[German Hodgkin's Lymphoma Study Group].
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Combined Modality Therapy↗
Biomedical subjects
M Sieber
Publications and source records attributed to M Sieber.
Treatment of advanced stage Hodgkin's disease.
Hodgkin's disease remains one of the few malignant diseases which can be cured by modern chemotherapy in most cases even in advanced stages. Adriamycin-containing chemotherapy regimens are considered as the standard therapy which induce long-term remission in about 60-70% of patients. The ABVD scheme, developed by Bonadonna and colleagues in Milan, has a favorable toxicity profile and causes less myelotoxicity, acute leukemia or sterility relative to many previous treatment programs containing alkylating agents. However, 20- 30 % of patients eventually relapse and are then frequently treated with high-dose programs including stem cell transplantation. There are two major goals in advanced Hodgkin's disease: (1) to improve the cure rate and (2) to reduce acute and long-term toxicities. The recent definition of prognostic factors identified patients who are at a high risk of treatment failure as well as those in whom less toxic approaches can be applied. The optimal approach or program has not yet been defined, although new chemotherapy regimens such as BEACOPP and Stanford V with increased tumor response rates have been identified. These new drug combinations are currently analyzed and compared with ABVD in several international trials. While the addition of radiotherapy improved disease control in some trials a survival benefit was not identified and the role of radiotherapy remains controversial. High dose programs remain experimental in advanced stage Hodgkin's disease and should be restricted to prospective clinical trials.
Antineoplastic Combined Chemotherapy Protocols↗
Prognostic factors and treatment outcome in primary progressive Hodgkin lymphoma: a report from the German Hodgkin Lymphoma Study Group.
To determine prognostic factors and treatment outcome, patients with primary progressive Hodgkin lymphoma (HD) registered in the database of the German Hodgkin Lymphoma Study Group (GHSG) were analyzed retrospectively. Detailed records from randomized prospective multicenter trials performed between 1988 and 1998 of 3807 patients recruited in these trials were reviewed. The median age of the 206 patients available was 34 years (range, 16-71). Fifty-seven patients (28%) in intermediate stage and 149 patients (72%) in advanced stage developed progressive disease (PD). One hundred and fifty-three patients (74%) were treated with salvage chemotherapy, 47 patients (23%) with salvage radiotherapy, and 6 patients (3%) did not receive any therapy due to rapid PD. Seventy patients (34%) were treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation. The 5-year freedom from second failure (FF2F) and overall survival (OS) for all patients were 17% and 26%, respectively. The 5-year FF2F and OS for patients treated with HDCT were 31% and 43%, respectively. In multivariate analysis low Karnofsky performance score at the time of progression (P <.0001), age above 50 years (P =.019), and failure to attain a temporary remission on first-line treatment (P =.0003) were significant adverse prognostic factors for OS. Patients with none of these risk factors had a 5-year OS of 55% compared with 0% for patients with all 3 of these unfavorable prognostic factors. Although HDCT is a reasonable option for selected patients with primary progressive HD, the majority did not receive HDCT. Interestingly, salvage radiotherapy gave promising results in patients with localized PD. (Blood. 2000;96:1280-1286)
Adolescent↗
Thermodynamics of DNA binding of MM17, a 'single chain dimer' of transcription factor MASH-1.
