Primary Pancreatic Cancer Research Articles

Role of Mitochondrial and Cytosolic Folylpolyglutamate Synthetase in One-Carbon Metabolism and Antitumor Efficacy of Mitochondrial-Targeted Antifolates.

Folate-dependent one-carbon (C1) metabolism encompasses distinct cytosolic and mitochondrial pathways connected by an interchange among serine, glycine, and formate. In both the cytosol and mitochondria, folates exist as polyglutamates, with polyglutamylation catalyzed by folylpolyglutamate synthetase (FPGS), including cytosolic and mitochondrial isoforms. Serine is metabolized by serine hydroxymethyltransferase (SHMT)2 in the mitochondria and generates glycine and C1 units for cellular biosynthesis in the cytosol. AGF347 is a novel pyrrolo[3,2-day]pyrimidine antifolate that targets SHMT2 in the mitochondria and SHMT1 and de novo purine biosynthesis in the cytosol. FPGS is expressed in primary pancreatic cancer specimens, and FPGS levels correlate with in vitro efficacies of AGF347 toward human pancreatic cancer cells. MIA PaCa-2 pancreatic cancer cells with CRISPR knockout of FPGS were engineered to express doxycycline-inducible FPGS exclusively in the cytosol (cFPGS) or in both the cytosol and mitochondria (mFPGS). Folate and AGF347 accumulations increased in both the cytosol and mitochondria with increased mFPGS but were restricted to the cytosol with cFPGS. AGF347-Glu5 inhibited SHMT2 ∼19-fold greater than AGF347 By metabolomics analysis, mFPGS stimulated the C1 flux from serine in the mitochondria and de novo purine and dTTP synthesis far greater than cFPGS. mFPGS enhanced in vitro inhibition of MIA PaCa-2 cell proliferation by AGF347 (∼30-fold) more than cFPGS (∼4.9-fold). Similar results were seen with other pyrrolo[3,2-d]pyrimidine antifolates (AGF291, AGF320); however, elevated mFPGS adversely impacted inhibition by the nonclassical SHMT2/SHMT1 inhibitor SHIN1. These results suggest a critical role of mFPGS levels in determining antitumor efficacies of mitochondrial-targeted pyrrolo[3,2-d]pyrimidine antifolates for pancreatic cancer. SIGNIFICANCE STATEMENT: AGF347 is a novel pyrrolo[3,2-d]pyrimidine antifolate that targets serine hydroxymethyltransferase (SHMT)2 in the mitochondria and SHMT1 and de novo purine biosynthesis in the cytosol. AGF347 accumulation increases with folylpolyglutamate synthetase (FPGS) levels in both the cytosol and mitochondria. Increased mitochondrial FPGS stimulated one-carbon metabolic fluxes in the cytosol and mitochondria and substantially enhanced in vitro inhibition of pancreatic cancer cells by AGF347. Mitochondrial FPGS levels play important roles in determining the antitumor efficacies of pyrrolo[3,2-d]pyrimidine antifolates for pancreatic cancer.

Maintenance Therapy for Pancreatic Cancer, a New Approach Based on the Synergy between the Novel Agent GP-2250 (Misetionamide) and Gemcitabine.

The novel Oxathiazinane derivative GP-2250 (Misetionamide) displays antineoplastic activity in vitro and in vivo, as previously shown in pancreatic cancer cells and in patient-derived mouse xenografts (PDX). Currently, GP 2250 is under phase I clinical trial in pancreatic ductal adenocarcinoma (PDAC). GP-2250 in combination with Gemcitabine displays a high synergistic capacity in various primary and established pancreatic cancer cell lines. Additionally, in the eight PDX models tested, the drug combination was superior in reducing tumor volume with an aggregate tumor regression (ATR) of 74% compared to Gemcitabine alone (ATR: 10%). Similarly, in a PDX maintenance setting following two weeks of treatment with nab-Paclitaxel plus Gemcitabine, the combination of GP-2250 plus Gemcitabine resulted in outstanding tumor control (ATR: 79%) compared to treatment with Gemcitabine alone (ATR: 60%). Furthermore, GP-2250 reduced the ratio of tumor-initiating CD133+ markers on the surface of PDAC cells in spheroid cultures, indicating a possible mechanism for the synergistic effect of both substances. Considering the high tolerability of GP 2250, these results may open up a new approach to maintenance therapy with GP-2250/Gemcitabine combination following nab-Paclitaxel plus Gemcitabine as first-line treatment.

