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Reinduction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (HDCT + ASCT) is second-line standard of care for transplant-eligible patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) but has a high failure rate. Because response to reinduction is predictive of the outcome after HDCT + ASCT, we aimed to improve the standard dexamethasone, high-dose cytarabine and cisplatinum (DHAP) reinduction regimen by addition of the oral mammalian target of rapamycin inhibitor everolimus (everDHAP). Transplant-eligible patients aged 18–60 years with histologically confirmed r/r cHL were included in this experimental phase I/II trial. Everolimus (10 mg/day, determined in phase-I-part) was administered on day 0–13 of each DHAP cycle. From July 2014 to March 2018, 50 patients were recruited to the phase II everDHAP group; two were not evaluable, three discontinued due to toxicity. Randomization to a placebo group stopped in October 2015 due to poor recruitment after nine patients. The primary end-point of computed tomography (CT)-based complete remission (CR) after two cycles of everDHAP was expected to be ≥40%. With a CT-based CR rate of 27% (n = 12/45) after two cycles of everDHAP the trial did not meet the primary end-point. Adding everolimus to DHAP is thus feasible; however, the everDHAP regimen failed to show an improved efficacy.

Purpose: A primary analysis of the ongoing NIVAHL trial demonstrated unexpectedly high interim complete response rates to nivolumab-based first-line treatment in early-stage unfavorable Hodgkin lymphoma. However, biomarkers such as metabolic tumor volume (MTV) or total lesion glycolysis (TLG) and their change under treatment (ΔMTV and ΔTLG), measured on PET, might provide additional relevant information for response assessment in this setting. Hence, the current analysis aimed to investigate early response to checkpoint inhibitor therapy beyond conventional criteria. Patients and Methods: NIVAHL is a prospective, randomized phase II trial that recruited between April 2017 and October 2018. Patients in arms A and B were assessed for early treatment response after two courses of doxorubicin, vinblastine, and dacarbazine with two concomitant nivolumab infusions per cycle (2 × N-AVD) and 4 × nivolumab, respectively. In the current analysis, we included all 59 individuals with PET images available to the central review panel for quantitative analysis before April 30, 2019. Results: At interim restaging, we determined a mean ΔMTV and ΔTLG of −99.8% each in arm A after 2 × N-AVD, compared with −91.4% and −91.9%, respectively, for treatment group B undergoing 4 × nivolumab. This high decrease in MTV and TLG was observed regardless of the initial lymphoma burden. Conclusions: Our study showed that nivolumab-based first-line treatment leads to rapid, near-complete reduction of tumor metabolism in early-stage unfavorable Hodgkin lymphoma. Thus, PET-derived biomarkers might allow reduction or even omission of chemotherapy and radiotherapy. Furthermore, MTV and TLG could be also used to optimize immune checkpoint-targeting treatments in other cancers.

To evaluate patterns of rrHL after contemporary first-line treatment we studied 409 patients with first rrHL (HD13: n = 87, HD14: n = 118, HD15: n = 188, HDR3i: n = 51) at a median age of 37.4 years (18.4–76.8) from the GHSG database. Time to first relapse was ≤12 months in 49% and stage III/IV rrHL present in 52% of patients. In total, 291 patients received high-dose chemotherapy and autologous stem-cell transplantation (ASCT) and intended ASCT failed in 38 patients. ASCT was primarily not intended in 80 patients largely due to low risk disease or age/comorbidities. Overall, 10-year progression-free (PFS) and overall survival (OS) rates after first relapse were 48.2% (95% CI 41.9–54.2%) and 59.4% (95% CI 53.0–65.2%), respectively, with significant differences between subgroups. Inferior survival was observed with no ASCT due to advanced age/comorbidities (five-year PFS 36.2%, 95% CI 17.7–55.0%) or failure of salvage therapy (five-year PFS 36.3%, 95% CI 19.7–53.2%). Similarly, presence of primary refractory disease or stage IV at rrHL conferred inferior survival. In patients with low-risk disease, however, survival appeared favorable even without ASCT (10 y PFS 72.6%, 95% CI 53.7–84.8%). We herein confirm the curative potential of current rrHL treatments providing a robust benchmark to evaluate novel therapeutic strategies in rrHL. Approximately 50% of rrHL patients experienced a consecutive relapse.

We performed a survey in Hodgkin lymphoma survivors to learn more about their perspectives on treatment risks and benefits. We sent questions to 1149 survivors from the GHSG’s HD13-15 trials with (...

Classical Hodgkin Lymphoma (cHL) is a B cell-derived lymphoid malignancy, affecting 2.5–3/100,000 people per year. To date, in patients diagnosed with advanced cHL no reliable tool is able to—a priori—distinguish the subset of patients at high risk for relapse or refractory disease. Clinical risk indices for cHL, such as the International Prognostic Score (IPS), have not been successfully applied as a treatment decision tool in advanced stage cHL [1]. In this study we show, that a previously published gene expression-based predictor in advanced stage cHL patients treated with ABVD [2] does not prove prognostic in 401 BEACOPP-treated advanced stage cHL patients. Using transcriptome profiling, we identified however that three individual genes, PDGFRA, TNFRSF8 (encoding CD30) and CCL17 (encoding TARC), were significantly associated with progression-free survival (PFS) after multiple test correction in the BEACOPP-treated cohort, highlighting the potential of a modified gene expression profiling approach for pre-treatment risk assessment., Letter

Data on non-Hodgkin lymphoma (NHL) after classical Hodgkin lymphoma (cHL) are scarce. We therefore performed a retrospective analysis comprising 11·841 cHL patients who had first-line treatment within the randomized German Hodgkin Study Group (GHSG) HD7-HD15 studies. After a median follow-up of 106 months, 175 patients (1·5%) had developed NHL. The median time to NHL was 44 months, the median age at NHL diagnosis was 54 years. The five-year event-free survival and overall survival estimates from the diagnosis of NHL were 36·9% and 44·2%, respectively. Thus, NHL after cHL is a rare event primarily affecting older individuals and often resulting in the patient´s death.

