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Background Effective chemotherapy (CTx) protocols as induction treatment provide increasing opportunities for surgical resection of locally advanced pancreatic cancer (LAPC). Although improved survival after resection of LAPC with CTx has been reported for selected patients, reliable recommendations on the indication for conversion surgery after induction treatment are currently lacking. We investigated the factors predictive of prognosis in resected LAPC after FOLFIRINOX. Methods Consecutive patients with LAPC undergoing curative resection after FOLFIRINOX between 2011 and 2018 were identified from a prospectively maintained database. Relevant clinical parameters and CT findings were examined. A scoring system was developed based on the ratio of hazard ratios for overall survival of all significant predictors. Results A total of 62 patients with LAPC who underwent oncologic resection after FOLFIRINOX were analyzed. Tumor shrinkage, tumor density, and postchemotherapy CA19-9 serum levels were independently associated with overall survival (multivariate analysis: HR = 0.31, 0.17, and 0.18, respectively). One, two, and two points were allocated to these three factors in the proposed scoring system, respectively. The median overall survival of patients with a score from 0 to 2 was significantly shorter than that of patients with a score from 3 to 5 (22.1 months vs. 53.2 months, P < 0.001). Conclusions Tumor density is a novel predictive marker for the prognosis of patients with resected LAPC after FOLFIRINOX. A simple scoring model incorporating tumor density, the tumor shrinkage rate, and CA 19-9 levels identifies patients with a low score, who may be candidates for additional treatment.

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CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8+ T cells during early stages of activation. Mice receiving tumor-specific CD8+ T cells treated with CDK4/6 inhibitors displayed increased T-cell persistence and immunologic memory. CDK4/6 inhibition upregulated MXD4, a negative regulator of MYC, in both mouse and human CD8+ T cells. Silencing of Mxd4 or Myc in mouse CD8+ T cells demonstrated the importance of this axis for memory formation. We used single-cell transcriptional profiling and T-cell receptor clonotype tracking to evaluate recently activated human CD8+ T cells in patients with breast cancer before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8+ memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in patients with cancer may augment long-term protective immunity.Significance:CDK4/6 inhibition skews newly activated CD8+ T cells toward a memory phenotype in mice and humans with breast cancer. CDK4/6 inhibitors may have broad utility outside breast cancer, particularly in the neoadjuvant setting to augment CD8+ T-cell priming to tumor antigens prior to dosing with checkpoint blockade.This article is highlighted in the In This Issue feature, p. 2355

Cluster defining genes

Background The treatment of complicated intra-abdominal infections remains a challenge. Both optimal medical and surgical therapy (i.e., source control) are needed to achieve low mortality and morbidity. The objective of this systematic review and meta-analysis is to determine the impact of carbapenem antibiotic therapy compared to other antibiotics in complicated intra-abdominal infections (secondary peritonitis) with an emphasis on mortality and postoperative complications. Methods A systematic literature search from PubMed/Medline and Web of Science databases was carried out. The last search was conducted in August 2022. PRISMA guidelines were followed. Pre-defined outcomes were mortality, treatment success, treatment failure, and adverse events. Results Ten randomized controlled trials, published from 1983 to 2013 with a total of 2377 patients (1255 patients in the carbapenem antibiotics group and 1122 in the control group), were identified. A meta-analysis comparing patients undergoing carbapenem antibiotic therapy and patients receiving other antibiotics was performed. No significant difference regarding mortality (OR 1.19, 95% CI [0.79; 1.82], p = 0.40), treatment success (OR 1.17, 95% CI [0.72; 1.91], p = 0.53), and treatment failure (OR 0.84, 95% CI [0.48; 1.45], p = 0.52) was observed. Carbapenem therapy was associated with fewer adverse events compared to therapy with other antibiotics (OR 0.79, 95% CI [0.65; 0.97], p = 0.022). Conclusion There is currently no evidence that carbapenem antibiotics are superior in terms of mortality, and success or failure for the treatment of complicated intra-abdominal infections (secondary peritonitis). The rate of adverse events is lower under carbapenem therapy compared to control antibiotics. Trial Registration PROSPERO 2018 CRD42018108854.

