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Prognostically relevant risk factors in patients with diffuse large B-cell lymphoma (DLBCL) have predominantly been evaluated in elderly populations. We tested whether previously described risk factors are also valid in younger, poor-prognosis DLBCL patients. Paraffin-embedded samples from 112 patients with de novo DLBCL, enrolled in the R-MegaCHOEP trial of the German High Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) were investigated using immunohistochemistry (MYC, FOXP1, LMO2, GCET1, CD5, CD10, BCL2, BCL6, IRF4/MUM1) and fluorescence in situ hybridization (MYC, BCL2, BCL6). MYC, BCL2 and BCL6 breaks occurred in 14, 21 and 31%, respectively. In the majority of cases, MYC was simultaneously rearranged with BCL2 and/or BCL6. The adverse impact of MYC rearrangements was confirmed, but the sole presence of BCL2 breaks emerged as a novel prognostic marker associated with inferior overall survival (OS) (P=0.002). Combined overexpression of MYC and BCL2 showed only limited association with inferior OS. All immunohistochemical cell of origin classifiers applied failed to predict survival time. DLBCL tumors with significant proportion of immunoblastic and/or immunoblastic-plasmacytoid cells had inferior OS, independently from from BCL2 break. Younger, poor-prognosis DLBCL patients, therefore, display different biological risk factors compared with an elderly population, with BCL2 translocations emerging as a powerful negative prognostic marker. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) with a t(14;18) is a B-cell neoplasm clinically characterized by multiple recurrencies. In order to investigate the clonal evolution of this lymphoma, we studied paired primary and relapse tumor samples from 33 patients with recurrent non-transformed t(14;18)-positive FL. We reconstructed phylogenetic trees of the evolution by taking advantage of the activation-induced cytidine deaminase (AID)-mediated somatic hypermutation (SHM) active in the germinal center reaction using sequences of the clonal VHDHJH rearrangements of the immunoglobulin heavy chain (IGH) locus. Mutational analysis of the IGH locus showed evidence for ongoing somatic mutation and for counter-selection of mutations affecting the BCR conformation during tumor evolution. We further followed evolutionary divergence by targeted sequencing of gene loci affected by aberrant SHM as well as of known driver genes of lymphomagenesis, and by array-based genome-wide chromosomal imbalance and DNA methylation analysis. We observed a wide spectrum of evolutionary patterns ranging from almost no evolution to divergent evolution within recurrent non-transformed t(14;18) FL. Remarkably, we observed a correlation of the magnitude of evolutionary divergence across all genetic and epigenetic levels suggesting co-evolution. The distribution of coding mutations in driver genes and the correlation with SHM suggest CREBBP and AID to be potential modifiers of genetic and epigenetic co-evolution in FL. [ABSTRACT FROM AUTHOR]

The article presents a study which observes the more favorable non-Hodgkin lymphoma (NHL) subtypes found in children than in adults. It discusses whether the observation is linked to disease biology in age groups and the treatment regimens or factors connected to care delivery in the age group. Based on molecular analysis of pediatric mature beta-cell lymphomas, molecular Burkitt lymphoma is significantly higher in children compared with adults.

Bi-weekly (R)-CHOP therapy is one of the standard treatmentS for elderly patients with aggressive B-cell lymphoma, but it is only feasible with supportive G-CSF treatment. In the trials of the DSHNHL, either unpegylated G-CSF was given daily over 7 or 10 days or pegylated G-CSF was applied at day 4 of each cycle. These schedules were planned on the basis of simulations of a biomathematical pharmacokinetic/pharmacodynamic model. By analysing the observed data, we investigated whether our model predictions were correct and whether even better schedules can be proposed. We used data on 249 matched patients of two prospective trials, RICOVER-60 and PEGFILGRASTIM. The three G-CSF-schedules showed similar outcomes regarding leukocytopenia, infections and days in hospital, with pegylated G-CSF having slightly but not significantly better scores in all three endpoints. Regarding pegylated G-CSF, the best timing is predicted to be any day between days 4 and 7. With respect to unpegylated G-CSF, the starting day is less important, but it should be continued until the end of each cycle.The three G-CSF-schedules are interchangeable in (R)-CHOP-14 for elderly patients with aggressive B-cell lymphoma. Our model correctly predicts time courses of leukocytes. Further model predictions are presented, which can be tested in subsequent clinical trials. [ABSTRACT FROM AUTHOR]

