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OBJECTIVE To evaluate the ability of neoadjuvant axitinib to reduce the size of T2 renal cell carcinoma (RCC) for shifting from a radical nephrectomy (RN) to a partial nephrectomy (PN) indication, offering preservation of renal function. PATIENTS AND METHODS Patients with cT2aN0NxM0 clear-cell RCC, considered not suitable for PN, were enrolled in a prospective, multicentre, phase II trial (AXIPAN). Axitinib 5 mg, and up to 7-10 mg, was administered twice daily, for 2-6 months before surgery, depending on the radiological response. The primary outcome was the number of patients receiving PN for a tumour

Objectives: Patient adherence is a challenge in oncology and hematology practice. Hormone therapy data in breast cancer suggest insufficient adherence and poor persistence. Limited data are available for targeted therapies (TT) including tyrosine kinase and mammalian target of rapamycin inhibitors. Methods: We performed a prospective survey using a 15-item questionnaire in patients with solid tumors and hematologic malignancies receiving oral anticancer therapy. Treatment duration, setting (adjuvant vs. metastatic), cancer type, age, and comedication were recorded. Results: 201 patients (median age 65.5 years) participated, 102 with TT and 99 with hormone therapy or chemotherapy (HC). The median time of drug intake was 11.0 months. Written information was more frequently given to TT patients (68.6 vs. 23.2%, p < 0.0001). TT and HC patients showed equal adherence to therapy (72.5 vs. 69.6%, p = n.s.) despite TT patients experiencing more side effects (p < 0.0001) and taking more concomitant oral medication (p = 0.0042). Forgotten doses were the leading cause of nonadherence in HC patients (83%, as compared to 54% in the TT group), whereas dose reduction by the patient was higher in the TT group (32 vs. 17%). Conclusions: Despite advances in providing information to patients leading to better adherence among TT patients, efforts towards better patient education are warranted including dedicated staff for monitoring outpatient anticancer oral therapy.

To date, oral everolimus is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with vascular endothelial growth factor-targeted therapy, and intravenous temsirolimus for the first-line treatment of patients with poor prognosis metastatic renal cell carcinoma. However, some factors could guide the treatment choice aiming to individualize a treatment plan. Besides the crucial issue of treatment efficacy, other factors are to be considered such as disease status, histological subtype, extent of the disease, patient-specific factors, and agent-specific factors. All of these considerations have to stay in the frame of guideline recommendations which represent evidence-based medicine. The purpose of this article is to summarize the main pharmacological and pharmacokinetic characteristics of mTOR inhibitors, and to define targeted populations according to prognostic indexes.

International audience; BACKGROUND:Little is known about the cognitive effects of antiangiogenic therapies (AATs) in metastatic renal cell carcinoma (mRCC) and their relation with fatigue.OBJECTIVE:To evaluate the impact of AATs on cognition and its connection with fatigue and quality of life (QoL) in patients with mRCC.DESIGN, SETTING, AND PARTICIPANTS:This prospective study enrolled 75 patients starting AAT as first or second line for mRCC and assessed them at 3 mo (n=58) and 6 mo (n=50).OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:We assessed objective cognitive decline with a neuropsychological battery of tests and cognitive complaint, fatigue, and QoL with validated self-reported questionnaires using the Fisher exact test, Wilcoxon test, and Spearman correlation coefficient.RESULTS AND LIMITATIONS:A decline of cognitive functions was observed in 18 patients (31%) including 13 without cognitive impairment at baseline. The score of fatigue was increased in all patients except one. A relationship between cognitive complaints and fatigue was observed (p

Purpose Complete remission (CR) is uncommon during treatment for metastatic renal cell carcinoma (mRCC) with tyrosine kinase inhibitors (TKIs), but it may occur in some patients. It remains a matter of debate whether therapy should be continued after CR. Methods A multicenter, retrospective analysis of a series of patients with mRCC who obtained CR during treatment with TKIs (sunitinib or sorafenib), either alone or with local treatment (surgery, radiotherapy, or radiofrequency ablation), was performed. Results CR was identified in 64 patients; 36 patients had received TKI treatment alone and 28 had also received local treatment. Most patients had clear cell histology (60 of 64 patients), and all had undergone previous nephrectomy. The majority of patients were favorable or intermediate risk; however, three patients were poor risk. Most patients developed CR during sunitinib treatment (59 of 64 patients). Among the 36 patients who achieved CR with TKI alone, eight continued TKI treatment after CR, whereas 28 stopped treatment. Seventeen patients who stopped treatment (61%) are still in CR, with a median follow-up of 255 days. Among the 28 patients in CR after TKI plus local treatment, 25 patients stopped treatment, and 12 of these patients (48%) are still in CR, with a median follow-up of 322 days. Conclusion CR can occur after TKI treatment alone or when combined with local treatment. CR was observed at every metastatic site and in every prognostic group.

