Outcome In Pancreatic Adenocarcinoma Research Articles

Evaluating the Association of Area Deprivation Index (ADI) on Postoperative Outcomes in Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) is a challenging disease, with outcomes influenced by several factors including socioeconomic status. The area deprivation index (ADI) has been used to understand how neighborhood disadvantages affect healthcare outcomes. Prior research has indicated that a higher ADI, reflective of a greater neighborhood disadvantage, is associated with an increased risk of major complications and unplanned readmission following PDAC resection. This study aimed to extend this investigation to the Northwell Health System in New York and explore the association between neighborhood ADI and surgical outcomes in patients with PDAC. A retrospective analysis of the Northwell Health multicenter pancreatic cancer database from 2014 to 2023 included patients who underwent PDAC resection. The ADI scores were divided into low (1-3), moderate (4-6), and high (7-10), as previously described. Multinomial regression models and Kaplan-Meier log-rank tests were used to compare differences in surgical outcomes between the patients in each ADI group. Out of 314 PDAC patients who underwent resection and had available ADI data, 116 (36.9%) were in the low, 163 (51.9%) in the moderate, and 35 (11.2%) in the high ADI category. The median ADI score was 4 (IQR: 3-5). Adjusted multinomial regression analysis revealed the following disparities: compared to the low ADI group, patients in the moderate ADI group demonstrated a significantly higher risk of diabetes (RR: 1.76, 95% CI 1.06-2.90, p = 0.028); high ADI was associated with a poorer response to neoadjuvant therapy (RR 3.13, 95% CI 1.11-8.82, p = 0.031), higher incidence of microscopic positive margins (RR 1.87, 95% CI 1.11-5.17, p = 0.028), increased severe complications (Clavien-Dindo class III-IV) (RR 1.36, 95% CI 1.04-1.80, p = 0.027), and a higher failure-to-rescue (FTR) rate (RR 1.44, 95% CI 1.12-1.85, p = 0.048). Although readmission and mortality rates at 30 and 90 days did not show significant differences (p > 0.05), the Kaplan-Meier log-rank test indicated a marked disparity in survival probabilities among ADI ranks (p = 0.0025). This study underscores a pronounced survival disparity across ADI categories among PDAC patients, suggesting an association between socioeconomic status and postoperative survival. Consideration of patient ADI may guide tailored healthcare strategies, such as the distribution of navigation and resources, to bridge the gap in survival outcomes and ensure equitable care for all socioeconomic strata.

Effects of treatment delays on outcomes in pancreatic adenocarcinoma

Effects of treatment delays on outcomes in pancreatic adenocarcinoma

Association of personalized and tumor-informed ctDNA with patient survival outcomes in pancreatic adenocarcinoma.

Personalized and tumor-informed circulating tumor DNA (ctDNA) testing is feasible and allows for molecular residual disease (MRD) identification in patients with pancreatic ductal adenocarcinoma (PDAC). In this retrospective analysis of commercial cases from multiple US institutions, personalized, tumor-informed, whole-exome sequenced, and germline-controlled ctDNA levels were quantified and analyzed in patients with PDAC. Plasma samples (n = 1329) from 298 clinically validated patients were collected at diagnosis, perioperatively (MRD-window; within 2-12 weeks after surgery, before therapy), and during surveillance (>12 weeks post-surgery if no ACT or starting 4 weeks post-ACT) from November 2019 to March 2023. Of the initially diagnosed patients with stages I-III PDAC who went for resection, the median follow-up time from surgery was 13 months (range 0.1-214). Positive ctDNA detection rates were 29% (29/100) and 29.6% (45/152) during the MRD and surveillance windows, respectively. Positive ctDNA detection was significantly associated with shorter DFS within the MRD window (median DFS of 6.37 months for ctDNA-positive vs 33.31 months for ctDNA-negative patients; HR: 5.45, P < .0001) as well as during the surveillance period (median DFS: 11.40 months for ctDNA-positive vs NR for ctDNA-negative; HR: 12.38, P < .0001). Additionally, DFS was significantly better with KRAS wildtype status followed by KRASG12R (HR: 0.99, P = .97), KRASG12D (HR: 1.42, P = .194), and worse with KRASG12V (HR: 2.19, P = .002) status. In multivariate analysis, ctDNA detection at surveillance was found to be the most significant prognostic factor for recurrence (HR: 24.28, P < .001). Perioperative tumor-informed ctDNA detection in PDAC is feasible across all stages and is associated with patient survival outcomes.

