Detection of TP53 gene mutation in human meningiomas: A study using immunohistochemistry,polymerase chain reaction/single-strand conformation polymorphism and dna sequencing techniques on paraffin-embedded samples

Mutations in the TP53 tumor suppressor gene have been studied in different types of brain tumors. Little is known about this genetic event in human meningioma, a mostly benign tumor. To investigate the frequency of TP53 gene mutations in human tumors derived from meningeal tissues, paraffin-embedded tissues from 30 cases (including 2 malignant and 4 atypical meningiomas, as well as 2 hemangioblastomas and 3 hemangiopericytomas) were screened by immunohistochemistry. Polymerase chain reaction/single strand conformational polymorphism (PCR/SSCP) and direct DNA sequencing were thereafter performed in selected cases. Nuclear p53 staining was not seen in any of the 19 benign meningiomas tested, while atypical meningiomas, hemangioblastomas, and hemangiopericytomas displayed nuclear staining in a subpopulation of tumor cells in 4 out of 5, 2 out of 2, and 3 out of 3 cases, respectively. One malignant meningioma showed an intense nuclear staining and a band shift in SSCP. In this case, we identified a mutation in the TP53 gene at codon 161 changing GCC to ACC and resulting in an alteration of alanine to threonine in this position. Our results indicate that TP53 gene mutation may be considered as a marker for malignant transformation in meningioma. p53 immunoreactivity, even in the absence of detectable gene mutation, is also associated with atypia and does not appear in regular benign meningiomas. © 1995 Wiley-Liss, Inc.     

Synergistic inhibitory effects of interferon-alpha and 5-fluorouracil on meningioma cells in vitro

We have investigated the effects of interferon- (IFN-) and 5-fluorouracil (5-FU) on meningioma cells in two different culture systems, evaluated by the uptake of radiolabelled methionine. With both IFN- and 5-FU an inhibitory effect on the uptake of radiolabelled methionine by the meningioma cells was demonstrated, and we found a synergistic inhibitory effect with a combination of IFN- and 5-FU. To obtain a maximal inhibition of cell metabolism without causing cell toxicity, we were able to decrease the dose of 5-FU by simultaneously adding IFN-. Our results suggest that a combined treatment of IFN- and 5-FU may be a successful alternative for patients with inoperable meningiomas. A novel in vitro positron emission tomography technique was used for the study of metabolic changes in tumour cells caused by drug treatment, which is complementary to conventional cell culture techniques.     

Metastasis of mouse T lymphoma cells is controlled by the level of major histocompatibility complex class I H-2DK antigens

In vivo inoculation of a low metastatic BW 5147 derived T-cell lymphoma variant into syngeneic mice, had led to the generation of a highly metastatic variant. The shift towards a more metastatic phenotype is accompanied by an increase in major histocompatibility class I H-2D^k antigen expression. This suggests that H-2D^k antigens may control the metastatic potential of BW T lymphoma cells. Our present findings indicate that H-2D^k expression is directly correlated with the metastatic potential of BW cells. We have confirmed such correlation by specifically altering the level of H-2D^k expression by: I) FACS analysis, 2) IFN-_γ treatment, 3) H-2D^k gene transfection. Cells sorted for low H-2D^k expression had a significantly reduced metastatic potential. Induction of H-2D^k expression on these cells by either IFN-_γ treatment or H-2D^k gene transfection concomitantly led to increased metastasis. We also assessed metastatic potential of BW cells in irradiated, immunocompromised recipients. Our results show that the immune system is implicated and we further tested which immune effectors are involved, In vivo depletion of natural killer (NK) and CD8⁺ T-cells revealed that the difference in metastatic potential of the H-2D^k variants relies upon an NK-dependent mechanism, whereas CD8⁺ T-cells are not implicated. Our observations suggest that highly metastatic cells, expressing a high level of H-2D^k antigens are more resistant to NK-cell-mediated cytotoxicity in vivo. We have confirmed our in vivo results by in vitro cytotoxicity assays using poly I:C induced NK and IL-2 activated LAK cells. We conclude that a NK-dependent mechanism accounts for the association between differential H-2D^k antigen expression and metastasis.     

Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt-protoporphyrin for the induction of heme oxygenase-1

Today, the major problem in organ transplantation is not acute graft rejection but chronic graft deterioration. In addition to alloantigen-specific events, alloantigen independent factors like donor age, previous diseases, consequences of brain death, and perioperative events of ischemia/reperfusion injury have a major impact on long-term graft function. The induction of the stress protein heme oxygenase-1 (HO-1) protects cells from injury and apoptosis. Here, we tested the protective effects of HO-1 induction in a clinically relevant kidney transplant model. Induction of HO-1 expression following cobalt-protoporphyrin (CoPP) treatment in organ donors prolonged graft survival and long-term function remarkably following extended periods of ischemia. Positive effects were observed with both optimal and marginal grafts from old donor animals. Structural changes characteristic for chronic rejection, as well as graft infiltration by monocytes/macrophages and CD8+ T cells, were substantially reduced following HO-1 induction. Up-regulation of HO-1 expression before organ transplantation was also associated with reduced levels for tumor necrosis factor (TNF)-alpha mRNA, increased levels for interferon (IFN)-gamma, and bcl-x, and insignificant differences for CD25, interleukin (IL)-2, IL-4, IL-6, and IL-10 mRNA levels. The significant improvement of long-term graft function following induction of HO-1 expression in donor organs suggests that this strategy may be a novel clinical treatment option with particular relevance for transplantation of marginal organs.     

Segregating early physical and syntactic processes in auditory sentence comprehension

Auditory language comprehension involves physical as well as syntactic processing. The present study examined whether early physical and syntactic processes in spoken sentence comprehension can be segregated using event-related brain potentials (ERPs). In the physical manipulation condition, the terminal word of the sentence was presented either from the same or from a different location to the preceding sentence fragment. In the syntactic manipulation condition, the terminal word was either a syntactically correct continuation of the preceding sentence fragment or violated syntactic constraints. These two factors were completely crossed. Physical deviances elicited the mismatch negativity (MMN) and syntactic deviances the early syntax-related negativity, both deviance-related components of the ERP. Sentences which violated physical as well as syntactic constraints elicited a negativity which was larger than that elicited by only a physical or only a syntactic deviance. The elicitation of the MMN in connected speech demonstrates that this component can be used as a probe for auditory change-detection even in ecologically highly valid situations. The increase of deviance-related effects with double deviants suggests that the early physical and syntactic processing systems act, to a high degree, in parallel and independently of each other.     

Predictive Genetic Screening and Clinical Findings in Multiple Endocrine Neoplasia Type I Families

Germline mutations of the MEN1 gene have been identified as the causative genetic defect of multiple endocrine neoplasia type I (MEN-I), an autosomal dominantly inherited condition. To establish the basis for predictive family screening we evaluated the spectrum of MEN1 gene mutations in MEN-I patients treated at our institution. Relatives at risk were subjected to predictive genetic screening after genetic counseling. Gene carriers were subjected to extensive clinical screening for MEN-I, including biochemical tests for basal hormone concentrations in blood and urine, a standardized meal stimulation test and imaging procedures (ultrasonography, computed tomography, magnetic resonance imaging). Among index patients of 15 independent MEN-I kindreds, 14 heterozygous MEN1 germline mutations were identified by single-strand conformational variant analysis (SSCV) and direct DNA sequence analysis. Of 51 individuals at risk, 26 predictively tested relatives with the wild-type MEN1 gene could be excluded from further screening procedures because they had not inherited the disease. In all previously presumed unaffected relatives with the mutant gene, our extensive clinical screening program revealed at least one manifestation of MEN-I. Furthermore, 22 additional diagnoses could be established in identified MEN-I patients. We show that mutation analysis enables predictive genetic screening for MEN-I families, providing a valuable tool for genetic counseling and clinical management. An extensive clinical screening program focusing on genetically proven individuals at risk allows detection of MEN-I manifestations at an early, asymptomatic stage of the disease. Controlled, prospective studies are now required to prove whether timely appropriate treatment on the basis of predictive screening might help improve disease-related quality of life and prolong life expectancy in MEN-I kindreds.     

