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THE PATIENT A 24-year-old male patient, known to have tuberous sclerosis complex, developed renal epithelioid angiomyolipomas with hepatic metastasis. Everolimus treatment failed, this lead to a switch to temsirolimus treatment without more efficiency that appeared later on was due to drug-drug interaction which was dealt with in an effective manner

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings.METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants.FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

International audience; OBJECTIVES. As vascular endothelial growth factor (VEGF) is expressed in ovarian cancer, we assessed the efficacy and safety of bevacizumab (a monoclonal antibody targeting VEGF) plus microtubule targeting agents for heavily pre-treated ovarian carcinoma patients. METHODS. We retrospectively reviewed 43 patients with recurrent epithelial ovarian carcinoma. Combined treatment included bevacizumab with paclitaxel in 32 (74%), docetaxel in 10 (23%), and vinorelbine in one (2.3%) patients, respectively. RESULTS. The median number of combined treatment was six cycles (range 1-29). On RECIST criteria, the objective response rate (ORR) was 40% (16% CR and 24% PR). Clinical benefit (complete response [CR] plus partial response [PR] and stable disease [SD] lasting ≥ 3 months) was 74% (CI95%: 46.7-77%). Median duration of treatment and overall survival were 3.9 months (range 0.2-14.4 months) and 20.1 months (CI95%: 13.8-20.1) respectively. No toxic death was reported. Grade 3-4 toxicity occurred in 30% of patients. Gastrointestinal perforations and fistula occurred in 3 (7%) and 6 (14%) patients, respectively. CONCLUSION. Although being active in terms of ORR, bevacizumab plus microtubule targeting agents - mainly taxanes - leads to a high rate of gastro-intestinal perforations and fistula in heavily pre-treated ovarian carcinoma patients.

The aim of our work was to assess the potential clinical impact of therapeutic education in patients treated with anticancer drugs. One hundred-one ambulatory adult patients (mean age: 60 years, range: 24-88) treated by anticancer chemotherapy were included. The occurrence of adverse events was reported by 83% of the patients. Twenty-one percent (14/67) of the patients were not compliant with their supportive care treatment, 60% (60/101) took over-the-counter medications (one contraindication identified) and 14% (14/101) claimed they had received no counsel on risk behaviour (UV exposure, lack of contraception, driving) from health care professionals. Overall, 11% (44/397) of adverse events were associated with a lack of information. Twelve percent (4/33) of the calls to the doctor, 6% (1/17) of the visits to the physician and 21% (3/14) of the hospitalizations could be associated with a lack of therapeutic education. These data enlighten the importance of therapeutic education of cancer patients treated by chemotherapy.

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.

Background A number of studies have shown that elderly cancer patients were denied optimal anticancer treatment because of age. Colorectal cancer is among the most frequent cancers in Western countries, and adjuvant chemotherapy has proven efficacy and tolerance in this condition. This study was undertaken to explore the current approaches to adjuvant chemotherapy in elderly cancer patients in a single institution. Patients and methods We retrospectively analyzed all patients' files that were discussed in the gastro-intestinal tumor board of the Hopitaux Universitaires de Strasbourg during 3 years (2004–2006). The recorded variables included sex, age, tumor stage, cancer location colon vs rectum, number of comorbidities, occurrence of an oncogeriatric assessment, type and tolerance of chemotherapy. We investigated the reason to not administer adjuvant therapy in patients whom should have received this treatment if guidelines had to be applied. Results A total of 193 consecutive patients' files were extracted from colorectal cancer patients that had been discussed in the gastro-intestinal tumor board. Among these, we isolated patients over 70 years old who were proposed with either adjuvant chemotherapy (group A, n =65) or follow up (group B, n =128). The median age in group A was 75.3 years old. Tumor board recommendations were in accordance with guidelines in 91% of cases. Chemotherapy was delivered in 44 pts (76%) and completed in 42 (95%). The median age in group B was 78.6 years old, and in this group tumor board proposal met the guidelines in 83% of cases. In the logistic regression model, disease stage was the major variable leading to adjuvant treatment recommendation, age and comorbidities being of lesser importance. Conclusions In our series, elderly colorectal cancer patients are not undertreated. Efforts should be maintained to educate physicians with regard to feasibility of adjuvant chemotherapy in elderly patients.

Aggressive fibromatosis (AF) or desmoid tumor is a rare condition, characterized by deep tissue invasion by a monoclonal fibroblastic neoplasm, developed from musculoaponeurotic structures. Surgery is the treatment of choice, but negative margins can hardly been achieved in large tumors, and can lead to major functional disability. AF medical therapy includes nonsteroids anti-inflammatory drugs, tamoxifen, with inconsistent results. Several reports of imatinib efficacy in AF appear in the literature. Here, we describe for the first time a V530IKITexon 10 mutant that was associated to a dramatic imatinib response in an extraabdominal aggressive fibromatosis. The previously discovered V530I substitution was characterized in the core binding factor AML, but had never been reported in any other condition, so far. In this paper, we discuss theKITexon 10 mutations or polymorphisms that have been described in a variety of KIT-related conditions, including acute myelogenous leukemia, mastocytosis, and aggressive fibromatosis.

