JAK1 promotes HDV replication and is a potential target for antiviral therapy.

BACKGROUND & AIMS: Chronic co-infection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. To date, no treatment induces efficient viral clearance, and a better characterization of virus-host interactions is required to develop new therapeutic strategies. METHODS: Using loss-of-function strategies, we validated the unexpected proviral activity of Janus kinase 1 (JAK1) - a key player in innate immunity - in the HDV life cycle and determined its mechanism of action on HDV through various functional analyses including co-immunoprecipitation assays. RESULTS: We confirmed the key role of JAK1 kinase activity in HDV infection. Moreover, our results suggest that JAK1 inhibition is associated with a modulation of ERK1/2 activation and S-HDAg phosphorylation, which is crucial for viral replication. Finally, we showed that FDA-approved JAK1-specific inhibitors are efficient antivirals in relevant in vitro models including primary human hepatocytes. CONCLUSIONS: Taken together, we uncovered JAK1 as a key host factor for HDV replication and a potential target for new antiviral treatment. IMPACT AND IMPLICATIONS: Chronic hepatitis D is the most aggressive form of chronic viral hepatitis. As no curative treatment is currently available, new therapeutic strategies based on host-targeting agents are urgently needed. Here, using loss-of-function strategies, we uncover an unexpected interaction between JAK1, a major player in the innate antiviral response, and HDV infection. We demonstrated that JAK1 kinase activity is crucial for both the phosphorylation of the delta antigen and the replication of the virus. By demonstrating the antiviral potential of several FDA-approved JAK1 inhibitors, our results could pave the way for the development of innovative therapeutic strategies to tackle this global health threat.

Robotic Left Pancreatectomy with Perirenal Tissue Excision and Left Adrenalectomy (Posterior Ramps) for Pancreatic Ductal Adenocarcinoma Abutting the Adrenal Gland.

BACKGROUND: Radical antegrade modular pancreato-splenectomy (RAMPS) has been largely described in left-sided pancreatic cancers.1.J Hepato-Biliary-Pancreat Sci 29:1156-1165 Its prognostic advantage is not clear, although a theoretical improvement in R0 resection rate has been shown.2.J Am Coll Surg 204:244-249 Furthermore, RAMPS is usually carried out without adrenal gland removal, the so-called anterior RAMPS, while extending the resection to the adrenal plane could impair perioperative outcomes.3.HPB 25:311-319 METHODS: A 40 mm pancreatic ductal adenocarcinoma (PDAC) was found in a 70-year-old patient. Tumor infiltrates the adrenal gland and a robotic posterior RAMPS was indicated. RESULTS: After sectioning the splenic vessels and the pancreatic neck, the dissection was directed vertically in a sagittal plane along the left border of the superior mesenteric artery to identify the left renal vein. Our dissection plane was then directed on a caudo-cranial axis, after identification of the left renal artery and below the adrenal gland. The resection was also delimitated medially by the left borders of the superior mesenteric artery and the aorta, and posteriorly by the renal parenchyma. Postoperative course was marked by a biochemical leak. The patient was discharged on postoperative day (POD) 5 and the drain removed at POD 18. Pathological examination confirmed a pT2N2 PDAC with negative margins, with 4/18 positive nodes. CONCLUSIONS: The robotic platform is routinely employed in pancreatic surgery. Thanks to its increased degree of movement, its dexterity, and the magnification, this approach can help surgeons with vascular identification and control, in performing extended lymphadenectomies, and finding the correct planes of dissection. All these elements are crucial in a well-performed posterior RAMPS.

Prognostic benefit of preoperative transarterial chemoembolization in upfront resectable large hepatocellular carcinoma: a multicentric propensity score based analysis of European high-volume centers.

BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Combining Radiofrequency Ablation with Hepatic Resection for Liver-Only Colorectal Metastases: A Propensity-Score Based Analysis of Long-Term Outcomes.

