BACKGROUND:Surgeons rarely encounter solid pseudopapillary neoplasms (SPNs) of the pancreas. Contemporary clinicopathologic features, operative interventions, and oncologic outcomes remain under-reported. METHODS:We reviewed clinical data and pathology from a single institution's experience of patients who underwent surgical resection with primary and recurrent SPNs treated between January 2004 and December 2023. Patient demographics, imaging results, tumor characteristics, treatment methods, genomic testing outcomes, recurrence-free survival, and survival were recorded and analyzed. RESULTS:Fifty patients comprised the study group, forty-eight were females, with a median age of 33 years (IQR:15.95, 16-53 years). Thirty patients were symptomatic, most commonly presenting with abdominal pain (n = 24). SPNs frequently demonstrated solid and cystic components and a 4.1 cm median tumor size. At a median follow-up of 53 months, three patients (6%) had recurrence of disease. Ten patient tumors underwent genomic sequencing: all containing a CTNNB1 mutation. Co-occurring PTEN and TP53 mutations were identified in two patient tumors that recurred. Treatments entailed cytoreductive surgical procedures, regional, and systemic therapies. One patient succumbed to disease progression. CONCLUSION:Patients with solid pseudopapillary neoplasms had a favorable oncologic outcome. Recurrence/metachronous metastasis occurred in older patients with larger tumors, each containing a pathogenic co-mutation, and one patient experiencing traumatic tumor rupture.

BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with poor survival. Recent reports suggest that tissue hypercapnia (elevated levels of CO2) promotes an aggressive PDAC phenotype and resistance to therapy. End-tidal carbon dioxide (ETCO2) measurement offers a composite measure of ventilation, systemic perfusion, and tissue CO2 production. We hypothesized that ETCO2 levels in patients with PDAC undergoing curative-intent pancreaticoduodenectomy could serve as a prognostic marker: (1) low levels indicating decreased circulatory reserves, and (2) high levels indicating increased tissue hypercapnia-both of which may result in worse oncologic outcomes. STUDY DESIGN:This was a single, high-volume, institutional, retrospective cohort study of patients who underwent pancreaticoduodenectomy for PDAC (2017 to 2023). Intraoperative ETCO2 data were obtained from anesthesia records. Mean ETCO2 was calculated for each patient. ETCO2 groups were stratified by quartiles (Q1 to Q4): low (Q1), normal (Q2 to Q3), and high (Q4). The primary endpoints were disease-free survival and overall survival (OS). RESULTS:The final cohort included 243 patients (49% men, median age 68.5 years [interquartile range 61.3 to 74.9]). Both low and high ETCO2 were associated with poorer OS compared with normocapnia (p < 0.05 for both). Cox regression analysis identified both low and high ETCO2 as independent and significant factors for disease-free survival (hazard ratio 1.80 and 1.65, respectively) and identified high ETCO2 as a risk factor for OS (hazard ratio 1.65) compared with normocapnia. CONCLUSIONS:Mean intraoperative ETCO2 is a strong marker of oncologic outcomes in patients with PDAC after pancreaticoduodenectomy, with both extremes of the spectrum linked to a worse disease course. This observation has implications for patient selection and decision-making in cancer care.

Introduction: Solid pseudopapillary epithelial neoplasm (SPEN) is a rare pancreatic tumor that typically presents in adult women and is usually asymptomatic. Case presentation: A 12-year-old male presented to the emergency department with worsening abdominal pain one day after suffering mild abdominal trauma during a soccer match. Physical exam showed diffuse abdominal tenderness and guarding. CT abdomen with IV contrast showed a heterogeneous, round structure adjacent to the pancreatic tail with mass effect upon the spleen. MRI abdomen revealed a "claw sign" of pancreatic tissue surrounding the structure, suggesting a an underlying pancreatic mass with capsular rupture measuring 8.3 x 8.1 x 8cm. This finding indicated the need for open distal pancreatectomy. Intraoperatively, safe separation of the splenic vasculature from the mass proved impossible and splenectomy was performed. A drain was left in place. Postoperatively, the patient recovered without complication. At one month follow-up, the patient was seen doing well. A drain amylase did not show evidence of a pancreatic leak and was removed. Histopathology later confirmed the diagnosis of SPEN of the pancreas. Conclusion: Traumatic rupture of SPEN of the pancreas is a rare initial presentation. Distal pancreatectomy shortly after presentation appears to be safe and may require splenectomy if the splenic vasculature appears inseparable from the tumor.

