Pancreatic cancer cells rely on glutamine to sustain their survival in the stiff and poorly vascularized tumor microenvironment (TME). Inhibiting glutamic-oxaloacetic transaminase 1 (GOT1) is a strategy to target glutamine metabolism and impair cancer cell functions. However, it remains unclear how cellular and extracellular elements of the TME respond to GOT1 inhibition. We engineered a pancreatic TME model 'on a dish' and recreated the metabolic interactions. Stromal cells remodeled the extracellular matrix and upregulated metabolic programs, including glutamine metabolism, oxidative phosphorylation, and central carbon metabolism. Cell responses to GOT1 inhibition were modulated by TME elements, with reductions in cell viability and proliferation occurring only under tissue-like conditions. GOT1 inhibition altered matrix organization by upregulating different matrix-related proteins, while it did not enhance cell responses to cytotoxic drugs. Our findings uncover the metabolic crosstalk within the TME and show that metabolism-targeting treatments directly impact stromal elements of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is driven by genetic alterations in the pancreatic epithelium (e.g., KRAS) coupled with dysregulated innate immunity that triggers tumor-promoting chronic inflammation. However, the identity of innate immune molecular regulators as therapeutic targets in PDAC is ill-defined. Here, we show in PDAC patients that elevated tumoral expression of the inflammasome adaptor protein ASC and its downstream effector Caspase-1 is primarily colocalized to the pancreatic ductal epithelium and prognostic for poor survival. In the mutant Kras-driven KPC PDAC mouse model, global and conditional (pancreatic epithelial) ablation of ASC, or nanobody-mediated targeting of extracellular ASC, suppresses pancreatic tumorigenesis. Whole transcriptome profiling and multiplex immunofluorescence reveal that the tumor-promoting activities of epithelial-derived ASC align with molecular pathways for mitochondrial respiration, metabolism (glycolysis), and immune responses. Our discovery that ASC-containing inflammasomes promote PDAC by acting as a molecular bridge between innate immunity, mitochondrial dysfunction and metabolic reprogramming provides the rationale to therapeutically target ASC in cancers.

Background and study aims Pancreatic ductal adenocarcinoma (PDAC) is a poor prognostic malignancy. Comprehensive genomic profiling (CGP) has improved outcomes in many cancers, but widespread uptake in PDAC remains elusive. This study investigated the feasibility of using endoscopic ultrasound with fine-needle biopsy (EUS-FNB) for CGP in advanced PDAC. Patients and methods (experimental design) A multicenter prospective cohort study was conducted to assess the feasibility of using DNA and RNA extracted from fresh frozen or archival formalin-fixed paraffin-embedded (FFPE) EUS-FNB for CGP on advanced PDAC using the TSO-500 gene panel testing. Results of the CGP were reviewed at a molecular tumor board (MTB) and subsequent treatment recommendations were forwarded to the referring clinicians. Results CGP was successful in 129 of 143 patients (90%) enrolled between May 2020 to September 2023. Fresh frozen EUS-FNB provided suitable genetic material for CGP in 123 of 133 patients (92%). Conversely, CGP was successful on FFPE biopsy blocks from only six of 16 patients (38%). Fifty-two of 143 patients (36%) had a potentially targetable mutation detected, and eight of these patients (6%) were treated with targeted therapy based on their EUS-FNB-derived molecular profile. Patients who received personalized therapy had a significant ( P < 0.0001) increase in survival versus standard or no therapy at 12 and 36 months. Median patient survival on standard therapy was 9.47 months versus > 18 months for personalized therapy. Conclusions This real-world study confirms the feasibility and utility of CGP using EUS-FNB in advanced PDAC. It illustrates the importance of timely access to personalized therapy informed by CGP, which can impact the treatment pathway and improve survival outcomes.

