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R Parwaresch

Publications and source records attributed to R Parwaresch.

At least 37 records · Page 2Linked to original sources
PubMed2001

Favorable outcome for children and adolescents with T-cell lymphoblastic lymphoma with an intensive ALL-type therapy without local radiotherapy.

In study NHL-BFM 90 we investigated the efficacy of an ALL-type treatment without local radiotherapy for childhood T-cell lymphoblastic lymphoma (T-LBL). In particular, the prognostic impact of the speed of tumor regression was evaluated. From April 1990 to March 1995, 105 evaluable patients, 1.1-16.4 years of age, with T-LBL were enrolled into study NHL-BFM 90. Patients with stage I and II received an 8-drug induction followed by a consolidation including high-dose-methotrexate (MTX) and maintenance therapy up to a total therapy duration of 24 months. Patients with stage III and IV received an additional reinduction and cranial radiotherapy (CRT) (12 Gy for prophylaxis) between consolidation and maintenance. Residual tumor after completion of induction had to be resected. No local RT was applied. Patients received intensified chemotherapy if tumor regression on day 33 of induction was <70% or when vital residual tumor was present after the induction phase. With a median follow-up of 6.41 years, pEFS at 5 years is 91.4% (SE+/-2.7%). 101 patients were evaluable for the speed of tumor response. Two patients received intensified therapy due to <70% tumor regression on day 33. Of 19 patients with tumor residues after induction, 2 relapsed as compared to 4 of 80 patients with complete tumor regression. Our data demonstrate that, with intensive ALL-type chemotherapy but no local radiotherapy, an event-free survival rate of 90% can be achieved in childhood T-LBL. Providing tumor regression within 5 weeks is sufficient, tumor remnants after induction have weak prognostic impact.

Adolescent↗
PubMed2001

A distinctive melanocytic lesion associated with melanoma-prone dysplastic naevus syndrome: the hybrid naevus.

Clinically and histologically, the concept of dysplastic nevi remains controversial. To elaborate more precise criteria for the nevi of patients with dysplastic naevus syndrome (DNS), we examined 58 nevi from seven DNS patients who developed one or several malignant melanomas. Clinical presentation and histomorphology were evaluated, and immunohistochemistry was performed using proliferation marker Ki-S5 and antibody DO-7 to the p53 protein. Sixty nevi from individuals without history of melanoma served as controls. Of the DNS nevi, 21 (36.2%) exhibited no morphological particularities. The remaining 37 nevi presented distinctive histological features consisting of a slight epidermal acanthosis, spitzoid vertically oriented nests of dyscohesive nevus cells, and single-standing atypical melanocytes in the basal cell layer of the epidermis. Immunohistochemical analysis revealed an average proliferation index of 2.5%, which significantly surpassed the mean growth fraction of conventional dysplastic nevi (<1%). No increase in p53 expression was observed. Characteristically, active proliferation was found in junctional single-standing melanocytes with or without nuclear atypia rather than in nest-shaped compounds. In conclusion, certain moles of patients with DNS possess distinctive features. The newly characterized criteria may provide a basis for the diagnosis of DNS and might help to identify patients at increased risk for malignant melanoma by examination of a single biopsy.

Adolescent↗
PubMed2001

Regulation of telomerase activity by alternate splicing of human telomerase reverse transcriptase mRNA in a subset of neuroblastomas.

