Phase II trial of vaccination with autologous, irradiated melanoma cells engineered by adenoviral mediated gene transfer to secrete granulocyte-macrophage colony stimulating factor in patients with stage III and IV melanoma.

Background: In the era of immune checkpoint blockade, the role of cancer vaccines in immune priming has provided additional potential for therapeutic improvements. Prior studies have demonstrated delayed type hypersensitivity and anti-tumor immunity with vaccines engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). The safety, efficacy and anti-tumor immunity of GM-CSF secreting vaccine in patients with previously treated stage III or IV melanoma needs further investigation. Methods: In this phase II trial, excised lymph node metastases were processed to single cells, transduced with an adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1x106, 4x106, or 1x107 tumor cells, and were injected intradermally and subcutaneously at weekly and biweekly intervals. The primary endpoints were feasibility of producing vaccine in stage III patients and determining the proportion of patients alive at two years in stage IV patients. Results: GM-CSF vaccine was successfully developed and administered in all 61 patients. Toxicities were restricted to grade 1-2 local skin reactions. The median OS for stage III patients (n = 20) was 71.1 (95% CI, 43.7 to NR) months and 14.9 (95%CI, 12.1 to 39.7) months for stage IV patients. The median PFS in stage III patients was 50.7 (95%CI, 36.3 to NR) months and 4.1 (95% CI, 3.0-6.3) months in stage IV patients. In the overall population, the disease control rate was 39.3% (95%CI, 27.1 to 52.7%). In stage III patients, higher pre-treatment plasma cytokine levels of MMP-1, TRAIL, CXCL-11, CXCL-13 were associated with improved PFS (p<0.05 for all). An increase in post-vaccination levels of IL-15 and TRAIL for stage III patients was associated with improved PFS (p=0.03 for both). Similarly, an increase in post-vaccination IL-16 level for stage IV patients was associated with improved PFS (p=0.02) and clinical benefit. Conclusions: Vaccination with autologous melanoma cells secreting GM-CSF augments antitumor immunity in stage III and IV patients with melanoma, is safe, and demonstrates disease control. Luminex data suggests that changes in inflammatory cytokines and immune cell infiltration promote tumor antigen presentation and subsequent tumor cell destruction. Additional investigation to administer this vaccine in combination with immune checkpoint inhibitors is needed.

PD-1 Blockade Induces Reactivation of Nonproductive T-Cell Responses Characterized by NF-κB Signaling in Patients with Pancreatic Cancer.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) trials have evaluated CTLA-4 and/or PD-(L)1 blockade in patients with advanced disease in which bulky tumor burden and limited time to develop antitumor T cells may have contributed to poor clinical efficacy. Here, we evaluated peripheral blood and tumor T cells from patients with PDAC receiving neoadjuvant chemoradiation plus anti-PD-1 (pembrolizumab) versus chemoradiation alone. We analyzed whether PD-1 blockade successfully reactivated T cells in the blood and/or tumor to determine whether lack of clinical benefit could be explained by lack of reactivated T cells versus other factors. EXPERIMENTAL DESIGN: We used single-cell transcriptional profiling and TCR clonotype tracking to identify TCR clonotypes from blood that match clonotypes in the tumor. RESULTS: PD-1 blockade increases the flux of TCR clonotypes entering cell cycle and induces an IFNγ signature like that seen in patients with other GI malignancies who respond to PD-1 blockade. However, these reactivated T cells have a robust signature of NF-κB signaling not seen in cases of PD-1 antibody response. Among paired samples between blood and tumor, several of the newly cycling clonotypes matched activated T-cell clonotypes observed in the tumor. CONCLUSIONS: Cytotoxic T cells in the blood of patients with PDAC remain sensitive to reinvigoration by PD-1 blockade, and some have tumor-recognizing potential. Although these T cells proliferate and have a signature of IFN exposure, they also upregulate NF-κB signaling, which potentially counteracts the beneficial effects of anti-PD-1 reinvigoration and marks these T cells as non-productive contributors to antitumor immunity. See related commentary by Lander and DeNardo, p. 474.

Protein biomarkers and alternatively methylated cell-free DNA detect early stage pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed. DESIGN: To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites. RESULTS: Comparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92). CONCLUSION: A combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.

A blood-based metabolomic signature predictive of risk for pancreatic cancer.

