Prevalence of vascular-endothelial growth factor, matrix metalloproteinases and tissue inhibitors of metalloproteinases in primary breast cancer

Our objective was to determine the presence of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2) and MMP-9 and specific tissue inhibitors of matrix metalloproteinase (TIMP-1 and TIMP-2) in tumor samples obtained from patients with primary breast cancer. We attempted to correlate these findings with the status of the sentinel lymph node (SLN) and clinical-pathological characteristics such as age, tumor size, histological type, histological grade, and vascular invasion. Tumor samples from 88 patients with primary breast cancer were analyzed. The immunoreactivity of VEGF, MMP-2, MMP-9, TIMP-1, and TIMP-2 in tumors was correlated with clinical and pathological features, as well as SLN status. Nonparametric, Mann-Whittney, Kruskal-Wallis, and Spearmann tests were used. Categorical variables were analyzed by the Pearson test. No statistically significant correlation was found between the amount of VEGF, MMP-2, MMP-9, TIMP-1, and TIMP-2 and the presence of tumor cells in the SLN. However, larger tumor diameter (P < 0.01) and the presence of vascular invasion (P < 0.01) were correlated positively with a positive SLN. A significant correlation of higher VEGF levels (P = 0.04) and lower TIMP-1 levels (P = 0.04) with ductal histology was also observed. Furthermore, lower TIMP-2 levels showed a statistically significant correlation with younger age (<50 years) and larger tumor diameter (2.0-5.0 cm). A positive SLN correlated significantly with a larger tumor diameter and the presence of vascular invasion. Higher VEGF and lower TIMP-1 levels were observed in patients with ductal tumors, while higher TIMP-1 levels were observed in lobular tumors.

Cáncer de mama Latinoamericano / Breast cancer in Latin America

La incidencia del cáncer de mama en países latinoamericanos es menor que en países más desarrollados, mientras que la tasa de mortalidad es mayor. Estas diferencias están relacionadas probablemente con diferencias en estrategias de despistaje y acceso al tratamiento. Se necesitan datos basados en población a fin de que sea posible tomar decisiones informadas. En el año 2006 se llevó a cabo una encuesta telefónica de 65 preguntas, que incluyó a 100 expertos en cáncer de mama de 12 países latinoamericanos, efectuando un análisis exploratorio del estado actual del tratamiento de cáncer de mama en estas regiones, tanto a nivel país como a nivel centro. Más del 90% de los países no tienen ley nacional o guía para screening mamográfico. La tasa de acceso a mamografía fue del 66,3% a nivel país y del 47,0% a nivel centro. La diferencia en la atención, basada en el nivel (país versus centro), fue indicada por la iniciación del tratamiento luego del diagnóstico, el tiempo desde el diagnóstico inicial al tratamiento y el tiempo desde la cirugía hasta la quimioterapia inicial. Sin embargo, las pruebas diagnósticas más sofisticadas para receptores hormonales y moleculares están disponibles en la mayoría de los centros (>80%), y en total, casi el 80% de las pacientes comenzaron el tratamiento dentro de los 3 meses del diagnóstico. La variación en la atención entre el nivel del centro versus el nivel del país para la atención del cáncer de mama, indica una necesidad de programas nacionales para el cuidado del cáncer. También se concluye que son necesarias estrategias alternativas de recolección de datos, a fin de comprender mejor el estado de los programas de control del cáncer de mama en países en desarrollo

Potentiation of carbon tetrachloride hepatotoxicity by pentosan polysulfate in rats

Few data are available in the literature regarding the effect of pentosan polysulfate (PPS) on normal and fibrotic rat livers. In addition, the combination of PPS and carbon tetrachloride (CCl4) has not been studied so far. The objective of this study was to assess the effect of PPS on rat livers treated or not with CCl4 for the induction of liver fibrosis. The study consisted of four stages: 1) hepatic fibrosis induction with CCl4 (N = 36 rats); 2) evaluation of the effect of PPS on CCl4-induced hepatic fibrosis (N = 36 rats); 3) evaluation of the effect of higher doses of PPS in combination with CCl4 (N = 50 rats); 4) evaluation of the presence of an enzymatic inductor effect by PPS (N = 18 rats) using the sodium pentobarbital test which indirectly evaluates hepatic microsomal enzyme activity in vivo. Adult (60 to 70 days) male Wistar rats weighing 180 to 220 g were used. All animals receiving 0.5 ml 8 percent CCl4 (N = 36) developed hepatic fibrosis, and after 8 weeks they also developed cirrhosis. No delay or prevention of hepatic fibrosis was observed with the administration of 5 mg/kg PPS (N = 8) and 1 mg/kg PPS (N = 8) 1 h after the administration of CCl4, but the increased hepatotoxicity resulting from the combination of the two substances caused massive hepatic necrosis in most rats (N = 45). PPS (40 mg/kg) alone caused hepatic congestion only after 8 weeks, but massive hepatic necrosis was again observed in association with 0.5 ml CCl4 after 1 to 4 weeks of treatment. Unexpectedly, sleeping time increased with time of PPS administration (1, 2, or 3 weeks). This suggests that PPS does not function as an activator of the hepatic microsomal enzymatic system. Further studies are necessary in order to clarify the unexpected increase in hepatotoxicity caused by the combination of CCl4 and high doses of PPS, which results in massive hepatic necrosis

