A multicentric study regarding the use of hormone therapy during female mid-age (REDLINC VI).

BACKGROUND: Menopausal hormone therapy (HT) has shown benefits for women; however, associated drawbacks (i.e. risks, costs, fears) have currently determined its low use. OBJECTIVE: To determine the prevalence of current HT use among mid-aged women and describe the characteristics of those who have never used, have abandoned or are currently using HT. In addition, reasons for not using HT were analyzed. METHOD: This was a cross-sectional study that analyzed a total of 6731 otherwise healthy women (45-59 years old) of 15 cities in 11 Latin American countries. Participants were requested to fill out the Menopause Rating Scale (MRS) and a questionnaire containing sociodemographic data and items regarding the menopause and HT use. RESULTS: The prevalence of current HT use was 12.5%. Oral HT (43.7%) was the most frequently used type of HT, followed by transdermal types (17.7%). The main factors related to the current use of HT included: positive perceptions regarding HT (odds ratio (OR) 11.53, 95% confidence interval (CI) 9.41-14.13), being postmenopausal (OR 3.47, 95% CI 2.75-4.36) and having a better socioeconomic level. A total of 48.8% of surveyed women had used HT in the past, but abandoned it due to symptom improvement or being unconcerned; fear of cancer or any other secondary effects were also reported but in less than 10%. Among women who had never used HT, 28% reported the lack of medical prescription as the main reason, followed by the absence of symptoms (27.8%). Among those reporting lack of prescription as the main reason for not using HT, 30.6% currently had severe menopausal symptoms (total MRS score > 16); 19.5% of women were using alternative 'natural' therapies, with 35.1% of them displaying severe menopausal symptoms as compared to a 22.5% observed among current HT users. CONCLUSION: The use of HT has not regained the rates observed a decade ago. Positive perceptions regarding HT were related to a higher use. Lack of medical prescription was the main reason for not using HT among non-users, many of whom were currently displaying severe menopausal symptoms.

Expression of endogenous retroviruses is negatively regulated by the pluripotency marker Rex1/Zfp42.

Rex1/Zfp42 is a Yy1-related zinc-finger protein whose expression is frequently used to identify pluripotent stem cells. We show that depletion of Rex1 levels notably affected self-renewal of mouse embryonic stem (ES) cells in clonal assays, in the absence of evident differences in expression of marker genes for pluripotency or differentiation. By contrast, marked differences in expression of several endogenous retroviral elements (ERVs) were evident upon Rex1 depletion. We demonstrate association of REX1 to specific elements in chromatin-immunoprecipitation assays, most strongly to muERV-L and to a lower extent to IAP and musD elements. Rex1 regulates muERV-L expression in vivo, as we show altered levels upon transient gain-and-loss of Rex1 function in pre-implantation embryos. We also find REX1 can associate with the lysine-demethylase LSD1/KDM1A, suggesting they act in concert. Similar to REX1 binding to retrotransposable elements (REs) in ES cells, we also detected binding of the REX1 related proteins YY1 and YY2 to REs, although the binding preferences of the two proteins were slightly different. Altogether, we show that Rex1 regulates ERV expression in mouse ES cells and during pre-implantation development and suggest that Rex1 and its relatives have evolved as regulators of endogenous retroviral transcription.

Burden of infant bronchiolitis: data from a hospital network.

In France, surveillance of bronchiolitis is based on a pilot network of hospital emergency departments. The study was a 1-year observational study (2007-2008) carried out in a central region of metropolitan France. The hospitalization rate for bronchiolitis was 17.7/1000 children aged <1 year and the estimated prevalence of bronchiolitis ranged from 17.7% to 34.4% in children aged <1 year. Such a network constitutes a valuable tool to estimate the dynamic and the burden of infant bronchiolitis.

Brain metastases: Single-dose radiosurgery versus hypofractionated stereotactic radiotherapy: A retrospective study.

