Resected Pancreatic Ductal Adenocarcinoma Patients Research Articles

TRIANGLE operation, combined with adequate adjuvant chemotherapy, can improve the prognosis of pancreatic head cancer: A retrospective study.

The TRIANGLE operation involves the removal of all tissues within the triangle bounded by the portal vein-superior mesenteric vein, celiac axis-common hepatic artery, and superior mesenteric artery to improve patient prognosis. Although previously promising in patients with locally advanced pancreatic ductal adenocarcinoma (PDAC), data are limited regarding the long-term oncological outcomes of the TRIANGLE operation among resectable PDAC patients undergoing pancreaticoduodenectomy (PD). To evaluate the safety of the TRIANGLE operation during PD and the prognosis in patients with resectable PDAC. This retrospective cohort study included patients who underwent PD for pancreatic head cancer between January 2017 and April 2023, with or without the TRIANGLE operation. Patients were divided into the PDTRIANGLE and PDnon-TRIANGLE groups. Surgical and survival outcomes were compared between the two groups. Adequate adjuvant chemotherapy was defined as adjuvant chemotherapy ≥ 6 months. The PDTRIANGLE and PDnon-TRIANGLE groups included 52 and 55 patients, respectively. There were no significant differences in the baseline characteristics or perioperative indexes between the two groups. Furthermore, the recurrence rate was lower in the PDTRIANGLE group than in the PDnon-TRIANGLE group (48.1% vs 81.8%, P < 0.001), and the local recurrence rate of PDAC decreased from 37.8% to 16.0%. Multivariate Cox regression analysis revealed that PDTRIANGLE (HR = 0.424; 95%CI: 0.256-0.702; P = 0.001), adequate adjuvant chemotherapy ≥ 6 months (HR = 0.370; 95%CI: 0.222-0.618; P < 0.001) and margin status (HR = 2.255; 95%CI: 1.252-4.064; P = 0.007) were found to be independent factors for the recurrence rate. The TRIANGLE operation is safe for PDAC patients undergoing PD. Moreover, it reduces the local recurrence rate of PDAC and may improve survival in patients who receive adequate adjuvant chemotherapy.

Abstract 7615: Epithelial-mesenchymal-transition gene signature changes and poor oncological outcome in Candida-positive pancreatic ductal adenocarcinoma

Abstract Candida are commonly found in bile collected during surgery in pancreatic ductal adenocarcinoma (PDAC) patients. However, their significance in tumor biology and oncological outcome is unclear. PDAC patients receiving neoadjuvant therapy and pancreatectomy with intraoperative bile fungal culture were identified (N=40) in a prospective single-institution cohort. Tumor regression scores (TRS) were abstracted from pathology reports and correlated with bile fungal cultures. Bulk tumor RNASeq data were obtained from the Oncology Research Information Exchange Network (ORIEN). Tumor microbiome data of non-metastatic PDAC patients with upfront surgery were extracted using the {exotic} tool (Hoyd et al. Cancer Res. Commun., 2023). Gene expression profiles were compared between Candida+ and Candida- tumors, defined by a cutoff microbial count of 0. Overall survival (OS) of resected PDAC patients with Candida+ and Candida- tumors was compared using Kaplan Meier survival analysis. From the single-institution PDAC cohort, Candida+ bile was associated with poor pathological response to neoadjuvant therapy (Table 1). Using the ORIEN cohort, Candida were detected in 67% (106/158) of the PDAC tumors. Patients with Candida+ tumors had worse OS (median 28 vs. 56 months, Log-Rank p&amp;lt;0.008). Gene Set Enrichment Analysis (GSEA) using Hallmark gene sets showed an enrichment of epithelial-mesenchymal-transition (EMT) gene set and a reduction of metabolic and DNA repair gene sets in Candida+ tumors. GSEA for Immune signature and Tumor Immune Microenvironment Deconvolution (TIMEx) cell types showed an enrichment of Stromal-Fibroblast and EMT signature in Candida+ tumors. Further investigations are underway to determine the causal and metabolic relationship between Candida and this tumor microenvironment with EMT and stromal fibroblasts which is a well-known contributor to poor chemotherapy response and oncological outcome of PDAC. Table 1: Pathological Response to Neoadjuvant Therapy for PDAC Bile Culture TRS0/1 TRS2 TRS3 Candida - 5 (25%) 15 (75%) 0 (0%) Candida + 1 (5%) 11 (55%) 8 (40%) TRS: Tumor Regression Score (TRS0: complete response; TRS1: near-complete response; TRS2: partial response; TRS3: no response). Chi-Square Test, P=0.0035. Citation Format: Po Hien Ear, Min Hu, Jonathan S. Shilyansky, Naomi H. Fei, Sam Coleman, Rebecca Hoyd, Caroline E. Wheeler, Kelsey L. Steckly, Michelle L. Churchman, Nicholas Denko, Rebecca D. Dodd, Sheetal Hardikar, Ning Jin, Qin Ma, Martin D. McCarter, Abdul Rafeh Naqash, Afaf E. Osman, Gregory Riedlinger, Lary A. Robinson, Bryan P. Schneider, Eric A. Singer, Ahmad A. Tarhini, Gabriel Tinoco, Cornelia M. Ulrich, Yousef Zakharia, Daniel Spakowicz, Aik Choon Tan, Carlos H. Chan. Epithelial-mesenchymal-transition gene signature changes and poor oncological outcome in Candida-positive pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7615.

