High-resolution and quantitative spatial analysis reveal intra-ductal phenotypic and functional diversification in pancreatic cancer.

A 'classical' and a 'basal-like' subtype of pancreatic cancer have been reported, with differential expression of GATA6 and different dosages of mutant KRAS. We established in situ detection of KRAS point mutations and mRNA panels for the consensus subtypes aiming to project these findings to paraffin-embedded clinical tumour samples for spatial quantitative analysis. We unveiled that, next to inter-patient and intra-patient inter-ductal heterogeneity, intraductal spatial phenotypes exist with anti-correlating expression levels of GATA6 and KRASG12D . The basal-like mRNA panel better captured the basal-like cell states than widely used protein markers. The panels corroborated the co-existence of the classical and basal-like cell states in a single tumour duct with functional diversification, i.e. proliferation and epithelial-to-mesenchymal transition respectively. Mutant KRASG12D detection ascertained an epithelial origin of vimentin-positive cells in the tumour. Uneven spatial distribution of cancer-associated fibroblasts could recreate similar intra-organoid diversification. This extensive heterogeneity with functional cooperation of plastic tumour cells poses extra challenges to therapeutic approaches. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Optimizing adjuvant treatment strategies for non-pancreatic periampullary cancers.

Non-pancreatic periampullary tumors have long been neglected, leading to blurred adjuvant treatment strategies. Recent research, like the ISGACA group's study, is uncovering nuances in chemotherapy efficacy for these diverse cancers. Tailored approaches show promise, with artificial intelligence (AI) aiding in personalized treatment plans.

EUS-Guided Choledocho-duodenostomy Using Lumen Apposing Stent Versus ERCP With Covered Metallic Stents in Patients With Unresectable Malignant Distal Biliary Obstruction: A Multicenter Randomized Controlled Trial (DRA-MBO Trial).

BACKGROUND & AIMS: Several studies have compared primary endoscopic ultrasound (EUS)-guided biliary drainage to endoscopic retrograde cholangiopancreatography (ERCP) with insertion of metal stents in unresectable malignant distal biliary obstruction (MDBO) and the results were conflicting. The aim of the current study was to compare the outcomes of the procedures in a large-scale study. METHODS: This was a multicenter international randomized controlled study. Consecutive patients admitted for obstructive jaundice due to unresectable MDBO were recruited. Patients were randomly allocated to receive EUS-guided choledocho-duodenostomy (ECDS) or ERCP for drainage. The primary outcome was the 1-year stent patency rate. Other outcomes included technical success, clinical success, adverse events, time to stent dysfunction, reintervention rates, and overall survival. RESULTS: Between January 2017 and February 2021, 155 patients were recruited (ECDS 79, ERCP 76). There were no significant differences in 1-year stent patency rates (ECDS 91.1% vs ERCP 88.1%, P = .52). The ECDS group had significantly higher technical success (ECDS 96.2% vs ERCP 76.3%, P < .001), whereas clinical success was similar (ECDS 93.7% vs ERCP 90.8%, P = .559). The median (interquartile range) procedural time was significantly shorter in the ECDS group (ECDS 10 [5.75-18] vs ERCP 25 [14-40] minutes, P < .001). The rate of 30-day adverse events (P = 1) and 30-day mortality (P = .53) were similar. CONCLUSION: Both procedures could be options for primary biliary drainage in unresectable MDBO. ECDS was associated with higher technical success and shorter procedural time then ERCP. Primary ECDS may be preferred when difficult ERCPs are anticipated. This study was registered to Clinicaltrials.gov NCT03000855.

Partially covered versus uncovered pyloro-duodenal stents for unresectable malignant gastric outlet obstruction: Randomized controlled study.

