Surveillance after surgery for pancreatic cancer: a global scoping review of guidelines and a nordic Survey of contemporary practice.

OBJECTIVES: Most patients with pancreatic cancer who have undergone surgical resection eventually develop disease recurrence. |This study aimed to investigate whether there is evidence to support routine surveillance after pancreatic cancer surgery, with a secondary aim of analyzing the implementation of surveillance strategies in the Nordic countries. MATERIALS AND METHODS: A scoping review was conducted to identify clinical practice guidelines globally and research studies relating to surveillance after pancreatic cancer resection. This was followed by a survey among 20 pancreatic units from four Nordic countries to assess their current practice of follow-up for operated patients. RESULTS: Altogether 16 clinical practice guidelines and 17 research studies were included. The guidelines provided inconsistent recommendations regarding postoperative surveillance of pancreatic cancer. The clinical research data were mainly based on retrospective cohort studies with low level of evidence and lead-time bias was not addressed. Active surveillance was recommended in Sweden and Denmark, but not in Norway beyond the post-operative/adjuvant period. Finland had no national recommendations for surveillance. The Nordic survey revealed a wide variation in reported practice among the different units. About 75% (15 of 20 units) performed routine postoperative surveillance. Routine CA 19-9 testing was used by 80% and routine CT by 67% as part of surveillance. About 73% of centers continued follow-up until 5 years postoperatively. CONCLUSION: Evidence for routine long-term (i.e. 5 years) surveillance after pancreatic cancer surgery remains limited. Most pancreatic units in the Nordic countries conduct regular follow-up, but protocols vary.

Evolution of pancreatic surgery over time and effects of centralization-a single-center retrospective cohort study.

Background: Short-term outcomes of pancreatic surgery have improved globally during the last two decades. Long-term survival of resectable pancreatic ductal adenocarcinoma (PDAC) has also shown slight improvement. We describe a cohort of 566 consecutive pancreatectomies performed at a Northern Finnish tertiary center. We analyze the trends in short-term outcomes of all-cause pancreatic surgery and long-term survival of PDAC patients. Methods: All pancreatic resections performed at the Oulu University Hospital during years 2000-2020 were included. Patient data was analyzed in four time periods (2000-2005, 2006-2010, 2011-2015 and 2016-2020). Clinicopathological parameters of patients and tumors, complication data and short-term mortality were recorded for all patients and compared between time quartiles. Long-term survival and administration rates of neo-, and/or adjuvant therapy of PDAC patients were analyzed. Results: A total of 566 pancreatectomies were performed during the study period: 359 (63%) pancreatoduodenectomies (PDs), 130 (23.0%) open left pancreatectomies (LPs), 45 (8.0%) laparoscopic LPs, 26 (5.1%) total pancreatectomies (TPs), and 6 (1.1%) enucleations. Median age of patients was 63 [57-71] years, and 49% [267] of patients were men. Number of pancreatectomies per time period increased from 67 in 2000-2005 to 266 in 2016-2020. American Society of Anesthesiologists (ASA) Physical Classification III patients and T3 tumors were more frequently operated on in later time periods. Complication rates remained at constant low levels throughout the study period, but reoperation rate increased from 9.4% in 2000-2010 to 16.2% in 2011-2020. Short-term (90-day) mortality after pancreatectomy decreased from 3.1% to 0.74%, while 5-year survival improved from 14.3% in 2006-2011 to 21.4% in 2011-2015. Resection rate of diagnosed PDAC cases, as reported by the Finnish Cancer Registry (FCR) for the catchment area, increased from 3.2% to 14.9% over the study period. Conclusions: The hospital volume of pancreatectomies has increased substantially, while complications and postoperative mortality have remained at acceptable levels. Long-term survival and resection rate of PDAC patients showed notable improvement over two decades.

Hospital volume and outcomes of pancreatic cancer: a Finnish population-based nationwide study.

BACKGROUND: Pancreatic cancer surgery is associated with high incidence of short- and long-term morbidity and mortality. The aim of this study was to assess whether the hospital volume of pancreatic surgery is associated with better survival in a population-based setting. METHODS: All patients who underwent pancreatic resection for cancer in Finland during 1997-2016 were identified from nationwide registries. The follow-up ended on 31 December 2019. Patients were divided into quintiles based on annual hospital volume (4-year moving average): ≤4, 5-9, 10-18, 19-36 and ≥ 37 resections per year. Cox regression provided hazard ratios (HR) and 95% confidence intervals (CI), adjusted for age, sex, comorbidity and year of surgery. RESULTS: The number of diagnosed pancreatic cancers was 22,724. Of these, 1514 underwent pancreatic surgery due to pancreatic ductal adenocarcinoma. The 5-year survival ranged from 12% to 28%, increasing with higher annual operative volume. Adjusted 5-year mortality was higher in all other quintiles compared to the highest annual volume quintile (HR 1.43, 95% CI 1.16-1.75). Thirty and 90-day mortality were higher in the three lowest volume, compared to the highest quintile. CONCLUSION: Higher annual hospital volume of pancreatic surgery for pancreatic ductal adenocarcinoma is associated with improved short- and long-term survival.

Carbonic Anhydrases II, IX, and XII in Reflux Esophagitis.

