Poor Prognostic Factors in Long-Term Survivors of Resected Pancreatic Ductal Adenocarcinoma: An International, Multicenter Cohort Study.

OBJECTIVE: To measure the rate of LTS in resected PDAC and determine the association between predictors of OS and LTS. SUMMARY BACKGROUND DATA: Long-term survival (>5 y, LTS) remains rare in pancreatic ductal adenocarcinoma (PDAC). Multiple predictors of overall survival (OS) are known but their association with LTS remains unclear. METHODS: An international, multicenter retrospective study was conducted. Included were patients from 2012-2019 with resected PDAC. Excluded were those with metastases at diagnosis or resection, R2 resections, and 90-day mortality. Predictors of OS were identified using multivariable Cox regression and their prevalence in patients with LTS assessed. LTS was calculated by excluding patients with shorter follow-up and predictors of LTS were identified using multivariable logistic regression. RESULTS: 3,003 patients were included (27.4% received neoadjuvant chemotherapy). Elevated baseline CA19-9, high tumor grade, nodal disease, and perineural and lymphovascular invasion were negative independent predictors of OS, while receipt of adjuvant chemotherapy predicted improved OS (all P<0.05). LTS was observed in 220/2,436 patients (9.0%), of whom 198 (90%) harbored poor prognostic factors: elevated baseline CA19-9 (58.1%), poor tumor differentiation (51.0%), nodal disease (46.8%), and perineural invasion (76.0%). Of those without any of these four features, 50.0% achieved LTS as compared to 21.3%, 13.3%, 5.2%, and 3.5% in those with 1, 2, 3, or 4 features. CONCLUSIONS: This bi-national cohort demonstrates a true LTS rate of 9.0% in resected PDAC. Clinicians should remain aware that presence of poor prognostic factors does not preclude LTS.

Patient-derived Organoid Pharmacotyping As A Predictive Tool for Therapeutic Selection in Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: We integrate a new approach to chemosensitivity data for clinically-relevant regimen matching, and demonstrate the relationship with clinical outcomes in a large PDO biobank. SUMMARY BACKGROUND DATA: Pancreatic ductal adenocarcinoma (PDAC) usually recurs following potentially curative resection. Prior studies related patient-derived organoid (PDO) chemosensitivity with clinical responses. METHODS: PDOs were established from pre-treatment biopsies in a multi-institution clinical trial (n=21) and clinical specimens at a high-volume pancreatectomy center (n=74, of which 48 were pre-treated). PDO in vitro chemosensitivities to standard-of-care chemotherapeutics (pharmacotypes) were matched to potential clinically-relevant regimens by a weighted nearest-neighbors analysis. Clinical outcomes were then compared for patients who had well-matched versus poorly-matched treatment according to this metric. RESULTS: Our function matched 91% of PDOs to a standard-of-care regimen (9% pan-resistant). PDOs poorly-matched to the neoadjuvant regimen received would have matched to an alternative in 34% of cases. Patients receiving neoadjuvant chemotherapy well-matched to their pharmacotype experienced improved CA 19-9 response (60% decreased to normal when well-matched, 29% when poorly-matched, P<0.05) and lymph node down-staging (33% N0 after poorly-matched, 69% after well-matched, P<0.05). Patients receiving both well-matched neoadjuvant and adjuvant chemotherapy experienced improved recurrence-free- and overall survival (median RFS 8.5 mo poorly-matched, 15.9 mo well-matched, P<0.05; median OS 19.5 vs. 30.3 mo, P<0.05). CONCLUSION: In vitro PDO pharmacotyping can inform PDAC therapy selection. We demonstrate improved outcomes including survival for patients treated with regimens well-matched to their PDO chemosensitivities. A subsequent prospective study using PDO pharmacotype matching could improve oncologic outcomes and improve quality of life by avoiding therapies not expected to be effective.

Impact of Neoadjuvant Immunotherapy on Recurrence-Free Survival in Patients with High-Risk Localized HCC.