BACKGROUND:Pancreatic cancer causes non-specific symptoms, potentially leading to delays in diagnosis. Decision support tools may help primary care practitioners to triage patients for pancreatic imaging. AIM:To investigate the sensitivity of three different tools for identifying patients who may have pancreatic cancer. DESIGN & SETTING:An observational study in Australia. METHOD:We investigated the performance of the Risk Assessment Tool (RAT) for pancreatic cancer, the QCancer® tool, and a tool developed through a consensus process led by QIMR Berghofer (the QPaC Tool). We applied these tools to people with pancreatic cancer who were interviewed about their symptoms on first presentation to a clinician. We designated patients as 'flagged' by each tool if they met specific criteria, and calculated the percentage flagged (that is, the sensitivity). Participants with jaundice were excluded from analyses of QCancer®. RESULTS:We included 190 participants in analyses of the RAT and QPaC Tool (142 in analyses of QCancer®). The sensitivity of the QPaC Tool and the RAT were 54% and 27%, respectively. QCancer® had a sensitivity of 14%, at a probability threshold of 1%; in the same 142 participants, QPaC and the RAT flagged 44% and 7%, respectively. CONCLUSION:The QPaC Tool was the most sensitive, largely owing to its inclusion of severe epigastric pain and emphasis on diabetes, but it has unknown specificity. More research is needed to determine whether any tool could reduce delays in diagnosis; in the interim, the QPaC Tool may support clinicians to consider pancreatic cancer in their differential diagnoses.

BACKGROUND:As obesity becomes more common, understanding its risks in routine operations is increasingly important. This study assessed the impact of obesity on intraoperative complications during elective laparoscopic cholecystectomy. METHODS:Retrospective data on elective laparoscopic cholecystectomies across a single metropolitan health network were collected from July 2021-June 2023. Patients were stratified into WHO-defined obesity classes. Intraoperative complication (measured by ClassIntra classification), intraoperative and postoperative outcomes were compared. RESULTS:There were 713 patients included. Intraoperative complications graded as ClassIntra 1 and 2 were 11.0% and 6.1% for non-overweight patients and rose to 35.3% and 13.2% respectively for class III obesity (p < 0.001). Increasing obesity class was independently associated with higher intraoperative complication severity, with a 2.59-fold increase in the odds of a more severe complication category per class increase (p < 0.001). Obesity was associated with increased operative duration (p = 0.006) but did not increase the risk of postoperative morbidity (p = 0.88). CONCLUSION:Obesity significantly increases the risks of intraoperative complications in patients undergoing elective cholecystectomy, as measured by the ClassIntra classification, and contributes to increased operative duration. Despite this, postoperative morbidity remains low with no significant difference in length of stay, complications or readmissions across obesity classes.

Background/Objectives: Circulating tumour DNA (ctDNA) assays enable non-invasive assessment of tumour burden and treatment response in oncology. However, quantitative ctDNA outputs (such as variant allele frequency, tumour fraction, and aggregate burden scores) remain difficult to interpret and compare across platforms. This evidence-mapping review evaluates current quantitative reporting approaches in pancreatic ductal adenocarcinoma (PDAC) and examines the potential role of KRAS mutant ctDNA as a biologically grounded reference metric. Methods: A systematic literature search was conducted across PubMed/MEDLINE and Scopus to identify studies reporting quantitative ctDNA metrics in PDAC. Eligible studies included those measuring plasma KRAS mutations and/or reporting variant allele frequency, tumour fraction, or multi-locus aggregate metrics. Additional relevant primary studies identified through broader manual searching of PubMed were assessed against the same prespecified eligibility and classification criteria before inclusion. Data were synthesised narratively, focusing on reporting frameworks, units of measurement, assay characteristics, and the interpretability of quantitative outputs across platforms. Results: Substantial heterogeneity was observed in ctDNA quantification methods and reporting standards. Ratio-based metrics such as variant allele frequency and tumour fraction were commonly used but varied according to assay design, plasma input volume, and background cell-free DNA levels. Few studies reported absolute mutant molecule counts per unit volume. Given that approximately 90-95% of PDACs harbour truncal activating KRAS mutations, plasma KRAS was consistently represented across platforms and demonstrated potential as a shared quantitative anchor. Limited standardisation was noted in distinguishing detectability from quantifiability based on sampling depth and counting statistics. Conclusions: Current ctDNA reporting in PDAC lacks a shared quantitative reference, limiting cross-study comparability. Reporting KRAS mutant molecules per millilitre and adopting an assay-agnostic framework distinguishing detection from quantification may improve interpretability, support harmonisation across platforms, and facilitate cumulative learning in pancreatic cancer ctDNA research.

