Superior mesenteric vein/portal vein (SMV/PV) resection is often required in borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC) after neoadjuvant therapy (NAT), but its prognostic relevance and the role of histopathologic venous invasion remain unclear. We retrospectively analyzed BR/LA PDAC patients undergoing pancreatectomy after NAT and compared perioperative and oncologic outcomes between patients requiring SMV/PV resection and those with venous preservation. Subgroup analyses assessed histopathologic venous invasion within the resection cohort. Kaplan–Meier analysis was used to evaluate overall survival (OS) and disease-free survival (DFS), and Cox regression was used to identify factors associated with OS. Among 117 patients, 65 (55.6

Neuron-tumor communication is emerging as a distinct layer of tumor-host interaction beyond conventional stromal, vascular, and immune regulation. Recent studies show that malignant cells can detect neuronal activity and convert neural signals into growth-promoting cellular responses. In the brain, glioma cells can become electrically integrated into neuronal circuits, where glutamatergic input drives depolarization, calcium influx, and downstream signaling. In extracranial tumors, neural influence appears more heterogeneous, involving spatially organized neurochemical niches, receptor-enriched cancer-nerve contacts ('pseudo-synapses'), autonomic pathways, and injury-associated neuroimmune remodeling. These findings raise important questions about how neural input regulates tumor cell state, metabolism, immune tone, and therapeutic adaptation. This review evaluates the evidence linking neural activity to cancer progression across anatomical contexts and outlines the experimental standards needed to distinguish structured neuron-tumor interfaces from broader neural effects within the tumor microenvironment.

Background/Objectives: Neoadjuvant therapy (NAT) is now central to the management of borderline resectable (BRPC) and locally advanced (LAPC) pancreatic ductal adenocarcinoma (PDAC). This narrative review summarizes contemporary evidence and guidelines from a surgical perspective, with emphasis on pretreatment classification, post-NAT selection for exploration, intraoperative vascular strategy, and postoperative management. Methods: We conducted a structured narrative review of randomized and prospective studies, high-quality observational cohorts, and major international guidelines published through 31 July 2025. Results: BRPC and LAPC remain primarily defined by vascular anatomy, but biologic and conditional factors are increasingly integrated into decision-making. NAT is the preferred initial strategy for BRPC and the standard induction approach for LAPC, with resection considered only in carefully selected responders. After NAT, contrast-enhanced CT combined with CA19-9 kinetics remains the core restaging platform, while FDG-PET, diffusion-weighted MRI, radiomics, and circulating biomarkers may serve as adjuncts in equivocal cases. Surgical exploration should be guided by physiologic recovery, the absence of metastatic progression, and multidisciplinary reassessment. Staging laparoscopy remains useful for detecting occult metastatic disease. Intraoperatively, vascular resection should be margin-driven rather than routine, with portal-mesenteric venous resection established in expert centers, whereas arterial resection remains highly selective. Periarterial divestment represents an artery-sparing alternative in selected cases. NAT does not appear to worsen short-term postoperative outcomes, but anticoagulation after venous reconstruction remains non-standardized. Conclusions: NAT has transformed BRPC/LAPC PDAC into a biology-gated, time-sequenced surgical pathway. Standardized reassessment, careful candidate selection, and the centralization of complex vascular procedures are essential to optimize outcomes.

