Cost-utility analysis of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in combination with gemcitabine in metastatic pancreatic cancer in Spain: results of the PANCOSTABRAX study.

The PANCOSTABRAX study evaluated the cost-effectiveness of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in combination with gemcitabine (GEM) versus GEM alone in the treatment of patients with metastatic pancreatic cancer in Spain. Efficacy data were obtained from the MPACT study and were modeled to a lifetime horizon using a Markov model. The analysis was performed from the payer's perspective. Use of resources and key assumptions of the analysis were validated by a panel of oncologists. The addition of nab-paclitaxel to GEM showed higher effectiveness results (0.156 additional quality adjusted life years) at a higher cost (€6,477), resulting in a cost per quality-adjusted life years gained of €41,519. The combination of nab-paclitaxel and GEM has been shown to be an effective and well-tolerated option for the treatment of metastatic pancreatic cancer and, in addition to becoming the new standard of care, could also be considered a cost-effective option.

Darbepoetin alpha for the treatment of anemia in patients with myelodysplastic syndromes.

BACKGROUND: Anemia occurs as a comorbidity in from 80% to 85% of patients with myelodysplastic syndromes (MDS): It causes fatigue, increases transfusion needs, and reduces quality of life. Darbepoetin alpha (DA) is an erythropoiesis-stimulating protein (ESP) that is more highly glycosylated and has a longer half-life relative to recombinant human erythropoietin (rHuEPO), thus, allowing less frequent administration, increased convenience, and better compliance. METHODS: This retrospective analysis included 81 patients with MDS who were enrolled at 9 Spanish centers and who received once-weekly, subcutaneous DA (75-300 microg) for 16 weeks. RESULTS: Fifty-five percent of all patients (38 of 69 evaluable patients) achieved responses; 30.4% of were major responses, and 24.6% were minor responses; 64.7% of rHuEPO-naive patients and 45.7% rHuEPO-treated patients responded; and 43.2% had received previous rHuEPO. Most responses (65.8%) occurred at or before Week 8. The median age at diagnosis was 70 years (range, 38-87 years), the median age at the initiation of DA treatment was 75 years (range, 39-91 years), and 56.8% of patients were women. The median time from last ESP dose to DA initiation was 16.8 weeks (range, 0.0-159.0 weeks; <1 week in 53.1% of patients). According to the French-American-British classification system (n = 81 patients), 39.5% had refractory anemia (RA), 46.9% had RA with ringed sideroblasts, 9.9% had RA with excess blasts (RAEB), 1.2% had RAEB in transformation, and 2.5% had chronic myelomonocytic leukemia. According to the International Prognostic Scoring System (n = 47 patients), 55.3% of patients were in the low-risk group, and 36.2% of patients were in the intermediate-1-risk group. The median baseline hemoglobin level was 8.9 g/dL (range, 8.4-9.1 g/dL). The Starting DA dose was 75 microg per week in 3.7% of patients, 150 microg per week in 65.4% of patients, and 300 microg per week in 29.6% of patients (the dose was increased in 18.5% of patients and reduced in 9.9% of patients; median time to dose adjustment, 8 weeks). Five patients received granulocyte colony-stimulating factors. No DA-related adverse reactions occurred. CONCLUSIONS: In the current study, 55% of evaluable patients with MDS safely achieved an erythroid response.

PTOV1 enables the nuclear translocation and mitogenic activity of flotillin-1, a major protein of lipid rafts.

PTOV1 is a mitogenic protein that shuttles between the nucleus and the cytoplasm in a cell cycle-dependent manner. It consists of two homologous domains arranged in tandem that constitute a new class of protein modules. We show here that PTOV1 interacts with the lipid raft protein flotillin-1, with which it copurifies in detergent-insoluble floating fractions. Flotillin-1 colocalized with PTOV1 not only at the plasma membrane but, unexpectedly, also in the nucleus, as demonstrated by immunocytochemistry and subcellular fractionation of endogenous and exogenous flotillin-1. Flotillin-1 entered the nucleus concomitant with PTOV1, shortly before the initiation of the S phase. Protein levels of PTOV1 and flotillin-1 oscillated during the cell cycle, with a peak in S. Depletion of PTOV1 significantly inhibited nuclear localization of flotillin-1, whereas depletion of flotillin-1 did not affect nuclear localization of PTOV1. Depletion of either protein markedly inhibited cell proliferation under basal conditions. Overexpression of PTOV1 or flotillin-1 strongly induced proliferation, which required their localization to the nucleus, and was dependent on the reciprocal protein. These observations suggest that PTOV1 assists flotillin-1 in its translocation to the nucleus and that both proteins are required for cell proliferation.

