Surgical Resection For Pancreatic Adenocarcinoma Research Articles

HPB P27 Prognostication for Patterns of Recurrence After Surgical Resection for Pancreatic Adenocarcinoma

Abstract Background This study aims to investigate patterns and factors affecting recurrence after curative resection for pancreatic adenocarcinoma (PDAC). Methods Consecutive patients who underwent curative resection for PDAC (2011-21) and consented to data and tissue collection (Barts Pancreas Tissue Bank) Were followed up till May 2023. Clinico-pathological variables were analysed using Cox proportional hazards model. Results Some 91 people (median age 71 years) had a median follow-up of 51 months, with a recurrence rate of 72.5% (n=66: 12 loco-regional alone, 11 liver alone, 5 lung alone, 3 peritoneal alone, 29 simultaneous loco-regional and distant metastases and 6 multi-focal distant metastases at first recurrence diagnosis). The median time to recurrence was 8.5 months (95% CI: 6.6-10.5) and median survival after recurrence was 5.8 months (95% CI: 4.2-7.3). Stratification by recurrence location revealed no differences in time to recurrence. Significant predictors for recurrence by multivariate analysis were lymph node ratio, adjuvant chemotherapy and systemic inflammation index. Conclusions No significant patterns of recurrence were found. Lymph node ratio, adjuvant chemotherapy and systemic inflammation index were predictors of PDAC recurrence. More research is needed to investigate predictive factors for PDAC recurrence after curative resection in large prospective national cohorts.

Disparities in Surgical Treatment of Resectable Pancreatic Adenocarcinoma at Minority Serving Hospitals

IntroductionMinority serving hospitals (MSH) are those serving a disproportionally high number of minority patients. Previous research has demonstrated that treatment at MSH is associated with worse outcomes. We hypothesize that patients treated at MSH are less likely to undergo surgical resection of pancreatic adenocarcinoma compared to patients treated at non-MSH. MethodsPatients with resectable pancreatic cancer were identified using the National Cancer Database. Institutions treating Black and Hispanic patients in the top decile were categorized as an MSH. Factors associated with the primary outcome of definitive surgical resection were evaluated using multivariable logistic regression. Univariate and multivariable survival analysis was performed. ResultsOf the 75,513 patients included in this study, 7.2% were treated at MSH. Patients treated at MSH were younger, more likely to be uninsured, and higher stage compared to those treated at non-MSH (P < 0.001). Patients treated at MSH underwent surgical resection at lower rates (MSH 40% versus non-MSH 44.5%, P < 0.001). On multivariable logistic regression, treatment at MSH was associated with decreased likelihood of undergoing definitive surgery (odds ratio 0.91, P = 0.006). Of those who underwent surgical resection, multivariable survival analysis revealed that treatment at an MSH was associated with increased morality (hazard ratio 1.12, P < 0.001). ConclusionsPatients with resectable pancreatic adenocarcinoma treated at MSH are less likely to undergo surgical resection compared to those treated at non-MSH. Targeted interventions are needed to address the unique barriers facing MSH facilities in providing care to patients with pancreatic adenocarcinoma.

795 Predictors and Timing of Recurrence After Surgical Resection of Pancreatic Adenocarcinoma

Abstract Aim To investigate the predictors and timing of recurrence after curative resection for pancreatic adenocarcinoma (PDAC). Method Consecutive patients who underwent curative resection for PDAC (2011-21) and consented to data and tissue collection, were followed up prospectively in a single institution. Clinico-pathological variables were analysed using the Cox proportional hazards model. Results 91 patients (median age 71 years (range 43 – 86)) had a median follow-up of 51 (95% CI 40–61) months. 66 (72.5%) patients experienced recurrence (12 locoregional, 11 liver, 5 lung, 3 peritoneal, 29 simultaneous locoregional and distant and 6 multi-focal distant). Median time to recurrence was 8.5 (95% CI 6.6-10.5) months and median survival after recurrence was 5.8 (95% CI 4.2-7.3) months. Stratification by recurrence location revealed no significant differences in time to recurrence (p = 0.24). Significant predictors for any recurrence were lymph node ratio ≥0.33 (p = 0.005, HR 2.8, 95% CI 1.4 – 5.8), adjuvant chemotherapy (p = 0.002, HR 0.4, 95% CI 0.2 – 0.7) and systemic inflammation score ≥500 (p = 0.01, HR 4.5, 95% CI 1.4 – 14.3). Conclusions Lymph node ratio, adjuvant chemotherapy and systemic inflammation score were significant predictors for recurrence after curative resection for PDAC: this needs validation in large national cohorts.

