Liver Resection in Synchronous Bilobar versus Unilobar Colorectal Liver Metastases: A Retrospective Analysis of Oncological Outcomes and Patient Survival.

INTRODUCTION: Resection of colorectal liver metastasis has emerged as the standard treatment. Our study compares oncological outcomes of patients with resected synchronous bilobar versus unilobar colorectal liver metastasis. METHODS: This retrospective study presents long-term follow-up data of 105 consecutive patients with primary colorectal cancer and synchronous liver metastasis. All patients underwent primary tumor and metastasis resections between 2007 and 2019. RESULTS: Fifty-five patients with bilobar and 50 patients with unilobar colorectal liver metastases were included. No significant difference in overall, tumor-specific, or recurrence-free survival was observed between patients with bilobar and unilobar metastases. After case-control matching, the results were confirmed in patients with similar tumor burdens. In the multivariate analysis, chemotherapy following liver metastasis resection was a significant prognostic factor associated with improved overall survival (hazard ratio 0.518, 95% confidence interval: 0.302-0.888, p = 0.017). CONCLUSION: Overall survival, as well as tumor-specific and recurrence-free survival, did not differ between patients with unilobar and bilobar liver metastasis. These findings contribute to the understanding that primary tumor and metastasis resection in eligible patients improve long-term outcomes.

Neoadjuvant chemotherapy is associated with suppression of the B cell-centered immune landscape in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at advanced stages and associated with early distant metastasis and poor survival. Besides clinical factors, the tumor microenvironment (TME) emerged as a crucial determinant of patient survival and therapy response in many tumors, including PDAC. Thus, the presence of tumor-infiltrating lymphocytes and the formation of tertiary lymphoid structures (TLS) is associated with longer survival in PDAC. Although neoadjuvant therapy (NeoTx) has improved the management of locally advanced tumors, detailed insight into its effect on various TME components is limited. While a remodeling towards a proinflammatory state was reported for PDAC-infiltrating T cells, the effect of NeoTx on B cell subsets, including plasma cells, and TLS formation is widely unclear. We thus investigated the frequency, composition, and spatial distribution of PDAC-infiltrating B cells in primary resected (PR) versus neoadjuvant-treated patients using a novel multiplex immunohistochemistry panel. The NeoTx group displayed significantly lower frequencies of pan B cells, GC B cells, plasmablasts, and plasma cells, accompanied by a reduced abundance of TLS. This finding was supported by bulk RNA-sequencing analysis of an independent fresh frozen tissue cohort, which revealed that major B cell pathways were downregulated in the NeoTx group. We further observed that plasma cells frequently formed aggregates that localized close to TLS and that TLS+ patients displayed significantly higher plasma cell frequencies compared to TLS- patients in the PR group. Additionally, high densities of CD20+ intratumoral B cells were significantly associated with longer overall survival in the PR group. While CD20+ B cells held no prognostic value for NeoTx patients, an increased frequency of proliferating CD20+Ki67+ B cells emerged as an independent prognostic factor for longer survival in the NeoTx group. These results indicate that NeoTx differentially affects PDAC-infiltrating immune cells and may have detrimental effects on the existing B cell landscape and the formation of TLS. Gaining further insight into the underlying molecular mechanisms is crucial to overcome the intrinsic immunotherapy resistance of PDAC and develop novel strategies to improve the long-term outcome of PDAC patients.

The mesenteric entry site as a potential weak point in gastrointestinal anastomoses - findings from an ex-vivo biomechanical analysis.

PURPOSE: Gastrointestinal disorders frequently necessitate surgery involving intestinal resection and anastomosis formation, potentially leading to severe complications like anastomotic leakage (AL) which is associated with increased morbidity, mortality, and adverse oncologic outcomes. While extensive research has explored the biology of anastomotic healing, there is limited understanding of the biomechanical properties of gastrointestinal anastomoses, which was aimed to be unraveled in this study. METHODS: An ex-vivo model was developed for the biomechanical analysis of 32 handsewn porcine end-to-end anastomoses, using interrupted and continuous suture techniques subjected to different flow models. While multiple cameras captured different angles of the anastomosis, comprehensive data recording of pressure, time, and temperature was performed simultaneously. Special focus was laid on monitoring time, location and pressure of anastomotic leakage (LP) and bursting pressures (BP) depending on suture techniques and flow models. RESULTS: Significant differences in LP, BP, and time intervals were observed based on the flow model but not on the suture techniques applied. Interestingly, anastomoses at the insertion site of the mesentery exhibited significantly higher rates of leakage and bursting compared to other sections of the anastomosis. CONCLUSION: The developed ex-vivo model facilitated comparable, reproducible, and user-independent biomechanical analyses. Assessing biomechanical properties of anastomoses offers an advantage in identifying technical weak points to refine surgical techniques, potentially reducing complications like AL. The results indicate that mesenteric insertion serves as a potential weak spot for AL, warranting further investigations and refinements in surgical techniques to optimize outcomes in this critical area of anastomotic procedures.

