Prophylactic abdominal drainage after distal pancreatectomy (PANDORINA): an international, multicentre, open-label, randomised controlled, non-inferiority trial.

BACKGROUND: Prophylactic passive abdominal drainage is standard practice after distal pancreatectomy. This approach aims to mitigate the consequences of postoperative pancreatic fistula (POPF) but its added value, especially in patients at low risk of POPF, is currently being debated. We aimed to assess the non-inferiority of a no-drain policy in patients after distal pancreatectomy. METHODS: In this international, multicentre, open-label, randomised controlled, non-inferiority trial, we recruited patients aged 18 years or older undergoing open or minimally invasive elective distal pancreatectomy for all indications in 12 centres in the Netherlands and Italy. We excluded patients with an American Society of Anesthesiology (ASA) physical status of 4-5 or WHO performance status of 3-4, added by amendment following the death of a patient with ASA 4 due to a pre-existing cardiac condition. Patients were randomly assigned (1:1) intraoperatively by permuted blocks (size four to eight) to either no drain or prophylactic passive drain placement, stratified by annual centre volume (<40 or ≥40 distal pancreatectomies) and low risk or high risk of grade B or C POPF. High-risk was defined as a pancreatic duct of more than 3 mm in diameter, a pancreatic thickness at the neck of more than 19 mm, or both, based on the Distal Pancreatectomy Fistula Risk Score. Other patients were considered low-risk. The primary outcome was the rate of major morbidity (Clavien-Dindo score ≥III), and the most relevant secondary outcome was grade B or C POPF, grading per the International Study Group for Pancreatic Surgery. Outcomes were assessed up to 90 days postoperatively and analysed in the intention-to-treat population and per-protocol population, which only included patients who received the allocated treatment. A prespecified non-inferiority margin of 8% was compared with the upper limit of the two-sided 95% CI (Wald) of unadjusted risk difference to assess non-inferiority. This trial is closed and registered in the Netherlands Trial Registry, NL9116. FINDINGS: Between Oct 3, 2020, and April 28, 2023, 376 patients were screened for eligibility and 282 patients were randomly assigned to the no-drain group (n=138; 75 [54%] women and 63 [46%] men) or the drain group (n=144; 73 [51%] women and 71 [49%] men). Seven patients in the no-drain group received a drain intraoperatively; consequently, the per-protocol population included 131 patients in the no-drain group and 144 patients in the drain group. The rate of major morbidity was non-inferior in the no-drain group compared with the drain group in the intention-to-treat analysis (21 [15%] vs 29 [20%]; risk difference -4·9 percentage points [95% CI -13·8 to 4·0]; pnon-inferiority=0·0022) and the per-protocol analysis (21 [16%] vs 29 [20%]; risk difference -4·1 percentage points [-13·2 to 5·0]; pnon-inferiority=0·0045). Grade B or C POPF was observed in 16 (12%) patients in the no-drain group and in 39 (27%) patients in the drain group (risk difference -15·5 percentage points [95% CI -24·5 to -6·5]; pnon-inferiority<0·0001) in the intention-to-treat analysis. Three patients in the no-drain group died within 90 days; the cause of death in two was not considered related to the trial. The third death was a patient with an ASA score of 4 who died after sepsis and a watershed cerebral infarction at second admission, leading to multiple organ failure. No patients in the drain group died within 90 days. INTERPRETATION: A no-drain policy is safe in terms of major morbidity and reduced the detection of grade B or C POPF, and should be the new standard approach in eligible patients undergoing distal pancreatectomy. FUNDING: Ethicon UK (Johnson & Johnson Medical, Edinburgh, UK).

Cholangiocyte Organoids: The New Frontier in Regenerative Medicine for the Study and Treatment of Cholangiopathies.

Cholangiopathies include a group of chronic progressive disorders, affecting the cholangiocytes, the epithelial cells that line the biliary tree, leading to liver parenchymal fibrosis and eventually end-stage liver disease necessitating transplantation. Experimental modeling of these multifactorial cholestatic diseases faces challenges due to the lack of adequate experimental in vitro and in vivo models. A novel approach employs three-dimensional organoid systems that offer several advantages for modeling disease and testing drug response in vitro. Organoids mimic intercellular communication, replicate the architecture of organs, and maintain the cell's original phenotype. Cholangiocyte organoids provide an in vitro model to study the pathogenesis and pharmacotherapeutic treatment of cholangiopathies and show great promise for regenerative therapies. In particular, patient-derived organoids allow personalized medicine approaches and the study of individual disease characteristics. This review highlights the significance of cholangiocyte organoid models in advancing our understanding of cholangiopathies and driving advancements in regenerative medicine strategies.

