[Therapy of Hodgkin's disease. Optimization over 4 study generations].
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Combined Modality Therapy↗
Biomedical subjects
J Wolf
Publications and source records attributed to J Wolf.
Effects of acute administration of ethanol and the mu-opiate agonist etonitazene on thyroid hormone metabolism in rat brain.
The effects of acute, low-dose administration of ethanol (1 g/kg bodyweight) and the mu-opioid receptor agonist etonitazene (30 microg/kg bodyweight) on the activities of the iodothyronine deiodinase isoenzymes were investigated in nine regions of the rat brain. The experiments were performed at three different times of the 24-h cycle (1300, 2100 and 0500 hours) and the rats were decapitated 30 and 120 min after administration of the respective drugs. Interest was focused on changes in the two enzymes that catalyze 1) 5'-deiodination of thyroxine (T4) to the biologically active triiodothyronine (T3), i.e. type II 5'-deiodinase (5'D-II) and 2) 5 (or inner-ring) deiodination of T3 to the biologically inactive 3'3-T2, i.e. type III deiodinase (5D-III). 120 min after administration of ethanol and etonitazene 5D-III activity was selectively inhibited in the frontal cortex (at 1300 and 1700 hours) and the amygdala (at all three measuring times). The 5'D-II activity was significantly enhanced 30 min after administration of etonitazene in the frontal cortex, amygdala and limbic forebrain, and after administration of ethanol in the amygdala alone. These effects on 5'D-II activity were seen at 2100 hours only. In conclusion, the two different addictive drugs both reduced the inactivation of the physiologically active thyroid hormone T3 and enhanced its production. These effects occurred almost exclusively in the brain regions which were most likely to be involved in the rewarding properties of addictive drugs. As thyroid hormones have stimulating and mood-elevating properties, an involvement of these hormones in the reinforcing effects of addictive drugs seems conceivable.
Animals↗
Impaired oral health in patients with aspartylglucosaminuria.
OBJECTIVE: The aim of this study was to assess the oral health of patients with aspartylglucosaminuria, a heritable lysosomal storage disorder, and to recommend guidelines for treatment. STUDY DESIGN: Eighty-two patients with aspartylglucosaminuria and 122 control subjects were examined clinically; in addition, panoramic radiographs were evaluated in 61 patients with aspartylglucosaminuria and 61 control subjects. RESULTS: High prevalences of caries, gingivitis, and oral Candida (P < .001), extensive gingival overgrowths (18%; P < .001), benign odontogenic tumors or tumorlike lesions (8%; P = .057), reduced maxillary sinuses (P < .001), limited mouth opening (P < .001), and food retention in the mouth (45%) were the major oral findings that distinguished the patients with aspartylglucosaminuria from the control subjects. Adults with aspartylglucosaminuria had diverse oral health problems, early loss of several permanent teeth being the most disabling feature. CONCLUSIONS: Patients with aspartylglucosaminuria appear to be at a higher risk for a number of oral disorders; however, poor oral hygiene and failure to cooperate increase these patients' risk of dental and periodontal diseases, making successful prevention crucial.
Acetylglucosamine↗
Detection of identical Hodgkin-Reed Sternberg cell specific immunoglobulin gene rearrangements in a patient with Hodgkin's disease of mixed cellularity subtype at primary diagnosis and in relapse two and a half years later.
BACKGROUND: The malignant nature of Hodgkin-Reed Sternberg (H-RS) cells has been questioned due to their scarcity in lymphoma tissues. Recently, using micromanipulation of H-RS cells and single cell PCR evidence was obtained that H-RS cells represent a clonal B-cell population. In these studies H-RS cells were isolated from each one lymph node for a given case. In classical Hodgkin's disease (HD) it thus could not be ruled out that H-RS cell clonality reflected a locally restricted clonal proliferation. We analysed biopsy specimens from a patient suffering from HD for the presence of clonally related H-RS cells at primary diagnosis and during relapse of the disease. MATERIALS AND METHODS: In 1994 the H-RS cell line L1236 was generated from the peripheral blood of a patient suffering from a disseminating relapse of HD of mixed cellularity subtype. The patient had relapsed despite intensive treatment including high dose chemotherapy and autologous bone marrow transplantation. The clonal identity of this cell line with H-RS cells in situ was proven by amplifying identical Ig gene rearrangements of the cell line as well as of single H-RS cells picked from the patients bone marrow. Primers covering the CDR3 region were chosen from the H-RS cell specific VH1 gene rearrangement to detect H-RS cells of the identical clone by amplifying the rearranged VH1 genes in tissue samples obtained during disseminating relapsing disease and at primary diagnosis of HD in 1991. RESULTS: The H-RS cell specific DNA sequence was detected in all affected tissues analysed including the cervical lymph node which has been exstirpated at primary diagnosis. CONCLUSION: This finding indicates the existence of a clonal H-RS cell population during the first manifestation of HD and persistence and dissemination of this clone despite aggressive treatment. Thus, in the described case the malignant nature of H-RS cells defined by dissemination and recurrence of the identical H-RS cell clone in relapsing disease is proven.