PURPOSE We evaluated disease and treatment characteristics of patients with relapse after risk-adapted first-line treatment of early-stage, favorable, classic Hodgkin lymphoma (ES-HL). We compared second-line therapy with high-dose chemotherapy and autologous stem cell transplantation (ASCT) or conventional chemotherapy (CTx). METHODS We analyzed patients with relapse after ES-HL treated within the German Hodgkin Study Group HD10+HD13 trials. We compared, by Cox proportional hazards regression, progression-free survival (PFS) after relapse (second PFS) treated with either ASCT or CTx and performed sensitivity analyses with overall survival (OS) from relapse and Kaplan-Meier statistics. RESULTS A total of 174 patients’ disease relapsed after treatment in the HD10 (n = 53) and HD13 (n = 121) trials. Relapse mostly occurred > 12 months after first diagnosis, predominantly with stage I-II disease. Of 172 patients with known second-line therapy, 85 received CTx (49%); 70, ASCT (41%); 11, radiotherapy only (6%); and 4, palliative single agent therapies (2%). CTx was predominantly bleomycin, etoposide, doxorubicin cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP [68%]), followed by the combination regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (19%), or other regimens (13%). Patients aged > 60 years at relapse had shorter second PFS (hazard ratio [HR], 3.0; P = .0029) and were mostly treated with CTx (n = 33 of 49; 67%) and rarely with ASCT (n = 8; 16%). After adjustment for age and a disadvantage of ASCT after the more historic HD10 trial, we did not observe a significant difference in the efficacy of CTx versus ASCT for second PFS (HR, 0.7; 95% CI, 0.3 to 1.6; P = .39). In patients in the HD13 trial who were aged ≤ 60 years, the 2-year, second PFS rate was 94.0% with CTx (95% CI, 85.7% to 100%) versus 83.3% with ASCT (95% CI, 71.8% to 94.8%). Additional sensitivity analyses including OS confirmed these observations. CONCLUSION After contemporary treatment of ES-HL, relapse mostly occurred > 12 months after first diagnosis. Polychemotherapy regimens such as BEACOPP are frequently administered and may constitute a reasonable treatment option for selected patients with relapse after ES-HL.

PURPOSE Many important details of health-related quality of life (HRQoL) after diagnosis and treatment of Hodgkin lymphoma (HL) are still unknown because large longitudinal studies of HRQoL are rare. Therefore, we analyzed a systematically assessed, comprehensive range of HRQoL domains in patients with HL of all stages from diagnosis up to 5 years of survivorship. PATIENTS AND METHODS We included patients with HL age 18-60 years at diagnosis from the German Hodgkin Study Group trials HD13, HD14, and HD15. We analyzed HRQoL using all functional and symptom scales of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 including deviations from reference values. We estimated the effect of different disease, patient, and treatment characteristics using multiple regression and repeated measures analysis and computed correlations of HRQoL scores. RESULTS We analyzed 4,215 patients with any HRQoL assessment within 5 years after treatment. Higher tumor burden at diagnosis was associated with impaired baseline scores in many HRQoL domains. During survivorship, cognitive, emotional, role, and social functioning and fatigue, dyspnea, sleep, and financial problems were severely and persistently affected. From year 2 on, mean deviations from reference values ranged between 12 and 29 points, with 10 points being a commonly used margin of clinical relevance. In all 3 trials, HRQoL domains 2 and 5 years after therapy were significantly influenced by baseline scores and age but not by randomized treatments. Fatigue was most closely correlated with other symptoms and scales. CONCLUSION Our results show a high and persistent amount of different HRQoL deficits in survivors of HL that are largely independent of the applied chemotherapies. Our analysis underscores the high, unmet medical need of these rather young survivors of HL regarding the psychosocial adverse effects of the cancer experience.

Rationale: (18F)fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) for staging Hodgkin lymphoma may allow for accurate and reliable assessment of the metabolic tumour volume (MTV) as baseline risk factor. Our aim was to analyse the prognostic impact of MTV measurements, obtained by different means in advanced-stage Hodgkin lymphoma patients treated within the German Hodgkin Study Group HD18 trial. Methods: Within the German Hodgkin Study Group trial HD18, 310 patients underwent 18F-FDG PET/CT scanning for staging which was available to the central review panel for quantitative analysis. We calculated the MTV by four different thresholding methods and performed receiver operating characteristic (ROC) analysis to evaluate the potential for prediction of early response determined by PET after two cycles (PET-2) dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP). Logistic regression was used to evaluate its prognostic value concerning progression-free survival (PFS) and overall survival (OS). Results: All different MTV calculations used predicted PET-2 response to a moderate and comparable degree (area under the curve = 0.62-0.63, P = 0.01-0.06). With none of the measuring methods did the ROC curves point to any unique cut-off values, but indicated a wide range of possible cut-offs. However, none of the MTV measurements was prognostic for PFS (Hazard ratio 1.2-1.5, P = 0.15-0.52) or OS (Hazard ratio 1.0-1.5, P = 0.95 - 0.27). Conclusion: Baseline MTV as determined by different means, is a predictive factor for early response to eBEACOPP after two cycles. However, value as a prognostic factor after highly effective PET-2 adapted treatment strategy could not be observed.

Purpose Combined-modality treatment is widely considered the standard of care in early-stage Hodgkin lymphoma (HL), and treatment intensity has been reduced over the last years. Long-term follow-up is important to judge both efficacy and safety of the different therapies used. Patients and Methods We analyzed updated follow-up data on 4,276 patients treated within the German Hodgkin Study Group trials HD7 and HD10 for early-stage favorable HL and HD8 and HD11 for early-stage unfavorable HL between 1993 and 2003. Results In HD7 (N = 627; median follow-up, 120 months), combined-modality treatment was superior to extended-field radiotherapy (RT), with 15-year progression-free survival (PFS) of 73% versus 52% (hazard ratio [HR], 0.5; 95% CI, 0.3 to 0.6; P < .001), without differences in overall survival (OS). In HD10 (N = 1,190; median follow-up, 98 months), noninferiority of two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) plus 20 Gy involved-field (IF)–RT to more intensive four cycles of ABVD plus 30 Gy IF-RT was confirmed with 10-year PFS of 87% each (HR, 1.0; 95%, 0.6 to 1.5) and OS of 94% each (HR, 0.9; 95% CI, 0.5 to 1.6), respectively. In both trials, no differences in second neoplasias were observed. In HD8 (N = 1,064; median follow-up, 153 months), noninferiority of involved-field RT to extended-field RT regarding PFS was confirmed (HR, 1.0; 95% CI, 0.8 to 1.2). In HD11 (N = 1,395; median follow-up, 106 months), superiority of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone at baseline over ABVD was not observed. After BEACOPPbaseline, 20 Gy IF-RT was noninferior to 30 Gy (10-year PFS, 84% v 84%; HR, 1.0; 95% CI, 0.7 to 1.5). In contrast, PFS was inferior in ABVD-treated patients receiving 20 Gy instead of 30 Gy IF-RT (10-year PFS, 76% v 84%; HR, 1.5; 95% CI, 1.0 to 2.1). No differences in OS or second neoplasias were observed in in both trials. Conclusion Long-term follow-up data of the four randomized trials largely support the current risk-adapted therapeutic strategies in early-stage HL. Nevertheless, continued follow-up is necessary to assess the long-term safety of currently applied therapeutic strategies.

