Cellular and transcriptional dynamics of human neutrophils at steady state and upon stress.

Traditionally viewed as poorly plastic, neutrophils are now recognized as functionally diverse; however, the extent and determinants of neutrophil heterogeneity in humans remain unclear. We performed a comprehensive immunophenotypic and transcriptome analysis, at a bulk and single-cell level, of neutrophils from healthy donors and patients undergoing stress myelopoiesis upon exposure to growth factors, transplantation of hematopoietic stem cells (HSC-T), development of pancreatic cancer and viral infection. We uncover an extreme diversity of human neutrophils in vivo, reflecting the rates of cell mobilization, differentiation and exposure to environmental signals. Integrated control of developmental and inducible transcriptional programs linked flexible granulopoietic outputs with elicitation of stimulus-specific functional responses. In this context, we detected an acute interferon (IFN) response in the blood of patients receiving HSC-T that was mirrored by marked upregulation of IFN-stimulated genes in neutrophils but not in monocytes. Systematic characterization of human neutrophil plasticity may uncover clinically relevant biomarkers and support the development of diagnostic and therapeutic tools.

IL-1ß+ macrophages fuel pathogenic inflammation in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies1. Inflammatory and immunomodulatory signals co-exist in the pancreatic tumour microenvironment, leading to dysregulated repair and cytotoxic responses. Tumour-associated macrophages (TAMs) have key roles in PDAC2, but their diversity has prevented therapeutic exploitation. Here we combined single-cell and spatial genomics with functional experiments to unravel macrophage functions in pancreatic cancer. We uncovered an inflammatory loop between tumour cells and interleukin-1ß (IL-1ß)-expressing TAMs, a subset of macrophages elicited by a local synergy between prostaglandin E2 (PGE2) and tumour necrosis factor (TNF). Physical proximity with IL-1ß+ TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells. This occurrence was an early event in pancreatic tumorigenesis and led to persistent transcriptional changes associated with disease progression and poor outcomes for patients. Blocking PGE2 or IL-1ß activity elicited TAM reprogramming and antagonized tumour cell-intrinsic and -extrinsic inflammation, leading to PDAC control in vivo. Targeting the PGE2-IL-1ß axis may enable preventive or therapeutic strategies for reprogramming of immune dynamics in pancreatic cancer.

Impact of age, comorbidities and relevant changes on surveillance strategy of intraductal papillary mucinous neoplasms: a competing risk analysis.

OBJECTIVE: Cost-effectiveness of surveillance for branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) is debated. We combined different categories of risks of IPMN progression and of IPMN-unrelated mortality to improve surveillance strategies. DESIGN: Retrospective analysis of 926 presumed BD-IPMNs lacking worrisome features (WFs)/high-risk stigmata (HRS) under surveillance. Charlson Comorbidity Index (CACI) defined the severity of comorbidities. IPMN relevant changes included development of WF/HRS, pancreatectomy or death for IPMN or pancreatic cancer. Pancreatic malignancy-unrelated death was recorded. Cumulative incidence of IPMN relevant changes were estimated using the competing risk approach. RESULTS: 5-year cumulative incidence of relevant changes was 17.83% and 1.6% developed pancreatic malignancy. 5-year cumulative incidences for IPMN relevant changes were 13.73%, 19.93% and 25.04% in low-risk, intermediate-risk and high-risk groups, respectively. Age ≥75 (HR: 4.15) and CACI >3 (HR: 3.61) were independent predictors of pancreatic malignancy-unrelated death. 5-year cumulative incidence for death for other causes was 15.93% for age ≥75+CACI >3 group and 1.49% for age <75+CACI ≤3. 5-year cumulative incidence of IPMN relevant changes were 13.94% in patients with age <75+CACI ≤3 compared with 29.60% in those with age ≥75+CACI >3. In this group 5-year rate of malignancy-free patients was 95.56% with a 5-year survival of 79.51%. CONCLUSION: Although it is not uncommon the occurrence of changes considered by current guidelines as relevant during surveillance of low risk BD-IPMNs, malignancy rate is low and survival is significantly affected by competing patients' age and comorbidities. IPMN surveillance strategy should be tailored based on these features and modulated over time.