Surgical resection for localized hepatocellular carcinoma (HCC) is typically reserved for a minority of patients with favorable tumor features and anatomy. Neoadjuvant immunotherapy can expand the number of patients who are candidates for surgical resection and potentially reduce the chance for recurrence, but its role in HCC not defined. We retrospectively examined the outcomes of patients who underwent surgical resection for HCC at the Johns Hopkins Hospital and compared the clinical outcomes of patients who received neoadjuvant immunotherapy with those who underwent upfront resection. The clinical cohort included a total of 92 patients, 36 of whom received neoadjuvant immune checkpoint inhibitor (ICI)-based treatment. A majority of patients (61.1%) who received neoadjuvant ICI-based therapy were outside of standard resectability criteria and were more likely to have features known to confer risk of disease recurrence, including α-fetoprotein ≥ 400 ng/mL (P = 0.02), tumor diameter ≥ 5 cm (P = 0.001), portal vein invasion (P < 0.001), and multifocality (P < 0.001). Patients who received neoadjuvant immunotherapy had similar rates of margin-negative resection (P = 0.47) and recurrence-free survival (RFS) as those who underwent upfront surgical resection (median RFS 44.8 months compared with 49.3 months, respectively, log-rank P = 0.66). There was a nonsignificant trend toward superior RFS in the subset of patients with a pathologic response (tumor necrosis ≥ 70%) with neoadjuvant immunotherapy. Neoadjuvant ICI-based therapy may allow high-risk patients, including those who are outside traditional resectability criteria, to achieve comparable clinical outcomes with those who undergo upfront resection. SIGNIFICANCE: Surgical resection for localized HCC is typically only reserved for those with solitary tumors without vascular invasion. In this retrospective analysis, we show that neoadjuvant immunotherapy may allow high-risk patients, including those who are outside of standard resection criteria, to undergo successful margin-negative resection and achieve comparable long-term clinical outcomes compared with upfront resection. These findings highlight need for prospective studies on neoadjuvant immunotherapy in HCC.

Sociodemographic variation in the utilization of minimally invasive surgical approaches for pancreatic cancer.

BACKGROUND: Minimally invasive pancreatic surgery (MIPS), when selectively utilized, has been shown to hasten recovery with outcomes comparable to open approaches, but access may not be equitable. This study explored variation in utilization of MIPS for pancreatic cancer. METHODS: The National Cancer Database was queried to identify patients diagnosed with a primary pancreatic neoplasm from 2010 to 2020. Study participants had diagnoses of clinical or pathologic stage 1-3 disease and received curative-intent surgery. Multivariable analyses assessed the association between surgical approach and patient and disease factors. RESULTS: Inclusion criteria identified 73,137 patients: 51,408 underwent open surgery and 21,729 received MIPS. In our multivariable analysis, Black race was associated with reduced odds of MIPS (AOR 0.88; p = 0.02), while older age (AOR 1.17; p = 0.01), later year of diagnosis (AOR 1.57; p < 0.001), and private insurance coverage (AOR 1.30; p = 0.05) were associated with increased odds. When patients with adenocarcinoma were analyzed in isolation, disparities in MIPS utilization persisted even when controlling for disease stage. CONCLUSION: Sociodemographic factors like age, race, and insurance coverage appear to vary in the utilization of MIPS technologies for the treatment of pancreatic malignancy. Addressing variation with robust mixed methods approaches in the future is proposed to incorporate prospective interventions with highly annotated outcomes for additional study.

Clinical Relevance of Cancerization of Ducts in Resected Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: Although prevalent in 50%-90% of pancreatic ductal adenocarcinomas, the clinical relevance of "cancerization of ducts" (COD) remains unknown. METHODS: Pathologists retrospectively reviewed slides classifying prevalence of COD. Histopathological parameters, location of first recurrence, recurrence-free survival (RFS), and overall survival (OS) were collected from the institutional pancreatectomy registry. RESULTS: Among 311 pancreatic ductal adenocarcinomas, COD was present in 216 (69.5%) and more prevalent in the cohort that underwent upfront surgery (75.3% vs 63.1%, P = 0.019). Furthermore, COD was associated with female gender (P = 0.040), advanced T stage (P = 0.007), perineural invasion (P = 0.014), lymphovascular invasion (P = 0.025), and R1 margin (P = 0.009), but not N stage (P = 0.401) or tumor differentiation (P = 0.717). In multivariable regression, COD was associated with less liver recurrence (odds ratio, 0.44; P < 0.005). This association was driven by the cohort of patients who had received preoperative treatment (odds ratio, 0.18; P < 0.001). COD was not predictive for RFS or OS. CONCLUSIONS: Cancerization of ducts was not associated with RFS or OS. Currently underrecognized, standardized implementation into histopathological reports may have merit, and further mechanistic scientific experiments need to illuminate its clinical and biologic impact.

