Adjuvant chemotherapy for adenocarcinoma arising from intraductal papillary mucinous neoplasia: multicentre ADENO-IPMN study.

BACKGROUND: The clinical impact of adjuvant chemotherapy after resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia is unclear. The aim of this study was to identify factors related to receipt of adjuvant chemotherapy and its impact on recurrence and survival. METHODS: This was a multicentre retrospective study of patients undergoing pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasia between January 2010 and December 2020 at 18 centres. Recurrence and survival outcomes for patients who did and did not receive adjuvant chemotherapy were compared using propensity score matching. RESULTS: Of 459 patients who underwent pancreatic resection, 275 (59.9%) received adjuvant chemotherapy (gemcitabine 51.3%, gemcitabine-capecitabine 21.8%, FOLFIRINOX 8.0%, other 18.9%). Median follow-up was 78 months. The overall recurrence rate was 45.5% and the median time to recurrence was 33 months. In univariable analysis in the matched cohort, adjuvant chemotherapy was not associated with reduced overall (P = 0.713), locoregional (P = 0.283) or systemic (P = 0.592) recurrence, disease-free survival (P = 0.284) or overall survival (P = 0.455). Adjuvant chemotherapy was not associated with reduced site-specific recurrence. In multivariable analysis, there was no association between adjuvant chemotherapy and overall recurrence (HR 0.89, 95% c.i. 0.57 to 1.40), disease-free survival (HR 0.86, 0.59 to 1.30) or overall survival (HR 0.77, 0.50 to 1.20). Adjuvant chemotherapy was not associated with reduced recurrence in any high-risk subgroup (for example, lymph node-positive, higher AJCC stage, poor differentiation). No particular chemotherapy regimen resulted in superior outcomes. CONCLUSION: Chemotherapy following resection of adenocarcinoma arising from intraductal papillary mucinous neoplasia does not appear to influence recurrence rates, recurrence patterns or survival.

Identifying predictors for comorbidities related mortality versus pancreatic cancer related mortality in patients with intraductal papillary mucinous neoplasm.

BACKGROUNDS: Few data are available for surveillance decisions focusing on factors related to mortality, as the primary outcome, in intraductal papillary mucinous neoplasm (IPMN) patients. AIMS: We aimed to identify imaging features and patient backgrounds associated with mortality risks by comparing pancreatic cancer (PC) and comorbidities. METHODS: We retrospectively conducted a multicenter long-term follow-up of 1864 IPMN patients. Competing risk analysis was performed for PC- and comorbidity-related mortality. RESULTS: During the median follow-up period of 5.5 years, 14.0% (261/1864) of patients died. Main pancreatic duct ≥5 mm and mural nodules were significantly related to all-cause and PC-related mortality, whereas cyst ≥30 mm did not relate. In 1730 patients without high-risk imaging features, 48 and 180 patients died of PC and comorbidity. In the derivation cohort, a prediction model for comorbidity-related mortality was created, comprising age, cancer history, diabetes mellitus complications, chronic heart failure, stroke, paralysis, peripheral artery disease, liver cirrhosis, and collagen disease in multivariate analysis. If a patient had a 5 score, 5- and 10-year comorbidity-related mortality is estimated at 18.9% and 50.2%, respectively, more than 7 times higher than PC-related mortality. The model score was also significantly associated with comorbidity-related mortality in a validation cohort. CONCLUSIONS: This study demonstrates main pancreatic duct dilation and mural nodules indicate risk of PC-related mortality, identifying patients who need periodic examination. A comorbidity-related mortality prediction model based on the patient's age and comorbidities can stratify patients who do not require regular tests, especially beyond 5 years, among IPMN patients without high-risk features. CLINICAL TRIAL REGISTRATION: T2022-0046.

Gastrointestinal cancer precursor risk and mortality in pancreatic intraductal papillary mucinous neoplasms: a nationwide cohort study.

