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.

Advances in cutaneous melanoma

After several decades of slow progress in the field of melanoma, significant advances have been reported in recent years. These include a better understanding of the molecular biology of the tumour, a new staging classification system, insights into the patterns of relapse in early stage, and new drugs for the treatment of advanced disease. Ipilimumab and vemurafenib have just been approved and provide a survival benefit in stage IV. Both compounds are under evaluation in the adjuvant setting, where interferon remains the only drug with proven efficacy. Further investigation is required to treat patients with primary or secondary resistance to new drugs (AU)

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.

Estudio preliminar de mutaciones germinales en el gen MYH en población aragonesa con cáncer de colon / No disponible

No disponible

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.

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 (AU)

Desmoplastic small round cell tumor of the abdomen

Una mujer de 21 años consultó por dolor abdominalde dos meses de evolución. El estudio que sele practicó puso de manifiesto la existencia de unamasa intraperitoneal de 17 cm. La biopsia demostrabala existencia de islotes de células pequeñas yredondas, rodeadas de abundante estroma desmoplásico.La inmunohistoquímica fue fuertementepositiva para desmina y débilmente positiva para vimentinay enolasa neuronal específica. Con estoshallazgos el diagnóstico anatomopatológico fue detumor desmoplásico de célula pequeña intraabdominal.La paciente inició tratamiento con un esquemaintensivo de altas dosis de quimioterapia basada enagentes alquilantes, de acuerdo con el Servicio dePediatría del Memorial Sloan-Kettering CancerCenter, denominado protocolo P61. Tras el mismopresentó respuesta parcial siendo sometida a cirugíade las masa residuales y a continuación a quimioterapiade altas dosis con trasplante autólogo de médulaósea. Diez meses después la paciente presentóprogresión de la enfermedad por lo que está recibiendoun asegunda línea de quimioterapia

A 21-year old woman presented with a 2-monthhistory of abdominal pain. The diagnostic work-updisclosed a 17-cm intraperitoneal mass. Biopsyshowed islets containing small round cellssurrounded by abundant desmoplastic stroma.Immunohistochemistry was strongly positive fordesmin and weakly positive for vimentin andneuron-specific enolase. Pathological diagnosis wasintraabdominal round cell desmoplastic tumor. Thepatient underwent an intensive schedule of highdosealkylator-based chemotherapy, the P6 protocol,designed by the Pediatrics Division of the MemorialSloan-Kettering Cancer Center. She had a partialresponse and subsequently underwent resection ofthe residual mass followed by high-dosechemotherapy with stem cell support. Ten monthslater, the patient had disease progression and iscurrently receiving second-line chemotherapy

Prognostic value of quantitative immune alterations in melanoma patients

Introducción y objetivos: Los pacientes con cáncer presentan una alteración de la respuesta inmune.La inmunosupresión en melanoma, juega un papel importante. El objetivo de este estudio fue valorar las alteracionescueantitativas de la inmunidad en pacienets con melanoma.• Pacientes y métodos: Se obtuvieron muestras de sangre periférica en EDTA de 86 pacientes con melanoma(63 pacientes libres de enfermedad y 23 pacientes con metástasis a distancia). Los niveles de leucocitostotales, linfocitos totales, linfocitos CD3, linfocitos CD4, linfocitos CD8, linfocitos B (CD19) y linfocitosNK (CD56) fueron valorados mediante marcadores de superficie por citometría de flujo usando un CoulterEpics Elite (Coulter Corp). Los niveles de IgA, IgG, IgE e IgM fueron valorados por nefelometría usando unnefelómetro Hyland PDQ laser.• Resultados: Hubo diferencias significativas entre pacienets metastásicos y pacientes libres de enfermedaden los niveles de linfocitos totales (mediana: 2251.57 vs 1783.04/mm3, p=.001), linfocitos B (CD19)(216.1 vs 108.36/mm3, p=.010), linfocitos NK (CD56) (149.54 vs 115.2/mm3, p=.016) y niveles de IgA(241.59 vs 300.55 mg dL, p=.044) al considerarlas como variables continuas. Al considerar cada parámetro deestudio como una variable cualitativa, sólo se observaron diferencias significativas en los niveles totales delinfocitos, existiendo un 73.9% d elos pacientes con enfermedad a distancia niveles d elinfocitos por debajo de2000 células/mm3 frente a un 36.5% de pacienets libres de enfermedad (χ2 Pearson = 9.476, df = 1, p = .002).La mediana de supervivencia para 46 pacientes con niveles totales de linfocitos por encima de 2000células/mm3 fue de 965 días (DF= 65.03, IC 95% = 792.72 - 1090.30) frente a 441 días (DF= 75.61, IC 95% =292.81 - 589.19) para 40 pacientes con niveles totales de linfocitos 2000 células / mm3 (log rank = 4.54, df=1,p= .0331).• Conclusiones: Existen diferencias significativas en los niveles de algunas subpoblaciones linfocitariasy en los niveles de IgA entre pacienets metastásicos y pacienets libres de enfermedad. Los pacientes con melanomacon niveles de linfocitos totales por encima de 2000 cells/mm3 tiene una mayor supervivencia que aquelloscon niveles por debajo de 2000 cells/mm3

