Novel serum protein biomarker panel for early diagnosis of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Late presentation of disease at the time of diagnosis is one of the major reasons for dismal prognostic outcomes for PDAC patients. Currently, there is a lack of clinical biomarkers, which can be used to diagnose PDAC patients at an early resectable stage. This study performed proteomic mass spectrometry to identify novel blood-based biomarkers for early diagnosis of PDAC. Serum specimens from 88 PDAC patients and 88 healthy controls (60 discovery cohort and 28 validation cohort) were analyzed using data independent acquisition high resolution mass spectrometry to identify candidate biomarker proteins. A total of 249 proteins were identified and quantified by the mass spectrometric analysis. Six proteins were markedly (>1.5 fold) and significantly (p < .05; q < 0.1) increased in PDAC patients compared to healthy controls in discovery cohort. Notably, four of these six proteins were significantly upregulated in an independent validation cohort. The top three upregulated proteins (i.e., Polymeric Immunoglobulin Receptor [PIGR], von Willebrand Factor [vWF], and Fibrinogen) were validated using enzyme linked immunosorbent assay, which led to selection of PIGR and vWF as a diagnostic biomarker panel for PDAC. The panel showed high ability to diagnose early stage (stage I and II) PDAC patients (area under the curve [AUC]: 0.8926), which was further improved after the addition of clinically used prognostic biomarker (Ca 19-9) to the panel (AUC: 0.9798). In conclusion, a novel serum protein biomarker panel for early diagnosis of PDAC was identified.

Serum and tissue metallome of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) patients have late presentation at the time of diagnosis and a poor prognosis. Metal dyshomeostasis is known to play a role in cancer progression. However, the blood and tissue metallome of PDAC patients has not been assessed. This study aimed to determine the levels of essential and toxic metals in the serum and pancreatic tissue from PDAC patients. Serum samples were obtained from PDAC patients before surgical resection. Tissue (tumor and adjacent normal pancreas) were obtained from the surgically resected specimen. Inductively coupled plasma-mass spectrometry (ICP-MS) analysis was performed to quantify the levels of 10 essential and 3 toxic metals in these samples. Statistical analysis was performed to identify dysregulated metals in PDAC and their role as potential diagnostic and prognostic biomarkers. Significantly decreased serum levels of magnesium, potassium, calcium, iron, zinc, selenium, arsenic, and mercury and increased levels of molybdenum were shown to be associated with PDAC. There were significantly decreased levels of zinc, manganese and molybdenum, and increased levels of calcium and selenium in the pancreatic tumor tissue compared with the adjacent normal pancreas. Notably, lower serum levels of calcium, iron, and selenium, and higher levels of manganese, were significantly associated with a poor prognosis (i.e., overall survival) in PDAC patients. In conclusion, this is the first study to comprehensively assess the serum and tissue metallome of PDAC patients. It identified the association of metals with PDAC diagnosis and prognosis.

Centralization of Pancreaticoduodenectomy: A Systematic Review and Spline Regression Analysis to Recommend Minimum Volume for a Specialist Pancreas Service.

OBJECTIVE: Through a systematic review and spline curve analysis, to better define the minimum volume threshold for hospitals to perform (pancreaticoduodenectomy) and the high-volume center. BACKGROUND: The pancreaticoduodenectomy (PD) is a resource-intensive procedure, with high morbidity and long hospital stays resulting in centralization towards high-volume hospitals; the published definition of high volume remains variable. MATERIALS AND METHODS: Following a systematic review of studies comparing PD outcomes across volume groups, semiparametric regression modeling of morbidity (%), mortality (%), length of stay (days), lymph node harvest (number of nodes), and cost ($USD) as continuous variables were performed and fitted as a smoothed function of splines. If this showed a nonlinear association, then a "zero-crossing" technique was used, which produced "first and second derivatives" to identify volume thresholds. RESULTS: Our analysis of 33 cohort studies (198,377 patients) showed 55 PDs/year and 43 PDs/year were the threshold value required to achieve the lowest morbidity and highest lymph node harvest, with model estimated df 5.154 ( P <0.001) and 8.254 ( P <0.001), respectively. The threshold value for mortality was ~45 PDs/year (model 9.219 ( P <0.001)), with the lowest mortality value (the optimum value) at ~70 PDs/year (ie, a high-volume center). No significant association was observed for cost ( edf =2, P =0.989) and length of stay ( edf =2.04, P =0.099). CONCLUSIONS: There is a significant benefit from the centralization of PD, with 55 PDs/year and 43 PDs/year as the threshold value required to achieve the lowest morbidity and highest lymph node harvest, respectively. To achieve mortality benefit, the minimum procedure threshold is 45 PDs/year, with the lowest and optimum mortality value (ie, a high-volume center) at approximately 70 PDs/year.