Checkpoint blockade immunotherapy has failed in pancreatic cancer and other poorly responsive tumor types in part due to inadequate T cell priming. Naive T cells can receive costimulation not only via CD28 but also through TNF superfamily receptors that signal via NF-κB. Antagonists of the ubiquitin ligases cellular inhibitor of apoptosis protein (cIAP)1/2, also called second mitochondria-derived activator of caspases (SMAC) mimetics, induce degradation of cIAP1/2 proteins, allowing for the accumulation of NIK and constitutive, ligand-independent activation of alternate NF-κB signaling that mimics costimulation in T cells. In tumor cells, cIAP1/2 antagonists can increase TNF production and TNF-mediated apoptosis; however, pancreatic cancer cells are resistant to cytokine-mediated apoptosis, even in the presence of cIAP1/2 antagonism. Dendritic cell activation is enhanced by cIAP1/2 antagonism in vitro, and intratumoral dendritic cells show higher expression of MHC class II in tumors from cIAP1/2 antagonism-treated mice. In this study, we use in vivo mouse models of syngeneic pancreatic cancer that generate endogenous T cell responses ranging from moderate to poor. Across multiple models, cIAP1/2 antagonism has pleiotropic beneficial effects on antitumor immunity, including direct effects on tumor-specific T cells leading to overall increased activation, increased control of tumor growth in vivo, synergy with multiple immunotherapy modalities, and immunologic memory. In contrast to checkpoint blockade, cIAP1/2 antagonism does not increase intratumoral T cell frequencies. Furthermore, we confirm our previous findings that even poorly immunogenic tumors with a paucity of T cells can experience T cell–dependent antitumor immunity, and we provide transcriptional clues into how these rare T cells coordinate downstream immune responses.

Background Malnutrition is associated with poor survival in pancreatic cancer patients. Nutritional scores show great heterogeneity diagnosing malnutrition. The aim of this study was to find the score best suitable to identify patients with malnutrition related to worse survival after surgery for pancreatic ductal adenocarcinoma (PDAC). This study represents a follow‐up study to the prospective NURIMAS Pancreas trial that evaluated short term impact of nutritional score results after surgery. Methods Risk of malnutrition was evaluated preoperatively using 12 nutritional assessment scores. Patients were followed‐up prospectively for at least 3 years. Patients at risk for malnutrition were compared with those not at risk according to each score using Kaplan–Meier survival statistics. Results A total of 116 patients receiving a PDAC resection in curative intent were included. Malnutrition according to the Subjective Global Assessment score (SGA), the Short Nutritional Assessment Questionnaire (SNAQ), and the INSYST2 score was associated with worse overall survival (SGA: at‐risk: 392 days; not at‐risk: 942 days; P = 0.001; SNAQ: at‐risk: 508 days; not at‐risk: 971 days; P = 0.027; INSYST2: at‐risk: 538 days; not at risk: 1068; P = 0.049). In the multivariate analysis, SGA (hazard ratio of death 2.16, 95% confidence interval 1.34–3.47, P = 0.002) was associated with worse overall survival. Conclusions Malnutrition as defined by the Subjective Global Assessment is independently associated with worse survival in resected PDAC patients. The SGA should be used to stratify PDAC patients in clinical studies. Severely malnourished patients according to the SGA profit from intensified nutritional therapy should be evaluated in a randomized controlled trial.

CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8+ T cells during early stages of activation. Mice receiving tumor-specific CD8+ T cells treated with CDK4/6 inhibitors displayed increased T-cell persistence and immunologic memory. CDK4/6 inhibition upregulated MXD4, a negative regulator of MYC, in both mouse and human CD8+ T cells. Silencing of Mxd4 or Myc in mouse CD8+ T cells demonstrated the importance of this axis for memory formation. We used single-cell transcriptional profiling and T-cell receptor clonotype tracking to evaluate recently activated human CD8+ T cells in patients with breast cancer before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8+ memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in patients with cancer may augment long-term protective immunity. Significance: CDK4/6 inhibition skews newly activated CD8+ T cells toward a memory phenotype in mice and humans with breast cancer. CDK4/6 inhibitors may have broad utility outside breast cancer, particularly in the neoadjuvant setting to augment CD8+ T-cell priming to tumor antigens prior to dosing with checkpoint blockade. This article is highlighted in the In This Issue feature, p. 2355