The Impact of Postoperative Complications on Recovery of Health-Related Quality of Life and Functional Capacity after Pancreatectomy: Findings From a Prospective Observational Study.

OBJECTIVE: To evaluate the extent to which postoperative complications impact on patient health-related quality of life (HRQoL) and survival after pancreatic surgery. SUMMARY BACKGROUND DATA: Pancreatectomy is frequently associated with severe postoperative morbidity, which can affect patient recovery. Few and conflicting data are available regarding the effect of post-pancreatectomy complications on patient reported HRQoL. METHODS: This is an observational cohort study including consecutive patients enrolled in a prospective clinical trial (NCT04431076) who underwent elective pancreatectomy (2020-2022). Before surgery and on postoperative days (PODs) 15, 30, 90, 180, patients completed PROMIS-29 profile and Duke Activity Status Index questionnaires to assess their HRQoL and functional capacity. Mean differences in HRQoL scores were obtained using multivariable linear regression adjusting for preoperative scores and confounders. RESULTS: Of 528 patients, 370 (70%) experienced morbidity within 90 days, 154 (29%) severe complications (Clavien-Dindo grade >2). Delayed gastric emptying had the greatest impact on HRQoL, showing decreased mental health up to POD90 and physical health up to POD180 compared to uncomplicated patients. An inverse relationship between complication severity grade and HRQoL was evident for most domains, with Clavien-Dindo grade 3b-4 patients showing worse HRQoL and functional capacity scores up to 6 months after surgery. In 235 pancreatic cancer patients, grade 3b and 4 complications were associated with reduced disease specific survival (median 25 versus 41 mo, P<0.001). CONCLUSION: In patients undergoing pancreatic resection, postoperative complications significantly impact on all domains of patient quality of life with a dose-effect relationship between complication severity and impairment of HRQoL and functional capacity.

Reappraising the Role of Intraoperative Neck Margin Revision in Post-Neoadjuvant Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma: A Multi-Institutional Analysis.

OBJECTIVE: To investigate whether revision of pancreatic neck margin based on intraoperative frozen section analysis has oncologic value in post-neoadjuvant pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: The role of intraoperative neck margin revision has been controversial, with little information specific to post-neoadjuvant PD. METHODS: Patients who underwent post-neoadjuvant PD (2013-2019) for conventional PDAC with frozen section analysis of neck margin at three academic institutions were included. Overall survival (OS) and recurrence-free survival (RFS) were compared across three groups: complete resection achieved en-bloc (CR-EB), complete resection achieved non-en-bloc (CR-NEB), and incomplete resection (IR). RESULTS: Among the 671 patients included, 524 (78.1%) underwent CR-EB, 119 (17.7%) CR-NEB and 28 (4.2%) IR. Patients undergoing CR-NEB and IR exhibited larger tumors and lower rates of RECIST response, requiring vascular resections more often. Likewise, CR-NEB and IR were associated with a worse pathological profile than CR-EB. The incidence of postoperative complications and access to adjuvant treatment were comparable among groups. A CR-EB was associated with the longest OS duration (34.3 mo). In patients with positive neck margin, obtaining a CR-NEB via re-excision was associated with a comparable OS relative to patients with an IR (26.9 vs. 27.1 mo, P=0.901). Similar results were observed for RFS. At multivariable analysis, neck margin status was not independently associated with survival and recurrence. CONCLUSION: Conversion of an initially positive pancreatic neck margin by additional resection is not associated with oncologic benefits in post-neoadjuvant PD and cannot be routinely recommended.

Surveillance for Presumed BD-IPMN of the Pancreas: Stability, Size, and Age Identify Targets for Discontinuation.