BACKGROUND AND AIMS: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a precursor of pancreatic cancer. While earlier research has shown a high prevalence of synchronous/metachronous extrapancreatic tumors in IPMN patients, these studies have often been small with retrospective data collection. The aim of the study was to examine absolute and relative risks of non-pancreatic gastrointestinal (GI) cancer precursors and mortality in histologically confirmed IPMN. METHODS: Through the nationwide ESPRESSO histopathology cohort, we retrieved data on IPMN between 1965 and 2016. Each index case was matched to ≤5 general population controls. Through Cox regression, we estimated hazard ratios (HRs) for future GI cancer precursors and death. RESULTS: A total of 117 patients with IPMN and 539 age- and sex-matched controls were included. Over a median of 2.1 years of follow up, we confirmed two (1.7%) incident GI cancer precursors in IPMN vs. four (0.7%) in controls, corresponding to an HR of 1.89 (95%CI = 0.34-10.55). By contrast, IPMN patients were at increased risk of death (HR 3.61 (95%CI = 1.79-7.27)). The most common cause of death in IPMN was pancreatic cancer (n = 14; 45.2% of all deaths). CONCLUSIONS: We found no association between IPMN and other GI cancer precursors. This argues against comprehensive routine surveillance for other GI cancer precursors in IPMN patients. Mortality was increased in IPMN with pancreatic cancer being the most common cause of death, indicating the need for lifelong follow up in all resected and non-resected patients with IPMN. However, results should be confirmed in larger cohorts.

Histopathological evaluation of resected intraductal papillary mucinous neoplasms reveals distinct patterns of invasion in associated carcinomas.

Invasive intraductal papillary mucinous neoplasms (inv-IPMNs) have a better prognosis than regular pancreatic ductal adenocarcinoma (PDAC), but no association with status of surgical margins and microscopic infiltration patterns has previously been described. The aim of this study is to review patterns of invasion and the predictive value of clinical guidelines in terms of rates of resection of high-grade dysplasia (HGD) and cancer among intraductal papillary mucinous neoplasms (IPMNs). Consecutively, resected IPMNs between 2011 and 2017 were analyzed. Data were obtained from a prospectively maintained database. A total of 132 patients were identified. Out of these, 38 patients with inv-IPMNs, initially identified as solid lesions suspicious of cancer, were compared with a control group of 101 patients with ordinary PDAC. Lower rates of vascular invasion, perineural invasion, lymph node metastasis, advanced T stage, and R1 status were characteristic of the inv-IPMNs in addition to better overall survival (OS) for a low tumor stage. Furthermore, as novel findings, the PDACs presented with resection margin involvement of 3 or more positive margins (31.3% vs. 9.5%, p = 0.044), associated with poor OS. Of the patients presenting as pT3, the inv-IPMN less often invaded more than one extrapancreatic anatomical structure (40.1% vs. 63.9%, p = 0.03). Regarding the predictive value of clinical guidelines, the frequency of resected HGD in IPMNs with high-risk stigmata (n = 54) and IPMNs with worrisome features was 30.7%, and the frequency of invasive carcinoma was 5.7%. In conclusion, we report a low resection rate of high-risk IPMNs and present novel findings describing inv-IPMNs as a less infiltrative phenotype compared with regular PDAC.

Artificial neural networks versus LASSO regression for the prediction of long-term survival after surgery for invasive IPMN of the pancreas.

Prediction of long-term survival in patients with invasive intraductal papillary mucinous neoplasm (IPMN) of the pancreas may aid in patient assessment, risk stratification and personalization of treatment. This study aimed to investigate the predictive ability of artificial neural networks (ANN) and LASSO regression in terms of 5-year disease-specific survival. ANN work in a non-linear fashion, having a potential advantage in analysis of variables with complex correlations compared to regression models. LASSO is a type of regression analysis facilitating variable selection and regularization. A total of 440 patients undergoing surgical treatment for invasive IPMN of the pancreas registered in the Surveillance, Epidemiology and End Results (SEER) database between 2004 and 2016 were analyzed. The dataset was prior to analysis randomly split into a modelling and test set (7:3). The accuracy, precision and F1 score for predicting mortality were 0.82, 0.83 and 0.89, respectively for ANN with variable selection compared to 0.79, 0.85 and 0.87, respectively for the LASSO-model. ANN using all variables showed similar accuracy, precision and F1 score of 0.81, 0.85 and 0.88, respectively compared to a logistic regression analysis. McNemar´s test showed no statistical difference between the models. The models showed high and similar performance with regard to accuracy and precision for predicting 5-year survival status.