BACKGROUND:This meta-analysis aimed to evaluate the association between distinct KRAS mutations and overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS:A comprehensive literature search was conducted across major databases to identify studies reporting hazard ratios (HRs) and 95% confidence intervals (CIs) for OS associated with key KRAS mutations (G12D, G12R, and G12V) in PDAC patients, from inception until January 2025. Subgroup analyses were carried out based on disease stage (resectable and borderline resectable as early-stage disease and locally advanced and metastatic as late-stage disease) and treatment approaches (operation, chemotherapy, or combination of both). RESULTS:KRAS G12D mutation was significantly associated with poor OS (HR = 1.64, 95% CI: 1.28-1.99, p < 0.05). In subgroup analysis, G12D mutation was significantly associated with poor OS in those receiving chemotherapy (HR = 1.29, 95%CI: 1.18-1.39, p < 0.05) and in those with late-stage disease (HR = 1.29, 95%CI: 1.18-1.39, p < 0.05). G12R was significantly associated with improved OS in patients receiving chemotherapy (HR = 0.74, 95% CI: 0.56-0.99, p = 0.042). G12V had a significant association with improved OS in patients with early-stage disease (HR = 0.67, 95% CI: 0.52-0.86, p = 0.002). CONCLUSIONS:The study highlights the heterogeneous prognostic impact of KRAS mutations in PDAC. These findings suggest that the prognostic relevance of KRAS mutations in PDAC may depend on clinical factors such as treatment modality and disease stage.

Despite guidelines, enteral tube feeding is not routinely provided to advanced upper gastrointestinal (UGI) cancer patients who cannot consume adequate nutrition and who have an expected survival of at least 3 months. This review examined its effect on nutrition status, survival, and quality of life (QOL) in these patients. Five databases (CINAHL, Cochrane, Embase, Ovid, Web of Science) were searched for original research on nutrition, survival, and/or QOL outcomes in adults with inoperable UGI cancers receiving enteral tube feeding. Quality was assessed using the Academy of Nutrition and Dietetics Quality Criteria Checklist: Primary Research, and a narrative synthesis was conducted. Five studies were eligible for inclusion, most participants were male (n = 205), with low sample sizes across all studies (n = 16–131). Enteral tube feeding resulted in a similar proportion of participants with weight loss above or below 5

BACKGROUND:Evidence shows that high body mass index (BMI) contributes to increased postoperative complications in gastrointestinal surgery and suggests that it may contribute to intraoperative adverse events. We primarily aimed to determine if high BMI results in increased intraoperative adverse events in liver resections using the ClassIntra classification. METHODS:A retrospective audit of liver resections under a single adult Hepatobiliary unit was performed from February 2018 to October 2023. We compared intraoperative adverse events and postoperative complications between BMI groups ('Normal/low' BMI < 25, 'Overweight' BMI 25-30 and Obese > 30). Resections were divided by complexity into minor, intermediate and major resections by extent of liver resection. RESULTS:One hundred and ninety-nine patients were included in the analyses. Higher BMI was associated with a significantly greater proportion of intraoperative complications using the ClassIntra classification (p = 0.022). At least one intraoperative complication was sustained by 33.3% and 38.2% of overweight and obese patients, respectively, compared to 19.1% in normal/low weight individuals. There were no differences in other intraoperative or postoperative outcomes or complications with a higher BMI, including estimated blood loss, morbidity by Clavien-Dindo classification, 30-day readmission or mortality. Multivariate analysis showed that BMI class and diabetes status were significantly related to higher ClassIntra complication level (p = 0.0086). CONCLUSION:Higher BMI is associated with increased rates of intraoperative adverse events during liver resection surgery, by measure of ClassIntra classification. Prospective standardised assessment of intraoperative complications is required to confirm these findings.