Several types of cardiovascular complications can occur during treatment with targeted therapies: heart failure, QTc lengthening, arterial and venous thrombosis. A clinical examination, ECG and cardiac ultrasound are essential before starting treatment with targeted therapy. Patients with no medical history, who are asymptomatic with a normal ECG and a left ventricular ejection fraction (LVEF) greater than 50% can begin molecular targeted therapy (MTT). Patients must be assessed by a cardiologist before the introduction of MTT if they have a history of ischemic or valvular heart disease, heart failure, atrial fibrillation, stroke, transient ischemic attack, or ECG anomalies (Q wave, supraventricular arrhythmia, QT greater than 500ms), or LVEF less than 50%. In patients who are symptomatic (dyspnoea, angina, syncope, embolism etc.) and/or present with a modification to the ECG or alteration to the LVEF, MTT must be stopped and reassessment by a cardiologist is indicated. The restarting of MTT following a cardiovascular complication must be subject to a multidisciplinary discussion taking into account the severity of the cardiac event, its reversibility with cardiac treatment, life expectancy of the patient as well as the expected efficacy of the drug.

Three clinical cases have shown the superiority of sunitinib in first line therapy intermediate risk metastatic clear cell renal carcinoma and a best safety of bevacizumab plus interferon, the current lack of high level of evidence arguments for the neo-adjuvant treatment of kidney cancer, the importance to prevent mucositis during a mTOR inhibitors treatment and the diagnostic pitfalls of its pulmonary complications.

Although advanced prostate cancer patients respond very well to front-line androgen deprivation, failure to hormonal therapy most often occurs after a median time of 18–24 months. The care of castration-resistant prostate cancer (CRPC) has significantly evolved over the past decade, with the onset of first-line therapy with docetaxel. Although numerous therapy schedules have been investigated alongside docetaxel, in either first-line or salvage therapy, results were dismal. However, CRPC chemotherapy is currently evolving, with, on the one hand, new agents targeting androgen metabolism and, on the other hand, significant progress in chemotherapy drugs, particularly for second-line therapy. The aim of the present review is to describe the current treatments for CRPC chemotherapy alongside their challengers that might shortly become new standards. In this article, we discuss the most recent data from clinical trials to provide the reader with a comprehensive, state-of-the-art overview of CRPC chemotherapy and hormonal therapy.

Direct side effects of the inhibition of activation of VEGF receptors are well known and could be easily explained (HTA). The indirect toxicity of the inhibitors of tyrosinekinases is much less known and several hypotheses appear. Usually, the common side effects of the inhibitors of tyrosine-kinases can be easily managed and are reversible when the treatment is stopped. Their management is essentially based on prevention measures. It is necessary to stop definitively or temporarily the treatment in case of intensification of pre-existing comorbidities or side effects of rank 3 or 4. There is no predictive factor of treatment toxicity and, at the moment, there is thus no indication in a previous dose adaptation.

Purpose Temsirolimus, an inhibitor of the mammalian target of rapamycin, has single-agent activity against advanced renal cell carcinoma (RCC). A recommended dose and safety profile for the combination of temsirolimus and interferon alfa (IFN) were determined in patients with advanced RCC. Patients and Methods Patients were enrolled onto a multicenter, ascending-dose study of temsirolimus (5, 10, 15, 20, or 25 mg) administered intravenously once a week combined with IFN (6 or 9 million units [MU]) administered subcutaneously three times per week. An expanded cohort was treated at the recommended dose to obtain additional safety and efficacy information. Results Seventy-one patients were entered to receive one of six dose levels. The recommended dose was temsirolimus 15 mg/IFN 6 MU based on dose-limiting toxicities of stomatitis, fatigue, and nausea/vomiting, which were observed at higher doses of temsirolimus and IFN. The most frequent grade 3 or 4 toxicities occurring in any cycle included leukopenia, hypophosphatemia, asthenia, anemia, and hypertriglyceridemia for all patients and those who received the recommended dose. Among patients who received the recommended dose (n = 39), 8% achieved partial response and 36% had stable disease for at least 24 weeks. Median progression-free survival for all patients in the study was 9.1 months. Conclusion The combination of temsirolimus and IFN has an acceptable safety profile and displays antitumor activity in patients with advanced RCC. Temsirolimus 15 mg plus IFN 6 MU is the recommended dose for evaluation in a randomized phase III study.

Collecting duct carcinoma of the kidney is a rare and aggressive neoplasm of the distal collecting tubules for which there is no established treatment. Since the histology of collecting duct carcinoma is similar to that of urothelial carcinoma, the standard chemotherapy regimen defined by a gemcitabine and platinum salts combination was prospectively investigated in patients with metastatic collecting duct carcinoma.A total of 23 patients with metastatic collecting duct carcinoma with no prior systemic chemotherapy were treated with 1,250 mg/m(2) gemcitabine on days 1 and 8 plus 70 mg/m(2) cisplatin or carboplatin (AUC 5) in patients with renal insufficiency on day 1. The drugs were repeated every 21 days for 6 cycles according to toxicity and efficacy. The objective response rate was the primary end point.There were 1 complete and 5 partial responses for an objective response rate of 26% (95% CI 8 to 44). Median progression-free and overall survival was 7.1 (95% CI 3 to 11.3) and 10.5 months (95% CI 3.8 to 17.1), respectively. Toxicity was mainly hematological with grade 3-4 neutropenia and thrombocytopenia in 52% and 43% of patients, respectively. The severity of granulocytopenia and the number of metastatic sites were associated with overall survival on univariate and multivariate analyses.To our knowledge this is the first prospective, multicenter, phase II study showing that the platinum salts combination is an active and safe regimen as first line treatment in patients with metastatic collecting duct carcinoma. This platinum based chemotherapy should be considered the standard regimen in these patients.