Prostate cancers are considered to be immunologically ‘cold’ tumors given the very few patients who respond to checkpoint inhibitor (CPI) therapy. Recently, enrichment of interferon-stimulated genes (ISGs) predicted a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and known to negatively regulate ISGs. In the present study, we demonstrate that EZH2 inhibition in prostate cancer models activates a double-stranded RNA–STING–ISG stress response upregulating genes involved in antigen presentation, Th1 chemokine signaling and interferon response, including programmed cell death protein 1 (PD-L1) that is dependent on STING activation. EZH2 inhibition substantially increased intratumoral trafficking of activated CD8(+) T cells and increased M1 tumor-associated macrophages, overall reversing resistance to PD-1 CPI. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. These data suggest EZH2 inhibition as a therapeutic direction to enhance prostate cancer response to PD-1 CPI.

Objective Advances in multimodality treatment paralleled increasing numbers of complex pancreatic procedures with major vascular resections. The aim of this meta-analysis was to evaluate the current outcomes of arterial resection (AR) in pancreatic surgery. Methods A systematic literature search was carried out from January 2011 until January 2020. MOOSE guidelines were followed. Predefined outcomes were morbidity, pancreatic fistula, postoperative bleeding and delayed gastric emptying, reoperation rate, mortality, hospital stay, R0 resection rate, and lymph node positivity. Duration of surgery, blood loss, and survival were also analyzed. Results Eight hundred and forty-one AR patients were identified in a cohort of 7111 patients. Morbidity and mortality rates in these patients were 66.8% and 5.3%, respectively. Seven studies (579 AR patients) were included in the meta-analysis. Overall morbidity (48% vs 39%, p = 0.1) and mortality (3.2% vs 1.5%, p = 0.27) were not significantly different in the groups with or without AR. R0 was less frequent in the AR group, both in patients without (69% vs 89%, p p p = 0.037). Conclusions Arterial resections increase the complexity of pancreatic surgery, as demonstrated by relevant morbidity and mortality rates. Careful patient selection and multidisciplinary planning remain important.

Pancreatic ductal adenocarcinoma (PDA) is the third most common cause of cancer death in the US with a 11% 5-year survival rate. A key contributor of this dismal prognosis is early and frequent metastatic spread with limited treatment options for patients. Metastasis in PDA is facilitated by a robust fibroinflammatory response in the primary tumor site, a large portion of which is composed of infiltrating immune cells, and survival during transit to establish in the secondary site. In the primary tumor reactive stroma, we found increased eosinophils in both human and mouse PDA compared to the normal pancreas. Eosinophils are an innate immune cell best known for their ability to control parasite responses and have been implicated in either pro- or anti-cancer roles in various solid tumors. We used the ΔdblGata mice, which lack eosinophils, to study the role of eosinophils during metastatic spread using a resectable model of PDA metastasis. This model of metastasis was developed to facilitate consistent seeding of lung metastasis in approximately 50 percent of mice from a transient subcutaneous tumor which undergoes subsequent surgical removal and harvest to evaluate metastasis at 4 weeks. We found that mice lacking eosinophils have increased metastasis to the lung in our resectable model of PDA metastasis but no difference in establishment of IV injected PDA tumor cells, suggesting eosinophil control at the primary tumor site. Single cell sequencing of the subcutaneous tumors finds differences in the angiogenic subtypes, tip and stalk cells, in mice lacking eosinophils. Sequencing of eosinophil populations in humans and mice find an increase in angiogenic signaling suggesting a regulatory role in tumor cell access to the circulation. We conclude that eosinophils in PDA inhibit the metastatic process through control of angiogenic signaling. Citation Format: Megan T. Hoffman, Patrick J. Lenehan, Jennifer Wang, Lestat Ali, Li Qiang, Amiko Uchida, Sara Vayrynen, Andressa Dias Costa, Michael Dougan, Max Heckler, Jonathan Nowak, Brian W. Wolpin, Stephanie K. Dougan. Eosinophils alter metastatic spread in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B018.

