Defining the Minimal and Optimal Thresholds for Lymph Node Resection and Examination for Intraductal Papillary Mucinous Neoplasm Derived Pancreatic Cancer: A Multicenter Retrospective Analysis.

OBJECTIVE: To establish minimal and optimal lymphadenectomy thresholds for intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) and evaluate their prognostic value. BACKGROUND: Current guidelines recommend a minimum of 12-15 lymph nodes (LNs) in PDAC. This is largely based on pancreatic intraepithelial neoplasia (PanIN)-derived PDAC, a biologically distinct entity from IPMN-derived PDAC. METHODS: Multicenter retrospective study including consecutive patients undergoing upfront surgery for IPMN-derived PDAC was conducted. The minimum cut-off for lymphadenectomy was defined as the maximum number of LNs where a significant node positivity difference was observed. Maximally selected log-rank statistic was used to derive the optimal lymphadenectomy cut-off (maximize survival). Kaplan-Meier curves and log-rank tests were used to analyze overall survival (OS) and recurrence-free survival (RFS). Multivariable Cox-regression was used to determine hazard ratios (HR) with 95% confidence intervals (95%CI). RESULTS: In 341 patients with resected IPMN-derived PDAC, the minimum number of LNs needed to ensure accurate nodal staging was 10 (P=0.040), whereas ≥20 LNs was the optimal number associated with improved OS (80.3 vs. 37.2 mo, P<0.001). Optimal lymphadenectomy was associated with improved OS [HR:0.57 (95%CI 0.39-0.83)] and RFS [HR:0.70 (95%CI 0.51-0.97)] on multivariable Cox-regression. On sub-analysis the optimal lymphadenectomy cut-offs for pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy were 20 (P<0.001), 23 (P=0.160), and 25 (P=0.008). CONCLUSION: In IPMN-derived PDAC, lymphadenectomy with at least 10 lymph nodes mitigates under-staging, and at least 20 lymph nodes is associated with the improved survival. Specifically, for pancreatoduodenectomy and total pancreatectomy, 20 and 25 lymph nodes were the optimal cut-offs.

The impact of metastatic sites on survival Rates and predictors of extended survival in patients with metastatic pancreatic cancer.

BACKGROUND OBJECTIVES: The aim of this study was to determine the role of site-specific metastatic patterns over time and assess factors associated with extended survival in metastatic PDAC. Half of all patients with pancreatic ductal adenocarcinoma (PDAC) present with metastatic disease. The site of metastasis plays a crucial role in clinical decision making due to its prognostic value. METHODS: We examined 56,757 stage-IV PDAC patients from the National Cancer Database (2016-2019), categorizing them by metastatic site: multiple, liver, lung, brain, bone, carcinomatosis, or other. The site-specific prognostic value was assessed using log-rank tests while time-varying effects were assessed by Aalen's linear hazards model. Factors associated with extended survival (>3years) were assessed with logistic regression. RESULTS: Median overall survival (mOS) in patients with distant lymph node-only metastases (9.0 months) and lung-only metastases (8.1 months) was significantly longer than in patients with liver-only metastases (4.6 months, p < 0.001). However, after six months, the metastatic site lost prognostic value. Logistic regression identified extended survivors (3.6 %) as more likely to be younger, Hispanic, privately insured, Charlson-index <2, having received chemotherapy, or having undergone primary or distant site surgery (all p < 0.001). CONCLUSION: While synchronous liver metastases are associated with worse outcomes than lung-only and lymph node-only metastases, this predictive value is diminished after six months. Therefore, treatment decisions beyond this time should not primarily depend on the metastatic site. Extended survival is possible in a small subset of patients with favorable tumor biology and good conditional status, who are more likely to undergo aggressive therapies.

Outcomes in intraductal papillary mucinous neoplasm-derived pancreatic cancer differ from PanIN-derived pancreatic cancer.