BACKGROUND: Radiosurgery is employed for the treatment of brain metastases. The aim of this study is to evaluate the efficacy and tolerability of single-dose radiosurgery (SRS) compared to hypofractionated stereotactic radiotherapy (hFSRT). MATERIALS AND METHODS: Between 2004 and 2018, we analyzed treatments of 97 patients with 135 brain metastases. Fifty-six patients were treated with SRS, and 41 patients were treated with hFSRT. Median dose was 16 Gy (12-20 Gy) for the SRS group and 30 Gy in 5-6 fractions for the hFSRT group. hFSRT was used for larger lesions and lesions located near critical structures. Kaplan-Meier curves were constructed for overall survival (OS) and local control (LC). RESULTS: Median age was 64 years (range, 32-89 years). Median survival was 10 months (1-68 months). With a median follow-up of 10 months, no significant differences in OS between groups were found (P=0.21). LC for all patients was 67%. Local progression-free survival (LPFS) at 6 months and 1 year was 71% and 60% for the SRS group, respectively, and 80% and 69% for the hFSRT group, respectively (P=0.93). Although hFSRT was used for larger lesions and lesions in adverse locations, LPFS was not inferior compared to lesions treated with SRS. We observed acute toxicity grade 1-2 in 25 patients (25.8%). Late complications were observed in 11 patients (11.3%). Acute and late toxicity was similar in the SRS- and hFSRT-treated patients (P=0.63 and P=0.11, respectively). Brain recurrence occurred in 37.5% and 14.6% in the hFSRT and SRS group, respectively (P=0.06). CONCLUSIONS: Since patients treated with hFSRT exhibited similar survival and LPFS rates without differences in toxicity compared to those treated with SRS, hFSRT can be beneficial, particularly for patients with brain metastases. RELEVANCE FOR PATIENTS: Hypofractionated schemes in stereotactic radiosurgery offers treatment alternatives to patients with large lesions or lesions near critical structures.

Agreements and uncertainties in autologous haematopoietic stem cell mobilization and collection. A Spanish consensus document.

Although many experts position statements on autologous stem cell mobilization have been published, there are some aspects that are still under discussion. A Spanish Hematologist expert group was summoned to settle on agreements and uncertainties on PBSCs mobilization, including factors not always considered; as apheresis and cytometry key factors that determine a successful PBSC collection. This document reviews critical factors that define poor mobilizer patients and the tools to better collect the desired stem cells for a successful autologous haematopoietic stem cell transplant.

Strategies for the management of invasive fungal infections due to filamentous fungi in high-risk hemato-oncological patients.

OBJECTIVE: In recent years, the introduction of new antifungals for the prevention of invasive fungal infections (IFIs) in hemato- oncological patients, particularly extended-spectrum azoles, has led to a change in the diagnostic and therapeutic strategies for established or suspected breakthrough IFI. The aim of the study was to identify the diagnostic and therapeutic strategies used in the management of IFIs in hemato-oncological patients in Spain, and to assess compliance with the recommendations of the consensus documents and clinical practice guidelines. METHODS: An online, anonymous, cross-sectional survey was conducted between January and September 2016 involving 137 specialists from third-level hospitals in Spain with Departments of Hematology that regularly deal with IFIs. RESULTS: Galactomannan test was available to 95.6% of specialists, and was used in 61.7% of the cases for diagnostic confirmation and early treatment. The (1 → 3) ß-D-glucan test was only available to 10.2%. A total of 75.3% of the participants estimated the incidence of breakthrough IFI due to filamentous fungus as being 1-10%. In turn, 83.3% of the participants decided a change in antifungal class after failure of prophylaxis, in concordance with the recommendations of the national and international consensus documents. CONCLUSIONS: The present study, the first of its kind conducted in Spain, shows that a high percentage of the medical professionals implicated in the management of hemato-oncological patients at high risk of suffering IFIs follow the recommendations of the national and international consensus documents and guidelines.