Patterns and Predictors of Recurrence After Surgical Resection of Pancreatic Adenocarcinoma

Patterns and Predictors of Recurrence After Surgical Resection of Pancreatic Adenocarcinoma

A case of paraneoplastic alopecia in cat with recurrence of skin lesions after surgical resection of pancreatic adenocarcinoma

A case of paraneoplastic alopecia in cat with recurrence of skin lesions after surgical resection of pancreatic adenocarcinoma

Patient Perceptions of Decision-making and Quality-of-life Following Surgical Resection of Pancreatic Adenocarcinoma

We performed a convergent, mixed-methods study with patients who underwent resection of PDAC between January 1, 2019, and January 8, 2020. Quantitative data (medical record review and 3 questionnaires) were analyzed using descriptive statistics. Qualitative data (semistructured interviews) were analyzed using the constant comparative method. Data were then compared for congruence. Eighteen of 22 eligible participants completed interviews and 11 completed questionnaires. Data collection occurred at a median of 14.2 months (IQR 11.6-16.3) from surgery. We identified 4 main themes. First, persistent negative symptoms were common for patients, but patients adapt to these and are satisfied with their "new normal." Second, patients have varied and continually evolving mindsets throughout their cancer journey. Third, despite decreased quality-of-life, patients have a high degree of satisfaction with their decision to pursue surgery. Finally, patients were okay with a passive role in decision-making around surgery. Despite variable involvement in decision-making and outcomes, no participants reported regret over the decision to pursue surgery. This nuanced account of patients' lived experiences following surgery for PDAC allows for an improved understanding of the impact of pancreatic resection on patients. Surgeons can use these data to improve preoperative counseling for patients with PDAC and help guide them to making the correct decisions about surgery.

Aggregate Risk of Major Adverse Events in Patients Undergoing Neoadjuvant Chemotherapy and Surgical Resection for Pancreatic Adenocarcinoma

Introduction: Neoadjuvant chemotherapy followed by surgical resection is the standard of care for many patients with pancreatic adenocarcinoma, yet the aggregate risk of major adverse event during both neoadjuvant therapy and the postoperative period has not been described.

Carbon-Ion Radiotherapy for Local Recurrence Following Pancreatic Cancer Surgery

70% of patients able to receive surgical resection for pancreatic adenocarcinoma may ultimately experience recurrence; 25-35% have disease in the remnant pancreas or tumor bed. Surgical re-resection carries notable risks for morbidity, while success with photon irradiation has been limited. Carbon-ion radiotherapy (CIRT) has demonstrated unique promise in the treatment of locally advanced pancreatic cancer (LAPC). An initial cohort from 2011-2015 was published in 2017; here, we provide an update on CIRT safety and efficacy for post-surgical salvage of locally recurrent pancreatic cancer, with 60 cases from 2007 to 2020.Patients with locoregional recurrence following resection of pancreatic cancer were eligible. CIRT was conducted using 48.0 to 55.2 Gy (RBE) in 12 fractions, delivered over 3 weeks. Inclusion criteria included: 1) unresectable disease due to tumor invasion or patient refusal of re-resection; 2) absence of distant metastasis, 3) ECOG performance of 0 to 2. Patients with disease invading the GI tract, previous radiotherapy, or metallic stent placement were excluded.A total of 60 patients treated between January 2007 and 2020 were retrospectively reviewed. Median age was 65, with pancreatic head primary in 34 cases and body/tail in 26 cases. 34 cases underwent pancreaticoduodenectomy, with 26 distal pancreatectomies. 14 cases recurred in the residual pancreas, while 46 cases recurred in surrounding tissue. 16 cases received 48 - 52.8 Gy (RBE) via dose escalation, with 44 cases receiving 55.2 Gy (RBE). Grade 3 hematologic toxicity was seen in 3 cases, with no other G3+ acute or late toxicity was noted. 2-year local control was achieved in 56% for 48-52.8 Gy (RBE) and 61% for 55.2 Gy (RBE) cohorts. 2-year survival was 48% in the high dose cohort, with median survival time (MST) of 23 months.CIRT for postoperative recurrence of pancreatic cancer compared favorably to conventional chemoradiation salvage (2-year survival 38%, 16-month MST), with acceptable toxicity. CIRT may be a viable treatment alternative when re-resection is difficult.

