Background The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is poor and selection of patients for surgery is challenging. This study examined the impact of a positive resection margin (R1) on locoregional recurrence (LRR) and overall survival (OS); and also aimed to identified tumour characteristics and/or technical factors associated with a positive resection margin in patients with PDAC. Methods Patients scheduled for pancreatic resection for PDAC between 2006 and 2016 were identified from an institutional database. The effect of resection margin status, patient characteristics and tumour characteristics on LRR, distant metastasis and OS was assessed. Results A total of 322 patients underwent pancreatectomy for PDAC. A positive resection (R1) margin was found in 129 patients (40·1 per cent); this was associated with decreased OS compared with that in patients with an R0 margin (median 15 (95 per cent c.i. 13 to 17) versus 22 months; P < 0·001). R1 status was associated with reduced time to LRR (median 16 versus 36 (not estimated, n.e.) months; P = 0·002). Disease recurrence patterns were similar in the R1 and R0 groups. Risk factors for early recurrence were tumour stage, positive lymph nodes (N1) and perineural invasion. Among 100 patients with N0 disease, R1 status was associated with shorter OS compared with R0 resection (median 17 (10 to 24) versus 45 (n.e.) months; P = 0·002), whereas R status was not related to OS in 222 patients with N1 disease (median 14 (12 to 16) versus 17 (15 to 19) months after R1 and R0 resection respectively; P = 0·068). Conclusion Although pancreatic resection with a positive margin was associated with poor survival and early recurrence, particularly in patients with N1 disease, disease recurrence patterns were similar between R1 and R0 groups.

ObjectiveA comprehensive understanding of anticancer immune responses is paramount for the optimal application and development of cancer immunotherapies. We unravelled local and systemic immune profiles in patients with colorectal cancer (CRC) by high-dimensional analysis to provide an unbiased characterisation of the immune contexture of CRC.DesignThirty-six immune cell markers were simultaneously assessed at the single-cell level by mass cytometry in 35 CRC tissues, 26 tumour-associated lymph nodes, 17 colorectal healthy mucosa and 19 peripheral blood samples from 31 patients with CRC. Additionally, functional, transcriptional and spatial analyses of tumour-infiltrating lymphocytes were performed by flow cytometry, single-cell RNA-sequencing and multispectral immunofluorescence.ResultsWe discovered that a previously unappreciated innate lymphocyte population (Lin–CD7+CD127–CD56+CD45RO+) was enriched in CRC tissues and displayed cytotoxic activity. This subset demonstrated a tissue-resident (CD103+CD69+) phenotype and was most abundant in immunogenic mismatch repair (MMR)-deficient CRCs. Their presence in tumours was correlated with the infiltration of tumour-resident cytotoxic, helper and γδ T cells with highly similar activated (HLA-DR+CD38+PD-1+) phenotypes. Remarkably, activated γδ T cells were almost exclusively found in MMR-deficient cancers. Non-activated counterparts of tumour-resident cytotoxic and γδ T cells were present in CRC and healthy mucosa tissues, but not in lymph nodes, with the exception of tumour-positive lymph nodes.ConclusionThis work provides a blueprint for the understanding of the heterogeneous and intricate immune landscape of CRC, including the identification of previously unappreciated immune cell subsets. The concomitant presence of tumour-resident innate and adaptive immune cell populations suggests a multitargeted exploitation of their antitumour properties in a therapeutic setting.

Risk for lymph node metastasis associated with deep submucosal invasion should be balanced against mortality and morbidity of total mesorectal excision (TME). Dissection through the submucosa (ESD), hinders radical deep resection margins, and full thickness resection (TEM/TAMIS) may influence the outcome of completion TME. Endoscopic intermuscular dissection (EID) in between the circular and longitudinal part of the muscularis propria could potentially provide an R0 resection while leaving the rectal wall intact. In this prospective cohort study, data of patients treated with EID for suspect deep submucosal invasive rectal cancer between 2018-2020 were analysed. Study outcomes were the percentages of technical success, R0 resections, curative resections, and adverse events. In total 67 cases (age 67 yrs; 73% male) were included. Median lesion size was 25 mm (IQR 20-33). Overall technical success, R0 resection, and curative resection rates were (96%; 95%CI 90-100%), 81% (95%CI 72-90%) and 45% (95%CI 33-57%). Only minor adverse events occurred in 8 patients (12%). EID for deep invasive T1 rectal cancer appears to be feasible and safe, and the high R0 resection rate creates a rectal preserving potential in 45% of patients.

BackgroundThe efficacy of checkpoint blockade immunotherapies in colorectal cancer is currently restricted to a minority of patients diagnosed with mismatch repair-deficient tumors having high mutation burden. However, this observation does not exclude the existence of neoantigen-specific T cells in colorectal cancers with low mutation burden and the exploitation of their anti-cancer potential for immunotherapy. Therefore, we investigated whether autologous neoantigen-specific T cell responses could also be observed in patients diagnosed with mismatch repair-proficient colorectal cancers.MethodsWhole-exome and transcriptome sequencing were performed on cancer and normal tissues from seven colorectal cancer patients diagnosed with mismatch repair-proficient tumors to detect putative neoantigens. Corresponding neo-epitopes were synthesized and tested for recognition by in vitro expanded T cells that were isolated from tumor tissues (tumor-infiltrating lymphocytes) and from peripheral mononuclear blood cells stimulated with tumor material.ResultsNeoantigen-specific T cell reactivity was detected to several neo-epitopes in the tumor-infiltrating lymphocytes of three patients while their respective cancers expressed 15, 21, and 30 non-synonymous variants. Cell sorting of tumor-infiltrating lymphocytes based on the co-expression of CD39 and CD103 pinpointed the presence of neoantigen-specific T cells in the CD39+CD103+ T cell subset. Strikingly, the tumors containing neoantigen-reactive TIL were classified as consensus molecular subtype 4 (CMS4), which is associated with TGF-β pathway activation and worse clinical outcome.ConclusionsWe have detected neoantigen-targeted reactivity by autologous T cells in mismatch repair-proficient colorectal cancers of the CMS4 subtype. These findings warrant the development of specific immunotherapeutic strategies that selectively boost the activity of neoantigen-specific T cells and target the TGF-β pathway to reinforce T cell reactivity in this patient group.

HighlightsScoring the tumor-stroma ratio is a simple and reproducible method.Tumor-stroma ratio and response to neoadjuvant chemoradiotherapy are correlated.Stroma-low tumors are likely to respond better to neoadjuvant chemoradiotherapy.