INTRODUCTION:The detection of bacterial colonization in postoperative pancreatic fistula (POPF) fluid has renewed interest in the role of bacterial translocation during pancreatic surgery. In this context, we hypothesized that peripancreatic lymph nodes (PLNs) might similarly harbor bacterial colonization. This study aimed to investigate the presence of bacteria in these lymph nodes, identify factors potentially contributing to their colonization, and assess the clinical significance of these findings. METHODS:In this observational pilot study, PLNs (station 8a) resected during pancreatic surgery were analyzed for bacterial DNA using 16S rDNA-PCR, and the microbiological findings were correlated with detailed perioperative and postoperative clinical data. RESULTS:Between 2019 and 2026, lymph node station 8a was resected and analyzed in 37 patients undergoing pancreatic surgery. Bacterial colonization was found in 3 patients (8.1%). No significant association was observed between lymph node colonization and the type of surgical procedure, histopathological diagnosis, or the development of clinically relevant POPF or other major postoperative complications. All cases with bacterial colonization had undergone preoperative endoscopic retrograde cholangiopancreatography (ERCP; p = 0.230). CONCLUSION:In this pilot study, bacterial colonization of PLNs was uncommon and was observed only in patients with a history of ERCP. Although no association with POPF was identified, a potential relationship with overall postoperative morbidity cannot be ruled out. Further studies with larger patient cohorts are needed to better define the clinical relevance and underlying mechanisms of lymphatic bacterial translocation.

Background Fibrosis and tumour innervation are two features of the tumour microenvironment (TME) that contribute directly to the lethality of pancreatic ductal adenocarcinoma (PDAC), but their potential interactions have not been explored. Moreover, although it is known that activated Schwann cells (SCs) stimulate cancer cell invasion, it remains unclear how SCs are activated. Objective We determined how SCs are activated in the pancreatic fibrotic microenvironment. Design The correlation between physical features of the microenvironment and SC activation was assessed in human patient samples and in mice by SC c-Jun phosphorylation monitoring, atomic force microscopy and multiphoton live imaging. Several in vitro models in which forces were applied to SCs expressing a reporter for c-Jun phosphorylation and RNA-Seq analysis were used to decipher the cellular and molecular mechanisms of SC activation. Results Nerves surrounded by stiff stroma present higher SC activation. Intravital imaging shows a matrix-dependent SC activation. Mechanical forces on SCs induce c-Jun phosphorylation in SCs in a non-canonical manner that involves a nuclear sensing machinery with the pro-inflammatory enzyme phospholipase A2. Conclusion Fibrosis enhances the protumorigenic impact of innervation by activating SCs via a mechanism in which nuclear compression triggers non-canonical activation of the AP-1 transcription factor complex. Pancreatic fibrosis alone, without cancer cells, is sufficient to activate SCs, suggesting this mechanism may be common across non-malignant pancreatic diseases. Notably, SCs are more sensitive to mechanical activation than PDAC cells. These findings reveal TME interactions that may guide future microenvironment-targeted PDAC therapies.

Few studies have examined delayed gastric emptying (DGE) following left pancreatectomy (LP). This study aimed to assess the incidence and impact and identify predictive pre/intra-operative predictors. We conducted a retrospective, single-centre cohort including all adult patients who underwent LP from 2017 to 2024. Variables were analyzed using univariate and multivariable analysis. Among 213 LP patients, 34 (16.0

