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Background: It is unclear whether pathological staging is significant prognostically and can inform the delivery of adjuvant therapy after pancreatectomy preceded by neoadjuvant therapy. Methods: This multicentre retrospective study included patients who underwent pancreatectomy for pancreatic ductal adenocarcinoma after neoadjuvant treatment at two Italian centres between 2013 and 2017. T and N status were assigned in accordance with the seventh and eighth editions of the AJCC staging system, as well as according to a modified system with T status definition combining extrapancreatic invasion and tumour size. Patients were then stratified by receipt of adjuvant therapy. Survival analysis and multivariable interaction analysis of adjuvant therapy with pathological parameters were performed. The results were validated in an external cohort from the USA. Results: The developmental set consisted of 389 patients, with a median survival of 34.6 months. The modified staging system displayed the best prognostic stratification and the highest discrimination (C-index 0.763; 1-, 2- and 3-year time-dependent area under the curve (AUC) 0.746, 0.722, and 0.705; Uno's AUC 0.710). Overall, 67.0 per cent of patients received adjuvant therapy. There was no survival difference by receipt of adjuvant therapy (35.0 versus 36.0 months; P = 0.772). After multivariable adjustment, interaction analysis suggested a benefit of adjuvant therapy for patients with nodal metastases or with tumours larger than 2 cm with extrapancreatic extension, regardless of nodal status. These results were confirmed in the external cohort of 216 patients. Conclusion: Modified staging with a T status definition combining extrapancreatic invasion and tumour size is associated with better prognostic segregation after postneoadjuvant pancreatectomy. This system allows identification of patients who might benefit from adjuvant therapy. [ABSTRACT FROM AUTHOR]

The ABO blood type has been associated with risk of development of several malignancies, including pancreatic cancer. Data regarding IPMN is equivocal. To investigate this further, we analyzed the association between the ABO blood group and the presence of malignancy in a large cohort of resected IPMN and its influence in survival. 819 patients who underwent pancreatic resection for IPMN in the Massachusetts General Hospital (MGH) and Cambridge University Hospitals NHS Foundation Trust (CUH) from January 1993 to December 2020 were identified from prospective institutional databases. Pathological characteristics and blood type were correlated. The distribution of blood types A, B, AB and O was 384 (47%), 92 (11%), 44 (5%) and 299 (37%), respectively. This blood type distribution was different than the reference population of the MGH and the CUH, which is 55% non-O blood group, and 45% type O. There was a significant predominance of non-O blood types when compared with O-blood type in patients with malignant IPMN (i.e. patients with high-grade dysplasia and invasive cancer) (67% vs 33%, OR 1.31 95%CI: 0.98–1.75, p = 0.069). The association was stronger for IPMN with invasive cancer (OR 1.43 95%CI: 1.01–2.02, p = 0.039). Blood group did not influence survival. Non-O blood type is associated with need for resection in IPMN and with presence of invasive carcinoma. [ABSTRACT FROM AUTHOR]