BACKGROUND AND AIM: Intraductal papillary mucinous neoplasm (IPMN)-derived pancreatic ductal adenocarcinoma (PDAC) management is generally extrapolated from pancreatic intraepithelial neoplasia (PanIN)-derived PDAC guidelines. However, these are biologically divergent, and heterogeneity further exists between tubular and colloid subtypes. METHODS: Consecutive upfront surgery patients with PanIN-derived and IPMN-derived PDAC were retrospectively identified from international centers (2000-2019). One-to-one propensity score matching for clinicopathologic factors generated three cohorts: IPMN-derived versus PanIN-derived PDAC, tubular IPMN-derived versus PanIN-derived PDAC, and tubular versus colloid IPMN-derived PDAC. Overall survival (OS) was compared using Kaplan-Meier and log-rank tests. Multivariable Cox regression determined corresponding hazard ratios (HR) and 95% confidence intervals (95% CI). RESULTS: The median OS (mOS) in 2350 PanIN-derived and 700 IPMN-derived PDAC patients was 23.0 and 43.1 months (P < 0.001), respectively. PanIN-derived PDAC had worse T-stage, CA19-9, grade, and nodal status. Tubular subtype had worse T-stage, CA19-9, grade, nodal status, and R1 margins, with a mOS of 33.7 versus 94.1 months (P < 0.001) in colloid. Matched (n = 495), PanIN-derived and IPMN-derived PDAC had mOSs of 30.6 and 42.8 months (P < 0.001), respectively. In matched (n = 341) PanIN-derived and tubular IPMN-derived PDAC, mOS remained poorer (27.7 vs 37.4, P < 0.001). Matched tubular and colloid cancers (n = 112) had similar OS (P = 0.55). On multivariable Cox regression, PanIN-derived PDAC was associated with worse OS than IPMN-derived (HR: 1.66, 95% CI: 1.44-1.90) and tubular IPMN-derived (HR: 1.53, 95% CI: 1.32-1.77) PDAC. Colloid and tubular subtype was not associated with OS (P = 0.16). CONCLUSIONS: PanIN-derived PDAC has worse survival than IPMN-derived PDAC supporting distinct outcomes. Although more indolent, colloid IPMN-derived PDAC has similar survival to tubular after risk adjustment.

What is the optimal surgical approach for ductal adenocarcinoma of the pancreatic neck? - a retrospective cohort study.

BACKGROUND: The appropriate surgical approach for pancreatic ductal adenocarcinoma (PDAC) is determined by the tumor's relation to the porto-mesenteric axis. Although the extent and location of lymphadenectomy is dependent on the type of resection, a pancreatoduodenectomy (PD), distal pancreatectomy (DP), or total pancreatectomy (TP) are considered equivalent oncologic operations for pancreatic neck tumors. Therefore, we aimed to assess differences in histopathological and oncological outcomes for surgical approaches in the treatment of pancreatic neck tumors. METHODS: Patients with resected PDAC located in the pancreatic neck were identified from the National Cancer Database (2004-2020). Patients with metastatic disease were excluded. Furthermore, patients with 90-day mortality and R2-resections were excluded from the multivariable Cox-regression analysis. RESULTS: Among 846 patients, 58% underwent PD, 25% DP, and 17% TP with similar R0-resection rates (p = 0.722). Significant differences were observed in nodal positivity (PD:44%, DP:34%, TP:57%, p < 0.001) and mean-number of examined lymph nodes (PD:17.2 ± 10.4, DP:14.7 ± 10.5, TP:21.2 ± 11.0, p < 0.001). Furthermore, inadequate lymphadenectomy (< 12 nodes) was observed in 30%, 44%, and 19% of patients undergoing PD, DP, and TP, respectively (p < 0.001). Multivariable analysis yielded similar overall survival after DP (HR:0.83, 95%CI:0.63-1.11), while TP was associated with worse survival (HR:1.43, 95%CI:1.08-1.89) compared to PD. CONCLUSION: While R0-rates are similar amongst all approaches, DP is associated with inadequate lymphadenectomy which may result in understaging disease. However, this had no negative influence on survival. In the premise that an oncological resection of the pancreatic neck tumor is feasible with a partial pancreatectomy, no benefit is observed by performing a TP.

Conduits in Vascular Pancreatic Surgery: Analysis of Clinical Outcomes, Operative Techniques, and Graft Performance.

OBJECTIVES: We analyze successes and failures of pushing the boundaries in vascular pancreatic surgery to establish safety of conduit reconstructions. BACKGROUND: Improved systemic control from chemotherapy in pancreatic cancer is increasing the demand for surgical solutions of extensive local vessel involvement, but conduit-specific data are scarce. METHODS: We identified 63 implanted conduits (41% autologous vessels, 37% allografts, 18% PTFE) in 56 pancreatic resections of highly selected cancer patients between October 2013 and July 2020 from our prospectively maintained database. Assessed parameters were survival, perioperative complications, operative techniques (anatomic and extra-anatomic routes), and conduit patency. RESULTS: For vascular reconstruction, 25 arterial and 38 venous conduits were utilized during 39 pancreatoduodenectomies, 14 distal pancreatectomies, and 3 total pancreatectomies. The median postoperative survival was 2 years. A Clavien-Dindo grade ≥IIIa complication was apparent in 50% of the patients with a median Comprehensive Complication Index of 29.6. The 90-day mortality in this highly selected cohort was 9%. Causes of mortality were conduit related in 3 patients, late postpancreatectomy hemorrhage in 1 patient, and early liver metastasis in 1 patient. Image-based patency rates of conduits were 66% and 45% at postoperative days 30 and 90, respectively. CONCLUSIONS: Our perioperative mortality of vascular pancreatic surgery with conduits in the arterial or venous system is 9%. Reconstructions are technically feasible with different anatomic and extra-anatomic strategies, while identifying predictors of early conduit occlusion remains challenging. Optimizing reconstructed arterial and venous hemodynamics in the context of pancreatic malignancy will enable long-term survival in more patients responsive to chemotherapies.