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, characterized by early metastasis, profound therapy resistance, and the highest prevalence of perineural invasion (PNI) among solid tumors. PNI fosters neuropathic pain and recurrence, ultimately correlating with poor survival. Sensory neurons promote PNI via neuropeptidergic signaling, including substance P (SP), while Schwann cells undergo injury-like reprogramming (GFAP+/p75NTRhigh), facilitating tumor invasion through chemoattractant secretion. Although the activation of neurokinin-1 receptor (NK-1R) via SP is implicated in tumor invasion and pain signaling, its role in coordinating bidirectional crosstalk within the PDAC neural niche remains elusive. In this study, we investigated the SP/NK-1R axis as a mediator of bidirectional crosstalk between tumor cells, sensory neurons, and Schwann cells in pancreatic cancer.MethodsTo elucidate the role of the SP/NK-1R axis in perineural invasion, we employed a series of complementary in vitro approaches. First, NK-1R expression was assessed by immunofluorescence in both primary PDAC tissue slices and PDAC tumor cell lines. To model the tumor-neural niche, MiaPaCa-2 cells were exposed to conditioned medium derived from iPSC-derived sensory neurons and primary human Schwann cells. Furthermore, to investigate the functional consequences of this signaling axis, we established a co-culture system composed of MiaPaCa-2 cells and Schwann cells, in which the number of invaded MiaPaCa-2 cells was quantified. Axon-guided tumor invasion was further examined using the OrganoPlate® Graft platform, where MiaPaCa-2 spheroids were co-cultured with sensory neurons. Moreover, NK-1R was pharmacologically inhibited using the FDA-approved antagonist aprepitant, and its effect on MiaPaCa-2 cell invasion was evaluated in both co-culture settings. Finally, the potential for therapeutic synergy was explored by combining aprepitant with the chemotherapeutic agent paclitaxel to assess potential synergy on cytotoxicity.ResultsImmunofluorescence analysis of MiaPaCa-2, patient-derived tumor cells and primary PDAC tissue slices, revealed high NK-1R protein expression, establishing NK-1R as a putative clinically relevant target in PDAC. To model the bidirectional crosstalk within the PDAC niche, we examined NK-1R regulation under co-culture conditions. Conditioned media from sensory neurons and primary human Schwann cells significantly upregulated NK-1R expression in the MiaPaCa-2 cells. Reciprocally, exposure of both sensory neurons or Schwann cells to MiaPaCa-2 cells conditioned medium induced NK-1R upregulation, confirming bidirectional signaling. Consistent with this, supernatant from MiaPaCa-2/sensory neuron or MiaPaCa-2/Schwann cells co-cultures demonstrated a substantial increase in SP levels, indicating active neuropeptidergic communication within the tumor-neural niche. To assess the functional consequences of this crosstalk on tumor invasiveness, we employed our co-culture invasion models. Schwann cells significantly increased the number of invaded MiaPaCa-2 cells in co-culture. Furthermore, using the OrganoPlate® Graft platform, co-culture of MiaPaCa-2 spheroids and iPSC-derived sensory neurons demonstrated pronounced axon-guided tumor, validating the human 3D PNI model. Finally, to evaluate the therapeutic potential of NK-1R inhibition, we treated co-cultures with the FDA-approved NK-1R antagonist aprepitant. Pharmacological NK-1R blockade significantly reduced MiaPaCa-2 cell invasion in both sensory neuron and Schwann cell co-cultures. Moreover, combining aprepitant with paclitaxel synergistically enhanced cytotoxicity, revealing a dual role for NK-1R in driving both invasion and chemoresistance.ConclusionCollectively, our findings confirm and extend previous work by implicating SP/NK-1R axis as a potential driver of perineural invasion in PDAC. By leveraging a human 3D microfluidic co-culture PNI model, we provide evidence that NK-1R signaling contributes to sustaining bidirectional tumor-neural crosstalk and promoting invasive progression. Critically, pharmacological inhibition of NK-1R using the FDA-approved antagonist aprepitant not only suppressed perineural invasion but also synergistically enhanced paclitaxel-induced cytotoxicity, highlighting dual vulnerability in both neural invasion and chemoresistance. Together, these findings position SP/NK-1R as a target, offering a novel and translationally relevant strategy to simultaneously disrupt tumor-nerve interactions and improve chemotherapy response in PDAC.

Cancer neuroscience is an emerging field at the intersection of oncology, neuroscience, and immunology in which the interactions between cancer cells and neural and immune systems generate extraordinary biological complexity. Thus, artificial intelligence may be a technological tool that is increasingly necessary to decode nonlinear cancer-neuron networks and to translate this complexity into biological and therapeutic insight.