BACKGROUND: The pathogenesis of gastroesophageal reflux disease (GERD) has not been resolved in detail. Esophageal epithelial cells provide resistance to acidic reflux via several mechanisms, many of which involve buffering acid with bicarbonate and transporting protons. Carbonic anhydrases (CAs) are enzymes that control the acid-base balance by catalyzing the reversible hydration of carbon dioxide to produce bicarbonate and hydrogen ions. AIMS: We aimed to determine the immunohistochemical expression patterns of CAII, CAIX, and CAXII in the normal esophageal squamous epithelium and in patients with GERD. METHODS: We evaluated 82 biopsy samples, including 26 with a histologically normal esophagus, 26 with histologically mild esophagitis, and 30 with severe esophagitis. Expression patterns of CAII, CAIX, and CAXII in the esophageal squamous epithelium were determined by immunohistochemical staining. RESULTS: Cytoplasmic CAII expression was predominantly detected in the upper luminal part of the squamous epithelium and was significantly (p < 0.01) increased in GERD. Expression of CAIX was essentially membranous. The isozyme was constantly present in the peripapillary cells. In the interpapillary areas, clustered expression was observed to emerge and increase significantly (p < 0.01) in esophagitis. CAXII expression was the most abundant of the isozymes and was mainly membranous. In the normal squamous epithelium, CAXII expression was confined to the basal layer; in severe esophagitis, CAXII expression increased significantly in both basal (p < 0.05) and superficial (p < 0.01) halves of the epithelium. CONCLUSIONS: We demonstrate upregulated expression of CAII, CAIX, and CAXII in GERD. The increase in expression likely contributes to esophageal epithelial resistance to acidic reflux.

Carbonic Anhydrases II and IX in Non-ampullary Duodenal Adenomas and Adenocarcinoma.

Non-ampullary duodenal adenocarcinoma (DAC) is a rare malignancy. Little information is available concerning the histopathological prognostic factors associated with DAC. Carbonic anhydrases (CAs) are metalloenzymes catalyzing the universal reaction of CO2 hydration. Isozymes CAII, CAIX, and CAXII are associated with prognosis in various cancers. Our aim was to analyze the immunohistochemical expressions of CAII, CAIX, and CAXII in normal duodenal epithelium, duodenal adenomas, and adenocarcinoma and their associations with clinicopathological variables and survival. Our retrospective study included all 27 DACs treated in Oulu University Hospital during years 2000-2020. For comparison, samples of 42 non-ampullary adenomas were collected. CAII expression was low in duodenal adenomas and adenocarcinoma. CAIX expression in adenomas and adenocarcinoma was comparable with the high expression of normal duodenal crypts. Expression patterns in carcinomas were largely not related to clinicopathological features. However, low expression of CAII associated with poorer differentiation of the tumor (p=0.049) and low expression of CAIX showed a trend for association with nodal spread, although statistical significance was not reached (p=0.091). CAII and CAIX lost their epithelial polarization and staining intensity in adenomas. CAXII expression was not detected in the studied samples. CAs were not associated with survival. The prognostic value of CAII and CAIX downregulation should be further investigated. Both isozymes may serve as biomarkers of epithelial dysplasia in the duodenum.

Pathophysiology of reflux oesophagitis: role of Toll-like receptors 2 and 4 and Farnesoid X receptor.

The pathogenesis of gastroesophageal reflux disease (GERD) is not fully understood. It involves the activation of mucosal immune-mediated and inflammatory responses. Toll-like receptors (TLR) 2 and TLR4 are pattern-recognition receptors of the innate immune system; they recognize microbial and endogenous ligands. Farnesoid X receptor (FXR) is a bile acid receptor that regulates the inflammatory response. We aimed to evaluate TLR2, TLR4 and FXR expression patterns in GERD. We re-evaluated 84 oesophageal biopsy samples according to the global severity (GS) score, including 26 cases with histologically normal oesophagus, 28 with histologically mild oesophagitis and 30 with severe oesophagitis. We used immunohistochemistry and in situ hybridization to assess the expression patterns of TLR2, TLR4 and FXR in oesophageal squamous cells. Immunohistochemistry showed that nuclear and cytoplasmic TLR2 was expressed predominantly in the basal layer of normal oesophageal epithelium. In oesophagitis, TLR2 expression increased throughout the epithelium, and the superficial expression was significantly more intensive compared to normal epithelium, p <0.01. Nuclear and cytoplasmic TLR4 was expressed throughout the thickness of squamous epithelium, with no change in oesophagitis. FXR was expressed in the nuclei of squamous cells, and the intensity of the expression increased significantly in oesophagitis (p <0.05). FXR expression correlated with basal TLR2. In situ hybridization confirmed the immunohistochemical expression patterns of TLR2 and TLR4. In GERD, TLR2, but not TLR4, expression was upregulated which indicates that innate immunity is activated according to a specific pattern in GERD. FXR expression was increased in GERD and might have a regulatory connection to TLR2.

Carbonic anhydrases II, IX, and XII in Barrett's esophagus and adenocarcinoma.

The aim of our retrospective study was to investigate the expression and clinical significance of the cancer-associated carbonic anhydrases (CAs) II, IX, and XII in Barrett's esophagus and esophageal adenocarcinoma (EAC). We evaluated 101 archival specimens from patients with EAC as well as seven and 26 samples from patients with high-and low-grade dysplasia, respectively. In addition, normal esophageal squamous epithelium, gastric, and intestinal metaplasia were analyzed when present. The expression patterns of isozymes were detected by immunohistochemistry. CAII and CIX expression levels were lower in the squamous epithelium than in the columnar cells while CAXII showed an opposite pattern and was present mainly in squamous epithelium. Expression patterns in benign, dysplastic, or malignant esophageal columnar lesions were not significantly different. The assessment of clinicopathological associations showed that CAII was significantly downregulated in metastatic disease (p = 0.026). CAIX showed no association with prognosis, although there appeared to be an association (p = 0.056) between high expression and nodal spread. In conclusion, CAII, CAIX, and CAXII do not serve as biomarkers for different phases in the development of EAC.