Survival after biochemical failure in prostate cancer treated with radiotherapy: Spanish Registry of Prostate Cancer (RECAP) database outcomes.

INTRODUCTION: The clinical course in patients with prostate cancer (PCa) after biochemical failure (BF) has received limited attention. This study analyzes survival time from recurrence, patterns of progression, and the efficacy of salvage therapies in patients treated with radical or postoperative radiotherapy (RT). METHODS: This is a multicenter retrospective comparative study of 1135 patients diagnosed with BF and treated with either radical (882) or postoperative (253) RT. Data correspond to the RECAP database. Clinical, tumor, and therapeutic characteristics were collected. Descriptive statistics, survival estimates, and comparisons of survival rates were calculated. RESULTS: Time to BF from initial treatment (RT or surgery) was higher in irradiated patients (51 vs 37 months). At a median follow-up of 102 months (14-254), the 8-year cause-specific survival (CSS) was 80.5%, without significant differences between the radical (80.1%) and postoperative (83.4%) RT groups. The 8-year metastasis-free survival rate was 57%. 173 patients (15%) died of PCa and 29 (2.5%) of a second cancer. No salvage therapy was given in 15% of pts. Only 5.5% of pts who underwent radical RT had local salvage treatment and 71% received androgen deprivation (AD) ± chemotherapy. The worst outcomes were in patients who developed metastases after BF (302 pts; 26.5%) and in cases with a Gleason > 7. CONCLUSIONS: In PCa treated with radiotherapy, median survival after BF is relatively long. In this sample, no differences in survival rates at 8-years have been found, regardless of the time of radiotherapy administered. AD was the most common treatment after BF. Metastases and high Gleason score are adverse variables. To our knowledge, this is the first study to compare outcomes after BF among patients treated with primary RT vs. those treated with postoperative RT and to evaluate recurrence patterns, treatments administered, and causes of death. The results allow avoiding overtreatment, improving quality of life, without negatively affecting survival.

Analysis of FK506-mediated protection in an organotypic model of spinal cord damage: heat shock protein 70 levels are modulated in microglial cells.

Functional loss after spinal cord injuries is originated by primary and secondary injury phases whose underlying mechanisms include massive release of excitatory amino acids to cytotoxic levels that contribute to neural death. Attenuation of this excitotoxicity is a key point for improving the functional outcome after injury. One of the drugs with potential neuroprotective actions is FK506, a molecule widely used as an immunosuppressant. FK506 may exert neuroprotection via inhibition of calcineurin by binding the FKBP12, or by binding other immunophilins such as FKBP52, leading to modulation of heat shock proteins (Hsp) 90 and 70. In the present study, we used an in vitro model of organotypic culture of rat spinal cord slices to assess whether FK506 is able to protect them against glutamate excitotoxicity. The results showed that FK506 promoted a significant protective effect on the spinal cord tissue at concentrations of 50 and 100 nM. Hsp70 induction was restricted to microglial cells in spinal cord slices treated with either glutamate or FK506. In contrast, the combination of both agents led to a transient reduction in Hsp70 levels in parallel to a marked reduction in IL-1beta precursor production by glial cells. The use of geldanamycin, which promotes persistent induction of Hsp70 in these cells as well as in motoneurons, did not produce tissue neuroprotection. These observations suggest that FK506 might protect spinal cord tissue by targeting on microglial cells and that transient downregulation of Hsp70 on these cells after excitotoxicity is a relevant mechanism of action of FK506.

Donor age and degree of HLA matching have a major impact on the outcome of unrelated donor haematopoietic cell transplantation for chronic myeloid leukaemia.

