Critical appraisal of the clinical and pathologic predictors of survival after resection of large hepatocellular carcinoma

HYPOTHESIS: A subset of patients with hepatocellular carcinoma (HCC) with a diameter of 10 cm or larger may benefit from hepatic resection. DESIGN: Retrospective study of a multi-institutional database. SETTING: Five major hepatobiliary centers. PATIENTS: We identified 300 patients who underwent hepatic resection for HCC 10 cm or larger. MAIN OUTCOME MEASURES: Clinical and pathologic data were collected, and prognostic factors were evaluated by univariate and multivariate analyses. Patient survival was stratified according to a clinical scoring system and pathologic T classification. RESULTS: The perioperative mortality rate was 5%. At a median follow-up of 32 months, the median survival was 20.3 months, and the 5-year actuarial survival rate was 27%. Four clinical factors-alpha-fetoprotein of 1000 ng/mL or higher, multiple tumor nodules, the presence of major vascular invasion, and the presence of severe fibrosis-were significant predictors of poor survival (all P<.05). Patients were assigned a clinical score according to the following risk factors: 1, no factor; 2, one or two factors; or 3, three or four factors. On the basis of the clinical score, patients could be stratified into only 2 distinct prognostic groups: no factor (score of 1) vs 1 or more factors (score of 2 or 3) (P<.001). In contrast, when patients were stratified according to pathologic T classification, 3 distinct groups were identified: T1 vs T2 vs T3 and T4 combined (P<.001). Fifty-six percent of the patients with a clinical score of 2 and 20% of patients with a clinical score of 3 actually had T1 or T2 disease on pathologic examination. CONCLUSIONS: Patients with large HCCs should be considered for liver resection as this treatment is associated with a 5-year survival rate exceeding 25%. Clinical predictors should not be used to exclude patients from surgical resection because these factors do not reliably predict outcome.     

Inhibitory and stimulatory effects of cyclosporine A on the development of regulatory T cells in vivo

BACKGROUND: Regulatory T cells (Tregs) are increasingly recognized as playing a major role in nondeletional tolerance. To avoid rejection before tolerance is established, clinical trials of tolerance induction include immunosuppressive drugs early posttransplant. It is therefore essential that immunosuppressive protocols do not block Tregs generation. Tregs function has been shown to depend upon interleukin-2 signaling, but there are limited data available on how calcineurin inhibitors influence Tregs development and function in vivo. METHODS: To study this, we used a previously established rat cardiac allograft model where donor-specific Tregs and tolerance are induced by pretransplant donor-specific blood transfusion (DSBT). RESULTS: In this model, we found that adjunction of 50 mg/kg cyclosporine (CsA) (not a lower dose, 10 mg/kg) at the time of DSBT (not at the time of transplantation) abrogates Tregs development and causes rejection. Interestingly, 10 mg/kg CsA given posttransplant (day 0-11) in the absence of pretransplant DSBT induced the development of Tregs and provoked a state of tolerance indistinguishable from the one induced by DSBT. Finally, DSBT given the day of transplantation did not promote tolerance, unless recipients also received a delayed short course (day 5-9) of 10 mg/kg CsA. CONCLUSIONS: Adjunction of high-dose CsA to pretransplant DSBT abrogates Tregs generation. On the contrary, a lower dose (10 mg/kg) of CsA promotes Tregs development either in synergy with perioperative DSBT (providing that a drug-free interval is respected) or by its own effect. These data provide new guidelines for a more tolerogenic use of calcineurin inhibitors in the clinic, particularly when immunomodulatory strategies aimed at inducing Tregs are applied.     

Anti-CD2 monoclonal antibody and tacrolimus in adult liver transplantation

BACKGROUND: Blockade of costimulation and adhesion signaling is an attractive approach to interfere with graft rejection METHODS: Between January 1997 and May 1999, forty adults having benign liver diseases were included in a prospective, randomized study comparing tacrolimus plus low-dose short-term steroids without (n=20, TAC group) or with a 10-day course of antihuman CD2 monoclonal antibody (n=20, BTI group). RESULTS: At day 7, histological rejection expressed by mean Banff scores (2.3+/-1.6 vs. 5.4+/-1.6 in the TAC group; P<0.0001) and incidence of moderate to severe rejection (score>or=6) (0 vs. 10 [50%] in the TAC group; P<0.001) were significantly lower in the BTI group. Rejection was treated in 10% (two patients) of BTI patients during the first 3 months and in 15% during the whole follow-up and in 25% (five patients) of TAC patients (P=NS). None of the BTI-patients presented with an adverse event. Three-month, 1-year, and 5-year actual patient survival rates were 100%, 95%, and 95% in the BTI group and 100%, 100%, and 85% in the TAC group. Graft survival rates were 100%, 90%, and 90% in the BTI group and 95%, 95%, and 80% in the TAC group (P=NS). The mAb had no negative impact on infectious or tumor events. CONCLUSIONS: Antihuman CD2 monoclonal antibody is a safe immunosuppressive drug which has a favorable impact on early immunological follow-up of liver transplanted patients. The antibody had no impact on late patient and graft survival.     

