Abstract Introduction The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor. Tumour location within the pancreas may influence resectability, metastatic patterns, and survival, potentially reflecting underlying biological differences. This retrospective study aimed to evaluate differences in protein expression between tumours of the pancreatic head and body–tail, and their associations with survival. Methods Tissue microarray specimens from 144 patients who underwent resection for PDAC were analysed using immunohistochemistry for 15 protein markers identified from prior mass spectrometry studies of proteins upregulated in pancreatic cancer. Differences in protein expression by tumour location were examined using linear regression adjusted for age, sex, AJCC 8th edition stage, and tumour differentiation. Survival was analysed using Cox proportional hazards regression with the same covariates plus adjuvant therapy. Results Body–tail tumours (n = 24) demonstrated significantly higher YAP1 expression than head tumours (n = 120), with an adjusted mean H-score difference of 30 points (95% confidence interval 1.8 to 62; P = 0.005). Body–tail location was associated with significantly worse overall survival (hazard ratio 2.0, 95% confidence interval 1.1 to 3.6; P = 0.020). Discussion PDAC arising in the pancreatic body–tail exhibited distinct protein expression patterns and was associated with worse survival compared with head tumours. Increased YAP1 expression may reflect location-specific tumour biology and a more aggressive disease phenotype.

Background:Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic stroma, which plays a crucial role in tumor biology and treatment resistance. While the stromal compartment is a defining histopathological feature of PDAC, its prognostic significance remains incompletely understood. This study aimed to quantify the stromal content in PDAC using digital pathology and evaluate its association with patient outcomes. Methods:Tissue microarrays (TMAs) were constructed from resected PDAC specimens (n = 142). Digital analysis of tumor stroma percentage (TSP) was performed on tissue sections labeled with CA19-9. Cases were stratified into low and high TSP groups based on an optimized threshold of 44.2%. Associations between TSP and clinicopathological variables were assessed, and survival outcomes were analyzed using Kaplan-Meier and Cox proportional hazards models. Results:Digital quantification revealed wide intertumoral variability in TSP. A total of 127 (89%) patients were categorized into the high TSP group (>44.2% stroma). A high TSP was significantly associated with anatomic location of the tumor in the head of the pancreas. Patients with high TSP exhibited significantly prolonged overall survival (median: 27.8 months vs 12 months, p < 0.001). In multivariable analysis, high TSP remained an independent predictor of favorable prognosis (HR = 0.26, 95% CI: 0.13-0.52, p < 0.001). Conclusion:A high TSP is independently associated with improved survival in PDAC. These findings challenge traditional views of the stroma as purely tumor-promoting and suggest a potential protective role of the stromal compartment in certain contexts.

Background In epidemiological and outcomes research, “pancreatic cancer” is frequently used interchangeably with pancreatic ductal adenocarcinoma (PDAC), the most common and most lethal pancreatic cancer subtype. However, relying solely on an anatomic site code may capture a mix of pancreatic tumor types with better prognoses than PDAC, leading to inflated survival estimates. Methods We used the Surveillance, Epidemiology, and End Results (SEER) registry to compare data derived from site-only case ascertainment (C25.x, excluding C25.4) versus histologically confirmed PDAC using ICD-O-3 morphology codes. Only microscopically confirmed cases were included. We quantified differences in patient demographics, tumor characteristics, and overall survival between the two case-selection strategies. Survival estimates were generated using Kaplan-Meier methods and multivariable Cox regression models. Results A total of 283,465 patients with C25 tumors (excluding C25.4) were identified. Based on morphology coding, 233,421 (82.3%) tumors were classified as PDAC and 50,044 (17.7%) as non-PDAC histology. The 5-year survival rate in the C25 cohort (excluding C25.4) was 12.1%, whereas survival among PDAC patients alone was 6.0%. For surgically resected patients, the 5-year survival rate in the C25 cohort (excluding C25.4) was 35.3%, compared to 21.0% for those with PDAC histology. In multivariable Cox regression analysis, PDAC histology was significantly associated with reduced overall survival (HR 2.57, 95% CI 2.54–2–61, p < 0.001). Conclusion Case definitions based on the C25 site code alone lead to overestimation of true PDAC survival. Histology-based selection is necessary for accurate research on PDAC, underscoring the importance of precise tumor classification in registry-based research.

