Which protocol for prostate biopsies in patients with a positive MRI? Interest of systematic biopsies by sectors.

BACKGROUND: Current prostate biopsy (PBx) protocol for prostate cancer (PCa) diagnosis is to perform systematic biopsies (SBx) combined with targeted biopsies (TBx) in case of positive MRI (i.e. PI-RADS ≥ 3). To assess the utility of performing SBx in combination with TBx, we determined the added value of SBx brought to the diagnosis of PCa according to their sextant location and MRI target characteristics. METHODS: In our local prospectively collected database, we conducted a single-center retrospective study including all patients with a suspicion of PCa, who underwent transrectal ultrasound-guided (TRUS) prostate biopsies (PBx) with a prior MRI and a single lesion classified as PI-RADS ≥ 3. We have characterized the SBx according to their location on MRI: same sextant (S-SBx), adjacent sextant (A-SBx), ipsilateral side (I-SBx) and contralateral side (C-SBx). The added value of SBx and TBx was defined as any upgrading to significant PCa (csPCa) (ISUP ≥2). RESULTS: 371 patients were included in the study. The added value of SBx was 10% overall. Regarding the lesion location and the SBx sextant, the added value of SBx was: 5.1% for S-SBx, 5.4% for A-SBx, 4.9% for I-SBx and 1.9% for C-SBx. The overall added value of SBx was 6.8% for PI-RADS 3 lesions, 14% for PI-RADS 4 lesions and 6.7% for PI-RADS 5 lesions (p = 0.063). The added value of SBx for contralateral side was 1.9% (2/103), 3.1% (5/163) and 0% (0/105) for PI-RADS 3, PI-RADS 4 and PI-RADS 5 lesions, respectively (p = 0,4). The added value of SBx was lower when the number of TBx was higher (OR 0.57; CI 95% 0.37-0.85; p = 0.007). CONCLUSIONS: Our results suggest that the utility of performing SBx in the contralateral lobe toward the MRI lesion was very low, supporting that they might be avoided.

Prognostic factors after adrenalectomy for adrenal metastasis.

PURPOSE: Very few studies have sought prognostic factors after adrenalectomy for metastasis. The aim of this study was to assess prognostic factors for oncological outcomes after adrenalectomy for adrenal metastasis. METHODS: All adrenalectomies for metastases performed in seven centers between 2006 and 2016 were included in a retrospective study. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method. Prognostic factors for CSS and RFS were sought by Cox regression analyses. RESULTS: 106 patients were included. The primary tumors were mostly renal (47.7%) and pulmonary (32.3%). RFS and CSS estimated rates at 5 years were 20.7% and 63.7%, respectively. In univariate analysis, tumor size (HR 3.83; p = 0.04) and the metastasis timing (synchronous vs. metachronous; HR 0.47; p = 0.02) were associated with RFS. In multivariate analysis, tumor size (HR 8.28; p = 0.01) and metastasis timing (HR 18.60; p = 0.002) were significant factors for RFS. In univariate analysis, the renal origin of the primary tumor (HR 0.1; p < 0.001) and the disease-free interval (DFI; HR 0.12; p = 0.02) were associated with better CSS, positive surgical margins with poorer CSS (HR 3.4; p = 0.01). In multivariate analysis, the renal origin of the primary tumor vs. pulmonary (HR 0.13; p = 0.03) and vs. other origins (HR 0.10; p = 00.4) and the DFI (HR 0.01; p = 0.009) were prognostic factors for CSS. CONCLUSION: In this study, tumor size and synchronous occurrence of the adrenal metastasis were associated with poorer RFS. Renal origin of the primary tumor and longer DFI were associated with better CSS. These prognostic factors might help for treatment decision in the management of adrenal metastasis.

[Outcomes of GreenLight XPS-180W laser photovaporization for BPH larger than 80mL]. / Résultats de la photovaporisation prostatique par laser GreenLight XPS-180W dans l'hyperplasie bénigne de prostate (HBP) de gros volume (≥80mL).

