Biomedical subjects

A Dam

Publications and source records attributed to A Dam.

At least 19 recordsLinked to original sources

PubMed2000

Recurrent astrocytoma in a child: a report of cytogenetics and TP53 gene mutation screening.

An 8-year-old girl presented with a cerebral tumor and 3 recurrences within 15 months. The primary tumor was a low-grade astrocytoma, but the recurrences showed progressively malignant phenotypes with increasing mitotic activity and MIB-1 labeling indices. Radiotherapy was given between the first and the second recurrences. Cytogenetic analysis of the first and the second recurrences showed abnormal karyotypes. There seemed to be 2 common breakpoints in these 2 recurrences. TP53 gene mutation screening, using comprehensive denaturing gradient gel electrophoresis, revealed among others a possibly causative mutation of exon 5 in 3 of 4 tumor samples. The meaning of TP53 mutations in low-grade astrocytomas is still unclear, but the highly abnormal karyotypes, which are unusual in these tumors, probably provide genetic evidence for the unexpected aggressive behavior of the tumor in this patient.

Antigens, Nuclear↗

PubMed1999

Cytogenetic analysis of a mature teratoma and a yolk sac tumor component of a late relapse of a disseminated testicular nonseminoma.

We report on the cytogenetics of a primary testicular nonseminoma, a residual mature teratoma after remission-induction chemotherapy, and a late relapse after 9 years of follow-up, in one patient. The late relapse was composed of a mature teratoma and a yolk sac tumor component. Cytogenetic comparison of the different tumors shows that progression of primary testicular nonseminoma to residual mature teratoma and to a late-relapse lesion is accompanied by net loss of chromosomes. In addition, our findings may suggest that transformation to viable cancer in a late-relapse lesion is accompanied by further chromosomal losses.

Adult↗

PubMed1999

High frequency of TP53 mutations in juvenile pilocytic astrocytomas indicates role of TP53 in the development of these tumors.

In adults, the TP53 tumor suppressor gene is frequently mutated in astrocytic brain tumors which is supposed to represent an early event in their development. In juvenile pilocytic and low-grade astrocytomas, however, TP53 mutations have until now been reported as rare, which has led to the suggestion that these tumors may follow a different molecular pathogenesis with an involvement of genes other than TP53. Our analysis of 20 pilocytic and two low-grade astrocytomas of childhood, based on a comprehensive denaturing gradient gel electrophoresis (DGGE) mutation detection assay of the entire coding region, including all splice site junctions of TP53, showed mutations considered as causative in 7 of the 20 (35%) pilocytic astrocytomas and in one of the two low-grade astrocytomas. Our finding is significantly different from the mutation frequency of 1.3% (2/155) previously reported for these tumor types. This may be attributed to the mutation detection system used, which also detects mutations occurring outside the evolutionary conserved region of TP53. Our results suggest that, contrary to the present notion, TP53 mutations may well play a role in the development of juvenile astrocytomas. Furthermore, no mutations were found in tumors of patients with progression of residual tumor after postoperative follow-up. This suggests that TP53 mutations may be associated with less aggressive forms of juvenile astrocytomas, analogous to the situation in adult astrocytomas.

Adolescent↗

PubMed1998

Liver cell proliferation after partial hepatectomy in rats with liver metastases.

OBJECTIVE: To validate proliferating cell nuclear antigen (PCNA) expression and flow cytometry as proliferation markers in regenerating rat liver containing metastases. STUDY DESIGN: Rats containing colorectal liver metastases were killed at various days after 70% partial hepatectomy or a sham operation. [3H]thymidine and 5-bromo-2'deoxyuridine (BrdU) incorporation, PCNA expression and flow cytometry were used to evaluate liver cell proliferation. RESULTS: The assessment of proliferating liver cells by PCNA expression and BrdU incorporation was more reliable than autoradiography. PCNA expression correlated well with BrdU incorporation (r = .68, P = .003) and autoradiography (r = .57, P = .02) in regenerating liver. BrdU incorporation and PCNA expression were higher in hepatectomized rats as compared to sham-operation rats at days 1-4 after hepatectomy. Flow cytometry of propidium-stained nuclei from livers of hepatectomized rats showed a higher proportion of S-phase nuclei as compared to S-phase nuclei in control rats. The correlation coefficients of the number of S-phase nuclei, BrdU-positive nuclei and PCNA-positive nuclei were .39 (P < .02) and .56 (P < .0005), respectively. CONCLUSION: Flow cytometry and PCNA expression are simple and reliable methods of studying proliferation in metastases containing rat liver after partial hepatectomy.