7 Laboratoire d'Epidemiologie et de SantePublique, Faculted e Medecine, UniversiteLouis Pasteur, Strasbourg, France (See the editorial commentary by Kohno on pages XXX-XX) Background. Invasive aspergillosis is associated with high death rates. Factors associated with increased mor- tality have not yet been identified in a large population of patients with various underlying conditions. Methods. We retrospectively reviewed 385 cases of suspected or documented aspergillosis that occurred during a 9-year period. We identified 289 episodes that fulfilled the criteria for possible, probable, or proven invasive aspergillosis according to the international definition criteria and that was treated with an anti-Aspergillus active antifungal drug. Clinical and microbiological variables were analyzed for their effects on overall and attributable mortality. Significant variables in univariate analysis were introduced into a multivariate Cox model. Results. Twelve-week overall and disease-specific survival rates were 52.2% (95% confidence interval, 46.5%- 57.9%) and 59.8% (95% confidence interval, 54.0%-65.4%), respectively. Receipt of allogeneic hematopoietic stem cell or solid-organ transplant, progression of underlying malignancy, prior respiratory disease, receipt of corti- costeroid therapy, renal impairment, low monocyte counts, disseminated aspergillosis, diffuse pulmonary lesions, pleural effusion, and proven or probable (as opposed to possible) aspergillosis are predictors of increased overall mortality. Similar factors are also predictors of increased attributable mortality, with the following exceptions: pleural effusion and low monocyte counts have no impact, whereas neutropenia is associated with a higher attributable mortality. Conclusions. Identification of predictors of death helps in the identification of patients who could benefit from more-aggressive therapeutic strategies. Initiation of therapy at the stage of possible infection improves out- come, and this finding calls for the development of efficient preemptive strategies to fill the gap between empirical and directed therapy.

The androgen receptor (AR) is a ligand-activated transcription factor that displays genomic actions characterized by binding to androgen-response elements in the promoter of target genes as well as nongenomic actions that do not require nuclear translocation and DNA binding. In this study, we report exclusive cytoplasmic actions of a splicing variant of the AR detected in a metastatic prostate cancer. This AR variant, named AR23, results from an aberrant splicing of intron 2, wherein the last 69 nucleotides of the intronic sequence are retained, leading to the insertion of 23 amino acids between the two zinc fingers in the DNA-binding domain. We show that the nuclear entry of AR23 upon dihydrotestosterone (DHT) stimulation is impaired. Alternatively, DHT-activated AR23 forms cytoplasmic and perinuclear aggregates that partially colocalize with the endoplasmic reticulum and are devoid of genomic actions. However, in LNCaP cells, this cytoplasmic DHT-activated AR23 remains partially active as evidenced by the activation of transcription from androgen-responsive promoters, the stimulation of NF-κB transcriptional activity and by the decrease of AP-1 transcriptional activity. Our data reveal novel cytoplasmic actions for this splicing AR variant, suggesting a contribution in prostate cancer progression.

Adjuvant hormone therapy is indicated only in patients whose tumors express estrogen or progesterone receptors. Aromatase inhibitors (AI) are indicated only in postmenopausal patients. AI are significantly more effective than tamoxifen in terms of disease-free survival and distant recurrence-free survival; these advantages will probably result in a significant overall survival benefit after sufficient follow-up. This benefit justifies the use of AI in all postmenopausal patients in the absence of contraindications and after complete explanations of the benefit/risk ratio and potential side effects of this treatment. The benefit of AI over tamoxifen may be particularly pronounced for tumors overexpressing HER-2 and perhaps for ER+PR- tumors. Replacement of tamoxifen by AI or first-line treatment with AI is advised in patients with such tumors. Extended adjuvant treatment with AI for 5 years significantly increases survival among patients already treated with tamoxifen for 5 years; it also provides a significant overall survival benefit to patients with positive axillary nodes and should be used in this group. AI may cause several generally mild side effects, including insomnia, arthralgia, bone loss, vaginal dryness, dyspareunia and loss of libido. Tamoxifen may be appropriate for well-informed patients with these side effects, especially those with RE+ RP+ tumors and a low risk of thromboembolic or endometrial complications. The effects of AI on memory and cognition should also be investigated thoroughly before its long-term use, especially in the elderly.

The emergence of mutations in the androgen receptor (AR) gene is a recurrent event during progression of prostate cancer (PCa) on androgen ablation therapy. In this study, we show that nonsense mutations that lead to carboxyl-terminal end truncated ARs are found at high frequency in metastatic PCas. Transcriptional activities of the Q640X mutant AR in the androgen-sensitive LNCaP cell line differ to those of the wild-type AR. Indeed, this mutant AR exhibits strong and ligand-independent transcriptional activities from an artificial promoter construct containing two repeats of androgen-responsive elements, but is inactive on the human PSA gene promoter. Nevertheless, the expression of the Q640X mutant AR in LNCaP cells is accompanied by an increase in the level of PSA protein, and by an increase in the expression of the endogenous AR gene. This enhanced expression of the endogenous AR gene is not limited to the sole transfected cells, but is observed in non-transfected neighboring cells. Additionally, in co-cultures of transfected and non-transfected LNCaP cells, the Q640X mutant AR leads to an unpredicted nuclear localization of the endogenous AR protein in the two cellular populations and this, in the absence of androgen. These data indicate that cells expressing the Q640X mutant AR acquire the property to emit a signal that activates the AR in neighboring cells by a paracrine mechanism and in a ligand-independent manner. Our data strongly support the notion of cooperation among tumor cells in PCa and could be of relevance for the understanding of progression on androgen ablation therapy.

High linear energy transfer (LET) radiation have the ability to kill cancer cells resistant to conventional radiotherapy. On the other hand, protocols combining radiotherapy and chemotherapy are effective in eradicating certain inoperable cancers. In this study, we investigated the cytotoxicity of a co-treatment with fast neutrons and cisplatin in a human glioblastoma cell line, U-87. Cells cultured in vitro were irradiated with p(65)+Be neutrons in the presence of cisplatin. Cell survival and the induction of apoptosis and premature senescence were assessed at different time intervals thereafter, using a variety of methods. A marked reinforcement of the cytotoxicity was obtained when irradiation and cisplatin were associated. This reflected both an amplification of the apoptotic process and the induction of premature cell senescence. The efficiency of a combination between fast neutrons and cisplatin in inducing cell death in U-87 is more than additive. The present data concur with those we previously reported in a mouse lymphoma and suggest the potential utility of platinum compounds as adjuncts to future cancer therapy protocols using high-LET radiation.

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.

