Addressing COVID-19 challenges in a randomised controlled trial on exercise interventions in a high-risk population.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is a threat to ongoing clinical trials necessitating regular face-to-face, in-person meetings, particularly in participants with a high risk of complications. Guidance on how to handle and safely continue such trials is lacking. Chronically ill elderly individuals require-in addition to protection from infection-regular physical exercise and social contact to remain healthy. Solutions on how to handle these conflicting necessities are needed. The ENTAIER-randomised controlled trial was investigating the influence of mindful movements on fall risk, fear of falling, mobility, balance, life quality, and other outcomes. The study population was planned to comprise of 550 chronically ill elderly individuals with a high risk of falling. The movements were regularly performed in coached groups over 6 months. After the trial began, COVID-19 lockdowns stopped all in-person meetings, and it was expected that the limitations of this pandemic would continue for a long term. Therefore, the exercise programme, which involved complex movements and was typically conducted face-to-face in groups, had to be substituted by a telemedicine programme within a short timeframe. The objectives, therefore, were to identify challenges and tasks that could to be resolved and steps that could to be taken to achieve high-quality, efficacy, safety, and enable human encounter and motivation. METHODS: We proceeded with four steps: 1) A literature review on the quality and feasibility issues of telemedicine in general, and specifically, in exercise training in elderly individuals. 2) Participation in two international telemedicine task forces on integrative medicine, particularly, mind-body medicine. 3) Interviews with study therapists, (for practical purposes, eurythmy therapists and Tai Chi teachers are summarized here as therapists) personnel, and international experts on providing mindful movement exercises and other physiotherapies via live telecommunication technology, and with scientists and patient representatives. 4) Final evaluation by the core trial team and subsequent planning and implementation of changes in the trial organisation. RESULTS: Various tasks and challenges were identified: for the technical equipment for therapists and patients; for the ability of therapists and trial participants to adequately manage the technology and telemedicine intervention; the reservations and concerns about the technology among therapists and participants; safety and data protection in using the technology; and study design. The two major options found on how to continue the trial in the COVID-19 situation were a complete switch to telemedicine and a partial switch in the form of risk management implemented into the former design. CONCLUSIONS: The management of an ongoing clinical trial in a national or international crisis with a minimum of available time and extra financial resources, alongside with two checklists on steps and procedures for trial continuation and telemedicine implementation, may be informative for other researchers or healthcare providers faced with similar challenges and making similar decisions in the current situation or similar future scenarios. TRAIL REGISTRATION: www.drks.de . DRKS00016609. Registered July 30, 2019.

Differences between prolonged weaning patients from medical and surgical intensive care units.

BACKGROUND: It is not clear whether patients entering a specialized, interdisciplinary weaning unit from surgical or medical intensive care units (ICU) distinguish substantially. The purpose of the present study was to assess differences in patients with prolonged weaning being referred from surgical and medical ICU. METHODS: Data collected from April 2013 to April 2014 was conducted for retrospective analysis. Mortality rates, demographic data, clinical, and microbial differences in 150 patients with prolonged weaning were assessed (80 surgical and 70 medical). RESULTS: Surgical ICU referrals tended to be older (70.7 ± 11.3 vs. 67.3 ± 12.3, P = 0.051) and had fewer underlying pulmonary diseases (45% vs. 60%, P = 0.067). Sodium values at the time of referral to the weaning unit were significantly higher in surgical (147.1 ± 9.6) vs. medical (141.3 ± 6.7 mmol/l) patients (P < 0.001). Each 10-unit increase in sodium at the time of referral to the weaning unit was associated with a 2.5-day (95% CI -0.4, 5.4; P = 0.09) prolongation of stay in the weaning unit. Although significant differences in microbiological agents from tracheal aspiration were seen, the infection rate on the weaning unit was similar in both groups. There was no difference in weaning unit mortality between surgical and medical ICU patients (18% vs. 23%; P = 0.41). CONCLUSION: Few differences were found between patients being referred to a specialized weaning unit from surgical vs. medical ICUs. Besides differences in microbiological characteristics of tracheal secretions, there were also differences in sodium levels, which appear to influence on treatment duration.

Distribution of internal carotid artery plaque locations among patients with central retinal artery occlusion in the Eagle study population.