The rate of long-term remissions after treatment of peripheral T cell lymphomas (PTCL) with standard CHOP-like protocols is unsatisfactory. A prospective multicenter phase II trial was initiated in untreated patients with PTCL of all International Prognostic Index-risk groups, evaluating alemtuzumab consolidation in patients with complete or good partial remission after CHO(E)P-14 induction. Twenty-nine (70.7 %) of the 41 enrolled patients received alemtuzumab consolidation (133 mg in total). The main grades 3-4 toxicities during alemtuzumab therapy were infections and neutropenia with one potentially treatment-related death. Complete responses were seen in 58.5 %, partial responses in 2.4 % and 29.3 % had progressive disease. After a median observation time of 46 months, 19 patients have died, 16 of them due to lymphoma and/or salvage therapy complications. Event-free and overall survival at 3 years in the whole intent to treat population are 32.3 and 62.5 %, respectively, and 42.4 and 75.1 % in the patients who received alemtuzumab. In conclusion, application of a short course of alemtuzumab after CHO(E)P-14 induction is feasible although complicated by severe infections. A current phase III trial, applying alemtuzumab as part of the initial chemotherapy protocol to avoid early progression, will further clarify its significance for the therapeutic outcome. [ABSTRACT FROM AUTHOR]

Background: Mortality in intensive care unit (ICU) patients is affected by multiple variables. The possible impact of the mode of ventilation has not yet been clarified; therefore, a secondary analysis of the "epidemiology of sepsis in Germany" study was performed. The aims were (1) to describe the ventilation strategies currently applied in clinical practice, (2) to analyze the association of the different modes of ventilation with mortality and (3) to investigate whether the ratio between arterial partial pressure of oxygen and inspired fraction of oxygen (PF ratio) and/or other respiratory variables are associated with mortality in septic patients needing ventilatory support.Methods: A total of 454 ICUs in 310 randomly selected hospitals participated in this national prospective observational 1-day point prevalence of sepsis study including 415 patients with severe sepsis or septic shock according to the American College of Chest Physicians/Society of Critical Care Medicine criteria.Results: Of the 415 patients, 331 required ventilatory support. Pressure controlled ventilation (PCV) was the most frequently used ventilatory mode (70.6 %) followed by assisted ventilation (AV 21.7 %) and volume controlled ventilation (VCV 7.7 %). Hospital mortality did not differ significantly among patients ventilated with PCV (57 %), VCV (71 %) or AV (51 %, p=0.23). A PF ratio equal or less than 300 mmHg was found in 83.2 % of invasively ventilated patients (n=316). In AV patients there was a clear trend to a higher PF ratio (204±70 mmHg) than in controlled ventilated patients (PCV 179±74 mmHg, VCV 175±75 mmHg, p=0.0551). Multiple regression analysis identified the tidal volume to pressure ratio (tidal volume divided by peak inspiratory airway pressure, odds ratio OR=0.94, 95 % confidence interval 95% CI=0.89-0.99), acute renal failure (OR=2.15, 95% CI=1.01-4.55) and acute physiology and chronic health evaluation (APACHE) II score (OR=1.09, 95% CI=1.03-1.15) but not the PF ratio (univariate analysis OR=0.998, 95 % CI=0.995-1.001) as independent risk factors for in-hospital mortality.Conclusions: This representative survey revealed that severe sepsis or septic shock was frequently associated with acute lung injury. Different ventilatory modes did not affect mortality. The tidal volume to inspiratory pressure ratio but not the PF ratio was independently associated with mortality. [ABSTRACT FROM AUTHOR]

Previous studies have shown that intravenously applied bacteria can accumulate in tumors and lead to sporadic tumor regression. Recently, systemic administration of attenuated Salmonella typhimurium was demonstrated to generate no significant side effects in humans, but also no antitumor responses. We report the enhanced antitumor activity in preclinical mouse cancer models of nonvirulent S. typhimurium engineered to synthesize the cytokine Interleukin-18 (IL-18). IL-18-producing bacteria (but not control bacteria) inhibit the growth of primary subcutaneous tumors as well as pulmonary metastases in immunocompetent mice challenged with syngeneic multidrug-resistant clones of murine carcinoma cell lines, without overt toxicity to normal tissues. Antitumor activity was associated with increased accumulation of T-lymphocytes and NK cells in tumors, and massive infiltration of granulocytes, as well as increased intra-tumoral production of several cytokines. In summary, these findings provide evidence of promising preclinical antitumor activity of IL-18-expressing, attenuated S. typhimurium, suggesting a novel strategy for cancer immunotherapy.Cancer Gene Therapy (2008) 15, 787–794; doi:10.1038/cgt.2008.48; published online 25 July 2008 [ABSTRACT FROM AUTHOR]

