Biomedical subjects

F W Rath

Publications and source records attributed to F W Rath.

At least 19 recordsLinked to original sources

PubMed2001

Tumor hypoxia, p53, and prognosis in cervical cancers.

BACKGROUND: The p53 protein is involved in the regulation of initiation of apoptosis. In vitro, p53-deficient cells do not respond to hypoxia with apoptosis as do p53-normal cells, and this may lead to a relative growth advantage of cells without a functioning p53 under hypoxia. On the basis of this hypothesis, a selection of cells with a functionally inactive p53 may occur in hypoxic tumors. The development of uterine cervical carcinomas is closely associated with infections of human papilloma viruses, which may cause a degradation of the tumor suppressor gene p53, resulting in a restriction of apoptosis. Thus, cervical cancers have often a functionally inactive p53. The purpose of our clinical study was therefore to investigate the association between p53, hypoxia, and prognosis in cervical cancers in which the oxygenation status can be determined by clinical methods. MATERIAL AND METHODS: Seventy patients with locally advanced squamous cell cervical cancer Stages IIB (n = 14), IIIB (n = 49), and IVA (n = 7) were investigated in the period from 1996 through 1999. All were treated with definitive radiotherapy with curative intent by a combination of external radiotherapy plus high-dose-rate afterloading. Before therapy, tumor oxygenation was measured with a needle probe polarographically using the Eppendorf histograph. Hypoxic tumors were defined as those with pO(2) measurements below 5 mm Hg (HF5). Pretreatment biopsies were taken and analyzed immunohistologically for p53 protein expression with the DO-7 antibody. The DNA index was measured by flow cytometry. The statistical data analysis was done with SPSS 9.0 for Windows. RESULTS: The 3-year overall survival was 55% for the whole group of patients. Clinical prognostic factors in a multivariate analysis were pretreatment hemoglobin level (3-year survival 62% for patients with a pretreatment hemoglobin > or =11 g/dl vs. 27% for hemoglobin <11 g/dl, p = 0.006) and FIGO stage (Stage IIB: 65%; Stage IIIB: 60%; Stage IVA: 29%, p = 0.01). Sixty of the 70 tumors showed positive immunohistologic staining for p53 protein (transformed p53 = tp53), and 10/70 were negative (wild-type p53 = wtp53); p53 expression had no significant impact on survival (50% for tp53 vs. 79% for wtp53, p = 0.11). FIGO stage and anemia had no impact on p53 expression. Forty-nine of 70 tumors were hypoxic (HF5+), and 21 showed no hypoxia (HF5-). Hypoxic carcinomas were more frequently positive for p53 as compared to nonhypoxic tumors (27% vs. 13%, p = 0.011) and showed a trend toward a lower survival (48% vs. 70%, p = 0.07). In a further multivariate analysis, the impact of a combination of p53 expression and hypoxia on survival was examined. After adjusting for FIGO stage and pretreatment anemia, patients with wtp53 tumors had the best prognosis (3-year survival 79%) followed by tp53-HF5(-) patients (57%), and the most unfavorable prognosis was observed for tp53-HF5(+) patients (47%). The DNA index was higher in tp53 carcinomas compared to wtp53 tumors, 1.97 +/- 0.4 vs. 1.67 +/- 0.1, p = 0.05. The highest DNA index was found in hypoxic tumors with transformed p53 (2.2 +/- 3.1). CONCLUSIONS: Advanced stage and pretreatment hemoglobin level are independent prognostic factors in cervical carcinomas. The immunohistologic detection of (a functionally inactive) p53 and the presence of hypoxia had no prognostic impact, if analyzed as single parameters. However, the combination of both parameters was able to discriminate different prognostic subgroups. Moreover, hypoxic cancers were more often immunohistologically positive for tp53 protein and had a higher DNA index with the highest DNA index in tumors with both hypoxia and tp53 protein expression. These findings in summary support the theory that the tumor's microenvironment may influence the biologic behavior via hypoxia.

Adult↗

PubMed2001

Loss of G2/M arrest correlates with radiosensitization in two human sarcoma cell lines with mutant p53.

