A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 × 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 × 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10(-4)), COPD (OR=3.22, P=2.9 × 10(-4)), PAD (OR=3.47, P=9.2 × 10(-3)) and AAA (OR=6.44, P=6.3 × 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10(-5)), particularly for early-onset cases (P=2.1 × 10(-7)). Our results are in agreement with functional studies showing that the human α4ß2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

Gemcitabine and capecitabine in previously anthracycline-treated metastatic breast cancer: a multicenter phase II study (SOLTI 0301 trial).

BACKGROUND: On the basis of clinical activity of capecitabine and gemcitabine for metastatic breast cancer, we carried out a multicenter phase II clinical trial on the combination of these two agents in advanced anthracycline-pretreated breast cancer patients. Main objectives were to assess its efficacy and safety profile. PATIENTS AND METHODS: Seventy-six anthracycline-pretreated breast cancer patients were evaluated and were stratified according to previous treatment of advanced disease (group-1: not previously treated and group-2: previously treated). Study treatment consisted of gemcitabine 1000 mg/m(2), i.v., as 30 min-infusion, days 1 and 8 every 21 days, plus oral capecitabine 830 mg/m(2) b.i.d., days 1-14 every 21 days. RESULTS: Overall response rate was 61% for group-1, 48.5% for group-2 and 55.2% for the whole population. Clinical benefit rate was 73% for group-1, 80% for patients in group-2 and 76% for all patients. Median time to progression was 13.0 months for group-1, 8.2 months for group-2 and 11.1 months for the whole population. Most frequent grade 3-4 observed toxic effects per patient were neutropenia (60%), asymptomatic liver toxicity (13.5%), asthenia (14%) and hand-foot syndrome (16%). Only one patient presented febrile neutropenia. No treatment-related deaths occurred. CONCLUSION: Combination of gemcitabine and capecitabine is an active and safe regimen in anthracycline-pretreated breast cancer patients.

Dendritic cell uptake of iron-based magnetic nanoparticles.

We have investigated the internalization of magnetic nanoparticles (NPs) into dendritic cells (DCs) in order to assess both the final location of the particles and the viability of the cultured cells. The particles, consisting of a metallic iron core covered with carbon, showed no toxic effects on the DCs and had no effect in their viability. We found that mature DCs are able to incorporate magnetic nanoparticles in a range of size from 10 nm to ca. 200 nm, after 24 h of incubation. We describe a method to separate cells loaded with NPs, and analyze the resulting material by electron microscopy and magnetic measurements. It is found that NPs are internalized in lysosomes, providing a large magnetic signal. Our results suggest that loading DCs with properly functionalized magnetic NPs could be a promising strategy for improved vectorization in cancer diagnosis and treatment.

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.

Biweekly gemcitabine plus vinorelbine in first-line metastatic breast cancer: efficacy and correlation with HER2 extracellular domain.

Purpose. To assess the toxicity and efficacy of biweekly gemcitabine plus vinorelbine in first-line advanced breast cancer, and to establish whether circulating HER2 ECD levels correlate with the efficacy of the combination. Patients and methods. 52 patients were treated with gemcitabine 2500 mg/m(2) plus vinorelbine 30 mg/m(2), both on day 1 of 14-day cycles, for a maximum of 10 cycles. Baseline serum levels of HER2 ECD were assessed with an ELISA. Results. All patients were evaluable for toxicity, and 50 for efficacy. Overall toxicity was moderate. Grade 3 neutropenia occurred in 35% of patients and grade 4 in 19%. Other grade 3 toxicities were observed in less than 6%. There was one episode of febrile neutropenia, and one death after cycle three. Overall response rate was 52% (95% CI: 38% to 66%), with 2 patients achieving a CR (4%). Response rate did not correlate with HER2 ECD, with 50% of HER2 ECD positive patients responding, vs 48.5% of the HER2 ECD negative. Median overall survival was 24.6 months. Conclusion. Gemcitabine plus vinorelbine, given as an every-two-week schedule, is an active regimen in advanced breast carcinoma. This combination can be an option when anthracyclines and taxanes are not preferred. HER2 ECD has no predictive value in this non-taxane combination.

