Treatment with mTOR inhibitors after liver transplantation enables a sustained increase in regulatory T-cells while preserving their suppressive capacity.

BACKGROUND: The mammalian targets of rapamycin (mTOR) inhibitors (sirolimus [SRL] and everolimus [EVR]) are used after transplantation for their immunosuppressive activity. Regulatory T-cells (Tregs) play a crucial role in immune tolerance. mTOR inhibitors appear to preserve Tregs, unlike Tacrolimus (Tac). AIM: The aim of this study was to evaluate the number and function of Tregs in liver transplant recipients before and after conversion from Tac to mTOR inhibitors. METHODS: Fifteen patients with stable graft function where converted to SRL (n=5) or EVR (n=10). Tregs (CD4+ CD25+ FoxP3+ CD127low) number and activity were analysed prospectively in blood cells using flow cytometry, and functional assay. RESULTS: Patients of both groups displayed a sustained rise in Treg levels after introduction of mTOR inhibitors (Treg levels at 3 months: 6.45±0.38% of CD4 T-cells, vs. baseline level of 3.61±0.37%, P<0.001; mean fold increase 2.04±0.73). In SRL group, 3-month Treg levels were 6.01±0.53 vs. 3.79±0.39; P=0.037, while in EVR group they were 6.63±0.67 vs. 3.54±0.51; P=0.001. By contrast, no statistical change was observed in an unconverted Tac control group. Tregs also preserved their functional ability to suppress activated T-cells. CONCLUSION: These results suggest that mTOR inhibitors induce a significant increase in Tregs while maintaining suppressive activity after LT.

Antenatal prognostic factor of fetal echogenic bowel.

OBJECTIVE: The aim of this study was to identify antenatal prognostic factors of neonatal outcomes in cases of fetal echogenic bowel (FEB). STUDY DESIGN: A retrospective study in three tertiary referral centers including fetal echogenic bowel over a 10-year period (from January 2003 to December 2013). The echogenicity of the fetal bowel was graded from 1 to 3, according to Slotnick's definition. Associated echographic findings such as bowel dilations, gallbladder abnormalities, calcifications, extra-abdominal abnormalities, intrauterine growth restriction (IUGR) and a decrease in amniotic fluid volume, if present were also recorded. This was followed by the FEB's sonographic evolution. The sonographic evolution was considered favorable if it was stable or decreasing and unfavorable if the echogenicity of the bowel increased or if additional sonographic findings appeared. Neonates had a pediatric examination in the delivery room and upon discharge from the maternity hospital. An outcome was considered good in the case of on-term delivery of a newborn with normal clinical examination and meconium elimination. RESULTS: Complete pregnancy outcome data were available for 409 pregnancies. 338 newborns had uneventful outcomes (82.6%). Antenatal exploration diagnosed 4 cases of aneuploidy (1 case of trisomy 13, 1 case of trisomy 18 and 2 cases of triploidies), 16 cases of congenital infections, 9 cases of cystic fibrosis and 11 cases of bowel abnormalities. After a multivariate analysis, we discovered the sonographic grade of the echogenic bowel was not a prognostic factor of neonatal outcome. The isolated fetal echogenic bowel had a 6.6-fold increase chance of uneventful outcomes (adjusted odd ratio (aOR) 6.6, 95% CI 3-14.4). Notably, favorable sonographic evolution (aOR 8.1, 95% CI 4.1-16) and late gestational age at the time of the diagnosis (aOR 1.17, 95% CI 1.07-1.27) are independent, good prognostic factors of good neonatal outcomes. None of the 180 fetuses with isolated fetal echogenic bowel and favorable sonographic evolution had adverse outcomes. Among these, 4 cases (0.98%) of aneuploïdy, 17 cases (4.2%) of congenital infections and 9 cases (2.2%) of cystic fibroses were also diagnosed. No cases of Down syndrome (DS) were reported. CONCLUSION: Our study shows that the grade should not be considered a prognostic factor of neonatal outcomes. Our data suggests the need to reevaluate the concept of systematic amniocentesis. Sonographic evolution of fetal bowel is an independent, strong prognostic factor for good neonatal outcomes. It also better defines the FEB prognostic.