Adult↗
The Lancashire Quality of Life Profile: first experiences in The Netherlands.
In the Netherlands, as in many other European countries, there is a strong desire for a reliable, valid and feasible instrument to assess the quality of life of people with long-term mental illness. After careful evaluation, it was decided to translate and adapt the Lancashire Quality of Life Profile (LQOP) developed by Oliver and associates. This article presents the preliminary results of a pilot study using the LQOLP. Emphasis is given to describing the psychometric properties of the extended Dutch version and its clinical applicability. Results indicate that the psychometric properties of the translated LQOLP are encouraging and that the instrument can be used for people with mental illness who live in the Netherlands.
Adult↗
Improved bone metabolism in female elite athletes after vitamin K supplementation.
In female elite athletes strenuous exercise may result in hypoestrogenism and amenorrhoea. As a consequence a low peak bone mass and rapid bone loss are often seen in relatively young athletes. In postmenopausal women, increased intake of vitamin K may result in an increase of serum markers for bone formation, a decrease of urinary markers for bone resorption, and a decrease in urinary calcium loss. In the present paper we report an intervention study among eight female athletes, four of whom had been amenorrhoeic for more than one year, whereas the others had been using oral contraceptives. All participants received vitamin K supplementation (10 mg/day) during one month, and various bone markers were measured before and after treatment. At baseline the athletes not using oral contraceptives were biochemically vitamin K-deficient as deduced from the calcium binding capacity of the circulating bone protein osteocalcin. In all subjects increased vitamin K was associated with an increased calcium-binding capacity of osteocalcin. In the low-estrogen group vitamin K supplementation induced a 15-20% increase of bone formation markers and a parallel 20-25% decrease of bone resorption markers. This shift is suggestive for an improved balance between bone formation and resorption.
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↗
Current clinical trials for the treatment of adult Hodgkin's disease: common strategies and perspectives.
Strategies in the treatment of adult Hodgkin's disease (HD) are changing strikingly in current clinical trials. In early as well as in intermediate stage HD a common aim of most study groups now is the reduction of radiation dose and volume in order to minimize severe late effects like myocardial damage and secondary neoplasias. As a consequence extended field irradiation is abandoned in nearly all trials, and combined modality treatment will be used not only in intermediate, but also in early stage HD. In advanced stage HD new chemotherapy regimens, based on the principle of a moderate dose escalation, for the first time seem to improve the therapeutic outcome. Thus, the priority in current clinical trials for advanced stage HD is the long-term evaluation of these new regimens with regard to treatment efficacy and toxicity.
Adult↗
Issues in the treatment of Hodgkin's disease.
The treatment of Hodgkin's disease is changing strikingly. In early stages of disease, extended field irradiation to date has been the standard treatment resulting in excellent cure rates. Due however to the recognition of the fatal long-term effects, especially the high rates of second solid tumors, extended field radiation therapy is now being abandoned by most study groups. Instead, mild chemotherapy for control of occult disease is combined with involved field irradiation. In intermediate stage Hodgkin's disease, where combined modality treatment already is the treatment of choice, extended field irradiation is substituted by involved field irradiation for the same reasons. In advanced stage Hodgkin's disease, eight cycles of standard polychemotherapy (plus additional radiotherapy for large tumor masses and residual lymphomas after chemotherapy) for decades has cured only about 50% of the patients. While until recently all modifications of the standard chemotherapy regimens could not change the poor outcome of advanced-stage patients, the development of new dose-intensified regimens now for the first time has significantly improved their prognosis. In patients with relapse of Hodgkin's disease after polychemotherapy, long-term survival after salvage chemotherapy is low. Numerous phase II studies suggest an improvement of their poor prognosis by high-dose chemotherapy followed by autologous bone marrow transplantation or peripheral-blood stem cell transplantation. There are still no results of prospective, randomized trials which convincingly demonstrate the benefit of this therapeutic approach, however.
Antineoplastic Combined Chemotherapy Protocols↗
Radiographic periodontal findings in an elderly Finnish population.