The risk of pancreatic ductal adenocarcinoma (PDAC) is increased in patients with diabetes mellitus (DM), particularly in those with new-onset DM. However, the impact of DM on outcomes following pancreatic surgery is not fully understood. We sought to explore the effects of DM on post-resection outcomes in patients undergoing either upfront resection or following neoadjuvant treatment (NAT). Resections for PDAC between 2007 and 2016 were identified from a prospectively-maintained database. Data on demographics, pathology, and perioperative outcomes were compared between patients with or without DM. Survival analysis was performed using Kaplan-Meier curves and adjusted for confounders by a Cox-proportional hazards model. 662 patients were identified, of whom 277 (41.8%) had DM. Diabetics were more likely to be male, had higher BMI, and higher ASA-scores. At pathology, DM was associated with larger tumors (30 vs. 26 mm; p = 0.041), higher rates of lymph-node involvement (69% vs. 59%; p = 0.031) and perineural invasion (88% vs. 82%; p = 0.026). Despite having similar rates of complications, diabetics experienced higher 30-day mortality (3.2% vs. 0.8%; p = 0.019). Median overall survival was worse in diabetic patients (18 vs. 34 months; p < 0.001); this effect was more pronounced in patients with NAT (18 vs. 54 months; p < 0.001). At multivariate analysis, DM was confirmed as an independent predictor of post-resection survival. DM is a common comorbidity in PDAC and is associated with unfavorable pathology, as well as worse postoperative and oncologic outcomes. The blunted effect on survival is more pronounced in patients who undergo resection following NAT. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: To establish an international core set of patient-reported outcomes (PROs) selected by both patients and healthcare providers (HCPs) from the United States (US), Europe, and Asia. Summary Background Data: PROs are increasingly recognized in pancreatic cancer studies. There is no consensus on which of the many available PROs are most important. Methods: A multicenter Delphi study among patients with pancreatic cancer (curative- and palliative-setting) and HCPs in 6 pancreatic centers in the US (Baltimore, Boston), Europe (Amsterdam, Verona), and Asia (Mumbai, Seoul) was performed. In round 1, participants rated the importance of 56 PROs on a 1 to 9 Likert scale. PROs rated as very important (scores 7–9) by the majority (≥80%) of curative- and/or palliative-patients as well as HCPs were included in the core set. PROs not fulfilling these criteria were presented again in round 2, together with feedback on individual and group ratings. Remaining PROs were ranked based on the importance ratings. Results: In total 731 patients and HCPs were invited, 501 completed round 1, and 420 completed both rounds. This included 204 patients in curative-setting, 74 patients in palliative-setting, and 142 HCPs. After 2 rounds, 8 PROs were included in the core set: general quality of life, general health, physical ability, ability to work/do usual activities, fear of recurrence, satisfaction with services/care organization, abdominal complaints, and relationship with partner/family. Conclusions: This international Delphi study among patients and HCPs established a core set of PROs in pancreatic cancer, which should facilitate the design of future pancreatic cancer trials and outcomes research. [ABSTRACT FROM AUTHOR]

Background While the association between Diabetes Mellitus (DM) and pancreatic ductal adenocarcinoma is well recognized, its importance in intraductal papillary mucinous neoplasm of the pancreas (IPMN) is not well-defined. We sought to examine the associations of DM with degree of dysplasia and morphological subtypes in IPMN. Methods In 454 patients with resected IPMN, we evaluated associations of DM with high-grade dysplasia (HGD), invasive carcinoma, precursor epithelial subtype (gastric, intestinal, oncocytic, pancreatobiliary), and histological type of invasive carcinomas (tubular, colloid, oncocytic) using logistic regression. We performed multivariate analyses adjusting for worrisome features and high-risk stigmata of malignancy in a subset of 289 patients with annotated radiological characteristics. Results The prevalence of DM in our study was 34%. DM was significantly associated with HGD (OR 2.02, 95% CI 1.02–4.01, P = 0.045) and invasive carcinoma (OR 2.05, 95% CI 1.08–3.87, P = 0.027) after adjusting for worrisome features. Compared to patients without DM, those with recent-onset DM (≤5 years before surgery) had 6.9-fold (95% CI 2.38–19.92, P < 0.001) higher risk of invasive carcinoma. DM was associated with increased likelihood of intestinal-type precursor epithelium (OR 1.63, 95% CI 1.07–2.47, P = 0.022) and colloid carcinomas (OR 2.46, 95% CI 1.01–5.99, P = 0.047) Conclusion Preoperative DM was associated with significantly higher risk of HGD and invasive carcinoma in resected IPMN, and risk of invasive carcinoma was highest in patients with recent-onset DM. Patients with DM were more likely to harbor intestinal-type IPMN and colloid carcinomas. Our findings suggest that a diagnosis of DM in patients with IPMN may warrant more aggressive surveillance. [ABSTRACT FROM AUTHOR]

The management of intraductal papillary mucinous neoplasm (IPMN) continues to evolve. In particular, the indications for resection of branch duct IPMN have changed from early resection to more deliberate observation as proposed by the international consensus guidelines of 2006 and 2012. Another guideline proposed by the American Gastroenterological Association in 2015 restricted indications for surgery more stringently and recommended physicians to stop surveillance if no significant change had occurred in a pancreatic cyst after five years of surveillance, or if a patient underwent resection and a non-malignant IPMN was found. Whether or not it is safe to do so, as well as the method and interval of surveillance, has generated substantial debate. Based on a consensus symposium held during the meeting of the International Association of Pancreatology in Sendai, Japan, in 2016, the working group has revised the guidelines regarding prediction of invasive carcinoma and high-grade dysplasia, surveillance, and postoperative follow-up of IPMN. As the working group did not recognize the need for major revisions of the guidelines, we made only minor revisions and added most recent articles where appropriate. The present guidelines include updated information and recommendations based on our current understanding, and highlight issues that remain controversial or where further research is required. [ABSTRACT FROM AUTHOR]

