Exploring the prognostic value of circular RNAs in pancreatic ductal adenocarcinoma using genome-wide expression profiling.

BACKGROUND/OBJECTIVES: Median survival of pancreatic ductal adenocarcinoma (PDAC) is around eight months and new prognostic tools are needed. Circular RNAs (circRNAs) have gained interest in different types of cancer. However, only a few studies have evaluated their potential in PDAC. We aimed to identify the most differentially expressed circRNAs in PDAC compared to controls and to explore their potential as prognostic markers. METHODS: Using frozen specimens with PDAC and controls, we performed RNA sequencing and identified 20,440 unique circRNAs. A custom code set of capture- and reporter probes for NanoString nCounter analysis was designed to target 152 circRNAs, based on abundancy, differential expression and a literature study. Expression of these 152 circRNAs was examined in 108 formalin-fixed and paraffin-embedded surgical PDAC specimens and controls. The spatial expression of one of the most promising candidates, ciRS-7 (hsa_circ_0001946), was evaluated by chromogenic in situ hybridization (CISH) using multi-punch tissue microarrays (TMAs) and digital imaging analysis. RESULTS: Based on circRNA expression profiles, we identified different PDAC subclusters. The 30 most differentially expressed circRNAs showed log2 fold changes from -3.43 to 0.94, where circNRIP1 (hsa_circ_0004771), circMBOAT2 (hsa_circ_0007334) and circRUNX1 (hsa_circ_0002360) held significant prognostic value in multivariate analysis. CiRS-7 was absent in PDAC cells but highly expressed in the tumor microenvironment. CONCLUSIONS: We identified several new circRNAs with biomarker potential in surgically treated PDAC, three of which showed an independent prognostic value. We also found that ciRS-7 is absent in cancer cells but abundant in tumor microenvironment and may hold potential as marker of activated stroma.

Prognostic importance of margin clearance in ampullary adenocarcinoma following pancreaticoduodenectomy in a Danish population-based nationwide study.

BACKGROUND: In this Danish nationwide population-based study, we evaluated the prognostically relevant minimum tumour-free margin width following pancreaticoduodenectomy (PD) for ampullary adenocarcinoma (AAC) and evaluated whether certain margins hold independent prognostic information. METHODS: We included 128 patients who underwent PD for AAC from 2015 to 2019. Clinical and pathological data including well-known prognostic factors were retrieved from the Danish Pancreatic Cancer Database. Missing data were obtained by review of pathology reports and re-microscopy of resection specimens. All PD specimens were examined using a standardised pathological protocol including multicolour inking, axial slicing and exact reporting of margin widths. The cohort was dichotomised into involved and uninvolved groups, using different margin clearance definitions (0.5-≥3.0 mm). RESULTS: Following PD for AAC, margin clearance of ≥1 mm was independently associated with improved chance of survival compared with <1 mm (HR: 0.30, 95 % CI: 0.14-0.64 (p = 0.002)). Posterior and anterior margin widths were narrower compared with superior mesenteric artery and vein margins. Posterior margin and anterior surface had isolated prognostic significance in multivariable analysis. CONCLUSION: Following PD for AAC, margin clearance of at least 1 mm is independently associated with improved survival. Our data further indicate that anterior surface and posterior margin hold particular prognostic value.

Prognostic significance of margin clearance in pancreaticoduodenectomy specimens with pancreatic ductal adenocarcinoma in a Danish population-based nationwide study.

BACKGROUND: In this nationwide population-based cohort study, we investigated the overall minimum margin width that is independently associated with improved survival following pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) and evaluated whether certain margins or surfaces hold independent prognostic significance. METHODS: Data from 367 patients who underwent PD for PDAC in the period 2015-2019 were retrieved from the Danish Pancreatic Cancer Database. Missing data were obtained by review of pathology reports and re-microscopy of resection specimens. Surgical specimens were evaluated using a standardised pathological protocol involving multicolour inking, axial slicing and exact reporting of circumferential margin clearances in 0.5 mm increments. RESULTS: When categorised according to margin widths of <0.5, <1.0, <1.5, <2.0, <2.5 and <3.0 mm, R1 resections were detected in 34%, 57%, 75%, 78%, 86% and 87% of cases, respectively. In multivariable analyses, an overall margin clearance of ≥1.5 mm was associated with improved survival compared with a clearance of <1.5 mm (HR 0.70 95% CI 0.51-0.97 (p = 0.031)). When evaluating the margins separately, no margin had independent prognostic significance. CONCLUSION: Margin clearance of at least 1.5 mm was independently associated with improved survival following PD for PDAC.