Refined prognostic staging for resected pancreatic cancer by modified stage grouping and addition of tumour grade

BackgroundWith changes in T and N categories the 8th edition of the AJCC/UICC TNM staging system for pancreatic cancer resulted in improved prognostic staging, but inconsistencies were observed with specific stage groups. Tumour grading remains disregarded in prognostic staging. We aimed to validate the current staging system and to investigate the possibility of further optimization by integration of grading. Methods1946 patients undergoing upfront surgical resection for pancreatic adenocarcinoma from 10/2001 to 12/2015 were identified from a prospective institutional database. Survival analyses based on the 8th UICC TNM edition were performed and rare TNM subgroups were reallocated based on survival. The impact of tumour grade on stage-specific survival was assessed and a TNMG staging system was developed. ResultsThe 8th UICC staging system accurately stratified prognosis except for comparable survival in stages IB (pT2N0M0) and IIA (pT3N0M0). Regrouping of pT3N0M0 and pT1N1M0 to IB and of pT1N2M0 to II resulted in a modified staging system with higher consistency. High tumour grade (G3&G4 vs G1&G2) was associated with a significantly shorter survival in all new stage groups except for stage IV modified UICC. A TNMG-based prognostic stage grouping in which high tumour grade results in grouping with tumours of the next higher pTNM-stage resulted in improvement of prognostication in non-metastatic pancreatic cancer. ConclusionsThe 8th edition of the UICC TNM staging system leaves room for improvement. A TNMG staging system with adjustments in group-allocation of specific rarely occurring pTNM subgroups and integration of tumour grade results in improved prognostic stratification.

Place of hyperthermic intraperitoneal chemotherapy in the armament against pancreatic adenocarcinoma: A survival, mortality and morbidity systematic review.

Pancreatic adenocarcinoma is one of the deadliest types of cancer worldwide, with a 5-year survival rate of 8% despite recent treatment advancements. The present systematic review aimed to investigate the role of hyperthermic intraperitoneal chemotherapy (HIPEC) following surgical resection for pancreatic adenocarcinoma, with or without peritoneal carcinomatosis. A systematic search of the MEDLINE and SCOPUS electronic databases was performed according to PRISMA guidelines. All possible relevant articles published between January 1980 and May 2019 were retrieved using multiple search terms associated with HIPEC and pancreatic adenocarcinoma. The initial search resulted in 1,244 reports, which condensed to 41 reports following screening of titles and abstracts, and subsequently to four reports following full-text thorough examination. The four reports included involved a prospective cohort study of HIPEC use in resectable pancreatic adenocarcinoma, and three retrospective studies of HIPEC use following cytoreductive surgery for peritoneal carcinomatosis due to pancreatic adenocarcinoma, resulting in a total of 47 patients. The overall survival ranged between 2 and 62 months, and the hospital mortality rate was 8.5%. Morbidity (34%) was mainly attributed to anastomotic leak or respiratory failure. Due to the small sample size and low quality of evidence of the included studies, no valid conclusions could be drawn. Therefore, further studies are required to justify the use of HIPEC as an adjuvant therapy in resectable pancreatic adenocarcinoma, while cytoreductive surgery and HIPEC in peritoneal carcinomatosis of pancreatic origin seems not only not useful but also unsafe at this level of evidence.

A modern era analysis of elderly patients undergoing surgical resection for pancreatic adenocarcinoma- Is it worth the risk?

