Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-beta 3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.

Snail heterogeneity in clear cell renal cell carcinoma

Background: Intratumor heterogeneity may be responsible of the unpredictable aggressive clinical behavior that some clear cell renal cell carcinomas display. This clinical uncertainty may be caused by insufficient sampling, leaving out of histological analysis foci of high grade tumor areas. Although molecular approaches are providing important information on renal intratumor heterogeneity, a focus on this topic from the practicing pathologist' perspective is still pending. Methods: Four distant tumor areas of 40 organ-confined clear cell renal cell carcinomas were selected for histopathological and immunohistochemical evaluation. Tumor size, cell type (clear/granular), Fuhrman's grade, Staging, as well as immunostaining with Snail, ZEB1, Twist, Vimentin, E-cadherin, beta-catenin, PTEN, p-Akt, p110 alpha, and SETD2, were analyzed for intratumor heterogeneity using a classification and regression tree algorithm. Results: Cell type and Fuhrman's grade were heterogeneous in 12.5 and 60 % of the tumors, respectively. If cell type was homogeneous (clear cell) then the tumors were low-grade in 88.57 % of cases. Immunostaining heterogeneity was significant in the series and oscillated between 15 % for p110a and 80 % for Snail. When Snail immunostaining was homogeneous the tumor was histologically homogeneous in 100 % of cases. If Snail was heterogeneous, the tumor was heterogeneous in 75 % of the cases. Average tumor diameter was 4.3 cm. Tumors larger than 3.7 cm were heterogeneous for Vimentin immunostaining in 72.5 % of cases. Tumors displaying negative immunostaining for both ZEB1 and Twist were low grade in 100 % of the cases. Conclusions: Intratumor heterogeneity is a common event in clear cell renal cell carcinoma, which can be monitored by immunohistochemistry in routine practice. Snail seems to be particularly useful in the identification of intratumor heterogeneity. The suitability of current sampling protocols in renal cancer is discussed.

Sobrevida e fatores prognósticos em uma coorte hospitalar de pacientes com câncer de próstata localizado

O câncer de próstata é a neoplasia mais incidente entre os homens brasileiros. Atualmente, grande parte destes tumores é confinada à próstata no momento do diagnóstico. No entanto, muitos tumores clinicamente classificados como localizados não o são de fato, levando a indicações terapêuticas curativas não efetivas. Por outro lado, muitos pacientes com câncer sem significância clínica são tratados desnecessariamente em função da limitação prognóstica do estadiamento clínicos (pré-tratamento) de pacientes com diagnóstico histológico de adenocarcinoma de próstata localizado (estágios I e II), em coorte hospitalar composta por pacientes tratados no Instituto Nacional de Câncer, Rio de Janeiro, matriculados entre 1990 a 1999. As funções de sobrevida foram calculadas empregando-se o estimados de Kaplan-Meier tomando-se como início a data do diagnóstico histológico e como eventos os óbitos cuja causa básica foi o câncer de próstata. Para avaliação dos fatores prognósticos clínicos foram calculadas as hazard ratios (HR), com intervalos de confiança de 95%, seguindo-se o modelo de riscos proporcionais de Cox. Foram analisadas como fatores prognósticos independentes as variáveis: idade, cor, grau de instrução, data do primeiro tratamento, grau de diferenciação celular d o tumor primário biopsiado (Gleason), estadiamento clínico e PSA total pré-tratamento. O pressuposto dos riscos proporcionais foi avaliado pela análise dos resíduos de Schoenfeld e a influência de valores aberrantes pelos resíduos martingale e escore. Foram selecionados 258 pacientes pelos critérios de elegibilidade do estudo, dos quais 46 foram a óbito durante o período de seguimento. A sobrevida global foi de 88% em 5 anos e de 71% em 10 anos. Idade maior que 80 anos, classificação de Gleason maior que 6, PSA maior que 40ng/ml, estádio B2 e cor branca foram marcadores independentes de pior prognóstico. Fatores prognósticos clássicos na literatura foram úteis na estimativa do prognóstico nesta coorte hospitalar. Os resultados mostram que para pacientes diagnosticados em fases iniciais, os fatores sócio-econômico analisados, não influenciaram o prognóstico. Outros estudos devem ser conduzidos no país para investigar as diferenças no prognóstico em relação à etnia.