Use and outcome of minimally invasive pancreatic surgery in the European E-MIPS registry.

BACKGROUND: The European registry for minimally invasive pancreatic surgery (E-MIPS) collects data on laparoscopic and robotic MIPS in low- and high-volume centers across Europe. METHODS: Analysis of the first year (2019) of the E-MIPS registry, including minimally invasive distal pancreatectomy (MIDP) and minimally invasive pancreatoduodenectomy (MIPD). Primary outcome was 90-day mortality. RESULTS: Overall, 959 patients from 54 centers in 15 countries were included, 558 patients underwent MIDP and 401 patients MIPD. Median volume of MIDP was 10 (7-20) and 9 (2-20) for MIPD. Median use of MIDP was 56.0% (IQR 39.0-77.3%) and median use of MIPD 27.7% (IQR 9.7-45.3%). MIDP was mostly performed laparoscopic (401/558, 71.9%) and MIPD mostly robotic (234/401, 58.3%). MIPD was performed in 50/54 (89.3%) centers, of which 15/50 (30.0%) performed ≥20 MIPD annually. This was 30/54 (55.6%) centers and 13/30 (43%) centers for MIPD respectively. Conversion rate was 10.9% for MIDP and 8.4% for MIPD. Overall 90 day mortality was 1.1% (n = 6) for MIDP and 3.7% (n = 15) for MIPD. CONCLUSION: Within the E-MIPS registry, MIDP is performed in about half of all patients, mostly using laparoscopy. MIPD is performed in about a quarter of patients, slightly more often using the robotic approach. A minority of centers met the Miami guideline volume criteria for MIPD.

Disparity in use of modern combination chemotherapy associated with facility type influences survival of 2655 patients with advanced pancreatic cancer.

AIM: Academic and high volume hospitals have better outcome for pancreatic cancer (PC) surgery, but there are no reports on oncological treatment. We aimed to determine the influence of facility types on overall survival (OS) after treatment with chemotherapy for inoperable PC. MATERIAL AND METHODS: 2,657 patients were treated in Denmark from 2012 to 2018 and registered in the Danish Pancreatic Cancer Database. Facilities were classified as either secondary oncological units or comprehensive, tertiary referral cancer centers. RESULTS: The average yearly number of patients seen at the four tertiary facilities was 71, and 31 at the four secondary facilities. Patients at secondary facilities were older, more frequently had severe comorbidity and lived in non-urban municipalities. As compared to combination chemotherapy, monotherapy with gemcitabine was used more often (59%) in secondary facilities than in tertiary (34%). The unadjusted median OS was 7.7 months at tertiary and 6.1 months at secondary facilities. The adjusted hazard ratio (HR) of 1.16 (confidence interval 1.07-1.27) demonstrated an excess risk of death for patients treated at secondary facilities, which disappeared when taking type of chemotherapy used into account. Hence, more use of combination chemotherapy was associated with the observed improved OS of patients treated at tertiary facilities. Declining HR's per year of first treatment indicated improved outcomes with time, however the difference among facility types remained significant. DISCUSSION: Equal access to modern combination chemotherapy at all facilities on a national level is essential to ensure equality in treatment results.

Healthcare use in the year preceding a diagnosis of pancreatic cancer: a register-based cohort study in Denmark.

OBJECTIVE: To describe the use of healthcare prior to a diagnosis of pancreatic cancer in Denmark. DESIGN: A population-based cohort study using prospectively recorded data from Danish National Health Registries. SETTING: Danish general practice and hospitals. SUBJECTS: A total of 5926 patients diagnosed with pancreatic cancer in 2012-2018 and 59,260 matched references without pancreatic cancer from the Danish general population. MAIN OUTCOME MEASURES: The monthly frequency of healthcare use (contacts and tests in general practice and contacts and diagnostic investigations in hospitals) during the 12 months preceding the pancreatic cancer diagnosis and a corresponding index date assigned to the references. RESULTS: Compared to the references, the patients had increased contacts and diagnostic tests, especially blood glucose testing, in general practice from 7 to 12 months before diagnosis. Hospital contacts and diagnostic imaging increased from 5 months before the diagnosis. CONCLUSIONS: The pattern of increasing healthcare contacts before a diagnosis of pancreatic cancer may represent a window of opportunity to diagnose pancreatic cancer earlier. The increased use of blood glucose test in general practice may represent an important sign of an underlying disease. Key pointsPancreatic cancer is a rapidly progressing and highly lethal disease. Focus on early diagnosis is essential to improve the prognosis.Patients with pancreatic cancer had increased number of healthcare contacts from 7 months before the diagnosis.Patients with pancreatic cancer had increased number of blood glucose tests taken throughout almost the entire year before the diagnosis.The results may indicate that a window of opportunity exists to diagnose pancreatic cancer earlier.