Neoadjuvant chemotherapy vs upfront resection: A challenging choice in resectable pancreatic ductal adenocarcinoma.

620 Background: Pancreatic ductal adenocarcinoma (PDAC) remains an immense challenge within oncology, with only 15-20% of cases initially qualifying as resectable. Based on National Cancer Database analyses there is an increase in neoadjuvant chemotherapy (NACT) use, with potential downstaging effects. Yet, a subset of neoadjuvant-treated patients fail to proceed with curative-intent surgery, leading to worse outcomes. This retrospective analysis aims to uncover factors that predict NACT use and the impact on survival outcomes. Methods: A cohort of 543 consecutive non-metastatic PDAC patients treated at an NCCN-designated comprehensive cancer center between 2015 and 2022 were prospectively enrolled into a REDCap database. Based on NCCN resectability criteria, initial CT staging placed 96 patients as upfront resectable. Survival outcomes were compared using univariate and multivariate cox regression analyses. Results: Within 96 resectable patients, 45 (47%) underwent upfront surgery, 36 (37%) received NACT followed by surgery and 15 (16%) only received chemotherapy. The majority were CA19-9 secretors (94%) with 54% lower values during chemotherapy. While 60% of patients experienced up to 35% tumor size reductions on NACT, 20% had stable disease, and 20% showed progressive disease. The patients who received NACT were significantly younger (p = 0.01), with higher baseline CA19-9 (p &lt; 0.01) and more frequently underwent stent placement (p = 0.01), table 1. Median overall survival for the upfront surgery, NACT+surgery and chemotherapy groups were 32.8, 23.7 and 20.2 months (log-rank test p&lt;0.01) subsequently. On univariate analysis initial presentation with weight loss (p = 0.02, HR = 2.08) and high baseline CA19-9 (log2-scaled, p = 0.01, HR = 1.13) were predictive of worse overall survival. After adjusting for potential confounding variables, patients in chemotherapy group had significantly worse survival compared to the upfront surgery group (P &lt; 0.01, HR = 3.14). These 15 patients failed to undergo surgery due to diverse reasons, including distant progression (7), local progression (3), performance status decline or death during chemotherapy (2), refusal due to chemotherapy side effects (2), and indecision and loss to follow-up (1). Conclusions: These findings underscore the need for more robust selection criteria in resectable PDAC patients to undergo NACT. Leveraging real-world data helps identify predictive factors of treatment decision making and their impact on patient survival outcomes. [Table: see text]

Association of Long-Term, New-Onset, and Postsurgical Diabetes With Survival in Patients With Resectable Pancreatic Cancer: A Retrospective Cohort Study.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Identifying modifiable risk factors, such as diabetes, is crucial. In the context of PDAC diagnosis, diabetes manifests as long-term (LTD), new-onset (NOD), or postsurgical (PSD) phenotypes. The link between these diabetes phenotypes and PDAC survival is debated. We performed a retrospective study on patients with resectable PDAC who underwent pancreatectomy at Johns Hopkins Hospital from 2003 to 2017. We utilized the National Death Index and electronic medical records to determine vital status. We categorized diabetes as LTD, NOD, or PSD based on the timing of diagnosis relative to pancreatic resection. Using multivariable Cox models, we assessed hazard ratios (HRs) for survival times associated with each phenotype, considering known PDAC prognostic factors. Of 1556 patients, the 5-year survival was 19% (95% CI, 17-21). No significant survival differences were observed between diabetes phenotypes and non-diabetic patients. NOD and PSD presented nonsignificant increased risks of death (aHR: 1.14 [95% CI, 0.8-1.19] and 1.05 [95% CI, 0.89-1.25], respectively). LTD showed no survival difference (aHR, 0.98; 95% CI, 0.99-1.31). No link was found between diabetes phenotypes and survival in resectable PDAC patients. Comprehensive prospective studies are required to validate these results.