Laparoscopic sleeve gastrectomy and gastroesophageal reflux.

Bariatric surgery is the only effective procedure that provides long-term sustained weight loss. Sleeve gastrectomy (SG) has emerged over the last few years to be an ideal bariatric procedure because it has several advantages compared to more complex bariatric procedures, including avoiding an intestinal bypass. However, several published follow-up studies report an increased rate of gastroesophageal reflux (GERD) after a SG. GERD is described as either de novo or as being caused by aggravation of preexisting symptoms. However, the literature on this topic is ambivalent despite the potentially increased rate of GERDs that may occur after this common bariatric procedure. This article reviews the mechanisms responsible for GERD in obese subjects as well as the results after a SG with respect to GERD. Future directions for clinical research are discussed along with the current surgical options for morbidly obese patients with GERD and undergoing bariatric surgery.

Pure laparoscopic left lateral sectionectomy in living donors: from innovation to development in France.

OBJECTIVE: In this study, we report the results obtained from 70 living donors in France. BACKGROUND: Left lateral sectionectomy for pediatric live donor liver transplantation is a well-standardized surgical procedure. Our team introduced the laparoscopic approach to live donation in 2002, and the reproducibility and safety of this method was discussed in 2006. METHODS: Between March 2001 and October 2012, a total of 70 donors underwent a liver procurement. Sixty-seven donors (95.7%) underwent a left lateral sectionectomy, and 3 underwent a left hepatectomy without middle hepatic vein procurement. All data were prospectively recorded in a database. RESULTS: Of the 70 donors, 66 (94%) liver grafts were procured by laparoscopy, whereas 4 (6%) patients required conversion into an open technique. Seventeen donors experienced complications, leading to an overall complication rate of 24.2%. Eleven donors (16%) had grade 1 complications, according to the Clavien system. Five donors (7.1%) presented grade 2 complications, and 1 donor (1.4%) had a grade 3 complication. No death occurred. Overall, patient and graft survival rates for pediatric recipients were 95% and 92% at 1 year, 95% and 88% at 3 years, and 95% and 84% at 5 years, respectively. CONCLUSIONS: The laparoscopic retrieval of the left lateral section for live donor liver transplantation is safe and reproducible and has transitioned from an innovative surgery to a development phase in France.

Split liver transplantation using extended right grafts: the natural history of segment 4 and its impact on early postoperative outcomes.

Split liver transplantation (SLT) using extended right grafts is associated with complications related to ischemia of hepatic segment 4 (S4), and these complications are associated with poor outcomes. We retrospectively analyzed 36 SLT recipients so that we could assess the association of radiological, biological, and clinical features with S4 ischemia. The overall survival rates were 84.2%, 84.2%, and 77.7% at 1, 3, and 5 years, respectively. The recipients were mostly male (24/36 or 67%) and had a median age of 52 years (range = 13-63 years), a median body mass index of 22.9 kg/m(2) (range = 17.3-29.8 kg/m(2) ), and a median graft-to-recipient weight ratio of 1.3% (range = 0.9%-1.9%). S4-related complications were diagnosed in 22% of the patients (8/36) with a median delay of 22 days (range = 10-30 days). Secondary arterial complications were seen in 3 of these patients and led to significantly decreased graft survival in comparison with the graft survival of patients without complications (50.0% versus 85.6%, P = 0.017). Patients developing S4-related complications had significantly elevated aspartate aminotransferase (AST) levels (>1000 IU/L) on postoperative day (POD) 1 and elevated gamma-glutamyl transpeptidase (GGT) levels (>300 IU/L) on PODs 7 and 10 (P < 0.05). These AST and GGT elevations conferred a significantly high risk of developing these complications (odds ratio = 42, 95% confidence interval = 4-475, P < 0.05). The ischemic volume of S4 was extremely variable (0%-95%) and did not correlate with S4-related complications. In conclusion, our results suggest that S4-related complications are risk factors for worse graft survival, and the development of these complications can be anticipated by the early identification of a specific biological profile and a routine radiological examination.

Decreases in circulating CD4+CD25hiFOXP3+ cells and increases in intragraft FOXP3+ cells accompany allograft rejection in pediatric liver allograft recipients.

