Randomized, controlled trial investigating short-term health-related quality of life with doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: European Organization for Research and Treatment of Cancer Breast Cancer Group, Investigational Drug Branch for Breast Cancer and the New Drug Development Group Study.

PURPOSE: To compare health-related quality of life (HRQOL) in patients with metastatic breast cancer receiving the combination of doxorubicin and paclitaxel (AT) or doxorubicin and cyclophosphamide (AC) as first-line chemotherapy treatment. PATIENTS AND METHODS: Eligible patients (n = 275) with anthracycline-naive measurable metastatic breast cancer were randomly assigned to AT (doxorubicin 60 mg/m(2) as an intravenous bolus plus paclitaxel 175 mg/m(2) as a 3-hour infusion) or AC (doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2)) every 3 weeks for a maximum of six cycles. Dose escalation of paclitaxel (200 mg/m(2)) and cyclophosphamide (750 mg/m(2)) was planned at cycle 2 to reach equivalent myelosuppression in the two groups. HRQOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and the EORTC Breast Module at baseline and the start of cycles 2, 4, and 6, and 3 months after the last cycle. RESULTS: Seventy-nine percent of the patients (n = 219) completed a baseline measure. However, there were no statistically significant differences in HRQOL between the two treatment groups. In both groups, selected aspects of HRQOL were impaired over time, with increased fatigue, although some clinically significant improvements in emotional functioning were seen, as well as a reduction in pain over time. Overall, global quality of life was maintained in both treatment groups. CONCLUSION: This information is important when advising women patients of the expected HRQOL consequences of treatment regimens and should help clinicians and their patients make informed treatment decisions.

Doxorubicin-paclitaxel: a safe regimen in terms of cardiac toxicity in metastatic breast carcinoma patients. Results from a European Organization for Research and Treatment of Cancer multicenter trial.

BACKGROUND: The potential cardiotoxicity of the doxorubicin-paclitaxel regimen, when paclitaxel is given shortly after the end of the anthracycline infusion, is an issue of concern, as suggested by small single institution Phase II studies. METHODS: In a large multicenter Phase III trial, 275 anthracycline naive metastatic breast carcinoma patients were randomized to receive either doxorubicin (60 mg/m(2)) followed 30 minutes later by paclitaxel (175 mg/m(2) 3-hour infusion; AT) or a standard doxorubicin-cyclophosphamide regimen (AC; 60/600 mg/m(2)). Both treatments were given once every 3 weeks for a maximum of six cycles. Close cardiac monitoring was implemented in the study design. RESULTS: Congestive heart failure (CHF) occurred in three patients in the AT arm and in one patient in the AC arm (P = 0.62). Decreases in left ventricular ejection fraction to below the limit of normal were documented in 33% AT and 19% AC patients and were not predictive of CHF development. CONCLUSIONS: AT is devoid of excessive cardiac risk among metastatic breast carcinoma patients, when the maximum planned cumulative dose of doxorubicin does not exceed 360 mg/m(2).

Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial.

PURPOSE: To compare the efficacy and tolerability of the combination of doxorubicin and paclitaxel (AT) with a standard doxorubicin and cyclophosphamide (AC) regimen as first-line chemotherapy for metastatic breast cancer. PATIENTS AND METHODS: Eligible patients were anthracycline-naive and had bidimensionally measurable metastatic breast cancer. Two hundred seventy-five patients were randomly assigned to be treated with AT (doxorubicin 60 mg/m(2) as an intravenous bolus plus paclitaxel 175 mg/m(2) as a 3-hour infusion) or AC (doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2)) every 3 weeks for a maximum of six cycles. A paclitaxel (200 mg/m(2)) and cyclophosphamide (750 mg/m(2)) dose escalation was planned at cycle 2 if no grade >or= 3 neutropenia occurred in cycle 1. The primary efficacy end point was progression-free survival (PFS). Secondary end points were response rate (RR), safety, overall survival (OS), and quality of life. RESULTS: A median number of six cycles were delivered in the two treatment arms. The relative dose-intensity and delivered cumulative dose of doxorubicin were lower in the AT arm. Dose escalation was only possible in 17% and 20% of the AT and AC patients, respectively. Median PFS was 6 months in the two treatments arms. RR was 58% versus 54%, and median OS was 20.6 versus 20.5 months in the AT and AC arms, respectively. The AT regimen was characterized by a higher incidence of febrile neutropenia, 32% versus 9% in the AC arm. CONCLUSION: No differences in the efficacy study end points were observed between the two treatment arms. Treatment-related toxicity compromised doxorubicin-delivered dose-intensity in the paclitaxel-based regimen

Promising results with exemestane in the first-line treatment of metastatic breast cancer: a randomized phase II EORTC trial with a tamoxifen control.