Docetaxel (Taxotere) is a member of the taxane class of anticancer agents to reach clinical use. This semisynthetic analog of paclitaxel (Taxol) is one of the newer potent anti-neoplastic agents now undergoing extensive laboratory and clinical investigations. Several studies indicate that antimicrotubule agents are potent promoters of apoptosis in cancer cells. Cytotoxic mechanisms of antimitotic taxoids are not yet fully understood, but it has been demonstrated that docetaxel increases tubulin polymerisation, promotes microtubule assembly and also inhibits tubulin depolymerisation. Disruption of microtubules results also in the induction of tumor suppressor gene p53 and inhibitor of cyclin-dependent kinases and activation/inactivation of several protein kinases. As a consequence cells are arrested in the G2-M phase of the cell cycle, after which they may either undergo cell death by apoptosis or necrosis or overcome the G2-M stop and continue in the division cycle (often toward a post-mitotic cell death) depending on the tumor cell type. Nevertheless, how docetaxel induces apoptotic cell death or caspases activation is not yet defined. One may assume that taxanes are able to induce the phosphorylation of Bcl-X(L)/Bcl-2 members and thus inactivate their anti-apoptotic capacities. The down-regulation of Bcl-2 and/or the upregulation of p53 and p21/WAF-1 are certainly one of the important modes of apoptosis induction by taxanes. The aim of this framework is to summarize the effects of microtubuline targeting agents on apoptotic signal transduction and new molecular pathways. Finally, we will also discuss the potential therapeutic interest in the association of docetaxel and ionizing radiation.

The objective of this study was to characterize the apoptotic pathways activated by fast neutrons in the human lymphoblastoid cell line TK6 and in its p53 -/- derivative. Our results demonstrate that while p53 is not required for neutron-induced apoptosis, as previously shown, it does affect the kinetics of apoptosis and the molecular pathways leading to the activation of effector caspases. Indeed, rapid p53-dependent apoptosis was associated with the activation of caspase 9, 8, 3, and 7 and the cleavage of BID by caspase 8. In contrast, the slow-occurring p53-independent apoptotic process, mediated by caspase 7, took place without BID cleavage and loss of transmembrane mitochondrial potential. Altogether, our findings highlight an essential role for caspase 8-mediated BID cleavage, in the course of p53-dependent apoptosis triggered by fast neutrons in lymphoid cells. They also demonstrate that this mechanism is not involved in p53-independent apoptosis.

Aim: p53 is the most frequently altered gene in human cancer. It was expected to be the principle marker for chemo/radiosensitivity, resistance, tumor recurrence and ultimate survival, but is no longer con- sidered a universal prognostic factor. Different altera- tions in the p53 gene have led to conflicting results depending on cell/tissue specificities and on radiation and drug specificities. Methods: We evaluated the properties of isogenic and isophenotypic cell lines from the K1 papillary thyroid carcinoma in which p53 func- tion was disrupted either by mutation (expression of dominant-negative p53, 143 ala ) or by inactivation (ex- pression of human papilloma virus protein HPV16 E6). Their proliferation, their propensity to trigger apoptosis and their survival were analyzed after treatment with cisplatin (CDDP). Results: Only K1 lines with wild-type p53 had significantly accumulated apoptotic bodies 72 h after treatment. Despite their incapacity to trigger apoptosis in response to CDDP treatment, the survival of K1 cell lines in which p53 expression was altered was not significantly different from the survival of K1 cell lines expressing wild-type p53. In addition, the order of magnitude of resistance of K1 cells in which p53 was mutated was similar to that in which p53 was totally inactivated, although the pathways involved may be different. Conclusions: These results show that the means by which p53 expression is disrupted and the consequence on downstream pathways regulated by p53 deserve to be considered in order to elucidate some ap- parently conflicting responses of this gene.

PURPOSE: To assess the Aspergillus galactomannan enzyme-linked immunosorbent assay (ELISA) in the diagnosis of invasive aspergillosis (IA) in adult and pediatric oncohematologic patients. PATIENTS AND METHODS: The study was conducted in four patient groups: those with fever of unknown origin (FUO) during neutropenia, suspected pulmonary infection (PI), or nonpulmonary aspergillosis (NPA) and those undergoing surveillance (S) after hematopoietic stem-cell transplantation (HSCT). IA was classified as definite, probable, or possible, according to European Organization for Research and Treatment of Cancer/Mycosis Study Group definitions. RESULTS: A total of 3,294 serum samples were collected during 797 episodes (FUO, 261; PI, 297; NPA, 28; and surveillance, 211), and 153 episodes of IA were diagnosed (31 definite, 67 probable, and 55 possible). Three episodes were first suspected from galactomannan ELISA; the remaining 150 cases were diagnosed from clinical or radiologic evidence. Sensitivity of the ELISA was 64.5%, 16.4%, and 25.5% in definite, probable, and possible episodes of IA, respectively, and was lower in patients positive for anti-Aspergillus antibodies than in antibody-negative patients. Most false-positive results occurred in children and in allogeneic HSCT (allo-HSCT) patients. Overall specificity of the ELISA was 94.8%. It was lower in children compared with adults (P < .0001) and in allo-HSCT patients compared with non–allo-HSCT adults (P = .0002). Lowering the ELISA cutoff value from 1.500 to 0.700 seemed more relevant for non–allo-HSCT adults (sensitivity, 73.1%, 44.3%, and 44.7% in definite, probable, and possible IA, respectively; specificity, 94%). CONCLUSION: Galactomannan ELISA seems less sensitive than previously described, and sensitivity can be further reduced by the presence of anti-Aspergillus antibodies. A new cutoff value for the ELISA of 0.700 is proposed for non–allo-HSCT adults.

A 32-year-old patient was diagnosed with a gastrointestinal stromal tumor of the small bowel. The pathologic diagnosis was confirmed by positive immunochemistry against CD34, and against CD117, the tyrosine-kinase c-kit. We performed a karyotypic analysis on the basis of the patient's tall stature and speech difficulties. One hundred thirty-two metaphases were obtained on PHA-stimulated peripheral blood; 123 of them presented an extra chromosome Y. Fluorescence in situ hybridization using a Y satellite III probe showed the presence of a sole copy of chromosome Y in the tumor cells precluding a direct relationship between the extra chromosome Y and the initiation of the tumor. This is, to our knowledge, the second occurrence of a nonhematologic malignancy reported in this genetic disorder. A review of the malignancies observed in men with the XYY constitution is presented.

