Stromal hyaluronan accumulation is associated with low immune response and poor prognosis in pancreatic cancer.

Hyaluronan (HA) accumulation has been associated with poor survival in various cancers, but the mechanisms for this phenomenon are still unclear. The aim of this study was to investigate the prognostic significance of stromal HA accumulation and its association with host immune response in pancreatic ductal adenocarcinoma (PDAC). The study material consisted of 101 radically treated patients for PDAC from a single geographical area. HA staining was evaluated using a HA-specific probe, and the patterns of CD3, CD8, CD73 and PD-L1 expression were evaluated using immunohistochemistry. HA staining intensity of tumour stromal areas was assessed digitally using QuPath. CD3- and CD8-based immune cell score (ICS) was determined. High-level stromal HA expression was significantly associated with poor disease-specific survival (p = 0.037) and overall survival (p = 0.013) In multivariate analysis, high-level stromal HA expression was an independent negative prognostic factor together with histopathological grade, TNM stage, CD73 positivity in tumour cells and low ICS. Moreover, high-level stromal HA expression was associated with low ICS (p = 0.017). In conclusion, stromal HA accumulation is associated with poor survival and low immune response in PDAC.

Prognostic impact of CD73 expression and its relationship to PD-L1 in patients with radically treated pancreatic cancer.

Immune suppressing molecule CD73 is overexpressed in various cancers and associated with poor survival. Little is so far known about the predictive value of CD73 in pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to investigate the prognostic significance of CD73 in PDAC. The study material consisted of 110 radically treated patients for PDAC. Tissue microarray blocks were constructed and stained immunohistochemically using CD73 antibody. Staining intensity and numbers of stained tumour cells, inflammatory cells, stroma, and blood vessels were assessed. High-level CD73 expression in tumour cells was positively associated with PD-L1 expression, perineural invasion, and histopathological grade. CD73 positivity in tumour-infiltrating lymphocytes was significantly associated with lymph node metastasis. Lymphocytic CD73 positivity was also associated with staining positivity in both stroma and vascular structures. In addition, CD73 positivity in vascular structures and stroma were associated with each other. There were no significant associations between CD73 positive tumour cells and CD73 positivity in any other cell types. PD-L1 expression was associated with CD73 staining positivity in stroma (p = 0.007) and also with histopathological grade (p = 0.033) and T class (p = 0.016) of the primary tumour. CD73 positivity in tumour cells was significantly associated with poor disease-specific (p = 0.021) and overall survival (p = 0.016). In multivariate analysis, CD73 positivity in tumour cells was an independent negative prognostic factor together with histopathological grade, TNM stage, and low immune cell score. In conclusion, high CD73 expression in tumour cells is associated with poor survival in PDAC independently of the number of tumour-infiltrating lymphocytes or TNM stage.

Critical evaluation of quality of hepatopancreatic surgery in a medium-volume center in Finland using the Accordion Severity Grading System and the Postoperative Morbidity Index.

BACKGROUND: Hepatopancreatobiliary surgery is prone to complications. Methods are needed to monitor surgical outcomes and enable comparison between institutions. METHODS: Complications were collected prospectively and reviewed using the modified Accordion Severity Grading System (MASGS) and the Postoperative Morbidity Index (PMI). RESULTS: This study included 527 consecutive patients receiving either pancreatic or liver resection in 2000-2017 in Central Finland Central Hospital. The PMI was 0.177 for all patients, and 0.192, 0.094, 0.285, and 0.129 for patients receiving major pancreatic (n=218), minor pancreatic (n=93), major liver (n=73), and minor liver (n=143) resection, respectively. The rates of postoperative pancreatic fistula (POPF) after pancreaticoduodenectomies (n=200) were 6.5% for grade B and 5.5% for grade C; rates for biliary leak were 1.0% (grade A), 2.5% (grade B), and 0.5% (grade C). Similarly, the rates for delayed gastric emptying (DGE) were 2.8% (grade A), 15.6% (grade B), and 3.7% (grade C). Postoperative hepatic dysfunction occurred in 2.3%, major surgical site bleeding in 2.3%, and biloma in 7.9% of patients after liver resection. Ninety-day mortality rates were 3.7% and 1.1% in major and minor pancreatic resections, and 8.2% and 0.7% in major and minor liver resections. Major complications occurred in 13.3% and 3.3% in pancreatic, and 19.2% and 6.3% in liver resections, respectively. CONCLUSIONS: Major pancreatic and hepatic surgery are associated with significant morbidity and burden in our center, comparable with previous population-based studies. PMI is an informative way to monitor surgical outcomes and enable comparison between institutions.

Preoperative computed tomography is poor in detecting tumors of the appendix among patients with acute appendicitis: A cohort study of 5,224 appendectomies.

