Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in pancreatic ...ductal adenocarcinoma (PDAC) has not been explored. Here, we develop a DUB discovery pipeline, combining activity-based proteomics with a loss-of-function genetic screen in patient-derived PDAC organoids and murine genetic models. This approach identifies USP25 as a master regulator of PDAC growth and maintenance. Genetic and pharmacological USP25 inhibition results in potent growth impairment in PDAC organoids, while normal pancreatic organoids are insensitive, and causes dramatic regression of patient-derived xenografts. Mechanistically, USP25 deubiquitinates and stabilizes the HIF-1α transcription factor. PDAC is characterized by a severely hypoxic microenvironment, and USP25 depletion abrogates HIF-1α transcriptional activity and impairs glycolysis, inducing PDAC cell death in the tumor hypoxic core. Thus, the USP25/HIF-1α axis is an essential mechanism of metabolic reprogramming and survival in PDAC, which can be therapeutically exploited.
Most primary liver cancers diagnosed in allograft livers are recurrent tumors of the native liver origin, while donor‐derived primary liver cancers are markedly less common. A 21‐year‐old woman who ...had liver transplantation for post‐Kasai biliary atresia was recently referred for post‐transplant biliary stricture. Her transplantation was performed at the age of 6 years using the whole liver graft from a 10‐year‐old donor and choledocho‐jejunostomy. The post‐transplant course was uneventful in the first 15 years until she presented with obstructive jaundice. The stricture was located at the level of the hepaticojejunostomy, and required percutaneous transhepatic drainage and bile duct dilatation. She underwent an exploratory laparotomy, which suggested a neoplastic process widely involving the extrahepatic and intrahepatic large bile ducts. The histological examination of the resected extrahepatic bile duct confirmed infiltrating moderately differentiated adenocarcinoma. Molecular tests of multiple short tandem repeat loci confirmed the donor origin of the tumor. After four cycles of chemotherapy with gemicitabine and cisplatin, she is currently on radiotherapy in view of potential re‐transplantation. De novo, post‐transplant cholangiocarcinoma of graft origin is extremely uncommon with only three other cases reported. Two were associated with recurrent primary sclerosing cholangitis, and all had choledocho‐jejunostomy at the time of transplantation.
Abstract
Duodenal neuroendocrine neoplasms (dNENs) are rare neoplasms but their incidence is on the rise. They are classified into 5 sub-types but there remains much heterogeneity in behaviour in ...particular of non-functioning dNENs. To retrospectively analyse outcomes for all types of dNENs, and highlight prognostic factors associated with worse outcome. 102 (57 m/45f.) patients were identified with mean age at diagnosis 62 (range 32–87) years. The majority were non-functioning tumours 87/102 and median size was 10 mm (range 0.9–130 mm). 83 patients had Stage I or II disease, of which 17 underwent endoscopic resection with R1 rate of 45% and complication rate 12%. 36 patients were kept under endoscopic surveillance. There were 11 deaths of which 4 were disease related. Age and Ki67 > 20% were associated with worse OS in all dNENs. In non-functioning dNENs Ki67 > 3% was a predictor of lymph nodes metastases with OR 18.2 (2.54–13) (
p
< 0.005) in univariate analyses and liver metastases with OR 6.79 (1.56–29.5) (
p
< 0.05) in the multivariate analysis. Lesions 11–20 mm in size had OR 11.1 (1.16–106) compared to lesions < 11 mm for the prediction of lymph node metastases in the multivariate analysis (
p
< 0.05). ROC analysis of size of non-functioning dNENs to predict LN metastases found < 15 mm had an AUROC of 0.9 (0.81–0.99) with a sensitivity of 85% and specificity of 88%. dNENs are increasing in incidence, however low grade and smaller lesions have an indolent course and the role of endoscopic resection and active surveillance needs to be reviewed.
Background
Early detection of pancreatic fistula (PF) may improve the outcome after pancreaticoduodenectomy, and exclusion of PF may allow earlier drain removal and accelerate recovery. The aim of ...the present study was to evaluate the relationship between drain fluid amylase on the first postoperative day (DFA
1
) and PF.
Patients and methods
This work was designed as a prospective study and included patients undergoing pancreaticoduodenectomy in a single center. For each patient, DFA was measured on the first and fifth postoperative days, and PF was defined by drainage of amylase-rich fluid on the fifth postoperative day (DFA
5
>300 U/l). A cut-off value of DFA
1
was derived, which yielded sensitivity and negative predictive value of 100% for predicting a PF.
