Progression from biochemical leak to pancreatic fistula after distal pancreatectomy. Don't cry over spilt amylase.

BACKGROUND: Postoperative pancreatic fistula (POPF) is a frequent complication after distal pancreatectomy (DP), but its upgrading from biochemical leak (BL) still represents an unexplored phenomenon. This study aims at identifying risk factors of the clinical evolution from BL to grade-B POPF after DP. METHODS: Patients who underwent DP between 2015 and 2019 and who developed either BL (n = 89,56%) or BL upgraded to late B fistula (LB) after postoperative day 5 (n = 71,44%) were included. Preoperative, surgical, postoperative predictors were compared between the two groups. RESULTS: Patients with LB were significantly older (61 vs 56 years, P < 0.025) and received neoadjuvant chemotherapy more frequently (22.5% vs 8.5%,P = 0.017). Extended lymphadenectomy (52.8% vs 31.0%,P = 0.006), longer operative times (OT) (307 vs 250 min,P = 0.002), greater estimated blood loss (250 vs 150 ml, P = 0.021), and the appearance of purulent fluid in surgical drains (58.4% vs 21.1%; P < 0.001) were more frequently observed in LB group. Only purulent fluid in surgical drains and longer OT were confirmed as independent predictors of BL clinical progression. CONCLUSIONS: Purulent fluid from surgical drains should be suspicious of BL upgrading. Frail patients undergoing longer interventions may represent key targets of mitigation strategies to minimize the magnitude of an incipient fistula and its increase in morbidity.

Reshaping preoperative treatment of pancreatic cancer in the era of precision medicine.

This review summarises the recent evidence on preoperative therapeutic strategies in pancreatic cancer and discusses the rationale for an imminent need for a personalised therapeutic approach in non-metastatic disease. The molecular diversity of pancreatic cancer and its influence on prognosis and treatment response, combined with the failure of 'all-comer' treatments to significantly impact on patient outcomes, requires a paradigm shift towards a genomic-driven approach. This is particularly important in the preoperative, potentially curable setting, where a personalised treatment allocation has the substantial potential to reduce pancreatic cancer mortality.

Predictors for Survival in an International Cohort of Patients Undergoing Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Surgical factors, including resection of Gerota's fascia, R0-resection, and lymph node yield, may be associated with survival after distal pancreatectomy (DP) for pancreatic ductal adenocarcinoma (PDAC), but evidence from large multicenter studies is lacking. This study aimed to identify predictors for overall survival after DP for PDAC, especially those related to surgical technique. PATIENTS AND METHODS: Data from an international retrospective cohort including patients from 11 European countries and the USA who underwent DP for PDAC (2007-2015) were analyzed. Cox proportional hazard analyses were performed and included Gerota's fascia resection, R0 resection, lymph node ratio, extended resection, and a minimally invasive approach. RESULTS: Overall, 1200 patients from 34 centers with median follow-up of 15 months [interquartile range (IQR) 5-31 months] and median survival period of 30 months [95% confidence interval (CI), 27-33 months] were included. Gerota's fascia resection [hazard ratio (HR) 0.74; p = 0.019], R0 resection (HR 0.70; p = 0.006), and decreased lymph node ratio (HR 0.28; p < 0.001) were associated with improved overall survival, whereas extended resection (HR 1.75; p < 0.001) was associated with worse overall survival. A minimally invasive approach did not improve survival as compared with an open approach (HR 1.14; p = 0.350). Adjuvant chemotherapy (HR 0.67; p = 0.003) was also associated with improved overall survival. CONCLUSIONS: This international cohort identified Gerota's fascia resection, R0 resection, and decreased lymph node ratio as factors associated with improved overall survival during DP for PDAC. Surgeons should strive for R0 resection and adequate lymphadenectomy and could also consider Gerota's fascia resection in their routine surgical approach.

Actual malignancy risk of either operated or non-operated presumed mucinous cystic neoplasms of the pancreas under surveillance.