BACKGROUND: Combining liver resection (LR) with radiofrequency ablation (RFA) is nowadays an accepted option for treating colorectal liver metastases (CRLMs), but the number of lesions ablated is regularly described as a recurrence risk factor. In this study, we report our experience and determine the impact of RFA on long-term outcomes. METHOD: This is a retrospective study including patients undergoing LR with or without RFA for CRLM. All variables influencing disease-free survival (DFS) and disease-specific survival (DSS) were examined through a Cox regression analysis before and after propensity-score matching (PSM). RESULTS: Among the 128 patients included, 71 (55.5%) underwent LR alone and 57 (44.5%) underwent LR+RFA. With univariate analysis, LR+RFA showed a significantly worse DFS than LR alone (p = 0.028), which was not confirmed after PSM (p = 0.064). Thermal ablation did not influence DSS before or after matching (p = 0.282 and p = 0.189). When analyzing the subgroups of patients according to number of RFAs performed, no difference in long-term outcomes was observed (after PSM: p = 0.192 for DFS and p = 0.624 for DSS). Analysis of site of recurrence revealed that neither performing an RFA (p = 0.893) nor the number of lesions ablated (p = 0.093, p = 0.550, and p = 0.087 for 1, 2, and ≥ 2 RFAs) were associated with an increased risk of liver-only relapse. DISCUSSION: In the setting of a parenchymal sparing strategy, combining RFA with LR is safe in terms of oncological outcomes. Tumor burden, rather than RFA performed, independently influences risk of recurrence and patient survival.

A Single-center Prospective Observational Study Investigating the Accuracy of Preoperative Diagnostic Procedures in the Assessment of Lymph Node Metastases in Nonfunctioning Pancreatic Neuroendocrine Tumors.

OBJECTIVE: To determine the accuracy of preoperative imaging, including contrast-enhanced computed tomography (CE-CT), endoscopic ultrasound (EUS), and 68 Gallium-DOTATOC positron emission tomography ( 68 Ga-DOTATOC PET), in identifying nodal metastases (N+) in sporadic nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). BACKGROUND: An accurate preoperative identification of N+ in NF-PanNETs is critical for surgical planning. The accuracy of different imaging techniques in detecting lymph node (LN) metastases in NF-PanNETs has been poorly investigated. METHODS: All consecutive patients undergoing surgery for sporadic NF-PanNETs (2018-2021) were enrolled in a prospective study (DETECTYON; NCT03918759). The accuracy of preoperative imaging techniques in detecting N+ was assessed through sensitivity, specificity positive and negative predictive values. RESULTS: Overall, 100 patients with NF-PanNETs underwent CE-CT, EUS, and 68 Ga-DOTATOC PET before pancreatic resection. LN metastases were found in 42 cases (42%). Sensitivity, specificity, positive predictive value, and negative predictive value of different imaging techniques were 26%, 95%, 79%, 64% for CE-CT, 19%, 98%, 89%, 63% for EUS, and 12%, 95%, 63%, 60% for 68 Ga-DOTATOC PET, respectively. Radiologic tumor size >4 cm and the presence of radiologic N+ at ≥1 imaging were independent predictors of N+ at pathology. The identification of N+ at ≥1 imaging technique was associated with a higher number of positive LNs compared with negative imaging (4 vs 2) ( P =0.012). CONCLUSIONS: CE-CT, EUS, and 68 Ga-DOTATOC PET are poorly sensitive in predicting nodal status in NF-PanNETs despite a high specificity.

Improving diagnostic accuracy and appropriate indications for surgery in pancreatic cystic neoplasms: the role of EUS.