BACKGROUND & AIMS: Currently, most patients with branch duct intraductal papillary mucinous neoplasms (BD-IPMN) are offered indefinite surveillance, resulting in health care costs with questionable benefits regarding cancer prevention. This study sought to identify patients in whom the risk of cancer is equivalent to an age-matched population, thereby justifying discontinuation of surveillance. METHODS: International multicenter study involving presumed BD-IPMN without worrisome features (WFs) or high-risk stigmata (HRS) at diagnosis who underwent surveillance. Clusters of individuals at risk for cancer development were defined according to cyst size and stability for at least 5 years, and age-matched controls were used for comparison using standardized incidence ratios (SIRs) for pancreatic cancer. RESULTS: Of 3844 patients with presumed BD-IPMN, 775 (20.2%) developed WFs and 68 (1.8%) HRS after a median surveillance of 53 (interquartile range 53) months. Some 164 patients (4.3%) underwent surgery. Of the overall cohort, 1617 patients (42%) remained stable without developing WFs or HRS for at least 5 years. In patients 75 years or older, the SIR was 1.12 (95% CI, 0.23-3.39), and in patients 65 years or older with stable lesions smaller than 15 mm in diameter after 5 years, the SIR was 0.95 (95% CI, 0.11-3.42). The all-cause mortality for patients who did not develop WFs or HRS for at least 5 years was 4.9% (n = 79), and the disease-specific mortality was 0.3% (n = 5). CONCLUSIONS: The risk of developing pancreatic malignancy in presumed BD-IPMN without WFs or HRS after 5 years of surveillance is comparable to that of the general population depending on cyst size and patient age. Surveillance discontinuation could be justified after 5 years of stability in patients older than 75 years with cysts <30 mm, and in patients 65 years or older who have cysts ≤15 mm.

Very Early Recurrence After Curative Resection for Pancreatic Ductal Adenocarcinoma: Proof of Concept for a "Biological R2 Definition".

PURPOSE: Very early recurrence after radical surgery for pancreatic ductal adenocarcinoma (PDAC) has been poorly investigated. This study was designed to evaluate this group of patients who developed recurrence, within 12 weeks after surgery, defined as "biological R2 resections (bR2)." METHODS: Data from patients who underwent surgical resection as upfront procedure or after neoadjuvant treatment for PDAC between 2015 and 2019 were analyzed. Disease-free, disease-specific survival, and independent predictors of early recurrence were examined. The same analysis was performed separately for upfront and neoadjuvant treated patients. RESULTS: Of the 573 patients included in the study, 63 (11%) were classified as bR2. The rate of neoadjuvant treatment was similar in bR2 and in the remaining patients (44 vs. 42%, p = 0.78). After a median follow-up of 27 months, median DFS and DSS for the entire cohort were 17 and 43 months, respectively. Median DSS of bR2 group was 13 months. The only preoperative identifiable independent predictor of very early recurrence was body-tail site lesion, whereas all other were pathological: higher pT (8th classification), G3 differentiation, and high lymph node ratio. These predictors were confirmed for patients undergoing upfront surgery, whereas in the neoadjuvant group the only independent predictor was pT. CONCLUSIONS: One of ten patients with "radical" resected PDAC relapses very early after surgery (bR2); hence, imaging must be routinely repeated within 12 weeks. Despite higher biological aggressiveness and worse pathology, this bR2 cluster eludes our preoperative examinations.

Implications of pregnancy on MCN of the pancreas: A multicentric case-control study.

BACKGROUND: Mucinous cystic neoplasms (MCN) of the pancreas express estrogen and progesterone receptors. Several case reports describe MCN increasing in size during gestation. The aim of this study is to assess if pregnancy is a risk factor for malignant degeneration of MCN. METHODS: All female patients who underwent pancreatic resection of a MCN between 2011 and 2021 were included. MCN resected or diagnosed within 12 months of gestation were defined perigestational. MCN with high grade dysplasia or an invasive component were classified in the high grade (HG) group. The primary outcome was defined as the correlation between exposure to gestation and peri-gestational MCN to development of HG-MCN. RESULTS: The study includes 176 patients, 25 (14 %) forming the HG group, and 151 (86 %) forming the low grade (LG) group. LG and HG groups had a similar distribution of systemic contraceptives use (26 % vs. 16 %, p = 0.262), and perigestational MCN (7 % vs 16 %, p = 0.108). At univariate analysis cyst size ≥10 cm (OR 5.3, p < 0.001) was associated to HG degeneration. Peri gestational MCN positively correlated with cyst size (R = 0.18, p = 0.020). In the subgroup of 14 perigestational MCN patients 29 % had HG-MCN and 71 % experienced cyst growth during gestation with an average growth of 55.1 ± 18 mm. CONCLUSIONS: Perigestational MCN are associated to increased cyst diameter, and in the subset of patients affected by MCN during gestation a high rate of growth was observed. Patients with a MCN and pregnancy desire should undergo multidisciplinary counselling.

