Triple therapy with ursodeoxycholic acid, budesonide and mycophenolate mofetil in patients with features of severe primary biliary cirrhosis not responding to ursodeoxycholic acid alone.

BACKGROUND/AIMS: To assess the benefit of the UDCA-budesonide combination in association with mycophenolate mofetil (MMF) in patients with primary biliary cirrhosis (PBC) at high risk of developing cirrhosis or liver failure. METHODS: Inclusion criteria for this three-year open study were: 1) suboptimal biochemical response to one-year UDCA therapy at 13-15 mg/kg/d; 2) significant interface hepatitis without cirrhosis at liver biopsy. Treatment regimen included UDCA (13-15 mg/kg/d), budesonide (6 mg/d) and MMF (1.5 g/d). All patients underwent a control biopsy at three years. RESULTS: Fifteen patients fulfilled the inclusion criteria. Six patients (41%) normalized biochemistries and seven (47%) had a partial but significant biochemical response, as defined by a serum bilirubin less than 17 micromol/L, alanine aminotransferase less than 70 UI/L and alkaline phosphatase less than 250 UI/L. Histological activity and fibrosis were markedly improved. Side effects were minimal or absent. CONCLUSIONS: Triple therapy with UDCA, budesonide and MMF may provide benefit in non-cirrhotic PBC patients with features of severe disease not responding to UDCA.

Testing treatment effects in unconfounded studies under model misspecification: logistic regression, discretization, and their combination.

Logistic regression is commonly used to test for treatment effects in observational studies. If the distribution of a continuous covariate differs between treated and control populations, logistic regression yields an invalid hypothesis test even in an uncounfounded study if the link is not logistic. This flaw is not corrected by the commonly used technique of discretizing the covariate into intervals. A valid test can be obtained by discretization followed by regression adjustment within each interval.

[Place of nephrectomy in patients with autosomal dominant polycystic kidney disease waiting for renal transplantation]. / Place de la néphrectomie chez les patients atteints de polykystose rénale autosomique dominante de l'adulte en attente de transplantation rénale.

OBJECTIVE: To define the indications, results and place of nephrectomy for autosomal dominant polycystic kidney disease (ADPKD) in relation to renal transplantation. MATERIAL AND METHODS: Between October 1998 and February 2006, 145 patients with ADPKD were followed in our institution; 38 of them underwent nephrectomy via a subcostal incision, mainly in preparation for renal transplantation. The decision to perform nephrectomy in preparation for renal transplantation was based on clinical examination and CT findings. RESULTS: Indications for nephrectomy were preparation for renal transplantation (n=28, 68%), severe urological complications (n=12) and malignant tumour (n=1). Forty-one nephrectomies were performed, pretransplantation in 36 cases (88%) and five post-transplantation nephrectomies in three patients. The nephrectomy rate was 26%. The median kidney weight was 2800 grams. The mean operating time was 100 minutes and mean blood loss was 76 ml. The overall morbidity was 36.6% with 7.3% of serious complications. The mean hospital stay was 14.5 days. No patient nephrectomized before transplantation (n=13) developed any complications of the contralateral native kidney with a mean follow-up of 33 months. The mean interval between initiation of dialysis and transplantation and between nephrectomy and transplantation was 30 and 16 months, respectively. CONCLUSIONS: The optimal timing and incision for nephrectomy for ADPKD are still a subject of debate. In the absence of urological complications, nephrectomy, associated with considerable morbidity, should only be performed when very large kidneys truly interfere with graft implantation. Systematic unilateral or bilateral nephrectomy must therefore no longer be proposed. To avoid the complications of the anephric state, it is preferable to wait, whenever possible, until the patient is placed on dialysis, but the development of pre-emptive transplantation raises the issue of concomitant nephrectomy and transplantation, which may be a feasible option.

Mutations in BHD and TP53 genes, but not in HNF1beta gene, in a large series of sporadic chromophobe renal cell carcinoma.

BHD, TP53, and HNF1beta on chromosome 17 were studied in 92 cases of renal cell carcinoma (46 chromophobe, 19 clear cell, 18 oncocytoma, and nine papillary). Six, thirteen, and zero cases had, respectively BHD, TP53, and HNF1beta mutations, (84% mutations involved chromophobe), suggesting a role for BHD and TP53 in chromophobe subtype.

Influence of HFE gene polymorphism on the progression and treatment of chronic hepatitis C.

