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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. 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. 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). 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.

BackgroundNeoadjuvant therapy (NAT) is used for borderline-resectable or locally advanced pancreatic cancer (PDAC) and exhibits promising results in terms of pathological outcomes. However, little is known about its effect on surgical complications.MethodsWe analyzed 445 pancreatic resections for PDAC from 2014 to 2016 at The Pancreas Institute, Verona University Hospital. The Modified Accordion Severity Grading System and average complication burden (ACB) were used to compare patients treated with NAT with patients who underwent upfront surgery (UFS).ResultsOf 305 pancreaticoduodenectomies (PD), patients treated with NAT (n = 99) had less pancreatic fistula (POPF, 9.1% vs. 15.6%, p = 0.05) without grade C cases, but grade B ACB was increased (0.28 for NAT vs. 0.24 for UFS, p = 0.05). The postpancreatectomy hemorrhage (PPH) rate was lower in the NAT group (9.1% vs. 14.6%, p = 0.02), but ACB grades B (0.37 for NAT vs. 0.26 for UFS, p = 0.03) and C (0.43 for NAT vs. 0.29 for UFS, p = 0.05) were increased. Delayed gastric emptying (DGE) was increased in NAT cases (15.2% vs. 8.3%, p = 0.04), with higher grade C ACB (0.43 for NAT vs. 0.29 for UFS, p = 0.03). Of 94 distal pancreatectomies (DP), NAT patients (n = 26) developed more grade C POPF (11.5% vs. 1.5%, p = 0.04) and DGE (11.5% vs. 2.9%, p = 0.01) without differences in ACB.ConclusionsPatients undergoing PD for PDAC after NAT exhibited reduced incidence of POPF and PPH but increased incidence of DGE compared with patients treated with UFS. Among patients developing postoperative complications after PD, those receiving NAT were associated with increased clinical burden.

BackgroundResection of initially oligometastatic pancreatic ductal adenocarcinoma (PDAC) following response to first-line chemotherapy is controversial. We herein updated a previous case series to investigate the oncologic outcomes and preoperative factors that could drive the decision-making process.MethodsThis retrospective analysis was limited to patients with liver-only synchronous metastases who experienced complete regression of the metastatic component and underwent pancreatectomy between October 2008 and July 2020 at two high-volume institutions. Clinical-pathologic variables were captured, and inflammation-based prognostic scores were calculated. Recurrence and survival analyses were performed using standard statistical methods.ResultsOverall, 52 patients were included. FOLFIRINOX was the most employed chemotherapy regimen (63.5%). Post-treatment tumor size, serum carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) were significantly decreased relative to baseline evaluation. The median time from diagnosis to pancreatectomy was 10.2 months, while the median time from chemotherapy completion to pancreatectomy was 2 months. Major postoperative complications occurred in 26.9% of patients, while postoperative mortality was nil. The median disease-free survival (DFS) and overall survival (OS) from pancreatectomy were 16.5 and 23.0 months, respectively, and the median OS from diagnosis was 37.2 months. At multivariable analysis, vascular resection, operative time, prognostic nutrition index (PNI) and neutrophil-to-lymphocyte ratio (NLR) were associated with OS. Operative time, platelet × neutrophil/lymphocyte count (SII), and PNI were associated with DFS.ConclusionsWe confirm promising outcomes of selected patients who underwent pancreatectomy following downstaging of liver metastases. The absence of vascular involvement of the primary tumor, good nutritional status, and low inflammatory index scores could be useful to select candidates for resection.

Background Pancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is currently unclear what chemotherapy should be preferred for patients with BRPC or LAPC. Methods We performed a systematic review and multi-institutional meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC. Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based. Results A total of 23 studies comprising 2930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment. OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) ( p < 0.0001). In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p < 0.0001). This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens. The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO. In patients with LAPC, resection rates were 0.19 with Gemcitabine and 0.28 with FIO. In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083). A similar trend was observed in resected patients converted from LAPC. Conclusions In patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with Gemcitabine-based chemotherapy appears to provide a survival benefit for patients that are ultimately unresectable. For patients that undergo surgical resection, outcomes are similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting.

ObjectiveIntraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression.DesignWe performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples.ResultsOur multiregion whole exome sequencing identified KLF4, a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in KLF4 were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in KLF4 were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs.ConclusionHotspot mutations in KLF4 occur at high prevalence in IPMNs. Unique among pancreatic driver genes, KLF4 mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due to KRAS mutation, which is present in 90% of cases. The genetic landscape of KRAS wild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due to BRAF mutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting of KRAS is an unresolved challenge, KRAS -wild type PDACs have potential options for tailored treatments, including BRAF antagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group. This calls for a complementation of the histological diagnosis of PDAC with a routine determination of KRAS followed by a comprehensive molecular profiling of KRAS -negative cases.