Association of autoimmune pancreatitis and intraductal papillary mucinous neoplasm. A retrospective analysis from a tertiary care referral center.

BACKGROUND: Autoimmune Pancreatitis (AIP) is a rare chronic inflammatory disease affecting the pancreas. Chronic pancreatic inflammation represents a risk factor for pre-neoplastic conditions such as Intraductal Papillary Mucinous Neoplasia (IPMN). Due to the rarity of AIP, the incidence, and clinical features of IPMN occurring in AIP patients remains unknown. AIMS: In the present study we aimed to explore the relationship between AIP and IPMN and to characterize the clinical features and outcomes of IPMN occurring in the context of AIP. METHODS: We retrospectively (2008-2020) analyzed the clinical and radiological records of a large single center cohort of patients with AIP and investigated the prevalence of IPMN. We then compared the clinical, laboratory and radiological characteristics of patients with IPMN and AIP with a cohort of patients with isolated IPMN. RESULTS: Five hundred and nineteen patients were included in this retrospective study. Sixteen patients had concomitant IPMN and AIP(3%); 61 patients had isolated AIP (12%); 442 patients had isolated IPMN (85%). The prevalence of IPMN in patients with AIP was higher than that observed in the general population (21%vs8-10%). Worrisome Features and High-Risk Stigmata were more frequently observed in IPMN occurring together with AIP compared to isolated IPMN(p < 0.05). Based on radiological features IPMN in the context of AIP was more frequently of main-duct type compared to isolated IPMN(p < 0.05). CONCLUSION: Our data suggest that AIP represents a chronic inflammatory condition that might favor IPMN development with high-risk features. Prolonged surveillance of these patients and longitudinal studies are required to further test the association with AIP and malignant and pre-malignant conditions.

Recovery of health-related quality of life after laparoscopic versus open distal pancreatectomy.

BACKGROUND: Limited data comparing recovery of health-related quality of life (HRQoL) after laparoscopic (LDP) versus open distal pancreatectomy (ODP) are available. The aim of this study was to assess the impact of laparoscopy on postoperative HRQOL after DP using the Patient-Reported Outcomes Measurement Information System (PROMIS). METHODS: Data from consecutive patients who underwent DP (2020-2022) enrolled in a prospective clinical trial were reviewed. Patients completed PROMIS-29 plus 2 profile preoperatively, at postoperative day (POD) 15, 30, 90, and 180. Linear regression analysis adjusting for confounders including preoperative PROMIS scores, age, gender, ASA score, diagnosis, and multivisceral resection was used to estimate mean between-group differences (MD) in postoperative PROMIS domains T scores. RESULTS: Overall, 202 patients (118 laparoscopic, 86 open) underwent DP (median age 66 years, pancreatic cancer 41%, multivisceral resection 10%, median LOS 6 days). At POD15, LDP was associated with higher physical function (MD 5.6) and participation in social roles and activities scores (MD 3.8), reduced fatigue (MD - 2.7) and sleep disturbance (MD - 3.8) compared to ODP. At POD30, LDP patients had higher physical function (MD 5.2) and participation in social roles and activities scores (MD 6.0), reduced fatigue (MD - 3.5), and anxiety (MD - 4.0) compared to ODP. No between-group differences were found in HRQoL domains at POD90 and 180. Six months after surgery, the proportions of patients who had not recovered to preoperative physical function, participation in social roles and activities, fatigue, pain interference, sleep disturbance, cognitive function, depression, and anxiety were 31%, 31%, 28%, 20%, 15%, 14%, 8%, and 7%, respectively. CONCLUSIONS: According to PROMIS, LDP resulted in improved physical and social functioning and reduced anxiety and fatigue up to 30 days after surgery compared to ODP. At 6 months after surgery, recovery of physical domains is still incomplete in up to 30% of patients.

Validation of the PROMIS-29 Questionnaire as a Measure of Recovery After Pancreatic Surgery.