Several inhibitors of angiogenesis have been identified in bovine and shark cartilage. One of them is troponin I, which is the molecule responsible for the inhibition of the actomyosin ATPase during muscle contraction. In this study we sought to investigate if the active site of troponin I (peptide Glu94-Leu123; pTnI) is also the one responsible for the antiangiogenic properties of this protein. The effects of pTnI on endothelial cell tube formation and endothelial cell division were investigated using human umbilical vein endothelial cells, Matrigel, light microscopy, carboxyfluorescein diacetate, succinimidyl esterlabeling, and flow cytometry. Its effects on induction of ICAM-1 and production of vascular endothelial growth factor by pancreatic cancer cells (CAPAN-1) were also investigated, as was its efficacy in a mouse model of pancreatic cancer metastases. Our results show that concentrations as low as 1 pg/ml of pTnI significantly inhibit endothelial cell tube formation, and that endothelial cell division was inhibited at 96 hours by 3 μg/ml pTnI (P = 0.0001). No effects were seen using troponin peptide 124-181 as a control. pTnI-treated supernatant from the pancreatic cancer cell line CAPAN-1 downregulated ICAM-1 expression on human umbilical vein endothelial cells up to 10 ng/ml pTnI, and a significant reduction in vascular endothelial growth factor production was seen by treating CAPAN-1 cells with up to 1 μg/ml pTnI. After intrasplenic injection of CAPAN-1 cells, mice treated with pTnI had fewer liver metastases compared to control mice (liver/body weight 5.5 vs. 11.1; P = 0.03). The active region of troponin I is the one responsible for its antiangiogenic effect. The mechanism of action of this peptide is probably multifactorial. [Copyright &y& Elsevier]

Background & Aims: Pancreatic intraepithelial neoplasia (PanIN) are pancreatic cancer precursor lesions of unclear origin and significance. PanIN aberrantly express sonic hedgehog (Shh), an initiator of pancreatic cancer, and gastrointestinal mucins. A majority of PanIN are thought to arise from ducts. We identified a novel ductal compartment that is gathered in gland-like outpouches (pancreatic duct glands [PDG]) of major ducts and characterized its role in injury and metaplasia. Methods: The ductal system was analyzed in normal pancreata and chronic pancreatitis in humans and mice. Anatomy was assessed by serial hematoxylin and eosin sections and scanning electron microscopy of corrosion casts. Expression of mucins and developmental genes and proliferation were assessed by immunohistochemistry or real-time quantitative polymerase chain reaction. Effects of Shh on ductal cells were investigated by exposure to Shh in vitro and transgenic misexpression in vivo. Results: Three-dimensional analysis revealed blind-ending outpouches of ducts in murine and human pancreata. These PDG are morphologically and molecularly distinct from normal ducts; even in normal pancreata they display PanIN and metaplastic features, such as expression of Shh and gastric mucins. They express other developmental genes, such as Pdx-1 and Hes-1. In injury, Shh is up-regulated along with gastric mucins. Expansion of the PDG compartment results in a mucinous metaplasia. Shh promotes this transformation in vitro and in vivo. Conclusions: PDG are distinct gland-like mucinous compartments with a distinct molecular signature. In response to injury, PDG undergo an Shh-mediated mucinous gastrointestinal metaplasia with PanIN-like features. PDG may provide a link between Shh, mucinous metaplasia, and neoplasia. [Copyright &y& Elsevier]

Hedgehog signalling-an essential pathway during embryonic pancreatic development, the misregulation of which has been implicated in several forms of cancer-may also be an important mediator in human pancreatic carcinoma. Here we report that sonic hedgehog, a secreted hedgehog ligand, is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions: pancreatic intraepithelial neoplasia (PanIN). Pancreata of Pdx-Shh mice (in which Shh is misexpressed in the pancreatic endoderm) develop abnormal tubular structures, a phenocopy of human PanIN-1 and -2. Moreover, these PanIN-like lesions also contain mutations in K-ras and overexpress HER-2/neu, which are genetic mutations found early in the progression of human pancreatic cancer. Furthermore, hedgehog signalling remains active in cell lines established from primary and metastatic pancreatic adenocarcinomas. Notably, inhibition of hedgehog signalling by cyclopamine induced apoptosis and blocked proliferation in a subset of the pancreatic cancer cell lines both in vitro and in vivo. These data suggest that this pathway may have an early and critical role in the genesis of this cancer, and that maintenance of hedgehog signalling is important for aberrant proliferation and tumorigenesis. [ABSTRACT FROM AUTHOR]