Recent retrospective studies of heterogeneously treated patients have suggested that chromosomal aberrations of the MYC gene locus indicate an unfavorable prognosis in diffuse large B-cell lymphoma (DLBCL). Here, we investigated the prognostic impact of MYC aberrations analyzed by interphase fluorescence in situ hybridization in 177 patients with de novo DLBCL treated within the two prospective, randomized trials non-Hodgkin's lymphoma NHL-B1 and NHL-B2. MYC aberrations were detected in 14 DLBCL (7.9%). In a univariate analysis compared with MYC-negative DLBCL, MYC-positive cases showed a significantly shorter overall survival (OS) (P=0.047) and relevantly, though not significantly, shorter event-free survival (EFS) (P=0.062). In a Cox model adjusted for the international prognostic index, the presence of a MYC gene rearrangement was the strongest statistically independent predictor of OS (relative risk 3.4, P=0.004) and EFS (relative risk 2.5, P=0.015), and this also held true when the cell-of-origin signature detected by immunohistochemistry was included in the model.Leukemia (2008) 22, 2226–2229; doi:10.1038/leu.2008.230; published online 28 August 2008 [ABSTRACT FROM AUTHOR]

Deregulation of cell signaling pathways controlling cell growth and cell survival is a common feature of all cancers. Although a core repertoire of oncogenic mechanisms is widely conserved between various malignancies, the constellation of pathway activities can vary even in patients with the same malignant disease. Modern molecularly targeted cancer drugs intervene in cell signaling compensating for pathway deregulation. Hence characterizing tumors with respect to pathway activation will become crucial for treatment decisions. Here we have used semi-supervised machine learning methodology to generate signatures of eight oncogene-inducible pathways, which are conserved across epithelial and lymphoid tissues. We combined them to patterns of pathway activity called PAPs for pathway activation patterns and searched for them in 220 morphologically, immunohistochemically and genetically well-characterized mature aggressive B-cell lymphomas including 134 cases with clinical data available. Besides Burkitt lymphoma, which was characterized by a unique pattern, the PAPs identified four distinct groups of mature aggressive B-cell lymphomas across independent gene expression studies with distinct biological characteristics, genetic aberrations and prognosis. We confirmed our findings through cross-platform analysis in an independent data set of 303 mature aggressive B-cell lymphomas.Leukemia (2008) 22, 1746–1754; doi:10.1038/leu.2008.166; published online 26 June 2008 [ABSTRACT FROM AUTHOR]

Objectives: To determine the outcome of patients with a serum prostate-specific antigen (PSA) level >20 ng/ml that underwent radical prostatectomy (RP).Methods: We retrospectively reviewed the medical records of 147 patients who underwent RP for clinically localized prostate cancer with a pre-treatment PSA (PSApt) >20 ng/ml. Fifty-two patients had positive pelvic lymph nodes and were excluded from analysis. Of 95 patients remaining, 15 were lost to follow-up. Therefore, the study group included 80 patients. The end points for this analysis were biochemical relapse-free survival (bRFS), surgical and post-operative complications and urinary continence. PSApt, pathological grade, surgical margin status, age, clinical stage and immediate androgen ablation were evaluated in a multivariate analysis regarding bRFS.Results: Forty-nine resected specimens (61.2%) were pathologically classified as pT3 or pT4. After a mean follow-up of 64 months, the estimated 5-year bRFS rate was 58% for the overall group. Immediate androgen ablation was the only independent prognostic factor for biochemical relapse (P=0.001). Concerning the 21 patients who received an immediate androgen ablation after RP, the estimated 5-year bRFS rate was 92%. Complete urinary continence was achieved in 76.5% of patients. Early complications occurred in 13 patients (16.2%).Conclusions: Clinically localized prostate cancer with a PSApt >20 ng/ml is considered as having a poor prognosis. However, RP performed in these patients led to an acceptable morbidity and good functional results. Immediate adjuvant hormonal therapy seems mandatory in this setting to improve bRFS.Prostate Cancer and Prostatic Diseases (2006) 9, 239–244. doi:10.1038/sj.pcan.4500892; published online 11 July 2006 [ABSTRACT FROM AUTHOR]