It has been proposed that the regulation of telomerase takes place at the transcriptional level, the expression of the catalytic subunit human telomerase reverse transcriptase (hTERT) being crucial for telomerase activity (TA). Recently, differential splicing of hTERT mRNA has been demonstrated in various tissues during embryonal development, and it has been suggested that only full-length transcripts translate into functionally active telomerase. With this in view, we analyzed the different hTERT transcripts by reverse transcriptase-polymerase chain reaction in neuroblastic tumors and compared the results with the TA, the tumor growth fraction, and the MYCN status. In a series of 38 neuroblastic tumors, high TA and full-length hTERT transcripts were found in nine samples, whereas nine samples showed absence of both enzymatic activity and hTERT transcripts. Interestingly, in another eight samples, low or absent TA coincided with a lack of full-length hTERT transcripts. Eleven samples contained hTERT transcripts with low or undetectable TA and one sample had low TA but no hTERT transcripts. TA correlated with MYCN amplification and was weakly associated with the proliferative activity. Moreover, a significant correlation with tumor progression was observed. Our findings point at a posttranscriptional regulation of TA in a subset of neuroblastic tumors. Because high TA was detected only in tumors with full-length hTERT transcripts, reverse transcriptase-polymerase chain reaction analysis of archival neuroblastic tumor samples might help to appraise the malignant potential in individual cases.

Alternative Splicing↗
PubMed2001

Early mycosis fungoides: molecular analysis for its diagnosis and the absence of p53 gene mutations in cases with progression.

The histological diagnosis of initial mycosis fungoides (MF) and the molecular mechanisms that are responsible for its progression and transformation to the more highly malignant variants of MF remain largely unknown. Because of the rare occurrence of these tumours, the need for snap frozen skin biopsy specimens and the difficulty to obtain suitable material for karyotypic and genotypic analysis, specific cytogenetic and molecular lesions have not yet been identified. In particular the role of known oncogenes and tumour suppressor genes, including the p53 gene, in the pathogenesis and clinical progression of MF has not been extensively investigated. The present study was carried out using the polymerase chain reaction (PCR) technique combined with temperature gradient gel electrophoresis (TGGE) to detect mutations of the p53 gene in 58 patients with MF. TGGE analysis was also used in combination with clonality analysis by means of T-cell receptor gamma (TCRG) gene rearrangement studies to distinguish parapsoriasis en plaque and initial MF from patch/plaque stage MF. More than 83% of the diagnoses of initial MF could be confirmed using PCR-TGGE analysis. However, although the sensitive TGGE analysis was used for all exons, p53 gene polymorphisms were found in 4 and p53 gene mutation in only 1 of 58 biopsy specimens. It appears unlikely that p53 gene mutations play a role in either the pathogenesis of parapsoriasis and initial MF or their progression to advanced stages of MF. However, TCRG gene rearrangement studies by means of TCR-TGGE analysis may be useful for distinguishing histologically discordant cases of initial MF.

Biopsy↗
PubMed2001

Concurrent overexpression of p53 and c-erbB-2 correlates with accelerated cycling and concomitant poor prognosis in node-negative breast cancer.

Simultaneous overexpression of c-erbB-2 and p53 has been reported to be prognostically unfavorable in breast cancer. Herein, we show that concurrent overexpression of these 2 proteins is associated with a marked reduction in the relative fraction of cells in G(1) phase of the cell cycle, indicating an accelerated cell cycle progression. Using an immunohistochemical approach, we examined 261 cases of node-negative infiltrating ductal carcinomas of the breast with respect to c-erbB-2 and p53 expression and to the proliferative activity measured by the Ki-67 index. By means of a novel monoclonal antibody, Ki-S2, which exclusively recognizes proliferating cells in the S, G(2), and M phases of the reproductive cycle, we were further able to calculate the relative fraction of the cells having passed the restriction point at the G(1)/S boundary, thus defining a cycling ratio (CR). The results were correlated with clinical outcome; median follow-up time was 96 months. Tumors that simultaneously overexpressed c-erbB-2 and p53 had a high median CR and followed an unfavorable course. However, increased CRs were also observed independently of c-erbB-2 and p53 overexpression, suggesting that other molecular mechanisms may contribute to acceleration of cell cycle progression. In a multivariate analysis that included patient age, tumor size, hormone receptor status, c-erbB-2 and p53 expression, and the Ki-67 index, CR emerged as the most significant independent predictor of overall and disease-free survival (P <.0001). It is concluded that the CR is a gauge of cell cycle deregulation and therefore may be a powerful indicator of the biologic behavior of cancers. HUM PATHOL 32:311-319.

