The Effect of Intratumor Heterogeneity in Pancreatic Ductal Adenocarcinoma Progression and Treatment.

BACKGROUND AND OBJECTIVES: Pancreatic cancer is one of the most lethal malignancies. Even though many substantial improvements in the survival rates for other major cancer forms were made, pancreatic cancer survival rates have remained relatively unchanged since the 1960s. Even more, no standard classification system for pancreatic cancer is based on cellular biomarkers. This review will discuss and provide updates about the role of stem cells in the progression of PC, the genetic changes associated with it, and the promising biomarkers for diagnosis. MATERIALS AND METHODS: The search process used PubMed, Cochrane Library, and Scopus databases to identify the relevant and related articles. Articles had to be published in English to be considered. RESULTS: The increasing number of studies in recent years has revealed that the diversity of cancer-associated fibroblasts is far greater than previously acknowledged, which highlights the need for further research to better understand the various cancer-associated fibroblast subpopulations. Despite the huge diversity in pancreatic cancer, some common features can be noted to be shared among patients. Mutations involving CDKN2, P53, and K-RAS can be seen in a big number of patients, for example. Similarly, some patterns of genes and biomarkers expression and the level of their expression can help in predicting cancer behavior such as metastasis and drug resistance. The current trend in cancer research, especially with the advancement in technology, is to sequence everything in hopes of finding disease-related mutations. CONCLUSION: Optimizing pancreatic cancer treatment requires clear classification, understanding CAF roles, and exploring stroma reshaping approaches.

Smoking history is associated with reduced efficacy of neoadjuvant therapy in pancreatic adenocarcinoma.

BACKGROUND: Differential responses to neoadjuvant therapy (NAT) exist in pancreatic ductal adenocarcinoma (PDAC); however, contributing factors are poorly understood. Tobacco smoke is a common risk factor for PDAC, with nicotine-induced chemoresistance observed in other cancers. This study aimed to explore the potential association between tobacco use and NAT efficacy in PDAC. METHODS: A single-center, retrospective analysis was conducted that included all consecutive patients with PDAC who underwent surgical resection after NAT with a documented smoking history (N = 208). NAT response was measured as percentage fibrosis in the surgical specimen. Multivariable models controlled for covariates and survival were modeled using the Kaplan-Meier method. RESULTS: Postoperatively, major responses to NAT (>95% fibrosis) were less frequently observed in smokers than in nonsmokers (13.7% vs 30.4%, respectively; P = .021). Pathologic complete responses were similarly less frequent in smokers than in nonsmokers (2.1% vs 9.9%, respectively; P = .023). On multivariate analysis controlling for covariates, smoking history remained independently associated with lower odds of major fibrosis (odds ratio [OR], 0.25; 95% CI, 0.10-0.59; P = .002) and pathologic complete response (OR, 0.21; 95% CI, 0.03-0.84; P = .05). The median overall survival was significantly longer in nonsmokers than in smokers (39.1 vs 26.6 months, respectively; P = .05). CONCLUSION: Tobacco use was associated with diminished pathologic responses to NAT. Future research to understand the biology underlying this observation is warranted and may inform differential NAT approaches or counseling among these populations.

Irreversible electroporation promotes a pro-inflammatory tumor microenvironment and anti-tumor immunity in a mouse pancreatic cancer model.

Pancreatic cancer is a significant cause of cancer-related mortality and often presents with limited treatment options. Pancreatic tumors are also notorious for their immunosuppressive microenvironment. Irreversible electroporation (IRE) is a non-thermal tumor ablation modality that employs high-voltage microsecond pulses to transiently permeabilize cell membranes, ultimately inducing cell death. However, the understanding of IRE's impact beyond the initiation of focal cell death in tumor tissue remains limited. In this study, we demonstrate that IRE triggers a unique mix of cell death pathways and orchestrates a shift in the local tumor microenvironment driven, in part, by reducing the myeloid-derived suppressor cell (MDSC) and regulatory T cell populations and increasing cytotoxic T lymphocytes and neutrophils. We further show that IRE drives induce cell cycle arrest at the G0/G1 phase in vitro and promote inflammatory cell death pathways consistent with pyroptosis and programmed necrosis in vivo. IRE-treated mice exhibited a substantial extension in progression-free survival. However, within a span of 14 days, the tumor immune cell populations reverted to their pre-treatment composition, which resulted in an attenuation of the systemic immune response targeting contralateral tumors and ultimately resulting in tumor regrowth. Mechanistically, we show that IRE augments IFN- Î³ signaling, resulting in the up-regulation of the PD-L1 checkpoint in pancreatic cancer cells. Together, these findings shed light on potential mechanisms of tumor regrowth following IRE treatment and offer insights into co-therapeutic targets to improve treatment strategies.