MASH-1, a member of the basic helix-loop-helix (bHLH) family of transcriptional regulators, is a central factor for the regulation of the differentiation of committed neuronal precursor cells of the peripheral nervous system. We have previously produced MM17, a single chain version of this dimeric protein, by linking the C-terminal end of the first subunit to the N-terminal residue of the second subunit through a flexible peptide linker. We have now determined by isothermal titration calorimetry the thermodynamic parameters characterising the DNA binding reactions of MM17. The DNA binding specificity was relatively low and comparable to that observed for wild-type MASH bHLH. At 32 degrees C and pH 7, the concentration of MM17 at which 50% DNA binding occurred was determined as 22.8 and 152 nM for binding to MCK-S and the heterologous SP-1, respectively. Similarly to MASH bHLH the free energy of the association was only slightly temperature dependent, while both the entropy and the enthalpy change were strong functions of temperature. The free energy of DNA binding was independent of the pH for the pH range between 6 and 8. Dissection of the entropy change of the association reaction suggested that the two basic domains and the linker region between the subunits underwent a folding transition from a mainly unfolded to a predominantly ordered conformation. Therefore, like wild-type MASH bHLH, the DNA binding reaction of MM17 follows an induced fit mechanism.
Amino Acid Sequence↗
Analysis of lung surfactant model systems with time-of-flight secondary ion mass spectrometry.
An often-used model lung surfactant containing dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylglycerol (DPPG), and the surfactant protein C (SP-C) was analyzed as Langmuir-Blodgett film by spatially resolved time-of-flight secondary ion mass spectrometry (TOF-SIMS) to directly visualize the formation and composition of domains. Binary lipid and lipid/SP-C systems were probed for comparison. TOF-SIMS spectra revealed positive secondary ions (SI) characteristic for DPPC and SP-C, but not for DPPG. SI mapping results in images with domain structures in DPPC/DPPG and DPPG/SP-C, but not in DPPC/SP-C films. We are able to distinguish between the fluid and condensed areas probably due to a matrix effect. These findings correspond with other imaging techniques, fluorescence light microscopy (FLM), scanning force microscopy (SFM), and silver decoration. The ternary mixture DPPC/DPPG/SP-C transferred from the collapse region exhibited SP-C-rich domains surrounding pure lipid areas. The results obtained are in full accordance with our earlier SFM picture of layered protrusions that serve as a compressed reservoir for surfactant material during expansion. Our study demonstrates once more that SP-C plays a unique role in the respiration process.
1,2-Dipalmitoylphosphatidylcholine↗
Formation of three-dimensional protein-lipid aggregates in monolayer films induced by surfactant protein B.
This study focuses on the structural organization of surfactant protein B (SP-B) containing lipid monolayers. The artificial system is composed of the saturated phospholipids dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) in a molar ratio of 4:1 with 0.2 mol% SP-B. The different "squeeze-out" structures of SP-B were visualized by scanning probe microscopy and compared with structures formed by SP-C. Particularly, the morphology and material properties of mixed monolayers containing 0.2 mol% SP-B in a wide pressure range of 10 to 54 mN/m were investigated revealing that filamentous domain boundaries occur at intermediate surface pressure (15-30 mN/m), while disc-like protrusions prevail at elevated pressure (50-54 mN/m). In contrast, SP-C containing lipid monolayers exhibit large flat protrusions composed of stacked bilayers in the plateau region (app. 52 mN/m) of the pressure-area isotherm. By using different scanning probe techniques (lateral force microscopy, force modulation, phase imaging) it was shown that SP-B is dissolved in the liquid expanded rather than in the liquid condensed phase of the monolayer. Although artificial, the investigation of this system contributes to further understanding of the function of lung surfactant in the alveolus.
1,2-Dipalmitoylphosphatidylcholine↗
Distribution of the surfactant-associated protein C within a lung surfactant model film investigated by near-field optical microscopy.
Lung surfactant films at the air/water interface exhibit the particularity that surfactant molecules are expelled from the surface monolayer into a surface associated multilamellar phase during compression. They are able to re-enter the surface film during the following expansion. The underlying mechanism for this behavior is not fully understood yet. However, an important role is ascribed to the surfactant-associated protein C (SP-C). Here, we studied a model lung surfactant, consisting of dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylglycerol (DPPG), and SP-C, by means of scanning near-field optical microscopy (SNOM). Attaching a fluorescent dye to the protein allowed the localization of its lateral distribution at various surface pressures with high resolution. At an early stage of compression, the film appears demixed into a pure lipid phase and a protein-enriched phase. Within the latter phase, protein aggregations are revealed. They show a uniform density, having three times the fluorescence intensity of their surroundings. Across the phase boundary between the lipid phase and the protein-rich phase, there is a protein density gradient rather than an abrupt border. When the film is highly compressed, we observe the formation of multilamellar structures that are fluorescent. They are often surrounded by a slightly fluorescent monolayer. The fluorescence of the multilayer stacks (i. e., the protein content per unit area) is proportional to the height of the stacks.
