Volumetric Remodeling of the Left Liver After Right Hepatectomy: Analysis of Factors Predicting Degree of Hypertrophy and Post-hepatectomy Liver Failure.

BACKGROUND: This study investigated the volumetric remodeling of the left liver after right hepatectomy looking for factors predicting the degree of hypertrophy and severe post-hepatectomy liver failure (PHLF). METHODS: In a cohort of 121 right hepatectomies, we performed CT volumetrics study of the future left liver remnant (FLR) preoperatively and postoperatively. Factors influencing FLR degree of hypertrophy and severe PHLF were identified by multivariate analysis. RESULTS: After right hepatectomy, the mean degree of hypertrophy and kinetic growth rate of the left liver remnant were 25% and 3%/day respectively. The mean liver volume recovery rate was 77%. Liver remodeling volume was distributed for 79% on segments 2 and 3 and 21% on the segment 4 (p<0.001). Women showed a greater hypertrophy of segments 2 and 3 compared with men (p=0.002). The degree of hypertrophy of segment 4 was lower in case of middle hepatic vein resection (p=0.004). Left liver remnant kinetic growth rate was associated with the standardized future liver remnant (sFLR) (p<0.001) and a two-stage hepatectomy (p=0.023). Severe PHLF were predicted by intraoperative transfusion (p=0.009), biliary tumors (p=0.013), and male gender (p=0.022). CONCLUSIONS: Volumetric remodeling of the left liver after right hepatectomy is not uniform and is mainly influenced by gender and sacrifice of middle hepatic vein. Male gender, intraoperative transfusion, and biliary tumors increase the risk of postoperative liver failure after right hepatectomy.

Additional value of interleukin-6 level to predict histopathological features of hepatocellular carcinoma before liver transplantation.

BACKGROUND & AIMS: Inflammatory biomarkers are increasingly used as outcome predictors in the field of oncology and liver transplantation for HCC, but no study has shown the prognostic value of IL6 after LT. The goal of this study was to evaluate the predictive value of IL-6 on histopathological features of HCC on explant, its predictive value on recurrence risk and its additional value to other scores and inflammatory markers at the time of transplantation. METHODS: From 2009 to 2019, all adults transplanted with a first liver graft and diagnosed with HCC on the explant analysis were retrospectively included (n = 229). Only patients who had a pre-LT IL6 level determination were analysed in this study (n = 204). RESULTS: High IL-6 level at transplantation was associated with a significantly higher risk of vascular invasion (15% vs 6%; p = 0.023), microsatellitosis (11% vs 3%; p = 0.013), lower rate of histological response both in terms of complete response (2% vs 14%, p = 0.004) and of necrosis (p = 0.010). Patients with pre-LT IL-6 level > 15 ng/ml had a lower overall and cancer-specific survival (p = 0.013). Recurrence-free survival was lower in patients with IL-6 > 15 ng/ml with a 3-year recurrence-free survival of 88% versus 78% (p = 0.034). IL6 levels were significantly higher in patients with early recurrence compared to patients without (p = 0.002) or with late recurrence (p = 0.044). CONCLUSIONS: IL6 level at transplantation is an independent predictor of pejorative histological features of HCC and is associated to the risk of recurrence.

Predicting Limited Survival After Resection of Synchronous Colorectal Liver Metastases: a Propensity Score Matched Comparison Between The Primary First And The Simultaneous Strategy.

