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Primitive Neuroectodermal tumor belongs to the family of Ewing's tumor and is characterized by at (11;22) (q24;ql2) or at (21;22) (q22;ql2) translocation. Retroperitoneal primitive neuroectodermal tumor (PNET) are rare, usually affect young adults, and are often diagnosed late. There is no specific characteristics for imaging. The diagnosis is made on histological examination of the surgical spec- imen or biopsies. Radiotherapy and chemotherapy complete the treatment. The authors report the case of a 26-year-old patient who only had pelvic discomfort. Diagnostic laparoscopy showed a retroperitoneal and retrovesical mass of five centimeters. The patient benefited from adjuvant chemotherapy and radiotherapy. She is free of disease 30 months after treatment.

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.

Background: 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., Case Report: 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., Conclusion: Trastuzumab can be safely administered after acute heart failure secondary to postoperative Takotsubo cardiomyopathy., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

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.

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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: 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., Patients and Methods: 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., Results: 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%., Conclusion: 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.

Almost all prostate cancers respond to androgen deprivation treatment but many recur. We postulated that risk of hormone escape--frequency and delay--are influenced by hormone therapy modalities. More, hormone therapies induce crucial biological changes involving androgen receptors; some might be targets for escape prevention. We investigated the relationship between the androgen deprivation treatment and the risk of recurrence using nude mice bearing the high grade, hormone-dependent human prostate cancer xenograft PAC120. Tumor-bearing mice were treated by Luteinizing-Hormone Releasing Hormone (LHRH) antagonist alone, continuous or intermittent regimen, or combined with androgen receptor (AR) antagonists (bicalutamide or flutamide). Tumor growth was monitored. Biological changes were studied as for genomic alterations, AR mutations and protein expression in a large series of recurrent tumors according to hormone therapy modalities. Therapies targeting Her-2 or AKT were tested in combination with castration. All statistical tests were two-sided. Tumor growth was inhibited by continuous administration of the LH-RH antagonist degarelix (castration), but 40% of tumors recurred. Intermittent castration or complete blockade induced by degarelix and antiandrogens combination, inhibited tumor growth but increased the risk of recurrence (RR) as compared to continuous castration (RR(intermittent): 14.5, RR(complete blockade): 6.5 and 1.35). All recurrent tumors displayed new quantitative genetic alterations and AR mutations, whatever the treatment modalities. AR amplification was found after complete blockade. Increased expression of Her-2/neu with frequent ERK/AKT activation was detected in all variants. Combination of castration with a Her-2/neu inhibitor decreased recurrence risk (0.17) and combination with an mTOR inhibitor prevented it. Anti-hormone treatments influence risk of recurrence although tumor growth inhibition was initially similar. Recurrent tumors displayed genetic instability, AR mutations, and alterations of phosphorylation pathways. We postulated that Her-2/AKT pathways allowed salvage of tumor cells under castration and we demonstrated that their inhibition prevented tumor recurrence in our model.

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.

Purpose of the Study: Elderly breast cancer (EBC) patients are often denied adjuvant chemotherapy because of age. Breast cancer is among the most frequent cancer in Western Countries and recent data suggest that adjuvant chemotherapy could be active in selected elderly patients. We investigated the impact of age and comprehensive geriatric assessment (CGA) among other variables taken into account in tumor boards to recommend adjuvant chemotherapy in EBC patients., Method(s): We retrospectively reviewed breast cancer tumor board records of all consecutive EBC patients (over 70 years old) discussed from July 2006 to July 2009 in our institution. The recorded variables included age, comorbidities, tumor stage, grade, ER/PR and HER2 status, treatment characteristics and CGA conclusions. Agreement with breast cancer treatment guidelines was verified. Reasons for deviations were recorded., Result(s): A total of 192 early EBC patients files (mean age 76.7 years, range 70-98) were analyzed. Elderly patients were less likely to receive adjuvant chemotherapy even when deemed appropriate by guidelines (p<.001). Out of 118 patients with ≥1 risk factors (pT2-4, N+, RH-, SBR III), 70 were proposed adjuvant chemotherapy. In multivariate analysis, age >80 years, but not CGA result, was an independent variable associated with a decreased likelihood to receiving adjuvant chemotherapy. Moreover, 93 patients (48.4%) underwent CGA, of whom no Balducci's class III patient received adjuvant chemotherapy. An appropriate treatment was administered in only 69% and 42% of Balducci's class I and II patients, respectively., Conclusion(s): Our results suggest that age remains an independent variable associated with a decreased use of adjuvant chemotherapy. However, in our series systemic adjuvant chemotherapy was probably underused in "fit" patients. Further efforts are needed to better integrate CGA into tumor boards proposals for early EBC patients., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: 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., Patients and Methods: 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., Results: 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., Conclusion: 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.