PURPOSE: Arterial emboli in the internal carotid artery (ICA) mainly cause cerebral ischemia; only 10 % of emboli reach the retinal arteries. Computational blood flow studies suggest that plaques situated in the ICA siphon may be a source of embolism to the ophthalmic artery (OA). To validate these calculated probabilities in patients with central retinal artery occlusion (CRAO), we reanalyzed digital subtraction angiography (DSA) images from the Multicenter Study of the European Assessment Group for Lysis in the Eye (EAGLE) study, a multicenter randomized study in patients with nonarteritic CRAO. METHODS: A reevaluation of 34 DSA studies was done from the interventional arm of the EAGLE study with regards to distribution of arterial plaques at specific ICA siphon locations and ICA stenosis. A comparison was made of plaque distribution to calculated probabilities for emboli reaching the OA from a computational fluid dynamics (CFD) model of a patient-specific ICA siphon. RESULTS: Most of the ICA plaques near the OA's origin were located in the cavernous ICA portion (31.3%). Of these, 12.5 % had plaques in the curvature opposite the OA origin, a location carrying the highest risk for embolization into the OA (according to the CFD model 12.6-13.2 % probability of embolisation into the OA). Also, 15.6 % had plaques in the paraclinoid ICA portion distal to the OA origin. CONCLUSIONS: There were 40.6% of the patients that had plaques in the cavernous and clinoid ICA portions presenting possible sources for embolic material generating RAO.

Transcatheter closure of atrial septal defects in children and adolescents: single-center experience with the GORE® septal occluder.

OBJECTIVES: Device closure of atrial septal defects (ASD II) is an alternative to surgery. ASD morphology and intracardiac relationships may influence device selection. Biocompatibility, techniques for closing large or multiple defects, and the risk of erosion are main issues in children BACKGROUND: The GORE® Septal Occluder (GSO) is a non-self-centering device with a flat and conformable nitinol-frame covered with expanded polytetrafluoroethylene. We hereby evaluate our initial experience in children to demonstrate feasibility, efficacy, and safety. METHODS: Single-center retrospective intention-to-treat analysis of GSO procedures in children and adolescents with hemodynamically significant ASD. All procedures were conducted under general anesthesia, fluoroscopy and transesophageal echocardiography. All defects were sized using stop-flow-technique. GSOs of 20-30 mm disc-diameter were implanted. RESULTS: GSO implantation was attempted in 45 with technical success in 41 patients, median age 6 (range 3-17) years, bodyweight 19 (12-95) kg. Median balloon-sized diameter was 13 (8-19) mm resulting in a GSO-to-ASD-ratio of 2 (1.7-2.5). Deficient retro-aortic rims (<3 mm) were found in 12 patients, and 10 of these 12 defects could be closed. We observed no complications. Four extensive or multiple ASDs were not treated successfully with GSO. After retrieval, one was closed with a different device; three patients needed surgical therapy. The median follow-up of four (range 0.2-22) months was uneventful in all patients CONCLUSIONS: We found the GSO device closure of ASDs in children to be effective. However, our initial experience is limited to short- and mid-term-follow-up of a low number of patients.

Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer.

BACKGROUND: New therapeutic options for metastatic pancreatic cancer are urgently needed. In pancreatic cancer, overexpression of the epidermal growth factor receptor 2 (HER2) has been reported in up to 45%. This multicentre phase II study investigated the efficacy and toxicity of the HER2 antibody trastuzumab combined with capecitabine in the patients with pancreatic cancer and HER2 overexpression. METHODS: Primary endpoint was progression-free survival (PFS) after 12 weeks. A total of 212 patients were screened for HER2 expression. RESULTS: Immunohistochemical (IHC) HER2 expression was: 83 (40%) grade 0, 71 (34%) grade 1, 31 (15%) grade 2, 22 (11%) grade 3. A total of 17 patients with IHC +3 HER2 expression or gene amplification could be assessed for the treatment response. Grade 3/4 treatment toxicities were: each 7% leucopenia, diarrhoea, nausea and hand-foot syndrome. Progression-free survival after 12 weeks was 23.5%, median overall survival (OS) 6.9 months. CONCLUSION: This study demonstrates +3 HER2 expression or gene amplification in 11% of patients. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC +3 HER2 expression showed gene amplification. Although the therapy was well tolerated, PFS and OS did not perform favourably compared with standard chemotherapy. Together, we do not recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer.

Randomized trial of high-dose adjuvant chemotherapy with autologous hematopoietic stem-cell support versus standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: overall survival after 6 years of follow-up.