AIM: To evaluate the results of GreenLight XPS photovaporization (PVP/XPS) with intraoperative transrectal ultrasonographic monitoring for the treatment of large Benign Prostatic Hyperplasia (BPH) (>80mL). PATIENTS AND METHODS: Operative and perioperative data of 82 patients were collected prospectively. Complications and functional outcomes (IPSS, quality of life (QoL) score, maximal flow rate and post-void residual (PVR)) were evaluated at 1, 3, 12 months post-operatively prostate volume and PSA were assessed at 3 and 12 months post-operatively. RESULTS: Median patient age was 68.5years (50-85). Twenty percent had an indwelling catheter and 5%/22% were on anticoagulant/antiplatelet therapy. Median prostate volume and PSA were 103mL (80-220) and 6.4ng/mL (0.66-44.0). Median operative time and energy delivered were 107min (46-219) and 581kJ (212-1193). Energy delivered/prostate volume was 5.4kJ/mL (1.6-10.5). Transurethral catheter was removed at day 1 or 2 in 96% of cases. Patients were discharged as outpatient, p.o. day 1 or day 2 in 4%, 55% and 21% of cases, respectively. Transfusion and Clavien≥3 complication rates were 1.2% and 3.7%. Significant improvement of IPSS (4 vs 19.5), QoL (1 vs 5), maximum flow rate (19.1 vs 8.2mL/s) and PVR (26 vs 100mL) was observed (P<0.001) at 12-months evaluation. PSA and prostate volume were decreased by 61 and 62%. Late complications were urethral strictures (6%), stress incontinence (1.2%). Eighty-five percent of patients had no antegrade ejaculation. CONCLUSION: The treatment of large BPH with PVP/XPS is safe and effective, with a long operative time. The functional outcomes are good and stable at mid-term evaluation. LEVEL OF EVIDENCE: 4.

[Comparison of the morbidity between limited and extended pelvic lymphadenectomy during laparoscopic radical prostatectomy]. / Comparaison de la morbidité entre curage étendu et curage limité au cours de la prostatectomie radicale laparoscopique.

OBJECTIVE: To compare the morbidity of limited pelvic lymphadenectomy to extended lymphadenectomy in patients undergoing LRP (Laparoscopic Radical Prostatectomy) for clinically localized prostate cancer. PATIENTS AND METHODS: We performed a prospective monocentric study focused on 303 consecutive patients having a pelvic lymphadenectomy during LRP from June 2000 to April 2010. One hundred and seventy six patients had a limited pelvic lymphadenectomy (June 2000-June 2006, group 1). One hundred and twenty seven patients had an extended pelvis lymphadenectomy (June 2006-April 2010, group 2) including two sub-groups according to the lateral limit of the procedure i.e. with (group 2a, 60 patients) or without dissection of the lateral side of the iliac artery (group 2b, 67 patients). RESULTS: Preoperative data (age, BMI, cTNM, Gleason score and PSA) were comparable between the groups. The number of lymph nodes and the incidence of metastatic lymph nodes were lower in group 1 (6,7 lymph nodes and 5,7%) compared to group 2 (a+b) (15.6 lymph nodes and 18.9%) (P=0.001 and P=0.0004). However, there was no difference between groups 2a and 2b (15.4 and 16.7% vs 15,8 and 20.8% P=0.65 respectively). There were more complications in the extended lymphadenectomy group compared to the limited procedure (35.4% vs 14.2%, P=0.0001), in particular more lymphatic complications (27.5% vs 10.2% P=0.0001) and lymphoedema (LO) (15.7% vs 0.6% P=0.00001). However the lymphorhea (LR) and lymphocele (LC) rate was not different (P=0.11 and P=0.17). All complications were mainly of low Clavien's classification grade (1+2) whatever the group of lymphadenectomy. The hospital stay was not increased in group 2a or 2b in regard to group 1. The rate of LR and LC was higher in group 2a than in group 1 (P=0.02 and P=0.05) but not between group 2b and 1 (P=0.81 and P=0.47). CONCLUSION: Our study showed a higher rate of complications after extended pelvic lymphadenectomy but of low grade in most cases. Moreover the lateral dissection sparing the lateral side of the iliac artery reduced the risk of lymphatic complications without decreasing the number of lymph nodes removed and the rate of metastasis.

[Urinary continence following laparoscopic radical prostatectomy: qualitative analysis]. / Étude qualitative de la continence urinaire après prostatectomie radicale laparoscopique.