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., (Copyright © 2011 S. Karger AG, Basel.)

An accidental transmission of placental choriocarcinoma (CC) from a multiorgan donor to four recipients is reported. The donor was a 26-year-old pregnant woman, died from a cerebral hemorrhage. Histological examination demonstrated the presence of a placental CC. Diagnosis of CC transmission was established on the basis of an increase of human chorionic gonadotrophin hormone (hCG) level. The recipient of combined pancreas-kidney is still in complete remission 2 years after the beginning of chemotherapy without removal of the grafted organs which show optimal function. The recipient of a single kidney was rapidly transplantectomized and treated with actinomycin. At 2 years, she remains in remission. Liver recipient showed intestinal metastasis and died from digestive hemorrhage after an initial response to chemotherapy. Heart recipient had an initial remission under EMA-CO, but at the last report, he showed diffuse metastasis. Published reports on CC transmission are rare. The long-lasting remission of our pancreas-kidney recipient and her good outcome after 2 years make our observation original. Moreover, the high rate of transmission demonstrates the high malignant potential of CC in immunosuppressed patients. Chemotherapy combined or not with transplantectomy in case of nonvital organ, should be discussed., (©2010 The Authors Journal compilation©2010 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

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 Hôpitaux 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., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: Delayed elimination of methotrexate associated with serious side-effects has been attributed to the co-administration of benzimidazole proton pump inhibitors., Patients and Methods: 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., Results: 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., Conclusion: 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.

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.

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.

Aim: 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., Patients and Methods: 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., Results: 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., Conclusion: 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.

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., ((c) 2008 Wiley-Liss, Inc.)

Background: Invasive aspergillosis is associated with high death rates. Factors associated with increased mortality 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 corticosteroid 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 outcome, and this finding calls for the development of efficient preemptive strategies to fill the gap between empirical and directed therapy.

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.

Trastuzumab is a monoclonal antibody that targets the extracellular domain of HER2, a member of the epidermal growth factor receptor (EGFR) family. Trastuzumab is currently approved for the treatment of breast cancer overexpressing HER2, given alone or in combination with paclitaxel or docetaxel. Trastuzumab pharmacokinetics are characterized by a low systemic clearance, a low volume of distribution (4l) and a very long half-life (28 days) comparable to that of endogenous immunoglobulins G. The elimination pathways are not yet defined and the clinical relevance of trastuzumab kinetic variability is unknown. Whether exposure might correlate with toxic effects or inadequate response has not been explored. No drug-drug interactions have been reported. This is not surprising because based on the current knowledge, no monoclonal antibody (including trastuzumab) has been found to interact with major molecular pharmacokinetic determinants such enzymes, drug transporters or orphan nuclear receptors. Dosage regimens of trastuzumab are similar either it is used in the adjuvant setting (postoperative) or in metastatic disease. According to the official labelling, trastuzumab is given by intravenous perfusion at a dose based on body weight, weekly (metastatic, adjuvant) or 3-weekly (adjuvant). The schedule also includes a loading dose at the initiation of the treatment. The recommended duration of treatment is currently one year (adjuvant) or until the progression of the disease (metastatic). Regarding the adjuvant setting, different dosage regimens have been tested (from 9 weeks to 2 years) but the optimal duration of treatment is unknown. The short course of trastuzumab (9 weeks) appears promising in terms of activity, tolerance and cost but should be compared to 1 or 2-years treatments. In addition, dosing regimens might be optimized by integrating pharmacokinetic elements. In the adjuvant setting, given the more favorable kinetic situation (absence of tumor penetration), a less intense dosage regimen might be appropriate when compared with that used in metastatic disease. Further body weight is weakly related to trastuzumab exposure and it is not proven that it significantly affects clinical activity. These pharmacokinetic considerations may support the use of fixed doses given monthly, on short periods, for the treatment of early breast cancer.