Investigation of high-dose chemotherapy (HD-CT) compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and >/=10 axillary lymph nodes. From November 1993 to September 2000, 307 patients were randomized to receive after four cycles of epirubicin (90 mg/m(2)), cyclophosphamide (600 mg/m(2)) i.v. (every 21 days) and either HD-CT of cyclophosphamide (1500 mg/m(2)), thiotepa (150 mg/m(2)) and mitoxantrone (10 mg/m(2)) i.v. for four consecutive days followed by stem cell transplantation or a SD-CT of three cycles CMF (cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), 5-fluorouracil 600 mg/m(2), i.v. on day 1 and 8, respectively, every 28 days). After a median follow-up of 6.1 years, 166 events with respect to event-free survival (EFS) (SD-CT: 91, HD-CT: 75) have been observed. The hazard ratio of HD-CT versus SD-CT is estimated as 0.80 [95% confidence interval (0.59, 1.08)], P = 0.15. The trend to a superiority of HD-CT as compared with SD-CT with respect to EFS seems to be more pronounced in premenopausal patients as compared with postmenopausal patients and in patients with tumor grade 3 as compared with patients with tumor grade 1/2. With a follow-up of 6 years, there was a trend in favor of HD-CT with respect to EFS not being significant. A proper meta-analysis needs to be undertaken for an evaluation of subgroups of patients who might benefit from HD-CT.

The sequence complexity of exons trapped from the mouse genome.

BACKGROUND: A central issue in genome analysis is the identification and characterization of coding regions. Estimating the coding complexity of vertebrate genomes by measuring the kinetic complexity of mRNA populations and by sequence analysis of cDNAs is limited by the fact that any given source of mRNA represents a very biased sample of all genes. Exon trapping is a method that enables the identification of genes irrespective of their transcriptional status. RESULTS: Exons were trapped from the entire mouse genome, and the resulting fragments cloned. About 7% of a random sample of exons taken from this library have significant structural homology or sequence similarity to previously sequenced genes. Using cDNAs derived from several stages of mouse development, evidence for expression of about 62% of this sample of exons was found. These data suggest that the great majority of 'exons' in the library are derived from genes. We estimate that the fraction of the genome contained in trapped exons is 2.4%; this corresponds to a sequence complexity of about 72 megabases. CONCLUSIONS: The library of exons trapped from the entire mouse genome probably represents one of the least biased and most comprehensive libraries of mouse coding regions, and should therefore prove very useful for finding genes during genome mapping and sequencing.

Effects on pulmonary rehabilitation in patients with COPD or ILD: A retrospective analysis of clinical and functional predictors with particular emphasis on gender.

BACKGROUND: The response of patients in a pulmonary rehabilitation (PR) is essentially good. However, not all patients benefit from PR to the same extent. In this analysis we wanted to identify the impact of gender and other factors on PR outcomes in patients with chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD). METHODS: Patients suffering from COPD (n = 1492) or ILD (n = 599), treated during an inpatient PR between 1997 and 2015, were analysed according to the effects of PR on exercise capacity and quality of life with regard to the impact of gender or other predictors by univariate and multivariate analyzes. RESULTS: In the group of COPD patients, 30% did not achieve the expected physical performance during the 6-min walk test (28% of female and 32% of male patients). However, the non-responders initially have had a higher 6-min walking distance (6-MWD) (p < 0.001) and both male and female showed a significant lower BODE index (p = 0.025) in the multivariate analysis. In the ILD-group, 37% females and 43% males were classified as non-responders with regard to the 6-MWD. Also in this group, the non-responders initially have had a higher 6-MWD (p < 0.001). All other variables (age, BMI, lung function, blood gases, C-reactive Protein, Haemoglobin or rehabilitation duration) had no influence on the outcome. CONCLUSION: Our study supports the positive effects of PR in COPD and ILD patients. In both groups, patients with the biggest limitations benefit most from PR. However, relevant gender differences or other predictors could not be found.

Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation.