[Surveillance of commensal flora evolution and infections in neutropenic cancer patients submitted to chemoprophylaxis]. / Vigilancia de la evolución de la flora comensal y de las infecciones en pacientes oncológicos con neutropenia sometidos a quimioprofilaxis.

The evolution of the flora and its resistance to different antimicrobials in neutropenic patients submitted to high-dose chemotherapy with autologous blood stem-cell transplantation, and the relation of these findings to the etiology of the infections the patients developed was studied in order to evaluate the suitability of the chemoprophylaxis and the empirical antibiotic therapy used. Forty-one patients were analyzed in a period of 28 months. The chemoprophylaxis used was levofloxacin, fluconazole and acyclovir. The empirical sequential treatment was an initial administration of cefepime, followed by teicoplanin and amikacin. Cultures were done of nasal and pharyngeal smears, Hickman catheter and stools, 1 day before chemoprophylaxis started and then on days 5 and 9. In the case of fever, three sets of blood cultures and urine cultures were done and samples from areas related to the clinical condition were analyzed. Levofloxacin induced the selection of resistant strains or species in the flora and in the infectious agents. Fluconazole also selected resistant species in the flora. Seventeen infections were documented in eleven patients, produced by Gram-positive bacteria in thirteen cases (81.25%) and by Gram-negative bacteria in three (18.75%). The coagulase negative staphylococci and Enterococcus faecalis were the most frequent agents of infection. We identified on nine occasions the same microorganism in the flora and in the pathological product; this suggests its endogenous origin and supports the use of prospective cultures of the flora, monitoring the sensibility of the microorganisms isolated to the antimicrobials used in chemoprophylaxis and empirical treatment.

A multicentre, randomised phase II study of weekly or 3-weekly docetaxel in patients with metastatic breast cancer.

BACKGROUND: A phase II randomised trial was conducted to evaluate the tolerability and activity of weekly or 3-weekly docetaxel in patients with metastatic breast cancer. PATIENTS AND METHODS: Eighty-three patients with histologically proven metastatic breast cancer were randomised to receive either docetaxel 40 mg/m2 weekly for 6 consecutive weeks followed by 2 weeks without treatment (n = 41), or docetaxel 100 mg/m2 on day 1 every 3 weeks (n = 42). RESULTS: The incidence of all grade 3-4 adverse events was higher in the 3-weekly group than in the weekly group (96 versus 44), and the number of patients with grade 3-4 adverse events was also greater in the 3-weekly group (31 versus 20). Analysis of individual adverse events tended to favour the weekly regimen. Intent-to-treat overall response rate was 34% and 33% in the weekly and 3-weekly groups, respectively. Median time to progression was 5.7 and 5.3 months after weekly and 3-weekly docetaxel, respectively, and median time to treatment failure was 4.1 and 4.9 months, respectively. CONCLUSION: Weekly docetaxel is an active regimen in metastatic breast cancer with comparable efficacy to 3 weekly docetaxel. Although both schedules were well tolerated, weekly docetaxel appears to have a more favourable toxicity profile.

Dolor lumbar: sindrome o enfermedad? / Low back pain; syndrome or disease?

O estudo apresenta a Dor Lombar e analisa os aspectos que podem considerá-la como uma síndrome ou uma doença

Phase I trial of weekly irinotecan combined with UFT as second-line treatment for advanced colorectal cancer.