Cell Death in Liver Disease and Liver Surgery.

Cell death is crucial for maintaining tissue balance and responding to diseases. However, under pathological conditions, the surge in dying cells results in an overwhelming presence of cell debris and the release of danger signals. In the liver, this gives rise to hepatic inflammation and hepatocellular cell death, which are key factors in various liver diseases caused by viruses, toxins, metabolic issues, or autoimmune factors. Both clinical and in vivo studies strongly affirm that hepatocyte death serves as a catalyst in the progression of liver disease. This advancement is characterized by successive stages of inflammation, fibrosis, and cirrhosis, culminating in a higher risk of tumor development. In this review, we explore pivotal forms of cell death, including apoptosis, pyroptosis, and necroptosis, examining their roles in both acute and chronic liver conditions, including liver cancer. Furthermore, we discuss the significance of cell death in liver surgery and ischemia-reperfusion injury. Our objective is to illuminate the molecular mechanisms governing cell death in liver diseases, as this understanding is crucial for identifying therapeutic opportunities aimed at modulating cell death pathways.

Liver Fibrosis Is Associated with Poorer Overall Survival and Higher Recurrence Rate in Patients with Cholangiocarcinoma.

INTRODUCTION: Cholangiocarcinoma is the second most common primary liver tumour worldwide with an increasing incidence in recent decades. While the effects of fibrosis on hepatocellular carcinoma have been widely demonstrated, the impact on cholangiocarcinoma remains unclear. The aim of this study was to evaluate the impact of liver fibrosis on overall survival (OS) and disease-free survival (DFS) in patients who have undergone liver resection for cholangiocarcinoma. METHODS: Eighty patients with cholangiocarcinoma who underwent curatively intended liver surgery between January 2007 and December 2020 were included in this retrospective single-centre study. Clinical and histopathological features were analysed. The primary endpoint was cause-specific survival. Secondary endpoints were DFS and identification of prognostic factors. RESULTS: The present study shows that the median OS is significantly reduced in patients with fibrosis (p < 0.001). The median OS in patients with fibrosis was three times shorter than in the group without fibrosis. In addition, a significantly shorter DFS was observed in patients with fibrosis (p < 0.002). Multivariate analysis showed that fibrosis is the strongest independent factor with a negative impact on OS and DFS. CONCLUSION: Liver fibrosis has a significant impact on OS and DFS in patients with cholangiocarcinoma. Patients with known liver fibrosis require thorough perioperative care and postoperative follow-up.

Intraoperative Wound Irrigation for the Prevention of Surgical Site Infection After Laparotomy: A Randomized Clinical Trial by CHIR-Net.