We analysed liver histology findings in a large cohort of patients with chronic hepatitis C and in roughly half of them their response to interferon-alpha-based on iron parameters and HFE status. Histological activity and virological response to antiviral therapy (n = 146) were analysed in 273 immunocompetent and nonalcoholic patients with chronic hepatitis C, in terms of serum iron load, intrahepatic iron load (n = 110) and HFE mutations. Patients who were heterozygous for the C282Y and H63D mutations exhibited higher iron serum parameters than subjects without these mutations. The intrahepatic iron load was higher in H63D patients only. No association was observed between HFE mutations and histological activity. Increased iron parameters were associated with liver disease severity by univariate analysis only. Genotype 1 and ferritinaemia were associated with a poor response to antiviral therapy, whereas the H63D mutation emerged as a positive predictive factor for end of treatment and sustained antiviral response. Therefore, in chronic hepatitis C patients serum and intrahepatic iron levels were weakly correlated with histological activity, while HFE mutations were not. As for the response to interferon-alpha, elevated ferritinaemia constituted a negative predictive factor whereas the H63D mutation was a positive one. The H63D mutation might form part of an immunogenetic profile influencing the response to interferon therapy.

[Systematic conservative surgery for kidney cancer smaller than 4 cm: multicenter study]. / Chirurgie conservatrice de principe pour cancer du rein inférieur à 4 cm: étude multicentrique.

OBJECTIVE: To evaluate tumour control and morbidity of systematic conservative surgery for patients with a renal cancer < or = 4 cm. MATERIALS AND METHODS: A retrospective multicentre study was performed in 73 patients undergoing systematic conservative surgery for renal cancer < or = 4 cm. The mean age of the patients was 55.8 years (range: 19-82). The mean diameter of the tumour was 2.8 cm +/- 0.9. Tumour stage was pT1 in 97% of cases and pT3a in 3% of cases. The mean follow-up was 46.2 months (range: 12-138). RESULTS: The postoperative morbidity was 11%, including urinary fistulas in 5 cases and haemorrhage in 3 cases. No patient has developed local recurrence. One patient died from metastases. The 5-year recurrence-free survival was 97.4%. CONCLUSION: Systematic partial nephrectomy has a low morbidity in patients with a renal cancer less than 4 cm. It ensures satisfactory medium-term tumour control. However, only long-term follow-up can establish the place of systematic partial nephrectomy in the treatment of renal cancer.

[Prevention of renal carcinoma: the nutri-genetic approach]. / Prévention du carcinoma rénal: l'approche nutrigénétique.

The development of renal cell carcinoma (RCC) has been associated with both genetic and environmental factors, with somatic and germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and with tobacco smoking, obesity, long term exposure to some nutrients, pollutants, and industrial solvents such as trichloroethylene. Intra and interfamilial variability of expression of germline mutations in the VHL gene and variable susceptibility to carcinogens in the sporadic forms strongly suggest the involvement of conditional modifier genes. In order to identify sub groups of individuals at increased risk because of susceptibility genotypes, we have collected a series of 460 patients who developed an RCC and 79 families with the von Hippel Lindau disease. To collect clinical and mutational data for correlation analysis we have developed a unique tool the Universal Mutation Database. Comparison of the spectrum of germline and somatic mutations in the VHL gene showed that: 1) in sporadic RCC mutations lead more often to truncated proteins (83%), while the remaining mutations (17%), include 3/4 of transversions and 1/4 of transitions. This high proportion of transversions supports the involvement of carcinogens the impact of which is conditioned by the genetic variability of xenobiotic metabolizing enzymes; 2) whereas in familial cases missense mutations are more common; this difference allowed us to define a prognostic factor for the occurrence of RCC in a VHL context. In order to look for genotypes conferring a higher risk we genotyped the RCC patients for 8 different genes (50 genotypes). A significant relationship was observed for several combinations of alleles including CYP1A1 ("variant"), NAT2 and NAT1 (slow) and GSTM1 (null allele). Associations between specific mutational profiles and at risk genotypes at different tumoral stages should allow us to: 1) define more precisely the nature of specific patterns of mutations in relation with the deficiency or overexpression of such or such enzymes in presence of particular carcinogens; 2) demonstrate that certain combinations of genotypes confer a particular risk to develop a specific type of tumor in VHL patients. Thus tracking of potentially carcinogenic substances, through their footprints and through identification of conditionally detrimental genotypes of genes participating in their detoxification should permit a better prevention through an appropriate nutrition adapted to each individual.

