Faculty Bibliography

INTRODUCTION/BACKGROUND:Current guidelines for treatment for locally advanced pancreatic cancer recommend chemotherapy ± radiation, or radiation alone when multimodal therapy is contraindicated. In a subset of patients, guideline-recommended treatment (GRT) achieves sufficient response to qualify for potentially curative resection. This study evaluated trends in treatment utilization and aimed to identify barriers to GRT. METHODS:Patients with clinical T4M0 disease in the National Cancer Database from 2010 to 2017 were included. Potential predictors were assessed by relative risk regression with Poisson distribution and compared by log-link function. RESULTS:In total, 28 056 patients met the criteria. Among 17 059 (67.67%) patients treated primarily with chemotherapy, 41.19% also had radiation and 8.89% went onto resection. Many received no cancer-directed treatment or failed to receive GRT. Another 710 patients had radiation (±surgery) without chemotherapy despite few contraindications to chemotherapy. Over time, patients were more likely to undergo resection after chemotherapy (aRR = 1.58; p < 0.0001) and less likely to have chemoradiation (aRR = 0.78; p < 0.0001) or go untreated (aRR = 0.90; p < 0.0001). Socioeconomic factors (race, education, income, and insurance status) affected the likelihood of receiving chemotherapy and surgery. Median overall survival (OS) was significantly improved for patients treated with chemotherapy and particularly in those patients who went on to receive RT or undergo surgical resection. OS was also longer for patients treated at high-volume academic centers. Patients insured by Medicaid, Medicare, or those without insurance had worse OS. CONCLUSIONS:Despite improvement over time, many patients go untreated. Clinical factors were influential, but the impact of vulnerable social standing suggests persistent inequity in access to care.

BACKGROUND/OBJECTIVES/OBJECTIVE:Overall survival for patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) remains limited, with a median survival of 12 to 15 months. Irreversible electroporation (IRE) is a local tumor ablation method that induces cancerous cell death by disrupting cell membrane homeostasis. The DIRECT Registry study was designed to assess the effectiveness and safety of IRE when combined with standard of care (SOC) treatment for Stage 3 PDAC versus SOC alone in a real-world setting after at least 3 months of induction chemotherapy; Methods: Patients with Stage 3 PDAC treated with IRE plus SOC or SOC alone were prospectively enrolled in a multicenter registry study. Enrollment required 3 months of active multi-agent chemotherapy with no progression before enrollment. Endpoints were 30- and 90-day mortality and adverse events (AEs). RESULTS:= 0.0066). All IRE procedures were performed using an open approach. The 90-day all-cause mortality was 5/83 (6.0%) and 2/27 (7.4%) for the IRE and SOC groups, respectively. Two subjects in the IRE group died from treatment-related complications, and one patient in the SOC group died due to chemotherapy-related complications. CONCLUSIONS:Initial results from the DIRECT registry study indicate the use of IRE for curative intent tumor ablation in combination with induction chemotherapy has equivalent morbidity and mortality rates when compared to standard-of-care chemotherapy alone.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations^1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants³. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS⁴. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