Distinctive Pathology Associated With Focal Stenosis of the Main Pancreatic Duct Secondary to Remote Trauma: A Long-term Complication of Seat Belt Pancreatitis.

The radiologic finding of focal stenosis of the main pancreatic duct is highly suggestive of pancreatic cancer. Even in the absence of a mass lesion, focal duct stenosis can lead to surgical resection of the affected portion of the pancreas. We present four patients with distinctive pathology associated with non-neoplastic focal stenosis of the main pancreatic duct. The pathology included stenosis of the pancreatic duct accompanied by wavy, acellular, serpentine-like fibrosis, chronic inflammation with foreign body-type giant cell reaction, and calcifications. In all cases, the pancreas toward the tail of the gland had obstructive changes including acinar drop-out and interlobular and intralobular fibrosis. Three of the four patients had a remote history of major motor vehicle accidents associated with severe abdominal trauma. These results emphasize that blunt trauma can injure the pancreas and that this injury can result in long-term complications, including focal stenosis of the main pancreatic duct. Pathologists should be aware of the distinct pathology associated with remote trauma and, when the pathology is present, should elicit the appropriate clinical history.

Clinical and pathological factors associated with survival in patients with pancreatic cancer who receive adjuvant therapy after neoadjuvant therapy: A retrospective multi-institutional analysis.

BACKGROUND: Neoadjuvant therapy is being increasingly used for patients with pancreatic cancer. The role of adjuvant therapy in these patients is unclear. The purpose of this study was to identify clinical and pathologic characteristics that are associated with longer overall survival in patients with pancreatic cancer who receive adjuvant therapy after neoadjuvant therapy. METHODS: This study was conducted using multi-institutional data. All patients underwent surgery after at least 1 cycle of neoadjuvant therapy for pancreatic cancer. Patients who died within 3 months after surgery and were known to have distant metastasis or macroscopic residual disease were excluded. Mann-Whitney U test, χ2 analysis, Kaplan-Meier plot, and univariate and multivariate Cox regression analysis were performed as statistical analyses. RESULTS: In the present study, 529 patients with resected pancreatic cancer after neoadjuvant therapy were reviewed. For neoadjuvant therapy, 177 (33.5%) patients received neoadjuvant chemotherapy, and 352 (66.5%) patients received neoadjuvant chemoradiotherapy. The median duration of neoadjuvant therapy was 7.0 months (interquartile range, 5.0-8.7). Patients were followed for a median of 23.0 months after surgery. Adjuvant therapy was administered to 297 (56.1%) patients and was not associated with longer overall survival for the entire cohort (24 vs 22 months, P = .31). Interaction analysis showed that adjuvant therapy was associated with longer overall survival in patients who received less than 4 months neoadjuvant therapy (hazard ratio 0.40; 95% confidence interval 0.17-0.95; P = .03) or who had microscopic margin positive surgical resections (hazard ratio 0.56; 95% confidence interval 0.33-0.93; P = .03). CONCLUSION: In this retrospective study, there was a survival benefit associated with adjuvant therapy for patients who received less than 4 months of neoadjuvant therapy or had microscopic positive margins.

Exploring the Clinical Use of Molecular Profiling of Intrahepatic Cholangiocarcinoma in a Comprehensive Multidisciplinary Clinic.