Long-term Outcomes following Resection of Adenocarcinoma Arising from Intraductal Papillary Mucinous Neoplasm (A-IPMN) versus Pancreatic Ductal Adenocarcinoma (PDAC): A Propensity-score Matched Analysis.

OBJECTIVE: The aim of the present study was to compare long-term post-resection oncological outcomes between A-IPMN and PDAC. SUMMARY BACKGROUND DATA: Knowledge of long term oncological outcomes (e.g recurrence and survival data) comparing between adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMN) and pancreatic ductal adenocarcinoma (PDAC) is scarce. METHODS: Patients undergoing pancreatic resection (2010-2020) for A-IPMN were identified retrospectively from 18 academic pancreatic centres and compared with PDAC patients from the same time-period. Propensity-score matching (PSM) was performed and survival and recurrence were compared between A-IPMN and PDAC. RESULTS: 459 A-IPMN patients (median age,70; M:F,250:209) were compared with 476 PDAC patients (median age,69; M:F,262:214). A-IPMN patients had lower T-stage, lymphovascular invasion (51.4%vs. 75.6%), perineural invasion (55.8%vs. 71.2%), lymph node positivity (47.3vs. 72.3%) and R1 resection (38.6%vs. 56.3%) compared to PDAC(P<0.001). The median survival and time-to-recurrence for A-IPMN versus PDAC were 39.0 versus19.5months (P<0.001) and 33.1 versus 14.8months (P<0.001), respectively (median follow-up,78 vs.73 months). Ten-year overall survival for A-IPMN was 34.6%(27/78) and PDAC was 9%(6/67). A-IPMN had higher rates of peritoneal (23.0 vs. 9.1%, P<0.001) and lung recurrence (27.8% vs. 15.6%, P<0.001) but lower rates of locoregional recurrence (39.7% vs. 57.8%; P<0.001). Matched analysis demonstrated inferior overall survival (P=0.005), inferior disease-free survival (P=0.003) and higher locoregional recurrence (P<0.001) in PDAC compared to A-IPMN but no significant difference in systemic recurrence rates (P=0.695). CONCLUSIONS: PDACs have inferior survival and higher recurrence rates compared to A-IPMN in matched cohorts. Locoregional recurrence is higher in PDAC but systemic recurrence rates are comparable and constituted by their own distinctive site-specific recurrence patterns.

Precursor Epithelial Subtypes of Adenocarcinoma Arising from Intraductal Papillary Mucinous Neoplasms (A-IPMN): Clinicopathological Features, Recurrence and Response to Adjuvant Chemotherapy.

BACKGROUND: The clinico-oncological outcomes of precursor epithelial subtypes of adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMN) are limited to small cohort studies. Differences in recurrence patterns and response to adjuvant chemotherapy between A-IPMN subtypes are unknown. METHODS: Clincopathological features, recurrence patterns and long-term outcomes of patients undergoing pancreatic resection (2010-2020) for A-IPMN were reported from 18 academic pancreatic centres worldwide. Precursor epithelial subtype groups were compared using uni- and multivariate analysis. RESULTS: In total, 297 patients were included (median age, 70 years; male, 78.9%), including 54 (18.2%) gastric, 111 (37.3%) pancreatobiliary, 80 (26.9%) intestinal and 52 (17.5%) mixed subtypes. Gastric, pancreaticobiliary and mixed subtypes had comparable clinicopathological features, yet the outcomes were significantly less favourable than the intestinal subtype. The median time to recurrence in gastric, pancreatobiliary, intestinal and mixed subtypes were 32, 30, 61 and 33 months. Gastric and pancreatobiliary subtypes had worse overall recurrence (p = 0.048 and p = 0.049, respectively) compared with the intestinal subtype but gastric and pancreatobiliary subtypes had comparable outcomes. Adjuvant chemotherapy was associated with improved survival in the pancreatobiliary subtype (p = 0.049) but not gastric (p = 0.992), intestinal (p = 0.852) or mixed subtypes (p = 0.723). In multivariate survival analysis, adjuvant chemotherapy was associated with a lower likelihood of death in pancreatobiliary subtype, albeit with borderline significance [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.31-1.01; p = 0.058]. CONCLUSIONS: Gastric, pancreatobiliary and mixed subtypes have comparable recurrence and survival outcomes, which are inferior to the more indolent intestinal subtype. Pancreatobiliary subtype may respond to adjuvant chemotherapy and further research is warranted to determine the most appropriate adjuvant chemotherapy regimens for each subtype.