Animals↗

PubMed1997

Clinical outcome of patients with previously untreated soft tissue sarcomas in relation to tumor grade, DNA ploidy and karyotype.

The most important prognostic factor in soft tissue sarcomas (STS) is tumor grade. Since most grading methods are subject to the interpretation of the individual pathologist, there is a need for objective criteria such as DNA ploidy and karyotype, which are of prognostic value in several types of malignancy. We have analyzed the relationships among tumor grade, DNA ploidy, cytogenetic abnormalities and the clinical outcome of 44 previously untreated patients with 12 different histological types of primary STS. The tumors were graded according to the method of Coindre, which resulted in 9 grade I (20%), 18 grade II (41%) and 17 grade III (39%) STS. DNA flow cytometry and chromosomal analysis were performed using standard techniques. After a median follow-up time of 39 (range, 2-124) months, Kaplan-Meier survival analysis was performed. Significant differences in 5-year overall survival were found between patients with grade I or II and grade III STS (p < 0.05). Seventeen STS were aneuploid and 26 were euploid. In 21 of 39 successfully cultured STS an abnormal karyotype was found. There were no significant differences in survival in relation to DNA ploidy or the presence of chromosomal abnormalities. Our results show that grading had higher prognostic value than DNA ploidy or the presence of cytogenetic abnormalities in this heterogeneous group of STS.

Aneuploidy↗

PubMed1997

Genetics as a diagnostic tool in sarcomatoid renal-cell cancer.

Renal-cell cancer comprises a heterogeneous group of tumors, which currently can be sub-divided into morphologically distinct entities, each characterized by a specific combination of genetic changes. Sarcomatoid transformation might occur in any of the sub-types, resulting in tumors consisting of both carcinomatous and sarcomatous components. The specific diagnosis of these neoplasms, as to tumor sub-type, is usually made on the histologic properties of the carcinomatous tissue present. However, this might not reflect the true nature of the sarcomatous component. Since the genetic changes associated with the development of the different sub-types of renal-cell cancer are well established, this knowledge might serve as a tool in diagnosing sarcomatoid tumors. Assessing the genetic constitution of the latter may lead to correct diagnosis. It may also provide valuable information about the genetic changes associated with sarcomatoid transformation. Hence we performed a genetic characterization of a case of sarcomatoid renal-cell cancer, histologically diagnosed as being of the chromophilic type. The observed genetic changes included loss of 3p, 6q, 8p, 9, 13, 14 and 17p, and gain of 5, 12 and 20, as well as a mutation in the coding region of the p53 gene. This combination of genetic changes points to clear-cell rather than chromophilic origin of the sarcomatoid tumor investigated, indicating that the genetic constitution of sarcomatoid tumors may be a more reliable indicator of tumor sub-type than histologic appearance.

Biomarkers, Tumor↗

PubMed1997

Comparison of the chromosomal pattern of primary testicular nonseminomas and residual mature teratomas after chemotherapy.

About 70 to 75% of patients with nonseminomatous testicular germ cell tumors (NSs) present with metastases. When these metastases are treated with chemotherapy, often residual mature teratoma (RMT) is left. RMT is composed of fully differentiated somatic tissue. Untreated metastases of NSs rarely consist exclusively of mature somatic tissue. Apparently, after chemotherapy treatment there is a shift towards higher degrees of differentiation. Investigating tumor progression and the mechanism(s) involved in therapy-related differentiation, we compared the cytogenetically abnormal karyotypes of a series of 70 NSs with those of 31 RMTs. In NSs and RMTs, the modal total chromosome number does not differ and is in the triploid range. Both the frequency and the average copy number of i(12p) are the same, and the pattern of chromosomal over- and underrepresentation and distribution of breakpoints do not differ significantly in these series. So, we found the chromosomal pattern of RMTs as abnormal as those of primary NSs. Based on cytogenetics, we found no indication that specific chromosomal alterations parallel metastasis and therapy-related differentiation of the metastases. The cytogenetic data suggest that both induction of differentiation of (selected) cells or selection of cells with capacity to differentiate are possible mechanisms for the therapy-related differentiation of RMTs.