Pancreatic ductal adenocarcinoma (PDAC) is an oligosymptomatic disease, that is usually diagnosed in an advanced tumor stage. Traditionally, only the small subset of patients with tumors that showed no signs of vascular infiltration and distant metastases proceeded to surgery-still the only curative therapeutic modality to date. The remaining majority of patients received palliative chemotherapy or chemoradiation, usually with gemcitabine monotherapy. While gemcitabine monotherapy results in improved survival compared to best supportive care, most patients still succumb to the disease under therapy in a relatively short amount of time. Over the last years and decades, paradigms have shifted in PDAC treatment and potent multidrug chemotherapy protocols, including gemcitabine plus nab-paclitaxel and FOLFIRINOX, result in sufficient downstaging of advanced tumors in many patients. In this context, more and more patients are eligible for exploration and often resection. In this review we discuss the current state of the art in the clinical management and surgical treatment of patients with locally advanced pancreatic cancer, including classifications of locally advanced and borderline disease and surgical strategies for extended resections. An emphasis is put on arterial and venous resections and their outcome. In the end, we discuss current gaps in the literature and propose directions future research endeavors should focus on.

Loss of major histocompatibility complex (MHC) class I and interferon (IFN)-γ sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. Thus, additional treatment options are needed for tumors that lose expression of MHC class I. The cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) regulate classical and alternative nuclear factor kappa B (NF-κB) signaling. Induction of non-canonical NF-κB signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting anti-tumor immunity. We show that induction of non-canonical NF-κB signaling induces T cell-dependent immune responses, even in beta-2-microglobulin (β2M)-deficient tumors, demonstrating that direct CD8 T cell recognition of tumor cell expressed MHC class I is not required. Instead, T cell-produced lymphotoxin reprograms both mouse and human macrophages to be tumoricidal. In wild type mice, but not mice incapable of antigen-specific T cell responses, cIAP1/2 antagonism reduces tumor burden by increasing phagocytosis of live tumor cells. Efficacy is augmented by combination with CD47 blockade. Thus, activation of non-canonical NF-κB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade due to loss of MHC class I or IFN-γ sensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.

Objective Malnutrition is associated with poor survival in pancreatic cancer patients. Nutritional scores show great heterogeneity diagnosing malnutrition. The aim of this study was to find the score best suitable to identify patients with malnutrition related to worse survival after surgery for PDAC. Methods Risk of malnutrition was evaluated preoperatively using twelve nutritional assessment scores. Patients were followed-up prospectively for at least 3 years. Patients at risk for malnutrition were compared to those not at risk according to each score using Kaplan Meier survival statistics. Results A total of 116 Patients receiving a PDAC resection in curative intent were included. Malnutrition according to the Subjective Global Assessment score (SGA), the Short Nutritional Assessment Questionnaire (SNAQ) and the INSYST2 score was associated with worse overall survival (SGA: at-risk: 392 days; not at-risk: 942 days; p = 0.001; SNAQ: at-risk: 508 days; not at-risk: 971 days; p = 0.027; INSYST2: at-risk: 538 days; not at risk: 1068; p = 0.049). In the multivariate analysis SGA (HR of death 2.22, 95% CI 1.37-3.6, p = 0.002) was associated with worse overall survival. Conclusion Malnutrition as defined by the Subjective Global Assessment is independently associated with worse survival in resected PDAC patients. The SGA should be used to stratify PDAC patients in clinical studies. If severely malnourished patients according to the SGA profit from intensified nutritional therapy should be evaluated in a randomized controlled trial.

Background Acute pancreatitis (AP) is defined as an acute inflammatory attack of the pancreas of sudden onset. Around 25% of patients have either moderately severe or severe disease with a mortality rate of 15–20%. Purpose The aim of this article was to summarize the advances being made in the understanding of this disease and the important role of surgery. Results and conclusions An accurate diagnosis should be made a soon as possible, initiating resuscitation with large volume intravenous fluids and oxygen by mask. Predicted severe disease will require intensive monitoring. Most deaths within the first week are due to multi-organ failure; thus, these patients will require intensive therapy unit management. During the second phase of the disease, death is due to local complications arising from the pancreatic inflammation, requiring accurate identification to determine the correct form of treatment. Acute peripancreatic fluid collections arise 4 weeks and largely resolve on conservative management. Necrotizing pancreatitis causing acute necrotic collections and later walled-off necrosis will require treatment if symptomatic or infected. Initial endoscopic transgastric or percutaneous drainage will resolve less serious collections but necrosectomy using minimally invasive approaches will be needed for more serious collections. To prevent recurrent attacks of AP, causative factors need to be removed where possible such as cholecystectomy and cessation of alcohol. Future progress requires improved management of multi-organ failure and more effective minimally invasive techniques for the removal of necrosis.