BACKGROUND: Molecular profiling of intrahepatic cholangiocarcinoma (ICC) can detect actionable molecular alterations and guide targeted therapies. We explore the clinical use of molecular profiling of ICC in our comprehensive multidisciplinary clinic. STUDY DESIGN: Patients with a tissue diagnosis of ICC seen between 2019 and 2023 were identified. A retrospective review was performed to identify their molecular profiles and targeted therapy. The association between the detection of actionable molecular alterations and overall survival (OS) from the first clinic visit date was studied. Patients with an OS of less than 2 months were excluded. RESULTS: Among 194 patients with ICC, 125 had molecular profiling. Actionable molecular alterations were detected in 56 (45%) patients, including microsatellite instability (n = 3), high tumor mutational burden (>10 muts/mb; n = 5), isocitrate dehydrogenase 1 and 2 mutations (n = 22 and 6, respectively), BRAF V600E mutations (n = 2), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha mutations (n = 7), breast cancer 1 and breast cancer 2 mutations (n = 5), mesenchymal epithelial transition amplification (n = 2), fibroblast growth factor receptor 2 and 3 fusions (n = 13), erb-b2 receptor tyrosine kinase 2 overexpression (n = 6), and receptor tyrosine kinase 1 fusion (n = 1). Twenty-one patients received targeted therapies during their treatment course. Survival analysis revealed that for 120 patients with molecular profiling, the detection of an actionable molecular alteration was associated with improved mean OS (34.1 vs 23.6 months, p = 0.008). Among 70 patients with nonmetastatic ICC, the detection of an actionable molecular alteration was associated with improved mean OS (32.1 vs 27.5 months, p = 0.02). CONCLUSIONS: Actionable molecular alterations were frequently observed in patients with ICC. Detection of actionable alterations was associated with improved OS. The role of targeted therapy needs further exploration in prospective multicenter studies.

Notch Signaling Regulates Immunosuppressive Tumor-Associated Macrophage Function in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. The poor survival of patients with PDA has been attributed to a high rate of early metastasis and low efficacy of current therapies, which partly result from its complex immunosuppressive tumor microenvironment. Previous studies from our group and others have shown that tumor-associated macrophages (TAM) are instrumental in maintaining immunosuppression in PDA. Here, we explored the role of Notch signaling, a key regulator of immune response, within the PDA microenvironment. We identified Notch pathway components in multiple immune cell types within human and mouse pancreatic cancer. TAMs, the most abundant immune cell population in the tumor microenvironment, expressed high levels of Notch receptors, with cognate ligands such as JAG1 expressed on tumor epithelial cells, endothelial cells, and fibroblasts. TAMs with activated Notch signaling expressed higher levels of immunosuppressive mediators, suggesting that Notch signaling plays a role in macrophage polarization within the PDA microenvironment. Genetic inhibition of Notch in myeloid cells led to reduced tumor size and decreased macrophage infiltration in an orthotopic PDA model. Combination of pharmacologic Notch inhibition with PD-1 blockade resulted in increased cytotoxic T-cell infiltration, tumor cell apoptosis, and smaller tumor size. Our work implicates macrophage Notch signaling in the establishment of immunosuppression and indicates that targeting the Notch pathway may improve the efficacy of immune-based therapies in patients with PDA.

Relationship of Hepatocellular Carcinoma Stage and Hepatic Function to Health-Related Quality of Life: A Single Center Analysis.

Health-related quality of life (HRQoL) is known to be an important prognostic indicator and clinical endpoint for patients with hepatocellular carcinoma (HCC). However, the correlation of the Barcelona Clinic Liver Cancer (BCLC) stage with HRQoL in HCC has not been previously studied. We examined the relationship between BCLC stage, Child-Pugh (CP) score, and Eastern Cooperative Oncology Group (ECOG) performance status on HRQoL for patients who presented at a multidisciplinary liver cancer clinic. HRQoL was assessed using the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire. Fifty-one patients met our inclusion criteria. The FACT-Hep total and subscales showed no significant association with BCLC stages (p = 0.224). Patients with CP B had significantly more impairment in FACT-Hep than patients with CP A. These data indicate that in patients with HCC, impaired liver function is associated with reduced quality of life, whereas the BCLC stage poorly correlates with quality of life metrics. Impairment of quality of life is common in HCC patients and further studies are warranted to determine the impact of early supportive interventions on HRQoL and survival outcomes.

CLDN18.2 BiTE Engages Effector and Regulatory T Cells for Antitumor Immune Response in Preclinical Models of Pancreatic Cancer.