OBJECTIVE: To contribute evidence for the reliability, construct validity, and responsiveness of the Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29) profile questionnaire as a measure of recovery after pancreatic surgery. BACKGROUND: PROMIS questionnaires have been recommended to evaluate postdischarge recovery after surgery. Evidence supporting their measurement properties in pancreatic surgery is missing. METHODS: An observational validation study designed according to the COSMIN checklist was conducted including data from a prospective clinical trial. Patients undergoing pancreatectomy completed PROMIS-29 preoperatively and on postoperative days (PODs) 15, 30, 90, and 180. Reliability was assessed by internal consistency using Cronbach α. Construct validity was assessed by known-groups comparison. Responsiveness was evaluated hypothesizing that scores would be higher (1) preoperatively versus POD15, (2) on POD30 versus POD15, (3) on POD90 versus POD30, and (4) on POD180 versus POD90. RESULTS: Overall, 510 patients were included in the study. Reliability was good to excellent (α values ranged from 0.82 to 0.97). Data supported 4 of 5 hypotheses tested for construct validity for 5 domains (physical function, anxiety, depression, fatigue, and ability to participate in social roles) at most time points. Responsiveness hypotheses 1, 2, and 3 were supported by the data for physical function, fatigue, sleep disturbance, pain interference, and ability to participate in social roles domains. CONCLUSIONS: PROMIS had excellent reliability, discriminated between most groups expected to have different recovery trajectories and was responsive to the expected trajectory of recovery up to 90 days after surgery. Our findings support the use of PROMIS-29 profile as a patient-reported outcome measure of postdischarge recovery after pancreatectomy.

Cure Probabilities After Resection Of Pancreatic Ductal Adenocarcinoma: A Multi-Institutional Analysis Of 2554 Patients.

OBJECTIVE: To assess the probability of being cured from pancreatic ductal adenocarcinoma (PDAC) by pancreatic surgery. SUMMARY BACKGROUND DATA: Statistical cure implies that a patient treated for a specific disease will have the same life expectancy as if he/she never had that disease. METHODS: Patients who underwent pancreatic resection for PDAC between 2010 and 2021 were retrospectively identified using a multi-institutional database. A non-mixture statistical cure model was applied to compare disease-free survival to the survival expected for matched general population. RESULTS: Among 2554 patients, either in the setting of upfront (n=1691) or neoadjuvant strategy (n=863), the cure model showed that the probability that surgery would offer the same life-expectancy (and tumor-free) as the matched general population was 20.4% (95%CI: 18.3, 22.5). Cure likelihood reached the 95% of certainty (time-to-cure) after 5.3 years (95%CI: 4.7, 6.0). A preoperative model was developed based on tumor stage at diagnosis (P=0.001), radiological size (P=0.001), response to chemotherapy (P=0.007), American Society of Anesthesiology class (P=0.001) and pre-operative Ca19-9 (P=0.001). A post-operative model with the addition of surgery type (P=0.015), pathological size (P=0.001), tumour grading (P=0.001), resection margin (P=0.001), positive lymphnode ratio (P=0.001) and the receipt of adjuvant therapy (P=0.001) was also developed. CONCLUSIONS: Patients operated for PDAC can achieve a life-expectancy similar to that of general population and the likelihood of cure increases with the passage of recurrence-free time. An online calculator was developed and available at https://aicep.website/?cff-form=15.

Total Pancreatectomy With Islet Autotransplantation as an Alternative to High-risk Pancreatojejunostomy After Pancreaticoduodenectomy: A Prospective Randomized Trial.