We have examined the modulation of radiosensitivity by using caffeine in two human sarcoma cell lines both with a p53 mutation (US8-93 and LMS6-93). In both cell lines a strong irradiation-induced G2/M arrest was coupled with a low rate of apoptosis. Incubation with caffeine resulted in a low percentage of S and G2/M cells, associated with an accumulation in G1. With a higher caffeine concentration, we detected a lower clonogenic survival with IC(50) at 2 mM. In both cell lines incubation with caffeine completely prevents the irradiation-induced G2/M arrest. This was connected to radiosensitization, but without direct correlation to an induction of apoptosis. The effect of radiosensitization rose with higher irradiation doses. However, in comparison with LMS6-93, it was stronger in cell line US8-93. A higher radiosensitization in US8-93 correlated with the prevention of strong irradiation-induced G2/M response and higher initial DNA damage. Results of Western hybridization reveal a p53-independent mechanism of radiosensitization caused by caffeine. Our findings suggest that modulation in G2/M regulation may affect a common checkpoint for tumor cells with defective p53 function. Furthermore, our results show that the enhancer effect of caffeine is dependent on a strong reduction in the number of G2/M arrested cells and on an inhibition of DNA damage repair after irradiation.

Adenocarcinoma↗

PubMed2001

Cerebral heterotopia appearing as an extranasal polyp.

Cerebral heterotopia represents a rare tumorlike lesion related in its development to the encephaloceles but differing from these by non-connection to the cranial cavity. We describe an unusual case of cerebral heterotopia appearing as a pedunculated polyp on the upper lip of a newborn. As the distinction between encephaloceles and cerebral heterotopias is based on the correlation of radiologic and clinical findings, the surgical treatment of tumorlike lesions of the nasal and pharyngeal region in children requires a careful preoperative evaluation of their possible connection to the cranial cavity.

Brain Neoplasms↗

PubMed2001

[Association between elevated serum VEGF and polarographically measured tumor hypoxia in head and neck carcinomas].

PURPOSE: Clinical investigation of a potential relationship between VEGF concentration in serum (sVEGF) and polarographically measured tumor oxygenation in patients with squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: In 56 patients with SCCHN we estimated the classical tumor parameters, the sVEGF concentration (immunoassay) and the tumor oxygenation (Eppendorf pO2 histograph). The platelet count and the tumor volume were evaluated simultaneously. RESULTS: In a unifactorial analysis the total volume (132 cm3 vs. 38 cm3), the hypoxic subvolume (HSV = total volume multiplied with the relative frequency of values < or = 5 mm Hg/63 cm3 vs. 10 cm3) and the platelet count (380 10(9)/l vs. 271 10(9)/l) were significantly higher in the patient group with a sVEGF level > 707 pg/ml compared to the group with a sVEGF below this threshold. The multifactorial analysis confirmed significant effects for the hypoxic subvolume and the platelet count. Regarding hypoxic subvolume and sVEGF as continuous parameters a significantly positive correlation was found. This correlation remained somewhat weaker but significant after inclusion of the platelet count as covariate. CONCLUSION: On base of our data a clinical association between elevated sVEGF and polarographically measured tumor hypoxia could be confirmed. This was possible considering not only the relative grade of hypoxia but also the absolute amount of hypoxic regions. The VEGF released from platelets during blood clotting influences the sVEGF level essentially, however, the hypoxia effect was not completely deleted. Due to the platelet effect an estimation of sVEGF is not able to substitute polarographical measurement of tumor pO2. Therefore in an ongoing study we investigate whether VEGF values estimated in plasma are better correlated with the polarographically measured tumor pO2 than serum VEGF levels.

Adult↗

PubMed2000

[No association between p53 overexpression and polarographically measured tumor oxygenation in patients with head and neck carcinomas].

