Survival In Pancreatic Cancer Research Articles

Abstract LB274: Nuclear transporter HIKESHI is a novel independent poor overall survival for pancreatic cancer; targeting can inhibit pancreatic cancer growth via HSP70 suppression

Abstract HIKESHI, under heat stress conditions, has been reported to transport molecular chaperone HSP70 into the nucleus to prevent cancer cell death from heat stress. The tumor-supporting roles of molecular chaperones in various solid tumors are explored extensively. Yet, the sole targeting of the molecular chaperones could not significantly impact anticancer treatment. Thus, we hypothesized that the specific transporter protein HIKESHI might improve this outcome. However, understanding of the clinical relevance of HIKESHI in pancreatic cancer remained unclear, and few studies addressed the HIKESHI role in cancer and whether targeting can inhibit pancreatic cancer cell viability and the other HSPs. Here, we first investigated the expression pattern of the HIKESHI protein in surgically resected pancreatic cancer samples (n=142) and analyzed the clinical relevance of the HIKESHI. We found that the HIKESHI protein was overexpressed in cancer compared to the adjacent normal tissue, and positive expression of cancer HIKESHI was related to poor overall survival. In addition, HIKESHI-positive expression in cancer was identified as an independent prognostic marker for overall survival. Next, using shRNA, we established the stable HIKESHI-suppressed pancreatic cancer cell line (PANC-1). HIKESHI suppression inhibited cell growth and colony formation ability in vitro. The expression and nuclear translocation of HSP70 and HSP110/105 were suppressed in HIKESHI-suppressed cells compared to the control shRNA cells despite no heat stress conditions. Furthermore, we found that the tumor growth, HIKESHI, and Ki67 expression in HIKESHI-suppressed tumors were inhibited compared to the control shRNA tumors. Next, we performed Cap Analysis of Gene Expression and IP-MS analysis to discover the potential downstream and novel interactive partner of the HIKESHI protein. The extensive mechanism of these analyses is under investigation. Our findings suggest that targeting HIKESHI may be a promising therapeutic strategy against refractory pancreatic cancer. Citation Format: Bilguun Erkhem-Ochir, Takehiko Yokobori, Gendensuren Dorjkhorloo, Haruka Okami, Takaomi Seki, Norifumi Harimoto, Ryo Muranushi, Kouki Hoshino, Kei Hagiwara, Norihiro Ishii, Mariko Tsukagoshi, Kenichiro Araki, Hiroshi Saeki, Ken Shirabe. Nuclear transporter HIKESHI is a novel independent poor overall survival for pancreatic cancer; targeting can inhibit pancreatic cancer growth via HSP70 suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB274.

Metabolomics for early pancreatic cancer detection in plasma samples from a Swedish prospective population-based biobank.

Pancreatic ductal adenocarcinoma (pancreatic cancer) is often detected at late stages resulting in poor overall survival. To improve survival, more patients need to be diagnosed early when curative surgery is feasible. We aimed to identify circulating metabolites that could be used as early pancreatic cancer biomarkers. We performed metabolomics by liquid and gas chromatography-mass spectrometry in plasma samples from 82 future pancreatic cancer patients and 82 matched healthy controls within the Northern Sweden Health and Disease Study (NSHDS). Logistic regression was used to assess univariate associations between metabolites and pancreatic cancer risk. Least absolute shrinkage and selection operator (LASSO) logistic regression was used to design a metabolite-based risk score. We used receiver operating characteristic (ROC) analyses to assess the discriminative performance of the metabolite-based risk score. Among twelve risk-associated metabolites with a nominal P value <0.05, we defined a risk score of three metabolites [indoleacetate, 3-hydroxydecanoate (10:0-OH), and retention index (RI): 2,745.4] using LASSO. A logistic regression model containing these three metabolites, age, sex, body mass index (BMI), smoking status, sample date, fasting status, and carbohydrate antigen 19-9 (CA 19-9) yielded an internal area under curve (AUC) of 0.784 [95% confidence interval (CI): 0.714-0.854] compared to 0.681 (95% CI: 0.597-0.764) for a model without these metabolites (P value =0.007). Seventeen metabolites were significantly associated with pancreatic cancer survival [false discovery rate (FDR) <0.1]. Indoleacetate, 3-hydroxydecanoate (10:0-OH), and RI: 2,745.4 were identified as the top candidate biomarkers for early detection. However, continued efforts are warranted to determine the usefulness of these metabolites as early pancreatic cancer biomarkers.