Importance: Surgical site infections frequently occur after open abdominal surgery. Intraoperative wound irrigation as a preventive measure is a common practice worldwide, although evidence supporting this practice is lacking. Objective: To evaluate the preventive effect of intraoperative wound irrigation with polyhexanide solution. Design, Setting, and Participants: The Intraoperative Wound Irrigation to Prevent Surgical Site Infection After Laparotomy (IOWISI) trial was a multicenter, 3-armed, randomized clinical trial. Patients and outcome assessors were blinded to the intervention. The clinical trial was conducted in 12 university and general hospitals in Germany from September 2017 to December 2021 with 30-day follow-up. Adult patients undergoing laparotomy were eligible for inclusion. The main exclusion criteria were clean laparoscopic procedures and the inability to provide consent. Of 11 700 screened, 689 were included and 557 completed the trial; 689 were included in the intention-to-treat and safety analysis. Interventions: Randomization was performed online (3:3:1 allocation) to polyhexanide 0.04%, saline, or no irrigation (control) of the operative wound before closure. Main Outcome and Measures: The primary end point was surgical site infection within 30 postoperative days according to the US Centers for Disease Control and Prevention definition. Results: Among the 689 patients included, 402 were male and 287 were female. The median (range) age was 65.9 (18.5-94.9) years. Participants were randomized to either wound irrigation with polyhexanide (n = 292), saline (n = 295), or no irrigation (n = 102). The procedures were classified as clean contaminated in 92 cases (8%). The surgical site infection incidence was 11.8% overall (81 of 689), 10.6% in the polyhexanide arm (31 of 292), 12.5% in the saline arm (37 of 295), and 12.8% in the no irrigation arm (13 of 102). Irrigation with polyhexanide was not statistically superior to no irrigation or saline irrigation (hazard ratio [HR], 1.23; 95% CI, 0.64-2.36 vs HR, 1.19; 95% CI, 0.74-1.94; P = .47). The incidence of serious adverse events did not differ among the 3 groups. Conclusions and Relevance: In this study, intraoperative wound irrigation with polyhexanide solution did not reduce surgical site infection incidence in clean-contaminated open abdominal surgical procedures compared to saline or no irrigation. More clinical trials are warranted to evaluate the potential benefit in contaminated and septic procedures, including the emergency setting. Trial Registration: drks.de Identifier: DRKS00012251.

Fractal analysis of extracellular matrix for observer-independent quantification of intestinal fibrosis in Crohn's disease.

Prevention of intestinal fibrosis remains an unresolved problem in the treatment of Crohn's disease (CD), as specific antifibrotic therapies are not yet available. Appropriate analysis of fibrosis severity is essential for assessing the therapeutic efficacy of potential antifibrotic drugs. The aim of this study was to develop an observer-independent method to quantify intestinal fibrosis in surgical specimens from patients with CD using structural analysis of the extracellular matrix (ECM). We performed fractal analysis in fibrotic and control histological sections of patients with surgery for CD (n = 28). To specifically assess the structure of the collagen matrix, polarized light microscopy was used. A score to quantify collagen fiber alignment and the color of the polarized light was established. Fractal dimension as a measure for the structural complexity correlated significantly with the histological fibrosis score whereas lacunarity as a measure for the compactness of the ECM showed a negative correlation. Polarized light microscopy to visualize the collagen network underlined the structural changes in the ECM network in advanced fibrosis. In conclusion, observer-independent quantification of the structural complexity of the ECM by fractal analysis is a suitable method to quantify the degree of intestinal fibrosis in histological samples from patients with CD.

Lymph node examination and survival in resected pancreatic ductal adenocarcinoma: retrospective study.

BACKGROUND: The minimum number of examined lymph nodes (ELN) required for adequate staging and best prediction of survival has not been established in pancreatic ductal adenocarcinoma (PDAC). The aim of the study was to investigate the influence of ELN on staging and survival in PDAC. METHODS: Patients undergoing partial or total pancreatectomy for PDAC at two European university hospitals between 2007 and 2018 were retrospectively reviewed. Multivariate Cox regression model and survival analyses were performed to verify adequate staging. RESULTS: Overall 341 (73 per cent) patients showed lymph node metastasis (N1/N2), whereas 125 (27 per cent) patients had no lymph node involvement (N0). With increasing number of ELN, the proportion of positive lymph nodes increased. The minimum number of ELN needed to detect lymph node involvement was 21. In multivariate analysis, examination of <21 lymph nodes was a significant negative predictor for survival. Examination of ≥21 ELN reversed this effect and ruled out possible misclassification. CONCLUSION: The number of ELN affects survival in PDAC. Possible misclassification was identified when <21 lymph nodes were examined. Therefore, at least 21 lymph nodes must be examined to avoid false lymph node classification in all types of resection.

A Modern Series of Secondary Aortoenteric Fistula - A 19-Year Experience.

