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International audience; Context: Although antiangiogenic treatments and immunotherapies have significantly improved the prognosis of metastatic renal cell carcinoma (RCC), many patients will develop resistance, leading to treatment failure. Genetic tumor heterogeneity is a major cause of this resistance.Objective: To perform a meta-analysis of genomic data for clear-cell RCC obtained from primary tumors and metastases to assess the prevalence of gene mutations and copy number alterations (CNAs).Evidence acquisition: Articles were selected from Medline and Embase libraries using the search algorithm ("Kidney Neoplasms"[Mesh] OR "Renal Cell Carcinoma") AND ("Genomics"[Mesh] OR "Mutation") from January 1999 to February 2021. A critical review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. Ninety-three publications were selected for inclusion in this meta-analysis.Evidence synthesis: Our meta-analysis included a total 14 696 patients, 14 299 primary tumor samples, and 969 metastatic samples. We evaluated the overall and subgroup prevalence of gene mutations and CNAs, including comparisons between primary tumors and metastases. In particular, for metastases we observed that the mutation prevalence was significantly more marked for ten genes compared to primary tumors, with no or little heterogeneity across studies. The VHL mutation prevalence increased significantly from 64% in primary tumors to 75% in metastases (p < 0.001). There was a significant increase in CNA prevalence from primary tumors to metastases for chromosomes 1p36.11, 9p21.3, and 18 in terms of losses, and for chromosomes 1q21.3, 7q36.3, 8q, and 20q11.21 in terms of gains. CDKN2A, also called p16 and involved in cell-cycle progression, is located at the 9p21.3 locus and was lost in 76% of metastatic samples. ASXL1, located on 20p11.21 and amplified in 50% of metastatic RCCs compared to 21% of primary tumors (p < 0.001), is closely linked to BAP1 function.Conclusions: Our results underline the added value of preferential biopsies on RCC metastases to fully explore the biology of metastatic disease for therapeutic purposes.Patient summary: We reviewed the literature on genetic mutations in primary tumors and metastatic lesions in kidney cancer. Our pooled results for all the relevant studies show a higher level of mutations in metastases than in primary tumors. This highlights the importance of taking biopsies of metastases to analyze genetic mutations and potentially guide selection of the most suitable treatment strategy.

Resume Objectifs On observe dans l’Herault une nette augmentation de l’incidence des cancers urologiques. Le registre des tumeurs de l’Herault (RTH) a recueilli 1961 tumeurs urologiques en 2016, soit 21,4 % de l’ensemble des tumeurs de l’Herault pour cette annee-la. La creation d’un registre specialise en onco-urologie nous est apparue necessaire. L’objectif de cet article est de decrire le fonctionnement de RHESOU et de donner quelques exemples de resultats. Materiel et methodes En novembre 2018, RHESOU (Registre de l’herault specialise en onco-urologie) a ete cree sur le meme mode de fonctionnement qu’un registre. Il permet de completer les donnees du RTH sur beaucoup d’autres parametres oncologiques. Pour chaque type de cancer urologique et genital masculin et urologique feminin, une fiche de recueil a ete realisee pour recueillir le maximum de donnees presentes dans le dossier des cas signales. Cette etude a evalue les donnees concernant les patients domicilies dans l’Herault pour l’annee 2017. Resultats Nous avons denombre pour l’annee 2017, 970 cancers de la prostate, 581 tumeurs de vessie, 212 cancers du rein, 51 tumeurs de la voie excretrice superieure, 28 cancers du testicule et 9 cancers du penis. Le recueil de ces donnees permet de creer des requetes et de fournir des analyses pertinentes et detaillees sur les cancers urologiques et genitaux masculins. Nous rapportons les donnees analysees sur le rein, la vessie et la prostate. Conclusions RHESOU est un outil accessible pour permettre une vue d’ensemble sur les cancers en urologie dans l’Herault et leur prise en charge. Avec l’apparition de nouveaux traitements, il saura s’adapter en permettant une evolution des fiches. Niveau de preuve 3.