Gene expression profiling of morphologic subtypes of pancreatic ductal adenocarcinoma using surgical and EUS-FNB specimens.

BACKGROUND/OBJECTIVES: Various classifications of pancreatic ductal adenocarcinoma (PDAC) based on RNA profiling resulted in two main subtypes. Kalimuthu and coworkers proposed a morphology-based classification that concurred with these subtypes. Immune therapy approaches in PDAC were so far disappointing. Morphologic PDAC subtypes may differ regarding key immune-oncology pathways. We aimed to examine the reproducibility and prognostic value of Kalimuthu's morphologic classification, and to evaluate differences between subtypes regarding gene expression related to tumor biology and immune-oncology. METHODS: PDAC specimens from 196 patients were included, 108 consecutive chemotherapy-naïve surgical specimens and 88 endoscopic ultrasound-guided fine needle biopsies (EUS-FNBs). The specimens were evaluated as per Kalimuthu by two pancreatic pathologists, resulting in Group A and Group B tumors. Digital mRNA expression profiling was performed, on the surgical specimens using the NanoString IO360 panel of 770 key tumor biology related and 30 custom-genes, and on the EUS-FNBs using a targeted panel of 123 genes. RESULTS: Morphologic subtyping reached substantial interobserver agreement between the two pathologists. In the surgical and EUS-FNB cohorts, 44.4% and 38.6% were Group A tumors, which were associated with improved survival. Group A showed higher expression of immune-related genes and cytokine/chemokine/interleukin signaling and Group B of genes related to cancer cell proliferation and cell cycle regulation. Hierarchical clustering based on significant differences in gene expression levels between Groups A and B revealed clusters with prognostic value. CONCLUSIONS: Morphologic subtyping according to Kalimuthu is reproducible and holds prognostic value, in surgical as well as EUS-FNB specimens. As upregulation of immune-related genes was found in Group A, future studies should evaluate the potential of immune therapy approaches with special emphasis on this subtype of PDAC.

Intra-observer agreements in multidisciplinary team assessments of pancreatic cancer patients.

BACKGROUND AND METHODS: Treatment strategies for pancreatic cancer patients are made by a multidisciplinary team (MDT) board. We aimed to assess intra-observer variance at MDT boards. Participating units staged, assessed resectability, and made treatment allocations for the same patients as they did two years earlier. We disseminated clinical information and CT images of pancreatic cancer patients judged by one MDT board to have nonmetastatic pancreatic cancer to the participating units. All units were asked to re-assess the TNM stage, resectability, and treatment allocation for each patient. To assess intra-observer variance, we computed %-agreements for each participating unit, defined as low (<50%), moderate (50%-75%), and high (>75%) agreement. RESULTS: Eighteen patients were re-assessed by six MDT boards. The overall agreement was moderate for TNM-stage (ranging from 50%-70%) and resectability assessment (53%) but low for treatment allocation (46%). Agreement on resectability assessments was low to moderate. Findings were similar but more pronounced for treatment allocation. We observed a shift in treatment strategy towards increasing use of neoadjuvant chemotherapy, particularly in patients with borderline resectable and locally advanced tumors. CONCLUSIONS: We found substantial intra-observer agreement variations across six different MDT boards of 18 pancreatic cancer patients with two years between the first and second assessment.

Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations.

OBJECTIVE: Resection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation. DESIGN: Data from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003-2016 were analysed. Age-standardised resection rates for overall and stage I-II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models. RESULTS: A total of 153 698 records were analysed. In population-based registries in 2012-2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I-II tumours, with great international variations. During 2003-2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I-II tumours: 0.05-0.18 and 0.01-0.06 across countries) and increasing age (ORs for patients 70-79 and ≥80 versus those <60 years: 0.37-0.63 and 0.03-0.16 across countries). Patients with advanced-stage tumours (stage III-IV: 63.8%-81.2%) and at older ages (≥70 years: 52.6%-59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application. CONCLUSION: Rates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations.