DLL3 Is a Prognostic and Potentially Predictive Biomarker for Immunotherapy Linked to PD/PD-L Axis and NOTCH1 in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplasm with very poor patient survival outcomes despite available treatments. There is an urgent need for new potential treatment options and novel biomarkers for these patients. Delta-like canonical Notch ligand 3 (DLL3) interacts with the Notch receptor and causes inhibition of Notch signaling, which confers a survival advantage to PDAC cells. Thus, DLL3 expression could affect cell survival, and its inhibition could increase a patient's survival. To test this hypothesis, a survival analysis was conducted using the progression-free and overall survival from two independent datasets of PDAC patients, with one using mRNA z-score levels and the other using the Hscore protein expression level; both were carried out using a log-rank test and plotted using Kaplan-Meier curves. DLL3 at the mRNA expression level showed an association between high mRNA expression and both a longer progression-free survival (PFS) and overall survival (OS) of patients. Then, we designed a retrospective study with resected PDAC samples. Our primary objective with this dataset was to assess the relationship between PFS and OS and DLL3 protein expression. The secondary assessment was to provide a rationale for the use of anti-DLL3-based treatments in combination with immunotherapy that is supported by the link between DLL3 and other factors that are involved in immune checkpoints. The survival analyses revealed a protective effect of high DLL3 protein expression levels in both PFS and OS. Interestingly, high DLL3 protein expression levels were significantly correlated with PD-L1/2 and negatively correlated with NOTCH1. Therefore, DLL3 could be considered a biomarker for better prognosis in resectable PDAC patients as well as a therapeutic biomarker for immunotherapy response. These facts set a rationale for testing anti-DLL3-based treatments either alone or combined with immunotherapy or other NOTCH1 inhibitors.

Improving the Reliability of Medical Diagnostic Models through Rule-Based Decision Deferral

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, and accurate assessment of tumor resectability is crucial for determining appropriate treatment. AI-based models have shown promise in classifying tumor resectability, but reliability concerns have impeded clinical implementation. We propose extending the AI-based VasQNet model for classifying tumor resectability on AI-generated segmentations of computed tomography scans (CTs) to improve the models’ reliability. This extension allows VasQNet to defer decisions when the AI-generated segmentations violate pre-established rules on vascular anatomy, tumor location, and tumor size. We conducted experiments using CTs of (borderline) resectable and non-resectable PDAC patients. We evaluated the performance of the baseline VasQNet and the extended VasQNet with rule-based decision deferral (RBDD) by comparing their classifications to a ground-truth provided by a radiologist, employing agreement as a metric. Our results demonstrate that the extended VasQNet achieved a significantly higher agreement (90%) with the radiologist’s classification than the baseline VasQNet (67%). Notably, 17/31 (54%) deferred decisions would have been incorrect had they not been deferred. Our study demonstrates the effectiveness of RBDD in improving the reliability of clinical diagnostic models through the exemplification of VasQNet. In conclusion, RBDD can enhance the reliability of clinical diagnostics models, facilitating integration into clinical practice. The documented code is available on GitHub (https://github.com/PHAIR-Consortium/Vessel-Involvement-Quantifier).

Standard versus delayed initiation of S-1 adjuvant chemotherapy after surgery for pancreatic cancer: a secondary analysis of a nationwide cohort by the Japan Pancreas Society

BackgroundBased on the Japan Adjuvant Study Group of Pancreatic Cancer-01 results, S-1 adjuvant chemotherapy has been the standard in resected pancreatic ductal adenocarcinoma (PDAC) patients in Japan and elsewhere, initiated within 10 weeks after surgery. To assess the clinical impact of this timing, we conducted a secondary analysis of a nationwide survey by the Japan Pancreas Society.MethodsA total of 3361 patients were divided into two groups: 2681 (79.8%) initiating the therapy within 10 weeks after surgery (standard) and 680 (20.2%) after 10 weeks (delayed). We compared recurrence-free survival (RFS) and overall survival (OS) using the log-rank test and Cox proportional hazards model with conditional landmark analysis between the groups. Results were verified by adjustment with inverse-probability-of-treatment weighting (IPTW) analysis.ResultsThe median timing of S-1 adjuvant chemotherapy initiation was 50 days (interquartile range: 38–66). In the standard group, 5-year RFS and OS rates were 32.3–48.7%, respectively, compared with 25.0–38.7% in the delayed group. Hazard ratios (HRs) and 95% confidence intervals were 0.84 (0.76–0.93) for RFS (p < 0.001) and 0.77 (0.69–0.87) for OS (p < 0.001). The IPTW analysis yielded 5-year RFS rates of 32.1% and 25.3% in the standard versus delayed group, respectively [HR = 0.86 (0.77–0.96), p < 0.001] and 5-year OS rates of 48.3% and 39.8%, respectively [HR = 0.81 (0.71–0.92), p < 0.001]. ConclusionsInitiation of S-1 adjuvant chemotherapy in resected PDAC patients within 10 weeks after surgery may offer survival benefit over later initiation.