Endorectal color doppler sonography and endorectal MR imaging features of nonpalpable prostate cancer: correlation with radical prostatectomy findings.

OBJECTIVE: The purpose of this study was to describe endorectal sonography and color Doppler sonography features of nonpalpable prostate cancer and to assess the value of endorectal MR imaging for the preoperative local staging of these tumors. MATERIALS AND METHODS: Ninety-four patients with nonsuspicious findings on digital rectal examination and a mean prostate-specific antigen level of 16.3 +/-10 ng/mL (median, 13 ng/mL) underwent endorectal sonography, color Doppler sonography, sextant endorectal sonographically guided biopsy, and endorectal MR imaging before radical prostatectomy. RESULTS: Tumors were visible in 48 cases and not visible in 46. The mean Gleason biopsy score, the frequency of tumors involving three sextants or more of the prostate gland at biopsies, and the frequency of stage pT3 tumors were significantly higher in patients with visible tumors (5.9+/-0.9, 42%, and 37.5%) than in those with invisible tumors (5.4+/-1.1, 17%, and 17%). The 42 hypervascular tumors were hypoechoic in every case and had a higher rate of Gleason tumor grades 4 and 5 at biopsy than did the 52 hypovascular tumors (33% versus 11.5%). Six hypovascular tumors (6/52, 11.5%, two visible) had an insignificant tumor volume. Established extraprostatic tumor spread was detected on MR imaging in six of 18 cases (sensitivity, 33%; specificity, 100%0, all of which had the following four features: hypervascularity, prostate-specific antigen level greater than 20 ng/mL, three or more sextants of the gland having positive findings at biopsy, and seminal vesicle invasion. CONCLUSION: Endorectal sonography and color Doppler sonography are useful to differentiate low-risk invisible and hypovascular tumors from high-risk visible and hypervascular tumors. However, MR imaging has a poor sensitivity for the detection of extraprostatic spread and is accurate only in a minority of highly selected high-risk hypervascular tumors.

Randomized trial of interferon-alpha plus ursodeoxycholic acid versus interferon plus placebo in patients with chronic hepatitis C resistant to interferon.

BACKGROUND: Ursodeoxycholic acid (UDCA) could potentiate the effect of interferon (IFN) in patients with chronic hepatitis C resistant to IFN. We compared the efficacy of IFN with that of a combination of IFN and UDCA. METHODS: Patients were randomized to receive UDCA (13-15 mg/kg/day) (n = 47) or placebo (n = 44) plus interferon (3 MU three times weekly) for 6 months and were then followed up for 6 additional months. RESULTS: At entry 30% of patients had cirrhosis, and 70% had HCV genotype 1. Five and four patients withdrew from the combination and the monotherapy groups, respectively. At 6 months alanine aminotransferase (ALAT) and gamma-glutamyl transferase (GGT) activities were significantly lower (P < 0.001) in the combination group than in the monotherapy group; the differences were no longer significant at 1 year. At 6 months ALAT activities normalized in 10 and 8 patients in the combination and the monotherapy groups, respectively (P = 0.67). In 10 of them (5 in each group) HCV RNA levels became undetectable. At 1 year four versus one patient had a sustained normalization of ALAT, and in one patient the HCV RNA became negative. There was no difference in the histologic progression. In this setting, in contrast to chronic cholestasis, UDCA administration induced an increase in total serum bile acids and did not change primary bile acids. CONCLUSIONS: An IFN plus UDCA combination is more effective than IFN alone in terms of ALAT but not in terms of the virologic response. These results favor the hypothesis that UDCA has an effect on the biochemical indices of cellular injury independent of a change in primary bile acids.

HBV genotypic resistance to lamivudine in kidney recipients and hemodialyzed patients.