International audience; In recent years, a growing number of studies have evaluated the role of exosomes in pancreatic ductal adenocarcinoma cancer (PDAC) demonstrating their involvement in a multitude of pathways, including the induction of chemoresistance. The aim of this review is to present an overview of the current knowledge on the role of exosomes in the resistance to gemcitabine and nab-paclitaxel, which are two of the most commonly used drugs for the treatment of PDAC patients. Exosomes are vesicular cargos that transport multiple miRNAs, mRNAs and proteins from one cell to another cell and some of these factors can influence specific determinants of gemcitabine activity, such as the nucleoside transporter hENT1, or multidrug resistance proteins involved in the resistance to paclitaxel. Additional mechanisms underlying exosome-mediated resistance include the modulation of apoptotic pathways, cellular metabolism, or the modulation of oncogenic miRNA, such as miR-21 and miR-155. The current status of studies on circulating exosomal miRNA and their possible role as biomarkers are also discussed. Finally, we integrated the preclinical data with emerging clinical evidence, showing how the study of exosomes could help to predict the resistance of individual tumors, and guide the clinicians in the selection of innovative therapeutic strategies to overcome drug resistance.

International audience; BACKGROUND: The prognostic impact of multifocal upper-tract urothelial carcinoma (UTUC) is poorly understood. OBJECTIVE: To investigate the association between tumor multifocality and clinicopathologic features and outcomes of UTUC in patients managed by radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS: The study included 2492 patients treated with either open or laparoscopic RNU. Tumor and patient characteristics included tumor stage, tumor grade, lymph node status, lymphovascular invasion (LVI), tumor architecture, tumor location, unifocal or multifocal disease, gender, age, history of bladder cancer (BCa), Eastern Cooperative Oncology Group (ECOG) performance status (PS), and adjuvant chemotherapy. tumor multifocality of UTUC was defined as the synchronous presence of multiple tumors in the renal pelvis or ureter. INTERVENTION: All patients were treated with either open or laparoscopic RNU. MEASUREMENTS: Univariable and multivariable models tested the effect of tumor multifocality on disease progression and cancer-specific mortality. RESULTS AND LIMITATIONS: Five hundred ninety patients (23.7%) had tumor multifocality at the time of RNU. The median follow-up was 45 mo (interquartile range [IQR]: 0-101). Tumor multifocality was significantly associated with a history of previous BCa (p=0.032), lymph node involvement (p=0.036), tumor location in the ureter (p=0.003), higher tumor stage (p

International audience; PURPOSE: The polyamines spermine and spermidine are ubiquitous polycationic structures which are essential for cell proliferation and differentiation. Circulating polyamines, spermine and spermidine, represent valuable prognostic markers in prostate cancer, acute leukemia and supratentorial malignant glioma. We tested whether spermine and spermidine could improve the prognostic ability of several established predictors of cancer specific mortality after partial or radical nephrectomy for renal cell carcinoma. MATERIALS AND METHODS: Testing was performed on 399 patients with stages T(1-4), N(0-2), M(0-1) renal cell carcinoma who were treated with radical or partial nephrectomy at a single institution between 1990 and 2007. Univariable and multivariable Cox regression models tested the prognostic ability of spermine and spermidine levels in cancer specific mortality predictions. Covariates consisted of TNM stage, Fuhrman grade, tumor size and symptom classification. Harrell's concordance index (c-index) quantified accuracy and 200 bootstrap resamples were used to correct for overfit bias. RESULTS: The 5-year cancer specific mortality-free survival of patients with spermine levels 3 or less, 3.1 to 8, 8.1 to 13 and greater than 13 nmol/8x10(9) erythrocytes was 88.8%, 75.8%, 40.2% and 21.8%, respectively. Similarly the 5-year cancer specific mortality-free survival of patients with spermidine levels 12 or less, 12.1 to 15, 15.1 to 21 and greater than 21 nmol/8x10(9) erythrocytes was 79.0%, 56.6%, 53.2% and 27.4%, respectively. On multivariable analyses addressing cancer specific mortality after surgery spermine (p = 0.007) and spermidine (p = 0.04) achieved independent predictor status. Consideration of spermine and spermidine also improved the accuracy of established cancer specific mortality predictors by 2.2% (p

International audience; Prognostic factors in the setting of treated metastatic renal cell carcinoma (mRCC) can theoretically predict drug response, progression-free survival or overall survival. These factors are potentially useful for informing patients and for tailoring medical treatment according to risk assessment. Prognostic factors were well defined in the era of immunotherapy. Since 2006, tyrosine kinase inhibitors and anti-angiogenic drugs have revolutionized the treatment of mRCC by improving progression-free survival and overall survival. Physicians now need new predictive tools adapted to targeted therapies. The aim of our study was to review the current knowledge about prognostic factors in mRCC by focusing on anatomical, clinical, biological, histological, radiological and molecular parameters. The most recent integrated prognostic models will be reviewed as well.

