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Background: Improvement of lymphoma therapy is largely driven by clinical therapy optimization protocols (TOPs). It is unclear, however, whether the patients treated in clinical TOP are representative for all patients., Patients and Methods: TOP participants were compared with nonstudy patients in a population-based approach. The study included patients with Hodgkin lymphoma (HL) and high-grade non-Hodgkin lymphoma (hgNHL). Incident cases (N = 743) were ascertained in a large population-based epidemiologic survey. Each patient's status with respect to exclusion criteria of the pertinent TOP was abstracted from primary data sources. TOP participants were identified on the basis of the trial databases. Baseline characteristics and risk factor prevalence were compared between nonstudy and TOP patients., Results: Eligible for the respective TOPs were 64.1% of all incident HL patients and 29.6% of all hgNHL patients in the population. Main exclusion criterion was age (HL: 15.2%; hgNHL: 27.4%). Only 71 HL patients (23.0%) and 11 hgNHL patients (3.4%) had actually been enrolled in the respective TOPs., Conclusions: TOP participants do not represent all patients with hgNHL and HL in the population. TOP inclusion criteria caused considerable selection among the participants. Further investigation is required to clarify possible limitations for the application of the outcomes observed in TOP patients for all patients with these diseases.

Background: The purpose of this study was to compare the efficacy of the hybrid chemotherapeutic regimen COPP/ABV/IMEP (cyclophosphamide-vincristine-procarbazine-prednisone-doxorubicin-bleomycin-vinblastine-ifosfamide-methotrexate-etoposide) (CAI) with that of the standard regimen COPP/ABVD (COPP/ABV, dacarbacine) (CA) in the treatment of advanced-stage Hodgkin's disease (HD)., Patients and Methods: Between January 1988 and January 1993, 588 eligible patients with HD in stages IIIB and IV were randomly assigned to a treatment or control group. The treatment group received four cycles of CAI over a complete cycle duration of 43 days. The control group received four cycles of CA over 57 days. Both groups then received consolidating radiotherapy., Results: Five hundred and eighty-four patients were suitable for arm comparison. Patients in each group were similar in age, sex, histological subtype and clinical risk factors. Complete remission rates, overall survival and freedom from treatment failure at 7 years were similar for the two groups: 77% versus 78%, 73% versus 73% and 54% versus 56% for CAI and CA, respectively. Differences in acute chemotherapy-related toxicity were significant, however. Prognostic factor analysis confirmed the relevance of the International Prognostic Index and revealed that stage IVB, low hemoglobin, low lymphocyte count, high age and male gender were associated with a poor prognosis, Conclusion: The rapidly alternating hybrid CAI did not give superior results when compared with the standard regimen CA in advanced-stage HD.

Background: The seven-factor International Prognostic Score (IPS) has been developed and verified for patients with advanced stage Hodgkin's disease (HD). This report aims to assess the predictive power of the IPS for early stage HD patients., Patients and Methods: Data on patient characteristics, therapy and follow-up were available for 1424 adult patients in clinical stages I-IIIA treated for primary HD in two German Hodgkin's Lymphoma Study Group (GHSG) trials (1988-1994). Patients with risk factors or in stage IIIA received chemo radiotherapy (CMT; trial HD5); others received extended field radiotherapy (RT) alone (HD4). The IPS could be calculated for 712 HD5 and 249 HD4 patients (70%). The prognostic value of the IPS and its component factors was assessed using Cox proportional hazards regression. A search was made for additional factors which could add predictive power to the IPS., Results: The IPS identified 40% of the unfavourable early stage patients with an 8% lower disease-free survival at six years (hazard ratio 1.66, P = 0.0018). The factor 'low albumin' was the only score component giving a significant individual contribution. Allowing for the IPS, extranodal involvement, particularly in stages IIB-IIIA, was associated with worse prognosis, but no further significantly prognostic factors were revealed. The IPS identified a similar hazard ratio in HD4, although here the effect was not significant., Conclusions: The IPS for advanced HD has modest predictive ability in unfavourable early stage patients. Modification of the IPS for use with early stages may improve its prognostic power.

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.

Antibodies against CD15, -30, and -20 are often used to support morphological diagnosis of Hodgkin's Disease (HD). The classical HD, i.e., the non-lymphocyte-predominance types, are CD15+, CD30+, and CD20- in general. However, the results for CD15 are less clear-cut in many studies, showing up to 40% of classical HD that lack positivity for this maker. Little is currently known about the relevance of antigen expression in relation to clinical outcome in HD. Therefore, the three markers were analyzed in 1751 cases from the German Hodgkin Study Group, using micro-wave epitope retrieval to optimize staining sensitivity. Eighty-three percent of the cases showed a classical immunophenotype (CD15+, CD30+, CD20-), twelve percent lacked CD15 positivity (CD15-, CD30+, CD20-), and five percent showed other combinations. For 1286 cases, clinical follow-up was available, which revealed significant differences for freedom from treatment failure (P = 0.0022) and overall survival (P = 0.0001) between cases with classical immunophenotype and CD15 negativity (CD30+, CD20-). Multivariate Cox regression using the three markers, age, sex, histology, stage, B-symptoms (fever, sweats, weight loss > 10% of body weight), hemoglobin, and erythrocyte sedimentation rate as factors showed that lack of CD15 expression in classical HD is an independent negative prognostic factor for relapses (P = 0.022) and survival (P = 0.0035). In conclusion, immunohistochemistry is able to identify classical HD cases with unfavorable clinical outcome.

The organization and control of stem cells is a key issue in epithelial cell biology. The small intestinal murine crypt is a useful tissue to study such problems since stem cells are known to be located at specific positions at the bottom of the crypt where they are self maintaining. Recent data suggest, that (1) the number of active stem cells in a crypt can fluctuate, (2) the immediate progeny of a single stem cell can replace other stem cells eventually leading to monoclonality and (3) the life cycle of crypts may be linked to stem cell dynamics. It is the objective of this paper to suggest a stochastic state-dependent model of stem cell and crypt growth which can explain and-link these phenomena into one comprehensive framework. Monte Carlo simulations are performed to show consistently with available data. The model explains the size distribution of small intestinal crypts in steady state, the observations of stem cell fluctuations and monoclonality conversion, recovery of the crypt population after moderate damage and the rate of crypt fission and extinction. The key assumption of this model is an autoregulatory control of stem cell growth.

Cichlid fish larvae were reared from hatching to active free swimming under different gravity conditions: natural environment, increased acceleration in a centrifuge, simulated weightlessness in a clinostat and near weightlessness during space flight. Cytochrome oxidase activity was analyzed semiquantitatively on the ultrastructural level as a marker of regional neuronal activity in a primary, vestibular brainstem nucleus and in gravity receptive epithelia in the inner ear. Our results show, that gravity seems to be positively correlated with cytochrome oxidase activity in the magnocellular nucleus of developing fish brain. In the inner ear the energy metabolism is decreased under microgravity concerning utricle but not saccule. Hypergravity has no effect on cytochrome oxidase activity in sensory inner ear epithelia.