A Delay in Adjuvant Therapy Is Associated With Worse Prognosis Only in Patients With Transitional Circulating Tumor Cells After Resection of Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: The aim of the study was to assess the association of circulating tumor cells (CTCs) with survival as a biomarker in pancreatic ductal adenocarcinoma (PDAC) within the context of a delay in the initiation of adjuvant therapy. BACKGROUND: Outcomes in patients with PDAC remain poor and are driven by aggressive systemic disease. Although systemic therapies improve survival in resected patients, factors such as a delay in the initiation of adjuvant therapy are associated with worse outcomes. CTCs have previously been shown to be predictive of survival. METHODS: A retrospective study was performed on PDAC patients enrolled in the prospective CircuLating tUmor cellS in pancreaTic cancER trial (NCT02974764) on CTC-dynamics at the Johns Hopkins Hospital. CTCs were isolated based on size (isolation by size of epithelial tumor cells; Rarecells) and counted and characterized by subtype using immunofluorescence. The preoperative and postoperative blood samples were used to identify 2 CTC types: epithelial CTCs (eCTCs), expressing pancytokeratin, and transitional CTCs (trCTCs), expressing both pancytokeratin and vimentin. Patients who received adjuvant therapy were compared with those who did not. A delay in the receipt of adjuvant therapy was defined as the initiation of therapy ≥8 weeks after surgical resection. Clinicopathologic features, CTCs characteristics, and outcomes were analyzed. RESULTS: Of 101 patients included in the study, 43 (42.5%) experienced a delay in initiation and 20 (19.8%) did not receive adjuvant therapy. On multivariable analysis, the presence of trCTCs ( P =0.002) and the absence of adjuvant therapy ( P =0.032) were associated with worse recurrence-free survival (RFS). Postoperative trCTC were associated with poorer RFS, both in patients with a delay in initiation (12.4 vs 17.9 mo, P =0.004) or no administration of adjuvant chemotherapy (3.4 vs NR, P =0.016). However, it was not associated with RFS in patients with timely initiation of adjuvant chemotherapy ( P =0.293). CONCLUSIONS: Postoperative trCTCs positivity is associated with poorer RFS only in patients who either experience a delay in initiation or no receipt of adjuvant therapy. This study suggests that a delay in the initiation of adjuvant therapy could potentially provide residual systemic disease (trCTCs) a window of opportunity to recover from the surgical insult. Future studies are required to validate these findings and explore the underlying mechanisms involved.

Progression of Site-Specific Recurrence of Pancreatic Cancer and Implications for Treatment.

OBJECTIVE: This study aimed to analyze post-recurrence progression in context of recurrence sites and assess implications for post-recurrence treatment. BACKGROUND: Most patients with resected pancreatic ductal adenocarcinoma (PDAC) recur within two years. Different survival outcomes for location-specific patterns of recurrence are reported, highlighting their prognostic value. However, a lack of understanding of post-recurrence progression and survival remains. METHODS: This retrospective analysis included surgically treated PDAC patients at the NYU-Langone Health (2010-2021). Sites of recurrence were identified at time of diagnosis and further follow-up. Kaplan-Meier curves, log-rank test, and Cox-regression analyses were applied to assess survival outcomes. RESULTS: Recurrence occurred in 57.3% (196/342) patients with a median time to recurrence of 11.3 months (95%CI:12.6 to 16.5). First site of recurrence was local in 43.9% patients, liver in 23.5%, peritoneal in 8.7%, lung in 3.6%, while 20.4% had multiple sites of recurrence. Progression to secondary sites was observed in 11.7%. Only lung involvement was associated with significantly longer survival after recurrence compared to other sites (16.9 months vs. 8.49 months, P=0.003). In local recurrence, 21 (33.3%) patients were alive after one year without progression to secondary sites. This was associated with a CA19-9 of <100U/ml at time of primary diagnosis (P=0.039), nodal negative disease (P=0.023), and well-moderate differentiation (P=0.042) compared to patients with progression. CONCLUSION: Except for lung recurrence, post-recurrence survival after PDAC resection is associated with poor survival. A subset of patients with local-only recurrence do not quickly succumb to systemic spread. This is associated with markers for favorable tumor biology, making them candidates for potential curative re-resections when feasible.