IF 11.855; International audience; Background:Novel agents are changing the treatment of relapsed or refractory Hodgkin lymphoma (HL). Nevertheless, high-dose chemotherapy and autologous stem-cell transplantation (ASCT) are considered standard of care in eligible patients. To identify patients who could benefit most from novel therapeutic approaches, we investigated a comprehensive set of risk factors (RFs) for survival after ASCT.Methods:In this multinational prognostic multivariable modeling study, 23 potential RFs were retrospectively evaluated in HL patients from nine prospective trials with multivariable Cox proportional hazards regression analyses (part I). The resulting prognostic score was then validated in an independent clinical sample (part II).Results:In part I, we identified 656 patients treated for relapsed/refractory HL between 1993 and 2013 with a median follow-up of 60 months after ASCT. The majority of potential RFs had significant impact on progression-free survival (PFS) with hazard ratios (HR) ranging from 1.39 to 2.22. The multivariable analysis identified stage IV disease, time to relapse ≤3 months, ECOG performance status ≥1, bulk ≥5 cm and inadequate response to salvage chemotherapy [

BACKGROUND The prognosis of Hodgkin lymphoma (HL) is excellent rendering research into treatment complications highly important. An important complication of cancer and its treatment is thrombosis. Thrombotic events are regularly observed in HL patients but precise information on incidence and risk factors is lacking and the value of prophylactic anticoagulation unclear. PATIENTS AND METHODS Thus, we comprehensively studied thrombotic events in 5773 patients from the German Hodgkin Study Group (GHSG) HD13-15 trials in early-favorable, intermediate and advanced HL. We estimated the incidence of and identified risk factors for thrombotic events. Additionally, we provide detailed data on the time course and characteristics of thrombotic events. RESULTS A total of 193 thrombotic events occurred for an incidence of 3.3%. Out of these, 175 (90.7%) were venous thromboses, 3 (1.5%) newly emerging post-thrombotic syndromes and 15 (7.8%) arterial thromboses. There were 11 (0.7%) events in early-favorable, 27 (1.3%) in early-unfavorable and 155 (7.3%) in advanced patients, the latter incidence being significantly higher (P

INTRODUCTION: Thromboembolism (TE) in lymphoma patients is gathering substantial attention due to its impact on morbidity and mortality of those patients. The association between lymphoma and increased risk for TE development, especially venous thromboembolism (VTE), has lately been well established through numerous publications. Thrombosis Lymphoma (ThroLy) score has been initially developed as a simple risk assessment model for the risk of TE development in lymphoma patients. It has been both internally and externally validated in several studies, which dominantly included patients with non-Hodgkin lymphoma (NHL). Therefore, aim of our study is to analyse and validate ThroLy score in an extensive cohort of Hodgkin lymphoma (HL) patients. METHODS: A total of 5509 newly diagnosed HL patients, from the German Hodgkin Study Group (GHSG) HD13-15 trials, were included in this study. Data has been obtained for all venous and arterial TE events in HL patients from time of diagnosis to 3 months after the last cycle of therapy. TE was diagnosed objectively based on radiographic studies (duplex venous ultrasound, contrast-enhanced thoracic computed tomography scan, magnetic resonance imaging (MRI) - for central nervous system (CNS) thrombosis, or angiograms (for arterial thrombosis), clinical examination and laboratory evaluation. Based on ThroLy score, patients were divided in three risk categories: low (score 0-1), intermediate (score 2-3) and high risk (score >3). Patients with intermediate and high-risk score were classified at risk. The validation was conducted through Chi-square test, ROC analysis and logistic regression. RESULTS: The mean patients' age was 35.9 years (range, 18-75 years); 55.7% were males. The majority of patients had limited or intermediate stage of disease: Ann Arbor stage I 10.6%, and stage II 57.5%. 190 (3.4%) patients developed thromboembolic events, 173 patients with VTE (3.14%), and 17 with arterial TE (0.31%), respectively. Chi-square test showed statistically significant association between TE and ThroLy score, both in three risk groups (chi-square = 18.236, p≤0.001) and two risk groups: low and at risk (chi-square = 18.029, p≤0.001). The sensitivity, specificity, negative and positive predictive value were 49%, 65%, 95%, and 97%, respectively. Binary logistic regression of ThroLy score showed statistically significant performance in prediction of TE events in HL patients, with satisfactory validity indicators (Ombinus Test chi-square = 11.668, p=0.001; AIC=44.956, BIC = 97.869). Diagnostic accuracy of ThroLy score was calculated via ROC curve (area under curve (AUC)=0.57). CONCLUSION: ThroLy score demonstrated its capability of risk prediction for TE events in HL patients. The limited statistical performance of the ThroLy score requires further research towards possible score enhancement. Disclosures Engert: AstraZeneca: Honoraria; MSD Sharp & Dohme: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Affimed Therapeutics: Research Funding; Sandoz: Honoraria; Takeda: Honoraria, Research Funding.

Item does not contain fulltext Only 50% of patients with relapsed Hodgkin lymphoma (HL) can be cured with intensive induction chemotherapy, followed by high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). Based on the results of the HDR2 trial two courses of DHAP and subsequent HDCT/ASCT are the current standard of care in relapsed HL. In order to assess the prognostic relevance of DHAP dose density, we performed a retrospective multivariate analysis of the HDR2 trial (N = 266). In addition to four risk factors (early or multiple relapse, stage IV disease or anemia at relapse, and grade IV hematotoxicity during the first cycle of DHAP) a delayed start of the second cycle of DHAP > day 22 predicted a significantly poorer progression-free survival (PFS, p = 0.0356) and overall survival (OS, p = 0.0025). In conclusion, our analysis strongly suggests that dose density of DHAP has a relevant impact on the outcome of relapsed HL patients.

