Epidemiology and etiology of Hodgkin's lymphoma.
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Age of Onset↗
Biomedical subjects
V Diehl
Publications and source records attributed to V Diehl.
Population pharmacokinetics of cyclophosphamide, doxorubicin and etoposide in 30 patients with BEACOPP chemotherapy.
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Adolescent↗
Echocardiographic evaluation of acute cardiotoxicity in the treatment of Hodgkin disease according to the German Hodgkin's Lymphoma Study Group.
Echocardiography is a sensitive method for detecting wall motion abnormalities, as well as for monitoring cardiotoxicity during treatment with anthracyclines. Using echocardiography, this study investigated possible acute cardiotoxicty associated with primary treatment of Hodgkin's disease according to German Hodgkin's Lymphoma Study Group (GHSG) clinical trial protocols for adults. A group of 88 patients (48 men) was registered in the prospective, randomized clinical trial involving the treatment of Hodgkin's disease using third and fourth generation GHSG protocols. These patients were monitored by echocardiography. The average age was 34 years (range, 18-65; median, 32). The average anthracycline dose was 174 mg/m2 (median 200 mg/m2), and the average mediastinum irradiation dose was 21 Gy (median 30 Gy). Left ventricle end-systolic diameter (ESD) and left ventricle end-diastolic diameter (EDD), as well as fractional shortening (FS) and ejection fraction (EF) (M-mode calculation) were evaluated, as was the presence of pericardial effusion and wall motion abnormalities. The examinations were conducted before and at the end of therapy (up to 2 months). Results show that all evaluated parameters changed from one follow-up examination to the other, but these changes did not reach statistical significance. ESD increased from 30 +/- 4 to 31 +/- 4 mm. EDD increased from 49 +/- 4 to 49 +/- 5 mm. Ejection fraction changed from 69 +/- 7 to 66 +/- 7% and fractional shortening was unchanged (from 38 +/- 7 to 38 +/- 7%). In seven patients (8%), we observed new wall motion abnormalities characterized by hypokinesis without decrease of left ventricular function. Significant changes in the amount of pericardial effusion were not observed. In four patients (5%), there was progression of Hodgkin's disease. In conclusion, treatment according to third and fourth generation clinical trial protocols of the GHSG leads only to minimal wall motion changes, without concomitant reduction of left ventricular function, thus not meeting the criteria, acute cardiotoxicity.
Acute Disease↗
Retrobulbar, intracranial, and cutaneous secondary plasmacytomas in a patient with atypical multiple myeloma.
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Adult↗
Monoclonal antibody therapy with CAMPATH-1H in patients with relapsed high- and low-grade non-Hodgkin's lymphomas: a multicenter phase I/II study.
CAMPATH-1H (CP-1H) is a humanized monoclonal antibody directed against the CD52 antigen with promising therapeutic effects in patients with small cell lymphocytic non-Hodgkin's lymphomas (NHL) of B- and T-cell type. We report about the response and toxicity of CP-1H in 18 patients with B-cell NHL who were treated in four clinical centers in Germany. Sixteen patients suffered from a low-grade and two from a high-grade NHL. All patients had received chemotherapy before and had either relapsed or were refractory to conventional therapy. Two patients received CP-1H in a dose-range finding trial once weekly and 16 patients as a fixed dose of 30 mg three times weekly. Of 18 patients, 8 (44%) achieved a clinical response, 2 (11%) had stable disease, and 5 (28%) had progressive disease. Four patients could not be evaluated for response because of death (two patients) and serious adverse events (two patients). All patients with response to CP-1H had a low-grade NHL. Nonhematological toxicity was severe in two patients who suffered from WHO grade III/IV bronchospasm. Common acute adverse events (WHO grade I-III) included fever, chills, rigor, urticaria, nausea, and vomiting. Eleven patients suffered from bacterial or viral infections; some had recurrent infections. A total of 12 different infections were reported. The most frequent infections were caused by herpesvirus (seven patients). Hematological toxicity included thrombocytopenia in four and lymphocytopenia in seven patients. Although the antibody is humanized, the nonhematological toxicity was substantial and probably due to a cytokine release syndrome. Prophylactic treatment of the side effects is strongly recommended for patients treated either with CP-1H alone or in combination with chemotherapy.