Short-course neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer: A multicenter randomized phase-II trial (NORPACT-1).

LBA4005 Background: Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) has shown improved survival in metastatic pancreatic cancer, and promising results as downstaging chemotherapy in locally advanced pancreatic cancer. The efficacy of neoadjuvant FOLFIRINOX in patients with resectable pancreatic cancer is unknown. Methods: This is a randomized phase II trial with patients included from 12 Nordic centers in the period 2017-2021. Patients with resectable pancreatic head cancer were randomly assigned to receive either four neoadjuvant cycles of FOLFIRINOX followed by surgery and eight adjuvant cycles mFOLFIRINOX, or upfront surgery and adjuvant mFOLFIRINOX (12 cycles). The primary endpoint was overall survival at 18 months after date of randomization (intention-to-treat [ITT]). Overall survival was estimated with the Kaplan-Meier method, and differences between the respective treatment arms were analyzed with log rank tests. Results: In NORPACT-1, 140 patients were randomly assigned (neoadjuvant chemotherapy, n=77;upfront surgery, n=63). Median age was 66.5 years (IQR 59, 72), while 115 (82.1%) and 25 (17.9%) patients were ECOG 0 and 1, respectively. Median OS by ITT was 25.1 months [95% CI 17.2-34.9] with neoadjuvant chemotherapy and 38.5 months [95% CI 27.6-not reached] with upfront surgery (p=0.096). The proportion of patients alive at 18 months by ITT was 59.7 % [95% CI 48.9-70.7] and 73.0 % [95% CI 62.0-84.0], respectively (p=0.100). Resection rates were 81.8% (63/77) in the neoadjuvant group and 88.9% (56/63) in the upfront surgery group (p=0.342). In the neoadjuvant group 61 (79.2%) patients initiated neoadjuvant FOLFIRINOX. Completion of the four planned cycles was 60%, with dose reductions and delays in 70% and 28.3%. Per-protocol (PP) analysis of 60 patients with pancreatic ductal adenocarcinoma (PDAC) who received minimum one cycle neoadjuvant FOLFIRINOX compared with 55 patients in the upfront surgery arm who were explored showed median OS of 23.0 months [95% CI 16.2-34.9] and 34.4 months [95% CI 19.4-not reached] (p=0.158). Adjuvant chemotherapy initiation rate was 66.2% and 74.6% (p=0.282) by ITT. In resected PDAC patients the rate was 86.4% and 89.8% (p=0.593). Of 120 patients receiving at least one dose of neoadjuvant and/or adjuvant chemotherapy (safety population), 57.5% (42/73) in the neoadjuvant group and 40.4% (19/47) in the upfront surgery group experienced at least one grade ≥3 adverse event (p=0.067). In PP analysis neoadjuvant FOLFIRINOX was associated with significantly higher rate of N0 (p=0.002) and R0 resection (p=0.011). Conclusions: Neoadjuvant FOLFIRINOX did not improve OS compared with upfront surgery in resectable pancreatic head cancer. Our results do not support neoadjuvant chemotherapy as standard of care for these patients. Future trials should incorporate a biomarker-based design. Clinical trial information: NCT02919787 .

Neoadjuvant Treatments for Pancreatic Ductal Adenocarcinoma: Where We Are and Where We Are Going.

Pancreatic ductal adenocarcinoma (PDAC) represents a challenging disease for the surgeon, oncologist, and radiation oncologist in both diagnostic and therapeutic settings. Surgery is currently the gold standard treatment, but the role of neoadjuvant treatment (NAD) is constantly evolving and gaining importance in resectable PDACs. The aim of this narrative review is to report the state of the art and future perspectives of neoadjuvant therapy in patients with PDAC. A PubMed database search of articles published up to September 2022 was carried out. Many studies showed that FOLFIRINOX or Gemcitabine-nab-paclitaxel in a neoadjuvant setting had a relevant impact on overall survival (OS) for patients with locally advanced and borderline resectable PDAC without increasing post-operative complications. To date, there have not been many published multicentre randomised trials comparing upfront surgery with NAD in resectable PDAC patients, but the results obtained are promising. NAD in resectable PDAC showed long-term effective benefits in terms of median OS (5-year OS rate 20.5% in NAD group vs. 6.5% in upfront surgery). NAD could play a role in the treatment of micro-metastatic disease and lymph nodal involvement. In this scenario, given the low sensitivity and specificity for lymph-node metastases of radiological investigations, CA 19-9 could be an additional tool in the decision-making process. The future challenge could be to identify only selected patients who will really benefit from upfront surgery despite a combination of NAD and surgery.

