Flurbiprofen inhibits cAMP transport by MRP4/ABCC4 increasing the potency of gemcitabine treatment in PDAC cell models.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly malignant cancer with a grim prognosis due to its early metastasis and resistance to current chemotherapies, such as Gemcitabine (GEM). We have previously demonstrated that cAMP exclusion by MRP4 is critical for PDAC cell proliferation, establishing this transporter as a promising prognostic marker and therapeutic target. In search for novel therapeutic options to improve GEM efficacy, we conducted a drug repositioning screening to identify potential inhibitors of cAMP transport by MRP4. Several non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit the transport of certain MRP4 substrates. In this study, we assessed the efficacy of sixteen NSAIDs in inhibiting cAMP transport mediated by MRP4, identifying seven potent inhibitors based on their IC50 values. The most potent inhibitors were further tested for their effect on cell proliferation and migration. Flurbiprofen emerged as the most potent inhibitor of both MRP4-mediated cAMP transport and cell proliferation. Overexpression of MRP4 in BxPC-3 cells significantly increased GEM resistance, and co-administration of flurbiprofen with GEM markedly enhanced the latter's potency inhibiting PDAC cells proliferation. These findings position flurbiprofen as a potent inhibitor of cAMP transport by MRP4 and a promising adjunctive therapy to enhance GEM effectiveness in PDAC treatment.

5-nitro-thiophene-thiosemicarbazone derivative induces cell death, cell cycle arrest, and phospho-kinase shutdown in pancreatic ductal adenocarcinoma cells.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options. This study explores the potential of novel 5-nitro-thiophene-thiosemicarbazone derivatives as therapeutic agents for PDAC. METHODS: We evaluated the cytotoxicity of seven derivatives in peripheral blood mononuclear cells (PBMCs) and PDAC cell lines. Promising candidates (PR12 and PR17) were further analyzed for their effects on colony formation, cell cycle progression, and reactive oxygen species (ROS) production. PR17, the most promising derivative, was subjected to additional investigation, including analysis of autophagy-related genes and protein kinase inhibition. RESULTS: Three derivatives (PR16, PR19, and PR20) displayed cytotoxicity towards PBMCs. PR12 reduced colony formation and G0/G1 cell cycle arrest in PDAC cells. Notably, PR17 exhibited potent activity in MIA PaCa-2 cells, inducing S-phase cell cycle arrest, downregulating autophagy genes, and inhibiting key protein kinases. CONCLUSION: PR17, a 5-nitro-thiophene-thiosemicarbazone derivative, demonstrates promising antineoplastic activity against PDAC cells by potentially modulating cell cycle progression, autophagy, and protein kinase signaling. Further studies are warranted to elucidate the detailed mechanism of action and explore its efficacy in vivo.

Comprehensive exploration of immune checkpoint-related genes in the prognosis and tumor immune microenvironment of pancreatic adenocarcinoma.

BACKGROUND: To comprehensively analyze the clinical significance of Immune Checkpoint-Related Genes (ICRGs) in Pancreatic Adenocarcinoma (PAAD). METHOD: PAAD tissues and normal pancreatic tissues were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, and 283 ICRGs were integrated by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome datasets. Unsupervised clustering was used to obtain potential ICRGs-based PAAD subtypes. Wilcoxon test was performed to screen Differentially Expressed ICRGs (DEICRGs), while cox regression analyses were utilized to identify prognosis-related ICRGs and clinicopathological factors, and construct the corresponding models. The Tumor Immune Microenvironment (TIME) was evaluated. Moreover, the authors performed enrichment analysis, Gene Set Enrichment Analysis (GSEA), and transcription factor regulatory networks to realize underlying mechanisms. RESULTS: Three ICRGs-based PAAD subtypes were identified, and they were associated with three ESTIMATE scores, a Tumor Microenvironment (TMB) score, 14 therapeutic immune checkpoints, and infiltration levels of seven immune cells. On top of that, the authors constructed two signatures based on DEICRGs to predict the Overall Survival (OS) (Area Under the ROC Curve [AUC: 0.741∼0.778]) and Progression-Free Survival (PFS) (AUC: 0.746∼0.831) of patients. Two nomograms were established by combining clinical variables and signatures. In addition, the authors found higher infiltration of naïve B cells and CD8+ T-cells in low-risk PAAD patients, and higher infiltration of suppressive immune cells and cancer-related signaling pathways in high-risk PAAD patients. CONCLUSION: The present study suggested that ICRGs were associated with TIME formation and prognosis of PAAD patients, which may serve as novel clinical biomarkers and therapeutic targets.