Neutrophil-to-lymphocyte Ratio as a Predictor of Malignancy of Intraductal Papillary Mucinous Neoplasms.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) can lead, via the adenoma-carcinoma sequence, to invasive adenocarcinoma, which has a poor prognosis. Most IPMNs do not meet the indications for surgery and instead are monitored regularly, but no biomarkers of malignant transformation during surveillance have been established. PATIENTS AND METHODS: A total of 50 patients with IPMN who underwent pancreatectomy were evaluated retrospectively. Clinicopathological parameters during the surveillance period before surgery were assessed to explore biomarkers for predicting malignancy. RESULTS: The serum level of carbohydrate antigen 19-9 was significantly higher in IPMN-derived invasive adenocarcinoma. The neutrophil-to-lymphocyte ratio was significantly lower in low-grade IPMN than high-grade and Inv-IPMN cases by univariate and multivariate analysis. Disease-free survival was significantly shorter in patients with high-grade and invasive IPMN compared with those with low-grade IPMN. In patients whose preoperative surveillance was performed for more than 12 months, the neutrophil-to-lymphocyte ratio was significantly higher in those with high-grade and invasive IPMNs compared with patients with low-grade IPMN in the year before surgery. CONCLUSION: The NLR is a useful biomarker for distinguishing between low-grade and high-grade IPMN and thus should be monitored during surveillance.

Analyzing and predicting the LNM rate and prognosis of patients with intraductal papillary mucinous neoplasm of the pancreas.

BACKGROUND: Current the surveillance and management are controversial for patients with IPMN. We aimed to develop an alternative nomogram to individualize IPMN prognosis and LNM. METHODS: Based on the data from SEER database of patients diagnosed with IPMN between 2004 and 2015, a nomogram predicting the survival and LNM of IPMN based on univariate and multivariate and Lasso regression analysis was performed, internally and externally validated, and measured by C-index, and decision curve analysis (DCA), and compared to the 7th TNM stage. RESULTS: A total of 941 patients were included. Age, T stage examined nodes, tumor size, and pathology grade were identified as an independent factor for predicting LNM. The nomogram we established to predict LNM had a high predicting value with a C-index value of 0.735 and an AUC value of 0.753. Interestingly, including T1 stage, we found an inverse correlation was between age and LNM. In addition, nomogram for predicting CSS also performed better than TNM stage both in the internal validation group (1-year AUC:0.753 vs. 0.693, 3-year AUC: 0.801 vs. 0.731, 5-year AUC: 0.803 vs. 0.733) and external validation group (1-year AUC: 0.761 vs. 0.701, 3-year AUC: 0.772 vs. 0.713, 5-year AUC:0.811 vs. 0.735). DCA analysis showed the nomogram showed a greater benefit across the period of follow-up compared to 7th TNM stage. CONCLUSION: A nomogram based on multivariate and Lasso regression analysis showed great clinical usability compared with current criteria. Also, for LNM of IPMN, younger age patients with IPMN should be attached more importance.

Facility Type Affects Treatment Outcomes for Patients With Mucinous Cystic Neoplasms and Intraductal Papillary Mucinous Neoplasms of the Pancreas.

OBJECTIVE: Academic centers report better outcomes for pancreatic ductal adenocarcinoma. We hypothesized that treatment outcomes for mucinous cysts differ according to institution type. METHODS: Using the National Cancer Data Base, we analyzed data on patients with mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs). RESULTS: Of 3278 identified patients, 2622 (80%) had IPMNs and 656 (20%) had MCNs. While most academic/research programs (ARCPs, 84.9%) treated more than 10 patients/year, this was true for only 59% of integrated network cancer programs, 37.3% of comprehensive community cancer programs, and 0% of community cancer programs (P < 0.001). Surgery was used more often in ARCPs and for smaller tumors. The ARCPs had higher rates of margin negative resections with retrieval of 15 or more nodes with the lowest 30- and 90-day mortality rates. The median overall survival was better in ARCPs (110.3 months) than comprehensive community cancer programs (75.1 mo), community cancer programs (75.1 mo), or integrated network cancer programs (100.8 mo, P < 0.001). CONCLUSIONS: Treatment of MCNs and IPMNs of the pancreas at academic centers is associated with a higher probability of pancreatectomy, disease identification in a noninvasive stage, and better overall survival. Centralization of care for mucinous pancreatic cysts will lead to improved outcomes.

[Clinical profile and results of acute pancreatitis in the Intensive and Intermediate Care Unit of a general hospital]. / Perfil clínico y resultados de la pancreatitis aguda en la Unidad de Cuidados Intensivos e Intermedios de un hospital genera.