BACKGROUND: Relative to radical nephrectomy (RN), partial nephrectomy (PN) performed for renal cell carcinoma (RCC) may protect from non-cancer-related deaths. The authors tested this hypothesis in a cohort of PN and RN patients. METHODS: The Surveillance, Epidemiology, and End Results-9 database allowed identification of 2198 PN (22.4%) and 7611 RN (77.6%) patients treated for T1aN0M0 RCC between 1988 and 2004. Analyses matched for age, year of surgery, tumor size, and Fuhrman grade addressed the effect of nephrectomy type (RN vs PN) on overall mortality (Cox regression models) and on non-cancer-related mortality (competing-risks regression models). RESULTS: Relative to PN, RN was associated with 1.23-fold (P = .001) increased overall mortality rate, which translated into a 4.9% and 3.1% absolute increase in mortality at 5 and 10 years after surgery, respectively. Similarly, non-cancer-related death rate was significantly higher after RN in competing-risks regression models (P < .001), which translated into a 4.6% and 4.5% absolute increase in non-cancer-related mortality at 5 and 10 years after surgery, respectively. CONCLUSIONS: Relative to PN, RN predisposes to an increase in overall mortality and non-cancer-related death rate in patients with T1a RCC. In consequence, PN should be attempted whenever technically feasible. Selective referrals should be considered if PN expertise is unavailable Cancer 2009. © 2009 American Cancer Society.

Item does not contain fulltext PURPOSE: Fuhrman grade represents a key determinant of the natural history of small renal masses that represent renal cell carcinoma. We tested whether renal mass biopsy prediction of Fuhrman grade in the nephrectomy specimen could be safely substituted for by an accurate statistical model. To date the best available model has shown poor accuracy (55.6%), which is close to flipping a coin (50%) and clearly inadequate for use in clinical practice. MATERIALS AND METHODS: We identified 1,139 patients with T1aN0M0 renal cell carcinoma treated with partial or radical nephrectomy at 11 participating institutions from 1989 to 2004. This cohort was used in univariate and multivariate logistic regression models predicting high Fuhrman grade (III-IV) at nephrectomy. Predictors included age at diagnosis, gender, tumor size and symptom classification. Multivariate logistic regression coefficients were used to generate a nomogram. RESULTS: The rate of Fuhrman grade III-IV in patients with T1aN0M0 renal cell carcinoma was 12.3%. Stratifying patients with Fuhrman grade III-IV by age, gender, histological subtypes and sample size failed to reveal statistically significant differences. On univariate analysis predicting Fuhrman grade III-IV at nephrectomy only tumor size was a statistically significant predictor (p = 0.05). The most accurate multivariate nomogram for Fuhrman grade III-IV prediction was 58.3% (95% CI 57.8-58.9) accurate. Of all tested predictors only tumor size achieved independent predictor status (p = 0.009). CONCLUSIONS: Our analysis derived in European patients shows that statistical models cannot safely replace renal mass biopsy based prediction of Fuhrman grade III-IV at nephrectomy. Our findings corroborate a report from the United States in which a similar model had 55.6% accuracy. Jointly the studies indicate that statistical models are unreliable and cannot safely be substituted for renal mass biopsy in North American or European patients.

International audience; De novo tumors in renal allografts are rare and their prevalence is underestimated. We therefore analyzed renal cell carcinomas arising in renal allografts through a retrospective French renal transplant cohort. We performed a retrospective, multicentric survey by sending questionnaires to all French kidney transplantation centers. All graft tumors diagnosed after transplantation were considered as de novo tumors. Thirty-two centers participated in this study. Seventy-nine tumors were identified among 41 806 recipients (Incidence 0.19%). Patients were 54 men and 25 women with a mean age of 47 years old at the time of diagnosis. Mean tumor size was 27.8 mm. Seventy-four (93.6%), 53 (67%) and 44 tumors (55.6%) were organ confined (T1-2), low grade (G1-2) and papillary carcinomas, respectively. Four patients died of renal cell carcinomas (5%). The mean time lapse between transplantation and RCC diagnosis was 131.7 months. Thirty-five patients underwent conservative surgery by partial nephrectomy (n = 35, 44.3%) or radiofrequency (n = 5; 6.3%). The estimated 5 years cancer specific survival rate was 94%. Most of these tumors were small and incidental. Most tumors were papillary carcinoma, low stage and low grade carcinomas. Conservative treatment has been preferred each time it was feasible in order to avoid a return to dialysis.