New Smoothened ligands based on the purine scaffold as potential agents for treating pancreatic cancer.

Aberrant activation of the Hedgehog (Hh) signalling pathway has been associated with the development and progression of pancreatic cancer. For this reason, blockade of Hh pathway by inhibitors targeting the G protein-coupled receptor Smoothened (SMO) has been considered as a therapeutic target for the treatment of this cancer. In our previous work, we obtained a new SMO ligand based on a purine scaffold (compound I), which showed interesting antitumor activity in several cancer cell lines. In this work, we report the design and synthesis of 17 new purine derivatives, some of which showed high cytotoxic effect on Mia-PaCa-2 (Hh-dependent pancreatic cancer cell lines) and low toxicity on non-neoplastic HEK-293 cells compared with gemcitabine, such as 8f, 8g and 8h (IC50 = 4.56, 4.11 and 3.08 µM, respectively). Two of these purines also showed their ability to bind to SMO through NanoBRET assays (pKi = 5.17 for 8f and 5.01 for 8h), with higher affinities to compound I (pKi = 1.51). In addition, docking studies provided insight the purine substitution pattern is related to the affinity on SMO. Finally, studies of Hh inhibition for selected purines, using a transcriptional functional assay based on luciferase activity in NIH3T3 Shh-Light II cells, demonstrated that 8g reduced GLI activity with a IC50 = 6.4 µM as well as diminished the expression of Hh target genes in two specific Hh-dependent cell models, Med1 cells and Ptch1-/- mouse embryonic fibroblasts. Therefore, our results provide a platform for the design of SMO ligands that could be potential selective cytotoxic agents for the treatment of pancreatic cancer.

Radicality and safety of total mesopancreatic excision in pancreatoduodenectomy: a systematic review and meta-analysis.

BACKGROUND: Pancreatic head cancer patients who undergo pancreatoduodenectomy (PD) often experience disease recurrence, frequently associated with a positive margin status (R1). Total mesopancreas excision (TMpE) has emerged as a potential approach to increase surgical radicality and minimize locoregional recurrence. However, its effectiveness and safety remain under evaluation. METHODS: We conducted a systematic review and meta-analysis to synthesize current evidence on TMpE outcomes. A systematic search of MEDLINE, EMBASE, Cochrane, and Web of Science databases was conducted up to March 2024 to identify studies comparing TMpE with standard pancreatoduodenectomy (sPD). The risk ratio (RR) or mean difference (MD) was pooled using a random effects model. RESULTS: From 452 studies identified, 9 studies with a total of 738 patients were included, with 361 (49%) undergoing TMpE. TMpE significantly improved the R0 resection rate (RR 1.24; 95% CI 1.11-1.38; P < 0.05), reduced blood loss (MD -143.70 ml; 95% CI -247.92, -39.49; P < 0.05), and increased lymph node harvest (MD 7.27 nodes; 95% CI 4.81, 9.73; P < 0.05). No significant differences were observed in hospital stay, postoperative complications, or mortality between TMpE and sPD. TMpE also significantly reduced overall recurrence (RR 0.53; 95% CI 0.35-0.81; P < 0.05) and local recurrence (RR 0.39; 95% CI 0.24-0.63; P < 0.05). Additionally, the risk of pancreatic fistula was lower in the TMpE group (RR 0.66; 95% CI 0.52-0.85; P < 0.05). CONCLUSION: Total mesopancreas excision significantly increases the R0 resection rate and reduces locoregional recurrence while maintaining an acceptable safety profile when compared with standard pancreatoduodenectomy. Further prospective randomized studies are warranted to determine the optimal surgical approach for total mesopancreatic resection.

Robotic Pancreatoduodenectomy: Increasing Complexity and Decreasing Complications with Experience: Single-Center Results from 150 Consecutive Patients.