Resection of the celiac artery (CA) during surgery for locally advanced pancreatic cancer (LAPC) carries a significant risk of hepatic and gastric ischemia.^1,2 In addition, in the current context, where patients undergo intensive chemotherapy before surgery, a new complication has emerged: post-pancreatectomy liver injury (PPLI).³ PATIENT AND METHODS: A 59-year-old patient with biopsy-confirmed locally advanced pancreatic cancer arising from the pancreatic body (Video and Fig. 1) underwent extended neoadjuvant FOLFIRINOX (folinic acid [leucovorin], fluorouracil, irinotecan, and oxaliplatin). The patient was restaged using the A-B-C criteria,⁴ adding the target approach for anatomical feasibility,⁵ metabolic imaging, and survival prediction.⁶ Fig. 1 Preoperative planning and first operation: extended pancreatosplenectomy, including resection of the left adrenal gland and the celiac artery (CA) (Mayo Clinic class Ia), divestment of the superior mesenteric artery, and portal vein (PV)-superior mesenteric vein reconstruction using a left renal vein graft interposition (A and B). Abdominal phase computed tomography scan, axial view, showing the encasement of the CA but with a free proper hepatic artery (PHA) as a "suitable target" if needed. (C) Drawing of the tumoral involvement with CA encasement and left/anterior side of the superior mesenteric artery (SMA) abutment. PHA, gastroduodenal artery (GDA), and the biliary tract were free of tumor, allowing a Mayo Clinic class Ia CA resection. 15 mm was the distance measured from the tumor to the GDA, and 28 mm was the distance of SMA abutment on the left side. (D) Operative view highlighting the common hepatic artery (CHA) stump, the remnant head of the pancreas (HoP), the venous reconstruction with left renal vein interposition graft, SMA divestment, and the CA stump. IVC, inferior vena cava; LGA, left gastric artery; LGV, left gastric vein; LRV, left renal vein; SA, splenic artery; SMV, superior mesenteric vein PERIOPERATIVE MANAGEMENT: The patient underwent extended pancreatosplenectomy, including resection of the left adrenal gland and the CA (Mayo Clinic class Ia), divestment of the superior mesenteric artery, and portal-superior mesenteric vein reconstruction using a left renal vein graft interposition. Arterial reconstruction was initially deemed unnecessary, as proper hepatic artery flow was maintained-albeit dampened-via the gastroduodenal artery, confirmed by visual inspection and Doppler ultrasound. Postoperatively, the course was notable for a rapid rise in alanine aminotransferase levels without overt clinical or radiological deterioration (Fig. 2). Emergency re-exploration was undertaken with the objective of hepatic arterial revascularization (Fig. 3). We hypothesized that, in the setting of underlying metabolic dysfunction-associated steatotic liver disease, arterial inflow was insufficient to meet the demands of an already vulnerable parenchyma, with increased intrahepatic resistance further compounding ischemic liver injury consistent with clinically relevant (CR)-PPLI. Liver biopsy confirmed acute steatohepatitis and extensive ischemic necrosis. Fig. 2 Postoperative liver enzyme kinetics during the first postoperative week. Alanine aminotransferase (ALT) levels demonstrated a sharp and rapid increase from the day of surgery to postoperative day (POD) 2, leading to re-operation for a supercharged hepatic artery (HA) revascularization. Following revascularization, ALT levels decreased promptly, with complete normalization of liver biochemical parameters by POD 7. AST, aspartate aminotransferase; CAR, celiac artery resection; INR, international normalized ratio POD, postoperative day Fig. 3 Second surgical procedure: final reconstruction and liver biopsy. (A) Drawing of the final reconstruction with a zoom (B) on the arterial bypass between the right renal artery and the common hepatic artery. (C) Liver biopsy showing acute steatohepatitis, with 75% macro- and micro-vesicular steatosis and extensive ischemic necrosis. (D) Zoom on the area of ischemic necrosis, showing infiltration of the liver by neutrophils, lymphocytes, and plasma cells. CA, celiac artery; CHA, common hepatic artery; GDA, gastroduodenal artery; GSV, great saphenous vein; HoP, head of pancreas; IVC, inferior vena cava; LGA, left gastric artery; LGV, left gastric vein; LRV, left renal vein; PHA, proper hepatic artery; PV, portal vein; RRA, right renal artery; RRV, right renal vein; SMA, superior mesenteric artery; SMV, superior mesenteric vein CONCLUSION: Early postoperative recognition and grading of CR-PPLI is critical to prevent liver failure, as static imaging may fail to reflect dynamic hepatic perfusion. A disproportionate rise in alanine aminotransferase within 48 h is a key warning sign. Prospective multicenter studies are needed to better define the incidence, risk factors, and optimal management of CR-PPLI.

