The dysfunctional immune response in renal cell carcinoma correlates with changes in the metabolic landscape of ccRCC during disease progression.

Renal cell carcinoma is an immunogenic tumour with a prominent dysfunctional immune cell infiltrate, unable to control tumour growth. Although tyrosine kinase inhibitors and immunotherapy have improved the outlook for some patients, many individuals are non-responders or relapse despite treatment. The hostile metabolic environment in RCC affects the ability of T-cells to maintain their own metabolic programme constraining T-cell immunity in RCC. We investigated the phenotype, function and metabolic capability of RCC TILs correlating this with clinicopathological features of the tumour and metabolic environment at the different disease stages. Flow cytometric analysis of freshly isolated TILs showed the emergence of exhausted T-cells in advanced disease based on their PD-1high and CD39 expression and reduced production of inflammatory cytokines upon in vitro stimulation. Exhausted T-cells from advanced stage disease also displayed an overall phenotype of metabolic insufficiency, characterized by mitochondrial alterations and defects in glucose uptake. Nanostring nCounter cancer metabolism assay on RNA obtained from 30 ccRCC cases revealed significant over-expression of metabolic genes even at early stage disease (pT1-2), while at pT3-4 and the locally advanced thrombi stages, there was an overall decrease in differentially expressed metabolic genes. Notably, the gene PPARGC1A was the most significantly down-regulated gene from pT1-2 to pT3-4 RCC which correlated with loss of mitochondrial function in tumour-infiltrating T-cells evident at this tumour stage. Down-regulation of PPARGC1A into stage pT3-4 may be the 'tipping-point' in RCC disease progression, modulating immune activity in ccRCC and potentially reducing the efficacy of immunotherapies in RCC and poorer patient outcomes.

Histopathological assessment of prognostic factors in pancreatic resection specimens using a standardised protocol.

BACKGROUND: Adenocarcinoma involving the pancreas shows differences in prognostic parameters including resection margin status depending on subtype. AIM: To assess the reported incidence of each type and the rate of R1 resection using detailed histopathological examination protocol. METHODS: All pancreaticoduodenectomies between June 2011 and June 2013 at our institute were analysed. These were classified according to the site of origin, R1 status, size, stage at resection, lymph node status and the rate of lymphovascular and perineural invasion. RESULTS: 58 adenocarcinomas included 23 ductal, 16 intraductal papillary mucinous neoplasm (IPMN) related, 8 duodenal, 7 ampullary and 4 distal common bile duct (CBD) tumours. The CBD, pancreatic ductal and IPMN-related adenocarcinomas had the highest rates of R1 resection, at 75%, 69.5 and 62.5%, with the posterior and SMV margins most frequently involved. Ampullary adenocarcinoma had lower rates of R1 resection (14%) as well as perineural invasion (0%). CONCLUSION: Ampullary adenocarcinomas had a lower rate of R1 resection and perineural invasion, both of which are parameters associated with a poorer outcome. This correlates with literature indicating ampullary tumours have a better prognosis. Our study also highlights the high rate of detection of microscopic margin involvement when a detailed histopathological examination protocol is employed.

Ileal MALT lymphoma causing massive gastrointestinal haemorrhage revealed on computed tomography angiography.

Primary MALT lymphomas affecting the ileum are rare, and their presentation with massive haemorrhage exceptional. This report describes such a case. The patient presented with melaena and haemodynamic instability, but normal upper gastrointestinal endoscopy. Subsequent imaging with multi-detector row computed tomography angiography both localised the bleeding source to the ileum and identified the underlying tumour, resulting in considerably earlier introduction of appropriate management. The patient made an excellent recovery and remains in remission.