Presenter: Veronika Lobova BS | Washington State University Background: As the population of the United States continues to age, incidence of pancreatic adenocarcinoma (PDAC) is also expected to increase, making more elderly patients candidates for surgical resection. In patients over 75 years old, however, the risk of pancreatic resection may outweigh the survival benefits. Thus, the primary aim of this study was to evaluate both progression-free and overall survival among PDAC patients over 75 years old and to determine factors associated with survival duration. Methods: A retrospective chart review was conducted for patients older than 75 years old who underwent surgical resection (Whipple surgery and distal pancreatectomy) of PDAC from February 2014 to May 2020 at a single community-based hospital. Clinical parameters, additional treatments, complications, and survival curves were analyzed. Results: A total of 44 patients over the age of 75 years underwent surgical resection of PDAC (median age 79, 48% female). More patients underwent a Whipple procedure compared to distal pancreatectomy (73% vs. 27%, respectively). Fifty-five percent received adjuvant chemotherapy, 18% received neoadjuvant chemotherapy, and 20% had radiation. The median survival for all patients was 9.0 months (quartiles 3.5 - 15.5). Among patients who survived > 3 months (i.e. cancer specific survival) the median survival duration was 12 months (quartiles 8-18 months). Among patients who underwent Whipple surgery and survived there was only one case of progression, and median progression-free survival was 9.0 months (quartiles 4.0-14.0 months). There was no significant difference in survival between Whipple procedures and distal pancreatectomies. Perioperative complications occurred in 32% of patients within 30 days, respectively. Death occurred in 11% of patients within 30 days and 40% of deaths occurred due to cardiac arrest. Survival was significantly longer among patients who had adjuvant chemotherapy or radiation compared to those who did not (median 13.0 vs. 5.0 months, P=0.01, and 18.0 vs. 7.0 months, P=0.002, respectively, see Graph). Survival duration was not different between individuals who received neoadjuvant chemotherapy (median 6.5 months) and those who did not (9.5 months, P=0.45), and did not differ by number of regional nodes involved. Conclusion: The complication rate of surgical resection of PDAC in this elderly population is comparable to the generalized population. However, the mortality rate is higher. More comprehensive preoperative cardiovascular screening may be necessary in the elderly population to prevent cardiovascular related deaths.

Impact of Resection Margin Status in Patients with Pancreatic Cancer: a National Cohort Study

AimTo assess the predictors and influence of resection margins and the role of neoadjuvant and adjuvant therapy on survival for a national cohort of patients with resected pancreatic cancer. MethodsUsing the National Cancer Data Base between 2004 and 2016, 56,532 patients were identified who underwent surgical resection for pancreatic adenocarcinoma. Univariate and multivariate models were employed to identify factors predicting R0/R1 resection and assess the impact on survival. ResultsIn total, 48,367 (85.6%) patients were found to have negative margins (R0) compared to 8165 (14.4%) who had microscopic residual tumor (R1). Factors predicting positive margin on univariate analysis included male gender, Medicare, advanced stage, moderately or poorly differentiated tumor, lymphovascular invasion, and tumors > 2 cm. Factors predicting R0 resection included receipt of neoadjuvant therapy and treatment at an Academic/Research Center. Following adjustment for other factors, margin status remained an independent predictor for overall survival (HR: 1.24; 95% CI 1.22–1.27, p < 0.001) (1-, 3-, and 5-year overall survival rates (R0: 77%, 37%, and 25% vs R1: 62%, 19%, and 10%). ConclusionsA positive margin predicts a poorer survival than R0 resections regardless of stage and receipt of adjuvant therapy. Several modifiable factors significantly predict the likelihood of R0 resection including neoadjuvant treatment and treatment at Academic/Research Programs. Knowledge about these factors can help guide patient management by offering neoadjuvant treatment modalities at Academic as well as Community hospitals.

Tumor downsizing following neoadjuvant therapy for borderline-resectable pancreatic adenocarcinoma.

690 Background: Downstaging of pancreatic adenocarcinoma in patients presenting with nonmetastatic, unresectable disease has proven to be associated with improved clinical outcomes. Efforts at rescuing these patients to become surgical candidates are commonly attempted with a combination of systemic and radiation strategies. In this study, we aimed to determine tumor downsizing in patients that underwent neoadjuvant systemic therapy followed by a curative-intended surgical resection. Methods: A retrospective review of consecutive patients that underwent surgical resection for pancreatic adenocarcinoma following a course of neoadjuvant therapy was performed. Basic demographics, endoscopic ultrasound (EUS) findings, chemotherapy regimens and duration, rates of radiotherapy, type of surgical procedure and pathologic results were recorded. Tumor response to neoadjuvant therapy was established by correlating EUS- to pathologic tumor dimensions. Analysis of the data was done using Mann-Whitney U test, Pearson correlation and Chi-square when indicated. Results: A total of 97 patients were analyzed; 40 underwent neoadjuvant chemotherapy (13 patients also received concurrent radiation therapy). In those 57 patients that were resected upfront, EUS tended to underestimate tumor sizes significantly compared to pathologic dimensions, with an average difference between dimensions of 0.66 cm (p = 0.0004). Within the group treated with neoadjuvant chemotherapy, 90% of patients had downsizing at an average of 8% of tumor size. There were no differences in rates of tumor downsizing between FOLFIRINOX or Gemcitabine/Nac-paclitaxel treated patients. In addition, there were no correlations in margin status (R0) based on chemotherapy used, with both regimens achieving a similar rate of R0 resections (mean 61%). The type of chemotherapy regimen used did not affect the ratio of positive lymph nodes harvested. Conclusions: In patients that present with borderline resectable pancreatic adenocarcinoma, a course of neoadjuvant therapy results in tumor downsizing in a significant number allowing for margin negative resections. These results were seen regardless of the chemotherapeutic regimens utilized.