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.

The Impact of Molecular Subtyping on Pathological Staging of Pancreatic Cancer.

BACKGROUND: The long-term outcomes following surgical resection for pancreatic ductal adenocarcinoma (PDAC) remains poor, with only 20% of patients surviving 5 years after pancreatectomy. Patient selection for surgery remains suboptimal largely due to the absence of consideration of aggressive tumor biology. OBJECTIVE: The aim of this study was to evaluate traditional staging criteria for PDAC in the setting of molecular subtypes. METHODS: Clinicopathological data were obtained for 5 independent cohorts of consecutive unselected patients, totaling n = 1298, including n = 442 that underwent molecular subtyping. The main outcome measure was disease-specific survival following surgical resection for PDAC stratified according to the American Joint Commission for Cancer (TNM) staging criteria, margin status, and molecular subtype. RESULTS: TNM staging criteria and margin status confers prognostic value only in tumors with classical pancreatic subtype. Patients with tumors that are of squamous subtype, have a poor outcome irrespective of favorable traditional pathological staging [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.04-2.28, P = 0.032]. Margin status has no impact on survival in the squamous subtype (16.0 vs 12.1 months, P = 0.374). There were no differences in molecular subtype or gene expression of tumors with positive resection margin status. CONCLUSIONS: Aggressive tumor biology as measured by molecular subtype predicts poor outcome following pancreatectomy for PDAC and should be utilized to inform patient selection for surgery.

How i do it: microscope augmented pancreaticojejunostomy.

PURPOSE: Post-operative pancreatic fistula (POPF) is perhaps one of most dreaded pancreatoduodenectomy-related complications. Various approaches to mitigate this risk have been explored, with conflicting results and no clear consensus on the comparative superiority of any one technique. We postulate that regardless of technique, the key to reducing POPF is a robust pancreatic anastomosis with careful apposition of tissues, in particular the duct-to-mucosa anastomosis. METHOD: We describe the fashioning of a pancreatojejunostomy with an external pancreatic stent in the setting of a high-risk anastomosis with help of a 10 × magnification surgical microscope. A technical description with a short, edited video is presented.

Granular cell tumour of the pancreas: a case report and systematic review.

PURPOSE: Granular cell tumours (GCTs) of the pancreas are mostly benign and exceptionally rare, with no unique identifying radiological features. Following a case discussion of a patient with GCT, a comprehensive review of available literature was conducted to identify the common diagnostic features associated with GCT. METHODS: Following a case report identified in our institution, a systematic review was conducted by two authors in accordance with Preferred Reporting Items for Systematic review and Meta-Analysis protocols (PRISMA) guidelines. Databases MEDLINE, EMBASE, Scopus, World of Science, and grey literature were searched on August 2021. Inclusion criteria were histopathology diagnosed granular cell tumour of the pancreas. RESULTS: A 37-year-old male presented with 1 month of abdominal pain and an MRI demonstrating a dilated main pancreatic duct, distal parenchymal atrophy, but no focal lesion. Repeat MRI at 6 months re-demonstrated similar findings and subsequent endoscopic ultrasound was suspicious for main duct IPMN. Following multidisciplinary team discussion, a spleen-preserving distal pancreatectomy was performed. Histopathology demonstrated granular cell tumour with cells diffusely positive for S100 and no malignant transformation. 11 case reports were identified in the literature with diagnosis confirmed on tissue histopathology based on positive immunohistochemical staining for S-100 protein. Eight patients presented with gastrointestinal symptoms with abdominal pain the main presenting complaint (50%). 10 patients underwent CT with portal venous contrast and all underwent endoscopic examination. Imaging findings were similar in five studies for EUS which demonstrated a hypoechoic lesion with homogenous appearance. On non-contrast CT GCT was iso-enhancing, and with portal venous contrast demonstrated hypo-enhancement that gradually enhanced on late phases. Pre-operative diagnosis of pancreatic carcinoma was described in six cases based on imaging and biopsy, resulting in progression to surgical resection. Nine patients were managed surgically and no complications identified on follow-up (6-52 months). CONCLUSION: The currently proposed management pathway includes EUS with biopsy and CT, and surgical resection recommended due to malignancy risk. Improved sample collection with EUS-FNA and microscopic assessment utilising S-100 immunohistochemistry may improve pre-operative diagnosis. Limitations include rare numbers in reported literature and short follow-up not allowing an assessment of GCT's natural history and malignancy risk. Additional cases would expand the current dataset of GCTs of the pancreas, so that surgical resection may be avoided in the future.