Background/Aim:Pancreatic cancer is a highly aggressive disease, with limited prognostic tools available for risk stratification. This study aimed to evaluate the prognostic significance of nine tissue biomarkers and develop a biomarker-based risk score for predicting patient survival. Patients and Methods:Tumor samples from 141 resected patients with pancreatic cancer were analyzed with tissue microarrays and immunohistochemistry to assess the expression levels of CA 19-9, CA 50, CA 242, CA 724, GDF15, MMP7, MUC2, TFF1, and THBS2. A Lasso-Cox regression model was used to develop a prognostic risk score and the performance of the risk score was assessed using Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curves. Results:Among the nine biomarkers, CA19-9, CA50, CA242, CA724, and THBS2 were identified as significant predictors of survival in univariable analyses. A prognostic model was constructed and included CA19-9, CA724, THBS2, tumor location, resection margin status, grade, and American Joint Committee on Cancer stage. The prognostic risk score effectively stratified patients into high- and low-risk groups, demonstrating a significant difference in median survival (14.8 vs. 36.0 months) and 5-year survival (5.9% vs. 26.0%) (p<0.001). The model achieved good predictive performance for long-term survival with an AUC of 0.704. Conclusion:This study identifies several tissue biomarkers associated with survival and introduces an integrative risk model to stratify pancreatic cancer patients by outcomes. The model shows good discriminatory ability and may provide a basis for more personalized risk assessment and treatment planning, although additional validation is required.

Background:Pancreatic cancer continues to retain the highest mortality rate among all major organ cancers. New strategies for early detection are being proposed to increase long-term survival. A plethora of molecular markers are discovered yearly, but so far none have demonstrated screening utility. Summary:Promising discovery technologies include affinity-based proteomics and ddPCR. In the validation phase, researchers must decide on key benchmark criteria, what type of pancreatic lesions are desirable to find early through molecular screening, and when to terminate the biomarker study and return to the discovery phase. If the biomarkers meet set benchmarks, retrospective analysis should be conducted in relevant cohorts based on intended use, followed by prospective real-world evaluation. Lastly, regulatory approval, incorporation into clinical practice guidelines, and thorough health economic evaluations must be completed before the screening markers can be fully implemented. Key Messages:In this review, important strategies and phases for molecular biomarker development in pancreatic cancer have been outlined.

Pancreatic cancer continues to be a major cause of cancer deaths worldwide. Characterizing the tumors of long-term survivors (≥5 years survival) would create opportunities in prognostic and therapeutic strategies. In this study, RNA sequencing data was used to identify differentially expressed genes (DEGs) in tumors of long-term survivors (LTS) vs short-term survivors (STS). Using LASSO-Cox regression, 4 prognostic DEGs, along with tumor stage, were utilized to develop a model for identifying high- and low-risk tumors. In Kaplan-Meier survival analysis, the high-risk group had significantly worse prognosis in both the training and validation cohorts. Using KEGG pathway gene signature sets, the high-risk group was found to have amplification of pathways, such as focal adhesion and ECM receptor interaction. The low-risk group, meanwhile, showed upregulation of specific metabolic pathways. Using ESTIMATE analysis, the high-risk group was found to have more stromal cell infiltration. Increased unpolarized macrophages and decreased inflammatory/anti-tumoral macrophages were also found in the high-risk group. Lastly, drug sensitivities were calculated and found to be generally higher in the high-risk group. This study reveals a model for predicting survival and drug sensitivity in pancreatic cancer. Genetic, molecular and tumor microenvironment characteristics of tumors from LTS and STS have been identified, highlighting opportunities for further research.

