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F Berthold

Publications and source records attributed to F Berthold.

At least 73 records · Page 4Linked to original sources
PubMed1995

Comparison of DNA aneuploidy, chromosome 1 abnormalities, MYCN amplification and CD44 expression as prognostic factors in neuroblastoma.

A comparison of the prognostic impact of five molecular variables in a large series was made, including tests of their nonrandom association and multivariate analysis. Molecular data were available for 377 patients and MYCN amplification, cytogenetic chromosome 1p deletion, loss of chromosome 1p heterozygosity, DNA ploidy and CD44 expression were investigated. Their interdependence and influence on event-free survival was tested uni- and multivariately using Pearson's chi 2-test, Kaplan-Meier estimates, log rank tests and the Cox's regression model. MYCN amplification was present in 18% (58/322) of cases and predicted poorer prognosis in localised (P < 0.001), metastatic (P = 0.002) and even 4S (P = 0.040) disease. CD44 expression was found in 86% (127/148) of cases, and was a marker for favourable outcome in patients with neuroblastoma stages 1-3 (P = 0.003) and 4 (P = 0.017). Chromosome 1p deletion was cytogenetically detected in 51% (28/55), and indicated reduced event-free survival in localised neuroblastoma (P = 0.020). DNA ploidy and loss of heterozygosity on chromosome 1p were of less prognostic value. Most factors of prognostic significance were associated with each other. By multivariate analysis, MYCN was selected as the only relevant factor. Risk estimation of high discriminating power is, therefore, possible for patients with localised and metastatic neuroblastoma using stage and MYCN.

Aneuploidy↗
PubMed1995

Antiproliferative potential of cytostatic drugs on neuroblastoma cells in vitro.

The role of single drugs in the treatment of neuroblastoma is poorly defined. We, therefore, tested neuroblastoma cell survival after a 72 h exposure to one of 19 cytostatic drugs by monolayer proliferation assay. 6 cell lines (IMR-5, Kelly, SK-N-SH, GI-CA-N, CHP-100, CHP-134) were selected on the basis of MYCN amplification and PGY1 overexpression. ED50 drug concentrations were related to plasma levels achievable in patients during chemotherapy. More effective substances were mitoxantrone, doxorubicin, hydroxyurea, bleomycin, dactinomycin, cisplatinum, thiotepa, melphalan, carboplatinum, etoposide, vincristine, cytarabine, 6-thioguanine, cyclophosphamide, ifosfamide and zilascorb. Parental drugs (cyclophosphamide, cisplatinum) appeared more cytotoxic on a molar basis than derived drugs (ifosfamide, carboplatinum). Less effective drugs included 5-fluorouracil, 6-mercaptopurine, CCNU and procarbazine. Fractional application of a given dose was more efficient than a single dose of cyclophosphamide, ifosfamide and cisplatinum. The tested neuroblastoma cell lines showed distinct sensitivities to cytostatic drugs. Cell lines with MYCN amplification appeared more sensitive than PGY1 overexpressing cells. In conclusion, comparative in vitro testing of cytostatic drugs may provide a rationale for their clinical evaluation. Investigation of drug combinations and application of the monolayer proliferation assay to tumour biopsy material for preclinical chemosensitivity testing are clearly warranted.

Antineoplastic Agents↗
PubMed1995

Differentiation and prognosis of neuroblastoma in correlation to the expression of CD44s.

Cell-cell and cell-extracellular matrix interactions mediated by cell adhesion molecules (for example CD44) play an important role in the cascade of metastasis and the progression of human malignant tumours. The most important aim of this review was, on the basis of our results and the literature, to show the correlation between the expression of CD44s and differentiation and prognosis of neuroblastoma. Surprisingly and in contrast to most other malignant tumours, neuroblastomas exhibited an inverse correlation between CD44s expression and tumour progression. It can be stated that CD44s is a prognostic marker in neuroblastoma which correlates significantly with the grade of tumour cell differentiation, but not with clinical stage. Moreover, there exists a statistically significant correlation between MYCN oncogene amplification and the lack of CD44s expression.

Antigens, Neoplasm↗
PubMed1995

Steady-state levels and bone marrow toxicity of etoposide in children and infants: does etoposide require age-dependent dose calculation?