1,2-Dipalmitoylphosphatidylcholine↗
Treatment of Hodgkin's disease: results and current concepts of the German Hodgkin's Lymphoma Study Group.
BACKGROUND: Treatment strategies in Hodgkin's disease (HD) are changing fundamentally over the last decades. Both radiotherapy and combination chemotherapy are effective treatment modalities. However, the optimal choice of treatment or combinations of treatment is still debated for different prognostic groups. PATIENTS AND METHODS: The German Hodgkin's Lymphoma Study Group (GHSG) initiated randomized clinical trials since 1978. Over the past 20 years, more than 6000 patients with HD in all stages were randomized, treated and followed by the GHSG. Patients are now being recruited from more than 300 clinical centers. RESULTS: As a consequence of different clinical trials, it is now the policy of the GHSG to tailor treatment to the individual risk of patients, giving favorable patients less intensive and less toxic therapy than unfavorable patients. The treatment for early and intermediate stage HD becomes quite similar with few cycles of polychemotherapy followed by involved field irradiation. In advanced stage HD, the introduction of dose intensified chemotherapy (BEACOPP), has improved treatment results and thus will substitute the MOPP or ABVD regimens. CONCLUSIONS: Although most of the patients with HD will be cured by modern treatment strategies, several questions are still subjects of ongoing clinical trials: 1) which chemotherapy regimen in which quantity will be the best with respect to efficacy and toxicity and 2) which dose and field size of radiotherapy is adequate within the combined modality.
Antineoplastic Combined Chemotherapy Protocols↗
Prognostic factors for subdiaphragmatic involvement in clinical stage I-II supradiaphragmatic Hodgkin's disease: a retrospective analysis of the GHSG.
BACKGROUND: Staging laparotomy and splenectomy were routinely performed in patients with early-stage Hodgkin's disease (HD) qualifying for radiotherapy alone to determine the exact extent of disease. However, staging laparotomy is associated with a considerable number of side effects, warranting more sophisticated diagnostic procedures and new therapy strategies. We retrospectively analyzed patients undergoing staging laparotomy to identify pretherapy risk factors predicting the probability of abdominal disease and to define high-risk groups that might benefit from staging laparotomy and subsequent stage-adjusted treatment. PATIENTS AND METHODS: Between February 1988 and January 1993, 391 patients with CS I-II supradiaphragmatic Hodgkin's disease underwent staging laparotomy and splenectomy according to the treatment policy of the German Hodgkin's Lymphoma Study Group (GHSG) for early stages of Hodgkin's disease. Univariate and multivariate analysis of pretherapeutic clinical characteristics were performed in an attempt to predict staging laparotomy results and to identify risk groups. RESULTS: Of the 391 patients, 81 (21%) had subdiaphragmatic disease. Eighteen percent were upstaged to PS III and three percent to PS IV. By a multivariate model the following parameters were independent risk factors for positive surgical staging: left cervical involvement (P < 0.001), mediastinal involvement (P < 0.009), Karnofsky performance status (P < 0.004) and histology (P < 0.04). In our analysis gender (P < 0.08) and ESR (P < 0.06), often described as of high prognostic value, was not significant. The presence of systemic symptoms, number of involved areas and clinical stage were not associated with abdominal disease, as described in several former publications. To define high-risk groups, which comprise at least 15% of patients of the cohort and have a risk of subdiaphragmatic involvement of > 35%, combinations of only two or three of the predictive factors were analyzed. With respect to these criteria the following subgroups of patients were identified as having a high risk for subdiaphragmatic disease (> 35%): a) left cervical lymph node involvement and no mediastinal involvement (n = 98, observed risk 36%); b) no mediastinal involvement and MC/LD histology (n = 113, observed risk 40%). CONCLUSIONS: We conclude that initial clinical characteristics are predictive for occult abdominal involvement in early clinical stages of Hodgkin's disease. The impact of these risk factors on future therapeutical strategies have to be evaluated.