PTOV-1, a novel protein overexpressed in prostate cancer, shuttles between the cytoplasm and the nucleus and promotes entry into the S phase of the cell division cycle.

PTOV1 was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer. The PTOV1 protein consists of two novel protein domains arranged in tandem, without significant similarities to known protein motifs. By immunohistochemical analysis, we have found that PTOV1 is overexpressed in 71% of 38 prostate carcinomas and in 80% of samples with prostate intraepithelial neoplasia. High levels of PTOV1 in tumors correlated significantly with proliferative index, as assessed by Ki67 immunoreactivity, and associated with a nuclear localization of the protein, suggesting a functional relationship between PTOV1 overexpression, proliferative status, and nuclear localization. In quiescent cultured prostate tumor cells, PTOV1 localized to the cytoplasm, being excluded from nuclei. After serum stimulation, PTOV1 partially translocated to the nucleus at the beginning of the S phase. At the end of mitosis, PTOV1 exited the nucleus. Transient transfection of chimeric green fluorescent protein-PTOV1 forced the entry of cells into the S phase of the cell cycle, as shown by double fluorescent imaging for green fluorescent protein and for Ki67, and also by flow cytometry. This was accompanied by greatly increased levels of cyclin D1 protein in the transfected cells. These observations suggest that overexpression of PTOV1 can contribute to the proliferative status of prostate tumor cells and thus to their biological behavior.

Human hormone-refractory prostate cancers can harbor mutations in the O(2)-dependent degradation domain of hypoxia inducible factor-1alpha (HIF-1alpha).

PURPOSE: Androgen ablation, the preferred therapy for advanced prostate cancer, reduces blood flow and induces hypoxia in androgen-dependent tissues. Given the transient effectiveness of this therapy, we must consider whether a hypoxia-resistance mechanism might be involved in the development of therapeutic resistance by prostate cancer cells. The transcription factor protein, hypoxia-inducible factor 1alpha (HIF-1alpha), helps increase the expression of gene products that enable cells to survive conditions of hypoxic stress. Enhanced HIF-1alpha expression during hypoxia results from a drastic reduction of its degradation rate within a critical region of the protein referred to as the "oxygen-dependent degradation (ODD) domain". We sequenced HIF-1alpha cDNAs amplified from human prostate cancer cell lines and from hormone resistant prostate cancer specimens to determine whether prostate cancer cells might harbor mutations within the HIF-1alpha ODD domain. METHODS: HIF-1alpha cDNAs were RT-PCR amplified from three prostate cancer cell lines (LNCaP, PC-3, and DU145), from five different human hormone-resistant prostate cancers and one normal prostate, all microdissected, and were sequenced to determine whether the HIF-1alpha gene products were wildtype or mutant. One specimen containing a hormone-resistant prostate tumor that expressed a mutated HIF-1alpha cDNA was further microdissected into benign and tumorous regions and DNAs extracted from these regions were directly amplified by PCR and sequenced to determine whether the HIF-1alpha mutation was specific to the tumor. RESULTS: Although the HIF-1alpha cDNAs of all cell lines, the normal prostate, and three of the tumors were found to have a wildtype sequence, HIF-1alpha cDNAs amplified from two hormone-resistant tumors had nucleic acid substitutions that resulted in significant amino acid changes within the ODD domain of the HIF-1alpha protein. Analysis of the DNA extracted from a benign or tumorous region of one of these specimens showed that only the wildtype (nonmutated) form of the HIF-1alpha gene was amplified from the normal DNA whereas only the mutated form of the HIF-1alpha gene was amplified from the tumor. CONCLUSIONS: Some human hormone-refractory prostate cancers have mutations in a critical regulatory domain of the HIF-1alpha protein. We believe that these mutations might enable expression of this protein under inappropriate conditions and contribute to the development of therapeutic resistance by the cancer cells. This hypothesis is currently being tested.