Surgical Decision-Making in Pancreatic Ductal Adenocarcinoma: Modeling Prognosis Following Pancreatectomy in the Era of Induction and Neoadjuvant Chemotherapy.

OBJECTIVE: To develop a predictive model of oncologic outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) undergoing resection after neoadjuvant or induction chemotherapy use. BACKGROUND: Early recurrence following surgical resection for PDAC is common. The use of neoadjuvant chemotherapy prior to resection may increase the likelihood of long-term systemic disease control. Accurately characterizing an individual's likely oncologic outcome in the perioperative setting remains challenging. METHODS: Data from patients with PDAC who received chemotherapy prior to pancreatectomy at a single high-volume institution between 2007 and 2018 were captured in a prospectively collected database. Core clinicopathologic data were reviewed for accuracy and survival data were abstracted from the electronic medical record and national databases. Cox-proportional regressions were used to model outcomes and develop an interactive prognostic tool for clinical decision-making. RESULTS: A total of 581 patients were included with a median overall survival (OS) and recurrence-free survival (RFS) of 29.5 (26.5-32.5) and 16.6 (15.8-17.5) months, respectively. Multivariable analysis demonstrates OS and RFS were associated with type of chemotherapeutic used andthe number of chemotherapy cycles received preoperatively. Additional factors contributing to survival models included: tumor grade, histopathologic response to therapy, nodal status, and administration of adjuvant chemotherapy. The models were validated using an iterative bootstrap method and with randomized cohort splitting. The models were well calibrated with concordance indices of 0.68 and 0.65 for the final OS and RFS models, respectively. CONCLUSION: We developed an intuitive and dynamic decision-making tool that can be useful in estimating OS, RFS, and location-specific disease recurrence rates. This prognostic tool may add value to patient care in discussing the benefits associated with surgical resection for PDAC.

Resected Early-Onset Pancreatic Cancer: Practices and Outcomes in an International Dual-Center Study.

BACKGROUND: Early-onset pancreatic cancer (EOPC), defined as age ≤ 45 years at diagnosis, accounts for 3% of all pancreatic cancer cases. Although differences in tumor biology have been suggested, available data are sparse and specific treatment recommendations are lacking. This study explores the clinicopathological features and oncologic outcomes of resected EOPC. PATIENTS AND METHODS: Patients with EOPC undergoing resection between 2002 and 2018 were identified from the Heidelberg University Hospital and Johns Hopkins University registries. Median overall survival (OS) and recurrence-free survival (RFS) were analyzed, and prognostic factors were identified. RESULTS: The final cohort included 164 patients, most of whom had pancreatic ductal adenocarcinoma (PDAC, n = 136; 82.9%) or IPMN-associated pancreatic cancer (n = 17; 10.4%). Twenty (12.1%) patients presented with stage 1 disease, 42 (25.6%) with stage 2, 75 (45.7%) with stage 3, and 22 (13.4%) with oligometastatic stage 4 disease. Most patients underwent upfront resection (n = 113, 68.9%), whereas 51 (31.1%) individuals received preoperative treatment. Median OS and RFS were 26.0 and 12.4 months, respectively. Stage-specific median survival was 70.6, 41.8, 23.8, and 16.9 months for stage 1, 2, 3, and 4 tumors, respectively. Factors independently associated with shorter OS and RFS were R1 resections and AJCC stages 3 and 4. Notably, AJCC 3-N2 and AJCC 3-T4 tumors had a median OS of 20 months versus 29.5 months, respectively. CONCLUSION: Despite frequently presenting with advanced disease, oncologic outcomes in EOPC patients are satisfactory even in locally advanced cancers, justifying aggressive surgical approaches. Further research is needed to tailor current guidelines to this rare population.

Detecting Somatic Mutations for Well-Differentiated Pancreatic Neuroendocrine Tumors in Endoscopic Ultrasound-Guided Fine Needle Aspiration with Next-Generation Sequencing.

