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Biomedical subjects

J Wolf

Publications and source records attributed to J Wolf.

At least 37 records · Page 2Linked to original sources
PubMed2003

14-day variant of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced-stage Hodgkin's lymphoma: results of a pilot study of the German Hodgkin's Lymphoma Study Group.

PURPOSE: This multicenter pilot study assessed the feasibility and efficacy of a time-intensified bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen given in 14-day intervals (BEACOPP-14) with granulocyte colony-stimulating factor (G-CSF) support in advanced Hodgkin's lymphoma. PATIENTS AND METHODS: From July 1997 until March 2000, 94 patients with Hodgkin's lymphoma stage IIB, III, and IV were scheduled to receive eight cycles of BEACOPP-14. Consolidation radiotherapy was administered to regions with initial bulky disease or residual tumor after chemotherapy. RESULTS: All patients were assessable for toxicity and treatment outcome. Eighty-six patients received the planned eight cycles of BEACOPP-14. Consolidation radiotherapy was given in 66 patients. Chemotherapy could generally be administered on schedule. Dose reductions varied among drugs but were generally low. Acute toxicity was moderate, with World Health Organization grade 3/4 leukopenia in 75%, thrombocytopenia in 23%, anemia in 65%, and infection in 12% of patients. A total of 88 patients (94%) achieved a complete remission. Four patients had progressive disease. At a median observation time of 34 months, five patients have relapsed, one patient developed a secondary non-Hodgkin's lymphoma, and three deaths were documented. The overall survival and freedom from treatment failure rates at 34 months were 97% (95% confidence interval [CI], 93% to 100%) and 90% (95% CI, 84% to 97%), respectively. CONCLUSION: Acceleration of the BEACOPP baseline regimen by shortening cycle duration with G-CSF support is feasible and effective with moderate acute toxicity. On the basis of these results, the German Hodgkin's Lymphoma Study Group will compare the BEACOPP-14 regimen with BEACOPP-21 escalated in a prospective multicenter randomized trial.

Adolescent↗
PubMed2002

Preclinical evaluation of the antiproliferative potential of STI571 in Hodgkin's disease.

STI571 is a selective tyrosine kinase inhibitor with proven therapeutic potential in malignancies expressing c-kit. A strong c-kit and stem cell factor expression was detected in the Hodgkin and Reed Sternberg cell line L1236, but not in 20 primary cases of classical Hodgkin's disease. Proliferation of L1236 cells was neither affected by addition of stem cell factor nor by neutralising anti-stem cell factor antibodies or STI571. Results suggest that patients with Hodgkin's disease may not benefit from therapy with STI571.

Benzamides↗
PubMed2002

Long-term adverse effects on dentition in children with poor-risk neuroblastoma treated with high-dose chemotherapy and autologous stem cell transplantation with or without total body irradiation.

Chemo- and radiotherapy may have injurious effects on developing teeth. In this long-term follow-up study among poor-risk neuroblastoma (NBL) survivors our aims were: (1) to assess both the type and extent of the side-effects of the anticancer treatment on tooth development; and (2) to develop an index for expressing total damage to the permanent dentition. We studied the dental development from panoramic radiographs (PRG) of 18 long-term survivors treated under the age of 6 years with high-dose (HD) chemotherapy and autologous stem cell transplantation (ASCT) for poor-risk NBL. The myeloablative therapy was either HD chemotherapy and fractionated total body irradiation (TBI) of 10-12 Gy (TBI group, n = 10) or HD chemotherapy only (non-TBI group, n = 8). A defect index (DeI) was developed to describe the damage to the permanent dentition. The DeI was also tested in 18 healthy adolescents. All NBL patients had disturbances in dental development including short roots, arrested root development, microdontia and tooth aplasia. After TBI, 9/10 patients had very severe root defects, in contrast to none in the non-TBI group. All children in the TBI group had 2-12 (mean 6.6) missing permanent teeth, while 2/5 in the non-TBI group (3/8 excluded due to young age) had two and four missing permanent teeth, respectively. Microdontia was found at equal frequency in both groups. The mean value of the DeI was 70.0 (range 28-117) in the TBI group, 15.2 (range 4-34) in the non-TBI group (P<0.001, Mann-Whitney U test) and 1.8 (range 0-15) in healthy adolescents. Disturbances in dental development may compromise occlusal function in poor-risk NBL patients after ASCT, especially when TBI is included in the conditioning regimen. Long-term dental follow-up and rehabilitation is required.

Adolescent↗
PubMed2002

Gubernacular development in Müllerian inhibiting substance receptor-deficient mice.

