Carlos G. Jara

Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial

BACKGROUND We aimed to compare the additional benefit of gemcitabine when combined with vinorelbine above that of standard vinorelbine treatment in patients with metastatic breast cancer. METHODS In this phase III, multicentre, open-label, randomised study, 252 women with locally recurrent and metastatic breast cancer who had been pretreated with anthracyclines and taxanes were randomly assigned single-agent vinorelbine (30 mg/m(2), days 1 and 8) or gemcitabine plus vinorelbine (1200/30 mg/m(2), days 1 and 8). Both study treatments were administered intravenously every 21 days until disease progression, unacceptable toxic effects, or stoppage at the request of investigator or patient. The primary endpoint was median progression-free survival. Secondary objectives included assessments of response rate, disease duration, overall survival, and characterisation of the toxicity profiles of both regimens. This study is registered with ClinicalTrials.gov, number NCT00128310. FINDINGS Between 2001 and 2005, 252 women were recruited and randomised for treatment. One of these patients was ineligible. Prognostic factors were well balanced between treatment groups (median number of metastatic sites in combination group 2 (range 0-5) and in vinorelbine group 2 (range 1-6); visceral disease in 76% and 75% of patients, respectively). Median progression-free survival was 6.0 months (95% CI 4.8-7.1) for patients given gemcitabine plus vinorelbine and 4.0 months (2.9-5.1) for those assigned vinorelbine; there was 1.9 months of difference (hazard ratio 0.66 [0.50-0.88]; p=0.0028). Overall survival was 15.9 months (12.6-19.1) for the gemcitabine plus vinorelbine group and 16.4 months (11.6-21.0) for the vinorelbine group; there was 0.5 months of difference (hazard ratio 1.04 [0.78-1.39]; p=0.8046). Objective response rates were 36% for patients assigned gemcitabine plus vinorelbine (n=45) and 26% for those assigned vinorelbine (n=33) (p=0.093). Grade 3 or 4 neutropenia was reported in 75 (61% [52-70]) of the participants assigned gemcitabine plus vinorelbine, compared with 55 (44% [35-53]) of those assigned vinorelbine alone (p=0.0074). Febrile neutropenia occurred in 13 (11%) of those assigned gemcitabine plus vinorelbine, and in seven (6%) of those assigned vinorelbine alone (p=0.15). Incidences of grade 3 or 4 non-haematological toxic effects were similar between the two treatment groups. INTERPRETATION Patients with metastatic breast cancer assigned gemcitabine and vinorelbine had better progression-free survival compared with those assigned vinorelbine alone. However, this finding did not translate into a difference in overall survival. Although toxicity was manageable, patients in the combined group had more haematological toxic effects. These factors should be taken into account when deciding which chemotherapy patients should receive.

Adjuvant docetaxel for high-risk, node-negative breast cancer.

BACKGROUND A regimen of docetaxel, doxorubicin, and cyclophosphamide (TAC) is superior to a regimen of fluorouracil, doxorubicin, and cyclophosphamide (FAC) when used as adjuvant therapy in women with node-positive breast cancer. The value of taxanes in the treatment of node-negative disease has not been determined. METHODS We randomly assigned 1060 women with axillary-node-negative breast cancer and at least one high-risk factor for recurrence (according to the 1998 St. Gallen criteria) to treatment with TAC or FAC every 3 weeks for six cycles after surgery. The primary end point was disease-free survival after at least 5 years of follow-up. Secondary end points included overall survival and toxicity. RESULTS At a median follow-up of 77 months, the proportion of patients alive and disease-free was higher among the 539 women in the TAC group (87.8%) than among the 521 women in the FAC group (81.8%), representing a 32% reduction in the risk of recurrence with TAC (hazard ratio, 0.68; 95% confidence interval [CI], 0.49 to 0.93; P=0.01 by the log-rank test). This benefit was consistent, regardless of hormone-receptor status, menopausal status, or number of high-risk factors. The difference in survival rates (TAC, 95.2%; FAC, 93.5%) was not significant (hazard ratio, 0.76; 95% CI, 0.45 to 1.26); however, the number of events was small (TAC, 26; FAC, 34). Rates of grade 3 or 4 adverse events were 28.2% with TAC and 17.0% with FAC (P<0.001). Toxicity associated with TAC was diminished when primary prophylaxis with granulocyte colony-stimulating factor was provided. CONCLUSIONS As compared with adjuvant FAC, adjuvant TAC improved the rate of disease-free survival among women with high-risk, node-negative breast cancer. (Funded by GEICAM and Sanofi-Aventis; ClinicalTrials.gov number, NCT00121992.).