BACKGROUND: Despite the low malignant potential of pancreatic mucinous cystic neoplasms (MCNs), surgery is still performed. The aim of this pragmatic study was to assess the outcome of surgery and surveillance for patients presenting with a presumed MCN at the first evaluation. METHODS: Data for patients with a presumed MCN observed from 2000 to 2016 at the Verona Pancreas Institute and San Raffaele Hospital were extracted from prospective databases. The endpoints were risk of malignancy at pathology and rate of misdiagnosis for the surgical series, expressed as an odds ratio (OR) with 95 per cent confidence interval, and disease-specific survival (DSS) for the surveillance cohort investigated by the Kaplan-Meier method. RESULTS: A total of 424 patients were identified. In the surgical series (229 patients), the rate of misdiagnosis was 19.2 per cent. The rate of malignant MCNs was 10.9 per cent (25 patients). The overall rate of malignancy, including misdiagnoses, was 11.3 per cent (26 patients). Predictors of malignancy were mural nodules (OR 27.75, 95 per cent c.i. 4.44-173.61; P < 0.001), size at least 50 mm (OR 13.39, 2.01 to 89.47; P = 0.007), and carbohydrate antigen 19.9 level (OR 3.98, 1.19 to 13.30; P = 0.025). In the absence of mural nodules and enhancing walls, none of the resected presumed MCNs smaller than 50 mm were malignant. Only patients with high-risk stigmata undergoing surgery experienced a significantly reduced 5-year DSS compared with all other patients (88 versus 100 per cent; P = 0.031). CONCLUSION: Presumed MCNs with mural nodules, enhancing walls or cysts of 50 mm or larger should be considered for upfront surgical resection owing to the high risk of malignancy. In the absence of these features, the incidence of malignancy is negligible, favouring surveillance in selected patients given the low risk of malignancy and the high rate of misdiagnosis. LAY SUMMARY: Malignant degeneration of presumed pancreatic mucinous cystic neoplasms takes several years, if it occurs at all. Mural nodules, enhancing walls or cysts of 50 mm or larger call for surgical resection owing to an increased risk of malignancy; otherwise, surveillance seems a good option.

Malignant degeneration of presumed pancreatic mucinous cystic neoplasms takes several years, if it occurs at all. Mural nodules, enhancing walls or cysts of 50 mm or larger call for surgical resection owing to an increased risk of malignancy; otherwise, surveillance seems a good option.

Sporadic non-functioning pancreatic neuroendocrine tumours: multicentre analysis.

BACKGROUND: Outcomes after surgery for sporadic pancreatic neuroendocrine neoplasms (Pan-NENs) were evaluated. METHODS: This multicentre study included patients who underwent radical pancreatic resection for sporadic non-functioning Pan-NENs. In survival analysis, the risk of mortality in this cohort was analysed in relation to that of the matched healthy Italian population. Relative survival (RS) was calculated as the rate between observed and expected survival. Factors related to RS were investigated using multivariable modelling. RESULTS: Among 964 patients who had pancreatic resection for sporadic non-functioning Pan-NENs, the overall RS rate was 91.8 (95 per cent c.i. 81.5 to 96.5) per cent. 2019 WHO grade (hazard ratio (HR) 5.75 (s.e. 4.63); P = 0.030) and European Neuroendocrine Tumour Society (ENETS) TNM stage (6.73 (3.61); P < 0.001) were independent predictors of RS. The probability of a normal lifespan for patients with G1, G2, G3 Pan-NENS, and pancreatic neuroendocrine carcinomas (Pan-NECs) was 96.7, 54.8, 0, and 0 per cent respectively. The probability of a normal lifespan was 99.8, 99.3, 79.8, and 46.8 per cent for those with stage I, II, III, and IV disease respectively. The overall disease-free RS rate was 73.6 (65.2 to 79.5) per cent. 2019 WHO grade (HR 2.10 (0.19); P < 0.001) and ENETS TNM stage (HR 2.50 (0.24); P < 0.001) significantly influenced disease-free RS. The probability of disease-free survival was 93.2, 84.9, 45.2, and 6.8 per cent for patients with stage I, II, III, and IV disease, and 91.9, 45.2, 9.4, and 0.7 per cent for those with G1, G2, G3 Pan-NENS, and Pan-NECs, respectively. CONCLUSION: A surgical approach seems without benefit for Pan-NECs, and unnecessary for small G1 sporadic Pan-NENs. Surgery alone may be insufficient for stage III-IV and G3 Pan-NENs.