BACKGROUND: This report describes the authors' experience with 150 consecutive robotic pancreatoduodenectomies. METHODS: The study enrolled 150 consecutive patients who underwent robotic pancreatoduodenectomy between 2018 and 2023. Pre- and intraoperative variables such as age, gender, indication, operation time, diagnosis, and tumor size were analyzed. The patients were divided into two groups. Group 1 comprised the first 75 patients, and group 2 comprised the last 75 cases. The median age of the patients was 62.4 years and did not differ between the two groups. RESULTS: Morbidity was lower in group 2. The mortality rate was 0.7% at 30 days and 1.3% at 90 days, and there was no difference between the groups. There was a significant reduction (p < 0.05) in operative time, resection time, reconstruction time, and conversion to open surgery in group 2. Partial resection of the portal vein was performed in 17 patients and more common in group 2 (p < 0.01). The number of resected lymph nodes was higher in group 2. The indication for pancreatoduodenectomy did not differ between the two groups. There was no difference in tumor size or clinical characteristics of the patients. CONCLUSIONS: The robotic platform is useful for pancreatoduodenectomy, facilitates adequate lymphadenectomy, and is helpful for digestive tract reconstruction after resection. Robotic pancreatoduodenectomy is safe and feasible for selected patients. It should be performed in specialized centers by surgeons experienced in open and minimally invasive pancreatic surgery.

Laparoscopic Versus Open Pancreatoduodenectomy for Periampullary Tumors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

PURPOSE: Laparoscopic pancreatoduodenectomy (LPD) has emerged as an alternative to open technique in treating periampullary tumors. However, the safety and efficacy of LPD compared to open pancreatoduodenectomy (OPD) remain unclear. Thus, we conducted an updated meta-analysis to evaluate the efficacy and safety of LPD versus OPD in patients with periampullary tumors, with a particular focus on the pancreatic ductal adenocarcinoma patient subgroup. METHODS: According to PRISMA guidelines, we searched PubMed, Embase, and Cochrane Library in December 2023 for randomized controlled trials (RCTs) that directly compare LPD versus OPD in patients with periampullary tumors. Endpoints and sensitive analysis were conducted for short-term endpoints. All statistical analysis was performed using R software version 4.3.1 with a random-effects model. RESULTS: Five RCTs yielding 1018 patients with periampullary tumors were included, of whom 511 (50.2%) were randomized to the LPD group. Total follow-up time was 90 days. LPD was associated with a longer operation time (MD 66.75; 95% CI 26.59 to 106.92; p = 0.001; I2 = 87%; Fig. 1A), lower intraoperative blood loss (MD - 124.05; 95% CI - 178.56 to - 69.53; p < 0.001; I2 = 86%; Fig. 1B), and shorter length of stay (MD - 1.37; 95% IC - 2.31 to - 0.43; p = 0.004; I2 = 14%; Fig. 1C) as compared with OPD. In terms of 90-day mortality rates and number of lymph nodes yield, no significant differences were found between both groups. CONCLUSION: Our meta-analysis of RCTs suggests that LPD is an effective and safe alternative for patients with periampullary tumors, with lower intraoperative blood loss and shorter length of stay.

Immune cells and checkpoints in pancreatic adenocarcinoma: Association with clinical and pathological characteristics.

INTRODUCTION: Pancreatic adenocarcinoma is an extremely aggressive neoplasm, with many challenges to be overcome in order to achieve a truly effective treatment. It is characterized by a mostly immunosuppressed environment, with dysfunctional immune cells and active immunoinhibitory pathways that favor tumor evasion and progression. Thus, the study and understanding of the tumor microenvironment and the various cells subtypes and their functional capacities are essential to achieve more effective treatments, especially with the use of new immunotherapeutics. METHODS: Seventy cases of pancreatic adenocarcinoma divided into two groups 43 with resectable disease and 27 with unresectable disease were analyzed using immunohistochemical methods regarding the expression of programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), and human leukocyte antigen G (HLA-G) molecules as well as the populations of CD4+ and CD8+ T lymphocytes, regulatory T cells (Tregs), and M2 macrophages (MM2). Several statistical tests, including multivariate analyses, were performed to examine how those immune cells and immunoinhibitory molecules impact the evolution and prognosis of pancreatic adenocarcinoma. RESULTS: CD8+ T lymphocytes and M2 macrophages predominated in the group operated on, and PD-L2 expression predominated in the unresectable group. PD-L2 was associated with T stage, lymph node metastasis, and clinical staging, while in survival analysis, PD-L2 and HLA-G were associated with a shorter survival. In the inoperable cases, Tregs cells, MM2, PD-L1, PD-L2, and HLA-G were positively correlated. CONCLUSIONS: PD-L2 and HLA-G expression correlated with worse survival in the cases studied. Tumor microenvironment was characterized by a tolerant and immunosuppressed pattern, mainly in unresectable lesions, where a broad positive influence was observed between immunoinhibitory cells and immune checkpoint proteins expressed by tumor cells.