Several types of cardiovascular complications can occur during treatment with targeted therapies: heart failure, QTc lengthening, arterial and venous thrombosis. A clinical examination, ECG and cardiac ultrasound are essential before starting treatment with targeted therapy. Patients with no medical history, who are asymptomatic with a normal ECG and a left ventricular ejection fraction (LVEF) greater than 50% can begin molecular targeted therapy (MTT). Patients must be assessed by a cardiologist before the introduction of MTT if they have a history of ischemic or valvular heart disease, heart failure, atrial fibrillation, stroke, transient ischemic attack, or ECG anomalies (Q wave, supraventricular arrhythmia, QT greater than 500ms), or LVEF less than 50%. In patients who are symptomatic (dyspnoea, angina, syncope, embolism etc.) and/or present with a modification to the ECG or alteration to the LVEF, MTT must be stopped and reassessment by a cardiologist is indicated. The restarting of MTT following a cardiovascular complication must be subject to a multidisciplinary discussion taking into account the severity of the cardiac event, its reversibility with cardiac treatment, life expectancy of the patient as well as the expected efficacy of the drug.

Androgen receptor (AR) mutations that modify both the ligand binding and the transactivation capacities of the AR represent one of the mechanisms involved in the transition of prostate cancer (PCa) from androgen-dependent to androgen-independent growth. We use a yeast-based functional assay to detect and analyze mutant ARs in PCa. We report the detection of 2 different mutant ARs within the same metastatic tumour sample harvested in a patient with advanced PCa who had escaped androgen deprivation. Concomitantly to the widely described T877A mutant AR, we identified an additional double mutant AR harboring the nonsense mutation Q640Stop just downstream the DNA binding domain together with the T877A point mutation. This type of mutation, which leads to a c-terminal truncated AR, has not been described yet in PCa. Using luciferase reporter assays we demonstrated that this truncated AR exhibited constitutive transactivation properties. In conclusion, our data suggest that mutation-induced constitutive activation of the AR could be a mechanism used by PCa cells to escape androgen deprivation.

Summary Background: Advanced ovarian cancer is often a fatal disease, despite good initial response to chemotherapy. Dose-intense schedules have been reported, but faile

Objectifs La nephrectomie elargie (NE) est le traitement recommande des tumeurs renales cT2a. La nephrectomie partielle (NP) preserve la fonction renale a long terme avec un benefice possible en survie globale. L’axitinib peut reduire la taille de la tumeur primitive en situation metastatique. Notre objectif principal etait de tester la capacite de l’axitinib a transformer des tumeurs cT2 localisees en cT1 et de permettre une NP. Methodes Les patients atteints d’un cancer du rein localise (cT2N0M0) ont ete inclus prospectivement dans un essai de phase II evaluant l’effet de l’axitinib en neoadjuvant a la chirurgie (NP ou NE). Les principaux criteres d’inclusion etaient les suivants : âge ≥ 18, cancer du rein a cellule claire histologiquement prouve, clairance de la creatinine ≥ 60 mL/min, tumeurs cT2a N0NxM0 (O > 7 cm ; ≤ 10 cm). L’axitinib etait administre a une dose de 5 a 10 mg ×2/j pendant 2 a 6 mois avant la chirurgie selon la reponse radiologique. Resultats Dix-huit patients, d’âge median 60 ans ont ete inclus. La taille tumorale, le score RENAL et le debit de filtration glomerulaire (DFG) etaient : 7,6 cm, 11 et 96,5 mL/min respectivement. La duree du traitement etait de 2, 4 et 6 mois pour 12 (66 %), 3 (17 %) et 3 cas (17 %) respectivement. Apres traitement neoadjuvant la taille tumorale et le score RENAL ont diminues a 6,2 cm et 10. Quatre-vingt-neuf pour cent des patients presentaient une diminution du diametre maximal de la tumeur ( Tableau 1 ). Seize des 17 patients operes (94 %) ont eu une NP, dont 67 % des cas pour des tumeurs cT1 ≤ 7 cm. Douze complications ont ete rapportees dont 9 Clavien-Dindo I–II (75 %) et 1 deces par infarctus du myocarde a 1 mois de la chirurgie ( Tableau 2 ). Conclusion L’axitinib en situation neoadjuvante pour les tumeurs renales cT2 permet une reduction tumorale cT1 et une chirurgie d’epargne nephronique dans pres de 70 % des cas. Toutefois, les NP restaient des cas de complexite elevee necessitant une expertise chirurgicale adequate et l’information des patients sur une eventuelle morbidite de ces procedures.

The intestinal tissue is characterized by important morphogenetic movements during development as well as by a continuous dynamic crypt to villus epithelial cell migration leading to differentiation of specialized cells. In this study, we have examined the spatio-temporal distribution of laminin A and M chains as well as of alpha 6 and beta 4 integrin subunits in adult and developing human and mouse intestine by indirect immunofluorescence. Selective expression of the constituent polypeptides of laminin isoforms (A and M chains) was demonstrated. In the mature human intestine, A and M chains were found to be complementary, the M chain being restricted to the base of crypts and the A chain lining the villus basement membrane. In the developing human intestine, M chain expression was delayed as compared to that of A chain; as soon as the M chain was visualized, it exhibited the typical localization in the crypt basement membrane. A somewhat different situation was found in the adult mouse intestine, since both M and A chains were found in the crypts. During mouse intestinal development the delayed expression of the M chain as compared to that of the A chain was also obvious. The absence of M chain expression in mutant dy mouse did not impair intestinal morphogenesis nor cell differentiation. The expression of alpha 6 and beta 4 subunits was not coordinated. In both species the alpha 6 expression preceded that of beta 4. Furthermore, while beta 4 staining in adult mouse intestine was detected at the basal surface of all cells lining the crypt-villus, that of alpha 6 was mainly confined to the crypt cell compartment. An overall similarity of location between alpha 6 integrin subunit and laminin A chain at the epithelial/stromal interface was noted. These data indicate that the spatial and temporal distribution of laminin variants in the developing intestine may be characteristic for each species and that interactions of laminin variants with particular receptors may be important for induction and/or maintenance of differentiated cells.