We examined CD4(+)CD25(hi)FOXP3(+) cells Treg in children following liver transplantation and determined the relationship between Treg cell levels in the blood and in the graft. Peripheral blood was obtained from pediatric liver transplant patients at sequential time points: pre-transplant, one month, 3-4 months, 6-7 months, and 11-12 months post-transplant. PBMC were isolated, labeled for CD4, CD25 and FOXP3 expression and analyzed by flow cytometry for CD4(+)CD25(hi)FOXP3(+) cells. Sorted CD4(+)CD25(hi) cells were assessed for functional activity. Pretransplant blood levels of CD4(+)CD25(hi)FOXP3(+) Treg cells were not significantly different from post-transplant blood levels of CD4(+)CD25(hi)FOXP3(+) Treg cells. However, the blood levels of CD4(+)CD25(hi)FOXP3(+) Treg cells were significantly decreased during acute rejection compared with levels when graft function was stable. Immunohistochemistry revealed that FOXP3(+) cells were increased in the portal region of livers with histopathologic evidence of acute graft rejection compared with livers without evidence of rejection and were localized primarily within the inflammatory infiltrate. These data indicate that Treg cells are found at the site of allograft rejection and may play a role in regulation of alloreactivity. Moreover, monitoring peripheral CD4(+)CD25(hi)FOXP3(+) Treg cell levels may be useful in improving the post-transplant management of pediatric liver allograft recipients.

Alloimmunization to red blood cell antigens affects clinical outcomes in liver transplant patients.

Transfusion therapy of liver transplant patients remains a challenge. High volumes of intraoperative blood transfusion have been shown to increase the risk of poor graft or patient survival. We conducted a retrospective study of 209 consecutive liver transplant cases at our institution. Only patients receiving their first liver transplant, with no other simultaneous organ transplants, were included. Cox proportional hazard modeling was used to identify clinical variables correlated with postoperative patient mortality. Statistically significant variables for poor patient survival were the number of red blood cell and plasma units transfused, a history of red blood cell alloantibodies, and the immunosuppressive regimen used. History of pregnancy also approached statistical significance but was less robust than the other 3 variables. Our findings suggest that blood transfusion and immune modulation greatly affect the survival of patients after liver transplantation.

Laparoscopic left lateral sectionectomy in living donors: safety and reproducibility of the technique in a single center.

BACKGROUND DATA AND OBJECTIVE: Left lateral sectionectomy for liver transplantation in children performed through laparoscopy is an innovative procedure that was developed by considering our acquired experience in both laparoscopic liver resection and graft harvesting in living donors. The main goal was to minimize donor morbidity while preserving the abdominal wall. Herein, we report the technical feasibility and reproducibility, and compared it with open liver resection (OLR). METHODS: Sixteen successive donors underwent a laparoscopic liver resection (LLR) from 2001 to 2005. They were compared with 14 other donors who underwent a standard open liver resection (OLR) during a first period (1998-2004). First, this report describes the technical features of laparoscopic resection. Second, perioperative morbidity and graft characteristics were compared according to the use or not of the laparoscopic approach. RESULTS: Laparoscopic harvesting was successfully performed in 15 of 16 cases in an intention-to-treat basis. One conversion was required to ensure the quality of the laparoscopic repair of a left portal vein injury occurring during the pedicle dissection. No specific complication related to laparoscopy was observed. As compared with OLR, the operation was longer (320 +/- 67 vs. 244 +/- 55 minutes, P < 0.005). The blood loss was significantly lower in the LLR group (18.7 +/- 44.2 vs. 199.2 +/- 185.4 mL, P < 0.005). The morbidity rate was similar in both groups (18.7% in LLR vs. 35.7% in OLR). One donor in the LLR group experienced a bile leak treated by redo laparoscopy. Grafts were anatomically similar irrespective of the use of laparoscopy. The duration of hospital stay and use of self-infused morphine pump was not different between the 2 groups. CONCLUSION: Left lateral section harvesting by laparoscopy is a safe and reproducible procedure, allowing to obtain similar grafts as compared with laparotomy and can therefore be recommended to transplant centers that have previous experience in laparoscopic liver resection.