Importance Total pancreatectomy (TP) is indicated for advanced pancreatic cancer or multifocal tumors. Furthermore, TP may be performed to avoid the risk of pancreatic fistula in selected patients to improve the perioperative risk profile. Objective To define reference values for TP based on a low-risk cohort treated at expert centers. Design, Setting, and Participants This multicenter study analyzed outcomes from patients undergoing primary TP for malignant or benign lesions from 25 international expert centers from January 2017 to November 2023. Low-risk patients undergoing TP (LR-TP) were without vascular resections or significant comorbidities. Exposures TP. Main Outcomes and Measures Twenty reference values were derived from the 75th or the 25th percentile of the median values of all centers. Outcomes of LR-TP were compared with a cohort of TP with vascular resection, TP due to high-risk pancreatic anastomosis, and the benchmark values for low-risk pancreatoduodenectomy. Results Of 994 patients, 333 (33.5%; median [IQR] age, 66 [58-72] years; 171 male [51.4%]) qualified as the LR-TP cohort. Reference values included blood loss (≤1000 mL), major complications (≤37%), 3-month postoperative mortality (<6%), and retrieved lymph nodes (≥29). Compared with TP with vascular resections, reference cutoffs were not met for major complications (51% vs LR-TP ≤37%) and 90-day mortality (11% vs LR-TP ≤6%). For TP due to high-risk anastomosis, failure to rescue rate (38% vs ≤6%) and 90-day mortality (11% vs LR-TP ≤6%) were not met. Compared with pancreatoduodenectomy, reference values for postoperative mortality were 3 times higher for LR-TP (≤2% vs ≤6%) and less for resected lymph nodes (≥16 vs ≥29). Conclusions and Relevance This case-control study provided global reference values for TP, indicating significantly higher postoperative morbidity and mortality compared with pancreatoduodenectomy. Perioperative morbidity of TP was especially increased in patients with vascular resections. These reference values can serve for quality control of pancreatic surgery.

Objective:The aim of this study was to evaluate the different phases of the learning curve for robotic distal pancreatectomy (RDP) in international expert centers.Background:RDP is an emerging minimally invasive approach; however, only limited, mostly single-center data are available on its safe implementation, including the learning curve.Methods:Consecutive patients undergoing elective RDP from 16 expert centers across 3 continents were included to assess the learning curve. Based on the first 100 RDPs at each center, 3 cutoffs were used to define the learning curve: operative time for competency, major complications (Clavien-Dindo grade >= III) for proficiency, and textbook outcome for mastery. Clinical outcomes before and after the cutoffs were compared.Results:The learning curve analysis was conducted on 1109 of 2403 RDPs. Competency, proficiency, and mastery, respectively, were reached after 46, 63, and 73 RDP procedures. After competency, operative time decreased from 245 to 235 minutes (P = 0.002). Attaining proficiency was reflected by a reduction in the rate of major complications from 20% to 15% (P = 0.012), and mastery was associated with a higher proportion of patients with textbook outcomes (71% vs 63%; P = 0.028). The postoperative pancreatic fistula rate remained stable along the learning curve, ranging between 18.5% and 21.5%. Previous laparoscopic experience accelerated the learning process by virtue of reduced operative time and an earlier decrease in major complications.Conclusions:Competency, proficiency, and mastery for RDP were reached after 46, 63, and 73 procedures, respectively, at international expert centers. The findings highlight that the learning curves for intraoperative parameters are completed earlier; however, extensive experience is needed to master RDP.