No role for protease inhibitors as a mitigation strategy for postpancreatectomy acute pancreatitis (PPAP): Propensity score matching analysis.

BACKGROUND: While the use of protease inhibitor gabexate mesylate (GM) is still controversial in acute pancreatitis, it has never been tested for postpancreatectomy acute pancreatitis (PPAP). This study aims to assess the impact of GM on postoperative serum hyperamylasaemia (POH) or PPAP after pancreatoduodenectomy (PD). METHODS: Consecutive patients developing POH after PD between 2016 and 2021 were included. According to GM administration, patients were divided into GM-treated and control (CTR) groups. GM was administered from postoperative day 1-3 in POH patients who underwent surgery before 2017. A 2:1 propensity matching was used to minimize the risk of bias. RESULTS: Overall, 264 patients with POH were stratified in the GM (59 patients) and CTR (104 patients) cohorts, which showed balanced baseline characteristics after matching. No difference in postoperative complications was observed between the groups (all p > 0.05), except for PPAP occurrence, which was significantly higher in the GM group (37% vs. 22%, p = 0.037). A total of 45 patients (28%) evolved to PPAP. Comparing PPAP patients in the GM and CTR groups, no significant differences in POPF, relaparotomy, and mortality (all p > 0.09) were found. No difference in intravenous crystalloid administration was found in patients with PPAP, whether or not they developed major complications or pancreatic fistula (p > 0.05) CONCLUSION: Protease inhibitor seems ineffective in preventing a PPAP after PD once a POH has occurred. Further studies are needed to achieve benchmarks for treating PPAP and identify mitigation strategies to prevent the evolution of POH into additional morbidity.

Corrigendum: Body composition parameters, immunonutritional indexes, and surgical outcome of pancreatic cancer patients resected after neoadjuvant therapy: a retrospective, multicenter analysis.

[This corrects the article DOI: 10.3389/fnut.2023.1065294.].

Acute pancreatitis after pancreatoduodenectomy: A prospective study of diffusion-weighted magnetic resonance imaging, serum biomarkers, and clinical features.

BACKGROUND: Postpancreatectomy acute pancreatitis is challenging to diagnose and poorly characterized in its early phases. However, it represents the ideal target for novel therapeutic opportunities possibly gleaned from medical acute pancreatitis. This study aims to systematically investigate early radiologic, biochemical, and clinical features of postpancreatectomy acute pancreatitis. METHODS: This was a prospective observational study of patients undergoing pancreatoduodenectomy from September 2019 to January 2021. Diffusion-weighted magnetic resonance imaging was performed on postoperative day 3. Serum pancreatic amylase and lipase were assessed daily until postoperative day 5. Postoperative serum hyperamylasemia and postpancreatectomy acute pancreatitis were defined based on the International Study Group for Pancreatic Surgery definition. RESULTS: A total of 65 patients were enrolled according to the sample size calculation. Patients with postoperative serum hyperamylasemia and postpancreatectomy acute pancreatitis had significantly lower apparent diffusion coefficient values at diffusion-weighted magnetic resonance imaging but no macroscopic features consistent with acute pancreatitis. Subsequently, 21 patients (32.3%) underwent computed tomography imaging for clinical worsening, and 6 had radiologic features of acute pancreatitis. All these latter patients had postoperative serum hyperamylasemia and worse outcomes, characterized by local (postoperative pancreatic fistula: 83%) and systemic morbidity (sepsis: 66.7%). The postoperative serum hyperamylasemia incidence was 21.5% (n = 14), and postpancreatectomy acute pancreatitis occurred in 6 patients (9.2%), with 4 grade B (6.1%) and 2 grade C (3%). CONCLUSION: Postpancreatectomy acute pancreatitis is characterized by early serum hyperamylasemia and hyperlipasemia. Although pancreatic changes may appear at postoperative day 3 diffusion-weighted magnetic resonance imaging, its standard use has no impact on postoperative management. Macroscopic radiologic features appear later and correlate with worse clinical scenarios. This paper paves the ground for including postpancreatectomy acute pancreatitis in the spectrum of acute pancreatitis, promoting the transfer of treatment strategies for acute pancreatitis into managing postpancreatectomy acute pancreatitis.