The outcome of patients with therapy-related myelodysplasia (t-MDS) or t-AML is very poor. The only curative treatment option implements allogeneic hematopoietic cell transplantation (aHCT); however, long-term follow-up data beyond 5 years are scarce. Here we report on a cohort of 79 consecutive patients with a median age of 58 years (range (r): 20-76) at transplantation and a median follow-up of 7.5 years (r: 0.07-19.0). Only 19 (24.1%) patients were in CR before aHCT. Non-relapse mortality and relapse rates were 23% (95% confidence interval, 15-35%) and 42% (32-55%) at 5 years, and 32% (22-46%) and 44% (34-57%) at 10 years, respectively. Disease-free survival (DFS) and overall survival (OS) rates were 35% (24-46%) and 38% (27-49%) at 5 years, and 24% (14-36%) and 24% (13-36%) at 10 years, respectively. Although cytogenetic aberrations were associated with shorter DFS and higher relapse risk, persistent disease at the time of transplantation, an unrelated donor and patient age were not associated with shorter OS. In conclusion, long-term survival beyond 10 years of t-MDS/t-AML patients after aHCT is possible, even for refractory patients. Therefore, early donor search and rapid transplantation are warranted, also to decrease the risk of disease-related deterioration of patients' performance status.

Role of isolated locoregional recurrence of breast cancer: results of four prospective studies.

PURPOSE: We evaluated the effect on future prognosis of an isolated locoregional recurrence (ILRR) after the primary diagnosis of breast cancer. Using data from four prospective studies of the German Breast Cancer Study Group, we investigated factors influencing prognosis after ILRR and defined a simple classification of patients into groups with different prognoses. PATIENTS AND METHODS: From 1983 to 1989, 2,746 patients were recruited into four studies comparing different treatments in primary breast cancer. After a median follow-up time of 8 years, 337 patients developed an ILRR as the first event. The influence of ILRRs on disease progression was examined. The effects of different prognostic factors on progression-free survival (PFS) and overall survival after ILRR were analyzed after a median follow-up time of 4.5 years. RESULTS: ILRRs increased the risk with respect to distant recurrence and death. After ILRR, 185 events occurred with respect to the PFS end point, and 171 patients died. Primary nodal status, tumor grade, estrogen receptor status of the primary tumor, and length of the disease-free interval (DFI) until the time of the ILRR had a significant prognostic impact. CONCLUSION: Determinants of prognosis after the ILRR should be taken into account for designing future risk-adapted clinical studies for these patients. Risk strata can be defined by a simple classification scheme based on primary nodal status and DFI.

Randomized 2 x 2 trial evaluating hormonal treatment and the duration of chemotherapy in node-positive breast cancer patients: an update based on 10 years' follow-up. German Breast Cancer Study Group.

PURPOSE: In 1984, the German Breast Cancer Study Group started a multicenter randomized trial to compare six versus three cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) starting perioperatively and to investigate the additional effect of tamoxifen as adjuvant treatment in node-positive breast cancer patients treated with mastectomy. PATIENTS AND METHODS: From 1984 to 1989, 473 patients were randomized from 41 institutions. After a median follow-up of approximately 10 years for overall survival (OS) and 9 years for event-free survival (EFS), the treatment groups were compared with respect to OS and EFS. Results based on a median follow-up of 56 months have been published earlier. RESULTS: Estimated cumulative locoregional incidence rate after 10 years was 19.9%; the corresponding rate of distant recurrences was 41.3%. Concerning duration of chemotherapy, we did not find any difference between six and three cycles of CMF (EFS: relative risk [RR] in multivariate analysis = 0.95; 95% confidence interval [CI], 0.74 to 1.21 OS: RR = 0.90; 95% CI, = 0.69 to 1.18). Treatment with tamoxifen resulted in an improvement in outcome (EFS: RR = 0.81; 95% CI, 0.61 to 1.07, OS: RR = 0.74; 95% CI, 0.55 to 1.0) although it proved not significant. Number of positive lymph nodes and progesterone receptor were the dominant prognostic factors. CONCLUSION: In this study, we observed some tendency in favor of hormonal treatment, which is in agreement with the literature. Concerning duration of chemotherapy, the results of this study provide further evidence that a reduction to three cycles of CMF is possible without increasing the risk of recurrence or death. For a definitive conclusion, however, further investigations are required.

Randomized 2 x 2 trial evaluating hormonal treatment and the duration of chemotherapy in node-positive breast cancer patients. German Breast Cancer Study Group.