ABSTRACT Introduction Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a highly aggressive malignancy. Prior studies suggest that the initial site of metastasis may impact prognosis. This study investigates whether overall survival in mPDAC patients differs between patients first presenting with lung metastases versus those presenting with liver metastases. Methods This retrospective analysis utilized the multi‐institutional TriNetX database, identifying patients with histologically diagnosed PDAC who initially presented with either liver or lung metastases. Demographic, histologic, and outcome data were collected and analyzed. Patients were matched 1:1 using a nearest neighbor propensity score (PS) algorithm, and Kaplan–Meier survival analyses were performed. Cox regression was also used to further validate the results of the PS matching. Results A total of 6256 patients were identified, including 5390 patients presenting with liver and 866 patients presenting with lung metastases at diagnosis. The mean age was 66.6 ± 10.5, the male‐to‐female ratio was 54%:46%, the mean carbohydrate‐antigen (CA) 19‐9 level was 1309 ± 2078 ng/mL, the mean carcinoembryonic‐antigen (CEA) level was 117 ± 1044 U/mL. Propensity score matching yielded 848 matched pairs. Median survival from time of metastatic diagnosis was significantly longer for patients with lung metastases compared to liver (377 vs. 195 days, p < 0.0001). Cox regression identified several factors associated with increased risk of death: older age, obesity, malnutrition, and elevated CEA or CA 19‐9. Additionally, initial lung metastases were associated with decreased risk of death (HR = 0.61, p < 0.0001). Conclusion Initial presentation with lung metastases appears to be associated with improved survival outcomes as compared to initial presentation with liver metastases in patients with mPDAC.

Euglycemic diabetic ketoacidosis (EDKA) is associated with diabetes, alcohol use, pregnancy, and use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Thus far, it has been described in the setting of cardiac surgery and a cohort of patients undergoing pancreaticoduodenectomy (Whipple) surgery. This case series is the first to describe the occurrence of perioperative euglycemic diabetic ketoacidosis in a cohort of nondiabetic patients not on SGLT-2 inhibitors undergoing hyperthermic intraperitoneal chemotherapy (HIPEC). We recommend measurement of ketones during or after surgery when EDKA is suspected to initiate therapy in a timely fashion.

Objective: The aim of this study was to identify risk factors for conversion and assess its consequences on clinical outcomes after robotic distal pancreatectomy (RPD). Summary of Background Data: RDP has gained popularity due to its lower conversion rate (3–8%) when compared to laparoscopic distal pancreatectomy (10–20%). Methods: This retrospective multicenter study included RDPs performed at 16 international centers from May 2007 to March 2024. Perioperative outcomes of patients requiring conversion were compared to fully robotic RDP patients. Risk factors for conversion were identified by multivariable logistic regression analysis. Results: Of 2,452 patients undergoing RDP, 75 (3.1%) required conversion to open surgery. In converted RDPs, operative time was longer (300 (243–376) vs. 180 (120–240) minutes; P <0.001), and blood loss was greater (500 (200–990) vs. 100 (50–200) ml; P <0.001). Converted patients experienced more overall complications (53% vs. 39%; P =0.017), major complications (41% vs. 25%; P <0.001), and a higher 90-day mortality (5% vs. 3%; P <0.001). Furthermore, both postoperative pancreatic fistula (35% vs. 18%; P <0.001) and delayed gastric emptying (10% vs. 3%; P <0.001) were more frequent in the conversion group. The rate of patients achieving textbook outcome was lower after conversion (57% vs. 74%; P =0.003). In the multivariable analysis, lesion size (>51 mm; OR 2.86 (95% CI 1.56–5.08)), BMI (>28 kg/m 2 ; OR 3.03 (1.75–5.30)), previous abdominal surgery (OR 2.48 (1.31–4.51)), patients outside benchmark criteria (OR 2.09 (1.19–3.72)), and age (>62 years; OR 2.21 (1.24–4.05)) were associated with conversion. Conclusion: This international cohort study confirmed a very low conversion rate for RDP. Yet, converted cases experienced substantially impaired postoperative outcomes, highlighting the need for adequate patient selection through validated difficulty scoring systems.