Antineoplastic Agents↗

PubMed1996

CFTR chloride channel activation by genistein: the role of serine/threonine protein phosphatases.

We have previously shown [B. Illek, H. Fischer, G. F. Santos, J. H. Widdicombe, T. E. Machen, and W. W. Reenstra, Am. J. Physiol. 268 (Cell Physiol. 37): C886-C893, 1995] that genistein, a tyrosine kinase inhibitor, activates the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel in NIH/3T3 cells that have been stably transfected with an expression vector for the CFTR (NIH-CFTR cells). In this study, we present evidence suggesting that both genistein and the serine/threonine protein phosphatase (PPase) inhibitor calyculin A activate the CFTR by inhibiting PPase activity. As measured by 125I efflux, genistein and calyculin A stimulate the CFTR to approximately 50% of the maximal activity with forskolin. Neither agonist increases CFTR activity at saturating forskolin concentrations, but genistein and calyculin A have an additive effect on CFTR activity. Forskolin, but neither genistein nor calyculin A, stimulates protein kinase A(PKA) activity. The PKA inhibitor H-89 inhibits CFTR activation and in vivo phosphorylation by all three agonists. Proteolytic digestion of in vivo phosphorylated CFTR suggests that the CFTR is phosphorylated on the same sites during stimulation with genistein and forskolin but on different sites stimulation with calyculin A. The data suggest that genistein and calyculin A inhibit different PPase activities, allowing CFTR phosphorylation and partial stimulation, by a basal PKA activity.

3T3 Cells↗

PubMed1996

Corticosteroid-sparing effect of azelastine in the management of bronchial asthma.

The objective of this double-blind trial was to evaluate the corticosteroid-sparing effect of azelastine in patients with chronic bronchial asthma. A total of 193 subjects received either 6 mg of azelastine twice per day or placebo (in a 2:1 ratio) in combination with beclomethasone dipropionate (6 to 16 inhalations per day). The number of daily inhalations of the corticosteroid was reduced until maximum reduction or elimination was achieved. Patients then entered a 12-wk maintenance period, during which patients were maintained on their lowest possible dose of inhaled corticosteroid. Compared with placebo, the azelastine group had a statistically significantly greater overall median reduction in inhaled corticosteroids (4.9 puffs/day for azelastine versus 3.1 puffs/day for placebo; p < or = 0.010) during the maintenance period. The azelastine group also had a statistically significantly higher percentage of patients with reductions of > or = 50% and > or = 75% from the baseline level (53 and 31%, respectively, for azelastine versus 34 and 14%, respectively, for placebo; p < or = 0.028). The results demonstrated that azelastine, 6 mg twice per day, can reduce the need for inhaled corticosteroids in patients with chronic bronchial asthma and not lead to a deterioration in pulmonary function.

Administration, Inhalation↗

PubMed1996

Mixed testicular germ cell tumors: monoclonal or polyclonal.

Testicular germ cell tumors (TGCT) of adolescents and adults are, for clinical and pathological reasons, divided in seminomas (SE) and nonseminomatous germ cell tumors (NS). Whether and to what degree these two entities are pathogenetically related is still controversial and a matter of debate. TGCT may contain both SE and NS components. Cytogenetic studies of the SE and NS components of these mixed TGCT might shed light on the pathogenetic relationship between both components. Separate cytogenetic analysis was performed on both components of three cases of mixed TGCT with both SE and NS components. The karyotypes of both components were compared with each other. In one case, the SE and NS component share eight different structural chromosomal abnormalities, indicating that the SE and NS component are pathogenetically closely related and have a common neoplastic pathway for a considerable length. Both components of the other two cases have, respectively, i(12p) and no structural chromosomal abnormalities in common. Our results, together with data from the literature, indicate that in mixed TGCT with SE and NS components, both components may have either a monoclonal or a polyclonal origin.

Adolescent↗

PubMed1995

An important role for chromosome 17, band q25, in the histogenesis of alveolar soft part sarcoma.

A cytogenetic study of two cases of alveolar soft part sarcoma showed near-diploid karyotypes with multiple chromosomal rearrangements. An abnormality of the long arm of chromosome 17, involving band q25, is present in both cases and in 2 of 4 cases in the literature. This recurrent structural abnormality probably plays an important role in the histogenesis of this unusual neoplasm and therefore is important for further molecular investigation.