PURPOSE: In 1984, the German Breast Cancer Study Group (GBSG) started a multicenter randomized clinical trial to compare the effectiveness of three versus six cycles of 500 mg/m2 cyclophosphamide, 40 mg/m2 methotrexate, and 600 mg/m2 fluorouracil (CMF) on day 1 and 8 starting perioperatively with or without tamoxifen (TAM) (3 x 10 mg/d for 2 years). The aim of the trial was to compare recurrence-free and overall survival between the different treatment modalities. PATIENTS AND METHODS: During 5 years, 41 institutions randomized 473 patients (3 x CMF: 145; 3 x CMF + TAM: 93; 6 x CMF 144; 6 x CMF + TAM: 91). Until March 31, 1992, median follow-up time was 56 months with 197 events for disease-free survival and 116 deaths observed. This provides a power of approximately 80% to detect a potential treatment difference corresponding to a relative risk (RR) of 0.67 for recurrence-free survival. Treatment modalities and various patient characteristics were evaluated by means of a multivariate Cox regression analysis. RESULTS: No significant difference in recurrence-free survival was observed with respect to hormonal therapy (RR = 0.75 TAM v no TAM; 95% confidence interval [CI], 0.54 to 1.04; P = .08) as well as duration of chemotherapy (RR = 0.90 of 6 x CMF v 3 x CMF; 95% CI, 0.67 to 1.19; P = .45). Similar results were obtained for overall survival. The multivariate analysis revealed a significant prognostic impact of the number of positive lymph nodes and the progesterone receptor level on recurrence-free survival. Compliance with chemotherapy within the range of 85% to 115% of the target dose was achieved in 94% and 78% of the patients randomized to 3 x CMF and 6 x CMF, respectively. Sufficient compliance with TAM was reported for 141 patients (93%). CONCLUSION: At this stage of follow-up, six courses of CMF are not superior to three courses with respect to recurrence-free survival.

High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial.

PURPOSE: Investigation of high-dose chemotherapy (HD-CT) followed by autologous hematopoietic stem-cell support compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and 10 or more positive axillary lymph nodes. PATIENTS AND METHODS: Between November 1993 and September 2000, 307 patients were randomized to receive (following four cycles of epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2), intravenously every 21 days) either HD-CT of cyclophosphamide 1500 mg/m(2), thiotepa 150 mg/m(2), and mitoxantrone 10 mg/m(2), intravenously for 4 consecutive days followed by stem-cell support; or SD-CT in three cycles of cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) intravenously on days 1 and 8, every 28 days. The primary end point was event-free survival. RESULTS: After a median follow-up of 3.8 years, 144 events with respect to event-free survival have been observed (HD-CT: 63 events; SD-CT: 81 events). The first event of failure (HD-CT v SD-CT) was an isolated locoregional recurrence (nine v 11), a distant failure (52 v 68), and death without recurrence (two v two). The estimated relative risk of HD-CT versus SD-CT was 0.75 (95% CI, 0.54 to 1.06; P =.095). Overall survival showed no difference (HD-CT: 40 deaths; SD-CT: 49 deaths). CONCLUSION: There was a trend in favor of HD-CT with respect to event-free survival, but without statistical significance. Further follow-up and a meta-analysis of all randomized studies will reveal the effect of HD-CT as compared with SD-CT as adjuvant treatment in high-risk primary breast cancer.

NTS influence on transgene expression from mono- and bicistronic plasmid vectors after lipofection in a human fibroblast cell line.

We evaluated the survival, transgene production, and copy numbers of integrated plasmid units per host genome after lipofection with mono- and bicistronic plasmid vectors in different cell lines and under various conditions. The addition of an integration enhancing murine sequence nontranscribed spacer (NTS) to the plasmids increased transfection efficiency, survival, and transgene expression. However, in human fibroblast cells this sequence had only marginal effects on overall plasmid copy number in bulk cultures. Clones producing the highest amounts of the transgene contained only one or two copies of plasmid per genome, independent of cell type and plasmid design.

Good Medicine and Good Healthcare Demand Good Information (Systems).

The demand for evidence-based health informatics and benchmarking of 'good' information systems in health care gives an opportunity to continue reporting on recent papers in the German journal GMS Medical Informatics, Biometry and Epidemiology (MIBE) here. The publications in focus deal with a comparison of benchmarking initiatives in German-speaking countries, use of communication standards in telemonitoring scenarios, the estimation of national cancer incidence rates and modifications of parametric tests. Furthermore papers in this issue of MIM are introduced which originally have been presented at the Annual Conference of the German Society of Medical Informatics, Biometry and Epidemiology. They deal as well with evidence and evaluation of 'good' information systems but also with data harmonization, surveillance in obstetrics, adaptive designs and parametrical testing in statistical analysis, patient registries and signal processing.

The effect of oral contraceptive use on the prognosis of node positive breast cancer patients. German Breast Cancer Study Group.