We analysed the outcome of 92 consecutive unrelated donor haematopoietic cell transplantations (UD-HCTs) performed in Spain to treat adult patients with CML in the first chronic phase (1CP). Patients' and donors' median age was 32 (15-49) and 36 (22-56) years, respectively. In all, 73 pairs (79%) matched for A, B+/-C and DRB1+/-DQB1 loci and 19 had > or =1 mismatch. Their probability of survival and disease-free survival at 4 years were 50 and 46%, respectively. Pretransplant factors associated with a better survival were patient age <25 years (P=0.035), donor age < or =36 years (P=0.012), use of cyclosporine since day -7 (P=0.001), and matching 8/8, 9/10 or 10/10 loci at allele level (P=0.003). In multivariate analysis only donor age (P=0.003; RR=3.1 (95% CI: 1.3-7.1)) and degree of HLA-matching (P=0.009; RR: 7.7 (95% CI: 1.8-33)) maintained their significance. The addition of these two variables to the EBMT prognostic score allowed an adequate risk assessment for patients receiving a UD-HCT during 1CP. Our analysis shows that in patients with a young and fully allele-matched donor, UD-HCT should be considered in the initial therapeutic algorithm due to its excellent outcome (92% survival at 2 years).

Evidence-based recommendations of postoperative radiotherapy in lung cancer from Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society).

Locally advanced non-small cell lung cancer (NSCLC) is a diversified illness in which postoperative radiation therapy (PORT) for complete resection with positive hiliar (pN1) and/or mediastinal (pN2) lymph nodes is controversial. Although several studies have shown that PORT has beneficial effects, randomized trials are needed to demonstrate its impact on overall survival. In this review, the Spanish Radiation Oncology Group for Lung Cancer describes the most relevant literature on PORT in NSCLC patients stage pN1-2. In addition, we have outlined the current recommendations of different national and international clinical guidelines and have also specified practical issues regarding treatment volume definition, doses and fractionation.

UGT2B17 minor histocompatibility mismatch and clinical outcome after HLA-identical sibling donor stem cell transplantation.

Minor histocompatibility Ags (mHags) have been implicated in the pathogenesis of GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). Uridine diphospho-glucuronosyltransferase 2B17 (UGT2B17) gene deletion may act as a mHag and its association with acute GVHD (aGVHD) has been described. We retrospectively studied the clinical impact of a UGT2B17 mismatch in a cohort of 1127 patients receiving a HSCT from an HLA-identical sibling donor. UGT2B17 mismatch was present in 69 cases (6.1%). Incidence of severe aGVHD was higher in the UGT2B17 mismatched pairs (22.7% vs 14.6%), but this difference was not statistically significant (P: 0.098). We did not detect differences in chronic GVHD, overall survival, relapse-free survival, transplant-related mortality or relapse. Nevertheless, when we analyzed only those patients receiving grafts from a male donor (616 cases), aGVHD was significantly higher in the UGT2B17 mismatched group (25.1% vs 12.8%; P: 0.005) and this association was confirmed by the multivariate analysis (P: 0.043; hazard ratio: 2.16, 95% confidence interval: 1.03-4.57). Overall survival was worse for patients mismatched for UGT2B17 (P: 0.005). We conclude that UGT2B17 mismatch has a negative clinical impact in allogeneic HSCT from HLA-identical sibling donors only when a male donor is used. These results should be confirmed by other studies.

Toxicity and efficacy of busulfan and fludarabine myeloablative conditioning for HLA-identical sibling allogeneic hematopoietic cell transplantation in AML and MDS.

