Faculty Bibliography

BACKGROUND:Poor outcomes in pancreatic ductal adenocarcinoma (PDAC) are associated with delayed diagnosis and early systemic spread of disease. Development of liquid biopsies for screening could help detect low-stage disease in asymptomatic patients. We aimed to evaluate the association between incidental diagnosis on outcomes and assess the potential role of liquid biopsies. STUDY DESIGN/METHODS:An institutional registry was used to identify patients undergoing resection for PDAC at between 2010 and 2015. Patients were stratified based on presenting symptoms, and outcomes were analyzed. Preoperatively collected plasma that was available on these patients was analyzed using a multianalyte screening test based on ctDNA and proteins. RESULTS:Seventy-nine (9.6%) of 823 patients were diagnosed incidentally (asymptomatic at diagnosis). Incidental diagnosis was associated with type of surgery, and absence of nodal disease and lymphovascular invasion (all P<0.05). On multivariable analysis incidental diagnosis (HR, 0.561; 95%CI, 0.406-0.775; P<0.001) was independently associated with improved overall survival (OS), while tumor size ≥4cm (HR, 1.617; 95%CI, 1.201-2.176; P=0.002), nodal disease (HR, 1.259; 95%CI, 1.018-1.558; P=0.034), perineural invasion (HR,1.338; 95%CI, 1.030-1.739; P=0.029), and positive margins (HR,1.302; 95%CI, 1.058-1.602; P=0.013) were associated with poorer OS. Asymptomatic patients had a significantly longer OS (median-OS: 38 vs. 19 months (P<0.001). The rate of multianalyte test positivity was 75% (6/8) in asymptomatic patients compared to 73% (59/81) in symptomatic patients (P=0.895). CONCLUSION/CONCLUSIONS:Approximately 10% of patients with PDAC are diagnosed incidentally. In resected PDAC, incidental diagnosis is independently associated with improved OS. Multianalyte screening tests perform equally well in asymptomatic and symptomatic patients. These findings further reinforce the need for development of screening tools that can increase the rate of diagnosis at an asymptomatic stage and improve survival.

Currently, no consensus exists regarding the definition of oligometastatic pancreatic ductal adenocarcinoma, its necessary diagnostic measures, and potential treatment approaches. To address these knowledge gaps, the OligoPanc project brought together an interdisciplinary group of experts to establish consensus using a modified Delphi process and clinical vignettes. Participants agreed that the number of metastatic lesions and the number of affected organs are key elements in defining oligometastatic pancreatic ductal adenocarcinoma. Specifically, up to three lesions in a single organ, either the liver or the lung, define oligometastatic pancreatic ductal adenocarcinoma and could be either synchronous or metachronous. Necessary diagnostics include a triple-phase contrast-enhanced CT scan of the chest and abdomen and MRI of the liver with a hepatocyte-specific contrast agent. In unclear cases, [¹⁸F]fluorodeoxyglucose-PET CT or MRI can be considered. A multidisciplinary tumour board is essential. Patient-intrinsic factors, including age, do not define oligometastatic disease but should be considered for any treatment decision. Systemic treatment before any local consolidative treatment, including surgery, stereotactic ablative radiotherapy, or other locally ablative techniques, is mandatory. The proposed definition should be incorporated into future trials to improve comparability and enable validation.

BACKGROUND:Staging laparoscopy (SL) is performed to detect occult metastases in patients with localized pancreatic cancer. However, current guideline recommendations vary widely on routinely performing SL. This global survey investigated use and indications of SL. METHODS:An online survey was sent to members of nine international societies and working groups. Information was obtained about SL use, indications SL and adjunct diagnostic modalities across four clinical scenarios. RESULTS:Among 617 responding surgeons (76 countries, six continents), 82% used SL which varied between regions (Americas 90%, Asia 85%, Oceania 81%, Europe 76%, Africa 59%; P < 0.050). Most perform SL during the same session as the scheduled laparotomy (63-79%). A SL was mainly performed at the time of upfront surgery (71%), after (60%) or before (37%) neoadjuvant/induction therapy, and before radiotherapy (31%). SL was mainly performed in selected patients, either based on indeterminate/suspicious lesions on cross-sectional imaging (78-87%), resectability status (54-64%), and/or elevated CA19-9 level (60-69%). Most common used adjuncts were cytological lavage (37-55%) and intra-abdominal liver ultrasonography (36-50%). CONCLUSION/CONCLUSIONS:Despite considerable global variability, SL is widely used to detect occult metastases in pancreatic cancer, mainly in high-risk patients and often during the scheduled laparotomy. The observed variability highlights the need for more evidence leading to stronger guideline recommendations.