OBJECTIVES: Secondary aortoenteric fistula is a rare and life-threatening condition. Clear evidence on the ideal therapeutic approach is largely missing. This study aims to analyze symptoms, etiology, risk factors, and outcomes based on procedural details. PATIENTS AND METHODS: All patients with secondary aortoenteric fistula admitted between 2003 and 2021 were included. Patient characteristics, surgical procedure details, and postoperative outcomes were analyzed. Outcomes were stratified and compared according to the urgency of operation and the procedure performed. Descriptive statistics were used. The primary endpoint was in-hospital mortality. RESULTS: A total of twentytwo patients (68% male, median age 70 years) were identified. Main symptoms were gastrointestinal bleeding, pain, and fever. From the twentytwo patients ten patients required emergency surgery and ten urgent surgery. Emergency patients were older on average (74 vs 63 years, P = .015) and had a higher risk of postoperative respiratory complications (80% vs 10%, P = .005). Primary open surgery with direct replacement of the aorta or an extra-anatomic bypass with an additional direct suture or resection of the involved bowel was performed in sixteen patients. In four patients underwent endovascular bridging treatment with the definitive approach as a second step. Other two patients died without operation (1x refusal; 1x palliative cancer history). In-hospital mortality was 27%, respectively. Compared to patients undergoing urgent surgery, those treated emergently showed significantly higher in-hospital (50% vs 0%, P = .0033) mortalities. CONCLUSION: Despite rapid diagnosis and treatment, secondary aortoenteric fistula remains a life-threatening condition with 27% in-hospital mortality, significantly increased upon emergency presentation.

Goal-directed Perioperative Albumin Substitution Versus Standard of Care to Reduce Postoperative Complications: A Randomized Clinical Trial (SuperAdd Trial).

OBJECTIVE: To investigate whether goal-directed albumin substitution during surgery and postanesthesia care to maintain a serum albumin concentration >30 g/L can reduce postoperative complications. BACKGROUND: Hypoalbuminemia is associated with numerous postoperative complications. Since albumin has important physiological functions, substitution of patients with hypoalbuminemia is worth considering. METHODS: We conducted a single-center, randomized, controlled, outcome assessor-blinded clinical trial in adult patients, American Society of Anesthesiologists physical status classification 3 to 4 or undergoing high-risk surgery. Patients, whose serum albumin concentration dropped <30 g/L were randomly assigned to goal-directed albumin substitution maintaining serum concentration >30 g/L or to standard care until discharge from the postanesthesia intermediate care unit. Standard of care allowed albumin substitution in hemodynamic instable patients with serum concentration <20 g/L, only. Primary outcome was the incidence of postoperative complications ≥2 according to the Clavien-Dindo Classification in at least 1 of 9 domains (pulmonary, infectious, cardiovascular, neurological, renal, gastrointestinal, wound, pain, and hematological) until postoperative day 15. RESULTS: Of 2509 included patients, 600 (23.9%) developed serum albumin concentrations <30 g/L. Human albumin 60 g (40-80 g) was substituted to 299 (99.7%) patients in the intervention group and to 54 (18.0%) in the standard care group. At least 1 postoperative complication classified as Clavien-Dindo Classification ≥2 occurred in 254 of 300 patients (84.7%) in the intervention group and in 262 of 300 (87.3%) in the standard treatment group (risk difference -2.7%, 95% CI, -8.3% to 2.9%). CONCLUSION: Maintaining serum albumin concentration of >30 g/L perioperatively cannot generally be recommended in high-risk noncardiac surgery patients.

Erratum: Targeting sphingosine kinase 2 suppresses cell growth and synergizes with BCL2/BCL-XL inhibitors through NOXA-mediated MCL1 degradation in cholangiocarcinoma.

[This corrects the article on p. 546 in vol. 9, PMID: 30949409.].

Hepatocellular Brg1 promotes CCl4-induced liver inflammation, ECM accumulation and fibrosis in mice.

INTRODUCTION: Hepatic fibrosis is a progressive pathological process involving the exhaustion of hepatocellular regenerative capacity and ultimately leading to the development of cirrhosis and even hepatocellular carcinoma. Brg1, the core subunit of the SWI/SNF chromatin-remodeling complex, was recently identified as important for liver regeneration. This study investigates the role of Brg1 in hepatic fibrosis development. METHODS: Hepatocyte-specific Brg1 knockout mice were generated and injected with carbon tetrachloride (CCl4) for 4, 6, 8, and 12 weeks to induce liver fibrosis. Afterwards, liver fibrosis and liver damage were assessed. RESULTS: Brg1 expression was significantly increased in the fibrotic liver tissue of wild-type mice, as compared to that of untreated wild-type mice. The livers of the Brg1 knockout animals showed reduced liver inflammation, extracellular matrix accumulation, and liver fibrosis. TNF-α and NF-κB-mediated inflammatory response was reduced in Brg1 knockout animals. CONCLUSION: Brg1 promotes the progression of liver fibrosis in mice and may therefore be used as a potential therapeutic target for treating patients with liver fibrosis due to chronic injury.