Background. Localized granulocytic sarcoma of the uterine cervix in the absence of acute myelogenous leukemia (AML) at presentation is very rare, its diagnosis is often delayed, and its prognosis almost always ominous evolving into refractory AML.Case. We present the case of a 30-year-old woman with vaginal bleeding and a large cervical mass. Further evaluation confirmed the presence of a granulocytic sarcoma but failed to reveal systemic involvement.Results. AML type chemotherapy followed by radiotherapy of the uterus led to a durable complete remission. She remains in complete remission six years after diagnosis.Conclusion. Granulocytic sarcoma of the cervix is a rare entity for which early intensive AML type therapy is effective.

Advanced prostate cancer (PCa) has emerged as a public health concern due to population aging. Although androgen deprivation has proven efficacy in this condition, most advanced PCa patients will have to face failure of androgen deprivation as a treatment. Mutations in the androgen receptor (AR) from tumor cells have been shown to induce androgen independency both in PCa cell lines and in the clinic. We have investigated the molecular events leading to androgen independency in the 22Rv1 cell line, a commonly used preclinical model of PCa. Besides AR mutants that have been described so far, including nonsense mutations, recent data have focused on AR pre-mRNA aberrant splicing as a new mechanism leading to constitutively active truncated AR variants. In this article, we describe two novel variants arising from aberrant splicing of AR pre-mRNA, characterized by long mRNA transcripts that encode truncated, constitutively active proteins. We also describe several new nonsense mutants that share ligand independency and transcriptional activity. Finally, we show that alongside these mutants, 22Rv1 cells also express a mutant AR lacking exon 3 tandem duplication, a major feature of this cell line. By describing unreported AR mutants in the 22Rv1 cell line, our data emphasize the complexity and heterogeneity of molecular events that occur in preclinical models, and supposedly in the clinic. Future work on the 22Rv1 cell line should take into account the concomitant expression of various AR mutants.

Angiosarcoma represents 1 to 2% of soft tissue tumors. It originates from endothelial cells of small blood vessels and may affect a variety of organs, including the retroperitoneum, skeletal muscle, subcutis, liver, heart and breast. The outcome of angiosarcoma is poor for those patients in whom aggressive surgery cannot be considered. Chemotherapy, generally consisting of the combination of anthracyclines and ifosfamide, has little, but consistent effect. We report three cases of angiosarcoma in which first-line chemotherapy with adriamycin 40 mg/m2 day 1, ifosfamide 3 g/m2 day 1-2, cisplatin 35 mg/m2 day 1-2 and paclitaxel 175 mg/m2 day 3 led to clinically meaningful responses. The clinical relevance of incorporating paclitaxel in conventional soft tissue chemotherapy schedules in the light of both literature data and our experience is discussed. We emphasize the need for designing trials specifically dedicated to angiosarcomas, as this rare and severe condition may be a target for new antiangiogenic drugs.

575 Background: Laparoscopic Radical nephrectomy (RN) is the current standard of care for large organ confined renal tumors while partial nephrectomy (PN) is recommended for tumor sizes up to 7 cm. PN preserves long term renal function with possible effect on overall survival. Axitinib, a potent VEGFR TKI can reduce the size of primary tumor in metastatic setting. Our primary objective was to test the ability of axitinib to reduce the size of large tumors for shifting from a RN to a PN indication. Methods: Patients with localized (cT2N0M0) RCCs were enrolled in a prospective phase II trial assessing the effect of neoadjuvant axitinib prior to surgery (PN or RN). Main inclusion criteria were: age ≥ 18, histologically proven clear cell RCC, MDRD creatinine clearance ≥ 60 ml/min, cT2a N0NxM0 tumors ( Ø> 7cm; ≤ 10 cm). Medical treatment consisted in axitinib 5 mg up to 10 mg tw/d during 2 to 6 months prior surgery according to radiological response. Results: A total of 18 patients including 11 men (61%) and 7 women (39%) with a median age of 60 yrs were enrolled. Median baseline tumor size, R.E.N.A.L. score, serum creatinine and MDRD estimated GFR were: 7.5 cm, 11, 0.8 mg/dl and 96.5 ml/min respectively. Duration of treatment was 2, 4 and 6 months in 12 (66%), 3 (17%) and 3 cases (17%), respectively. After neoadjuvant treatment median tumor size and RENAL score decreased to 5.9 cm and 10. 93 % of patients presented a decrease in maximum tumor diameter, with median size reduction of 21.7%. Out of the 17 patients who were operated, 16 (94%) underwent a PN (9 robotic and 7 open), including 84% of the cases which were performed for tumors ≤ 7cm. At 1 month from surgery, median serum creatinine and MDRD estimated GFR were 0.88 mg/dl and 88 ml/min, respectively. Medical and surgical complications rate was 11% including 1 embolization for severe bleeding and 1 Clavien V complication at 1 month after surgery due to massive myocardial infarction. Conclusions: Neoadjuvant axitinib in cT2renal tumors allowed cT1 downstaging and nephron sparing surgery in more than 80% of the cases. However, PN procedures remained high complexity cases requiring adequate surgeon expertise and information of the patients for possible morbidity of these procedures. Clinical trial information: RECF2256.