A single-center retrospective analysis of allergies and survival outcomes in pancreatic adenocarcinoma.

e16299 Background: Survival from pancreatic adenocarcinoma (PDAC) remains poor, with a 5 year survival of 12.5%. A prior 2010 epidemiological study done at Memorial Sloan Kettering Cancer Center (MSKCC) found an association between self-reported allergies and improved survival in PDAC patients. In this retrospective study, we analyzed self-reported allergies and outcomes in both resected and unresected PDAC patients. Methods: Data including allergy status and clinical information were collected from an ongoing PDAC registry study at MSKCC. 1389 eligible PDAC patients were approached and 917 were enrolled between April 2004 and November 2017. 874 patients were included in our overall survival (OS) analysis using Kaplan-Meier methods. 43 patients were excluded due insufficient data or loss to follow up. Cox proportional hazards models were used to adjust for covariates. Results: Of the 874 patients analyzed, mean age at diagnosis was 63.5 years (standard deviation: 11.4), 52% were male, and race was 87% white, 6% black, 4% Asian, and 3% other race. 32.3% had surgery and 85% received chemotherapy. Median overall survival (OS) was 32.8 vs. 27.7 months [Hazard Ratio (HR) 0.95, p = 0.73] and 12.5 vs. 11.2 months [HR 1.04, p = 0.66] in for PDAC patients with allergies compared to those without in the resected and unresected cohorts, respectively. Advanced stage was associated with worse outcomes in both groups. Chemotherapy was significantly associated with improved survival only in the unresected group (HR 0.48, 95% CI 0.30-0.78, p = 0.030). Other established PDAC risk factors were also analyzed. Smoking history, diabetes, and family history were not associated with survival. Only obesity was significantly associated with worse outcomes in the unresected group (HR 1.3, 95% CI 1.01-1.67, p = 0.04). Conclusions: Contrary to previous findings, self-reported allergies were not significantly associated with improved survival in PDAC. In atopic patients, T helper type 2 cells are upregulated with allergen exposure and produce more IgE. Tumor-specific IgE has shown protective benefits in preclinical models but can be downregulated in the tumor microenvironment in PDAC. Further studies are needed to explore the relationship between allergies and PDAC and understand potential aspects of the immune system that can be harnessed to improve outcomes. One study limitation was that allergies were self-reported and not confirmed with allergy testing. We were also able to redemonstrate worse outcomes with more advanced stages and the benefit of chemo in the advanced setting. Further studies are needed to explore the mechanisms behind obesity and PDAC. [Table: see text]

A novel sphingolipid metabolism-related long noncoding RNA signature predicts the prognosis, immune landscape and therapeutic response in pancreatic adenocarcinoma

Sphingolipid metabolism affects prognosis and resistance to immunotherapy in patients with cancer and is an emerging target in cancer therapy with promising diagnostic and prognostic value. Long noncoding ribonucleic acids (lncRNAs) broadly regulate tumour-associated metabolic reprogramming. However, the potential of sphingolipid metabolism-related lncRNAs in pancreatic adenocarcinoma (PAAD) is poorly understood. In this study, coexpression algorithms were employed to identify sphingolipid metabolism-related lncRNAs. The least absolute shrinkage and selection operator (LASSO) algorithm was used to develop a sphingolipid metabolism-related lncRNA signature (SMLs). The prognostic predictive stability of the SMLs was validated using Kaplan–Meier. Univariate and multivariate Cox, receiver operating characteristic (ROC) and clinical stratification analyses were used to comprehensively assess the SMLs. Gene set variation analysis (GSVE), gene ontology (GO) and tumor mutation burden (TMB) analysis explored the potential mechanisms. Additionally, single sample gene set enrichment analysis (ssGSEA), ESTIMATE, immune checkpoints and drug sensitivity analysis were used to investigate the potential predictive function of the SMLs. Finally, an SMLs-based consensus clustering algorithm was utilized to differentiate patients and determine the suitable population for immunotherapy. The results showed that the SMLs consists of seven sphingolipid metabolism-related lncRNAs, which can well determine the clinical outcome of individuals with PAAD, with high stability and general applicability. In addition, the SMLs-based consensus clustering algorithm divided the TCGA-PAAD cohort into two clusters, with Cluster 1 showing better survival than Cluster 2. Additionally, Cluster 1 had a higher level of immune cell infiltration than Cluster 2, which combined with the higher levels of immune checkpoints in Cluster 1 suggests that Cluster 1 is more consistent with an immune ‘hot tumor’ profile and may respond better to immune checkpoint inhibitors (ICIs). This study offers new insights regarding the potential role of sphingolipid metabolism-related lncRNAs as biomarkers in PAAD. The constructed SMLs and the SMLs-based clustering are valuable tools for predicting clinical outcomes in PAAD and provide a basis for clinical selection of individualized treatments.

