The tumour microenvironment is of critical importance in cancer development and progression and includes the surrounding stromal and immune cells, extracellular matrix, and the milieu of metabolites and signalling molecules in the intercellular space. To support sustained mitotic activity cancer cells must reconfigure their metabolic phenotype. Lactate is the major by-product of such metabolic alterations and consequently, accumulates in the tumour. Lactate actively contributes to immune evasion, a hallmark of cancer, by directly inhibiting immune cell cytotoxicity and proliferation. Furthermore, lactate can recruit and induce immunosuppressive cell types, such as regulatory T cells, tumour-associated macrophages, and myeloid-derived suppressor cells which further suppress anti-tumour immune responses. Given its roles in oncogenesis, measuring intratumoural and systemic lactate levels has shown promise as a both predictive and prognostic biomarker in several cancer types. The efficacies of many anti-cancer therapies are limited by an immunosuppressive TME in which lactate is a major contributor, therefore, targeting lactate metabolism is a priority. Developing inhibitors of key proteins in lactate metabolism such as GLUT1, hexokinase, LDH, MCT and HIF have shown promise in preclinical studies, however there is a corresponding lack of success in human trials so far. This may be explained by a weakness of preclinical models that fail to reproduce the complexities of metabolic interactions in natura. The future of these therapies may be as an adjunct to more conventional treatments.

Enhanced Recovery After Surgery (ERAS) protocols are evidence-based care improvement pathways which are perceived to expedite patient recovery following surgery. Their utility in the setting of oesophagectomy remains unclear. The aim of this study was to perform a systematic review and meta-analysis of randomised clinical trials (RCTs) to evaluate the impact of ERAS protocols on recovery following oesophagectomy compared to standard care. A systematic review was performed in accordance with preferred reporting items for systematic reviews and meta-analyses guidelines. Meta-analysis was performed using Review Manager (Version 5.4). Six RCTs including 850 patients were included in this meta-analysis. Overall complication rate (Odds Ratio (OR): 0.35, Confidence Interval (CI): 0.21, 0.59, P < 0.0001), pulmonary complications (OR: 0.40, CI: 0.24, 0.67, P = 0.0005), post-operative length of stay (LOS) (OR -1.88, CI -2.05, −1.70, P < 0.00001) and time to post-operative flatus (OR: -5.20, CI: −9.46, −0.95, P = 0.02) favoured the ERAS group. There was no difference noted for anastomotic leak (OR: 0.55, CI: 0.24, 1.28, P = 0.17), cardiac complications (OR: 0.86, CI: 0.30, 2.46, P = 0.78), gastrointestinal complications (OR: 0.51, CI: 0.23, 1.17, P = 0.11), wound complications (OR: 0.85, CI: 0.28, 2.58, P = 0.78), mortality (OR: 1.37, CI: 0.26, 7.4, P = 0.71), and 30-day re-admission rate (OR: 1.29, CI: 0.30, 5.47, P = 0.73) between ERAS and standard care groups. ERAS implementation improved post-operative complications, LOS, and time to flatus following oesphagectomy. These results support the robust adoption of ERAS in patients indicated to undergo oesphagectomy.

Summary: Robot-assisted minimally invasive esophagectomy (RAMIE) for esophageal carcinoma has emerged as the contemporary alternative to conventional laparoscopic minimally invasive (LMIE), hybrid (HE) and open (OE) surgical approaches. No single study has compared all four approaches with a view to postoperative outcomes. A systematic search of electronic databases was undertaken. A network meta-analysis was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-network meta-analysis guidelines. Statistical analysis was performed using R and Shiny. Seven randomised controlled trials (RCTs) with 1063 patients were included. Overall, 32.9% of patients underwent OE (350/1063), 11.0% underwent HE (117/1063), 34.0% of patients underwent LMIE (361/1063), and 22.1% of patients underwent RAMIE (235/1063). OE had the lowest anastomotic leak rate 7.7% (27/350), while LMIE had the lowest pulmonary 10.8% (39/361), cardiac 0.56% (1/177) complications, re-intervention rates 5.08% (12/236), 90-day mortality 1.05% (2/191), and shortest length of hospital stay (mean 11.25 days). RAMIE displayed the lowest 30-day mortality rate at 0.80% (2/250). There was a significant increase in pulmonary complications for those undergoing OE (OR 3.63 [95% confidence interval: 1.4–9.77]) when compared to RAMIE. LMIE is a safe and feasible option for esophagectomy when compared to OE and HE. The upcoming RCTs will provide further data to make a more robust interrogation of the surgical outcomes following RAMIE compared to conventional open surgery to determine equipoise or superiority of each approach as the era of minimally invasive esophagectomy continues to evolve (International Prospective Register of Systematic Reviews Registration: CRD42023438790).

Hypoxia and its impact on the tumour microenvironment of gastroesophageal cancers

Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis and incidence is increasing rapidly in the Western world. Multi-modal treatment has improved survival outcomes but only for a minority of patients. Currently no markers have been identified to predict treatment response. This study investigated the association between clinical outcomes and pre-treatment levels of 54 serum proteins in n = 80 patients with EAC. Low tumor regression grade (TRG), corresponding to a favorable treatment response, was linked to prolonged overall survival (OS). CCL4 was higher in patients with a favorable treatment response, while Tie2 and CRP were higher in poor responders. Elevated CCL22 and CCL26 was associated with improved OS, while elevated IL-10 showed a negative association. CCL3, CCL4, IL-1α and IL-12/IL23p40 were highest in individuals with no adverse features of tumor biology, whereas levels of Tie2 and VEGF were lowest in this cohort. CCL4 was also elevated in patients with high tumor lymphocyte infiltration. Comparison of matched pre- and post-treatment serum (n = 28) showed a large reduction in VEGFC, and a concomitant increase in other cytokines, including CCL4. These data link several serum markers with clinical outcomes, highlighting an important role for immune cell trafficking in the EAC antitumor immune response.