Increased risk of multiple metastases and worse overall survival of metastatic pancreatic body and tail cancer: a retrospective cohort study.

Pancreatic cancer (PC) is a lethal disease, especially metastatic PC. And it can be divided into two types: head pancreatic cancer (H-PC) and body and tail pancreatic cancer (BT-PC). Prior studies have proved that they have different overall survival (OS) and should be regarded as two different categories of PC. At present, there remains a gap in the field regarding OS across different primary tumor locations and metastatic sites, as well as the metastatic patterns associated with various primary tumor locations in patients with metastatic PC. Thus, our study aims to address this gap by analyzing data from a large population sourced from the Surveillance, Epidemiology, and End Results (SEER) database. The different prognosis of different primary tumor locations and metastatic sites may indicate that different primary locations and metastatic sites may require different therapy and follow-up strategy. It is hoped that these findings will lay the groundwork for future guideline updates and related research. Patients with pathologically confirmed stage IV metastatic PC from the National Cancer Institute's SEER program between 2010 and 2015 were included, excluding patients with various tumors, without specifying age, specific sites of metastasis, or OS. Data including age, race, gender, tumor size, T stage, N stage, grade, sites, number of metastatic sites, surgery, radiotherapy, chemotherapy and years of diagnoses were collected from the SEER database. OS was defined as the period from initial diagnosis to the date of death. Specific metastatic sites for the different primary locations of tumor were compared. Survival was analyzed by Cox regression analyses. Overall, 14,406 patients with metastatic PC were included in this research (7,104 of H-PC and 7,302 of BT-PC). Gender proportion, tumor size, T stage, N stage, number of metastatic sites surgery of the primary lesions and radiotherapy were different between BT-PC and H-PC. The proportion of only 1 metastatic site was 68.3% in H-PC compared with 58.3% in the BT-PC. The BT-PC was an independent risk factor for liver metastases compared with the H-PC [odds ratio (OR) =1.510; 95% confidence interval (CI): 1.320-1.727]. No matter for those with multiple metastases, or for those with solitary liver or lung metastases, patients with metastatic H-PC showed better OS (P<0.001, P=0.001, P=0.04, respectively). In patients with solitary liver metastases, worse OS was observed in the BT-PC than the H-PC [hazard ratio (HR) =1.109; 95% CI: 1.046-1.175]. The metastatic BT-PC had worse OS and increased risk to suffer from liver and multiple metastases. Moreover, in patients with solitary metastases, those with liver metastases presented poorest survival.

Clinical efficacy and safety of erlotinib combined with chemotherapy in the treatment of advanced pancreatic cancer: A meta-analysis.

Advanced pancreatic cancer is resistant to chemotherapeutic drugs, resulting in limited treatment efficacy and poor prognosis. Combined administration of the chemotherapeutic gemcitabine and erlotinib is considered a potential first-line treatment for advanced pancreatic cancer. However, their comparative benefits and potential risks remain unclear. To assess the clinical efficacy and safety of erlotinib combined with other chemotherapy regimens for the treatment of advanced pancreatic cancer. Literature on the clinical efficacy and safety of erlotinib combined with chemotherapy for advanced pancreatic cancer was retrieved through an online search. The retrieved literature was subjected to a methodological qualitative assessment and was analyzed using the RevMan 5.3 software. Ten randomized controlled trials involving 2444 patients with advanced pancreatic cancer were included in the meta-analysis. Compared with chemotherapeutic treatment, erlotinib combined with chemotherapy significantly prolonged the progression-free survival time of pancreatic cancer patients [hazard ratio (HR) = 0.78, 95%CI: 0.66-0.92, P = 0.003]. Meanwhile, the overall survival (HR= 0.99, 95%CI: 0.72-1.37, and P = 0.95) and disease control rate (OR = 0.93, 95%CI: 0.45-0.91, P = 0.84) were not significantly favorable. In terms of safety, the erlotinib and chemotherapy combination was associated with a significantly higher risk of diarrhea (OR = 3.59, 95%CI: 1.63-7.90, P < 0.05) and rash (OR = 3.63, 95%CI: 1.64-8.01, P < 0.05) compared with single-agent chemotherapy. Moreover, the risk of vomiting (OR = 1.27, 95%CI: 0.62-2.59, P = 0.51), regurgitation/anorexia (OR = 1.61, 95%CI: 0.25-10.31, P = 0.62), and infection (OR = 0.72, 95%CI: 0.28-1.87, P = 0.50) were not significant in either group. Compared with a single chemotherapeutic modality, erlotinib combined with gemcitabine can prolong progression-free survival in pancreatic cancer, but does not improve survival benefit or disease control rate, and can increase the risk of diarrhea and rash.