Postoperative pancreatic fistula (POPF) remains the most common and impactful complication after distal (left) pancreatectomy (DP). While previous studies have identified histological features such as acinar cell content and fibrosis as risk factors for POPF after pancreatoduodenectomy (PD), their relevance in DP remains unclear. The aim of this study was to investigate whether histopathological features at the pancreatic transection margin are associated with clinically relevant POPF after DP. This retrospective pilot study included 51 patients who underwent DP between 2019 and 2022 at the Department of Surgery, Klinikum rechts der Isar, Technical University of Munich. Immunohistochemical staining of pancreatic resection (transection) margin tissue was performed for leukocytes (CD45), M1 macrophages (CD68), endothelial cells (CD31), exocrine cells (PanCK), and adipocytes. Quantitative analysis was conducted using the QuPath digital pathology platform, and associations between these histological features and clinically relevant POPF were assessed. CR-POPF occurred in 21 of 51 patients (41.2

Both the nervous system and cancer-intrinsic neural features can govern cancer initiation, growth, progression, metastasis, and treatment resistance, while cancer can likewise influence the nervous system, promoting neural reprogramming and neuropsychiatric symptoms that worsen patient outcomes. The field of cancer neuroscience seeks to unravel this complex neuro-cancer crosstalk and holds the promise to develop neuroscience-instructed cancer therapies that improve disease control and quality of life. Here, we summarize the key discoveries of neuro-cancer crosstalk to date, including neuron-to-cancer synapses and paracrine and neuro-immuno-oncological interactions, and then explore emerging topics such as downstream effects on cancer cell pathophysiology, circadian influences, brain-body-cancer communication, and neural regulation of the metastatic cascade and the tumor microenvironment. Finally, we distill overarching principles, highlight relevant ongoing research, and outline conclusions to guide the development of cancer neuroscience, proposing hypotheses for future experimental validation.

This international, multidisciplinary consensus report represents the first effort to systematically define and characterize fatty pancreas. A key outcome of this endeavor was the recommendation to adopt "fatty pancreas" as the standardized and inclusive term to describe all forms of fat accumulation in the pancreas. This terminological consensus provides a critical foundation for unified reporting and clinical communication. Another major contribution of the report is the consensus on diagnostic imaging findings, which was based on radiological and endoscopic modalities. The proposed criteria aim to enhance consistency in clinical assessment and support the development of standardized research protocols. In addition to establishing terminology and diagnostic frameworks, the report also synthesizes current knowledge across a wide range of relevant domains. These include the etiology and epidemiology of fatty pancreas, as well as its associations with alcohol consumption, smoking, acute and chronic pancreatitis, pancreatic exocrine insufficiency, type 2 diabetes mellitus, and surgical outcomes. The potential links between fatty pancreas and neoplastic conditions such as intraductal papillary mucinous neoplasms and pancreatic cancer are also addressed, alongside the current understanding of its metabolic implications (beta-cell function and glucose homeostasis) and treatment strategies. Throughout the consensus process, a consistent theme emerged: the limited availability of high-quality, prospective clinical data. Therefore, many of the recommendations in this report are based on expert consensus rather than strong empirical evidence. As such, the statements require rigorous prospective validation before they can be adopted into routine clinical practice. This underscores a critical need for further research, particularly studies aimed at clarifying causal relationships, validating diagnostic tools, and determining the clinical relevance of fatty pancreas across diverse patient populations. This report serves as both a summary of our current understanding and a roadmap for future investigations, aiming to close existing knowledge gaps and guide evidence-based clinical practice in this emerging field.

The management of patients with locally advanced pancreatic cancer (LAPC) in the era of promising neoadjuvant treatments and “conversion” surgery remains challenging. This survey sought to register the current practices and perspectives of recognized pancreatic surgeons and provide valuable insights for future research. An online survey consisting of 18 questions on real-life challenging clinical situations was conducted using Google Forms. Participants were asked about their approach in the management of a 60-year-old patient with LAPC after 8 weeks of neoadjuvant chemotherapy in different settings of response to the neoadjuvant treatments and of intraoperative findings. Seventy-three respondents from 19 different countries completed the survey. 74% (54/73) of the respondents declared working at centers performing more than 50 pancreatic resections per year. Overall, the answers among participants were very heterogeneous. There was no consensus regarding the optimal duration of neoadjuvant chemotherapy, nor on the appropriate timing and indications for regimen modification. Similarly, the criteria for surgical exploration, the intraoperative strategies in case of venous or arterial involvement, and the role of perivascular frozen-section analysis in guiding intraoperative decisions remained debated among the participating surgeons. Here, the lack of knowledge in the current literature on these issues and the subsequent reliance on individual expertise may account for this heterogeneity. Further research efforts are required to address existing knowledge gaps and to advance and standardize the management of patients with LAPC.