The modern use of neoadjuvant and conversion systemic therapy in patients with colorectal cancer liver metastasis (CRLM) has improved resection rates and changed the borders between “resectable” and “unresectable” disease. Also, the use of preoperative systemic therapy has resulted in an increased frequency of disappearing liver metastasis (DLM). The optimal management of DLM is still controversial. In this review, we explore the current literature and highlight key findings relating to the tumor biology, diagnosis and treatment options of DLM. The definition of DLM should be based on hepatobiliary contrast MRI, which is the most sensitive preoperative imaging method. Patients with DLM are younger and more often have normalized their CEA-levels, and they have a better survival than those without DLM, likely reflecting favorable tumor biology and effective treatment response. Recent data indicate that molecular profiling (e.g. APC mutations) may predict CRLM at highest risk for vanishing after chemotherapy. However, just because the lesion has disappeared on imaging does not mean that there is a complete histopathological response. However a “watch and wait” strategy for patients with DLM is not associated with a reduced survival compared to resected DLM, but may be associated with a higher rate of recurrence often available for “rescue therapy”, i.e. ablation or resection at the time when DLM recur and become visible. Furthermore, very few of “blind resections” of DLM contain viable tumor cells. International surveys among practicing hepatobiliary surgeons have revealed a widespread variation in the clinical management of DLM. In the future, biopsy and sequencing of metastases may be considered for therapeutic decision making in patients with CRLM considering the intricate tumor heterogeneity and clonal evolution of the disease.

BACKGROUND/AIM:To select and stratify patients for optimal treatment plans is challenging. Identification of cancer-related biomarkers that serve as predictors for prognosis and treatment response is essential to better predict treatment outcome and find future targets for therapy. Previous data has suggested ARHGAP4 as a relevant biomarker in colorectal cancer (CRC). The purpose of this study was to assess how ARHGAP4 expression affected patients undergoing surgery for colon liver metastasis (CLM) in terms of overall survival (OS).PATIENTS AND METHODS:A total of 251 patients undergoing resection of CLM from 2006 to 2017 were included. Corresponding resected tumor specimens were examined for ARHGAP4 expression levels by immunohistochemistry (IHC). The correlation between ARHGAP4 expression and postoperative survival was analyzed.RESULTS:High expression levels of ARHGAP4 were seen in 60% of patients. High expression levels of ARHGAP4 were correlated with adverse prognosis after hepatectomy due to CLM. Survival data generated using Cox proportional hazard model showed a statistically significant difference between high and low ARHGAP4 expression groups by univariate (HR=1.5, 95% CI=1.1-2.2) and multivariate (HR=1.5, 95% CI=1.0-2.1) analysis. In multivariate Cox regression, high ARHGAP4 expression, preoperative CEA levels and presence of vascular invasion by pathological examinations were independent predictive factors of overall survival.CONCLUSION:ARHGAP4 is a novel prognostic biomarker after resection of CLM.

The management of patients with suspicion of acute appendicitis is among the diagnoses young surgeons are supposed to master early in the career. The primary management of this large group of patients has to be based on the information from anamnesis, clinical signs, and basic laboratory examinations. The correct evaluation of the diagnostic value associated with each of these sources of information is not easy for an inexperienced surgeon. Some surgeons give too much attention to some less important factors, whereas other very important factors are not even looked at. An increased usage of diagnostic imaging may seem a possibility to cover up for deficient quality in the surgeon's primary clinical diagnostic ability. However, the unselected use of diagnostic imaging may give high rates of false-positive diagnoses in low-risk patients and may not help in the decision in high-risk patients. The risk of exposure to ionizing irradiation should also not be underestimated. The increased use of diagnostic imaging has also led to an increased incidence of appendicitis due to the increased detection of appendicitis that was previously allowed to resolve spontaneously.1, 2 The management of patients with suspicion of appendicitis can be improved considerably by the use of diagnostic scoring systems with the Alvarado and the Appendicitis Inflammatory Response (AIR) scores being the most cited. Based on such scores, objective clinical decision rules can be defined for a risk stratified management which can guide even an experienced surgeon. As an example, the AIR score performed just as well as an experienced surgeon in a head-to-head study.3 Patients with low risk (e.g., AIR score <4) can be safely observed, eventually at home, with a follow-up the next day.4 For patients with high risk (e.g., AIR score >8), a diagnostic laparoscopy can be the next step as imaging can seldom rule out appendicitis in patients at high risk. The AIR score is recommended in the World Society of Emergency Surgery Jerusalem guidelines for the diagnosis and treatment of acute appendicitis5 and is the recommended scoring system in the coming National Swedish Guidelines for the management of suspected appendicitis. Therefore, knowledge of any of the modern appendicitis scoring system should be obligate part of the curriculum for surgeons in training. From this perspective, the survey of Danish surgeons in training reported in this issue of the World Journal of Surgery gives a depressing impression.6 About half of the surgeons did not know about the existence of clinical scoring systems, and only 25% had ever used them. Reasons for this was simply unfamiliarity and to a lesser degree lack of trust. This lack of trust was evident when asked about how to handle a patient with a score indicating a high risk of appendicitis, a situation in which diagnostic laparoscopy is the recommended next step. However, in this situation, most of these young surgeons would trust their own intuition and not plan for a diagnostic laparoscopy. This shows an important deficiency in the training of these Danish surgeons. The responsibility for this must lie on those responsible for planning the curriculum and training of young surgeons. Roland E. Andersson: Conceptualization; writing—original draft; writing—review and editing. The authors declare no conflicts of interest.