Aged↗
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↗
[Artificial sweeteners--are they potentially carcinogenic?].
BACKGROUND: Artificial sweeteners have rapidly evolved over the last 20 years and are added to a broad variety of food, drinks, drugs, and hygiene products. Since their introduction, especially mass media have reported about potential cancer risks, which has attributed to undermine the people's sense of security. It can be assumed that every citizen of the western countries is using artificial sweeteners--knowingly or not. A cancer-inducing activity of one of these substances would mean a health risk to an entire population. STUDIES: This article gives an overview about the most important publications dealing with the cancerogenic potential of artificial sweeteners.
Animals↗
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↗
[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↗
STAT3 is constitutively activated in Hodgkin cell lines.
Hodgkin disease (HD) represents a malignant lymphoma in which the putative malignant Hodgkin and Reed-Sternberg cells are rare and surrounded by abundant reactive nonmalignant cells. It has been suggested that cytokines such as interleukin-6 (IL-6) are involved in the pathogenesis of the disease. The expression of the IL-6 receptor (IL-6R) complex and its link to the activation of signal transducers and activators of transcription (STAT) molecules in HD cell lines was investigated. Gel retardation and Western blot analyses revealed a high level of constitutively activated STAT3 in 5 of 7 HD cell lines, which could not be detected in Burkitt lymphoma cell lines. Different levels of IL-6R protein were measured in various HD cell lines: L428 and Dev cells were characterized by very low levels of gp80 and gp130, on KMH2 cells only gp130 but no gp80 was detected, whereas L540, L591, HDLM2, and L1236 were positive for both gp80 and gp130, suggesting a possible autocrine stimulation of STAT3. However, a further increase in STAT3 activation on IL-6 or IL-6/soluble IL-6R stimulation was not observed. Neutralizing monoclonal antibodies against IL-6, gp80, gp130, or both receptor subunits did not affect the proliferation or the constitutive activation of STAT molecules in HD cell lines. However, the tyrosine kinase inhibitor AG490 blocked the constitutive activation of STAT3 and inhibited spontaneous growth of HD tumor cells. The evidence suggests abnormal STAT signaling and growth regulation in Hodgkin cell lines. (Blood. 2001;98:762-770)
Antibodies, Monoclonal↗
[Thrombotic-thrombocytopenic purpura (Moschcowitz syndrome)].
BACKGROUND: Thrombotic thrombocytopenic purpura (TTP), in 1924 first described by Moschcowitz, is a clinically heterogeneous syndrome associated with thrombocytopenia, Coombs-negative hemolytic anemia, neurologic changes, renal impairment, and fever. TTP is found after various bacterial or viral infectious diseases, autoimmune diseases and also in association with different drugs. PATHOGENESIS: After initial endothelial cell injury unusually large von Willebrand factors (vWF) are found in plasma of patients with thrombotic thrombocytopenic purpura. Because of impaired proteolysis these large forms lead to thrombosis of the small vessels. The microangiopathy is followed by mechanical destruction of red cells. In peripheral blood smears these fragmentocytes are important for diagnosis and clinical course. THERAPY: The therapy of choice is plasma exchange against fresh frozen plasma, whereupon the mortality could be dramatically reduced in the past decades. In case of treatment resistance to plasma exchange there exists no common treatment schedule. One therapy option is immunosuppressive treatment with corticosteroids and vincristine. In case of chronic relapsing TTP splenectomy should be discussed. In spite of severe thrombocytopenia substitution of thrombocytes is contraindicated.
Diagnosis, Differential↗
Bone marrow features improve prognostic efficiency in multivariate risk classification of chronic-phase Ph(1+) chronic myelogenous leukemia: a multicenter trial.