Systematic review and meta-analysis of observational studies on BD-IPMNS progression to malignancy.

BACKGROUND: The vast majority of presumed branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) of the pancreas are referred to a surveillance program due to the relatively low risk of malignancy. We aim to evaluate all available data from observational studies focused on the risks of BD-IPMN progression and malignancy to provide vital insights into its management in clinical practice. METHODS: A comprehensive search was conducted at PubMed, Cochrane, Web of Science and Embase for observational studies published before January 1st, 2020. The progression of BD-IPMN was defined as the development of worrisome features (WFs) or high-risk stigmata (HRS) during surveillance. Overall malignancy was defined as all malignancies, such as malignant IPMN, concomitant pancreatic ductal adenocarcinoma (PDAC) and other malignancies, including BD-IPMN with high-grade sec. Baltimore consensus 2015 or BD-IPMN with high-grade dysplasia (carcinoma in situ) sec. WHO 2010. A meta-analysis was performed to investigate the presence of a mural nodule as a possible predictor of malignancy. RESULTS: Twenty-four studies were included, with a total of 8941 patients with a presumed BD-IPMN. The progression rate was 20.2%, and 11.8% underwent surgery, 29.5% of whom showed malignancy at the final pathology. Of those, 78% had malignant IPMNs, and 22% had concomitant pancreatic cancer. Overall, 0.5% had distant metastasis. The meta-analysis showed that the risk of malignancy in the presence of a mural nodule >5 mm had a RR of 5.457 (95% CI 1.404-21.353), while a nonenhancing mural nodule or an enhancing mural nodule < 5 mm had a RR of 5.286 (95% CI 1.805-15.481) of harboring malignancy. CONCLUSION: Most presumed BD-IPMNs entering surveillance do not become malignant. Of those submitted to surgery, concomitant PDAC adds to the overall risk of detecting malignancy.

Beyond neurotransmission: acetylcholine in immunity and inflammation.

Acetylcholine (ACh) is best known as a neurotransmitter and was the first such molecule identified. ACh signalling in the neuronal cholinergic system has long been known to regulate numerous biological processes (reviewed by Beckmann and Lips). In actuality, ACh is a ubiquitous signalling molecule that is produced by numerous non-neuronal cell types and even by some single-celled organisms. Within multicellular organisms, a non-neuronal cholinergic system that includes the immune system functions in parallel with the neuronal cholinergic system. Several immune cell types both respond to ACh signals and can directly produce ACh. Recent work from our laboratory has demonstrated that the capacity to produce ACh is an intrinsic property of T cells responding to viral infection, and that this ability to produce ACh is dependent upon IL-21 signalling to the T cells. Furthermore, during infection this immune-derived ACh is necessary for the T cells to migrate into infected tissues. In this review, we will discuss the various sources of ACh that are relevant during immune responses and describe how ACh acts on immune cells to influence their functions. We will also address the clinical implications of this fascinating aspect of immunity, focusing on ACh's role in the migration of T cells during infection and cancer.

Modelling centralization of pancreatic surgery in a nationwide analysis.

BACKGROUND: The benefits of centralization of pancreatic surgery have been documented, but policy differs between countries. This study aimed to model various centralization criteria for their effect on a nationwide cohort. METHODS: Data on all pancreatic resections performed between 2014 and 2016 were obtained from the Italian Ministry of Health. Mortality was assessed for different hospital volume categories and for each individual facility. Observed mortality and risk-standardized mortality rate (RSMR) were calculated. Various models of centralization were tested by applying volume criteria alone or in combination with mortality thresholds. RESULTS: A total of 395 hospitals performed 12 662 resections; 305 hospitals were in the very low-volume category (mean 2·6 resections per year). The nationwide mortality rate was 6·2 per cent, increasing progressively from 3·1 per cent in very high-volume to 10·6 per cent in very low-volume hospitals. For the purposes of centralization, applying a minimum volume threshold of at least ten resections per year would lead to selection of 92 facilities, with an overall mortality rate of 5·3 per cent. However, the mortality rate would exceed 5 per cent in 48 hospitals and be greater than 10 per cent in 17. If the minimum volume were 25 resections per year, the overall mortality rate would be 4·7 per cent in 38 facilities, but still over 5 per cent in 17 centres and more than 10 per cent in five. The combination of a volume requirement (at least 10 resections per year) with a mortality threshold (maximum RSMR 5 or 10 per cent) would allow exclusion of facilities with unacceptable results, yielding a lower overall mortality rate (2·7 per cent in 45 hospitals or 4·2 per cent in 76 respectively). CONCLUSION: The best performance model for centralization involved a threshold for volume combined with a mortality threshold.

