Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Despite the long-standing consensus on the importance of tumor size, tumor number and carcinoembryonic antigen (CEA) levels as predictors of long-term outcomes among patients with colorectal liver metastases (CRLM), optimal prognostic cut-offs for these variables have not been established. METHODS:Patients who underwent curative-intent resection of CRLM and had available data on at least one of the three variables of interest above were selected from a multi-institutional dataset of patients with known KRAS mutational status. The resulting cohort was randomly split into training and testing datasets and recursive partitioning analysis was employed to determine optimal cut-offs. The concordance probability estimates (CPEs) for these optimal cut offs were calculated and compared to CPEs for the most widely used cut-offs in the surgical literature. RESULTS:A total of 1643 patients who met eligibility criteria were identified. Following recursive partitioning analysis in the training dataset, the following cut-offs were identified: 2.95 cm for tumor size, 1.5 for tumor number and 6.15 ng/ml for CEA levels. In the entire dataset, the calculated CPEs for the new tumor size (0.52), tumor number (0.56) and CEA (0.53) cut offs exceeded CPEs for other commonly employed cut-offs. CONCLUSION/CONCLUSIONS:The current study was able to identify optimal cut-offs for the three most commonly employed prognostic factors in CRLM. While the per variable gains in discriminatory power are modest, these novel cut-offs may help produce appreciable increases in prognostic performance when combined in the context of future risk scores.

BACKGROUND:Pancreatoduodenectomies at high risk for clinically relevant pancreatic fistula are uncommon, yet intimidating, situations. In such scenarios, the impact of individual surgeon experience on outcomes is poorly understood. METHODS:The fistula risk score was applied to identify high-risk patients (fistula risk score 7-10) from 7,706 pancreatoduodenectomies performed at 18 international institutions (2003-2020). For each case, surgeon pancreatoduodenectomy career volume and years of practice were linked to intraoperative fistula mitigation strategy adoption and outcomes. Consequently, best operative approaches for clinically relevant pancreatic fistula prevention and best performer profiles were identified through multivariable analysis models. RESULTS:Eight hundred and thirty high-risk pancreatoduodenectomies, performed by 64 surgeons, displayed an overall clinically relevant pancreatic fistula rate of 33.7%. Clinically relevant pancreatic fistula rates decreased with escalating surgeon career pancreatoduodenectomy (-49.7%) and career length (-41.2%; both P < .001), as did transfusion and reoperation rates, postoperative morbidity index, and duration of stay. Great experience (≥400 pancreatoduodenectomies performed or ≥21-year-long career) was a significant predictor of clinically relevant pancreatic fistula prevention (odds ratio 0.52, 95% confidence interval 0.35-0.76) and was more often associated with pancreatojejunostomy reconstruction and prophylactic octreotide omission, which were both independently associated with clinically relevant pancreatic fistula reduction. A risk-adjusted performance analysis also correlated with experience. Moreover, minimizing blood loss (≤400 mL) significantly contributed to clinically relevant pancreatic fistula prevention (odds ratio 0.40, 95% confidence interval 0.22-0.74). CONCLUSION/CONCLUSIONS:Surgeon experience is a key contributor to achieve better outcomes after high-risk pancreatoduodenectomy. Surgeons can improve their performance in these challenging situations by employing pancreatojejunostomy reconstruction, omitting prophylactic octreotide, and minimizing blood loss.

OBJECTIVE:We evaluated survival outcomes in patients with distal pancreatic ductal adenocarcinoma (D-PDAC) after distal pancreatectomy (DP) and adjuvant chemotherapy or chemoradiation. METHODS:A retrospective analysis of patients who underwent DP for D-PDAC from 2000 to 2015 at the Johns Hopkins Hospital was performed. Demographics, baseline risk factors, and type of adjuvant treatment were assessed for associations with overall survival (OS) and disease-free survival (DFS). Comparisons were made with log-rank tests and Cox proportional hazards regression models. RESULTS:A total of 294 patients underwent DP for D-PDAC. Of these, 105 patients were followed at the Johns Hopkins Hospital. Forty-five patients received chemotherapy only and 60 patients received chemoradiation. The median OS with chemoradiation was 33.6 months and 27.9 months (P = 0.54) with chemotherapy only. The median DFS was 15.3 months with chemoradiation and 19.8 months with chemotherapy only (P = 0.89). Elevated carbohydrate antigen 19-9, stage II to III disease, splenic vein involvement, and vascular invasion were significant risk factors in multivariate analyses. CONCLUSIONS:In this retrospective analysis, there were no significant differences in OS or DFS with chemoradiation compared with chemotherapy alone after DP in patients with D-PDAC.