The safety and efficacy of a 4-day myeloablative conditioning (MAC) regimen consisting of Bu 3.2 mg/kg and fludarabine 40 mg/m(2)/day for HLA-identical sibling allogeneic hematopoietic cell transplantation (HCT) in myeloid malignancies was investigated in 133 patients (median age, 47 years; range 19-74 years) with de novo AML (60%), secondary AML (20%) or myelodysplastic syndrome (20%). All patients engrafted. Hepatic veno-occlusive disease occurred in five patients (4%), and severe toxicities, mostly mucositis, occurred in twenty-three (17%) patients. The non-relapse mortality (NRM) at 100 days was 1.5%. The incidences of acute GVHD grade 2-4 and grade 3-4 were 32 and 13%, respectively. At a median follow-up of 38 months, the cumulative incidence of chronic GVHD was 67%. The relapse incidence was 30% (27 and 31%, respectively, in patients with early- and late-stage disease), and the overall NRM was 15%. The actuarial 4-year disease-free survival (DFS) and overall survival (OS) were 54 and 62%, respectively. Patients aged <50 years had better outcomes compared with older patients (DFS 64 vs 42%, P=0.006; OS 73 vs 47%, P<0.001, respectively).

Illumina next generation sequencing data and expression microarrays data from retinoblastoma and medulloblastoma tissues.

Retinoblastoma (Rb) is a pediatric intraocular malignancy and probably the most robust clinical model on which genetic predisposition to develop cancer has been demonstrated. Since deletions in chromosome 13 have been described in this tumor, we performed next generation sequencing to test whether recurrent losses could be detected in low coverage data. We used Illumina platform for 13 tumor tissue samples: two pools of 4 retinoblastoma cases each and one pool of 5 medulloblastoma cases (raw data can be found at http://www.ebi.ac.uk/ena/data/view/PRJEB6630). We first created an in silico reference profile generated from a human sequenced genome (GRCh37p5). From this data we calculated an integrity score to get an overview of gains and losses in all chromosomes; we next analyzed each chromosome in windows of 40 kb length, calculating for each window the log2 ratio between reads from tumor pool and in silico reference. Finally we generated panoramic maps with all the windows whether lost or gained along each chromosome associated to its cytogenetic bands to facilitate interpretation. Expression microarrays was done for the same samples and a list of over and under expressed genes is presented here. For this detection a significance analysis was done and a log2 fold change was chosen as significant (raw data can be found at http://www.ncbi.nlm.nih.gov/geo/accession number GSE11488). The complete research article can be found at Cancer Genetics journal (Garcia-Chequer et al., in press) [1]. In summary here we provide an overview with visual graphics of gains and losses chromosome by chromosome in retinoblastoma and medulloblastoma, also the integrity score analysis and a list of genes with relevant expression associated. This material can be useful to researchers that may want to explore gains and losses in other malignant tumors with this approach or compare their data with retinoblastoma.

Overview of recurrent chromosomal losses in retinoblastoma detected by low coverage next generation sequencing.

Genes are frequently lost or gained in malignant tumors and the analysis of these changes can be informative about the underlying tumor biology. Retinoblastoma is a pediatric intraocular malignancy, and since deletions in chromosome 13 have been described in this tumor, we performed genome wide sequencing with the Illumina platform to test whether recurrent losses could be detected in low coverage data from DNA pools of Rb cases. An in silico reference profile for each pool was created from the human genome sequence GRCh37p5; a chromosome integrity score and a graphics 40 Kb window analysis approach, allowed us to identify with high resolution previously reported non random recurrent losses in all chromosomes of these tumors. We also found a pattern of gains and losses associated to clear and dark cytogenetic bands respectively. We further analyze a pool of medulloblastoma and found a more stable genomic profile and previously reported losses in this tumor. This approach facilitates identification of recurrent deletions from many patients that may be biological relevant for tumor development.

Dinucleosidasetetraphosphatase in rat liver and Artemia salina.

A comparative study of an enzymatic activity present in Artemia salina and rat liver which specifically splits dinucleoside tetraphosphates is presented. All the purine and pyrimidine dinucleoside tetraphosphates tested, i.e. diadenosine, diguanosine, dixanthosine and diuridine tetraphosphates, were substrates of both enzymes with similar maximum velocities and Km values, (around 10 muM). The inhibition by nucleotides of the enzyme from the two sources is also similar. Particularly relevant is the strong inhibition caused by nucleoside tetraphosphates which have Ki values in the nanomolar range. The Artemia enzyme has a slightly lower molecular weight (17 500) than the liver enzyme (21 000) and is more resistant to acidic pH. Based on previous findings, the enzyme from Artemia salina was named diguanosinetetraphosphatase (EC 3.6.1.17) by the Enzyme Commission. The results presented in this paper show that the liver and Artemia enzymes are similar, and we propose to name this enzyme as dinucleosidetetraphosphatase or dinucleoside-tetraphosphate nucleotidehydrolase.