Emerging evidence implicates microbiome involvement in the development of pancreatic cancer (PaCa). Here, we investigate whether increases in circulating microbial-related metabolites associate with PaCa risk by applying metabolomics profiling to 172 sera collected within 5 years prior to PaCa diagnosis and 863 matched non-subject sera from participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cohort. We develop a three-marker microbial-related metabolite panel to assess 5-year risk of PaCa. The addition of five non-microbial metabolites further improves 5-year risk prediction of PaCa. The combined metabolite panel complements CA19-9, and individuals with a combined metabolite panel + CA19-9 score in the top 2.5th percentile have absolute 5-year risk estimates of >13%. The risk prediction model based on circulating microbial and non-microbial metabolites provides a potential tool to identify individuals at high risk of PaCa that would benefit from surveillance and/or from potential cancer interception strategies.

Intertumoral lineage diversity and immunosuppressive transcriptional programs in well-differentiated gastroenteropancreatic neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare cancers that most often arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic (GEP)-NET growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we investigated the single-cell transcriptomes of tumor and immune cells from patients with gastroenteropancreatic NETs. Malignant GEP-NET cells expressed genes and regulons associated with normal, gastrointestinal endocrine cell differentiation, and fate determination stages. Tumor and lymphoid compartments sparsely expressed immunosuppressive targets commonly investigated in clinical trials, such as the programmed cell death protein-1/programmed death ligand-1 axis. However, infiltrating myeloid cell types within both primary and metastatic GEP-NETs were enriched for genes encoding other immune checkpoints, including VSIR (VISTA), HAVCR2 (TIM3), LGALS9 (Gal-9), and SIGLEC10. Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.

Oncogenic Drivers and Therapeutic Vulnerabilities in KRAS Wild-Type Pancreatic Cancer.

PURPOSE: Approximately 8% to 10% of pancreatic ductal adenocarcinomas (PDAC) do not harbor mutations in KRAS. Understanding the unique molecular and clinical features of this subset of pancreatic cancer is important to guide patient stratification for clinical trials of molecularly targeted agents. EXPERIMENTAL DESIGN: We analyzed a single-institution cohort of 795 exocrine pancreatic cancer cases (including 785 PDAC cases) with a targeted multigene sequencing panel and identified 73 patients (9.2%) with KRAS wild-type (WT) pancreatic cancer. RESULTS: Overall, 43.8% (32/73) of KRAS WT cases had evidence of an alternative driver of the MAPK pathway, including BRAF mutations and in-frame deletions and receptor tyrosine kinase fusions. Conversely, 56.2% of cases did not harbor a clear MAPK driver alteration, but 29.3% of these MAPK-negative KRAS WT cases (12/41) demonstrated activating alterations in other oncogenic drivers, such as GNAS, MYC, PIK3CA, and CTNNB1. We demonstrate potent efficacy of pan-RAF and MEK inhibition in patient-derived organoid models carrying BRAF in-frame deletions. Moreover, we demonstrate durable clinical benefit of targeted therapy in a patient harboring a KRAS WT tumor with a ROS1 fusion. Clinically, patients with KRAS WT tumors were significantly younger in age of onset (median age: 62.6 vs. 65.7 years; P = 0.037). SMAD4 mutations were associated with a particularly poor prognosis in KRAS WT cases. CONCLUSIONS: This study defines the genomic underpinnings of KRAS WT pancreatic cancer and highlights potential therapeutic avenues for future investigation in molecularly directed clinical trials. See related commentary by Kato et al., p. 4527.

Surgical Management of Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PNETs) are relatively uncommon malignancies, characterized as either functional or nonfunctional secondary to their secretion of biologically active hormones. A wide range of clinical behavior can be seen, with the primary prognostic indicator being tumor grade as defined by the Ki67 proliferation index and mitotic index. Surgery is the primary treatment modality for PNETs. While functional PNETs should undergo resection for symptom control as well as potential curative intent, nonfunctional PNETs are increasingly managed nonoperatively. There is increasing data to suggest small, nonfunctional PNETs (less than 2 cm) are appropriate follow with nonoperative active surveillance. Evidence supports surgical management of metastatic disease if possible, and occasionally even surgical management of the primary tumor in the setting of widespread metastases. In this review, we highlight the evolving surgical management of local and metastatic PNETs.

Anatomic Laparoscopic Partial Hepatectomy of a Segment 4a B-Catenin Mutated Adenoma.