Adult↗
PubMed2001

High telomerase activity is associated with cell cycle deregulation and rapid progression in endometrioid adenocarcinoma of the uterus.

Telomerase activity, a mechanism granting cellular immortality, has been detected in most cancer entities, but its association with clinical, histopathologic, and prognostic parameters is not fully understood. We investigated whether quantitative telomerase levels are correlated to established prognostic factors, telomere lengths, cell cycle kinetics, and the clinical course in endometrioid adenocarcinoma of the uterus (EC). A modified telomeric repeat amplification protocol (TRAP) was used to quantify the relative telomerase activity in a series of 53 primary tumors. Mean telomere length was determined by Southern blot analysis. Cell cycle kinetics were studied immunohistochemically on paraffin sections using monoclonal antibodies to 2 distinct proliferation-specific proteins: Ki-67, which is expressed throughout the cell cycle, and a novel cell cycle-associated protein, repp86, the expression of which is restricted to the cell cycle phases S, G2, and M. The ratio of the 2 immunolabeling indices defines the rate of transition through the restriction point. Telomerase activity was detected in 50 of 53 ECs (94%). Its levels correlated significantly with FIGO stage (P =.01) and FIGO grade (P =.003) but not with myometrial invasion. They were weakly associated with the overall proliferative activity (Ki-67, r =.48) but significantly with the repp86 index (r =.64) and even more strongly with the repp86:Ki-67 ratio (r =.77). There was no correlation with mean telomere length. In the group of tumors with high telomerase activity, 5 patients had relapses and 2 died of the disease within a median follow-up period of 29 months. Recurrence showed no relation to FIGO grade and stage. No events were observed in the group with low telomerase activity. In a multivariate model including tumor stage, histopathologic grade, depth of myometrial invasion, and Ki-67 indices, telomerase activity emerged as the only independent predictor of disease progression (P =.0002). It is concluded that beyond a link to proliferation, high telomerase activity reflects a deregulation of the cell cycle associated with an increased rate of cells entering S phase and a higher degree of malignancy. Therefore, quantitative analysis of telomerase activity may be useful for identifying EC patients at high risk for recurrence.

Adenocarcinoma↗
PubMed2001

High proliferative activity may predict early metastasis of thin melanomas.

Metastasis of thin melanomas is uncommon and unpredictable. We prospectively investigated the clinical course of 167 thin melanomas (<1 mm thickness) over a median observation period of 4 years (18 to 87 months). In addition to Breslow thickness, Clark level, and growth phase characteristics, we assessed cellular proliferation by counting mitoses and immunohistochemically using the monoclonal antibody Ki-S5 (Ki-67). Mitotic and Ki-S5 indices were correlated to tumor thickness, Clarks level, and radial/vertical growth phase (RGP/VGP). However, 5 tumors had proliferation indices above 25% (outside the range of a theoretical normal distribution). Four of these tumors metastasized, and none of the melanomas with lower proliferative activity progressed during the observation period. The metastatic behavior was independent of tumor thickness and Clark level and did not unconditionally coincide with VGP or high mitotic counts. It is concluded that the immunohistochemical proliferation index may be a powerful predictor of early systemic progression in thin melanomas, which may be helpful in making therapeutic decisions. Further investigations are needed to determine the value of proliferation measurements for the long-term prognosis of thin melanomas.

Adult↗
PubMed2001

Temporary response of localized intracranial mast cell sarcoma to combination chemotherapy.

Cerebral involvement of systemic mastocytosis and intracranial sarcoma of myelogenic origin are well known entities. An 8-year-old girl with an isolated cerebral mast cell tumor is presented. Specific histopathologic stains were used to confirm the diagnosis detecting immunophenotype and proliferative activity. Treatment with irradiation, intrathecal cytarabine, and interferon-alpha2b did not induce regression whereas polychemotherapy did. Systemic combination chemotherapy led to marked transient tumor regression in this proliferating mast cell sarcoma in an unusual intracranial location.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Primary lymph node plasmacytomas (plasmacytic lymphomas).