Vinorelbine as first-line chemotherapy for metastatic breast carcinoma.

PURPOSE: A phase II trial was performed to evaluate the efficacy and toxicity of vinorelbine (VNB) as first-line chemotherapy for metastatic breast carcinoma. PATIENTS AND METHODS: Between August 1991 and February 1993, 45 patients with metastatic breast cancer were entered onto the study. Therapy consisted of VNB 30 mg/m2 diluted in 500 mL of normal saline administered as a 1-hour intravenous infusion. Injections were repeated weekly until evidence of progressive disease (PD) or severe toxicity developed. RESULTS: One patient was considered not assessable for response. An objective response (OR) was observed in 18 of 44 patients (41%; 95% confidence interval, 26% to 56%). Three patients (7%) had a complete response (CR) and 15 (34%) had a partial response (PR). The median time to treatment failure for the entire group was 6 months (range, 1 to 15), and the median duration of response was 9 months (range, 1 to 15). The median survival duration has not been reached yet. There were no treatment-related deaths. The dose-limiting toxicity was myelosuppression. Leukopenia occurred in 35 patients (78%) and was grade 3 or 4 in 16 (36%). Phlebitis was observed in 19 of 29 patients (66%) who did not have central implantable venous systems. Fifteen patients (33%) developed peripheral neurotoxicity. Myalgia occurred in 20 patients (44%). CONCLUSION: VNB is an active drug against metastatic breast cancer with moderate toxicity, which justifies further evaluation in association with other agents.

Ifosfamide and mitoxantrone as first-line chemotherapy for metastatic breast cancer.

PURPOSE: A phase II trial was performed to evaluate the efficacy and toxicity of a combination of ifosfamide (IFX) and mitoxantrone (MXN) as first-line chemotherapy for metastatic breast carcinoma. PATIENTS AND METHODS: Between January 1990 and August 1991, 48 patients with metastatic breast cancer were entered onto the study. Therapy consisted of IFX 2 g/m2 given as a 1-hour intravenous (IV) infusion on days 1 to 3; mesna 400 mg/m2 as an IV bolus immediately before and 4 hours after IFX administration and 2,000 mg orally 8 hours after IFX administration on days 1 to 3; and MXN 12 mg/m2 as an i.v. bolus on day 3. Cycles were repeated every 21 days until progressive disease (PD) or severe toxicity developed. RESULTS: One patient was considered not assessable for response. Objective regression (OR) was observed in 28 of 47 patients (60%; 95% confidence interval, 46% to 74%). Six patients (13%) had a complete response (CR) and 22 (47%) had a partial response (PR). The median time to treatment failure for the whole group was 9 months (range, 1 to 28); median survival was 19 months (range, 2 to 28). There were no treatment-related deaths. The limiting toxicity was myelosuppression. Leukopenia occurred in 37 patients (77%) and was grade 3 or 4 in 19 patients (40%). Nausea and vomiting were observed in 38 patients (80%), mucositis in 16 patients (33%), and grade 2 hematuria in two patients (4%). Eight patients (16%) developed mild neurotoxicity. CONCLUSION: The combination of IFX plus MXN is an active regimen against metastatic breast cancer with moderate toxicity that deserves further evaluation.

Revertant and potentiating activity of lonidamine in patients with ovarian cancer previously treated with platinum.

