Transplantation of kidneys from donation after cardiocirculatory death (DCD) donors is becoming an ever-increasing reality. So far, biopsy histologic assessment is the main parameter for evaluation ...of graft suitability, but it has several drawbacks and has poor reliability. The aim of this study is to verify if real-time renal resistance (RR) measurement during hypothermic machine perfusion (HMP) can be used as a reliable parameter to evaluate the quality of grafts from DCD and extracorporeal membrane oxygenation (ECMO) donors.
From January 2015 to September 2018, HMP has been systematically applied to all organs from DCD and ECMO donors. All grafts underwent preimplantation biopsy histologic assessment with Karpinski’s score. Single kidney transplants (SKTs) or double kidney transplants (DKTs) were performed according to biopsy score results. Kidneys were considered suitable for transplant if RR reached ≤ 1.0 within 3 hours of perfusion. RR trend and postoperative outcome were analyzed considering biopsy score and donor type.
A total of 30 kidneys (15 from DCD and 15 from ECMO donors) were used to perform 26 transplants (22 SKTs and 4 DKTs). Considering RR trend, all grafts were considered suitable for transplant within 1 hour of perfusion. Biopsy confirmed this result in all cases, and median score was 3 (range, 0-7). SKT score kidneys had lower starting RR than DKT ones (1.88 vs 2.88; P = .04) but identical final RR (0.58 vs 0.57; P = .76). DKT recipients had faster postoperative creatinine reduction than SKT recipients but similar postoperative day 30 value (1.42 vs 1.15 mg/dL; P = .20). No differences were found between DCD and ECMO grafts in terms of RR trend and postoperative outcome.
HMP can be an alternative to histologic biopsy assessment for evaluation of transplant suitability of DCD and ECMO kidneys. If acceptability threshold is reached, SKT can be performed in all cases. ECMO donors should be considered like DCD donors.
Hepatocellular carcinoma (HCC) have a dismal prognosis and any effective neoadjuvant treatment has been validated to date. We aimed to investigate the role of neoadjuvant transarterial ...chemoembolization (TACE) in upfront resectable HCC larger than 5 cm.
This is a multicentric retrospective study comparing outcomes of large HCC undergoing TACE followed by surgery or liver resection alone before and after propensity-score matching (PSM).
A total of 384 patients were included of whom 60 (15.6%) received TACE. This group did not differ from upfront resected cases neither in terms of disease-free survival (p = 0.246) nor in overall survival (p = 0.276). After PSM, TACE still did not influence long-term outcomes (p = 0.935 and p = 0.172, for DFS and OS respectively). In subgroup analysis, TACE improved OS only in HCC ≥10 cm (p = 0.045), with a borderline significance after portal vein embolization/ligation (p = 0.087) and in single HCC (p = 0.052).
TACE should not be systematically performed in all resectable large HCC. Selected cases could however potentially benefit from this procedure, as patients with huge and single tumors or those necessitating of a PVE.
Cancer arising in the periampullary region can be anatomically classified in pancreatic ductal adenocarcinoma (PDAC), distal cholangiocarcinoma (dCCA), duodenal adenocarcinoma (DAC), and ampullary ...carcinoma. Based on histopathology, ampullary carcinoma is currently subdivided in intestinal (AmpIT), pancreatobiliary (AmpPB), and mixed subtypes. Despite close anatomical resemblance, it is unclear how ampullary subtypes relate to the remaining periampullary cancers in tumor characteristics and behavior.BACKGROUNDCancer arising in the periampullary region can be anatomically classified in pancreatic ductal adenocarcinoma (PDAC), distal cholangiocarcinoma (dCCA), duodenal adenocarcinoma (DAC), and ampullary carcinoma. Based on histopathology, ampullary carcinoma is currently subdivided in intestinal (AmpIT), pancreatobiliary (AmpPB), and mixed subtypes. Despite close anatomical resemblance, it is unclear how ampullary subtypes relate to the remaining periampullary cancers in tumor characteristics and behavior.This international cohort study included patients after curative intent resection for periampullary cancer retrieved from 44 centers (from Europe, United States, Asia, Australia, and Canada) between 2010 and 2021. Preoperative CA19-9, pathology outcomes and 8-year overall survival were compared between DAC, AmpIT, AmpPB, dCCA, and PDAC.METHODSThis international cohort study included patients after curative intent resection for periampullary cancer retrieved from 44 centers (from Europe, United States, Asia, Australia, and Canada) between 2010 and 2021. Preoperative CA19-9, pathology outcomes and 8-year overall survival were compared between