To determine whether primary lymph node plasmacytoma (PLNP) is a distinct entity among other types of plasma cell neoplasia, we analyzed a large series of PLNPs from 2 large lymphoma registries to compare histologic, immunophenotypic, and clinical features of PLNPs, nonnodal extramedullary plasmacytomas, and multiple myeloma. Twenty-five PLNPs (clinical data on 15 cases) were compared with 10 non-lymph node plasmacytomas and 51 cases of multiple myeloma; 36 cases of reactive plasmacytoses were used as controls. The histologic features of PLNP and other extramedullary plasmacytomas were similar. The histologic features of PLNPs were more immature than those of reactive plasmacytoses and less immature than in multiple myeloma. The immunophenotype of PLNPs significantly differed from that of reactive plasmacytoses, other extramedullary plasmacytomas, and multiple myeloma. PLNPs did not progress to multiple myeloma, unlike other extramedullary plasmacytomas, even though survival in PLNPs and other extramedullary plasmacytomas was similar. Our findings suggest that PLNPs may be distinct from other plasma cell dyscrasias.

Adolescent↗
PubMed2000

Cloning and localization of C2orf2(ropp120), a previously unknown WD repeat protein.

Ropp 120 (restrictedly overexpressed proliferation-associated protein) is a cytoplasmic protein of 120 kDa that is significantly overexpressed in mitotic cells. Protein sequencing of the immunoaffinity purified 120-kDa protein showed it to be an as yet unknown protein. DNA sequencing revealed a cDNA sequence of 3419 bases, which includes the complete coding region of ropp120 of 2943 bases (981 amino acids). Analysis of the deduced amino acid sequence showed that ropp 120 contains four WD repeats and a well-conserved consensus sequence of serine proteases. The gene encoding ropp120 (HGMW-approved gene symbol C2orf2) was assigned to chromosome 2p21-p22 by means of radiation hybrid and fluorescence in situ hybridization mapping.

Amino Acid Sequence↗
PubMed2000

Operative and conservative management of primary gastric lymphoma: interim results of a German multicenter study.

PURPOSE/OBJECTIVE: Biology and appropriate management of gastrointestinal (GI lymphomas are matters of an ongoing controversial debate. To evaluate histological features, sites of involvement and management of primary GI-lymphomas, a prospective multicentric study was initiated in 10/1992. Aim of study was the further standardization of operative and conservative treatment modalities. MATERIALS AND METHODS: Study started 10/1992 and was closed 11/1996. A total of 381 evaluable patients had been accrued then. Standardized diagnostic workup included endoscopic and radiological evaluation of the complete GI-tract as well as a central histological review. Diagnosis was established after Lewin, stage classification was made after Musshoff, and histological classification was made after Isaacson. Treatment decision concerning operative or conservative management was due to the initially acting physician. Patients with resection of low grade lymphoma received total abdominal irradiation 30 Gy + 10 Gy boost to incompletely resected areas. After resection of high grade lymphoma CHOP chemotherapy (4 cycles for stage IE, 6 cycles for higher stages) after McKelvy was followed by total abdominal irradiation 30 Gy for stage IE respectively involved field irradiation 30 Gy for higher stages with 10 Gy boost to incompletely resected areas. Primary conservative- treatment consisted of six cycles COP chemotherapy after Bagley for low grade lymphomas stage > IE and total abdominal irradiation 30 Gy + 10 Gy boost to involved areas for all stages. Patients with high grade lymphomas received 4 x CHOP followed by total abdominal irradiation 30 Gy + 10 Gy boost to involved areas or 6 x CHOP plus involved field radiation therapy with 40 Gy. 257 patients are considered for analysis due to exclusion criteria of the study, 190 of them were suffered from gastric lymphoma. Their median observation time is 29 months, maximum observation time is 68 months. RESULTS: Sites of involvement were stomach in 73.4%, small bowel 9.6%, ileocoecal region 6.9%, and other sites 3.2% More than one GI site was involved in 6.9%. Gastric lymphomas achieved a survival probability of 89% after 3 years. Though surgical and conservative treatment was not randomized, outcome was analyzed in gastric NHL stages I and II (histologic subtype not considered showing no significant influence). At 3 and 5 years survival is 88% in resected cases vs. 94% and 86% in conservatively treated patients (p = 0.350). Analyzing only stages I + II(1) surgery also seems of no advantage even considering only RO-resections. There was one acute gastrointestinal bleeding under primary chemotherapy for a high grade lymphoma. Toxicities of grade III and IV WHO were rarely seen during treatment. All other acute toxicities were not more than grade II WHO. CONCLUSION: Conservative treatment in this setting is feasible. The operative approach seems not to be advantageous compared to conservative treatment and should be critically reconsidered.