OBJECTIVE:The International Study Group of Pancreatic Surgery (ISGPS) aimed to uniform the definition and classification of mortality following pancreatic resections, to guide strategies for reducing preventable deaths and standardize reporting. BACKGROUND:Reported rates of mortality after pancreatic surgery vary widely depending on patient comorbidities, case mix, and institutional expertise and resources. Conventional reporting lacks granularity and fails to capture the mechanisms leading to death. A standardized classification rooted in causal analysis may provide a more meaningful framework to appraise outcomes and design targeted interventions. METHODS:A systematic review of the literature, focusing on mortality rates, causes of death, and existing classification systems after pancreatectomy was conducted. A consensus definition and tripartite classification were developed through iterative discussions, revisions, and final approval by the ISGPS board members. RESULTS:Postpancreatectomy mortality (PPM) was defined as death occurring within 90 days of any pancreatic resection, directly or indirectly attributable to a surgical complication and retrospectively linked to it through root-cause analysis. Three categories were established: PPM 1, vascular/technical complexity-related mortality (15-30%); PPM 2, pancreatectomy-specific complication-related deaths, mainly due to postoperative pancreatic fistula (POPF) and secondary systemic deterioration (45-65%); and PPM 3, cardiopulmonary and cerebrovascular deaths (10-25%). Each category reflects distinct mechanisms, timing of onset, intervention windows, and opportunities for rescue. DISCUSSION/CONCLUSIONS:The proposed ISGPS classification of mortality enables the development of targeted strategies to reduce potentially preventable deaths and provides a more robust framework for the appraisal and benchmarking of surgical outcomes. Prospective validation is warranted to standardize this newly defined quality metric, ensuring its consistent use in future reporting and ultimately enhancing surgical quality and patient safety on a global scale.

OBJECTIVE:We aimed to better understand patients' treatment preferences and quantify the level of cancer risk at which treatment preferences change (risk threshold) to inform better counseling of patients with intraductal papillary mucinous neoplasms (IPMNs). SUMMARY BACKGROUND DATA/BACKGROUND:The complexity of IPMN management provides an opportunity to align treatment with individual preference. METHODS:We surveyed a sample of healthy volunteers simulating a common scenario: undergoing an imaging study that incidentally identifies an IPMN. In the scenario, the estimated risk of cancer in the IPMN was 5%. Patients were asked their treatment preference (surgery or surveillance), to quantify the level of cancer risk in the IPMN at which their treatment preference would change (i.e. risk threshold), and their level of cancer anxiety as measured on a 5-point Likert scale. We examined associations between participant characteristics, treatment preferences, and risk threshold using multivariable linear regression. RESULTS:The median risk threshold among the 520 participants was 25% (IQR 2.3-50%). The risk threshold had a bimodal distribution: 40% of participants had a risk threshold between 0-10% and 47% had a risk threshold above 30%. When informed that the risk of cancer was 5%, 62% of participants (n=323) preferred surveillance, and the remaining 38% (n=197) preferred surgery. After adjusting for potential confounders, participants who expressed "worry" or "extreme worry" about the malignancy risk of IPMN had significantly lower risk thresholds than participants who were "not at all worried" (Coefficient -12, 95%CI -21 to -2, P=0.015 and Coefficient -18, 95%CI -29 to -8, P<0.001, respectively). CONCLUSIONS:Participants varied in treatment preference and risk threshold of incidentally identified IPMNs. Given the uncertainty in estimating the true malignant potential of IPMNs, a better understanding of a patient's risk threshold, as influenced by patient concern about malignancy, will help inform the shared decision-making process.