ANTECEDENTES: Los beneficios de la centralización de la cirugía pancreática están bien documentados, pero la política de actuación difiere entre los países. Este estudio tuvo como objetivo desarrollar modelos de centralización basados en varios criterios y analizar su aplicación en una cohorte nacional. MÉTODOS: Los datos de todas las resecciones pancreáticas realizadas entre 2014 y 2016 se obtuvieron del Ministerio de Salud italiano. La mortalidad se evaluó para diferentes categorías del volumen hospitalario y para cada centro individualmente. Se calculó la mortalidad observada y la tasa estandarizada de riesgo de mortalidad (risk standardized mortality rate, RSMR). Se analizaron varios modelos de centralización aplicando criterios de volumen solos o en combinación con umbrales de mortalidad. RESULTADOS: Un total de 395 hospitales realizaron 12.662 resecciones; 305 de ellos pertenecían a la categoría de muy bajo volumen (media de 2,6 resecciones/año). La mortalidad nacional fue del 6,2%, aumentando progresivamente del 3,1% en los hospitales de muy alto volumen al 10,6% en los hospitales de muy bajo volumen. Para fines de centralización, al aplicar un umbral de volumen mínimo ≥ 10 resecciones/año, se seleccionarían 92 centros, con una mortalidad global del 5,3%. Sin embargo, la mortalidad sería > 5% en 48 hospitales y > 10% en 17 hospitales. Si el volumen mínimo fuera de 25 resecciones/año, la mortalidad global sería del 4,7% en 38 hospitales, pero aún > 5% en 17 centros y > 10% en seis centros. La combinación de un volumen necesario (≥ 10 resecciones/año) con un umbral de mortalidad (RSMR ≤ 5% o ≤ 10%) permitiría excluir hospitales con resultados inaceptables, determinando una mortalidad global más baja (2,7% en 45 hospitales o 4,2% en 76 hospitales, respectivamente). CONCLUSIÓN: El mejor modelo para la centralización de resecciones pancreáticas incluyó un umbral para el volumen hospitalario combinado con un umbral de mortalidad.

Use of an intraoperative wound protector to prevent surgical-site infection after pancreatoduodenectomy: randomized clinical trial.

BACKGROUND: Surgical-site infection (SSI) increases treatment costs, duration of hospital stay and readmission rate after pancreatic surgery. This study aimed to assess whether a wound protector could reduce the risk of superficial incisional SSI after pancreatoduodenectomy. METHODS: This RCT included patients undergoing pancreatoduodenectomy at Verona University Hospital, between 2017 and 2018. The experimental group had a dual-ring wound protector, whereas the control group had standard surgical drapes. The groups were stratified by preoperative biliary stent placement. The primary outcome was the overall rate of superficial SSI. RESULTS: An interim analysis was conducted after 212 patients had been enrolled; 22 patients (10·4 per cent) were excluded owing to inability to complete the pancreatoduodenectomy, or the need for postoperative reintervention. Some 94 patients (49·5 per cent) had a wound protector and 96 (50·5 per cent) had standard drapes. There were no differences between groups in demographics, or in intraoperative findings, pathological data or surgical outcomes. The overall superficial SSI rate was 7·4 per cent, which did not differ between groups (7 per cent in each group; P = 0·585). Subanalysis of patients with a preoperative biliary stent showed a similar outcome (superficial SSI rate 9 versus 8 per cent with wound protector versus surgical drapes respectively; P = 0·536). The trial was stopped prematurely on the grounds of futility. CONCLUSION: Use of a wound protector did not reduce the rate of superficial SSI after pancreatoduodenectomy. Registration number: NCT03820648 (http://www.clinicaltrials.gov).