BACKGROUND:Total pancreatectomy can be associated with severe endocrine complications. This study compares endocrine outcomes of patients who underwent a single-stage total pancreatectomy versus a 2-stage completion pancreatectomy. METHODS:We used data from a multi-institutional research network (TriNetX), which identified 1,079 propensity score-matched total pancreatectomy and completion pancreatectomy patient pairs for age, gender, and race. These data were validated by a single-center review of a prospectively maintained database of 1,600 pancreatectomies, from which 88 completion and total pancreatectomy patients treated between 2013 and 2023 were identified. The primary endpoints were postoperative rates of hypoglycemia and diabetic ketoacidosis during the first year following surgery. RESULTS:The network analysis identified 1,079 propensity score-matched total pancreatectomy and completion pancreatectomy pairs with similar demographics. During the first year following the surgery, patients in the total pancreatectomy cohort had a 2.9-fold increased risk of endocrine complications compared with the completion pancreatectomy cohort (hazard ratio 2.9, 95% confidence interval 2.2-3.7, P < .00001). Total pancreatectomy patients had an increased risk of hypoglycemia (hazard ratio 3.0, 95% confidence interval 2.2-4.0, P < .00001) and an increased risk of diabetic ketoacidosis (hazard ratio 9.3, 95% confidence interval 4.0-21.7, P < .0001). In the single-center analysis, total pancreatectomy patients showed a 3.9-fold (hazard ratio 3.9, 95% confidence interval 1.2-13.0, P = .025) higher hypoglycemia rate than completion pancreatectomy patients. Kaplan-Meier analyses demonstrated that total pancreatectomy patients experienced earlier and more frequent hypoglycemic events compared with completion pancreatectomy patients both in the multi-institutional cohort (P < .00001) and in the single-center validation cohort (P < .01). CONCLUSIONS:Our findings indicate that 2-stage completion pancreatectomy patients experience fewer endocrine complications than total pancreatectomy patients. The higher early postoperative endocrine complication rates in total pancreatectomy patients underscore the need for vigilant monitoring and improved patient education in this patient cohort.

BACKGROUND:The P53 gene is the most common tumor-suppressor gene mutated in pancreatic ductal adenocarcinoma (PDAC). The gene's normal function is critical for regulation of replication, DNA repair, and apoptosis. The purpose of our study is to determine the impact of the various P53 mutation subtypes on survival in resected PDAC. METHODS:This is a retrospective cohort study assessing patients that underwent curative-intent resection for PDAC between the years of 2016-2022. Next generation sequencing (NGS) was performed on patient tumors. P53 tumor genotypes were grouped into wild-type (WT), gain-of-function (GOF) mutations (R175H, R248W, R248Q, R273H, R282W, G245S) and all other non-GOF mutations. RESULTS:The study included a total of 330 patients with resected PDAC. P53 mutations were found in tumors of 243 patients (74%), and 87 (26%) patients had WT P53. Among patients with mutant P53 tumors, 58 patients (24%) had a GOF mutation, and 185 patients (76%) had a non-GOF mutation. Survival analysis showed that non-GOF P53 mutations were associated with the shortest overall survival compared with WT and GOF (25.6 ± 2.4 months vs. 32.2 ± 3.6 months, vs. 36.2 ± 4.4 months, respectively. p = 0.038). Similarly, non-GOF mutations were associated with the shortest disease-free survival (14.6 ± 1.2 months, vs. 19.6 ± 3.5 months, vs. 18.3 ± 3.6 months, respectively. p = 0.039). CONCLUSIONS:Our data suggest that P53 mutations grouped by functional status may hold differential prognostic value regarding survival and recurrence of patients with PDAC. Further investigations are required to validate these findings.