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) exhibit heterogenous behavior, whereby some small tumors are aggressive with a propensity for metastasis. Detection of somatic mutations associated with aggressive biology may help with patient stratification and surgical decision-making in patients with well-differentiated PanNETs. Using next-generation sequencing (NGS), we investigated the feasibility of detecting somatic mutations in endoscopic ultrasound-guided, fine-needle aspiration (EUS-FNA) specimens and determining the mutational concordance between the EUS-FNA specimens and the primary tumors. METHODS: Thirty-eight patients with well-differentiated, nonfunctioning PanNETs were obtained from two tertiary referral centers. Patient demographic characteristics and tumor, clinicopathologic features were collected. Tissue from both the EUS-FNA specimen and the primary tumor was extracted from archival tissue blocks. NGS using a panel of ten genes was performed on both samples. RESULTS: In our series, the median age was 61.1 years. Tumors were predominantly left-sided (60.5%) and unifocal (94.7%). The median tumor size was 2.2 cm. NGS detected somatic mutations in 29% of primary tumors and 36.8% of EUS-FNA specimens. In primary tumors, DAXX/ATRX mutations were predominantly detected (63.6%). In EUS-FNA specimens, MEN1 mutations were predominantly detected (64.3%). Among non-wild-type specimens, mutational concordance was achieved in 31.6% of cases. In 11 patients with a detectable mutation in the primary tumor, a mutation was detected in the EUS-FNA specimen in 45.5% of cases, with a mutational concordance of 54.5%. CONCLUSIONS: NGS can detect somatic mutations in EUS-FNA specimens of well-differentiated PanNETs. Efforts to improve detection sensitivity and mutational concordance are required to overcome current technical limitations.

Concepts and techniques for revascularization of replaced hepatic arteries in pancreatic head resections.

BACKGROUND: The relationship of pancreatic ductal adenocarcinoma (PDAC) to important peripancreatic vasculature dictates resectability. As per the current guidelines, tumors with extensive, unreconstructible venous or arterial involvement are staged as unresectable locally advanced pancreatic cancer (LAPC). The introduction of effective multiagent chemotherapy and development of surgical techniques, have renewed interest in local control of PDAC. High-volume centers have demonstrated safe resection of short-segment encasement of the common hepatic artery. Knowledge of the unique anatomy of the patient's vasculature is important in surgical planning of these complex resections. Hepatic artery anomalies are common and insufficient knowledge can result in iatrogenic vascular injury during surgery. METHODS AND RESULTS: Here, we discuss different strategies to resect and reconstruct replaced hepatic arteries during pancreatectomy for PDAC to ensure restoration of adequate blood flow to the liver. Strategies include various arterial transpositions, in-situ interposition grafts and the use of extra-anatomic jump grafts. CONCLUSION: These surgical techniques allow more patients to undergo the only available curative treatment currently available for PDAC. Moreover, these improvements in surgical techniques highlight the shortcoming of current resectability criteria, which rely mainly on local tumor involvement and technical resectability, and disregards tumor biology.

Invasive and Noninvasive Progression After Resection of Noninvasive Intraductal Papillary Mucinous Neoplasms.

OBJECTIVE: To define frequencies, pattern of progression (invasive vs noninvasive), and risk factors of progression of resected noninvasive intraductal papillary mucinous neoplasms (IPMNs). BACKGROUND: There is a risk of progression in the remnant pancreas after resection of IPMNs. METHODS: Four hundred forty-nine consecutive patients with resected IPMNs from 1995 to 2018 were included to the study. Patients with invasive carcinoma or with follow-up <6 months were excluded. Noninvasive progression was defined as a new IPMN, increased main pancreatic duct size, and increased size of an existing lesion (5 mm compared with preoperative imaging). Invasive progression was defined as development of invasive cancer in the remnant pancreas or metastatic disease. RESULTS: With a median follow-up of 48.9 months, progression was identified in 124 patients (27.6%); 108(24.1%) with noninvasive and 16(3.6%) with invasive progression. Median progression follow-up was longer for invasive progression (85.4 vs 55.9 months; P = 0.001). Five-and 10-year estimates for a cumulative incidence of invasive progression were 6.4% and 12.9% versus 26.9% and 41.5% for noninvasive progression. After risk adjustment, multifocality (HR 4.53, 95% CI 1.34-15.26; P = 0.02) and high-grade dysplasia (HGD) in the original resection (HR 3.60, 95% CI 1.13-11.48; P = 0.03) were associated with invasive progression. CONCLUSIONS: Progression to invasive carcinoma can occur years after the surgical resection of a noninvasive IPMN. HGD in the original resection is a risk factor for invasive progression but some cases of low-grade dysplasia also progressed to cancer. Patients with high-risk features such as HGD and multifocal cysts should be considered for more intensive surveillance and represent an important cohort for future trials such as anti-inflammatory or prophylactic immunotherapy.

Comprehensive Analysis of Somatic Mutations in Driver Genes of Resected Pancreatic Ductal Adenocarcinoma Reveals KRAS G12D and Mutant TP53 Combination as an Independent Predictor of Clinical Outcome.