Purpose: The immune response is altered in patients with neoplasms. Immunosuppression hasimportant consequences in patients with melanoma. The aim of this study was to assess quantitative immunealterations in melanoma patients..• Material and methods: We obtained a peripheral blood sample in EDTA from 86 melanoma patients(63 of them disease-free and 23 with distant disease). Total leukocytes and lymphocytes, B lymphocytes(CD19), types CD3, CD4, CD8 lymphocytes, and NK lymphocytes (CD56) were counted by determining thesurface markers by flow cytometry, using a Coulter Epics Elite (Coulter Corp.). IgA, IgG, IgE and IgM wereassayed by nephelometric methods employing a Hyland PDQ laser nephelometer.• Results: We found significant differences between disease-free patients and those with active diseasewith regard to lymphocytes total count (median: 2251.57 vs. 1783.04/mm3, p=0.010), NK lymphocytes(CD56) (149.54 vs. 115.2/mm3, p=0.016), and IgA levels (241.59 vs. 300.55 mg/dl, p=0.044), when taken ascontinuous variables. When considering each parameter as a discontinuous variable, only changes in absolutelymphocyte count retained an statistical difference depending on the presence or absence of active disease,73.9% of the patients with active metastatic disease having a lymphocyte count below 2000 cells/mm3 versusonly 36.5% of the disease-free patients (c2 Pearson=9.476, df=1, p=0.002). The median survival for the 46patients with absolute lymphocyte count above 2000 cells/mm3 was 965 days (DF=65.03, IC 95%=792.72-1090.30) versus 441 days (DF=75.61, IC 95%=292.81-589.19) for the 40 patients with absolute lymphocytecount below 2000 cells/mm3 (log rank=4.54, df=1, p=0.0331).• Conclusions: There are significant differences in some lymphocyte populations and IgA levels betweenpatients with metastases and disease-free patients. Melanoma patients with absolute lymphocyte levels above2000 cells/mm3 have a longer survival than those with a lymphocyte count below 2000 cells/mm3

[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.

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

Estudiamos cómo evoluciona el tipo de flora comensal y su resistencia a distintos antimicrobianos en pacientes neurotropénicos sometidos a quimioterapia de altas dosis con autotrasplante de células madre autólogas hematopoyéticas periféricas, relacionando los hallazgos con la etiología de las infecciones que desarrollaron los pacientes, a fin de evaluar la idoneidad de la quimioprofilaxis y del tratamiento empírico utilizados. Se analizaron 41 pacientes en un periodo de 28 meses. La quimioprofilaxis se realizó con levofloxacino, fluconazol y aciclovir. El tratamiento empírico secuencial preveía la administación inicial de cefepima, seguida de teicoplanina y amikacina. Se realizaron cultivos de frotis nasales y faríngeo, catéter de Hickman y heces, un día antes de comenzar la quimioprofilaxis, a los cinco y nueve días. En caso de fiebre se realizaron tres hemocultivos y cultivo de orina y de muestras procedentes de focos relacionados con la clínica. El levofloxacino indujo la selección de cepas o especies resistentes, tanto en la flora comensal como en los agentes patógenos. El fluconazol seleccionó especies resistentes en la flora comensal. Se documentaron microbiológicamente 17 infecciones en 11 pacientes, producidas por gram positivos en 13 casos (81.25%) y por gramnegativos en 3 (18,75%). Los estafilococos coagulasa negativos y Enterococcus faecalis fueron los microorganismos más frecuentes. En nueve ocasiones recuperamos el mismo microorganismo en flora comensal y producto patológico, lo que sugiere su origen endógeno y apoya la realización prospectiva de cultivos de flora comensal, vigilando la sensibilidad de los microorganismos aislados a los antimicrobianos usados en quimioprofilaxis y tratamiento empírico

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 analysed 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 analysed. Levoflaxacin 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 suggest 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 chemoprophylasis 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.

Resultados a largo plazo del tratamiento del estesioneuroblastoma. Experiencia en Aragón (1981- / Long term results of the esthesioneuroblastoma treatment. Experience in Aragón (1981-2003)

Propósito: el estesioneuroblastoma o neuroblastoma olfatorio es un tumor infrecuente. Se han publicado sólo un millar de casos en la literatura médica. La edad media de presentación es a los 50 años, no teniendo predilección por ningún sexo. Es un tumor de agresividad local con recidivas locales tardías. Se han descrito metástasis a distancia, frecuentemente pulmón y hueso. Presentamos nuestra experiencia en el manejo y tratamiento de este tipo de tumor.- Material y métodos: entre 1981 y 2003, 8 casos de estesioneuroblastoma fueron diagnosticados en el Hospital Clínico Universitario de Zaragoza, un hospital terciario con 882 camas, que es referencia para radioterapia de alta energía en todo Aragón, por lo que con toda probabilidad, este número de casos corresponde al de diagnósticos en la Comunidad Autónoma de Aragón en ese período. Cinco varones y 3 mujeres con una mediana de edad de 60 años (rango 49-82). Los síntomas más frecuentes a la presentación incluyeron: obstrucción nasal, epistaxis, anosmia, exoftalmus, edema palpebral y tumefacción local. El estadio de Kadish al diagnóstico fue: 3 pacientes estadio B, 2 estadio C y 3 estadio D. Cirugía, radioterapia y quimioterapia fueron frecuentemente combinadas. En dos pacientes el tratamiento fue cirugía, sola en un paciente y en otro con radioterapia radical. Tres pacientes recibieron quimioterapia, sola en dos pacientes y combinada con radioterapia en el otro. Tres pacientes fueron tratados con radioterapia sólo.- Resultados: dos pacientes están vivos sin enfermedad tras 87 y 108 meses del diagnóstico y uno más está actualmente en tratamiento. Cuatro pacientes murieron con progresión a los 6, 8, 38 y 63 meses del diagnóstico. Un paciente falleció por un segundo tumor a los 36 meses del diagnóstico.- Conclusión: el control local es un requisito esencial para obtener supervivencias a largo plazo en el estesioneuroblastoma (AU)

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.