BACKGROUND AND AIMS: Pancreatic cystic neoplasms (PCNs) represent a difficult preoperative diagnosis despite improvements in imaging. In this study, we compared preoperative and final pathologic diagnosis in a large cohort of resected PCNs, evaluating diagnostic accuracy with a specific focus on the value of EUS. METHODS: A retrospective analysis of patients undergoing resection between 2009 and 2019 for presumed PCNs was performed. Preoperative workup was reviewed by analyzing the role of imaging and EUS. Patients with a benign histology who did not show absolute indication were categorized as "delayable surgery." RESULTS: Of 585 patients who were retrospectively analyzed, in 108 (18.5%) final histology did not confirm preoperative diagnosis. EUS was associated with a lower rate of incorrect diagnosis (16%; P = .03), but the risk of overtreatment was similar regardless of instrumental diagnostic path (33/131 vs 68/328, P = .298). Dilatation of the main pancreatic duct and cytologic sampling were the only variables independently associated with a correct diagnosis (P < .001 and P = .041, respectively). Based on clinical presentation and final histology, pancreatic resection could have been spared or delayed in 101 of 459 patients (22%), and this was influenced by age (odds ratio [OR], .97; P = .002), cyst larger than 30 mm (OR, 1.89; P = .005), and type of operation (OR, 3.46 [P < .001] and 3.18 [P = .023] for distal pancreatectomies and other resections, respectively). CONCLUSIONS: The overall risk of unnecessary immediate surgery for PCNs 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.

R Status is a Relevant Prognostic Factor for Recurrence and Survival After Pancreatic Head Resection for Ductal Adenocarcinoma.

BACKGROUND: The prognostic role of resection margins in pancreatic ductal adenocarcinoma (PDAC) is debated. This study aimed to investigate the impact that global and individual resection margin status after pancreatic head resection for PDAC has on disease-free survival (DFS) and disease-specific survival (DSS). METHODS: Surgical specimens of pancreaticoduodenectomy/total pancreatectomy performed for PDAC were examined with a standardized protocol. Surgical margin status (biliary, pancreatic neck, duodenal, anterior and posterior pancreatic, superior mesenteric vein groove and superior mesenteric artery margins) was classified as the presence of malignant cells (1) directly at the inked surface (R1 direct), (2) within less than 1 mm (R1 ≤ 1 mm), or (3) with a distance greater than 1 mm (R0). Patients with a positive neck margin at the final histology were excluded from the study. RESULTS: Of the 362 patients included in the study, 179 patients (49.4 %) had an R0 resection, 123 patients (34 %) had an R1 ≤ 1 mm resection, and 60 patients (16.6 %) had an R1 direct resection. The independent predictors of DFS were R1 direct resection (hazard ratio [HR], 1.49), R1 ≤ 1 mm resection (HR, 1.38), involvement of one margin (HR, 1.36), and involvement of two margins or more (HR, 1.55). When surgical margins were analyzed separately, only R1 ≤ 1 mm superior mesenteric vein margin (HR, 1.58) and R1 direct posterior margin (HR, 1.69) were independently associated with DFS. CONCLUSIONS: Positive R status is an independent predictor of DFS (R1 direct and R1 ≤ 1 mm definitions) and of DSS (R1 direct). The presence of multiple positive margins is a risk factor for cancer recurrence and poor survival. Different surgical margins could have different prognostic roles.

The Oncologic Impact of Pancreatic Fistula After Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma of the Body and the Tail: A Multicenter Retrospective Cohort Analysis.

OBJECTIVES: The aim of this study was to assess the impact of clinically relevant postoperative pancreatic fistula (CR-POPF) on patient disease-specific survival and recurrence after curative distal pancreatectomy (DP) for pancreatic cancer. DESIGN: This was a retrospective case-control analysis. METHODS: We examined the data of adult patients with a diagnosis of pancreatic ductal adenocarcinoma (PDAC) of the body and tail of the pancreas undergoing curative DP, over a 10-year period in 12 European surgical departments, from a prospectively implemented database. RESULTS: Among the 382 included patients, 283 met the strict inclusion criteria; 139 were males (49.1%) and the median age of the entire population was 70 years (range 37-88). A total of 121 POPFs were observed (42.8%), 42 (14.9%) of which were CR-POPFs. The median follow-up period was 24 months (range 3-120). Although poorer in the POPF group, overall survival (OS) and disease-free survival (DFS) did not differ significantly between patients with and without CR-POPF (p = 0.224 and p = 0.165, respectively). CR-POPF was not significantly associated with local or peritoneal recurrence (p = 0.559 and p = 0.302, respectively). A smaller percentage of patients benefited from adjuvant chemotherapy after POPF (76.2% vs. 83.8%), but the difference was not significant (p = 0.228). CONCLUSIONS: CR-POPF is a major complication after DP but it did not affect the postoperative therapeutic path or long-term oncologic outcomes. CR-POPF was not a predictive factor for disease recurrence and was not associated with an increased incidence of peritoneal or local relapse. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04348084.