Three Molecular Developmental Pathways of Remnant Pancreatic Cancer after Resection: A Nationwide Project Study of Japan Pancreas Society.

This study aimed to clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection. Molecular mechanisms of the development of remnant PCs following primary PC resection are largely unknown. Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathological features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated. These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop via three different molecular pathways: successional, showing identical and accumulated alterations (n=14); phylogenic, showing identical and distinct alterations (n=26); and distinct, showing independent distinctive alterations (n=3). The similarity of gene alterations was associated with time to the remnant PC development (r=－0.384, P=0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P=0.007). Patient survival did not differ significantly depending on these molecular pathways. Molecular profiling uncovered three pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs.

Co‑expression of SLC20A1 and ALDH1A3 is associated with poor prognosis, and SLC20A1 is required for the survival of ALDH1‑positive pancreatic cancer stem cells.

Solute carrier family 20 member 1 (SLC20A1) is a sodium/inorganic phosphate symporter, which has been identified as a prognostic marker in several types of cancer, including pancreatic cancer. However, to the best of our knowledge, the association between SLC20A1 expression and cancer stem cell (CSC) markers, such as aldehyde dehydrogenase 1 (ALDH1), in pancreatic ductal adenocarcinoma (PDAC), and the role of SLC20A1 in PDAC CSCs remains unclear. In the present study, a genomic dataset of primary pancreatic cancer (The Cancer Genome Atlas, Pan-Cancer Atlas) was downloaded and analyzed. Kaplan-Meier analysis and multivariate Cox regression analysis were performed to evaluate the overall survival, disease-specific survival (DSS), disease-free interval (DFI) and progression-free interval (PFI). Subsequently, SLC20A1 small interfering RNA (siRNA) knockdown (KD) was induced in the PANC-1 and MIA-PaCa-2 PDAC cell lines, and in sorted high ALDH1 activity (ALDH1high) cells, after which, cell viability, in vitro tumor sphere formation, cell death and caspase-3 activity were examined. The results revealed that patients with high expression of SLC20A1 (SLC20A1 high) at tumor stage I had a poor prognosis compared with patients with low expression of SLC20A1 (SLC20A1 low) in terms of DSS, DFI and PFI. In addition, patients with high expression of SLC20A1 and ALDH1A3 (SLC20A1 high ALDH1A3 high) exhibited poorer clinical outcomes than patients with high expression of SLC20A1 and low expression of ALDH1A3 (SLC20A1 high ALDH1A3 low), low expression of SLC20A1 and high expression of ALDH1A3 (SLC20A1 low ALDH1A3 high) and SLC20A1 low ALDH1A3 low. SLC20A1 siRNA KD in ALDH1high cells isolated from PANC-1 and MIA-PaCa-2 cell lines resulted in suppression of in vitro tumorsphere formation, and enhancement of cell death and caspase-3 activity. These results suggested that SLC20A1 was involved in cell survival via the suppression of caspase-3-dependent apoptosis, and contributed to cancer progression and poor clinical outcomes in PDAC. In conclusion, SLC20A1 may be used as a prognostic marker and novel therapeutic target of ALDH1-positive pancreatic CSCs.

Endoscopic Ultrasonography-Guided Fine-Needle Biopsy for Patients with Resectable Pancreatic Malignancies

Clinicians often use endoscopic ultrasonography to survey pancreatic tumors. When endoscopists conduct this examination and find the tumor to be unresectable, a fine-needle biopsy is subsequently performed for tissue confirmation. However, if the tumor is deemed resectable, the necessity of a pre-operative fine-needle biopsy remains debatable. Therefore, we performed a retrospective analysis of a single-center cohort of patients with pancreatic tumors who underwent an endoscopic ultrasound-guided fine-needle biopsy or aspiration (EUS-FNB or FNA) between 2020 and 2022. This study focused on patients diagnosed with resectable malignant pancreatic tumors. The exclusion criteria included individuals diagnosed with benign pancreatic lesions and those with unresectable tumors. A total of 68 patients were enrolled in this study. Histological examination revealed that pancreatic adenocarcinoma was the predominant type of tumor (n = 42, 61.8%), followed by neuroendocrine tumors (n = 22, 32.3%), and metastasis (n = 4, 5.9%). Notably, 17 patients had a history of other cancers, with 23.5% being diagnosed with a metastatic tumor rather than primary pancreatic cancer. Therefore, EUS-FNA/FNB is crucial in patients with a resectable pancreatic tumor and a history of cancer to differentiate between a primary and a metastatic tumor.