Sirolimus and tacrolimus trough concentrations and dose requirements after kidney transplantation in relation to CYP3A5 and MDR1 polymorphisms and steroids

BACKGROUND: CYP3A5 and MDR1 polymorphisms have been shown to influence tacrolimus blood concentrations and dose requirements. The aim is to determine whether these polymorphisms also affect sirolimus trough concentrations and dose requirements after kidney transplantation. METHODS: Eighty-five renal transplant recipients receiving sirolimus were included. Twenty-four were treated with a combined sirolimus-tacrolimus regimen. Eighty-one patients received steroids. Sirolimus and tacrolimus were adjusted to a target therapeutic window. CYP3A5 (intron 3) and MDR1 (exons 12, 21, 26) genotypes were correlated to the adjusted trough concentrations and dose requirements for both sirolimus and tacrolimus. RESULTS: There were no significant correlation between adjusted sirolimus trough concentrations or dose requirements and genetic polymorphisms. In a multiple regression model, adjusted-prednisone dose was involved with a positive or negative effect when considering sirolimus dose requirements or adjusted concentrations, respectively. In the subgroup of patients treated by tacrolimus and sirolimus, adjusted tacrolimus doses were higher in patients carrying at least one CYP3A5 *1 allele (median 0.083 vs. 0.035 mg/kg for CYP3A5*3/*3 patients, P<0.05). Adjusted-prednisolone dose and CYP3A5 polymorphism explained up to 61% of the variability in tacrolimus dose requirements. CONCLUSIONS: Unlike tacrolimus, sirolimus adjusted trough concentrations and dose requirements seem not affected by CYP3A5 and MDR1 polymorphisms. Adjusted-prednisone dose has a significant impact on tacrolimus and sirolimus dose requirements.     

Fast-track coronary artery bypass grafting surgery under general anesthesia with remifentanil and spinal analgesia with morphine and clonidine

OBJECTIVE: Effective postoperative analgesia is a critical part of fast-track cardiac surgery. This study compared the postoperative analgesic effect of fast-track anesthesia with remifentanil and spinal morphine and clonidine with that of sufentanil anesthesia followed by patient-controlled administration of intravenous morphine. DESIGN: Prospective, blinded, randomized study. SETTING: Single private institution. PARTICIPANTS: Forty patients selected for coronary artery bypass graft surgery allocated randomly into 2 groups. INTERVENTIONS: General anesthesia was performed with etomidate, isoflurane, cisatracurium, and either remifentanil (0.10-0.25 microg/kg/min) or sufentanil (up to 3.5 microg/kg). In the remifentanil group, patients received spinal morphine (4 microg/kg) and clonidine (1 microg/kg) before induction. Postoperatively, patients in both groups were connected to an intravenous patient-controlled analgesia (PCA) morphine pump that delivered a 1-g bolus with a 7-minute lockout interval. MEASUREMENTS AND MAIN RESULTS: Patients were evaluated for pain on a visual analog scale (VAS), at rest and on deep breathing, and for intravenous PCA morphine consumption during 24 hours. The intravenous PCA morphine 24-hour cumulative dose was lower in the fast-track than in the control group (15.8+/-12.6 v 32.7+/-22.3 mg, p<0.05). Before extubation, VAS scores were higher in the fast-track group, but after they were lower both at rest and during deep breathing. Extubation delay was shorter in the fast-track group (156.5+/-46.1 v 272+/-116.4 minutes, p<0.05). CONCLUSION: The combination of anesthesia with remifentanil and spinal analgesia with morphine and clonidine produces effective analgesia after coronary artery surgery and a rapid extubation time.     

Fusion of the planes of the liver: an anatomic entity merging the midplane and the left intersectional plane

BACKGROUND: Alignment of the gallbladder fossa and the round ligament may be associated with an almost unknown portal vein branching anomaly. STUDY DESIGN: Ultrasonographic imaging allowed detection of this anomaly, which we characterized as fusion of the planes of the liver. When appropriate, additional specific radiologic examinations were performed (CT scanner supplemented with a three-dimensional reconstruction, a biliary cartography, or an angiography). Surgical consequences were studied from this series and from the literature. RESULTS: Seven patients (0.5%) had the following criteria: 1) round ligament, gallbladder fossa, and termination of the portal vein occurring in the same plane; 2) typical portal vein branching, including a right posterior branch, left branches, and a main medial branch terminated by the Rex's recessus; 3) two main hepatic veins without a significant middle hepatic vein; and 4) absence of the horizontal part of the left hepatic duct. Fusion of the planes may have been involved in two cases of iatrogenic bile duct injury and contraindicated a tumor resection and a right-liver donation. A review of the literature revealed that lack of recognition of the fusion of the planes led to a high proportion of surgical iatrogenic injury. Fusion of the planes could result from incomplete development of the central part of the liver, in agreement with embryologic knowledge. CONCLUSIONS: Knowledge of the fusion of the planes by hepato-biliary surgeons is important. This anomaly may lead to serious complications if it remains undetected during liver resection or bile duct surgery.     