BACKGROUND: Prognosis in pancreatic ductal adenocarcinoma (PDAC) remains poor despite improved systemic therapies and surgical techniques. The identification of biomarkers to advance insight in tumor biology and achieve better individualized prognostication could help improve outcomes. Our aim was to elucidate the prognostic role of the four main driver mutations (KRAS, TP53, SMAD4, CDKN2A) and their combinations in resected PDAC. PATIENTS AND METHODS: A retrospective analysis was conducted utilizing the cBioPortal database and National Cancer Institute's Cancer Genomic Atlas (TCGA) on patients in whom next-generation sequencing was performed on upfront resected PDAC from 2012 to 2020. Multivariable Cox regression was implemented to elucidate risk-adjusted predictors of overall (OS) and recurrence-free survival (RFS). Results were validated employing a Johns Hopkins Hospital (JHH) cohort.' RESULTS: In the discovery cohort (n = 587), increased number of mutated driver genes was associated with worse OS (p = 0.047). Specifically, patients with mutations in ≥ 2 driver genes had worse OS than ≤ 1 mutated gene (18.2 versus 32.3 months, p = 0.033). Co-occurrence of mutant (mt)KRAS p.G12D with mtTP53 (median OS, 25.9 months) conferred better prognosis than co-occurrence of other mtKRAS variants (p.G12V/R/other) with mtTP53 (median OS, 16.9 months, p = 0.038). The findings were validated using a JHH cohort. Multivariable risk-adjustment found co-occurrence of mtKRAS p.G12D with mtTP53 to be an independent predictor of beneficial OS and RFS [HR (95% CI): 0.18 (0.03-0.81) and 0.31 (0.11-0.89) respectively]. CONCLUSION: In chemo-naïve resected PDAC, combinations of mutations in the four driver genes are associated with prognosis. In patients with combined mtKRAS and mtTP53, KRAS p.G12D variant confers a better OS and RFS.

Postoperative Chemotherapy is Associated with Improved Survival in Patients with Node-Positive Pancreatic Ductal Adenocarcinoma After Neoadjuvant Therapy.

BACKGROUND: Postoperative chemotherapy following pancreatic cancer resection is the standard of care. The utility of postoperative chemotherapy for patients who receive neoadjuvant therapy (NAT) is unclear. METHODS: Patients who underwent pancreatectomy after NAT with FOLFIRINOX or gemcitabine-based chemotherapy for non-metastatic pancreatic adenocarcinoma (2015-2019) were identified. Patients who received less than 2 months of neoadjuvant chemotherapy or died within 90 days from surgery were excluded. RESULTS: A total of 427 patients (resectable, 22.2%; borderline resectable, 37.9%; locally advanced, 39.8%) were identified with the majority (69.3%) receiving neoadjuvant FOLFIRINOX. Median duration of NAT was 4.1 months. Following resection, postoperative chemotherapy was associated with an improved median overall survival (OS) (28.7 vs. 20.4 months, P = 0.006). Risk-adjusted multivariable modeling showed negative nodal status (N0), favorable pathologic response (College of American Pathologists score 0 & 1), and receipt of postoperative chemotherapy to be independent predictors of improved OS. Regimen, duration, and number of cycles of NAT were not significant predictors. Thirty-four percent (60/176) of node-positive and 50.1% (126/251) of node-negative patients did not receive postoperative chemotherapy due to poor functional status, postoperative complications, and patient preference. Among patients with node-positive disease, postoperative chemotherapy was associated with improved median OS (27.2 vs. 10.5 months, P < 0.001). Among node-negative patients, postoperative chemotherapy was not associated with a survival benefit (median OS, 30.9 vs. 36.9 months; P = 0.406). CONCLUSION: Although there is no standard NAT regimen for patients with pancreatic cancer, postoperative chemotherapy following NAT and resection appears to be associated with improved OS for patients with node-positive disease.

Incidence and Contemporary Management of Delayed Bleeding Following Pancreaticoduodenectomy.