PURPOSE: Clinical investigation of a potential relationship between the polarographically measured tumor oxygenation and the p53 status in patients with squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: In 99 patients with mostly advanced, histologically proven squamous cell carcinoma of the head and neck we estimated the classical tumor parameters (TNM stage, histological grading) the immunohistochemical p53-overexpression (DO-7) and the tumor oxygenation status (Eppendorf pO2 Histograph). The tumor volume and the hemoglobin concentration were evaluated simultaneously. RESULTS: No statistically significant difference could be detected between immunohistological p53-positive (p53 > or = 10% stained cells) and p53-negative tumors (p53 < 10% stained cells) regarding both the median pO2 and the relative frequency of values < or = 5 mm Hg. Moreover, no statistically relevant differences could be seen between both p53-groups considering the hemoglobin concentration, the TNM stage, the histological grading and the tumor volume. CONCLUSION: Our data imply that there is no association between p53-overexpression and tumor hypoxia in head and neck carcinomas. However, this is not necessarily in contradiction to experimental or clinical data that confirmed a relationship between hypoxia and p53-mediated increased malignancy of tumor cells in other tumor entities. The comparable oxygenation status of p53-positive and p53-negative tumors in our study is associated with an analogous clinical tumor aggressiveness of both groups. That could be caused by a hypoxia related but p53-independent selection of tumor cells with a more malignant phenotype in head and neck carcinomas. However, further research is needed to prove this possible relationship.

Adult↗

PubMed2000

Regulation of proliferation and apoptosis in sporadic and hereditary medullary thyroid carcinomas and their putative precursor lesions.

C-cell hyperplasia (CCH) and medullary thyroid carcinoma (MTC) in patients affected by germline mutations of the RET oncogene represent an exceptional opportunity to study the regulation of proliferation and apoptosis during tumour initiation and progression. In 56 specimens [CCH, n=1; MTC with CCH, n=26; MTC, n=20; lymph-node metastasis (LNM), n=9] from 46 patients [multiple endocrine neoplasia type 2a (MEN2a), n=24; MEN2b, n=2; familiar MTC (FMTC), n=4; sporadic MTC, n-16] and 3 cases of non-neoplastic CCH, proliferation activity (MIB1), the rate of apoptosis [dUTP nick end labelling (TUNEL)] and expression of p53, bcl-2, bcl-x and bax were investigated and compared with clinical data. In MEN-associated CCH and small MTC, bcl-2 was strongly expressed, bcl-x was moderately expressed and bax was only weakly expressed. Advanced tumours and LNM did show a more heterogeneous bcl-2 staining accompanied by an increased bax expression and accelerated proliferation. The rate of apoptosis was extremely low in all investigated tumours. P53 was detectable in three patients with rapidly growing and extensively metastasising MTC. No somatic p53 mutations were found. Hereditary MTC with germline RET mutations at codon 918 (MEN2b) and codon 634 revealed a bias towards a higher proliferation activity at a younger age and are more frequently accompanied by LNM. CCH and MTC are characterised with a preponderance of bcl-2 as a factor blocking the programmed cell death. While MTC, in general, is a slowly growing tumour, a minority of tumours do progress rapidly with high proliferation. The factors leading to an accelerated tumour progression do not seem to take their effect via the regulation of apoptosis. Certain alterations of RET are supposed to have a direct or indirect implication on proliferation and, because of this, an effect on the clinical course.

Adolescent↗

PubMed2000

Simultaneously occurring liver metastases of pheochromocytoma and medullary thyroid carcinoma--a diagnostic pitfall with clinical implications for patients with multiple endocrine neoplasia type 2a.

Malignant pheochromocytoma is an exceptional complication in patients with Multiple Endocrine Neoplasia Type 2a (MEN2a). In this paper, we report on a 53-year-old male patient with an evident RET gene germline mutation, who simultaneously developed hepatic metastases of medullary thyroid carcinoma (MTC) and pheochromocytoma. Comprehensive immunohistochemical investigations were performed to elaborate markers which could be useful for differentiating between MTC metastases and pheochromocytoma, respectively. Calcitonin and CEA, in particular cytokeratins and trefoil factor family 1 (TFF1), were detectable exclusively in MTC, whereas all the other markers revealed a comparable expression in both MTC and pheochromocytoma. The only clues that could indicate a potential malignant course were size, a lack of sustentacular cells and hyaline globules, and a focal spindle cell pattern in pheochromocytoma. Owing to a wide agreement in cellular differentiation and a lack of specific, routinely applicable markers for pheochromocytomas, a comprehensive and goal-directed immunohistochemistry is required to rule out pheochromocytoma metastasis in patients with MEN2a. A misinterpretation could lead to harmful clinical complications, as shown in the present case.