BACKGROUND: The best surgical approach to treat synchronous colorectal liver metastases (CRLM) remains unclear. Here, we aimed to identify prognostic factors associated with limited survival comparing patients undergoing primary-first resection (PF) and simultaneous resection (SR) approaches. METHODS: We retrospectively reviewed clinical data of 217 patients who underwent resection for synchronous CRLMs between January 1, 2011, and December 31, 2021. There were 133 (61.2%) PF resection and 84 (38.8%) SRS. The two groups of patients were compared using propensity score matching (PSM) analysis and cox analysis was performed to identify prognostic factors for overall survival (OS). RESULTS: After PSM, two groups of 71 patients were compared. Patients undergoing SR had longer operative time (324 ± 104 min vs 250 ± 101 min; p < 0.0001), similar transfusion (33.3% vs 28.1%; p = 0.57), and similar complication rates (35.9% vs 27.2%; p = 0.34) than patients undergoing PF. The median overall survival and 5-year survival rates were comparable (p = 0.94) between patients undergoing PF (48.2 months and 44%) and patients undergoing SR (45.9 months and 30%). Multivariate Cox analysis identified pre-resection elevated CEA levels (HR: 2.38; 95% CI: 1.20-4.70; P = .01), left colonic tumors (HR: 0.34; 95% CI: 0.17-0.68; P = .002), and adjuvant treatment (HR: 0.43; 95% CI: 0.22-0.83; P = .01) as independent prognostic factors for OS. CONCLUSIONS: In the presence of synchronous CRLM, right colonic tumors, persistent high CEA levels before surgery, and the absence of adjuvant treatment identified patients characterized by a limited survival rate after resection. The approach used (PF vs SR) does not influence short and long-term outcomes.

Pancreatectomy After Neoadjuvant FOLFIRINOX Chemotherapy: Identifying Factors Predicting Long-Term Survival.

INTRODUCTION: We aimed to evaluate the long-term outcomes of the association of neoadjuvant chemotherapy with pancreatectomy with vascular resection in patients with locally advanced pancreatic cancer. METHODS: Clinical data from patients who underwent pancreatic resection after neoadjuvant FOLFIRINOX were retrospectively reviewed. Cox analyses were used to identify factors prognostic of overall survival (OS). RESULTS: FOLFIRINOX protocol was administered pre-operatively with a median number of nine cycles (range 2-18) in 98 patients. Types of resections included pancreaticoduodenectomy (n = 53), total pancreatectomy (n = 17), and distal spleno-pancreatectomy (n = 28). Venous resection and arterial resections were performed in 85 (86.7%) and 64 patients (65.3%), respectively. The overall 90-day mortality and morbidity rates were 6.1% (n = 6) and 47% (n = 47), respectively. The median OS was 31.08 months after surgery. OS rates at one, three, five, and 10 years were 82%, 47%, 28%, and 21%, respectively. According to the type of vascular resection, median OS and 5-year survival rates were exclusive venous resection (31.08 months; 23%) and arterial resections (24.7 months; 27%). Multivariate Cox analysis found lymph node involvement, venous invasion, and total pancreatectomy as independent prognostic factors for OS. According to the presence of 0 or 1-3 risk factors, 5-year survival (85% vs 16%) and median overall survival rates (not reached versus 24.7 months, respectively) were statistically significantly different (p < 0.0001). CONCLUSIONS: A multimodal treatment, including neoadjuvant FOLFIRINOX combined with pancreatectomy with venous and arterial resection, achieves long term survival rates in patients with locally advanced disease. Surgery, in experienced centers, should be integrated into the treatment of patients with locally advanced pancreatic adenocarcinomas.

Management of spontaneous portosystemic shunts at the time of liver transplantation: treatment or observation? Results of a systematic review.

BACKGROUND: Optimal treatment of spontaneous portosystemic shunts (SPSS) during liver transplantation (LT) remains debated. We systematically reviewed the literature on definitions, treatment and outcomes of patients presenting SPSS undergoing LT. METHODS: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we used PubMed to retrieve all studies dealing with SPSS and LT between January 1987 and January 2020. The primary endpoints were definitions and outcomes according to the management of SPSS (treatment vs observation). RESULTS: Thirteen studies detailing the management of 962 SPSS were retrieved. Hemodynamically significant SPSS were defined as those having diameter ≥ 10 mm in 41% (n = 395) of patients. SPSS were splenorenal (42%), cavo-gastric (15.2%), umbilical (7.4%), mesenterico-caval (n = 31; 3.2%), mesenterico-renal (0.1%) and unreported (31.9%), respectively. At the time of LT 372 shunts (38.7%) were treated while 590 were observed (61.3%). During a follow-up time ranging from 4 months to 5 years, the reported overall survival (OS) at 1 year was not significantly different except for one study. Portal vein anastomosis complications (i.e. reduced flow, stenosis or thrombosis) were similarly reported in observed [n = 26 (4%)] and ligated SPSS [n = 10 (2%)] (p = 0.22) but the rate of relaparotomy was significantly higher in observed SPPS (16 vs 2; p = 0.01) to rescue post LT portal vein thrombosis (n = 6) and reduced portal flow and graft dysfunction (n = 10). CONCLUSIONS: There was a heterogeneous management of SPSS during LT in the literature. Ligation of SPPS did not reduce vascular complications neither improved survival. A randomized prospective study might contribute to identify best management of SPSS at time of LT.