Adult↗
Hodgkin's disease - new treatment strategies toward the cure of patients.
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Antineoplastic Combined Chemotherapy Protocols↗
Universality in quantum parametric correlations.
We investigate the universality of correlation functions of chaotic and disordered quantum systems as an external parameter is varied. A general scaling procedure is introduced which makes the theory invariant under reparametrizations. Under certain general conditions we show that this procedure is unique. The approach is illustrated with the particular case of the distribution of eigenvalue curvatures. We also derive a semiclassical formula for the nonuniversal scaling factor, and give an explicit expression valid for arbitrary deformations of a billiard system.
Journal Article↗
Semiclassical treatment of diffraction in billiard systems with a flux line.
In billiard systems with a flux line, semiclassical approximations for the density of states contain contributions from periodic orbits as well as from diffractive orbits that are scattered on the flux line. We derive a semiclassical approximation for diffractive orbits that are scattered once on a flux line. This approximation is uniformly valid for all scattering angles. The diffractive contributions are necessary in order that semiclassical approximations are continuous if the position of the flux line is changed.
Journal Article↗
Treatment of Hodgkin's disease: current strategies of the German Hodgkin's Lymphoma Study Group.
At present over 90% of early stage Hodgkin's disease patients will be cured. Both radiotherapy and combination chemotherapy are effective treatment modalities. However, the optimal choice of treatment or combinations of treatment is still debated. Recently, several trials reported excellent treatment results with combined modality in early stages of Hodgkin's disease. The use of chemotherapy regimen not including alkylating agents may avoid the risk of infertility and secondary malignancies and facilitates reduction of dose and field size of radiotherapy in early stages. In intermediate stages new chemotherapy regimen (i.e., BEACOPP) will offer the chance to reduce the fraction of patients with initial treatment failure, while reducing the extent of radiotherapy. With the introduction of the escalated BEACOPP regiment it was demonstrated that the prognosis of the advanced stages could be positively influenced by intensification of therapy. Future trials aim to answer: 1) which chemotherapy regimen in which quantity will be the best with respect to efficacy and longterm toxicity and 2) which dose and field size of radiotherapy is adequate within the combined modality approach.
Antineoplastic Agents↗
Moderate dose escalation for advanced stage Hodgkin's disease using the bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone scheme and adjuvant radiotherapy: a study of the German Hodgkin's Lymphoma Study Group.
The BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen, a rearranged and accelerated version of the standard COPP/adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy, has been shown to be effective and safe in a previous pilot study for advanced stage Hodgkin's disease (HD). The present study aimed to determine a maximum practicable dose of three drugs, ie, etoposide, adriamycin, and cyclophosphamide, for which acute toxicities were acceptable and to assess the feasibility of the escalated scheme. Sixty untreated patients with advanced stage HD were enrolled in this study. Radiotherapy was given in 44 patients (73%) after chemotherapy to initial bulk lesions and residual disease. Granulocyte-colony stimulating factor (G-CSF) was given from day 8 to prevent prolonged neutrocytopenia and severe infections. The intended doses of adriamycin, etoposide, and cyclophosphamide in the BEACOPP schedule could be substantially escalated: adriamycin from 25 to 35, cyclophosphamide from 650 to 1,200, and etoposide from 100 to 200 mg/m2. The major toxicities were leukocytopenia and thrombocytopenia with considerable heterogeneity between individual patients. Of 60 patients, 56 (93%) achieved a complete remission (CR). At a median observation of 32 months, the rates of survival and freedom from treatment failure (FFTF) were estimated to be 91% (95% confidence interval 83% to 99%) and 90% (82% to 98%). These results show that a moderate dose escalation of adriamycin, cyclophosphamide, and etoposide of the baseline BEACOPP regimen is feasible. The escalated BEACOPP regimen shows very encouraging results in advanced stage HD and is now being compared in a randomized phase III study with BEACOPP at baseline dose level.