Atypical phosphatase DUSP11 inhibition promotes nc886 expression and potentiates gemcitabine-mediated cell death through NF-kB modulation.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers among all solid tumors. First-line treatment relies on gemcitabine (Gem) and despite treatment improvements, refractoriness remains a universal challenge. Attempts to decipher how feedback-loops control signaling pathways towards drug resistance have gained attention in recent years, particularly focused on the role of phosphatases. In this study, a CRISPR/Cas9-based phenotypic screen was performed to identify members from the dual-specificity phosphatases (DUSP) family potentially acting on Gem response in PDAC cells. The approach revealed the atypical RNA phosphatase DUSP11 as a potential target, whose inhibition creates vulnerability of PDAC cells to Gem. DUSP11 genetic inhibition impaired cell survival and promoted apoptosis, synergistically enhancing Gem cytotoxicity. In silico transcriptome analysis of RNA-seq data from PDAC human samples identified NF-ĸB signaling pathway highly correlated with DUSP11 upregulation. Consistently, Gem-induced NF-ĸB phosphorylation was blocked upon DUSP11 inhibition in vitro. Mechanistically, we found that DUSP11 directly impacts nc886 expression and modulates PKR-NF-ĸB signaling cascade after Gem exposure in PDAC cells resulting in resistance to Gem-induced cell death. In conclusion, this study provides new insights on DUSP11 role in RNA biology and Gem response in PDAC cells.

Rutinosides-derived from Sarocladium strictum 6-O-α-rhamnosyl-ß-glucosidase show enhanced anti-tumoral activity in pancreatic cancer cells.

BACKGROUND: Low targeting efficacy and high toxicity continue to be challenges in Oncology. A promising strategy is the glycosylation of chemotherapeutic agents to improve their pharmacodynamics and anti-tumoral activity. Herein, we provide evidence of a novel approach using diglycosidases from fungi of the Hypocreales order to obtain novel rutinose-conjugates therapeutic agents with enhanced anti-tumoral capacity. RESULTS: Screening for diglycosidase activity in twenty-eight strains of the genetically related genera Acremonium and Sarocladium identified 6-O-α-rhamnosyl-ß-glucosidase (αRßG) of Sarocladium strictum DMic 093557 as candidate enzyme for our studies. Biochemically characterization shows that αRßG has the ability to transglycosylate bulky OH-acceptors, including bioactive compounds. Interestingly, rutinoside-derivatives of phloroglucinol (PR) resorcinol (RR) and 4-methylumbelliferone (4MUR) displayed higher growth inhibitory activity on pancreatic cancer cells than the respective aglycones without significant affecting normal pancreatic epithelial cells. PR exhibited the highest efficacy with an IC50 of 0.89 mM, followed by RR with an IC50 of 1.67 mM, and 4MUR with an IC50 of 2.4 mM, whereas the respective aglycones displayed higher IC50 values: 4.69 mM for phloroglucinol, 5.90 mM for resorcinol, and 4.8 mM for 4-methylumbelliferone. Further, glycoconjugates significantly sensitized pancreatic cancer cells to the standard of care chemotherapy agent gemcitabine. CONCLUSIONS: αRßG from S. strictum transglycosylate-based approach to synthesize rutinosides represents a suitable option to enhance the anti-proliferative effect of bioactive compounds. This finding opens up new possibilities for developing more effective therapies for pancreatic cancer and other solid malignancies.

Calix[6]arene dismantles extracellular vesicle biogenesis and metalloproteinases that support pancreatic cancer hallmarks.