BACKGROUND & AIMS: BiTE (bispecific T-cell engager) immune therapy has demonstrated clinical activity in multiple tumor indications, but its influence in the tumor microenvironment remains unclear. CLDN18.2 is overexpressed in solid tumors including gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC), both of which are characterized by the presence of immunosuppressive cells, including regulatory T cells (Tregs) and few effector T cells (Teffs). METHODS: We evaluated the activity of AMG 910, a CLDN18.2-targeted half-life extended (HLE) BiTE molecule, in GC and PDAC preclinical models and cocultured Tregs and Teffs in the presence of CLDN18.2-HLE-BiTE. RESULTS: AMG 910 induced potent, specific cytotoxicity in GC and PDAC cell lines. In GSU and SNU-620 GC xenograft models, AMG 910 engaged human CD3+ T cells with tumor cells, resulting in significant antitumor activity. AMG 910 monotherapy, in combination with a programmed death-1 (PD-1) inhibitor, suppressed tumor growth and enhanced survival in an orthotopic Panc4.14 PDAC model. Moreover, Treg infusion enhanced the antitumor efficacy of AMG 910 in the Panc4.14 model. In syngeneic KPC models of PDAC, treatment with a mouse surrogate CLDN18.2-HLE-BiTE (muCLDN18.2-HLE-BiTE) or the combination with an anti-PD-1 antibody significantly inhibited tumor growth. Tregs isolated from mice bearing KPC tumors that were treated with muCLDN18.2-HLE-BiTE showed decreased T cell suppressive activity and enhanced Teff cytotoxic activity, associated with increased production of type I cytokines and expression of Teff gene signatures. CONCLUSIONS: Our data suggest that BiTE molecule treatment converts Treg function from immunosuppressive to immune enhancing, leading to antitumor activity in immunologically "cold" tumors.

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.

A platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma.

A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n = 16), with anti-PD-1 antibody nivolumab (Arm B; n = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells (p = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p = 0.242; HR = 0.51, p = 0.173) and overall survival (HR = 0.59, p = 0.377; HR = 0.53, p = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study.

Retrograde open celiac stenting for ischemic hepatitis after pancreaticoduodenectomy.

A 74-year-old man with pancreatic cancer had undergone pancreaticoduodenectomy and subsequently developed ischemic hepatitis secondary to high-grade celiac artery stenosis. Celiac antegrade stenting via brachial artery access was unsuccessful, and open antegrade bypass would have required takedown of the pancreatic and/or biliary anastomoses for adequate exposure. Retrograde open celiac stenting was, therefore, successfully performed via the gastroduodenal artery stump. His ischemic hepatitis resolved, and he was ultimately discharged with dual antiplatelet therapy. Computed tomography angiography at 6 months demonstrated a widely patent celiac stent. Retrograde open celiac stenting via the gastroduodenal artery stump is an alternative to open bypass for celiac revascularization not amenable to percutaneous antegrade stenting in patients who have undergone pancreaticoduodenectomy.

Cancer-cell-derived sialylated IgG as a novel biomarker for predicting poor pathological response to neoadjuvant therapy and prognosis in pancreatic cancer.

BACKGROUND: Neoadjuvant therapy (NAT) is increasingly applied in pancreatic ductal adenocarcinoma (PDAC); however, accurate prediction of therapeutic response to NAT remains a pressing clinical challenge. Cancer-cell-derived sialylated immunoglobulin G (SIA-IgG) was previously identified as a prognostic biomarker in PDAC. This study aims to explore whether SIA-IgG expression in treatment-naïve fine needle aspirate (FNA) biopsy specimens could predict the pathological response (PR) to NAT for PDAC. METHODS: Endoscopic ultrasonography-guided FNA biopsy specimens prior to NAT were prospectively obtained from 72 patients with PDAC at the Johns Hopkins Hospital. SIA-IgG expression of PDAC specimens was assessed by immunohistochemistry. Associations between SIA-IgG expression and PR, as well as patient prognosis, were analyzed. A second cohort enrolling surgically resected primary tumor specimens from 79 patients with PDAC was used to validate the prognostic value of SIA-IgG expression. RESULTS: SIA-IgG was expressed in 58.3% of treatment-naïve FNA biopsies. Positive SIA-IgG expression at diagnosis was associated with unfavorable PR and can serve as an independent predictor of PR. The sensitivity and specificity of SIA-IgG expression in FNA specimens in predicting an unfavorable PR were 63.9% and 80.6%, respectively. Both positive SIA-IgG expression in treatment-naïve FNA specimens and high SIA-IgG expression in surgically resected primary tumor specimens were significantly associated with shorter survival. CONCLUSIONS: Assessment of SIA-IgG on FNA specimens prior to NAT may help predict PR for PDAC. Additionally, SIA-IgG expression in treatment-naïve FNA specimens and surgically resected primary tumor specimens were predictive of the prognosis for PDAC.

Oncologic resection of pancreatic cancer with isolated liver metastasis: Favorable outcomes in select patients.