By means of panoramic radiography and additional intraoral radiographs, the occurrence of calculus, the extent of horizontal bone loss, the depth and number of infrabony pockets, the number of furcation lesions, and the number of interproximal restoration overhangs were studied in 169 dentate 76-, 81-, and 86-year-old subjects (54 male and 115 females) living at home. Alveolar bone loss (horizontal or vertical) among the participants was common, and in only 8 subjects (5%) was it judged non-existent. It was slight in 30 subjects (18%), moderate in 53 (31%), and advanced in 78 (46%). Infrabony pockets were found in 51% of the subjects and furcation lesions in 28%. The presence of calculus did not correlate with the other parameters. The number of interproximal overhangs was associated with the number of infrabony pockets and of furcation lesions (R=0.3, p<0.001 and p<0.0001) and the number of infrabony pockets with the number of furcation lesions (R=0.4, p<0.0001). Our study shows that periodontal findings are common in the dentate elderly, and associations recently found between periodontal infections and several serious diseases make radiographic examination an integral part of the oral examination of the elderly patient.
Aged↗
Stress-induced endocrine and immunological changes in psoriasis patients and healthy controls. A preliminary study.
BACKGROUND: Clinical observations suggest that psychological stress can induce exacerbation of psoriasis. It is hypothesized that these stress effects on the course and outcome of psoriasis are caused by neuroendocrine modulation of immune functions. Therefore we investigated the cardiovascular, endocrine and immunological response to a laboratory stressor in psoriasis patients and healthy controls. METHODS: Untreated (n = 7) and PUVA-treated (n = 4) psoriatics and healthy controls (n = 7) were exposed to a brief laboratory stressor (public speaking and mental arithmetic). Heart rate and blood pressure, catecholamine, cortisol, and DHEA plasma concentration, as well as distribution of T and NK lymphocytes were analyzed before, immediately after and 1 h after stress exposure. RESULTS: Heart rate and blood pressure increased in all three groups during stress exposure with the most pronounced changes in PUVA-treated patients. Psoriasis patients displayed higher adrenaline values but diminished cortisol and DHEA plasma concentrations compared to controls. NK cell numbers (CD16+, CD56+), but not T lymphocyte subsets, increased immediately after stress exposure in untreated patients and controls. This effect was significantly diminished in PUVA-treated patients. CONCLUSIONS: The data of this pilot study indicate an enhanced stress-induced autonomic response and diminished pituitary-adrenal activity in psoriasis patients. PUVA treatment seems to interfere with the cardiovascular and NK cell response to acute psychological stress. Future studies will analyze the stress-induced neuroimmunological mechanisms in psoriatics in more detail.
Adult↗
BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group.
PURPOSE: The HD9 trial aims to evaluate whether moderate dose escalation and/or acceleration of standard polychemotherapy is beneficial for advanced-stage Hodgkin's disease (HD). Two variants of a novel bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) scheme (standard and escalated dose) are compared with cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). PATIENTS AND METHODS: The randomized, three-arm trial recruited patients in stages IIB and IIIA with risk factors and stages IIIB and IV. BEACOPP in baseline dose contains all drug dosages of COPP/ABVD (except vincristine and procarbazine) rearranged in a shorter, 3-week cycle. Escalated BEACOPP uses higher doses of cyclophosphamide, doxorubicin, and etoposide with granulocyte colony-stimulating factor (G-CSF) support. After eight chemotherapy cycles, initial bulky and residual disease is irradiated. The trial is monitored and analyzed by means of a sequential strategy. RESULTS: An interim analysis with 505 assessable patients and a median follow-up of 23 months showed a significant inferiority (according to sequential monitoring strategy) of the COPP/ABVD regimen in progression rate and freedom from treatment failure (FFTF) compared with the pooled results of both BEACOPP variants. The 24-month FFTF rate was 75% for COPP/ABVD and 84% for BEACOPP pooled (P = .034). There was 12% progressive disease with COPP/ABVD and 6% with BEACOPP pooled. Differences in survival were not significant in sequential analysis. The acute toxicity of baseline BEACOPP resembled that of COPP/ABVD; escalated BEACOPP showed increased but manageable hematologic toxicity. CONCLUSION: Combined with local irradiation, BEACOPP in one or both variants shows superior disease control compared with COPP/ABVD, with acceptable acute toxicity. Further follow-up is required to assess the effect of dosage and the effect on survival and late toxicities.
Adolescent↗
Bone markers during a 6-month space flight: effects of vitamin K supplementation.