Secondary Primary Cancer Risk After Radiation Therapy in Rectal Cancer: A Population-Based Cohort Study With Propensity Score Matching.

BACKGROUND: It remains unclear whether radiation therapy (RT) has an impact on the development of secondary primary cancer (SC) in rectal cancer (RC) patients, especially within the true pelvis. AIM: To examine the incidence of SC in a population-based cohort of RC after surgical treatment with or without radiation therapy (RT, NRT). PATIENTS AND METHODS: The epidemiological cohort consisting of 13,919 RC patients with primary M0 stage diagnosed between 1998 and 2019 was collected from cancer registry data of Upper Bavaria. Competing risk analyses were conducted regarding the development of SC on 11 687 first malignancies, stratified by RT/NRT. A propensity score (PS) was generated by logistic regression modeling of RT to repeat competing risk analyses on a PS-matched cohort. RESULTS: The median age (interquartile range) of the epidemiological cohort was 68.9 years (60.4-76.7). About 60.8%, were men, 38.7% had UICC III, 35.8% of tumors were localized lower than 8 cm, 41.3% underwent RT. Only 17.1% of patients older than 80 years at diagnosis received RT. In general, RT patients were 5 years younger than NRT patients (65.9 years [58.0-73.0] vs. 71.3 years [62.4-79.2], P < .0001). The 20-year cumulative incidence of SC was 16.5% in RT and 17.4% in NRT patients (P = .2298). Men with RT had a lower risk of prostate cancer (HR = 0.55, 95%CI [0.34-0.91], P = .0168). In the PS-matched cohort, RT patients had a significantly higher risk of bladder cancer during follow-up (10-year cumulative incidence of 1.1% vs. 0.6% in NRT). The direction of the RT effects in men and women and different tumor sites may cancel each other. CONCLUSION: A protective effect of RT in rectal cancer patients on developing prostate SC by half is reproduced. Further analyses studying the long-term SC risks of RT should essentially focus on stratification by sex, and focus on more recent data.

Whipple Resection for Benign Tumors and Premalignant Neoplasms of the Pancreatic Head: Surgery-Associated Risk for Complications and Late Metabolic Morbidity Matters.

Benign and premalignant neoplasms of the pancreas are increasingly detected and recommended for surgical treatment. For tumors of the pancreatic head, the challenging decision is: multiorgan resection or local tumor extirpation? Compared with pancreaticoduodenectomy, duodenum-preserving pancreatic head resection is associated with significantly fewer surgery-related serious and severe complications and lower in-hospital mortality. The decisive advantage of duodenum-preserving pancreatic head resection is the maintenance of endocrine and exocrine pancreatic and upper gastrointestinal tract functions.

Arterial Resection for Pancreatic Cancer: Feasibility and Current Standing in a High-Volume Center.

Background: Arterial resection (AR) during pancreatectomy for curative R0 resection of pancreatic ductal adenocarcinoma (PDAC) remains a controversial procedure with high morbidity. Objective: To investigate the feasibility and oncological outcomes of pancreatectomy combined with AR at a high-volume center for pancreatic surgery. Methods: We retrospectively analyzed our experience in PDAC patients, who underwent pancreatic resection with AR and/or venous resection (VR) between 2007 and 2021. Results: In total 259 PDAC patients with borderline resectable (n = 138) or locally advanced (n = 121) PDAC underwent vascular resection during tumor resection. From these, 23 patients had AR (n = 4 due to intraoperative injury, n = 19 due to suspected arterial infiltration). However, 12 out of 23 patients (52.2%) underwent simultaneous VR including 1 case with intraoperative arterial injury. In comparison, 11 patients (47.8%) underwent AR only including 3 intraoperative arterial injury patients. Although the operation time and bleeding rate of patients with AR were respectively longer and higher than in VR, no significant difference was detected in postoperative complications between VR and AR (P = 0.11). The final histopathological findings of PDAC patients were similar, including M stage, regional lymph node metastases, and R0 margin resection. The mortality of the entire cohort was 6.2% (16/259), with a tendency to increase mortality in the AR cohort, yet without statistical significance (VR: 5% vs AR: 21.1%; P = 0.05). Although 19 (82.6%) patients had PDAC in the final histopathology, only 6 were confirmed to have infiltrated arteria. The microscopic distribution of PDAC in these infiltrated arterial walls on hematoxylin-eosin staining was classified into 3 patterns. Strikingly, the perivascular nerves frequently exhibited perineural invasion. Conclusions: AR can be performed in high-volume centers for pancreatic surgery with an acceptable morbidity, which is comparable to that of VR. However, the likelihood of arterial infiltration seems to be rather overestimated, and as such, AR might be avoidable or replaced by less invasive techniques such as divestment during PDAC surgery.