PURPOSE: Lonidamine (LND) is an energolytic derivative of indazol-carboxylic acid that has been shown to enhance cisplatin (CDDP) activity in both sensitive (A2780) and resistant (A2780/Cp8) ovarian cancer cell lines. The aim of this study was to confirm the potentiating or reverting activity of LND on CDDP activity obtained in experimental models in a phase II study of advanced ovarian cancer patients previously treated with platinum-based regimens. PATIENTS AND METHODS: Twenty-seven consecutive women with histologically proven and measurable ovarian cancer previously treated with platinum compounds were treated with CDDP plus LND. CDDP was administered at 1 mg/kg intravenously (IV) once weekly for 6 weeks and every 3 weeks thereafter until disease progression or toxicity. LND was administered at 450 mg daily (1 tablet every 8 hours) for the entire period of therapy starting 3 days before the first CDDP administration. In addition, a higher LND dosage was provided on the day of CDDP administration in an attempt to maximize the synergy of this drug with CDDP. RESULTS: Ten patients achieved a complete response (CR) or partial response (PR) for an overall response rate of 37% (95% confidence interval [CI], 19% to 55%). In particular, responses were observed in five of 18 (28%) refractory or early relapsed patients (one CR and four PRs) and in five of nine patients (55%) in the late-relapsed group (two CRs and three PRs). Grade 3 or 4 anemia, leukopenia, and thrombocytopenia were observed in 19%, 15%, and 11% of patients, respectively, whereas seven of 27 patients (26%) showed LND-related myalgia. Grade 3 renal toxicity was observed in two patients (8%). Neurotoxicity, often concealed by LND-related myalgia, was recorded as grade 1 or 2 in six patients (22%) and as grade 3 in one (4%). CONCLUSION: The 37% response rate observed in this study (28% in refractory or early-relapsed patients), suggests that the synergism between CDDP and LND observed in vitro against ovarian cancer cell lines can be clinically confirmed. However, larger series and randomized studies are needed to assess definitely the revertant activity of LND on CDDP-refractory patients.

Vinorelbine and paclitaxel as first-line chemotherapy in metastatic breast cancer.

PURPOSE: To evaluate the efficacy and toxicity of a combination of vinorelbine (VNB) and paclitaxel (PTX) as first-line chemotherapy in metastatic breast carcinoma (MBC). PATIENTS AND METHODS: Between August 1995 and August 1997, 49 patients with untreated MBC received a regimen that consisted of VNB 30 mg/m2 in a 20-minute intravenous (IV) infusion on days 1 and 8 and PTX 135 mg/m2 in a 3-hour IV infusion (starting 1 hour after VNB) on day 1. Cycles were repeated every 28 days. The median age of the patients was 52 years, and 59% of patients were postmenopausal. Median performance status was 1. Dominant sites of disease were soft tissue in 6%, bone in 29%, and viscera in 65%. RESULTS: Objective responses were recorded in 27 of 45 assessable patients (60%; 95% confidence interval, 46% to 74%). Complete remissions occurred in three patients (7%), and partial remissions occurred in 24 patients (53%). No change was recorded in 12 patients (27%), and progressive disease occurred in six patients (13%). The median time to treatment failure was 7 months, and median survival duration was 17 months. The limiting toxicity was myelosuppression, mainly leukopenia in 49 patients (100%) (grade 1 to grade 2, four patients; grade 3, 30 patients; and grade 4, 15 patients). Neutropenia was observed in 100% of patients (grade 1 to grade 2, three patients; grade 3, 11 patients; grade 4, 35 patients). Two treatment-related deaths due to febrile neutropenia were observed in patients with massive liver involvement. Peripheral neurotoxicity developed in 33 patients (67%) (grade 1, 25 patients; grade 2, eight patients); there were no grade 3 or grade 4 episodes. CONCLUSION: The combination of VNB-PTX showed significant activity as first-line chemotherapy for patients with MBC. Myelosuppression was the dose-limiting side effect, whereas neurotoxicity was mild to moderate.