Evaluation of Short- and Long-Term Outcomes After Resection in Patients with Locally Advanced versus (Borderline) Resectable Pancreatic Cancer.

This study aims to evaluate short- and long-term outcomes following pancreatectomy in patients with LAPC compared to (B)RPC patients. Selected patients diagnosed with locally advanced pancreatic cancer (LAPC) are increasingly undergoing resection following induction chemotherapy. To evaluate the benefit of this treatment approach, it is helpful to compare outcomes in resected patients with primary LAPC to outcomes in resected patients with primary (borderline) resectable pancreatic cancer ((B)RPC). Two prospectively maintained nationwide databases were used for this study. Patients with (B)RPC undergoing upfront tumor resection and patients with resected LAPC after induction therapy were included. Outcomes were postoperative pancreas-specific complications, 90-day mortality, pathological outcomes, disease-free interval (DFI), and overall survival (OS). Overall, 879 patients were included; 103 with LAPC (12%) and 776 with (B)RPC (88%). LAPC patients had a lower WHO performance score and CACI. Postoperative pancreas-specific complications were comparable between groups, except delayed gastric emptying grade C, which occurred more often in LAPC patients (9% vs. 3%, P=0.03). Ninety-day mortality was comparable. About half of the patients in both groups (54% in LAPC vs. 48% in (B)RPC), P=0.21) had a radical resection (R0). DFI was 13 months in both groups (P=0.12) and OS from date of diagnosis was 24 months in LAPC patients and 19 months in (B)RPC patients (P=0.34). In our nationwide prospective databases, pancreas-specific complications, mortality and survival in patients with LAPC following pancreatectomy are comparable with those undergoing resection for (B)RPC. These outcomes suggest that postoperative morbidity and mortality after tumor resection in carefully selected patients with LAPC are acceptable.

Abstract 7223: A triplet therapeutic strategy targeting MEK, BCL-XL, and EGFR, for KRAS-mutant pancreatic ductal adenocarcinoma

Abstract KRAS mutations drive over 90% of pancreatic cancers, but KRAS has been proven difficult to target. Downstream of KRAS, MEK inhibition in combination with BCL-XL inhibition is synthetically lethal and an effective treatment for gynecologic, but not colorectal malignancies. Like colorectal cancer, pancreatic cancer often exhibits aberrant HER/EGFR activity. We hypothesized that a triplicate regimen targeting MEK, BCL-XL, and EGFR/HER would be effective for pancreatic cancer. Trametinib (MEK inhibitor), Afatinib (pan-EGFR/HER inhibitor), and Navitoclax (BCL-XL inhibitor); or DT2216 (a BCL-XL/BCL-1 proteolysis targeting chimera, PROTAC) were explored using various combinatorial strategies. These drug combinations were tested using four primary human pancreatic cancer cell lines using live cell imaging (Incucyte) and an in vivo murine model. Group comparisons were analyzed using one-way ANOVAs, and adjusted p-values <0.05 were considered significant. We observed that no single-agent treatments were effective. MEK inhibition plus anti-BCL-XL (Trametinib + Navitoclax or Trametinib + DT2216) demonstrated efficacy in one of the four cell lines. We noted synergistic effects on reduced cell growth and increased cell death when EGFR/HER inhibition was included by the administration of Afatinib. The triplet combination resulted in synergistic effects in three of four cell lines with Navitoclax and four of four cell lines with DT2216 (q<0.05). This effect was confirmed with DT2216 inhibition of BCL-XL in an in-vivo murine model. In conclusion, our study shows that a combinatory strategy targeting MEK, BCL-XL, and pan-EGFR/HER receptor kinase shows significant synergistic effects in pancreatic cancer. Clinical trials that assess the efficacy and safety of this strategy for patients with KRAS-mutant pancreatic cancer are warranted. Our data also suggests that novel KRAS inhibitors as monotherapy are likely to fail. Citation Format: Gerik W. Tushoski-Alemán, Alexandra J. Crespin, Chibeze J. Oguejiofor, Jordan A. McKean, Kelly M. Herremans, Thomas J. George, Carmen J. Allegra, Steven J. Hughes, Song Han. A triplet therapeutic strategy targeting MEK, BCL-XL, and EGFR, for KRAS-mutant pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7223.