BACKGROUND: Delayed bleeding after pancreaticoduodenectomy (PD) is a life-threatening complication. However, the optimal management remains unclear. We summarize our experience of the management of delayed bleeding after PD and define the outcomes associated with different types of management. METHODS: All patients who underwent a PD between January 1987 and June 2020 at Johns Hopkins University were retrospectively reviewed. Delayed bleeding was defined as bleeding on or after postoperative day 5 following PD. Incidence, outcomes, and trends were reported. RESULTS: Among the 6201 patients that underwent PD, delayed bleeding occurred in 130 (2.1%) at a median of 12 days (IQR: 9, 24) postoperation. The pattern of bleeding was classified as intraluminal (51.5%), extraluminal (40.8%), and mixed (7.7%). A clinically relevant postoperative pancreatic fistula and an intraabdominal abscess preceded the delayed bleeding in 43.1% and 31.5% of cases, respectively. Arterial pseudoaneurysm or bleeding from peripancreatic vessels was the most common reason (54.6%) with the gastroduodenal artery being the most common source (18.5%). Endoscopy, angiography, and reoperation were performed as a first-line approach in 35.4%, 52.3%, and 6.2% of patients, respectively. The overall mortality was 16.2% and decreased over the study period (p < 0.01). CONCLUSIONS: Delayed bleeding following PD remains a life-threatening complication. The most common location of delayed bleeding is from the gastroduodenal artery. Angiography with embolization should be the initial approach for urgent bleeding with surgical re-exploration reserved for unstable patients or failed control of bleeding after interventional angiography or endoscopy.

Incidence and Predictors of Surgical Site Infection Complications in Diabetic Patients Undergoing Lower Limb Amputation.

BACKGROUND: Surgical site infections (SSIs) following lower extremity amputations (LEAs) are a major cause of patient morbidity and mortality. The objectives of this study are to investigate the annual incidence of SSI and risk factors associated with SSI after LEA in diabetic patients. METHODS: LEAs performed on diabetic patients between 2005 and 2017 were retrospectively analyzed from the American College of Surgeons National Surgical Quality Improvement Program database. Incidence rates were calculated and analyzed for temporal change. Multivariable logistic regression was conducted to identify the independent predictors of SSIs in LEA. RESULTS: In 21,449 diabetic patients, the incidence of SSIs was 6.8% after LEA, with an overall decreasing annual trend (P = 0.013). Amputation location (below-knee in reference to above-knee) [OR (95% CI): 1.35 (1.20 - 1.53), P <0.001], smoking [OR (95% CI): 1.25 (1.11 - 1.41), P <0.001)], female sex [OR (95% CI): 1.16 (1.03 - 1.30)], preoperative sepsis [OR (95% CI): 1.24 (1.10 - 1.40), P <0.001], P = 0.013], emergency status [OR (95% CI): 1.38 (1.17 - 1.63), P <0.001], and obesity [OR (95% CI): 1.59 (1.12 - 2.27), P = 0.009] emerged as independent predictors of SSIs, while moderate/severe anemia emerged as a risk-adjusted protective factor [OR (95% CI): 0.75 (0.62 - 0.91), P = 0.003]. Sensitivity analysis found that moderate/severe anemia, not body mass index (BMI) class, remained a significant risk factor in the development of SSIs in below-the-knee amputations; in contrast, higher BMI, not preoperative hematocrit, was significantly associated with an increased risk for SSI in above-the-knee amputations. CONCLUSIONS: The incidence of SSIs after LEA in diabetic patients is decreasing. Overall, below-knee amputation, smoking, emergency status, and preoperative sepsis appeared to be associated with SSIs. Obesity increased SSIs in above-the-knee amputations, while moderate/severe preoperative anemia appears to protect against below-the-knee SSIs. Surgeons should take predictors of SSI into consideration while optimizing care for their patients, and future studies should investigate the role of preoperative hematocrit correction and how it may influence outcomes positively or negatively.

Should non-invasive diffuse main-duct intraductal papillary mucinous neoplasms be treated with total pancreatectomy?

BACKGROUND: Main-duct (MD) intraductal papillary mucinous neoplasm (IPMN) is associated with malignancy risk. There is a lack of consensus on treatment (partial or total pancreatectomy) when the MD is diffusely involved. We sought to characterize the pancreatic remnant fate after partial pancreatectomy for non-invasive diffuse MD-IPMN. METHODS: Consecutive patients with partial pancreatectomy for non-invasive MD-IPMN from 2004 to 2016 were analyzed. Diffuse MD-IPMN was defined by preoperative imaging as dilation of the MD in the head of the pancreas more than 5 mm and involving the whole gland. RESULTS: Of 127 patients with resected non-invasive MD-IPMN, 47 (37%) had diffuse MD involvement. Eleven of 47(23%) patients developed imaging evidence of progression or new cystic disease in the pancreatic remnant. Patients with diffuse MD-IPMN were older (73yrs vs 67yrs, p = 0.009), more likely to receive a pancreaticoduodenectomy (96% vs 56%, p < 0.001) and have high-grade dysplasia (51% vs 31%, p = 0.025) than those with focal MD involvement. Diffuse MD involvement was not associated with shorter PFS following partial pancreatectomy (p = 0.613). CONCLUSION: Partial pancreatectomy is an appropriate surgical approach for diffuse MD-IPMN, and is not associated with earlier progression after surgery as compared to partial pancreatectomy for focal dilation.