Many challenges are faced in pancreatic cancer treatment due to late diagnosis and poor prognosis because of high recurrence and metastasis. Extracellular vesicles (EVs) and matrix metalloproteinases (MMPs), besides acting in intercellular communication, are key players in the cancer cell plasticity responsible for initiating metastasis. Therefore, these entities provide valuable targets for the development of better treatments. In this context, this study aimed to evaluate the potential of calix[6]arene to disturb the release of EVs and the activity of MMPs in pancreatic cancer cells. We found a correlation between the endocytic-associated mediators and the prognosis of pancreatic cancer patients. We observed a more active EV machinery in the pancreatic cancer cell line PANC-1, which was reduced three-fold by treatment with calix[6]arene at subtoxic concentration (5 µM; p ã€ˆ0,001). We observed the modulation of 186 microRNAs (164 miRNAs upregulated and 22 miRNAs downregulated) upon calix[6]arene treatment. Interestingly, some of them as miR-4443 and miR-3909, regulates genes HIF1A e KIF13A that are well known to play a role in transport of vesicles. Furthermore, Calix[6]arene downmodulated matrix metalloproteinases (MMPs) -2 and - 9 and disturbed the viability of pancreatic organoids which recapitulate the cellular heterogeneity, structure, and functions of primary tissues. Our findings shed new insights on calix[6]arene's antitumor mechanism, including its intracellular effects on vesicle production and trafficking, as well as MMP activity, which may harm the tumor microenvironment and contribute to a reduction in cancer cell dissemination, which is one of the challenges associated with high mortality in pancreatic cancer.

Chronological pattern of venous thromboembolism (VTE) occurrence impacts in survival of pancreatic ductal adenocarcinoma (PDAC).

BACKGROUND: Limited data exist on the prognostic significance of the chronology of VTE in patients with PDAC. METHODS: Medical data and survival characteristics of patients treated for PDAC from 2019 to 2021 were retrospectively reviewed. Early VTE was defined as occurring within the three months of PDAC diagnosis. RESULTS: 197 patients were included, 54 (27.4%) developed a VTE. Early appearance of VTE was associated with worse prognosis: median overall survival (mOS) VTE < 3 months 8.5 months (HR 1.65, 95% CI 1.11-2.46; p = 0.014), mOS VTE > 3 months 12.8 months (HR 0.78, 95% CI 0.39-1.54; p = 0.5) and mOS patients without VTE 11.4 months (95% CI 10.1-15.4). There was no significant association between the patient's VTE risk according to the Khorana risk score (KRS) (chi2 test p-value = 0.9). CONCLUSION: Early VTE is a prognostic factor in PDAC, which may identify a more aggressive subtype.

Linfangioma Quístico del Páncreas. Un Tumor poco Frecuente / Pancreas Cystic Lymphangioma. A Rare Tumor

El linfangioma quístico del páncreas (LQP), es un tumor extremadamente raro y representa solo el 1% de los linfangiomas abdominales. El objetivo de este manuscrito fue reportar un caso de LQP intervenido quirúrgicamente; y revisar la evidencia existente respecto de sus características morfológicas, terapéuticas y pronósticas. Mujer de 67 años, con LQP operada en Clínica RedSalud Mayor Temuco en septiembre de 2023. Se verificó un tumor sólido-quístico de 16 cm de diámetro mayor, adherido al páncreas a nivel del cuerpo de la glándula, de 867 gramos de peso, con líquido amarillento en su interior; la que fue extirpada completamente. Después del estudio histológico, se realizaron tinciones inmunohistoquímicas complementarias para CD31, D2-40 y calretina. La paciente tuvo un curso postoperatorio sin incidentes, siendo dado de alta al tercer día postoperatorio. En el control alejado, se encontraba en buenas condiciones generales. El LQP es un tumor muy poco frecuente. Las características clínicas e imágenes de este tipo de lesiones son inespecíficas. Debe considerarse en el diagnóstico diferencial de las lesiones quísticas pancreáticas. La resección quirúrgica completa con márgenes libres es el tratamiento de elección; y el pronóstico del LQP es favorable si se reseca por completo.

SUMMARY: Pancreas cystic lymphangioma (PCL) are extremely rare, accounting for only 1% of abdominal lymphangiomas. The aim of this study was to report a rare case of PCL, who underwent surgery; and review the existing evidence regarding its morphological, therapeutic and prognostic characteristics. 67-year-woman patient with PCL who underwent surgery at Clínica RedSalud Mayor Temuco in September 2023. In this case, a solid-cystic tumor with a major diameter of 16 cm was identified, adhering to the pancreas at the level of the body of the gland, weighing 867 grams and containing yellowish fluid in its interior. The tumor was completely excised. Subsequent to histological examination, additional immunohistochemical staining was performed for CD31, D2-40, and calretinin. The patient experienced an uneventful postoperative course and was discharged on the third postoperative day. During the follow-up, the patient remains in good general condition. LQP is a very rare tumor. Clinical features and images of this type of lesions are nonspecific. It should be considered in the differential diagnosis of pancreatic cystic lesions. Complete surgical resection with free margins is the treatment of choice; and the prognosis of LQP is favorable if it is completely resected.