Adolescent↗
Thermodynamics of the DNA binding reaction of transcription factor MASH-1.
MASH-1, a member of the basic helix-loop-helix (BHLH) family of transcription factors, promotes the differentiation of committed neuronal precursor cells. We have determined the thermodynamic parameters of the DNA binding reaction of the BHLH domain of MASH-1 (MASH-BHLH) by isothermal titration calorimetry and found that the specificity of the binding reaction was rather low. At 27 degrees C, the association constant for binding was 5.13 (+/-0.51) x 10(8) M-1 for an E-box containing oligonucleotide, while for a heterologous DNA sequence it was 5.14 (+/-1.93) x 10(7) M-1. The reaction enthalpy and the reaction entropy were strongly dependent on the temperature, but the reaction free energy was almost independent of temperature. The association reaction was enthalpically driven throughout the physiological temperature range and characterized by a large negative heat capacity change. No change in the protonation state of the protein and/or the DNA was observed at pH 6. Within experimental error, the reaction was independent of pH between pH 6 and 8. Dissection of the entropy change of the binding reaction indicated that binding was coupled to local protein folding of approximately 25 amino acids per protein subunit. The circular dichroism spectra of free and DNA-bound MASH-BHLH revealed the formation of additional alpha-helical structure comprising approximately 25 amino acids upon complex formation. Therefore, while the basic region was in an alpha-helical conformation in the DNA complex, in free MASH-BHLH it was substantially unfolded even at concentrations where the protein is mainly dimeric. The association between MASH-1 and DNA is therefore an example of "induced fit".
Amino Acid Sequence↗
Single chain dimers of MASH-1 bind DNA with enhanced affinity.
By designing recombinant genes containing tandem copies of the coding region of the BHLH domain of MASH-1 (MASH-BHLH) with intervening DNA sequences encoding linker sequences of 8 or 17 amino acids, the two subunits of the MASH dimer have been connected to form the single chain dimers MM8 and MM17. Despite the long and flexible linkers which connect the C-terminus of the first BHLH subunit to the N-terminus of the second, a distance of approximately 55 A, the single chain dimers could be produced in Escherichia coli at high levels. MM8 and MM17 were monomeric and no 'cross-folding' of the subunits was observed. CD spectroscopy revealed that, like wild-type MASH-BHLH, MM8 and MM17 adopt only partly folded structures in the absence of DNA, but undergo a folding transition to a mainly alpha-helical conformation on DNA binding. Titrations by electrophoretic mobility shift assays revealed that the affinity of the single chain dimers for E box-containing DNA sequences was increased approximately 10-fold when compared with wild-type MASH-BHLH. On the other hand, the affinity for heterologous DNA sequences was increased only 5-fold. Therefore, the introduction of the peptide linker led to a 4-fold increase in DNA binding specificity from -0.14 to -0.57 kcal/mol.
Amino Acid Sequence↗
Quality of life assessment in Hodgkin's disease: a new comprehensive approach. First experiences from the EORTC/GELA and GHSG trials. EORTC Lymphoma Cooperative Group. Groupe D'Etude des Lymphomes de L'Adulte and German Hodgkin Study Group.