Adult↗

PubMed1995

Chromosomal changes in renal oncocytomas. Evidence that t(5;11)(q35;q13) may characterize a second subgroup of oncocytomas.

Many of the reported oncocytomas have different chromosome abnormalities, indicating that they comprise a cytogenetically heterogenous group of tumors consisting of potentially cytogenetic subgroups. We have performed cytogenetic studies on nine renal oncocytomas. Clonal abnormalities were present in eight tumors. The findings most observed were the loss of the Y chromosome, and abnormalities of chromosomes 1 and 22. We also observed telomeric associations (tas) in two tumors and structural aberrations of chromosomes 9p and 19q, as well as monosomy 10. In two cases we found a similar reciprocal t(5;11)(q35;q13) in two cases. Review of the literature disclosed one other oncocytoma with a t(5;11) (q35;q13). This suggests that t(5;11)(q35;q13) defines a (second) subset of oncocytomas apart from the subgroup specifically associated with the loss of chromosomes 1 and Y.

Adenoma↗

PubMed1994

Cytogenetic analysis of a leiomyosarcoma of the kidney.

Nonepithelial malignant renal tumors are very rare, comprising approximately 2-3% of all malignant renal tumors. We were able to culture and subsequently karyotype a leiomyosarcoma (LMS) of the kidney that showed the following representative karyotype: 84,XY,add(X)(q25),-Y,add(1)(p11),dic(1;20) (p34;q13.3),-5,-6,dup(6)(q24),i(7)(p10),add(8)(p11),-9,-11,add(13)(p11), -15,-15 , add(17)(q24)x2,-18,-19,-21,-22,-22, +mar1(?hsr),+mar2,+2mar. A clonal add(1)(q11) was also evident. The DNA index was 1.9. Our results as compared with data from the literature suggest that LMS of the kidney has most cytogenetic aberrations reported to be characteristic of LMS, especially those located in the abdomen, and that different genetic mechanisms of initiation and progression appear to play a role in LMS of similar histology but from different anatomic sites.

Chromosome Aberrations↗

PubMed1994

Cytogenetics as a tool in the histologic subclassification of chondrosarcomas.

Chondrosarcomas are a heterogeneous group of bone neoplasms of which the basic neoplastic tissue is cartilaginous. Frequently the histologic diagnosis and grading of chondrosarcomas is difficult and the histologic appearance does not always reflect the biologic behavior of these tumors. Therefore, it is important to find other parameters that can be of help in the proper diagnosing and grading of these neoplasms. To this end, we attempted to correlate the chromosomal pattern of chondrosarcomas to their histologic subtypes and grades. The cytogenetic analysis of two intermediate-grade chondrosarcomas of bone, and a review of the literature, are presented.

Bone Neoplasms↗

PubMed1994

Comparison of cytogenetic abnormalities and deoxyribonucleic acid ploidy of benign, borderline malignant, and different grades of malignant soft tissue tumors.

BACKGROUND: Both DNA flow cytometry and cytogenetic analysis have been used to study soft tissue tumors. With flow cytometry, the DNA content of a relatively large number of cells can be examined, but cytogenetic analysis gives more detailed information about genomic changes. EXPERIMENTAL DESIGN: In order to compare the advantages and drawbacks of DNA flow cytometry versus chromosomal analysis, 92 primary or recurrent malignant, 16 borderline malignant, and 13 benign soft tissue tumors were karyotyped after short-term culture. DNA ploidy was determined by flow cytometry of suspensions prepared from frozen or paraffin-embedded samples. From 97 patients, 121 samples were analyzed. RESULTS: On the basis of the results, four groups were distinguished: DNA-euploid tumors with normal diploid karyotypes (group a) or with abnormal (group b) karyotypes, and DNA-aneuploid tumors with normal (group c) or abnormal (group d) karyotypes. The findings in group b show that structural chromosomal abnormalities or minor numerical aberrations of chromosomes are not detected by DNA flow cytometry. In group c, the finding of tumors with an aneuploid DNA-profile and cells with normal karyotypes is most likely due to overgrowth of fibroblasts during culture and subsequent karyotyping of normal cells. CONCLUSIONS: The findings show that a) DNA flow cytometry has a higher success rate than karyotyping, b) both techniques are complementary, such that DNA flow cytometry gives an "overview", whereas karyotyping gives more detailed information; comparison of both techniques in individual cases leads to a better understanding of the chromosomal events that occurred during oncogenesis, c) histologically low grade tumors are generally DNA-diploid, but may have an abnormal karyotype, and d) histologically high-grade sarcomas tend to have an aneuploid DNA-profile; they are generally more difficult to karyotype.