Reproducibility of the peritoneal regression grading score for assessment of response to therapy in peritoneal metastasis.

AIMS: The four-tiered peritoneal regression grading score (PRGS) assesses the response to chemotherapy in peritoneal metastasis (PM). The PRGS is used, for example, to assess the response to pressurised intraperitoneal aerosol chemotherapy (PIPAC). However, the reproducibility of the PRGS is currently unknown. We aimed to evaluate the inter- and intraobserver variability of the PRGS. METHODS AND RESULTS: Thirty-three patients who underwent at least three PIPAC treatments as part of the PIPAC-OPC1 or PIPAC-OPC2 clinical trials at Odense University Hospital, Denmark, were included. Prior to each therapy cycle, peritoneal quadrant biopsies were obtained and three haematoxylin and eosin (H&E)-stained step sections were scanned and uploaded to a pseudonymised web library. For determining interobserver variability, eight pathologists assessed the PRGS for each quadrant biopsy, and Krippendorff's alpha and intraclass correlation coefficients (ICCs) were calculated. For determining intraobserver variability, three pathologists repeated their own assessments and Cohen's kappa and ICCs were calculated. A total of 331 peritoneal biopsies were analysed. Interobserver variability for PRGS of each biopsy and for the mean and maximum PRGS per biopsy set was moderate to good/substantial. The intraobserver variability for PRGS of each biopsy and for the mean and maximum PRGS per biopsy set was good to excellent/almost perfect. CONCLUSIONS: Our data support the PRGS as a reproducible and useful tool to assess response to intraperitoneal chemotherapy in PM. Future studies should evaluate the prognostic and predictive role of the PRGS.

The impact of endoscopic ultrasound-guided fine-needle aspiration of lymph nodes on subsequent positron emission tomography/computed tomography imaging: a prospective study.

BACKGROUND: Modern cancer diagnostic work-up is based on multiple modalities within a short time period. The interplay between these modalities is complex and not well known. Performing biopsy procedures prior to (18)F-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) is considered to pose a risk of false-positive imaging results; however, this is not based on solid scientific evidence. The use of endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is commonly used in upper gastrointestinal malignancies, is proven safe, and has very little risk of complications. This study aimed to assess whether EUS-FNA induces inflammation that would increase FDG uptake on subsequent PET/CT. METHODS: 27 patients who were referred for upper gastrointestinal EUS for different reasons initially underwent FDG-PET/CT to detect biopsy-eligible lymph nodes with no FDG uptake. Patients then underwent EUS-FNA of the benign lymph nodes, with a minimum of three passes. Patients were re-evaluated with FDG-PET/CT 1 week later, with specific emphasis on the biopsied lymph nodes. RESULTS: None of the biopsied lymph nodes showed increased FDG uptake on follow-up FDG-PET/CT. No adverse events occurred. CONCLUSION: EUS-FNA prior to FDG-PET/CT did not lead to false-positive FDG uptake. The interpretive impact of minor procedures prior to FDG-PET/CT needs to be re-evaluated.

The effect of postoperative gemcitabine on overall survival in patients with resected pancreatic cancer: A nationwide population-based Danish register study.

Background: Adjuvant chemotherapy following curative resection is the standard treatment for pancreatic adenocarcinoma (PC). Randomized clinical trials using gemcitabine have shown a median overall survival (mOS) of 2 years and a 5-year survival rate of 15-20%. However, the effect of gemcitabine outside these trials is less clear. We examined the effect of postoperative gemcitabine on survival in an unselected cohort of patients receiving curative resection for PC in Denmark during a five-year period. Material and methods: From 1 May 2011 to 30 April 2016, 731 patients treated with curative resection were identified in the Danish Pancreatic Cancer Database (DPCD). Thirty patients died within 10 weeks postoperatively; 78 received other regimens or preoperative chemotherapy and were excluded. Of the remaining 623 patients, the chemotherapy (CT) group (n = 409, 66%) received gemcitabine within 10 weeks after resection, whereas the non-chemotherapy (NCT) group (n = 214, 34%) did not receive CT within 10 weeks. Results: CT patients were slightly younger than NCT patients but did not otherwise differ in baseline characteristics. The CT group showed a mOS of 24 months (95% CI; 21-27) and a 5-year survival rate of 22% (95% CI; 17-27); the NCT group had a mOS of 22 months (95% CI; 16-26, p = .27) and a 5-year survival rate of 26% (95% CI; 19-34, p = .66). Most patients (415/623) had lymph node metastases. Of these patients, those in the CT group (n = 280) had significantly longer mOS [20 months (95% CI; 18-24)] than those in the NCT group (n = 135) [14 months (95% CI; 11-17)]. Conclusions: In this national Danish cohort of PC patients undergoing resection between 2011 and 2016, the survival after postoperative gemcitabine was similar to that reported in previous clinical trials. However, the survival advantage of postoperative gemcitabine was limited to patients with lymph node metastases.