Selective extended dissection for pancreaticoduodenectomy is associated with better survival in pancreatic cancer patients: retrospective cohort study.

Pancreatic ductal adenocarcinoma is a highly malignant tumor with relatively poor survival. Surgery is the first choice for treating patients with early pancreatic cancer. However, the surgical approach and the extent of resection for patients with pancreatic cancer are currently controversial. The authors optimized the procedure of standard pancreaticoduodenectomy to selective extended dissection (SED), which is based on the extrapancreatic nerve plexus potentially invaded by the tumor. The authors retrospectively analyzed the clinicopathological data of patients with pancreatic adenocarcinoma who underwent radical surgery in our center from 2011 to 2020. Patients who underwent standard dissection (SD) were matched 2:1 to those who underwent SED using propensity score matching. The log-rank test and Cox regression model were used to analyze survival data. In addition, statistical analyses were performed for the perioperative complications, postoperative pathology, and recurrence pattern. A total of 520 patients were included in the analysis. Among patients with extrapancreatic perineural invasion (EPNI), disease-free survival was significantly longer in those who received SED than in those who received SD (14.5 months vs. 10 months, P <0.05). The incidence of metastasis in No. 9 and No. 14 lymph nodes was significantly higher in patients with EPNI. In addition, there was no significant difference in the incidence rate of perioperative complications between the two surgical procedures. Compared with SD, SED exhibits a significant prognostic benefit for patients with EPNI. The SED procedure aiming at specific nerve plexus dissection displayed particular efficacy and safety in resectable pancreatic ductal adenocarcinoma patients.

Development and validation of a radiomics model of magnetic resonance for predicting liver metastasis in resectable pancreatic ductal adenocarcinoma patients

BackgroundNearly one fourth of patients with pancreatic ductal adenocarcinoma (PDAC) occur to liver metastasis after surgery, and liver metastasis is a risk factor for prognosis for those patients with surgery therapy. However, there is no effective way to predict liver metastasis post-operation.MethodClinical data and preoperative magnetic resonance imaging (MRI) of PDAC patients diagnosed between July 2010 and July 2020 were retrospectively collected from three hospital centers in China. The significant MRI radiomics features or clinicopathological characteristics were used to establish a model to predict liver metastasis in the development and validation cohort.ResultsA total of 204 PDAC patients from three hospital centers were divided randomly (7:3) into development and validation cohort. Due to poor predictive value of clinical features, MRI radiomics model had similar receiver operating characteristics curve (ROC) value to clinical-radiomics combing model in development cohort (0.878 vs. 0.880, p = 0.897) but better ROC in validation dataset (0.815 vs. 0.732, p = 0.022). Radiomics model got a sensitivity of 0.872/0.750 and a specificity of 0.760/0.822 to predict liver metastasis in development and validation cohort, respectively. Among 54 patients randomly selected with post-operation specimens, fibrosis markers (α-smooth muscle actin) staining was shown to promote radiomics model with ROC value from 0.772 to 0.923 (p = 0.049) to predict liver metastasis.ConclusionThis study developed and validated an MRI-based radiomics model and showed a good performance in predicting liver metastasis in resectable PDAC patients.

TPX2 expression as a negative predictor of gemcitabine efficacy in pancreatic cancer

BackgroundTargeting protein for Xenopus kinesin-like protein 2 (TPX2) overexpression in human tumours is associated with increased malignancy. Its effect on gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) has not been studied yet.MethodsThe prognostic impact of TPX2 expression was examined in the tumour tissue of 139 patients with advanced PDAC (aPDAC) treated within the AIO-PK0104 trial or translational trials and of 400 resected PDAC (rPDAC) patients. The findings were validated using RNAseq data of 149 resected PDAC patients.ResultsIn the aPDAC cohorts, 13.7% of all samples showed high TPX2 expression, conferring significantly shorter progression-free survival (PFS, HR 5.25, P < 0.001) and overall survival times (OS, HR 4.36, P < 0.001) restricted to gemcitabine-based treated patients (n = 99). In the rPDAC cohort, 14.5% of all samples showed high TPX2 expression, conferring significantly shorter disease-free survival times (DFS, HR 2.56, P < 0.001) and OS times (HR 1.56, P = 0.04) restricted to patients treated with adjuvant gemcitabine. RNAseq data from the validation cohort confirmed the findings.ConclusionsHigh TPX2 expression may serve as a negative predictor of gemcitabine-based palliative and adjuvant chemotherapy in PDAC and could be used to inform clinical therapy decisions.Clinical trial registryThe clinical trial registry identifier is NCT00440167.

