Insulin-like growth factor binding protein-3 and insulin receptor substrate-1 in breast cancer: correlation with clinical parameters and disease-free survival.

Insulin-like growth factors (IGFs) interact with specific cell surface receptors to mediate cell growth. Intracellular effects of the IGFs are mediated by activation of secondary messenger molecules. One of these proteins, insulin receptor substrate-1 (IRS-1), is phosphorylated after type I IGF receptor activation and has a major role in IGF signaling. Receptor activation also is influenced by high-affinity IGF binding proteins (IGFBPs). In serum, IGFBP-3 is the predominant species. The role of IGFBP-3 in the regulation of breast cancer cell growth is unclear; both growth inhibition and stimulation have been documented in tissue culture systems. To investigate the influence of IGFBP-3 and IRS-1 in breast cancer, we measured levels of these proteins by ELISA and immunoblotting in 195 node-negative primary human breast cancers and compared their levels with known prognostic factors and disease-free survival (DFS). IGFBP-3 levels correlated positively with tumor size (r = 0.27, P < 0.0001) and negatively with estrogen receptor (r = -0.35, P < 0. 0001) and progesterone receptor (r = -0.16, P = 0.021). In contrast, IRS-1 did not correlate with prognostic factors, but higher levels of IRS-1 predicted worse DFS for the subset of patients with tumors

Correlation of insulin-like growth factor-binding protein-3 messenger RNA with protein expression in primary breast cancer tissues: detection of higher levels in tumors with poor prognostic features.

BACKGROUND: The insulin-like growth factor (IGF)-binding proteins (IGFBPs) regulate the actions of the IGFs by influencing interactions between the IGFs and the IGF receptors. IGFBP-3, one of the six known species of IGFBPs, is the predominant IGFBP in serum and is expressed by breast cancer cells. Compared with estrogen receptor (ER)-positive samples, ER-negative breast cancer cell lines and tumors express higher levels of IGFBP-3. Therefore, expression of IGFBP-3 may be relevant in breast cancer biology, although it is unknown whether IGFBP-3 levels correlate with other breast cancer prognostic factors besides ER status. It is also not known how different methods used to measure IGFBP-3 in breast cancer correlate. PURPOSE: We measured IGFBP-3 messenger RNA (mRNA) and protein levels in breast tumors by different methods to test how these methods compare and to investigate the relationship between IGFBP-3 and breast cancer prognostic factors. METHODS: We analyzed 40 human breast tumors and examined IGFBP-3 expression by ligand blot analysis, immunoblot analysis, immunoradiometric assay (IRMA), and ribonuclease protection assay. Another set of 40 breast tumors, selected according to ER and progesterone receptor (PR) status, S phase, and ploidy, was analyzed by IRMA. RESULTS: In 26 (65%) of 40 samples in which RNA could be isolated, IGFBP-3 mRNA levels correlated with IGFBP-3 levels measured by IRMA (two-sided; P = .0001) but not with IGFBP-3 levels measured by ligand blot or immunoblot. Protein levels were highly correlated among all protein assays. Because the IRMA was more sensitive and accurate than the ligand blot and immunoblot assays, we used IRMA to examine IGFBP-3 levels in an additional 20 primary breast tumors with poor prognostic features (ER and PR negativity, high S phase, and aneuploidy) and in 20 tumors with good prognostic factors (opposite features). IGFBP-3 levels were threefold higher in tumors with poor prognostic features (mean +/- standard deviation = 32.8 +/- 25.2 versus 11.8 +/- 9.7 ng/mg; two-sided; P = .003). CONCLUSIONS: These findings suggest that in human breast cancer, IGFBP-3 mRNA and protein levels are correlated and higher levels of IGFBP-3 are detectable in tumors with poor prognostic features. IMPLICATIONS: IGFBP-3 may be involved in the regulation of breast cancer cell growth.

Pathogenetic factors of acute schistosomiasis mansoni: correlation of worm burden, IgE, blood eosinophilia and intensity of clinical manifestations.

A clinical study of 34 previously healthy young patients simultaneously infected in an endemic area of schistosomiasis mansoni is presented, emphasizing the initial phase of the infection. Its intensity was established according to the occurrence, intensity, and duration of the signs and symptoms in order to investigate the possible correlations between the worm burden (estimated by the number of eggs in faeces), the blood eosinophilia and specific levels of IgE (estimated by the area of immediate intradermal reaction), with the clinical manifestations. A significant but low-level association was found between the worm burden and morbidity, suggesting that multiple factors, besides worm burden itself, may contribute to the pathogenesis of the disease.

Secondary cutaneous manifestations of acute schistosomiasis mansoni.