PURPOSE: The main purpose of this study was to report urinary continence after laparoscopic radical prostatectomy (LRP) for localised prostate cancer and the return to baseline rate for urinary continence. The minor purpose was to determine the risk factors, which influence return to baseline urinary continence after radical prostatectomy. METHODS: Prospective evaluation of urinary continence with self-administered questionnaire in 300 consecutive LRP for localized prostate cancer. RESULTS: After LRP, at 3, 6 and 12 months, respectively 12.5%, 23% and 33.7% of patients recover baseline urinary continence. Fifty-four percent, 72.3% and 78.4% of patients did not wear pads 3, 6 and 12 months after LRP. In patients without pad, 43 % recovered baseline continence one year after radical prostatectomy. In univariate analysis, age older than 60 years (P=0.003, P=0.003, P=0.02, 3, 6 and 12 months after LRP) and no sparing of neurovascular bundles (P=0.01, P=0.08 at 3 and 6 months after LRP) were risks factors of urinary incontinence. In multivariate analysis, only age older than 60 years (P=0.018, P=0.01 and P=0.01 at 3, 6 and 12 months after LRP) was a risk factor of urinary incontinence. CONCLUSION: One year after LRP, 66.3% of patients had urinary incontinence according to our evaluation using stringent criteria, i.e. return to baseline continence status. However, only 21.6% of patients wore pads and less than 2% wore more than two pads per day.

CXCR4 inhibitors selectively eliminate CXCR4-expressing human acute myeloid leukemia cells in NOG mouse model.

The chemokine receptor CXCR4 favors the interaction of acute myeloid leukemia (AML) cells with their niche but the extent to which it participates in pathogenesis is unclear. Here, we show that CXCR4 expression at the surface of leukemic cells allowed distinguishing CXCR4 (high) from CXCR4(neg/low) AML patients. When high levels of CXCR4 are expressed at the surface of AML cells, blocking the receptor function with small molecule inhibitors could promote leukemic cell death and reduce NOD/Shi-scid/IL-2Rγ(null) (NOG) leukemia-initiating cells (LICs). Conversely, these drugs had no efficacy when AML cells do not express CXCR4 or when they do not respond to chemokine CXC motif ligand 12 (CXCL12). Functional analysis showed a greater mobilization of leukemic cells and LICs in response to drugs, suggesting that they target the interaction between leukemic cells and their supportive bone marrow microenvironment. In addition, increased apoptosis of leukemic cells in vitro and in vivo was observed. CXCR4 expression level on AML blast cells and their migratory response to CXCL12 are therefore predictive of the response to the inhibitors and could be used as biomarkers to select patients that could potentially benefit from the drugs.

Targeting SKCa channels in cancer: potential new therapeutic approaches.

Many studies have reported changes in potassium channel expression in many cancers and the involvement of these channels in various stages of cancer progression. By contrast, data concerning SKCa channels (small conductance calcium-activated potassium channels) have only recently become available. This review aims i) to present the structure and physiology of SKCa channels, ii) to provide an overview of published data concerning the SKCa proteins produced in tumor cells, and, whenever possible, the biological function assigned to them and iii) to review previous and novel modulators of SKCa channels. SKCa channels are activated by low concentrations of intracellular calcium and consist of homo- or heteromeric assemblies of α-subunits named SK1, SK2 and SK3. SK2-3 channels are expressed in tumors and have been assigned a biological function in cancer cells: the enhancement of cell proliferation and cell migration by hijacking the functions of SK2 and SK3 channels, respectively. Two major classes of SKCa modulators have been described: toxins (apamin) and small synthetic molecules. Most SKCa blockers are pore blockers, but some modify the calcium sensitivity of SKCa channels without interacting with the apamin binding site. In this review, we present edelfosine and ohmline as atypical anticancer agents and novel SK3 inhibitors. Edelfosine and ohmline are synthetic alkyl-lipids with structures different from all previously described SKCa modulators. They should pave the way for the development of a new class of migration-targeted anticancer agents. We believe that such blockers have potential for use in the prevention or treatment of metastasis.

New alkyl-lipid blockers of SK3 channels reduce cancer cell migration and occurrence of metastasis.

Edelfosine is an inhibitor of SK3 channel mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, (125)I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl- 2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC(50) of 300 nM, did not displace apamin from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-antimetastatic agent.

The SK3/K(Ca)2.3 potassium channel is a new cellular target for edelfosine.

