Only 15% to 20% of patients with pancreatic ductal adenocarcinoma (PDAC) have access to surgical resection, which represents the only chance of curative treatment. Current resection classifications are almost exclusively anatomic and do not correlate sufficiently with patient survival. It is essential to develop preoperative prognostic factors to distinguish patients at high risk of early postoperative recurrence from those who will have prolonged survival after surgery. In some cases, PDACs may present biomolecular differences reflecting their aggressiveness that are not yet assessable by the current clinical-biologic assessment. This study aimed to assess the preoperative prognostic factors that are already available and the future perspectives being developed.

This study reviewed the literature using the PubMed public database for preoperative prognostic factors for resectable PDAC.

Validated preoperative prognostic factors, whether clinical, biologic, radiologic, or histologic, are very important in anticipating the course of each patient's disease. The identification of potential new prognostic biomarkers such as genomic, transcriptomic, and proteomic analyses and the dosage of circulating tumor DNA are very serious avenues to be developed, but the extraction and analysis techniques as well as the interpretation of their results need to be standardized in prospective studies.

Pancreatic ductal adenocarcinoma (PDAC) contains an extensive stroma that modulates response to therapy, contributing to the dismal prognosis associated with this cancer. Evidence suggests that PDAC stromal composition is shaped by mutations within malignant cells, but most previous work has focused on preclinical models driven by KrasG12D and mutant Trp53. Elucidation of the contribution of additional known oncogenic drivers, including KrasG12V mutation and Smad4 loss, is needed to increase the understanding of malignant cell-stromal cell cross-talk in PDAC. In this study, we used single-cell RNA sequencing to analyze the cellular landscape of Trp53-mutant mouse models driven by KrasG12D or KrasG12V, in which Smad4 was wild type or deleted. KrasG12DSmad4-deleted PDAC developed a fibro-inflammatory rich stroma with increased malignant JAK/STAT cell signaling and enhanced therapeutic response to JAK/STAT inhibition. SMAD4 loss in KrasG12V PDAC differently altered the tumor microenvironment compared with KrasG12D PDAC, and the malignant compartment lacked JAK/STAT signaling dependency. Thus, malignant cell genotype affects cancer cell and stromal cell phenotypes in PDAC, directly affecting therapeutic efficacy. Significance: SMAD4 loss differentially impacts malignant cell-stromal cell signaling and treatment sensitivity of pancreatic tumors driven by KRASG12D or KRASG12V, highlighting the importance of understanding genotype-phenotype relationships for precision therapy.

Surgical resection of pancreatic ductal adenocarcinoma (PDAC) modestly improves long-term survival due to the competing risk of metastatic disease. However, postoperative morbidity often interferes with administration of systemic therapy and may be unacceptable to some patients. Ablative radiation therapy (A-RT) has emerged as an effective noninvasive local treatment in many tumor types and may provide an alternative to surgery in select patients with resectable PDAC.

To estimate the efficacy of A-RT in technically resectable PDAC.

This cohort study of consecutive patients with histologically confirmed, radiographically resectable T1-2N0-1M0 PDAC treated with A-RT at Memorial Sloan Kettering Cancer Center between June 2016 and December 2022 were included from a prospectively maintained database. Patients were not eligible for surgery because of noncancer-related comorbidities. Data were frozen for analysis in December 2023, which took place between March and November 2024.

All patients received A-RT exceeding 97.5-Gy biologically effective dose with daily computed tomography or magnetic resonance imaging guidance, motion management, and daily or selective adaptation of the dose distribution.

The primary outcome was overall survival (OS). Secondary outcomes included biochemical and radiographic objective response rate, cumulative incidence of local progression, progression-free survival, and distant metastasis-free survival.

Of 25 patients with radiographically resectable PDAC who received A-RT, 13 (52%) were male, and the median (IQR) age at time of A-RT was 80 (74-87) years. A total of 20 patients (80%) had a Karnofsky Performance Status score of 80 or lower. A total of 15 tumors (60%) were T2, and 4 (16%) were node positive. A total of 17 patients (68%) received induction chemotherapy for a median (range) of 2.9 (1.0-6.1) months. Radiation therapy regimens delivered with conventional linear accelerators included 75 Gy in 25 fractions among 13 patients, 67.5 Gy in 15 fractions among 9 patients, 50 Gy in 5 fractions among 2 patients (magnetic resonance imaging-guided linear accelerator), and 60 Gy in 10 for 1 patient. OS, local progression, and distant metastasis-free survival at 2 years were 43.7% (95% CI, 27.4%-69.5%), 20.8% (95% CI, 7.3%-39.0%), and 20.0% (95% CI, 9.1%-43.8%), respectively. Grade 3 acute and late gastrointestinal tract toxic effects were noted in 3 and 1 patients, respectively, with no grade 4 or higher events.

In this cohort study, A-RT in patients with technically resectable PDAC led to effective local tumor control and favorable OS despite advanced age, poor Karnofsky Performance Status score, and conservative use of chemotherapy in the cohort studied. These data support a prospective study of A-RT for the management of resectable PDAC.