Acute pancreatitis (AP) is an acute inflammatory process of the pancreas that, according to the 2012 Atlanta classification, can be mild, moderate or severe. OBJECTIVE: Describe the epidemiological, clinical, therapeutic and outcomes of patients with AP admitted to the intensive care and intermediate care unit of a general hospital and compare them with those described in the national and international literature. MATERIALS AND METHODS: Observational study of patients with AP treated over a period of 3 years. RESULTS: 59 cases were included; the female sex prevailed (54.2%), the average age was 59.3 years, the most frequent etiology was biliary (84.7%). Average entry severity scores were APACHE II of 12.4 points, SOFA of 4.9 points and Marshall modified of 2.8 points; The most frequent organ failure was respiratory (47.5%). The average stay in care was 13.9 days and in the hospital it was 23.3 days. No patients with mild or moderate AP died during their hospital stay, 6 patients with severe AP died during their hospital stay (20% of cases of severe AP). CONCLUSION: The cases of our hospital had a clinical and therapeutic profile similar to that described in the world and Latin American literature. A hospital staying was greater than that described in recent works, but our mortality was lower.

Review of the diagnosis and management of intraductal papillary mucinous neoplasms.

Intraductal papillary mucinous neoplasms are common lesions with the potential of harbouring/developing a pancreatic cancer. An accurate evaluation of intraductal papillary mucinous neoplasms with high-resolution imaging techniques and endoscopic ultrasound is mandatory in order to identify patients worthy either of surgical treatment or surveillance. In this review, the diagnosis and management of patients with intraductal papillary mucinous neoplasms are discussed with a specific focus on current guidelines. Areas of uncertainty are also discussed, as there are controversies related to the optimal indications for surgery, surveillance protocols and surveillance discontinuation.

Nomograms predicting long-term survival in patients with invasive intraductal papillary mucinous neoplasms of the pancreas: A population-based study.

BACKGROUND: There are few effective tools to predict survival in patients with invasive intraductal papillary mucinous neoplasms of the pancreas. AIM: To develop comprehensive nomograms to individually estimate the survival outcome of patients with invasive intraductal papillary mucinous neoplasms of the pancreas. METHODS: Data of 1219 patients with invasive intraductal papillary mucinous neoplasms after resection were extracted from the Surveillance, Epidemiology, and End Results database, and randomly divided into the training (n = 853) and the validation (n = 366) cohorts. Based on the Cox regression model, nomograms were constructed to predict overall survival and cancer-specific survival for an individual patient. The performance of the nomograms was measured according to discrimination, calibration, and clinical utility. Moreover, we compared the predictive accuracy of the nomograms with that of the traditional staging system. RESULTS: In the training cohort, age, marital status, histological type, T stage, N stage, M stage, and chemotherapy were selected to construct nomograms. Compared with the American Joint Committee on Cancer 7th staging system, the nomograms were generally more discriminative. The nomograms passed the calibration steps by showing high consistency between actual probability and nomogram prediction. Categorial net classification improvements and integrated discrimination improvements suggested that the predictive accuracy of the nomograms exceeded that of the American Joint Committee on Cancer staging system. With respect to decision curve analyses, the nomograms exhibited more preferable net benefit gains than the staging system across a wide range of threshold probabilities. CONCLUSION: The nomograms show improved predictive accuracy, discrimination capability, and clinical utility, which can be used as reliable tools for risk classification and treatment recommendations.

Surgical strategy for intraductal papillary mucinous neoplasms of the pancreas.

The current treatment strategy for intraductal papillary mucinous neoplasms (IPMNs), based on the international consensus guideline, has been accepted widely. However, reported outcomes after surgical resection for IPMN show that once the tumor progresses to invasive intraductal papillary mucinous carcinoma (IPMC), recurrence is not uncommon. The surgical treatment for IPMN is invasive and sometimes followed by complications. Therefore, the best timing for resection might be at the point when high-grade dysplasia (HGD) is evident. According to previous reports, main duct type IPMN has a high malignant potential and its surgical resection is universally accepted, whereas, the incidence of HGD/invasive IPMC in branch duct and mixed type IPMNs is thought to be lower. In addition to mural nodules and a dilated main pancreatic duct, cytology and measurement of the carcinoembryonic antigen level in the pancreatic juice might be useful to differentiate HGD/invasive IPMC from low-grade dysplasia. The nomogram proposed recently to predict the risk of HGD/invasive IPMC in IPMN patients might help surgeons decide on the best treatment strategy, depending on the patient's age and general condition. Second resection for high-risk lesions in the remnant pancreas might improve the survival of IPMN patients.