DAC, AmpIT, AmpPB, dCCA, and PDAC.Overall, 3809 patients were analyzed, including 348 DAC, 774 AmpIT, 848 AmpPB, 1,036 dCCA, and 803 PDAC. The highest 8-year overall survival was found in patients with AmpIT and DAC (49.8% and 47.9%), followed by AmpPB (34.9%, P < 0.001), dCCA (26.4%, P = 0.020), and finally PDAC (12.9%, P < 0.001). A better survival was correlated with lower CA19-9 levels but not with tumor size, as DAC lesions showed the largest size.RESULTSOverall, 3809 patients were analyzed, including 348 DAC, 774 AmpIT, 848 AmpPB, 1,036 dCCA, and 803 PDAC. The highest 8-year overall survival was found in patients with AmpIT and DAC (49.8% and 47.9%), followed by AmpPB (34.9%, P < 0.001), dCCA (26.4%, P = 0.020), and finally PDAC (12.9%, P < 0.001). A better survival was correlated with lower CA19-9 levels but not with tumor size, as DAC lesions showed the largest size.Despite close anatomic relations of the five periampullary cancers, this study revealed differences in preoperative blood markers, pathology, and long-term survival. More tumor characteristics are shared between DAC and AmpIT and between AmpPB and dCCA than between the two ampullary subtypes. Instead of using collective definitions for "periampullary cancers" or anatomical classification, this study emphasizes the importance of individual evaluation of each histopathological subtype with the ampullary subtypes as individual entities in future studies.CONCLUSIONSDespite close anatomic relations of the five periampullary cancers, this study revealed differences in preoperative blood markers, pathology, and long-term survival. More tumor characteristics are shared between DAC and AmpIT and between AmpPB and dCCA than between the two ampullary subtypes. Instead of using collective definitions for "periampullary cancers" or anatomical classification, this study emphasizes the importance of individual evaluation of each histopathological subtype with the ampullary subtypes as individual entities in future studies.
Chronic HBV infection is the leading cause of liver disease and hepatocellular carcinoma. The improvement of antiviral therapies remains an unmet medical need. Capsid assembly modulators (CAMs) ...target the HBV core antigen (HBc) and inhibit HBV replication. While CAM-A compounds are well characterized for inducing aberrant viral capsid aggregates, their mechanisms of action on HBV-hepatocyte interactions are only poorly understood. Recently, we demonstrated that CAM-A molecules lead to a sustained reduction of HBsAg in the serum of HBV replicating mice and induce HBc aggregation in the nucleus of HBc-expressing cells leading to cell death.
In this study, we aimed to investigate the mechanism of action by which CAM-A compounds induce cell death using an HBV infection model, HBc-overexpressing HepG2-NTCP cells, primary human hepatocytes, and HBV replicating HepAD38 cells.
We first confirmed the decrease in HBsAg levels associated with CAM-A treatment and the induction of cell toxicity in HBV-infected differentiated HepaRG cells. Next, we showed that CAM-A-mediated nuclear aggregation of HBc was associated with cell death through the activation of apoptosis. Investigating the mechanism of action driving this phenotype, transcriptomic analysis demonstrated that CAM-A-induced HBc nuclear aggregation led to the upregulation of ANXA1 expression, a documented driver of apoptosis. Finally, the silencing of ANXA1 expression delayed cell death and apoptosis in CAM-A-treated cells, confirming its direct involvement in CAM-A-induced cell death.
Our results unravel a previously undiscovered mechanism of action of CAM-As and open the door to new therapeutic strategies based on CAM treatment for functional cure in chronically infected patients.
Chronic hepatitis B virus (HBV) infection is a global health threat. To date, no treatment allows viral clearance in chronically infected patients. In this study, we characterized a new mechanism of action of an antiviral molecule targeting the assembly of the viral capsid (CAM). We demonstrated that one type of CAM inducing the formation of aberrant structures from HBV core protein aggregating in the nucleus lead to cell death by ANXA1-driven apoptosis. Thus, CAM-A treatment may lead to the specific elimination of HBV-infected cells by apoptosis, paving the way to novel therapeutic strategies for viral cure.
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•CAM-A treatment is associated with a decrease in secreted HBsAg levels and cell toxicity in HBV-infected dHepaRG cells.•CAM-A treatment activates apoptosis in HBc-expressing cells through nuclear accumulation of HBc aggregates.•Nuclear accumulation of HBc aggregates induces the upregulation of ANXA1 expression.•ANXA1 drives apoptosis activation mediated by HBc aggregation and CAM-A treatment.