Introduction: Treatment options for lymph node positive prostate cancer are limited. We retrospectively compared patients who underwent external radiotherapy (ERT) to patients treated by radical prostatectomy (RPX).Materials and Methods: A total of 102 lymph node positive patients from the RPX series at Ulm University were evaluated. In all, 76 patients received adjuvant androgen withdrawal as part of their primary treatment. In the ERT group, 44 patients were treated at the University of Michigan using a fractionated regimen. Of these, 21 patients received early adjuvant hormonal therapy. Patients with neoadjuvant therapy before RPX or ERT were excluded.Results: In the RPX group, PSA nadir (nadir?0.2 vs>0.2?ng/ml) showed a strong association with outcome. In the ERT group, pretreatment PSA was an independent predictor of outcome (P=0.04) and patients with adjuvant hormonal therapy had a significant longer recurrence-free interval compared to patients without adjuvant therapy (P=0.004). Comparing only patients with adjuvant hormonal treatment after cancer-specific therapy, the ERT-treated patients had a borderline longer PSA recurrence-free survival time compared to the RPX-treated patients (P=0.05).Conclusions: In case of positive lymph nodes, RPX and ERT might be considered and need to be explained to the patient. For future treatment decisions, the presented findings and a potential survival benefit need to be evaluated in a larger prospective setting.Prostate Cancer and Prostatic Diseases (2004) 7, 343-349. doi:10.1038/sj.pcan.4500751 Published online 7 September 2004 [ABSTRACT FROM AUTHOR]

Chemotherapy-treated patients with advanced Hodgkin’s disease (HD) differ considerably in acute hematotoxicity. Hematotoxicity may be indicative of pharmacological and metabolic heterogeneity. We hypothesized that low hematotoxicity might correlate with reduced systemic dose and thus reduced disease control. A total of 266 patients with advanced HD treated with cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP-ABVD) were analyzed (HD6 trial of the German Hodgkin’s Lymphoma Study Group). The reported WHO grade of leukocytopenia was averaged over chemotherapy cycles given and weighted with the reciprocal dose intensity of the corresponding cycle. The low and high toxicity groups were defined in retrospect as having had an averaged WHO grade of leukocytopenia ≤2.1 and >2.1, respectively. The independent impact of low hematological toxicity on freedom from treatment failure (FFTF) was assessed multivariately adjusting for the international prognostic score for advanced HD. The results were validated in two independent cohorts [181 patients treated with COPP-ABVD (HD9-trial) and 250 patients treated with COPP-ABV-ifosfamide, methotrexate, etoposide, and prednisone (IMEP) (HD6 trial)]. The 5-year FFTF rates were 68% for patients with high toxicity vs 47% for patients with low toxicity [multivariate relative risk (RR) 2.0, 95% confidence interval (CI) 1.4–3.0, p=0.0002]. Patients with low toxicity received significantly higher nominal dose (p=0.02) and dose intensity (p<0.0001). This finding was confirmed in both validation cohorts (multivariate RR 2.1, 95% CI 1.2–3.8, p=0.01 and RR 1.5, 95% CI 1.01–2.26, p=0.04, respectively). Patients with low hematotoxicity have significantly higher failure rates despite higher doses and dose intensity. Hematotoxicity is an independent prognostic factor for treatment outcome. This observation suggests a strategy of individualized dosing adapted to hematotoxicity. [ABSTRACT FROM AUTHOR]

A post-traumatic composite skin, muscle and bone defect in the left thigh with a 14-cm bone gap in the femur was secondarily reconstructed with a salvage osseomyocutaneous microvascular free tissue transfer of the tibia (18 cm), calf muscles and overlying skin (26×13 cm) harvested from the lower leg. The latter was amputated for chronic trophic ulceration of the foot and causalgia resulting from damage to the femoral and sciatic nerve in the primary injury. This situation resulted in an above-the-knee amputation stump with a better fitting and a more convenient prosthesis, rather than amputation at the hip joint. [ABSTRACT FROM AUTHOR]

Reports that mitochondria can contain a pre-processed caspase isoform in non-apoptotic cells. Monoclonal antibody specific for N-terminus of caspase-9; Impact of permeability transition on caspase-9 activity.