Abstract A52: Modulation of Hedgehog signaling alters immune infiltration in pancreatic cancer

Abstract Background: Pancreatic ductal adenocarcinoma (PDA) has a dismal 5-year survival rate of 9%, making this disease one of the deadliest human malignancies. Primary barriers to the treatment of pancreatic cancer include extensive stromal interactions and sustained immune suppression. Aberrant Hedgehog (HH) pathway activity is a hallmark of pancreatic tumorigenesis. Tumor-derived HH ligands signal in a paracrine fashion to the surrounding stroma to influence tumor growth. Expression of HH ligands increases during PDA progression, and previous work has shown that genetic deletion of Sonic HH from the epithelium of mice with pancreatic tumors results in increased Indian HH (Ihh) expression. Methods: Ihh was deleted in tumor cells lines (IhhKO) derived from a genetically engineered mouse model of pancreatic cancer (KrasG12D;Trp;P48-Cre), using CRISPR/Cas-9 gene editing to assess the role of Ihh in the tumor microenvironment. The level of HH signaling was determined using tumor cell co-cultures with Gli1lacZ fibroblasts (derived from mice with a lacZ reporter allele knocked into the Gli1 locus), in which beta galactosidase activity serves as a readout for HH signaling. WT and IhhKO tumor cells were orthotopically transplanted into the pancreas of syngeneic C57BL/6 mice. Human pancreas samples were obtained from surgical resection of pancreatic adenocarcinoma or fine-needle biopsy procedure (FNB). Immune profiling of mouse and human pancreatic tumors was performed using Cytometry Time-of-Flight analysis, and tumor composition was analyzed by single-cell RNA sequencing. In vitro cultures with pancreatic fibroblasts treated with either WT or IhhKO tumor cell conditioned media (CM) were cultured to assess tumor crosstalk. Results: Tumor cells lacking Ihh were generated through CRISPR/Cas-9 deletion, and this was confirmed by qRT-PCR. Co-culture of IhhKO tumor cells with Gli1lacZ fibroblasts results in decreased Gli1 expression both in vitro and in vivo. Immune profiling revealed that tumors lacking Ihh have significantly fewer macrophages (CD11b+/F4/80+), resulting in decreased presence of immunosuppressive factors such as arginase 1 and PDL1. Immune profiling of human PDA revealed similar populations of immunosuppressive myeloid cells present in tumors. In vitro co-cultures demonstrated CCL2 expression was reduced in pancreatic fibroblasts cultured with IhhKO-CM, providing mechanistic insight into the in vivo phenotype observed. Further, scRNA seq analysis suggests that modulation of HH signaling in the tumor microenvironment alters chemokine and immunomodulatory signaling pathways driven by fibroblasts in the pancreatic tumor microenvironment. Significance of Impact: HH signaling in pancreatic fibroblasts contributes to the establishment of an immune-suppressive environment in pancreatic cancer. Combining methods to target HH signaling and immune checkpoint therapy has translational potential in treating pancreatic cancer patients. Citation Format: Nina Steele, Samantha Kemp, Valerie Irizarry-Negron, Veerin Sirihorachai, Ahmed Abbas, Eileen Carpenter, Christopher Halbrook, Carlos Espinoza, Costas Lyssiotis, Howard Crawford, Timothy Frankel, Filip Bednar, Ben Allen, Marina Pasca di Magliano. Modulation of Hedgehog signaling alters immune infiltration in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A52.

Adjuvant treatment for resected pancreatic adenocarcinoma: A systematic review and network meta-analysis.