BACKGROUND:Pancreatic cancer is a highly aggressive and lethal disease, characterized by a limited response to chemotherapy and overall poor prognosis. Pancreatic cancers with a distinct mismatch repair deficiency, although relatively rare, have been shown to be associated with markedly better outcomes in comparison. Furthermore, whereas pancreatic cancers are generally unresponsive to current immunotherapy, this specific group of tumors has been shown to have a notable susceptibility to immune checkpoint inhibitors. AIMS:In this review, we aim to summarize the relevant literature regarding mismatch-repair associated pancreatic cancers, the impacted biological mechanisms, and the resulting vulnerabilities for potential opportunistic immunotherapeutic treatment approaches. We will also review the current clinical studies assessing survival outcomes of mismatch repair deficient pancreatic cancers and ongoing clinical trials in this emerging field. RESULTS AND CONCLUSIONS:Patients with dMMR/MSI-H pancreatic cancers harbor a distinct phenotype that has increased immune activation, greater responsiveness to immune checkpoint inhibitor therapy and better overall survival when compared to other pancreatic cancers. Although this molecular subtype makes up a small minority of cases, emerging data suggest immunotherapy may offer benefit to these patients.

Background: Intraductal papillary mucinous neoplasms (IPMNs) are pre-malignant pancreatic lesions that may progress to invasive pancreatic ductal adenocarcinoma (PDAC). IPMN-associated invasive carcinoma (iIPMN) has been associated with more favorable survival outcomes compared to non-iIPMN-derived PDAC. Here, we aim to investigate the genetic landscape of IPMNs to assess their relevance to oncologic outcomes. Methods: This retrospective study used a large single-institution prospectively maintained database. Patients who underwent curative-intent pancreatic resection between 2016 and 2022 with histologically confirmed diagnosis of IPMN were included. Demographic, pathologic, molecular, and oncologic outcome data were recorded. Kaplan-Meier survival analyses were performed. PDAC data from public genetic databases were used for mutational correlation analysis. p-value ≤ 0.05 was considered as significant. Results: A total of thirty-nine patients with resected IPMN with complete clinical and sequencing data were identified and included in the final cohort. The male-to-female distribution was 21:18, and the mean age was 70.1 ± 9.1 years. GNAS mutations occurred in 23.1% of patients, and 89.7% of patients had iIPMN. In iIPMN patients, GNAS mutation was strongly associated with improved disease-free survival: all GNAS-mutant patients survived to follow-up with significantly fewer recurrences than in GNAS wild-type (WT) patients (p = 0.013). Mutated GNAS closely co-occurred with wild-type KRAS (p < 0.001), and further analysis of large genomic PDAC datasets validated this finding (OR 3.47, p < 0.0001). Conclusions: Our study suggests prognostic value of mutational status in malignant resected IPMNs. WT GNAS, mutant P53, and mutant KRAS each correlate with recurrence and decreased survival. Further studies are required to validate these preliminary observations.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignances with a 5-year survival rate at around 13%. This dismal prognosis is, in part, due to the dense desmoplastic stroma and low vascularity of PDAC tumors, leading to inefficient uptake of therapeutics. The combination of FDA-approved ultrasound contrast agents called microbubbles (MBs), and focused ultrasound (FUS) has the potential to increase drug uptake in PDAC tumors. Our team has developed a novel therapeutic that loads antisense oligonucleotides (ASOs) onto MBs for targeted drug delivery in vivo. The ASOs have been designed to target the pre-mRNA transcript of Negative Elongation Factor E (NELFE), a protein that is upregulated in multiple tumor types, including PDAC. In vitro ASO-only treatment was sufficient in significantly reducing cell proliferation, cell migration, and colony formation in three PDAC cell lines. To investigate the effects of ASO+MBs+FUS treatment in vivo, we performed intrapancreatic orthotopic injections of KPC-4662 cells derived from the KPC mouse model (LSL-Kras G12D/+ ;LSL-Trp53 R172H/+ ;Pdx-1-Cre) into C57BL/6 mice and recorded tumor growth over time using bioluminescence imaging. Once tumors were established, we performed 6 rounds of ASO+MBs+FUS treatment across a 2-week timespan. Mice treated with ASO+MBs+FUS had a significant reduction in tumor burden and increased overall survival compared to mice treated with MBs+FUS alone. In conclusion, targeting NELFE using ASO+MBs+FUS can be a potential therapeutic strategy for PDAC patients. Brittany N. Ruiz, Alvaro Lucci, Laura M. Reynolds, Pongsakorn Choochuen, Corinne Wessner, Christine Wiktor, Sarah Hynd, Christoph Eckert, Meghan Grim, Avinoam Nevler, Harish Lavu, Charles Yeo, Matthias M. Gaida, Elda Grabocka, John Eisenbrey, Hien Dang. Targeting NELFE using antisense oligonucelotides reduces tumor burden and increases overall survival in vivo [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B033.