Postoperative pancreatitis and pancreatic fistulae: a review of current evidence.

OBJECTIVES: Postoperative pancreatic fistula (POPF) represents one of the most severe complications following pancreatic surgery. Despite being a leading cause of morbidity and mortality, its pathophysiology is poorly understood. In recent years, there has been growing evidence to support the role of postoperative or post-pancreatectomy acute pancreatitis (PPAP) in the development of POPF. This article reviews the contemporary literature on POPF pathophysiology, risk factors, and prevention strategies. METHODS: A literature search was conducted using electronic databases, including Ovid Medline, EMBASE, and Cochrane Library, to retrieve relevant literature published between 2005 and 2023. A narrative review was planned from the outset. RESULTS: A total of 104 studies fulfilled criteria for inclusion. Forty-three studies reported on technical factors predisposing to POPF, including resection and reconstruction technique and adjuncts for anastomotic reinforcement. Thirty-four studies reported on POPF pathophysiology. There is compelling evidence to suggest that PPAP plays a critical role in the development of POPF. The acinar component of the remnant pancreas should be regarded as an intrinsic risk factor; meanwhile, operative stress, remnant hypoperfusion, and inflammation represent common mechanisms for acinar cell injury. CONCLUSIONS: The evidence base for PPAP and POPF is evolving. Future POPF prevention strategies should look beyond anastomotic reinforcement and target underlying mechanisms of PPAP development.

Clinical validation of the international study group of pancreatic surgery (ISGPS) definition for post-pancreatectomy acute pancreatitis.

BACKGROUND: The diagnosis of postoperative or post-pancreatectomy acute pancreatitis (PPAP) is controversial. In 2021, the International Study Group of Pancreatic Surgery (ISGPS) published the first unifying definition and grading system for PPAP. This study sought to validate recent consensus criteria, using a cohort of patients undergoing pancreaticoduodenectomy (PD) in a high-volume pancreaticobiliary specialty unit. METHODS: All consecutive patients undergoing PD at a tertiary referral centre between January 2016 and December 2021 were retrospectively reviewed. Patients with serum amylase recorded within 48h from surgery were included for analysis. Postoperative data were extracted and evaluated against the ISGPS criteria, including the presence of postoperative hyperamylasaemia, radiologic features consistent with acute pancreatitis, and clinical deterioration. RESULTS: A total of 82 patients were evaluated. The overall incidence of PPAP was 32% (26/82) in this cohort, of which 3/26 demonstrated postoperative hyperamylasaemia and 23/26 had clinically relevant PPAP (Grade B or C) when correlated radiologic and clinical criteria. CONCLUSIONS: This study is among the first to apply the recently published consensus criteria for PPAP diagnosis and grading to clinical data. While the results support their utility in establishing PPAP as a distinct post-pancreatectomy complication, there remains a need for future large-scale validation studies.

International Validation of a Nomogram to Predict Recurrence after Resection of Grade 1 and 2 Nonfunctioning Pancreatic Neuroendocrine Tumors.