Adjuvant chemotherapy has significantly improved outcomes following surgical resection for pancreatic adenocarcinoma; however, the optimal adjuvant strategy remains unclear. This systematic review and network meta-analysis was conducted to provide indirect comparative evidence across adjuvant chemotherapies. Electronic searches of EMBASE, MEDLINE, Cochrane and ASCO databases were conducted to identify eligible randomized controlled trials (RCT). Direct pairwise meta-analysis was conducted for disease-free survival (DFS), overall-survival (OS) and adverse events (AE). Network meta-analysis of DFS and OS was conducted to evaluate indirect comparisons. Ten publications of eleven RCT met eligibility criteria. Indirect DFS comparison demonstrated superiority of mFOLFIRINOX versus gemcitabine-capecitabine, gemcitabine-erlotinib and gemcitabine-nab-paclitaxel. S-1 demonstrated a DFS benefit versus gemcitabine-capecitabine, gemcitabine-erlotinib, gemcitabine-nab-paclitaxel. OS benefits were demonstrated for mFOLFIRINOX verus gemcitabine-erlotinib and for S-1 versus gemcitabine-based combination with erlotinib, capecitabine and nab-paclitaxel. In conclusion, mFOLFIRINOX is the preferred approach for adjuvant therapy. For mFOLFIRINOX-ineligible patients no additional benefit is seen with gemcitabine-nab-paclitaxel.

Role of neoadjuvant therapy (NAT) in pancreatic adenocarcinoma (PAC): A single center experience.

e15747 Background: Surgical resection of PAC followed by adjuvant therapy is the standard of care for non-metastatic resectable tumors. Surgical resection with clear margins of borderline (BR) or locally advanced (LA) tumors is either challenging or impossible. Furthermore, there are no clear recommendations concerning NAT for non-upfront resectable PAC. Thus we reviewed our own experience with different NAT modalities for BR and LA PAC. Methods: Medical records of patients identified by Tumor Board as BR or LA PAC and treated with NAT at Centre Hospitalier de l’Université de Montréal (CHUM) were retrospectively reviewed. Survival curves were estimated by the Kaplan-Meier method and compared with the Log-rank test. For both univariate and subgroup analyses, hazard ratio and 95% confidence interval were estimated by Cox proportional hazard regression. Results: Between 2009 and 2017, 90 patients (50 BR, 40 LA) were identified. Chemotherapy, mostly FOLFIRINOX, was the only NAT in 51 patients (56.6%), 23 patients (25.3%) received chemoradiotherapy alone and 16 patients (17.7%) received sequential treatment of both modalities. Tumor resection was achieved in 44 patients, with 32 BR patients (R0: 68.7%) and 12 LA patients (R0: 75%). Median Disease free survival (DFS) of patients that underwent resection was 12.3 months. mPFS was 29 vs 10 months (HR:0.2; p &lt; 0.001) and mOS was 41.7 vs 15.7 months (HR:0.3; p &lt; 0.001) in resected and non-resected patients, respectively. In subgroup analysis, resection statistically improved PFS and OS regardless of age, sex, T stage and type of vessel involvement. Treatment with more than one modality showed better clinical outcomes (PFS and OS) and a non-statistically higher R0 resection rate that was 100% in BR tumors. OS in patients with resected cancers was not reached for the multimodality group, 41.7 months for chemotherapy alone group and 22.4 months in patients treated with chemoradiotherapy group (p = 0.017). Conclusions: In this retrospective single center analysis, NAT with chemotherapy and/or chemoradiotherapy appears to improve patients’ clinical resection results and outcomes. These results validate previous retrospective studies but warrant large prospective trials to define the best NAT.