Over the past decade, trastuzumab was the only available monoclonal anti-HER2 antibody for the treatment of HER2 positive breast and gastric cancer. Recently, pertuzumab added to docetaxel and trastuzumab showed dramatic overall survival improvement in first line treatment of HER2 positive metastatic breast cancer. Pertuzumab is the first approved monoclonal antibody in a new class of drugs called dimerization inhibitors. This agent was also approved in association with trastuzumab for neoadjuvant HER2-positive breast cancer treatment. However, pertuzumab development was not confined to breast cancer and in the present review, we will focus on biological rational, preclinical data and clinical trial results of pertuzumab in solid tumors excluding breast cancer.

Trastuzumab is a humanized monoclonal antibody used for the treatment of HER2-positive breast cancer. Cardiotoxicity is a well-known adverse event of trastuzumab use but little has been documented regarding its use in patients with a history of cardiac disease.We describe a case in which trastuzumab treatment was administered to a 40-year-old female patient with early breast cancer after acute heart failure secondary to postoperative Takotsubo cardiomyopathy. After one year of follow-up with close monitoring by echocardiography, there have been no heart-related symptoms. Additional surgery was performed because of positive resection margins at first surgery, without complications, despite the risk of recurrence of Takotsubo cardiomyopathy.Trastuzumab can be safely administered after acute heart failure secondary to postoperative Takotsubo cardiomyopathy.

In the literature the sensitization of DNA to radiation-induced damage by caffeine has been attributed to an override of the G2/M block. This process was supposed to involve the tumor suppressor gene p53 as it was described that p53 negative cells were more sensitive to checkpoint inhibition by caffeine than the wildtype phenotype. We have recently shown that caffeine does not cause an override of the G2/M block induced by radiation in normal human fibroblasts. We demonstrate here that this also applies to a human transformed cell line, the thyroid carcinoma K1, when submitted to γ- rays irradiation. Within 9 hr after irradiation over 70% of the cells accumulated in the G2/M phase. This block persisted at 16 hr. In caffeine containing cultures the percentage of cells attaining the G2/M phase was reduced by over 30% at 16 hr. This was reflected in an accumulation of the cells in G1 phase and an inhibition of the S phase traverse. Cell cycle analyses from further time points combined with cell proliferation measurements confirmed these data. These results were independent of p53 status as experiments performed with variant K1 cell lines having defective p53 functions, led to similar conclusions. In addition, caffeine restored a G1 delay after irradiation in the cell lines with abrogated p53 functions. The effects of caffeine undeniably cumulate with damages induced by irradiation but probably by inhibiting DNA repair mechanisms or by intervening with purine and pyrimidine metabolisms and not by causing a G2/M block override. © 2001 Wiley-Liss, Inc.

The aim of this work was to evaluate the effects of SR 25989, a member of the thienopyridine family devoid of antiplatelet activity but possessing anti-angiogenic properties, on the regulation of proteins involved in matrix remodeling during wound healing or tumor progression. Human endothelial cells grown in the presence of SR 25989 showed moderate increases in the production of activators (tissue plasminogen activator and urokinase) and one inhibitor (plasminogen activator inhibitor type 1) of fibrinolysis, together with a significant rise in intracellular thrombospondin-1. SR 25989 induced a similar increase in thrombospondin-1 in human foreskin fibroblasts. This over-expression of thrombospondin-1 was correlated to a decrease in cell density. A concomitant increase in the tumor suppressor gene protein p53 was observed in endothelial cells and in fibroblasts, in which the slowing down of proliferation could be related to an accumulation of cells in the S and G2/M phases of the cell cycle. Northern blot analysis revealed a temporary rise in thrombospondin-1 transcripts, followed by a decrease along with a moderate increase in p53 transcripts. Thus the anti-angiogenic properties of SR 25989 appear to result from an upregulation of thrombospondin-1 which is possibly mediated by p53. The thienopyridine SR 25989 could therefore be a good candidate for adjuvant anti-angiogenic therapy in cancer.

New isoforms of CD44 with alternatively spliced exons have recently been described. Expression of exon v6 seems to be of particular interest. It has indeed been associated with poorer outcome of breast cancer patients with node invasion at diagnosis. However, no data were available for patients N0M0 (with neither metastasis nor node invasion at diagnosis). Moreover, previous statistical analyses were realized using immunohistochemical methods to detect CD44v6 expression although several variants with exon v6 have been described. We investigated expression of isoforms containing CD44v6 using an RT-PCR approach and a panel of 25 normal breast specimens, 10 mammary fibroadenomas, 8 cystic samples and 52 primary breast tumors (38 invasive N0M0). Normal breasts, fibroadenomas, and cysts all express the same variant, A (with exon v6 only), while several transcripts are amplified in tumors. Expression of variants other than A correlates with acquisition of a malignant phenotype. Invasive cancers also express additional variants in comparison with in situ carcinomas. Metastasis capacities seem to be associated with transcription of variants other than A but also with no transcription of some of them, variants D (with exons v6 and v10) and L (with exons v6 to v10). Expression of variants D and L correlates with higher percentages of disease-free survival and better outcome. Expression of CD44 splice variants with exon v6, as detected by RT-PCR, might be a useful prognostic factor for breast cancer. However, since the series size is small, our results need to be confirmed by later studies on a larger number of patients.