Adrenal Gland Neoplasms↗

PubMed1999

Clinical relevance of pRb and p53 co-overexpression in soft tissue sarcomas.

The goal of this study was to examine the relationship between immunohistochemical pRb detectability and p53 overexpression in 198 soft tissue sarcomas (STS) with regard to its clinical relevance. Distinct pRb detectability multivariately shows a correlation to survival rate (relative risk (RR)=1.59, P=0.037). p53 positivity was also multivariately correlated to poor prognosis (RR=2.17, P=0.0014). Stratification of pRb staining to p53 results shows a prognostical graduation. Patients with negativity for both proteins have the most favorable prognosis (projected 5-year survival rate (psr)=54.5%). In contrast to this, positivity for both antibodies has the highest risk (RR=2.48, P=0.02) and the poorest prognosis (psr=17.4%). To conclude, these results explain that the clinical relevance of immunohistochemical pRb positivity in STS is connected with p53 in the form of having an increasing effect on the known prognostic relevance of p53 overexpression.

Adolescent↗

PubMed1999

Significance of proliferative activity and DNA ploidy in pancreatic cancer and chronic pancreatitis.

BACKGROUND: Precise preoperative assessment of diagnosis and prognosis in patients with pancreatic tumors would facilitate improvement of treatment strategies. In this context, we evaluated the significance of the proliferative index and of static DNA cytophotometry in the diagnosis and prognosis of pancreatic tumors. METHODS: Consecutive surgical specimens from 26 patients with ductal pancreatic cancers and eight patients with chronic pancreatitis were investigated by: 1. Staging; 2. Conventional histological and cytological grading; 3. MIB-1 (Ki-67 labeling) proliferating index; and 4. Static DNA cytophotometry. RESULTS: All patients with chronic pancreatitis had a normal MIB-1 labeling index and a euploid DNA content. In contrast, patients with pancreatic cancers rarely had a normal labeling index (1 of 26 patients) or a euploid DNA content (6 of 26 patients). Staging significantly correlated with survival time. However, it did not correlate with cytological criteria. Cytological criteria, such as conventional grading, MIB-1 proliferating index, and DNA ploidy, were not significantly correlated with survival time. Conventional grading was significantly correlated (p < 0.02) with proliferating index, but not with DNA ploidy. CONCLUSION: Proliferating index and DNA ploidy are relevant cytological markers that can help to discriminate between chronic pancreatitis and pancreatic cancer. The prognostic significance of these markers in pancreatic cancer patients, however, seems to be less relevant than tumor stage and of limited relevance for the individual cancer patient.

Adult↗

PubMed1999

[Malignant epithelioid hemangioendothelioma of the liver - a very rare tumor in children].

We report on a 12-year old boy suffering from malignant epithelioid hemangioendothelioma of the liver, which is a very rare tumor in childhood. The tumor was detected by ultrasound examination at the age of 10 and appeared at that time as a solitary intrahepatic nodular lesion. During the following 2 years multiple nodular lesions developed in both hepatic lobes. There were neither any suspect anamnestic findings nor abnormal clinical or laboratory data. The tumor showed the typical histomorphological, immunohistochemical, and ultrastructural features of this entity, which is usually seen in older patients. We investigated proliferative activity, apoptotic regulation, and expression of VEGF and VEGF-receptor flk-1 by means of immunohistochemical techniques. According to the known slow growth activity of these tumors we found only a few Ki-67 positive tumor cells. We did not detect any apoptotic cells using TUNEL technique. The positive immunoreaction of the tumor cells with antibodies against VEGF and VEGF-receptor flk-1 may indicate the regulation of tumor growth by angiogenetic factors. We present our findings together with a summary of the most important publications of recent years concerning these tumors.

Apoptosis↗

PubMed1999

Assessment of genomic imbalances in malignant fibrous histiocytomas by comparative genomic hybridization.

In order to investigate genomic imbalances, comparative genomic hybridization was applied to 20 malignant fibrous histiocytomas. Deletions were rare and found mainly in chromosomes 2q33-35, 4q32-qter, 8p, 9p21-pter, 12p and 19p, whereas, over-representations frequently affected chromosomes 3, 4q31, 5p, 6, 7, 14q22-ter, 18p, as well as, five distinct amplifications within the regions 12q12-15 and 15q24-qter. The total number of genetic imbalances per tumor was slightly increased in primary tumors when compared to relapses. No relationship was found between the patterns of gain and loss when compared to the histological subtype, tumor grading, the clinical outcome and the p53 mutation status.