We sketch the development of the effective dose approach which provides a theoretical framework to interpret chemotherapy outcome data. Building on the generalised Skipper model of chemotherapy, a meta-regression method is derived to jointly analyse all chemotherapy comparing randomised clinical trials in a given malignancy in order to explore the slope of the effective dose/outcome relationship and the relative potency of cytostatic drugs. The model is applied to explain why treatment differences in aggressive NHL appear to differ by risk groups in aggressive NHL. A respective meta-subgroup analysis to confirm this interaction hypothesis is proposed. [ABSTRACT FROM AUTHOR]

Caspase activation may occur in a direct fashion as a result of CD95 death receptor crosslinking (exogenous pathway) or may be triggered indirectly, via a Bcl-2 inhibitable mitochondrial permeabilization event (endogenous pathway). Thymocyte apoptosis is generally accompanied by proteasome activation. If death is induced by DNA damage, inactivation of p53, overexpression of a Bcl-2 transgene, inhibition of protein synthesis, and antioxidants (N-acetylcyteine, catalase) prevent proteasome activation. Glucocorticoid-induced proteasome activation follows a similar pattern of inhibition except for p53. Caspase inhibition fails to affect proteasome activation induced by topoisomerase inhibition or glucocorticoid receptor ligation. In contrast, caspase activation (but not p53 knockout or Bcl-2 overexpression) does interfere with proteasome activation induced by CD95. Specific inhibition of proteasomes with lactacystin or MG123 blocks caspase activation at a pre-mitochondrial level if thymocyte apoptosis is induced by DNA damage or glucocorticoids. In strict contrast, proteasome inhibition has no inhibitory effect on the mitochondrial and nuclear phases of apoptosis induced via CD95. Thus, proteasome activation is a critical event of thymocyte apoptosis stimulated via the endogenous pathway yet dispensable for CD95-triggered death. [ABSTRACT FROM AUTHOR]

The clustering ofHTdR labelled cells in the epidermal basal layer and their changes with time have been modelled mathematically and cannot be adequately fitted by an earlier model of the cell kinetic organisation of the skin. A more refined model analysis was performed based on Monte Carlo computer simulations of cell layers which take cell division, cell aging and lateral as well as vertical cell migration into account. A large variety of hypothetical scenarios was tested to see if each could provide a fit to the clustering data. The analysis provides further support for the concept of a cell kinetic heterogeneity with a stemtransit-postmitotic differentiation scheme. In the best overall model scheme three transit divisions are predicted but unlike in the earlier model it is now postulated that postmitotic cells can be produced at all stages in the lineage rather than only at the end of the amplification scheme. Most important, the model predicts that stem cells and most of the transit cells differ in the way they processHTdR label. Grain dilution is an important mechanism to explain the fate of some labelled cells in the tissue, but on its own it can only consistently explain the data if the stem cells have a very low labelling index (LI ≤ 1 %) which implies a very short biologically unreasonable S-phase. If a higher LI (longer S-phase) is assumed for the stem-cells other mechanisms must be predicted to explain the lack of large clusters and the increase in time of the singles. The selective segregation of chromosomes at mitosis is one such mechanism. However, on its own a large number of cells would have to behave in this way (i.e. both stem and T cells). If combined with other assumptions such as some grain dilution this selective segregation may be restricted only to stem cells. In addition the model allows cell production and migration rates to be estimated and the analysis can be related to the EPU-concept. Indeed the model itself would tend to automatically generate an EPU like structure. The model quantitatively reproduces LI, PLM, CL and clustering data. [ABSTRACT FROM AUTHOR]

The use of mathematical models in haematology is shown by some examples concerning stem cell kinetics, erythropoiesis and thrombopoiesis. At first, model assumptions are formulated which include the biological knowledge and some regulatory hypotheses. Then, the reaction of the model on stimulation and suppression is calculated. Finally, by comparison with experimental or clincal data one can evaluate how far the model assumptions are sufficient to understand the measurements. Thus one can exclude wrong hypotheses and identify the important regulatory influences. [ABSTRACT FROM AUTHOR]

A human malignant melanoma was grown in nude mice. The tumour showed an exponential growth for several weeks which gradually slowed down, until following week 8 the tumour growth ceased. The reasons for this growth pattern were examined by labelling techniques (PLM, LI). The tumour cell production as quantified by the growth fraction, showed only a moderate reduction which, taken alone, could not explain the growth cessation. The important mechanism seems to be an increased loss of tumour cells during the intermitotic interval. While the loss of cells/h remains constant the total intermitotic cell loss is increased because the cell cycle times are prolonged by 50% from the exponential phase (45 h in week 3) to the plateau phase (66 h in week 8). [ABSTRACT FROM AUTHOR]