OBJECTIVE: To determine, in mice with disrupted Müllerian inhibiting substance (MIS) receptor genes, whether MIS affects gubernacular development; MIS causes Müllerian duct regression and is proposed to be involved in the first stage of testicular descent, because gubernacular development is abnormal in humans with persistent Müllerian duct syndrome. MATERIALS AND METHODS: Ten wild-type, 11 heterozygotic and 12 homozygotic mice for MIS receptor mutations were killed at 17.5 or 18.5 days after conception or at birth, to provide serial sagittal sections of the pelvis. The amount of cremaster muscle, mitotic bodies in the gubernacular bulb, and gubernacular size were quantified by computer analysis (four mice/group). RESULTS: Müllerian ducts were present in the homozygous mutants, partially present in the heterozygotes and absent in the wild-type controls. All mice had descended testes. The cremaster muscle was significantly less developed in homozygous mutants than in wild-type controls (P < 0.001) and heterozygotes (P < 0.01) at birth. The mitotic index between the gubernacula of all groups was indistinguishable. There was no statistical difference in gubernacular area amongst the groups. Poor cremaster muscle development in homozygous mutants gave the muscle a loose mesenchymal appearance. CONCLUSIONS: Although there was an observable effect on cremaster muscle development in these mutant mice, gubernacular development and testicular descent were otherwise normal, and thus there must be other reasons for the observed differences in humans with persistent Müllerian duct syndrome.

Abdominal Muscles↗
PubMed2002

Genetic instability in Hodgkin's lymphoma.

Genetic instability is a characteristic feature of the malignant Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin's lymphoma and the lymphocytic and histiocytic (L&H) cells in lymphocyte predominant Hodgkin's lymphoma. Genetic instability can be classified into four major categories: distinct DNA mutations (microsatellite instability); numerical aberrations (chromosomal instability); structural aberrations (translocation instability); and gains and losses of chromosomal regions. In Hodgkin's lymphoma (HL), HRS cells and L&H cells show somatically mutated clonally rearranged immunoglobulin genes, thus characterizing these cells genetically as germinal center B cells. These cells furthermore show mutations of oncogenes and tumor suppressor genes in some cases (p53, IkappaBalpha, CD95/Fas). They do not, however, display microsatellite instability, as they have a proficient mismatch repair machinery. In contrast, HRS and L&H cells frequently harbor recurrent but not specific numerical and structural aberrations as detected by classical cytogenetics and fluorescence in situ hybridization analysis. Results from molecular genetic studies using comparative genomic hybridization and allelotyping (LOH) indicate typical genetic patterns in HL with gains and losses of distinct chromosomal regions. In some instances, candidate genes possibly involved in the malignant transformation of HRS cells and L&H cells have been characterized (JAK2, c-REL, MDM2). In summary, using molecular genetics it might be possible in the near future to elucidate some of the complex genetic instabilities observed in HL.

Chromosome Aberrations↗
PubMed2002

Prognostic factors in Hodgkin's lymphoma.

Risk-adapted treatment strategies have constituted a major issue since the beginning of clinical research into Hodgkin's disease (HD). Various prognostic factors have been identified and several of those considered for staging procedures, resulting in strictly stage-dependent treatment recommendations for patients suffering from HD. These factors may be subdivided in host-related (e.g. age, sex) and tumour-related (e.g. number of tumour cells, growth characteristics, spread of tumour cells, resistance to apoptosis) factors. Owing to the striking improvement of the overall prognosis in HD patients it may be difficult to identify novel prognostic factors analysing the minority of patients with a fatal outcome. However, especially in advanced-stage disease, improved treatment results were achieved by the introduction of more aggressive treatment regimens, resulting in an increased toxicity rate. Thus, partially in contrast to earlier work in this field, future prognostic factors are needed for identification of those patients that have a good prognosis and might be susceptible to overtreatment. During the Fifth International Symposium on Hodgkin's Lymphoma, promising results on several new prognostic markers were presented. Furthermore, a joint effort to design new studies on large, well characterised patient groups has been initiated.

Biomarkers, Tumor↗
PubMed2002

A case study: development of a bioassay for IL-1ra.

The IL-1ra bioassay was overhauled in 1993 at Synergen, Inc. The team included bioassay specialists and two pre-clinical statisticians. We began by focusing on the technical aspects, optimizing the number of cells per well, altering the staining procedure, and checking incubation times. We then proceeded to revise the layout of the dose-response curves on the 96-well plates and included an internal control as well as a standard. Finally, we reconfigured the statistical modelling procedure to model each plate as a whole using a 9-parameter logistic curve. When the work was concluded, the precision (%CV) had improved from 44% to 10%, while the retest rate was reduced from 20-30% to less than 5%.

Biological Assay↗
PubMed2001

Whole-body positron emission tomography using 18F-fluorodeoxyglucose for initial staging of patients with Hodgkin's disease.