Abstract 3878: Therapy-associated remodeling of pancreatic cancer revealed by single-cell spatial transcriptomics and optimal transport analysis

Abstract The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) is driven by cell-intrinsic features and cell-extrinsic interactions between tumor cells and the desmoplastic stroma, which is infiltrated with heterogeneous populations of cancer-associated-fibroblasts (CAFs) and immune cells. These features are able to drive emergent properties such as chemoresistance through diverse and not yet fully elucidated mechanisms. Through single-nucleus RNA-seq and whole-transcriptome digital spatial profiling of PDAC patient tumors, we previously reported marked heterogeneity in the malignant cells and CAF composition of PDAC. In this project, we performed high-plex single-cell spatial molecular imaging (990-plex SMI, Nanostring) to dissect the therapy-remodeled multicellular neighborhoods and malignant-stroma cell interactions in primary resected human pancreatic cancer with (n = 6) or without (n = 7) neoadjuvant chemotherapy and radiotherapy. SMI of the PDAC samples yielded ~753,000 high-confidence single cells and captured the heterogeneity of malignant cells and CAFs. We identified three malignant subtypes: classical (CLS), basal-like (BSL), and the recently characterized neural-like progenitor (NRP) malignant subtype that exhibits stem-like and neurodevelopmental features. To leverage the single-cell spatial resolution of SMI to further dissect treatment-associated changes in cell-cell interactions, we developed Spatially Constrained Optimal Transport Interaction Analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand-receptor gene expression. Our results uncovered a marked enrichment in ligand-receptor interactions between CAFs and malignant cells in response to treatment. In combination with several complementary methods, including examination of downstream target gene expression and ex vivo 3D co-culture of CAF and PDAC cells, we found that IL-6 family signaling was the most consistently enriched interaction between CAFs and malignant cells after treatment. This led us to hypothesize that IL-6 signaling between CAFs and malignant cells may induce chemoresistance in cancer cells. To test this hypothesis, we treated three human cancer cell lines (AsPC1, Panc1, Panc0203) with 5FU with or without IL-6 and discovered that IL-6 induced chemoresistance for two of the lines (Panc1, Panc0203). Taken together, we have integrated novel experimental and computational approaches to enable high-resolution, spatially-guided discovery of treatment-associated remodeling in the pancreatic cancer microenvironment. Further studies will be conducted to dissect additional mechanisms by which candidate cell-cell interactions promote disease progression and/or resistance to cytotoxic therapy, with the ultimate goal of guiding novel therapeutic development. Citation Format: JINGYI CAO, Carina Shiau, Dennis Gong, Mark T. Gregory, Xunqin Yin, Jae-Won Cho, Peter L. Wang, Jennifer Su, Jason W. Reeves, Jimmy A. Guo, Nicole A. Lester, Jung Woo Bae, Ryan Zhao, Martin Hemberg, William L. Hwang. Therapy-associated remodeling of pancreatic cancer revealed by single-cell spatial transcriptomics and optimal transport analysis [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 3878.

Long-term outcomes of combined treatment of primary resectable pancreatic head cancer in patients over 70 years

Aim. To evaluate long-term oncological outcomes of pancreatoduodenectomy in resectable pancreatic head cancer in patients over 70 years of age. Materials and methods. A retrospective analysis of the Moscow Clinical Scientific Center registry revealed 63 patients aged > 70 years with resectable pancreatic head cancer. In 2016–2023, these patients underwent pancreatoduodenectomy. Males accounted for 35 %, and the median age comprised 75 years. Stage II was diagnosed in 44.4 % of patients, stage I – in 31.7 %, and stage III – in 23.8 %. Median follow-up accounted for 34.5 months. The authors analyzed the effect of patient characteristics, tumor, perioperative data and method of surgery on overall survival. Results. Adjuvant chemotherapy (p = 0.005; HR 0.28, CI 0.115–0.62) and low preoperative albumin levels (p = 0.004; HR 0.203, CI 0.28–0.61) had a significant impact on overall survival. After open surgery, 56 % of patients did not receive adjuvant chemotherapy, after minimally invasive surgery – 15.4 % (p = 0.0001). Conclusion. Minimally invasive pancreatoduodenectomy reveals no negative effect on the oncological outcomes of treatment for resectable pancreatic head cancer in patients ≥ 70 years old. Adjuvant chemotherapy and hypoalbuminemia prior to surgery are considered to be statistically significant factors influencing overall survival. Minimally invasive techniques enable adjuvant chemotherapy to be administered to a larger number of patients compared to open intervention.