Androgen receptor (AR) signaling pathway remains the foremost target of novel therapeutics for castration-resistant prostate cancer (CRPC). However, the expression of constitutively active AR variants lacking the carboxy-terminal region in CRPC may lead to therapy inefficacy. These AR variants are supposed to support PCa cell growth in an androgen-depleted environment, but their mode of action still remains unresolved. Moreover, recent studies indicate that constitutively active AR variants are expressed in primary prostate tumors and may contribute to tumor progression. The aim of this study was to investigate the impact of constitutively active AR variants on the expression of tumor progression markers. N-cadherin expression was analyzed in LNCaP cells overexpressing the wild type AR or a constitutively active AR variant by qRT-PCR, Western blot and immunofluorescence. We showed here for the first time that N-cadherin expression was increased in the presence of constitutively active AR variants. These results were confirmed in C4-2B cells overexpressing these AR variants. Although N-cadherin expression is often associated with a downregulation of E-cadherin, this phenomenon was not observed in our model. Nevertheless, in addition to the increased expression of N-cadherin, an upregulation of other mesenchymal markers expression such as VIMENTIN, SNAIL and ZEB1 was observed in the presence of constitutively active variants. In conclusion, our findings highlight novel consequences of constitutively active AR variants on the regulation of mesenchymal markers in prostate cancer.

Trastuzumab is used for the adjuvant (postoperative) treatment of (HER2)-positive early breast cancer. The duration of treatment is set at one year. The goal of our study was to examine the effective duration of trastuzumab treatment in routine clinical practice.We performed a retrospective review of all patients with early breast cancer, treated with trastuzumab at our hospital between 2005 and 2008. Data concerning patterns of use and safety were collected from patient charts and pharmacy records.The cohort comprised of 96 patients, with a median age of 50 years (range=25-79 years). The majority of patients (63.5%) had node-negative disease. Besides trastuzumab, most patients underwent chemotherapy (before or after surgery). Trastuzumab was administered every three weeks and the median duration of treatment was 52 weeks (range=6-81 weeks). Only half of the patients received the monoclonal antibody for 52 weeks, 36.6% had therapy more than 52 weeks and 12.5% discontinued treatment before 52 weeks due to adverse effects (8.4%) and refusal (4.1%). Two (2.1%) patients discontinued trastuzumab therapy because of cardiotoxicity, a recognized side-effect of the monoclonal antibody. Regarding treatment durations of more than 52 weeks, 15/35 were due to the off-label use of trastuzumab in the neoadjuvant setting (before surgery). The 3-year rate of disease-free survival was 91.6%.Half of the patients completed the 52-week treatment of trastuzumab after surgery for early breast cancer. Trastuzumab was well-tolerated and the rate of discontinuation due to cardiotoxicity was low, compared to published results.

International audience; AIMS: A minority of patients with advanced sarcoma achieve prolonged progression free survival (PFS) with insulin growth factor type 1 receptor (IGF-1R) monoclonal antibody (Ab) therapy. A biomarker identifying those patients beforehand would be useful to select patients for the development of these agents. METHODS: This single centre series includes patients with unresectable or metastatic soft tissue sarcomas (STS), Ewing sarcoma (ES) and osteosarcoma treated with IGF-1R Ab (R1507, IMC-A12, SCH 717454 and CP-751.871) in the Centre Léon Bérard. Tumour samples were analysed by immunohistochemistry for expression of IGF-1R, insulin-like growth factor binding protein type 3 (IGFBP-3), Ki67, epidermal growth factor receptor (HER1) and human epidermal growth factor receptor 2 (HER2). Predictive factors for PFS and overall survival (OS) were investigated. RESULTS: All tumour samples had a positive IGF-1R immunostaining on 60% to 100% of tumour cells. IGFBP-3 immunostaining was observed in 12 (75%) samples with 5% to 100% of positive cells. IGF-1R immunostaining was nuclear (n=9, 56%), cytoplasmic (n=4, 25%), or nuclear +cytoplasmic (n=3, 19%). Neither IGFBP-3 expression, nor Ki67 was correlated to PFS. HER2 and HER1 staining were positive in 0 and 2 samples respectively (both primary resistant to IGF-1R Ab therapy). Exclusive intra-nuclear immunoreactivity for IGF-1R was significantly associated with a better PFS (p=0.01) and OS (p=0.007). CONCLUSION: Exclusive nuclear localisation of IGF-1R is an easily testable biomarker associated with a better PFS and OS for patients treated with IGF-1R Ab therapy. Nuclear localisation of IGF-1R in tumour cells might be a hallmark of pathway activation.

Pulmonary invasive aspergillosis is a frequent and poor prognosis complication of immuno-deficiency and prolonged neutropenia. Its treatment is usually based on amphotericin B (0.7 to 1 mg/kg/d) given as intravenous infusions for at least 2 months. This therapy is limited by the side-effects of the drug including renal failure, myelosuppression, chills and fever. We present here the case of women with pulmonary invasive aspergillosis treated with a different modality of administration. The amphotericin B was given as a continuous infection at 2 mg/kg/d diluted in Intralipid, a triglyceridic mixture used in parenteral nutrition. Given by this way amphotericin B seems to have a good therapeutic efficiency and a mild toxicity limited to transient reduction in creatinine clearance with increased kaliuria. Other current approaches of invasive aspergillosis include the amphotericin B in liposomes, combination of amphotericin B with 5-fluorouracil and the triazolated compounds.

Oxaliplatin is an anticancer agent only approved for treatment of colorectal cancer, but that has shown some activity in metastatic breast cancer in phase II studies. Herein, we examine the off-label use of oxaliplatin in unselected patients with metastatic breast cancer.A retrospective review was performed of all patients with metastatic breast cancer treated with oxaliplatin at our hospital between February 2003 and November 2009. Data concerning patterns of use, safety and activity were collected from patient charts.The cohort comprised 30 female patients with a median age of 49 (range, 34-68 years) and a median of two involved organs (range, 1-4). All patients had been pretreated for metastatic breast cancer (median number of previous lines: 3; range:1-6). Oxaliplatin was only given in association either with fluorouracil and folinic acid (n=23) or with gemcitabine (n=7). The most commonly used dose was 100 mg/m(2) given every other week or every 3 weeks. As of December 15, 2009, the median duration of treatment was 4 (range, 0.75-11) months. Most of the discontinuations occured due to disease progression (n=11) and adverse effects or worsening condition (n=8). Twelve (40%) patients presented side-effects related to oxaliplatin use including hematotoxicity (n=8), gastrointestinal disorders (n=4) and neuropathies (n=2). Among patients evaluable for antitumoral activity (n=15), one patient achieved a complete response and one patient demonstrated a partial response. Most of the patients (57%) continued to be treated by chemotherapy after oxaliplatin. Median overall survival for the evaluable patients was 10 (range, 1-51) months.In our population of heavily pretreated women with metastatic breast cancer, off-label use of oxaliplatin was of little worth. This off-label treatment was not the last therapeutic option for most of these patients.