Forty-three patients with nonmetastatic inflammatory breast carcinoma have been treated by initial doxorubicin, 5-fluorouracil, and cyclophosphamide (FAC) combination chemotherapy. After three chemotherapy cycles, responding patients underwent surgery. Chemotherapy was then completed for nine cycles of FAC followed by locoregional radiation therapy. All patients received tamoxifen 40 mg/day for 1 year from the time of diagnosis. Thirty-eight patients (88%) had a clinical response to chemotherapy and underwent surgery. On histologic examination 17 patients had a residual tumor mass less than 1 cm diameter or a complete tumor disappearance; lymph nodes dissection was negative in 15 patients. With a median follow-up of 48 months, the predicted 5-year disease-free survival (DFS) is 48% (median DFS, 46 months). Analysis of prognosis factors shows that age, menopausal status, and histologic grade have no predictive value. The DFS and overall survival were significantly improved by the presence of hormonal receptors and a low number of positive lymph nodes (less than 4) at surgery. The most significant prognosis factor was the residual tumor mass after initial chemotherapy with an 80% predicted 5-year DFS for the responding patients versus 30% for the no responding patients (P less than 0.001).

227 Background: Cross-resistance between taxanes and androgen receptor axis targeted agents is a matter of debate in metastatic castration-resistant prostate cancer (mCRPC). Preclinical data about response to taxanes after prior enzalutamide suggest some level of cross-resistance (van Soest et al, Eur J Cancer 2013) though this was not confirmed in other models (Al Nakouzi N, Eur Urol 2014). The first objective of this study was to assess the impact of previous enzalutamide therapy on the efficacy of subsequent taxane-based chemotherapy. The second objective was to investigate the prognosis of patients when chemotherapy was initiated in enzalutamide-pretreated patients. Methods: Data from 96 enzalutamide- and placebo-treated patients enrolled in the Prevail phase III trial were retrospectively collected from 14 centers in France. Changes in prostate specific antigen (PSA) levels, progression free survival (PFS) and RECIST criteria v 1.1 were used to determine the activity of docetaxel (n=89) or cabazitaxel (n=7) treatment. The Halabi model was used to predict survival probabilities for the enzalutamide- or placebo-pretreated patients when chemotherapy was initiated (Halabi et al, J Clin Oncol 2014). Results: Overall, 96 patients were included in this analysis (58 in the placebo arm vs. 38 in enzalutamide arm). PSA response to taxanes (defined as a decline of ≥50% from baseline) was marginally lower in enzalutamide-vs. placebo-pretreated patients (34% vs. 53%, p=0.10). PSA response in enzalutamide-pretreated patients was not different from that observed with docetaxel given every 3 weeks in TAX 327 trial (Tannock et al, NEJM 2004) (45%, p=0.20, binomial test). Median PFS and objective response rates were similar between the two groups (4.8m vs 6.7 m;p=0.14 and 45% vs 43%;p=0.83 respectively). Halabi score was well-balanced between the two groups (p=0.30). Conclusions: Taxanes retain efficacy in enzalutamide-pretreated mCRPC. At the time of first-line taxane-based chemotherapy initiation, the prognosis of enzalutamide-treated patients according to the Halabi score was not different from that of enzalutamide-naïve patients.

Human androgen receptor (AR) mutation is a possible alternative used by prostate adenocarcinoma (PCA) cells to escape androgen dependence. These mutations may broaden the specificity and/or the sensitivity of the AR to other hormones, resulting in the inappropriate receptor activation, and thus, affecting the PCA response to hormonal therapies. We have developed a yeast-based functional assay to detect mutant ARs in PCA by analyzing their transactivation capacities in response to different ligands. We report herein the detection of two different mutant ARs within the same metastatic tumor sample. Concomitantly to the T877A mutant AR, we identified an additional double mutant AR harboring the nonsense mutation Q640Stop, just downstream of the DNA binding domain together with the T877A point mutation. This mutation leads to a C-terminal truncated AR. This study is the first description of this type of mutation in PCA. We demonstrated that this truncated AR exhibited constitutive transactivation properties. In conclusion, our data suggest that mutation-induced constitutive activation of the AR may be an alternative mechanism used by PCA cells to escape androgen deprivation.

The major mechanisms of cell function, such as metabolic pathways, DNA repair and cell cycle control have been conserved throughout DNA evolution from yeast to human, despite the former lacks cancer-related features. The S. cerevisiae genome has been entirely sequenced and not only reveals sequence similarity to the human, but a number of proteins also have a conserved function. Owing to its genetic features, yeast has been used as a remarkable model and tool to study important enzymes that are also targets for anticancer drugs, particularly in the field of the pyrimidine salvage pathway. In this review, we describe the recent developments in using yeast for anticancer research, focusing on metabolic pathway analysis, systematic drugs screening with yeast mutants or prospects in gene therapy with yeast enzymes.