Trends from NSQIP 2015 to 2017 in neoadjuvant therapy use before pancreatic adenocarcinoma resection.

e15685 Background: Morbidity and mortality associated with surgical resection of pancreatic adenocarcinoma remains high, and prognosis is poor even after R0 resection. Preoperative chemoradiation, previously only indicated to downstage borderline-resectable disease, has been increasingly used even in cases that appear resectable at time of diagnosis. Response to therapy can be prognostic and guide clinical decision-making. We investigated significant trends over time in neoadjuvant treatment of patients within the National Surgical Quality Improvement Project (NSQIP) database treated surgically for pancreatic adenocarcinoma. Methods: We queried NSQIP data for patients who underwent pancreaticoduodenectomy or subtotal pancreatectomy for pancreatic adenocarcinoma in 2015-2017. We examined differences by year in neoadjuvant treatment use with Chi-square test. Results: There were 8626 patients included. Use of neoadjuvant treatment (chemotherapy or chemoradiotherapy) increased over the study period, and complication by pancreatic fistula and delayed gastric emptying decreased qualitatively over the same time (12% to 9%; 14% to 12%). This increase in use of neoadjuvant chemotherapy was significant among patients with T1, T2, and T3 tumors (Table 1). However, despite NCCN/ASCO guidelines recommending neoadjuvant for all patients with T4 tumors, only about a quarter of these patients received it, and this proportion did not change over time. Conclusions: Preoperative chemotherapy is particularly important in ≥T3 disease because of low rates (50%) of adjuvant therapy, likely secondary to postoperative morbidity. The NSQIP data reflects the trend toward increasing neoadjuvant therapy in lower-T stage disease, but not among patients with T4 disease. This may be because NSQIP data largely reflects community hospital populations, and this practice was first adopted by academic institutions. Based on our findings, it is important that medical oncology be involved early in the multidisciplinary care of patients with pancreatic adenocarcinoma.[Table: see text]

3373 Modulation of Hedgehog Signaling Alters Immune Infiltration in Pancreatic Cancer

OBJECTIVES/SPECIFIC AIMS: Pancreatic ductal adenocarcinoma (PDA) has a dismal 5-year survival rate of 9%, making this disease one of the deadliest human malignancies (https://seer.cancer.gov/). Primary barriers to the treatment of pancreatic cancer include extensive stromal interactions and sustained immune suppression. Aberrant Hedgehog (HH) pathway activity is a hallmark of pancreatic tumorigenesis. Tumor-derived HH ligands signal in a paracrine fashion to the surrounding stroma to influence tumor growth. Expression of HH ligands increases during PDA progression, and previous work has shown that genetic deletion of Sonic HH (Shh) from the epithelium of mice with pancreatic tumors results in increased Indian HH (Ihh) expression. This research aims to investigate the translational impact of changes in immune infiltration following deletion of IHH in a preclinical mouse model of pancreatic cancer. METHODS/STUDY POPULATION: Ihh was deleted in tumor cells lines (IhhKO) derived from a genetically engineered mouse model of pancreatic cancer (LSL-KrasG12D/+;LSL-TrpR270H;P48-Cre), using CRISPR/Cas-9 gene editing to assess the role of Ihh in the tumor microenvironment. The level of HH signaling was determined using tumor cell co-cultures with Gli1lacZ fibroblasts (derived from mice with a lacZ reporter allele knocked into the Gli1 locus), in which Beta Galactosidase activity serves as a readout for HH signaling. WT and IhhKO tumor cells were orthotopically transplanted into the pancreas of syngeneic C57BL/6 mice. Human pancreas samples were obtained from surgical resection of pancreatic adenocarcinoma, or fine needle biopsy procedure (FNB). Immune profiling of mouse and human pancreatic tumors was performed using Cytometry Time-of-Flight analysis (CyTOF), and tumor composition was analyzed by single-cell RNA sequencing (scRNA seq). In vitro cultures with pancreatic fibroblasts treated with either WT or IhhKO tumor cell conditioned media (CM) were cultured with bone-marrow derived macrophages to assess tumor crosstalk. RESULTS/ANTICIPATED RESULTS: Tumor cells lacking Ihh were generated through CRISPR/Cas-9 deletion, and this was confirmed by qRT-PCR. Co-culture of IhhKO tumor cells with Gli1lacZ fibroblasts results in decreased Gli1 expression both in vitro and in vivo. Immune profiling revealed that tumors lacking Ihh have significantly fewer tumor associated macrophages (CD11b+/F4/80+/CD206+), resulting in decreased presence of immunosuppressive factors such as arginase 1 and PDL1. Immune phenotyping of human pancreatic tissues revealed similar populations of immunosuppressive myeloid cells present in tumors. In vitro co-cultures demonstrated that, in the presence of bone-marrow derived macrophages, immunosuppressive IL-6 production was reduced in pancreatic fibroblasts cultured with IhhKO-CM, as compared to fibroblasts cultured with WT-CM, providing mechanistic insight into the in vivo phenotype observed. Further, scRNA seq analysis suggests that modulation of HH signaling in the tumor microenvironment alters chemokine and immunomodulatory signaling pathways driven by fibroblasts in the pancreatic tumor microenvironment. DISCUSSION/SIGNIFICANCE OF IMPACT: HH signaling in pancreatic fibroblasts contributes to the establishment of an immune suppressive environment in pancreatic cancer. Combining methods to target HH signaling and immune checkpoint therapy has translational potential in treating pancreatic cancer patients.