The aim of this study was to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly Irinotecan (CPT-11) plus UFT, and to assess the antitumour activity of this combination as second-line chemotherapy in patients with advanced colorectal carcinoma, 31 patients with measurable advanced colorectal carcinoma were treated. Cohorts of 3 patients received increasing dose levels of the combination. Levels 1 to 4 included a fixed dose of oral (p.o.) UFT (250 mg/m(2)/day) for 21 days of a 28-day cycle combined with increasing intravenous (i.v.) doses of CPT-11 (80, 100, 110 and 120 mg/m(2)) on days 1, 8 and 15. Levels 5 and 6 included a higher fixed dose of oral UFT (300 mg/m(2)) combined with increasing i.v. doses of CPT-11 (100 and 110 mg/m(2)) on days 1, 8 and 15. 147 courses were administered. MTD were reached at level 4 (2 cases of grade 4 diarrhoea and 1 grade 3 asthenia), and level 6 (1 grade 4 diarrhoea, 1 grade 3 diarrhoea and 1 grade 3 febrile neutropenia). Responses in 30 evaluable patients were: 3 partial responses (10%), 15 stable disease (50%) and progressive disease in 12 patients (40%). Median time to progression was 4.5 months (95% Confidence Interval (CI): 3.4-6.6 months) and median survival was 11 months (95% CI: 7.9-14.1 months). The recommended doses for phase II trials are: (a) CPT-11 110 mg/m(2) i.v. on days 1, 8 and 15 every 28 days plus UFT 250 mg/m(2) p.o. on days 1 through to 21 or (b) CPT-11 100 mg/m(2) and UFT 300 mg/m(2).

Combination chemotherapy with docetaxel plus vinorelbine in metastatic breast cancer patients with prior exposure to anthracyclines.

PURPOSE: To evaluate the anti-tumor activity and tolerance of docetaxel plus vinorelbine in metastatic breast cancer (MBC) patients previously treated with anthracyclines. PATIENTS AND METHODS: Fifty patients with MBC were treated with docetaxel 75 mg/m2 (subsequently reduced to 60 mg/m2) plus vinorelbine 30 mg/m2 (subsequently reduced to 24 mg/m2). both on day 1, every 3 weeks, for a maximum of six cycles. All patients had previously received anthracyclines as adjuvant treatment (< 12 months disease-free interval) or first-line therapy for MBC. Thirty-seven patients had received at least one prior regimen for MBC. Twenty-five patients had prior high-dose chemotherapy with stem-cell rescue. Thirty patients had multiple metastatic sites. Liver and lung disease were the predominant metastatic site in 31 patients. RESULTS: Forty-nine patients were assessable for response. Nineteen patients achieved a partial response and four a complete response (overall response rate, 46%; 95% confidence interval (95% CI): 32%-60%). Fourteen patients (28%) had stable disease on treatment. Median Kaplan-Meier estimated progression-free and duration of response times are 21 and 29 weeks. Median survival time is 47 weeks. Hematological dose-limiting toxicity, prompted a 20% dose reduction for both drugs after the first thirteen patients were treated. Neutropenia > or = grade 3 occurred in nineteen (34%) patients, neutropenic fever in 15 (7) courses, and mucositis > or = grade 3 in 6 (3%) courses. CONCLUSIONS: The combination of docetaxel plus vinorelbine on day 1 every 3 weeks is feasible and active in MBC patients with prior anthracycline exposure. This regimen is safe, well-tolerated and convenient for the patients.

Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: a multicenter randomized trial.