A 15-Year Single-Institution Retrospective Study of Primary Pancreatic Cancer Treated with Non-Ablative Palliative Radiotherapy.

We studied the use of palliative radiotherapy (RT) among patients with primary, non-curable, locally advanced pancreatic cancer. In this subset of patients, with very poor survival, various palliative RT dose fractionation schemes are used; but, in the absence of a guideline, practice patterns vary, and dose choice is mainly based on the physician's intuition. We divided the patients into three groups, according to the dose fractionation schedules received: low (A), intermediate (B), and high (C) dose groups, to study the potential differences in outcome between the different dose prescriptions. Cohort: n = 184. Median age: 69 years. Male: n = 105 (57%), female: n = 79 (43%). Stage IV: n = 117 (64%). T4: n = 127 (69%). Tumor location: head: n = 109 (59%), body: n = 37 (20%), tail: n = 25 (14%), neck: n = 11 (6%), and uncinate: n = 2 (1%). Prior systemic therapy: n = 66 (36%). Most common dose fractionations received: 20 Gy in five fractions n = 67 (36%), 30 Gy in 10 fractions n = 49 (27%), and 8 Gy in one fraction n = 23 (13%). Group A: n = 33 (18%), median overall survival (OS) 19 days (95% CI 4-33). Group B: n = 84 (46%), median OS 52 days (95% CI 43-60). Group C: n = 67 (36%), median OS 126 days (95% CI 77-174). Median days to in-field progression: Group A 59 days (range 7-109), Group B 96 days (range 19-173), and Group C 97 days (range 13-475). To our knowledge, this is the largest reported retrospective cohort of patients receiving non-ablative palliative RT to treat their primary pancreatic tumors. Most patients had metastatic disease, T4 tumors of the pancreatic head and had not received prior systemic therapy. A significant survival benefit was seen favoring the high dose/longer RT fractionation group, presumably due to appropriate patient selection rather than an RT effect. Despite the relatively short median overall survival, one fifth of the patients were found to experience an in-field progression following RT.

Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy

BackgroundPrevious studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille’s heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking.MethodsThe safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action.ResultsWe show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration.ConclusionsOverall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.

Molecular mechanisms of pancreatic cancer liver metastasis: the role of PAK2.

Pancreatic cancer remains an extremely malignant digestive tract tumor, posing a significant global public health burden. Patients with pancreatic cancer, once metastasis occurs, lose all hope of cure, and prognosis is extremely poor. It is important to investigate liver metastasis of Pancreatic cancer in depth, not just because it is the most common form of metastasis in pancreatic cancer, but also because it is crucial for treatment planning and prognosis assessment. This study aims to delve into the mechanisms of pancreatic cancer liver metastasis, with the goal of providing crucial scientific groundwork for the development of future treatment methods and drugs. We explored the mechanisms of pancreatic cancer liver metastasis using single-cell sequencing data (GSE155698 and GSE154778) and bulk data (GSE71729, GSE19279, TCGA-PAAD). Initially, Seurat package was employed for single-cell data processing to obtain expression matrices for primary pancreatic cancer lesions and liver metastatic lesions. Subsequently, high-dimensional weighted gene co-expression network analysis (hdWGCNA) was used to identify genes associated with liver metastasis. Machine learning algorithms and COX regression models were employed to further screen genes related to patient prognosis. Informed by both biological understanding and the outcomes of algorithms, we meticulously identified the ultimate set of liver metastasis-related gene (LRG). In the study of LRG genes, various databases were utilized to validate their association with pancreatic cancer liver metastasis. In order to analyze the effects of these agents on tumor microenvironment, we conducted an in-depth analysis, including changes in signaling pathways (GSVA), cell differentiation (pseudo-temporal analysis), cell communication networks (cell communication analysis), and downstream transcription factors (transcription factor activity prediction). Additionally, drug sensitivity analysis and metabolic analysis were performed to reveal the effects of LRG on gemcitabine resistance and metabolic pathways. Finally, functional experiments were conducted by silencing the expression of LRG in PANC-1 and Bx-PC-3 cells to validate its influence to proliferation and invasiveness on PANC-1 and Bx-PC-3 cells. Through a series of algorithmic filters, we identified PAK2 as a key gene promoting pancreatic cancer liver metastasis. GSVA analysis elucidated the activation of the TGF-beta signaling pathway by PAK2 to promote the occurrence of liver metastasis. Pseudo-temporal analysis revealed a significant correlation between PAK2 expression and the lower differentiation status of pancreatic cancer cells. Cell communication analysis revealed that overexpression of PAK2 promotes communication between cancer cells and the tumor microenvironment. Transcription factor activity prediction displayed the transcription factor network regulated by PAK2. Drug sensitivity analysis and metabolic analysis revealed the impact of PAK2 on gemcitabine resistance and metabolic pathways. CCK8 experiments showed that silencing PAK2 led to a decrease in the proliferative capacity of pancreatic cancer cells and scratch experiments demonstrated that low expression of PAK2 decreased invasion capability in pancreatic cancer cells. Flow cytometry reveals that PAK2 significantly inhibited apoptosis in pancreatic cancer cell lines. Molecules related to the TGF-beta pathway decreased with the inhibition of PAK2, and there were corresponding significant changes in molecules associated with EMT. PAK2 facilitated the angiogenic potential of cancer cells and promotes the epithelial-mesenchymal transition process by activating the TGF-beta signaling pathway. Simultaneously, it decreased the differentiation level of cancer cells, consequently enhancing their malignancy. Additionally, PAK2 fostered communication between cancer cells and the tumor microenvironment, augments cancer cell chemoresistance, and modulates energy metabolism pathways. In summary, PAK2 emerged as a pivotal gene orchestrating pancreatic cancer liver metastasis. Intervening in the expression of PAK2 may offer a promising therapeutic strategy for preventing liver metastasis of pancreatic cancer and improving its prognosis.