S3 Improved Survival Outcomes in Pancreatic Adenocarcinoma Associated With Intratumoral Bacteroides Abundance and Decreased Regulatory T-Cell Infiltrate

S3 Improved Survival Outcomes in Pancreatic Adenocarcinoma Associated With Intratumoral Bacteroides Abundance and Decreased Regulatory T-Cell Infiltrate

Macrophage-organoid co-culture model for identifying treatment strategies against macrophage-related gemcitabine resistance

BackgroundGemcitabine resistance (GR) is a significant clinical challenge in pancreatic adenocarcinoma (PAAD) treatment. Macrophages in the tumor immune-microenvironment are closely related to GR. Uncovering the macrophage-induced GR mechanism could help devise a novel strategy to improve gemcitabine treatment outcomes in PAAD. Therefore, preclinical models accurately replicating patient tumor properties are essential for cancer research and drug development. Patient-derived organoids (PDOs) represent a promising in vitro model for investigating tumor targets, accelerating drug development, and enabling personalized treatment strategies to improve patient outcomes.MethodsTo investigate the effects of macrophage stimulation on GR, co-cultures were set up using PDOs from three PAAD patients with macrophages. To identify signaling factors between macrophages and pancreatic cancer cells (PCCs), a 97-target cytokine array and the TCGA-GTEx database were utilized. The analysis revealed CCL5 and AREG as potential candidates. The role of CCL5 in inducing GR was further investigated using clinical data and tumor sections obtained from 48 PAAD patients over three years, inhibitors, and short hairpin RNA (shRNA). Furthermore, single-cell sequencing data from the GEO database were analyzed to explore the crosstalk between PCCs and macrophages. To overcome GR, inhibitors targeting the macrophage-CCL5-Sp1-AREG feedback loop were evaluated in cell lines, PDOs, and orthotopic mouse models of pancreatic carcinoma.ResultsThe macrophage-CCL5-Sp1-AREG feedback loop between macrophages and PCCs is responsible for GR. Macrophage-derived CCL5 activates the CCR5/AKT/Sp1/CD44 axis to confer stemness and chemoresistance to PCCs. PCC-derived AREG promotes CCL5 secretion in macrophages through the Hippo-YAP pathway. By targeting the feedback loop, mithramycin improves the outcome of gemcitabine treatment in PAAD. The results from the PDO model were corroborated with cell lines, mouse models, and clinical data.ConclusionsOur study highlights that the PDO model is a superior choice for preclinical research and precision medicine. The macrophage-CCL5-Sp1-AREG feedback loop confers stemness to PCCs to facilitate gemcitabine resistance by activating the CCR5/AKT/SP1/CD44 pathway. The combination of gemcitabine and mithramycin shows potential as a therapeutic strategy for treating PAAD in cell lines, PDOs, and mouse models.

Impact of Adherence to Operative Standards and Stage-Specific Guideline-Recommended Therapy in Nonmetastatic Pancreatic Adenocarcinoma.