An accurate initial staging of patients with Hodgkin's disease (HD) is important for the evaluation of clinical stage and risk factors, which are crucial for the choice of an appropriate treatment. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is useful for detecting active tumor tissue in patients with lymphoproliferative diseases and may contribute to conventional staging methods in patients with HD. Twenty-two patients who presented with newly diagnosed HD underwent conventional staging methods including computed tomography (CT) as well as FDG PET. Lesions apparent in FDG PET and CT were correlated to each other. Seventy-seven lesions were observed either in PET or CT or in both. In 48 (62%) lesions PET and CT were both positive. In 20 (26%) sites, PET was positive and CT negative. Of 22 patients (18%) 4 were upstaged due to these positive PET findings, and as a result one patient received a different therapeutic regimen. PET failed to detect nine (12%) CT-positive sites in six patients. Statistically, these data are reflected by a sensitivity for PET and CT of 88% and 74%, respectively. Specificity of both imaging modalities was 100%. PET can contribute valuable information as an additional staging examination and led to an upstaging in some patients with primary HD. However, PET should not be used as the only imaging modality as it failed to detect CT-positive, active tumor regions in some cases.

Adult↗
PubMed2001

Thoracic positron emission tomography using 18F-fluorodeoxyglucose for the evaluation of residual mediastinal Hodgkin disease.

Residual mediastinal masses are frequently observed in patients with Hodgkin disease (HD) after completed therapy, and the discrimination between active tumor tissue and fibrotic residues remains a clinical challenge. We studied the diagnostic value of metabolic imaging by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in detecting active mediastinal disease and predicting relapse. Twenty-eight HD patients with a residual mediastinal mass of at least 2 cm after initial therapy or after salvage chemotherapy were prospectively assigned to 29 examinations with FDG PET and were evaluated as 29 "subjects." Patients were monitored for at least 1 year after examination and observed for signs of relapse. Median follow-up was 28 months (range, 16 to 68 months). A PET-negative mediastinal tumor was observed in 19 subjects, of whom 16 stayed in remission and 3 relapsed. Progression or relapse occurred in 6 of 10 subjects with a positive PET, whereas 4 subjects remained in remission. The negative predictive value (negative PET result and remission) at 1 year was 95%, and the positive predictive value (positive PET result and relapse) was 60%. The disease-free survival for PET-negative and PET-positive patients at 1 year was 95% and 40%, respectively. The difference was statistically significant. A negative FDG PET indicates that an HD patient with a residual mediastinal mass is unlikely to relapse before 1 year, if ever. On the other hand, a positive PET result indicates a significantly higher risk of relapse and demands further diagnostic procedures and a closer follow-up.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

E-cadherin regulates cell growth by modulating proliferation-dependent beta-catenin transcriptional activity.

beta-Catenin is essential for E-cadherin-mediated cell adhesion in epithelial cells, but it also forms nuclear complexes with high mobility group transcription factors. Using a mouse mammary epithelial cell system, we have shown previously that conversion of epithelial cells to a fibroblastoid phenotype (epithelial-mesenchymal transition) involves downregulation of E-cadherin and upregulation of beta-catenin transcriptional activity. Here, we demonstrate that transient expression of exogenous E-cadherin in both epithelial and fibroblastoid cells arrested cell growth or caused apoptosis, depending on the cellular E-cadherin levels. By expressing E-cadherin subdomains, we show that the growth-suppressive effect of E-cadherin required the presence of its cytoplasmic beta-catenin interaction domain and/or correlated strictly with the ability to negatively interfere with beta-catenin transcriptional activity. Furthermore, coexpression of beta-catenin or lymphoid enhancer binding factor-1 or T cell factor 3 with E-cadherin rescued beta-catenin transcriptional activity and counteracted E-cadherin-mediated cell cycle arrest. Stable expression of E-cadherin in fibroblastoid cells decreased beta-catenin activity and reduced cell growth. Since proliferating cells had a higher beta-catenin activity than G1 phase-arrested or contact-inhibited cells, we conclude that beta-catenin transcriptional activity is essential for cell proliferation and can be controlled by E-cadherin in a cell adhesion-independent manner.

Animals↗
PubMed2001

[Factitious disorders. Hematologic, neurologic and dermatologic symptoms in a physician with factitious disorder].