Carcinoma epidermóide invasivo de pênis: subexpressão dos fragmentos C3 e C4A/B do sistema complemento detectado no plasma pela plataforma proteômica ClinProt/MALDI/TOF

O carcinoma epidermóide de pênis (CEP) representa 95% das neoplasias penianas e afeta quase sempre pacientes não circuncidados estando muitas vezes associado à falta de higiene local adequada e à fimose. No Brasil a sua incidência é de 2,7 % porém em algumas áreas do país pode chegar a 17% dos casos diagnosticados por ano. O tumor pode ocorrer em qualquer parte do órgão sexual masculino e o tipo de estadiamento empregado é controverso. A classificação de Broders é a mais utilizada. Estudos sugerem a relação entre o desenvolvimento do carcinoma de pênis com a infecção por HPV (Papiloma Vírus Humano). O método de avaliação dos linfonodos inguinais permanece controverso sendo difícil a diferenciação entre linfadenomegalia inflamatória reacional e metastática. O exame físico não é um preditor confiável do comprometimento linfonodal pois pacientes com linfonodos palpáveis podem não apresentar metástases. Há poucas publicações sobre os mecanismos moleculares envolvidos na gênese e progressão do CEP. Apesar de vários marcadores terem sido avaliados, atualmente a aplicação clínica destes é limitada. A maior parte dos marcadores estudados requer procedimentos invasivos para obtenção do tecido tumoral. Existe a necessidade de encontrar através de uma técnica pouco invasiva marcadores tumorais circulantes capazes de diferenciar portadores de CEP com e sem envolvimento metastático. Neste tipo de neoplasia, a descoberta de biomarcadores que avaliem o prognóstico é relevante, pois o exame físico não é um indicador confiável do comprometimento linfonodal e da sobrevida.Os objetivos foram 1) revisar e discutir a epidemiologia, a etiologia, os diversos tipos de abordagem cirúrgica e as controvérsias no tratamento cirúrgico do câncer de pênis 2) investigar através da plataforma ClinProt/ MALDI / TOF a presença de marcadores plasmáticos capazes de discriminar indivíduos saudáveis de pacientes afetados por carcinoma epidermóide de pênis (CEP) 3) avaliar a importância destes marcadores na evolução da doença. Foram coletados e analisados pela plataforma ClinProt / MALDI / TOF o plasma de 36 indivíduos saudáveis e 25 pacientes com CEP invasivo, submetidos a tratamento cirúrgico entre junho de 2010 e junho de 2011, nos serviços de urologia do Instituto Nacional de Câncer e do Hospital Mário Kröeff (Rio de Janeiro). Nossos resultados apontaram para um conjunto de dois peptídeos (A = m / z 1897,22 + -9 Da e B = m / z 2021,99 + -9 Da) que foram capazes de diferenciar pacientes com CEP de indivíduos controles. Esses peptídeos foram posteriormente identificados como fragmentos C3 e C4 A/B do sistema complemento. A validação cruzada, utilizando toda casuística apresentou 62,5% e 86,76% de sensibilidade e de especificidade, respectivamente, com uma alta sensibilidade (100%) e especificidade (97%) nos pacientes que morreram pela doença. Além disso, os pacientes com envolvimento ganglionar obtiveram uma sensibilidade e uma especificidade de 80 % e 97%, respectivamente. Ficou demonstrado que à medida que a doença progride mais subexpressos está o conjunto de peptídeos quando comparados com indivíduos saudáveis. Estes resultados podem ser úteis como ferramentas para a avaliação do prognóstico destes pacientes.

Impacto orçamentário da incorporação da tomografia de emissão de pósitrons (PET scan) no estadiamento do câncer de pulmão na perspectiva do Sistema Único de Saúde