Augmentation Patch V-venoplasty to Correct Atretic Changes of the Portal Vein During Adult Liver Transplantation.

The development of large spontaneous portosystemic shunts (PSS) is a common finding in liver cirrhosis. The diversion of the portal flow through PSS directly into the caval system causes progressive liver atrophy and atretic changes of the portal vein. During both living and deceased donor liver transplantation (LT), persistence of large PSS has been associated to portal flow steal phenomena causing decreased patients and graft survival. Atretic changes of the portal vein and large PSS often coexist potentially representing a technical challenge during portal vein reconstruction. We herein describe (with a didactical video) an easy augmentation patch V-venoplasty used in the presence of atretic changes of the portal vein LT.

Predicting the available space for liver transplantation in cirrhotic patients: a computed tomography-based volumetric study.

BACKGROUND: Anthropometric parameters (weight, height) are usually used for quick matching between two individuals (donor and recipient) in liver transplantation (LT). This study aimed to evaluate clinical factors influencing the overall available space for implanting a liver graft in cirrhotic patients. METHODS: In a cohort of 275 cirrhotic patients undergoing LT, we calculated the liver volume (LV), cavity volume (CV), which is considered the additional space between the liver and the right hypocondrium, and the overall volume (OV = LV + CV) using a computed tomography (CT)-based volumetric system. We then chose the formula based on anthropometric parameters that showed the best predictive value for LV. This formula was used to predict the OV in the same population. Factors influencing OV variations were identified by multivariable logistic analysis. RESULTS: The Hashimoto formula (961.3 × BSA_D-404.8) yielded the lowest median absolute percentage error (21.7%) in predicting the LV. The median LV was 1531 ml. One-hundred eighty-five patients (67.2%) had a median CV of 1156 ml (range: 70-7006), and the median OV was 2240 ml (range: 592-8537). Forty-nine patients (17%) had an OV lower than that predicted by the Hashimoto formula. Independent factors influencing the OV included the number of portosystemic shunts, right anteroposterior abdominal diameter, model for end-stage liver disease (MELD) score > 25, high albumin value, and BMI > 30. CONCLUSIONS: Additional anthropometric characteristics (right anteroposterior diameter, body mass index) clinical (number of portosystemic shunts), and biological (MELD, albumin) factors might influence the overall volume available for liver graft implantation. Knowledge of these factors might be helpful during the donor-recipient matching.

The 1-year Renal Biopsy Index: a scoring system to drive biopsy indication at 1-year post-kidney transplantation.

Surveillance biopsies after renal transplantation remain debatable. To drive the decision of such intervention, we propose a predictive score of abnormal histology at 1-year post-transplantation, named 1-year Renal Biopsy Index (1-RBI). We studied 466 kidney recipients from the DIVAT cohort alive with a functioning graft and a surveillance biopsy at 1-year post-transplantation. Patients displaying abnormal histology (49%) (borderline, acute rejection, interstitial fibrosis and tubular atrophy [IFTA] grade 2 or 3, glomerulonephritis) were compared to the normal or subnormal (IFTA grade 1) histology group. Obtained from a lasso penalized logistic regression, the 1-RBI was composed of recipient gender, serum creatinine at 3, 6, and 12 month post-transplantation and anticlass II immunization at transplantation (internal validation: AUC = 0.71, 95% CI [0.53-0.83]; external validation: AUC = 0.62, 95% CI [0.58-0.66]). While we could not determinate a threshold able to identify patients at high chance of normal or subnormal histology, we estimated and validated a discriminating threshold capable of identifying a subgroup of 15% of the patients with a risk of abnormal histology higher than 80%. The 1-RBI is computable online at www.divat.fr. The 1-RBI could be a useful tool to standardize 1-year biopsy proposal and may for instance help to indicate one in case of high risk of abnormal histology.