Summary Objectives: Cachexia is a systemic metabolic disorder characterized by loss of fat and muscle mass, which disproportionately impacts patients with gastrointestinal malignancies such as pancreatic cancer. While the immunologic shifts contributing to the development of other adipose tissue (AT) pathologies such as obesity have been well described, the immune microenvironment has not been studied in the context of cachexia. Methods: We performed bulk RNA-sequencing, cytokine arrays, and flow cytometry to characterize the immune landscape of visceral AT (VAT) in the setting of pancreatic and colorectal cancers. Results: The cachexia inducing factor IL-6 is strongly elevated in the wasting VAT of cancer bearing mice, but the regulatory type 2 immune landscape which characterizes healthy VAT is maintained. Pathologic skewing toward Th1 and Th17 inflammation is absent. Similarly, the VAT of patients with colorectal cancer is characterized by a Th2 signature with abundant IL-33 and eotaxin-2, albeit also with high levels of IL-6. Conclusions: Wasting AT during the development of cachexia may not undergo drastic changes in immune composition like those seen in obese AT. Our approach provides a framework for future immunologic analyses of cancer associated cachexia., Graphical Abstract Graphical Abstract

The number of lymph nodes to be resected in surgery for non-pancreatic periampullary cancer remains unclear.The Surveillance, Epidemiology, and End Results (SEER) database was used to gather information from a large retrospective cohort. To define a novel, reasonable cut-off associated with survival, we stratified patients into subgroups depending on the number of resected lymph nodes.1481 nodal-negative patients resected for periampullary cancer (excluding pancreatic ductal adenocarcinoma) were included. The median number of resected lymph nodes was ten. Median overall survival in the subgroup with less than 10 removed lymph nodes was 40 months, while median survival for patients with ≥10 lymph nodes was 97 months (p 0.001). A significant survival benefit was seen if ≥ 16 lymph nodes were harvested (median survival, 117 months), while no further benefit was observed if more than 21 nodes were removed (median survival,120 months).Sixteen or more resected lymph nodes are associated with improved survival in node-negative periampullary carcinoma. We propose to aim at harvesting and analyzing at least 16 lymph nodes.

Background Estimation of the risk of malignancy in intraductal papillary mucinous neoplasia (IPMN) of the pancreas is a clinical challenge. Several routinely used clinical factors form the basis of the current consensus guidelines. This study aimed to determine the predictive values of the most commonly assessed risk factors. Methods A meta-analysis of individual risk factors of malignancy in IPMN was performed. Contingency tables were derived from these data, and sensitivity, specificity, negative and positive predictive values, and diagnostic odds ratios (DOR) were determined. Hierarchical summary receiver operating characteristic (HSROC) curves for each factor were calculated and the respective area under the curve (AUC) was assessed. Results A total of 3443 studies were screened initially. Analysis of recent literature revealed 60 studies with 13 relevant risk factors including clinical, serological and radiological parameters. The largest area under the HSROC curve was found for weight loss (0·84) and jaundice/raised bilirubin level (0·80), followed by increased carcinoembryonic antigen (CEA) (0·79) or carbohydrate antigen (CA) 19-9 (0·78) levels. The most sensitive factors were patient age (71 per cent) and mural nodules (65 per cent), and jaundice/raised bilirubin level (97 per cent) and increased CEA level (95 per cent) were most specific. None of the analysed factors reached a positive or negative level of prediction beyond 90 per cent. Conclusion None of the established criteria safely distinguishes malignant from non-malignant lesions.