O aumento exponencial dos gastos em saúde demanda estudos econômicos que subsidiem as decisões de agentes públicos ou privados quanto à incorporação de novas tecnologias aos sistemas de saúde. A tomografia de emissão de pósitrons (PET) é uma tecnologia de imagem da área de medicina nuclear, de alto custo e difusão ainda recente no país. O nível de evidência científica acumulada em relação a seu uso no câncer pulmonar de células não pequenas (CPCNP) é significativo, com a tecnologia mostrando acurácia superior às técnicas de imagem convencionais no estadiamento mediastinal e à distância. Avaliação econômica realizada em 2013 aponta para seu custo-efetividade no estadiamento do CPCNP em comparação à estratégia atual de manejo baseada no uso da tomografia computadorizada, na perspectiva do SUS. Sua incorporação ao rol de procedimentos disponibilizados pelo SUS pelo Ministério da Saúde (MS) ocorreu em abril de 2014, mas ainda se desconhecem os impactos econômico-financeiros decorrentes desta decisão. Este estudo buscou estimar o impacto orçamentário (IO) da incorporação da tecnologia PET no estadiamento do CPCNP para os anos de 2014 a 2018, a partir da perspectiva do SUS como financiador da assistência à saúde. As estimativas foram calculadas pelo método epidemiológico e usaram como base modelo de decisão do estudo de custo-efetividade previamente realizado. Foram utilizados dados nacionais de incidência; de distribuição de doença e acurácia das tecnologias procedentes da literatura e de custos, de estudo de microcustos e das bases de dados do SUS. Duas estratégias de uso da nova tecnologia foram analisadas: (a) oferta da PET-TC a todos os pacientes; e (b) oferta restrita àqueles que apresentem resultados de TC prévia negativos. Adicionalmente, foram realizadas análises de sensibilidade univariadas e por cenários extremos, para avaliar a influência nos resultados de possíveis fontes de incertezas nos parâmetros utilizados. A incorporação da PET-TC ao SUS implicaria a necessidade de recursos adicionais de R$ 158,1 (oferta restrita) a 202,7 milhões (oferta abrangente) em cinco anos, e a diferença entre as duas estratégias de oferta é de R$ 44,6 milhões no período. Em termos absolutos, o IO total seria de R$ 555 milhões (PET-TC para TC negativa) e R$ 600 milhões (PET-TC para todos) no período. O custo do procedimento PET-TC foi o parâmetro de maior influência sobre as estimativas de gastos relacionados à nova tecnologia, seguido da proporção de pacientes submetidos à mediastinoscopia. No cenário por extremos mais otimista, os IOs incrementais reduzir-se-iam para R$ 86,9 (PET-TC para TC negativa) e R$ 103,9 milhões (PET-TC para todos), enquanto no mais pessimista os mesmos aumentariam para R$ 194,0 e R$ 242,2 milhões, respectivamente. Resultados sobre IO, aliados às evidências de custo-efetividade da tecnologia, conferem maior racionalidade às decisões finais dos gestores. A incorporação da PET no estadiamento clínico do CPCNP parece ser financeiramente factível frente à magnitude do orçamento do MS, e potencial redução no número de cirurgias desnecessárias pode levar à maior eficiência na alocação dos recursos disponíveis e melhores desfechos para os pacientes com estratégias terapêuticas mais bem indicadas.

Influência do polimorfismo genético de citocinas na hepatite C crônica em uma população do Rio de Janeiro

A infecção pelo vírus da hepatite C (VHC) é uma das mais comuns infecções ao redor do mundo. Aproximadamente, 20% dos pacientes infectados eliminam espontaneamente o vírus, porém a maioria dos indivíduos infectados desenvolve infecção crônica com amplo espectro de lesões hepáticas, desde inflamação leve até cirrose. A resposta imune do hospedeiro exerce grande influência sobre o desfecho da infecção pelo VHC. O objetivo deste trabalho foi analisar a influência dos polimorfismos genéticos de citocinas na susceptibilidade ou persistência da infecção por VHC e no clareamento espontâneo em uma amostra de pacientes da população do Rio de Janeiro (Brasil). Os polimorfismos genéticos das citocinas TNFA (-308), TGFB1 (codon 10 e 25), IL10 (-1082, -592), IL6 (-174) e IFNG (+874) foram analisados por PCR-SSP em 245 pacientes com hepatite C crônica (HCC), 41 pacientes que alcançaram o clareamento viral espontâneo e 189 indivíduos controle saudáveis. Além disso, os polimorfismos próximos ao gene da citocina IL28B (rs12979860, rs12980275 e rs8099917) foram analisados por PCR em tempo real em todos os grupos. O grau de fibrose e inflamação, a resposta ao tratamento e o genótipo do vírus também foram levados em consideração quanto ao desfecho da HCC Os genótipos IL28B rs12979860 CC e CT e rs12980275 AA e AG foram significativamente associados ao clareamento espontâneo e à resposta à terapia anti-viral. Da mesma forma, o alelo C (rs12979860) e o alelo A (rs12980275) foram significativamente maior no grupo Clareamento. O alelo C de IL6 (-174) foi associado com o Clareamento. Nenhuma associação entre as demais citocinas e o desfecho da HCC foi encontrada. O Genótipo TNFA (-308) GG parece estar associado com menor grau de inflamação. Além disso, a etnia auto declarada influencia a distribuição dos polimorfismos em IL6 (-174) e IL28B rs12979860 e rs8099917. Nossas observações indicam que os polimorfismos próximos ao gene da IL28B estão associados com o clareamento viral e resposta ao tratamento na população do Rio de Janeiro. Além disso, nossos resultados podem ser úteis para futuras investigações entre os polimorfismos de citocinas e a infecção por VHC numa população heterogênea como a Brasileira.