BEYOND TRADITIONAL TOOLS: EXPLORING CONVOLUTIONAL NEURAL NETWORKS AS INNOVATIVE PROGNOSTIC MODELS IN PANCREATIC DUCTAL ADENOCARCINOMA.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal form of cancer with limited prognostic accuracy using traditional factors. This has led to the exploration of innovative prognostic models, including convolutional neural networks (CNNs), in PDAC. CNNs, a type of artificial intelligence algorithm, have shown promise in various medical applications, including image analysis and pattern recognition. Their ability to extract complex features from medical images makes them suitable for improving prognostication in PDAC. However, implementing CNNs in clinical practice poses challenges, such as data availability and interpretability. Future research should focus on multi-center studies, integrating multiple data modalities, and combining CNN outputs with biomarker panels. Collaborative efforts and patient autonomy should be considered to ensure the ethical implementation of CNN-based prognostic models. Further validation and optimisation of CNN-based models are necessary to enhance their reliability and clinical utility in PDAC prognostication. BACKGROUND: •Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited prognostic accuracy through traditional methods. BACKGROUND: •Convolutional neural networks (CNNs) are being explored for prognostic models in PDAC. BACKGROUND: •They can extract complex features from images, aiding PDAC prognostication. BACKGROUND: •Further validation and optimization of CNN-based models are needed for better reliability and clinical utility in PDAC.

Assessing EUS-guided radiofrequency ablation in unresectable pancreatic ductal adenocarcinoma: a single-center historic cohort study.

BACKGROUND AND AIMS: EUS-guided radiofrequency ablation (EUS-RFA) has emerged as an alternative for the local treatment of unresectable pancreatic ductal adenocarcinoma (PDAC). We assessed the feasibility and safety of EUS-RFA in patients with unresectable PDAC. METHODS: This study followed an historic cohort compounded by locally advanced (LA-) and metastatic (m)PDAC-naïve patients who underwent EUS-RFA between October 2019 and March 2022. EUS-RFA was performed with a 19-gauge needle electrode with a 10-mm active tip for energy delivery. Study primary endpoints were feasibility, safety, and clinical follow-up, whereas secondary endpoints were performance status (PS), local control, and overall survival (OS). RESULTS: Twenty-six patients were selected: 15 with locally advanced pancreatic duct adenocarcinoma (LA-PDAC) and 11 with metastatic pancreatic duct adenocarcinoma (mPDAC). Technical success was achieved in all patients with no major adverse events. Six months after EUS-RFA, OS was seen in 11 of 26 patients (42.3%), with significant PS improvement (P = .03). Local control was achieved, with tumor reduction from 39.5 mm to 26 mm (P = .04). A post-treatment hypodense necrotic area was observed at the 6-month follow-up in 11 of 11 patients who were still alive. Metastatic disease was a significant factor for worsening OS (hazard ratio, 5.021; 95% confidence interval, 1.589-15.87; P = .004). CONCLUSIONS: EUS-RFA for the treatment of pancreatic adenocarcinoma is a minimally invasive and safe technique that may have an important role as targeted therapy for local treatment of unresectable cases and as an alternative for poor surgical candidates. Also, RFA may play a role in downstaging cancer with a potential increase in OS in nonmetastatic cases. Large prospective cohorts are required to evaluate this technique in clinical practice.

Update on the management of older patients with pancreatic adenocarcinoma: a perspective from medical oncology.

In the context of pancreatic cancer, surgical intervention is typically recommended for localized tumours, whereas chemotherapy is the preferred approach in the advanced and/or metastatic setting. However, pancreatic cancer is closely linked to ageing, with an average diagnosis at 72 years. Paradoxically, despite its increased occurrence among older individuals, this population is often underrepresented in clinical studies, complicating the decision-making process. Age alone should not determine the therapeutic strategy but, given the high comorbidity and mortality of this disease, a comprehensive geriatric assessment (CGA) is necessary to define the best treatment, prevent toxicity, and optimize older patient care. In this review, a group of experts from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica, SEOM), the Spanish Cooperative Group for the Treatment of Digestive Tumours (Grupo Español de Tratamiento de los Tumores Digestivos, TTD), and the Multidisciplinary Spanish Group of Digestive Cancer (Grupo Español Multidisciplinar en Cáncer Digestivo, GEMCAD) have assessed the available scientific evidence and propose a series of recommendations on the management and treatment of the older population with pancreatic cancer.