International audience; OBJECTIVE: *To assess the impact of differences in ethnicity on clinico-pathological characteristics and outcomes of patients with upper urinary tract urothelial carcinoma (UTUC) in a large multi-center series of patients treated with radical nephroureterectomy (RNU). MATERIALS AND METHODS: *We retrospectively collected the data of 2163 patients treated with RNU at 20 academic centres in America, Asia, and Europe. *Univariable and multivariable Cox regression models addressed recurrence-free survival (RFS) and cancer-specific survival (CSS). RESULTS: *In all, 1794 (83%) patients were Caucasian and 369 (17%) were Japanese. All the main clinical and pathological features were significantly different between the two ethnicities. *The median follow-up of the whole cohort was 36 months. At last follow-up, 554 patients (26%) developed disease recurrence and 461 (21%) were dead from UTUC. *The 5-year RFS and CSS estimates were 71.5% and 74.2%, respectively, for Caucasian patients compared with 68.8% and 75.4%, respectively, for Japanese patients. *On univariable Cox regression analyses, ethnicity was not significantly associated with either RFS (P= 0.231) or CSS (P= 0.752). *On multivariable Cox regression analyses that adjusted for the effects of age, gender, surgical type, T stage, grade, tumour architecture, presence of concomitant carcinoma in situ, lymphovascular invasion, tumour necrosis, and lymph node status, ethnicity was not associated with either RFS (hazard ratio [HR] 1.1; P= 0.447) or CSS (HR 1.0; P= 0.908). CONCLUSIONS: *There were major differences in the clinico-pathological characteristics of Caucasian and Japanese patients. *However, RFS and CSS probabilities were not affected by ethnicity and race was not an independent predictor of either recurrence or cancer-related death.

Item does not contain fulltext CONTEXT AND OBJECTIVES: The European Association of Urology Guideline Group for renal cell carcinoma (RCC) has prepared these guidelines to help clinicians assess the current evidence-based management of RCC and to incorporate the present recommendations into daily clinical practice. EVIDENCE ACQUISITION: The recommendations provided in the current updated guidelines are based on a thorough review of available RCC guidelines and review articles combined with a systematic literature search using Medline and the Cochrane Central Register of Controlled Trials. EVIDENCE SYNTHESIS: A number of recent prospective randomised studies concerning RCC are now available with a high level of evidence, whereas earlier publications were based on retrospective analyses, including some larger multicentre validation studies, meta-analyses, and well-designed controlled studies. CONCLUSIONS: These guidelines contain information for the treatment of an individual patient according to a current standardised general approach. Updated recommendations concerning diagnosis, treatment, and follow-up can improve the clinical handling of patients with RCC. 01 september 2010

International audience; AIMS: In clear cell renal cell carcinoma (CCRCC), vascular endothelial growth factor (VEGF) represents the central positive mediator of tumour angiogenesis while VEGF receptor (VEGFR) is the primary target of anti-angiogenic therapies. TIMP3 is a physiological VEGFR-2 antagonist and thus could be considered as an anti-angiogenic factor. We therefore determined the status of this physiological inhibitor in CCRCC. PATIENTS AND METHODS: Archival tumour from 105 patients was studied. TIMP3 expression was analysed using immuno-histochemistry and real-time RT-PCR. Results were correlated with clinicopathological variables. To analyse the mechanisms of gene silencing involved, we performed Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-specific MLPA (MS-MLPA). At last, we evaluated the main upstream pathway described implicating TGFbetaRII, which induces TIMP3 expression. RESULTS: A down-expression of TIMP3, determined by immunohistochemistry, affected 100/105 renal cancers (95.2%). TIMP3 mRNA levels were significantly lower in high-grade tumours. Loss of heterozygosity of the TIMP3 gene was observed in 8 tumours (7.6%) and the 5'CpG island of the TIMP3 promoter was found to be methylated in 25 tumours (23.8%). A down-expression of TGFbetaRII was found in 85/105 CCRCCs (80.9%). A significant correlation was found between TIMP3 expression and TGFbetaRII expression. CONCLUSIONS: This is the first demonstration that the loss of TIMP3 expression is observed in almost all CCRCCs. This loss of expression is a common molecular event in CCRCC. It may be an important initiation step for tumour development in a complex process implicating loss of heterozygosity on chromosome 22q, promoter hyper-methylation and inactivation of the TGFbetaRII pathway.