Avaliação por ressonância magnética funcional da necrose coagulativa por ablação de radiofrequência nas metástases hepáticas colorretais

A maioria dos pacientes que apresentam metástases hepáticas colorretais (MHCR) não são elegíveis para ressecção. Por isso, outras técnicas para se alcançar o controle locorregional da doença têm sido utilizadas. A Ablação por Radiofrequência (ARF) hepática tem sido empregada frequentemente para o tratamento desta condição devido às boas taxas de resposta, principalmente quando associada ao emprego de quimioterápicos modernos. Apesar da caracterização das MHCR no pré-operatório estar bem estabelecida, os parâmetros de ressonância magnética (RM) após ARF no período pós-cirúrgico requerem maior padronização objetiva. O coeficiente de difusão aparente de água (CDA) tem sido usado na RM como um parâmetro de isquemia e necrose. Entretanto, não está ainda bem definido seu papel e das imagens ponderadas de difusão (DWI) na avaliação da necrose coagulativa gerada pela ARF, especificamente em pacientes com MHCR. O objetivo deste estudo consiste em avaliar o espectro de mudança em RM funcional após a ARF de MHCR. Foi realizado estudo retrospectivo entre 2001 e 2006, avaliando 51 pacientes que foram submetidos à ARF por MHCR no Hospital Johns Hopkins (Baltimore, EUA) dos quais 16 preencheram os critérios de inclusão. Os critérios de inclusão foram: (1) apresentar MHCR tratada cirurgicamente com intenção curativa por ARF guiados por ultrassom per-operatório, e (2) ter uma RM anterior e imediatamente após a cirurgia (até 10 dias). As imagens de RMs antes e após a ablação hepática para MCHR foram identificadas e revistas. As imagens de RM de difusão e captação de contraste foram feitas numa unidade de 1.5 T. Imagens em T2 e T1 foram realizadas na presença e ausência de contraste venoso. Todos os exames tiveram a espessura de 4 a 6 mm e um intervalo de 2 mm, apresentando um angulo de rotação de 150. O índice de difusão foi determinado com um b-valor (intensidade do gradiente de difusão) de 500 seg/mm2. As análises de parâmetros para avaliar e comparar o pré e pós ARF através da RM funcional incluiram: (1) valores do mapa de CDA, (2) captação de contraste, (3) difusão e (4) mudança no tamanho da lesão. Em adição, a sobrevida mediana global e tempo para recorrência local foram calculados. As imagens foram avaliadas por um consenso de dois radiologistas/cirurgiões. Foram avaliados no total 65 lesões, com tamanho médio pré-ablação de 1,7 cm. Após ablação o tamanho médio da lesão aumentou para 3,5 cm (p<0,001). A captação de contraste nas fases arterial e venosa diminuíram significativamente após ARF (diminuição média 10% e 17,5%, respectivamente, p = 0,002 e <0,001). O valor médio do mapa de CDA da lesão foi de 2.79 x 10-3 mm2/seg pré-ARF, e após ARF diminui em média para 1.75 x 10-3 mm2/seg (p<0.001). A sobrevida mediana global foi de 34,7 meses. A ressonância magnética funcional através da captação de contraste e difusão pode prover uma estimativa subjetiva e objetiva da necrose coagulativa tissular e da desidratação celular na área ablada por radiofrequência. Quando combinada ao aumento no tamanho do tumor, podem atuar como um marcador adicional de resposta tumoral.

