Therapeutic targeting of FOSL1 and RELA-dependent transcriptional mechanisms to suppress pancreatic cancer metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer often diagnosed at an advanced stage, leading to a poor prognosis. The tumor microenvironment (TME) plays a crucial role in driving metastasis, with inflammatory signaling pathways contributing to tumor progression and therapy resistance. However, the combined effects of inflammatory and oncogenic signaling on the epigenetic regulation of PDAC metastasis are poorly understood.

Molecular KRAS ctDNA Predicts Metastases and Survival in Pancreatic Cancer: A Prospective Cohort Study.

Background: Patients with pancreatic ductal adenocarcinoma (PDAC) commonly have occult metastatic dissemination and current standard staging methods have significant limitations in identifying these patients. A clinically available assay allows for the identification of mutant KRAS (mKRAS) circulating tumor DNA (ctDNA) from patient plasma and peritoneal fluid that may identify these patients and impact treatment decision making. We investigated the patterns of diagnostic and prognostic capabilities of mKRAS ctDNA in patients with localized PDAC.

Aptamer-directed, nanovesicle-mediated targeting of undruggable molecules in preclinical cholangiocarcinoma models.

Background And Aims: Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the biliary epithelium with limited therapeutic options and poor long-term survival rates. To address the limitations of CCA treatment, we investigated cell-targeted nanovesicles as a delivery platform for transcriptome-targeting therapeutics.

Approach And Results: Milk-derived nanovesicles were loaded with short interfering RNAs targeting Yes-associated protein (YAP), the downstream effector of the Hippo pathway; LCK, an upstream regulator of YAP; and tafazzin, a protein critical for the integrity of the inner mitochondrial membrane.

Glucocorticoid receptor suppresses GATA6-mediated RNA polymerase II pause release to modulate classical subtype identity in pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a 5-year survival rate of 12%. It has two major molecular subtypes: classical and basal, regulated by the master transcription factors (MTFs) GATA6 and ΔNp63, respectively.

Objective: This study sought to uncover the transcriptional regulatory mechanisms controlling PDAC subtype identity.

YAP-TEAD inhibition is associated with upregulation of an androgen receptor mediated transcription program providing therapeutic escape.

Cholangiocarcinoma (CCA) is a highly aggressive form of liver cancer and is an increasing cause of cancer-related death worldwide. Despite its increasing incidence globally and alarming mortality, treatment options for CCA have largely remained unchanged, stressing the importance of developing new effective therapies. YAP activation is common in CCA, and its major transcriptional signaling partners are the TEAD proteins.

Metabolome-wide association identifies altered metabolites and metabolic pathways in the serum of patients with cholangiocarcinoma.

Background & Aims: Metabolomic and lipidomic analyses provide an opportunity for novel biological insights. Cholangiocarcinoma (CCA) remains a highly lethal cancer with limited response to systemic, targeted, and immunotherapeutic approaches. Using a global metabolomics and lipidomics platform, this study aimed to discover and characterize metabolomic variations and associated pathway derangements in patients with CCA.

Baseline Characteristics and Use of Pretherapeutic 18 F-Fluorodeoxyglucose-PET for Pancreatic Cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy. Surgical resection is the only curative modality combined with neoadjuvant chemotherapy to improve survival. Given the limitations of traditional responses such as cross-sectional imaging (CT/MRI) or tumor markers, carbohydrate antigen 19-9 (CA19-9), the 2023 National Comprehensive Cancer Network guidelines included 18 F-fluorodeoxyglucose (FDG)-PET as an adjunct to assess response to neoadjuvant chemotherapy.

In vivo label-free optical signatures of chemotherapy response in human pancreatic ductal adenocarcinoma patient-derived xenografts.

Pancreatic cancer is a devastating disease often detected at later stages, necessitating swift and effective chemotherapy treatment. However, chemoresistance is common and its mechanisms are poorly understood. Here, label-free multi-modal nonlinear optical microscopy was applied to study microstructural and functional features of pancreatic tumors in vivo to monitor inter- and intra-tumor heterogeneity and treatment response.

Therapeutic Efficacy of Temsirolimus in a Patient-derived Model of Metastatic Fibrolamellar Hepatocellular Carcinoma.

Background/aim: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare tumor presenting in younger patients without chronic liver disease. Up to 80-100% develop recurrent disease, necessitating additional surgery or systemic treatment. Systemic options and pre-clinical treatment studies are lacking.

Cancer "Avatars": Patient-Derived Xenograft Growth Correlation with Postoperative Recurrence and Survival in Pancreaticobiliary Cancer.

Background: Pancreaticobiliary (PB) cancers are a diverse group of cancers with poor prognoses and high rates of recurrence after resection. Patient-derived xenografts (PDX), created from surgical specimens, provide a reliable preclinical research platform and high-fidelity cancer model from which to study these malignancies with consistent recapitulation of their original patient tumors in vivo. However, the relationship between PDX engraftment success (growth or no growth) and patient oncologic outcomes has not been well studied.

Identification of a ΔNp63-Dependent Basal-Like A Subtype-Specific Transcribed Enhancer Program (B-STEP) in Aggressive Pancreatic Ductal Adenocarcinoma.

Unlabelled: A major hurdle to the application of precision oncology in pancreatic cancer is the lack of molecular stratification approaches and targeted therapy for defined molecular subtypes. In this work, we sought to gain further insight and identify molecular and epigenetic signatures of the Basal-like A pancreatic ductal adenocarcinoma (PDAC) subgroup that can be applied to clinical samples for patient stratification and/or therapy monitoring. We generated and integrated global gene expression and epigenome mapping data from patient-derived xenograft models to identify subtype-specific enhancer regions that were validated in patient-derived samples.