Because tamoxifen (TAM), a nonsteroidal antiestrogen, is routinely used in the adjuvant setting, other hormone therapies are needed as alternatives for first-line treatment of metastatic breast cancer (MBC). Currently, exemestane (EXE) and other antiaromatase agents are indicated for use in patients who experience failure of TAM. In this multicenter, randomized, open-label, TAM-controlled (20 mg/day), phase II trial, we examined the activity and tolerability of EXE 25 mg/day for the first-line treatment of MBC in postmenopausal women. Exemestane was well tolerated and demonstrated substantial first-line antitumor activity based on intent-to-treat analysis of peer-reviewed responses. In the EXE arm, values for complete, partial, and objective response, clinical benefit, and time to tumor progression (TTP) exceeded those reported for TAM although no statistical comparison was made. Based on these encouraging results, a phase III trial will compare EXE and TAM.

The effect of exemestane on serum lipid profile in postmenopausal women with metastatic breast cancer: a companion study to EORTC Trial 10951, 'Randomized phase II study in first line hormonal treatment for metastatic breast cancer with exemestane or tamoxifen in postmenopausal patients'.

BACKGROUND: The impact of aromatase inhibitors (AIs) on non-cancer-related outcomes, which are known to be affected by oestrogens, has become increasingly important in postmenopausal women with hormone-dependent breast cancer. So far, data related to the effect of AIs on lipid profile in postmenopausal women is scarce. This study, as a companion substudy of an EORTC phase II trial (10951), evaluated the impact of exemestane, a steroidal aromatase inactivator, on the lipid profile of postmenopausal metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: The EORTC trial 10951 randomised 122 postmenopausal breast cancer patients to exemestane (E) 25 mg (n = 62) or tamoxifen (T) 20 mg (n = 60) once daily as a first-line treatment in the metastatic setting. Exemestane showed promising results in all the primary efficacy end points of the trial (response rate, clinical benefit rate and response duration), and it was well tolerated with low incidence of serious toxicity. As a secondary end point of this phase II trial, serum triglycerides (TRG), high-density lipoprotein cholesterol (HDL), total cholesterol (TC), lipoprotein a (Lip a), and apolipoproteins (Apo) B and A1 were measured at baseline and while on therapy (at 8, 24 and 48 weeks) to assess the impact of exemestane and tamoxifen on serum lipid profiles. Of the 122 randomised patients, those who had baseline and at least one other lipid assessment are included in the present analysis. The patients who received concomitant drugs that could affect lipid profile are included only if these drugs were administered throughout the study treatment. Increase or decrease in lipid parameters within 20% of baseline were considered as non-significant and thus unchanged. RESULTS: Seventy-two patients (36 in both arms) were included in the statistical analysis. The majority of patients had abnormal TC and normal TRG, HDL, Apo A1, Apo B and Lip a levels at baseline. Neither exemestane nor tamoxifen had adverse effects on TC, HDL, Apo A1, Apo B or Lip a levels at 8, 24 and 48 weeks of treatment. Exemestane and tamoxifen had opposite effects on TRG levels: exemestane lowered while tamoxifen increased TRG levels over time. There were too few patients with normal baseline TC and abnormal TRG, HDL, Apo A1, Apo B and Lip a levels to allow for assessment of E's impact on these subsets. The atherogenic risk determined by Apo A1:Apo B and TC:HDL ratios remained unchanged throughout the treatment period in both the E and T arms. CONCLUSIONS: Overall, exemestane has no detrimental effect on cholesterol levels and the atherogenic indices, which are well-known risk factors for coronary artery disease. In addition, it has a beneficial effect on TRG levels. These data, coupled with E's excellent efficacy and tolerability, support further exploration of its potential in the metastatic, adjuvant and chemopreventive setting.

Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial.

BACKGROUND: Trastuzumab (Herceptin(R)) improves disease-free survival (DFS) and overall survival for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess the magnitude of its clinical benefit for subpopulations defined by nodal and steroid hormone receptor status using data from the Herceptin Adjuvant (HERA) study. PATIENTS AND METHODS: HERA is an international multicenter randomized trial comparing 1 or 2 years of trastuzumab treatment with observation after standard chemotherapy in women with HER2-positive breast cancer. In total, 1703 women randomized to 1-year trastuzumab and 1698 women randomized to observation were included in these analyses. Median follow-up was 23.5 months. The primary endpoint was DFS. RESULTS: The overall hazard ratio (HR) for trastuzumab versus observation was 0.64 [95% confidence interval (CI) 0.54-0.76; P < 0.0001], ranging from 0.46 to 0.82 for subgroups. Estimated improvement in 3-year DFS in subgroups ranged from +11.3% to +0.6%. Patients with the best prognosis (those with node-negative disease and tumors 1.1-2.0 cm) had benefit similar to the overall cohort (HR 0.53, 95% CI 0.26-1.07; 3-year DFS improvement +4.6%, 95% CI -4.0% to 13.2%). CONCLUSIONS: Adjuvant trastuzumab therapy reduces the risk of relapse similarly across subgroups defined by nodal status and steroid hormone receptor status, even those at relatively low risk for relapse.

Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial.

To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial.