BACKGROUND: Although a ß-catenin mutated hepatocellular adenoma (HCA) is a benign liver tumor, it can cause bleeding, obstruction, pain, and hepatocellular carcinoma.1-3 Because surgery needs to balance these risks with its morbidity, a minimally invasive approach may be well suited.4-6 In this report, a strategic approach to minimally invasive resection of HCA encompassing segment 4a (S4a) is reviewed. PATIENT: A 22-year-old woman with abdominal pain was found to have two liver lesions involving segment 4a (5 cm) and segment 8 (S8) (4.5 cm). Liver biopsy confirmed a ß-catenin mutated HCA in the S4a lesion. After embolization, an anatomic S4a segmentectomy and a partial S8 resection were planned. TECHNIQUE: Three-dimensional modeling was used to perform a preoperative virtual hepatectomy; to visualize the spatial relationship between the HCA, the portal bifurcation, and the hepatic veins; and to preplan the port sites.7 With the patient in the French position, after port placement, intraoperative ultrasound was performed to identify the transection plane.8 The main left portal pedicle and Rex's recessus were exposed, and the branches of S4a were dissected out, clipped, and divided. Using ultrasound, the middle hepatic vein was exposed to define the lateral border of the dissection plane. CONCLUSION: Although a ß-catenin mutated HCA in S4a does not necessitate a formal segmentectomy, understanding the anatomic structures outlining its borders can facilitate the resection, especially for a large HCA. Virtual hepatectomy helps to achieve a detailed comprehension of the complex borders of segment 4a. Preoperative embolization can firm up the tumor and minimize the risk of intraoperative rupture from manipulation.

Four-Day Robotic Whipple: Early Discharge after Robotic Pancreatoduodenectomy.

BACKGROUND: The authors aimed to assess the safety of an enhanced recovery after surgery (ERAS) and early discharge pathway in a robotic pancreatoduodenectomy (PD) program and compared outcomes with an open PD control cohort to identify the synergistic effects of robotic surgery and an ERAS pathway on lengths of stay (LOS). STUDY DESIGN: Consecutive patients undergoing open or robotic PD from a single surgeon between March 2020 and July 2022 were identified. Logistic regression models were used for adjusted analyses of postoperative outcomes. RESULTS: There were 134 consecutive PD patients, of which 40 (30%) were performed robotically. Pancreatic adenocarcinoma was the most common indication in both open (56%) and robotic (55%, p = 0.51) groups, with a similar proportion of them being borderline resectable or locally advanced tumors (78% vs 82% in robotic group, p = 0.82). The LOS was significantly shorter in the robotic PD group (median, 5 [IQR 4 to 7] days) when compared with the open PD group (median, 6 [IQR 5 to 8] days, p < 0.001). LOS of 4 days or fewer were observed in 40% of the robotic PD group compared with only 3% of patients in the open PD group (p < 0.001). There was no difference in the overall readmission rate (10% vs 12% in the robotic PD group, p = 0.61). On multivariable logistic regression, robotic PD was independently associated with higher odds of LOS of 4 days or fewer (odds ratio 22.4, p = 0.001) when compared with open PD. CONCLUSIONS: An ERAS and early discharge pathway could be safely implemented in a robotic PD program. Patients undergoing robotic PD have significantly shorter length of stay without increased complication or readmission rate compared with open PD, with 40% of patients undergoing robotic PD achieving a LOS of 4 days or fewer.

Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity.

Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed at the scale of individual glands, and was significantly reduced in patient-derived organoid cultures. Tumor cells co-expressing classical and basal markers were present in > 90% of tumors, existed on a basal-classical polarization continuum, and were enriched in tumors containing a greater admixture of basal and classical cell populations. Cell-cell neighbor analyses within tumor glands further suggested that co-expressor cells may represent an intermediate state between expression subtype poles. The extensive intratumoral heterogeneity identified through this clinically applicable mIF pipeline may inform prognosis and treatment selection for patients with PDAC. SIGNIFICANCE: A high-throughput pipeline using multiplex immunofluorescence in pancreatic cancer reveals striking expression subtype intratumoral heterogeneity with implications for therapy selection and identifies co-expressor cells that may serve as intermediates during subtype switching.

Neoadjuvant Chemotherapy Is Associated with Altered Immune Cell Infiltration and an Anti-Tumorigenic Microenvironment in Resected Pancreatic Cancer.

PURPOSE: Neoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood. DESIGN: We employed quantitative, spatially resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states, and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n = 299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n = 36) or up-front surgery (n = 30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient outcomes. RESULTS: In the multi-institutional resection cohort, immune cells exhibited substantial heterogeneity across patient tumors and were located predominantly in stromal regions. Unsupervised clustering using immune cell densities identified four main patterns of immune cell infiltration. One pattern, seen in 20% of tumors and characterized by abundant T cells (T cell-rich) and a paucity of immunosuppressive granulocytes and macrophages, was associated with improved patient survival. Neoadjuvant chemotherapy was associated with a higher CD8:CD4 ratio, greater M1:M2-polarized macrophage ratio, and reduced CD15+ARG1+ immunosuppressive granulocyte density. Within neoadjuvant-treated tumors, 72% showed a T cell-rich pattern with low immunosuppressive granulocytes and macrophages. M1-polarized macrophages were located closer to tumor cells after neoadjuvant chemotherapy, and colocalization of M1-polarized macrophages and tumor cells was associated with greater tumor pathologic response and improved patient survival. CONCLUSIONS: Neoadjuvant chemotherapy with FOLFIRINOX shifts the PDAC immune microenvironment toward an anti-tumorigenic state associated with improved patient survival.