A composite score associated with spontaneous operational tolerance in kidney transplant recipients.

New challenges in renal transplantation include using biological information to devise a useful clinical test for discerning high- and low-risk patients for individual therapy and ascertaining the best combination and appropriate dosages of drugs. Based on a 20-gene signature from a microarray meta-analysis performed on 46 operationally tolerant patients and 266 renal transplant recipients with stable function, we applied the sparse Bolasso methodology to identify a minimal and robust combination of six genes and two demographic parameters associated with operational tolerance. This composite score of operational tolerance discriminated operationally tolerant patients with an area under the curve of 0.97 (95% confidence interval 0.94-1.00). The score was not influenced by immunosuppressive treatment, center of origin, donor type, or post-transplant lymphoproliferative disorder history of the patients. This composite score of operational tolerance was significantly associated with both de novo anti-HLA antibodies and tolerance loss. It was validated by quantitative polymerase chain reaction using independent samples and demonstrated specificity toward a model of tolerance induction. Thus, our score would allow clinicians to improve follow-up of patients, paving the way for individual therapy.

Central Role of CD45RA- Foxp3hi Memory Regulatory T Cells in Clinical Kidney Transplantation Tolerance.

The role of Foxp3(+) regulatory T cells (Tregs) in operational tolerance remains elusive, as initial results revealed an increased frequency of this subset in tolerant patients but no functional differences compared with immunosuppressed recipients. In addition, recent studies of regulatory B cells strongly suggest that Tregs may not have a central role in kidney transplantation tolerance. However, recent investigations of the crucial role of Foxp3 demethylation in Treg function and the possibility of identifying distinct Foxp3 T cell subsets prompted us to more thoroughly characterize Tregs in operationally tolerant patients. Thus, we studied the level of demethylation of the Foxp3 Treg-specific demethylated region (TSDR) in circulating CD4(+) T cells and analyzed Treg subset frequency in tolerant patients, healthy volunteers, patients with stable graft function under immunosuppression, and chronically rejecting recipients. We observed a higher proportion of CD4(+) T cells with demethylated Foxp3 and a specific expansion of CD4(+) CD45RA(-) Foxp3(hi) memory Tregs exclusively in tolerant patients. The memory Tregs of tolerant recipients exhibited increased Foxp3 TSDR demethylation, expressed higher levels of CD39 and glucocorticoid-induced TNF-related receptor, and harbored greater suppressive properties than memory Tregs from patients with stable graft function. Taken together, our data demonstrate that operationally tolerant patients mobilize an array of potentially suppressive cells, including not only regulatory B cells but also Tregs. Our results also indicate that tolerant patients have potent CD4(+)CD45RA(-) Foxp3(hi) memory Tregs with a specific Foxp3 TSDR demethylation pattern, which may contribute to the maintenance of graft tolerance.

A common gene signature across multiple studies relate biomarkers and functional regulation in tolerance to renal allograft.

Patients tolerant to a kidney graft display a specific blood cell transcriptional pattern but results from five different studies were inconsistent, raising the question of relevance for future clinical application. To resolve this, we sought to identify a common gene signature, specific functional and cellular components, and discriminating biomarkers for tolerance following kidney transplantation. A meta-analysis of studies identified a robust gene signature involving proliferation of B and CD4 T cells, and inhibition of CD14 monocyte related functions among 96 tolerant samples. This signature was further supported through a cross-validation approach, yielding 92.5% accuracy independent of the study of origin. Experimental validation, performed on new tolerant samples and using a selection of the top-20 biomarkers, returned 91.7% of good classification. Beyond the confirmation of B-cell involvement, our data also indicated participation of other cell subsets in tolerance. Thus, the use of the top 20 biomarkers, mostly centered on B cells, may provide a common and standardized tool towards personalized medicine for the monitoring of tolerant or low-risk patients among kidney allotransplant recipients. These data point to a global preservation of genes favoring the maintenance of a homeostatic and 'healthy' environment in tolerant patients and may contribute to a better understanding of tolerance maintenance mechanisms.