Results
A total of 70 patients (47% male) who underwent pancreaticoduodenectomy (Whipple procedure: 37; pylorus-preserving procedure: 33) between April 2009 and March 2010 were included. Nine of those patients developed a PF (grade A-2; B-5; C-2). There were two postoperative deaths (3%). The DFA
1
value significantly correlated with DFA
5
(Spearman rank coefficient 0.68;
p
< 0.0001). The median DFA
1
of patients with a PF (6,205; range 357–23,391) was significantly higher than in patients without a PF (69; range 5–5,180;
p
= 0.01; unpaired
t
test). No patient with a PF had a DFA
1
≤350 U/l, compared to 48/61 patients (79%) without a PF. Using 350 U/l as a cut-off, a low DFA
1
excluded a PF with a sensitivity, specificity, positive and negative predictive values of 100, 79, 41, and 100%, respectively.
Conclusions
Drain fluid amylase on the DFA
1
after pancreaticoduodenectomy stratifies patients according to likelihood of developing a PF.
The scope of the present study is to review the topics of initial assessment, diagnosis and clinical management of an isolated abdominal trauma.
Progress in the management of trauma patients ...increasing survival includes a multidisciplinary approach involving multiple specialties at presentation. If immediate surgical intervention is needed, 'damage control' is the best option; if not, it has been proven that conservative management is superior to operative, in terms of survival for the majority of intraabdominal injury. 'Open abdomen' should be performed in major abdominal traumas when indicated. Early enteral feeding is beneficial, even in the presence of 'open abdomen'.
Abdominal trauma is a complex injury; the multidisciplinary approach has made nonoperative management feasible and effective. When surgical intervention is needed, it should be performed in an orderly fashion, within the context of the overall management.
Neuroendocrine liver metastases (LM-NEN) develop in a considerable proportion of patients with gastroenteropancreatic neuroendocrine neoplasms. There is a paucity of experimental models that ...accurately recapitulate this complex metastatic human liver microenvironment precluding scientific and clinical advancements. Here, we describe the development of a novel personalised immunocompetent precision cut tumour slice (PCTS) model for LM-NEN using resected human liver tissue. The histological assessment throughout the culture demonstrated that slices maintain viability for at least 7 days and retain the cellular heterogeneity of the original tumour. Essential clinical features, such as patient-specific histoarchitecture, tumour grade, neuroendocrine differentiation and metabolic capacity, are preserved in the slices. The PCTS also replicate the tumor-specific immunological profile as shown by the innate and adaptive immunity markers analysis. Furthermore, the study of soluble immune checkpoint receptors in the culture supernatants proves that these immunomodulators are actively produced by LM-NEN and suggests that this process is epithelium-dependent. This model can be employed to investigate these pathways and provides a powerful platform for mechanistic, immunological and pre-clinical studies.
Donation after cardiac death (DCD) livers are marginal organs for transplant and their use is associated with a higher risk of primary non function (PNF) or early graft dysfunction (EGD). The aim was ...to determine if microRNA (miRNA) was able to discriminate between DCD livers of varying clinical outcome. DCD groups were categorized as PNF retransplanted within a week (n=7), good functional outcome (n=7) peak aspartate transaminase (AST) ≤ 1000 IU/L and EGD (n=9) peak AST ≥ 2500 IU/L. miRNA was extracted from archival formalin fixed post-perfusion tru-cut liver biopsies. High throughput expression analysis was performed using miRNA arrays. Bioinformatics for expression data analysis was performed and validated with real time quantitative PCR (RT-qPCR). The function of miRNA of interest was investigated using computational biology prediction algorithms. From the array analysis 16 miRNAs were identified as significantly different (p<0.05). On RT-qPCR miR-155 and miR-940 had the highest expression across all three DCD clinical groups. Only one miRNA, miR-22, was validated with marginal significance, to have differential expression between the three groups (p=0.049). From computational biology miR-22 was predicted to affect signalling pathways that impact protein turnover, metabolism and apoptosis/cell cycle. In conclusion, microRNA expression patterns have a low diagnostic potential clinically in discriminating DCD liver quality and outcome.
The SARS-CoV-2 (COVID-19) pandemic is having a large effect on the management of cancer patients. This study reports on the approach and outcomes of cancer patients receiving radical surgery with ...curative intent between March and September 2020 (in comparison to 2019) in the European Institute of Oncology, IRCCS (IEO) in Milan and the South East London Cancer Alliance (SELCA). Both institutions implemented a COVID-19 minimal pathway where patients were required to self-isolate prior to admission and were swabbed for COVID-19 within 72 h of surgery. Positive patients had surgery deferred until a negative swab. At IEO, radical surgeries declined by 6% as compared to the same period in 2019 (
= 1477 vs. 1560, respectively). Readmissions were required for 3% (
= 41), and <1% (
= 9) developed COVID-19, of which only one had severe disease and died. At SELCA, radical surgeries declined by 34% (
= 1553 vs. 2336). Readmissions were required for 11% (
= 36), <1% (
= 7) developed COVID-19, and none died from it. Whilst a decline in number of surgeries was observed in both centres, the implemented COVID-19 minimal pathways have shown to be safe for cancer patients requiring radical treatment, with limited complications and almost no COVID-19 infections.
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