High endothelial venules as potential gateways for therapeutics.

High endothelial venules (HEVs) are specialized blood vessels that support the migration of lymphocytes from the bloodstream into lymph nodes (LNs). They are also formed ectopically in mammalian organs affected by chronic inflammation and cancer. The recent arrival of immunotherapy at the forefront of many cancer treatment regimens could boost a crucial role for HEVs as gateways for the treatment of cancer. In this review, we describe the microanatomical and biochemical characteristics of HEVs, mechanisms of formation of newly made HEVs, immunotherapies potentially dependent on HEV-mediated T cell homing to tumors, and finally, how HEV-targeted therapies might be used as a complementary approach to potentially shape the therapeutic landscape for the treatment of cancer and immune-mediated diseases.

Association of Liver Resection and Visiting More Than One Commission on Cancer Hospital for Colorectal Cancer With Liver Metastasis.

INTRODUCTION: Despite the advances in treatment, there are low rates of liver metastasectomy for colorectal cancer with liver metastasis (CRLM) in the United States. The aim of this study was to investigate the association between likelihood of liver metastasectomy for CRLM and seeking care at >1 versus 1 Commission on Cancer (CoC) hospital. METHODS: We performed a retrospective analysis of the National Cancer Database (2011-2017) for patients with CRLM. Patients were grouped based on seeking care at 1 CoC hospital or >1 CoC hospital. An adjusted multivariable Poisson regression interaction analysis was used to evaluate likelihood of liver metastasectomy for CRLM according to race and whether care was sought at >1 CoC hospital. RESULTS: We identified 25,956 patients with CRLM without extra-hepatic disease. 23,088 (89.0%) patients visited 1 CoC hospital and 2868 (11.1%) visited >1 CoC hospital. Black patients were less likely to seek care at >1 CoC hospital (relative risk [RR] 0.68, confidence intervalCI 0.60-0.76, P < 0.001). Undergoing liver metastasectomy was associated with higher likelihood of seeking care at >1 CoC hospital (RR 1.27, CI 1.26-1.52, P < 0.001). Among patients who sought care at >1 CoC hospital, there was no significant difference between White and Black patients undergoing liver metastasectomy (RR 0.86, 95% CI 0.71-1.04, P = 0.11). CONCLUSIONS: Patients with CRLM who sought care at >1 CoC hospital were more likely to undergo a liver metastasectomy. Among White and Black patients who sought care at >1 CoC hospital, there was no difference in likelihood of undergoing a liver metastasectomy.

Association between race, hospital volume of major liver surgery, and access to metastasectomy for colorectal liver metastasis.

BACKGROUND: Previous studies have demonstrated that non-White patients with colorectal liver metastasis (CRLM) were significantly less likely to undergo liver metastasectomy compared to White patients. The aim of this study is to evaluate differences in access to liver metastasectomy for CRLM according to race and hospital-year volume of liver surgery (HVLS). METHODS: The National Cancer Database (2011-2017) was used to identify patients with CRLM. Hospitals were stratified into quartiles according to HVLS. An adjusted Poisson regression model was used to evaluate the interaction between race and HVLS and access to liver metastasectomy. RESULTS: We identified 27,340 patients with CRLM. Non-White patients were less likely to undergo a liver metastasectomy compared to White patients (RR 0.87, 95% CI 0.82-0.91, p < 0.001). This racial disparity persisted at the highest quartile HVLS hospitals. CONCLUSIONS: Receiving cancer care at hospitals with the highest HVLS did not translate into equal access to liver metastasectomy for non-White patients with CRLM.

AHPBA guidelines for managing VTE prophylaxis and anticoagulation for pancreatic surgery.

