p53 mutation in breast cancer. Correlation with cell kinetics and cell of origin

AIM: Several studies have investigated the expression of the cytokeratins (CKs), vimentin, the epithelial growth factor receptor (EGFR), the oestrogen receptor (ER), and the progesterone receptor (PgR), in breast cancer, but no study has directly compared p53 mutations with these phenotypic and differentiation markers in the same case. The present study was designed to provide some of this information. METHODS: The expression of the p53 and bcl-2 proteins was evaluated by immunohistochemistry in relation to phenotypic characteristics and cellular kinetic parameters (mitotic index and apoptotic index) in 37 cases of ductal carcinoma in situ (DCIS) and 27 cases of infiltrating ductal carcinoma (IDC) of the breast. In addition, p53 gene mutation was examined by polymerase chain reaction single strand conformation polymorphism analysis (SSCP). RESULTS: Thirteen cases (eight DCIS and five IDC) showed expression of CK8, CK14, CK18, vimentin, and EGFR, consistent with a stem cell phenotype, whereas 44 cases (27 DCIS and 17 IDC) showed expression of CK8 and CK1, weak or negative expression of CK18, but were negative for vimentin and EGFR, consistent with a luminal cell phenotype. DCIS and IDC cases with a stem cell phenotype were ER/PgR negative and intermediately or poorly differentiated. In contrast, the cases with luminal cell phenotype were ER/PgR positive and well or intermediately differentiated. In addition, intermediately or poorly differentiated cases with a stem cell phenotype showed higher proliferative activity (per cent of MIB-l positive cells) than did intermediately or well differentiated cases with a luminal cell phenotype. Both DCIS and IDC cases with a stem cell phenotype were p53 positive and bcl-2 negative by immunohistochemistry. In IDC, p53 expression was associated with a reduction of both mitotic index and apoptotic index compared with DCIS. Most of the tumours showing a more differentiated phenotype (luminal) were p53 negative and bcl-2 positive. In these cases, cell kinetic parameters increased from DCIS to IDC. These data suggest the existence of subsets of DCIS and IDC that, because of their phenotypic characteristics, could be derived from subpopulations of normal breast cells having different control mechanisms of cell proliferation and neoplastic progression. CONCLUSIONS: These results are compatible with the hypothesis that the phenotype of the cell of origin constrains both tumour phenotype and the choice of genetic events; however, the occurrence of p53 mutants by chance during neoplastic transformation cannot be excluded.     

Evaluation of tumor thrombi in the inferior vena cava with intraoperative ultrasound

To report and discuss four cases of renal cell carcinoma (RCC) in which preoperative investigations yielded contradictory results regarding the cranial extension of propagation of the tumor thrombus into the vena cava. An intraoperative ultrasound scan (IOU) was performed in all cases to identify the exact level of the tumor thrombus. We have performed an IOU of the vena cava in four patients with RCC propagation into the inferior vena cava. Preoperative investigations were performed in all patients and consisted of abdominal Ultrasound scan (USS), contrast enhanced CT scan and gadolinium enhanced MRI scan. Intraoperative ultrasound has identified correctly the cranial extension and the absence of tumor thrombus infiltration in all patients. The thrombus reached the suprahepatic vena cava in two cases and was confined to the infrahepatic vena cava in the remainder. Preoperative imaging investigation had failed to determine the correct cranial extension of the tumor thrombus in two patients.IOU is a very useful tool to accurately assess the precise extent of tumor thrombus and eventually the presence of vein wall infiltration. These data are of paramount importance to plan the optimal surgical approach. According to our experience this type of investigation identifies the cranial extent of a tumor thrombus inside the vena cava better than standard imaging techniques.     

Phase I study of thymidine (dThd) and cisplatin (DDP) given in combination

Twenty-three patients with a variety of solid tumors were given thymidine (dThd) at a single dose of 30 g/m2 along with cisplatin (DDP) at escalating doses ranging from 25 to 120 mg/m2. The dThd was administered first, and then after 50% of the total dThd dose had been infused over 1 h, the remaining 50% was given simultaneously with DDP at a separate intravenous site over the next 2 h. Treatment was repeated at 3-week intervals. Gastrointestinal toxicity was dose-limiting and dose-related with increasing dosages of DDP. Central nervous system manifestations occurred in 17% of the patients. Mild myelosuppression was observed only at DDP doses of greater than or equal to 75 mg/m2. Thrombocytopenia was more severe than leukopenia. The maximum tolerated doses on this schedule were 30 g/m2 of dThd and 100 mg/m2 of DDP.     

Enhanced production of interferon-gamma by T lymphocytes cloned from rejected kidney grafts.