Peritoneal microdialysis as a tool for detecting anastomotic leakage in patients after left-side colon and rectal resection. A systematic review.

OBJECTIVE: The objective was to evaluate peritoneal microdialysis in the detection of clinical anastomotic leakage after left-sided colon and rectal resection through a systematic review. METHODS: A systematic review (PRISMA guidelines) based on a systematic search through PubMed, Cochrane Library, and EMBASE (1 February 2017) was performed. Methodological index of non-randomised studies score was selected to assess the methodological quality. Patient demographics and raw data for intraperitoneal microdialysis concentrations of glucose, lactate, glycerol and pyruvate for 5 d postoperative were obtained from the respective study groups. RESULTS: Ten studies with a total of 128 patients were included. Thirty (23%) patients developed clinical anastomotic leakage. The area under the curve for intraperitoneal lactate concentration was significant higher in patients with anastomotic leakage (58.2; 95% CI 39.2, 77.2) compared with the no leakage group (41.0; 95% CI 35.2, 46.1; p = .007). Receiver operating characteristic curve analysis of the maximum measured lactate concentration demonstrated 25% sensitivity, 88% specificity and 74% accuracy for AL at a cut-off value of 9.8 mmol/L. The odds ratio for a 5 mmol/L increase in lactate in relation to the risk of AL was 2.9 (CI 1.1, 8.0). CONCLUSIONS: Increased intraperitoneal lactate concentration within the first 5 d postoperative was significantly associated with clinical anastomotic leakage, but with low predictive values. The microdialysis method is not yet ready for clinical implication before large prospective studies have defined cut off values for a biologic marker in the setting of a clear definitions of leakage.

The value of contrast-enhanced laparoscopic ultrasound during robotic-assisted surgery for primary colorectal cancer.

AIM: The aim of this study was to assess the potential clinical value of contrast enhanced laparoscopic ultrasonography (CE-LUS) as a screening modality for liver metastases during robotic assisted surgery for primary colorectal cancer (CRC). METHOD: A prospective, descriptive (feasibility) study including 50 consecutive patients scheduled for robotic assisted surgery for primary CRC. CE-LUS was performed by 2 experienced specialists. Only patients without metastatic disease were included. Follow-up was obtained with contrast-enhanced CT imaging at 3 and 12 months postoperatively. RESULTS: Fifty patients were included; 45 patients were available for final analysis. The patients were equally distributed between stage I, II, and III according to the TNM classification system. No liver metastasis was detected during LUS and CE-LUS. CE-LUS was easy to perform and there was no complication. Follow-up revealed no liver metastasis in any of the patients. CONCLUSION: CE-LUS did not increase the detection rate of occult liver metastasis during robotic assisted primary CRC surgery. The use of CE-LUS as a screening modality for detection of liver metastasis cannot be recommended based on this study, but larger controlled studies on high-risk patients seem relevant.

Long-term outcome after early repair of iatrogenic bile duct injury. A national Danish multicentre study.

BACKGROUND: The aim of this retrospective study was to evaluate the peri-operative and long-term outcome after early repair with a hepaticojejunostomy (HJ). METHODS: Between 1995 and 2010, a nationwide, retrospective multi-centre study was conducted. All iatrogenic bile duct injury (BDI) sustained during a cholecystectomy and repaired with HJ in the five Hepato-Pancreatico-Biliary centres in Denmark were included. RESULTS: In total, 139 patients had an HJ repair. The median time from the BDI to reconstruction was 5 days. A concomitant vascular injury was identified in 26 cases (19%). Post-operative morbidity was 36% and mortality was 4%. Forty-two patients (30%) had a stricture of the HJ. The median follow-up time without stricture was 102 months. Nineteen out of the 42 patients with post-reconstruction biliary strictures had a re-HJ. Twenty-three patients were managed with percutaneous transhepatic cholangiography and dilation. The overall success rate of re-establishing the biliodigestive flow approached 93%. No association was found between timing of repair, concomitant vascular injury, level of injury and stricture formation. CONCLUSION: In this national, unselected and consecutive cohort of patients with BDI repaired by early HJ we found a considerable risk of long-term complications (e.g. 30% stricture rate) and mortality in both the short- and the long-term perspective.

