Peripheral PMN-MDSC correlate with tumor grade, suggesting prognostic significance. Anti-CXCR2 and anti-PD1 synergized to reduce tumor weight and enhanced CD4+ and CD8+ T-cell infiltration in a Renca murine model, suggesting that CXCR2+ PMN-MDSC are important in reducing activity of anti-PD1 antibody. Finally, anti-IL1β decreases MDSC and delayed tumor growth, suggesting a potential target for MDSC inhibition. Clin Cancer Res; 23(9); 2346–55. ©2016 AACR.

Background Low body mass index ( BMI ) and serum creatinine are surrogate markers of frailty and sarcopenia. Their relationship with cause‐specific mortality in elderly patients undergoing percutaneous coronary intervention is not well studied. Methods and Results We determined long‐term cardiovascular and noncardiovascular mortality in 9394 consecutive patients aged ≥65 years who underwent percutaneous coronary intervention from 2000 to 2011. BMI and serum creatinine were divided into 4 categories. During a median follow‐up of 4.2 years (interquartile range 1.8–7.3 years), 3243 patients (33.4%) died. In the multivariable model, compared with patients with normal BMI , patients with low BMI had significantly increased all‐cause mortality (hazard ratio [ HR ] 1.4, 95% CI 1.1–1.7), which was related to both cardiovascular causes (HR 1.4, 95% CI 1.0–1.8) and noncardiovascular causes (HR 1.4, 95% CI 1.06–1.9). Compared with normal BMI , significant reduction was noted in patients who were overweight and obese in terms of cardiovascular mortality (overweight: HR 0.77, 95% CI 0.67–0.88; obese: HR 0.80, 95% CI 0.70–0.93) and noncardiovascular mortality (overweight: HR 0.85, 95% CI 0.74–0.97; obese: HR 0.82, 95% CI 0.72–0.95). In a multivariable model, in patients with normal BMI , low creatinine (≤0.70 mg/dL) was significantly associated with increased all‐cause mortality (HR 1.8, 95% CI 1.3–2.5) and cardiovascular mortality (HR 2.3, 95% CI 1.4–3.8) compared with patients with normal creatinine (0.71–1.0 mg/dL); however, this was not observed in other BMI categories. Conclusions We identified a new subgroup of patients with low serum creatinine and normal BMI that was associated with increased all‐cause mortality and cardiovascular mortality in elderly patients undergoing percutaneous coronary intervention. Low BMI was associated with increased cardiovascular and noncardiovascular mortality. Nutritional support, resistance training, and weight‐gain strategies may have potential roles for these patients undergoing percutaneous coronary intervention.