Objective: To assess the implications of positive cytology for malignant cells (positive results) from peritoneal washings in the management of patients with pancreatic cancer. Design: Retrospective cohort study. Setting: Referral practice in a university hospital. Patients: A total of 32 consecutive pancreatic cancer patients with positive results from peritoneal washings during a 4-year period, 17 with visible biopsy-proven intra-abdominal metastases at the time of laparoscopy or laparotomy and 15 without visible metastases. A treatment-matched control group of 30 patients was randomly selected from a group of 105 patients with negative cytology for malignant cells (negative results) from peritoneal-fluid cytology. Interventions: Eight of 17 patients with visible metastases underwent treatment with chemotherapy, radiation, or both; 13 of the 15 patients with no visible metastases underwent further treatment, including pancreatic resection in 2 patients and external beam radiation in 13 patients (3 with intraoperative radiation therapy). Main Outcome Measures: Time to metastases and mortality. Results: Median survival among patients with and without visible metastasis was 7.8 months and 8.6 months, respectively (P=.95), despite the fact that patients without visible metastases received more treatment. Patients without visible metastases at presentation were found to have metastatic disease as documented by computed tomographic scan or subsequent laparotomy at a median time of 2.9 months. The survival of treatment-matched patients with negative cytology was significantly longer (median, 13.5 months; P=.04). Conclusions: Pancreatic cancer patients with peritoneal micrometastases have a dismal outcome even without macroscopic metastases. Since these patients do not benefit from local therapy, the finding of a positive result from peritoneal-fluid cytologic testing contraindicates further irradiation or surgery, except for specific complications. [ABSTRACT FROM AUTHOR]

The testosterone:dihydrotestosterone ratio (T:DHT) and the antigenic marker CA 19-9 were studied in the serum of 21 male patients with pancreatic cancer and 62 controls with other gastrointestinal malignancies or benign pancreatobiliary disease. Specificity of the T:DHT ratio was 98%, significantly better than the specificity of CA 19-9 at both a 37 U/ml cutoff level (61%) and at 100 U/ml (79%). Sensitivity+ of the T:DHT ratio was 67%, and that of CA 19-9, 71% and 90% at the upper and lower cutoff levels, respectively. False-negative results of the T:DHT ratio were found predominantly in cases of advanced pancreatic cancer, whereas all four stage I patients had an abnormal (< 5) T:DHT ratio. These results suggest that the T:DHT ratio is a useful marker for pancreatic cancer in males. It can be used alone or in combination with CA 19-9, and should be further evaluated in the differential diagnosis of patients with the early stages of this disease. [ABSTRACT FROM AUTHOR]

Advances in cross-sectional imaging have resulted in increased detection of intraductal papillary mucinous neoplasms (IPMNs), and their management remains controversial. At present, there is no reliable noninvasive method to distinguish between indolent and high risk IPMNs. We performed extracellular vesicle (EV) analysis to identify markers of malignancy in an attempt to better stratify these lesions. Using a novel ultrasensitive digital extracellular vesicle screening technique (DEST), we measured putative biomarkers of malignancy (MUC1, MUC2, MUC4, MUC5AC, MUC6, Das-1, STMN1, TSP1, TSP2, EGFR, EpCAM, GPC1, WNT-2, EphA2, S100A4, PSCA, MUC13, ZEB1, PLEC1, HOOK1, PTPN6, and FBN1) in EV from patient-derived cell lines and then on circulating EV obtained from peripheral blood drawn from patients with IPMNs. We enrolled a total of 133 patients in two separate cohorts: a clinical discovery cohort (n = 86) and a validation cohort (n = 47). From 16 validated EV proteins in plasma samples collected from the discovery cohort, only MUC5AC showed significantly higher levels in high-grade lesions. Of the 11 patients with invasive IPMN (inv/HG), 9 had high MUC5AC expression in plasma EV of the 11 patients with high-grade dysplasia alone, only 1 had high MUC5AC expression (sensitivity of 82%, specificity of 100%). These findings were corroborated in a separate validation cohort. The addition of MUC5AC as a biomarker to imaging and high-risk stigmata allowed detection of all cases requiring surgery, whereas imaging and high-risk stigmata alone would have missed 5 of 14 cases (36%). MUC5AC in circulating EV can predict the presence of invasive carcinoma within IPMN. This approach has the potential to improve the management and follow-up of patients with IPMN including avoiding unnecessary surgery. [Display omitted] [ABSTRACT FROM AUTHOR]