Anoikis is programmed cell death occurring upon cell detachment from the extracellular matrix. Cancer cells need to evade anoikis to be able to metastasize to distant sites. However, the molecular features and prognostic value of anoikis-related genes (ARGs) in pancreatic cancer remain unclear. In this study, we utilized transcriptome data from the TCGA and GSE102238 databases to identify 64 ARGs significantly associated with prognosis. We used the “ConsensusClusterPlus” R package to stratify patients into high and low-risk prognostic subgroups. The KEGG and GSEA analyses revealed that the clusters with poor prognosis were enriched for the ECM receptor interaction pathway, the TP53 signaling pathway, and the galactose metabolism pathway, and that the cell cycle pathway was upregulated. A prognostic model consisting of seven ARGs (SERPINE1, EGF, E2F1, MSLN, RAB27B, ETV7, MST1) was constructed using LASSO regression and when combined with clinicopathological parameters using Cox regression, a prognostic Nomogram was created, which demonstrated high prognostic utility. Among the biomarker candidates, we report ETV7 as a novel, independent prognostic marker in pancreatic cancer. ETV7 was highly expressed in KRAS and TP53 co-occurrent mutant TCGA patients, indicating that it may be regulated by the two major driver genes of pancreatic cancer.Therefore, targeting ETV7 could be a potential focus for future therapeutic studies.

Inflammation, apoptosis and oxidative stress play crucial roles in the deterioration of severe acute pancreatitis-associated acute respiratory distress syndrome (SAP-ARDS). Unfortunately, despite a high mortality rate of 45 %[1], there are limited treatment options available for ARDS outside of last resort options such as mechanical ventilation and extracorporeal support strategies[2]. This study investigated the potential therapeutic role and mechanisms of AQP9 inhibitor RG100204 in two animal models of severe acute pancreatitis, inducing acute respiratory distress syndrome: 1) a sodium-taurocholate induced rat model, and 2) and Cerulein and lipopolysaccharide induced mouse model. RG100204 treatment led to a profound reduction in inflammatory cytokine expression in pancreatic, and lung tissue, in both models. In addition, infiltration of CD68 + and CD11b + cells into these tissues were reduced in RG100204 treated SAP animals, and edema and SAP associated tissue damage were improved. Moreover, we demonstrate that RG100204 reduced apoptosis in the lungs of rat SAP animals, and reduces NF-κB signaling, NLRP3, expression, while profoundly increasing the Nrf2-dependent anti oxidative stress response. We conclude that AQP9 inhibition is a promising strategy for the treatment of pancreatitis and its systemic complications, such as ARDS.