Chloroxine inhibits pancreatic cancer progression through targeted antagonization of the PI3K/AKT/mTOR signaling pathway.

BACKGROUND: Patients with pancreatic cancer have a dismal prognosis due to tumor cell infiltration and metastasis. Many reports have documented that EMT and PI3K-AKT-mTOR axis control pancreatic cancer cell infiltration and metastasis. Chloroxine is an artificially synthesized antibacterial compound that demonstrated anti-pancreatic cancer effects in our previous drug-screening trial. We have explored the impact of chloroxine on pancreatic cancer growth, infiltration, migration, and apoptosis. METHODS: The proliferation of pancreatic cancer cell lines (PCCs) treated with chloroxine was assessed through real-time cell analysis (RTCA), colony formation assay, CCK-8 assay, as well as immunofluorescence. Chloroxine effects on the infiltrative and migratory capacities of PCCs were assessed via Transwell invasion and scratch experiments. To assess the contents of EMT- and apoptosis-associated proteins in tumor cells, we adopted Western immunoblotting as well as immunofluorescence assays, and flow cytometry to determine chloroxine effects on PCCs apoptosis. The in vivo chloroxine antineoplastic effects were explored in nude mice xenografts. RESULTS: Chloroxine repressed pancreatic cancer cell growth, migration, and infiltration in vitro, as well as in vivo, and stimulated apoptosis of the PCCs. Chloroxine appeared to inhibit PCC growth by Ki67 downregulation; this targeted and inhibited aberrant stimulation of the PI3K-AKT-mTOR signaling cascade, triggered apoptosis in PCC via mitochondria-dependent apoptosis, and modulated the EMT to inhibit PCC infiltration and migration. CONCLUSIONS: Chloroxine targeted and inhibited the PI3K-AKT-mTOR cascade to repress PCCs growth, migration, as well as invasion, and triggered cellular apoptosis. Therefore, chloroxine may constitute a potential antineoplastic drug for the treatment of pancreatic cancer.

Biopsias endoscópicas en la era de la inmunoterapia y oncogenética: ¿podemos cumplir los requerimientos? / Endoscopic biopsies in the era of immunotherapy and oncogenetics: can we meet the requirements?

Pancreatic ductal adenocarcinoma has increased its incidence in recent years. In approximately half of the cases, the diagnosis is made when the disease is in the metastatic stage. In advanced stages, treatment with immunotherapy is included with promising results. Histopathological diagnosis is required for the administra - tion of chemotherapy. Endosonography biopsy has benefits due to its high sensitivity and specificity, absence of the need for hospitalization, and low adverse events. Fine biopsy needles are classified according to two characteristics: diameter (19, 22 and 25 G) and tissue acquisition mechanism (FNA and FNB). The emergence of immunotherapy guided by tumor oncogenetics requires an increase in sample size. There are no significant differences between the presence of the pathologist in taking the sample (rapid on-side evaluation, ROSE) over the macroscopic visualization of the biopsy by the endosonographer (macroscopic on-side evaluation, MOSE). The use of FNB for biopsy is recommended over FNA with ROSE when it is necessary to make a diagnosis or genetic study and it is not possible to perform it with the ROSE modality. The factors that determine an adequate sample collection are the location of the biopsy (pancreas 54.3% vs. lymph nodes/metastasis 76.5%) and the diameter/type of needle.

El adenocarcinoma ductal pancreático ha presentado un aumento de su incidencia en los últimos años En aproximadamente la mitad de los casos se realiza el diagnóstico cuando la enfermedad se encuentra en etapa metastásica. En etapas avanzadas se incluye el tratamiento con inmunoterapia con resultados promisorios. Para la administración de quimioterapia se requiere el diagnóstico histopatológico. La biopsia por endosonografía presenta beneficios debido a su alta sensibilidad y especificidad, ausencia de necesidad de hospitalización y bajos eventos adversos. Las agujas finas de biopsia se clasifican según dos características: diámetro (19, 22 y 25 G) y mecanismo de adquisición del tejido (FNA y FNB). La aparición de la inmunoterapia guiada por la oncogenética tumoral requiere un incremento del tamaño de las muestras. No existen diferencias significativas entre la presencia del anatomopatólogo en la toma de la muestra ( rapid on-side evaluation, ROSE) por sobre la visualización macroscópica de la biopsia por parte del endosonografista (macroscopic on-side evaluation, MOSE). Se recomienda el uso de FNB para toma de biopsia por sobre FNA con ROSE cuando es necesario hacer diagnóstico, estudio genético y no es posible realizarlo con modalidad ROSE. Los factores que determi - nan una toma de muestra adecuada son la localización de la biopsia (páncreas 54,3% vs. linfonodos/metástasis 76,5%) y el diámetro/tipo de aguja