Diffusion of laparoscopic major hepatectomies is experiencing a steady increasing trend, although slower compared to minor resections. The aim of this single-center study is to discuss current trends ...and indications in the application of minimally invasive techniques to major hepatic resections. Preoperative patients and disease characteristics of 49 laparoscopic major hepatectomies (LPS group), performed between 2005 and 2015, were compared with 585 open hepatectomies (Open group) to analyze differences in patients recruitment. Factors which were found to be differently distributed between groups were used as covariates in a propensity score-based case-matched analysis with a 1:3 ratio between LPS group and 147 patients from the Open group (constituting Open-mat group). Short-term outcome was analyzed in matched groups. ASA score, previous abdominal surgery, previous interventional procedures, indication, lesion size and associated procedures were significantly different between the LPS and the Open group. Short-term outcome analysis revealed that blood loss (200 vs 350 mL,
p
= 0.044) and time for functional recovery (3 vs 4 days,
p
= 0.05) were reduced in the LPS compared to the Open-mat group, in spite of longer length of surgery (260 vs 170 min,
p
= 0.041) and comparable oncological adequacy. Even though data on technical feasibility of laparoscopic major resections and their benefits in terms of blood loss and functional recovery support the diffusion of minimally invasive approach, the limit of the technique is still represented by the reduced pool of suitable candidates.
Pancreatic Cystic Neoplasms (PCNs) represent a difficult preoperative diagnosis despite imaging improvement. In this study, we compare preoperative and final pathological diagnosis in a large cohort ...of resected PCNs, evaluating diagnostic accuracy with a specific focus on the value of Endoscopic Ultrasound (EUS).
A retrospective analysis of patients undergoing resection between 2009 and 2019 for presumed PCNs was performed. Preoperative workup was reviewed analyzing the role of imaging and EUS. Patients with a benign histology who did not show absolute indication were categorized as "delayable surgery".
585 patients were retrospectively analyzed and in 108 cases (18.5%) final histology did not confirm preoperative diagnosis. EUS was associated with lower rate of incorrect diagnosis (16%; p= 0.03), but the risk of overtreatment was similar regardless instrumental diagnostic path (33/131 vs 68/328, p= 0.298). Main pancreatic duct dilatation and cytologic sampling were the only variables independently associated with a correct diagnosis (p <0.001 and p= 0.041, respectively). Based on clinical presentation and final histology, pancreatic resection could have been spared/delayed in 101/459 patients (22%) and this was influenced by age (OR: 0.97, p= 0.002), cyst larger than 30 mm (OR: 1.89, p= 0.005) and type of operation (OR: 3.46 with p <0.001 and OR: 3.18 with p= 0.023 for distal pancreatectomies and other resections, respectively).
The overall risk of unnecessary immediate surgery for PCN is about 22% in a high-volume referral center. EUS with cytologic sampling is a useful procedure in the diagnostic management of PCNs, improving their diagnostic accuracy.
To evaluate whether, in a sample of patients radically treated for colorectal carcinoma, the preoperative determination of the carcinoembryonic antigen (p-CEA) may have a prognostic value and ...constitute an independent risk factor in relation to disease-free survival. The preoperative CEA seems to be related both to the staging of colorectal neoplasia and to the patient's prognosis, although this-to date-has not been conclusively demonstrated and is still a matter of intense debate in the scientific community. This is a retrospective analysis of prospectively collected data. A total of 395 patients were radically treated for colorectal carcinoma. The preoperative CEA was statistically compared with the 2010 American Joint Committee on Cancer (AJCC) staging, the T and N parameters, and grading. All parameters recorded in our database were tested for an association with disease-free survival (DFS). Only factors significantly associated (P < 0.05) with the DFS were used to build multivariate stepwise forward logistic regression models to establish their independent predictors. A statistically significant relationship was found between p-CEA and tumor staging (P < 0.001), T (P < 0.001) and N parameters (P = 0.006). In a multivariate analysis, the independent prognostic factors found were: p-CEA, stages N1 and N2 according to AJCC, and G3 grading (grade). A statistically significant difference (P < 0.001) was evident between the DFS of patients with normal and high p-CEA levels. Preoperative CEA makes a pre-operative selection possible of those patients for whom it is likely to be able to predict a more advanced staging.
Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major ...hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC).
The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity.
On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 0.84–1.29, p = 0.711 and HR 1.18 0.95–1.46, p = 0.13 respectively) or OS (HR 0.96 0.79–1.17, p = 0.67 and HR 1.48 1.16–1.88, p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 1.02–1.74, p = 0.037) and OS (HR 1.26 1.03–1.53, p = 0.022). Furthermore, EBDR (OR 2.86 2.3–3.52, p < 0.0010), resection of additional organs (OR 2.22 1.62–3.02, p < 0.0010) and major hepatectomy (OR 3.81 2.55–5.73, p < 0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 1.02–1.37, p = 0.031) but not OS (HR 1.05 0.91–1.22, p = 0.48). Adjuvant and neoadjuvant treatments were infrequently used.
In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international collaborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit.
Cambridge Hepatopancreatobiliary Department Research Fund.
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