Sex-specific growth and mortality, spawning season, and female maturation of the stripey bass (Lutjanus carponotatus) on the Great Barrrier Reef

Sex-specific demography and reproductive biology of stripey bass (Lutjanus carponotatus) (also known as Spanish flag snapper, FAO) were examined at the Palm and Lizard island groups, Great Barrier Reef (GBR).Total mortality rates were similar between the sexes. Males had larger L∞ at both island groups and Lizard Island group fish had larger overall L∞. Female:male sex ratios were 1.3 and 1.1 at the Palm and Lizard island groups, respectively. The former is statistically different from 1, but is unlikely significantly different in a biological sense. Females matured on average at 2 years of age and 190 mm fork length at both locations. Female gonadal lipid body indices peaked from August through October, preceding peak gonadosomatic indices in October, November, and December that were twice as great as in any other month. However, ovarian staging revealed 50% or more ovaries were ripe from September through February, suggesting a more protracted spawning season and highlighting the different interpretations that can arise between gonad weight and gonad staging methods. Gonadosomatic index increases slightly with body size and larger fish have a longer average spawning season, which suggests that larger fish produce greater relative reproductive output. Lizard Island group females had ovaries nearly twice as large as Palm Island group females at a given body size. However, it is unclear whether this reflects spatial differences akin to those observed in growth or effects of sampling Lizard Island group fish closer to their date of spawning. These results support an existing 250 mm minimum size limit for L. carponotatus on the GBR, as well as the timing of a proposed October through December spawning closure for the fishery. The results also caution against assessing reef-fish stocks without reference to sex-, size-, and location-specific biological traits.

Embryonic stages and eye-specific gene expression of the local cyprinoid fish Anabarilius grahami in Fuxian Lake, China

Anabarilius grahami is a cyprinoid fish endemic to Fuxian Lake, Yunnan, China. In this study, a comprehensive staging series of A. grahami was produced. The embryonic development of A. grahami was divided into six main periods: zygote period, cleavage per

Study on the reproductive biology of Pinctada fucata (Gould) (Mollusca: Pteriidae)

Annual cycle of gonad development and spawning in pearl oyster, Pinctada ficata (Gould) in Nakhiloo, Northeast Persian Gulf, was investigated over two years from August 1994 to June 1996. Gonadal condition was assessed by staging criteria to describe gametogenic development from histological preparations of randomly collected individuals of all sizes. A bimodal gametogenic pattern with summer and autumn spawning periods was evident throughout the study. Gametogensis commenced in November-December which proceeded by major gonadal maturation during February-April. Summer spawning was observed from April to July with major spawning at the latter end. During spawning peak in July, low level of gametogensis was noticed. Gametogenic activity was picked up again in August-September which proceeded by autumn spawning from September to December. Towards the end of spawning season, incidence of gonadal inactivation increased. Minimum level of gonadal activity was observed in November. Temperature regime appears to have influential role in regulation of gametogenic and spawning processes. Gonadal development and spawning trends were similar in both sexes. P. radiaata was found to be protandrous hermaphrodite which matured as a male at shell height greater than 20 mm. Biseivality was uncommon and the sex ratio was about 1:1. Ultrastructure of gametes were investigated in the Pictada fucata (Gould). "Auxiliary cells" closely accociated with developing oocytes were observed. Each oocyte seems to be associated with only one secretory cell. which is characterized by an abundant rough endoplasmic reticulum at the onset of vitellogenesis. Contact between this cell and a developing oocytes is maintained by a desmosome-like junction which can be observed when the vitelline coat is formed. these "auxiliary or nursing cells" seem to play a tropic role in vitellogenesis, and may be involved in the formation of the vitelline coat of the oocytes. Oocytic degeneration is observed in this species, it is a continuous phenomenon of varing intensity throughout the year. The ultrastructural changes resulting in lysis of the oocyte are described. Mature spermatozoa consist of a broad, cap-shaped acrosomal vesicle, subacrosomal material, a round nucleus, two triplet substructure centrioles surrounded by four spherical mitochondria, and a flagellum anchored to the distal centriole and plasma membrane. Spermatozoa of Plucata closley resemble to those of other investigated Pteriidae. Changes in proximate composition of soft tissue and gonadal cycle of Pinctada fucata was studied. Mobilization and utilization of stored reserves are apparent during gametogenesis and gonadal maturation. Protein reserves are utilized during spermatogenesis while reserved carbohydrates form the main energy donor in oogenesis. The role of lipid as am.: energy reserve is second to that of carbohydrate.