Abstract 6984: Investigating the function of the OSM-OSMR axis in pancreatic ductal adenocarcinoma (PDAC)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, characterized by a low survival rate and a significant global mortality impact. The interaction between PDAC and the immune system is complex and plays a crucial role in the progression of the disease. PDAC creates an immunosuppressive tumor microenvironment, which hampers the ability of immune cells to effectively infiltrate the tumor and mount an anti-cancer immune response. Additionally, there is an imbalance of cytokines, with an overabundance of immunosuppressive factors and a deficiency in pro-inflammatory cytokines. This hostile immunological landscape contributes to the aggressive nature of PDAC and hinders the success of immunotherapies and adjuvant treatments. One cytokine of particular interest is oncostatin M (OSM), a member of the interleukin-6 (IL-6) family. OSM has been implicated in the regulation of cancer and has been associated with poor overall survival in pancreatic cancer and other malignancies. Similar to other cytokines, OSM is secreted by immune cells and acts as a regulator of the inflammatory microenvironment surrounding the tumor. The levels of OSM in this milieu can potentially influence cancer development and regulation through multiple mechanisms. Despite the growing understanding of cytokines in cancer, research on the role of OSM in PDAC is still limited and requires further investigation to identify potential therapeutic targets. Therefore, there is a critical need to delve deeper into the functions of OSM and its receptor, oncostatin M receptor (OSMR), in the initiation and progression of pancreatic cancer. As such, our goal is to examine the functions of OSM and its receptor (OSMR) in initiating and advancing pancreatic cancer to better comprehend the role of the OSM-OSMR axis in PDAC, both in vivo and in vitro. Citation Format: Yuan Sui, Tony Hunter. Investigating the function of the OSM-OSMR axis in pancreatic ductal adenocarcinoma (PDAC) [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 6984.

Abstract 6534: Overcoming B regulatory cell induced STING resistance by dual functional albumin nanomedicine to prolong survival of pancreatic cancer

Abstract Pancreatic cancer is the most lethal form of cancer with a 5-year survival at 11% and lacks treatment options. Immunotherapy, specifically anti-PD-1/PD-L1 antibody, proves ineffective for pancreatic cancer patients due to the immunosuppressive tumor microenvironment (TME). STING agonist has emerged as the most effective immune modulator to regulate immunosuppressive TME to enhance the efficacy of immunotherapy across many different cancer types. However, two challenges hinder the use of STING agonist in pancreatic cancer: (A) STING agonist strongly stimulates induction of B regulatory cells (Bregs) in pancreatic tumor and lymph node, leading to an intrinsic resistance to STING agonist and a severe compromised efficacy. (B) Most STING agonists are used by local intra-tumor injection in clinical trials, which only shrinks the local tumors without inhibiting distal tumors or metastasis, whereas it is also not feasible for intra-tumor injection for pancreatic cancer in clinical trials. In response, we developed a first-in-class dual functional drug (SH-273) to overcome STING resistance by eliminating Bregs in both tumors and lymph nodes for long-term efficacy in pancreatic cancer. SH-273 has dual function to stimulates STING function (EC50 100 nM) and inhibits PI3Kγ (IC50 7 nM) that eliminate Bregs to overcome STING resistance. Interestingly, SH-273 achieved dual function with an opposite mechanism in regulating IRF3 phosphorylation in myeloid cells (increase) vs. in Bregs (decrease). In addition, we developed an albumin nanoparticle of SH-273 (Nano-273) for systemic delivery to enhance drug targeting to tumor and lymph node to activate systemic anticancer immunity. 3D imaging results indicated that albumin nano formulation greatly enhanced drug lymphoid draining and pancreatic tumor penetrating. Nano-273, combined with anti-PD-1, achieved long-term median survival of 200 days in LSL-KrasG12D; LSL-Trp53R172H/+; Pdx1cre/+ (KPC) mice (a substantial 67% increase from 120 days without treatment). The 80-day survival extension is significant as KPC mice mimic human pancreatic cancers with Kras/P53 mutations that are unresponsive to other available therapies. Single cell RNA-sequencing and flow cytometry revealed that Nano-273, combined with anti-PD-1, reduces Bregs by 5 to 7-fold while increasing other B cell subtypes by 4-fold in both pancreatic tumors and lymph nodes, compared to control group or group treated with STING agonist alone. These findings suggest that Nano-273 overcomes STING resistance by eliminating Bregs and induced systemic immunity to achieve long-term anti-tumor efficacy in pancreatic cancer. Citation Format: Chengyi Li, Shuai Mao, Hongyi Zhao, Djibo Mahamadou, Zhongwei Liu, Hanning Wen, Miao He, Meilin Wang, Jinsong Tao, Bo Wen, Trang Hoang, Binyamin Jacobovitz, Fei Wen, Wei Gao, Duxin Sun. Overcoming B regulatory cell induced STING resistance by dual functional albumin nanomedicine to prolong survival of pancreatic cancer [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 6534.

