BACKGROUND:For patients with locally advanced esophagogastric cancer, the standard of care in the UK is neoadjuvant chemotherapy (NAC) followed by surgery. Prehabilitation exercise training can improve physiological function and fitness. If such improvements translate to increased immune infiltration of tumors, exercise could be prescribed as an immune adjuvant during NAC and potentially improve clinical outcomes. As such, we aimed to determine whether prehabilitation increased tumor infiltrating lymphocytes (TILs). METHODS:We assessed 22 patients with locally advanced esophageal cancer on a randomized control trial comparing 16 weeks of low-to-moderate intensity twice weekly supervised and thrice weekly home-based exercise (Prehab: n = 11) to no prehabilitation (Control: n = 11). Our primary outcome was to compare tumor-immune responses between Controls and Prehab. We compared formalin-fixed paraffin-embedded tumors by high-resolution multispectral immunohistochemistry (mIHC) and NanoString spatial transcriptomics. Secondarily, we determined relationships between changes in fitness to the exercise training and tumor-immune measures. Specifically, we assessed percentage changes in peak cardiorespiratory fitness as assessed by peak oxygen uptake (V̇O2peak) before NAC (Baseline) and after 8 weeks of NAC (Post-NAC), and changes between Baseline and following 8 weeks of NAC recovery before surgery (Pre-surgery) and correlated changes in fitness with tumor-immune responses. Finally, as an exploratory aim, we assessed clinical outcomes between groups, including survival, therapy tolerance, and tumor regrading. RESULTS:We observed that Prehab had significantly more CD8+ lymphocytes in their tumors (mean difference (diff.) = 1.79, 95% confidence interval (95%CI): 0.76‒2.82, p < 0.001) and their stroma (mean diff. = 1.59, 95%CI: 0.66‒2.52, p < 0.001) than the Controls. When normalized to total numbers of TILs, Prehab had higher levels of CD56+ natural killer (NK) cells (median diff. = 0.87, 95%CI: 0.25‒2.18), p = 0.0274), consisting primarily of CD56dim NK cells (median diff. = 0.48, 95%CI: 0.03‒2.53), p = 0.0464). Evaluation of the presence and localization of tumor-associated tertiary lymphoid structures (TLS) in the esophageal tumors revealed that most TLS were in the peritumoral regions. Prehab had a higher TLS cell density (cells/mm2; median diff. = 18,959, 95%CI: 13,518‒22,635), p < 0.001) and more clearly defined germinal centers indicative of mature TLS visually. We observed that Prehab maintained their V̇O2peak during NAC while the Controls' V̇O2peak reduced by 9.0% ± 10.2% (mean ± SD) (Post-NAC: p = 0.018). Pre-surgery, Prehab V̇O2peak was a clinically meaningful 3.27 ± 1.31 mL/kg/min higher than Controls (p = 0.022). Between Baseline and Post-NAC, where the Prehab maintained V̇O2peak better than Controls, there were significant positive associations with percentage changes in V̇O2peak and the frequencies of CD8+ TILs (r = 0.531, p = 0.016), programmed death-ligand 1+ (PDL1+) cells (r = 0.566, p = 0.009), and granzyme B+ (GrzB+) TILs (r = 0.582, p = 0.007). Similar relationships were observed for changes in V̇O2peak from Baseline to Pre-Surgery only in the Prehab group. We observed no differences between groups regarding clinical outcomes such as survival, therapy tolerance, or tumor regrading. CONCLUSION:We show that exercise training during NAC, which promotes higher levels of cardiorespiratory fitness than no exercise, is associated with increased frequencies of TILs and maturity of TLS. These data suggest that exercise during NAC enhances the immune system. Future studies are warranted to understand the clinical consequences of this.