PURPOSE: Multivariate risk classifications for chronic (stable)-phase Ph(1+) chronic myelogenous leukemia (CML) are generally focused on hematologic variables, and the putative prognostic property of bone morphology has been neglected or even contested so far. PATIENTS AND METHODS: A total of 510 consecutively recruited patients in first chronic phase Ph(1+) CML and pretreatment bone marrow biopsy specimens were entered onto this multicenter observational trial to evaluate the effect of bone marrow histopathology. According to generally accepted criteria, patients with any signs of accelerated disease were excluded. Treatment modalities included administration of interferon alfa-2b (IFN) and chemotherapy with hydroxyurea (HU) or busulfan. Immunohistochemical and morphometric techniques were applied to identify marrow cells and to quantify fiber density. Patients were separated into learning and validation samples, and classification and regression tree (CART) analysis was performed to establish a prognostic decision tree. RESULTS: CART analysis of the validation sample (123 patients with HU therapy) revealed the amount of erythroid precursors in the bone marrow, myelofibrosis, and splenomegaly as the most important prognostic features. Three risk profiles with significantly different survival patterns were established, with median survival times ranging from 33 to 108 months (two-sided log-rank test, P =.0001). The new score was confirmed by application to the learning sample with IFN therapy (two-sided log-rank test, P =.0002). Furthermore, risk status defined by the new score was significantly correlated with the occurrence of blast transformation. CONCLUSION: Our data strongly implicate that prognostic classification of chronic-phase Ph(1+) CML can be significantly improved by the inclusion of morphologic parameters. The variables of the presented scoring system may be easily assessed by routinely processed aspirates and bone marrow trephines.
Antineoplastic Agents↗
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↗
Resistance to CD95-mediated apoptosis in breast cancer is not due to somatic mutation of the CD95 gene.
Resistance to CD95 (Apo-1/Fas)-mediated apoptosis is a typical feature of breast cancer cells. Recent studies identified deleterious mutations of the CD95 gene not only in a variety of B cell lymphomas but also in a number of solid tumor entities. Therefore, we amplified and sequenced selected regions of the CD95 gene from 48 breast cancer cases and 10 cell lines but no mutation was found. In the presence of both polymorphic alleles, loss of heterozygosity was excluded in 27 informative cases. We conclude, that relevant somatic mutations of the CD95 gene occur, if at all, at a low frequency and are not the primary cause for resistance to CD95-mediated apoptosis in breast cancer.
Apoptosis↗
Non-Hodgkin's lymphoma after primary Hodgkin's disease in the German Hodgkin's Lymphoma Study Group: incidence, treatment, and prognosis.
PURPOSE: The cumulative incidence for non-Hodgkin lymphoma's (NHL) after primary Hodgkin's disease (HD) ranges between 1% and 6%. To investigate the course of disease for secondary NHL, we retrospectively analyzed patients treated within clinical trials of the German Hodgkin's Lymphoma Study Group (GHSG) since 1981. PATIENTS AND METHODS: From 1981 to 1998, the GHSG conducted three generations of clinical trials for the treatment of primary HD involving a total of 5,406 patients. Reference histology by an expert panel was obtained for 4,104 of the patients. Data on incidence, treatment, and outcome of secondary NHL were updated in March 1999. RESULTS: At first diagnosis of HD, the pathologists rejected 114 (2.1%) of 5,520 cases initially diagnosed as HD and rediagnosed them as primary NHL. Fifty-two (0.9%) of the remaining 5,406 patients developed a secondary NHL. One patient was excluded from further analyses because of insufficient documentation. Six patients had no further therapy because of patient refusal (n = 1) or rapidly progressive disease (n = 5). For the remaining 45 patients, overall response rate was 43% (36% complete response and 7% partial response). The actuarial 2-year freedom from treatment failure (FFTF) and overall survival (OS) for all patients was 24% and 30%, respectively, and for patients with diffuse large-cell lymphoma, it was 28% and 35%, respectively. Time of occurrence of secondary NHL after first diagnosis of HD and variables employed in the age-adjusted International Prognostic Factor Index (IPFI) significantly influenced treatment outcome. CONCLUSION: In the GHSG, the incidence of secondary NHL with 0.9% is relatively low compared with previously reported series. The prognosis of secondary NHL seems dismal and is significantly influenced by time of occurrence and the age-adjusted IPFI. In a subset of patients with secondary NHL, long-term disease-free survival could be achieved.
Actuarial Analysis↗
Oct-2 and Bob-1 deficiency in Hodgkin and Reed Sternberg cells.