PURPOSE: Most pediatric treatment protocols specify dose calculations for cytostatic drugs based on body-surface area (BSA). However, for children less than 1 year of age, calculation guidelines vary. Normally, reduced dosages are recommended with calculations based on body weight (BW). However, the optimal dose for infants should take age-dependent and drug-specific pharmacokinetic parameters into account. PATIENTS AND METHODS: The current investigation focused on the effects of different dose-reduction rules on the steady-state levels (Css) of etoposide and related bone marrow toxicity. One hundred seventy three treatment courses in 78 children on a 96-hour continuous infusion schedule were monitored for Css (determined by high-performance liquid chromatography [HPLC]), and 100 courses were documented in detail with regard to dose calculation (125 mg/m2, 4.17/kg, or 2/3 x 4.17/kg) and toxicity. RESULTS: Dose calculation on the basis of BSA led to Css of 4.9 +/- 1.2 micrograms/mL, which on the basis of BW was 3.5 +/- 1.1 micrograms/mL and 1.95 +/- 0.6 micrograms/mL (2/3.kg-dose), respectively. However, conversion of the latter levels to those expected with the regular square-meter-dose, resulted in values of 4.7 +/- 1.4 micrograms/mL and 4.2 +/- 1.2 micrograms/mL (/125 mg/m2). Lower etoposide Css levels resulted in less pronounced thrombocyte and WBC nadirs in the respective groups. The dose-calculation rules for infants, therefore, decreased both dose-intensity and related toxicity. Etoposide clearance rates related to BW (0.8 +/- 0.3 mL/min/kg) or BW (19 +/- 6 mL/min/m2) did not show any differences between children and infants, even in the age range of 3 to 12 months. CONCLUSION: In the case of etoposide, special dose-calculation guidelines for infants are not substantiated by age-dependent pharmacokinetics or tolerance.

Adolescent↗
PubMed1994

Antidisialoganglioside ricin A-chain immunotoxins show potent antitumor effects in vitro and in a disseminated human neuroblastoma severe combined immunodeficiency mouse model.

Several monoclonal antibodies (mAbs) were screened on different neuroblastoma cell lines to evaluate ricin A-chain immunotoxins for possible use against human neuroblastoma. Four mAbs were identified that exhibited high antitumor activity against neuroblastoma cell lines as measured in an indirect cytotoxicity assay. These mAbs, including 14G2a (antidisialoganglioside), ch14.18 (a humanized switch variant), BW704 (antidisialoganglioside), and chCE7 (anti-glycoprotein of M(r) 190,000), were subsequently linked via the bivalent linker N-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-piridyldithio++ +)toluene to deglycosylated ricin A chain. The most potent immunotoxin, 14G2a.dgA, inhibited the protein synthesis of neuroblastoma cell lines IMR5 and NMB by 50% at concentrations of 6 x 10(-12) M. To test the antitumor efficacy of these immunotoxins in vivo, we developed a disseminated human neuroblastoma model in severe combined immunodeficiency mice. Treatment of tumor-bearing mice with 14G2a.dgA 12 days after tumor challenge resulted in a significant prolongation of survival as compared with phosphate-buffered saline-treated controls (16.8 versus 6.5 weeks). We conclude that ricin A-chain immunotoxins might be of potential use in the treatment of human neuroblastoma.

Animals↗
PubMed1994

Infradiaphragmatic bronchogenic cyst with high CT numbers in a boy with primitive neuroectodermal tumor.

Abdominal bronchogenic cysts are very rare with less than 20 published cases. We report the case of a retroperitoneal bronchogenic cyst in a 12-year-old boy, who initially presented with a primitive neuroectodermal tumor of the pelvis. Computed tomography (CT) showed a small, hyperdense nonenhancing mass adjacent to the right crus of the diaphragm. Follow-up CT after chemotherapy showed a decrease in CT attenuation of this mass, but a slight increase in size. At surgery the mass was loosely attached to the diaphragm and final pathology confirmed the diagnosis of a bronchogenic cyst.

Bronchogenic Cyst↗
PubMed1994

Applied Sciences: Absence of CD44-standard in human neuroblastoma correlates with histological dedifferentiation, N-myc amplification and reduced survival probability.

