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Biomedical subjects

R Parwaresch

Publications and source records attributed to R Parwaresch.

At least 19 recordsLinked to original sources
PubMed2003

Primary mediastinal large B-cell lymphoma with sclerosis in pediatric and adolescent patients: treatment and results from three therapeutic studies of the Berlin-Frankfurt-Münster Group.

PURPOSE: Primary mediastinal large B-cell lymphoma with sclerosis (PMLBL) is a rare entity of non-Hodgkin's lymphoma (NHL) arising from thymic mature B cells. Optimal treatment strategies remain to be established, especially in pediatric patients. PATIENTS AND METHODS: This study analyzes clinical characteristics and treatment outcome of 30 pediatric patients with PMLBL, diagnosed in multicenter therapy NHL-Berlin-Frankfurt-Münster Group (BFM) trials. Treatment was stratified by stage and serum lactate dehydrogenase (LDH) and consisted of four to six 5-day courses of chemotherapy using steroids, oxazaphosphorine alkylating agents, methotrexate, cytarabine, etoposide, and doxorubicin. Radiation was not part of the protocol. RESULTS: From April 1986 to August 1999, 1,650 patients with newly diagnosed NHL were enrolled in the NHL-BFM trials; 30 patients (1.8%) had PMLBL. Median age was 14.3 years (range, 1.4 to 16.7 years); 15 patients were male and 15 patients were female. With a median observation time of 5 years (range, 1 to 12 years), probability of event-free survival (pEFS) at 5 years was 0.70 (SE, 0.08). Two patients erroneously diagnosed as T-cell NHL received non-B-cell therapy and died from progress of disease. Events in 28 patients receiving B-cell therapy included early progress during therapy (n = 1) and relapse (n = 6). Residual mediastinal masses were present in 23 patients after two courses of therapy and in 15 patients after the end of therapy. LDH > or = 500 U/L was associated with increased risk of failure in multivariate analysis. CONCLUSION: PMLBL mainly is found in adolescents. Dose-intense chemotherapy including high-dose methotrexate yields a pEFS at 5 years of 0.70 (SE, 0.08). LDH is of prognostic value in pediatric patients with PMLBL.

Adolescent↗
PubMed2001

Primary gastrointestinal non-Hodgkin's lymphoma: I. Anatomic and histologic distribution, clinical features, and survival data of 371 patients registered in the German Multicenter Study GIT NHL 01/92.

PURPOSE: The study was initiated to obtain epidemiologic data and information on anatomic and histologic distribution, clinical features, and treatment results in patients with primary gastrointestinal non-Hodgkin's lymphomas (PGI NHL). PATIENTS AND METHODS: Between October 1992 and November 1996, 371 PGI NHL patients were eligible to evaluate clinical features. Radiotherapy and chemotherapy were stratified according to histologic grading, stage, and whether surgery had been carried out or not. RESULTS: A total of 74.8% patients had gastric NHL (PGL). Within the intestine, the small bowel and the ileocecal region were involved in 8.6% and 7.0% of the cases, respectively. Multiple GI involvement (MGI) was 6.5%. Approximately 90% of the GI NHL were in stages IE/IIE. Aggressive NHL accounted for the majority, with a distinguishable pattern in several sites. Forty percent of PGL were of low-grade mucosa-associated lymphatic tissue type. One third of large-cell lymphomas had low-grade components. Most intestinal NHL were germinal-center lymphomas. The site of origin was prognostic. In gastric and ileocecal lymphoma, event-free (EFS) and overall survival (OS) were significantly higher as compared with the small intestine or MGI (median time of observation, 51 months). In PGL, localized disease was prognostic for EFS and OS. Histologic grade influenced only EFS significantly. Numbers in intestinal lymphomas were too small for subanalyses. CONCLUSION: PGI NHL are heterogeneous diseases. The number of localized PGL allowed for detailed analyses. Larger studies are needed for stages III and IV and for intestinal NHL. A uniform reporting system for PGI NHL, in terms of definitions and histologic and staging classifications, is needed to facilitate comparison of treatment results.

Adolescent↗
PubMed2001

Primary gastrointestinal non-Hodgkin's lymphoma: II. Combined surgical and conservative or conservative management only in localized gastric lymphoma--results of the prospective German Multicenter Study GIT NHL 01/92.