Uma nova variante de splicing STK3/MST2 que exibe atividade de quinase reduzida e potencial clínico / A novel STK3/MST2 splicing variant displays impaired kinase activity and clinical potential

A via Hippo consiste em uma cascata de serina-treonina quinases que desempenha um papel central na transdução de sinais mecânicos. Em mamíferos, o eixo canônico da via consiste na ativação das quinases MST1 e MST2 (codificadas pelos genes STK4 e STK3, respectivamente) e LATS1 e LATS2. A ativação dos dois últimos culmina na fosforilação, retenção citoplasmática e inativação dos coativadores transcricionais YAP e TAZ. A inativação de Hippo resulta na localização nuclear de YAP/TAZ, aumento da proliferação e contribui para a transformação maligna em células epiteliais. No presente trabalho, identificamos que o exon 7, que codifica um segmento do domínio quinase de MST2, estava ausente em células malignas da glândula mamária humana, T4-2, mas não na linhagem não maligna, S1. A exclusão do exon 7 compromete a interação de MST2 com MOB1, um dos principais substratos de MST2. Ao contrário da proteína completa, a superexpressão de MST2 sem o exon 7 não resultou em aumento da morte celular, bem como, não diminuiu a proliferação celular. Esta nova variante de STK3/MST2, a qual denominamos STK3Δ7/MST2Δ7 é produto de um exon skipping e foi encontrada em amostras de tumores de pacientes, mas pouco predominante em amostras de tecidos normais. Além disso, em pacientes com câncer pancreático, a expressão STK3Δ7 resultou em menor sobrevida específica da doença. A retenção do exon 7 foi menor em tumores mais agressivos e com alto grau histológico. Em ensaio 3D, células não malignas com expressão ectópica de MST2Δ7 não respondem aos sinais inibitórios da membrana basal reconstituída e formam estruturas tumor-like. Esta nova variante perde sua atividade quinase e pode perturbar a homeostase tecidual pela incapacidade de ativar morte e inibir a proliferação celular, mesmo em microambientes repressores desses processos em células normais, como na presença membrana basal. Esses achados podem avançar o nosso conhecimento sobre progressão tumoral com possível relevância clínica

The Hippo pathway consists of a cascade of serine-threonine kinases that plays a central role in the transduction of mechanical signals. In mammals, the canonical axis of the pathway consists of the activation of the kinases MST1 and MST2 (encoded by the genes STK4 and STK3, respectively) and LATS1 and LATS2 and their activation culminates in the phosphorylation, cytoplasmic retention and inactivation of the transcriptional coactivators YAP and TAZ. Hippo inactivation results in nuclear localization of YAP/TAZ, increased cell proliferation, and contributes to malignant transformation in epithelial cells. In the present work, we identified that exon 7, which encodes a segment of the kinase domain of MST2, was absent in malignant cells of the human mammary gland, T4-2, but not in the non-malignant S1 cell line. Exclusion of exon 7 compromises the interaction of MST2 with one of its main substrates, MOB1. Unlike the full-length protein, overexpression of MST2 without exon 7 did not result in increased cell death, nor decreased cell proliferation. This new variant of STK3/MST2, which we named STK3Δ7/MST2Δ7, is the product of an exon skipping and was found in tumor samples, but seldomly found in samples of normal tissues. Furthermore, in patients with pancreatic cancer, STK3Δ7 expression resulted in lower disease-specific survival. Exon 7 retention was reduced in aggressive tumors with a high histological grade. In a 3D assay, non-malignant cells with ectopic expression of MST2Δ7, even at low concentrations, do not respond to inhibitory signals from a reconstituted basement membrane and form tumor-like structures. This new variant loses its kinase activity and may disturb the tissue homeostasis due to its inability to activate death and to inhibit cell proliferation, even in microenvironments that repress these processes in normal cells, such as the basement membrane. These findings may advance our knowledge about tumor progression and might be clinically relevant