Achieving optimal surgical outcomes in pancreatic adenocarcinoma requires a combination of both curative-intent resection to oncologic standards and stage-specific neoadjuvant or adjuvant therapy. This investigation sought to examine factors associated with receipt of standard-adherent surgery (SAS) and guideline-recommended therapy (GRT) and determine the impact of compliance on patient survival. From the 2006-2016 National Cancer Database, 21,304 patients underwent resection for nonmetastatic pancreatic adenocarcinoma. SAS was defined as pancreatic resection with negative margins and ≥15 lymph nodes examined. Stage-specific GRT was defined by current National Comprehensive Cancer Network guidelines. Multivariable models were used to determine predictors of adherence to SAS and GRT and prognostic impact on overall survival. Overall, SAS was achieved in 39% and GRT in 65% of patients, but only 30% received both SAS and GRT. Increasing age, minority race, uninsured status, and greater comorbidities were associated with a decreased odds of receiving both SAS and GRT (all p<0.05). SAS (HR 0.79; CI 0.76-0.81; p<0.001) and GRT (HR 0.67; CI 0.65-0.69; p<0.001) were each independently associated with a survival advantage. Receipt of both SAS and GRT was associated with significant improvement in median OS compared with receiving neither (2.2years vs 1.1 years; p<0.001) which was independently associated with a 78% increased risk of death (HR 1.78; CI 1.70-1.86; p<0.001). Despite survival benefits associated with adherence to operative standards and receipt of guideline-recommended therapy, compliance remains poor. Future efforts must be directed toward improved education and implementation efforts around both operative standards and therapy guidelines.

Accuracy of models to prognosticate survival after surgery for pancreatic cancer in the era of neoadjuvant therapy.

Outcomes for pancreatic adenocarcinoma (PDAC) remain difficult to prognosticate. Multiple models attempt to predict survival following the resection of PDAC, but their utility in the neoadjuvant population is unknown. We aimed to assess their accuracy among patients that received neoadjuvant chemotherapy (NAC). We performed a multi-institutional retrospective analysis of patients who received NAC and underwent resection of PDAC. Two prognostic systems were evaluated: the Memorial Sloan Kettering Cancer Center Pancreatic Adenocarcinoma Nomogram (MSKCCPAN) and the American Joint Committee on Cancer (AJCC) staging system. Discrimination between predicted and actual disease-specific survival was assessed using the Uno C-statistic and Kaplan-Meier method. Calibration of the MSKCCPAN was assessed using the Brier score. A total of 448 patients were included. There were 232 (51.8%) females, and the mean age was 64.1 years (±9.5). Most had AJCC Stage I or II disease (77.7%). For the MSKCCPAN, the Uno C-statistic at 12-, 24-, and 36-month time points was 0.62, 0.63, and 0.62, respectively. The AJCC system demonstrated similarly mediocre discrimination. The Brier score for the MSKCCPAN was 0.15 at 12 months, 0.26 at 24 months, and 0.30 at 36 months, demonstrating modest calibration. Current survival prediction models and staging systems for patients with PDAC undergoing resection after NAC have limited accuracy.

Molecular subtypes based on cuproptosis-related genes and tumor microenvironment infiltration characteristics in pancreatic adenocarcinoma

BackgroundMultiple molecular subtypes with distinct clinical outcomes in pancreatic adenocarcinoma (PAAD) have been identified in recent years. Cuproptosis is a new form of cell death that likely involved in tumor progression. However, the cuproptosis-related molecular subtypes as well as its mediated tumor microenvironment (TME) cell infiltration characteristics largely remain unclear.MethodsExpression profiles of 10 cuproptosis-related genes (CRGs) and their association with patient survival, TME, cancer stemness and drug resistance were studied in 33 cancer types using the TCGA pan-cancer data. Using 437 PAAD samples from five cohorts (TCGA-PAAD cohort and four GEO cohorts), we explored the molecular subtypes mediated by CRGs, along with the associated TME cell infiltration. Unsupervised methods were utilized to perform cuproptosis subtype clustering. The cuproptosis score was constructed using the COX regression model with least absolute shrinkage and selection operator regression (LASSO) algorithm to quantify the cuproptosis characteristics of a single tumor.ResultsThe expression of 10 CRGs varies in different cancer types with striking inter- and intra- cancer heterogeneity. We integrated the genomic profiling of the CRGs and identified three distinct cuproptosis subtypes, and found that multi-layer CRG alterations were correlated with patient prognosis and TME cell infiltration characteristics. In addition, a cuproptosis score signature was constructed to predict prognosis, and its clinical impacts were characterized in the TCGA-PAAD cohort. The cuproptosis signature was significantly associated with prognosis, tumor subtypes, CD8 T-cell infiltration, response to immune checkpoint inhibitors (ICIs) and chemotherapeutic drug sensitivity. Furthermore, the expression patterns of CRGs in pancreatic cancer cells and normal controls were validated, which was almost consistent with the results from the public database. The expression level and prognostic predictive capability of DLAT were verified in 97 PAAD patients from our patient cohort.ConclusionsThese findings may help understand the roles of CRGs in PAAD and the molecular characterization of cuproptosis subtypes. In addition, the cuproptosis score could serve as a promising biomarker for predicting prognosis and response to immunotherapy in PAAD patients.