Irinotecan and oxaliplatin: an overview of the novel chemotherapeutic options for the treatment of advanced colorectal cancer

Colorectal cancer is one of the most frequent malignancies in humans and an important cause of cancer death. Metastatic colorectal cancer remains incurable with available systemic therapeutic options. The most active cytotoxic drug against this malignancy, the antimetabolite 5-fluorouracil, was developed more than forty years ago, and as a single agent produces responses in only 10 to 15 percent of patients which in general last less than one year. Efforts to ameliorate these poor results resulted in the 5-fluorouracil/leucovorin combination, which enhances response rates about two-fold, without, however, significantly improving survival rates. The recent emergence of a handful of new 5-fluorouracil analogues and folate antagonists, as well as the topoisomerase I inhibitor irinotecan, and the third-generation platinum compound oxaliplatin, is likely to alter this gloomy scenario. These agents are at least as effective as 5-fluorouracil in patients with advanced colorectal carcinoma, both untreated and previously treated with 5-fluorouracil-based regimens. This has led to the approval of irinotecan as second-line treatment for 5-fluorouracil-refractory disease, while the use of oxaliplatin has been suggested for patients having a defective 5-fluorouracil catabolism. Recently, FDA approved the combination of irinotecan with 5-fluorouracil and leucovorin for first-line treatment of advanced colon cancer. Based on the synergistic preclinical antitumor effects of some of these agents, their meaningful single-agent activity, distinct mechanisms of cytotoxicity and resistance, and only partially overlapping toxicity profiles, effective combination regimens are now being developed, which are likely to lead to a new, more hopeful era for patients suffering from advanced colorectal carcinoma

von Willebrand factor antigen levels in plasma of patients with malignant breast disease

von Willebrand factor (vWF) is a protein that mediates platelet adherence to the subendothelium during primary hemostasis. High plasma vWF concentrations have been reported in patients with various types of cancer, such as head and neck, laryngeal and prostatic cancer, probably representing an acute phase reactant. In the present study we determined the plasma levels of vWF antigen (vWF:Ag) by quantitative immunoelectrophoresis in 128 female patients with breast cancer as well as in 47 women with benign breast disease and in 27 healthy female controls. The levels of vWF:Ag were 170.7 + or - 78 U/dl in patients with cancer, 148.4 + or - 59 U/dl in patients with benign disease and 130.6 + or - 45 U/dl in controls (P<0.005). We also detected a significant increase in the levels of vWF:Ag (P<0.0001) in patients with advanced stages of the disease (stage IV = 263.3 + or - 113 U/dl, stage IIIB = 194.0 + or - 44 U/dl) as compared to those with earlier stages of the disease (stage I = 155.3 + or - 65 U/dl, stage IIA = 146.9 + or - 75 U/dl). In conclusion, vWF levels were increased in plasma of patients with malignant breast disease, and these levels correlated with tumor progression

Intercellular contact-dependent survival of human A549, NCI-H596 and NCI-H520 non-small cell lung carcinoma cell lines

In the present study, we examined the relationship between cell phenotype and cell survival of three human non-small cell lung carcinoma cell lines (A549, NCI-H596 and NCI-H520). Cells in exponential growth at various densities were incubated for 24 h at 37ºC in a 5 percent CO2 humidified atmosphere and then exposed to UV radiation for 1 min (256 nm, 40 W, source-to-target distance 100 cm). After two days the surviving cells were quantified by sulforhodamine á staining and DNA fragmentation assay. The differences in UV sensitivity at 60 x 10(3) cells/cm(2) among the cell lines were not related to the proliferative state of the cells but to the extent of intercellular contact. In contrast to A549 and NCI-H596, irradiated NCI-H520 cells presented lower DNA fragmentation and an aggregated cell culture phenotype even prior to confluence, suggesting that a contact-effect mechanism provides further protection against UV radiation