Expression of CD44 was examined by immunohistochemistry in 205 primary neuroblastomas together with histological grading according to the Shimada classification at the time of diagnosis. In addition, Southern blot analysis to determine N-myc gene amplification was carried out in the same tissue. When compared with clinical data such as stage, age and event-free survival probability it was found that CD44 expression characterizes well differentiated tumours and thus correlates with prognosis (event-free survival probability in CD44 positive patients 0.6 (n = 129) vs. 0.0 (n = 21) in CD44 negative patients). In tumours with N-myc = 1, CD44 positivity was found in 91% of patients as compared to 57% of patients with N-myc > 1 in tumours. All tumours of 13 patients with metastatic stage 4s (with good prognosis) showed CD44s expression. Thus, detection of CD44s expression might serve as a prognostic indicator which can be rapidly detected at diagnosis.

Journal Article↗
PubMed1994

Loss of the putative tumor suppressor-gene locus 1p36 as investigated by a PCR-assay and N-myc amplification in 48 neuroblastomas: results of the German Neuroblastoma Study Group.

48 primary neuroblastomas have been examined for an amplified N-myc and loss of the putative tumor suppressor-gene locus 1p36 by loss of heterozygosity studies (LOH 1p36). In 25% of these tumors N-myc amplification and/or a LOH 1p36 was detected, and these patients had a bad prognostic clinical outcome. 75% of the tumors neither had an amplified N-myc nor a LOH 1p36, and these patients had a much better prognosis. Thus, tumor genetic changes can subdivide two types of neuroblastoma with profound different clinical behavior. Detection of these genetic changes at diagnosis could help in front-line risk adapted therapy stratifications in neuroblastoma.

Base Sequence↗
PubMed1994

Multivariate evaluation of prognostic factors in localized neuroblastoma.

PURPOSE: A multitude of risk factors has been described for patients with neuroblastoma. Little is known about the mutual interrelationship of these factors and their impact on patients with localized disease only. PATIENTS AND METHODS: We investigated the possible influence of 37 variables univariately on event-free survival (EFS) in 308 consecutive patients with neuroblastoma stages I-III using Kaplan-Meier estimates. The chi 2 test was applied to detect nonrandom correlations, and the Cox's regression model was used for the multivate evaluation of identified factors. RESULTS: Seventeen factors appeared to influence EFS in stage I-III patients (p < 0.05, log-rank > 3.84), whereas 10 factors were found in the subgroup of stage III patients with midline crossing tumors (= stage III*, n = 128). The majority of univariately identified risk factors showed a nonrandom correlation to several others (p < 0.05). The multivariate analysis according to Cox selected for the patients with stages I-III the factors lactate dehydrogenase (LDH) (p = 0.0011), resectability (p = 0.0167), weight loss (p = 0.0185), tumor extension beyond midline (p = 0.0207), and age (p = 0.0233). For stage III* patients the model identified the factors LDH (p = 0.0089), weight loss (p = 0.0135), resectability (p = 0.0408), and age (p = 0.0700). The identification of these independent risk factors permitted the description of risk groups with EFS ratios after > 6 years between 22% and 96%. CONCLUSIONS: Risk estimation of high discriminating power is possible for patients with localized neuroblastoma using simple, readily available clinical data.

Age Factors↗
PubMed1993

Mutation of the p53 gene in neuroblastoma and its relationship with N-myc amplification.

Mutation of the p53 tumor suppressor gene frequently occurs in a variety of tumors including lung, breast, gastrointestinal, and brain, as well as lymphomas-leukemias. Neuroblastoma, one of the most common solid tumors in childhood, often has amplification of the N-myc gene. We examined for mutations of the p53 tumor suppressor gene by single-strand conformational polymorphism using polymerase chain reaction products and direct sequencing method in neuroblastoma; in addition, we assessed the relationship between p53 mutation and N-myc gene amplification in the disease. Of 86 DNA samples from patients with neuroblastoma, two mutations (2%) were found in the coding region of the p53 gene. Each mutation caused a substitution of amino acid residues. One mutation was located in exon 5, and another was in exon 6. N-myc gene was amplified in 26% of the samples. No p53 mutations were found in neuroblastoma samples with N-myc amplification. In the two individuals, p53 mutations appeared as their disease became more progressive. The neurofibromatosis 1 (NF1) gene is frequently abnormal in another neural disorder, neurofibromatosis type 1; in addition, a potential mutational hot spot of NF1 at lysine at codon 1423 has been identified in several types of tumors. Using single-strand conformational polymorphism, we were unable to detect an abnormality in this region of NF1 in 50 samples of neuroblastoma. The data suggest that p53 mutations occasionally are associated with progression of neuroblastomas, and tumorigenetic influences of mutant p53 may differ from those of N-myc.