Technical Outcomes of Porto-Mesenteric Venous Reconstruction in Pancreatic Resection Using Autologous Left Renal Vein Graft as Conduit.

Background: Portal or superior mesenteric vein (PV-SMV) resection and reconstruction is sometimes required during pancreatic tumor resection. In patients requiring segmental venous resection with interposition grafting, the left renal vein (LRV) is an accessible autologous solution. However, long-term patency outcomes of the LRV as an interposition conduit in this setting have not been analyzed.

Interactive enhancer hubs (iHUBs) mediate transcriptional reprogramming and adaptive resistance in pancreatic cancer.

Objective: Pancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In this study, we aimed to identify novel mechanistic approaches to overcome or prevent resistance in PDAC.

Mixed Acinar Neuroendocrine Carcinoma of the Pancreas: Comparative Population-Based Epidemiology of a Rare and Fatal Malignancy in The United States.

Mixed acinar neuroendocrine carcinoma of the pancreas (MANEC-P) is an extremely rare malignancy with a poor prognosis. However, epidemiological estimates of MANEC-P remain unknown. This study aimed to estimate and compare the incidence, prevalence, and cancer-specific survival (CSS) of MANEC-P in the United States (US).

FDG-PET Predicts Neoadjuvant Therapy Response and Survival in Borderline Resectable/Locally Advanced Pancreatic Adenocarcinoma.

Background: Neoadjuvant therapy (NAT) is used in borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). Anatomic imaging (CT/MRI) poorly predicts response, and biochemical (CA 19-9) markers are not useful (nonsecretors/nonelevated) in many patients. Pathologic response highly predicts survival post-NAT, but is only known postoperatively.

Patency rates of hepatic arterial resection and revascularization in locally advanced pancreatic cancer.

Background: Arterial resection (AR) for pancreatic adenocarcinoma is increasingly considered at specialized centers. We aimed to examine the incidence, risk factors, and outcomes of hepatic artery (HA) occlusion after revascularization.

Methods: We included patients undergoing HA resection with interposition graft (IG) or primary end-to-end anastomoses (EE).

Microsurgical skills training course and impact on trainee confidence and workload.

Introduction: Our objective was to measure the impact of a basic microsurgery training course on trainees' confidence and workload in performing microsurgery.

Methods: A prospective study of participants in an accredited 5-day microsurgery course over a 3-month period. The confidence and workload of the participants were assessed after the first and final day.

"Answers in hours": A prospective clinical study using nanopore sequencing for bile duct cultures.

Background: Surgical site infection is a major source of morbidity in patients undergoing pancreatic head resection and is often from organisms in intraoperative bile duct cultures. As such, many institutions use prolonged prophylactic antibiotics and tailor based on bile duct cultures. However, standard cultures take days, leaving many patients unnecessarily on prolonged antibiotics.

Neoadjuvant Chemotherapy Switch in Borderline Resectable/Locally Advanced Pancreatic Cancer.

Background: Neoadjuvant chemotherapy (NAC) is an integral part of preoperative treatment for patients with borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). The identification of a chemotherapeutic regimen that is both effective and tolerable is critical for NAC to be of oncologic benefit. After initial first-line (FL) NAC, some patients have lack of response or therapeutic toxicities precluding further treatment with the same regimen; optimal decision making regarding this patient population is unclear.

Synergistic combination of cytotoxic chemotherapy and cyclin-dependent kinase 4/6 inhibitors in biliary tract cancers.

Background And Aims: Biliary tract cancers (BTCs) are uncommon, but highly lethal, gastrointestinal malignancies. Gemcitabine/cisplatin is a standard-of-care systemic therapy, but has a modest impact on survival and harbors toxicities, including myelosuppression, nephropathy, neuropathy, and ototoxicity. Whereas BTCs are characterized by aberrations activating the cyclinD1/cyclin-dependent kinase (CDK)4/6/CDK inhibitor 2a/retinoblastoma pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident preclinical efficacy, and development of acquired drug resistance.

Intraoperative bile duct cultures in patients undergoing pancreatic head resection: Prospective comparison of bile duct swab versus bile duct aspiration.

Background: Postoperative surgical site infection is a major source of morbidity after pancreatic head resections, and data suggest bacterobilia as a leading cause. Some centers use intraoperative bile duct cultures to guide postoperative antimicrobial prophylaxis. This prospective study evaluates culture differences between traditional bile duct swab versus bile duct aspiration intraoperative samples.

Molecular Peritoneal Staging for Pancreatic Ductal Adenocarcinoma Using Mutant KRAS Droplet-Digital Polymerase Chain Reaction: Results of a Prospective Clinical Trial.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with predilection for peritoneal dissemination. Accurate peritoneal staging is imperative for treatment recommendations, as one-third of patients develop peritoneal recurrence after resection. Because >90% of PDAC tumors harbor mutant KRAS (mKRAS), we sought to determine feasibility of mKRAS DNA detection in peritoneal lavage (PL) fluid using droplet-digital polymerase chain reaction (ddPCR) via a prospective trial.

Biliary tract cancer patient-derived xenografts: Surgeon impact on individualized medicine.

Background & Aims: Biliary tract tumors are uncommon but highly aggressive malignancies with poor survival outcomes. Due to their low incidence, research into effective therapeutics has been limited. Novel research platforms for pre-clinical studies are desperately needed.

Surgical team workload comparison for 4-port and single-port laparoscopic cholecystectomy procedures.

Advanced minimally invasive procedures may cause postural constraints and increased workload and stress for providers. This study compared workload and stress across surgical team roles for 48 laparoscopic cholecystectomies (4-port vs single-port) using a task load index (NASA-TLX), a procedural difficulty question, and salivary stress hormones. Statistical analyses were performed based on the presence intra-cluster correlation within team roles, at α=0.