Postangioplasty restenosis: a practical model in the porcine carotid artery

Transluminal coronary angioplasty is a routine therapeutic intervention in coronary heart disease. Despite the high rate of primary success, restenosis continues to be its major limitation. Porcine models have been considered to be the most adequate experimental models for studying restenosis. One limitation of porcine models is the need for radiological guidance and the expenses involved. The objective of the present study was to adapt an experimental model of angioplasty in the porcine carotid artery that does not require radiological equipment. Eight animals were used to develop the technique of balloon injury to the common carotid artery by dissection without radiological guidance. This technique was then employed in six other animals. Under anesthesia, the left common carotid artery was dissected and incised at the carotid sinus for insertion of an over-the-wire angioplasty balloon towards the aorta. Overstretch injury of the carotid artery was performed under direct visualization. After 30 days, the arteries were excised and pressure-fixated. Uninjured carotid arteries from 3 additional animals were used as controls. A decreased luminal area associated with intimal hyperplasia and medial reaction was observed in all injured arteries. Immunohistochemistry identified the intimal hyperplastic cells as smooth muscle cells. Computerized morphometry of the ballooned segments revealed the following mean areas: lumen 2.12mm2 (+ 1.09), intima 0.22mm2 (+ 0.08), media 3.47mm2 (+ 0.67), and adventitia 1.11mm2 (+ 0.34). Our experimental model of porcine carotid angioplasty without radiological guidance induced a vascular wall reaction and permitted the quantification of this response. This porcine model may facilitate the study of vascular injury and its response to pharmacological interventions.

A phase II study of recombinant interleukin-2 (IL-2) plus interferon-alfa-2A (IFN-ALFA) given subcutaneously in patients with metastatic malignant melanoma (MMM)

O objetivo deste estudo foi avaliar o perfil de toxicidade, índices de respostas objetivas e sobrevida de pacientes portadores de melanoma maligno metastático tratados com a combinação de Interleucina-2 (IL-2)e Interferon-alfa (IFN-alfa) administrados por via subcutânea (SC). Vinte e cinco pacientes com diagnóstico histopatológico de melanoma maligno metastático e doença mensurável foram tratados com IL-2 na dose de 18 milhões de unidades/m2 e IFN-alfa na dose de 3 milhões de unidades/m2 por via SC diariamente nos dias 1-5 e 8-12 de ciclos com 21 dias. Os pacientes foram todos avaliáveis quanto a toxicidade de acordo com o Common Toxicity Criteria do Instituto Nacional do Câncer dos EUA (CTC-NCI), enquanto que as respostas foram codificadas segundo os critérios da OMS. Os pacientes não haviam recebido tratamento químico, rádio ou imunoterápico prévio. Uma mediana de 3 (2-4) ciclos foram administrados. A toxicidade consistiu sobretudo de fadiga, artralgia, mialgias, febre e calafrios e retenção líquida. Não foram observadas toxicidades com risco severo de óbito. Quatro dos 25 pacientes (17 por cento) apresentaram respostas objetivas. Em 2 destes casos foi possível a ressecção completa de massas residuais pós-tratamento imunoterápico, com remissões mantidas por 6 e 24+ meses, respectivamente. Nos outros 2 casos com resposta parcial, progressão clínica foi observada após 7 e 8 meses, respectivamente. Os pacientes que não responderam inicialmente ou apresentaram progressão posterior foram ao óbito após um seguimento mediano de 3 (1-7) meses. Em conclusão, a combinação de IL-2 e IFN-alfa por via SC produziu respostas limitadas em pacientes com melanoma maligno metastático. Ainda que a toxicidade tenha sido manejável, os resultados acima descritos não recomendam esta abordagem para uso clínico de rotina.

Clorambucil-cisplatinum versus clorambucil-cisplatinum-adriamicina em carcinoma avancado de ovario: avaliacao de resultados a longo prazo. / Chlorambucil - cisplatinum versus chlorambucil-cisplatinum - adriamycin in advanced ovarian carcinoma:evaluation of long-term results

Cento e uma pacientes com carcinoma avancado de ovario foram estudadas prospectivamente atraves de dois regimes quimioterapicos: Regime A, contendo cisplatinum em doses baixas e clorambucil, e Regime B, contendo ambas as drogas acrescidas de adriamicina. As taxas de resposta e proporcao de respostas completas foram semelhantes em ambos os grupos. A duracao media das remissoes para pacientes com resposta completa foi superior a 35 meses em ambos os grupos. A analise apos cinco anos revelou que apenas sete das 101 pacientes permanecem vivas e todas em remissao completa da doenca