International audience

OBJECTIVE To examine population-based rates of cancer-specific and other-cause mortality after either non-surgical management (NSM) or nephrectomy, in patients with small renal masses, as several reports from selected institutions support the applicability of surveillance in patients with small renal masses, but there are no population-based studies confirming the general applicability of this therapy. PATIENTS AND METHODS Of 43 143 patients with renal cell carcinoma identified in the 1988–2004 Surveillance, Epidemiology and End Results database, 10 291 had localized small renal masses (≤4 cm) and were offered NSM (433, 4.2%) or nephrectomy (9858, 95.8%). Univariable matched and multivariable unmatched competing-risks regression models were used in the analyses. RESULTS Cumulative incidence plots based on unmatched data, where the effect of other-cause mortality was controlled for, showed a 5.2%, 6.5% and 9.4% survival benefit for nephrectomy vs NSM at 1, 2 and 5 years after nephrectomy or diagnosis, respectively. The same magnitude of the benefit (4.5%, 5.6% and 8.0%) persisted in analyses matched for age, tumour size and year of diagnosis or of nephrectomy. Finally, in multivariable analyses, treatment type, age, tumour size and year of diagnosis or of nephrectomy were independent predictors. CONCLUSION Relative to nephrectomy, NSM appears to undermine the overall and cancer-specific survival of patients with small renal masses by as much as 9.4%, at 5 years.

International audience; OBJECTIVE: To identify independent predictors of renal failure after partial nephrectomy (PN) in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: Data were available for 166 patients with pathological T1-3 N0M0 RCC treated with PN. Renal failure after PN was defined as a decrease in glomerular filtration rate (GFR) of >25% (RIFLE criteria). The GFR before and after PN was estimated using the Modification of Diet in Renal Disease study group equation. Univariable and multivariable logistic regression models were used to assess a decrease of >25% in GFR from the preoperative level. Candidate predictor variables were age, gender, PN indication (absolute vs relative), preoperative GFR, tumour size, perioperative blood loss, surgery duration and clamping time. RESULTS: After PN, 22 (13.3%) patients had a decrease in GFR of >25%. The perioperative blood loss (P = 0.02), clamping time (P = 0.04) and preoperative GFR (P = 0.002) were independent predictors of a decrease in GFR of >25%. CONCLUSIONS: We identified two important potentially modifiable variables that should be considered in the planning of PN, i.e. the clamping time and blood loss. It is possible that selective referral to experienced surgeons who can perform PN within short surgical and clamping times, and with minimal blood loss, could minimize the rate of renal failure, especially in patients with an underlying renal function impairment.

The treatment of cancer usually involves lethal effect on normal body cells as side effects. Cheminformatics methodology can play a significant role in biomed/clinical scientific research. Similarity searching is a standard cheminformatics tool in drug discovery area and database design. In this study, five novel herbal extracts in combination with doxorubicin and cisplatin have been used to sensitize ACHN and A2780/cp cells. These herbal extracts have been selected on the basis of novel cheminformatics methodology and assayed for the first time. The findings confirmed predicted outcomes from the in silico research and the results introduced may bring to use the effects of these herbs in reversing of multidrug resistance (MDR) phenomenon. Highlights? These herbal extracts have been selected on the basis of novel cheminformatics methodology and assayed for the first time. ? Results introduce selectivity effect of extract in inducing cytotoxicity on cancerous cell lines with synergistic effect. ? The findings confirmed that in silico predictions can bring to use the effects of these herbs in reversing of MDR phenomenon.