Viewing the immune checkpoint VISTA: landscape and outcomes across cancers

Optimizing immune checkpoint inhibitor (ICI) therapy may require identification of co-targetable checkpoint pathways via immune profiling. Herein, we analyzed the transcriptomic expression and clinical correlates of V-domain immunoglobulin suppressor of T-cell activation (VISTA), a promising targetable checkpoint. RNA sequencing was carried out on 514 tissues reflecting diverse advanced/metastatic cancers. Expression of eight immune checkpoint markers [lymphocyte-activation gene 3 (LAG-3), tumor necrosis factor receptor superfamily 14 (TNFRSF14), programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), programmed death-ligand 2 (PD-L2), B- and T-lymphocyte attenuator (BTLA), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), cytotoxic T-lymphocyte antigen 4 (CTLA-4)], in addition to VISTA, was analyzed, along with clinical outcomes. High VISTA RNA expression was observed in 32% of tumors (66/514) and was the most common highly expressed checkpoint among the nine assessed. High VISTA expression was independently correlated with high BTLA, TIM-3, and TNFRSF14, and with a diagnosis of pancreatic, small intestine, and stomach cancer. VISTA transcript levels did not correlate with overall survival (OS) from metastatic/advanced disease in the pan-cancer cohort or with immunotherapy outcome (progression-free survival and OS from the start of ICI) in 217 ICI-treated patients. However, in ICI-treated pancreatic cancer patients (n = 16), median OS was significantly shorter (from immunotherapy initiation) for the high- versus not-high-VISTA groups (0.28 versus 1.21 years) (P= 0.047); in contrast, VISTA levels were not correlated with OS in 36 pancreatic cancer patients who did not receive ICI. High VISTA expression correlates with high BTLA, TIM-3, and TNFRSF14 checkpoint-related molecules and with poorer post-immunotherapy survival in pancreatic cancer, consistent with prior literature indicating that VISTA is prominently expressed on CD68+ macrophages in pancreatic cancers and requiring validation in larger prospective studies. Immunomic analysis may be important for individualized precision immunotherapy.

Construction and validation of a nomogram for cancer specific survival of postoperative pancreatic cancer based on the SEER and China database

BackgroundThe recurrence rate and mortality rate among postoperative pancreatic cancer patients remain elevated. This study aims to develop and validate the cancer-specific survival period for individuals who have undergone pancreatic cancer surgery.MethodsWe extracted eligible data from the Surveillance, Epidemiology, and End Results database and randomly divided all patients into a training cohort and an internal validation cohort. External validation was performed using a separate Chinese cohort. The nomogram was developed using significant risk factors identified through univariate and multivariate Cox proportional hazards regression. The effectiveness of the nomogram was assessed using the area under the time-dependent curve, calibration plots, and decision curve analysis. Kaplan–Meier survival curves were utilized to visualize the risk stratification of nomogram and AJCC stage.ResultsSeven variables were identified through univariate and multivariate analysis to construct the nomogram. The consistency index of the nomogram for predicting overall survival was 0.683 (95% CI: 0.675–0.690), 0.689 (95% CI: 0.677–0.701), and 0.823 (95% CI: 0.786–0.860). The AUC values for the 1- and 2-year time-ROC curves were 0.751 and 0.721 for the training cohort, 0.731 and 0.7554 for the internal validation cohort, and 0.901 and 0.830 for the external validation cohorts, respectively. Calibration plots demonstrated favorable consistency between the predictions of the nomogram and actual observations. Moreover, the decision curve analysis indicated the clinical utility of the nomogram, and the risk stratification of the nomogram effectively identified high-risk patients.ConclusionThe nomogram guides clinicians in assessing the survival period of postoperative pancreatic cancer patients, identifying high-risk groups, and devising tailored follow-up strategies.