Phenotypic plasticity of gut structure and function during periods of inactivity in Apostichopus japonicus

Apostichopus japonicus is a common sea cucumber that undergoes seasonal inactivity phases and ceases feeding during the summer months. We used this sea cucumber species as a model in which to examine phenotypic plasticity of the digestive tract in response to food deprivation. We measured the body mass, gross gut morphology and digestive enzyme activities of A. japonicus before, during, and after the period of inactivity to examine the effects of food deprivation on the gut structure and function of this animal. Individuals were sampled semi-monthly from June to November (10 sampling intervals over 178 days) across temperature changes of more than 18 degrees C. On 5 September, which represented the peak of inactivity and lack of feeding, A. japonicus decreased its body mass, gut mass and gut length by 50%, 85%, and 70%, respectively, in comparison to values for these parameters preceding the inactive period. The activities of amylase, cellulase and lipase decreased by 77%, 98%, and 35% respectively, in comparison to mean values for these enzymes in June, whereas pepsin activity increased two-fold (luring the inactive phase. Alginase and trypsin activities were variable and did not change significantly across the 178-day experiment. With the exception of amylase and cellulase, all body size indices and digestive enzyme activities recovered and even surpassed the mean values preceding the inactive phase during the latter part of the experiment (October-November). Principal Component Analysis (PCA) utilizing the digestive enzyme activity and body size index data divided the physiological state of this cucumber into four phases: an active stage, prophase of inactivity peak inactivity, and a reversion phase. These phases are all consistent with previously suggested life stages for this species, but our data provide more defined characteristics of each phase. A. japonicus clearly exhibits phenotypic plasticity (or life-cycle staging) of the digestive tract during its annual inactive period. (C) 2008 Elsevier Inc. All rights reserved.