BACKGROUND: Despite the low recurrence rate of resected nonfunctional pancreatic neuroendocrine tumors (NF-pNETs), nearly all patients undergo long-term surveillance. A prediction model for recurrence may help select patients for less intensive surveillance or identify patients for adjuvant therapy. The objective of this study was to assess the external validity of a recently published model predicting recurrence within 5 years after surgery for NF-pNET in an international cohort. This prediction model includes tumor grade, lymph node status and perineural invasion as predictors. METHODS: Retrospectively, data were collected from 7 international referral centers on patients who underwent resection for a grade 1-2 NF-pNET between 1992 and 2018. Model performance was evaluated by calibration statistics, Harrel's C-statistic, and area under the curve (AUC) of the receiver operating characteristic curve for 5-year recurrence-free survival (RFS). A sub-analysis was performed in pNETs >2 cm. The model was improved to stratify patients into 3 risk groups (low, medium, high) for recurrence. RESULTS: Overall, 342 patients were included in the validation cohort with a 5-year RFS of 83% (95% confidence interval [CI]: 78-88%). Fifty-eight patients (17%) developed a recurrence. Calibration showed an intercept of 0 and a slope of 0.74. The C-statistic was 0.77 (95% CI: 0.70-0.83), and the AUC for the prediction of 5-year RFS was 0.74. The prediction model had a better performance in tumors >2 cm (C-statistic 0.80). CONCLUSIONS: External validity of this prediction model for recurrence after curative surgery for grade 1-2 NF-pNET showed accurate overall performance using 3 easily accessible parameters. This model is available via www.pancreascalculator.com.

Anatomy of the neural fibers at the superior mesenteric artery-a cadaver study.

PURPOSE: Most surgeons perform right-sided semicircular clearance of the superior mesenteric artery (SMA) nerve plexus for pancreatic head carcinoma, presuming a linear course of the SMA nerve fibers. The hypothesis was that the SMA nerve plexus fibers follow a non-linear course, and the goal of the present study was to assess the neural fibers distribution along the SMA. METHODS: The course of neural fibers along the retropancreatic and suprapancreatic SMA was assessed in 7 cadavers. RESULTS: In the retropancreatic course of the vessel, the main nerve cords branch and form a large number of finer nerve branches performing an anti-clockwise rotation of slightly less than 90° around the SMA. Finer nerve branches are located rather close to the vessel, while the main nerve cords are localized in the loose connective tissue of the peripheral parts of the vascular sheath. Nerve fibers around the suprapancreatic SMA run as two main nerve cords framing the artery on the right lateral-ventral and the left lateral to lateral-dorsal side. CONCLUSION: The rotation of the nerve fiber around the SMA indicates that a more radical resection of at least 180° of neural tissue around the SMA might be required to achieve tumor clearance in pancreatic cancer with perineural invasion at the uncinate margin.

The role of staging laparoscopy in pancreatic adenocarcinoma and its effect on patients' survival.

BACKGROUND: Prompt and accurate staging of pancreatic cancer is essential to distinguish patients to benefit from resection with curative intent and those with unresectable disease. A staging laparoscopy is used preoperatively to identify macroscopic or occult metastases not identified on imaging. This single-institution study aims to evaluate the role of staging laparoscopy in patients with pancreatic adenocarcinoma and its effect on overall survival. METHOD: Clinicopathologic data were evaluated for all patients undergoing staging laparoscopy for pancreatic adenocarcinoma from July 2014 to December 2019. The study identified 155 patients eligible for analysis. All patients were followed for at least 2 years. Clinical backgrounds, survival curves and prognostic factors were investigated. RESULTS: Resectability status among the cohort was 62 (40%) upfront resectable, 53 (34%) borderline resectable and 40 (26%) locally advanced disease. The median age was 69, with 44% male patients. Median CA19-9 value was 125 kU/L, and median CA125 value was 22 kU/L. Staging laparoscopy resulted in upstaging nine (15%) upfront resectable patients, five (9%) borderline resectable patients and ten (25%) locally advanced patients. There was positive cytology in 19 (12%), peritoneal deposits in six (4%) and peritoneal liver deposits in seven (5%) patients. Overall, the number needed to treat (NNT) to avoid an unnecessary laparotomy was eight patients. CONCLUSION: Staging laparoscopy continues to be a valuable investigation of pancreatic adenocarcinoma. In this institution, one in every eight patients undergoing a staging laparoscopy was upstaged to metastatic disease, thus avoiding an unnecessary laparotomy or a non-curative resection.

Rare anastomosis between a replaced right hepatic artery and left branch of the proper hepatic artery.