The secondary cutaneous manifestations of the initial phase of schistosomiasis mansoni were studied in 34 patients who had been infected simultaneously in the same location. Sixteen of the patients developed angioedema and/or urticaria, generally of short duration and of mild intensity and usually about 30 days post-infection. There was no apparent association between the occurrence of these skin manifestations and the patients' worm burdens, blood eosinophilias or areas of immediate reaction to an intradermal inoculation with worm antigen. Other factors, particularly host immunological reactivity, are thought to be important elements in the genesis of the manifestations.

Pulmonary manifestations in the initial phase of schistosomiasis mansoni.

The clinical and radiological pulmonary manifestations in the initial phase of schistosomiasis mansoni were studied in thirty previously healthy individuals who were simultaneously infected. The findings were compared with those concerning a control group and related to possible pathogenetic factors. The respiratory manifestations were of light or of moderate intensity, the dry cough being the most common symptom. The significant radiological alterations were: thickening of bronchial walls and beaded micronodulation, predominantly localized in the lower pulmonary fields. It was observed significant association between wheezing and IgE levels, estimated by the area of immediate intradermal reaction, as well as between the number of blood eosinophils and the occurrence of radiological changes. Moreover, there was correlation between the worm burden and the presence of wheezing, thoracic pain and beaded micronodulation. Thus, the clinical and radiological pulmonary manifestations described are significant part of the initial phase of schistosomiasis mansoni and present the worm burden, eosinophilia and levels of IgE as probable pathogenetic factors.

Egg excretion in the initial phase of experimental murine schistosomiasis mansoni: stability and association with worm burden.

Stability of faecal egg excretion and correlation with results related to worm burden at the initial phase of schistosomiasis mansoni were observed in two groups of mice infected with different Schistosoma mansoni cercarial burdens, by means of analysis of quantitative parasitological studies and schistosome counts after perfusion. Thus, it may be stated that few quantitative parasitological stool examinations could be sufficient to express the infection intensity at the initial phase, on the same grounds that it was already demonstrated at the chronic phase. Furthermore, it is confirmed that the use of the number of eggs passed in the faeces as a tool to estimate the worm burden at the initial phase of schistosome infection is adequate.

Gastro-intestinal manifestations of the initial phase of schistosomiasis mansoni.

Clinical gastro-intestinal manifestations were studied in 34 patients in the initial phase of schistosomiasis mansoni. The patients, all men, were of similar age and in similar nutritional condition and had been infected simultaneously at the same transmission site. Most (85%) showed some gastro-intestinal sign or symptom, generally of light or moderate intensity; 56% had liquid or pasty diarrhoea, 41% abdominal pain, 29% hepatomegaly, 21% dysentery, 15% anorexia, 12% pain on colon palpation and 9% nausea and/or vomiting. High worm burden was associated with blood in faeces but apparently not with any other clinical manifestation. There was no apparent association between any clinical manifestation and peripheral-blood eosinophil counts or titres of IgE specific for Schistosoma mansoni (evaluated by the area of immediate intradermal reaction to injected adult worm antigen). The absence of association between worm burden and nearly all the clinical gastro-intestinal manifestations strengthens the concept that factors other than worm burden, such as host reactivity, constitute important pathogenetic elements in the initial phase of schistosomiasis mansoni.

Characterization of the non-apparent clinical form in the initial phase of schistosomiasis mansoni.

In this paper the history of 115 recruits that had bathed simultaneously in streams contaminated with Schistosoma mansoni, during military maneuvers, is reported. Thirty four of the infected patients presented the initial phase of the infection diagnosed through epidemiologic, clinical and laboratory parameters. Three out of the 34 patients did not reveal the clinical picture of the infection, thus being considered representatives of the non-apparent form of the disease. Differences between the intensity of blood eosinophilia, the area of immediate cutaneous reaction and the number of Schistosoma eggs eliminated in the stools proved not to be statistically significant (p > 0.05) when the non-apparent and acute cases of schistosomiasis were compared. These cases actually may be considered evidences of the non-apparent form hitherto merely taken for granted in the literature.

[Chronic pulmonary form of schistosomiasis mansoni. Clinico-radiologic evaluation]. / Forma pulmonar crônica da esquistossomose mansoni. Avaliação clínico-radiológica.

One hundred and fifteen patients with schistosomiasis mansoni were studied: 31 with a normal chest x-rays and no signs of pulmonary hypertension (PH) and 84 with x-rays compatible with cardiopulmonary abnormalities (73 without symptoms and 11 with symptoms of PH). The chronic pulmonary form (CPF) without pulmonary hypertension is frequent and benign. There was no association between the CPF and the hepatosplenic form (HEF), nor with age, sex or patient origin. Pulmonary hilum alterations were the most common x-ray findings, followed by parenchymatous abnormalities (micronodules). The CPF was associated with a low to medium worm burden. The incidence of CPF with pulmonary hypertension is low but usually related to significant heart abnormalities. It is more common in patients over 12 years, with the HEF of the disease and has no correlation with sex, race or place of birth. Chest x-ray alterations are seen with similar frequency both in parenchymatous and hilar regions.