BACKGROUND:Although main duct (MD) and branch duct (BD) IPMNs differ in preoperative risk of malignant transformation, it remains unclear whether ductal subtype influences outcomes once invasive carcinoma develops and is resected. We compared recurrence and survival outcomes between these subtypes. METHODS:We identified patients with resected IPMN-derived pancreatic ductal adenocarcinoma (PDAC) from three institutions. Overall survival (OS) and recurrence-free survival (RFS) were estimated using Kaplan-Meier methods and compared with log-rank tests. Multivariable Cox regression models adjusted for age, T-stage, N-stage, histologic subtype, and adjuvant chemotherapy. RESULTS:Among 136 patients, 106 (78%) had MD-derived and 30 (22%) had BD-derived IPMN-associated PDAC. Median OS was 36.6 months and did not differ by subtype on log-rank (p = 0.472) or multivariable analysis (HR 0.45, 95% CI 0.15-1.31; p = 0.143). Median RFS was 41.8 months without significant difference by subtype on log-rank (p = 0.362) or adjusted analysis (HR 0.56, 95% CI 0.21-1.46; p = 0.234). CONCLUSIONS:In patients with resected IPMN-derived PDAC, ductal subtype was not significantly associated with OS. While clinically meaningful differences in RFS cannot be excluded, these findings suggest that once invasive cancer arises and is resected, ductal subtype alone may not provide additional prognostic information.

PURPOSE/OBJECTIVE:To evaluate radiology-pathology concordance and interobserver agreement of intraductal papillary mucinous neoplasm (IPMN) subtype classification, and to determine whether categorical subtype classification adds value for malignancy risk stratification beyond main pancreatic duct (MPD) features. METHODS:In this single-center retrospective study, 144 consecutive patients who underwent surgical resection of an IPMN between 2005 and 2025 and had preoperative CT or MRI within 6 months of surgery were included. Images were independently reviewed by two blinded radiologists, with discrepancies adjudicated by a third. Adjudicated radiologic subtype classification was used for radiology-pathology concordance, logistic regression, and receiver operating characteristic (ROC) analyses; interobserver agreement was assessed using the independent reader interpretations. Logistic regression and ROC analyses identified predictors of malignancy. RESULTS:Overall radiology-pathology concordance under the radiologic classification was 60.4% (87/144). Among pathologic mixed-type IPMNs, 60.3% (38/63) were classified as branch-duct IPMNs on imaging. Interobserver agreement was moderate for radiologic subtype (κ = 0.509) but excellent for MPD diameter (ICC = 0.909). On multivariable analysis, MPD diameter independently predicted malignancy (aOR, 1.31; 95% CI, 1.12-1.53; p = .001), whereas radiologic subtype was not. MPD diameter outperformed radiologic subtype for discrimination of malignancy (AUC, 0.737 vs. 0.624; p = .001). Adding radiologic subtype to MPD diameter provided no incremental discriminative value for malignancy (AUC, 0.739 vs. 0.737; p = .61). CONCLUSION/CONCLUSIONS:Radiologic IPMN subtype classification demonstrated only modest concordance with pathology and moderate interobserver agreement. MPD diameter demonstrated higher interobserver agreement and superior discrimination for IPMN malignancy risk stratification. These findings suggest that the mixed-type IPMN subtype may not be necessary as a distinct category for malignancy risk stratification, and that greater emphasis on objective MPD measurement may provide a more reproducible and clinically informative approach.

BACKGROUND:Symptomatic postoperative fluid collections (POFCs) can result in significant morbidity and mortality after abdominal surgery requiring timely intervention. EUS-guided drainage is traditionally delayed up to four weeks to allow wall maturation and reduce perforation or peritonitis risk. However, some POFCs may be suitable for earlier intervention. This study compared the efficacy and safety of acute (≤ 15 days), early (16-30 days), and delayed (> 30 days) EUS-guided drainage. METHODS:A retrospective cohort of patients undergoing EUS-guided drainage for symptomatic POFCs between 2013 and 2023 at a single tertiary center was evaluated. Technical success was defined as accessing and draining a POFC by transmural stent placement on initial endoscopy. Clinical success was defined as radiographically or endosonographically confirmed symptomatic POFC improvement without further percutaneous or surgical intervention. RESULTS:Among 85 patients with POFCs, most (61%) had undergone distal pancreatectomy with splenectomy. 59% required drainage ≤ 30 days after surgery, with 28% managed acutely. Most (83%) received lumen-apposing metal stents. Overall technical and clinical success rates were 94% and 79%, respectively, after a median 2 endoscopies (IQR 2-3). Success did not differ by timing (technical: 92% vs. 96% vs. 94%; clinical: 83% vs. 85% vs. 71%; P = 0.86 and P = 0.37). Adverse event rates were similar across groups (P = 0.85). Transgastric access was associated with clinical success (P < 0.001) and fewer adverse events (P = 0.03). Transduodenal access predicted technical (P = .05) and clinical failure (P = 0.02). CONCLUSIONS:In this large single-center experience of symptomatic POFCS, acute and early EUS-guided drainage with lumen-apposing metal stents in carefully selected patients was found to be technically safe and clinically effective, potentially avoiding more morbid interventions such as ERCP, percutaneous drainage, or surgery. Further randomized, prospective studies are needed to define predictors of technical and clinical success as well as adverse events.