Dose-escalated radiation therapy is increasingly used in the treatment of pancreatic cancer; however, approaches to target delineation vary widely. We present the first North American cooperative group consensus contouring atlas for dose-escalated pancreatic cancer radiation therapy.

An expert international panel comprising 15 radiation oncologists, 2 surgeons, and 1 radiologist was recruited. Participants used MimCloud software to contour high- and low-risk clinical target volumes (CTVs) on 3 pancreatic cancer cases: a borderline resectable head tumor, a locally advanced head tumor, and a medically inoperable tail tumor. Simultaneous Truth and Performance Level Estimation volumes were created, and contours were analyzed using Dice similarity coefficients.

The contoured gross tumor volume for the borderline head, locally advanced head, and unresectable tail tumor cases were 156.7, 58.2, and 9.0 cc, respectively, and the Dice similarity coefficients (SD) for the high- and low-risk CTV ranged from 0.45 to 0.82. Consensus volumes were agreed upon by authors. High-risk CTVs comprised the tumor plus abutting vessels. Low-risk CTVs started superiorly at (tail and distal body tumors) or 1 cm above (head, neck and proximal body tumors) the celiac takeoff and extended inferiorly to the superior mesenteric artery at the level of the first jejunal takeoff. For head, neck, and proximal body tumors, the lateral volume encompassed the entire pancreas head and 5 to 10 mm around the celiac, superior mesenteric artery, superior mesenteric vein, including the common hepatic artery and medial portal vein, consistent with a "Triangle" volume-based approach. For distal body and tail tumors, the entire tail was included, along with the splenic vessels and the takeoffs of celiac artery.

Through multidisciplinary collaboration, we created consensus contouring guidelines for dose-escalated pancreatic cancer radiation therapy. These volumes include not only gross disease, but also routine elective coverage, and can be used to standardize practice for future trials seeking to define the role of dose-escalated radiation therapy in pancreatic cancer.

Local and distant progression remains common following resection of resectable pancreatic ductal adenocarcinoma (PDAC) despite adjuvant multiagent chemotherapy. We report a prospective institutional phase 1 trial incorporating adjuvant GVAX vaccine, low-dose cyclophosphamide (Cy), and stereotactic body radiation therapy (SBRT) followed by FOLFIRINOX (FFX) among patients who underwent resection of high-risk PDAC.

The study design was a modified 3+3. Cohort 1 received 5-fraction SBRT to 33 Gy to the tumor bed and 25 Gy to elective nodes followed by 6 cycles of full-dose FFX. After toxicity review, cohort 2 had SBRT and was switched to modified FFX (mFFX). Cohort 3 had 1 cycle of Cy/GVAX followed by SBRT, mFFX, and 4 cycles of maintenance Cy/GVAX with 6-month Cy/GVAX boosts until progression.

Nineteen patients were enrolled with a median follow-up of 36.2 months. To be eligible, patients were required to have close/positive margins (within ≤1 mm) (71%) and/or lymph node metastasis (79%). Overall, 63% of patients had both. In cohort 1, 67% of patients received 6 cycles of FFX; in cohort 2, 75% received 6 cycles of modified FFX. In cohort 3, 12 patients received the first dose of Cy/GVAX and SBRT with 10 individuals (83%) receiving 6 cycles of mFFX. Cohort 3 had acceptable levels of grade ≥3 thrombocytopenia, neutropenia, and diarrhea after 2 cycles of mFFX. Median overall survival (OS)/disease-free survival (DFS) for the overall cohort and cohort 3 was 36.2/18.2 months and 61.3/24.1 months, respectively. One- and 2-year OS for cohort 3 was 83%/75%, respectively. At the last follow-up (median = x), 5 patients were alive (42%) in cohort 3.

This is the first prospective trial to evaluate adjuvant GVAX, Cy, SBRT, and mFFX in resected PDAC patients with high-risk features. This combination regimen was well tolerated with limited toxicity and promising survival outcomes, warranting future studies to validate this regimen in the adjuvant setting.

Surgery combined with chemotherapy provides the best chance of survival in pancreatic cancer. This study investigated whether increasing the resection rate at a population level improves overall survival and modelled the interaction between resection rate, perioperative mortality rate, and population survival.

A systematic review was conducted on studies reporting resection rate and survival outcomes in patients with pancreatic cancer at a population level. MEDLINE, Embase and Evidence-Based Medicine Reviews were searched up to February 2024. The primary outcome was overall population-level survival. A model for 1-year survival incorporating varying resection and perioperative mortality rates was developed.

The search identified 3967 studies; 19 were eligible (516 789 patients). A significant association was observed between resection rate and pancreatic cancer population survival at 1 year (r2 = 0.46, P = 0.001). A weak but significant association was noted between resection rate and (neo)adjuvant chemotherapy (r2 = 0.26, P = 0.03). One-year pancreatic cancer population survival was significantly associated with chemotherapy (r2 = 0.63; P = 0.004), but the effect was weaker than for resection rate (regression slope 0.26 versus 0.94 respectively). According to the developed model, for example, increasing the resection rate from 10 to 15% and perioperative mortality rate from 2 to 3% would lead to a 1-year survival increase from 17.6% to 22.1%.