Multicenter Randomized Trial Comparing Sequential With Concomitant Administration of Doxorubicin and Docetaxel As First-Line Treatment of Metastatic Breast Cancer: A Spanish Breast Cancer Research Group (GEICAM-9903) Phase III Study

PURPOSE This randomized, multicenter, phase III trial evaluated whether sequential doxorubicin and docetaxel (A-->T) reduced hematological toxicity, especially febrile neutropenia, compared with concomitant (AT) administration as first-line chemotherapy in metastatic breast cancer (MBC). PATIENTS AND METHODS One hundred forty-four patients were randomly assigned to receive three cycles of doxorubicin 75 mg/m(2) every 21 days followed by three cycles of docetaxel 100 mg/m(2), every 21 days (A-->T) or six cycles of the combination doxorubicin 50 mg/m(2) and docetaxel 75 mg/m(2) (AT) every 21 days. Patients previously treated with anthracyclines received two cycles of doxorubicin followed by four cycles of docetaxel (A-->T), or three cycles of AT followed by three cycles of docetaxel 100 mg/m(2) every 21 days. RESULTS Febrile neutropenia was less common in the A-->T arm (29.3% of patients, 6.9% of cycles) compared with the AT arm (47.8% of patients, 14.8% of cycles; P =.02 and P =.0004, respectively). Asthenia, diarrhea, and fever occurred more frequently in the AT arm. The overall responses rates were 61% in the A-->T arm (95% CI, 50% to 72%) and 51% in the AT arm (95% CI, 39% to 63%). The median duration of response was 8.7 months (A-->T) and 7.6 months (AT); the median time to progression was 10.5 months (A-->T) and 9.2 months (AT); the median overall survival was 22.3 months (A-->T) and 21.8 months (AT); and no significant differences were found. CONCLUSION A-->T significantly reduced febrile neutropenia compared with AT in MBC patients and maintains comparable antitumoral efficacy. A-->T represents a valid option for the treatment of MBC.

Southern Chile, trout and salmon country: invasion patterns and threats for native species

Para evaluar la distribucion y abundancia actual de salmonidos y peces nativos muestreamos 11 lagos grandes y 105 arroyos, cubriendo 13 cuencas principales en el sur de Chile desde 39° a 52°S. En general las truchas (Salmo trutta y Oncorhynchus mykiss) representaron mas de 60 % de la abundancia total de peces y mas de 80 % de la biomasa total, ademas 40 % de los arroyos muestreados no presentaron peces nativos. Los salmones traidos para acuicultura tales como O. kisutch, Salmo salar, y O. tshawytscha solo estuvieron presentes en lagos que tenian salmonicultura, aun cuando no parecen reproducirse exitosamente en los arroyos afluentes. Pusimos a prueba el efecto del origen de los arroyos (cordillera de los Andes, valle central o cordillera de la Costa) sobre la abundancia de las especies y encontramos que la trucha arco iris estuvo mas restringida a los arroyos preandinos con mayor descarga, mientras la trucha cafe se distribuyo ampliamente no respondiendo a otras caracteristicas o atributos especificos de las cuencas que se midieron. La abundancia relativa de peces nativos fue mayor en los lagos que en los arroyos, en tanto la mayor biodiversidad de peces nativos se encontro en arroyos del valle central. Las especies mas comunes fueron Galaxias maculatus, G. platei, Brachygalaxias bullocki, Aplochiton zebra y Basilichthys australis. Arroyos con mayor conductividad, mas areas de pozones, mas sedimentos finos y con bajas densidades de trucha cafe fueron mas adecuados para peces nativos. Es asi que cuencas con mayor disturbio antropogenico parecen ser refugio para los mismos. Dada la naturaleza descriptiva de nuestro estudio solo podemos presumir los efectos negativos de truchas y salmones sobre los peces nativos, efecto que debiera estar sobreimpuesto a los condicionantes biogeograficos de la distribucion actual. Aun asi, basado en las presentes distribuciones de salmonidos y peces nativos, los efectos negativos son muy probables. La conservacion de la biodiversidad de peces nativos plenamente expuestos a perturbaciones humanas en el valle central, lejos de areas protegidas y parques nacionales, presenta un gran desafio. Proponemos incentivar la conservacion ejerciendo una mayor presion de pesca deportiva sobre las truchas en esos ambientes