Quality control systems for satellite laser ranging (SLR) observations have been developed at a number of analysis institutes worldwide, using various software packages of precise orbit determination and data analysis. Satellite laser range observations, primarily from the two LAGEOS satellites but also from other satellites in low-Earth orbits and up to GNSS altitude, are being processed on a sub-daily to weekly basis. The generated quality control reports are widely used to detect various kinds of problems and quickly provide anomalous information to laser ranging stations. They have been effective in shortening the time to return to normal operations when anomalous data are detected and in quantifying the performance of laser ranging stations. Consequently, a rapid feedback loop has now been incorporated in the modern SLR operation.

The majority of patients with Hodgkin Lymphoma (HL) can be cured with stage and risk adapted treatment today. Therefore, current research focuses on reducing long-term sequelae of treatment. Osteonecrosis (ON) is a severe long-term complication of HL treatment which has so far not been systematically evaluated. Hence, we investigated incidence, risk factors and timing of symptomatic ON in HL patients. Further endpoints included localization, intervention and outcome of ON. We included all qualified HL patients of the randomized German Hodgkin Study Group trials HD10-15 and HD18, recruited between 05/1998 and 07/2014 and aged from 16 to 60 years. Among 11 330 patients, 66 developed symptomatic ON after first-line treatment, 83.3% within three years. The incidence of symptomatic ON was 0.2% in early-stage HL and 1.0% in advanced-stage HL. Logistic regression revealed the total cumulative corticosteroid dose to be a strong risk factor interacting with younger age. Male sex additionally increased the risk of symptomatic ON. The prognostic value of the corresponding logistic regression model was rather high (AUC = 0.78). Other tested potential risk factors including obesity, IPS and radiotherapy did not further increase the risk of ON. Further development of current treatment protocols should aim to reduce the cumulative corticosteroid dose.

Purpose Cancer-related fatigue occurs frequently in patients with Hodgkin lymphoma (HL) and has a major impact on their quality of life. We hypothesized that severe fatigue (sFA) might have an impact on patients’ treatment outcome and social reintegration. Methods Of 5,306 patients enrolled in the German Hodgkin Study Group’s fifth generation of clinical trials in HL (HD13, HD14, and HD15; nonqualified and older [> 60 years] patients excluded), 4,529 provided data on health-related quality of life. We describe sFA (defined as a score ≥ 50 on the 0 to 100 scale from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30) before and up to 9 years after therapy and analyze its impact on treatment outcome and social reintegration. Results The proportion of patients reporting sFA was 37% at baseline and ranged from 20% to 24% during follow-up. Baseline sFA was associated with significantly impaired progression-free survival and a trend to impaired overall survival, which can be overcome in patients receiving highly effective HL therapies as applied in our fifth-generation trials. Our analysis revealed a significant negative association of sFA and employment in survivors: 5 years after therapy, 51% and 63% of female and male survivors, respectively, with sFA were working or in professional education, compared with 78% and 90% without sFA, respectively ( P < .001 adjusted for age, sex, stage, baseline employment status, and treatment outcome). sFA was also associated with financial problems and the number of visits to a general practitioner and medical specialists. Conclusion sFA is an important factor preventing survivors from social reintegration during follow-up. This observation underscores the need to address fatigue as a significant diagnosis when treating patients with and survivors of cancer.

Background: Health-related quality of life (HRQoL) comprises different domains of physical, mental, and social well-being. In this analysis, we focus on sexual quality of life in Hodgkin Lymphoma (HL) patients. Methods: Four-thousand one-hundred and sixty patients enroled in the HD10–HD12 trials underwent HRQoL assessment. Instruments included the Quality of Life Questionnaire for survivors (QLQ-S), combining the European Organisation for Research and Treatment of Cancer QLQ-C30, Multidimensional fatigue (FA) inventory (MFI-20) and an additional sexual functioning (SX) scale. We describe SX up to 27 months after therapy and analyse relationship to stage, age, gender, FA, social functioning, and therapy. Statistical methods range from descriptive statistics to a classification of SX courses, and a longitudinal structural equations model with full information maximum likelihood estimation of missing data. In the analysis, a score below 50 was used to describe severe sexual dysfunction. Results: Three-thousand two-hundred and eight patients provided data on SX. Patients in advanced stages reported lower SX than patients in early stages both, before and after the treatment. During follow-up, an improvement of SX compared with baseline was detected, except for those ⩾50 years. Patients in early stages reached normal SX, whereas advanced-stage patients remained below the reference value for healthy controls. Sexual functioning during follow-up was significantly and strongly related to previous SX, other HRQoL measures, age, and stage, and to lesser degree with gender and chemotherapy. Conclusion: Overall, HL patients have a decreased sexual quality of life at baseline, which improves after therapy and normalises in early-stage patients. Importantly, long-term SX is more closely related to patient characteristics and SX at baseline than to the intensity of treatment.

In preparation of activities planned for the realization of the Global Geodetic Observing System (GGOS), a group of German scientists has carried out a study under the acronym GGOS-D which closely resembles the ideas behind the GGOS initiative. The objective of the GGOS-D project was the investigation of the methodological and information-technological realization of a global geodetic-geophysical observing system and especially the integration and combination of the space geodetic observations. In the course of this project, highly consistent time series of GPS, VLBI, and SLR results were generated based on common state-of-the-art standards for modeling and parameterization. These series were then combined to consistently and accurately compute a Terrestrial Reference Frame (TRF). This TRF was subsequently used as the basis to produce time series of station coordinates, Earth orientation, and troposphere parameters. In this publication, we present results of processing algorithms and strategies for the integration of the space-geodetic observations which had been developed in the project GGOS-D serving as a prototype or a small and limited version of the data handling and processing part of a global geodetic observing system. From a comparison of the GGOS-D terrestrial reference frame results and the ITRF2005, the accuracy of the datum parameters is about 5–7 mm for the positions and 1.0–1.5 mm/year for the rates. The residuals of the station positions are about 3 mm and between 0.5 and 1.0 mm/year for the station velocities. Applying the GGOS-D TRF, the offset of the polar motion time series from GPS and VLBI is reduced to 50 μas (equivalent to 1.5 mm at the Earth’s surface). With respect to troposphere parameter time series, the offset of the estimates of total zenith delays from co-located VLBI and GPS observations for most stations in this study is smaller than 1.5 mm. The combined polar motion components show a significantly better WRMS agreement with the IERS 05C04 series (96.0/96.0 μas) than VLBI (109.0/100.7 μas) or GPS (98.0/99.5 μas) alone. The time series of the estimated parameters have not yet been combined and exploited to the extent that would be possible. However, the results presented here demonstrate that the experiences made by the GGOS-D project are very valuable for similar developments on an international level as part of the GGOS development.