Adult↗
PubMed2000

Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report.

The purpose of our study was to investigate the efficacy of an acute lymphoblastic leukemia (ALL)-type treatment with moderate-dose, prophylactic cranial irradiation and without local radiotherapy for childhood T-cell lymphoblastic lymphoma (T-LBL). From April 1990 to March 1995, 105 evaluable patients, 1.1 to 16.4 years of age, with T-LBL were enrolled in study NHL-BFM 90 (non-Hodgkin's lymphoma-Berlin-Frankfurt-Munster 90). They received an 8-drug induction over 9 weeks followed by an 8-week consolidation including methotrexate (MTX) 5 g/m(2) x 4. Patients with stage I (n = 2) and II (n = 2) continued with maintenance therapy (6-mercaptopurine daily and MTX weekly, both orally) until a total therapy duration of 24 months. Patients with stage III (n = 82) and IV (n = 19) received an 8-drug intensification over 7 weeks and cranial radiotherapy (12 Gy for prophylaxis) after consolidation, followed by maintenance. Residual tumor after induction had to be resected. Patients received intensified chemotherapy if tumor regression on day 33 of induction was less than 70% or when vital residual tumor was present after the complete induction phase. With a median follow-up of 4.5 years, the estimated event-free survival at 5 years is 90% (95% confidence interval, 82%-100%). Events were 1 early death, 8 tumor failures, and 1 secondary acute myeloid leukemia. A total of 101 patients were evaluable for the speed of tumor response. Two patients received intensified therapy due to less than 70% tumor regression on day 33. Of 19 patients with tumor residues after induction, 2 relapsed as compared to 4 of 80 patients with complete tumor regression. We conclude that, with intensive ALL-type chemotherapy including moderate cumulative doses of anthracyclines 240 mg/m(2) and cyclophosphamide (3 g/m(2)) and moderate-dose prophylactic cranial irradiation but no local radiotherapy, an event-free survival rate of 90% can be achieved in childhood T-LBL. (Blood. 2000;95:416-421)

Adolescent↗
PubMed2000

Cell proliferation, carcinogenesis and diverse mechanisms of telomerase regulation.

Replication of linear genomes is incomplete and leaves terminal gaps. Solutions to this 'end replication' problem can be traced back to the prebiotic RNA world: 'fossils' of the presumptive archetypes of telomere structure and of the telomerase enzyme are retained in the terminal structures of some RNA viruses. Telomerase expression in mammals is ubiquitous in embryonic tissues but downregulated in somatic tissues of adults. Exceptions are regenerative tissues and, notably, tumor cells. Telomerase activation is controlled by cellular proliferation, and it is an early step in the development of many tumors. In contrast to mammals, indeterminately growing multicellular organisms, such as fish and crustaceae, maintain telomerase competence in all somatic tissues. In human tumor diagnostics, detection of proliferation markers with monoclonal antibodies is well established, and in this review, the significance of additional telomerase assays is evaluated. Telomerase inhibitors are attractive goals for application in tumor therapy, and telomerase knockout mice have proven that telomere erosion limits the lifespan of cells in vivo. In contrast, telomerase stimulation can be used to expand the potential of cellular proliferation in vitro, with possible applications for transplantation of in vitro expanded human cells, for immortalizing primary human cells as improved tissue models and for the isolation of otherwise intractable products, such as genuine human monoclonal antibodies.