Radiofrequency ablation for the treatment of gastric antral vascular ectasia.

BACKGROUND AND STUDY AIMS: The traditional endoscopic treatment for gastric antral vascular ectasia (GAVE) is argon plasma coagulation, but results are not always positive. Radiofrequency ablation (RFA) is a new endoscopic therapy that may be an attractive option for the treatment of GAVE. The aim of this study was to assess the efficacy and safety of RFA for the treatment of GAVE. PATIENTS AND METHODS: This was an open-label, retrospective, case series study. The main outcome measures were number of red blood cell (RBC) packs transfused (transfusion requirement) and hemoglobin concentrations (g/dL) in the 6 months prior to and after RFA. Success was defined as a decrease in transfusion requirement in the 6 months after RFA compared with before treatment. RESULTS: A total of 24 patients underwent a mean of 1.8 ± 0.8 RFA sessions. No complications were reported. One patient was referred for additional argon plasma coagulation during follow-up. The mean number of RBC packs decreased in all 23 transfusion-dependent patients, from a mean of 10.6 ± 12.1 during the 6 months prior to RFA, to a mean of 2.5 ± 5.9 during the 6 months after RFA treatment (P < 0.001), and 15 patients (65.2 %) were weaned off transfusions completely. An increase in the hemoglobin concentration was reported in all patients after RFA (from 6.8 ± 1.4 g/dL to 9.8 ± 1.8 g/dL; P < 0.001). CONCLUSION: RFA for the treatment of GAVE seems feasible and safe, and significantly reduced the need for RBC transfusion and increased the hemoglobin level in this retrospective case series.

Characteristics, therapy and outcome in an unselected and prospectively registered cohort of patients with gastro-oesophageal cancer.

PURPOSE: The purpose was to examine characteristics, treatment and outcome in an unselected, prospectively registered complete population of patients with gastro-oesophageal adenocarcinoma cancer (GEA). METHODS: All cases diagnosed with GEA between 2008 and 2009 in the Region of Southern Denmark (pop: 1,200,000) were registered. Patient characteristics, including performance status, stage and therapy, were retrieved from patient charts and used to compare sub-groups of patients. RESULTS: Three hundred and thirty patients were registered as having GEA. Patients were divided into three clinical subgroups based on initial treatment option: group 1: patients with resectable GEA (n = 113); group 2: patients receiving first-line therapy (n = 107); group 3: patients receiving no tumour-directed therapy (n = 110). Median overall survival (95% CI) in the three groups was 36 months (25-not reached), 7.1 months (7-9) and 2.4 months (2-3), respectively. Seven percent of patients participated in clinical trials. CONCLUSION: Among patients not amendable to resection, around 30% are candidates for three-drug combination chemotherapy. Age > 65 years was found not to be a poor prognostic factor for survival, giving the possibility of treating elderly patients in the future. Many patients (approx. 30%), however, never received cancer-directed therapy. In order to improve survival in the entire population, it is important that future trials also focus on this group of patients.

RNA expression profiling of peritoneal metastasis from pancreatic cancer treated with Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).