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) and liver metastasis are treated with palliative chemotherapy, whereas similar patients with metastatic colorectal cancer are considered for aggressive surgery. METHODS: Using an institutional database, PDAC patients undergoing liver resection for isolated metastasis were identified. Their overall survival (OS), treatment factors, and clinicopathological variables associated with survival were also evaluated. RESULTS: Forty-seven patients underwent curative-intent surgery for metastatic PDAC to the liver between 2000 and 2019. Median OS was 21.9 months from diagnosis. Fourteen patients underwent unplanned resection of radiographically occult liver metastasis during pancreatectomy with median OS of 8.7 months. On the other hand, 29 patients received systemic chemotherapy followed by planned resection; this cohort had the most favorable prognosis following aggressive surgery with median OS being 38.1 months from diagnosis and 24.1 months from surgery. Preoperative chemotherapy (HR = 7.1; p = .002) and moderate to well differentiation of the primary tumor (HR = 3.7; p = .003) were associated with prolonged survival in multivariate analysis, whereas lymph node metastases, response to preoperative therapy, number of liver metastasis, and extent of liver surgery were not. CONCLUSIONS: In select patients with PDAC and isolated liver metastasis, curative-intent surgery can result in meaningful survival. This aggressive approach seems most beneficial in patients following induction chemotherapy.

Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. The poor survival of patients with PDA has been attributed to a high rate of early metastasis and low efficacy of current therapies, which partly result from its complex immunosuppressive tumor microenvironment. Previous studies from our group and others have shown that tumor-associated macrophages (TAMs) are instrumental in maintaining immunosuppression in PDA. Here, we explored the role of Notch signaling, a key regulator of immune response, within the PDA microenvironment. We identified Notch pathway components in multiple immune cell types within human and mouse pancreatic cancer. TAMs, the most abundant immune cell population in the tumor microenvironment, express high levels of Notch receptors with cognate ligands such as JAG1 expressed on tumor epithelial cells, endothelial cells and fibroblasts. TAMs with activated Notch signaling expressed higher levels of immunosuppressive mediators including arginase 1 (Arg1) suggesting that Notch signaling plays a role in macrophage polarization within the PDA microenvironment. Combination of Notch inhibition with PD-1 blockade resulted in increased cytotoxic T cell infiltration, tumor cell apoptosis, and smaller tumor size. Our work implicates macrophage Notch signaling in the establishment of immunosuppression and indicates that targeting the Notch pathway may improve the efficacy of immune-based therapies in PDA patients.

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.

Tailoring Adjuvant Chemotherapy to Biologic Response Following Neoadjuvant Chemotherapy Impacts Overall Survival in Pancreatic Cancer.

BACKGROUND: The role of postoperative chemotherapy in patients with resected pancreatic cancer who receive neoadjuvant treatment is unknown. Clinicians use changes in CA19-9 and histopathologic scores to assess treatment response. We sought to investigate if CA19-9 normalization in response to NAT can help guide the need for postoperative treatment. METHODS: Patients with elevated baseline CA19-9 (CA19-9 > 37U/mL) who received NAT followed by surgery between 2011 and 2019 were retrospectively reviewed. Treatment response was determined by CA19-9 normalization following NAT and histopathologic scoring. The role of postoperative chemotherapy was analyzed in light of CA19-9 normalization and histopathologic response. RESULTS: We identified and included 345 patients. Following NAT, CA19-9 normalization was observed in 125 patients (36.2%). CA19-9 normalization was associated with a favorable histopathologic response (41.6% vs 23.2%, p < 0.001) and a lower ypT (p < 0.001) and ypN stage (p = 0.003). Receipt of adjuvant chemotherapy was associated with improved overall survival in patients in whom CA19-9 did not normalize following NAT (26.8 vs 16.4 months, p = 0.008). In patients who received 5FU-based NAT and in whom CA19-9 did not normalize, receipt of 5FU-based adjuvant chemotherapy was associated with improved OS (p = 0.014). CONCLUSION: CA19-9 normalization in response to NAT was associated with favorable outcomes and can serve as a biomarker for treatment response. In patients where CA19-9 did not normalize, receipt of postoperative chemotherapy was associated with improved OS. These patients also benefited from additional 5FU-based postoperative chemotherapy following 5FU-based NAT.