A Quality Assessment of the Information Accessible to Patients on the Internet About the Whipple Procedure.

BACKGROUND: The Internet has become a central source of information on health-related issues. The aim of this study is to assess the quality and readability of online information present on the Whipple surgical procedure by applying recognized scoring tools. METHODS: A search using the top three online search engines (Google, Bing and Yahoo) was conducted in July 2020. Websites were classified as academic, physician, commercial or unspecified. The quality of information was assessed using the JAMA and DISCERN assessment instruments and presence of a HONcode seal. Readability was assessed using the Flesch Reading Ease Score (FRES). RESULTS: A total of 34 unique sources were included in our study. The average JAMA and DISCERN scores of all websites were 2.22 ± 0.48 and 47.28 ± 1.17, respectively, with a median of 1.9 (range 0-4) and 47 (range 18-71), respectively. Website classification distribution was 38% academic, 18% commercial, 9% unspecified, and 1% from physician-based websites. Physician websites had the highest JAMA score with a mean of 3 ± 0.46. Unspecified websites had the highest DISCERN score with a mean of 54.60 ± 1.09. Only 3 websites had the HONcode seal. Physician websites had a significantly higher JAMA mean score than academic websites (p-value = 0.004). Readability was difficult and is on the level of university students. CONCLUSION: The results of this study show a poor quality of online information present on the Whipple surgery. Academic and physician websites need to improve the quality of their websites on the procedure. More HONcode-certified websites are needed as they are the best source for information on this operation.

Treatment and Prognosis of Hepatic Epithelioid Hemangioendothelioma: A SEER Database Analysis.

BACKGROUND: Hepatic epithelioid hemangioendothelioma (HEH) is a rare tumor that can affect multiple organs. Little is known about the pathophysiology, clinical course and management of this disease. The aim of this study is to determine survival rates and elucidate the role of various prognostic factors and therapeutic modalities as compared to surgery on patients with HEH. METHODS: A retrospective analysis on patients diagnosed with HEH between 2004 and 2016 was performed utilizing the SEER database. Kaplan-Meier curves were constructed to determine overall and cancer-specific survival, and the log-rank test was used to compare between groups. To explore prognostic factors and treatment outcomes, univariable and multivariable Cox proportional hazard models were developed. RESULTS: A total of 353 patients with HEH (median age: 50.4 years) were identified. The most common surgery performed was liver resection (90.8%). One-year OS in the surgical group and non-surgical group was 86.6% and 61.0%, respectively, while 5-year OS was 75.2% and 37.4%, respectively. On multivariable analysis, surgery emerged as a favorable prognostic factor [HR (95%CI): 0.404 (0.215-0.758) p value = 0.005]. Age > 65 years [HR (95%CI): 2.548 (1.442-4.506) p value = 0.001] and tumor size > 10 cm [HR (95%CI): 2.401 (1.319-4.37) p value = 0.004] were shown to be poor survival prognostic factors. CONCLUSION: HEH is a rare disease that is poorly understood. Surgical intervention is associated with improved survival rates. Multicenter prospective collaborations are needed to improve our limited knowledge about this neoplasm and determine the optimal treatment strategy.

Ovarian Metastasis from Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a high propensity for systemic dissemination. Ovarian metastases are rare and poorly described. METHODS: We identified PDAC cases with ovarian metastasis from a prospectively maintained registry. We reported on the association between outcomes and clinicopathologic factors. Recurrence-free (RFS) and overall survival (OS) were calculated using Kaplan-Meier analysis. RESULTS: Twelve patients with PDAC and synchronous or metachronous ovarian metastases were identified. Nine patients (75%) underwent pancreatectomy for localized PDAC and developed metachronous ovarian recurrence. The median OS for all patients was 25.4 (IQR:15.4-82.9) months. For the nine patients with metachronous ovarian metastasis, the median RFS and OS were 14.2 (IQR:7.2-58.3) and 44.6 (IQR:18.6-82.9) months, respectively. Nodal disease, poor grade, vascular invasion in the pancreatic primary, and bilateral ovarian disease tended to confer worse outcomes. CONCLUSION: Patients with resected PDAC and ovarian recurrence tend to have a comparable disease course to more common patterns of recurrence. Primaries with nodal disease, poorer grade, vascular invasion, and bilateral ovarian disease were indicative of more aggressive disease biology. The ideal management remains largely unknown, and future collaborative efforts should optimize therapeutic strategies.