Faculty Bibliography

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.

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.

OBJECTIVE:To develop a nomogram estimating the probability of recurrence free at 5 years after resection for localized grade 1 (G1)/ grade 2 (G2) pancreatic neuroendocrine tumors (PanNETs). BACKGROUND:Among patients undergoing resection of PanNETs, approximately 17% experience recurrence. It is not established which patients are at risk, with no consensus on optimal follow-up. METHOD/METHODS:A multi-institutional database of patients with G1/G2 PanNETs treated at 2 institutions was used to develop a nomogram estimating the rate of freedom from recurrence at 5 years after curative resection. A second cohort of patients from 3 additional institutions was used to validate the nomogram. Prognostic factors were assessed by univariate analysis using Cox regression model. The nomogram was internally validated using bootstrap resampling method and on the external cohort. Performance was assessed by concordance index (c-index) and a calibration curve. RESULTS:The nomogram was constructed using a cohort of 632 patients. Overall, 68% of PanNETs were G1, the median follow-up was 51 months, and we observed 74 recurrences. Variables included in the nomogram were the number of positive nodes, tumor diameter, Ki-67, and vascular/perineural invasion. The model bias-corrected c-index from the internal validation was 0.85, which was higher than European Neuroendocrine Tumors Society/American Joint Committee on Cancer 8th staging scheme (c-index 0.76, P = <0.001). On the external cohort of 328 patients, the nomogram c-index was 0.84 (95% confidence interval 0.79-0.88). CONCLUSION/CONCLUSIONS:Our externally validated nomogram predicts the probability of recurrence-free survival at 5 years after PanNETs curative resection, with improved accuracy over current staging systems. Estimating individual recurrence risk will guide the development of personalized surveillance programs after surgery.

BACKGROUND:Nodal involvement has been identified as one of the strongest prognostic factors in patients with nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs). Sufficient lymphadenectomy and evaluation is vital for accurate staging. The purpose of this study was to identify the optimal number of examined lymph nodes (ELN) required for accurate staging. METHODS:The SEER database was used to identify patients with resected NF-PanNETs between 2004 and 2014. The distributions of positive lymph nodes (PLN) ratio and total lymph nodes were used to develop a mathematical model. The sensitivity of detecting nodal disease at each cutoff of ELN was estimated and used to identify the optimal cutoff for ELN. RESULTS:A total of 1098 patients were included in the study of which 391 patients (35.6%) had nodal disease. The median ELN was 12 (interquartile range [IQR]: 7-19.5), and the median PLN was 2 (IQR: 1-4) for patients with nodal disease. With an increase in ELN, the sensitivity of detecting nodal disease increased from 12.0% (ELN: 1) to 92.2% (ELN: 20), plateauing at 20 ELN (< 1% increase in sensitivity with an additional ELN). This sensitivity increase pattern was similar in subgroup analyses with different T stages. CONCLUSIONS:The sensitivity of detecting nodal disease in patients with NF-PanNETs increases with an increase in the number of ELN. Cutoffs for adequate nodal assessment were defined for all T stages. Utilization of these cutoffs in clinical settings will help with patient prognostication and management.

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.

MINI: An international survey of high-volume pancreas cancer surgeons revealed wide variations in management preferences, attitudes regarding contraindications to surgery, and the propensity to offer exploration. When presented with 6 hypothetical clinical vignettes using details from real patients that have received R0 resection, only 14% to 53% of participating surgeons were willing to offer exploration following neoadjuvant therapy.

OBJECTIVE:To examine the prognostic impact of tumor laterality in colon cancer liver metastases (CLM) after stratifying by Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutational status. BACKGROUND:Although some studies have demonstrated that patients with CLM from a right sided (RS) primary cancer fare worse, others have found equivocal outcomes of patients with CLM with RS versus left-sided (LS) primary tumors. Importantly, recent evidence from unresectable metastatic CRC suggests that tumor laterality impacts prognosis only in those with wild-type tumors. METHODS:Patients with rectal or transverse colon tumors and those with unknown KRAS mutational status were excluded from analysis. The prognostic impact of RS versus LS primary CRC was determined after stratifying by KRAS mutational status. RESULTS:277 patients had a RS (38.6%) and 441 (61.4%) had a LS tumor. Approximately one-third of tumors (28.1%) harbored KRAS mutations. In the entire cohort, RS was associated with worse 5-year overall survival (OS) compared with LS (39.4% vs 50.8%, P = 0.03) and remained significantly associated with worse OS in the multivariable analysis (hazard ratio 1.45, P = 0.04). In wild-type patients, a worse 5-year OS associated with a RS tumor was evident in univariable analysis (43.7% vs 55.5%, P = 0.02) and persisted in multivariable analysis (hazard ratio 1.49, P = 0.01). In contrast, among patients with KRAS mutated tumors, tumor laterality had no impact on 5-year OS, even in the univariable analysis (32.8% vs 34.0%, P = 0.38). CONCLUSIONS:This study demonstrated, for the first time, that the prognostic impact of primary tumor side differs according to KRAS mutational status. RS tumors were associated with worse survival only in patients with wild-type tumors.

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.

BACKGROUND:The aim of this study was to determine the incidence of high-grade dysplasia (HGD) or invasive carcinoma in patients with small branch duct intraductal papillary mucinous neoplasms (BD-IPMNs). METHODS:923 patients who underwent surgical resection for an IPMN were identified. Sendai-negative patients were identified as those without history of pancreatitis or jaundice, main pancreatic duct size (MPD) <5 mm, cyst size <3 cm, no mural nodules, negative cyst fluid cytology for adenocarcinoma, or serum carbohydrate antigen 19-9 (CA 19-9) <37 U/L. RESULTS:BD-IPMN was identified in 388 (46.4%) patients and 89 (22.9%) were categorized as Sendai-negative. Overall, 68 (17.5%) of BD-IPMN had HGD and 62 (16.0%) had an associated invasive-carcinoma. Among the 89 Sendai-negative patients, 12 (13.5%) had IPMNs with HGD and only one patient (1.1%) had invasive-carcinoma. Of note, older age (OR 1.13, 95% CI 1.03-1.23; P = 0.008) and minimal dilation of MPD (OR 11.3, 95% CI 2.40-53.65; P = 0.002) were associated with high-risk disease in Sendai-negative patients after multivariable risk adjustment. CONCLUSION/CONCLUSIONS:The risk of harboring a high-risk disease remains low in small BD-IPMNs. However, Sendai-negative patients who are older than 65 years old and those with minimal dilation of MPD (3-5 mm) are at greater risk of high-risk lesions and should be given consideration to be included as a "worrisome feature" in a future guidelines update.

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.