Adolescent↗

PubMed1993

Cytogenetic analysis of epithelial renal-cell tumors: relationship with a new histopathological classification.

Renal-cell carcinomas (RCC) are clinically, histologically and cytogenetically very heterogeneous. The present histological WHO classification shows no clear correlation between histologic subtypes and specific chromosomal abnormalities. In 1986, a new classification was proposed by Thoenes and Störkel based on the cell type from which the tumor arises. They distinguish 5 cell types: clear-cell, chromophilic, chromophobic, ductus Bellini and oncocytic. Results of 105 primary tumors show that, in this new classification, there is a correlation between different subtypes of renal-cell tumor and specific chromosomal abnormalities at a microscopic and/or molecular level. The clear-cell compact type shows structural aberrations of chromosomes I, 3, 4, 5q, 6, 10q, 11q and 12q, together with polysomy of chromosomes X, 4, 5, 7, 10, 12, 15, 16, 19, 20, 21 and 22, monosomy of chromosomes 3, 8, 9, 13, 14, and loss of Y. The main characteristics of the chromophilic tubulo-papillary type are trisomies 7 and 17, and loss of the Y-chromosome. Chromophobic carcinoma seems to be correlated with, inter alia, polysomy 7, trisomies 12, 16, 18, 19, structural abnormalities of 11q, and telomeric associations. Oncocytomas do not reveal any specific chromosomal anomaly, except for trisomy 7. Loss of heterozygosity on 3p is only found in the clear-cell compact type. Some specific chromosomal abnormalities correlate with a particular grade of the tumor. These correlations support the hypothesis that specific chromosomal abnormalities play a role in the histogenesis and oncogenesis of RCC. They may be important for tumor diagnosis and clinical prognosis.

Carcinoma, Renal Cell↗

PubMed1993

Significance of aneuploid stemlines in testicular nonseminomatous germ cell tumors.

BACKGROUND: Hyperpentaploidy in testicular nonseminomatous germ cell tumors (TNSGCT) has been associated with progression of disease of patients who initially had TNSGCT in Stage I. METHODS: The authors used flow cytometry to investigate the relationship between ploidy and the clinical behavior in TNSGCT, focusing on hypertetraploid values (DNA index, > 2.00). RESULTS: Patients with TNSGCT containing an aneuploid stemline with a hypertetraploid value more often had higher clinical stage of disease and a higher chance of relapse in advanced stages. The presence of multiple aneuploid stemlines in the tumors was found more frequently in patients who had higher clinical stage disease. CONCLUSIONS: The results suggest that the presence of highly aneuploid or multiple aneuploid stemlines in TNSGCT are associated with a clinically more malignant behavior.

Adolescent↗

PubMed1993

Retinoic acid and cisdiaminodichloroplatinum in the treatment of murine teratocarcinomas in vivo in a nullipotent model.

Induction of differentiation as a treatment modality for nonseminomatous germ cell tumors (NSGCTs) may promote the development of residual mature teratoma (RMT), which is usually associated with primary tumors that are capable of spontaneous somatic differentiation. Therefore, we studied the combination of a cytotoxic drug and a differentiation-inducing agent in vivo in three murine teratocarcinoma models with different levels of spontaneous somatic differentiation: E86-379 (moderate differentiation); NF-1 (poor differentiation); and MH-15 (no differentiation). We used retinoic acid (RA) as differentiation-inducing agent and cisdiaminodichloroplatinum (CDDP) as cytotoxic drug, plus a combination of both. In four separate experiments, the combination of RA and CDDP gave a significant further reduction of tumor size as compared with treatment with either RA or CDDP alone. Morphologically intact tumor after treatment with combined RA-CDDP contained a smaller proportion of undifferentiated tissue (embryonal carcinoma) than after CDDP alone. However, somatic differentiation was not induced in the tumor model lacking spontaneous somatic differentiation. Toxicity was reflected in loss of body weight and death of some animals and closely paralleled the degree of tumor reduction in all experiments.

Animals↗