Purpose The standard of care for adolescent patients with Hodgkin's lymphoma (HL) is undefined, particularly the choice between pediatric and adult protocols. Thus, we compared risk factors and outcome of adolescents and young adults treated within study protocols of the German Hodgkin Study Group (GHSG). Patients and Methods Three thousand seven hundred eighty-five patients treated within the GHSG studies HD4 to HD9 were analyzed; 557 patients were adolescents age 15 to 20 years, and 3,228 patients were young adults age 21 to 45 years. Results Large mediastinal mass and involvement of three or more lymph node areas were more frequent in adolescents (P < .001). The incidence of other risk factors did not differ significantly between age groups. With a median observation time of 81 months for freedom from treatment failure (FFTF) and 85 months for overall survival (OS), log-rank test showed no significant differences between age groups regarding FFTF (P = .305) and a superior OS (P = .008) for adolescents. Six-year estimates for FFTF and OS were 80% and 94%, respectively, for adolescents and 80% and 91%, respectively, for young adults. After adjustment for other predictive factors, Cox regression analysis revealed age as a significant predictor for OS (P = .004), with a higher mortality risk for young adults. Secondary malignancies were more common in young adults (P = .037). Conclusion Outcome of adolescent and young adult patients treated within GHSG study protocols is comparable. These data suggest that adult treatment protocols exhibit a safe and effective treatment option for adolescent patients with HL. However, longer follow-up, including assessment of late toxicity, is necessary for final conclusions.

The immune enhancing properties of probiotics are scientifically well documented. Whether Kanne- Brottrunk® (Selm-Bork, Germany) may play a preventive role in Pollinosis, was investigated in this study for the first time. Participants and Methods: 30 volunteers with pollinosis and a mean disease duration of 20 years agreed to consume 0.7 l Kanne-Brottrunk® daily for one year. At the beginning and at the end of the study and one year later they retrospectively rated their pollinosis related quality of life during the previous pollinosis season with a disease specific questionnaire (FLQA: Freiburg Life Quality Assessment). Additionally, the change was rated directly and status was assessed in November 2002, January 2003, May 2003 and November 2003. Results: 24 volunteers finished the study, although some of them consumed less than 0.7 l daily. 17 out of 20 assessed participants (85%) rated their pollinosis in the treatment year as ‘very much better’ or ‘much better’ (57% in the follow-up year). In 2003, the FLQA showed clinically relevant effect sizes (0.85-2.29) and statistically significant improvements (p

Recent solutions of the terrestrial reference frame such as ITRF2000 are combined from multi-year data sets that contain station positions at a reference epoch and constant velocities. Analysis of time series of station positions of the geodetic space techniques SLR, GPS, VLBI and DORIS show, however, that these techniques allow to detect variations in station position series with up to a few millimetre accuracy. Therefore, the underlying reference frame needs to assure the same accuracy. In this paper we analyse systematic effects in station position and transformation parameter time series that need to be taken into account for future TRF realisations. These are mainly annual signals that show up as common variations of the global networks as well as local effects on individual stations. These annual signals differ significantly from technique to technique for some co-location sites. Apart from periodic signals the time series show discontinuities (e.g. due to earthquakes or instrumentation changes) and periods of non-linear motion (e.g. post-seismic relaxation). We compute TRF technique solutions of five years of epoch normal equations, which allows to adapt the parameterisation in order to account for the effects mentioned above. The accuracy of the technique-specific solutions is evaluated by comparing the results at co-location sites. For this purpose, we transform the VLBI, SLR and DORIS solutions to the GPS solution by using the measured local ties between GPS and the other techniques.

According to national and international guidelines, the target serum low-density lipoprotein (LDL) cholesterol (LDL-C) level in secondary prevention of coronary heart disease is < 100 mg/dl. The EUROASPIRE-II study has clearly shown that this goal is far from being achieved in daily practice. The aim of the present study was to look at the distribution of LDL-C in 661 patients with CHD participating in outpatient exercise groups for cardiac rehabilitation. Although this preselection should have resulted in a sample of relatively well-guided and informed patients, 67% (58% with lipid-lowering drugs [LLD] and 78% without LLD) did not show the target LDL-C < 100 mg/dl. In a subgroup analysis, we investigated the influence of items such as physical activity (PA), BMI, and dosage of LLD on LDL-C. As expected, patients taking high doses of LLD (equivalent to 20 mg atorvastatin) showed lower levels of LDL-C as well as those exhibiting a higher degree of PA (3 times PA/w) and a lower BMI (

Fragestellung Der Einsatz des 36 Item Short-Form Health Survey (SF-36) in Kliniken ist problematisch, da einige Formulierungen in dem Fragebogen explizit auf den hauslichen bzw. beruflichen Kontext bezogen und damit in einer Klinik sehr unpassend sind. Um diesem bereits bekannten Problem zu begegnen, entfernten wir aus drei einleitenden Formulierungen die fur einen Klinikkontext klar unpassenden Ausdrucke-insgesamt 23 Worter-und erstellten so eine modifizierte Version des SF-36, den SF-36m. In der vorliegenden Arbeit werden in erster Linie zwei Fragen untersucht: Inwieweit beseitigt die angedeutete Modifikation die beschriebenen Probleme bei Applikation des SF-36 in Kliniken, und inwieweit sind SF-36 und SF-36m noch aquivalent?