The aim of our work was to assess the potential clinical impact of therapeutic education in patients treated with anticancer drugs. One hundred-one ambulatory adult patients (mean age: 60 years, range: 24-88) treated by anticancer chemotherapy were included. The occurrence of adverse events was reported by 83% of the patients. Twenty-one percent (14/67) of the patients were not compliant with their supportive care treatment, 60% (60/101) took over-the-counter medications (one contraindication identified) and 14% (14/101) claimed they had received no counsel on risk behaviour (UV exposure, lack of contraception, driving) from health care professionals. Overall, 11% (44/397) of adverse events were associated with a lack of information. Twelve percent (4/33) of the calls to the doctor, 6% (1/17) of the visits to the physician and 21% (3/14) of the hospitalizations could be associated with a lack of therapeutic education. These data enlighten the importance of therapeutic education of cancer patients treated by chemotherapy.

Delayed elimination of methotrexate associated with serious side-effects has been attributed to the co-administration of benzimidazole proton pump inhibitors.We have retrospectively analyzed the causes of delayed methotrexate elimination in patients who had received the rescue agent glucarpidase to evaluate the potential implication of benzimidazoles.Between 2002 and 2008, six patients (mean age: 30 years; range: 4-74 years) were treated with glucarpidase. Delayed elimination associated with impaired renal function occured after the first cycle except in 2 patients (2nd and 8th administration of high-dose methotrexate). The possible causes of delayed elimination identified were: insufficient hydration (n=1) and drug-drug interactions (n=5). The potential drug-drug interactions included the co-administration of piperacillin/tazobactam (n=1) and proton pump inhibitors (omeprazole, n=3; esomeprazole, n=2). Impaired elimination of methotrexate was not observed either in the 3 patients who were treated further or during the previous cycles of the 2 pretreated patients in relation to the absence of co-prescription of proton pump inhibitors.In line with the recent literature and given the prohibitive cost of glucarpidase, we have advocated the cessation of proton pump inhibitors administration during methotrexate treatment.

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.

Castration resistance in prostate cancer (PCa) constitutes an advanced, aggressive disease with poor prognosis, associated with uncontrolled cell proliferation, resistance to apoptosis, and enhanced invasive potential. The molecular mechanisms involved in the transition of PCa to castration resistance are obscure. Here, we report that the nonselective cationic channel transient receptor potential vanilloid 2 (TRPV2) is a distinctive feature of castration-resistant PCa. TRPV2 transcript levels were higher in patients with metastatic cancer (stage M1) compared with primary solid tumors (stages T2a and T2b). Previous studies of the TRPV2 channel indicated that it is primarily involved in cancer cell migration and not in cell growth. Introducing TRPV2 into androgen-dependent LNCaP cells enhanced cell migration along with expression of invasion markers matrix metalloproteinase (MMP) 9 and cathepsin B. Consistent with the likelihood that TRPV2 may affect cancer cell aggressiveness by influencing basal intracellular calcium levels, small interfering RNA–mediated silencing of TRPV2 reduced the growth and invasive properties of PC3 prostate tumors established in nude mice xenografts, and diminished expression of invasive enzymes MMP2, MMP9, and cathepsin B. Our findings establish a role for TRPV2 in PCa progression to the aggressive castration-resistant stage, prompting evaluation of TRPV2 as a potential prognostic marker and therapeutic target in the setting of advanced PCa. Cancer Res; 70(3); 1225–35

The extent of potential pharmacokinetic drug-drug interactions affecting anticancer agents disposition has not been specifically investigated. The prevalence of this type of interaction in adult ambulatory patients receiving systemic chemotherapy in our institution was examined.The medication list of 200 consecutive cancer patients receiving intravenous chemotherapy was prospectively collected by means of the prescriptions (chemotherapy, supportive care, medications for comorbidities) and a questionnaire (over-the-counter products). Interacting drugs had to have been taken in the previous 7 days. Data concerning the type of cancer and the nature of the comorbidities were also collected. Potential pharmacokinetic drug interactions affecting the activity of the anticancer agent were identified using the guide of drug interactions of the French drug agency (June 2007) and the literature.A total of 200 patients (mean age 60 years; range 17-96 years) entered the study and 73.5% were female. The most common cancer types were breast cancer (41%), non-Hodgkin's lymphomas (17.5%), and gastrointestinal tumors (12.5%). The majority of the patients (58.5%) had a comorbid illness (cardiovascular diseases, hypothyroidism, diabetes, depression). The median number of medications per patient was 4 (range 1-14). All the patients received systemic chemotherapy but 29 (14.5%) also took anticancer drugs at home. Nine potential pharmacokinetic interactions were found in nine patients (frequency: 4.5%; 95% confidence interval: 1.6-7.4%). Most of the interactions (7/9) involved fluconazole that might alter the metabolism of oxazaphosphorines or the elimination of bortezomib and paclitaxel. One association was contraindicated. Five interactions were not associated with a published clinical effect. No interaction with an enzyme or drug transporter inducer (e.g., rifampin, St. John's wort) was encountered.The frequence of potential pharmacokinetic interactions affecting the disposition of antitumor drugs was low in this population of ambulatory adult cancer patients and mostly involved the antifungal agent fluconazole.

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.