Body composition parameters, immunonutritional indexes, and surgical outcome of pancreatic cancer patients resected after neoadjuvant therapy: A retrospective, multicenter analysis.

Background and aims: Body composition parameters and immunonutritional indexes provide useful information on the nutritional and inflammatory status of patients. We sought to investigate whether they predict the postoperative outcome in patients with pancreatic cancer (PC) who received neoadjuvant therapy (NAT) and then pancreaticoduodenectomy. Methods: Data from locally advanced PC patients who underwent NAT followed by pancreaticoduodenectomy between January 2012 and December 2019 in four high-volume institutions were collected retrospectively. Only patients with two available CT scans (before and after NAT) and immunonutritional indexes (before surgery) available were included. Body composition was assessed and immunonutritional indexes collected were: VAT, SAT, SMI, SMA, PLR, NLR, LMR, and PNI. The postoperative outcomes evaluated were overall morbidity (any complication occurring), major complications (Clavien-Dindo ≥ 3), and length of stay. Results: One hundred twenty-one patients met the inclusion criteria and constituted the study population. The median age at the diagnosis was 64 years (IQR16), and the median BMI was 24 kg/m2 (IQR 4.1). The median time between the two CT-scan examined was 188 days (IQR 48). Skeletal muscle index (SMI) decreased after NAT, with a median delta of -7.8 cm2/m2 (p < 0.05). Major complications occurred more frequently in patients with a lower pre-NAT SMI (p = 0.035) and in those who gained in subcutaneous adipose tissue (SAT) compartment during NAT (p = 0.043). Patients with a gain in SMI experienced fewer major postoperative complications (p = 0.002). The presence of Low muscle mass after NAT was associated with a longer hospital stay [Beta 5.1, 95%CI (1.5, 8.7), p = 0.006]. An increase in SMI from 35 to 40 cm2/m2 was a protective factor with respect to overall postoperative complications [OR 0.43, 95% (CI 0.21, 0.86), p < 0.001]. None of the immunonutritional indexes investigated predicted the postoperative outcome. Conclusion: Body composition changes during NAT are associated with surgical outcome in PC patients who receive pancreaticoduodenectomy after NAT. An increase in SMI during NAT should be favored to ameliorate the postoperative outcome. Immunonutritional indexes did not show to be capable of predicting the surgical outcome.

Early and Sustained Elevation in Serum Pancreatic Amylase Activity: A Novel Predictor of Morbidity After Pancreatic Surgery.

OBJECTIVE: To characterize early postoperative serum pancreatic amylase (spAMY) trends after pancreatic resections. SUMMARY BACKGROUND DATA: A postoperative spAMY elevation is a common finding but uncertainties remain about its meaning and prognostic implications. METHODS: Analysis of patients who consecutively underwent pancreatectomy from 2016 to 2019. spAMY activity was assessed from postoperative day (POD) 0 to 3. Different patterns of spAMY have been identified based on the spAMY standard range (10-52 U/l). RESULTS: Three patterns were identified: (#1) spAMY values always < the lower limit of normal/within the reference range /a single increase in spAMY > upper limit of normal at any POD; (#2) Sustained increase in spAMY activity on POD 0 + 1; (#3) Sustained increase in spAMY activity including POD 1 + 2. Shifting through spAMY patterns was associated with increase morbidity (21% in #1 to 68% in #3 at POD 7; log rank < 0.001). Almost all severe complications (at least Clavien-Dindo ≥3) occurred in patients with pattern #3 (15% vs 3% vs 5% in #1 and #2 at POD 7, P = 0.006), without difference considering >3-times or >the spAMY normal limit ( P = 0.85). POPF (9% in #1 vs 48% in #3, P < 0.001) progressively increased across patterns. Pre-operative diabetes (OR 0.19), neoadjuvant therapy (OR 0.22), pancreatic texture (OR 8.8), duct size (OR 0.78), and final histology (OR 2.2) were independent predictors of pattern #3. CONCLUSIONS: A sustained increase in spAMY activity including POD 1 + 2 (#3) represents an early postoperative predictor of overall and severe early morbidity. An early and dynamic evaluation of spAMY could crucially impact the subsequent clinical course with relevant prognostic implications.