OBJECTIVES: The aim of the current study was to compare the efficacy of partially covered duodenal stent (PCDS) vs. uncovered duodenal stent (UCDS) in patients suffering from unresectable primary malignant gastric outlet obstruction (GOO). METHODS: This was a prospective international randomized controlled study conducted in 10 high-volume institutions. Consecutive patients suffering from malignant GOO were recruited. The primary outcome measurement was the reintervention rate. Secondary outcomes included technical and clinical success, 30-day adverse events, 30-day mortality, causes of stent dysfunction, and the duration of stent patency. RESULTS: Between March 2017 and October 2020, 115 patients (59 PCDS, 56 UCDS) were recruited. The 1-year reintervention was not significantly different (PCDS vs. UDCS = 12/59, 20.3% vs. 14/56, 25%, P = 0.84). There was a trend to fewer patients with tumor ingrowth in the PCDS group (6/59 [10.2%]) vs. 13/56 [23.2%], P = 0.07). There were no significant differences in the technical success (100% vs. 100%, P = 1), clinical success (91.5% vs. 98.2%, P = 0.21), procedural time (21.5 [interquartile range [IQR] 17-30] vs. 20.0 [IQR 15-34.75], P = 0.62), hospital stay (4 [IQR 3-12] vs. 5 [IQR 3-8] days, P = 0.81), 30-day adverse events (18.6% vs. 14.3%, P = 0.62), or 30-day mortality (6.8% vs. 5.2%, P = 1.00). CONCLUSION: The use of PCDS was associated with a lower risk of tumor ingrowth but did not improve on reintervention rates or stent patency. Both kinds of stents could be used in this group of patients.

Radiomics using computed tomography to predict CD73 expression and prognosis of colorectal cancer liver metastases.

BACKGROUND: Finding a noninvasive radiomic surrogate of tumor immune features could help identify patients more likely to respond to novel immune checkpoint inhibitors. Particularly, CD73 is an ectonucleotidase that catalyzes the breakdown of extracellular AMP into immunosuppressive adenosine, which can be blocked by therapeutic antibodies. High CD73 expression in colorectal cancer liver metastasis (CRLM) resected with curative intent is associated with early recurrence and shorter patient survival. The aim of this study was hence to evaluate whether machine learning analysis of preoperative liver CT-scan could estimate high vs low CD73 expression in CRLM and whether such radiomic score would have a prognostic significance. METHODS: We trained an Attentive Interpretable Tabular Learning (TabNet) model to predict, from preoperative CT images, stratified expression levels of CD73 (CD73High vs. CD73Low) assessed by immunofluorescence (IF) on tissue microarrays. Radiomic features were extracted from 160 segmented CRLM of 122 patients with matched IF data, preprocessed and used to train the predictive model. We applied a five-fold cross-validation and validated the performance on a hold-out test set. RESULTS: TabNet provided areas under the receiver operating characteristic curve of 0.95 (95% CI 0.87 to 1.0) and 0.79 (0.65 to 0.92) on the training and hold-out test sets respectively, and outperformed other machine learning models. The TabNet-derived score, termed rad-CD73, was positively correlated with CD73 histological expression in matched CRLM (Spearman's ρ = 0.6004; P < 0.0001). The median time to recurrence (TTR) and disease-specific survival (DSS) after CRLM resection in rad-CD73High vs rad-CD73Low patients was 13.0 vs 23.6 months (P = 0.0098) and 53.4 vs 126.0 months (P = 0.0222), respectively. The prognostic value of rad-CD73 was independent of the standard clinical risk score, for both TTR (HR = 2.11, 95% CI 1.30 to 3.45, P < 0.005) and DSS (HR = 1.88, 95% CI 1.11 to 3.18, P = 0.020). CONCLUSIONS: Our findings reveal promising results for non-invasive CT-scan-based prediction of CD73 expression in CRLM and warrant further validation as to whether rad-CD73 could assist oncologists as a biomarker of prognosis and response to immunotherapies targeting the adenosine pathway.

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.

Prognostic implications of adaptive immune features in MMR-proficient colorectal liver metastases classified by histopathological growth patterns.