Purpose To describe the patterns of care of elderly cancer patients (ECPs) (>70 years old) and the factors affecting the referral by general practitioners (GPs) of patients to cancer specialists (SPs), in Alsace France. Methods A postal mail questionnaire was sent to a total of 2818 physicians including primary care physicians and specialists. The factors possibly responsible for a poor referral rate of ECPs and the factors affecting treatment implementation by specialists were explored. We also searched for unmet needs such as the incorporation of geriatric assessment into routine practice and continuous medical education (CME) programs. Results A total of 1217 questionnaires were returned (46.9%) from 1053 GPs and 214 SPs. Patients’ age did not negatively impact referral to SPs as opposed to patients’ performance status, wishes, and co-morbidities. Conversely, a significant decrease in patients’ file presentation by SPs to tumor boards was observed for patients over 80 years old. Neither reimbursement nor SPs’ waiting lists were an issue. The need for CME programs in geriatric oncology was emphasized by both GPs and SPs. Conclusions Age was not the governing variable that impacted patient referral. The need for CME in geriatrics was highlighted for both GPs and SPs.

The androgen receptor (AR) signaling pathway plays an important role during the development of the normal prostate gland, but also during the progression of prostate cancer on androgen ablation therapy. Mutations in the AR gene emerge to keep active the AR signaling pathway and to support prostate cancer cells growth and survival despite the low levels of circulating androgens. Indeed, mutations affecting the ligand binding domain (LBD) of the AR have been shown to generate so-called "promiscuous" receptors that present widened ligand specificity and allow the stimulation of these receptors by a larger spectrum of endogenous hormones. Another class of mutations, arising in the amino-terminal domain (NTD) of the receptor, modulate AR interactions with coregulators involved in cell proliferation regulation. Besides characteristics of these well-known types of mutations, the properties of other classes of AR mutants recently described in prostate cancer are currently under investigation. Most interestingly, in addition to their potential role in the mechanisms which allow prostate cancer cells to escape androgen ablation therapy, data suggest that certain AR mutations are present early in the natural history of the disease and may play a role in many aspects of prostate cancer progression. Surprisingly, singular truncated AR devoid of their carboxy-terminal end (CTE) region seem to exert specific paracrine effects and to induce a clonal cooperation with neighboring prostate cancer cells, which may facilitate both the invasion and metastasis processes. In this article, we review the functional properties of different classes of AR mutants and their potential impact on the natural history of prostate cancer. Hum Mutat 0, 1-14, 2008. (c) 2008 Wiley-Liss, Inc.

Mutations in the human androgen receptor (AR) gene that lead to C-terminus truncated AR variants are frequently detected in prostate cancer (PC). These AR variants lack both the ligand-binding domain (LBD) and the AF-2 region. The aim of this study was to delineate the alternative mechanisms that lead to the activation of such AR variants as they are unresponsive to hormone stimulation, and to outline consequences of the loss of the LBD/AF-2 region on their functional properties. By using an MMTV-luciferase reporter construct and LY294002, UO126, or ZD1839, inhibitor of PI3K, MEK1/2, and EGFR signaling pathway respectively, we demonstrated that phosphorylation was required for full transcriptional activities of one these AR variants, the Q640X mutant AR. Western-blot analyses confirmed that these inhibitors affect the phosphorylation status of this AR variant. Furthermore, studies of the intranuclear colocalization of the Q640X AR with cofactors, such as CBP, GRIP-1, and c-Jun, reveal that the transcriptional complex that forms around the mutant AR is different to that formed around the wild type AR. We demonstrated that CBP and c-Jun are highly recruited by the mutant AR, and this leads to an unexpected activation of AP-1, NFAT, and NFkappaB transcriptional activities. Similar enhanced activities of these transcription factors were not observed with the wild type AR. The importance of the LBD/AF-2 for the regulation of AR transcriptional activities, the impact of the presence of such AR variants on PC cells proliferation and survival, and on progression to androgen independence are discussed.

Two chemosensitive cell lines, LoVo-fusoid (LoVo-f) and LoVo-small cells (LoVo-sc) were derived from the original LoVo cell line. These two variants and the multidrug-resistant (MDR) cell line LoVo-Dox were screened for various properties. In non-permeabilized cells, only LoVo-sc showed mucin-2 staining whereas labelling was positive in all permeabilized cell lines. As shown by electron microscopy screening and by relative resistance to trypsin detachment, only LoVo-sc cells showed strong mucus secretion. All three cell lines displayed strong staining for P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and lung-resistance-related protein (LRP) in different locations according to the drug resistance state. The three cell lines showed intracellular labelling of LRP and MRP. The sensitive cells showed P-gp in a large perinuclear ring and in the cytoplasm, but little (LoVo-sc cells) or no staining (LoVo-f cells) was shown at the plasma membrane level. For the Lovo-Dox cells, P-gp was located in the plasma membrane, in cellular anchorages and in the cytoplasm as well. Cell resistance against antineoplastic agents often results from mobilization of various factors, the modulation of which is linked to the culture conditions. As most of the protocols utilize cells growing in (air + 5-10% CO2) atmosphere e.g. 20% O2, balance of the respective participants in the MDR multi-modal mechanism may not be representative of the in vivo situation and may lead to erratic pharmacological response. Indeed, cells within solid tumours were exposed to low pO2, most of them being under hypoxic condition (0.1-5% O2). In the absence of anticancer drugs, all LoVo cell lines grew notably faster at 20% O2 than at 5% O2. Moreover, respective sensitivities of both non-MDR variants to doxorubicin were altered according the pO2. Whatever the pO2 was, virtually none of the antioxidants tested affected the cytotoxic activity of doxorubicin for the three cell lines. By contrast, trolox showed a strong inhibitory effect on doxorubicin activity. These results underline the importance of evaluating the role of hypoxia on the cytotoxic effect of chemotherapeutic agents used either as single drugs or in combination therapy.