ANTECEDENTES: La infección de la herida quirúrgica (surgical-site infection, SSI), especialmente de la incisión, aumenta sobremanera los costes del tratamiento, la duración de la estancia y la tasa de reingresos en la cirugía de páncreas. En los últimos años se han introducido los protectores de las heridas (wound protectors, WP) con la intención de reducir la tasa de SSI. Este estudio tuvo como objetivo evaluar si un WP podría reducir la incidencia de la SSI superficial de la incisión (superficial incisional surgical-site infection, SI-SSI) en pacientes sometidos a duodenopancreatectomía cefálica (pancreaticoduodenectomy, PD). MÉTODOS: Ensayo aleatorizado controlado en el que se incluyeron los pacientes a los que se realizó una PD en la Universidad de Verona entre 2017 y 2018. En el grupo experimental se utilizó un WP de doble anillo, mientras que el grupo control se utilizaron tallas quirúrgicas convencionales (standard drape, SD). Los grupos se estratificaron también según la colocación preoperatoria de una prótesis biliar. RESULTADOS: Se incluyeron 212 pacientes, de los que 22 (10%) abandonaron el estudio debido a la imposibilidad de realizar la DP o a la necesidad de una reintervención durante el curso postoperatorio. Los pacientes se dividieron en 94 (49%) en el grupo WP y 96 (51%) en el grupo SD. No se detectaron diferencias entre grupos en cuanto a las variables demográficas y a los resultados intraoperatorios, patológicos o quirúrgicos. La tasa global de SI-SSI fue del 7,4%, que no difirió entre los grupos (WP 7,5% versus SD 7,3%, P = 0,585). Teniendo en cuenta los resultados descritos, se cumplieron los criterios de futilidad del análisis y el ensayo se interrumpió prematuramente. CONCLUSIÓN: En el entorno de un centro de alto volumen, la WP por si sola no redujo la tasa de SI-SSI. Cabría plantear su utilización dentro de un programa multimodal, que debería incluir un replanteamiento interno de la institución encaminado a la reducción de complicaciones infecciosas.

Gemcitabine-based adjuvant chemotherapy in subtypes of ampullary adenocarcinoma: international propensity score-matched cohort study.

BACKGROUND: Whether patients who undergo resection of ampullary adenocarcinoma have a survival benefit from adjuvant chemotherapy is currently unknown. The aim of this study was to compare survival between patients with and without adjuvant chemotherapy after resection of ampullary adenocarcinoma in a propensity score-matched analysis. METHODS: An international multicentre cohort study was conducted, including patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma between 2006 and 2017, in 13 centres in six countries. Propensity scores were used to match patients who received adjuvant chemotherapy with those who did not, in the entire cohort and in two subgroups (pancreatobiliary/mixed and intestinal subtypes). Survival was assessed using the Kaplan-Meier method and Cox regression analyses. RESULTS: Overall, 1163 patients underwent pancreatoduodenectomy for ampullary adenocarcinoma. After excluding 187 patients, median survival in the remaining 976 patients was 67 (95 per cent c.i. 56 to 78) months. A total of 520 patients (53·3 per cent) received adjuvant chemotherapy. In a propensity score-matched cohort (194 patients in each group), survival was better among patients who received adjuvant chemotherapy than in those who did not (median survival not reached versus 60 months respectively; P = 0·051). A survival benefit was seen in patients with the pancreatobiliary/mixed subtype; median survival was not reached in patients receiving adjuvant chemotherapy and 32 months in the group without chemotherapy (P = 0·020). Patients with the intestinal subtype did not show any survival benefit from adjuvant chemotherapy. CONCLUSION: Patients with resected ampullary adenocarcinoma may benefit from gemcitabine-based adjuvant chemotherapy, but this effect may be reserved for those with the pancreatobiliary and/or mixed subtype.