Racial and socioeconomic disparities in survival improvement of eight cancers

BackgroundMany studies have characterized racial differences in cancer outcomes, demonstrating that black and Hispanic patients have lower cancer-specific survival compared to white patients. However, to our knowledge, a gap in the literature exists regarding racial, socioeconomic, age, and sex-related differences in survival improvement in cancer.MethodsWe perform a population-based cohort study of 1,875,281 patients with eight common cancer sites from the Surveillance, Epidemiology, and End Results (SEER) database.ResultsThe longitudinal data demonstrates that while overall cancer-free survival has improved from 2004 to 2018, certain groups have seen lower rates of improvement. Black patients have the lowest cancer-specific survival (CSS) in breast, prostate, ovarian, colon, liver, lung, and pancreatic cancers. However, from 2009 to 2018, black patients have seen the greatest survival improvement in breast, ovarian, colorectal, liver, lung, and pancreatic cancer, though CSS for black patients still lags behind other groups. Strikingly, however, in breast and prostate cancer, black patient CSS from 2014 to 2018 remains lower than white patient CSS from 2004 to 2008 after controlling for income, age, and stage.ConclusionsWhile the racial disparity gap is closing in some forms of cancer, future research should focus on identifying factors causing disparate outcomes to help reduce cancer-related disparities.

Nano-Drug Delivery Systems Targeting CAFs: A Promising Treatment for Pancreatic Cancer.

Currently, pancreatic cancer (PC) is one of the most lethal malignant tumors. PC is typically diagnosed at a late stage, exhibits a poor response to conventional treatment, and has a bleak prognosis. Unfortunately, PC's survival rate has not significantly improved since the 1960s. Cancer-associated fibroblasts (CAFs) are a key component of the pancreatic tumor microenvironment (TME). They play a vital role in maintaining the extracellular matrix and facilitating the intricate communication between cancer cells and infiltrated immune cells. Exploring therapeutic approaches targeting CAFs may reverse the current landscape of PC therapy. In recent years, nano-drug delivery systems have evolved rapidly and have been able to accurately target and precisely release drugs with little or no toxicity to the whole body. In this review, we will comprehensively discuss the origin, heterogeneity, potential targets, and recent advances in the nano-drug delivery system of CAFs in PC. We will also propose a novel integrated treatment regimen that utilizes a nano-drug delivery system to target CAFs in PC, combined with radiotherapy and immunotherapy. Additionally, we will address the challenges that this regimen currently faces.

Integrated chromosomal instability and tumor microbiome redefined prognosis-related subtypes of pancreatic cancer

BackgroundPancreatic cancer is a common malignancy with poor prognosis and limited treatment. Here we aimed to investigate the role of host chromosomal instability (CIN) and tumor microbiome in the prognosis of pancreatic cancer patients. MethodsOne hundred formalin-fixed paraffin-embedded (FFPE) pancreatic cancer samples were collected. DNA extracted from FFPE samples were analyzed by low-coverage whole-genome sequencing (WGS) via a customized bioinformatics workflow named ultrasensitive chromosomal aneuploidy detector. ResultsSamples are tested according to the procedure of ultrasensitive chromosomal aneuploidy detector (UCAD). We excluded 2 samples with failed quality control, 1 patient lost to follow-up and 6 dead in the perioperative period. The final 91 patients were admitted for the following analyses. Thirteen (14.3%) patients with higher CIN score had worse overall survival (OS) than those with lower CIN score. The top 20 microbes in pancreatic cancer samples included 15 species of bacteria and 5 species of viruses. Patients with high human herpesvirus (HHV)-7 and HHV-5 DNA reads exhibited worse OS. Furthermore, we classified 91 patients into 3 subtypes. Patients with higher CIN score (n =13) had the worst prognosis (median OS 6.9 mon); patients with lower CIN score but with HHV-7/5 DNA load (n = 24) had worse prognosis (median OS 10.6 mon); while patients with lower CIN score and HHV-7/5 DNA negative (n = 54) had the best prognosis (median OS 21.1 mon). ConclusionsHigh CIN and HHV-7/5 DNA load were associated with worse survival of pancreatic cancer. The novel molecular subtypes of pancreatic cancer based on CIN and microbiome had prognostic value.