DSCR9/miR-21-5p axis inhibits pancreatic cancer proliferation and resistance to gemcitabine via BTG2 signaling.

The outcome of pancreatic adenocarcinoma (PAAD) patients is poor, given resistance to gemcitabine. Long noncoding RNA (lncRNA) has been implicated in the carcinogenesis of pancreatic cancer; however, its function and mechanism in PAAD resistance to gemcitabine (GEM) are yet unknown. Herein, we demonstrate that lncRNA DSCR9 is significantly reduced in PAAD in vitro and in vivo. CCK-8, BrdU and flow cytometry assays show that overexpression of DSCR9 markedly suppresses pancreatic cancer cell proliferation and invasion, and promotes apoptosis under gemcitabine treatment. BTG2 acts as a tumor suppressor by reducing the proliferation and invasion of pancreatic cancer cells and increasing gemcitabine-induced apoptosis. Immunofluorescence (IF) staining combined with fluorescence in situ hybridization (FISH) of pancreatic cancer tissues shows that DSCR9 and BTG2 are both increased in pancreatic cancer tissues. Luciferase assay shows that miR-21-5p simultaneously binds to DSCR9 and 3'UTR of BTG2; DSCR9 relieves miR-21-5p-induced inhibition of BTG2 by competing with BTG2 for miR-21-5p binding. Overexpression of miR-21-5p enhances the invasiveness of pancreatic cancer cells by promoting cancer cell proliferation and invasion and attenuating gemcitabine-induced apoptosis. Overexpression of miR-21-5p attenuates the effect of DSCR9 overexpression on BTG2 expression and invasiveness of pancreatic cancer cells. Finally, miR-21-5p expression is increased, while BTG2 expression is decreased in pancreatic cancer tissues. miR-21-5p is negatively correlated with DSCR9 and BTG2. In conclusion, the DSCR9/miR-21-5p/BTG2 axis modulates pancreatic cancer proliferation, invasion, and gemcitabine resistance.

Development of a Transcription Factor-Based Prognostic Model for Predicting the Immune Status and Outcome in Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is the most common primary malignancy of the pancreas. Growing studies indicate that transcription factors (TFs) are abnormally expressed in PAAD. We, therefore, aimed to evaluate the effect of TFs in PAAD and develop a TF-based prognostic signature for the patients. The expression of the TFs and the clinical characteristics were obtained from TCGA datasets. The levels of the TFs were evaluated in PAAD tissues or nontumor tissues. Kyoto Encyclopedia of Genes and Genomes (KEGG) was used to determine the potential function of the dysregulated TFs. To create a prognostic signature, we used univariate and multivariate Cox regression. In addition, the relationship between risk score and tumor microenvironment was analyzed. In this study, we observed 19 increased and 10 decreased TFs in PAAD tissues. KEGG assays indicated that dysregulated TFs were involved in transcriptional misregulation in cancer. Multivariate Cox analysis identified two prognostic factors, Zinc finger protein 488 and BCL11A; and we developed a risk score model by these two factors. The Kaplan-Meier estimator suggested that patients with high risk exhibited a shorter overall survival than those with low risk. The receiver operating characteristic curve proved that the accuracy of this prognostic signature was 0.686 in predicting the 5-year survival. In addition, we observed that the high score was distinctly related to advanced tumor stage and immune infiltrates. Taken together, we developed a novel TF-related model which could be applied as a potential prognostic tool for PAAD and may guide the choice of immunotherapies.

Association of personalized and tumor-informed ctDNA with patient survival outcomes in pancreatic adenocarcinoma.