BACKGROUND: After resection, colorectal cancer liver metastases (CRLM) surrounded by a desmoplastic rim carry a better prognosis than the metastases replacing the adjacent liver. However, these histopathological growth patterns (HGPs) are insufficient to guide clinical decision-making. We explored whether the adaptive immune features of HGPs could refine prognostication. METHODS: From 276 metastases resected in 176 patients classified by HGPs, tissue microarrays were used to assess intratumoral T cells (CD3), antigen presentation capacity (MHC class I) and CD73 expression producing immunosuppressive adenosine. We tested correlations between these variables and patient outcomes. RESULTS: The 101 (57.4%) patients with dominant desmoplastic HGP had a median recurrence-free survival (RFS) of 17.1 months compared to 13.3 months in the 75 patients (42.6%) with dominant replacement HGP (p = 0.037). In desmoplastic CRLM, high vs. low CD73 was the only prognostically informative immune parameter and was associated with a median RFS of 12.3 months compared to 26.3, respectively (p = 0.010). Only in dominant replacement CRLM, we found a subgroup (n = 23) with high intratumoral MHC-I expression but poor CD3+ T cell infiltration, a phenotype associated with a short median RFS of 7.9 months. CONCLUSIONS: Combining the assessments of HGP and adaptive immune features in resected CRLM could help identify patients at risk of early recurrence.

Novel 15-mm-long lumen-apposing metal stent for endoscopic ultrasound-guided drainage of pancreatic fluid collections located ≥10 mm from the luminal wall.

BACKGROUND: Endoscopic ultrasound (EUS)-guided drainage of pancreatic fluid collections (PFCs) by cautery-enhanced lumen-apposing metal stents (LAMS) has largely been limited to collections located < 10 mm from the luminal wall. We present outcomes of the use of a novel 15-mm-long cautery-enhanced LAMS for drainage of PFCs located ≥ 10 mm away. METHODS: This international, multicenter study analyzed all adults with PFCs located ≥ 10 mm from the luminal wall who were treated by EUS-guided drainage using the 15-mm-long cautery-enhanced LAMS. The primary outcome was technical success. Secondary outcomes included clinical success (decrease in PFC size by ≥ 50 % at 30 days and resolution of clinical symptoms without surgical intervention), complications, and recurrence. RESULTS: 35 patients (median age 57 years; interquartile range [IQR] 47-64 years; 49 % male) underwent novel LAMS placement for drainage of PFCs (26 walled-off necrosis, 9 pseudocysts), measuring 85 mm (IQR 64-117) maximal diameter and located 11.8 mm (IQR 10-12.3; range 10-14) from the gastric/duodenal wall. Technical and clinical success were high (both 97 %), with recurrence in one patient (3 %) at a median follow-up of 123 days (58-236). Three complications occurred (9 %; one mild, two moderate). CONCLUSIONS: The 15-mm-long cautery-enhanced LAMS was feasible and safe for drainage of PFCs located 10-14 mm from the luminal wall.

Study International Multicentric Pancreatic Left Resections (SIMPLR): Does Surgical Approach Matter?

BACKGROUND: Minimally invasive surgery is increasingly preferred for left-sided pancreatic resections. The SIMPLR study aims to compare open, laparoscopic, and robotic approaches using propensity score matching analysis. METHODS: This study included 258 patients with tumors of the left side of the pancreas who underwent surgery between 2016 and 2020 at three high-volume centers. The patients were divided into three groups based on their surgical approach and matched in a 1:1 ratio. RESULTS: The open group had significantly higher estimated blood loss (620 mL vs. 320 mL, p < 0.001), longer operative time (273 vs. 216 min, p = 0.003), and longer hospital stays (16.9 vs. 6.81 days, p < 0.001) compared to the laparoscopic group. There was no difference in lymph node yield or resection status. When comparing open and robotic groups, the robotic procedures yielded a higher number of lymph nodes (24.9 vs. 15.2, p = 0.011) without being significantly longer. The laparoscopic group had a shorter operative time (210 vs. 340 min, p < 0.001), shorter ICU stays (0.63 vs. 1.64 days, p < 0.001), and shorter hospital stays (6.61 vs. 11.8 days, p < 0.001) when compared to the robotic group. There was no difference in morbidity or mortality between the three techniques. CONCLUSION: The laparoscopic approach exhibits short-term benefits. The three techniques are equivalent in terms of oncological safety, morbidity, and mortality.