How a significant increase in survival in pancreatic cancer is achieved. The role of nutritional status and supportive care: A review

Pancreatic cancer (PC) is a serious public health problem. The mortality rate of patients with PC remains one of the highest among cancers. Early diagnosis of PC is challenging, so it is often diagnosed in the later stages. Current treatment approaches, including surgery, neoadjuvant and adjuvant chemotherapy, chemoradiotherapy, and supportive care, have demonstrated improved outcomes. A significant problem remains exocrine pancreatic insufficiency (EPI) in patients with PC, which requires enzyme replacement therapy. However, this is not given due attention in the Russian literature. This review addresses the survival trends of patients with PC, current therapies, and enzyme replacement therapy as an integral part of supportive care and improvement of nutritional status; also, the issues of routing patients with PC are addressed. It is emphasized that the diagnosis and treatment of EPI are mandatory to improve and maintain the nutritional status and quality of life; failure to treat EPI renders antitumor treatment ineffective.

Exhausted Tumor-infiltrating CD39+CD103+ CD8+ T Cells Unveil Potential for Increased Survival in Human Pancreatic Cancer.

Patients with pancreatic cancer with a high proportion of CD39+CD103+ CD8+ T cells exhibiting a tumor-reactive phenotype have improved survival rates, suggesting their potential utility in selecting candidates for immunotherapy trials.

Infiltration of CD3+ and CD8+ lymphocytes in association with inflammation and survival in pancreatic cancer.

Pancreatic ductal adenocarcinomas (PDAC) have heterogeneous tumor microenvironments relatively devoid of infiltrating immune cells. We aimed to quantitatively assess infiltrating CD3+ and CD8+ lymphocytes in a treatment-naïve patient cohort and assess associations with overall survival and microenvironment inflammatory proteins. Tissue microarrays were immunohistochemically stained for CD3+ and CD8+ lymphocytes and quantitatively assessed using QuPath. Levels of inflammation-associated proteins were quantified by multiplexed, enzyme-linked immunosorbent assay panels on matching tumor and tissue samples. Our findings revealed a significant increase in both CD3+ and CD8+ lymphocytes populations in PDAC compared with non-PDAC tissue, except when comparing CD8+ percentages in PDAC versus intraductal papillary mucinous neoplasms (IPMN) (p = 0.5012). Patients with quantitatively assessed CD3+ low tumors (lower 50%) had shorter survival (median 273 days) compared to CD3+ high tumors (upper 50%) with a median overall survival of 642.5 days (p = 0.2184). Patients with quantitatively assessed CD8+ low tumors had significantly shorter survival (median 240 days) compared to CD8+ high tumors with a median overall survival of 1059 days (p = 0.0003). Of 41 proteins assessed in the inflammation assay, higher levels of IL-1B and IL-2 were significantly associated with decreased CD3+ infiltration (r = -0.3704, p = 0.0187, and r = -0.4275, p = 0.0074, respectively). Higher levels of IL-1B were also significantly associated with decreased CD8+ infiltration (r = -0.4299, p = 0.0045), but not IL-2 (r = -0.0078, p = 0.9616). Principal component analysis of the inflammatory analytes showed diverse inflammatory responses in PDAC. In this work, we found a marked heterogeneity in infiltrating CD3+ and CD8+ lymphocytes and individual inflammatory responses in PDAC. Future mechanistic studies should explore personalized therapeutic strategies to target the immune and inflammatory components of the tumor microenvironment.

Effect of surgery versus chemotherapy in pancreatic cancer patients: a target trial emulation.

To estimate the causal effect of surgery vs chemotherapy on survival in patients with T1-3NxM0 pancreatic cancer in a rigorous framework addressing selection bias and immortal time bias. We used population-based Danish health-care registries to conduct a cohort study emulating a hypothetical randomized trial to estimate the absolute difference in survival, comparing surgery with chemotherapy. We included pancreatic cancer patients diagnosed during 2008-2021. Exposure was surgery or chemotherapy initiated within a 16-week grace period after diagnosis. At the time of diagnosis, data of each patient were duplicated; one copy was assigned to the surgery protocol, and one copy to the chemotherapy protocol of the hypothetical trial. Copies were censored when the assigned treatment deviated from the observed treatment. To account for informative censoring, uncensored patients were weighted according to confounders. For comparison, we also applied a more conventional analysis using propensity score-based inverse probability weighting. We included 1744 patients with a median age of 68 years: 73.6% underwent surgery, and 18.6% had chemotherapy without surgery; 7.8% received no treatment. The 3-year survival was 39.7% (95% confidence interval [CI] = 36.7% to 42.6%) after surgery and 22.7% (95% CI = 17.7% to 28.4%) after chemotherapy, corresponding to an absolute difference of 17.0% (95% CI = 10.8% to 23.1%). In the conventional survival analysis, this difference was 23.0% (95% CI = 17.0% to 29.0%). Surgery was superior to chemotherapy in achieving long-term survival for pancreatic cancer. The difference comparing surgery and chemotherapy was substantially smaller when using the clone-censor-weight approach than conventional survival analysis.