Complete Primary Pathological Response Following Neoadjuvant Treatment and Radical Resection for Pancreatic Ductal Adenocarcinoma.

Neoadjuvant treatment (NAT) for borderline (BD) or locally advanced (LA) primary pancreatic cancer (PDAC) is now a widely adopted approach. We present a case series of patients who have achieved a complete pathological response of the primary tumour on final histology following neoadjuvant chemotherapy +/- chemoradiation and radical surgery. Patients who underwent radical pancreatic resection following neoadjuvant treatment between March 2006 and March 2023 at a single institution were identified by retrospective case note review of a prospectively maintained database. Ten patients were identified to have a complete primary pathological response (ypT0) on postoperative histology. Before treatment, five patients were considered BD and five were LA according to National Comprehensive Cancer Network guidelines. All patients underwent staging Computed Tomography (CT) and nine underwent 18Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET/CT) imaging, with a mean maximum standardized uptake value (SUVmax) of the primary lesion at 6.14 ± 1.98 units. All patients received neoadjuvant chemotherapy, and eight received further chemoradiotherapy prior to resection. Mean pre- and post-neoadjuvant treatment serum Ca19-9 was 148.0 ± 146.3 IU/L and 18.0 ± 18.7 IU/L, respectively (p = 0.01). The mean duration of NAT was 5.6 ± 1.7 months. The mean time from completion of NAT to surgery was 13.1 ± 8.3 weeks. The mean lymph node yield was 21.1 ± 10.4 nodes, with one patient found to have 1 lymph node involved. All resections were reported to be R0. The mean length of stay was 11.8 ± 6.2 days. At the time of analysis, one death was reported at 35 months postoperatively. Two cases of recurrence were reported at 16 months (surgical bed) and 33 months (pulmonary). All other patients remain alive and under active surveillance. The current overall survival is 26.6 ± 20.7 months and counting. Complete primary pathological response is uncommon but possible following neoadjuvant treatment in patients with PDAC. Further work to identify the common denominator within this unique cohort may lead to advances in the therapeutic approach and offer hope for patients diagnosed with borderline or locally advanced pancreatic ductal adenocarcinoma.

Patterns of surgery and adjuvant therapy in pancreatic carcinoid tumor: An NCDB analysis.