Continuous irrigation after pancreatectomy: a systematic review.

PURPOSE: Prevention and management of postoperative pancreatic fistula (POPF) after pancreatic resections is still an unresolved issue. Continuous irrigation of the peripancreatic area is frequently used to treat necrotizing pancreatitis, but its use after elective pancreatic surgery is not well-known. With this systematic review, we sought to evaluate the current knowledge and expertise regarding the use of continuous irrigation in the surgical area to prevent or treat POPF after elective pancreatic resections. METHODS: A systematic search of the literature was conducted according to the PRISMA 2020 guidelines, screening the databases of Pubmed, Scopus, Web of Science, and Ovid MEDLINE. Because of the heterogeneity of the included articles, a statistical inference could not be performed and the literature was reviewed only descriptively. The study was pre-registered online (OSF Registry). RESULTS: Nine studies were included. Three studies provided data regarding the prophylactic use of continuous irrigation after distal and limited pancreatectomies. Here, patients after irrigation showed a lower rate of clinically relevant POPF, related complications, lengths of stay, and mortality. Six other papers reported the use of local lavage to treat clinically relevant POPF and subsequent fluid collections, with successful outcomes. CONCLUSION: In the current literature, only a few publications are focused on the use of continuous irrigation after pancreatic resection to prevent or manage POPF. The included studies showed promising results, and this technique may be useful in patients at high risk of POPF. Further investigations and randomized trials are needed.

Proteogenomic analysis reveals RNA as a source for tumor-agnostic neoantigen identification.

Systemic pan-tumor analyses may reveal the significance of common features implicated in cancer immunogenicity and patient survival. Here, we provide a comprehensive multi-omics data set for 32 patients across 25 tumor types for proteogenomic-based discovery of neoantigens. By using an optimized computational approach, we discover a large number of tumor-specific and tumor-associated antigens. To create a pipeline for the identification of neoantigens in our cohort, we combine DNA and RNA sequencing with MS-based immunopeptidomics of tumor specimens, followed by the assessment of their immunogenicity and an in-depth validation process. We detect a broad variety of non-canonical HLA-binding peptides in the majority of patients demonstrating partially immunogenicity. Our validation process allows for the selection of 32 potential neoantigen candidates. The majority of neoantigen candidates originates from variants identified in the RNA data set, illustrating the relevance of RNA as a still understudied source of cancer antigens. This study underlines the importance of RNA-centered variant detection for the identification of shared biomarkers and potentially relevant neoantigen candidates.

Phenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasion.

Solid cancers like pancreatic ductal adenocarcinoma (PDAC), a type of pancreatic cancer, frequently exploit nerves for rapid dissemination. This neural invasion (NI) is an independent prognostic factor in PDAC, but insufficiently modeled in genetically engineered mouse models (GEMM) of PDAC. Here, we systematically screened for human-like NI in Europe's largest repository of GEMM of PDAC, comprising 295 different genotypes. This phenotype screen uncovered 2 GEMMs of PDAC with human-like NI, which are both characterized by pancreas-specific overexpression of transforming growth factor α (TGF-α) and conditional depletion of p53. Mechanistically, cancer-cell-derived TGF-α upregulated CCL2 secretion from sensory neurons, which induced hyperphosphorylation of the cytoskeletal protein paxillin via CCR4 on cancer cells. This activated the cancer migration machinery and filopodia formation toward neurons. Disrupting CCR4 or paxillin activity limited NI and dampened tumor size and tumor innervation. In human PDAC, phospho-paxillin and TGF-α-expression constituted strong prognostic factors. Therefore, we believe that the TGF-α-CCL2-CCR4-p-paxillin axis is a clinically actionable target for constraining NI and tumor progression in PDAC.