Postoperative Serum Hyperamylasemia Adds Sequential Value to the Fistula Risk Score in Predicting Pancreatic Fistula after Pancreatoduodenectomy.

OBJECTIVE: To evaluate whether postoperative serum hyperamylasemia (POH), with drain fluid amylase (DFA) and C-reactive protein (CRP), improves the Fistula Risk Score (FRS) accuracy in assessing the risk of a postoperative pancreatic fistula (POPF). SUMMARY BACKGROUND DATA: The FRS predicts POPF occurrence using intraoperative predictors with good accuracy but intrinsic limits. METHODS: Outcomes of patients who underwent pancreaticoduodenectomies between 2016 and 2021 were evaluated across FRS-risk zones and POH occurrence. POH consists of serum amylase activity greater than the upper limit of normal (52 U/l), persisting within the first 48 hours postoperatively (postoperative day -POD- 1 and 2). RESULTS: Out of 905 pancreaticoduodenectomies, some FRS elements, namely soft pancreatic texture (odds ratio (OR) 11.6), pancreatic duct diameter (OR 0.80), high-risk pathologic diagnosis (OR 1.54), but not higher blood loss (OR 0.99), were associated with POH. POH was an independent predictor of POPF, which occurred in 46.8% of POH cases ( P <0.001). Once POH occurs, POPF incidence rises from 3.8% to 42.9%, 22.9% to 41.7%, and 48.9% to 59.2% in patients intraoperatively classified at low, moderate and high FRS risk, respectively. The predictive ability of multivariable models adding POD 1 drain fluid amylase, POD 1-2 POH and POD 3 C-reactive protein to the FRS showed progressively and significantly higher accuracy (AUC FRS=0.82, AUC FRS-DFA=0.85, AUC FRS-DFA-POH=0.87, AUC FRS-DFA-POH-CRP=0.90, DeLong always P <0.05). CONCLUSIONS: POPF risk assessment should follow a dynamic process. The stepwise retrieval of early, postoperative biological markers improves clinical risk stratification by increasing the granularity of POPF risk estimates and affords a possible therapeutic window before the actual morbidity of POPF occurs.

Postoperative serum hyperamylasemia (POH) predicts additional morbidity after pancreatoduodenectomy: It is not all about pancreatic fistula.

BACKGROUND: The association between postoperative serum hyperamylasaemia (POH) and morbidity has been hypothesized but rarely explored once occurring with or without (POH-exclusive) a combined postoperative pancreatic fistula (POPF). METHODS: Analysis of patients who consecutively underwent pancreaticoduodenectomy from 2016 to 2020. POH was defined as serum amylase activity greater than the institutional upper limit of normal (52 U/L), persisting within the first 48 hours postoperatively (postoperative day [POD] 1 and 2). RESULTS: Among 852 patients, 15.8% developed POH-exclusive. Compared with patients without POH or POPF (64.3%), they showed a significantly higher postoperative burden (Clavien-Dindo ≥II: 52.6% vs 30.8%) with increased rates of bacteraemia (12.6% vs 6%), pleural effusion (13.3% vs 5.3%), postpancreatectomy haemorrhage (13.3% vs 7.5%), postpancreatectomy acute pancreatitis (PPAP) (10.3% vs 0%), and organ site infections (18.5% vs 10.9%; all P < .05). A total of 13.8% experienced POH with POPF leading to the worse outcome. The combined occurrence of POH with POPF led to a shorter median time to morbidity (3 PODs, 95% confidence interval [CI] 2.2-3.7 vs 6 PODs, 95% CI 4.2-8; P < .001) than patients experiencing POPF-exclusive (5.9%). In all, 46.6% of POH patients developed POPF. Body mass index (BMI) (odds ratio [OR] 1.1), male sex (OR 2.1), increased drain fluid amylase on POD 1 (OR 1.001), and increased C-reactive protein (OR 1.01) were independent risk factors for POPF once POH has occurred. CONCLUSION: POH has relevant postoperative clinical implications, independently from POPF occurrence. Developing POH with POPF leads to an earlier onset of higher postoperative burdens. Once POH is diagnosed, risk factors for additional POPF could identify patients who may benefit from additional surveillance, specific drains protocols, and preventive strategies.