Adult↗
PubMed2000

Telomeres, telomerase and cancer: an up-date.

In the mid 1990s, the hypothesis emerged that the upregulation or re-expression of a telomere-synthesising ribonucleoprotein, called telomerase, is a critical event responsible for continuous tumour cell growth. In contrast to normal cells, in which gradual mitosis-related erosion of telomeres eventually limits replicative life span, tumour cells have telomerase and show no loss of these chromosomal ends. These data suggest that telomere stabilisation may be required for cells to escape replicative senescence and to proliferate indefinitely. Because of the close association between telomerase and malignancy, both pathologists and clinicians expect this molecule to be a useful malignancy-marker and a new therapeutic target. This review focuses on the components of the human telomere and of the human telomerase enzyme. A synopsis of reports studying the clinical-diagnostic value of telomere length measurements, of telomerase activity analyses and of the in situ telomerase detection is given. Finally, a summary of recent experimental work that sheds new light on the biological role of this fascinating molecule is presented.

Aging↗
PubMed2000

In situ reverse-transcriptase polymerase chain reaction demonstration of the EWS/FLI-1 fusion transcript in Ewing's sarcomas and peripheral primitive neuroectodermal tumors.

It is now widely accepted that the EWS/FLI-1 fusion transcript is associated with tumors of the Ewing family. To test whether it is possible to detect the fusion transcript by means of combining polymerase chain reaction (PCR) methodology and immunohistochemistry, we investigated tumors of the Ewing family using in situ reverse transcriptase (RT)-PCR. We were able to demonstrate the t(11;22) fusion transcript in five of six cases of Ewing's sarcoma and four of four peripheral primitive neuroectodermal tumors. These results were confirmed using fluorescence in situ hybridization in seven tumor samples. In situ RT-PCR-labeled fusion transcripts were found in virtually all tumor cells within a given sample, indicating that each cell possessed the t(11;22) transcript. We conclude from these results that in situ RT-PCR can be used for the rapid detection of EWS/FLI-1 fusion transcripts in biopsy material. The findings also suggest that all cells of the tumors of the Ewing family carry the EWS/FLI-1 fusion transcript.

Adolescent↗
PubMed2000

Telomerase activity in melanocytic lesions: A potential marker of tumor biology.

Telomerase activation, being a cardinal requirement for immortalization, is a crucial step in the development of malignancy. With a view toward diagnostic and biological aspects in melanocytic neoplasia, we investigated the relative levels of telomerase activity in 72 nevi and 16 malignant melanomas by means of a modified telomeric repeat amplification protocol (TRAP) assay, including an internal amplification standard. We further compared telomerase activity with the expression of two different proliferation-specific proteins, Ki-67 and repp86, a protein expressed exclusively in the cell cycle phases S, G2, and M. Telomerase activity was associated with the overall growth fraction (Ki-67) but showed a closer correlation with the expression of repp86. Both telomerase activity and proliferation indices discriminated clearly between malignant melanomas and nevi, but not between common and dysplastic nevi. Nonetheless, a portion of nevi exhibited markedly elevated telomerase activity levels without proportionally increased proliferation. This was independent of discernible morphological changes. Clinicopathological correlations showed an association between high telomerase activity and early metastatic spread in melanomas, linking telomerase to tumor biology. Our results provide arguments in favor of an occasional progression from nevi to melanomas and imply that proliferation measurements in combination with telomerase assays may help to elicit early malignant transformation that is undetectable by conventional morphology.

Adolescent↗