BACKGROUND:Historically, a positive margin after pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) was associated with decreased survival. In an era when neoadjuvant chemotherapy (NAC) is being used frequently, the prognostic significance of margin status is unclear. STUDY DESIGN/METHODS:Patients with localized PDAC who received NAC and underwent pancreatectomy from 2011-2018 were identified from a single-institution database. Patients with fewer than 2 months of NAC, R2 resection, or less than 90-day follow-up were excluded. A positive margin included tumors within 1 mm of the surgical margin. RESULTS:468 patients met inclusion criteria. The median age was 65 and 53% were female. Preoperative clinical staging demonstrated most had locally advanced (n=222, 47%) or borderline resectable (n=172, 37%) disease. The median follow-up was 18.5 (10.6-30.0) months. The median duration of NAC was 119 (IQR:87-168) days. FOLFIRINOX was first-line therapy for 67%, and 73% received neoadjuvant radiotherapy. Most underwent pancreaticoduodenectomy (69%). 40% were node positive and 80% had an R0 resection. 56% received at least one cycle of adjuvant therapy. Median overall survival (OS) and recurrence-free survival (RFS) were 22.0 (CI: 19.4-25.1) and 11.0 (CI: 10.0-12.1) months. On multivariate analysis, margin status was not a significant predictor of OS or RFS. Factors associated with OS included: clinical stage, duration of NAC, nodal status, histopathologic treatment response score, and receipt of adjuvant chemotherapy. CONCLUSIONS:Microscopic margin positivity is not associated with recurrence and survival in localized PDAC patients resected after treatment with NAC. Aggressive surgical extirpation in high volume centers should be considered in selected patients after extensive NAC.

PURPOSE/OBJECTIVE:Immunotherapy is currently ineffective for nearly all pancreatic ductal adenocarcinomas(PDAC), largely due to its tumor microenvironment(TME) that lacks antigen experienced T effector cells(Teffs). Vaccine-based immunotherapies are known to activate antigen-specific Teffs in the peripheral blood. To evaluate the effect of vaccine therapy on the PDAC TME, we designed a neoadjuvant and adjuvant clinical trial of an irradiated, granulocyte-macrophage colony-stimulating factor(GM-CSF)-secreting, allogeneic PDAC vaccine(GVAX). EXPERIMENTAL DESIGN/METHODS:Eighty-seven eligible patients with resectable PDAC were randomly assigned(1:1:1) to receive GVAX alone or in combination with two forms of low-dose cyclophosphamide(Cy). Resected tumors following neoadjuvant immunotherapy were assessed for the formation of tertiary lymphoid aggregates(TLA) in response to treatment. The clinical endpoints are disease-free survival(DFS) and overall survival(OS). RESULTS:The neoadjuvant treatment with GVAX either alone or with two forms of low dose Cy is safe and feasible without adversely increasing the surgical complication rate. Patients in Arm A who received neoadjuvant and adjuvant GVAX alone had a trend toward longer median OS(35.0 months) than that(24.8 months) in the historical controls who received adjuvant GVAX alone. However, Arm C, who received low dose oral Cy in addition to GVAX, had a significantly shorter DFS than Arm A. When comparing patients with OS>24 months to those with OS<15 months, longer OS was found to be associated with higher density of intratumoral TLA. CONCLUSIONS:It is safe and feasible to use a neoadjuvant immunotherapy approach for PDACs to evaluate early biologic responses. In-depth analysis of TLAs is warranted in future neoadjuvant immunotherapy clinical trials.

INTRODUCTION/BACKGROUND:Robotic pancreaticoduodenectomy is slowly gaining acceptance within pancreatic surgery. Advantages have been demonstrated for robotic surgery in other fields, but robust data for pancreaticoduodenectomy is limited. The aim of this study was to compare the short-term outcomes of robotic pancreaticoduodenectomy (RPD) to open pancreaticoduodenectomy (OPD) and laparoscopic pancreaticoduodenectomy (LPD). METHODS:Patients who underwent a pancreaticoduodenectomy between January 2011 and July 2019 at the Johns Hopkins Hospital were included in this retrospective propensity-matched analysis. The RPD cohort was matched to patients who underwent OPD in a 1:2 fashion and LPD in a 1:1 fashion. Short-term outcomes were analyzed for all three cohorts. RESULTS:In total, 1644 patients were included, of which 96 (5.8%) underwent RPD, 131 (8.0%) LPD, and 1417 (86.2%) OPD. RPD was associated with a decreased incidence of delayed gastric emptying (9.4%) compared to OPD (23.5%; P = 0.006). The median estimated blood loss was significantly less in the RPD cohort (RPD vs OPD, 150 vs 487 mL; P < 0.001, RPD vs LPD, 125 vs 300 mL; P < 0.001). Compared to OPD, the robotic approach was associated with a shorter median length of stay (median 8 vs 9 days; P = 0.014) and a decrease in wound complications (4.2% vs 16.7%; P = 0.002). The incidence of other postoperative complications was comparable between RPD and OPD, and RPD and LPD. CONCLUSION/CONCLUSIONS:In the hands of experienced surgeons, RPD may have a modest yet statistically significant reduction in estimated blood loss, postoperative length of stay, wound complications, and delayed gastric emptying comparing to OPD in similar patients.