A higher resection rate at a population level was associated with improved survival of the pancreatic cancer population. While some of this benefit was linked to increasing (neo)adjuvant chemotherapy use, the effect of resection rate was stronger. Strategies to enhance the resection rate at national and regional levels should be explored. Establishing a benchmark for resection rate could support patient-centred healthcare and promote equitable access to high-quality pancreatic cancer care.

Unusual symptoms, rapid progression, lack of reliable early diagnostic biomarkers, and lack of efficient treatment choices are the ongoing challenges of pancreatic cancer. Numerous research studies have demonstrated the correlation between exosomes and various aspects of pancreatic cancer. In light of these facts, exosomes possess the potential to play functional roles in the treatment, prognosis, and diagnosis of the pancreatic cancer. In the present study, we reviewed the most recent developments in approaches for exosome separation, modification, monitoring, and communication. Moreover, we discussed the clinical uses of exosomes as less invasive liquid biopsies and drug carriers and their contribution to the control of angiogenic activity of pancreatic cancer. Better investigation of exosome biology would help to effectively engineer therapeutic exosomes with certain nucleic acids, proteins, and even exogenous drugs as their cargo. Circulating exosomes have shown promise as reliable candidates for pancreatic cancer early diagnosis and monitoring in high-risk people without clinical cancer manifestation. Although we have tried to reflect the status of exosome applications in the treatment and detection of pancreatic cancer, it is evident that further studies and clinical trials are required before exosomes may be employed as a routine therapeutic and diagnostic tools for pancreatic cancer.

The examination of small pancreatic biopsies is a difficult task for pathologists. This is due to the scant and fragmented material often obtained from diagnostic procedures as well as the significant overlap between different neoplastic and nonneoplastic entities. In the upcoming neoadjuvant era, biopsies could become even more important, representing the only possibility to look at the real histomorphology of tumors before chemotherapy-induced modifications.

To summarize and discuss the state-of-the-art diagnostic workflow for small pancreatic biopsies, including the most important morphologic and immunohistochemical features and molecular alterations. The main diagnostic pearls and pitfalls of this challenging scenario are also discussed. The most important topics of this review are represented by: (1) pancreatic ductal adenocarcinoma, along with its main differential diagnoses, including autoimmune pancreatitis; (2) solid hypercellular neoplasms, including neuroendocrine neoplasms, acinar cell carcinoma, pancreatoblastoma, and solid pseudopapillary neoplasms; and (3) cystic lesions. Real-world considerations will also be presented and discussed.

Sources included a literature review of published studies and the author's own work.

The correct diagnosis of pancreatic lesions is a crucial step in the therapeutic journey of patients. It should be based on robust, standardized, and reliable hallmarks. As presented and discussed here, the integration of morphology with immunohistochemistry, and, in selected cases, with molecular analysis, represents a decisive step in this complex scenario.

Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic malignancy, has a dismal 5-year survival rate, making palliative chemotherapy the only treatment option. Targeted therapy has limited efficacy in PDAC, underscoring the need for novel therapeutic approaches. The inducible stress-response protein, haem oxygenase-1 (HMOX1), has been implicated in treatment failure in PDAC. Copper coordination complexes have shown promise as anticancer agents against various cancers, and are associated with apoptotic cell death. The different ligands to which copper is complexed, determine the specificity and efficacy of each complex. Three different classes of copper complexes were evaluated for anti-cancer activity against AsPC-1 and MIA PaCa-2 pancreatic cancer cell lines. A copper-phenanthroline-theophylline complex (CuPhTh2), a copper-8-aminoquinoline-naphthyl complex (Cu8AqN), and two copper-aromatic-isoindoline complexes (CuAIsI) were effective inhibitors of cell proliferation with clinically relevant IC50 values below 5 μM. The copper complexes caused reactive oxygen species (ROS) formation, promoted annexin-V binding, disrupted the mitochondrial membrane potential (MMP) and activated caspase-9 and caspase-3/7, confirming apoptotic cell death. Expression of nuclear HMOX1 was increased in both cell lines, with the CuPhTh2 complex being the most active. Inhibition of HMOX1 activity significantly decreased the IC50 values of these copper complexes suggesting that HMOX1 inhibition may alter treatment outcomes in PDAC.

Multiple randomized trials have suggested that the addition of comprehensive metastasis-directed therapy to best systemic therapy improves disease control and survival among patients with oligometastatic disease, even for histologies with a high propensity for rapid spread. Here, we review the growing literature supporting the oligometastatic paradigm in pancreatic ductal adenocarcinoma. We summarize key details from nascent institutional series and reflect on the recently reported phase II randomized EXTEND trial. We discuss various strategies for enhancing the clinical and technical implementation of metastasis-directed therapy in this patient population. Lastly, we highlight multiple ongoing landmark trials seeking to optimize and validate the role of metastasis-directed therapy in oligometastatic pancreatic cancer. Ultimately, these and other continued clinical and translational research efforts will be critical to improve care and outcomes for patients with oligometastatic pancreatic ductal adenocarcinoma.