Estimating the distribution of malaria in Namibia in 2009: assembling the evidence and modeling risk

info:eu-repo/semantics/published

Immune response to B. pertussis infection and vaccine in infants

info:eu-repo/semantics/nonPublished

Humoral and B-cell memory responses in children five years after pertussis acellular vaccine priming.

The resurgence of pertussis suggests the need for greater efforts in understanding the long-lasting protective responses induced by vaccination. In this paper we dissect the persistence of humoral and B-cell memory responses induced by primary vaccination with two different acellular pertussis (aP) vaccines, hexavalent Hexavac(®) vaccine (Hexavac) (Sanofi Pasteur MSD) and Infanrix hexa(®) (Infanrix) (GlaxoSmithKline Biologicals). We evaluated the specific immune responses in the two groups of children, 5 years after primary vaccination by measuring the persistence of IgG and antibody secreting cells (ASC) specific for vaccine antigens. Part of the enrolled children received only primary vaccination, while others had the pre-school boost dose. A similar level of antigen-specific IgG and ASC was found in Infanrix and Hexavac vaccinated children. The mean IgG levels were significantly higher in children that received the pre-school boost as compared with children that did not receive the boost dose. A longer persistence after the pre-school boost of IgG-Pertussis Toxin (PT) and IgG-pertactin levels was observed in Infanrix primed children, but it was not statistically significant. More than 80% of children presented a positive ASC B memory response. Around 50% of children still presented protective IgG-PT levels which are reduced to 36% in no-boosted children. The pre-school booster dose restores the percentage of protected children above 50%. In conclusion our data underline the importance of giving a booster dose 5 years after primary vaccination and suggest the need for a new vaccine able to induce a long lasting protective response.

Adjuvant portal-vein infusion of fluorouracil and heparin in colorectal cancer: A randomised trial

Background. There is conflicting evidence on the efficacy of regional adjuvant chemotherapy, via portal-vein infusion (PVI), after resection of colorectal cancer. We undertook a randomised controlled multicentre trial to investigate the efficacy of PVI (500 mg/m2 fluorouracil plus 5000 IU heparin daily for 7 days). Methods. 1235 of about 1500 potentially eligible patients were randomly assigned surgery plus PVI or surgery alone (control). The patients were followed up for a median of 63 months, with yearly screening for recurrent disease. The primary endpoint was survival; analyses were by intention to treat. Findings. 619 patients in the control group and 616 in the PVI group met eligibility criteria. 164 (26%) control-group patients and 173 (28%) PVI-group patients died. 5-year survival did not differ significantly between the groups (73 vs 72%; 95% CI for difference -6 to 4). The control and PVI groups were also similar in terms of disease-free survival at 5 years (67 vs 65%) and the number of patients with liver metastases (79 vs 77%). Interpretation. PVI of fluorouracil, at a dose of 500 mg/m2 for 7 days, cannot be recommended as the sole adjuvant treatment for high-risk colorectal cancer after complete surgical excision. However, these results cannot eliminate a small benefit when PVI is used at a higher dosage or in combination with mitomycin.

Modulation of the infant immune responses by the firts pertussis vaccine administrations

info:eu-repo/semantics/nonPublished

Acquired epidermodysplasia verruciformis syndrome in HIV-infected pediatric patients: Prospective treatment trial with topical glycolic acid and human papillomavirus genotype characterization

SCOPUS: ar.j

Modulation of the infant immune responses by the first pertussis vaccine administrations.

Many efforts are currently made to prepare combined vaccines against most infectious pathogens, that may be administered early in life to protect infants against infectious diseases as early as possible. However, little is known about the general immune modulation induced by early vaccination. Here, we have analyzed the cytokine secretion profiles of two groups of 6-month-old infants having received as primary immunization either a whole-cell (Pw) or an acellular (Pa) pertussis vaccine in a tetravalent formulation of pertussis-tetanus-diphtheria-poliomyelitis vaccines. Both groups of infants secreted IFN-gamma in response to the Bordetella pertussis antigens filamentous haemagglutinin and pertussis toxin, and this response was correlated with antigen-specific IL-12p70 secretion, indicating that both pertussis vaccines induced Th1 cytokines. However, Pa recipients also developed a strong Th2-type cytokine response to the B. pertussis antigens, as noted previously. In addition, they induced Th2-type cytokines to the co-administrated antigen tetanus toxoïd, as well as to the food antigen beta-lactoglobulin. Furthermore, the general cytokine profile of the Pa recipients was strongly Th2-skewed at 6 months, as indicated by the cytokines induced by the mitogen phytohaemagglutinin. These data demonstrate that the cytokine profile of 6-month-old infants is influenced by the type of formulation of the pertussis vaccine they received at 2, 3 and 4 months of life. Large prospective studies would be warranted to evaluate the possible long-term consequences of this early modulation of the cytokine responses in infants.

The mycobacterial heparin-binding hemagglutinin, virulence factor and antigen useful for diagnostics and vaccine development.

info:eu-repo/semantics/published