Is the Real Prevalence of Pancreatic Neuroendocrine Tumors Underestimated? A Retrospective Study on a Large Series of Pancreatic Specimens.

BACKGROUND/AIMS: The annual incidence of pancreatic neuroendocrine tumors (PanNET) has been estimated to be around 0.8/100,000 inhabitants. The aim of this study was to determine the frequency of incidental histological diagnosis of PanNET in pancreatic specimen evaluation for a purpose other other than PanNET diagnosis. METHODS: One thousand seventy-four histopathological examinations of pancreatic specimens performed in 3 centers in Italy were retrospectively reviewed. All cases with a main pathological diagnosis of PanNET were excluded. RESULTS: An incidental associated diagnosis of PanNET was made in 41 specimens (4%). Among those 41 cases, 29 (71%) had a largest diameter <5 mm (microadenoma), whereas the other 12 (29%) had a maximum size ≥5 mm (median diameter of the whole series = 3 mm, range 1-15). The association with a main diagnosis of intraductal papillary mucinous neoplasms (IPMN) was significantly higher for patients who had an incidental PanNET (p = 0.048). There was no association between incidental diagnosis of PanNET and age, gender, BMI, smoking habit, diabetes, and type of operation. CONCLUSIONS: The frequency of incidental histological diagnosis of PanNET is considerably high, suggesting that their real prevalence is probably underestimated. The present study suggests a possible correlation between the incidental occurrence of PanNET and IPMN.

Renal Resistance Trend During Hypothermic Machine Perfusion Is More Predictive of Postoperative Outcome Than Biopsy Score: Preliminary Experience in 35 Consecutive Kidney Transplantations.

Hypothermic machine perfusion (HPM) grants a better postoperative outcome in transplantation of organs procured from extended criteria donors (ECDs) and donors after cardiac death (DCD). So far, the only available parameter for outcome prediction concerning those organs is pretransplant biopsy score. The aim of this study is to evaluate whether renal resistance (RR) trend during HPM may be used as a predictive marker for post-transplantation outcome. From December 2015 to present, HMP has been systematically applied to all organs from ECDs and DCD. All grafts underwent pretransplantation biopsy evaluation using Karpinski's histological score. Only organs that reached RR value ≤1.0 within 3 hours of perfusion were transplanted. Single kidney transplantation (SKT) or double kidney transplantation (DKT) were performed according to biopsy score results. Sixty-five HMPs were performed (58 from ECDs and 7 from DCD/ECMO donors). Fifteen kidneys were insufficiently reconditioned (RR > 1) and were therefore discarded. Forty-nine kidneys were transplanted, divided between 21 SKT and 14 DKT. Overall primary nonfunction (PNF) and delayed graft function (DGF) rate were 2.9 and 17.1%, respectively. DGF were more common in kidneys from DCD (67 vs. 7%; P = 0.004). Biopsy score did not correlate with PNF/DGF rate (P = 0.870) and postoperative creatinine trend (P = 0.796). Recipients of kidneys that reached RR ≤ 1.0 within 1 hour of HMP had a lower PNF/DGF rate (11 vs. 44%; P = 0.033) and faster serum creatinine decrease (POD10 creatinine: 1.79 mg/dL vs. 4.33 mg/dL; P = 0.019). RR trend is more predictive of post-transplantation outcome than biopsy score. Hence, RR trend should be taken into account in the pretransplantation evaluation of the organs.