Tumor mutational burden (TMB) is a numeric index that expresses the number of mutations per megabase (muts/Mb) harbored by tumor cells in a neoplasm. TMB can be determined using different approaches based on next-generation sequencing. In the case of high values, it indicates a potential response to immunotherapy. In this systematic review, we assessed the potential predictive role of high-TMB in pancreatic ductal adenocarcinoma (PDAC), as well as the histo-molecular features of high-TMB PDAC. High-TMB appeared as a rare but not-negligible molecular feature in PDAC, being present in about 1.1% of cases. This genetic condition was closely associated with mucinous/colloid and medullary histology (p < 0.01). PDAC with high-TMB frequently harbored other actionable alterations, with microsatellite instability/defective mismatch repair as the most common. Immunotherapy has shown promising results in high-TMB PDAC, but the sample size of high-TMB PDAC treated so far is quite small. This study highlights interesting peculiarities of PDAC harboring high-TMB and may represent a reliable starting point for the assessment of TMB in the clinical management of patients affected by pancreatic cancer.

Postoperative pancreatic fistula (POPF), the major driver of morbidity and mortality following pancreatectomy, is caused by an abnormal communication between the pancreatic ductal epithelium and another epithelial surface containing pancreas-derived, enzyme-rich fluid. There is a strong correlation between the amylase content in surgically-placed drains early in the postoperative course and the development of POPF. A simple and cheap method to determine the amylase content from the drain effluent has been eagerly advocated. Here, we developed an amylase optical biosensor, based on a surface plasmon resonance (SPR) plastic optical fiber (POF), metallized with a 60 nm layer of gold and interrogated with white light. The sensor was made specific by coupling it with an anti-amylase antibody. Each surface derivatization step was optimized and studied by XPS, contact angle, and fluorescence. The POF-biosensor was tested for its response to amylase in diluted drain effluents. The volume of sample required was 50 µL and the measurement time was 8 min. The POF-biosensor showed selectivity for amylase, a calibration curve log-linear in the range of 0.8–25.8 U/L and a limit of detection (LOD) of ~0.5 U/L. In preliminary tests, the POF-biosensor allowed for the measurement of the amylase content of diluted surgically-placed drain effluents with an accuracy of >92% with respect to the gold standard. The POF-biosensor allows for reliable measurement and could be implemented to allow for a rapid bedside assessment of amylase value in drains following pancreatectomy.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with an overall 5-year survival rate of less than 8%. New evidence indicates that PDAC cells release pro-inflammatory metabolites that induce a marked alteration of normal hematopoiesis, favoring the expansion and accumulation of myeloid-derived suppressor cells (MDSCs). We report here that PDAC patients show increased levels of both circulating and tumor-infiltrating MDSC-like cells.MethodsThe frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in three independent cohorts of PDAC patients (total analyzed patients, n = 117). Frequency of circulating MDSCs was correlated with overall survival of PDAC patients. We also analyzed the frequency of tumor-infiltrating MDSC and the immune landscape in fresh biopsies. Purified myeloid cell subsets were tested in vitro for their T-cell suppressive capacity.ResultsCorrelation with clinical data revealed that MDSC frequency was significantly associated with a shorter patients’ overall survival and metastatic disease. However, the immunosuppressive activity of purified MDSCs was detectable only in some patients and mainly limited to the monocytic subset. A transcriptome analysis of the immunosuppressive M-MDSCs highlighted a distinct gene signature in which STAT3 was crucial for monocyte re-programming. Suppressive M-MDSCs can be characterized as circulating STAT3/arginase1-expressing CD14+ cells.ConclusionMDSC analysis aids in defining the immune landscape of PDAC patients for a more appropriate diagnosis, stratification and treatment.

BackgroundDecision-making in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas depends on scaling the risk of malignancy with the surgical burden of a pancreatectomy. This study aimed to develop a preoperative, disease-specific tool to predict surgical morbidity for IPMNs.MethodsBased on preoperative variables of resected IPMNs at two high-volume institutions, classification tree analysis was applied to derive a predictive model identifying the risk factors for major morbidity (Clavien–Dindo ≥3) and postoperative pancreatic insufficiency.ResultsAmong 524 patients, 289 (55.2%) underwent pancreaticoduodenectomy (PD), 144 (27.5%) underwent distal pancreatectomy (DP), and 91 (17.4%) underwent total pancreatectomy (TP) for main-duct (18.7%), branch-duct (12.6%), or mixed-type (68.7%) IPMN. For 98 (18.7%) of the patients, major morbidity developed. The classification tree distinguished different probabilities of major complications based on the type of surgery (area under the surve [AUC] 0.70; 95% confidence interval [CI], 0.63–0.77). Among the DP patients, the presence of preoperative diabetes identified two risk classes with respective probabilities of 5% and 25% for the development of major morbidity, whereas among the PD/TP patients, three different classes with respective probabilities of 15%, 20%, and 36% were identified according to age and body mass index (BMI). Overall, history of diabetes, age, and cyst size segregated three different risk classes for new-onset/worsening diabetes.ConclusionsIn presumed IPMNs, the disease-specific risk of major morbidity and pancreatic insufficiency can be determined in the preoperative setting and used to personalize the possible surgical indication. Age and overweight status in case of PD/TP and diabetes in case of DP tip the scale toward less aggressive clinical management in the absence of features suggestive for malignancy.