Prognostic Value of Peritoneal Lavage Cytology in Potentially Resectable Pancreatic Cancer Stratified by Cytologic Status.

Patients with pancreatic ductal adenocarcinoma (PDAC) with positive peritoneal lavage cytology (CY) reportedly have poor prognoses. However, the value of diagnosis of suspicious for malignancy on CY is unknown. This study aimed to elucidate the prognostic impact of CY by focusing on CY subgroups. Data were collected from 231 resectable PDAC patients who underwent curative-intent resection. Patients were divided into three CY-based groups: negative (CY0), suspicious for malignancy (CY-S), and positive (CY1). Clinicopathological characteristics and prognostic factors were analyzed. CY1 and CY-S were diagnosed in 7.8% and 3.9% of the patients, respectively. The CY1 group had significantly larger tumors and higher frequencies of distal tumors, anterior pancreatic tissue invasion, retropancreatic tissue invasion, and R1 resection than the CY0 group. Patient characteristics did not differ between the CY0 and CY-S groups. The CY1 group exhibited worse survival than the CY0 and CY-S groups (median survival time: 18.8 vs. 39.6 months, p=0.0021 and vs. 62.2 months, p=0.018). Multivariate analysis for survival indicated that a tumor size >2 cm, preoperative CA19-9 value >100 U/ml, CY1, lymph node metastasis, R1 resection, and lack of adjuvant chemotherapy were associated with poor prognosis. Both the CY1 and CY-S groups had higher frequencies of peritoneal recurrence than the CY0 group (50% vs. 11.8%, p<0.001 and 44.4% vs. 11.8%, p=0.019). The prognosis of the CY1 group was poor. Although CY-S was associated with a higher frequency of peritoneal recurrence than CY0, the long-term outcomes of patients with surgical treatment were acceptable.

Predicting post-recurrence survival for patients with pancreatic cancer recurrence after primary resection: A Bi-institutional validated risk classification

BackgroundOver 80% of patients will develop disease recurrence after radical resection of pancreatic ductal adenocarcinoma (PDAC). This study aims to develop and validate a clinical risk score predicting post-recurrence survival (PRS) at time of recurrence. MethodsAll patients who had recurrence after undergoing pancreatectomy for PDAC at the Johns Hopkins Hospital or at the Regional Academic Cancer Center Utrecht during the study period were included. Cox proportional hazard model was used to develop the risk model. Performance of the final model was assessed in a test set after internal validation. ResultsOf 718 resected PDAC patients, 72% had recurrence after a median follow-up of 32 months. The median overall survival was 21 months and the median PRS was 9 months. Prognostic factors associated with shorter PRS were age (hazard ratio [HR] 1.02; 95% confidence interval [95%CI] 1.00–1.04), multiple-site recurrence (HR 1.57; 95%CI 1.08–2.28), and symptoms at time of recurrence (HR 2.33; 95%CI 1.59–3.41). Recurrence-free survival longer than 12 months (HR 0.55; 95%CI 0.36–0.83), FOLFIRINOX and gemcitabine-based adjuvant chemotherapy (HR 0.45; 95%CI 0.25–0.81; HR 0.58; 95%CI 0.26–0.93, respectively) were associated with a longer PRS. The resulting risk score had a good predictive accuracy (C-index: 0.73). ConclusionThis study developed a clinical risk score based on an international cohort that predicts PRS in patients who underwent surgical resection for PDAC. This risk score will become available on www.evidencio.com and can help clinicians with patient counseling on prognosis.

Diagnostic Bioliquid Markers for Pancreatic Cancer: What We Have vs. What We Need.