Spontaneous idiopathic liver hemorrhage: a systematic review of a rare entity.

BACKGROUND: Spontaneous idiopathic liver hemorrhage (SILH) is a rare life-threatening condition occurring without a clear and specific etiology. A systematic review was performed to provide guidelines for the perioperative management of patients affected by SILH. A case report was also included. METHODS: A systematic search of the last 24-year literature was conducted and the manuscript was structured following point-by-point the PRISMA guidelines. RESULTS: After an initial selection of 6995 titles, 15 articles were considered for the final qualitative analysis (n = 22 patients, including the present report). Conservative treatment was chosen in 12 cases (54.5%) with stable clinical conditions, while 9 patients (40.9%) required a primary operative approach for emergency presentation at diagnosis. Direct liver resection was the preferred surgical treatment (n = 6), mostly major hepatectomies (n = 4). Hepatic arterial embolization was performed as the primary operative approach in three patients, followed by emergency laparotomy during the same hospitalization because of rebleeding in one case. Contrast-enhanced CT scan was the gold standard for diagnosis (n = 19). CONCLUSIONS: Conservative treatment of SILH is mainly based on stable clinical conditions and may be considered even in case of a limited arterial blush found on imaging. The absence of underlying hepatic or systemic disorders seems to correlate with favorable outcomes and no mortality.

Inflammation-related prognostic markers in resected hepatocellular carcinoma.

Hepatocellular carcinoma is usually detected late and therapeutic options are unsatisfactory. Despite marked progress in patient care, HCC remains among the deadliest cancers world-wide. While surgical resection remains a key option for early-stage HCC, the 5-year survival rates after surgical resection are limited. One reason for limited outcomes is the lack of reliable prognostic biomarkers to predict HCC recurrence. HCC prognosis has been shown to correlate with different systemic and pathological markers which are associated with patient survival and HCC recurrence. Liver inflammatory processes offer a large variety of systemic and pathological markers which may be exploited to improve the reliability of prognosis and decision making of liver surgeons and hepatologists. The following review aims to dissect the potential tools, targets and prognostic meaning of inflammatory markers in patients with resectable HCC. We analyze changes in circulant cellular populations and assess inflammatory biomarkers as a surrogate of impaired outcomes and provide an overview on predictive gene expression signatures including inflammatory transcriptional patterns, which are representative of poor survival in these patients.

Surgical Models of Liver Regeneration in Pigs: A Practical Review of the Literature for Researchers.

The remarkable capacity of regeneration of the liver is well known, although the involved mechanisms are far from being understood. Furthermore, limits concerning the residual functional mass of the liver remain critical in both fields of hepatic resection and transplantation. The aim of the present study was to review the surgical experiments regarding liver regeneration in pigs to promote experimental methodological standardization. The Pubmed, Medline, Scopus, and Cochrane Library databases were searched. Studies evaluating liver regeneration through surgical experiments performed on pigs were included. A total of 139 titles were screened, and 41 articles were included in the study, with 689 pigs in total. A total of 29 studies (71% of all) had a survival design, with an average study duration of 13 days. Overall, 36 studies (88%) considered partial hepatectomy, of which four were an associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Remnant liver volume ranged from 10% to 60%. Only 2 studies considered a hepatotoxic pre-treatment, while 25 studies evaluated additional liver procedures, such as stem cell application, ischemia/reperfusion injury, portal vein modulation, liver scaffold application, bio-artificial, and pharmacological liver treatment. Only nine authors analysed how cytokines and growth factors changed in response to liver resection. The most used imaging system to evaluate liver volume was CT-scan volumetry, even if performed only by nine authors. The pig represents one of the best animal models for the study of liver regeneration. However, it remains a mostly unexplored field due to the lack of experiments reproducing the chronic pathological aspects of the liver and the heterogeneity of existing studies.