Heterodimerization of T cell engaging bispecific antibodies to enhance specificity against pancreatic ductal adenocarcinoma.

BACKGROUND: EGFR and/or HER2 expression in pancreatic cancers is correlated with poor prognoses. We generated homodimeric (EGFRxEGFR or HER2xHER2) and heterodimeric (EGFRxHER2) T cell-engaging bispecific antibodies (T-BsAbs) to direct polyclonal T cells to these antigens on pancreatic tumors. METHODS: EGFR and HER2 T-BsAbs were constructed using the 2 + 2 IgG-[L]-scFv T-BsAbs format bearing two anti-CD3 scFvs attached to the light chains of an IgG to engage T cells while retaining bivalent binding to tumor antigens with both Fab arms. A Fab arm exchange strategy was used to generate EGFRxHER2 heterodimeric T-BsAb carrying one Fab specific for EGFR and one for HER2. EGFR and HER2 T-BsAbs were also heterodimerized with a CD33 control T-BsAb to generate 'tumor-monovalent' EGFRxCD33 and HER2xCD33 T-BsAbs. T-BsAb avidity for tumor cells was studied by flow cytometry, cytotoxicity by T-cell mediated 51Chromium release, and in vivo efficacy against cell line-derived xenografts (CDX) or patient-derived xenografts (PDX). Tumor infiltration by T cells transduced with luciferase reporter was quantified by bioluminescence. RESULTS: The EGFRxEGFR, HER2xHER2, and EGFRxHER2 T-BsAbs demonstrated high avidity and T cell-mediated cytotoxicity against human pancreatic ductal adenocarcinoma (PDAC) cell lines in vitro with EC50s in the picomolar range (0.17pM to 18pM). They were highly efficient in driving human polyclonal T cells into subcutaneous PDAC xenografts and mediated potent T cell-mediated anti-tumor effects. Both EGFRxCD33 and HER2xCD33 tumor-monovalent T-BsAbs displayed substantially reduced avidity by SPR when compared to homodimeric EGFRxEGFR or HER2xHER2 T-BsAbs (∼150-fold and ∼6000-fold respectively), tumor binding by FACS (8.0-fold and 63.6-fold), and T-cell mediated cytotoxicity (7.7-fold and 47.2-fold), while showing no efficacy against CDX or PDX. However, if either EGFR or HER2 was removed from SW1990 by CRISPR-mediated knockout, the in vivo efficacy of heterodimeric EGFRxHER2 T-BsAb was lost. CONCLUSION: EGFR and HER2 were useful targets for driving T cell infiltration and tumor ablation. Two arm Fab binding to either one or both targets was critical for robust anti-tumor effect in vivo. By engaging both targets, EGFRxHER2 heterodimeric T-BsAb exhibited potent anti-tumor effects if CDX or PDX were EGFR+HER2+ double-positive with the potential to spare single-positive normal tissue.

MicroRNAs in Pancreatic Cancer: Advances in Biomarker Discovery and Therapeutic Implications.

Pancreatic cancer remains a formidable malignancy characterized by high mortality rates, primarily attributable to late-stage diagnosis and a dearth of effective therapeutic interventions. The identification of reliable biomarkers holds paramount importance in enhancing early detection, prognostic evaluation, and targeted treatment modalities. Small non-coding RNAs, particularly microRNAs, have emerged as promising candidates for pancreatic cancer biomarkers in recent years. In this review, we delve into the evolving role of cellular and circulating miRNAs, including exosomal miRNAs, in the diagnosis, prognosis, and therapeutic targeting of pancreatic cancer. Drawing upon the latest research advancements in omics data-driven biomarker discovery, we also perform a case study using public datasets and address commonly identified research discrepancies, challenges, and limitations. Lastly, we discuss analytical approaches that integrate multimodal analyses incorporating clinical and molecular features, presenting new insights into identifying robust miRNA-centric biomarkers.