ANTECEDENTES: Actualmente se desconoce si la quimioterapia adyuvante ofrece un beneficio en la supervivencia de los pacientes que se someten a resección de un adenocarcinoma ampular. El objetivo de este estudio fue comparar la supervivencia mediante la concordancia estimada por emparejamiento por puntaje de propensión, entre pacientes con y sin quimioterapia adyuvante después de la resección de un adenocarcinoma ampular. MÉTODOS: Se realizó un estudio internacional de cohortes multicéntrico, que incluyó a los pacientes que se sometieron a una duodenopancreatectomía por adenocarcinoma ampular (2006-2017) en 13 centros de seis países. Los puntajes de propensión se usaron para emparejar a los pacientes que recibieron quimioterapia adyuvante con los que no; tanto en la cohorte completa como en dos subgrupos (subtipo pancreaticobiliar / mixto e intestinal). La supervivencia se evaluó utilizando el método de Kaplan-Meier y las regresiones de Cox. RESULTADOS: En total, 1.163 pacientes fueron sometidos a una duodenopancreatectomía por adenocarcinoma ampular. Después de excluir a 179 pacientes, la mediana de supervivencia de los 976 pacientes restantes fue de 67 meses (i.c. del 95%, 56-78), de los cuales un total de 520 pacientes (53%) recibieron quimioterapia adyuvante. En una cohorte de emparejamiento por puntaje de propensión (194 versus 194 pacientes), la mediana de supervivencia fue mejor en los pacientes tratados con quimioterapia adyuvante en comparación con aquellos sin quimioterapia adyuvante (no se alcanzó la mediana de supervivencia versus 60 meses, respectivamente; P = 0,051). En el subtipo pancreaticobiliar/mixto se observó un beneficio en la supervivencia; no se alcanzó la mediana de supervivencia en pacientes que recibieron quimioterapia adyuvante versus 32 meses en el grupo sin quimioterapia, P = 0,020. El subtipo intestinal no mostró beneficio en la supervivencia de la quimioterapia adyuvante. CONCLUSIÓN: Los pacientes con adenocarcinoma ampular resecado pueden beneficiarse de la quimioterapia adyuvante basada en gemcitabina, pero este efecto podría reservarse para aquellos pacientes con subtipo de tumor pancreaticobiliar y/o mixto.

Pancreaticoduodenectomy for paraduodenal pancreatitis is associated with a higher incidence of diabetes but a similar quality of life and pain control when compared to medical treatment.

BACKGROUND: Paraduodenal pancreatitis is a focal form of chronic pancreatitis that affects the groove area between the duodenum and the head of the pancreas. Consensus regarding surgical or nonsurgical management as the best treatment option is still lacking. METHODS: We retrospectively evaluated all patients managed for PP at The Pancreas Institute of the University Hospital Trust of Verona from 1990 to 2017. The outcomes of surgical vs. medical treatment with regard to pain control, quality of life and pancreatic insufficiency were evaluated through specific questionnaires. RESULTS: The final study population consisted of 75 patients: 62.6% underwent surgery, and 37.4% were managed without surgery. All surgical procedures consisted of pancreaticoduodenectomy. The median follow-up from the diagnosis of paraduodenal pancreatitis was 60 (12-240) months. Patients who underwent surgery experienced a similar incidence of steatorrhea (44.7 vs. 52.6%; p = 0.4) but a significantly higher incidence of diabetes (59.6 vs. 10.7%; p < 0.01) when compared to those managed without surgery. There was no difference in terms of reported chronic pain (Graded Chronic Pain Scale, median 0 vs. 1; p = 0.1) and quality of life (Pancreatitis QoL Instrument, median 82 vs. 79; p = 0.2). However, surgical patients reported a worse level of self-care activities associated with glycemic control (Diabetes Self-Management Questionnaire, median 20 vs. 28, p = 0.02). CONCLUSION: In patients affected by paraduodenal pancreatitis, surgery and medical therapy seem to obtain similar results in terms of quality of life and pain control. However, surgery is associated with an increased prevalence of postoperative diabetes with consequent relevant issues with self-care management. Surgery should be considered only in selected patients after adequate medical treatment.

Risk of malignancy in small pancreatic cysts decreases over time.