Rapid bone loss is a serious health problem for astronauts during long lasting missions in space. We have recorded the changes of biochemical markers for bone metabolism in one of the astronauts during the 6-month space flight of the EUROMIR-95 mission. Immediately after launch both bone resorption markers and urinary calcium excretion increased about two fold, whereas bone formation markers remained unchanged. After 12 1/2 weeks the astronaut received vitamin K1 (10 mg/day for 6 weeks). Vitamin K is known to be involved in the formation of gamma-carboxyglutamate (Gla) in proteins, such as the calcium-binding bone Gla-proteins osteocalcin and matrix Gla-protein. Concomitant with the start of vitamin K treatment, the calcium-binding capacity of osteocalcin increased, and so did the urinary excretion of free Gla. This is suggestive for a subclinical vitamin K-deficiency in the astronaut before vitamin K-supplementation. During periods of high vitamin K status markers for bone formation (osteocalcin and bone alkaline phosphatase) had increased as compared to the first part of the flight. The mean increases were 14 and 23%, respectively. Our data suggest that increased intake of vitamin K may contribute to counteracting microgravity-induced loss of bone mass during long lasting space missions, but need confirmation in more astronauts.
1-Carboxyglutamic Acid↗
The role of combination effects on the etiology of malignant nasal tumours in the wood-working industry.
Adenocarcinomas of the nose are regarded as an occupational disease in Germany and other European countries, and workers exposed to oak or beech wood-dust in the course of their work receive compensation if they incur adenocarcinoma of the nose. This has prompted a joint research project to record the functional and morphological changes of the nasal mucosa and/or paranasal sinus of 149 exposed subjects and 33 controls in accordance with a defined occupational exposure. To ensure the quantitative and qualitative reliability of the exposure data, 1,349 measurements at the company workplace were taken and analyses of 614 wood samples performed; parallel to this, the genotoxic effects of the most important substances used in the wood-working industry were tested. Apart from this, latency periods and morbidity rates in Germany were investigated. Partial findings of this research projects have been evaluated by the International Agency for Research on Cancer (IARC). According to these evaluations and the findings presented here, the following points can be made: i) Morphological changes in the nasal mucosa after exposure to wood-dust resulted in an increase in cylindrocellular hyperplasias and, in functional terms, a tendency towards improved nasal clearance was observed. Chromium and formaldehyde, on the other hand, tended to give rise to an increase in the number of squamous metaplasias. This might explain the preference for the histological types of adenocarcinoma among subjects exposed to wood-dust. ii) In tissue samples more dysplasias were found among those exposed to oak and beech wood-dust. Subjects exposed to wood preserving agents had dysplasias only if they were simultaneously exposed to oak and beech wood-dust. The latter effect did not quite reach the level of significance (p = 0.07) on account of the low numbers of cases. iii) The investigation of genotoxic effects showed that oak and beech contain genotoxic substances that can be dissolved by means of ethanol and cyclohexane; they also showed that 3 out of 8 wood preservatives, 5 out of 16 stains, and 2 out of 11 paints from the wood-working industry are genotoxic too. Apart from this, lindane and PCP have proved to be genotoxic in the nasal cells of rats and human beings. Analysis of 614 wood samples from wood-preserving agents showed that almost 73% contained agents of this type, even in woods described by the companies as being guaranteed free of wood preservatives. iv) According to an analysis of 147 cases accepted since 1985 as a pensionable occupational illness by the Holz-Berufsgenossenschaft (an industrial compensation society for employees in the wood-working industry), the disease was much more apparent in small companies where there is multi-factorial exposure, than in large companies where the exposure factor tends to have a single component. This points to the combined effects of hardwood dusts and chemicals as being the cause. v) According to published findings, the incidence of the disease in England seems to be on the decline. In Germany, increasing latency periods also point to a decline in the number of cases, although both countries have only very recently introduced effective prevention measures against exposure to wood-dust. This also leads to the assumption that wood-dusts cannot be the only cause of this type of cancer. vi) These findings tally with the evaluation by the IARC confirming the special part that hardwood dusts play in the development of nasal cancer. The findings presented here also indicate combined effects as being the cause of this type of cancer. This hypothesis cannot be confirmed until the conclusion of long-term animal experiments, currently being conducted, to test how the effects of chemicals such as lindane, PCP, and chromate compare with use of oak wood-dust.
Adenocarcinoma↗
Efficient gene transfer in primitive CD34+/CD38lo human bone marrow cells reselected after long-term exposure to GALV-pseudotyped retroviral vector.