OBJECTIVE:To validate the International Study Group for Pancreatic Surgery (ISGPS) definition and grading system of post-pancreatectomy acute pancreatitis (PPAP) after pancreatoduodenectomy (PD). BACKGROUND:In 2022, the ISGPS defined PPAP and recommended a prospective validation of its diagnostic criteria and grading system. METHODS:This was a prospective, international, multicenter study including patients undergoing PD at 17 referral pancreatic centers across Europe, Asia, Oceania, and the United States. PPAP diagnosis required the following 3 parameters: (1) postoperative serum hyperamylasemia /hyperlipasemia (POH) persisting on postoperative days 1 and 2, (2) radiologic alterations consistent with PPAP, and (3) a clinically relevant deterioration in the patient's condition. To validate the grading system, clinical and economic parameters were analyzed across all grades. RESULTS:Among 2902 patients undergoing PD, 7.5% (n=218) developed PPAP (6.3% grade B and 1.2% grade C). POH occurred in 24.1% of patients. Hospital stay was associated with PPAP grades [no POH/PPAP 10 days [interquartile range (IQR): 7-17] days, grade B 22 days (IQR: 15-34) days, and grade C 43 days (IQR: 27-54) days; P <0.001], as well as intensive care unit admission (no POH/PPAP 5.4%, grade B 12.6%, grade C 82.9%; P <0.010), and hospital readmission rates (no POH/PPAP 7.3%, grade B 16.1%, grade C 18.5%; P <0.05). Costs of grade B and C PPAP were 2 and 11 times greater than uncomplicated clinical courses, respectively ( P <0.001). CONCLUSIONS:This first prospective, international validation study of the ISGPS definition and grading system for PPAP highlighted the relevant clinical and financial implications of this condition. These results stress the importance of routine screening for PPAP in patients undergoing PD.

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.

PURPOSE:Pancreatic ductal adenocarcinoma (PDAC) can be classified into distinct histological subtypes based on the WHO nomenclature. The aim of this study was to compare the prognosis of conventional PDAC (cPDAC) against the other histological variants at the population level. METHODS:The Surveillance, Epidemiology and End Results (SEER) database was used to identify patients with microscopically confirmed PDAC. These patients were divided into 9 histological subgroups. Overall survival was assessed using the Kaplan-Meier method and Cox regression models stratified by tumor histology. RESULTS:A total of 159,548 patients with PDAC were identified, of whom 95.9% had cPDAC, followed by colloid carcinoma (CC) (2.6%), adenosquamous carcinoma (ASqC) (0.8%), signet ring cell carcinoma (SRCC) (0.5%), undifferentiated carcinoma (UC) (0.1%), undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) (0.1%), hepatoid carcinoma (HC) (0.01%), medullary carcinoma of the pancreas (MCP) (0.006%) and pancreatic undifferentiated carcinoma with rhabdoid phenotype (PUCR) (0.003%). Kaplan-Meier curves showed that PUCR had the worst prognosis (median survival: 2 months; 5-year survival: 0%), while MCP had the best prognosis (median survival: 41 months; 5-year survival: 33.3%). In a multivariable Cox model, several histological subtypes (i.e. CC, ASqC, SRCC, UCOGC) were identified as independent predictors of overall survival when compared to cPDAC. CONCLUSION:PDAC is a heterogenous disease and accurate identification of variant histology is important for risk stratification, as these variants may have different biological behavior.

BACKGROUND AND OBJECTIVE:Surveillance following resection with curative intent of pancreatic cancer varies widely, and supporting evidence is limited. Recurrence is although frequent, not at least during the first 2 years. Surveillance may be costly, but evidence on how this influences overall survival is not fully elucidated.METHODS, RESULTS:There are reports implying that signs of biological recurrence (increasing CA 19-9) precede radiologically demonstrated recurrence by months.CONCLUSIONS:The possibility of initiating salvage therapy earlier is discussed, potentially based on improved future biomarker panels.

"Acute pancreatitis – one key to early detection of pancreatic cancer?." Scandinavian Journal of Gastroenterology, ahead-of-print(ahead-of-print), pp. 1–2 Disclosure statementNo potential conflict of interest was reported by the author(s).Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.