Pleistocene glaciation leaves deep signature on the freshwater crab Aegla alacalufi in Chilean Patagonia

Quaternary glacial cycles have played an important role in shaping the biodiversity in temperate regions. This is well documented in Northern Hemisphere, but much less understood for Southern Hemisphere. We used mitochondrial DNA and nuclear elongation factor 1α intron sequences to examine the Pleistocene glacial impacts on the phylogeographical pattern of the freshwater crab Aegla alacalufi in Chilean Patagonia. Phylogenetic analyses, which separated the glaciated populations on eastern continent into a north group (seven populations) and a south group (one population), revealed a shallow phylogenetic structure in the north group but a deep one in the non‐glaciated populations on western islands, indicating the significant influence of glaciation on these populations. Phylogenies also identified the Yaldad population on Chiloé Island as a potentially unrecognized new species. The non‐glaciated populations showed higher among population genetic divergence than the glaciated ones, but lower population genetic diversity was not detected in the latter. The two glaciated groups, which diverged from the non‐glaciated populations at ~96 800–29 500 years ago and ~104 200–73 800 years ago, respectively, seem to have different glacial refugia. Unexpectedly, the non‐glaciated islands did not serve as refugia for them. Demographic expansion was detected in the glaciated north group, with a constant population increase after the last glacial maximum. Nested clade analyses suggest a possible colonization from western islands to eastern continent. After arriving on the continent and surviving the last glacial period there, populations likely have expanded from high to low altitude, following the flood of melting ice. Aegla alacalufi genetic diversity has been primarily affected by Pleistocene glaciation and minimally by drainage isolation.

Spanish Mediterranean diet and other dietary patterns and breast cancer risk: case-control EpiGEICAM study

Background:Although there are solid findings regarding the detrimental effect of alcohol consumption, the existing evidence on the effect of other dietary factors on breast cancer (BC) risk is inconclusive. This study aimed to evaluate the association between dietary patterns and risk of BC in Spanish women, stratifying by menopausal status and tumour subtype, and to compare the results with those of Alternate Healthy Index (AHEI) and Alternate Mediterranean Diet Score (aMED).Methods:We recruited 1017 incident BC cases and 1017 matched healthy controls of similar age (±5 years) without a history of BC. The association between ‘a priori’ and ‘a posteriori’ developed dietary patterns and BC in general and according to menopausal status and intrinsic tumour subtypes (ER+/PR+ and HER2−; HER2+; and ER−/PR− and HER2−) was evaluated using logistic and multinomial regression models.Results:Adherence to the Western dietary pattern was related to higher risk of BC (OR for the top vs the bottom quartile 1.46 (95% CI 1.06–2.01)), especially in premenopausal women (OR=1.75; 95% CI 1.14–2.67). In contrast, the Mediterranean pattern was related to a lower risk (OR for the top quartile vs the bottom quartile 0.56 (95% CI 0.40–0.79)). Although the deleterious effect of the Western pattern was similarly observed in all tumour subtypes, the protective effect of our Mediterranean pattern was stronger for triple-negative tumours (OR=0.32; 95% CI 0.15–0.66 and Pheterogeneity=0.04). No association was found between adherence to the Prudent pattern and BC risk. The associations between ‘a priori’ indices and BC risk were less marked (OR for the top vs the bottom quartile of AHEI=0.69; 95% CI 0.51–0.94 and aMED=0.74; 95% CI 0.46–1.18)).Conclusions:Our results confirm the harmful effect of a Western diet on BC risk, and add new evidence on the benefits of a diet rich in fruits, vegetables, legumes, oily fish and vegetable oils for preventing all BC subtypes, and particularly triple-negative tumours.

Conservation phylogenetics of Chilean freshwater crabs Aegla (Anomura, Aeglidae): assigning priorities for aquatic habitat protection

Recently, a molecular phylogeny based on four mtDNA gene regions has been estimated for 17 species and subspecies of Aegla freshwater crabs from Chile. With this phylogenetic hypothesis and information on geographic distribution, environmental conditions, habitat requirements, and population abundance, Chilean aeglids were assessed for conservation status based on the criteria included in the IUCN Red List Categories (2001). Aegla concepcionensis and Aegla expansa qualify as ‘‘Extinct in the Wild’’ and nine other taxa fall within the threatened category: three as ‘‘Critically Endangered’’ (A. laevis laevis, A. papudo and A. spectabilis) and six as ‘‘Vulnerable’’ (A. alacalufi, A. bahamondei, A. cholchol, A. hueicollensis, A. laevis talcahuano and A. manni). Six hydrographic regions within temperate Chile were ranked for conservation priority using species richness, and phylogenetic and genetic