Lokale Tumorkontrolle und kosmetisches Ergebnis nach brusterhaltender Operation und Strahlentherapie bis 56 Gy Gesamtdosis ohne Boost beim Mammakarzinom

PURPOSE: To evaluate overall survival, local tumor control and cosmetic outcome after breast-conserving surgery followed by radiotherapy without boost irradiation. PATIENTS AND METHODS: In a retrospective study 270 breast cancer patients were treated with breast conserving surgery combined with a homogenous radiation of the tumor bearing breast up to a total dose of 56 Gy without local boost irradiation. Mean follow-up was 48 months. Local tumor control, side effects, cosmetic results and contentment with treatment were assessed using physical examinations and interviews based on a standardized questionnaire. RESULTS: Cause-specific survival at 5 years after treatment was 88.3%, actuarial disease-free survival at 5 years was 76.1%. Within 23 to 78 months after treatment 12 patients suffered from ipsilateral breast recurrence. The actuarial freedom from local recurrence (single tumor manifestation) was 96.8% at 5 years after treatment, 89% at 10 years. The occurrence of local failures was not significantly correlated to tumor size, margins, grading, nodal status, age or lymphangiosis. 15.6% of the patients developed distant metastases. In all patients treatment was performed without interruption. Side effects were predominantly of mild degree, no severe side effects were detected. 73% of physicians and 81% of patients scored their cosmetic outcome as excellent or good. 93% of patients would again decide in favor of this procedure. Whereas use of adjuvant chemotherapy as well as subcutaneous reconstruction of breast tissue did not significantly affect breast cosmesis, analysis demonstrated impaired cosmetic results related to a larger breast size. CONCLUSION: The data of this study show that tumor control achieved by breast conserving surgery in combination with a radiation technique up to a total dose of 56 Gy which omits boost irradiation is within the range of literature data. Side effects of the therapy were tolerable. The treatment displayed a good compatibility with tolerable side effects and good cosmetic results.     

Serum levels of C-peptide, IGFBP-1 and IGFBP-2 and endometrial cancer risk; results from the European prospective investigation into cancer and nutrition

We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition, to examine the associations between prediagnostic serum concentrations of C-peptide, insulin-like growth factor binding protein (IGFBP)-1 and IGFBP-2, and endometrial cancer risk. Among pre- and post-menopausal women, who were not currently using exogenous hormones, 286 women developed incident endometrial cancer during an average 5.1 years follow-up. Using risk set sampling, 555 matched control subjects were selected. In conditional logistic regression models adjusted for matching factors only, endometrial cancer risk increased with increasing serum levels of C-peptide (relative risks (RR) for the top vs. bottom quartile = 2.13 [95% confidence interval (CI) 1.33-3.41], p(trend) = 0.001, and decreasing serum levels of IGFBP-2 (RR for the top vs. bottom quartile = 0.56 [95% CI 0.35-0.90], p(trend) = 0.03, but was not significantly associated with IGFBP-1 levels (RR for the top vs. bottom quartile = 0.76 [95% CI 0.47-1.21], p(trend) = 0.25). In BMI-adjusted models, only the C-peptide association remained marginally statistically significant (RR for the top vs. bottom quartile = 1.56 [95% CI 0.94-2.57], p(trend) = 0.05 for C-peptide; 0.84 [95% CI 0.50-1.40], p(trend) = 0.74 for IGFBP-2; and 1.08 [95% CI 0.65-1.78], p(trend) = 0.86 for IGFBP-1 levels). These associations were stronger among nonfasting women (< or =< or =6 hr since last meal; 63% of subjects) but were not evident among fasting women, although the interactions were not statistically significant. The C-peptide-risk association was substantially attenuated after adjustment for free estradiol in postmenopausal women (RR for the top vs. bottom quartile = 1.28 [95% CI 0.67-2.45], p(trend) = 0.42. Our results provide modest support to the hypothesis that hyperinsulinaemia is a risk factor for endometrial cancer.