BACKGROUND: Lamivudine is a potent inhibitor of human immunodeficiency virus reverse transcriptase and hepatitis B virus (HBV) DNA polymerase. Its overall efficiency is clearly hampered by relapse at discontinuation and by risk of genotypic resistance. We describe herein the first cases of HBV resistance to lamivudine in kidney recipients and hemodialyzed patients. METHODS: We analyzed 26 HBV-infected kidney recipients and five hemodialyzed patients treated with lamivudine who became serum HBV DNA-negative (by Digene test). The biological and virological follow-up identified breakthrough as defined by the reappearance of serum HBV DNA. In two cases of breakthrough, HBV DNA was amplified and sequenced through the polymerase domain, including the YMDD motif, before the beginning of treatment and at time of breakthrough to determine genotypic mutations. RESULTS: Ten breakthroughs (reappearance of serum HBV DNA) were observed after a median follow-up of 11 months in eight kidney recipients and two hemodialyzed patients after a median duration of treatment of 16.5 (from 4 to 31) months of treatment. Previous HBe/anti-HBe seroconversion was not observed in the patients who escaped. In two kidney recipients, the comparison of HBV-DNA sequences before the treatment and after the breakthrough identified in one case a mutation of the highly conserved YMDD motif (YVDD), whereas in the second case, no genotypic mutation was observed in the sequenced region. CONCLUSION: We report the first cases of HBV genotypic resistance to lamivudine in kidney recipients and hemodialysis patients. Genotypic resistance is observed after 4-31 months of therapy. The YMDD mutation does not account for all cases of virological escape.

Renal lesions in von Hippel-Lindau disease: immunohistochemical expression of nephron differentiation molecules, adhesion molecules and apoptosis proteins.

AIMS: Renal lesions in von Hippel-Lindau disease comprise clear cell simple cysts, atypical cysts and carcinomas. Although histological and molecular studies suggest that cystic lesions may represent precursors of carcinomas, there is no detailed phenotypic evidence of their relationship. METHODS AND RESULTS: To investigate such a possible relationship between cystic lesions and solid carcinomas, we studied the pathological and immunohistochemical features of 328 lesions of 33 kidneys originating from 23 patients with von Hippel-Lindau disease, using a panel of antibodies directed against cytoskeleton proteins, cell surface proteins, integrin subunits, adhesion molecules, lectins, and apoptosis and proliferation markers. Solid carcinomas (n = 175) were all of clear cell type and mostly nuclear grade 1. Cystic lesions (n = 138) consisted of cystic clear cell carcinomas (n = 15), atypical cysts (n = 20) and simple cysts (n = 103). Clear cells of the simple cysts, atypical cysts and solid carcinomas coexpressed cytokeratins (CK8, CK19) and vimentin, and expressed a similar pattern of tubular markers (CD24, tetraglonolobus), integrin subunits (alpha3, alpha5, alpha6, alphav, beta1) and cell adhesion molecules (ICAM 1, VCAM 1). In all lesions studied, proliferation rate (MIB1 index) was low, and apoptosis marker expression (fragmented DNA, p53, bcl-2) inconspicuous. CONCLUSIONS: Phenotypic alterations found in solid renal cell carcinomas are already present in simple and atypical renal cysts of von Hippel-Lindau disease.

Detection of circulating prostate derived cells in patients with prostate adenocarcinoma is an independent risk factor for tumor recurrence.

PURPOSE: To determine whether the presence of prostate-derived cells in the peripheral blood circulation is a marker of prostate cancer and to define the clinical impact of the test. MATERIALS AND METHODS: We tested the peripheral blood of 99 patients with prostate adenocarcinoma (PAC), 79 of them undergoing radical prostatectomy, and 92 controls (31 healthy volunteers, 50 patients with adenoma and 11 with prostatitis) using a highly controlled procedure including reverse-transcriptase polymerase chain reaction (RT-PCR) targeted to prostate-specific antigen (PSA) mRNA. Patients were followed for 26 +/- 12 (range: 4 to 49) months. Forty tumor tissues were analyzed by immunohistochemistry for expression of p53 and E-cadherin antigens. RESULTS: Thirty three (33%) patients with PAC and 2 (2%) controls scored positive (p <0.0001) for the test. Detection of circulating prostatic cells was associated with development of metastases (p <0. 001), with relapse (p <0.001) and with a serum PSA level at diagnosis higher than 15 ng./ml. (p = 0.009). The rate of development of metastases according to time was significantly higher in patients who scored positive for the test (p <0.04). In a multivariate analysis, only the RT-PCR test was an independent risk factor associated with relapse (RR: 6.7). Finally, E-cadherin expression was significantly lower in the tumor tissues of positive patients as compared with those who scored negative for the test (p <0.01). CONCLUSIONS: This RT-PCR procedure, performed at diagnosis and with appropriate controls, is a clinically useful assay in evaluating the risk of tumor recurrence after radical prostatectomy in patients with PAC.

[Conservative surgical techniques in the treatment of kidney tumors]. / Les techniques de chirurgie conservatrice pour tumeur du rein.

Several conservative operations are available for renal tumours. This article describes the anatomical bases, the measures designed to protect the parenchyma from ischaemia and the various resection techniques. Wedge resection is described in detail, as it appears to be the most rigorous technique.