Gene Amplification↗
PubMed1993

In vivo metabolism of childhood posterior fossa tumors and primitive neuroectodermal tumors before and after treatment.

BACKGROUND: Despite an increasing interest in the clinical application of positron emission tomography (PET) in tumors of the adult patient as a diagnostic and prognostic tool, only a few studies have been concerned with the usefulness of PET with [18F]2-deoxy-2-fluoro-D-glucose (FDG) in childhood tumors. METHODS: Fifteen children and young adults (0.5-26.0 years of age) with histologically confirmed brain tumors were studied with PET and FDG. Seven children with medulloblastoma (n = 5) or primitive neuroectodermal tumor (PNET) (n = 2) underwent repeated PET studies during their therapy. The other eight children with medulloblastoma (n = 5) or astrocytoma (n = 3) were studied only once before initiation of treatment. A close clinical follow-up was performed in every case. RESULTS: Comparison of local glucose metabolic rates obtained in the various tumor lesions revealed that the mean rates found in medulloblastomas (mean glucose metabolic rate, 42.8 +/- 14.03 mumol/100 g/min) were twice as high as the rates measured in either PNET (17.3 +/- 4.5 mumol/100g/min) or infratentorial gliomas (21.8 +/- 4.2 mumol/100g/min). The high metabolism of medulloblastomas enabled the observer to identify the tumor more easily and to clearly separate it from the surrounding unaffected brain tissue. In the seven patients with follow-up PET studies during therapy, decreasing or increasing ratios of tumor-to-white matter metabolic rate were not only commensurate with neuroradiologically defined tumor reduction or growth, but also corresponded to the duration of initial clinical improvement. CONCLUSIONS: These preliminary results suggest that PET with FDG may be a useful tool to evaluate metabolic activity of pediatric brain tumors over time and to assess response to treatment.

Adolescent↗
PubMed1993

Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment.

PURPOSE AND METHODS: Based on preliminary experience, there was a need for modifications and clarifications in the International Neuroblastoma Staging System (INSS) and International Neuroblastoma Response Criteria (INRC). In 1988, a proposal was made to establish an internationally accepted staging system for neuroblastoma, as well as consistent criteria for confirming the diagnosis and determining response to therapy (Brodeur GM, et al: J Clin Oncol 6:1874-1881, 1988). A meeting was held to review experience with the INSS and INRC and to revise or clarify the language and intent of the originally proposed criteria. Substantial changes included a redefinition of the midline, restrictions on age and bone marrow involvement for stage 4S, and the recommendation that meta-iodobenzylguanidine (MIBG) scanning be implemented for evaluating the extent of disease. Other modifications and clarifications of the INSS and INRC are presented. In addition, the criteria for the diagnosis of neuroblastoma were modified. Finally, proposals were made for the development of risk groups that incorporate both clinical and biologic features in the prediction of prognosis. The biologic features that were deemed important to evaluate prospectively included serum ferritin, neuron-specific enolase (NSE), and lactic dehydrogenase (LDH); tumor histology; tumor-cell DNA content; assessment of N-myc copy number; assessment of 1p deletion by cytogenetic or molecular methods; and TRK-A expression. RESULTS AND CONCLUSION: Modifications of the INSS and INRC made at this conference are presented. In addition, proposals are made for future modifications in these criteria and for the development of International Neuroblastoma Risk Groups.

Humans↗
PubMed1993

[Peripheral neurogenic tumors--surgical therapy of neuroblastoma. Review and personal results].

From January 1, 1982 to November 1, 1992 24 patients suffering from neuroblastoma were operated in the course of a neuroblastoma study at the Department of Surgery, Cologne University. 23 patients were in advanced stages 3, 4 and 4s. In 13 cases the initial operation was prior to applying chemotherapy, whereas in 10 cases chemotherapeutical treatment had taken place before. As a result of preoperative chemotherapy operation time and blood loss could be reduced, respectively, and despite delayed operative treatment a better demarcation of the tumor and an easier preparation were seen. Due to the preoperative treatment, tumors could be operated on more radically without increasing the rate of complications. Utilizing all possible surgical means, secondary and tertiary operative procedures and chemotherapeutical treatment. all patients in stage 2, 3 and 4s survived with safe remission. Nine of the fifteen patients in stage 4 died due to side effects from bone marrow transplantation or from recurrent neuroblastomas and not because of the surgical procedures. In the light of existing current multicenter neuroblastoma studies stage oriented surgical and chemotherapeutical concepts were developed, that are presented in this paper.