OBJECTIVE: To compare pancreaticoduodenectomy (PD) and total pancreatectomy (TP) with islet autotransplantation (IAT) in patients at high risk of postoperative pancreatic fistula (POPF). BACKGROUND: Criteria to predict the risk of POPF occurrence after PD are available. However, even when a high risk of POPF is predicted, TP is not currently accepted as an alternative to PD, because of its severe consequences on glycaemic control. Combining IAT with TP may mitigate such consequences. METHODS: Randomized, open-label, controlled, bicentric trial (NCT01346098). Candidates for PD at high-risk pancreatic anastomosis (ie, soft pancreas and duct diameter ≤3 mm) were randomly assigned (1:1) to undergo either PD or TP-IAT. The primary endpoint was the incidence of complications within 90 days after surgery. RESULTS: Between 2010 and 2019, 61 patients were assigned to PD (n=31) or TP-IAT (n=30). In the intention-to-treat analysis, morbidity rate was 90·3% after PD and 60% after TP-IAT ( P =0.008). According to complications' severity, PD was associated with an increased risk of grade ≥2 [odds ratio (OR)=7.64 (95% CI: 1.35-43.3), P =0.022], while the OR for grade ≥3 complications was 2.82 (95% CI: 0.86-9.24, P =0.086). After TP-IAT, the postoperative stay was shorter [median: 10.5 vs 16.0 days; P <0.001). No differences were observed in disease-free survival, site of recurrence, disease-specific survival, and overall survival. TP-IAT was associated with a higher risk of diabetes [hazard ratio=9.1 (95% CI: 3.76-21.9), P <0.0001], but most patients maintained good metabolic control and showed sustained C-peptide production over time. CONCLUSIONS: TP-IAT may become the standard treatment in candidates for PD, when a high risk of POPF is predicted.

CA19.9 Response and Tumor Size Predict Recurrence Following Post-neoadjuvant Pancreatectomy in Initially Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Data on recurrence after post-neoadjuvant pancreatectomy are scant. This study investigated the incidence and pattern of recurrence in patients with initially resectable and borderline resectable pancreatic ductal adenocarcinoma who received post-neoadjuvant pancreatectomy. Furthermore, preoperative predictors of recurrence-free survival (RFS) and their interactions were determined. PATIENTS AND METHODS: Patients undergoing post-neoadjuvant pancreatectomy at two academic facilities between 2013 and 2017 were analyzed using standard statistics. The possible interplay between preoperative parameters was scrutinized including interaction terms in multivariable Cox models. RESULTS: Among 315 included patients, 152 (48.3%) were anatomically resectable. The median RFS was 15.7 months, with 1- and 3-year recurrence rates of 41.9% and 74.2%, respectively. Distant recurrence occurred in 83.3% of patients, with lung-only patterns exhibiting the most favorable prognostic outlook. Normal posttreatment CA19.9, ΔCA19.9 (both in patients with normal and elevated baseline levels), and posttreatment tumor size were associated with RFS. Critical thresholds for ΔCA19.9 and tumor size were set at 50% and 20 mm, respectively. Interaction between ΔCA19.9 and posttreatment CA19.9 suggested a significant risk reduction in patients with elevated values when ΔCA19.9 exceeded 50%. Moreover, posttreatment tumor size interacted with posttreatment CA19.9 and ΔCA19.9, suggesting an increased risk in the instance of elevated posttreatment CA19.9 values and a protective effect associated with CA19.9 response in patients with tumor size >20 mm. CONCLUSION: Recurrence following post-neoadjuvant pancreatectomy is common. Preoperative tumor size <20 mm, normal posttreatment CA19.9 and ΔCA19.9 > 50% were associated with longer RFS. These variables should not be taken in isolation, as their interaction significantly modulates the recurrence risk.

Prognostic Significance and Predictors of Nodal Recurrence After Surgery for Non-Functioning Pancreatic Neuroendocrine Tumors.

BACKGROUND: The prognosis of nodal recurrence after surgery for non-functioning pancreatic neuroendocrine tumors (NF-PanNETs) and its predictors have been poorly investigated. This study aimed to compare clinicopathologic features and survival between patients with nodal relapse and those with distant relapse and to identify predictors of nodal relapse after surgery for NF-PanNETs. METHODS: All patients (n = 321) submitted to surgery for NF-PanNETs were included. Nodal recurrence was defined as the presence of one or more enlarged LNs at high-quality radiologic examinations and always confirmed by 68Ga-DOTA-PET or biopsy. RESULTS: Altogether, 21 patients (6 %) experienced nodal (± distant) relapse, and 35 patients (11 %) had distant recurrence alone. Isolated nodal recurrence occurred for 23 % of patients with recurrence. Overall, 11 patients died of disease, one of whom (pT3N1G3) had an isolated nodal relapse. The rate of LN metastases (81 % vs 54 %; p = 0.044) and median number of positive LNs (PLN) (3 vs 0; p = 0.019) both were significantly higher for the patients with nodal (± distant) relapse than for those with distant relapse alone. Microvascular invasion (p = 0.046), T stage (p = 0.004), N stage (N1 [p = 0.049]; N2 [p = 0.001]), M stage (p < 0.001), and necrosis (p = 0.011) independently predicted nodal relapse. After distal pancreatectomy (n = 182), 13 patients experienced nodal recurrence, 9 of whom had left paraortic LNs involvement. DISCUSSION: Lymph nodes are not rare sites of recurrence after surgery for NF-PanNETs. Lymph node involvement is a powerful determinant of nodal relapse. Nodal relapse frequently involves LNs that are not removed during standard lymphadenectomy.