The role of intraoperative radiation therapy (IORT) in the management of resectable pancreatic cancer (RPC) remains unclear. To date, the application of IORT using a low-energy X-ray source has not been extensively investigated. Therefore, this study was conducted to evaluate the safety and efficacy of IORT using a 50 kV X-ray source in treating RPC.

Patients with RPC who underwent radical pancreatectomy and IORT were enrolled. The primary endpoint was time to treatment failure (TTF) survival, whereas the secondary endpoints were safety and overall survival (OS).

By November 2023, 35 patients with RPC were treated according to the study protocol. The median TTF was 11.67 months, whereas the median OS for the cohort was 22.2 months. The local recurrence rate was 20%. The most common postoperative complication was pancreatic fistula. The incidence of delayed gastric emptying was 20%. Within 30 days after surgery, one patient experienced abdominal pain, another experienced vomiting, and one died because of abdominal infection and a grade C pancreatic fistula. Carcinoembryonic antigen (CEA) and D-dimer levels significantly correlated with TTF and OS in multivariate analyses. The carbohydrate antigen 19-9 (CA19-9) level was another prognostic factor significantly associated with OS. Patients with low D-dimer and normal CA19-9 levels showed prolonged OS with an IORT dose ≤ 15 Gy.

This study supports use of IORT with a 50 kV X-ray source in treating RPC. IORT using a low-energy X-ray source was well-tolerated and feasible. Additionally, D-dimer, CEA, and CA19-9 levels may help identify patient profiles potentially benefitting from IORT.

Pancreatic cancer and prediabetes pose significant public health challenges. Given the lack of strong evidence we performed a meta-analysis to assess the risk of pancreatic cancer in prediabetes.

We performed a thorough search of the major databases over the last 10 years to identify relevant articles. The pooled odds ratio (OR) and hazard ratio (HR) were combined to calculate the effect size (ES).

We analyzed 5 studies including 5,425,111 prediabetic individuals and 16,096,467 normoglycemic population across 5 countries with a median follow-up of 8.5 years. We identified a noteworthy association between prediabetes and pancreatic cancer, reporting an unadjusted ES of 1.36 (95% confidence interval [CI] 1.05-1.77, P = 0.02) and an adjusted ES of 1.40 (1.23-1.59, P < 0.01). Subgroup analyses by age revealed variations in risk, with studies involving participants aged 60 and above exhibiting a higher ES (ES 1.83, 95% CI 1.28-2.62, P < 0.01). Geographical differences were also observed, with Japanese studies reporting a higher risk (ES 1.89, 95% CI 1.15-3.10, P < 0.01) compared with those from the United States (ES 1.32, 95% CI 1.13-1.53, P < 0.01).

We identified 40% higher risk of pancreatic cancer in patients with prediabetes than those with normal blood glucose necessitating urgent attention for further research and policy change.

Metastatic cancer affects millions of people worldwide annually and is the leading cause of cancer-related deaths. Most patients with metastatic disease are not eligible for surgical resection, and current therapeutic regimens have varying success rates, some with 5-year survival rates below 5%. Here, we test the hypothesis that metastatic cancer can be genetically targeted by exploiting single base substitution mutations unique to individual cells that occur as part of normal aging prior to transformation. These mutations are targetable because ~10% of them form novel tumor-specific "NGG" protospacer adjacent motif (PAM) sites targetable by CRISPR-Cas9.

Whole genome sequencing was performed on five rapid autopsy cases of patient-matched primary tumor, normal and metastatic tissue from pancreatic ductal adenocarcinoma decedents. CRISPR-Cas9 PAM targets were determined by bioinformatic tumor-normal subtraction for each patient and verified in metastatic samples by high-depth capture-based sequencing.

We found that 90% of PAM targets were maintained between primary carcinomas and metastases overall. We identified rules that predict PAM loss or retention, where PAMs located in heterozygous regions in the primary tumor can be lost in metastases (private LOH), but PAMs occurring in regions of loss of heterozygosity (LOH) in the primary tumor were universally conserved in metastases.

Regions of truncal LOH are strongly retained in the presence of genetic instability and, therefore, represent genetic vulnerabilities in pancreatic adenocarcinomas. A CRISPR-based gene therapy approach targeting these regions may be a novel way to genetically target metastatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an increasingly diagnosed cancer that kills 90% of afflicted patients, with most patients receiving palliative chemotherapy. We identified neuronal pentraxin 1 (NPTX1) as a cancer-secreted protein that becomes overexpressed in human and murine PDAC cells during metastatic progression and identified adhesion molecule with Ig-like domain 2 (AMIGO2) as its receptor. Molecular, genetic, biochemical, and pharmacologic experiments revealed that secreted NPTX1 acts cell-autonomously on the AMIGO2 receptor to drive PDAC metastatic colonization of the liver-the primary site of PDAC metastasis. NPTX1-AMIGO2 signaling enhanced hypoxic growth and was critically required for hypoxia-inducible factor-1α (HIF1α) nuclear retention and function. NPTX1 is overexpressed in human PDAC tumors and upregulated in liver metastases. Therapeutic targeting of NPTX1 with a high-affinity monoclonal antibody substantially reduced PDAC liver metastatic colonization. We thus identify NPTX1-AMIGO2 as druggable critical upstream regulators of the HIF1α hypoxic response in PDAC. Significance: We identified the NPTX1-AMIGO2 axis as a regulatory mechanism upstream of HIF1α-driven hypoxia response that promotes PDAC liver metastasis. Therapeutic NPTX1 targeting outperformed a common chemotherapy regimen in inhibiting liver metastasis and suppressed primary tumor growth in preclinical models, revealing a novel therapeutic strategy targeting hypoxic response in PDAC.