Mutations in the human androgen receptor (AR) gene that lead to C-terminus truncated AR variants are frequently detected in prostate cancer (PC). These AR variants lack both the ligand-binding domain (LBD) and the AF-2 region. The aim of this study was to delineate the alternative mechanisms that lead to the activation of such AR variants as they are unresponsive to hormone stimulation, and to outline consequences of the loss of the LBD/AF-2 region on their functional properties. By using an MMTV-luciferase reporter construct and LY294002, UO126, or ZD1839, inhibitor of PI3K, MEK1/2, and EGFR signaling pathway respectively, we demonstrated that phosphorylation was required for full transcriptional activities of one these AR variants, the Q640X mutant AR. Western-blot analyses confirmed that these inhibitors affect the phosphorylation status of this AR variant. Furthermore, studies of the intranuclear colocalization of the Q640X AR with cofactors, such as CBP, GRIP-1, and c-Jun, reveal that the transcriptional complex that forms around the mutant AR is different to that formed around the wild type AR. We demonstrated that CBP and c-Jun are highly recruited by the mutant AR, and this leads to an unexpected activation of AP-1, NFAT, and NFκB transcriptional activities. Similar enhanced activities of these transcription factors were not observed with the wild type AR. The importance of the LBD/AF-2 for the regulation of AR transcriptional activities, the impact of the presence of such AR variants on PC cells proliferation and survival, and on progression to androgen independence are discussed.

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).

Adjuvant hormone therapy is indicated only in patients whose tumors express estrogen or progesterone receptors. Aromatase inhibitors (AI) are indicated only in postmenopausal patients. AI are significantly more effective than tamoxifen in terms of disease-free survival and distant recurrence-free survival; these advantages will probably result in a significant overall survival benefit after sufficient follow-up. This benefit justifies the use of AI in all postmenopausal patients in the absence of contraindications and after complete explanations of the benefit/risk ratio and potential side effects of this treatment. The benefit of AI over tamoxifen may be particularly pronounced for tumors overexpressing HER-2 and perhaps for ER+PR- tumors. Replacement of tamoxifen by AI or first-line treatment with AI is advised in patients with such tumors. Extended adjuvant treatment with AI for 5 years significantly increases survival among patients already treated with tamoxifen for 5 years; it also provides a significant overall survival benefit to patients with positive axillary nodes and should be used in this group. AI may cause several generally mild side effects, including insomnia, arthralgia, bone loss, vaginal dryness, dyspareunia and loss of libido. Tamoxifen may be appropriate for well-informed patients with these side effects, especially those with RE+ RP+ tumors and a low risk of thromboembolic or endometrial complications. The effects of AI on memory and cognition should also be investigated thoroughly before its long-term use, especially in the elderly.

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.

Summary Post-transplant lymphoproliferative disorders (PTLD) are severe complications after solid organ transplantation with no consensus on best treatment practice. Chemotherapy is a therapeutic option with a high response and a significant relapse rate leading to a low long-term tolerance rate. Currently, most centres use anthracycline-based drug combinations, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone). We assessed the efficacy and safety of a dose-adjusted ACVBP (doxorubicin reduced to 50 mg/m2, cyclophosphamide adjusted to renal function, vindesine, bleomycin, prednisone) regimen in patients failing to respond to a reduction in immunosuppressive therapy. Favourable responses were observed in 24 (73%) of the 33 treated patients. Fourteen (42%) patients died, mostly from PTLD progression. Actuarial survival was 60% at 5 years and 55% at 10 years. Survival prognostic factors were: number of involved sites (P = 0·007), clinical stage III/IV (P = 0·004), bulky tumour (P

The combination of high-linear energy transfer (LET) radiation with chemotherapeutic agents may offer new perspectives in cancer treatment. We therefore assessed the consequences of a treatment in which U-87 human glioblastoma cells were irradiated with p(65) + Be neutrons in the presence of oxaliplatin, a third generation platinum anticancer drug having higher apoptosis-inducing activity than cisplatin. Cell survival, apoptosis, cell cycle progression as well as p21 and p53 protein expressions were analyzed. Results show that an enhanced cytotoxic effect was obtained when the two treatments were combined and that, unlike what we previously observed with cisplatin, this was not due to a reinforcement of apoptosis. Altogether, our results also indicate the potential of oxaliplatin for use in association with high-LET radiation against tumors refractory to conventional photon radiotherapy. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

International audience; Apple procyanidins have chemopreventive properties in a model of colon cancer, they affect intracellular signalling pathways, and trigger apoptosis in a human adenocarcinoma-derived metastatic cell line (SW620). In the present study we investigated relationships between procyanidin-induced alterations in polyamine metabolism and apoptotic effects. Apple procyanidins diminish the activities of ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase, key enzymes of polyamine biosynthesis, and they induce spermidine/spermine N1-acetyltransferase, which initiates retroconversion of poly-amines. As a consequence of the enzymatic changes polyamine concentrations are diminished, and N1-acetyl-polyamines accumulate in SW620 cells. In contrast with expectations MDL 72527, an inactivator of polyamine oxidase (PAO), improved the anti-proliferative effect of procyanidins, and caused an increase of the proportion of apoptotic cells, although it prevented the formation of hydrogen peroxide and 3-acetamidopropanal, the cytotoxic products of PAO-catalysed degradation of N1-acetylspermidine and N1-acetylspermine. Addition of 500 µM N1-acetylspermidine to the culture medium in the presence of procyanidins mimicked the effect of MDL 72527. Therefore we presume that the enhanced procyanidin-triggered apoptosis by MDL 72527 is mediated by the accumulation of N1-acetyl-polyamines. The observation that apple procyanidins enhance polyamine catabolism and reduce polyamine biosynthesis activity similar to known inducers of SSAT, without sharing their toxicity, and the potentiation of these effects by low concentrations of MDL 72527 suggests apple procyanidins for chemopreventive and therapeutic interventions.

We have previously shown that ionizing radiation-induced apoptosis in human lymphoblastoid cells differs according to their p53 status, and that caspase 8-mediated cleavage of BID is involved in the p53-dependent pathway. In the present study, we investigated the role of Fas signaling in caspase 8 activation induced by fast neutrons irradiation in these cells. Fas and FasL expression was assessed by flow cytometry and by immunoblot. We also measured Fas aggregation after irradiation by fluorescence microscopy. We found a decrease of Fas expression after irradiation, but no change in Fas ligand expression. We also showed that, in contrast to the stimulation of Fas by an agonistic antibody, Fas aggregation did not occur after irradiation. Altogether, our data strongly suggest that fast neutrons induced-apoptosis is Fas-independent, even in p53-dependent apoptosis.