BACKGROUND: Neoplastic processes are among the known etiologies for acute appendicitis. While conservative treatment with antibiotics alone has been proposed as a treatment for uncomplicated appendicitis, the presence of tumors should be excluded when offering patients this option. The aim of this study was to assess the accuracy of computed tomography (CT) in detecting appendiceal tumors. METHOD: Consecutive patients operated on for acute appendicitis between January 2007 and October 3, 2018, in our university hospital were included. Whenever appendiceal tumor was histopathologically confirmed, CT interpretations and surgical reports were carefully reviewed. All CT scans were reanalyzed by consultant body radiologists. Discrepancies between the preliminary and final radiological interpretations were noted. RESULTS: A total of 5,224 patients underwent appendectomy, of whom 4,766 had histopathologically confirmed acute appendicitis. Eighty-four patients (median, 61 (13-89) years; 54% female) were diagnosed with appendiceal tumor. Fifty-two patients (62%) had uncomplicated appendicitis. Although incidence of tumors was associated with older age, tumors were found in all ages. The share of tumors increased from 1.7% to 3.0%/year during the study. The most common tumors were neuroendocrine tumors (n = 33), low-grade appendiceal mucinous neoplasms (n = 14), and adenocarcinomas (n = 11). Sixty-one patients (73%) underwent preoperative CT. Computed tomography interpretation during on-call hours suspected tumor in only one case (3.4%) with invasive tumor, and in five cases (16%) with noninvasive tumor. CONCLUSION: Appendiceal tumors are possible findings in appendix specimens, and most patients had uncomplicated acute appendicitis. In light of findings we conclude that CT cannot be used to exclude neoplastic etiology underlying acute appendicitis. LEVEL OF EVIDENCE: Diagnostic, level IV.

Immune cell score in pancreatic cancer-comparison of hotspot and whole-section techniques.

An immune cell score (ICS) was introduced for predicting survival in pancreatic ductal adenocarcinoma (PDAC). Few studies have compared different methods of evaluating immune infiltrate. This study compared ICSs determined in whole sections or tissue microarray-like hotspots for predicting survival after PDAC surgery. We included in 79 consecutive patients from a single geographical area that underwent surgery for PDAC (R0/R1, stages I-III). We performed digital image analyses to evaluate CD3 and CD8 staining. ICSs were classified as low, moderate, or high, based on the numbers of immune cells in the tumour core and invasive margin. We compared ICS groups determined with the hotspot and whole-section techniques. Associations between ICS and survival were analysed with Cox regression models, adjusted for sex, age, tumour stage, differentiation grade, perineural invasion, and resection radicality. In hotspot ICS analysis, 5-year overall survival rates for low, moderate, and high groups were 12.1%, 26.3%, and 26.8%, respectively (p = 0.193). In whole-section analyses, overall survival rates were 5.3%, 26.4%, and 43.8%, respectively (p = 0.030). In the adjusted Cox model, whole-section ICS groups were inversely associated with the overall mortality hazard ratio (HR): low, moderate, and high ICS groups had HRs of 1.00, 0.42 (95% CI 0.20-0.88), and 0.27 (95% CI 0.11-0.67), respectively. The number of immune cells per square millimetre in the tumour core and the invasive margin were significantly higher and had a wider range in hotspots than in whole-tissue sections. Accordingly, ICS could predict survival in patients with PDAC after surgery. Whole tissue section ICSs exhibited better prognostic value than hotspot ICSs.

High immune cell score predicts improved survival in pancreatic cancer.

Increasing evidence suggests that cancer progression is strongly influenced by host immune response, which is represented by immune cell infiltrates. T-lymphocyte-based immunoscore has proved to be a prognostic factor in colon cancer, but its significance in pancreatic cancer is poorly known. Total of 108 patients operated (R0/R1) for pancreatic ductal adenocarcinoma (PDAC) (TNM stage I-II) were included in the study. Immune cell score (IS) was determined by scoring the samples from grade 0 to 4 according to the number of immune cells (CD3+ and CD8+) in tumor core and invasion margin using tissue microarrays, immunohistochemistry, and digital analysis. Tumors with microsatellite instability were identified by MLH1 immunostaining. High IS and low histological grade were significantly associated with better disease-specific survival (DSS) and overall survival (OS). The 5-year DSS rate for low, moderate, and high IS groups were 5.0, 15.2, and 33.4%, respectively (p = 0.007). The 5-year OS rate for the low, moderate, and high IS groups were 4.2, 13.4, and 31.5%, respectively (p = 0.004). In addition, IS and prognosis varied within a single TNM stage. There was no association between IS and any of the clinicopathological variables. IS was shown to be an independent prognostic factor for better DSS and OS in multivariate analysis, together with the histological grade of the tumor and perineural invasion. Five MLH1-negative tumors (4.6%) were found showing no correlation with IS. IS could be a useful prognostic marker in patients with PDAC treated by primary surgery.