Thrombotic events are regularly observed in patients receiving treatment for Hodgkin Lymphoma (HL). However, sound data on incidence and risk factors are not known. The aim of the present study was thus to provide a comprehensive analysis of thrombotic events after multimodality treatment for HL. A total of 5,773 patients ≤ 60 years treated within the German Hodgkin Study Group (GHSG) trials HD13-15 between January 2003 and December 2009 were included in this analysis. All reported venous and arterial thrombotic events occurring within 1 year after trial enrollment were evaluated and detailed information on patient characteristics, localizations, time of occurrence and risk factors were collected. We excluded thromboses of superficial veins and thrombophlebitis. Descriptive statistics and logistic regression were used for statistical analysis. A total of 193 thrombotic events occurred for an incidence of 3.3%; there were 11 events in early-favorable, 27 in early-unfavorable and 155 in advanced stage HL, resulting in incidence rates of 0.7%, 1.3% and 7.3%, respectively. The incidence in advanced stage HL was significantly higher than in early stage HL (p We found that 2.6% (n=5), 77.2% (n=149) and 20.2% (n=39) of cases occurred before, during and after chemotherapy respectively. In advanced HL patients treated with 8 x BEACOPPesc, 6 x BEACOPPesc or 8 x BEACOPP-14 , the incidence rates were 6.2% (n=44), 5.5% (n=39) and 10.1% (n=72) respectively. The incidence in patients treated with BEACOPP-14 was significantly higher than in patients treated with the other two regimens (p We then analyzed potential risk factors in advanced stage patients using logistic regression analysis, adjusting for treatment in order to identify a high-risk group for developing a thrombotic event. The well-established Khorana score was not associated with a higher risk of thrombosis (odds ratio (OR) per unit [95% confidence interval]: 0.91 [0.76-1.1], p=0.33). Additionally, we screened 21 potential risk factors, including the thrombocyte-to-lymphocyte ratio. Only age (OR per year: 1.02 [1.01-1.03], p=0.01) and smoking (OR: 1.61 [1.07-2.43], p=0.02) emerged as significant risk factors. None of the other following potential risk factors was prognostic: thrombocyte-to-lymphocyte ratio, thrombocytes, leukocytes, lymphocytes, hemoglobin, albumin, WHO activity index, erythropoietin treatment, sex, body mass index, B-symptoms, erythrocyte sedimentation rate, extranodal disease, large mediastinal mass, more than 2 affected areas or Ann Arbor stage (all p≥0.10). Yet, when only including venous events, which are potentially preventable by prophylactic anticoagulation, neither age nor smoking were significant risk factors anymore (p≥0.10). This study is the largest and most comprehensive analysis of thrombotic events in HL patients to date. Compared to both, early-favorable and early-unfavorable HL, advanced stage patients are at higher risk for thrombotic events. The most widely used Khorana score estimating thrombosis risk in cancer outpatients was not prognostic in the HL population investigated here. This is unsurprising considering the young age of the patient population investigated. Other risk factors were also not prognostic. This data does not imply a need for prophylactic anti-coagulation in outpatients treated for early-stage HL. In advanced-stage HL patients, routine prophylactic anticoagulation is not warranted. However, individual patients with additional risk factors that could not be evaluated such as history of thrombosis or reduced mobility might still benefit from prophylactic treatment. Disclosures Engert: Takeda, BMS: Consultancy, Honoraria, Research Funding.

It has been previously described that Hodgkin lymphoma (HL) exhibits a seasonal incidence and mortality pattern. However, these findings arise from small datasets and are partially conflicting. The aim of the present study is to provide the most comprehensive analysis of seasonal variation in incidence and mortality risk of HL with a focus on geographic differences in a very large, high-quality dataset. All HL cases diagnosed between 1973 and 2012 in the 18 Surveillance, Epidemiology and End Results (SEER) registries were eligible (n=50,179). We excluded all death certificate and autopsy only cases (n=281), cases with unknown month of diagnosis (n=257), the "Alaska natives" (n=17) and "Rural Georgia" (n=57) registries due to low case numbers and cases with missing information on age at diagnosis (n=5) and Ann-arbor stage (n=8157), resulting in 41,405 cases being included in the study. All cases were grouped into quartiles according to the latitude of the case's county (Quartile 1: HL exhibits a highly significant (p Considering all cases, a diagnosis in winter does not significantly increase the risk of dying compared to being diagnosed in summer (HR=1.030 [0.981; 1.081], p=0.234). However, looking at cases diagnosed in the two northern (≥38.05°N) quartiles showed an increased risk of death within 3 years after HL diagnosis (HR=1.082 [1.009; 1.161], p=0.027), whereas no such relationship was evident for cases diagnosed in the two southern ( To conclude, HL exhibits a seasonal incidence and mortality pattern in this study, the most comprehensive analysis on this topic performed to date. The seasonal effect on the incidence of HL is exacerbated and the seasonal effect on mortality risk is only present at higher latitudes. Increased seasonal variations in Vitamin D levels at higher latitudes have been previously described. Therefore, a twofold protective effect of Vitamin D, where it both prevents HL development and increases the chance of survival after a diagnosis of HL is a possible explanation. Further studies, particularly those directly measuring Vitamin D levels in HL patients, are needed to improve the understanding of the role of Vitamin D in HL. Disclosures Engert: Takeda, BMS: Consultancy, Honoraria, Research Funding.

Background: Systemic PUVA therapy may be useful in the treatment of chronic palmoplantar eczema. Topical PUVA-paint avoids some of the unwanted side effects of systemic psoralens and has been used successfully in the treatment of palmoplantar eczema and psoriasis. However, few data are available on the effectiveness of local bath-PUVA therapy in palmoplantar eczema. Objective: Our purpose was to assess the effectiveness of local bath-PUVA therapy in 28 patients with chronic palmar or plantar eczema or both who were resistant to conventional topical treatment. Methods: After fungal or bacterial infection had been excluded in all patients, hands or feet or both were soaked for 15 minutes in warm water containing 1 mg/L 8-methoxypsoralen. Immediately after, the skin was irradiated with increasing doses of UVA, starting with 0.5 J/cm 2 . PUVA-bath therapy was performed 4 times a week up to a total of 25 treatments. No additional therapy was allowed except emollients. Results: Excellent or good effects were achieved in 93% of the patients with dyshidrotc and in 86% of the patients with hyperkeratotic eczema. In the patients with dyshidrotic eczema, the cumulative doses and the highest single doses of UVA were lower than those in the patients with hyperkeratotic eczema (21.4 vs 27.9 J/cm 2 and 2.4 vs 3.0 J/cm 2 of UVA), but this was not statistically significant. No phototoxic reactions were observed. Conclusion: Local bath-PUVA therapy is of value in the management of chronic palmoplantar eczema resistant to standard modes of topical treatment. Compared with topical PUVA-paint, local bath-PUVA therapy has several advantages, particularly the absence of phototoxic reactions, severe hyperpigmentation, and protracted photosensitivity.

Today, more than 80% of patients with Hodgkin lymphoma (HL) can be cured with first-line treatment [1–3]. For patients with HL suffering from relapse or progression after first-line therapy, high d...