Primary pleural angiosarcoma is an extremely rare tumor. We report the case of a patient who presented with recurrent massive bilateral hemothoraxes. Although thoracoscopy was performed, biopsy samples of the pleura were inconclusive. The delayed onset of skin metastases led to the diagnosis of angiosarcoma, however the patient died from pleuropulmonary progression before treatment could be started. We review the literature of primary pleuropulmonary angiosarcoma and discuss its treatment modalities.

Androgen receptor (AR) mutations that modify both the ligand binding and the transactivation capacities of the AR represent one of the mechanisms involved in the transition of prostate cancer (PCa) from androgen-dependent to androgen-independent growth. We use a yeast-based functional assay to detect and analyze mutant ARs in PCa. We report the detection of 2 different mutant ARs within the same metastatic tumour sample harvested in a patient with advanced PCa who had escaped androgen deprivation. Concomitantly to the widely described T877A mutant AR, we identified an additional double mutant AR harboring the nonsense mutation Q640Stop just downstream the DNA binding domain together with the T877A point mutation. This type of mutation, which leads to a c-terminal truncated AR, has not been described yet in PCa. Using luciferase reporter assays we demonstrated that this truncated AR exhibited constitutive transactivation properties. In conclusion, our data suggest that mutation-induced constitutive activation of the AR could be a mechanism used by PCa cells to escape androgen deprivation.

OBJECTIVE: Mutations in the ligand-binding domain of the human androgen receptor (AR) figure among the ways used by prostate adenocarcinoma (PCa) cells to escape androgen dependence. These mutations may broaden the specificity and/or affinity of the AR to other hormones, resulting in inappropriate receptor activation and thus affecting the PCa response to physiological stimuli and hormonal therapies. DESIGN: In order to clarify the impact of these mutations on disease progression and treatment, we have developed a yeast-based functional assay that allows the detection of mutant ARs and the analysis of their transactivation capacities in response to different ligands. METHODS: AR cDNA was directly cloned into an expression vector in a yeast strain that carries a reporter gene (ADE2) linked to an androgen-dependent promoter. The expression of the ADE2 gene and consequently the yeast cell growth in a selective medium depleted in adenine depends on the specificity of the AR for the ligand added to the medium. RESULTS: By analysing the transactivation capacities of different AR molecules in response to a broad range of steroid and non-steroid ligands, we have demonstrated that this assay can discriminate among wild-type AR, T877A, C685Y and L701H mutant ARs and that at least 1% of mutant ARs could be detected when mutant and wild-type ARs were mixed at the cDNA level. CONCLUSIONS: The data presented here show that this simple AR assay is convenient for the routine detection of mutant ARs in PCa and is also suitable to evaluate the antagonist activities of anti-androgen molecules.

The CML 88 study was designed to evaluate the efficacy of maintenance therapy in a multicentric randomised protocol using IFN combined with low-dose Ara-C versus IFN alone, following an induction with IFN + HU. Between April 1988 and February 1991, 237 patients from 36 French Hematology Centres were entered in the study. Preliminary cytogenetic results show a slightly higher, although not statistically significant, proportion of major chromosomal responses, including complete cytogenetic remissions, in the IFN + Ara C arm.

Recently we demonstrated, using normal human fibroblasts (NHFs), that UVc radiation induces a G2/M arrest which was even more pronounced when p53 expression was inhibited. So, the aim of this study was to evaluate in NHFs the relationship between UV-induced G2/M arrest and cyclin B1 regulation and to investigate if p53 could contribute to the cyclin B1 regulation in these conditions. Following exposure of asynchronous NHFs to UV light, we showed that the induced G2/M arrest was accompanied by a dose-dependent down-regulation of cyclin B1 mRNA as evaluated by RT-PCR. Concomitantly, using flow cytometric analysis, we observed a strong accumulation of cyclin B1 protein which was correlated to the apparition of the G2/M arrest. In order to study the contribution of p53 to the cyclin B1 accumulation in response to UV exposure, we inhibited p53 induction using p53 antisense oligonucleotides. We found that the inhibition of p53 protein induction after UV exposure had no effect on the level of cyclin B1 mRNA. Moreover, although inhibition of p53 protein induction increased the number of the cells in the G2-M phase, the mean content of cyclin B1 protein was not augmented in these cells. These results indicate clearly that the induction of p53 protein following UV exposure does not regulate the level of cyclin B1 mRNA or protein in normal cells.

Despite high response rates with platinum-based front-line chemotherapy, the prognosis for advanced ovarian carcinoma (AOC) is poor. Salvage chemotherapy for recurrent AOC was of little benefit before paclitaxel as single-agent therapy showed appreciable efficacy. Anthracyclines are effective, but are not often part of first-line therapy. In this pilot study, we investigated the feasibility of an anthracycline plus paclitaxel combination therapy for recurrent AOC. Twenty-four patients received 150 mg/m 2 paclitaxel on day 1, with either 50 mg/m 2 doxorubicin on day 1 or 75 mg/m 2 epirubicin on day 1 every 3 weeks. A 27% overall response rate was obtained. Myelosuppression was the major toxicity, but was manageable. No myocardiac toxicity was observed. We conclude that paclitaxel–anthracyclines is a promising salvage combination therapy in AOC that should be investigated further.

