Deciphering the phospho-signature induced by hepatitis B virus in primary human hepatocytes.

Phosphorylation is a major post-translation modification (PTM) of proteins which is finely tuned by the activity of several hundred kinases and phosphatases. It controls most if not all cellular pathways including anti-viral responses. Accordingly, viruses often induce important changes in the phosphorylation of host factors that can either promote or counteract viral replication. Among more than 500 kinases constituting the human kinome only few have been described as important for the hepatitis B virus (HBV) infectious cycle, and most of them intervene during early or late infectious steps by phosphorylating the viral Core (HBc) protein. In addition, little is known on the consequences of HBV infection on the activity of cellular kinases. The objective of this study was to investigate the global impact of HBV infection on the cellular phosphorylation landscape early after infection. For this, primary human hepatocytes (PHHs) were challenged or not with HBV, and a mass spectrometry (MS)-based quantitative phosphoproteomic analysis was conducted 2- and 7-days post-infection. The results indicated that while, as expected, HBV infection only minimally modified the cell proteome, significant changes were observed in the phosphorylation state of several host proteins at both time points. Gene enrichment and ontology analyses of up- and down-phosphorylated proteins revealed common and distinct signatures induced by infection. In particular, HBV infection resulted in up-phosphorylation of proteins involved in DNA damage signaling and repair, RNA metabolism, in particular splicing, and cytoplasmic cell-signaling. Down-phosphorylated proteins were mostly involved in cell signaling and communication. Validation studies carried out on selected up-phosphorylated proteins, revealed that HBV infection induced a DNA damage response characterized by the appearance of 53BP1 foci, the inactivation of which by siRNA increased cccDNA levels. In addition, among up-phosphorylated RNA binding proteins (RBPs), SRRM2, a major scaffold of nuclear speckles behaved as an antiviral factor. In accordance with these findings, kinase prediction analysis indicated that HBV infection upregulates the activity of major kinases involved in DNA repair. These results strongly suggest that HBV infection triggers an intrinsic anti-viral response involving DNA repair factors and RBPs that contribute to reduce HBV replication in cell culture models.

Dissection of the Celiac Trunk Is a Mild Disease.

BACKGROUND: The purpose of this study was to assess whether the presence of an aneurysmal or dissecting arterial disease was a risk factor of poor prognosis in patients presenting a dissection of the celiac trunk (CT). METHODS: All patients presenting a CT dissection between January 1, 2014, and June 30, 2022, were included. Patients with a CT dissection due to the extension of an aortic dissection were excluded. Les antécédents familiaux de dissection, de maladie anévrysmale, de maladie athéromateuse ou du tissu conjonctif, la pratique d'une activité physique ou sportive, un effort inhabituel les jours précédant la dissection ainsi qu'un traumatisme étaient recherchés. Family history of dissection, aneurysmal disease, atheromatous or connective tissue disease, physical activity or sport, an unusual effort in the days prior to the dissection and trauma were sought after. Ischemic or aneurysmal complications in the acute phase and the evolution of the dissection were evaluated and compared between patients with an isolated dissection and those presenting an aneurysmal or dissecting arterial disease. RESULTS: 45 patients were included in the study. Twenty-three (51.1%) patients presented with symptomatic CT dissection, and 22 (48.9%) with asymptomatic CT dissection. All the patients initially had medical management alone. The mean follow-up was 32 ± 25 months and all patients were asymptomatic at the time last news. 24 (53.3%) presented an isolated CT dissection, and 21 (46.7%) a CT dissection associated with aneurysmal or dissecting arterial disease. There was no significant difference between patients with an isolated CT dissection and those with an associated dissecting or aneurysmal pathology. CONCLUSIONS: CT dissection is a stable disease in the midterm, which makes it a mild arterial pathology, with or without aneurysmal or dissecting anomalies in another territory. The mechanical stress exerted on the CT by the arcuate ligament could be responsible for parietal trauma and favor the occurrence of a CT dissection.

Metastatic Colorectal Cancer Treated with Combined Liver Resection, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Predictive Factors for Early Recurrence.