Adjuvant chemotherapy for adenocarcinoma arising from intraductal papillary mucinous neoplasia: multicentre ADENO-IPMN study.

BACKGROUND: The clinical impact of adjuvant chemotherapy after resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia is unclear. The aim of this study was to identify factors related to receipt of adjuvant chemotherapy and its impact on recurrence and survival. METHODS: This was a multicentre retrospective study of patients undergoing pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia between January 2010 and December 2020 at 18 centres. Recurrence and survival outcomes for patients who did and did not receive adjuvant chemotherapy were compared using propensity score matching. RESULTS: Of 459 patients who underwent pancreatic resection, 275 (59.9%) received adjuvant chemotherapy (gemcitabine 51.3%, gemcitabine-capecitabine 21.8%, FOLFIRINOX 8.0%, other 18.9%). Median follow-up was 78 months. The overall recurrence rate was 45.5% and the median time to recurrence was 33 months. In univariable analysis in the matched cohort, adjuvant chemotherapy was not associated with reduced overall (P = 0.713), locoregional (P = 0.283) or systemic (P = 0.592) recurrence, disease-free survival (P = 0.284) or overall survival (P = 0.455). Adjuvant chemotherapy was not associated with reduced site-specific recurrence. In multivariable analysis, there was no association between adjuvant chemotherapy and overall recurrence (HR 0.89, 95% c.i. 0.57 to 1.40), disease-free survival (HR 0.86, 0.59 to 1.30) or overall survival (HR 0.77, 0.50 to 1.20). Adjuvant chemotherapy was not associated with reduced recurrence in any high-risk subgroup (for example, lymph node-positive, higher AJCC stage, poor differentiation). No particular chemotherapy regimen resulted in superior outcomes. CONCLUSION: Chemotherapy following resection of adenocarcinoma arising from intraductal papillary mucinous neoplasia does not appear to influence recurrence rates, recurrence patterns or survival.

Integrated bioinformatics analysis reveals upregulated extracellular matrix hub genes in pancreatic cancer: Implications for diagnosis, prognosis, immune infiltration, and therapeutic strategies.

BACKGROUND: Pancreatic cancer (PC) stands out as one of the most formidable malignancies and exhibits an exceptionally unfavorable clinical prognosis due to the absence of well-defined diagnostic indicators and its tendency to develop resistance to therapeutic interventions. The primary objective of this present study was to identify extracellular matrix (ECM)-related hub genes (HGs) and their corresponding molecular signatures, with the intent of potentially utilizing them as biomarkers for diagnostic, prognostic, and therapeutic applications. METHODS: Three microarray datasets were sourced from the NCBI database to acquire upregulated differentially expressed genes (DEGs), while MatrisomeDB was employed for filtering ECM-related genes. Subsequently, a protein-protein interaction (PPI) network was established using the STRING database. The created network was visually inspected through Cytoscape, and HGs were identified using the CytoHubba plugin tool. Furthermore, enrichment analysis, expression pattern analysis, clinicopathological correlation, survival analysis, immune cell infiltration analysis, and examination of chemical compounds were carried out using Enrichr, GEPIA2, ULCAN, Kaplan Meier plotter, TIMER2.0, and CTD web platforms, respectively. The diagnostic and prognostic significance of HGs was evaluated through the ROC curve analysis. RESULTS: Ten genes associated with ECM functions were identified as HGs among 131 DEGs obtained from microarray datasets. Notably, the expression of these HGs exhibited significantly (p < 0.05) higher in PC, demonstrating a clear association with tumor advancement. Remarkably, higher expression levels of these HGs were inversely correlated with the likelihood of patient survival. Moreover, ROC curve analysis revealed that identified HGs are promising biomarkers for both diagnostic (AUC > 0.75) and prognostic (AUC > 0.64) purposes. Furthermore, we observed a positive correlation between immune cell infiltration and the expression of most HGs. Lastly, our study identified nine compounds with significant interaction profiles that could potentially act as effective chemical agents targeting the identified HGs. CONCLUSION: Taken together, our findings suggest that COL1A1, KRT19, MMP1, COL11A1, SDC1, ITGA2, COL1A2, POSTN, FN1, and COL5A1 hold promise as innovative biomarkers for both the diagnosis and prognosis of PC, and they present as prospective targets for therapeutic interventions aimed at impeding the progression PC.