631 Background: Pancreatic Carcinoid Tumor (PCT) is a neuroendocrine tumor (NET) of the gastrointestinal (GI) tract composed of Argentaffin cells. Of the primary pancreatic cancers, NETs are exceedingly rare in comparison to pancreatic adenocarcinoma, accounting for less than 2% of pancreatic cancer diagnoses. PCTs constitute for only a subset of these and hold a better prognosis than adenocarcinoma (What Is a Pancreatic Neuroendocrine Tumor? | American Cancer Society, n.d.). GI carcinoid tumors classically originate in the appendix, ileum, or rectum, and are seldom a primary neoplasm of the pancreas. PCTs generate secretory products with Serotonin being the most frequently isolated. Some cases may produce a carcinoid syndrome with characteristic diarrhea, cutaneous flushing, and bronchospasm (Ha & Tan, 2012). Surgical resection is the hallmark of treatment, though other modalities of management are available. Due to the rarity of PCT, no significant study exists in the literature analyzing the association of survival with receipt of surgery or predictors of receipt of surgery. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with PCT from 2004 to 2019 using the histology codes 8240 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA Chi-Square, Binary Logistic Regression and Cox Proportional Hazards tests were performed. Data was analyzed using SPSS version 29 and statistical significance was set at α = 0.05. Results: 2237 patients with PCT formed the final sample, with an average age of 61 years of age. 724 patients (32.3%) underwent surgery of the primary site, 72 (3.2%) received adjuvant chemotherapy, and 9 (0.4%) received adjuvant radiation. Surgery alone was associated with the longest median survival ( 198.5 months) compared to the other treatments ( Adjuvant chemotherapy=155.3 months, Adjuvant radiation=122.7 months, No surgery=73.95 months; p<0.05). After controlling for covariates, receipt of surgery was independently associated with decreased overall mortality ( HR=.380; p<0.05). Decreased age, lower grade tumors, and fewer positive regional lymph nodes were significantly associated with increased odds of receiving surgery. Additionally, treatment at an academic facility and private insurance status was associated with significantly higher rates of surgery. Patients who did not receive surgery were significantly older, had later stage disease, higher co-morbidity scores, and larger tumor size. Income level and race had no effect on treatment selection. Conclusions: This study found that surgery alone without adjuvant therapy is independently associated with improved survival. Favorable clinical characteristics may be contributing to this discrepancy in survival. Further exploration of treatment strategies in PCT may benefit patients through the creation of definitive treatment guidelines to manage this disease.

Upfront surgery vs neoadjuvant therapy for primary resectable pancreatic cancer, an ITT analysis

Upfront surgery vs neoadjuvant therapy for primary resectable pancreatic cancer, an ITT analysis

Uncovering the role of FXYD3 as a potential oncogene and early biomarker in pancreatic cancer.

Pancreatic cancer is an aggressive cancer with silent symptoms and high mortality with less than 11% of the 5-year survival rate. Until now, the significance of genes as clinical biomarkers in the early stages of pancreatic cancer has not been fully understood. Hence, this study aims to reveal the significant genes in the early stages of pancreatic cancer using bioinformatic analysis and in vitro experiments, and to serve as clinical biomarkers for early detection. We used Cancer RNA-Seq Nexus database and identified one tumor suppressor gene (NAGK), and five oncogenes (FXYD3, ACTR1A, B3GNT3, SIGIRR, and EXOC1) that are significant in the early stages of pancreatic cancer. The expression of NAGK, FXYD3, ACTR1A, B3GNT3, SIGIRR, and EXOC1 were determined from the GEPIA, UALCAN, and HPA database. It has been shown that pancreatic cancer tumor dissemination is an event that can occur in early lesions, rather than being solely restricted in the developed primary tumor. Thus, the six hub genes that were differentially expressed between stage I and stage II of primary pancreatic cancer tumors were compared to metastasis-related genes (1938 genes) in the human cancer metastasis database (HCMDB), yielding two overlapped genes (B3GNT3 and FXYD3). To establish the expression correlation between these two specific genes with metastatic characteristics of the early stage of pancreatic cancer and migratory ability in pancreatic cancer cell lines, the expression patterns of B3GNT3 and FXYD3 were examined in four different migratory abilities of pancreatic cancer cell lines, including HPAC, BxPC-3, AsPC-1, and PANC-1, as well as the normal pancreatic duct epithelial cell line HPDE6-C7. The results displayed that the expression of the FXYD3 gene was dramatically increased with the migratory ability enhanced of four pancreatic cancer cell lines. Thus, in the follow-up study, we will demonstrate the functional role of FXYD3 in pancreatic cancer tumorigenesis. This study revealed that the FXYD3 may act as a significant oncogene in the early stage of pancreatic cancer.

The Importance of Reading the Skin: Cutaneous Metastases of Pancreatic Cancer, a Systematic Review.