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.

Purpose: To evaluate the outcome of patients treated for soft tissue sarcoma using three different post-operative radiotherapy schedules., Methods and Materials: Between 1990 and 2003, 89 patients (median age 50.8 years) presenting with soft tissue sarcoma (located to the limbs for 66 of them) underwent post-conservative-surgery radiotherapy. Pathology was liposarcoma in 35 cases and 54 others tumors. Tumors grades (FNCLCC classification) were 1, 2, 3 or unknown in 29, 32, 19 and 9 cases, respectively. Surgery was considered as complete in 68 patients. Irradiation was normofractionated (NF) in 62 cases, hyperfractionated (BF) in 19 cases and hypofractionated (HF) in 8 cases. For all the patients, median delivered dose was 61 Gy [34-76 Gy]., Results: Median follow-up of alive patients was 73,8 months [3-184]. Five-year local control (LC) and overall survival (OS) rates were 85.5 and 71.2% respectively. According to multifactorial analysis, favourable prognostic factors were for local control, complete surgery (P=0.0075) and for overall survival, complete surgery (P=0.0267), grade 1 tumor (P=0.012) and absence of distant recurrence (P=0.0488). There was no statistical evidence of difference for the five-year LC and OS rates between the patients who received NF, BF or HF. There were few complications and there were comparable in the three groups., Conclusions: This retrospective serie showed similar results for all the schedules. There is no evidence to recommend bifractionation. Hypofractionation should be used only in selected patients with poor performans status.

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., ((c) 2007 Wiley-Liss, Inc.)

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-kappaB 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.

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.

A cytological, immunophenotypical and cytogenetical study of 136 chronic B-cell proliferations (93 CLL, 43 B-cell lymphomas) was led in order to precise diagnosis and to characterize and appreciate chromosomal rearrangements. In this series, mainly selected on blood lymphocytosis criteria, B-CLL were twice more frequent than small B-cell lymphomas. Probes used revealed cryptic abnormalities, which remained unknown by conventional cytogenetics (CC). The frequency of clonal abnormalities (CC and FISH) was 74.8% for this series, with 74.4% for lymphomas and 75.3% for CLL, mainly of Binet stage A (69 A, 13 B, 1 C, 10 unspecified). Proportion was 88.4% in A stages and 84.6% in B stages. In CLL, 13q14 cryptic deletions and translocations were widely majority, 14q32 translocations and trisomy 12 being predominant in lymphoma series. Interphase FISH study of non-clonal metaphasic abnormalities with locus-specific probes often revealed unrecognised clones.

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.

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/m(2), 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 < 0.0001), B symptoms (P = 0.03), decreased serum albumin (P = 0.03) and poor performance status (P = 0.06). Both the international and the PTLD prognostic index were predictive for survival (P = 0.001 and P = 0.002, respectively). Overall 128 cycles were given. Grade 3 or 4 neutropenia was recorded after 26 (20%) chemotherapy cycles in 19 (58%) patients. Forty-one (32%) infections were recorded in 26 (79%) patients. This study demonstrated that an individual dose-adjustment of ACVBP regimen was manageable in PTLD patients and favourably impacted on long-term survival.

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 N(1)-acetyltransferase, which initiates retroconversion of poly-amines. As a consequence of the enzymatic changes polyamine concentrations are diminished, and N(1)-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 N(1)-acetylspermidine and N1-acetylspermine. Addition of 500 microM 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 N(1)-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.

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.

Missense mutations in the androgen receptor (AR) contribute to the failure of hormonal therapy for prostate cancer (PCa), but the underlying molecular bases remain uncharacterized. Here, we describe a new AR variant found in a hormone-refractory metastatic PCa, in which threonine 575 in the DNA binding domain, and threonine 877 in the ligand-binding domain, were both replaced by an alanine. Using gene reporter assays, we demonstrate that the T575A mutation weakened transcriptional activity from promoters containing AR-specific responsive elements, while activity from promoters with AR-non-specific elements was enhanced. Data from gel shift experiments revealed a preferential binding of the T575A mutant to AR-non-specific motifs. We demonstrate that the two mutations T575A and T877A cooperate to confer new functional properties on the AR, and that the mutant AR functions simultaneously as a promiscuous AR due to the T877A mutation, and an unfaithful AR due to the T575A mutation.