BACKGROUND: Selection of colorectal cancer patients with concomitant peritoneal (PM) and liver metastases (LM) for radical treatment with cytoreductive surgery (CRS), including liver resection and hyperthermic intraperitoneal chemotherapy (HIPEC), needs improvement. This retrospective, monocentric study was designed to evaluate the predictive factors for early recurrence, disease-free survival (DFS), and overall survival (OS) in such patients treated in a referral center. METHODS: Consecutive colorectal cancer patients with concomitant LM and PM treated with curative intent with perioperative systemic chemotherapy, simultaneous complete CRS, liver resection, and HIPEC in 2011-2022 were included. Clinical, radiological (before and after preoperative chemotherapy), surgical, and pathological data were investigated, along with long-term oncologic outcomes. A multivariate analysis was performed to identify predictive factors associated with early recurrence (diagnosed <6 months after surgery), DFS, and OS. RESULTS: Of more than 61 patients included, 31 (47.1%) had pT4 and 27 (40.9%) had pN2 primary tumors. Before preoperative chemotherapy, the median number of LM was 2 (1-4). The median surgical PCI (peritoneal carcinomatosis index) was 3 (5-8.5). The median DFS and OS were 8.15 (95% confidence interval [CI] 5.5-10.1) and 34.1 months (95% CI 28.1-53.5), respectively. In multivariate analysis, pT4 (odds ratio [OR] = 4.14 [1.2-16.78], p = 0.032]) and pN2 (OR = 3.7 [1.08-13.86], p = 0.042) status were independently associated with an early recurrence, whereas retroperitoneal lymph node metastasis (hazard ratio [HR] = 39 [8.67-175.44], p < 0.001) was independently associated with poor OS. CONCLUSIONS: In colorectal cancer patients with concomitant PM and LM, an advanced primary tumor (pT4 and/or pN2) was associated with a higher risk of early recurrence following a radical multimodal treatment, whereas RLN metastases was strongly detrimental for OS.

Robotic surgery for inguinal and ventral hernia repair: a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis assessed the effectiveness of robotic surgery compared to laparoscopy or open surgery for inguinal (IHR) and ventral (VHR) hernia repair. METHODS: PubMed and EMBASE were searched up to July 2022. Meta-analyses were performed for postoperative complications, surgical site infections (SSI), seroma/hematoma, hernia recurrence, operating time (OT), intraoperative blood loss, intraoperative bowel injury, conversion to open surgery, length of stay (LOS), mortality, reoperation rate, readmission rate, use of opioids, time to return to work and time to return to normal activities. RESULTS: Overall, 64 studies were selected and 58 were used for pooled data analyses: 35 studies (227 242 patients) deal with IHR and 32 (158 384 patients) with VHR. Robotic IHR was associated with lower hernia recurrence (OR 0.54; 95%CI 0.29, 0.99; I2: 0%) compared to laparoscopic IHR, and lower use of opioids compared to open IHR (OR 0.46; 95%CI 0.25, 0.84; I2: 55.8%). Robotic VHR was associated with lower bowel injuries (OR 0.59; 95%CI 0.42, 0.85; I2: 0%) and less conversions to open surgery (OR 0.51; 95%CI 0.43, 0.60; I2: 0%) compared to laparoscopy. Compared to open surgery, robotic VHR was associated with lower postoperative complications (OR 0.61; 95%CI 0.39, 0.96; I2: 68%), less SSI (OR 0.47; 95%CI 0.31, 0.72; I2: 0%), less intraoperative blood loss (- 95 mL), shorter LOS (- 3.4 day), and less hospital readmissions (OR 0.66; 95%CI 0.44, 0.99; I2: 24.7%). However, both robotic IHR and VHR were associated with significantly longer OT compared to laparoscopy and open surgery. CONCLUSION: These results support robotic surgery as a safe, effective, and viable alternative for IHR and VHR as it can brings several intraoperative and postoperative advantages over laparoscopy and open surgery.

Negative-Pressure Wound Therapy for Open Abdomen in Surgical Reintervention after Curative Surgery of Peritoneal Malignancy Increases the Risk of Recurrence.