A Humanized Patient-Derived Xenograft Model for Pancreatic Cancer.

Pancreatic cancer is associated with a high mortality rate, and there are still very few effective treatment options. Patient-derived xenografts have proven to be invaluable preclinical disease models to study cancer biology and facilitate testing of novel therapeutics. However, the severely immune-deficient mice used to generate standard models lack any functional immune system, thereby limiting their utility as a tool to investigate the tumor-immune cell interface. This chapter will outline a method for establishment of "humanized" patient-derived xenografts, which are reconstituted with human immune cells to imitate the immune-rich microenvironment of pancreatic cancer.

Treatment patterns and survival outcomes in patients with non-metastatic early-onset pancreatic cancer.

BACKGROUND: The incidence of patients with early-onset pancreatic cancer (EOPC; age ≤ 50 years at diagnosis) is on the rise, placing a heavy burden on individuals, families, and society. The role of combination therapy including surgery, radiotherapy, and chemotherapy in non-metastatic EOPC is not well-defined. AIM: To investigate the treatment patterns and survival outcomes in patients with non-metastatic EOPC. METHODS: A total of 277 patients with non-metastatic EOPC who were treated at our institution between 2017 and 2021 were investigated retrospectively. Overall survival (OS), disease-free survival, and progression-free survival were estimated using the Kaplan-Meier method. Univariate and multivariate analyses with the Cox proportional hazards model were used to identify prognostic factors. RESULTS: With a median follow-up time of 34.6 months, the 1-year, 2-year, and 3-year OS rates for the entire cohort were 84.3%, 51.5%, and 27.6%, respectively. The median OS of patients with localized disease who received surgery alone and adjuvant therapy (AT) were 21.2 months and 28.8 months, respectively (P = 0.007). The median OS of patients with locally advanced disease who received radiotherapy-based combination therapy (RCT), surgery after neoadjuvant therapy (NAT), and chemotherapy were 28.5 months, 25.6 months, and 14.0 months, respectively (P = 0.002). The median OS after regional recurrence were 16.0 months, 13.4 months, and 8.9 months in the RCT, chemotherapy, and supportive therapy groups, respectively (P = 0.035). Multivariate analysis demonstrated that carbohydrate antigen 19-9 level, pathological grade, T-stage, N-stage, and resection were independent prognostic factors for non-metastatic EOPC. CONCLUSION: AT improves postoperative survival in localized patients. Surgery after NAT and RCT are the preferred therapeutic options for patients with locally advanced EOPC.

Self-propelling bacteria-based magnetic nanoparticles (BacMags) for targeted magnetic hyperthermia therapy against hypoxic tumors.

Magnetic hyperthermia-based cancer therapy (MHCT) holds great promise as a non-invasive approach utilizing heat generated by an alternating magnetic field for effective cancer treatment. For an efficacious therapeutic response, it is crucial to deliver therapeutic agents selectively at the depth of tumors. In this study, we present a new strategy using the naturally occurring tumor-colonizing bacteria Escherichia coli (E. coli) as a carrier to deliver magnetic nanoparticles to hypoxic tumor cores for effective MHCT. Self-propelling delivery agents, "nano-bacteriomagnets" (BacMags), were developed by incorporating anisotropic magnetic nanocubes into E. coli which demonstrated significantly improved hyperthermic performance, leading to an impressive 85% cell death in pancreatic cancer. The in vivo anti-cancer response was validated in a syngeneic xenograft model with a 50% tumor inhibition rate within 20 days and a complete tumor regression within 30 days. This proof-of-concept study demonstrates the potential of utilizing anaerobic bacteria for the delivery of magnetic nanocarriers as a smart therapeutic approach for enhanced MHCT.

Understanding autoimmune pancreatitis: Clinical features, management challenges, and association with malignancies.