Recent research on genomic profiling of pancreatic ductal adenocarcinoma (PDAC) has identified many potentially actionable alterations. However, the feasibility of using genomic profiling to guide routine clinical decision making for PDAC patients remains unclear. We retrospectively reviewed PDAC patients between October 2013 and December 2017, who underwent treatment at the Johns Hopkins Hospital and had clinical tumor next-generation sequencing (NGS) through commercial resources. Ninety-two patients with 93 tumors tested were included. Forty-eight (52%) patients had potentially curative surgeries. The median time from the tissue available to the NGS testing ordered was 229 days (interquartile range 62-415). A total of three (3%) patients had matched targeted therapies based on genomic profiling results. Genomic profiling guided personalized treatment for PDAC patients is feasible, but the percentage of patients who receive targeted therapy is low. The main challenges are ordering NGS testing early in the clinical course of the disease and the limited evidence of using a targeted approach in these patients. A real-time department level genomic testing ordering system in combination with an evidence-based flagging system for potentially actionable alterations could help address these shortcomings.

OBJECTIVE:The aim of this study was to characterize the patterns and treatment of disease recurrence in patients achieving a pathological complete response (pCR) following neoadjuvant chemoradiation for advanced pancreatic ductal adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA/BACKGROUND:A pCR is an independent predictor for improved survival in PDAC. However, disease recurrence is still observed in these patients. METHODS:Patients with advanced PDAC who were treated with neoadjuvant therapy and had a pCR were identified between 2009 and 2017. Overall survival (OS) was determined from the initiation of neoadjuvant, disease-free survival (DFS) from the date of surgery, and post-recurrence survival (PRS) from the date of recurrence. Factors associated with recurrence were analyzed using a Cox-regression model. RESULTS:Of 331 patients with borderline resectable or locally advanced PDAC, 30 achieved a pCR following neoadjuvant treatment and pancreatectomy. The median DFS for pCR patients was 29 months and OS 76 months. Recurrence was observed in 14 patients. No clinicopathologic or treatment characteristics were associated with survival. The median PRS following recurrence was 25 months. Treatment following recurrence included chemotherapy, radiation or ablation, and surgical resection. Hepatectomy or completion pancreatectomy was accomplished in 2 patients that remain alive 13 and 62 months, respectively, following metastasectomy. CONCLUSIONS:A pCR following neoadjuvant therapy in patients with advanced PDAC is associated with remarkable survival, although recurrence occurs in about half of patients. Nevertheless, patients with pCR and recurrence respond well to treatment and survival remains encouraging. Advanced molecular characterization and longitudinal liquid biopsy may offer additional assistance with understanding tumor biologic behavior after achieving a pCR.

BACKGROUND:Lymph node (LN) metastasis is associated with decreased survival following resection for pancreatic ductal adenocarcinoma (PDAC). In N0 disease, increasing total evaluated LN (ELN) correlates with improved outcomes suggesting patients may be understaged when LNs are undersampled. We aim to assess the optimal number of examined lymph nodes (ELN) following pancreatectomy. METHODS:Data from 1837 patients undergoing surgery were prospectively collected. The binomial probability law was utilized to analyze the minimum number of examined LNs (minELN) and accurately characterize each histopathologic stage. LN ratio (LNR) was compared to American Joint Committee on Cancer (AJCC) guidelines. RESULTS:As ELN total increased, the likelihood of finding node positive disease increased. An evaluation based upon the binomial probability law suggested an optimal minELN of 12 for accurate AJCC N staging. As the number of ELNs increased, the discriminatory capacity of alternative strategies to characterize LN disease exceeded that offered by AJCC N stage. CONCLUSION/CONCLUSIONS:This is the first study dedicated to optimizing histopathologic staging in PDAC using models of minELN informed by the binomial probability law. This study highlights two separate cutoffs for ELNs depending upon prognostic goal and validates that 12 LNs are adequate to determine AJCC N stage for the majority of patients.

PURPOSE/OBJECTIVE:To evaluate somatic mutations, circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in patients with Pancreatic ductal adenocarcinoma (PDAC) with pathologic complete response (pCR) to neoadjuvant therapy (NAT) and find their associations with outcome. EXPERIMENTAL DESIGN/METHODS:. RESULTS:= 0.081). Five patients available for CTCs data were all positive for CTCs and seven of 16 patients with pCR were detected with ctDNA at surgery. We proposed a new concept of regression assessment combining genomic analysis of resected specimens and liquid biopsy data for PDAC, namely, molecular complete response (mCR). Three of six patients with mCR recurred as compared with six in 15 non-mCR patients. Seven of 15 non-mCR patients died during follow-up, while there was only one in six patients with mCR. CONCLUSIONS:This study first reports that somatic mutations, CTCs, and ctDNA existed even in patients with PDAC with pCR to NAT, which could possibly predict early recurrence and reduced survival. The current regression evaluation system of PDAC needs to be reassessed at a molecular level.