Orphan receptor GPR176 in hepatic stellate cells exerts a profibrotic role in chronic liver disease.

Background & Aims: Chronic liver disease (CLD) remains a global health issue associated with a significant disease burden. Liver fibrosis, a hallmark of CLD, is characterised by the activation of hepatic stellate cells (HSCs) that gain profibrotic characteristics including increased production of extracellular matrix protein. Currently, no antifibrotic therapies are available clinically, in part because of the lack of HSC-specific drug targets. Here, we aimed to identify HSC-specific membrane proteins that can serve as targets for antifibrotic drug development. Methods: Small interfering RNA-mediated knockdown of GPR176 was used to assess the in vitro function of GPR176 in HSCs and in precision cut liver slices (PCLS). The in vivo role of GPR176 was assessed using the carbon tetrachloride (CCl4) and common bile duct ligation (BDL) models in wild-type and GPR176 knockout mice. GPR176 in human CLD was assessed by immunohistochemistry of diseased human livers and RNA expression analysis in human primary HSCs and transcriptomic data sets. Results: We identified Gpr176, an orphan G-protein coupled receptor, as an HSC-enriched activation associated gene. In vitro, Gpr176 is strongly induced upon culture-induced and hepatocyte-damage-induced activation of primary HSCs. Knockdown of GPR176 in primary mouse HSCs or PCLS cultures resulted in reduced fibrogenic characteristics. Absence of GPR176 did not influence liver homeostasis, but Gpr176-/- mice developed less severe fibrosis in CCl4 and BDL fibrosis models. In humans, GPR176 expression was correlated with in vitro HSC activation and with fibrosis stage in patients with CLD. Conclusions: GPR176 is a functional protein during liver fibrosis and reducing its activity attenuates fibrogenesis. These results highlight the potential of GPR176 as an HSC-specific antifibrotic candidate to treat CLD. Impact and implications: The lack of effective antifibrotic drugs is partly attributed to the insufficient knowledge about the mechanisms involved in the development of liver fibrosis. We demonstrate that the G-protein coupled receptor GPR176 contributes to fibrosis development. Since GPR176 is specifically expressed on the membrane of activated hepatic stellate cells and is linked with fibrosis progression in humans, it opens new avenues for the development of targeted interventions.

Human iPSC-derived liver co-culture spheroids to model liver fibrosis.

The lack of adequate humanin vitromodels that recapitulate the cellular composition and response of the human liver to injury hampers the development of anti-fibrotic drugs. The goal of this study was to develop a human spheroid culture model to study liver fibrosis by using induced pluripotent stem cell (iPSC)-derived liver cells. iPSCs were independently differentiated towards hepatoblasts (iHepatoblasts), hepatic stellate cells (iHSCs), endothelial cells (iECs) and macrophages (iMΦ), before assembly into free floating spheroids by culturing cells in 96-well U-bottom plates and orbital shaking for up to 21 days to allow further maturation. Through transcriptome analysis, we show further maturation of iECs and iMΦ, the differentiation of the iHepatoblasts towards hepatocyte-like cells (iHeps) and the inactivation of the iHSCs by the end of the 3D culture. Moreover, these cultures display a similar expression of cell-specific marker genes (CYP3A4, PDGFRß, CD31andCD68) and sensitivity to hepatotoxicity as spheroids made using freshly isolated primary human liver cells. Furthermore, we show the functionality of the iHeps and the iHSCs by mimicking liver fibrosis through iHep-induced iHSC activation, using acetaminophen. In conclusion, we have established a reproducible human iPSC-derived liver culture model that can be used to mimic fibrosisin vitroas a replacement of primary human liver derived 3D models. The model can be used to investigate pathways involved in fibrosis development and to identify new targets for chronic liver disease therapy.