ON THE PHYLOGENETIC POSITIONING OF THE SOUTH AMERICAN FRESHWATER CRAYFISH GENERA (DECAPODA: PARASTACIDAE)

Abstract South America contains three endemic genera of parastacid freshwater crayfishes (i.e., Parastacus Huxley, Samastacus Riek, and Virilastacus Hobbs), with a current total of ten described species. A previous author has argued that each of these genera has closer affinities with genera from Australia than to each other. We sequenced approximately 500 nucleotides of the 16S gene from mitochondrial DNA to estimate phylogenetic relationships among the South American genera of freshwater crayfishes and determined their phylogenetic positioning relative to the Australian genera. We sampled seven species representing all three genera from South America with 19 individuals. These sequences were combined with other Australasian crayfishes for a total representation of 54 sequences covering 13 genera. Our results indicate that the South American genera form a well-supported monophyletic group closely related to a subset of the Australasian crayfishes (Paranephrops and Parastacoides). Our results also provide...

Conservation assessment of southern South American freshwater ecoregions on the basis of the distribution and genetic diversity of crabs from the genus Aegla.

We assessed the conservation priority of 18 freshwater ecoregions in southern South America on the basis of Aegla (genus of freshwater crabs) genetic diversity and distribution. Geographical distributions for 66 Aegla species were taken from the literature and plotted against ecoregions and main river basins of southern South America. Species richness and number of threatened and endemic species were calculated for each area. To assess taxonomic and phylogenetic diversity, we generated a molecular phylogeny based on DNA sequences for one nuclear (28S) and 4 mitochondrial (12S, 16S, COI, and COII) genes. All species richness and phylogenetic methods agreed, to a large extent, in their rankings of the importance of conservation areas, as indicated by the Spearmans rank correlation coefficient (p < 0.01); nonetheless, some of the lowest correlations were observed between taxonomic and phylogenetic diversity indices. The 5 ecoregions of the Laguna dos Patos Basin (Eastern Brazil), Central Chile, South Brazilian Coast, Chilean Lakes, and Subtropical Potamic Axis (northern Argentina and southern Uruguay and Paraguay) had the highest biodiversity scores. Conservation of these regions will preserve the largest number of species and the greatest amount of genetic diversity within the South American freshwater Aegla fauna. Biodiversity across rivers and within areas was heterogeneously distributed in the ecoregions of Upper Paraná, Ribeira do Iguape, Upper Uruguay, and South Brazilian Coast (i.e., one river showed significantly more biodiversity than any other river from the same ecoregion), but homogeneously distributed in the other ecoregions. Hence, conservation plans in the former regions will potentially require less effort than plans in the latter regions.

Estado de conocimiento de los malacostráceos dulceacuícolas de Chile

La fauna de crustaceos malacostraceos limneticos, en el territorio de Chile continental, esta compuesta por seis especies de camarones, i.e., cinco parastacidos de los generos Parastacus, Samastacus y Virilastacus y un palemonido del genero Cryphiops, 18 especies de anomuros del genero Aegla, siete especies de anfipodos gamarideos del genero Hyallela y una especie de isopodo aselotano del genero Heterias. La distribucion conjunta abarca desde Arica a Punta Arenas, pero la mayor parte de las especies tiene rango geografico restringido. La mayor densidad de taxa ocurre entre las regiones VIII y X, donde el numero de taxa por Region varia entre 11 y 15, siendo la X Region la que tiene el numero mayor. Indices derivados de un estudio sobre relaciones filogeneticas de las especies chilenas de Aegla, combinados con criterios propuestos por IUCN (2001), califico a A. concepcionensis y A. expansa como especies Extintas y a A. papudo, A. l. laevis y A. spectabilis como Criticamente Amenazadas. Ademas, asigno maxima prioridad de conservacion a la zona comprendida entre las cuencas del rio Tucapel y del rio Tolten. El estado de conservacion de las especies de Parastacidae fue establecido por Bahamonde et al. (1998) y complementado por Rudolph & Crandall (2005). El estado de conservacion de las especies de Hyalella y del isopodo Heterias exul no ha sido determinado. Se percibe que las amenazas a la conservacion de las especies de malacostraceos limneticos en Chile derivan principalmente de perturbaciones antropogenicas de la integridad y salud ambiental de las cuencas hidrograficas, particularmente entre las Regiones IV a VIII.