BACKGROUND AND PURPOSE: The 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (edelfosine) is an ether-linked phospholipid with promising anti-cancer properties but some side effects that preclude its full clinical therapeutic exploitation. We hypothesized that this lipid could interact with plasma membrane ion channels and modulate their function. EXPERIMENTAL APPROACH: Using cell migration-proliferation assays, patch clamp, spectrofluorimetry and ¹²5I-Apamin binding experiments, we studied the effects of edelfosine on the migration of breast cancer MDA-MB-435s cells, mediated by the small conductance Ca²(+) -activated K(+) channel, SK3/K(Ca)2.3. KEY RESULTS: Edelfosine (1 µM) caused plasma membrane depolarization by substantially inhibiting activity of SK3/K(Ca)2.3 channels, which we had previously demonstrated to play an important role in cancer cell migration. Edelfosine did not inhibit ¹²5I-Apamin binding to this SK(Ca) channel; rather, it reduced the calcium sensitivity of SK3/K(Ca)2.3 channel and dramatically decreased intracellular Ca²(+) concentration, probably by insertion in the plasma membrane, as suggested by proteinase K experiments. Edelfosine reduced cell migration to the same extent as known SK(Ca) channel blockers. In contrast, K+ channel openers prevented edelfosine-induced anti-migratory effects. SK3 protein knockdown decreased cell migration and totally abolished the effect of edelfosine on MDA-MB-435s cell migration. In contrast, transient expression of SK3/K(Ca)2.3 protein in a SK3/K(Ca)2.3-deficient cell line increased cell migration and made these cells responsive to edelfosine. CONCLUSIONS AND IMPLICATIONS: Our data clearly establish edelfosine as an inhibitor of cancer cell migration by acting on SK3/K(Ca)2.3 channels and provide insights into the future development of a new class of migration-targeted, anti-cancer agents.

Hepatic expression of SV40 small-T antigen blocks the in vivo CD95-mediated apoptosis.

We have previously demonstrated that CD95-mediated apoptosis of hepatocytes is blocked in a murine model of hepatocarcinogenesis due to the expression of SV40 early sequences encoding the large-T and small-t antigens. In this study, we set out to pinpoint the sequences involved in this apoptosis-resistant phenotype, and tested several mutants of the SV40 early region for their ability to confer protection against CD95-induced apoptosis in transgenic mice. We show that resistance to apoptosis is independent of the transforming character of the mutants and demonstrate that the expression of the small-t antigen alone in transgenic mice is sufficient to confer this resistance. Our data also reveal an increased level of activated Akt kinase in these transgenic mice, and this could account for this hitherto unknown function of the SV40 small-t antigen.

The consequence of p53 overexpression for liver tumor development and the response of transformed murine hepatocytes to genotoxic agents.

To analyse the effect of p53 on liver tumor development, we generated transgenic mice overexpressing wild-type p53 in the liver and crossed them with transgenic mice in which the expression of the SV40 large T antigen (TAg) induces hepatic tumors. Remarkably, whereas preneoplastic TAg liver exhibited anisocaryosis and anisocytosis, TAg/p53 liver never presented any dysplastic cells. Moreover, whereas expression of p53 did not affect hepatic development, its constitutive expression in tumorigenic livers resulted in a significantly enhanced apoptosis once nodules had appeared. In contrast, p53 overexpression did not modify the elevated proliferation of TAg-transformed hepatocytes and had no effect on hepatocarcinoma progression. In vitro analysis of primary hepatocytes exposed to various genotoxic agents showed that p53 failed to sensitize normal or TAg-transformed hepatocytes to apoptosis, except when high doses of doxorubicin, UV-B and UV-C radiation were used. Our results confirmed that the hepatocyte cell type is very resistant to genotoxic agents and showed that constitutive expression of p53 failed to improve their responsiveness. In addition, our results showed that suppression of dysplastic cells, probably by restoring normal cytokinesis and karyokinesis, and enhancement of apoptosis by means of p53 overexpression were insufficient to counteract or delay the TAg-induced liver tumoral progression. Oncogene (2000) 19, 3498 - 3507

GATA-1 is a potential repressor of anti-Müllerian hormone expression during the establishment of puberty in the mouse.

Anti-Müllerian hormone (AMH), also known as Müllerian inhibiting substance (MIS), is one of the earliest and best-known markers of Sertoli cell differentiation and is expressed until around puberty. The present study is aimed at the better understanding of the molecular pathways involved in testicular development and establishment of adult functions with regards to AMH regulation. We found, within the mouse AMH promoter, putative GATA motifs (A/T)GATA(A/G), known to be specifically bound by members of the GATA transcription factor family. We then carried out RNase protection assays and immunohistochemical techniques aimed at comparing precisely the chronological expression patterns of AMH and GATA-1, this latter being expressed in the testis after birth. Using both approaches we found an inverse and close relationship between AMH and GATA-1 mRNA and protein expression during the pre-pubertal period. These results allowed us to define a transitory 4-5-day period, starting from 3 dpp when both proteins are heterogeneously expressed in Sertoli cells and showed that the appearance of GATA-1 is associated with the decrease of AMH expression in these cells. Furthermore DNA-protein interaction in in vitro studies showed first that GATA-1 binds with various affinities on sites found in the AMH promoter and second that the proximity of the two strongest affinity sites leads to a synergistic binding effect. Altogether, the present study suggests that GATA-1 participates in AMH gene repression during the pre-pubertal period.