Background & Aims Little is known about the development of branch duct intraductal papillary mucinous neoplasms (BD-IPMNs). We evaluated long-term outcomes of a large cohort of patients with BD-IPMNs to determine risk of malignancy and define a subset of low-risk BD-IPMNs. Methods We performed a retrospective analysis of data from 577 patients with suspected or presumed BD-IPMN under surveillance at the Massachusetts General Hospital. Patients underwent cross-sectional imaging analysis at 3 months or later after their initial diagnosis. The diagnosis of BD-IPMN was based on the presence of unilocular or multilocular cysts of the pancreas and a non-dilated main pancreatic duct (<5 mm). We collected demographic, clinical, and pathology data. Cysts were characterized at the time of diagnosis and during the follow-up period. Follow-up duration was time between initial cyst diagnosis and date of last visit or death for patients without development of pancreatic cancer, date of surgery for patients with histologically confirmed malignancy, or date of first discovery of malignancy by imaging analysis for patients with unresectable tumors or who underwent neoadjuvant treatment before surgery. The primary outcome was risk of malignancy, with a focus on patients followed for 5 years or more, compared with that of the US population, based on standardized incidence ratio. Results Of the 577 patients studied, 479 (83%) were asymptomatic at diagnosis and 363 (63%) underwent endoscopic ultrasound at least once. The median follow-up time was 82 months (range, 6−329 months) for the entire study cohort; 363 patients (63%) underwent surveillance for more than 5 years, and 121 (21%) for more than 10 years. Malignancies (high-grade dysplasia or invasive neoplasm) developed after 5 years in 20 of 363 patients (5.5%), and invasive cancer developed in 16 of 363 patients (4.4%). The standardized incidence ratio for patients with BD-IPMNs without worrisome features of malignancy at 5 years was 18.8 (95% confidence interval, 9.7−32.8; P < .001). One hundred and eight patients had cysts ≤1.5 cm for more than 5 years of follow-up; only 1 of these patients (0.9%) developed a distinct ductal adenocarcinoma. By contrast, among the 255 patients with cysts >1.5 cm, 19 (7.5%) developed malignancy ( P = .01). Conclusions In a retrospective analysis of patients with BD-IPMNs under surveillance, their overall risk of malignancy, almost 8%, lasted for 10 years or more, supporting continued surveillance after 5 years. Cysts that remain ≤1.5 cm for more than 5 years might be considered low-risk for progression to malignancy. [ABSTRACT FROM AUTHOR]

Background The different epithelial phenotypes of intraductal papillary mucinous neoplasms (IPMNs) are predictors of tumor biology and post-surgical outcomes. Oncocytic-type IPMN (O-IPMN) seems to have a unique natural history, but not much information is available because of its rarity. We sought to describe the characteristics of a cohort of patients resected for O-IPMNs, focusing on their long-term outcomes after surgery. Study Design We conducted a retrospective review of the demographics, clinical presentation, pathology, and survival of a cohort of patients resected for IPMN between 1990 and 2013, comparing O-IPMN with other IPMN subtypes. Results Eighteen of 400 patients (4.5%) who underwent resection for IPMN had the oncocytic subtype. Compared with other IPMN patients, those with O-IPMNs were more likely to be male (72% vs 45%; p = 0.02) and to have main pancreatic duct involvement (72% vs 42%; p = 0.01). Oncocytic IPMNs occurred in asymptomatic individuals in 67% of cases. They had either invasive carcinoma (61%) or high-grade dysplasia (39%), and the proportions in other epithelial subtypes were 19% and 21%, respectively (p < 0.001). After resection, the 10-year recurrence rate for O-IPMNs was 46%. Recurrences occurred up to 11 years after the initial resection and a completion total pancreatectomy was performed in 4 patients. At a median follow-up of 7 years, no patients with O-IPMN had died from the disease. Conclusions Oncocytic IPMN is a unique tumor subtype that occurs mostly in the main pancreatic duct and is malignant. Recurrences after resection are not uncommon and can occur more than 10 years after the initial resection. Reoperations for recurrent O-IPMN are often feasible and have excellent results in terms of survival. [ABSTRACT FROM AUTHOR]