BACKGROUND: Pancreatic cysts <15 mm without worrisome features have practically no risk of malignancy at the time of diagnosis but this can change over time. Optimal duration of follow-up is a matter of debate. We evaluated predictors of malignancy and attempted to identify a time to safely discontinue surveillance. METHODS: Bi-centric study utilizing prospectively collected databases of patients with pancreatic cysts measuring <15 mm and without worrisome features who underwent surveillance at the Massachusetts General Hospital (1988-2017) and at the University of Verona Hospital Trust (2000-2016). The risk of malignant transformation was assessed using the Kaplan-Meier method and parametric survival models, and predictors of malignancy were evaluated using Cox regression. RESULTS: 806 patients were identified. Median follow-up was 58 months (6-347). Over time, 58 (7.2%) cysts were resected and of those, 11 had high grade dysplasia (HGD) or invasive cancer. Three additional patients had unresectable cancer for a total rate of malignancy of 1.7%. Predictors of development of malignancy included an increase in size ≥2.5 mm/year (HR = 29.54, 95% CI: 9.39-92.91, P < 0.001) and the development of worrisome features (HR = 9.17, 95% CI: 2.99-28.10, P = 0.001). Comparison of parametric survival models suggested that the risk of malignancy decreased after three years of surveillance and was lower than 0.2% after five years. CONCLUSIONS: Pancreatic cysts <15  mm at the time of diagnosis have a very low risk of malignant transformation. Our findings indicate the risk decreases over time. Size increase of ≥2.5 mm/year is the strongest predictor of malignancy.

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.

Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas).

OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2-200)), 9% had resection beyond 1 year of follow-up (3 years (1-20), size at diagnosis: 25 mm (4-140)) and 39% had no surgery (3.6 years (1-23), 25.5 mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. TRIAL REGISTRATION NUMBER: IRB 00006477.

Characterization of nuclear PTEN and its post translational modifications.

Somatic loss-of-function mutations of PTEN are found in a variety of human malignancies. Our recent work demonstrated that the nuclear function of PTEN is implicated in the maintenance of genome integrity. Proper subcellular localization of PTEN following genotoxic stress is coordinated by a cellular mechanism that involves post-translational modification by SUMOylation and ATM-mediated phosphorylation. Here we summarize biochemical and cell-based methodologies that can be used to characterize the SUMOylation and phosphorylation state of nuclear PTEN in the context of DNA damage. In addition, we describe assays to determine the biological function of SUMO-PTEN in homologous recombination DNA repair. These methods will help elucidate the precise molecular mechanisms of PTEN's role in the maintenance of genomic stability.

Prevalence and risk factors of extrapancreatic malignancies in a large cohort of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas.

BACKGROUND: The objectives of this study are to estimate prevalence and incidence of extrapancreatic malignancies (EPMs) among intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, and to identify risk factors for their occurrence. PATIENTS AND METHODS: We conducted multicentric cohort study in Italy from January 2010 to January 2011 including 390 IPMN cases. EPMs were grouped as previous, synchronous (both prevalent) and metachronous (incident). We calculated the observed/expected (O/E) ratio of prevalent EPMs, and compared the distribution of demographic, medical history and lifestyle habits. RESULTS: Ninety-seven EPMs were diagnosed in 92 patients (23.6%), among them 78 (80.4%) were previous, 14 (14.4%) were synchronous and 5 (5.2%) were metachronous. O/E ratios for prevalent EPMs were significantly increased for colorectal carcinoma (2.26; CI 95% 1.17-3.96), renal cell carcinoma (6.00; CI 95% 2.74-11.39) and thyroid carcinoma (5.56; CI 95% 1.80-12.96). Increased age, heavy cigarette smoking, alcohol consumption and first-degree family history of gastric cancer are significant risk factors for EPMs, while first-degree family history of colorectal carcinoma was borderline. CONCLUSION: We report an increased prevalence of EPMs in Italian patients with IPMN, especially for colorectal carcinoma, renal cell and thyroid cancers. A systematic surveillance of IPMN cases for such cancer types would be advised.

A systematic review and meta-analysis of germline BRCA mutations in pancreatic cancer patients identifies global and racial disparities in access to genetic testing.