Management and outcomes of intraductal papillary mucinous neoplasms.

Background: This study evaluated the outcome and survival of patients with radiologically suspected intraductal papillary mucinous neoplasms (IPMNs). Methods: IPMN management was reviewed according to Fukuoka risk factors and IPMN localization, differentiating main-duct (MD), mixed-type (MT) and branch-duct (BD) IPMNs. Perioperative results were compared with those of patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) over the same interval (2010-2014). Overall (OS) and disease-specific (DSS) survival rates were calculated and subgroups compared. Results: Of 142 patients with IPMNs, 26 had MD-IPMN, eight had MT-IPMN and 108 had BD-IPMN. Some 74 per cent of patients with MD- and MT-IPMN were managed by primary resection, whereas this was used in only 27·8 per cent of those with BD-IPMN. The risk of secondary resection and malignant transformation for BD-IPMNs smaller than 20 mm was 8 and 2 per cent respectively during follow-up. Pancreatic head resection of IPMNs was associated with an increased risk of postoperative pancreatic fistula grade B/C compared with resection of PDAC (12 of 33 (36 per cent) versus 41 of 221 (18·6 per cent) respectively; P = 0·010), and greater morbidity and mortality (Clavien-Dindo grade III: 15 of 33 (45 per cent) versus 56 of 221 (25·3 per cent) respectively; grade IV: 1 (3 per cent) versus 7 (3·2 per cent); grade V: 2 (6 per cent) versus 2 (0·9 per cent); P = 0·008). Five-year OS and DSS rates in patients with MD-IPMN were worse than those for MT- and BD-IPMN (OS: 44, 86 and 97·4 per cent respectively, P < 0·001; DSS: 60, 100 and 98·6 per cent; P < 0·001). Patients with invasive IPMN had worse OS and DSS rates than those with non-invasive dysplasia (OS: IPMN-carcinoma (10 patients) 33 per cent, high-grade dysplasia 100 per cent, intermediate-grade dysplasia 63 per cent, low grade-dysplasia 100 per cent, P < 0·001; DSS: IPMN-carcinoma 43 per cent, all grades of dysplasia 100 per cent, P < 0·001). Patients with high-risk stigmata had poorer survival than those without risk factors (OS: high-risk stigmata (35 patients) 55 per cent, worrisome features (31) 95 per cent, no risk factors (76) 100 per cent, P < 0·001; DSS: 71, 100 and 100 per cent respectively, P < 0·001). Conclusion: The risk of malignant transformation was very low for BD-IPMNs, but the development of high-risk stigmata was associated with disease-specific mortality. Patients with IPMN had greater morbidity after resection than those having resection of PDAC.

"Trivial" Cysts Redefine the Risk of Cancer in Presumed Branch-Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas: A Potential Target for Follow-Up Discontinuation?

OBJECTIVES: The management of small and incidental branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) still is of concern. The aim is assessing the safety of a surveillance protocol through the evaluation of their progression to malignancy. METHODS: All presumed BD-IPMNs observed from 2000 to 2016 were included. Only patients presenting without worrisome features (WFs) and high-risk stigmata (HRS) at diagnosis were included. Development of WF, HRS, pancreatic cancer (PC), and survival were analyzed. BD-IPMNs were defined as trivial in the continuing absence of WF/HRS after 5 years of surveillance. The age-specific standardized incidence ratio of PC in the general population was used for comparison. RESULTS: A total of 1,036 BD-IPMNs without WF/HRS at diagnosis were included, 4.2% developed WF or HRS, and 1.1% developed PC after a median of 62 months. The median cyst growth rate was 0 mm/yr. A growth rate ≥2.5 mm/yr and the development of WF resulted independent predictors of PC. The standardized incidence ratio of PC for trivial BD-IPMN (n = 378) was 22.45 (95% confidence interval 8.19-48.86), but considering only patients aged >65 years (n = 198), it decreased to 3.84 (95% confidence interval 0.77-11.20). DISCUSSION: Surveillance of the vast majority of presumed BD-IPMNs is safe, as the risk of PC is comparable to postoperative mortality of pancreatic surgery. A growth rate ≥2.5 mm/yr is the main predictor of PC, reinforcing the role of repeated observations. A trivial BD-IPMN in patients aged >65 years might not increase the risk of developing PC compared with general population, identifying potential targets for follow-up discontinuation.