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, currently has a dismal five-year survival rate of approximately 10% due to late diagnosis and a lack of efficient treatment options such as surgery. Furthermore, the majority of PDAC patients have surgically unresectable cancer, meaning cancer cells have either reached the surrounding blood vessels or metastasized to other organs distant from the pancreas area, resulting in low survival rates as compared to other types of cancers. In contrast, the five-year survival rate of surgically resectable PDAC patients is currently 44%. The late diagnosis of PDAC is a result of little or no symptoms in its early stage of development and a lack of specific biomarkers that may be utilized in routine examinations in the clinic. Although healthcare professionals understand the importance of early detection of PDAC, the research on the subject has lagged and no significant changes in the death toll of PDAC patients has been observed. This review is focused on understanding potential biomarkers that may increase the early diagnosis of PDAC patients at its surgically resectable stage. Here, we summarize the currently available biomarkers used in the clinic as well as those being developed with the hope of providing insight into the future of liquid biomarkers to be used in routine examinations for the early diagnosis of PDAC.

The prognostic significance of serum lactate dehydrogenase to albumin ratio in pancreatic ductal adenocarcinoma

Objective: This study was performed to investigate the prognostic role of lactate dehydrogenase/albumin ratio (LAR) and pancreatic ductal adenocarcinoma (PDAC) with initial curable resection treatment. Materials and Methods: This retrospective study was conducted with the data of patients with resectable PDAC. The (ROC) analysis showed that the optimal sill value for pretreatment LAR was 91.43 and this threshold value was used in other analyses. Univariate and multivariate analyses were performed to determine the prognostic factors for overall survival (OS). Results: Our study consisted of 70 patients with a mean age of 59.5±13.2 years and 37 (52,9%) women. OS was 50 months in LAR &lt;91.43 (n = 32) patients and 27,7 months in LAR≥91.43 (n=38) patients, respectively. Kaplan–Meier curves showed that LAR≥91.43 was significantly associated with worse OS (p=0.029). Multivariate analyses proved that LAR was an independent predictor in resectable PDAC patients (p=0.017). Conclusion: Our results showed that a high pre-treatment LAR level was a unfavorable prognosticator in PDAC patients undergoing curative resection. LAR has the potential to be a prognostic biomarker in clinical practice.

Abstract 2315: Temporal changes in circulating tumor cells and circulating tumor DNA in patients with resectable pancreatic ductal adenocarcinoma

Abstract Background: Circulating tumor cells (CTCs), circulating cell-free DNA (cfDNA), and circulating tumor DNA (ctDNA) are minimally invasive biomarkers that carry vital tumor onset, progression, and metastasis information, which is crucial for cancer diagnosis, prognosis, and management. We report here our longitudinal study of these circulating biomarkers in resectable pancreatic ductal adenocarcinoma (PDAC) patients. Although the overall 5-year survival rate of PDAC is low (~6%), truly resectable patients are expected to have better outcomes than non-resectable PDAC patients, especially if liquid biopsy can help guide anticancer treatment selection. Method: We evaluated temporal changes in CTCs, cfDNA, and ctDNA in peripheral blood samples in a cohort of patients with resectable PDAC treated with pre-operative chemotherapy and surgical excision. Five PDAC survivors in complete remission for three years without evidence of disease served as negative controls. Samples of peripheral blood were collected prior to the start of treatment and every two weeks while patients underwent neoadjuvant chemotherapy, followed by surgical excision of the pancreatic tumor. CTCs were enumerated using a previously reported microfluidic device [1] that integrates immunoaffinity-based isolation with size-based filtration, while cfDNA and ctDNA were measured using quantitative polymerase chain reaction (qPCR) and droplet digital PCR (ddPCR). Results: Among the initial seven patients who have completed the treatment sequences [2], CTCs were detectable in all patients (100%) at some points during treatment, but only 50% of patients had detectable CTCs before the start of chemotherapy. Median cfDNA concentrations were comparable to those negative controls throughout treatment. Using ddPCR to analyze peripheral blood samples, KRAS mutations were detected in in 71% of patients during anticancer therapy, but only in 29% patients prior to treatment. Overall, the majority of circulating biomarkers (81% for CTCs and 91% for ctDNA) were detected in blood samples collected after the start of neoadjuvant therapy and before surgery. Conclusion: This study suggests that a longitudinal study of circulating biomarkers provides additional data compared to single-point liquid biopsy, and that biologic “release” of biomarkers due to therapy can increase detectability. -Further study is needed to determine the clinical utility of liquid biopsy for resectable PDAC patients. [1] Chen, et al., Angew. Chem. Int. Ed., 58, 2019, 7606-7610. [2] Dopico, et al., Biosensors, 12, 2022, 206. Citation Format: Yang Zhang, Pablo J. Dopico, Minh-Chau N. Le, Zhijie Yang, Youxiang Wang, Sherise C. Rogers, Thomas J. George, Hugh Z. Fan. Temporal changes in circulating tumor cells and circulating tumor DNA in patients with resectable pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2315.