OBJECTIVE: Negative-pressure wound therapy for open abdomen (NPWTOA) helps reduce the risk of abdominal compartment syndrome. However, the risk of recurrence of cancer is unclear when NPWTOA is applied after oncologic resection. The aim of this study was to evaluate the effects of NPWTOA used for major complications on patients treated with cytoreductive surgery for peritoneal malignancy (PM). METHODS: All patients who underwent an NPWTOA after potentially curative surgery of PM in a single institution were included. These patients were pair matched 1:3 on the Peritoneal Cancer Index, completeness of cytoreduction using a scoring index, and PM origin with patients who underwent surgical reintervention without NPWTOA after curative surgery of PM. Survival among the two groups was compared using the Kaplan-Meier method. RESULTS: Between 2011 and 2017, among 719 curative surgeries for PM, 13 patients underwent an NPWTOA after surgical reintervention. Researchers paired 9 of these patients to 27 others without NPWTOA after surgical reintervention. Median overall survival was 4.8 and 35 months (P = .391), and median disease-free survival was 4.0 and 13.9 months (P = .022) for the NPWTOA and non-NPWTOA groups, respectively. CONCLUSIONS: The use of the NPWTOA during surgical reintervention after curative surgery for PM may increase the risk of early recurrence.

Surgical management of parastomal hernia following radical cystectomy and ileal conduit: A french multi-institutional experience.

BACKGROUND: Parastomal incisional hernia (PH) is a frequent complication following the creation of an ileal conduit (IC), and it can be a significant detriment to quality of life. The aim of this study was to evaluate outcomes of PH repair following IC for urinary diversion. METHOD: A multicenter retrospective study was conducted of 6 academic hospitals in France. The study's population included patients who underwent surgical treatment for parastomal hernia following IC creation from 2013 to 2021. RESULTS: Fifty-one patients were included in the study. Median follow up was 15.3 months. Eighteen patients presented with a recurrence (35%), with a median time to recurrence of 11.1 months. The vast majority of PH repair was performed through an open approach (88%). With regard to technique, Keyhole was the most reported technique (46%) followed by Sugarbaker (22%) and suture only (20%). The Keyhole technique was associated with a higher risk of recurrence compared to the Sugarbaker technique (52% vs 10%, p = 0.046). Overall, there was a 7.8% rate of major complications without a statistical difference between PH repair techniques for major complications. CONCLUSION: Surgical treatment of parastomal hernia following IC was associated with a high risk of recurrence. Novel surgical approaches to PH repair should be considered.

Complete pathological response after chemotherapy or immune checkpoint inhibitors in deficient MMR metastatic colorectal cancer: Results of a retrospective multicenter study.

About 5% of the patients with metastatic colorectal cancers (mCRC) present microsatellite instability (MSI)/deficient mismatch repair system (dMMR). While metastasectomy is known to improve overall and progression-free survival in mCRC, specific results in selected patients with dMMR/MSI mCRC are lacking. Our study aimed to describe metastasectomy results, characterize histological response and evaluate pathological complete response (pCR) rate in patients with dMMR/MSI mCRC. We retrospectively reviewed data from all consecutive patients with dMMR/MSI mCRC who underwent surgical metastasectomy between January 2010 and June 2021 in 17 French centers. Primary outcome was to assess the pCR rate defined by tumor regression grade (TRG) 0. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), and explored TRG as predictive factor for RFS and OS. Among the 88 patients operated, 109 metastasectomies were performed in 81 patients after neoadjuvant treatment [chemotherapy ± targeted therapy (CTT): 69, 85.2%; immunotherapy (ICI): 12, 14.8%], and pCR was achieved in 13 (16.1%) patients. Among the latter, pCR rate were 10.2% in the patients having received CTT (N = 7) and 50.0% in the patients treated with ICI (N = 6). Radiological response did not predict TRG. With a median follow-up of 57.9 (IQR 34.2-81.6) months, median RFS was 20.2 (15.4-not reached) months, median OS was not reached. Major pathological responses (TRG0 + TRG1) were significantly associated with longer RFS (HR 0.12, 95% CI 0.03-0.55; P = .006). The pCR rate of 16.1% achieved with neoadjuvant treatment in patients with dMMR/MSI mCRC is consistent with previously reported rates in pMMR/MSS mCRC. Immunotherapy showed better pCR rate than chemotherapy ± targeted therapy. Further prospective trials are needed to validate immunotherapy as neoadjuvant treatment in resectable/potentially resectable dMMR/MSI mCRC and identify predictive factors for pCR.