Aneuploidy↗

PubMed1998

High prognostic significance of Mdm2/p53 co-overexpression in soft tissue sarcomas of the extremities.

Soft tissue sarcomas are a heterogeneous group of neoplasms with various histological subtypes. Up to now, no individual causal molecular markers for prognosis and therapeutic success have been identified. A tumorigenic connection between the oncogene product Mdm2 and tumor suppressor p53 is generally accepted, but their possible clinical relevance has not yet been investigated sufficiently in soft tissue sarcoma. In 86 primary soft tissue sarcoma of the extremities (RO-resected, T1/2 N0 M0), Mdm2 and p53 overexpression were investigated by immunohistochemistry. The results were adjusted to clinico-pathological characteristics and evaluated for their prognostic relevance by multivariate analysis. In Cox's multivariate analysis with stratification of Mdm2 to p53 results, we determined four groups which had different prognostic values for relapse-free and overall survival (Mdm2-/p53- < Mdm2-/p53+ < Mdm2+/p53- < Mdm2+/p53+). The most striking finding was a relative risk (rr) for overall survival of 18.77 (P=0.006) for patients with Mdm2/p53 co-overexpression (n=40). It is noticeably higher than the additive risk from both factors. Coincident Mdm2/p53 overexpression is an independent molecular marker with the highest prognostic relevance described for soft tissue sarcoma. Thus, a high risk sarcoma group has been defined which we believe requires alternative therapeutic approaches.

Adult↗

PubMed1998

How is the mutational status for tumor suppressors p53 and p16(INK4A) in MFH of the bone?

Both tumor suppressor genes p53 and p16(INK4A) play a crucial role in the control of cell cycle and tumor development. In this study 19 malignant fibrous histiocytomas of the bone (MFH-b), a very rare sarcoma entity, were investigated for mutations in p53 and p16 genes by a PCR-SSCP-sequencing analysis. In the tumor samples two p53 mutations and two polymorphisms (one in the p53 gene and one in the p16 gene) were found. The occurrence rate for p53 mutations and the absence of p16 mutations in MFH-b are comparable to the findings for MFH of soft tissues (MFH-st) and osteosarcomas, suggesting that p53 rather than p16 may play a role in tumorigenesis of MFH-b.

Bone Neoplasms↗

PubMed1998

Cytogenetic characterization of ten malignant fibrous histiocytomas.

We examined 10 malignant fibrous histiocytomas (MFHs) using metaphase preparations. Six tumors showed clonal structural and/or numerical chromosomal aberrations, and four tumors had normal karyotypes. For the most part, chromosomes 1, 3, 6, 9, 12, 16, 18, and 20 were involved in structural aberrations. The breakpoint regions most frequently were in 1p32, 3p25, and the centromeric region of chromosomes 1 and 16. There was a conspicuous loss in chromosome 18. We detected ring chromosomes in two tumors. One tumor showed a high percentage of near-haploid cells. Our results show many parallels to data which have already been published. MFHs include a broad spectrum of tumors of widely different histology and clinical course. So it is not surprising to find a cytogenetic diversity of chromosomal aberrations in this study.

Aged↗

PubMed1998

No p16INK4A/CDKN2/MTS1 mutations independent of p53 status in soft tissue sarcomas.

The p16INK4A/CDKN2/MTS1 gene encodes a specific inhibitor of cyclin-dependent kinases (CDKs) 4 and 6. This study investigates p16INK4A gene status and expression in mesenchymal tumours, in particular soft tissue sarcomas (STSs). Employing non-radioactive polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) sequencing, no p16INK4A mutation was found in 86 samples taken from 74 mesodermal tumours with known p53 gene status. This suggests that p16INK4A gene alterations, inc contrast to p53, are not involved in the progression of STS. This finding is supported by the reports of a low frequency of deletions and intragenic mutations in STS. Furthermore, by immunohistochemistry (IHC), an inverse correlation was established between p16INK4A and RB positivity for 62 per cent of the frozen tumour samples investigated. However, alterations in other components of the pRh/p16INK4A/ CDK4/cyclin D1/E2F pathway have been proven crucial for tumourigenesis in human sarcomas.