Pathological staging in postneoadjuvant pancreatectomy for pancreatic cancer: implications for adjuvant therapy.

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.

European' health care indicators and pancreatic cancer incidence and mortality: A mediation analysis of Eurostat data and Global Burden of Disease Study 2019.

AIM: To highlight correlations existing between incidence and mortality of pancreatic cancer, and health care indicators in 36 European countries. METHODS: The Global Burden of Disease (GBD) and Eurostat databases were queried between 2004 and 2019. Incidence and mortality were age-standardized. From Eurostat, indicators regarding expenditure, hospital beds, medical technology, health personnel, physicians by medical specialty and unmet needs for medical examination were extracted. Correlations between GBD and Eurostat data were analysed through mediation analysis applying clustering for countries. RESULTS: Incidence increased by +0.6% per year (p = 0.001) and mortality by +0.3% (p = 0.001), being increasing for most of the European countries considered. Incidence and mortality were strongly positively correlated (p = 0.001). Higher current health expenditure, expenditure in inpatient curative care, the number of available beds, the number of computed tomography scan, magnetic resonance units, practising medical doctors were all related to higher incidence (p < 0.05), whereas the unmet need for medical examinations was related to lower incidence. When the mediator' effect of incidence was handled, these indicators, together with expenditure on outpatient curative cares, the number of pet scanners and of radiation therapy equipment, were related to lower mortality (p < 0.05). CONCLUSIONS: Health care environment correlates with reported incidence and mortality of pancreatic cancer. This highlights both that ameliorated socio-economic societies suffer from higher incidence but lower mortality, as well as the epidemiological bias originating from countries' diagnostic ability.

EUS-guided gastroenterostomy for management of malignant gastric outlet obstruction: a prospective cohort study with matched comparison with enteral stenting.

BACKGROUND AND AIMS: Retrospective studies on malignant gastric outlet obstruction (mGOO) highlighted several advantages of EUS-guided gastroenterostomy (EUS-GE) over enteral stenting (ES). However, no prospective evidence is available. The aim of this study was to report on clinical outcomes of EUS-GE in a prospective cohort study, with a subgroup comparison versus ES. METHODS: All consecutive patients endoscopically treated for mGOO between December 2020 and December 2022 in a tertiary, academic center were enrolled in a prospective registry (Prospective Registry of Therapeutic Endoscopic Ultrasound [PROTECT]; NCT04813055) and followed up every 30 days to register efficacy/safety outcomes. EUS-GE and ES cohorts were matched according to baseline frailty and oncologic disease. RESULTS: A total of 104 patients were treated for mGOO during the study; 70 (58.6% male subjects; median age, 64 [interquartile range, 58-73] years; 75.7% pancreatic cancer, 60.0% metastatic cancer) underwent EUS-GE via the wireless simplified technique. Technical success was 97.1% and clinical success was 97.1% after a median of 1.5 (interquartile range, 1-2) days. Adverse events occurred in 9 (12.9%) patients. After a median follow-up of 105 (49-187) days, symptom recurrence was 7.6%. In the matched comparison versus ES (28 patients per arm), EUS-GE-treated patients experienced higher and faster clinical success (100% vs 75.0%, P = .006), reduced recurrences (3.7% vs 33.3%, P = .02), and a trend toward shorter time to chemotherapy. CONCLUSIONS: In this first, prospective, single-center comparison, EUS-GE showed excellent efficacy in treating mGOO, with an acceptable safety profile and long-term patency, and several clinically significant advantages over ES. While awaiting randomized trials, these results might endorse EUS-GE as first-line strategy for mGOO, where adequate expertise is available.