Neuroendocrine tumors (NETs) associated with the intrapancreatic bile duct are rare and poorly characterized. Their relationship to conventional pancreatic neuroendocrine tumors (PanNETs) and to neuroendocrine cells of the periampullary and peribiliary regions remains unclear. A total of 199 resected NETs from the pancreas were evaluated for anatomical location and intrapancreatic bile duct narrowing. Transcription factor and hormone expression were assessed by whole-slide immunohistochemistry. For comparison, 22 duodenal NETs, 6 ampullary NETs and non-neoplastic duodenal, ampullary, and bile duct tissues were examined. Nineteen tumors (10%) were associated with bile duct narrowing, including 11 lower (periampullary) and 8 upper bile duct lesions. Compared with NETs without bile duct narrowing, these tumors were exclusively non-functioning, occurred more frequently in women and exhibited higher Ki-67 indices. Lower bile duct-narrowing tumors were associated with shorter progression-free survival. All but one bile duct-narrowing tumor expressed PDX1 (18/19, 95%), whereas CDX2 expression was observed in 73% (8/11) of lower bile duct-narrowing tumors. These tumors frequently expressed gastrin (73%) and somatostatin (73%), occasionally serotonin (27%), and lacked glucagon and insulin expression. Their transcription factor and hormone expression profiles closely resembled those of duodenal NETs and neuroendocrine cells of periampullary and peribiliary glands and differed from those of conventional PanNETs. Bile duct-narrowing NETs from the pancreas, particularly those involving the lower bile duct, represent a distinct clinicopathological subgroup characterized by a PDX1-positive, frequently CDX2-positive phenotype and enrichment for gastrin and somatostatin expression. Their resemblance to duodenal NETs and periampullary/peribiliary neuroendocrine cells supports a shared differentiation program and suggests a possible non-islet cell origin.

The immunosuppressive tumor microenvironment (TME) fosters cancer progression, yet overarching determinants of cancer-borne immunoinstruction remain ill-defined. By multimodal integration of single-nucleus and bulk transcriptomics, proteomics, functional approaches, and clinical parameters, we discover a cancer-immunoinstructive secretory signature (CISS) across multiple human cancers-a set of inflammatory proteins correlated with poor prognosis and pro-tumorigenic TMEs. In pancreatic cancer (PC), CISS arises in pre-malignant epithelium, intensifies along transformation toward most malignant basal-like PC, and particularly correlates with suppressed natural killer (NK) cell activity. The CISS is quantitatively dominated by tissue inhibitor of metalloproteinases (TIMP)-1, most prevalent in TIMP-1hi/CISShi basal-like PC, and causal for PC-cell-mediated NK cell suppression, reflected by impaired cytotoxicity, interleukin-2 (IL-2) responses, and mammalian target of rapamycin (mTOR) signaling. In pre-clinical PC, TIMP-1/CISS proves targetable through combined inhibition of upstream kinases with clinically approved drugs trametinib and nintedanib. Collectively, CISS represents a ubiquitous signature of pro-tumor immunoinstruction with actionable diagnostic and therapeutic potential across human cancers.

Pancreatic tumours hijack neuronal signalling mechanisms to boost cancer growth. A technology to identify and profile mouse neurons that connect the spinal cord to pancreatic cancer might improve treatment of this disease. Method to identify neurons associated with pancreatic cancer.