PURPOSE: The aim of the study was to obtain data on anatomic and histologic distribution, clinical features, and treatment results of patients with primary gastrointestinal non-Hodgkin's lymphomas, particularly combined surgical and conservative treatment (CSCT) versus conservative treatment (CT) alone for primary gastric lymphoma (PGL) in localized stages. PATIENTS AND METHODS: Whether the treatment included surgery was left to the discretion of each participating center. Radiotherapy (Rx) and chemotherapy were stratified according to histologic grading, stage, and the inclusion or omission of surgery as follows: patients with low-grade PGL were treated with extended-field (EF) Rx (30 Gy). In case of residual tumor after surgery or in case of CT only (in stage IIE after six cycles of cyclophosphamide, vincristine, and prednisone), an additional boost of 10 Gy was given. All patients with high-grade PGL were treated with four (stage IE) or six (stage IIE) cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone followed by EF Rx (stage IE) or involved-field (IF) Rx (stage IIE). Rx dosage corresponded to low-grade NHL. RESULTS: Between October 1992 and November 1996, 106 patients had CT only. The survival rate (SR) after 5 years was 84.4% and was influenced neither by patients' characteristics nor by stage or histologic grade. Seventy-nine patients had CSCT. Their SR was 82.0%. Complete resection of the tumor (R0) was prognostic for the overall survival (P =.0165) as compared with incomplete resection. CONCLUSION: Although the study was not randomized, a stomach-conserving approach may be favored.

Aged↗
PubMed2001

Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90.

Anaplastic large-cell lymphoma (ALCL) accounts for approximately 10% of pediatric non-Hodgkin lymphoma (NHL). Previous experience from NHL-Berlin-Frankfurt-Münster (BFM) trials indicated that the short-pulse B-NHL-type treatment strategy may also be efficacious for ALCL. The purpose of this study was to test the efficacy of this protocol for treatment of childhood ALCL in a large prospective multicenter trial and to define risk factors. From April 1990 to March 1995, 89 patients younger than 18 years of age with newly diagnosed ALCL were enrolled in trial NHL-BFM 90. Immunophenotype was T-cell in 40 patients, B-cell in 5, null in 31, and not determined in 13. Stages were as follows: I, n = 8; II, n = 20; III, n = 55; IV, n = 6. Extranodal manifestations were as follows: mediastinum, n = 28; lung, n = 13; skin, n = 16; soft tissue, n = 13; bone, n = 14; central nervous system, n = 1; bone marrow, n = 5. After a cytoreductive prephase, treatment was stratified into 3 branches: patients in K1 (stage I and II resected) received three 5-day courses (methotrexate [MTX] 0.5 g/m(2), dexamethasone, oxazaphorins, etoposide, cytarabine, doxorubicin, and intrathecal therapy); patients in K2 (stage II nonresected and stage III) received 6 courses; patients in K3 (stage IV or multifocal bone disease) received 6 intensified courses including MTX 5 g/m(2), high-dose cytarabine/etoposide. The Kaplan-Meier estimate for a 5-year event-free survival was 76% +/- 5% (median follow-up, 5.6 years) for all patients and 100%, 73% +/- 6%, and 79% +/- 11% for K1, K2, and K3, respectively. Events were as follows: progression during therapy, n = 2; progression or relapse after therapy, n = 20; second malignancy, n = 1. It was concluded that short-pulse chemotherapy, stratified according to stage, is effective treatment for pediatric ALCL. B symptoms were associated with increased risk of failure. (Blood. 2001;97:3699-3706)

Adolescent↗
PubMed2001

Telomere biology in human aging and aging syndromes.

Telomeres, the extreme ends of the chromosomes play a key role in the process of cellular aging. Due to the 'end-replication-problem', successive shortening of the telomeres with each cell division results in a mitotic clock and it was shown in vitro that this clock limits the replicative capacity of cell proliferation. Telomerase counteracts telomere erosion and provides some somatic cells an unlimited proliferative potential in vitro. The present views of telomeres and telomerase functions in cellular aging in vitro are presented. Possibilities and limitations in the evaluation of the in vivo impact of telomere erosion on human aging, aging syndromes and age related diseases are reviewed. Unresolved questions, future experimental approaches and emerging therapeutic applications are discussed.

Aging↗
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↗