东天山镁铁-超镁铁岩铜镍硫化物矿床通道式成矿机制与岩体含矿性评价研究

A mafic-ultramafic complex belt well developed in Eastern Tianshan, Xinjiang, NW China, which contains a series of Cu-Ni sulfide deposits. This area is the important production basis for Cu-Ni deposits, including Tulargen deposit, Hulu deposit, Huangshan-Huangshandong deposit, Hulu deposit, Xiangshan deposit, Tianyu deposit, Chuanzhu deposit. In China, especially Eastern Tianshan, it is prevalent that large Cu-Ni deposits occurred in small intrusions, typically including Jinchuan, Kalatongke, et al., so the ore-forming mechanism and evaluation rule for those small intrusions are very meaningful and of universal significance. On the basis of the research to typical Cu-Ni deposits, ore-forming conditions and processes are summarized through which to evaluate the ore-bearing potential for barren intrusions and unexplored mafic-ultramafic intrusions. By the contrast, metallogenic rule and mechanism of ore genesis are concluded, and evaluation system is preliminarily set up on the basis of these conclusions. Quantitatively simulation for the composition of olivine is introduced for the first time in China to discuss the interaction between magma and sulfide, and a new method to calculate the Mg-Fe composition of primitive magma is developed. Interaction between magma and sulfide liquid is used to get the Ni content in sulfide liquid. Sulfur isotopic characteristics in sulfide minerals in country rocks and ores are used to judge crustal sulfur introduction, which is applied for the first time in China. Re-Os isotopic characteristics are related to the ore-forming process, to interpret the process of enrichment of chalcophile elements. On the basis of the evaluation system, Mati, Chuanzhu, Luodong, Xiadong, those intrusions are evaluated to their ore-bearing potential. According to the studies to typical Cu-Ni deposits, conduit-type ore-forming model is set up, and the characteristics of the model are concluded systematically. The evaluation system and conduit-type ore-forming model can be helpful to the evaluation of mafic-ultramafic intrusions in this and similar mafic-ultramafic intrusion belts. The studied typical deposits and mafic-ultramafic intrusion include Tulargen deposit, Hulu deposit, Huangshandong deposit, Chuanzhu deposit, Mati intrusion，Luodong intrusion, Xiadong intrusion, and others. Through studies, there are similar characteristics for Tulargen and Hulu deposits in magma origin, composition of primitive magma（MgO=12.5%, FeO=12% and MgO=11%, FeO=10.5% respectively）, magma evolution, mechanism of sulfide segregation and conduit-type ore-forming process. By Re-Os isotopic system, the ore forming date of Tulargen deposit is 265.6±9.2Ma, which is consistent to regional metallogenic event, but little younger. The Mg-Fe composition of primitive magma of Baishiquan, Huangshandong area, Kalatongke is lower than that of Tulargen and Hulu deposit, showing common basalt composition. The Mg# value（Mg#=(Mg/Mg+Fe）increases gradually from Kalatongke to Baishiquan to Huangshan-Huangshandong East. Baishiquan intrusions show relatively higher crustal contamination by evidence of trace element, which indicates the lower magma original source, from depleted mantle to crust. One break is the discovery of komatiitic intrusion, Xiadong intrusion, which shows characteristics of highly magnesium (Max Fo=96). The primitive magma is calculated of MgO=28%，FeO=9%, belonging to komatiitic magma. Tectonic evolution of Eastern Tianshan is discussed. By the statistics of ore-forming data of porphyry copper deposits, magmatic sulfide Cu-Ni deposits, orogenic hydrothermal gold deposits, we believe that those deposits are the successive products of oceanic subduction, are and back-arc basin collision and post-orogenic extention. And Cu-Ni sulfide deposits and orogenic gold deposits occurred in the stage of post-orogenic extention. According to the conclusions, the conduit-type ore-forming mechanism of magmatic sulfide deposit is set up, and its characteristics and conditions are concluded as well. The conduit-type ore-forming system includes magma generation, sulfide segregation, enrichment of chalcophile elements, interaction of sulfide and magma, sulfide collection in limited space in magma conduit and bottom of the chamber, which make a whole ore-forming system.The ore-forming process of Cu-Ni sulfide deposits is concluded as three steps: 1. mantle derived magma rises upward to the middle-upper crust; 2. magma suffers crustal contamination of different degrees and assimilates crustal sulfur, which leads to sulfur saturation and sulfide segregation. Sulfide liquid interacts with magma and concentrates chalcophile elements; 3. enriched sulfide located in the conduit(Tulargen) or bottom of the chamber (Hulu). Depleted magma rises upward continuously to form barren complexes. For the practical cases, Tulargen deposit represents the feeding conduit, and Hulu deposit represents the bottom of the staging magma chamber. So the deeper of west of Tulargen and southwest of Hulu are the favorite locate for ore location. The evaluation for ore potential can be summarized as follows: (1) Olivine can be served as indicator for magma evolution and events of sulfide segregation; (2) Sulfur isotopic characteristics is an efficient method to judge sulfur origin for magmatic sulfide deposit; (3) Re-Os content of the ores can indicate interaction between sulfide and silicate magma and crustal contamination; (4) PGE mineralization is effected by degree of partial melting of mantle; (5) Cu/Zr is efficient parameter to judge sulfide segregation; (6) The effects of multiple magma fractionation and emplacement are important, for inverse order shows the destruction to previous solid lithofacies and orebodies. Mati, Chuanzhu, Xiadong, Luodong, mafic-ultramafic intrusions are evaluated using evaluation system above. Remarkable Ni depletion is found in olivine of Mati, and southwest of the intrusion can be hopeful location for ore location. Chuanzhu intrusion has remarkable evidence of sulfide segregation, but the intrusion represents the narrow feeder conduit, so the wide part of the conduit maybe the favorite location for sulfide to deposit. The ore potential of Luodong and Xiadong is not good. Both the intrusions show no Ni depletion in olivine, and there is no sulfide in country rocks, so no crustal sulfur is added into the magmatic system. For Sidingheishan, a very large intrusion, the phenomenon of sulfide segregation is found, but there are no favorite places for sulfide to deposit. So the Cu-Ni ore potential maybe not good, but PGE mineralization should be evaluated further.

Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organization for Research and Treatment of Cancer Randomized Study with cross-over.