The use of radiation therapy (RT) for pancreatic cancer continues to be controversial, despite recent technical advances. Improvements in systemic control have created an evolving role for RT and the need for improved local tumor control, but currently, no standardized approach exists. Advances in stereotactic body RT, motion management, real-time image guidance, and adaptive therapy have renewed hopes of improved outcomes in this devastating disease with one of the lowest survival rates. This case-based guide provides a practical framework for delivering stereotactic body RT for locally advanced pancreatic cancer. In conjunction with multidisciplinary care, an intradisciplinary approach should guide treatment of the high-risk cases outlined within these guidelines for prospective peer review and treatment safety discussions.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy due to the difficulty in diagnosis and poor prognosis because of the high recurrence rate, necessitating reliable biomarkers to improve the diagnosis and prognosis. However, the existing markers have limitations. We previously identified extracellular vesicles (EVs) recognized by O-glycan-binding lectins (Amaranthus caudatus agglutinin [ACA]) as a novel diagnostic biomarker for PDAC using an EV-counting system (ExoCounter). This retrospective study analyzed changes in ACA-positive EVs in perioperative PDAC serum and its association with prognosis using ExoCounter. Absolute EV levels in the pre- and postoperative sera of 44 patients who underwent curative pancreatectomy for PDAC were quantified using ExoCounter. The carbohydrate antigen 19-9 levels declined in most samples postoperatively, and presented no correlation with poor prognosis. In contrast, ACA-positive EVs increased in serum at 7 days postoperatively in 27 of 44 patients (61.4%). We therefore divided participants with ACA-positive EVs before and after surgery into elevation and decline groups. The overall survival (OS) and recurrence-free survival (RFS) of patients with higher ACA-positive EVs were significantly shorter than those with lower ACA-positive EVs (26.1 months vs. not reached, P = 0.018; 11.9 vs. 38.6 months, P = 0.013). Multivariable analysis revealed that ACA-positive EV elevation in postoperative serum was an independent prognostic factor for poor OS (hazard ratio [HR] = 3.891, P = 0.023) and RFS (HR = 2.650, P = 0.024). The detection of ACA-positive EVs in perioperative serum may be used to predict the prognosis of PDAC in the early postoperative period.

This study aimed to examine postoperative recurrence after curative pancreatic resection following neoadjuvant chemoradiotherapy (NACRT) in patients with resectable (R-) and borderline resectable (BR-) pancreatic ductal adenocarcinoma (PDAC), focusing on its relationship with the standardized uptake value (SUV) on 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET).

The postoperative initial recurrence patterns were examined in patients with R- and BR-PDAC who underwent NACRT followed by curative pancreatic resection. Data collected from three prospective clinical trials were retrospectively analysed.

After a median follow-up of 29 months, 91 (60 %) of 151 patients experienced postoperative recurrence. The median recurrence-free survival (RFS) for all patients was 18 months. The sites of first recurrence were lung-only in 24 (26 %) patients, liver-only in 23 (25 %), local-only in 11 (12 %), peritoneum-only in 10 (11 %), other single site in 5 (5 %), and multiple sites in 19 (21 %) patients. Multivariate analysis identified the maximum standardized uptake value (SUVmax) on FDG-PET at diagnoses ≥5.40 (hazard ratio [HR], 1.62; 95 % confidence interval [CI], 1.01-2.61; p = 0.045) and node-positive pathology (HR, 2.01; 95 % CI, 1.32-3.08; p = 0.001) as significant predictors of RFS. Furthermore, the SUVmax at initial diagnosis and after NACRT correlated with liver metastasis.

R- and BR-PDACs with high SUV on FDG-PET at diagnosis are risk factors for postoperative recurrence. Among patients who undergo surgery after NACRT, those with a high SUVmax at diagnosis or post-NACRT require careful attention for postoperative liver recurrence.

Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite the improvement of multi-modality treatment strategies, the prognosis of pancreatic cancer was not improved dramatically. For resectable or borderline resectable patients, the surgical strategy centered on improving R0 resection rate is consensus; however, the role of neoadjuvant therapy in resectable patients and the optimal neoadjuvant therapy of chemotherapy with or without radiotherapy in borderline resectable patients were debated. Postoperative adjuvant chemotherapy of gemcitabine/capecitabine or mFOLFIRINOX is recommended regardless of the margin status. Chemotherapy as the first-line treatment strategy for advanced or metastatic patients included FOLFIRINOX, gemcitabine/nab-paclitaxel, or NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan was the only standard of care second-line therapy. Immunotherapy is an innovative therapy although anti-PD-1 antibody is currently the only agent approved by for MSI-H, dMMR, or TMB-high solid tumors, which represent a very small subset of pancreatic cancers. Combination strategies to increase the immunogenicity and to overcome the immunosuppressive tumor microenvironment may sensitize pancreatic cancer to immunotherapy. Targeted therapies represented by PARP and KRAS inhibitors are also under investigation, showing benefits in improving progression-free survival and objective response rate. This review discusses the current treatment modalities and highlights innovative therapies for pancreatic cancer.

More than half of pancreatic ductal adenocarcinomas (PDACs) recur within 12 months after curative-intent resection. This systematic review and meta-analysis was conducted to identify all reported prognostic factors for early recurrence in resected PDACs.

After a systematic literature search, a meta-analysis was conducted using a random effects model. Separate analyses were performed for adjusted vs unadjusted effect estimates as well as reported odds ratios (ORs) and hazard ratios (HRs). Risk of bias was assessed using the Quality in Prognostic Studies tool, and evidence was rated according to Grading of Recommendations Assessment, Development and Evaluation recommendations.

After 2903 abstracts were screened, 65 studies were included. Of these, 28 studies (43.1%) defined early recurrence as evidence of recurrence within 6 months, whereas 34 (52.3%) defined it as evidence of recurrence within 12 months after surgery. Other definitions were uncommon. Analysis of unadjusted ORs and HRs revealed 41 and 5 prognostic factors for early recurrence within 6 months, respectively. When exclusively considering adjusted data, we identified 25 and 10 prognostic factors based on OR and HR, respectively. Using a 12-month definition, we identified 38 (OR) and 15 (HR) prognostic factors from unadjusted data and 38 (OR) and 30 (HR) prognostic factors from adjusted data, respectively. On the basis of frequency counts of adjusted data, preoperative carbohydrate antigen 19-9, N status, nondelivery of adjuvant therapy, grading, and tumor size based on imaging were identified as key prognostic factors for early recurrence.

Reported prognostic factors of early recurrence vary considerably. Identified key prognostic factors could aid in the development of a risk stratification framework for early recurrence. However, prospective validation is necessary.

RNAi therapeutics possess the potential to cure many uncurable human diseases. For instance, RNAi therapeutics using liposomes showed remarkable survival benefits in patients with liver diseases. However, the extension of liposomes to deliver RNA to cure other ailments has largely been unsuccessful. Therefore, researchers are focusing on designing and testing different combinations of materials for versatile RNA delivery applications. Yet, an efficient and safe RNA delivery platform has not been identified. In this work, we have developed a new class of RNA-delivery vehicle called "Gelasomes," using an incongruous combination of gelatin and lipidoid to exploit each material's unique properties while overcoming their inherent limitations. The low in vivo toxicity of Gelasomes is attributed to the exterior gelatin layers that shield the exposure of cationic lipidoid-siRNA clusters and yet present a biocompatible surface. Indeed, toxicity studies in mice indicate that repeated administration of Gelasomes (up to 48 mg/kg BW) is well-tolerated with no notable changes in body weight, hematology, or serum chemistry. Interestingly, the gelatin outer layer efficiently protects siRNA from serum degradation (48 h), preserving its functionality beyond two months of storage. Notably, Gelasomes possess dual siRNA conjugation modes, i.e., electrostatic binding with lipidoid core and covalent attachment to gelatin surface. The bivalency coupled with lipidoids' high transfection efficiency rendered Gelasomes with remarkably high gene silencing efficiency (>90 %) at very low treatment doses in vitro (40 μg/mL). In vivo studies further confirmed the high gene silencing ability of Gelasomes in non-small cell lung tumor mouse models. This new platform is tunable on all fronts: size, degree of surface coating, and biomolecule functionalization. Truncating the lipidoid C14-tail to a C8-tail yielded Gelasomes of reduced size. As lipidoids with different carbon lengths are synthesizable, we can develop a library of Gelasomes with different sizes. The surface coating with less gelatin resulted in high transfection efficiency at low doses of Gelasomes. The structure of Gelasomes offers chemical handles to couple target-specific molecules like antibodies to tune their properties for efficient biological application.

Sarcomatoid carcinoma of the pancreas (SCP) is a rare and aggressive subtype of undifferentiated pancreatic ductal adenocarcinoma, with a generally poor prognosis and only sporadic cases reported worldwide. Histologically, the most notable feature of SCP is the presence of abundant of mesenchymatoid spindle tumor cells in the tumor, which lack glandular differentiation. Immunohistochemically, SCP is characterized by the expression of both mesenchymal and epithelial markers. With only a few reported cases, there is limited knowledge about its molecular and clinicopathological characteristics. Therefore, the present study performed a literature search to identify all relevant published studies. The present review provides an overview of the histogenesis, diagnosis, genetic features, prognosis and treatment of SCP, specifically focusing on the molecular alterations. Furthermore, a single-center experience is reported, which adds to the limited evidence available in the literature.