Prostate cancers are considered immunologically ‘cold’ tumors given the very few patients who respond to checkpoint inhibitor therapy (CPI). Recently, enrichment of interferon (IFN) response genes predicts a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is over-expressed in prostate cancer and is known to negatively regulate IFN response genes. Here, we demonstrate that inhibition of EZH2 catalytic activity in prostate cancer models derepresses expression of double-strand RNA (dsRNA), associated with upregulation of genes involved in antigen presentation, Th-1 chemokine signaling, and interferon (IFN) response, including PD-L1. Similarly, application of a novel EZH2 derived gene signature to human prostate sample analysis indicated an inverse correlation between tumor EZH2 activity/expression with T-cell inflamed and IFN gene signatures and PD-L1 expression. EZH2 inhibition combined with PD-1 CPI significantly enhances antitumor response that is dependent on up-regulation of tumor PD-L1 expression. Further, combination therapy significantly increases intratumoral trafficking of activated CD8+ T-cells and M1 tumor associated macrophages (TAMs) with concurrent loss of M2 TAMs. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. This data suggests EZH2 inhibition as a novel therapeutic direction to enhance prostate cancer response to PD-1 CPI.

As a potent radiosensitizer nitric oxide (NO) may be a putative adjuvant in the treatment of malignant gliomas which are known for their radio- and chemoresistance. The NO donor prodrug JS-K (O2-(2.4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazin-1-yl] diazen-1-ium-1,2-diolate) allows cell-type specific intracellular NO release via enzymatic activation by glutathione-S-transferases overexpressed in glioblastoma multiforme. The cytotoxic and radiosensitizing efficacy of JS-K was assessed in U87 glioma cells in vitro focusing on cell proliferation, induction of DNA damage, and cell death. In vivo efficacy of JS-K and repetitive irradiation were investigated in an orthotopic U87 xenograft model in mice. For the first time, we could show that JS-K acts as a potent cytotoxic and radiosensitizing agent in U87 cells in vitro. This dose- and time-dependent effect is due to an enhanced induction of DNA double-strand breaks leading to mitotic catastrophe as the dominant form of cell death. However, this potent cytotoxic and radiosensitizing effect could not be confirmed in an intracranial U87 xenograft model, possibly due to insufficient delivery into the brain. Although NO donor treatment was well tolerated, neither a retardation of tumor growth nor an extended survival could be observed after JS-K and/or radiotherapy.

Background & Aims Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas can progress to cancer. Biomarkers have been identified that were reported to increase the accuracy of identification of malignant lesions; we performed a systematic review of the accuracy of these markers. Methods We performed a systematic review of published studies on biomarkers of malignant IPMNs by searching MEDLINE and Web of Science databases from January 2005 through December 2017. Our methods were developed based on the Meta-analysis Of Observational Studies in Epidemiology guidelines. Pooled sensitivity, specificity, receiver operating characteristic curves, and their respective areas under the curve (AUC) were calculated from groups of markers (cell-, protein-, or DNA-based) measured in samples collected before and after surgery. A hypothetical test model was developed to determine how to meaningfully amend the revised Fukuoka guidelines, focusing on increasing test specificity for patients with IPMNs that have worrisome features. Results We collected data from 193 published studies, comprising 12,297 patients, that analyzed 7 preoperative and 21 postoperative markers of IPMNs. The 3 biomarkers that identified malignant IPMNs with the largest AUC values were pancreatic juice cytology (AUC, 0.84; sensitivity, 0.54; specificity, 0.91), serum protein carbohydrate antigen 19-9 (AUC, 0.81; sensitivity, 0.45; specificity, 0.90), and cyst fluid cytology (AUC, 0.82; sensitivity, 0.57; specificity, 0.84). A combination of cytologic and immunohistochemical analysis of MUC1 and MUC2 in pancreatic juice samples identified malignant IPMNs with the largest AUC and sensitivity values (AUC, 0.85; sensitivity, 0.85; specificity, 0.65). In a test model, inclusion of cytologic analysis of pancreatic juice in the guideline algorithm significantly increased the specificity of detection of malignant IPMNs. Conclusions In a systematic review, we found cytologic analysis of pancreatic juice to have the greatest effect in increasing the specificity of detection of malignant IPMNs. We propose addition of this test to the Fukuoka guidelines for assessment of patients with IPMNs with worrisome features.