LPS challenge in D-galactosamine-sensitized mice accounts for caspase-dependent fulminant hepatitis, not for septic shock.

Experimental models of sepsis using endotoxin challenges, including studies with sensitized animals with D-galactosamine, have largely contributed to the basic rationale for innovative clinical trials in human septic shock, which have, to date, failed. The ability of these models to reproduce human disease has been highly discussed. We report here that the widely used D-galactosamine/LPS model does not account for septic shock. Treatment with YVAD-CMK, a potent tetrapeptide inhibitor of caspases of the interleukin (IL)-1beta converting enzyme (ICE) family, protects from LPS-induced liver apoptosis and mortality in D-galactosamine-sensitized mice when administered either before or up to 2 h after the lethal challenge. This curative effect is related to complete inhibition of caspase-3 activity in the liver. However, YVAD-CMK does not affect LPS-induced release of IL-1beta and does not protect from a lethal dose of LPS in unsensitized mice. These experiments demonstrate the difference between these two widely recognized experimental models of sepsis. LPS toxicity in D-galactosamine-treated mice, leading to blocked gene transcription, results from tumor necrosis factor (TNF)-alpha-induced caspase-3-dependent liver injury, not from the systemic inflammatory response. These results provide evidence that inhibitors of the ICE caspase family can prevent or even overcome the ongoing hepatic injury induced by TNF-alpha during sepsis, ischemia-reperfusion, or severe hepatitis.

The amino-terminal region of SV40 large T antigen is sufficient to induce hepatic tumours in mice.

The transforming activity of SV40 large T-antigen (Tag) depends on its binding to cellular proteins involved in the control of the cell cycle (p53, pRb, p300..) and on the J-domain region in the amino-terminus. We established transgenic lines expressing wild-type or Tag mutant proteins lacking one of the three transforming domains, to determine the respective contributions of these domains to hepatic tumour formation. Tag mutants with no pRb-binding domain or N-terminal fragment did not cause neoplastic liver abnormalities. The d11137 Tag mutant protein, which inhibits pRb function without affecting p53, induced hepatic tumours. These tumours grew significantly faster than those induced by wild-type Tag. Our results demonstrate different requirements for each of the inactivating functions of SV40 Tag in hepatocyte transformation and show that the loss of p53 function has only a moderate effect on hepatic tumour formation.

[Apoptosis and liver diseases]. / Apoptose et pathologies hépatiques.

Regulation of homeostasic balance between cell proliferation and cell death, called apoptosis, is essential for development and maintenance of multicellular organisms. Recent research into the molecular mechanisms of apoptosis has revealed that apoptosis is a genetically and evolutionarily conserved process that can become deranged when the components of the cellular apoptotic machinery are mutated, perturbated by viral gene products or present in inappropriated quantities. Analysis of the regulatory apoptotic pathways has led to a better understanding of the etiology and pathogenesis of many human diseases, notably cancers, infectious diseases or autoimmune diseases. Our understanding of the regulation of apoptosis in health and disease is far from complete and the use of understanding into new therapeutic modalities has only begun to be approached.

Fas-mediated liver damage in MRL hemopoietic chimeras undergoing lpr-mediated graft-versus-host disease.