Influence of Extraperitoneal Metastases on the Curative-Intent Management of Colorectal Peritoneal Metastases.

BACKGROUND: Selected patients with colorectal cancer peritoneal metastasis (CRPM) and extraperitoneal disease could be treated radically with a multimodal approach combining complete cytoreductive surgery, thermoablation, radiotherapy, and systemic and intraperitoneal chemotherapy. The impact of extraperitoneal metastatic sites (EPMS) in this setting remains unclear. PATIENTS AND METHODS: Patients with CRPM undergoing complete cytoreduction in 2005-2018 were grouped in: peritoneal disease only (PDO), one EPMS (1 + EPMS), two or more EPMS (2 + EPMS). A retrospective analysis compared overall survival (OS) and postoperative outcomes. RESULTS: Of 433 patients, 109 had 1 + EPMS and 31 had 2 + EPMS. Overall, 101 patients had liver metastasis, 19 lung metastasis, and 30 retroperitoneal lymph node (RLN) invasion. The median OS was 56.9 months. There was no significant OS difference between PDO and 1 + EPMS groups (64.6 and 57.9 months, respectively), whereas OS was lower in the 2 + EPMS group (29.4 months, p = 0.005). In multivariate analysis, 2 + EPMS [hazard ratio (HR) 2.86, 95% confidence interval (CI) 1.33-6.12, p = 0.007], Sugarbaker's Peritoneal Carcinomatosis Index (PCI) > 15 (HR 3.86, 95% CI 2.04-7.32, p < 0.001), poorly differentiated tumors (HR 2.62, 95% CI 1.21-5.66, p = 0.015), and BRAF mutation (HR 2.10, 95% CI 1.11-3.99, p = 0.024) were independent poor prognostic factors, while adjuvant chemotherapy was beneficial (HR 0.33, 95% CI 0.20-0.56, p < 0.001). Patients with liver resection did not show higher severe complication rates. CONCLUSION: In patients with CRPM selected for a radical surgical approach, limited extraperitoneal disease involving one site, notably the liver, does not seem to significantly impair postoperative results. RLN invasion appeared as a poor prognostic factor in this population.

Comparison of Neoadjuvant Systemic Chemotherapy Protocols for the Curative-Intent Management of Peritoneal Metastases from Colorectal Cancer, Regarding Morphological Response, Pathological Response, and Long-Term Outcomes: A Retrospective Study.

BACKGROUND: Selected patients with colorectal cancer peritoneal metastases (CRPM) could be offered a curative-intent strategy based on complete cytoreductive surgery (CRS), potentially combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and perioperative systemic chemotherapy. The impact of different neoadjuvant systemic chemotherapy (NACT) regimens remains unclear due to a lack of comparative data. METHODS: Consecutive CRPM patients from a monocentric database who were treated with complete CRS after single-line NACT were included in this study. Chemotherapy regimens were tailored as a doublet drug (FOLFOX/FOLFIRI) with/without targeted therapy (anti-epidermal growth factor receptor/bevacizumab) and triplet-drug combination (FOLFIRINOX). Morphological response (MR) was assessed using the Response Evaluation Criteria in Solid Tumors criteria, and pathological response (PR) was assessed using the Peritoneal Regression Grading Score (PRGS). Long-term oncologic outcomes were compared. RESULTS: The cohort comprised 388 patients, including 127, 202, and 59 patients in the doublet, doublet + targeted, and triplet groups, respectively. MR rates were higher in the triplet (68.0%) and doublet + targeted groups (64.2%) when compared with the doublet group (42.4%, p = 0.003). Complete and major PRs were observed in 13.6% and 32.0% of patients, respectively. Higher MR rates were observed after doublet + targeted or triplet regimens, while no difference was observed for PR rates. In multivariate analysis, FOLFIRINOX was independently associated with better overall survival (hazard ratio 0.49, 95% confidence interval 0.25-0.96; p = 0.037). FOLFIRINOX also resulted in a higher rate of severe postoperative complications. CONCLUSIONS: In this retrospective study, a FOLFIRINOX regimen as NACT seemed to result in better long-term outcomes for CRPM patients after complete CRS/HIPEC, although with higher morbidity. Prospective studies are needed, including groups without NACT and those with FOLFIRINOX + bevacizumab.