p53 mutations are found in about 70% of human cancers. In order to evaluate the role of these mutations in response to chemotherapeutic agents, it is important to distinguish between p53 response to DNA-damaging agents in normal and in tumour cells. Here, using normal human fibroblasts (NHFs), we show that cisplatin and UV radiation induce G2/M arrest which is temporally linked to p53-protein induction. To study the contribution of p53 to this G2/M arrest, we inhibited p53 induction in NHFs using p53 anti-sense oligonucleotides. Following exposure of NHFs to UV radiation, the inhibition of p53-protein induction leads to a greater accumulation of cells in the G2/M phase, but also to a decreased fraction of cells in the G1 phase. We propose that p53 does not induce G2/M arrest directly, and that the extent of this arrest may depend on the fraction of cells that do not stop at the G1 phase following exposure to DNA-damaging agents. Furthermore, inhibition of p53-protein induction leads to increased sensitivity of NHFs to UV radiation. These results suggest that inhibition of p53 protein enhances sensitivity to DNA-damaging agents in normal human cells.

212 Background: Spironolactone is an effective drug to treat arterial hypertension as well as fluid retention and hypokalemia. Recently, some data suggested that spironolactone might induce progression in castration-resistant prostate cancer (CRPC) patients treated by abiraterone acetate, a recently approved selective CYP17 inhibitor. Nevertheless, no biological data are available to explain these clinical observations. The purpose of this study was to identify the potential underlying molecular mechanism. Methods: Effect of spironolactone with or without Abiraterone acetate (AA) on androgen receptor (AR) was assessed on LNCaP cells in this study. We performed a yeast-based functional assay with different levels of spironolactone with and without AA. The nuclear localization and activation of androgen receptor (AR) were detected by immunofluorescence and luciferase assays. Results: Results from the yeast-based functional assay show that the wild type androgen receptor is activated by high concentrations of spironolactone in an androgen-depleted environment. Moreover, spironolactone-induced AR transcriptional activity is downregulated by different AR antagonists as well as high concentrations of AA. These results suggest that spironolactone is possibly a potential AR modulator. Luciferase reporter assays showed that AR transcriptional activity in LNCaP cells was upregulated by spironolactone as well. Finally, AR immunoreactivity was almost nuclear in spironolactone-exposed cells. Taken together, these results suggest that spironolactone is a selective androgen receptor modulator. Conclusions: Spironolactone is a selective androgen receptor modulator and should be used with caution in routine practice in patient with metastatic prostate cancer treated by hormonotherapy especially AA.

e17543 Background: Patients’ adherence has been identified as a challenge in oncology and hematology practice. Hormone therapy data in breast cancer suggest insufficient adherence and poor persistence. Limited data is available for targeted therapies such as tyrosine kinase (TK) and mTOR inhibitors whereas poor adherence to TK treatment was linked to treatment failure in GIST and CML. Methods: We report the result of a prospective survey in 226 patients (pts), with solid tumors and hematologic malignancies receiving oral anticancer therapy including chemotherapy or hormone therapy (CT), and targeted therapies (TT). Treatment duration and setting (adjuvant vs metastatic), cancer type, age, co-medication were analyzed. Patients were given a 15-item questionnaire and asked to anonymously answer questions regarding their attitude towards oral anticancer drugs. To analyze adherence, patients were asked whether they voluntarily or not missed any drug dosing during the last month. Results: 226 patients (median age 65.5 y.o) participated, 115 with TT and 111 with CT, with a median time of drug intake of 10.5 months. Both TT and CT patients stated to be well informed about treatment modalities in (92%), mostly by their oncologist or hematologist (87%). Written information was more frequently given in TT pts (67.0 vs 27.0%, p

Summary Background In 1989, S. Wadler reported very promising results (76% response rate) with a combination of 5-fluorouracil (5-FU) plus α-2a interferon (IFN) in the treatment of metastatic colorectal carcinoma (MCRC). in vitro, there are several potential explanations for synergism between the two agents. We therefore decided in 1989 to start a randomized study comparing 5-FU alone with 5-FU plus IFN. Patients and methods 105 non-pretreated patients with measurable metastatic colorectal carcinoma entered into this study. The patients were randomly allocated either in arm A (n = 49) with 5-FU: 750 mg/m2 i.v. CI d1-d5 followed by 750 mg/m2 iv. bolus once a week, or in arm B (n = 56) with 5-FU as in arm A plus IFN 9 × 106 IU sub-cutaneously three times a week. Results After two months of treatment we observed 1 CR and 2 PR in arm A (response rate 6.1%), 3 CR and 8 PR in arm B (response rate 19.6%), i.e., a significant difference (P = 0.05). Event-free survival was significantly higher in arm B (6 months) than in arm A (2 months) (P