BACKGROUND/PURPOSE/OBJECTIVE:Intraductal papillary mucinous neoplasms (IPMNs) progress from low-grade dysplasia to high-grade dysplasia (HGD) or invasive carcinoma (IC). High diagnostic accuracy is critical for surgical decision-making. METHODS:We searched Medline, Embase, and Cochrane Library from January 1, 2015, to January 27, 2025. Eligible studies reported on resected IPMNs, assessing diagnostic features for HGD/IC. Two reviewers screened articles, extracted data, and assessed bias using the Newcastle-Ottawa scale. Descriptive statistics summarized outcomes. The performance of worrisome features (WFs) and high-risk stigmata (HRS) based on International Association of Pancreatology guidelines were evaluated. RESULTS:In the 53 studies, 12 953 patients were included. HRS including obstructive jaundice and enhancing mural nodules ≥5mm showed robust specificity for HGD/IC, while main pancreatic duct size ≥10mm showed variable diagnostic accuracy. WFs such as cyst size ≥3 cm performed poorly, while cyst growth rate >3.5 mm/year demonstrated higher sensitivity (88%) and specificity (91%). Although rare, abrupt caliber change with distal atrophy was a robust predictor of malignancy (median odds ratio: 3.01). Acute pancreatitis and lymphadenopathy displayed variable value. Incremental improvement in diagnostic accuracy was observed with additional HRS or WFs. CONCLUSIONS:Current diagnostic markers are valuable but provide limited guidance for surgical decision-making in IPMNs, highlighting the need for further refinement of diagnostic tools.

AIM/OBJECTIVE:To evaluate whether transitional circulating tumor cells (trCTCs) predict systemic recurrence of pancreatic ductal adenocarcinoma (PDAC) and assess their potential role in risk stratification for systemic treatment. BACKGROUND:The high metastatic potential of PDAC is believed to be associated with early dissemination after cancer cell reprogramming via an epithelial-to-mesenchymal transition. These cells are detectable in circulation as trCTCs and could serve as valuable biomarker capturing systemic disease involvement. METHODS:The prospective CLUSTER trial enrolled patients scheduled for PDAC resection (2016-2018). Pre- and postoperative CTCs were isolated with the Isolation-by-SizE-of-Tumor-Cells device and characterized by immunofluorescence. Cox regression with spline terms assessed associations between preoperative biomarkers and systemic recurrence, while multivariable subgroup analyses with interaction tests evaluated overall survival (OS) stratified by adjuvant chemotherapy. RESULTS:In preoperative samples, trCTCs were detected in 82 (67%) of 123 patients with a median number of two cells per ml (IQR 1-3). A linear association between preoperative trCTC counts and systemic recurrence (χ²=13.2, P=0.004) was observed, but no relevant correlation with CA19-9 levels was found (Pearson correlation=0.05, 95% CI:-0.13-0.23). Furthermore, trCTC-positivity after resection predicts recurrence and is associated with prolonged OS associated with adjuvant therapy (HR 0.21, 95%CI: 0.09-0.49) after adjustment for tumor stage and neoadjuvant chemotherapy. CONCLUSIONS:Preoperatively, higher trCTC counts are associated with increased risk of systemic recurrence, while postoperative presence reflects minimal residual disease. Integrating trCTC assessment alongside currently used biomarkers into the clinical pathway for patients with PDAC could enhance risk stratification and support more personalized treatment decisions.

BACKGROUND:Indocyanine green fluorescence imaging can be used for intraoperative assessment of pancreatic stump perfusion with the aim to guide strategies to prevent postoperative pancreatic fistula in pancreatic surgery. The impact of indocyanine green in this setting is unknown since a systematic review is lacking. This review aimed to assess the relationship between indocyanine green fluorescence imaging of pancreatic stump perfusion and the risk of clinically relevant postoperative pancreatic fistula after pancreatic surgery. METHODS:A systematic literature search and meta-analysis were conducted, including studies published up to June 2025 that reported postoperative pancreatic fistula rate after pancreatic resection in relation to intraoperative pancreatic stump perfusion assessed by intraoperative indocyanine green fluorescence imaging. Hypoperfusion was defined as a heterogeneous or completely absent signal. Primary outcome was postoperative pancreatic fistula of which only grade B/C were included. Secondary outcome was postpancreatectomy acute pancreatitis. RESULTS:All 3 studies included analyzed patients who underwent pancreatoduodenectomy, comprising a total of 100 patients, with 18 (18%) presenting pancreatic stump hypoperfusion. No studies analyzing left pancreatectomy were identified, whereas only 1 paper analyzed the association between pancreatic hypoperfusion and postpancreatectomy acute pancreatitis. In that study, no patients developed postpancreatectomy acute pancreatitis after revision of the transection line initially found to be hypoperfused. The overall rate of postoperative pancreatic fistula was 13%. After robotic pancreatoduodenectomy (n = 27), stump hypoperfusion was associated with postoperative pancreatic fistula (67% vs 17%; P = .026), compared to the normally perfused group. No significant association of hypoperfusion and postoperative pancreatic fistula was observed after open pancreatoduodenectomy (n = 73). Meta-analysis confirmed the association of stump hypoperfusion with postoperative pancreatic fistula (odds ratio, 8.83; 95% confidence interval, 2.21-35.23; P = .005). CONCLUSION/CONCLUSIONS:A hypoperfused pancreatic stump, assessed intraoperatively using indocyanine green fluorescence imaging, appears to be associated with postoperative pancreatic fistula after pancreatoduodenectomy. Further research is needed to confirm these results in left pancreatectomy and develop a standardized indocyanine green protocol for pancreatic surgery.