Same-session double EUS-guided bypass versus surgical gastroenterostomy and hepaticojejunostomy: an international multicenter comparison.

BACKGROUND AND AIMS: Gastric outlet and biliary obstruction are common manifestations of GI malignancies and some benign diseases for which standard treatment would be surgical gastroenterostomy and hepaticojejunostomy (ie, "double bypass"). Therapeutic EUS has allowed for the creation of an EUS-guided double bypass. However, same-session double EUS-guided bypass has only been described in small proof-of-concept series and lacks a comparison with surgical double bypass. METHODS: A retrospective multicenter analysis was performed of all consecutive same-session double EUS-guided bypass procedures performed in 5 academic centers. Surgical comparators were extracted from these centers' databases from the same time interval. Efficacy, safety, hospital stay, nutrition and chemotherapy resumption, long-term patency, and survival were compared. RESULTS: Of 154 identified patients, 53 (34.4%) received treatment with EUS and 101 (65.6%) with surgery. At baseline, patients undergoing EUS exhibited higher American Society of Anesthesiologists scores and a higher median Charlson Comorbidity Index (9.0 [interquartile range {IQR}, 7.0-10.0] vs 7.0 [IQR, 5.0-9.0], P < .001). Technical success (96.2% vs 100%, P = .117) and clinical success rates (90.6% vs 82.2%, P = .234) were similar when comparing EUS and surgery. Overall (11.3% vs 34.7%, P = .002) and severe adverse events (3.8% vs 19.8%, P = .007) occurred more frequently in the surgical group. In the EUS group, median time to oral intake (0 days [IQR, 0-1] vs 6 days [IQR, 3-7], P < .001) and hospital stay (4.0 days [IQR, 3-9] vs 13 days [IQR, 9-22], P < .001) were significantly shorter. CONCLUSIONS: Despite being used in a patient population with more comorbidities, same-session double EUS-guided bypass achieved similar technical and clinical success and was associated with fewer overall and severe adverse events when compared with surgical gastroenterostomy and hepaticojejunostomy.

Endoscopic papillectomy for ampullary lesions in patients with familial adenomatous polyposis compared with sporadic lesions: a propensity score-matched cohort.

BACKGROUND: Familial adenomatous polyposis (FAP) is a rare inherited syndrome that predisposes the patient to cancer. Treatment of FAP-related ampullary lesions is challenging and the role of endoscopic papillectomy has not been elucidated. We retrospectively analyzed the outcomes of endoscopic papillectomy in matched cohorts of FAP-related and sporadic ampullary lesions (SALs). METHODS: This retrospective multicenter study included 1422 endoscopic papillectomy procedures. Propensity score matching including age, sex, comorbidity, histologic subtype, and size was performed. Main outcomes were complete resection (R0), technical success, complications, and recurrence. RESULTS: Propensity score matching identified 202 patients (101 FAP, 101 SAL) with comparable baseline characteristics. FAP patients were mainly asymptomatic (79.2 % [95 %CI 71.2-87.3] vs. 46.5 % [95 %CI 36.6-56.4]); P < 0.001). The initial R0 rate was significantly lower in FAP patients (63.4 % [95 %CI 53.8-72.9] vs. 83.2 % [95 %CI 75.8-90.6]; P = 0.001). After repeated interventions (mean 1.30 per patient), R0 was comparable (FAP 93.1 % [95 %CI 88.0-98.1] vs. SAL 97.0 % [95 %CI 93.7-100]; P = 0.19). Adverse events occurred in 28.7 %. Pancreatitis and bleeding were the most common adverse events in both groups. Severe adverse events were rare (3.5 %). Overall, 21 FAP patients (20.8 % [95 %CI 12.7-28.8]) and 16 SAL patients (15.8 % [95 %CI 8.6-23.1]; P = 0.36) had recurrence. Recurrences occurred later in FAP patients (25 [95 %CI 18.3-31.7] vs. 2 [95 %CI CI 0.06-3.9] months). CONCLUSIONS: Endoscopic papillectomy was safe and effective in FAP-related ampullary lesions. Criteria for endoscopic resection of ampullary lesions can be extended to FAP patients. FAP patients have a lifetime risk of relapse even after complete resection, and require long-time surveillance.