BZW1 is a prognostic and immunological biomarker in pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is the most common malignant tumor of the digestive system and is called the "king of cancer" because it has been labeled with high malignancy, rapid progression, poor survival, and poor prognosis. Previously, it was reported that the basic leucine zipper and W2 domains 1 (BZW1) is involved in the progression of many tumors. However, its research in digestive system tumors such as pancreatic cancer is rarely studied. To explore potential biomarkers related to survival and prognosis of pancreatic cancer and provide a new targeted therapy for it. We first analyzed the mRNA and protein expression of BZW1 in pancreatic cancer. We then explored the correlation of BZW1 with survival prognosis and immune infiltration in pancreatic cancer patients. Finally, we explored BZW1-related gene enrichment analysis, including protein-protein interaction networks, gene ontology functional enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The mRNA and protein expression of the BZW1 gene in pancreatic cancer tissues were higher than those in adjacent normal tissues, and pancreatic cancer patients with high BZW1 expression had a poor prognosis. In addition, the expression of BZW1 was positively or negatively correlated with different immune cells of pancreatic cancer, such as CD4 + T lymphocytes, CD8 + T lymphocytes, B cells, macrophages, neutrophils, etc. Correlation enrichment analysis showed that we obtained 50 available experimentally determined BZW1-binding proteins and 100 targeted genes related to BZW1, and the intersection genes were eukaryotic translation termination factor 1 and Guanine nucleotide binding protein, alpha inhibiting activity polypeptide 3. Moreover, there was a positive correlation between BZW1 and eukaryotic translation termination factor 1 and Guanine nucleotide binding protein, alpha inhibiting activity polypeptide 3 genes in pancreatic cancer. Gene ontology enrichment analysis showed BZW1 was mainly related to biological processes such as "mRNA processing," "RNA splicing," "regulation of translational initiation," and "activation of innate immune response." The results of Kyoto Encyclopedia of Genes and Genomes pathway analysis further indicated that BZW1 may be involved in pancreatic carcinogenesis through the "spliceosome" and "ribosome." The BZW1 gene may be a potential immunotherapy target and a promising prognostic marker for pancreatic cancer.

Early Diagnosis and Prognosis Prediction of Pancreatic Cancer Using Engineered Hybrid Core-Shells in Laser Desorption/Ionization Mass Spectrometry.

Effective detection of bio-molecules relies on the precise design and preparation of materials, particularly in laser desorption/ionization mass spectrometry (LDI-MS). Despite significant advancements in substrate materials, the performance of single-structured substrates remains suboptimal for LDI-MS analysis of complex systems. Herein, designer Au@SiO2@ZrO2 core-shell substrates are developed for LDI-MS-based early diagnosis and prognosis of pancreatic cancer (PC). Through controlling Au core size and ZrO2 shell crystallization, signal amplification of metabolites up to 3 orders is not only achieved, but also the synergistic mechanism of the LDI process is revealed. The optimized Au@SiO2@ZrO2 enables a direct record of serum metabolic fingerprints (SMFs) by LDI-MS. Subsequently, SMFs are employed to distinguish early PC (stage I/II) from controls, with an accuracy of 92%. Moreover, a prognostic prediction scoring system is established with enhanced efficacy in predicting PC survival compared to CA19-9 (p < 0.05). This work contributes to material-based cancer diagnosis and prognosis.

Codon-specific KRAS mutations predict survival in advanced pancreatic cancer

Codon-specific KRAS mutations predict survival in advanced pancreatic cancer

A phase I/II study of antroquinonol in combination with nab-paclitaxel and gemcitabine for patients with metastatic pancreatic cancer.