OBJECTIVES:Low skeletal muscle index (SMI) and radiodensity (SMD) are established prognostic indicators in cancer. This study investigated risk factors for low and decreasing SMI and low SMD in upper gastrointestinal cancer and examined the influence of malnutrition risk on the association between SMI and health-related quality of life (HRQOL). DESIGN:Longitudinal analysis of randomised controlled trial outcome data. SETTING:Three health services in Victoria, Australia. PARTICIPANTS:Adults newly diagnosed with oesophageal, gastric or pancreatic cancer. MEASUREMENTS:Outcomes assessed at diagnosis, and three- and six-month follow-up. SMI and SMD were assessed via computed tomography imaging analysis, with low values determined using established sex-specific thresholds. Malnutrition risk was assessed using the Patient Generated Subjective Global Assessment (Short Form), and HRQOL with the EORTC QLQ-C30. Multiple logistic regression identified risk factors for low SMI and low SMD at baseline, and SMI decline (≥5%) from baseline to 3 months. Associations between SMI and HRQOL were examined using multiple linear regression, adjusting for malnutrition risk. RESULTS:Among 105 participants (43% oesophageal, 20% gastric, 37% pancreatic cancer), older age predicted low SMI and low SMD. Low SMI risk was higher in females and lower with higher BMI. At three months, 57% (37/65) experienced ≥5% SMI loss, associated with higher malnutrition risk, higher baseline SMI, and post-diagnosis weight loss. Malnutrition risk was a strong independent predictor of poorer HRQOL score at all timepoints. Lower or decreasing SMI (≥5%) was also independently associated with poorer HRQOL on some scales. CONCLUSION:Malnutrition risk independently predicted lower HRQOL and muscle loss, and may confound the relationship between SMI and HRQOL. As a modifiable factor, addressing malnutrition risk could improve HROQL and preserve muscle in upper gastrointestinal cancer. TRIAL REGISTRATION:Australian New Zealand Clinical Trials Registry, 27 January 2017 (12617000152325).

Assess anticoagulation practice and portal vein thrombosis (PVT) risk following pancreaticoduodenectomy (PD) or total pancreatectomy (TP) with venous resection (VR). Retrospective studies suggest an increased risk of PVT following PD/TP with VR. However, anticoagulation practice is variable and its efficacy at preventing PVT is unknown. This multicentre cohort study (Europe, USA, Mexico, Turkey, Australia, New Zealand) included consecutive patients undergoing PD/TP with VR between 2018-2022. A 1:1 age and sex matched cohort undergoing PD/TP without VR was also collected to assess PVT risk without VR. Among 972 patients who underwent PD/TP with VR, 259 (26.6%) received inpatient therapeutic anticoagulation and 242 (25.0%) were discharged on therapeutic anticoagulation. Thirty-day, 90-day and one-year PVT risk following VR was 5.1%, 7.3%, and 11.6%, versus 1.0%, 1.3% and 2.6% in patients without VR (P<0.001). Predictors of 90-day PVT included prior history of venous thromboembolism (odds ratio [OR] 2.67), VR type (OR 2.29, 6.28, 6.90 and 23.75 for type 1-4 VR, P<0.001) and graft material (OR 0.78, 0.94, 5.28, 4.90 and 5.99 for peritoneal, autologous vein, cadaveric vein, bovine and synthetic grafts, P<0.001). Postoperative therapeutic anticoagulation reduced 30-day PVT risk (OR 0.06, P<0.001), but not 90-day (OR 0.06, P=0.075) or >90-day PVT risk (OR 1.23, P=0.466). The strongest predictor of >90-day PVT was cancer recurrence (OR 3.96, P<0.001). VR increases PVT risk following PD/TP, with technical factors influencing <90-day PVT and cancer-related factors influencing >90-day PVT. The benefits of early postoperative anticoagulation in preventing PVT post-VR remain unclear.

Background: Pancreatoduodenectomy with venous resection (PDVR) may be performed to achieve tumour clearance in patients with a pancreatic ductal adenocarcinoma (PDAC) with venous involvement. This study aimed to evaluate the impact of PDVR on PDAC outcomes. Methods: In total, 435 PDAC patients with either R0 status (n = 322) or R1 status within the superior mesenteric vein groove (n = 113) were extracted from the Recurrence After Whipple’s (RAW) study dataset. PDVR patients were matched in a 1:2 ratio with standard PD patients. Comparisons were then made between the two groups (surgical radicality and survival). Results: A total of 81 PDVRs were matched with 162 PDs. Neoadjuvant chemotherapy (5.7% vs. 13.6%, p = 0.032) and R1 resection rates (17.9% vs. 42%, p < 0.001) were higher in the PDVR group. Risk factors for R1 resection included venous resection (p < 0.001 for sleeve and p = 0.034 for segmental resection), pT3 (p = 0.007), and pN1 stage (p = 0.045). PDVR patients had lower median overall survival (OS, 21 vs. 30 months (m), p = 0.023) and disease-free survival (DFS, 17 m vs. 24 m, p = 0.043). Among PDVR patients, R status did not impact on OS (R0: 23 m, R1: 21 m, p = 0.928) or DFS (R0: 18 m, R1: 17 m, p = 0.558). Irrespective of R status, systemic recurrence was higher in the PDVR group (p = 0.034). Conclusions: Independent of R status, the PDVR group had lower overall survival and higher systemic recurrence rates.