Seventy-seven T cell clones were generated from cell blasts infiltrating rejected kidney allografts. All clones, either CD4 or CD8, displayed cytolytic activity evaluated by lectin-dependent cell-mediated cytotoxicity (LDCC) and natural killer activities. Furthermore, both types of clones were able to produce IFN-gamma following PHA stimulation. These data suggest that the graft infiltrate is characterized by T cell clones with cytolytic potential responsible for the killing of graft cells. The production of IFN-gamma, enhancing the class II MHC expression, may amplify the recipient immune response.     

In vitro and in vivo studies with anionic sulfatide-liposomes containing adriamycin

Neutral and negatively charged liposomes containing Adriamycin (ADM) were examined for efficiency of drug entrapment and stability in serum. The greatest entrapment of ADM was obtained with negatively charged liposomes containing sulfatide. Moreover, these sulfatide-containing liposomes were more stable than other liposomes in the presence of serum. Tissue distribution studies indicated that the levels of ADM were increased several-fold in mouse liver and spleen after i.v. injection of the drug entrapped in sulfatide-liposomes, while levels of the drug were significantly diminished in the heart. Finally, the in vivo antitumor activity of ADM in liposomes containing sulfatides resulted in significantly greater survival rates than free ADM or ADM entrapped in liposomes without sulfatides.     

IgM-PRODUCING TUMORS IN THE BALB/c MOUSE : A MODEL FOR B-CELL MATURATION

Five adjuvant induced BALB/c tumors producing IgM—McPc 1748, W 3469, TEPC 183, McPc 774, and Y 5781—were characterized morphologically by electron microscopy, analysis of the distribution of surface-bound and intracytoplasmic IgM using immunofluorescence, and by biochemical study of IgM synthesis, turnover, and secretion. The cells of different tumors appear to represent different stages in B-cell maturation when compared to normal, lipopolysaccharide-stimulated B cells. Thus, McPc 1748 tumor cells resemble 10–25-h stimulated normal B cells, 3469 cells resemble 20–35-h stimulated B cells, TEPC 183 cells resemble 45–65-h stimulated B cells, Y 5781 cells resemble 80–110-h stimulated B cells, and McPc 774 cells resemble 100–130-h stimulated B cells.     

Effectiveness of community-based treatment on clinical outcome in children with autism spectrum disorders: An Italian prospective study

Objective: Little is known about outcomes of Autism Spectrum Disorders (ASDs) interventions in real-life settings. The main aim of this naturalistic study was to collect real-life data on the actual ASDs treatment practices in Italy.

Methods: A cohort of 48 children undergoing community-based interventions was observed in terms of personal and environmental characteristics, treatment typology and outcomes.

Results: An earlier start of treatment was associated with an improvement of autistic symptoms, independently from symptoms severity (p?<?0.05), but not with improvements in terms of intelligence quotient (p?=?0.8). Children belonging to lower socioeconomic status families began treatment later (48.0 months) than those belonging to middle (39.8 months) or upper (39.2 months) classes (p?<?0.05), and received less hours of treatment.

Conclusion: The study showed that ASDs interventions should be observed not only in experimental settings, but also in naturalistic environments, so to appraise the actual effectiveness of integrating different treatment methods in community settings.     

Hip fractures in Italy: 2000–2005 extension study

Summary

A total of 507,671 people ≥65 experienced hip fractures between 2000 and 2005. In 2005, 94,471 people ≥65 were hospitalized due to hip fractures, corresponding to a 28.5% increase over 6 years. Most fractures occurred in patients ≥75 (82.9%; n?=?420,890; +16% across 6 years), particularly in women (78.2%; n?=?396,967).

Introduction

We aimed to analyze incidence and costs of hip fractures in Italy over the last 6 years.

Methods

We analyzed the national hospitalization and DRG databases concerning fractures occurred in people ≥65 between 2000 and 2005.

Results

A total of 507,671 people ≥65 experienced hip fractures across 6 years, resulting in about 120,000 deaths. In year 2005 94,471 people aged ≥65 were hospitalized due to hip fractures, corresponding to a 28.5% increase over 6 years. The majority of hip fractures occurred in patients ≥75 (82.9%; n?=?420,890; +16% across 6 years) and particularly in women (78.2%; n?=?396,967). Among women, 84.2% of fractures (n?=?334,223; +28.0% over 6 years) were experienced by patients ≥75, which is known to be the age group with the highest prevalence of osteoporosis, accounting for 68.6% of the overall observed increase in the total number of fractures. Hip fractures in men ≥75 increased by 33.1% (up to 16,540). Hospitalization costs increased across the six examined years (+36.1%) reaching 467 million euros in 2005, while rehabilitation costs rose up to 531 million in the same year.

Conclusions

Hip fractures of the elderly are increasing and represent a major health problem in industrialized countries such as Italy.