Appreciation of the potential anatomical variation of the hepatic arterial supply and branches of the abdominal aorta is of paramount importance in pancreatic and hepatobiliary surgery. Here we describe a hitherto un-reported coelio-mesenteric anastomotic connection between a replaced right hepatic artery, originating from the superior mesenteric artery, and the left hepatic branch of the proper hepatic artery. The embryological origins of the variant anatomy as well as its potential surgical implications are discussed with a view to encourage thorough pre-operative interrogation of available imaging by radiologists and surgeons to successfully identify such variants and take advantage of their potentially useful functionality.

A unique urinary metabolomic signature for the detection of pancreatic ductal adenocarcinoma.

Our study aimed to identify a urinary metabolite panel for the detection/diagnosis of pancreatic ductal adenocarcinoma (PDAC). PDAC continues to have poor survival outcomes. One of the major reasons for poor prognosis is the advanced stage of the disease at diagnosis. Hence, identification of a novel and cost-effective biomarker signature for early detection/diagnosis of PDAC could lead to better survival outcomes. Untargeted metabolomics was employed to identify a novel metabolite-based biomarker signature for PDAC diagnosis. Urinary metabolites from 92 PDAC patients (56 discovery cohort and 36 validation cohort) were compared with 56 healthy volunteers using 1 H nuclear magnetic resonance spectroscopy. Multivariate (partial-least squares discriminate analysis) and univariate (Mann-Whitney's U-test) analyses were performed to identify a metabolite panel which can be used to detect PDAC. The selected metabolites were further validated for their diagnostic potential using the area under the receiver operating characteristic (AUROC) curve. Statistical analysis identified a six-metabolite panel (trigonelline, glycolate, hippurate, creatine, myoinositol and hydroxyacetone), which demonstrated high potential to diagnose PDAC, with AUROC of 0.933 and 0.864 in the discovery and validation cohort, respectively. Notably, the identified panel also demonstrated very high potential to diagnose early-stage (I and II) PDAC patients with AUROC of 0.897. These results demonstrate that the selected metabolite signature could be used to detect PDAC and will pave the way for the development of a urinary test for detection/diagnosis of PDAC.

RET gene rearrangements occur in a subset of pancreatic acinar cell carcinomas.

Pancreatic acinar cell carcinoma is relatively rare (1 to 2% of pancreatic malignancies) but may be under-recognized. In contrast to pancreatic ductal adenocarcinoma, most acinar cell carcinomas lack mutations in KRAS, DPC, CDKN2A or TP53, but appear to have a high incidence of gene rearrangements, with up to 20% reported to be driven by BRAF fusions. With the development of a new class of RET-specific tyrosine kinase inhibitors, which appear to have particularly strong activity against RET gene rearranged tumours, there is now considerable interest in identifying RET gene rearrangements across a wide range of cancers. RET rearrangements have been reported to occur at a very low incidence (<1%) in all pancreatic carcinomas. We postulated that given its unique molecular profile, RET gene rearrangements may be common in acinar cell carcinomas. We performed fluorescent in-situ hybridization (FISH) studies on a cohort of 40 acinar cell spectrum tumours comprising 36 pure acinar cell carcinomas, three pancreatoblastomas and one mixed acinar-pancreatic neuroendocrine tumour. RET gene rearrangements were identified in 3 (7.5%) cases and BRAF gene rearrangements in 5 (12.5%). All gene rearranged tumours were pure acinar cell carcinomas. Our findings indicate that amongst all pancreatic carcinomas, acinar carcinomas are highly enriched for potentially actionable gene rearrangements in RET or BRAF. FISH testing is inexpensive and readily available in the routine clinical setting and may have a role in the assessment of all acinar cell carcinomas-at this stage to recruit patients for clinical trials of new targeted therapies, but perhaps in the near future as part of routine care.

RAF1 rearrangements are common in pancreatic acinar cell carcinomas.