Homogeneity in immune features between colorectal liver metastases better identifies patients with good prognosis compared to pathological response to preoperative chemotherapy.

In colorectal cancer liver metastases (CRLM), the density of tumor-infiltrating lymphocytes, the expression of class I major histocompatibility complex (MHC-I), and the pathological response to preoperative chemotherapy have been associated with oncological outcomes after complete resection. However, the prognostic significance of the heterogeneity of these features in patients with multiple CRLMs remains under investigation. We used a tissue microarray of 220 mismatch repair-gene proficient CRLMs resected in 97 patients followed prospectively to quantify CD3+ T cells and MHC-I by immunohistochemistry. Histopathological response to preoperative chemotherapy was assessed using standard scoring systems. We tested associations between clinical, immunological, and pathological features with oncologic outcomes. Overall, 29 patients (30.2%) had CRLMs homogeneous for CD3+ T cell infiltration and MHC-I. Patients with immune homogeneous compared to heterogeneous CRLMs had longer median time to recurrence (TTR) (30 vs. 12 months, p = .0018) and disease-specific survival (DSS) (not reached vs. 48 months, p = .0009). At 6 years, 80% of the patients with immune homogeneous CRLMs were still alive. Homogeneity of response to preoperative chemotherapy was seen in 60 (61.9%) and 69 (80.2%) patients according to different grading systems and was not associated with TTR or DSS. CD3 and MHC-I heterogeneity was independent of response to pre-operative chemotherapy and of other clinicopathological variables for their association with oncological outcomes. In patients with multiple CRLMs resected with curative intent, similar adaptive immune features seen across metastases could be more informative than pathological response to pre-operative chemotherapy in predicting oncological outcomes.

Endoscopic ultrasound-guided gastroenterostomy for the management of gastric outlet obstruction: A large comparative study with long-term follow-up.

Background and study aims Gastric outlet obstruction (GOO) is traditionally managed with surgical gastroenterostomy (surgical-GE) and enteral stenting (ES). Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) is now a third option. Large studies assessing their relative risks and benefits with adequate follow-up are lacking. We conducted a comparative analysis of patients who underwent EUS-GE, ES, or surgical-GE for GOO. Patients and methods In this retrospective comparative cohort study, consecutive patients presenting with GOO who underwent EUS-GE, ES, or surgical-GE at two academic institutions were reviewed and independently cross-edited to ensure accurate reporting. The primary outcome was need for reintervention. Secondary outcomes were technical and clinical success, length of hospital stay (LOS), and adverse events (AEs). Results A total of 436 patients (232 EUS-GE, 131 ES, 73 surgical-GE) were included. The median duration of follow-up of the entire cohort was 185.5 days (interquartile range 55.25-454.25 days). The rate of reintervention in the EUS-GE group was lower than in the ES and surgical-GE groups (0.9 %, 12.2 %, and 13.7 %, P  < 0.0001). Technical success was achieved in 98.3 %, 99.2 %, and 100 % ( P  = 0.58), and clinical success was achieved in 98.3 %, 91.6 %, and 90.4 % ( P  < 0.0001) in the EUS-GE, ES, and surgical-GE groups, respectively. The EUS-GE group had a shorter LOS (2 days vs. 3 days vs. 5 days, P  < 0.0001) and a lower AE rate than the ES and surgical-GE groups (8.6 % vs. 38.9 % vs. 27.4 %, P  < 0.0001). Conclusion This large cohort study demonstrates the safety and palliation durability of EUS-GE as an alternative strategy for GOO palliation in select patients.

CD73 Inhibits cGAS-STING and Cooperates with CD39 to Promote Pancreatic Cancer.