Pancreatic cancer is notorious for its aggressive nature and low survival rate, with less than 10% of patients surviving beyond five years. Early detection is difficult, but skin metastases can be a rare but significant indicator. This systematic review focuses on the epidemiology, clinical features, and histology of skin metastases from pancreatic cancer to determine their importance in early diagnosis and overall management of the disease. Following PRISMA guidelines, we conducted an exhaustive search of MEDLINE/PubMed, EMBASE, and SCOPUS databases up to June 2023, using specific keywords. Four independent investigators screened the studies using predefined criteria, and two investigators checked the accuracy and consistency of the data extraction. We assessed the quality of the trials using adapted criteria from the Joanna Briggs Institute. A narrative synthesis rather than a meta-analysis was chosen because of the different study designs. The final analysis included 57 patients with skin metastases from pancreatic cancer. Cutaneous metastases, although rare, presented with approximately equal gender distribution and a mean age of 63.4 years. Predominantly non-umbilical (77%), these metastases showed clinical diversity, ranging from asymptomatic nodules to painful or ulcerated lesions. Notably, skin metastases often preceded the diagnosis of primary pancreatic cancer (58%). Primary tumor characteristics revealed different localizations, with adenocarcinoma being the most prevalent histological type (77%). A significant association (p = 0.008) was observed between pancreatic tumor location and the timing of presentation of skin metastases. Tumors located in the body and tail of the pancreas were more likely to manifest skin metastases as an initial clinical manifestation (62.2%) than those in the head of the pancreas (20.8%). In conclusion, although skin metastases are rare, they are important indicators of pancreatic cancer, highlighting the need for multidisciplinary healthcare collaboration and thorough skin examination. Recognizing them could lead to earlier diagnosis, which is crucial in a cancer with limited treatment options.

An evaluation of chemotherapy, surgery and immunotherapys effectiveness in tackling pancreatic cancer

Statistics show that among malignant tumors, pancreatic cancer has the poorest prognosis. Cancer has a low likelihood of survival, and early cancer diagnosis is challenging. The major therapies currently used include surgery, chemotherapy, and radiation, although the outcomes are not optimal. Treatments for pancreatic cancer using immunotherapy now appear more promising because to developments in molecular biology. The primary pancreatic cancer treatments will be analyzed and evaluated in this study, and it will be concluded that immunotherapy is the most promising course of action. The usage of patient range, toxicity, and other side effects are some of the difficulties, although it is still in the research and development stage.

Robotic Rar for Rectal Cancer with Partial Pelvic Peritonectomy for Carcinosis from Pancreatic Cancer

Introduction: Robotic technology can be used to address several common complications of solid organ malignancies. This case report deals with a patient with rectal cancer undergone robotic rectal resection for bleeding adenocarcinoma, with a new finding of primary pancreatic cancer at post-neoadjuvant re-evaluation. Materials and Methods: A 70-year-old female patient with adenocarcinoma of the rectum was referred to neoadjuvant treatment. Re-evaluation showed a new finding of a pancreatic tumor. CHT was halted for rectal tumor bleeding after 1 week. Palliative rectal surgery was recommended. Results: Patient was discharged on 6th postoperative day; CHT was resumed. No pelvic relapse was diagnosed, the pancreatic lesion reduced volumetrically and a RT was performed. After 1 year from surgery the patient referred to our ER for intestinal obstruction. An explorative laparoscopy revealed a diffuse carcinosis from pancreas. Conclusion: Robotic surgery is safe also in palliative surgery. Minimally-invasive approach minimizes adverse effects of surgical intervention.

Differential modulation of cellular phenotype and drug sensitivity by extracellular matrix proteins in primary and metastatic pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) is reported to be the third highest cause of cancer-related deaths in the United States. PDAC is known for its high proportion of stroma, which accounts for 90% of the tumor mass. The stroma is made up of extracellular matrix (ECM) and nonmalignant cells such as inflammatory cells, cancer-associated fibroblasts, and lymphatic and blood vessels. Here, we decoupled the effects of the ECM on PDAC cell lines by culturing cells on surfaces coated with different ECM proteins. Our data show that the primary tumor-derived cell lines have different morphology depending on the ECM proteins on which they are cultured, while metastatic lesion-derived PDAC lines' morphology does not change with respect to the different ECM proteins. Similarly, ECM proteins modulate the proliferation rate and the gemcitabine sensitivity of the primary tumor PDAC cell lines, but not the metastatic PDAC lines. Lastly, transcriptomics analysis of the primary tumor PDAC cells cultured on different ECM proteins reveals the regulation of various pathways, such as cell cycle, cell-adhesion molecules, and focal adhesion, including the regulation of several integrin genes that are essential for ECM recognition.