PURPOSE: To compare the efficacy of paclitaxel versus doxorubicin given as single agents in first-line therapy of advanced breast cancer (primary end point, progression-free survival ¿PFS) and to explore the degree of cross-resistance between the two agents. PATIENTS AND METHODS: Three hundred thirty-one patients were randomized to receive either paclitaxel 200 mg/m(2), 3-hour infusion every 3 weeks, or doxorubicin 75 mg/m(2), intravenous bolus every 3 weeks. Seven courses were planned unless progression or unacceptable toxicity occurred before the seven courses were finished. Patients who progressed within the seven courses underwent early cross-over to the alternative drug, while a delayed cross-over was optional for the remainder of patients at the time of disease progression. RESULTS: Objective response in first-line therapy was significantly better (P =.003) for doxorubicin (response rate ¿RR, 41%) than for paclitaxel (RR, 25%), with doxorubicin achieving a longer median PFS (7.5 months for doxorubicin v 3.9 months for paclitaxel, P <.001). In second-line therapy, cross-over to doxorubicin (91 patients) and to paclitaxel (77 patients) gave response rates of 30% and 16%, respectively. The median survival durations of 18.3 months for doxorubicin and 15.6 months for paclitaxel were not significantly different (P =.38). The doxorubicin arm had greater toxicity, but this was counterbalanced by better symptom control. CONCLUSION: At the dosages and schedules used in the present study, doxorubicin achieves better disease and symptom control than paclitaxel in first-line treatment. Doxorubicin and paclitaxel are not totally cross-resistant, which supports further investigation of these drugs in combination or in sequence, both in advanced disease and in the adjuvant setting.

An EORTC-IDBBC phase I study of gemcitabine and continuous infusion 5-fluorouracil in patients with metastatic breast cancer resistant to anthracyclines or pre-treated with both anthracyclines and taxanes.

The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and potential activity of combined gemcitabine and continuous infusion 5-fluorouracil (5-FU) in metastatic breast cancer (MBC) patients that are resistant to anthracyclines or have been pretreated with both anthracyclines and taxanes. 15 patients with MBC were studied at three European Organization for Research and Treatment of Cancer centres. 13 patients had received both anthracylines and taxanes. Gemcitabine was given intravenously (i.v.) on days 1 and 8, and 5-FU as a continuous i.v. infusion on days 1 through to 14, both drugs given in a 21-day schedule at four different dose levels. Both were given at doses commonly used for the single agents for the last dose level (dose level 4). One of 6 patients at level 4 (gemcitabine 1200 mg/m2 and 5-FU 250 mg/m2/day) had a DLT, a grade 3 stomatitis and skin toxicity. One DLT, a grade 3 transaminase rise and thrombosis, occurred in a patient at level 2 (gemcitabine 1000 mg/m2 and 5-FU 200 mg/m2/day). Thus, the MTD was not reached. One partial response and four disease stabilisations were observed. Only 1 patient withdrew from the treatment due to toxicity. The MTD was not reached in the phase I study. The combination of gemcitabine and 5-FU is well tolerated at doses up to 1200 mg/m2 given on days 1 and 8 and 250 mg/m2/day given on days 1 through to 14, respectively, every 21 days. The clinical benefit rate (responses plus no change of at least 6 months) was 33% with one partial response, suggesting that MBC patients with prior anthracycline and taxane therapy may derive significant benefit from this combination with minimal toxicity.

A joined analysis of two European Organization for the Research and Treatment of Cancer (EORTC) studies to evaluate the role of pegylated liposomal doxorubicin (Caelyx) in the treatment of elderly patients with metastatic breast cancer.

We have performed a retrospective analysis to evaluate the impact of age, using a 70 year cutoff, on the safety and efficacy of pegylated liposomal doxorubicin (Caelyx) given at 60 mg/m(2) every 6 weeks (treatment A) or 50 mg/m(2) every 4 weeks (treatment B) to 136 metastatic breast cancer patients in two EORTC trials, of whom 65 were 70 years of age or older. No difference in terms of toxicity was observed between younger and older patients treated with the 4-week schedule, while a higher incidence of hematological toxicity, anorexia, asthenia, and stomatitis was observed in older patients when the 6-week schedule was used. Antitumor activity was not affected by age. In the older cohort of patients, no dependence was found between the incidence of grade 3-4 toxicity or antitumor activity and patients' baseline performance status, number and severity of comorbidities, or number of concomitant medications. The higher therapeutic index of Caelyx 50 mg/m(2) every 4 weeks makes it, of the two dose schedules investigated, the preferred regimen in the elderly.