Macrophages represent the primary line of host defences in the peritoneal cavity. In order to study the metabolic activity and maturation stage of human resident peritoneal macrophages (PM phi). peritoneal fluid (PF) was taken by Douglas puncture from healthy hyperstimulated infertile women undergoing oocyte retrieval for in vitro fertilization. Peritoneal fluid and macrophage culture fluids were studied for different inflammatory mediators such as interleukin-1 (IL-1), tumour necrosis factor (TNF) and interleukin-6 (IL-6). The level of macrophage colony-stimulating factor (M-CSF), which represents a macrophage proliferation and differentiation factor, was determined in the PF and in the serum. Furthermore, the macrophage phenotypic profile was analysed, in particular the expression of sex steroid hormone receptors. IL-1. IL-6 and TNF were detectable in the PF and in the culture supernatants of PM phi whether stimulated or not by IFN-gamma and LPS. The mean level of M-CSF in the PF was 6.37 +/- 2.02 ng/ml as measured by RIA; this level did not correlate with the concentration of PM phi. The mean PF-M-CSF level was 1.4-fold higher than in the sera as measured by a EIA. Oestrogen and progesterone receptors could not be demonstrated on the PM phi analysed, so that a direct relationship between the ovarian steroid concentration in these women and the function of PM phi was unlikely. As compared to peripheral blood monocytes (Mo). PM phi showed a phenotypic profile, with some more mature features, e.g. increased expression of CD14, CD68, FcRII, FcRIII, CR3, CR4 and MHC class II determinants. These results indicate that resident PM phi have acquired in vivo a certain differentiation and/or activation state under micro-environmental factors where cytokines secreted by the M phi themselves or by other cells such as the mesothelium may play important roles.

BACKGROUND: Stages II-IV ovarian cancer in pathologic complete remission (pCR) at second-look surgery have a high relapse rate (50%) during the first 2 years. Considering relapse sites (abdomen and/or pelvis), intraperitoneal (IP) therapy is a logical approach. Mitoxantrone is an effective drug against ovarian cancer cells in vitro and is an attractive agent for IP therapy because of its very low peritoneal clearance. The value of IP mitoxantrone was studied as consolidation treatment of ovarian cancer in pCR at second-look surgery. METHODS: Fifty patients with Stages II-IV ovarian cancer (8, Stage II; 37, Stage III; 5, Stage IV) were included in this Phase II study, which began in June 1988. All patients had undergone initial cytoreductive surgery followed by 6 cyclophosphamide, doxorubicin, and cisplatin cycles. All patients were in pCR, as confirmed by second-look surgery. Consolidation treatment consists of 20 mg (total dose per cycle) IP mitoxantrone every 3 weeks for six cycles. RESULTS: Toxicity was limited to mild abdominal pain not requiring dose reduction (90% pain grade < or = 2). With a median follow-up of 2 years, the 5-year predicted survival is 59.8% (95% confidence interval [CI], 48.3 - 71.3), and the disease-free survival (DFS) rate is 47.3% (95% CI, 36.7 - 57.9). Patients with no or microscopic residual disease after initial surgery had a better 5-year DFS rate (75.8%) than those with macroscopic residual disease (31.2%) (P = 0.01). CONCLUSION: IP mitoxantrone (20 mg/cycle) is feasible with an acceptable abdominal toxicity. The results in terms of DFS are encouraging, but a randomized study versus no treatment is necessary to prove the value of this consolidation treatment.

4600 Background: Complete remission (CR) is uncommon with TKIs in metastatic renal cell carcinoma (mRCC), but may occur in few patients (pts). Currently, whether we should continue therapy after CR...

We assessed the efficacy of a piperacillin (3 x 4 g/d) and netilmicin (5 mg/kg/d) combination therapy for infections in febrile neutropenic patients. The study was conducted over a 30-month period and 203 patients were included. Bone marrow transplant recipients were not included in this study. Origin of infection was documented in 101 (50%) episodes: 33 fungal, viral or parasitic infections and 68 bacterial infections mainly composed of septicemia. Of the 169 evaluable patients with proved bacterial infections or non-documented infections, 129 (76%) recovered with the piperacillin and netilmicin combination treatment. All gram-positive bacterial infections failing first line therapy were cured after the addition of vancomycin. Piperacillin and netilmicin appeared very effective in this large monocentric prospective study. It does not seem necessary to include vancomycin in first line therapy of infections of the neutropenic patients in our institution; however, vancomycin must be added early in the case of suspected or documented staphylococcal infection failing empiric treatment.

4543 Background: Immunotherapy is rarely effective in patients (pts) with Bellini duct carcinoma (BDC), a rare (< 1% off all renal cancers) and aggressive variant of kidney cancer. Gemcitabine (GEM...

4513 Background: CCI-779 is an mTOR kinase inhibitor with activity in renal cell carcinoma (RCC, Atkins et al. J Clin Oncol, in press). A preliminary report of this phase 1/2 study of CCI-779 and interferon-α (IFN) in patients (pts) with advanced RCC described the safety and antitumor effects of the combination (Dutcher et al. Proc ASCO 22:213, 2003). We update these results. Methods: In an open-label, escalating-dose, single-arm study, CCI-779 was given intravenously once weekly, with IFN given subcutaneously 3 times weekly. The starting dose levels were 6 million units (MU) IFN, 5 mg CCI-779. Dose escalation was based on safety evaluation of pts (≥ 6/cohort) after 4 wks of treatment. Up to 40 pts will be evaluated at the maximum tolerated dose (MTD). Results: As of 01 Dec 2003, 71 pts with advanced RCC were enrolled; 27 continue treatment. Pts (73% men, 27% women) had ECOG performance status of 0: 53% and 1: 46% and median age of 59 yrs (range, 35–80); 45% had prior IL-2 treatment. In dose escalation, p...

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A total of 20 patients with intermediate or high-grade non-Hodgkin's lymphomas who failed to LNH 84 regimen were treated with a combination of VP 16, ifosfamide and methotrexate (VIM regimen). Nineteen patients are evaluable for response. Eight patients (42%) achieved complete responses and four (21%) attained partial responses. Most of the complete responders are still in remission with a follow-up of more than 30 months for 5 patients.