Adherence and patients' attitudes to oral anticancer drugs: a prospective series of 201 patients focusing on targeted therapies.

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

Transcriptome-Based SNP Discovery and Validation in the Hybrid Zone of the Neotropical Annual Fish Genus Austrolebias.

The genus Austrolebias (Cyprinodontiformes: Rivulidae) represents a specious group of taxa following annual life cycles in the neotropical ichthyofauna. They live in temporary ponds and each generation must be completed in a few months, depending on environmental stochasticity. Annual fish survive the dry season through diapausing eggs buried in the substrate of these ponds. A hypothesized bimodal hybrid zone between two taxa of the genus, A. charrua and A. reicherti from Dos Patos Merin lagoon system, was recently proposed based on genetics and morphological analyses. However, hundreds of additional nuclear molecular markers should be used to strongly support this hypothesized bimodal pattern. In the present paper, we conducted RNA-seq-based sequencing of the transcriptomes from pools of individuals of A. charrua, A. reicherti and their putative natural hybrids from the previously characterized hybrid zone. As a result, we identified a set of 111,725 SNP (single nucleotide polymorphism) markers, representing presumably fixed allelic differences among the two species. The present study provided the first panel of 106 SNP markers as a single diagnostic multiplex assay and validated their capacity to reconstruct the patterns of the hybrid zone between both taxa. These nuclear markers combined with Cytb gene and morphological analyses detected a population structure in which some groups among the hybrid swarms showed different level of introgression towards one or the other parental species according to their geographic distribution. High-quality transcriptomes and a large set of gene-linked SNPs should greatly facilitate functional and population genomics studies in the hybrid zone of these endangered species.

Specific properties of a C-terminal truncated androgen receptor detected in hormone refractory prostate 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.

A splicing variant of the androgen receptor detected in a metastatic prostate cancer exhibits exclusively cytoplasmic actions.

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.

Review of the family Rivulidae (Cyprinodontiformes, Aplocheiloidei) and a molecular and morphological phylogeny of the annual fish genus Austrolebias Costa 1998

The family Rivulidae is the fourth most diverse clade of Neotropical fishes. Together with some genera of the related African family Nothobranchiidae, many rivulids exhibit a characteristic annual life cycle, with diapausing eggs and delayed embryonic development, which allows them to survive in the challenging seasonal ponds that they inhabit. Rivulidae also includes two species known as the only the self-fertilizing vertebrates and some species with internal fertilization. The first goal of this article is to review the systematics of the family considering phylogenetic relationships and synapomorphies of subfamilial clades, thus unifying information that is dispersed throughout the literature. From this revision, it is clear that phylogenetic relationships within Rivulidae are poorly resolved, especially in one of the large clades that compose it, the subfamily Rivulinae, where conflicting hypotheses of relationships of non-annual and annual genera are evident. The second goal of this work is to present an updated phylogenetic hypothesis (based on mitochondrial, nuclear, and morphological information) for one of the most speciose genus of Rivulidae, Austrolebias. Our results confirm the monophyly of the genus and of some subgeneric clades already diagnosed, but propose new relationships among them and their species composition, particularly in the subgenus Acrolebias.

a familia Rivulidae es el cuarto clado más diverso dentro de los peces Neotropicales. Junto con algunos géneros de la familia Nothobranchiidae, muchos rivulidos presentan un característico ciclo de vida anual, con huevos resistentes a la desecación y embriones con diapausas que les permiten sobrevivir en los ambientes estacionales donde habitan. Los Rivulidae presentan también dos especies consideradas como los únicos vertebrados hermafroditas suficientes y algunas especies con inseminación interna. El primer objetivo de este artículo es actualizar la sistemática de la familia considerando las relaciones filogenéticas y las sinapomorfías de los clados que la componen, reuniendo información que se encuentra dispersa en la literatura. De esta revisión surge que las relaciones filogenéticas dentro de Rivulidae están todavía sin resolver, especialmente en uno de los grandes clados que la componen, la subfamilia Rivulinae, donde relaciones conflictivas entre géneros anuales y no anuales son evidentes. El segundo objetivo de este trabajo es presentar una hipótesis filogenética, basada en datos morfológicos, mitocondriales y nucleares, de uno de los géneros más diversos de la familia, el género Austrolebias. Nuestros resultados confirman la monofilia del género y de algunos clados subgenéricos previamente definidos, y propone nuevas relaciones entre ellos, particularmente de las especies del subgénero Acrolebias(AU)

[Potential clinical impact of therapeutic education in patients treated with anticancer drugs]. / Fréquence des effets indésirables graves imputables à un potentiel défaut d'éducation thérapeutique chez des patients traités par chimiothérapie anticancéreuse.

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.

Adjuvant chemotherapy in elderly patients with colorectal cancer. A retrospective analysis of the implementation of tumor board recommendations in a single institution.

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.

Unexpected paracrine action of prostate cancer cells harboring a new class of androgen receptor mutation--a new paradigm for cooperation among prostate tumor cells.

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.

Diffuse primary angiosarcoma of the pleura: a case report and review of the literature.

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