SUMMARY Background: The presumed benefits of centralization and minimum case numbers often guide health-policy decisions, but these benefits remain inadequately documented, particularly in oncology. In this study, we aim to measure the effect of the type of treatment center and/or the number of patients treated in it on the outcome of patients with Hodgkin’s lymphoma. Methods: From 1988 to 2002, 8121 patients with newly diagnosed Hodgkin’s lymphoma were treated in Germany in multicenter randomized and controlled trials (RCTs) of the German Hodgkin Study Group (GHSG). Center-related effects on progression-free survival (PFS) were assessed univariately with KaplanMeier plots and log-rank tests, as well as with a multivariate Cox regression model. Results: The 500 participating centers in Germany included 52 university hospitals, 304 non-university hospitals, and 144 medical practices specializing in hematology and oncology. No significant differences in PFS were found between patients from centers with high or low case numbers (5-year-PFS: 78.7% and 78.6% for centers with fewer than 50 and more than 50 patients, respectively) or from different types of centers [5-year-PFS: university hospital, 77.7%; non-university hospital, 79.4%; practice, 79.8%]. Even after statistical controls for the effect of other known and unknown prognostic factors and validation in further datasets, no center effects were found. Conclusions: The type of center and the minimum number of patients treated in a center have no impact on the treatment outcome of patients with Hodgkin’s lymphoma in Germany. In all GHSG centers, regardless of type, the quality standards for successful treatment are apparently met on all levels of patient care. ►Cite this as

Consistent and homogeneous long-time series of the space geodetic techniquesGlobal Positioning System (GPS), Satellite Laser Ranging (SLR), andVery Long Baseline Interferometry (VLBI) provide the basis for thecombination efforts of GGOS-D. For a consistent combination, thedefinition of common standards for parameterization and modeling isessential. These standards and the technique-specific processingoptions of all individual GPS, SLR, and VLBI solutions as well asthe combined SLR and VLBI solutions are discussed.

Purpose High-dose chemotherapy (HDCT) followed by autologous stem-cell transplantation (PBSCT) has become the standard treatment for patients with relapsed Hodgkin's lymphoma (HL). The intensity of treatment needed is unclear. This European intergroup study evaluated the impact of sequential high-dose chemotherapy (SHDCT) before myeloablative therapy. Patients and Methods Patients with histologically confirmed, relapsed HL were treated with two cycles of dexamethasone, cytarabine, and cisplatin, and those without disease progression were randomly assigned. In the standard arm (A), patients received myeloablative therapy with carmustine, BEAM (carmustine, etoposide, cytarabine, and melphalan) followed by PBSCT. Patients in the experimental arm (B) also received sequential cyclophosphamide, methotrexate, and etoposide in high-doses before BEAM. Freedom from treatment failure (FFTF) was the primary end point. Remission rates, overall survival (OS), and toxicity of treatment were secondary end points. Results From a total of 284 patients included, 241 responding patients were randomly assigned after two cycles of dexamethasone, cytarabine, and cisplatinum. Patients treated in arm B had longer treatment duration and experienced more toxicity and protocol violations (P < .05). Mortality was similar in both arms (20% and 18%). With a median observation time of 42 months, there was no significant difference in terms of FFTF (P = .56) and OS (P = .82) between arms. FFTF at 3 years was 62% (95% CI, 56% to 68%) and OS was 80% (95% CI, 75% to 85%). Patients with stage IV, early relapse, multiple relapse, anemia, or B symptoms had a higher risk of recurrence (P < .001). Conclusion Compared with conventional high-dose chemotherapy, additional SHDCT is associated with more adverse effects and does not improve the prognosis of patients with relapsed HL.

Mice with printing ability mastering every labyrinth are considered in respect to the number of states and print symbols needed. A mouse with four states and three print symbols is given, which is used for a simplified construction of a mouse with only one print symbol. Furthermore a labyrinth mastering mouse with only one state and four print symbols is given.

Study design Three-group, randomized, single blinded, controlled trial. Objective To test the effectiveness of physiotherapy-based rehabilitation starting 1 week after lumbar disc surgery. In addition, we tried to estimate the contribution of specific effects to the observed outcome (efficacy). Summary of background data Physiotherapy-based rehabilitation is usually recommended for patients following lumbar disc surgery. Few and conflicting data exist for the relative effectiveness of this intervention. Methods A total of 120 patients following first-time, uncomplicated lumbar disc surgery were randomly assigned to "comprehensive" physiotherapy, "sham" neck massage, or no therapy. Before enrollment, all subjects completed a minimal physiotherapeutic intervention. Physiotherapy was administered by experienced physiotherapists and consisted of 20 sessions per patient over 12 weeks. Masseurs administered "sham massage" to the neck. The amount of treatment time was equal to that of physiotherapy. The main outcome measure was the Low Back Pain Rating Score (LBPRS) at 6 and 12 weeks, and 1.5 years after randomization. Secondary parameters were patients' overall satisfaction with treatment outcome and socioeconomic and psychologic measures. Results At the end of therapy (12 weeks), the LBPRS revealed a significantly better improvement in the physiotherapy group than in the untreated group. LBPRS outcome, however, did not significantly differ between physiotherapy and "sham" therapy. There was a tendency toward significance between the sham therapy and no therapy. Within the 1.5-year follow-up, LBP rating scales remained significantly improved compared with baseline, but there were no significant outcome differences. No statistically significant between-group differences were found for the secondary outcome parameters. Conclusion As compared with no therapy, physiotherapy following first-time disc herniation operation is effective in the short-term. Because of the limited benefits of physiotherapy relative to "sham" therapy, it is open to question whether this treatment acts primarily physiologically in patients following first-time lumbar disc surgery, but psychological factors may contribute substantially to the benefits observed.

This paper investigates the time evolution of the terrestrial reference frame (TRF). We analysed time series of site positions and datum parameters obtained from VLBI, SLR, GPS and DORIS solutions with respect to non-linear motions (e.g. jumps, seasonal signals) and systematic differences. The time series of the translation and scale parameters were used to identify solution- and technique-related problems, and to investigate the contribution of the different techniques to realise the TRF origin and scale. The position time series reveal non-linear motions and jumps for many sites, which have to be considered for future TRF realisations.

The most precise space geodetic techniques for the realization of global terrestrial reference systems are VLBI, SLR and GPS. We focus on the contribution of these techniques to the determination of the vertical component. We discuss the strengths and weaknesses of each of the technique regarding the height determination as well as the effect of systematic errors. The quality of the ITRF (especially with respect to the vertical component) is assessed. Finally VLBI, SLR and GPS time series of position estimates are used to discuss the time—dependent stability of the solutions.