Pancreatic enucleation is a parenchymal-sparing procedure used for highly select patients with pancreatic neoplasms. We aim to utilize a multi-institutional health research network platform (TriNetX) and a single, high-volume center to assess complications and identify risk factors associated with post-operative pancreatic fistulas (POPF) after pancreatic enucleation. A two-tiered retrospective study was conducted. We identified 423 patients from TriNetX, and 34 patients from a single-institution IRB-approved database who underwent pancreatic enucleation between 2004–2025 and 2012–2023, respectively. Univariate and multivariate analyses were performed to determine risk factors associated with post-operative complications and occurrence of POPFs. In the TriNetX cohort, 128 (30.3

OBJECTIVE:The aim of this study was to identify risk factors for conversion and assess its consequences on clinical outcomes after robotic distal pancreatectomy (RPD). SUMMARY OF BACKGROUND DATA:RDP has gained popularity due to its lower conversion rate (3-8%) when compared to laparoscopic distal pancreatectomy (10-20%). METHODS:This retrospective multicenter study included RDPs performed at 16 international centers from May 2007 to March 2024. Perioperative outcomes of patients requiring conversion were compared to fully robotic RDP patients. Risk factors for conversion were identified by multivariable logistic regression analysis. RESULTS:Of 2,452 patients undergoing RDP, 75 (3.1%) required conversion to open surgery. In converted RDPs, operative time was longer (300 (243-376) vs. 180 (120-240) minutes; P<0.001), and blood loss was greater (500 (200-990) vs. 100 (50-200) ml; P<0.001). Converted patients experienced more overall complications (53% vs. 39%; P=0.017), major complications (41% vs. 25%; P<0.001), and a higher 90-day mortality (5% vs. 3%; P<0.001). Furthermore, both postoperative pancreatic fistula (35% vs. 18%; P<0.001) and delayed gastric emptying (10% vs. 3%; P<0.001) were more frequent in the conversion group. The rate of patients achieving textbook outcome was lower after conversion (57% vs. 74%; P=0.003). In the multivariable analysis, lesion size (>51 mm; OR 2.86 (95% CI 1.56-5.08)), BMI (>28 kg/m2; OR 3.03 (1.75-5.30)), previous abdominal surgery (OR 2.48 (1.31-4.51)), patients outside benchmark criteria (OR 2.09 (1.19-3.72)), and age (>62 years; OR 2.21 (1.24-4.05)) were associated with conversion. CONCLUSION:This international cohort study confirmed a very low conversion rate for RDP. Yet, converted cases experienced substantially impaired postoperative outcomes, highlighting the need for adequate patient selection through validated difficulty scoring systems.