Neural invasion is a prognostic hallmark of pancreatic ductal adenocarcinoma (PDAC), yet the underlying mechanisms behind the disruption of perineural barriers and access of cancer cells into intrapancreatic nerves remain poorly understood. This study aimed to investigate the role of epithelial-mesenchymal transformation (EMT) in perineural epithelial cells during neural invasion.Histopathological analysis of human and murine primary tumors using perineurium-specific GLUT1 antibody revealed a reduction in perineural integrity, which positively correlated with the extent of neural invasion in human PDAC cases. Human pancreatic cancer cell lines were found to secrete TGFbeta1, which induced EMT of perineural epithelial cells, characterized by the loss of epithelial markers (CK19-9) and the acquisition of mesenchymal markers (alphaSMA, N-Cadherin). Additionally, these transitioning perineural epithelial cells demonstrated increased matrix-degrading capabilities through the upregulation of matrix-metalloproteases 3 and 9 via SMAD2. In an autochthonous mouse model with elevated endogenous TGFbeta1 levels in addition to oncogenic Kras activation (Ptf1aCre/+, LSL-KrasG12D/+, LSL-R26Tgfβ/+), decreased perineural integrity could be reproduced in vivo.Collectively, these findings underscore the role played by TGFbeta1-overexpressing pancreatic cancer cells in the dismantling of perineural barriers during neural invasion.

Cancers thrive on neuronal input. Here, we demonstrate the presence of pseudo-synaptic connections between sensory nerve endings and cancer cells in an extracerebral cancer, i.e., pancreatic ductal adenocarcinoma (PDAC). These synaptic sites exhibit a selective enrichment of the glutamatergic N-methyl-D-aspartate receptor (NMDA) receptor subunit NMDAR2D (GRIN2D) on the cancer cells, which turns PDAC cells responsive to neuron-derived glutamate and promotes tumor growth and spread. Intriguingly, neurons transform a subset of co-cultured PDAC cells into calcium-responsive cells via GRIN2D-type glutamate receptors at the neuron-cancer pseudo-synapses. We found that the expression of this subunit is due to the increased glutamate availability provided by sensory innervation in a neurotrophic feedforward loop. Moreover, interference with the glutamate-GRIN2D signaling at these neuron-cancer pseudo-synapses markedly improved survival in vivo. This discovery of peripheral cancer-neuron pseudo-synapses may provide an opportunity for cancer-neuroscience-instructed oncological therapies.

OBJECTIVE:The aim was to build a calculator for personalized surveillance of BD-IPMNs. SUMMARY BACKGROUND DATA:The interval time for surveillance of low-risk branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) has not been established yet. METHODS:The study included an international cohort of BD-IPMNs without worrisome features (WFs) or high-risk stigmata (HRS). IPMN evolution was defined as the occurrence of HRS or WFs. The derivation cohort comprised 60% of patients. The validation group comprised the remaining patients. A parametric survival model was developed in the derivation cohort using Akaike (AIC) and Bayesian (BIC) information criteria and c-index. A "k-fold" validation was used to measure the covariate effect on the accelerated failure time. Two models ("standard" and "conservative") were built and validated using the second cohort. RESULTS:The derivation and validation cohorts included 1,992 and 1,119 BD-IPMNs. The lognormal distribution best fitted the derivation cohort (AIC=2673; BIC=2718). The pooled c-index was 0.689 (0.668 to 0.718, 95%CI). The factors reducing the time needed for IPMN evolution were age [- 2% (-1% to -3%) for each year] and cyst size [-2% (0% to -3%); for each mm]. The "conservative" model, called PANORAMA, was the only one that correctly classified the validation cohort (c-index 0.712 vs. 0.696; P=0.072). CONCLUSION AND RELEVANCE:The development of WF and HRS is influenced by the patient's age and cyst size. After a prudential first control at six months, repeating a semestral/annual follow-up in this time frame could be too tight.