517 Background: Pancreatic adenocarcinoma (PDAC) is the third leading cause of cancer-related death, with a recurrence rate of 85% after curative surgery and a 5-year survival rate of 10%. Serum biomarkers like CA 19-9 lack sensitivity and specificity (10% of patients fail to produce CA 19-9), and are poor indicators of molecular residual disease (MRD). Circulating tumor DNA (ctDNA) detection allows for MRD identification months ahead of radiological findings, and may assess molecular response and patient outcomes. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA in a prospective clinical cohort of patients. Serial time points were collected for unresectable, borderline resectable, and resectable subsets of patients to monitor ctDNA levels in response to treatment (see Table). Results: 93 patients were included, with a median age of 67.3 yrs and 45% female. 285 timepoints were analyzed for ctDNA presence, with each patient having between 1 and 7 timepoints (median 3 timepoints per patient). 46 patients had one or more samples positive for ctDNA, resulting in an anytime ctDNA positivity rate of 49.5%. Anytime positivity correlated with the stage of disease (p&lt;0.001). Within ctDNA-positive samples, observed levels were 0.04-1227 mean tumor molecules per mL of plasma (mean 35.1, median 1.02 MTM/mL). During the follow-up period (median 13.5 months, range 1-80 months), 36 patients had recurrence or disease progression events. Recurrence-free survival (RFS) strongly correlated with post-operative anytime ctDNA positivity: Hazards Ratio 8.0 (95% CI 3.4-18.7), p =1.6e-6. For 49 patients, CA 19-9 measurements were available. Elevated CA 19-9 was not correlated with RFS (p=0.35). Conclusions: Our study demonstrates the feasibility of tumor-informed ctDNA-based MRD testing in PDAC, in 93 patients of all stages. ctDNA positivity correlated with patient survival outcomes more strongly than CA19-9. Our data suggests patients can benefit from personalized and tumor-informed MRD testing.[Table: see text]

Pathological outcomes of pancreatic adenocarcinoma (PA) after preoperative high biological effective dose (BED) magnetic resonance image-guided radiation therapy (MRgRT).

573 Background: Pre-operative radiotherapy (RT) for PA has the potential to reduce positive surgical margin rates and increase pathologic tumor response, which has been associated with improved survival. Increasing the BED can improve local control and overall survival for patients with unresectable PA. Use of stereotactic body radiation therapy (SBRT) to achieve a higher BED has been limited by toxicity to adjacent radiosensitive structures, but this can be mitigated by MRgRT. We describe our use of MRgRT prior to potentially curative resection of localized PA. Methods: We performed a single institution retrospective analysis of all patients with localized PA who received high BED SBRT on the MR Linac followed by surgical resection with curative intent. Toxicity was evaluated according to Common Terminology Criteria for Adverse Events, version 5.0. Tumor response was evaluated according to the College of American Pathologists tumor regression grading criteria (CAP-TRG), ranging from CAP 0 indicating pathologic complete response to CAP grade 3 indicating no response. Ordinal logistic regression model was used to assess the association between time from RT to surgery and TRG. Follow up included MRI or CT scans at least every three months. Results: We analyzed 26 patients with borderline resectable (80.8%), locally advanced (11.5%), and resectable (7.7%) tumors who received high BED MRgRT followed by surgical resection. Median age at diagnosis was 68 years (34 - 86). Most patients received chemotherapy (80.8%) prior to RT, with 81% of these receiving FOLFINIRNOX and 19% receiving gemcitabine/nab-paclitaxel. All patients received MR-guided high BED SBRT to a median dose of 50 Gy (40 - 50) in 5 fractions. On-table adaptive replanning was performed in 88% of patients, with 74% having all 5 fractions adapted. No acute grade 2+ toxicity associated with RT was observed. The median time to resection was 50 days (37 – 115), and the procedure types included: Whipple (69%), distal (23%), or total pancreatectomy (8%). The R0 resection rate was 96% and no perioperative deaths occurred within 90 days. Complete (0) or near-complete (1) pathologic response was observed in 35% of cases and the time from RT to surgery was positively associated with TRG (R2= 0.22, p = 0.0003). The median follow-up after RT was 16.5 months (3.9- 26.2) during which 9 patients recurred, and 3 patients died of disease. The derived median progression-free survival from RT was 13.2 months. Conclusions: These initial pathology outcomes following high BED MR-guided SBRT are encouraging and suggest that the time from SBRT to surgical resection is associated with response. This finding is consistent with results from other preoperative GI tumor sites and results from prospective studies using high BED SBRT with MRI guidance in combined modality therapy against PA are eagerly awaited.