BACKGROUND: Granulocyte colony-stimulating factors (G-CSFs) have been shown to help prevent febrile neutropenia in certain subgroups of cancer patients undergoing chemotherapy, but their role in treating febrile neutropenia is controversial. The purpose of our study was to evaluate-in a prospective multicenter randomized clinical trial-the efficacy of adding G-CSF to broad-spectrum antibiotic treatment of patients with solid tumors and high-risk febrile neutropenia. METHODS: A total of 210 patients with solid tumors treated with conventional-dose chemotherapy who presented with fever and grade IV neutropenia were considered to be eligible for the trial. They met at least one of the following high-risk criteria: profound neutropenia (absolute neutrophil count <100/mm(3)), short latency from previous chemotherapy cycle (<10 days), sepsis or clinically documented infection at presentation, severe comorbidity, performance status of 3-4 (Eastern Cooperative Oncology Group scale), or prior inpatient status. Eligible patients were randomly assigned to receive the antibiotics ceftazidime and amikacin, with or without G-CSF (5 microg/kg per day). The primary study end point was the duration of hospitalization. All P values were two-sided. RESULTS: Patients randomly assigned to receive G-CSF had a significantly shorter duration of grade IV neutropenia (median, 2 days versus 3 days; P = 0.0004), antibiotic therapy (median, 5 days versus 6 days; P = 0.013), and hospital stay (median, 5 days versus 7 days; P = 0.015) than patients in the control arm. The incidence of serious medical complications not present at the initial clinical evaluation was 10% in the G-CSF group and 17% in the control group (P = 0.12), including five deaths in each study arm. The median cost of hospital stay and the median overall cost per patient admission were reduced by 17% (P = 0.01) and by 11% (P = 0.07), respectively, in the G-CSF arm compared with the control arm. CONCLUSIONS: Adding G-CSF to antibiotic therapy shortens the duration of neutropenia, reduces the duration of antibiotic therapy and hospitalization, and decreases hospital costs in patients with high-risk febrile neutropenia.

Cost-analysis of high-dose chemotherapy and peripheral blood stem-cell support in patients with solid tumors.

BACKGROUND: The use of High-dose chemotherapy (HDC) with peripheral blood stem cells (PBSC) rescue in the treatment of solid tumors is controversial, and may be an important determinant of HDC and PBSC use in the future. Until the use of these procedures is proven through disease-free survival and overall survival compared with standard-dose chemotherapy, the associated cost is also under discussion. PATIENTS AND METHODS: We evaluate 27 consecutive patients with solid tumors who underwent HDC and PBSC rescue, through an accurate review of medical records and cost estimate for each patient. RESULTS: Median age was 45 years. Fifteen had breast cancer, six non-Hodgkin's lymphoma and six other solid tumors. The mean hospital length of stay was 21 days and mean cost was 21,445 US dollars (21,232 euro). Mean cost was clearly lower for the 9 patients treated within phase III trials, 17,571 US dollars (17,747 euro) than for the remaining 18 patients, treated in phase I-II trials, 22,747 US dollars (22,975 euro) (P < 0.001). The distribution of costs shows that wages and pharmacy account for 72% of total cost. The distribution of pharmacy costs per patient shows that chemotherapy (56% of pharmacy costs) and antibiotics (26%) account for most of the cost of medication. CONCLUSIONS: Our cost estimates agree with those of most countries with national health insurance programs, and are lower than those from the USA. As wages and pharmacy account for more than 70% of the costs, the great different among the costs estimates compared are due essentialy to doctors fees or salary and drugs utilization. Anyway, taking HDC with PBSC rescue as a model for a therapy that is more aggressive than standard, and that is associated to a possible survival improvement in indications such as relapsed high-grade non-Hodgkin's lymphoma, an adequate cost analysis is crucial both to measure cost-effectiveness and to establish payment to health care providers.

[Peripheral nervous system neurotoxicity secondary to chemotherapy treatment] . / Neurotoxicidad en el sistema nervioso periférico secundaria a tratamiento con quimioterapia.

Peripheral neurotoxicity is a crucial side effect of chemotherapeutic agents. It is the only situation where there is no preventive treatment. Neuromuscular toxicity has become the major dose limiting side effect for many chemotherapeutic agents. The iatrogenic toxic neuropathy is a growing neurologic problem, as cancer patients are beign treated with increasing doses of chemotherapy drugs. Major advances in cancer treatment have resulted from the use of drug combinations; for some combinations this raises the possibility of sinergistic neurotoxicity. The following report reviews the SNP toxicities encountered with cisplatin, vincristine, taxanes and others, and methods to minimize the deleterious effect of chemotherapeutic agents.