Objectives: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an experimental treatment option in peritoneal metastasis from pancreatic cancer (PM-PC). Aims were to examine mRNA profile of fibrosis due to response after systemic chemotherapy and PIPAC (Regression) compared to treatment-naïve PM-PC and chronic cholecystitis-related peritoneal fibrosis (Controls). Methods: Peritoneal biopsies (PBs) from PM-PC patients who had undergone systemic chemotherapy and PIPAC were evaluated with Peritoneal Regression Grading Score (PRGS). We extracted RNA from PBs with Regression (PRGS 1, n=11), treatment-naïve PM-PC (n=10), and Controls (n=10). Profiling of 800 mRNAs was performed (NanoString nCounter, PanCancer Immuno-Oncology 360 (IO-360) and 30 additional stroma-related mRNAs). Results: Regression vs. PM-PC identified six up-regulated and 197 down-regulated mRNAs (FDR≤0.05), linked to TNF-α signaling via NF-kB, G2M checkpoint, epithelial-mesenchymal transition, estrogen response, and coagulation. Regression vs. Controls identified 43 significantly up-regulated mRNAs, linked to interferon-α response, and down-regulation of 99 mRNAs, linked to TNF-α signaling via NF-kB, inflammatory response, epithelial-mesenchymal transition, KRAS signaling, and hypoxia (FDR≤0.05). Conclusions: In regressive fibrosis of PM-PC after systemic chemotherapy and PIPAC (Regression), downregulation of mRNAs related to key tumor biological pathways was identified. Regression also showed transcriptional differences from unspecific, benign fibrosis (Controls). Future studies should explore whether mRNA profiling of PBs with PM from PC or other primaries holds prognostic or predictive value.

Effect of surgery versus chemotherapy in pancreatic cancer patients: a target trial emulation.

PURPOSE: To estimate the causal effect of surgery vs chemotherapy on survival in patients with T1-3NxM0 pancreatic cancer in a rigorous framework addressing selection bias and immortal time bias. METHODS: We used population-based Danish healthcare registries to conduct a cohort study emulating a hypothetical randomized trial to estimate the absolute difference in survival, comparing surgery with chemotherapy. We included pancreatic cancer patients diagnosed during 2008-2021. Exposure was surgery or chemotherapy initiated within a 16-week grace period after diagnosis. At the time of diagnosis, data of each patient was duplicated; one copy was assigned to the surgery protocol and one copy to the chemotherapy protocol of the hypothetical trial. Copies were censored when the assigned treatment deviated from the observed treatment. To account for informative censoring, uncensored patients were weighted according to confounders. For comparison, we also applied a more conventional analysis using propensity score-based inverse probability weighting. RESULTS: We included 1,744 patients with a median age of 68 years; 73.6% underwent surgery and 18.6% had chemotherapy without surgery. 7.8% received no treatment. The 3-year survival was 39.7% (95% CI 36.7% to 42.6%) after surgery and 22.7% (95% CI: 17.7% to 28.4%) after chemotherapy, corresponding to an absolute difference of 17.0% (95% CI: 10.8% to 23.1%). In the conventional survival analysis, this difference was 23.0% (95% CI: 17.0% to 29.0%). CONCLUSION: Surgery was superior to chemotherapy in achieving long-term survival for pancreatic cancer. The difference comparing surgery and chemotherapy was substantially smaller when using the clone-censor-weight approach than conventional survival analysis.

Prognostic value of margin clearance in total and distal pancreatectomy specimens with pancreatic ductal adenocarcinoma in a Danish population-based nationwide study.

BACKGROUND: The prognostic role of resection margin status following total (TP) and distal (DP) pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) is insufficiently evaluated. In Denmark, pancreatic surgery, including the postoperative pathological examination of the resection specimens, is confined to four centres, all reporting to the Danish Pancreatic Cancer Database (DPCD). In this Danish population-based nationwide study on TP and DP for PDAC from 2015-2019, based on data from DPCD, we evaluated whether there is a prognostically relevant minimum margin clearance definition and whether certain margins hold independent prognostic information. METHODS: Clinical and pathological data were retrieved from DPCD and supplemented by review of pathology reports and re-microscopy, if needed. One of the study pathologists performed all re-microscopy. The prognostic significance of margin status was evaluated by dichotomisation of the TP cohort (n = 101) and the DP cohort (n = 90) into involved and uninvolved groups, using different clearance definitions (0.5 - ≥3.0 mm). RESULTS: Following TP, direct involvement of the superior mesenteric artery (SMA) margin had independent prognostic value. When using a clearance definition of ≥ 0.5 or ≥ 1.5 mm for SMA, median survival for R0 versus R1 was 19 (95% CI 14-26) versus 10 (95% CI 5-20) months (p = 0.010), and 21 (95% CI 15-30) versus 10 (95% CI 8-19) months (p = 0.011), respectively. Overall margin status was not of significant prognostic importance following neither DP nor TP. CONCLUSION: In this Danish population-based nationwide study, SMA margin involvement was a significant isolated prognostic factor following TP, whereas combined assessment of all circumferential margins did not hold statistically significant prognostic information. Following DP, resection margin status did not affect survival.