Successful retroviral gene transfer into human hematopoietic stem cells was demonstrated in preliminary clinical trials at low efficiency. We have shown previously that gene transfer into committed hematopoietic progenitor cells is more efficient using a gibbon ape leukemia virus (GALV)-pseudotyped retroviral vector instead of an amphotropic retroviral vector. Here, we have conducted a systematic study of human hematopoietic progenitor cells after extended transduction with a GALV-pseudotyped retroviral vector. CD34+/CD38lo Cells were transduced for 5 days and reselected according to phenotype after culture and analyzed for cell cycle status, long-term culture-initiating cell (LTC-IC) activity, and gene transfer. Reselection of rare, very primitive progenitor cells was successful. Equal to fresh CD34+/CD38lo cells, >90% of reselected CD34+/CD38lo cells were in G0/G1. CD34+/CD38lo reselection enriched for LTC-IC (10-fold), as compared to freshly isolated CD34+/CD38lo cells with excellent specificity (82.7% of total LTC-IC were recovered in the reselected CD34+/CD38lo population) and recovery (62% of initial LTC-IC number in CD34+/CD38lo cells were recovered in the reselected fraction after transduction). Gene transfer into primitive progenitor cells was efficient with 50.5% G418-resistant LTC-IC colonies and more than 40 copies of vector provirus detectable per 100 nuclei of CD34+/CD38lo cells. To our knowledge, this is the first systematic analysis of phenotype, function, and cell cycle demonstrating retroviral gene transfer into rare, very primitive human hematopoietic progenitor cells. The chosen strategy should be of considerable value for analyzing and improving gene therapy of the hematopoietic system.
ADP-ribosyl Cyclase↗
Clonal relapse in Hodgkin's disease.
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B-Lymphocytes↗
Prevention of Epstein-Barr virus-induced human B-cell lymphoma in severe combined immunodeficient mice treated with CD3xCD19 bispecific antibodies, CD28 monospecific antibodies, and autologous T cells.
Bispecific CD3 x antitumor antibodies in combination with coactivating CD28 antibodies can induce resting T cells to proliferate and to lyse syngeneic tumor cells (M. Azuma et al., J. Immunol., 150: 2091-2101, 1993; M. Azuma et al., J. Exp. Med., 177: 845-850, 1993). This combination of antibodies may therefore be useful for active immunotherapy of malignant tumors. In this study, we present a preclinical model to evaluate CD3xCD19 bispecific antibodies. We investigated whether bispecific antibodies prevent the development of malignant EBV-induced lymphomas in severe combined immunodeficient (SCID) mice which lack functional B and T lymphocytes (G. C. Bosma et al., Immunogenetics, 29: 54-57, 1989). SCID mice were engrafted (i.p.) with peripheral blood lymphocytes and EBV and treated after 3 days with CD3xCD19 bispecific antibodies and CD28 antibodies. Our data demonstrate that the growth of B cell lymphomas can be prevented in SCID mice by treatment with CD3xCD19 bispecific antibodies and that B-lymphoma-specific T cells can be recruited. In contrast to in vitro experiments, there was no clear effect of CD28 administration which is due to high expression of B7-1 on the transplanted B cells. Lymphoma-bearing mice had elevated titers of interleukin10 in the serum, in contrast to tumor-free animals. As shown by PCR analysis, there was no evidence of dormant B-lymphoma cells in specimens from surviving mice. In the spleen of surviving mice, rearranged human T-cell receptor gamma gene segments were detectable. Furthermore, mice that were initially treated with CD3xCD19 and CD28 antibodies did not develop lymphomas upon rechallenge with EBV-infected mononuclear cells of the same donor, whereas control animals did. Our results obtained from this autologous human B-lymphoma model have implications for the design and evaluation of new immunotherapeutic modalities for the treatment of human B-cell lymphoma with bispecific antibodies.
Animals↗
Hodgkin's disease biology: recent advances.
The cellular origin of H-RS cells has been questioned for a long time. Recently, using single cell amplification of Ig genes evidence was obtained that H-RS cells clonally arise from B-cells. Sequence analysis of rearranged Ig genes demonstrated that H-RS cells develop within the germinal centre. H-RS cells in classical HD grow despite loss of function of their rearranged Ig genes. In contrast, the mutation pattern of rearranged Ig genes in L & H cells of lymphocyte-predominant HD frequently shows ongoing mutations indicating that these cell are still antigen selected. These molecular differences show that LP HD genetically differs from classical HD. H-RS cells escape from apoptosis within the germinal centre. However, the events leading to malignant transformation are still unknown. The association between EBV and HD has been repeatedly described, but the occurrence of EBV negative cases is hard to explain just by loss of EBV. The analysis of chromosomal aberrations in H-RS cells did not result in the description of a specific 'HD-gene'. Also the role of the T-lymphocytes surrounding the H-RS cells has remained an open question.
Apoptosis↗