Hepatitis D virus interferes with hepatitis B virus RNA production via interferon-dependent and -independent mechanisms.

BACKGROUND & AIMS: Chronic coinfection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. Herein, we aimed to elucidate the molecular mechanisms underlying the widely reported observation that HDV interferes with HBV in most coinfected patients. METHODS: Patient liver tissues, primary human hepatocytes, HepaRG cells and human liver chimeric mice were used to analyze the effect of HDV on HBV using virological and RNA-sequencing analyses, as well as RNA synthesis, stability and association assays. RESULTS: Transcriptomic analyses in cell culture and mouse models of coinfection enabled us to define an HDV-induced signature, mainly composed of interferon (IFN)-stimulated genes (ISGs). We also provide evidence that ISGs are upregulated in chronically HDV/HBV-coinfected patients but not in cells that only express HDV antigen (HDAg). Inhibition of the hepatocyte IFN response partially rescued the levels of HBV parameters. We observed less HBV RNA synthesis upon HDV infection or HDV protein expression. Additionally, HDV infection or expression of HDAg alone specifically accelerated the decay of HBV RNA, and HDAg was associated with HBV RNAs. On the contrary, HDAg expression did not affect other viruses such as HCV or SARS-CoV-2. CONCLUSIONS: Our data indicate that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms. Specifically, we uncover a new viral interference mechanism in which proteins of a satellite virus affect the RNA production of its helper virus. Exploiting these findings could pave the way to the development of new therapeutic strategies against HBV. IMPACT AND IMPLICATIONS: Although the molecular mechanisms remained unexplored, it has long been known that despite its dependency, HDV decreases HBV viremia in patients. Herein, using in vitro and in vivo models, we showed that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms affecting HBV RNA metabolism, and we defined the HDV-induced modulation signature. The mechanisms we uncovered could pave the way for the development of new therapeutic strategies against HBV by mimicking and/or increasing the effect of HDAg on HBV RNA. Additionally, the HDV-induced modulation signature could potentially be correlated with responsiveness to IFN-α treatment, thereby helping to guide management of HBV/HDV-coinfected patients.

The Angers CT Score is a Risk Factor for the Failure of the Conservative Management of Adhesive Small Bowel Obstruction: A Prospective Observational Multicentric Study.

BACKGROUND: Identifying the 30% of adhesive small bowel obstructions (aSBO) for which conservative management will require surgery is essential. The association between the previously described radiological score and failure of the conservative management of aSBO remains to be confirmed in a large prospective multicentric cohort. Our aim was to assess the risk factors of failure of the conservative management of aSBO considering the radiological score. MATERIAL AND METHODS: This prospective observational study took place in 15 French centers over 3 months. Consecutive patients experiencing aSBO with no early surgery were included. The six radiological features from the Angers radiological computed tomography (CT) score were noted (beak sign, closed loop, focal or diffuse intraperitoneal liquid, focal or diffuse mesenteric haziness, focal or diffuse mesenteric liquid, and diameter of the most dilated small bowel loop > 40 mm). RESULTS: Two hundred and seventy nine patients with aSBO were screened. Sixty patients (21.5%) underwent early surgery, and 219 (78.5%) had primary conservative management. In the end, 218 patients were included in the analysis of the risk factors for conservative treatment failure. Among them, 162 (74.3%) had had successful management while for 56 (25.7%) management had failed. In multivariate analysis, a history of surgery was not a significant risk factor for the failure of conservative treatment (OR = 0.11; 95%CI = 0-1.23). A previous episode of aSBO was protective against the failure of conservative treatment (OR = 0.36; 95%CI = 0.15-0.85) and an Angers CT score ≥ 5 as the only individual risk factor (OR = 2.39; 95%CI = 1.01-5.69). CONCLUSION: The radiological score of aSBO is a promising tool in improving the management of aSBO patients. A first episode of aSBO and/or a radiological score ≥5 should lead physicians to consider early surgical management.