Reversible peripheral neuropathy induced by a single administration of high-dose paclitaxel.

Peripheral neuropathy (PN) is the main side effect with cycles of paclitaxel at standard doses (175 mg/m2 for 21 days). Administration of a single high-dose paclitaxel (HDP) is a novel approach for the treatment of cancer. We have prospectively measured neurotoxicity induced by HDP during a phase I trial. Nineteen patients were treated with escalating doses of paclitaxel by 24-hour infusion. In our study, PN induced by HDP was moderate, reversible, and not dose limiting. Severe PN was seen in patients who had received previous neurotoxic chemotherapy, and caution on the administration of HDP in this setting is warranted.

A comparative evaluation of immunohistochemical markers for the differential diagnosis of malignant pleural tumours.

AIMS: To determine the value of immunocytochemistry in differentiation of malignant pleural mesothelioma from carcinoma in a pleural biopsy using commercially available monoclonal antibodies. METHODS AND RESULTS: A panel of monoclonal antibodies against keratins, epithelial membrane antigen (EMA), epithelial antigen Ber-EP4, carcinoembryonic antigen (CEA), tumour-associated glycoprotein (B72.3), Leu-M1, CD30 (Ber-H2), vimentin and desmin, was applied to 40 cases of malignant pleural mesothelioma and 23 cases of carcinoma metastatic to the pleura (16 pulmonary and seven extrapulmonary). Positivities for Ber-EP4, CEA, B72.3 and Leu-M1 were found to have the highest nosologic sensitivities (87.0%, 65.2%, 52.5% and 43.5%, respectively) and specificities (97.5%, 97.5%, 100% and 95%, respectively) for carcinoma. Positive staining for vimentin had the highest sensitivity (87.5%) with 95.7% specificity for mesothelioma. Positive staining for desmin was found in 45% of mesotheliomas and 0% of carcinomas. Diagnostic sensitivity and diagnostic specificity (P-values) were calculated for these markers. In respect to the diagnostic power defined by the clinically relevant predictive values of positive and negative tests, we found that a two-marker panel of antibodies including vimentin and Ber-EP4 is most useful for the histopathological distinction between carcinoma (pulmonary or extrapulmonary) and malignant pleural mesothelioma. CONCLUSIONS: A combination of Ber-EP4 and vimentin provides the most sensitive and specific pair of markers for distinguishing between malignant pleural mesothelioma and carcinoma metastatic to the pleura. The prevalence of the tested tumours should be taken into account when evaluating the clinical value of ancillary techniques in pathology.

Bone marrow-derived dendritic cells serve as potent adjuvants for peptide-based antitumor vaccines.

Dendritic cells (DCs) are considered the most effective antigen-presenting cells (APCs) for primary immune responses. Since presentation of antigens to the immune system by appropriate professional APCs is critical to elicit a strong immune reaction and DCs seem to be quantitatively and functionally defective in the tumor host, DCs hold great promise to improve cancer vaccines. Even though they are found in lymphoid organs, skin and mucosa, the difficulty of generating large numbers of DCs has been a major limitation for their use in vaccine studies. A simple method for obtaining DCs from mouse bone marrow cells cultured in the presence of GM-CSF + interleukin 4 is now available. In four different tumor models, mice injected with DCs grown in GM-CSF plus interleukin 4 and prepulsed with a cytotoxic T lymphocyte-recognized tumor peptide epitope developed a specific cytotoxic T lymphocyte response and were protected against a subsequent tumor challenge with tumor cells expressing the relevant tumor antigen. Moreover, treatment of day 5-14 tumors with peptide-pulsed DCs resulted in sustained tumor regression in five different tumor models. These results suggest that presentation of tumor antigens to the immune system by professional APCs is a promising method to circumvent tumor-mediated immunosuppression and is the basis for ongoing clinical trials of cancer immunotherapy with tumor peptide-pulsed DCs.