BACKGROUND: Germline BRCA1 and BRCA2 mutations (gBRCAm) can inform pancreatic cancer (PC) risk and treatment but most of the available information is derived from white patients. The ethnic and geographic variability of gBRCAm prevalence and of germline BRCA (gBRCA) testing uptake in PC globally is largely unknown. MATERIALS AND METHODS: We carried out a systematic review and prevalence meta-analysis of gBRCA testing and gBRCAm prevalence in PC patients stratified by ethnicity. The main outcome was the distribution of gBRCA testing uptake across diverse populations worldwide. Secondary outcomes included: geographic distribution of gBRCA testing uptake, temporal analysis of gBRCA testing uptake in ethnic groups, and pooled proportion of gBRCAm stratified by ethnicity. The study is listed under PROSPERO registration number #CRD42022311769. RESULTS: A total of 51 studies with 16 621 patients were included. Twelve of the studies (23.5%) enrolled white patients only, 10 Asians only (19.6%), and 29 (56.9%) included mixed populations. The pooled prevalence of white, Asian, African American, and Hispanic patients tested per study was 88.7%, 34.8%, 3.6%, and 5.2%, respectively. The majority of included studies were from high-income countries (HICs) (64; 91.2%). Temporal analysis showed a significant increase only in white and Asians patients tested from 2000 to present (P < 0.001). The pooled prevalence of gBRCAm was: 3.3% in white, 1.7% in Asian, and negligible (<0.3%) in African American and Hispanic patients. CONCLUSIONS: Data on gBRCA testing and gBRCAm in PC derive mostly from white patients and from HICs. This limits the interpretation of gBRCAm for treating PC across diverse populations and implies substantial global and racial disparities in access to BRCA testing in PC.

Combined modality treatment for patients with locally advanced pancreatic adenocarcinoma.

BACKGROUND: Radiofrequency ablation (RFA) is an emerging treatment for patients with locally advanced pancreatic carcinoma, and can be combined with radiochemotherapy and intra-arterial plus systemic chemotherapy. METHODS: This observational study compared two groups of patients with locally advanced pancreatic carcinoma treated with either primary RFA (group 1) or RFA following any other primary treatment (group 2). RESULTS: Between February 2007 and May 2010, 107 consecutive patients were treated with RFA. There were 47 patients in group 1 and 60 in group 2. Median overall survival was 25·6 months. Median overall survival was significantly shorter in group 1 than in group 2 (14·7 versus 25·6 months; P = 0·004) Patients treated with RFA, radiochemotherapy and intra-arterial plus systemic chemotherapy (triple-approach strategy) had a median overall survival of 34·0 months. CONCLUSION: RFA after alternative primary treatment was associated with prolonged survival. This was further extended by use of a triple-approach strategy in selected patients. Further evaluation of this approach seems warranted.

Substance P and neprilysin in chronic pancreatitis.

BACKGROUND/AIMS: We aimed to analyze substance P (SP) and neprilysin (NEP), the membrane metallopeptidase that degrades SP, in chronic pancreatitis (CP). METHODS: SP and NEP mRNA levels were analyzed by qRT-PCR in tissue samples from 30 patients with CP and 8 organ donors. In addition, SP serum levels were determined before and after surgery in the same patients, by means of a competitive ELISA assay. Genetic and epigenetic analyses of the NEP gene were also performed. RESULTS: SP mRNA expression levels were higher in CP tissues compared to controls (p = 0.0152), while NEP mRNA showed no significant differences between CP and healthy subjects (p = 0.2102). In CP patients, SP serum levels correlated with those in tissue, and after surgical resection SP serum levels were reduced compared to the preoperative values. Failure of NEP to overexpress in CP tissues was associated with significant miR-128a overexpression (p = 0.02), rather than with mutations in the NEP coding region or the presence of hypermethylation sites in the NEP promoter region. CONCLUSION: Tissue and serum levels of SP were increased in CP, while NEP levels remained unaltered. In an SP/NEP-mediated pathway, it would appear that NEP fails to provide adequate surveillance of SP levels. Failure of NEP to overexpress could be associated with miRNA regulation.