BACKGROUND:Postoperative pancreatic fistula (POPF) is the primary cause of morbidity after distal pancreatectomy (DP). This trial investigated the application of a combined polyethylene glycol (PEG) and recombinant human albumin sealant gel to the stapled, transected pancreatic margin to reduce clinically significant POPF. METHODS:A multicenter randomised controlled trial in patient candidates for DP with stapled transection was conducted. Participants were randomised to receive DP with or without PEG sealant applied to the stapled margin. The primary outcome was clinically significant POPF. Secondary outcomes included other complications, length of hospital stay and 90-day mortality. RESULTS:Seventy-eight patients with completed DP were included, 38 of whom underwent stapled DP combined with the use of PEG sealant (PEG group). No significant differences between the two groups were observed with respect to pathology type, operative approach or operative time. The PEG group exhibited significantly fewer complications (18% vs. 50% in the control group; p = 0.003), and a lower rate of POPF (11% vs. 28%; p = 0.08, respectively). Multivariate analysis revealed a significant association between spleen preservation and the rate of clinically significant fistula (OR 4.4; 95% CI 1.1-18.0; p = 0.038). The rate of POPF was lower in the PEG group but did not reach statistical significance (OR 0.3; 95% CI 0.1-1.2; p = 0.091). CONCLUSION:Stapled DP combined with PEG application was associated with reduced complications. There was a lower rate of POPF in the PEG sealant group that did not reach statistical significance. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY:ACTRN12620001336976p.

Colonic complications secondary to acute pancreatitis (AP) are rare. Management of these pathologies is inconsistent and non-standardized because of their rarity. A retrospective review was performed for patients admitted to our health network with colonic complications secondary to AP from 1st January 2009 to 31st December 2023. 13 patients were admitted at Monash Health between January 2009 and December 2023 for a colonic complication secondary to AP. One had a bowel obstruction secondary to retroperitoneal compression, four had pancreatic-colonic fistulas, three had colonic infarction, two presented with colonic perforation while three presented with obstructive colonic strictures. The most common aetiology was gallstone pancreatitis (n=4). Initial management for colonic fistulas and strictures were commonly with a diverting loop ileostomy, while perforations/necrosis required emergent colectomies with or without diverting stomas. Colonic fistulas in AP can be managed safely with a diverting loop ileostomy to delay or avoid the need for a major resection during the acute phase. However, emergency colonic resection should be performed in the case of colonic perforation or necrosis and is associated with worse outcomes.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal prognosis. Molecular profiling to improve the diagnosis and management of PDAC holds promise for informing more targeted therapies such as Kirsten rat sarcoma viral oncogene homologue (KRAS) G12C inhibition to deliver better outcomes for these patients. In this report, we present two patients with advanced PDAC with KRAS G12C mutations who achieved remarkable disease control and prolonged survival following treatment with the KRAS G12C inhibitor D1553 (garsorasib). Case 1, a 74-year-old woman with recurrent PDAC post-surgical resection and chemotherapy, exhibited a significant biochemical and radiologic response upon initiation of targeted therapy. Case 2, a 75-year-old woman initially treated with Folinic acid, fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) and stereotactic body radiotherapy (SBRT), demonstrated sustained disease stability for over three years on KRAS G12C inhibitor therapy. Both patients maintained excellent performance status with minimal treatment-related toxicity. These cases underscore the potential of KRAS-directed therapies in PDAC and illustrate the importance of molecular profiling in identifying eligible patients. The findings support further investigation into the durability of KRAS G12C inhibition, resistance mechanisms, and combination treatment strategies to optimize patient outcomes.