The extremophile Nicotiana benthamiana has traded viral defence for early vigour.

A single lineage of Nicotiana benthamiana is widely used as a model plant(1) and has been instrumental in making revolutionary discoveries about RNA interference (RNAi), viral defence and vaccine production. It is peerless in its susceptibility to viruses and its amenability in transiently expressing transgenes(2,3). These unparalleled characteristics have been associated both positively and negatively with a disruptive insertion in the RNA-dependent RNA polymerase 1 gene, Rdr1(4-6). For a plant so routinely used in research, the origin, diversity and evolution of the species, and the basis of its unusual abilities, have been relatively unexplored. Here, by comparison with wild accessions from across the spectrum of the species' natural distribution, we show that the laboratory strain of N. benthamiana is an extremophile originating from a population that has retained a mutation in Rdr1 for ∼0.8 Myr and thereby traded its defence capacity for early vigour and survival in the extreme habitat of central Australia. Reconstituting Rdr1 activity in this isolate provided protection. Silencing the functional allele in a wild strain rendered it hypersusceptible and was associated with a doubling of seed size and enhanced early growth rate. These findings open the way to a deeper understanding of the delicate balance between protection and vigour.

Expression of miR-142-5p in peripheral blood mononuclear cells from renal transplant patients with chronic antibody-mediated rejection.

In renal transplantation, the unresponsiveness of patients undergoing chronic antibody mediated rejection (CAMR) to classical treatment stress on the need for accurate biomarkers to improve its diagnosis. We aim to determine whether microRNA expression patterns may be associated with a diagnosis of CAMR. We performed expression profiling of miRNAs in peripheral blood mononuclear cells (PBMC) of kidney transplant recipients with CAMR or stable graft function. Among 257 expressed miRNAs, 10 miRNAs associated with CAMR were selected. Among them, miR-142-5p was increased in PBMC and biopsies of patients with CAMR as well as in a rodent model of CAMR. The lack of modulation of miR-142-5p in PBMC of patients with renal failure, suggests that its over-expression in CAMR was associated with immunological disorders rather than renal dysfunction. A ROC curve analysis performed on independent samples showed that miR-142-5p is a potential biomarker of CAMR allowing a very good discrimination of the patients with CAMR (AUC = 0.74; p = 0.0056). Moreover, its expression was decreased in PHA-activated blood cells and was not modulated in PBMC from patients with acute rejection, excluding a non-specific T cell activation expression. The absence of modulation of this miRNA in immunosuppressed patients suggests that its expression was not influenced by treatment. Finally, the analysis of miR-142-5p predicted targets under-expressed in CAMR PBMC in a published microarray dataset revealed an enrichment of immune-related genes. Altogether, these data suggest that miR-142-5p could be used as a biomarker in CAMR and these finding may improve our understanding of chronic rejection mechanisms.

Activated mTOR and PKR kinases in lymphocytes correlate with memory and cognitive decline in Alzheimer's disease.

BACKGROUND: The control of translation, involving the kinases mTOR (mammalian target of rapamycin) and PKR (double-stranded RNA-dependent protein kinase), modulates cell survival and death and is altered in the brains of patients with Alzheimer's disease (AD). In AD increased susceptibility of lymphocytes to apoptosis has been reported. METHODS: We investigated the level of the kinases mTOR and PKR and the eukaryotic initiation factor 2alpha (eIF2alpha) in lymphocytes of patients with AD in comparison with controls. In AD patients we also looked for a correlation between activated proteins and cognitive and memory tests. RESULTS: We report significant alterations of the levels of these kinases and eIF2alpha in lymphocytes of AD patients that were also significantly correlated with cognitive and memory test scores. CONCLUSION: These results suggest that the levels of mTOR, PKR and eIF2alpha in lymphocytes could follow the cognitive decline in AD.