Development and validation of a novel 3-gene prognostic model for pancreatic adenocarcinoma based on ferroptosis-related genes

BackgroundMolecular markers play an important role in predicting clinical outcomes in pancreatic adenocarcinoma (PAAD) patients. Analysis of the ferroptosis-related genes may provide novel potential targets for the prognosis and treatment of PAAD.MethodsRNA-sequence and clinical data of PAAD was downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) public databases. The PAAD samples were clustered by a non-negative matrix factorization (NMF) algorithm. The differentially expressed genes (DEGs) between different subtypes were used by “limma_3.42.2” package. The R software package clusterProfiler was used for functional enrichment analysis. Then, a multivariate Cox proportional and LASSO regression were used to develop a ferroptosis-related gene signature for pancreatic adenocarcinoma. A nomogram and corrected curves were constructed. Finally, the expression and function of these signature genes were explored by qRT-PCR, immunohistochemistry (IHC) and proliferation, migration and invasion assays.ResultsThe 173 samples were divided into 3 categories (C1, C2, and C3) and a 3-gene signature model (ALOX5, ALOX12, and CISD1) was constructed. The prognostic model showed good independent prognostic ability in PAAD. In the GSE62452 external validation set, the molecular model also showed good risk prediction. KM-curve analysis showed that there were significant differences between the high and low-risk groups, samples with a high-risk score had a worse prognosis. The predictive efficiency of the 3-gene signature-based nomogram was significantly better than that of traditional clinical features. For comparison with other models, that our model, with a reasonable number of genes, yields a more effective result. The results obtained with qPCR and IHC assays showed that ALOX5 was highly expressed, whether ALOX12 and CISD1 were expressed at low levels in tissue samples. Finally, function assays results suggested that ALOX5 may be an oncogene and ALOX12 and CISD1 may be tumor suppressor genes.ConclusionsWe present a novel prognostic molecular model for PAAD based on ferroptosis-related genes, which serves as a potentially effective tool for prognostic differentiation in pancreatic cancer patients.

Time interval from last visit to imaging diagnosis influences outcome in pancreatic adenocarcinoma: A regional population-based study on linked medico-administrative and clinical data.

Background:Excessive waiting time intervals for the diagnosis and treatment of patients with pancreatic cancer can influence their prognosis but they remain unclear. The objective was to describe time intervals from the medical visit to diagnostic imaging and to treatment and their prognostic impact in pancreatic cancer in one French region.Methods:This retrospective observational multicentre study included all patients with pancreatic cancer seen for the first time in 2017 in multidisciplinary team meetings (MTMs), where clinical data were collected. A probabilistic matching with the medico-administrative data from the French national healthcare database (Système National des Données de Santé) was performed to define the care pathway from clinical presentation to the beginning of treatment. Median key time intervals were estimated for both resected and unresected tumours. Factors associated with 1-year survival were studied using Cox model.Results:A total of 324 patients (88% of total patients with MTM presentation) were matched and included: male 54%, mean age 72 years ±9.2, Eastern Cooperative Oncology Group (ECOG) PS > 1 19.5%, metastatic disease at diagnosis 47.4%, tumour resection 16%. At 1 year, 57% had died (65% in the unresected group and 17% in the resected group). The median time interval from the medical visit to diagnostic imaging was 15 days [Q1–Q3: 8–44]. After imaging, median time intervals to definite diagnosis and to first treatment were 11 and 20 days, respectively. Significant prognostic factors associated with the risk of death at 1 year were ECOG PS > 1 (hazard ratio (HR) 2.1 [1.4–3.0]), metastasis (HR 2.7 [1.9–3.9]), no tumour resection (HR 2.7 [1.3–5.6]) and time interval between the medical visit and diagnostic imaging ⩾25 days (HR 1.7 [1.2–2.3]).Conclusion:Delay in access to diagnostic imaging impacted survival in patients with pancreatic cancer, regardless of whether tumour resection had been performed.

Germline Mutations in Other Homologous Recombination Repair-Related Genes Than BRCA1/2: Predictive or Prognostic Factors?

