Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both... Show morePancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both locally and systemically. Moreover, increasing evidence suggests that microbial compositions inside the tumor, as well as in the oral cavity and the gut, are important factors in shaping the PDAC immune landscape. However, the gut-associated lymphoid tissue (GALT) has not previously been explored in PDAC patients. In this study, we analyzed healthy vermiform appendix (VA) from 20 patients with PDAC and 32 patients with colon diseases by gene expression immune profiling, flow cytometry analysis, and microbiome sequencing. We show that the VA GALT of PDAC patients exhibits markers of increased inflammation and cytotoxic cell activity. In contrast, B cell function is decreased in PDAC VA GALT based on gene expression profiling; B cells express significantly fewer MHC class II surface receptors, whereas plasma cells express the immune checkpoint molecule HLA-G. Additionally, the vermiform appendix microbiome of PDAC patients is enriched with Klebsiella pneumoniae, Bifidobacterium animalis, and Adlercreutzia equolifaciens, while certain commensals are depleted. Our findings may suggest impaired B cell function within the GALT of PDAC patients, which could potentially be linked to microbial dysbiosis. Additional investigations are imperative to validate our observations and explore these potential targets of future therapies. Show less
Objective: Our aim was to determine the prognostic significance of the systemic-immune-inflammation index (SIII) in patients with resectable pancreatic cancer, using cancer-specific survival as the... Show moreObjective: Our aim was to determine the prognostic significance of the systemic-immune-inflammation index (SIII) in patients with resectable pancreatic cancer, using cancer-specific survival as the primary outcome.Background: Pancreatic cancer is associated with a dysfunctional immune system and poor prognosis. We examined the prognostic significance of the SIII in patients with resectable pancreatic ductal adenocarcinoma (PDAC) and the effects of bilirubin on this index.Methods: We retrospectively assessed all pancreatic resections performed between 2004 and 2015 at 4 tertiary referral centers to identify pathologically confirmed PDAC patients. Baseline clinicopathologic characteristics, preoperative laboratory values such as absolute neutrophil, lymphocyte, and platelet counts, C-reactive protein, albumin, bilirubin, and CA19-9 levels, and also follow-up information, were collected. The associations of the calculated inflammatory indices with outcome were both internally and externally validated.Results: In all, 590 patients with resectable PDAC were included. The discovery and validation cohort included 170 and 420 patients, respectively. SIII > 900 [hazard ratio (HR) 2.32, 95% confidence interval (CI) 1.55-3.48], lymph node ratio (HR 3.75, 95% CI 2.08-6.76), and CA19.9 > 200 kU/L (HR 1.62, 95% CI 1.07-2.46) were identified as independent predictors of cancer-specific survival. Separate model analysis confirmed that preoperative SIII contributed significantly to prognostication. However, SIII appeared to lose its prognostic significance in patients with bilirubin levels above 200 mu mol/L.Conclusions: SIII is an independent predictor of cancer-specific survival and recurrence in patients with resectable PDAC. SIII may lose its prognostic significance in patients with high bilirubin levels. Properly designed prospective studies are needed to further confirm this hypothesis. Show less
Background. The time interval between CRT and surgery in rectal cancer patients is still the subject of debate. The aim of this study was to first evaluate the nationwide use of restaging magnetic... Show moreBackground. The time interval between CRT and surgery in rectal cancer patients is still the subject of debate. The aim of this study was to first evaluate the nationwide use of restaging magnetic resonance imaging (MRI) and its impact on timing of surgery, and, second, to evaluate the impact of timing of surgery after chemoradiotherapy (CRT) on short- and long-term outcomes.Methods. Patients were selected from a collaborative rectal cancer research project including 71 Dutch centres, and were subdivided into two groups according to time interval from the start of preoperative CRT to surgery (< 14 and ae14 weeks).Results. From 2095 registered patients, 475 patients received preoperative CRT. MRI restaging was performed in 79.4% of patients, with a median CRT-MRI interval of 10 weeks (interquartile range [IQR] 8-11) and a median MRI-surgery interval of 4 weeks (IQR 2-5). The CRT-surgery interval groups consisted of 224 (< 14 weeks) and 251 patients (>= 14 weeks), and the long-interval group included a higher proportion of cT4 stage and multivisceral resection patients. Pathological complete response rate (n = 34 [15.2%] vs. n = 47 [18.7%], p = 0.305) and CRM involvement (9.7% vs. 15.9%, p = 0.145) did not significantly differ. Thirty-day surgical complications were similar (20.1% vs. 23.1%, p = 0.943), however no significant differences were found for local and distant recurrence rates, disease-free survival, and overall survival.Conclusions. These real-life data, reflecting routine daily practice in The Netherlands, showed substantial variability in the use and timing of restaging MRI after preoperative CRT for rectal cancer, as well as time interval to surgery. Surgery before or after 14 weeks from the start of CRT resulted in similar short- and long-term outcomes. Show less
Borstlap, W.A.A.; Deijen, C.L.; Dulk, M. den; Bonjer, H.J.; Velde, C.J. van de; Bemelman, W.A.; ... ; Dutch Snapshot Res Grp 2017
Aim A Snapshot study design eliminates changes in treatment and outcome over time. This population based Snapshot study aimed to determine current practice and outcome of rectal cancer treatment... Show moreAim A Snapshot study design eliminates changes in treatment and outcome over time. This population based Snapshot study aimed to determine current practice and outcome of rectal cancer treatment with published landmark randomized controlled trials as a benchmark.Method In this collaborative research project, the dataset of the Dutch Surgical Colorectal Audit was extended with additional treatment and long-term outcome data. All registered patients who underwent resection for rectal cancer in 2011 were eligible. Baseline characteristics and outcome were evaluated against the results of the Dutch TME trial and the COLOR II trial from which the original datasets were obtained.Results A total of 71 hospitals participated, and data were completed for 2102 out of the potential 2633 patients (79.8%). Median follow-up was 41 (interquartile range 25-47) months. Overall circumferential resection margin (CRM) involvement was 9.3% in the Snapshot cohort and 18.5% in the Dutch TME trial. CRM positivity after laparoscopic resection was 7.8% in the Snapshot and 9.5% in the COLOR II trial. Three-year overall local recurrence rate in the Snapshot was 5.9%, with a disease-free survival of 67.1% and overall survival of 79.5%. Benchmarking with the randomized controlled trials revealed an overall favourable long-term outcome of the Snapshot cohort.Conclusion This study showed that current rectal cancer care in a large unselected Dutch population is of high quality, with less positive CRM since the TME trial and oncologically safe implementation of minimally invasive surgery after the COLOR II trial. Show less