In a national multicentre trial in the FRG patients with Hodgkin's lymphoma in stages CS/PS III B/IV were entered into the HD 3 protocol and received induction chemotherapy with 3× (COPP+ABVD). Patients in complete remission (CR) received consolidation therapy by either radiotherapy (20 Gy IF) or chemotherapy (COPP+ABVD). Patients not in CR received salvage therapy (40 Gy in case of persisting nodal disease, else 4× CEVD chemotherapy). Between July 1983 and May 1987 230 untreated patients aged 15 to 60 qualified for this HD 3 protocol. This analysis is based on the first 137 patients evaluable for response. Of these, 86 (63%) achieved CR after induction chemotherapy. Including salvage therapy a total of 104 patients (76%) achieved CR. Univariate and multivariate prognostic risk factor analyses were performed using freedom from treatment failure (FFTF) as endpoint. Sex, age, splenectomy, bone marrow, liver and bone involvement had no prognostic impact nor had stage according to the Ann Arbor classification. In contrast, a pretreatment erythrocyte sedimentation rate (ESR) above 80 mm/h and a serum alkaline phosphatase (AP) above 230 IU/ml appeared as significant risk factors ( p<0.01, relative risk 2.3). The two parameters were not independent. Comparing a group A (ESR ≤ 80 and AP ≤ 230) versus a pooled group B (ESR>80 and/or AP>230) increased the difference ( p<0.001, relative risk of 2.8) which was also significant for survival ( p<0.04). [ABSTRACT FROM AUTHOR]

A previously described mathematical model of the hematopoietic stem cell system has been extended to permit a detailed understanding of the data during and after hypoxia. The model includes stem cells, erythroid and granuloid progenitors and precursors. Concerning the intramedullary feedback mechanisms two basic assumptions are made: 1) The fraction 'a' of CFU-S in active cell cycle is regulated. Reduced cell densities of CFU-S, progenitors or precursors lead to an accelerated stem cell cycling. Enlarged cell densities suppress cycling. 2) The self renewal probability 'p' of CFU-S is also regulated. The normal steady state is described by p=0.5, indicating that on statistical average each dividing mother stem cell is replaced by one daughter stem cell, while the second differentiates. Diminished cell densities of CFU-S or enlarged densities of progenitors and precursors induce a more intensive self renewal ( p>0.5), such that the stem cell number increases. The self renewal probability declines ( p<0.5) if too many CFU-S or too few progenitors and precursors are present. The model reproduces bone marrow data for CFU-S, BFU-E, CFU-C, CFU-E, 59 Fe-uptake and nucleated cells in hypoxia and posthypoxia. Although the ratio of differentiation into the erythroid and granuloid cell lines is kept constant in the model, a changing ratio of CFU-E and CFU-C results. The model suggests that stem cells and progenitor cells are regulated by a regulatory interference of erythropoiesis and granulopoiesis. [ABSTRACT FROM AUTHOR]

We discuss possible justifications to split study populations from a biometrical point of view. The existence of prognostic differences between subgroups are neither a sufficient nor a necessary reason to justify a splitting decision. There are essentially two separate types of relevant arguments to justify a split of patient study populations: a) Different toxicity/benefit trade-offs concerning the acceptability of a particularly aggressive treatment, b) Evidence for strong treatment by subgroup interactions, i.e. Treatment differences differ markedly by biologically defined subgroups. The latter is what the research ideal of biologically specific treatment asks for. Subgroup analysis is notoriously difficult. Formal statistical analysis must be complemented by specific evidence from basic sciences. Meta-subgroup analyses may be an option if a biologically specific hypothesis on which treatment component interacts with what biological feature allows to operationally identify all those randomised trials in which the effect should be present. In this conceptual and methodological paper we defend five theses concerning the clinical consequences of pathological and biological differences from a somewhat unorthodox biometrical point of view. [ABSTRACT FROM AUTHOR]

The impact of radiotherapy in aggressive NHL is not well defined. In the NHL B-94 trial of the DSHNHL, an irradiation of bulky disease areas was done after completing 6 cycles of CHOP/CHOEP chemotherapy. In the entire patient group, including those patients with extranodal disease and those who did not receive the complete chemotherapy, bulky disease was a significant independent prognostic factor concerning recurrence-free survival (66.1% (no bulk) vs. 53.3% (bulk), p=0.0001). Out of 366 patients with nodal disease only and 6 cycles of chemotherapy according to the protocol, 84 of 91 patients with bulky disease were irradiated with 36 Gy. In this group of patients the prognostic impact of bulky disease could not be shown any longer (recurrence-free survival 77.3% (no bulk) vs. 74.1% (bulk). Localized radiotherapy of bulky disease areas may therefore have contributed to an improvement in outcome in this high-risk group. [ABSTRACT FROM AUTHOR]