The homologous recombination repair (HRR) pathway repairs double-strand DNA breaks, mostly by BRCA1 and BRCA2, although other proteins such as ATM, CHEK2, and PALB2 are also involved. BRCA1/2 germline mutations are targeted by PARP inhibitors. The aim of this commentary is to explore whether germline mutations in HRR-related genes other than BRCA1/2 have to be considered as prognostic factors or predictive to therapies by discussing the results of two articles published in December 2020. The TBCRC 048 trial published by Tung et al. showed an impressive objective response rate to olaparib in metastatic breast cancer patients with germline PALB2 mutation compared to germline ATM and CHEK2 mutation carriers. Additionally, Yadav et al. observed a significantly longer overall survival in pancreatic adenocarcinoma patients with germline HRR mutations compared to non-carriers. In our opinion, assuming that PALB2 is a high-penetrant gene with a key role in the HRR system, PALB2 mutations are predictive factors for response to treatment. Moreover, germline mutations in the ATM gene provide a better outcome in pancreatic adenocarcinoma, being more often associated to wild-type KRAS. In conclusion, sequencing of HRR-related genes other than BRCA1/2 should be routinely offered as part of a biological characterization of pancreatic and breast cancers.

Prognosticating Outcome in Pancreatic Adenocarcinoma with the Use of a Machine Learning Algorithm

Journal of the American College of Surgeons 231(4):p e163, October 2020. | DOI: 10.1016/j.jamcollsurg.2020.08.431

Radiomics-Based Outcome Prediction for Pancreatic Cancer Following Stereotactic Body Radiotherapy.

(1) Background: Radiomics use high-throughput mining of medical imaging data to extract unique information and predict tumor behavior. Currently available clinical prediction models poorly predict treatment outcomes in pancreatic adenocarcinoma. Therefore, we used radiomic features of primary pancreatic tumors to develop outcome prediction models and compared them to traditional clinical models. (2) Methods: We extracted and analyzed radiomic data from pre-radiation contrast-enhanced CTs of 74 pancreatic cancer patients undergoing stereotactic body radiotherapy. A panel of over 800 radiomic features was screened to create overall survival and local-regional recurrence prediction models, which were compared to clinical prediction models and models combining radiomic and clinical information. (3) Results: A 6-feature radiomic signature was identified that achieved better overall survival prediction performance than the clinical model (mean concordance index: 0.66 vs. 0.54 on resampled cross-validation test sets), and the combined model improved the performance slightly further to 0.68. Similarly, a 7-feature radiomic signature better predicted recurrence than the clinical model (mean AUC of 0.78 vs. 0.66). (4) Conclusion: Overall survival and recurrence can be better predicted with models based on radiomic features than with those based on clinical features for pancreatic cancer.

Benefits of High-Volume Medical Oncology Care for Noncurable Pancreatic Adenocarcinoma: A Population-Based Analysis.

Although pancreatic adenocarcinoma (PA) surgery performed by high-volume (HV) providers yields better outcomes, volume-outcome relationships are unknown for medical oncologists. This study examined variation in practice and outcomes in noncurative management of PA based on medical oncology provider volume. This population-based cohort study linked administrative healthcare datasets and included nonresected PA from 2005 through 2016. The volume of PA consultations per medical oncology provider per year was divided into quintiles, with HV providers (≥16 patients/year) constituting the fifth quintile and low-volume (LV) providers the first to fourth quintiles. Outcomes were receipt of chemotherapy and overall survival (OS). The Brown-Forsythe-Levene (BFL) test for equality of variances was performed to assess outcome variability between provider-volume quintiles. Multivariate regression models were used to examine the association between management by HV provider and outcomes. A total of 7,062 patients with noncurable PA consulted with medical oncology providers. Variability was seen in receipt of chemotherapy and median survival based on provider volume (BFL, P<.001 for both), with superior 1-year OS for HV providers (30.1%; 95% CI, 27.7%-32.4%) compared with LV providers (19.7%; 95% CI, 18.5%-20.6%) (P<.001). After adjustment for age at diagnosis, sex, comorbidity burden, rural residence, income, and diagnosis period, HV provider care was independently associated with higher odds of receiving chemotherapy (odds ratio, 1.19; 95% CI, 1.05-1.34) and with superior OS (hazard ratio, 0.79; 95% CI, 0.74-0.84). Significant variation was seen in noncurative management and outcomes of PA based on provider volume, with management by an HV provider being independently associated with superior OS and higher odds of receiving chemotherapy. This information is important to inform disease care pathways and care organization. Cancer care systems could consider increasing the number of HV providers to reduce variation and improve outcomes.