International audience; We attempted to describe, in a series of clear cell renal cell carcinoma (RCC), the relationship between CAIX expression, VHL gene mutations, tumor characteristics and outcome. Radical nephrectomy was performed in 100 patients. Genomic DNA was extracted from frozen tumor samples. Four amplimers covering the whole coding sequence of the VHL gene were synthesized by PCR and sequenced. The monoclonal antibody M75 was used to evaluate CAIX protein expression immunohistochemically. VHL mutations were identified in 58 patients (58%) and high CAIX expression (>85%) was observed in 78 (78%). Tumors with VHL mutation showed higher CAIX expression than those without (p = 0.02). Low CAIX expression and absence of VHL mutation were associated with a more advanced tumors e.g., higher T stages and presence of metastases. VHL mutation and high CAIX expression predicted longer progression-free survival (p = 0.037) and disease-specific survival (p = 0.001), respectively. In combination, they defined three prognostic groups (p = 0.002): (i) good prognosis, defined as VHL mutation and high CAIX (2-year survival: 86%), (ii) intermediate prognosis with either VHL mutation or high CAIX (69%), and (iii) poor prognosis with no VHL mutation and low CAIX (45%, median survival 18 months). CAIX expression, but not VHL mutational status, was an independent prognostic factor in multivariate analysis. Taken together, CAIX expression and VHL mutational status are able to stratify patients with clear cell RCC into distinct groups with regards to clinicopathological variables and prognosis, with low CAIX expression and absence of VHL mutation being associated with a poor clinicopathological phenotype and diminished survival.

International audience; A 75-yr-old previously healthy woman presented with gross hematuria, European Cooperative Oncology Group 0, and an 11-cm renal mass with right atrial thrombus. The patient refused the sternotomy. She was offered two cycles of sunitinib maleate (Sutent) induction therapy to down-stage the thrombus and to reduce the extent of the surgery.

International audience; Over the past 2 decades, a greater understanding of the basic biology and genetics of kidney cancer has occurred. Surgical techniques have also evolved, and technological advances have made possible new methods of managing renal tumors. The most extensively used system to provide prognostic information for renal cell carcinoma (RCC) is currently the tumor, nodes, metastasis (TNM) staging system. Emerging data over the last few years has questioned whether further revisions are needed and if improvements can be made with the introduction of new, more accurate and predictive prognostic factors. The recent discovery of molecular tumor biomarkers are expected to revolutionize the staging of RCC and potentially lead to the development of new therapies based on molecular targeting. This review will examine the current staging modalities and prognostic factors associated with RCC as well as the selection of patients most likely to benefit from clinical trials.

The aim of this study is to evaluate immediate technical and clinical results of palliative transarterial renal embolization in patients with symptomatic renal tumors.Parenchymal embolization of 20 renal tumors was performed in 20 symptomatic patients with hematuria and/or lumbar pain and/or para-neoplastic syndrome. Seven patients were inoperable because of poor general condition, and 15 patients had metastatic lesions.Immediate technical success was observed, with post-infarction pain in all patients requiring analgesia in 12 cases (which was successful in 90%); 8 patients had transitory fever. With a median follow up of 8.1 (range 4-27) months, recurrent hematuria was noted in two patients for which partial embolization was initially chosen; pain did not recur in any patients.Palliative embolization of advanced symptomatic renal tumors is easy to accomplish with low morbidity. It helps to alleviate invalidating symptoms in a multidisciplinary management of advanced renal tumors.

BackgroundCD40L was found to reduce doxorubicin-induced apoptosis in non Hodgkin's lymphoma cell lines through caspase-3 dependent mechanism. Whether this represents a general mechanism for other tumor types is unknown.MethodsThe resistance induced by CD40L against apoptosis induced by a panel of cytotoxic chemotherapeutic drugs in non Hodgkin's lymphoma and breast carcinoma cell lines was investigated.ResultsDoxorubicin, cisplatyl, etoposide, vinblastin and paclitaxel increased apoptosis in a dose-dependent manner in breast carcinoma as well as in non Hodgkin's lymphoma cell lines. Co-culture with irradiated L cells expressing CD40L significantly reduced the percentage of apoptotic cells in breast carcinoma and non Hodgkin's lymphoma cell lines treated with these drugs. In breast carcinoma cell lines, these 5 drugs induced an inconsistent increase of caspase-3/7 activity, while in non Hodgkin's lymphoma cell lines all 5 drugs increased caspase-3/7 activity up to 28-fold above baseline. Co-culture with CD40L L cells reduced (-39% to -89%) the activation of caspase-3/7 induced by these agents in all 5 non Hodgkin's lymphoma cell lines, but in none of the 2 breast carcinoma cell lines. Co culture with CD40L L cells also blocked the apoptosis induced by exogenous ceramides in breast carcinoma and non Hodgkin's lymphoma cell lines through a caspase-3-like, 8-like and 9-like dependent pathways.ConclusionThese results indicate that CD40L expressed on adjacent non tumoral cells induces multidrug resistance to cytotoxic agents and ceramides in both breast carcinoma and non Hodgkin's lymphoma cell lines, albeit through a caspase independent and dependent pathway respectively.