Renal Cell Carcinoma Associated with Tumor Thrombus in the Inferior Vena Cava: Surgical Strategies

The purpose of this study was to evaluate strategies used for surgical management of renal cell carcinoma with a tumoral thrombus extension in the inferior vena cava (IVC). From January 2000 to December 2001, urological and vascular surgeons jointly undertook surgical treatment on 10 patients with renal cell carcinoma and tumor thrombus in the IVC. There were five women and five men, with a mean age of 60.2 years. The limit of thrombus extension, classified according to the Neves and Zincke system, was level I (renal) in one patient, level II (infrahepatic) in one, level III (retrohepatic) in three, and level IV (atrial) in five. Exposure was achieved by chevron bilateral subcostal laparotomy associated with sternotomy in three patients, bilateral subcostal laparotomy in six, and median sternolaparotomy in one. Radical nephrectomy associated with caval thrombectomy was performed in all patients. Cardiopulmonary bypass was used in four of the five level IV patients. The fifth patient was contraindicated for cardiopulmonary bypass. Transesophageal echography (TEE)-guided endoluminal occlusion of the unobstructed infradiaphragmatic IVC was performed in patients with level III thrombus. Clamping of the IVC was performed in patients with levels I and II thrombus. All procedures were assisted by continuous TEE surveillance. No intraoperative gas or tumor emboli were detected by TEE. The mean number of red blood cell units transfused during the course of hospitalization was 9.7 (range 2-22, median 9). One patient died of multiple organ failure on the day 28 after the procedure. The mean duration of hospitalization was 16 days. The mean duration of follow-up was 9.7 months. During follow-up, two of the remaining nine patients died due to tumor recurrence. Tumor recurrence was also detected in one of the seven surviving patients. Surgery for renal cell carcinoma with tumor thrombus in the IVC must be carried out in a specialized facility with the assistance of TEE surveillance and, in some cases, cardiopulmonary bypass. Operative treatment improves the prognosis of renal cell carcinoma with tumor thrombus in the IVC. In patients with level III thrombus, TEE-guided endoluminal occlusion of the unobstructed infradiaphragmatic IVC simplifies surgical management by obviating the need for exposure of the retrohepatic and supradiaphragmatic IVC.Presented at the Seventeenth Annual Meeting of the Société de Chirurgie Vasculaire de Langue Française, May 29-31, 2002, Liege, Belgium.     

Human tonsil implants xenotransplanted in SCID mice display broad lymphocytic diversity and cellular activation profile similar to those in the original lymphoid organ

BACKGROUND: Models consisting of human immune cells in suspension transferred to severe combined immune deficient (SCID) mice have been invaluable for studying immune response, autoimmunity, and lymphomagenesis. The dissemination of human cells within the mouse body hampers immune functionality with time and favorites the development of human graft vs. mouse host (GvH) disease. To circumvent these limitations we surgically implanted tonsil pieces subcutaneously in SCID animals (hu-ton-SCID mice). Recall humoral responses was elicited and animals did not suffer from signs of GvH disease. A detailed cell subset and cell activation analysis of implants has not yet been reported. METHODS: Implants from 86 hu-ton-SCID mice were evaluated by immunohistochemistry and flow cytometry analyses to assess human lymphoid cell subpopulation surviving with time after implantation, and to evaluate status of human cell activation. Results: B cells persist over 3 months in implants. The proportion of class and type-specific Ig+ cells varied between implants, but as a whole IgG+ cells were more abundant than IgA+, and IgM+ cells, and kappa+ cells predominated over lambda+ cells. The mean proportions of these cells resemble those in the original tonsil. Fine analysis of CD19+ B cells demonstrated no expansion of activated (CD5+, CD23+, CD69+) B cells in implants compared with tonsils, and a decrease of CD19+CD77+ B cells corresponding to a centroblastic phenotype, which is consistent with the disappearance of follicular structure in implants. Double positive CD20+CD27+ memory B cells were detected in implants by immunohistochemistry. T cell CD4+CD8-/CD4-CD8+ ratios were about 4 in implants, that is similar to those in tonsils, and there was no expansion of CD3+CD4+CD8+ and of CD3+CD4-CD8- T-cell subpopulations. T cells activation markers (CD25, CD69) were similarly expressed in implants and tonsils, and implants contained cells with a memory T cell phenotype (CD45RO). Finally cells within implants depicted a low rate of proliferation when assessed by Ki-67 expression levels. Conclusions: Compared with original tonsils, tonsil implants in hu-ton-SCID mice lose the germinal center architecture, which is correlated with the decrease of CD77+ B cells, but conserve T and B cell subpopulation diversity, notably memory cells. In addition, implant T and B cells are not differently activated when compared with those in original tonsils and do not proliferate extensively. These observations indicate indirectly absence of GvH reaction at the cellular level in this model. Collectively, the detailed implant cellular characterization in the hu-ton-SCID model provides a strong rationale for the use of this model in the study of human recall antibody response.