There is now evidence that gene fusions activating the MAPK pathway are relatively common in pancreatic acinar cell carcinoma with potentially actionable BRAF or RET fusions being found in ~30%. We sought to investigate the incidence of RAF1 fusions in pancreatic malignancies with acinar cell differentiation. FISH testing for RAF1 was undertaken on 30 tumors comprising 25 'pure' acinar cell carcinomas, 2 mixed pancreatic acinar-neuroendocrine carcinomas, 1 mixed acinar cell-low grade neuroendocrine tumor and 2 pancreatoblastomas. RAF1 rearrangements were identified in 5 cases and confirmed by DNA and RNA sequencing to represent oncogenic fusions (GATM-RAF1, GOLGA4-RAF1, PDZRN3-RAF1, HERPUD1-RAF1 and TRIM33-RAF1) and to be mutually exclusive with BRAF and RET fusions, as well as KRAS mutations. Large genome-wide copy number changes were common and included 1q gain and/or 1p loss in all five RAF1 FISH-positive acinar cell carcinomas. RAF1 expression by immunohistochemistry was found in 3 of 5 (60%) of fusion-positive cases and no FISH-negative cases. Phospho-ERK1/2 expression was found in 4 of 5 RAF1-fusion-positive cases. Expression of both RAF1 and phospho-ERK1/2 was heterogeneous and often only detected at the tumor-stroma interface, thus limiting their clinical utility. We conclude that RAF1 gene rearrangements are relatively common in pancreatic acinar cell carcinomas (14.3% to 18.5% of cases) and can be effectively identified by FISH with follow up molecular testing. The combined results of several studies now indicate that BRAF, RET or RAF1 fusions occur in between one third and one-half of these tumors but are extremely rare in other pancreatic malignancies. As these fusions are potentially actionable with currently available therapies, a strong argument can be made to perform FISH or molecular testing on all pancreatic acinar cell carcinomas.

Risk factors for development of diabetes mellitus (Type 3c) after partial pancreatectomy: A systematic review.

OBJECTIVES: Type 3c diabetes mellitus (T3cDM) occurring post pancreatectomy can be challenging to treat due to the frequent combination of decreased circulating levels of insulin and glucagon and concurrent exocrine insufficiency. Relatively, little is known regarding the risk factors for development of T3cDM post pancreatectomy. Our aim was to review the literature and assess what is known of the risk factors for the development of new-onset DM following partial pancreatic resection and where possible determines the incidence, time of onset and the management approach to hyperglycaemia in this context. DESIGN: Medline and Embase databases were reviewed using specific keyword criteria. Original manuscripts published in 1990 or later included. Articles with study population <20, lacking information on new-onset DM, follow-up duration or specifically targeting rare procedures/pathology were excluded. The Newcastle Ottawa Quality Assessment form was applied. Results reported according to PRISMA guidelines. Pooled effect size calculated using random effects model. PATIENTS: Thirty six articles were identified that described a total of 5636 patients undergoing pancreaticoduodenectomy, 3922 patients having distal pancreatectomy and 315 with central pancreatectomy. RESULTS: The incidence of new-onset DM was significantly different between different types of resection from 9% to 24% after pancreaticoduodenectomy (pooled estimate 16%; 95% CI: 14%-17%), 3%-40% after distal pancreatectomy (pooled estimate 21%; 95% CI: 16%-25%) and 0%-14% after central pancreatectomy (pooled estimate 6%; 95% CI: 3%-9%). Surgical site, higher preoperative HbA1c, fasting plasma glucose and lower remnant pancreatic volume had strongest associations with new-onset DM. CONCLUSIONS: This systematic review supports that risk of development of T3cDM is associated with type of pancreatic resection, lower remnant pancreatic volume and higher preoperative HbA1c.

Neoadjuvant therapy for pancreatic cancer changes the composition of the pancreatic parenchyma.

BACKGROUND: Postoperative pancreatic fistula (POPF) remains a prominent complication following pancreatic cancer resections. The primary aim of this study was to evaluate the histological changes that occur in the pancreas due to neoadjuvant therapy (NAT) by comparing the acinar, collagen and fat scores in resected PDAC specimens of patients who did and did not receive NAT. Secondary aims included (1) the difference in rates of POPF in PDAC patients who received NAT versus upfront resection; and (2) the association between acinar/collagen/fat scores and the development of POPF. METHODS: Consecutive patients who underwent pancreaticoduodenectomy for PDAC, with and without NAT were included for analysis. Acinar, collagen and fat scores were determined from histology slides of the pancreatic resection margin. RESULTS: One hundred and thirty-four patients were included. There was a significant decrease in the median acinar score (48 vs 23, p = 0.003) and increase in the collagen score (28 vs 50, p = 0.011) for patients who received NAT and a significant correlation with the number of cycles of NAT. This study found no statistical difference between NAT and the development of POPF. CONCLUSION: The use of NAT in the treatment of PDAC changes the composition of the pancreas.