The multi-centre two-stage SCALOP-2 trial (ISRCTN50083238) assessed whether dose escalation of consolidative chemoradiotherapy (CRT) or concurrent sensitization using the protease inhibitor nelfinavir improve outcomes in locally advanced pancreatic cancer (LAPC) following four cycles of gemcitabine/nab-paclitaxel.

In stage 1, the maximum tolerated dose (MTD) of nelfinavir concurrent with standard-dose CRT (50.4 Gy in 28 fractions) was identified from a cohort of 27 patients. In stage 2, 159 patients were enrolled in an open-label randomized controlled comparison of standard versus high dose (60 Gy in 30 fractions) CRT, with or without nelfinavir at MTD. Primary outcomes following dose escalation and nelfinavir use were respectively overall survival (OS) and progression free survival (PFS). Secondary endpoints included health-related quality of life (HRQoL).

High dose CRT did not improve OS (16.9 (60 % confidence interval, CI 16.2-17.7) vs. 15.6 (60 %CI 14.3-18.2) months; adjusted hazard ratio, HR 1.13 (60 %CI 0.91-1.40; p = 0.68)). Similarly, median PFS was not improved by nelfinavir (10.0 (60 %CI 9.9-10.2) vs. 11.1 (60 %CI 10.3-12.8) months; adjusted HR 1.71 (60 %CI 1.38-2.12; p = 0.98)). Local progression at 12 months was numerically lower with high-dose CRT than with standard dose CRT (n = 11/46 (23.9 %) vs. n = 15/45 (33.3 %)). Neither nelfinavir nor radiotherapy dose escalation impacted on treatment compliance or grade 3/4 adverse event rate. There were no sustained differences in HRQoL scores between treatment groups over 28 weeks post-treatment.

Dose-escalated CRT may improve local tumour control and is well tolerated when used as consolidative treatment in LAPC but does not impact OS. Nelfinavir use does not improve PFS.

For patients with locally advanced pancreatic cancer (LAPC), who are candidates for radiation therapy, dose-escalated radiation therapy (RT) offers unique benefits over traditional radiation techniques. In this review, we present a historical perspective of dose-escalated RT for LAPC. We also outline advances in SBRT delivery, one form of dose escalation and a framework for selecting patients for treatment with SBRT.

Techniques for delivering SBRT to patients with LAPC have evolved considerably, now allowing for dose-escalation and superior respiratory motion management. At the same time, advancements in systemic therapy, particularly the use of induction multiagent chemotherapy, have called into question which patients would benefit most from radiation therapy. Multidisciplinary assessment of patients with LAPC is critical to guide management and select patients for local therapy. Results from ongoing trials will establish if there is a role of dose-escalated SBRT after induction chemotherapy for carefully selected patients.

Patients with LAPC have more therapeutic options than ever before. Careful selection for SBRT may enhance patient outcomes, pending the maturation of pivotal clinical trials.

The administration of dose-escalated radiation for pancreatic adenocarcinoma remains challenging because of the proximity of dose-limiting stomach and bowel, particularly the duodenum for pancreatic head tumors. We explore whether endoscopic injection of a temporary, absorbable hydrogel into the pancreatico-duodenal (PD) groove is safe and feasible for the purpose of increasing spatial separation between pancreatic head tumors and the duodenum.

Six patients with localized pancreatic adenocarcinoma underwent endoscopic injection of hydrogel into the PD groove. Safety was assessed based on the incidence of procedure-related adverse events resulting in a delay of radiation therapy initiation. Feasibility was defined as the ability to create spatial separation between the pancreas and duodenum, as assessed on simulation CT.

All 6 patients were able to undergo endoscopic injection of hydrogel into the PD groove. No device-related events were experienced at any point in follow-up. Presence of hydrogel in the PD groove was apparent on simulation CT in all 6 patients. Mean space created by the hydrogel was 7.7 mm +/- 2.4 mm. In 3 patients who underwent Whipple resection, presence of hydrogel in the PD groove was pathologically confirmed with no evidence of damage to the duodenum.

Endoscopic injection of hydrogel into the PD groove is safe and feasible. Characterization of the dosimetric benefit that this technique may offer in the setting of dose-escalated radiation should also be pursued, as should the ability of such dosimetric benefit to translate into clinically improved tumor control.