No survival benefit with suboptimal CA19-9 response: defining effective neoadjuvant chemotherapy in resectable or borderline resectable pancreatic cancer

Background/purposeNeoadjuvant chemotherapy (NAC) is gaining popularity over a surgery-first (SF) approach in treating resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC). However, what constitutes effective neoadjuvant chemotherapy is unknown. MethodsWe retrospectively analyzed resectable and borderline resectable PDAC patients who underwent pancreaticoduodenectomy (2010–2019) at a single institution. Optimal CA19-9 response was defined as normalization AND >50% reduction. We utilized Kaplan-Meier and multivariable-adjusted Cox models and competing risk subdistribution methods for statistical analysis. Results586 patients were included in this study. The multivariable-adjusted analysis demonstrated OS benefit in the NAC group only when OS was calculated from diagnosis (HR = 0.72, p = 0.02), but not from surgery (HR = 0.81, p = 0.1). However, in 59 patients who achieved optimal CA19-9 response, OS is significantly longer than the 134 patients with suboptimal CA19-9 response (39.3 m vs. 21.5 m, p = 0.005) or the 117 SF patients (39.3 m vs. 19.5 m, p < 0.001). Notably, a suboptimal CA19-9 response conferred no OS advantage compared to SF patients. The accumulative incidence of liver metastases (but not other metastases) was significantly reduced only in patients with optimal CA19-9 response to NAC (multivariable-adjusted subdistribution HR = 0.26, p = 0.03). ConclusionCA19-9 response to NAC may serve as the marker for effective NAC. These findings warrant validation in a multi-institutional study.

C/EBP-Family Redundancy Determines Patient Survival and Lymph Node Involvement in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a poor clinical prognosis and unsatisfactory treatment options. We previously found that the transcription factor CCAAT/Enhancer-Binding Protein Delta (C/EBPδ) is lowly expressed in PDAC compared to healthy pancreas duct cells, and that patient survival and lymph node involvement in PDAC is correlated with the expression of C/EBPδ in primary tumor cells. C/EBPδ shares a homologous DNA-binding sequence with other C/EBP-proteins, leading to the presumption that other C/EBP-family members might act redundantly and compensate for the loss of C/EBPδ. This implies that patient stratification could be improved when expression levels of multiple C/EBP-family members are considered simultaneously. In this study, we assessed whether the quantification of C/EBPβ or C/EBPγ in addition to that of C/EBPδ might improve the prediction of patient survival and lymph node involvement using a cohort of 68 resectable PDAC patients. Using Kaplan-Meier analyses of patient groups with different C/EBP-expression levels, we found that both C/EBPβ and C/EBPγ can partially compensate for low C/EBPδ and improve patient survival. Further, we uncovered C/EBPβ as a novel predictor of a decreased likelihood of lymph node involvement in PDAC, and found that C/EBPβ and C/EBPδ can compensate for the lack of each other in order to reduce the risk of lymph node involvement. C/EBPγ, on the other hand, appears to promote lymph node involvement in the absence of C/EBPδ. Altogether, our results show that the redundancy of C/EBP-family members might have a profound influence on clinical prognoses and that the expression of both C/EPBβ and C/EBPγ should be taken into account when dichotomizing patients according to C/EBPδ expression.

The use of angiotensin system inhibitors correlates with longer survival in resected pancreatic adenocarcinoma patients

BackgroundActivities and inhibition of the Renin-Angiotensin-Aldosterone System (RAAS) may affect the survival of resected pancreatic ductal adenocarcinoma (PDAC) patients MethodA single-institution retrospective analysis of resected PDAC patients between 2010 and 2019. To estimate the effect of angiotensin system inhibitors (ASIs) on patient survival, we performed Kaplan Meier analysis, Cox Proportional Hazards model, Propensity Score Matching (PSM), and inverse probability weighting (IPW) analysis. Results742 patients were included in the analysis. The average age was 67.0 years, with a median follow-up of 24.1 months. The use of ASI was associated with significantly longer overall survival in univariate (p = 0.004) and multivariable (HR = 0.70 [0.56–0.88],p = 0.003) adjusted analysis. In a propensity score-matched cohort of 400 patients, ASI use was again associated with longer overall survival (p = 0.039). Lastly, inverse probability weighting (IPW) analysis suggested that the use of ASI was associated with an average treatment effect on the treated (ATT) of HR = 0.68 [0.53–0.86],p = 0.002) for overall survival. ConclusionIn this single-institution retrospective study focusing on resected PDAC patients, the use of ASI was associated with longer overall survival in multiple statistical models. Prospective clinical trials are needed before routine clinical implementation of ASI as an adjuvant to existing therapy can be recommended.