Hodgkin and Reed Sternberg (H-RS) cells represent the malignant cells in classical Hodgkin's disease. Although derived from germinal center B cells, they do not express surface immunoglobulin. This has been explained by the presence of crippling mutations within the immunoglobulin genes in numerous cases of Hodgkin's disease. As immunoglobulin gene expression in B cells requires an interaction between octamer sites and the transactivating factors Oct-2 and Bob-1, this study addresses the expression of the transcription factors Oct-2 and Bob-1 in H-RS cells. In Hodgkin's disease-derived cell lines, low levels of Oct-2 transcripts but no Oct-2 protein were detected. Transcripts of Bob-1, a B-cell-specific co-factor of Oct-2, could not be observed in these cell lines. Absence of Oct-2 and Bob-1 protein expression in primary H-RS cells was demonstrated by performing immunohistochemistry in 20 cases of classical Hodgkin's disease. H-RS cells stained negative for both proteins in all of the cases analyzed. In conclusion, absence of functional Oct-2 and Bob-1 cells represents a novel mechanism for immunoglobulin gene deregulation in H-RS cells. Lack of Oct-2 and Bob-1 points to a defect in transcription machinery in H-RS cells and is associated with lack of immunoglobulin gene expression in these cells.
3T3 Cells↗
Locoregional treatment of low-grade B-cell lymphoma with CD3xCD19 bispecific antibodies and CD28 costimulation. I. Clinical phase I evaluation.
We describe the first clinical application of T-cell-recruiting bispecific antibodies directly into the tumor without the need to preactivate the effector cells. In a Phase I clinical trial, 10 patients with low-grade B-cell lymphoma were treated by a single locoregional injection of CD3xCD19 bispecific antibodies. Costimulatory signaling, which is required for the optimal activation of resting T cells, was provided by the simultaneous administration of CD28 antibodies. Equal amounts of both antibodies were injected together at 4 different dose levels (30 microg: 3 patients; 270 microg: 3 patients; 810 microg: 3 patients; 1,600 microg: 1 patient). The injection was well tolerated with mild to moderate adverse effects (2/10 patients) consisting of erythema and fever at the third dose level. The maximum tolerated dose was not reached at 810 microg of injected antibodies. Three patients showed a serum peak of TNFalpha on day 2 or 3 after the antibody application, reflecting rather an activation of CD4-positive T cells than an FcR-mediated effect. Five patients developed anti-mouse antibodies after injection of the murine immunoglobulins. Nine patients were evaluable for restaging examinations 6 weeks after the antibody application, with 2 of them (22%) showing a local clinical response. We found that a single locoregional injection of CD3xCD19+CD28 antibodies is feasible up to a dose of at least 1,600 microg of each antibody. However, the development of human anti-mouse antibodies points toward the requirement for new formats of bispecific proteins with reduced immunogenicity.
Aged↗
Locoregional treatment of low-grade B-cell lymphoma with CD3xCD19 bispecific antibodies and CD28 costimulation. II. Assessment of cellular immune responses.
Ten patients with advanced B-cell lymphoma were treated with a single locoregional injection of CD3xCD19 bispecific and costimulating CD28 monospecific antibodies to activate tumor-infiltrating T-lymphocytes. Antibodies were administered at 4 different dose levels (30 microg, 270 microg, 810 microg, 1,600 microg of each antibody) either by intratumoral or intralymphatic injection. Most patients developed responses within different compartments of the immune systems (T cells, NK cells) subsequent to the antibody application. Comparative studies in 2 patients of which treated as well as untreated lymph nodes were available revealed the up-regulation of T-cell activation markers induced by the antibody injection. Additionally, in 1 patient the induction of apoptosis of lymphoma B cells in the antibody-treated lymph node was observed. Specificity analyses of peripheral blood T cells by means of IFN-gamma ELISpot measurement indicated the recruitment of idiotype-specific T cells, as in 1 out of 3 investigated patients an increased T-cell response toward autologous idiotype peptides could be demonstrated. We conclude that a single injection of CD3xCD19 bispecific antibodies is capable to induce an activation of autologous T lymphocytes if simultaneous costimulatory signaling by CD28 antibodies is provided. Furthermore, our data suggest that at least in some patients lymphoma-specific T cells can be recruited by this immunotherapeutic approach toward B-cell lymphoma.
Aged↗