Cyclin-Dependent Kinases↗

PubMed1998

p53 status in radiation-induced soft-tissue sarcomas.

BACKGROUND: Following therapeutic irradiation after a latency period of many years radiation-induced tumors, often sarcomas, can arise. Results of radiation-induced DNA damage can be 1. p53 over-expression, inducing growth arrest or apoptosis, and 2. occurrence of mutations, frequently including the p53 gene, as one molecular promotor for carcinogenesis. We were interested whether radiation-induced sarcomas are associated with alterations of the p53 status. MATERIAL AND METHODS: Samples from 11 radiation-induced soft-tissue sarcomas (STS) were studied by a non-radioactive PCR-SSCP sequencing analysis and by immunohistochemistry with five antibodies for their p53 status. RESULTS: A tumor of one patient possessed a G->A transition in codon 280 (exon 8). Of 11 tumors, 9 showed nuclear p53 positivity, detected by monoclonal antibody DO-1. Of these 9 patients, 7 died during the observation period, whereas the 2 patients with DO-1 negative tumor samples are still alive. CONCLUSIONS: p53 over-expression and p53 mutation occur in radiation-induced STS. p53 status is expected to have prognostic impact for radiation-induced STS.

Adult↗

PubMed1998

Significance of retinoblastoma and mdm2 gene expression as prognostic markers for soft-tissue sarcoma.

The growth regulatory function of the retinoblastoma protein (RB) can be suppressed by mdm2 via RB/mdm2 interaction by perturbation of the RB suppression of the E2F function. The goal of this study was to examine the clinical value of immunohistochemical (IHC) RB detection and its relationship to mdm2 overexpression in a cohort of 198 adult primary soft-tissue sarcomas (STS). RB overexpression reveals, multivariately, a correlation with survival (RR=1.59, P=0.037) as well as mdm2 positivity (RR=2.32, P=0.0035). Stratification of RB results to mdm2 staining shows a prognostic graduation in four levels. Patients with positivity for both antibodies have the highest risk (RR=3.30, P=0.002) and the poorest prognosis (projected 5-year survival rate, 18.6%); those with negativity for both antibodies show the most favourable prognosis (projected 5-year survival rate, 63.4%). Intermediately, an isolated RB overexpression (projected 5-year survival rate, 46.1%) is more favourable than an isolated mdm2 positivity (projected 5-year survival rate, 33.5%). To sum up, this study proves that RB and mdm2 overexpression have an individual and also an additive effect on prognosis in STS.

Adult↗

PubMed1998

Primary hereditary medullary thyroid carcinoma--C-cell morphology and correlation with preoperative calcitonin levels.

Early thyroidectomy offers an opportunity of preventing the development of medullary thyroid carcinoma (MTC) in patients at risk for hereditary MTC. We investigated the thyroid glands of 32 patients with hereditary MTC to identify the changes in C-cell morphology and to correlate these with plasma calcitonin (CT) levels and with clinical data. The entire thyroid gland was processed for histological examination including immunostaining for CT. All glands revealed C-cell hyperplasia (CCH), and MTC was found in 21 patients (66% of 32, youngest patient 6 years, youngest with lymph node metastases [LNM] 17 years). The transition from CCH to MTC was characterized by destruction of the follicular basement membrane and by diminished intensity of CT immunostaining. Normal plasma CT levels after provocation with pentagastrin were found only in patients with CCH. Basally elevated plasma CT levels were restricted to MTC. LNM were only found in multifocal tumours at least 4 mm in diameter. It is not yet clear whether or not CCH in patients at risk for hereditary MTC is a neoplastic change, but in these patients the term 'C-cell hyperplasia' is of doubtful value. All MEN gene carriers reveal CCH, and almost all of them will develop multifocal MTC, so that CCH is probably a precursor lesion of an indubitably malignant tumour. Prophylactic thyroidectomy is justified at the age of 6 to anticipate development of a MTC. Lymphadenectomy is necessary in children if they are older than 10 years or have elevated plasma CT levels.

Adolescent↗