Fas is an apoptosis-signaling receptor that triggers cell death upon binding to its ligand (FasL). Autoimmune-prone MRL/lpr mice, characterized by a spontaneous mutation of Fas, exhibit a defect in the activation-induced cell death of mature T cells through a Fas-mediated pathway. As a consequence of this defect, activated T cells accumulating in this strain overexpress the FasL and can therefore mediate in vitro Fas-dependent cytotoxicity. To determine whether hepatic injury could be the result of an interaction between T lymphocytes bearing FasL and Fas-expressing liver cells, the livers of lethally irradiated MRL+/+ recipients reconstituted with MRL/lpr lymphoid cells were studied. After transfer of MRL/lpr spleen cells, livers were infiltrated by polyclonal CD8+ T lymphocytes of lpr origin with a peak on day 21 postgrafting. These donor-derived intrahepatic lymphocytes overexpressed the FasL and exerted in vitro Fas-mediated cytotoxicity against Fas+ thymocytes, which was specifically inhibited by soluble recombinant Fas in a dose-dependent manner. These intrahepatic lymphocytes induced apoptosis in vitro, irrespective of MHC restriction, in Fas-expressing primary cultured hepatocytes. Histologic examination of the liver revealed severe endothelialitis as well as periportal and intralobular infiltrations of activated lymphocytes with apoptotic hepatocytes in their vicinity. Simultaneously, liver damage was ascertained by elevated serum transaminase levels. These observations support the notion that an Ag-independent mechanism involving FasL may play a role in certain liver pathologies.

Multiple pathways of Fas-induced apoptosis in primary culture of hepatocytes.

Fas (Apo1/CD95) is a member of the tumour necrosis factor/nerve growth factor receptor superfamily and mediates apoptosis in various cell types (for review sec [1]). Although this apoptotic activity has been clearly related to homeostasis in the immune system and pathological situations in non-lymphoid organs, the Fas signaling pathway remains mostly elusive. We and others previously showed that Fas-induced apoptosis of primary culture hepatocytes requires either an inhibitor of translation or a protein kinase inhibitor, suggesting that two distinct pathways of Fas signaling exist in hepatocytes. We report here that activation of ICE-like and CPP32-like cysteine proteases are required for Fas-mediated apoptosis, but that these pathways involve different subclasses of serine proteases and are selectively modulated by inhibitors of protein tyrosine kinases. These results confirm that distinct pathways can lead to Fas-induced apoptosis in hepatocytes. Further understanding of these pathways could facilitate the rational design of anti-apoptotic drugs in liver diseases associated with massive Fas-mediated hepatocyte apoptosis, including fulminant hepatitis.

Detection of bcl-2 rearrangement in HIV-related follicular lymphoid hyperplasia.

Rearrangement of the bcl-2 gene at the MBR (major breakpoint region) locus with the immunoglobulin heavy-chain joining region has been reported in a high proportion of follicular lymphomas. This rearrangement has also been reported in very few normal B cells of the blood, tonsils, follicular lymphoid hyperplasia (FLH) of the lymph nodes. HIV infection is often associated at the onset of the disease with FLH, but the presence of rearranged bcl-2 B cells in these lymph nodes has not been described. In using a standard PCR assay with Southern blot or a semi-nested PCR on 48 cases of FLH, we demonstrated that there were a few bcl-2 rearranged B cells in HIV FLH, at almost the same level as that in non-HIV-related FLH. The usual absence of bcl-2 rearrangement in the HIV-associated B-cell lymphomas suggests that the bcl-2 oncogene in the rearranged B cells of FLH is not cooperating with other oncogenes during HIV lymphomagenesis.

ICE inhibitor YVADcmk is a potent therapeutic agent against in vivo liver apoptosis.

In liver, apoptosis is a physiological process involved in the clearance of injured cells and in homeostatic control [1]. However, in patients with viral fulminant hepatitis or with nonacute liver diseases [2], dramatic liver failure or secondary cirrhosis results from the death of hepatocytes, which express the cell-surface receptor Fas, by apoptosis. To date, treatment of fulminant hepatitis relies mainly on orthotopic liver transplantation, which is limited by immunological complications and graft availability. Unravelling the molecular mechanisms that underlie acute liver failure could allow the design of an appropriate therapy. Ligand-bound Fas and tumour necrosis factor alpha (TNF-alpha) induce hepatic apoptosis in mice [3-6]. In various cell types, Fas- or TNF-alpha-induced apoptosis is blocked by viral proteins (such as p35 and CrmA) as well as by a decoy peptide (YVADcmk) [7-11], suggesting that these mechanisms of apoptosis involve ICE (interleukin-1 beta converting enzyme)-like proteases. Here, we report that, in vivo, pre-treatment of mice with YVADcmk protects them from the lethal effect of anti-Fas antibody and from liver failure induced by injection of TNF-alpha. Remarkably, YVADcmk administration is also highly effective in rescuing mice that have been pretreated with anti-Fas antibody from rapid death, despite extensive hepatic apoptosis. This dramatic curative effect could be of clinical benefit for the treatment of viral and inflammatory liver diseases.