648 Background: The survival of metastatic pancreatic cancer (mPC) is still disappointing though advancement in recent regimens. Antroquinonol, a new chemical entity, has been proposed for the treatment of neoplasms. In this phase I/II trial, we investigated the dose and efficacy of antroquinonol combined with gemcitabine and nab-paclitaxel (Gem/Nab-P) on mPC patients. Methods: Patients with chemo-naive, metastatic PDAC were enrolled. In the phase I, run-in drug-drug interaction (DDI) and dose escalation in a 3 + 3 designed to determine the maximal tolerated dose (MTD) of antroquinonol for phase II study. Gem/Nab-P (gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1, 8, and 15 every 4 weeks) was given from cycle 0 in phase I. The dose of antroquinonol was escalated from 200mg orally three times a day since the first cycle of Gem/Nab-P. The primary end points were median PFS and 6-month PFS rate. This trial is registered at ClinicalTrials.gov: NCT03310632. Results: In the phase I study of 15 patients, the MTD of antroquinonol was 300mg tid. In the phase II study of 40 patients, the median PFS was 5.3 (95% CI: 3.7–7.5) months and 6-month PFS rate was 40% (95% CI: 21%–57%), whereas median OS was 12.6 (95% CI: 8.8–15.8) months and12-month OS rate was 59.9% (95% CI: 37.8%–76.4%), respectively. The adverse events including hematological and non-hematological classes were decreased in the antroquinonol plus Gem/Nab-P, the GI discomforts were increased but manageable. Conclusions: In this phase I/II trial, antroquinonol plus Gem/Nab-P showed good efficacy in survival and less adverse events than a first-line strategy of Gem/Nab-P for mPC patients. Clinical trial information: NCT03310632 . [Table: see text]

Abstract A102: Secreted frizzled related-protein 2 is prognostic for survival in pancreatic cancer

Abstract INTRODUCTION: Secreted frizzled-related protein 2 (SFRP2) is overexpressed in several tumor types and blocks tumor apoptosis, increases angiogenesis, and promotes T-cell exhaustion. It has also been shown to be associated with fibrosis in non-neoplastic pathologies. We hypothesize SFRP2 is prognostic for survival and associated with PDAC fibrosis and mesenchymal transformation. METHODS: SFRP2 gene expression and protein levels in patients with PDAC were analyzed using NCI’s The Cancer Genome Atlas (TCGA) data and data from resected tumors analyzed for protein levels by western blot. Disease free survival (DFS) and overall survival (OS) were analyzed using Kaplan Meier test. The association of stroma content and SFPR2 RNA expression in human PDAC was studied using Spearman correlation between the ESTIMATE algorithm stromal score and TCGA data. The GEPIA tool was used to compare SFRP2 mRNA levels between PDAC and normal pancreas tissue. Immunohistochemistry (IHC) for SFRP2 in KPC PDAC tumors were correlated with fibrosis stains Picrosirus red and Massone trichome. The role of SFRP2 in mesenchymal transformation was assessed by western blot in fibroblasts. RESULTS: TCGA RNAseq analysis of SFRP2 expression showed highest SFRP2 mRNA levels in pancreatic cancer out of 32 cancer types. GEPIA analysis of PDAC (n=179) and normal pancreas (n=177) mRNA data showed higher levels of SFRP2 mRNA in PDAC compared to normal pancreas (p&amp;lt;.01). High SFRP2 mRNA levels were associated with decreased disease-free survival hazard ratio = 2.6; p=0.0097). PDAC tissue showed higher SFRP2 protein compared to matched normal-adjacent tissue (n=24, p=0.0003). High SFRP2 expression was associated with decreased OS (p=0.0158. The ESTIMATE stromal score correlated with SFRP2 expression in human PDAC (Spearman correlation coefficient 0.81). Fibrosis levels in KPC PDAC tumors correlated with SFRP2 IHC (Spearman correlation coefficient 0.75). Fibroblasts treated with SFRP2 and TGFβ showed higher mesenchymal markers compared to untreated control. CONCLUSIONS: SFRP2 is increased in PDAC, associated with tumor fibrosis, and prognostic for survival. SFRP2 is a novel therapeutic target in PDAC. Citation Format: Lillian Hsu, Julie Siegel, Patrick Nasarre, Rupak Mukherjee, Meghan Gormley, Bailey Richardson, Jordan Morningstar, Imran Khan, Eleanor Hilliard, John O’Bryan, Krist Helke, Laura Spruill, Nathan Dolloff, Nancy Klauber-Demore. Secreted frizzled related-protein 2 is prognostic for survival in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A102.