BACKGROUND:Pancreatic surgery is associated with significant morbidity. Cardiopulmonary fitness can predict postoperative outcomes. Similarly, poor insulin sensitivity is associated with postoperative complications. Supervised exercise training can improve cardiorespiratory fitness and insulin sensitivity. Immunonutrition may work synergistically with exercise. The study aimed to assess the impact of a 4-week multimodal prehabilitation programme on cardiopulmonary fitness and insulin sensitivity in patients awaiting pancreatic surgery, compared to a control group receiving standard postoperative care. METHODS:In this prospective, non-randomised pilot study, we recruited patients with benign or malignant pathology, listed for pancreatic resection. Subjects underwent a baseline cardiopulmonary exercise test. We measured insulin sensitivity using the gold standard technique, the hyperinsulinaemic-euglycaemic clamp. The 4-week intervention comprised: resistance and high intensity interval training (ten sessions) plus daily omega-3 fatty supplements (2g) and extra virgin olive oil (30 ml). Cardiopulmonary exercise tests and clamps were repeated after four weeks. These were compared with contemporaneous non-randomised controls. RESULTS:Of 21 recruited patients, 12 out of 12 (prehabilitation) and 6 out of 9 (control) completed the study. Prehabilitation led to an improvement in oxygen uptake at anaerobic threshold (+2.0 (95 per cent CI 0.1 to 4.0) ml kg-1 min-1) and peak exercise (+3.0 (95 per cent CI 0.7 to 5.3) ml kg-1 min-1), compared to controls. Within the prehabilitation group, there were significant improvements in peak power (P = 0.001), oxygen uptake at anaerobic threshold (P = 0.017) and peak exercise (P = 0.002). Cardiopulmonary fitness parameters were unchanged amongst controls. Insulin sensitivity did not change in either group. CONCLUSION:Prehabilitation resulted in a significant improvement in cardiopulmonary fitness, before pancreatic surgery. The potential benefits of improved cardiopulmonary fitness must be balanced against the oncological and metabolic consequences of delay.

The effects of perioperative carbohydrate supplementation on length of hospital stay and postoperative complications in older adult hip fracture patients: a systematic review and meta-analysis - Volume 82 Issue OCE3

Abstract Aim We aimed to assess the effect of prehabilitation on cardiopulmonary exercise test (CPET) performance in patients undergoing neoadjuvant chemotherapy (NAC) for oesophagogastric (OG) cancer. Background & Methods NAC reduces fitness as assessed by CPET1 and induces skeletal muscle loss (sarcopenia)2,3. Both are associated with poorer post-operative outcomes. A parallel-arm RCT was conducted (December 2016 to November 2018), with randomisation to receive a 15-week multi-modal prehabilitation programme (Prehab) or standard-care (Control). Prehab comprised twice-weekly supervised and thrice-weekly home exercise sessions, Medical Coaching, and tailored dietetic input. CPET was performed before and after NAC, and 1 week pre-operatively. On staging and re-staging CT, skeletal muscle cross-sectional area at L3 was analysed by a blinded investigator. Becks’ Depression Inventory questionnaires were completed pre- and post-surgery. Results Groups (Prehab n=25, Control n=28) were matched at baseline. Supervised and home exercise programme compliance was 76%, and 65% respectively, with no adverse events. Prehab resulted in an improvement in peak VO2 following NAC (Prehab +31.50ml/min/m2 vs Control -89.57 ml/min/m2; p=0.004) with a trend towards lesser reduction in anaerobic threshold (Prehab -0.87ml/kg/min vs Control -1.44ml/kg/min; p=0.342). A higher proportion of controls required NAC deferral or dose reduction (Prehab 16% (4/25) vs Control 43% (12/28); p=0.041), with 72% (Prehab) and 46% (Control) completing all cycles at full dose (p=0.076). There was no difference in chemotherapy-related toxicity. The Prehab group demonstrated less skeletal muscle loss following NAC (Prehab -11.62 vs Control -15.61; p=0.049). Controls showed a trend towards more sarcopenia development after NAC (Prehab: Pre-NAC 37% (9/24) and post-NAC 54% (13/24) vs Control: Pre-NAC 32% (9/28) and post-NAC 64% 18/28) (p=0.404). Prehab subjects had a significant improvement in depression scores following NAC (Prehab -2.71 vs Control +0.57; p=0.003). There was a trend towards shorter median length of stay in the Prehab group (Prehab 11 vs Control 16 days; p=0.155) and lower complication rates (Prehab 50% (11/22) vs Control 74% (17/23); p=0.89). Conclusion Multi-modal prehabilitation is safe and feasible in OG patients receiving NAC. Despite the effects of NAC, prehabilitation produced a significant improvement in peak VO2, depression scores and less skeletal muscle loss, with a trend towards improved clinical outcomes. This warrants further investigation.