Natural History and Treatment Trends in Pancreatic Cancer Subtypes.

BACKGROUND: While pancreatic ductal adenocarcinoma is the most common form of pancreatic cancer, many other histologic forms of pancreatic cancer are also recognized. These histologic variants portray unique characteristics in terms of patient demographics, tumor behavior, survival, and responsiveness to treatments. MATERIALS AND METHODS: Patients who underwent surgical resection of the pancreas for non-metastatic, invasive pancreatic cancer between 2004 and 2014 were selected from the National Cancer Data Base and categorized by histologic variant according to WHO classification guidelines. Patient demographics, tumor variables, treatment characteristics, and survival were compared between histologic groups and subgroups. RESULTS: A total of 57,804 patients met inclusion and exclusion criteria and were grouped into eight major histologic categories. Survival analysis by the histologic group showed median overall survival of 20.2 months for ductal adenocarcinoma, 20.5 months for squamous cell carcinoma, 26.8 months for mixed acinar-neuroendocrine carcinomas, 52.6 months for cystic mucinous neoplasms with an associated invasive carcinoma, 67.5 months for acinar cell carcinoma, and 69.3 months for mesenchymal tumors. Median survival was not reached for neuroendocrine tumors and solid-pseudopapillary neoplasms, with 5-year overall survival rates of 84% and 97% respectively. CONCLUSIONS: Rare subtypes of pancreatic cancer present unique clinicopathologic characteristics and display distinct tumor biologies. This study presents data on demographic, prognostic, treatment, and survival outcomes between rare forms of pancreatic neoplasms in order to aid understanding of the natural history and behavior of these neoplasms, with the hope of serving as a reference in clinical decision-making and ability to provide accurate prognostic information to patients.

Preoperative risk prediction for intraductal papillary mucinous neoplasms by quantitative CT image analysis.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are radiographically identifiable potential precursor lesions of pancreatic adenocarcinoma. While resection is recommended when main duct dilation is present, management of branch duct IPMN (BD-IPMN) remains controversial. This study sought to evaluate whether preoperative quantitative imaging features of BD-IPMNs could distinguish low-risk disease (low- and intermediate-grade dysplasia) from high-risk disease (high-grade dysplasia and invasive carcinoma). METHODS: Patients who underwent resection between 2005 and 2015 with pathologically proven BD-IPMN and a preoperative CT scan were included in the study. Quantitative image features were extracted using texture analysis and a novel quantitative mural nodularity feature developed for the study. Significant features on univariate analysis were combined with clinical variables to build a multivariate prediction model. RESULTS: Within the study group of 103 patients, 76 (74%) had low-risk disease and 27 (26%) had high-risk disease. Quantitative imaging features were prognostic of low-vs. high-risk disease. The model based only on clinical variables achieved an AUC of 0.67 and 0.79 with the addition of quantitative imaging features. CONCLUSION: Quantitative image analysis of BD-IPMNs is a novel method that may enable risk stratification. External validation may provide a reliable non-invasive prognostic tool for clinicians.

HHLA2 is a novel immune checkpoint protein in pancreatic ductal adenocarcinoma and predicts post-surgical survival.

HHLA2 is a newly identified member of the B7 immune checkpoint family, but its function and crosstalk with immune cells is not fully understood. To gain insights into the HHLA2 expression profile and to determine the clinical significance and function of HHLA2 in pancreatic cancer, we performed immunohistochemistry (IHC) analyses on tissue microarrays (TMAs) of pancreatic ductal adenocarcinoma (PDAC, n = 92) with matched peritumoral tissues as well as in cohorts of precancerous lesions: pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). We found that HHLA2 was rarely detected in normal acinar, islet, and ductal cells but widely expressed from early pancreatic precancerous lesions to invasive PDAC. The overall HHLA2 positivity was 95% (19/20) in low grade PanIN and 70.73% (29/41) in IPMN. HHLA2 expression was detected in 77.17% (71/92) of the PDAC cases and was significantly associated with better prognosis in this cohort. Our findings suggest that HHLA2 may behave as a costimulatory ligand in pancreatic cancer, which differs from other B7 family members that are largely characterized as checkpoint inhibitors. Further investigation of the HHLA2 signaling pathway and its receptors is warranted by our data and may lead to novel therapeutic interventions.