The ectonucleotidases CD39 and CD73 catalyze extracellular ATP to immunosuppressive adenosine, and as such, represent potential cancer targets. We investigated biological impacts of CD39 and CD73 in pancreatic ductal adenocarcinoma (PDAC) by studying clinical samples and experimental mouse tumors. Stromal CD39 and tumoral CD73 expression significantly associated with worse survival in human PDAC samples and abolished the favorable prognostic impact associated with the presence of tumor-infiltrating CD8+ T cells. In mouse transplanted KPC tumors, both CD39 and CD73 on myeloid cells, as well as CD73 on tumor cells, promoted polarization of infiltrating myeloid cells towards an M2-like phenotype, which enhanced tumor growth. CD39 on tumor-specific CD8+ T cells and pancreatic stellate cells also suppressed IFNγ production by T cells. Although therapeutic inhibition of CD39 or CD73 alone significantly delayed tumor growth in vivo, targeting of both ectonucleotidases exhibited markedly superior antitumor activity. CD73 expression on human and mouse PDAC tumor cells also protected against DNA damage induced by gemcitabine and irradiation. Accordingly, large-scale pharmacogenomic analyses of human PDAC cell lines revealed significant associations between CD73 expression and gemcitabine chemoresistance. Strikingly, increased DNA damage in CD73-deficient tumor cells associated with activation of the cGAS-STING pathway. Moreover, cGAS expression in mouse KPC tumor cells was required for antitumor activity of the CD73 inhibitor AB680 in vivo. Our study, thus, illuminates molecular mechanisms whereby CD73 and CD39 seemingly cooperate to promote PDAC progression.

Results of surgical treatment of athletes with sportsman's hernia.

Chronic groin pain in athletes is a difficult diagnostic and therapeutic condition. Between March 2004 and December 2009, 241 male athletes (mean age: 25.8 years, range: 16-41) in whom chronic sportsman's hernia was diagnosed, were surgically treated using a standardised technique. In this retrospective study, charts were analyzed for preoperative duration of symptoms and prior treatment. Perioperative complications were noted. Patients were contacted and were asked to answer a telephone questionnaire: 162 patients agreed to be questioned as part of the current study. A surgical intervention with reinforcement of the posterior inguinal wall and tenotomy of the adductors has lead to satisfactory results in over 90% of athletes with chronic groin pain who failed to improve with conservative treatment.

Step-up approach in emphysematous hepatitis: A case report.

BACKGROUND: Emphysematous hepatitis (EH) is a rare, rapidly progressive fulminant gas-forming infection of the liver parenchyma. It is often fatal and mostly affects diabetes patients. CASE SUMMARY: We report a case of EH successfully managed by a step-up approach consisting of aggressive hemodynamic support, intravenous antibiotics, and percutaneous drainage, ultimately followed by laparoscopic deroofing. Of 11 documented cases worldwide, only 1 of the patients survived, treated by urgent laparotomy and surgical debridement. CONCLUSION: EH is a life-threatening infection. Its high mortality rate makes timely diagnosis essential, in order to navigate treatment accordingly.

Improved Precision-Cut Liver Slice Cultures for Testing Drug-Induced Liver Fibrosis.

In vitro models of human liver disease often fail to mimic the complex 3D structures and cellular organizations found in vivo. Precision cut liver slices (PCLS) retain the complex physiological architecture of the native liver and therefore could be an exceptional in vitro liver model. However, the production of PCLS induces a spontaneous culture-induced fibrogenic reaction, limiting the application of PCLS to anti-fibrotic compounds. Our aim was to improve PCLS cultures to allow compound-induced fibrosis induction. Hepatotoxicity in PCLS cultures was analyzed by lactate dehydrogenase leakage and albumin secretion, while fibrogenesis was analyzed by qRT-PCR and western blot for hepatic stellate cell (HSC) activation markers and collagen 6 secretion by enzyme-linked immunosorbent assays (ELISA). We demonstrate that supplementation of 3 mm mouse PCLS cultures with valproate strongly reduces fibrosis and improves cell viability in our PCLS cultures for up to 5 days. Fibrogenesis can still be induced both directly and indirectly through exposure to TGFß and the hepatotoxin acetaminophen, respectively. Finally, human PCLS cultures showed similar but less robust results. In conclusion, we optimized PCLS cultures to allow for drug-induced liver fibrosis modeling.