Previous reports from available trials have dealt with negative long-term sequelae in Hodgkin's disease (HD) survivors. There is, however, a lack of longitudinal data showing the correlation between outcome and various treatment-related variables and the process of re-adaptation into normal life after the end of treatment. In order to investigate the quality of life (QoL) of patients with HD in different dimensions during active treatment and follow-up and to identify longitudinal patterns of QoL dimensions during re-adaptation to normal life within the EORTC Lymphoma Cooperative Group and Groupe D'Etude des Lymphomes de L'Adulte (EORTC/GELA) and the German Hodgkin Study Group (GHSG), QoL assessment strategies were put into use over the last three to five years. Furthermore, the efforts aimed at obtaining cross-cultural comparisons between the participating countries and study groups (EORTC/GELA and GHSG). Within the randomised EORTC/GELA Trial 'H8' for clinical stage I-II HD which started in September 1993, patients receive a QoL questionnaire for completion at each follow-up visit during the first 10 years after the end of active therapy. The corresponding 'HD8' study of the GHSG employs the assessment of QoL during and after active treatment periods. Within both studies, the EORTC QLQ C30 is used for QoL assessment incorporated in the QLQ-S (quality of life questionnaire for survivors), which additionally addresses the aspects of fatigue/malaise, sexuality, specific side effects, and retrospective evaluation of treatment. In total the QLQ-S includes 45 questions on 14 functional, symptom, and fatigue scales, 15 additional single items, and 3 open questions. In addition to the longitudinal QoL assessment, the GHSG carried out cross-sectional QoL trials with all cured surviving patients from the past HD1-6 studies and a matched normal control sample employing the QLQ-S and the life situation questionnaire (LSQ), an instrument covering objective data from 45 domains of life. To date, within the trials H8 and HD8 over 3000 QoL questionnaires from more than 800 patients from ten countries are available for analysis. Replication of the psychometric properties of the scales revealed satisfactory results using factor analyses and reliability testing across languages for the QLQ-S. A feasibility analysis showed generally a good acceptance of the questionnaire by the patients and physicians. QoL assessment within international multicentre trials in HD proved feasible within the two differently organised study groups of EORTC/GELA and GHSG. The use of subjective QoL data (QLQ-S) together with objective data (LSQ) in a combined cross-sectional and longitudinal trial system will give the most comprehensive insight into the problems of the re-integration process into normal life after cure. This information will provide the basis for the development of remedies/help measures and possible modifications of treatment strategies. The current approach will be further developed in close collaboration between both trial groups, and next steps will include translation of the LSQ into other languages and adaptation to various cultural circumstances.
Adult↗
BEACOPP: a new regimen for advanced Hodgkin's disease. German Hodgkin's Lymphoma Study Group.
The BEACOPP chemotherapy regimen for advanced Hodgkin's disease employs a rearranged schedule permitting a shortened three-week cycle. With haematological growth factor support, the dosages of cyclophosphamide, etoposide and adriamycin could be moderately escalated. The 3-armed multicentre HD9 trial (recruitment 1993-1998; 1300 patients randomised) aimed to compare BEACOPP with the standard COPP/ABVD chemotherapy and to detect and measure the gain in efficacy, if any, due to moderate dose escalation of BEACOPP. Eight cycles were given, followed by local irradiation. The most recent interim analysis, with 689 evaluable patients, circa 40% of all expected events and a median observation time of 27 months, showed significant differences in progression rate (P) and in two-year freedom from treatment failure (F) between the treatment arms, with escalated BEACOPP (P = 2%, F = 89%) better than baseline BEACOPP (P = 9%, F = 81%) better than COPP/ABVD (P = 13%, F = 72%). Survival was not significantly different. Acute toxicity was more severe due to dose escalation, but remained manageable. These preliminary results suggest that BEACOPP improves efficacy. Moderate dose escalation is feasible with G-CSF support and appears likely to make a worthwhile improvement in the cure rate. The results must await confirmation (or otherwise) by the final analysis including all randomised patients and sufficiently mature data.
Adolescent↗