While there is a great clinical need to understand the biology of metastatic cancer in order to treat it more effectively, research is hampered by limited sample availability. Research autopsy programmes can crucially advance the field through synchronous, extensive, and high-volume sample collection. However, it remains an underused strategy in translational research. Via an extensive questionnaire, we collected information on the study design, enrolment strategy, study conduct, sample and data management, and challenges and opportunities of research autopsy programmes in oncology worldwide. Fourteen programmes participated in this study. Eight programmes operated 24 h/7 days, resulting in a lower median postmortem interval (time between death and start of the autopsy, 4 h) compared with those operating during working hours (9 h). Most programmes (n = 10) succeeded in collecting all samples within a median of 12 h after death. A large number of tumour sites were sampled during each autopsy (median 15.5 per patient). The median number of samples collected per patient was 58, including different processing methods for tumour samples but also non-tumour tissues and liquid biopsies. Unique biological insights derived from these samples included metastatic progression, treatment resistance, disease heterogeneity, tumour dormancy, interactions with the tumour micro-environment, and tumour representation in liquid biopsies. Tumour patient-derived xenograft (PDX) or organoid (PDO) models were additionally established, allowing for drug discovery and treatment sensitivity assays. Apart from the opportunities and achievements, we also present the challenges related with postmortem sample collections and strategies to overcome them, based on the shared experience of these 14 programmes. Through this work, we hope to increase the transparency of postmortem tissue donation, to encourage and aid the creation of new programmes, and to foster collaborations on these unique sample collections. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Local treatment options for locally recurrent pancreatic adenocarcinoma (LR-PAC) are limited, with median survival time (MST) of 9-13 months (mos) following recurrence. MRI-guided stereotactic body radiation therapy (MRgSBRT) provides the ability to dose escalate while sparing normal tissue. Here we report on the early outcomes of MRgSBRT for LR-PAC.

Patients with prior resection of pancreatic adenocarcinoma with local recurrence treated with MRgSBRT at a single tertiary referral center from 5-2021 to 2-2023 were identified from our prospective database. MRgSBRT was delivered to 40-50 Gy in 4-5 fractions with target and OAR delineation per institutional standards. Endpoints included local control per RECIST v1.1, distant failure, overall survival (OS), and acute and chronic toxicities per Common Terminology Criteria for Adverse Events, v5.

Fifteen patients with LR-PAC were identified with median follow-up of 10.6 mos (2.8-26.5 mos) from MRgSBRT. There were 8 females and 7 males, with a median age of 69 years (50-83). One patient underwent neoadjuvant radiation for 50.4 Gy in 28 fractions followed by resection, and one underwent adjuvant radiation for 45 Gy in 25 fractions prior to recurrence. MRgSBRT was delivered a median of 18.8 mos (3.5-52.8 mos) following resection. OS following recurrence at 6 and 12 mos were 87% and 51%, respectively, with a median survival time of 14.1 mos (3.2-27.4 mos). Three patients experienced local failure at 5.9, 7.8, and 16.6 months from MgSBRT with local control of 92.3% and 83.9% at 6 and 12 months. 10 patients experienced distant failure at a median of 2.9 mos (0.3-6.7 mos). Grade 1-2 acute GI toxicity was noted in 47% of patients, and chronic GI toxicity in 31% of patients. No grade > 3 toxicities were noted.

This is the first report on toxicity and outcomes of MRgSBRT for LR-PAC in the literature. MRgSBRT is a safe, feasible treatment modality with the potential for improved local control in this vulnerable population. Future research is necessary to better identify which patients yield the most benefit from MRgSBRT, which should continue to be used with systemic therapy as tolerated.

Jefferson IRB#20976, approved 2/17/21.

Metastasis is one of the defining features of pancreatic ductal adenocarcinoma (PDAC) that contributes to poor prognosis. In this study, the palmitoyl transferase ZDHHC20 was identified in an in vivo short hairpin RNA (shRNA) screen as critical for metastatic outgrowth, with no effect on proliferation and migration in vitro or primary PDAC growth in mice. This phenotype is abrogated in immunocompromised animals and animals with depleted natural killer (NK) cells, indicating that ZDHHC20 affects the interaction of tumor cells and the innate immune system. Using a chemical genetics platform for ZDHHC20-specific substrate profiling, a number of substrates of this enzyme were identified. These results describe a role for palmitoylation in enabling distant metastasis that could not have been detected using in vitro screening approaches and identify potential effectors through which ZDHHC20 promotes metastasis of PDAC.

Pancreatic cancer is one of the most lethal malignancies. Even though many substantial improvements in the survival rates for other major cancer forms were made, pancreatic cancer survival rates have remained relatively unchanged since the 1960s. Even more, no standard classification system for pancreatic cancer is based on cellular biomarkers. This review will discuss and provide updates about the role of stem cells in the progression of PC, the genetic changes associated with it, and the promising biomarkers for diagnosis.

The search process used PubMed, Cochrane Library, and Scopus databases to identify the relevant and related articles. Articles had to be published in English to be considered.

The increasing number of studies in recent years has revealed that the diversity of cancer-associated fibroblasts is far greater than previously acknowledged, which highlights the need for further research to better understand the various cancer-associated fibroblast subpopulations. Despite the huge diversity in pancreatic cancer, some common features can be noted to be shared among patients. Mutations involving CDKN2, P53, and K-RAS can be seen in a big number of patients, for example. Similarly, some patterns of genes and biomarkers expression and the level of their expression can help in predicting cancer behavior such as metastasis and drug resistance. The current trend in cancer research, especially with the advancement in technology, is to sequence everything in hopes of finding disease-related mutations.

Optimizing pancreatic cancer treatment requires clear classification, understanding CAF roles, and exploring stroma reshaping approaches.