BACKGROUND: Major abdominal surgery and malignancy lead to a hypercoagulable state, with a risk of venous thromboembolism (VTE) of approximately 3% after pancreatic surgery. No guidelines exist to assist surgeons in managing VTE prophylaxis or anticoagulation in patients undergoing elective pancreatic surgery for malignancy or premalignant lesions. A systematic review specific to VTE prophylaxis and anticoagulation after resectional pancreatic surgery is herein provided. METHODS: Six topic areas are reviewed: pre- and perioperative VTE prophylaxis, early postoperative VTE prophylaxis, extended outpatient VTE prophylaxis, management of chronic anticoagulation, anti-coagulation after vascular reconstruction, and treatment of VTE. A Medline and PubMED search was completed with systematic medical literature review for each topic. Level of evidence was graded and strength of recommendation ranked according to the GRADE (Grades of Recommendation Assessment, Development and Evaluation) system for practice guidelines. RESULTS: Levels of evidence and strength of recommendations are presented. DISCUSSION: While strong data exist to guide management of chronic anticoagulation and treatment of VTE, data for anticoagulation after reconstruction is inconclusive and support for perioperative chemoprophylaxis with pancreatic surgery is similarly limited. The risk of post-pancreatectomy hemorrhage often exceeds that of thrombosis. The role of universal chemoprophylaxis must therefore be examined critically, particularly in the preoperative setting.

Socioeconomic Disparities in Pancreas Cancer Resection and Survival in the Veterans Health Administration.

BACKGROUND: Disparities based on socioeconomic factors such as race, ethnicity, marital status, and insurance status are associated with pancreatic cancer resection, but these disparities are usually not observed for survival after resection. It is unknown if there are disparities when patients undergo their treatment in a non-fee-for-service, equal-access healthcare system such as the Veterans Health Administration (VHA). METHODS: Patients having T1-T3 M0 pancreatic adenocarcinoma diagnosed between 2006 and 2017 were identified from the VHA Corporate Data Warehouse. Socioeconomic, demographic, and tumor variables associated with resection and survival were assessed. RESULTS: In total, 2580 patients with early-stage pancreatic cancer were identified. The resection rate was 36.5%. Surgical resection was independently associated with younger age [odds ratio (OR) 0.94, p < 0.001], White race (OR 1.35, p = 0.028), married status (OR 1.85, p = 0.001), and employment status (retired vs. unemployed, OR 1.41, p = 0.008). There were no independent associations with Hispanic ethnicity, geographic region, or Social Deprivation Index. Resection was associated with significantly improved survival (median 21 vs. 8 months, p = 0.001). Among resected patients, survival was independently associated with younger age (HR 1.019, p = 0.002), geographic region (South vs. Pacific West, HR 0.721, p = 0.005), and employment (employed vs. unemployed, HR 0.752, p = 0.029). Race, Hispanic ethnicity, marital status, and Social Deprivation Index were not independently associated with survival after resection. CONCLUSIONS: Race, marital status, and employment status are independently associated with resection of pancreatic cancer in the VHA, whereas geographic region and employment status are independently associated with survival after resection. Further studies are warranted to determine the basis for these inequities.

Benefit of Primary Tumor Resection in Stage IV, Grade 1 and 2, Pancreatic Neuroendocrine Tumors: A Propensity-Score Matched Cohort Study.

Objective: To determine the association of primary tumor resection in stage IV pancreatic neuroendocrine tumors (Pan-NET) and survival in a propensity-score matched study. Background: Pan-NET are often diagnosed with stage IV disease. The oncologic benefit from primary tumor resection in this scenario is debated and previous studies show contradictory results. Methods: Patients from 3 tertiary referral centers from January 1, 1985, through December 31, 2019: Uppsala University Hospital (Uppsala, Sweden), Sahlgrenska University Hospital (Gothenburg, Sweden), and Brigham and Women's Hospital/Dana-Farber Cancer Institute (Boston, USA) were assessed for eligibility. Patients with sporadic, grade 1 and 2, stage IV pan-NET, with baseline 2000-2019 were divided between those undergoing primary tumor resection combined with oncologic treatment (surgery group [SG]), and those who received oncologic treatment without primary tumor resection (non-SG). A propensity-score matching was performed to account for the variability in the extent of metastatic disease and comorbidity. Primary outcome was overall survival. Results: Patients with stage IV Pan-NET (n = 733) were assessed for eligibility, 194 were included. Patients were divided into a SG (n = 65) and a non-SG (n = 129). Two isonumerical groups with 50 patients in each group remained after propensity-score matching. The 5-year survival was 65.4% (95% CI, 51.5-79.3) in the matched SG and 47.8% (95% CI, 30.6-65.0) in the matched non-SG (log-rank, P = 0.043). Conclusions: Resection of the primary tumor in patients with stage IV Pan-NET and G1/G2 grade was associated with prolonged overall survival compared to nonoperative management. A surgically aggressive regime should be considered where resection is not contraindicated.