Percutaneous incision of stenotic uroenteric anastomoses with a cutting balloon catheter: long-term results.

PURPOSE: To describe the technique and results of incision of strictures in anastomotic urinary diversions with a commercially available cutting balloon catheter. MATERIALS AND METHODS: Thirty-seven stenoses were treated in 32 patients. Most (28 [88%]) of the patients had undergone surgery for bladder cancer 17.7 months +/- 17.4 (SD) (range, 3-72 months) before incision. Thirteen patients had undergone ileal conduit diversion, and nineteen had undergone enterocystoplasty. All stenoses were shorter than 3 cm. The presence of adjacent ileal loops and/or iliac vessels was assessed with computed tomography before incision. The cutting wire was oriented anteriorly or anterolaterally, and the balloon was inflated with diluted contrast material during the incision. A Kaplan-Meier survival curve was constructed to illustrate the success rates over time. RESULTS: No major complications occurred. Twelve (32%) stenoses recurred in nine patients 15 months +/- 10 (range, 6-36 months) after stent removal; the failure rate was 53% (eight of 15 stenoses) for ileal conduits and 18% (four of 22 stenoses) for enterocystoplasties. Late failure (>12 months) was observed in four patients. The patency of the other 25 stenoses (23 patients) was checked 25 months +/- 11 after stent removal (range, 5-43 months). The actuarial patency rate was 77% at 1 year, 68% at 2 years, and 62% at 3 years. CONCLUSION: Cutting balloon incision is a safe and simple alternative to surgery, particularly when the urinary diversion is enterocystoplasty.

[Fournier's gangrene involving all of the scrotum: treatment by multiple repeated surgical excisions, diversion colostomy, triple antibiotic therapy and postoperative intensive care]. / Gangrène de Fournier étendue à la totalité du scrotum: traitement par excisions chirurgicales itératives multiples, colostomie de dérivation, triple antibiothérapie et réanimation post-opératoire.

OBJECTIVES: To describe and analyse the proposed therapeutic modalities to treat a series of patients suffering from Fournier's gangrene involving the entire scrotum. MATERIAL AND METHODS: Four patients with macroscopically identical lesions of Fournier's gangrene involving the entire scrotum were managed by wide surgical debridement, diversion colostomy, triple combination antibiotic therapy, transfer to surgical intensive care, multiple repeated operations under general anaesthesia for excision of atonic tissues and mesh skin grafts. The colostomy was closed after 4 months. RESULTS: All patients survived after skin cover. Three of them were reviewed 2 months after restoration of gastrointestinal continuity and presented a good general status with a satisfactory esthetic result. The fourth patient was lost to follow-up. The mean reoperation rate was 6.5 per patient. The mean intensive care stay was 9.5 weeks. CONCLUSION: The choice of intensive treatment depends on the extent of the lesions. When the entire scrotum is involved, repeated surgical excisions and systematic colostomy, combined with the other treatment modalities appear to be necessary to manage this disease, which still has a serious prognosis.

Mortality and morbidity after nephrectomy for renal cell carcinoma using a transperitoneal anterior subcostal incision.

OBJECTIVES: We have reviewed our surgical experience to document intra- and postoperative mortality and morbidity in 656 patients with renal cell carcinoma who underwent nephrectomy through a transperitoneal anterior subcostal incision (TASI). MATERIALS AND METHODS: From 1986 to 1997 we performed 656 nephrectomies for renal cell carcinoma using a TASI. Details of the surgical procedure are presented together with a retrospective analysis of the postoperative data concerning both the patient and the complications related to this approach. RESULTS: The mean time of operation was 130 min and the mean discharge from hospital 11 days. An additional surgical procedure in relation with the cancer facilitated by this approach was necessary in 2.1% of cases. The rates of intra- and postoperative complications were respectively 6.4 and 29.7%. The rate of intestinal complications was 1.8% and a splenic injury occurred in 8% of left nephrectomy. The mortality rate was 0.6%. CONCLUSIONS: The TASI is a large convenient incision which allows safe control of the renal pedicle in a very large number of renal tumors, even those located in the upper pole of the kidney. The rate of gut complications is very acceptable. Splenic injury is the major problem during left nephrectomy but careful dissection and surgical experience could decrease this complication, especially in case of upper pole renal tumor. We consider the TASI to be the main radical nephrectomy incision for renal cell carcinoma.