Adolescent↗
PubMed1992

Serum vanillylmandelic acid/homovanillic acid contributes to prognosis estimation in patients with localised but not with metastatic neuroblastoma.

In 211 patients with neuroblastoma, serum vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels were determined and correlated to stage, histological differentiation, ferritin, neuron-specific enolase, lactate dehydrogenase (LDH) and outcome. Elevated serum VMA and/or HVA levels were found 16% less frequently than elevated urine levels. The incidence of the elevated serum levels increased with stage (stages I-III 58%, IV 78%, IVS 100%). Increased VMA/HVA ratios were not associated with a higher grade of tumour differentiation. Serum ferritin and neuron-specific enolase showed no correlation, and LDH a borderline non-random correlation with the serum catecholamine metabolites. Using age-related reference values a quotient of serum VMA/HVA (P = 0.061) < 0.7 indicated a poorer event-free survival (48 +/- 10%) than ratios > or = 0.7 (event-free survival 81 +/- 6%) for children with localised neuroblastoma (P = 0.0004). No correlation with prognosis was detected for patients with stage IV and stage IVS disease. We conclude that serum VMA and HVA determinations may be useful as tumour markers for 71% of neuroblastoma patients, and aid in estimating the prognosis in children with localised disease.

Biomarkers, Tumor↗
PubMed1992

Prognostic factors in metastatic neuroblastoma. A multivariate analysis of 182 cases.

The purpose of our study was to investigate the interrelationship of known and possible new risk factors in patients with metastatic neuroblastoma and to define groups at risk. The possible influence of 37 variables on event-free survival (EFS) was analyzed univariately in 308 consecutive patients using the Kaplan-Meier estimate. Fifteen factors were identified (p less than 0.05, logrank greater than 3.84) of whom eight showed a nonrandom correlation to several others (chi 2-test, p less than 0.05). Seven noncorrelated factors [lactate dehydrogenase (LDH) level, resectability of the primary tumor, histologic grade, leukopenia, presence of symptoms, general condition, and age at diagnosis] were included in the multivariate analysis of 182 patients according to the Cox model. The variables LDH (p = 0.0007), resectability (p = 0.0063), histologic grade (p = 0.0055), and leukopenia (p = 0.0470) were identified multivariately as prognostic factors for EFS. These results permitted the classification of patients into three prognostic groups. The 6 year event-free survival for group IV-A (LDH normal) was 0.37 +/- 0.12, for group IV-B (LDH abnormal, additional risk factors favorable) 0.18 +/- 0.10, and for group IV-C (LDH abnormal, 1-3 additional risk factors unfavorable) was 0.08 +/- 0.03. We conclude that the proposed clinicopathological classification may prove to be a reliable and easily applicable tool for estimating the outcome of metastatic neuroblastoma in children.

Child, Preschool↗
PubMed1992

[Response criteria for enzyme substitution in Gaucher disease].

Recently the intravenous enzyme replacement therapy with modified beta-glucocerebrosidase has become available for patients with M. Gaucher. We report here the considerable improvement of activity and vigor in a 5 year old girl with type 1 M. Gaucher administering 60 IU/kg every two weeks for 6 months. The platelet count increased from 82-96/nl to more than 150/nl and hemoglobin from 10.8 to more than 12 g/dl. Serum acid phosphatase decreased from 14.6 U/l to 5.9. U/l and angiotensin-converting enzyme from 327 to 102 U/l. The estimation of splenic volume by MRT showed a decrease by 40%, while liver size was not reduced within 6 months of therapy. MRT proved to be useful to demonstrate the bone marrow infiltration by Gaucher cells. The enzyme replacement therapy resulted in an objective response. No side effects have been observed so far. The extreme high treatment costs enforce a considerable dose reduction for maintenance therapy.

Acid Phosphatase↗