In this editorial we comment on the article by Jaber et al. Autoimmune pancreatitis (AIP) represents a distinct form of pancreatitis, categorized into AIP-1 and AIP-2, characterized by obstructive jaundice, lymphoplasmacytic infiltrate, and fibrosis. AIP-1, associated with elevated immunoglobulin G4 (IgG4) levels, exhibits higher relapse rates, affecting older males, while AIP-2 is less common and linked to inflammatory bowel disease. AIP is considered a manifestation of IgG4-related systemic disease, sharing characteristic histological findings. Steroids are the primary treatment, with emerging biomarkers like interferon alpha and interleukin-33. AIP poses an increased risk of various malignancies, and the association with pancreatic cancer is debated. Surgery is reserved for severe cases, necessitating careful evaluation due to diagnostic challenges. AIP patients may have concurrent PanINs but display favorable long-term outcomes compared to pancreatic cancer patients. Thorough diagnostic assessment, including biopsy and steroid response, is crucial for informed surgical decisions in AIP.

Promising Therapeutic Approach in Pancreatic Cancer: Metabolism-Related Genes.

Most pancreatic cancers are pancreatic ductal adenocarcinomas. This is an extremely lethal disease with poor prognosis and almost no treatment choices. Considering the profound role of the pancreas in the human body, malfunction of this organ can significantly affect quality of life. Although multiple metabolic pathways are altered in cancer cells, certain metabolic gene signatures may be critical for immunotherapy. The reprogrammed metabolism of glucose, amino acids, and lipids can nourish the tumor microenvironment (TME). Previous studies have also shown that reprogrammed metabolism influences immune responses. Tumor-infiltrating immune cells in the TME can adapt their metabolism to blunt the immune system, leading to immunosuppression and tumor progression. The identification of metabolism-related genes (MRGs) associated with immune reactions in pancreatic cancer may lead to improved treatments. This review highlights the characteristics of MRGs in pancreatic cancer and suggests that enhanced anti-cancer therapies could be used to overcome resistance to immunotherapy.

Pancreatic Cancer: Rapid Evidence Review.

Pancreatic cancer is relatively uncommon and carries a poor prognosis because patients often develop signs or symptoms at a late stage of illness. Patients with a family history, especially those with genetic syndromes, are at a significantly increased risk of pancreatic cancer. Modifiable risk factors include smoking, heavy alcohol use, and obesity. Although patients at increased risk should be screened, screening is not recommended for asymptomatic people at average risk. The differential diagnosis for a symptomatic patient is broad, including gastroesophageal reflux disease, gastritis, peptic ulcer disease, chronic pancreatitis, biliary dyskinesia, cholelithiasis, gastroparesis, or constipation. Initial serologic testing should include transaminase and bilirubin levels, and in patients with midepigastric pain, lipase levels. Pancreas-protocol, contrast-enhanced abdominal computed tomography is the imaging test of choice. Carbohydrate antigen 19-9 is the most studied cancer marker and moderately accurate in patients suspected of having cancer; however, the positive predictive value is 0.9% in asymptomatic patients. Treatment includes neoadjuvant or adjuvant chemotherapy and surgery if the cancer is resectable. The treatment approach is best determined by a multidisciplinary, high-volume center. For a patient undergoing chemotherapy, nutritional and psychosocial support and palliation of symptoms should be goals during treatment.

Advances in Systemic Therapy in Pancreatic Cancer.

Substantial progress has been made toward understanding biology and developing new therapies for pancreatic ductal adenocarcinoma (PDAC). In this review, new insights from genomic profiling, as well as implications for treatment and prognosis, are discussed. New standards of care approaches with a focus on drug therapies are discussed for the treatment of resectable and advanced PDAC. The role of targeted and immune therapies remains limited; cohorts likely to benefit from these approaches are discussed. Promising, preliminary results regarding experimental therapies are reviewed.

Efficacy and safety of neoadjuvant therapy in gastroenteropancreatic neuroendocrine neoplasms: A systematic review and meta-analysis.