This paper presents the results of the first steps to set up a rigorous adjustment of a European network including GPS, SLR and VLBI data by combining these on the normal equation level. The network consists of about 20 permanently operating GPS stations, of which ten provide colocations with SLR systems, and seven stations are colocated with VLBI.

Abstract 2633 Background: Today, most patients with Hodgkin Lymphoma (HL) can be cured at first diagnosis. For HL patients suffering from relapse or progression after first line therapy, high dose chemotherapy followed by autologous stem cell transplant (ASCT) is the treatment of choice and cures about 50% of these patients. Those who relapse or progress after ASCT have a very poor prognosis and clearly represent an area of unmet medical need. However, data on this small group of patients is rather limited and no established risk factors are available. Here, we present a recent retrospective analysis from the GHSG database to better characterize HL patients with relapse or progression after ASCT in order to define possible risk factors for the prediction of overall survival. Methods: All trials in the GHSG database were searched for HL patients who relapsed or progressed after ASCT. The information for this retrospective analysis was updated in May 2012. Overall survival after progression of HL following ASCT (OSrr) was the end point of this study. Descriptive statistics and Kaplan Meier estimates of OSrr were used and risk factors for OSrr analyzed. The significance level was set to 0.05. Results: 152 patients who relapsed or progressed with HL after ASCT were identified. 149 patients fulfilled the predefined inclusion criteria. With a median observation time of 65 months after progression, 112 patients (75%) had died. OSrr was 63% (95% confidence interval [CI]; 54% to 70%), 51% (95% CI 42% to 58%), and 20% (95% CI 13% to 28%) at 1, 2 and 5 years, respectively. From several risk factors tested, stage (p=0.044) and presence of B-symptoms (p=0.005), both at relapse before ASCT, significantly predicted OSrr. Combination of these two risk factors allowed the identification of three distinct risk categories for the 4 significantly different groups (p=0.013; Figure 1). Accordingly, patients in clinical stage I or II without B-symptoms had a somewhat better prognosis (OSrr 84% [95% CI 67% to 92%], 72% [95% CI 54% to 84%] and 33% [95% CI 18% to 49%] at 1, 2 and 5 years, respectively). Other potential risk factors such as stage at first diagnosis (p=0.80), early, late or multiple relapses before ASCT (p=0.95), and time from ASCT to further progression of HL (p=0.81) were not significant. Conclusions: Current treatment approaches for patients with relapsed or progressive HL after ASCT show disappointing results with 80% of this very high-risk group dying within 5 years. Emerging new drugs such as brentuximab vedotin might improve the outcome of these patients in the future. Disclosures: von Tresckow: Takeda Pharma GmbH: Honoraria, Travel Grants Other. Borchmann:Millenium The Takeda Oncology Company: Research Funding; Takeda Pharma GmbH: Travel Grants, Travel Grants Other. Engert:Millenium The Takeda Oncology Company: Honoraria.

Abstract 935 Background: Long term impairment of quality of life (QoL) and elevated fatigue levels in Hodgkin Lymphoma (HL) survivors have been reported. However, few longitudinal data and no conclusive knowledge on components and determinants of QoL exist so far. Therefore, the German Hodgkin Study Group (GHSG) assessed the patients` QoL within the prospectively randomized studies HD10-12 for a detailed longitudinal evaluation of QoL and fatigue. Methods: QoL was assessed with a psychometrically proven questionnaire (QLQ-S) which contains the EORTC QLQ-C30 among other scales and items. Patients answered the questionnaires before, during, and at the end of therapy and at regular follow-up visits. For all QLQ-C30 functional scales and fatigue, longitudinal courses up to 27 months from diagnosis are given with means and 95%-confidence intervals. Reference values from a German control population were used for interpretation of the results. Components and determinants of QoL were analyzed with special modeling software (MPlus) which allows for full information maximum likelihood estimation of multivariate longitudinal models in the presence of missing data. The predictive value of fatigue at baseline for progression free survival and overall survival was tested in Cox proportional hazards analyses together with other known risk factors. Results: 4,160 patients were included in HD10-12, and 3,208 are evaluable for this analysis (total of 15,722 assessments). Before therapy, HL patients had clearly poorer mean scores in each QoL scale when compared to the German reference population. All scales at baseline were negatively influenced by gender (females) and more advanced disease. Before therapy age ≥50 years was negatively related to physical functioning and cognitive functioning, but positively to social functioning. After a decrease of QoL during chemotherapy, all scales showed considerable improvement. However, usually long term QoL remained below normal reference values and this was most pronounced in patients ≥50 years of age and advanced stages. A QoL model with three factors (physical, mental, and social) showed very good fit (RMSEA Conclusion: This is the first detailed QoL and fatigue analysis in HL patients covering all stages of the disease before, during, and after therapy. QoL domains are clearly impaired before the onset of chemotherapy, but improve over time substantially. Baseline QoL is affected in considerable degree by tumor- and patient-specific characteristics. Importantly, type and intensity of HL treatment have no relevant negative impact on long term QoL or fatigue. The strong impact of severe fatigue at baseline on overall survival is currently analyzed in more detail and results will be presented. Disclosures: No relevant conflicts of interest to declare.

Japan's death rate from gastric ulcer is far higher than that in any other country. The time pattern of peptic ulcer mortality between 1937 and 1980 was analysed in order to find out whether gastric ulcer in Japan, compared with Europe, shows other epidemiologic features which may indicate a different type of gastric ulcer disease. The age-adjusted death rates of both ulcer types and sexes have continuously decreased. In spite of the much higher death rates in the years 1937-80, the mortality of gastric ulcer shows a similar cohort phenomenon both in Japan and in Europe. The Japanese generations born in the last quarter of the 19th century ran the highest risk of dying from peptic ulcer and carried it throughout their lives. The cohorts with a high risk for duodenal ulcer lag 10 yr behind those with a high risk for gastric ulcer. Male and female cohorts with the highest risk were born at the same time. The cohort effects of both ulcer types are superimposed by period effects. The most obvious period effect during 1946-50 is seen in the short-timed increase of the death rates in all age groups, both sexes, and both ulcer types. The similarities between Japan and Europe suggest that worldwide, at the same time, the same environmental factors have precipitated the risk of dying from gastric and duodenal ulcer.