Prognostic value of CD73 expression in resected colorectal cancer liver metastasis.

Immune checkpoint blockade has not yet been effective in patients with mismatch repair proficient metastatic colorectal cancer. Targeting immunosuppressive metabolic pathways is being explored as a new immunotherapeutic approach. We assessed whether CD73, the rate limiting enzyme that catalyzes the degradation of extracellular AMP into immunosuppressive adenosine, could be an immunological determinant of colorectal liver metastases (CRLMs). By immunofluorescence on tissue microarrays, intratumoral CD73 expression (tCD73) was analyzed in 391 CRLMs resected in 215 patients, and soluble CD73 (sCD73) was measured by ELISA in the pre-operative serum of 193 patients. High tCD73 was associated with worse pathological features, such as multiple and larger CRLMs, and poorer pathologic response to pre-operative chemotherapy. The median time to recurrence and disease-specific survival after CRLM resection was significantly shorter in patients with high tCD73 (11.0 and 46.4 months, respectively) compared with low tCD73 (19.0 and 61.5 months, respectively). tCD73 was strongly associated with patient outcomes independently of clinicopathological variables. sCD73 did not correlate with tCD73. Patients with high levels of sCD73 also had shorter disease-specific survival. Our results suggested that CD73 in CRLMs may be prognostically informative and may help select patients more likely to respond to adenosine pathway blocking agents.

Prediction of prolonged length of stay in the intensive care unit after cardiac surgery: the need for a multi-institutional risk scoring system.

BACKGROUND AND AIM OF THE STUDY: Predictive models for the length of stay (LOS) in the intensive care unit (ICU) following cardiac surgery have been developed in the last decade. These risk models use different endpoint and risk factor definitions. This review discusses the need for a uniform multi-institutional risk scoring system for a prolonged ICU LOS. METHODS: The MEDLINE database was searched for studies assessing the prognostic value of clinical variables predicting ICU LOS. Information on study design, patient population, extended ICU LOS definition, and predictors was retrieved. RESULTS: There is no consensus on the definition of a prolonged ICU LOS. This is mainly because some studies take the continuous variables of "days in the intensive care unit" and try to make it dichotomous when actually the LOS should be analyzed as a "continuous variable." We also report a cardiac surgeon-related component. The most important risk factors were: increased age, no elective surgery, type of cardiac surgery, low left ventricular ejection fraction, recent myocardial infarction, history of pulmonary disease, history of renal disease, and reoperation/reexploration. CONCLUSIONS: There is a need for the development of a multi-institutional risk scoring system for prolonged ICU LOS following cardiac surgery. This predictive model could aid in quality assessment, practice improvement, patient counseling, and decision making. In order to develop this risk model, uniformed and standardized definitions are needed.

Targeting the CD73-adenosine axis in immuno-oncology.

The ectonucleotidases CD39 and CD73 are cell surface enzymes that catabolize the breakdown of extracellular ATP into adenosine. As such, they constitute critical components of the extracellular purinergic pathway and play important roles in maintaining tissue and immune homeostasis. With the coming of age of cancer immunotherapy, ectonucleotidases and adenosine receptors have emerged as novel therapeutic targets to enhance antitumor immune responses. With early-phase clinical trials showing promising results, it is becoming increasingly important to decipher the distinct mechanisms-of-action of adenosine-targeting agents, identify patients that will benefit from these agents and rationally develop novel synergistic combinations. Given the broad expression of ectonucleotidases and adenosine receptors, a better understanding of cell-specific roles will also be key for successful implementation of this new generation of immuno-oncology therapeutics. We here review the latest studies on the roles of CD73 and adenosine in cancer with a focus on cell-specific function. We also discuss ongoing clinical trials and future avenues for adenosine-targeting agents.