OBJECTIVE: To determine the effectiveness and safety of neoadjuvant therapy in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) and provide evidence-based suggestions for clinical treatment. METHODS: The Cochrane Library, Embase, PubMed, and Web of Science were searched for articles published that analyzed the effectiveness and safety of GEP-NEN-targeted neoadjuvant therapy before March 2023. A confidence interval (CI) of 95%, a subgroup analysis, heterogeneity, and effect size (ES) were analyzed, and a meta-analysis of the literature was performed using the Stata BE17 software. RESULTS: A total of 417 patients from 13 studies were included in this meta-analysis. The primary variables comprised the objective response rate (ORR), disease control rate (DCR), surgical resection rate, and R0 resection rate with ES values of 0.42 (95% CI: 0.25-0.60), 0.96 (95% CI: 0.93-0.99), 0.67 (95% CI: 0.50-0.84), and 0.60 (95% CI: 0.54-0.67), respectively. The secondary variables were the incidence rates of treatment-related adverse events (TRAEs), Grade 3 or higher TRAEs, and surgical complications with ES values of 0.29 (95% CI: -0.03-0.21), 0.13 (95% CI: -0.07-0.33), and 0.35 (95% CI: 0.27-0.44), respectively. CONCLUSION: Neoadjuvant therapy is an effective and safe treatment method for GEP-NENs. However, further studies are required to determine the optimal regimen for this therapy in these tumors.

Multi-omics pan-cancer study of SPTBN2 and its value as a potential therapeutic target in pancreatic cancer.

SPTBN2 is a protein-coding gene that is closely related to the development of malignant tumors. However, its prognostic value and biological function in pan-cancer, especially pancreatic cancer (PAAD), have not been reported. In the present study, a novel exploration of the value and potential mechanism of SPTBN2 in PAAD was conducted using multi-omics in the background of pan-cancer. Via various database analysis, up-regulated expression of SPTBN2 was detected in most of the tumor tissues examined. Overexpression of SPTBN2 in PAAD and kidney renal clear cell cancer patients potentially affected overall survival, disease-specific survival, and progression-free interval. In PAAD, SPTBN2 can be used as an independent factor affecting prognosis. Mutations and amplification of SPTBN2 were detected, with abnormal methylation of SPTBN2 affecting its expression and the survival outcome of PAAD patients. Immunoassay results demonstrate that SPTBN2 was a potential biomarker for predicting therapeutic response in PAAD, and may influence the immunotherapy efficacy of PAAD by regulating levels of CD8 + T cells and neutrophil infiltration. Results from an enrichment analysis indicated that SPTBN2 may regulate the development of PAAD via immune pathways. Thus, SPTBN2 is a potential prognostic biomarker and immunotherapy target based on its crucial role in the development of PAAD.

Single dual-specific anti-PD-L1/TGF-ß antibody synergizes with chemotherapy as neoadjuvant treatment for pancreatic ductal adenocarcinoma: a preclinical experimental study.

AIMS: Chemotherapy resistance is an important cause of neoadjuvant therapy failure in pancreatic ductal adenocarcinoma (PDAC). BiTP (anti-PD-L1/TGF-ß bispecific antibody) is a single antibody that can simultaneously and dually target transforming growth factor-beta (TGF-ß) and programmed cell death ligand 1 (PD-L1). We attempted in this study to investigate the efficacy of BiTP in combination with first-line chemotherapy in PDAC. METHODS: Preclinical assessments of BiTP plus gemcitabine and nab-paclitaxel were completed through a resectable KPC mouse model (C57BL/6J). Spectral flow cytometry, tissue section staining, enzyme-linked immunosorbent assays, Counting Kit-8, transwell, and Western blot assays were used to investigate the synergistic effects. RESULTS: BiTP combinatorial chemotherapy in neoadjuvant settings significantly downstaged PDAC tumors, enhanced survival, and had a higher resectability for mice with PDAC. BiTP was high affinity binding to targets and reverse chemotherapy resistance of PDAC cells. The combination overcame immune evasion through reprogramming tumor microenvironment via increasing penetration and function of T cells, natural killer cells, and dendritic cells and decreasing the function of immunosuppression-related cells as regulatory T cells, M2 macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts. CONCLUSION: Our results suggest that the BiTP combinatorial chemotherapy is a promising neoadjuvant therapy for PDAC.