Importance of main pancreatic duct dilatation in IPMN undergoing surveillance.

BACKGROUND: The association between risk of pancreatic cancer and a dilated main pancreatic duct (MPD) in intraductal papillary mucinous neoplasm (IPMN) is debated. The aim of this study was to assess the role of MPD size in predicting pancreatic cancer in resected IPMNs and those kept under surveillance. METHODS: All patients with IPMN referred to the Pancreas Institute, University of Verona Hospital Trust, from 2006 to 2016 were included. The primary endpoint was the occurrence of malignancy detected at surgery or during follow-up. RESULTS: The final cohort consisted of 1688 patients with a median follow-up of 60 months. Main pancreatic duct dilatation was associated with other features of malignancy in both the resected and surveillance groups. In patients who underwent resection, only a MPD of at least 10 mm was an independent predictor of malignancy. In patients kept under surveillance, MPD dilatation was not associated with malignancy. Fifteen of 71 patients (21 per cent) with malignancy in the resection cohort had a dilated MPD alone, whereas only one of 30 (3 per cent) under surveillance with MPD dilatation alone developed malignancy. Patients with a dilated MPD and other worrisome features had an increased 5-year cumulative incidence of malignancy compared with those with a non-dilated duct (11 versus 1·2 per cent; P < 0·001); however, the risk of malignancy was not significantly increased in patients with a dilated MPD alone (4 versus 1·2 per cent; P = 0·448). CONCLUSION: In patients under surveillance, a dilated MPD alone was not associated with an increased incidence of malignancy in IPMN.

Intraductal papillary mucinous neoplasms of the pancreas - a cost-effectiveness analysis of management strategies for the branch-duct subtype.

BACKGROUND: Branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) presents a clinical conundrum. Rigorous long-term surveillance or surgical resection is recommended. The economic consequences of the management have not been fully investigated. METHODS: A Markov decision model compared 4 strategies for low-risk BD-IPMN: I = upfront total pancreatectomy, II = upfront partial pancreatectomy, III = initial surveillance, IV = watchful waiting. Surveillance was based on the Swedish Guidelines for Pancreatic Cancer. Probabilities and costs were obtained from the participating unit and from the scientific literature. The incremental cost-effectiveness ratios (ICERs) were calculated and sensitivity analyses were performed by varying relevant parameters. Survival was reported in quality-adjusted life-years (QALYs). RESULTS: Strategy III was the most cost-effective strategy with an ICER of €31 682 compared to strategy IV. Strategy I was the most expensive but yielded the best QALY (9.32). Total number of years, annual risk of pancreatic cancer and annual risk of a low-risk BD-IPMN turning into a high-risk lesion had the greatest impact in the model. CONCLUSIONS: Initial surveillance seems to be the most cost-effective strategy in the management of low-risk asymptomatic BD-IPMN. However, the possibility of personalized approaches remains to be investigated.

The role of age in pancreatic intraductal papillary mucinous neoplasms of the pancreas: Same risk of death but different implications for management.

BACKGROUND: Current guidelines do not address the role of age in the management of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. AIM: To evaluate whether clinical features and risk for malignancy are affected by patient's age at diagnosis. METHODS: In total, 2189 IPMNs, both surgically resected or surveilled, were dichotomized according to a 50-year-old cutoff and compared in terms of pathological features, cumulative risk of developing high-risk stigmata (HRS), overall survival (OS) and disease-specific survival (DSS). RESULTS: Patients <50 years had more frequent abdominal pain (38.5 vs. 22.4%; p < 0.01) and acute pancreatitis (20.4 vs. 9.3%; p < 0.01) at presentation. Patients ≥50 years old had more multifocal IPMNs (50 vs. 36.9%; p < 0.01), HRS (8.5% vs. 4.3%; p = 0.04) and invasive IPMNs (26.6% vs. 17.3%; p = 0.03) when resected. Moreover, patients ≥50 years old had a significantly higher cumulative risk of developing HRS over time, and a significantly lower OS, but similar DSS when compared with those <50 years old. CONCLUSIONS: IPMNs diagnosed in older patients are more likely to progress to HRS despite the fact that cancer-related death is not affected by age. The follow-up schedule should not be adjusted according to age, but one should take into account that IPMNs in younger individuals have more time to progress toward malignancy.