HISTORY AND FINDINGS: A 38-year-old female physician was admitted with the suspected diagnosis of a myelodysplastic syndrome. The self-reported history was inconsistent and incoherent. On physical examination neurological and dermatological disorders could be found. EXAMINATIONS: A bone marrow puncture revealed a toxicity-induced bone marrow damage. Extensive examinations to evaluate the neurological symptoms did not show any pathological findings. A toxicological screening identified opioids, benzodiazepines and promethazine. TREATMENT AND COURSE: Because of the inconsistent history and the contradictory results of our clinical tests, we asked in other hospitals for past admissions and were thus able to have insight into a hospital career that grasped numerous different admission diagnoses. All presented symptoms, especially the bone marrow damage, were self-induced by the patient. CONCLUSIONS: For the first time in this patient's history, a factitious disorder was diagnosed after a hospital career of almost 10 years. In this publication, the case is thoroughly presented. Additionally, the current literature is reviewed with latest recommendations for therapeutic strategies about this poorly understood disorder.

Adult↗
PubMed2001

[Cerebral vasculitis as the initial manifestation of systemic lupus erythematosus].

HISTORY AND CLINICAL FINDINGS: A 41-year-old man was admitted to the hospital because of a series of seizures. History revealed increasing weakness and generalized myalgia following a severe respiratory tract infection three months previously. The clinical examination was dominated by reduced alertness and cognitive impairment. INVESTIGATIONS: Positive ANA titres pointed to an autoimmune disease; further laboratory tests revealed an antiphospholipid syndrome. The clinical diagnosis of systemic lupus erythematosus was supported by renal biopsy. Transcranial Doppler sono-graphy and magnetic resonance imaging with angiography revealed cerebral vasculitis with multiple intracerebral grey and white matter lesions. TREATMENT AND COURSE: In addition to an immunosuppressive therapy with corticosteroids and intravenous pulses of high-dose cyclophosphamide, oral anticoagulation was given in order to prevent thromboembolic complications. Seizures were treated with valproate. A follow-up MRI revealed multiple glial cell reactions and reduced vasculitic changes. CONCLUSIONS: Initial neuropsychiatric symptoms and seizures prompted the diagnosis of systemic lupus erythematosus with cerebral vasculitis in a 41-year-old patient. Approximately 20 % of all lupus patients initially present with neuropsychiatric disorders. Central nervous system involvement and renal complications determine the course and prognosis of the disease as well as therapeutic decisions. Particularly in young patients with neuropsychiatric symptoms systemic lupus erythematosus should be excluded routinely.

Adult↗
PubMed2001

Mathematical analysis of a mechanism for autonomous metabolic oscillations in continuous culture of Saccharomyces cerevisiae.

Autonomous metabolic oscillations were observed in aerobic continuous culture of Saccharomyces cerevisiae. Experimental investigation of the underlying mechanism revealed that several pathways and regulatory couplings are involved. Here a hypothetical mechanism including the sulfate assimilation pathway, ethanol degradation and respiration is transformed into a mathematical model. Simulations confirm the ability of the model to produce limit cycle oscillations which reproduce most of the characteristic features of the system.

Cell Respiration↗
PubMed2001

Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin's disease: long-term results of a randomized trial of radiotherapy alone.

PURPOSE: To show that radiotherapy (RT) dose to the noninvolved extended field (EF) can be reduced without loss of efficacy in patients with early-stage Hodgkin's disease (HD). PATIENTS AND METHODS: During 1988 to 1994, pathologically staged patients with stage I or II disease who were without risk factors (large mediastinal mass, extranodal lesions, massive splenic disease, elevated erythrocyte sedimentation rate, or three or more involved areas) were recruited from various centers. All patients received 40 Gy total fractionated dose to the involved field areas but were randomly assigned to receive either 40 Gy (arm A) or 30 Gy (arm B) total fractionated dose for the clinically noninvolved EF. No chemotherapy was given. RT films were prospectively reviewed for protocol violations and recurrences retrospectively related to the applied RT. RESULTS: Of 382 recruited patients, 376 were eligible for randomized comparison, 190 in arm A and 186 in arm B. Complete remission was attained in 98% of patients in each arm. With a median follow-up of 86 months, 7-year relapse-free survival (RFS) rates were 78% (arm A) and 83% (arm B) (P =.093). The upper 95% confidence limit for the possible inferiority of arm B in RFS was 4%. Corresponding overall survival rates were 91% (arm A) and 96% (arm B) (P =.16). The most common causes of death (n = 27) were cardiorespiratory disease/pulmonary embolisms (seven), second malignancy (six), and HD (five). Protocol violation was associated with significantly poorer RFS. Nonirradiated nodes were involved in 42 of 52 reviewed relapses, infield areas in 18, marginal areas in 17, and extranodal sites in 16. CONCLUSION: EF-RT alone attains good survival rates in favorable early-stage HD. The 30-Gy dose is adequate for clinically noninvolved areas. Protocol violation worsens the subsequent prognosis. Relapse patterns suggest that systemic therapy can reduce the 20% long-term relapse rate.

Adolescent↗