BACKGROUND:Advances in pancreatic cancer surgery involve hepatotoxic chemotherapies and hepatic vasculature resections, increasing the risk of clinically relevant postpancreatectomy liver injury. The study aimed to analyze the incidence and impact of clinically relevant postpancreatectomy liver injury after pancreatectomy with hepatic vessel resection. METHODS:In this single-institutional study, patients undergoing pancreatectomy with resection of hepatic vessels (portal vein/superior mesenteric vein, celiac axis, and hepatic arteries) were analyzed. Arterial lactate, total bilirubin, alanine aminotransferase, aspartate aminotransferase, international normalized ratio, and Doppler ultrasound-derived resistive index were assessed postoperatively. Postoperative outcomes were assessed through 90 days. Clinically relevant postpancreatectomy liver injury was defined as American Association for the Study of Liver Diseases-defined liver failure and/or need for invasive treatment of liver complications. RESULTS:Among 116 patients (67% portal vein/superior mesenteric vein resection alone, 7% celiac axis/hepatic arteries alone, 26% portal vein/superior mesenteric vein + celiac axis/hepatic artery resection), 15 (13%) developed clinically relevant postpancreatectomy liver injury. Mortality was significantly higher in the clinically relevant postpancreatectomy liver injury group (47% vs 3%; P < .001). The proper hepatic artery resistive index was lower in the clinically relevant postpancreatectomy liver injury group (0.52 vs 0.65; P = .034), whereas the following 48-hour-peak blood tests were significantly higher in this group: Lac, bilirubin, aspartate aminotransferase, and alanine aminotransferase (all P < .01). Combined portal vein/superior mesenteric vein + celiac axis/hepatic arteries and elevated alanine aminotransferase 48-hour peak above 1680 U/L remained significantly associated with the occurrence of clinically relevant postpancreatectomy liver injury in multivariable analyses. Forty percent of clinically relevant postpancreatectomy liver injury occurred in the absence of vascular complications. CONCLUSION/CONCLUSIONS:Clinically relevant postpancreatectomy liver injury is associated with significant mortality. Low resistive index and markedly elevated biochemical markers within the first 48 hours correlate with clinically relevant postpancreatectomy liver injury and may be used to trigger earlier intervention. Given the associated morbidity and mortality, defining, preventing, and mitigating clinically significant postpancreatectomy liver injury is of the utmost importance.

Pancreatic ductal adenocarcinoma (PDAC) with extensive peripancreatic vessel involvement is classified as locally advanced pancreatic cancer (LAPC). For this group of patients, the current standard of care does not include considering a potentially curative oncologic resection. However, recent advances in multiagent chemotherapy and surgical techniques are challenging this paradigm. Moreover, the current determination of anatomic resectability is vague and unreliable. Here we propose a definition of local resectability, based on pre- and intra-operative assessment. This anatomic definition of resectability assumes careful patient selection based on tumor biology and patient condition. The pre-operative evaluation of vascular anatomy and tumor involvement is conducted using 3D-rendering of pancreas-protocol computed tomography. Identifying a disease-free arterial or venous segment above and below the tumor involvement ("suitable target") is the single critical factor that determines anatomic resectability. Intraoperative isolation of these target vessels confirms the feasibility of vascular reconstruction before resection. This approach, which focuses on identifying target vessels rather than circumferential involvement, offers a more straightforward and clinically relevant method for assessing surgical eligibility in LAPC patients at centers of excellence. In summary, reconstructability-based on surgical expertise and guided by tumor biology-now defines the modern paradigm of resectability in LAPC.