Neoadjuvant Therapy (NAT) in Pancreatic Adenocarcinoma (PAC): A Single Center Experience

Background: Surgical resection of PAC followed by adjuvant therapy is the standard of care for localized resectable tumors. Surgical resection, with clear margins, of borderline resectable (BR) or locally advanced (LA) tumors remains quite challenging. NAT could potentially improve outcomes but there are no clear recommendations in this regards for upfront unresectable PAC. Herein, we report our experience with different NAT modalities used in BR and LA PAC. Methods: Medical records of patients identified in our medical database as BR or LA PAC and treated with NAT at Centre Hospitalier de l’Universite de Montreal (CHUM) were retrospectively reviewed. Recist criteria were used for response assessment. Descriptive statistics and Kaplan-Meier were used for statistical purposes. Results: In total, ninety patients met the inclusion criteria (50 BR, 40 LA tumors). Chemotherapy, mostly FOLFIRINOX, was the only modality used in 51 patients (56.6%). Twenty-three patients (25.3%) received concurrent chemoradiation and sixteen patients (17.7%) received sequential chemotherapy and chemoradiation. Tumor resection was possible in 44 patients, 32 BR patients (R0: 68.7%) and 12 LA patients (R0: 75%). Median Disease free survival (DFS) of patients undergoing resection was 12.3 months. Median progression free survival (mPFS) was 29 vs 10 (HR: 0.2; p<0.001) and mOS was 41.7 vs 15.7 months (HR: 0.3; p<0.001) in resected and non-resected patients, respectively. Treatment with more than one modality showed better clinical outcomes (PFS and OS) and a non-statistically higher R0 resection rate that was 100% in BR tumors. OS in patients with resected cancers was not reached for the multimodality group, 41.7 months for chemotherapy alone group and 22.4 months in patients treated with chemoradiotherapy group (p=0.017). Conclusion: In this retrospective single center analysis, NAT appears to improve and enable resection of newly diagnosed PAC. These results validate previous retrospective studies, but warrant large prospective trials to better define the optimal neoadjuvant approach.

SBRT with Simultaneous Integrated Boost Results in High Rate of R0 Resection in Borderline Resectable Pancreatic Adenocarcinoma

Surgical resection for pancreatic adenocarcinoma offers a significantly improved prognosis with a distinct advantage of potentially curative (R0) versus palliative (R1/R2) surgery. Stereotactic body radiation therapy (SBRT) has emerged as a treatment option that has potential to pull the tumor off adjacent vascular structures and therefore improve surgical outcomes. We reviewed our rates of complete (R0) resection following neoadjuvant chemotherapy and SBRT for borderline resectable patients with pancreatic adenocarcinoma. Retrospective review of patients treated with SBRT to the pancreas between October 2015 and November 2017. A total of 26 patients were treated with SBRT to pancreas. All patients were treated with 5 fraction SBRT after fiducial marker placement and 4D treatment planning. Mean dose is 3250 cGy. Eight of the 26 patients received simultaneous integrated boost (SIB) to tumor vessel interface. Mean SIB dose 4150 cGy. Twelve medically operable patients received neoadjuvant chemotherapy; 7 FOLFIRINOX, 4 gemcitabine/abraxane, and one gemcitabine/pemetrexed. Of the 12 medically operable patients, 9 were classified as borderline resectable, and 3 were classified as unresectable based on NCCN criteria. Eight of 9 borderline resectable patients underwent successful pancreatoduodenectomy with R0 resection (89%). No severe toxicity was observed. SBRT provides a promising way to treat locally advanced and borderline resectable pancreatic cancer. A simultaneous integrated boost (SIB) to the region of vessel abutment or encasement during SBRT has the potential to downstage and improve the likelihood of R0 resection. Further exploration of SIB may be warranted in borderline resectable disease.