BACKGROUND:Prognostic factors in resected pancreatic ductal adenocarcinoma (PDAC) have been determined under the assumption that hazard ratios (HRs) remain static. However, PDAC is a dynamic disease with evolving conditional survival. The aim of this study was to determine if the impact of prognostic factors in PDAC is time-varying. METHODS:This was a multicenter, retrospective cohort study of the prospectively maintained Dutch Pancreatic Cancer Recurrence Database and New York University and Johns Hopkins Hospital Institutional Databases. Patients with complete macroscopic resection of histopathologically proven PDAC between 2014 and 2019 and available follow-up data were included. The time-varying impact of prognostic factors identified by univariable Cox regression was modeled using Aalen's Additive Regression Models (Aalen's models) and visualized as plots of cumulative hazard. RESULTS:In total, 3104 patients were included, of whom 938 (30.2%) received neoadjuvant therapy (NAT), whereas the rest underwent upfront surgery (US). A total of 201 (6.5%) patients achieved observed long-term survival (>5 years). Aalen's models showed that lymphovascular invasion, perineural invasion, and nodal disease were prognostic up to 2 years postoperatively. At varying points thereafter, these variables lost their impact in the NAT but not US patients. Similarly, during the fourth year of follow-up, American Society of Anesthesiology scores became impactful in the NAT but not in the US patients. CONCLUSION/CONCLUSIONS:The impact of prognostic factors in resected PDAC across NAT and US patients is time-varying. Our results suggest that aggressive disease drives early mortality but, after NAT, tumor-biological factors lose prognostic importance to frailty and comorbidities over time.

PURPOSE/OBJECTIVE:Histotripsy is a non-invasive ultrasound-based tumor ablation modality. This study aims to describe the preliminary safety and short-term imaging findings related to histotripsy of liver metastases. MATERIALS AND METHODS/METHODS:All patients who underwent histotripsy for liver metastases from February 2024 to January 2025 at a single center were retrospectively reviewed. Demographic, clinical, imaging, procedural, and adverse event data were collected via chart review. Immediate post-treatment ablation zones were measured on CT and compared to pretreatment tumor size and treatment cavity size on follow-up imaging. Untreated tumors were assessed using revised RECIST criteria to evaluate for off-target effects. RESULTS:Histotripsy was performed on 56 metastatic liver tumors (most common: 32% colorectal, 18% breast) in 26 patients (54% female, age 59.1 ± 15.6y). All patients were discharged within 36 h. Immediate post-procedural ablation zones (36.6 + 13.1 mm) were larger compared to pretreatment tumors (30.5 + 18.5 mm) (p = 0.0013). One-month ablation zones (31.5 + 16.7 mm) were smaller compared to immediate post-procedural ablation zones (p = 0.00064). Two patients experienced off-target effects in non-treated liver tumors following histotripsy while off cytotoxic therapy. One patient experienced a Grade 3 complication of bacteremia requiring prolonged inpatient admission. No deaths occurred within 30 days. CONCLUSION/CONCLUSIONS:Histotripsy demonstrates a favorable safety profile for liver metastases. Observed off-target effects in untreated lesions suggest systemic immunomodulatory responses. Further investigation is warranted to elucidate patient-specific factors (e.g., tumor biology, concurrent therapies) that optimize systemic immune activation. Larger prospective studies with longitudinal immune profiling are needed to validate histotripsy's potential dual role as a locoregional therapy and immune primer in metastatic liver disease. LEVEL OF EVIDENCE/METHODS:Level 2b, retrospective cohort study.