The effect of oral contraceptive (OC) use as a risk factor for breast cancer was recently assessed in a large meta-analysis, but currently available data on the prognostic effect are still insufficient. We investigated the relationship between OC use and standard prognostic factors and the effect of OC use on recurrence-free survival (RFS) and overall survival (OS) in 422 premenopausal pT1a-3aN + M0 patients from two trials of the German Breast Cancer Study Group (GBSG). 137 patients (32.5%) were OC users. They were younger on average (mean age 41.5 years versus 45 years for non-OC users) and the percentage of patients with smaller tumours was higher in the group of OC users. Based on 163 events for RFS and 103 events for OS, no significant effect of OC use on RFS and OS could be demonstrated in univariate and multivariate analyses. In our study of node positive breast cancer cases, OC users were younger and had smaller tumours. This may be an effect of earlier detection of breast cancer, but OC users did not have a better prognosis, both before and after adjustment for tumour size and other prognostic factors.

Long-term prognosis of breast cancer patients with 10 or more positive lymph nodes treated with CMF.

The purpose of this investigation was to study the long-term prognosis of breast cancer patients with 10 or more positive lymph nodes after conventional chemotherapy treatment with cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Between 1984 and 1989, 1048 node-positive patients were treated with CMF in two separate trials conducted by the German Breast Cancer Study Group (GBSG). Subgroups either received radiotherapy or tamoxifen in addition. In this study, long-term prognosis in the subgroup of 141 patients with 10 or more positive lymph nodes was investigated. Univariate and multivariate Cox models were used to evaluate the effect of prognostic factors on event-free survival (EFS) and overall survival (OS). Both univariate and multivariate analyses revealed the progesterone receptor (PR) status as the dominating prognostic factor for both EFS and OS, resulting in a strongly increased risk of more than 2-fold for receptor-negative patients. A large number of positive lymph nodes also affected the prognosis for EFS. In univariate analysis, the degree of lymph node involvement (i.e. percentage of positive nodes out of all examined nodes), oestrogen status (ER) status, and tumour grade also showed significant effects. To conclude, the prognosis in the subgroup of patients with 10 or more positive lymph nodes is heterogeneous. Some surprisingly high survival rates have been observed in case series of breast cancer patients treated with high-dose chemotherapy which may be explained by patient selection. From the usual factors investigated in this study, the PR status showed the strongest effect, and, at least this factor should be taken into account in the design and analysis of trials for breast cancer patients with a poor prognosis.

Eight-year results of a prospective non-randomised study on therapy of small breast cancer. The German Breast Cancer Study Group (GBSG).

In this report, the results of the first controlled clinical trial on breast cancer in Germany, begun in 1983, are presented after a median follow-up of 8 years. Four-year results have been previously published. In pT1 N0 M0 breast cancer, mastectomy as the standard treatment was to be compared with tumorectomy plus radiotherapy to the remaining breast tissue. The study design, originally planned as a comprehensive cohort study including randomised and non-randomised patients, had to be changed into a prospective observation study due to the low randomisation rate. 1036 out of 1119 recruited patients were evaluable. After a median follow-up of 97 months, 237 events (local recurrence, regional recurrence, distant metastases, contralateral breast cancer or death of the patient without previous recurrence) occurred. With the exception of death without recurrence, the events were evenly distributed among the two treatment groups. The 8-year local recurrence rate of the whole patient population is 8.8%. Out of all prognostic factors examined, only tumour size and grade had a significant influence on recurrent disease. Event-free survival decreased in cases with 'uncertain' tumour margins, whereas the width of the margin has no influence on disease recurrence. Based on 151 deaths observed so far, there was no significant difference in overall survival between the two treatment groups. The 8-year results of this study are in accordance with the 4-year results reported previously and with those of other breast-conserving treatment trials. There was no significant difference between the two treatment groups with regard to event-free and overall survival. Incomplete tumorectomy had a negative influence on recurrence.

Radiation therapy after breast-conserving surgery; first results of a randomised clinical trial in patients with low risk of recurrence.

To study the role of radiotherapy and tamoxifen after breast-conserving surgery (BCS) in patients with a favourable prognosis, a clinical trial was initiated by the German Breast Cancer Study Group. Between 1991 and 1998, 361 patients (pT1pN0M0, aged 45-75 years, receptor positive, grade I-II) were randomised to radiotherapy (yes/no) and tamoxifen for 2 years (yes/no) in a 2x2 factorial design; the exclusion of seven centres (14 patients) left 347 patients in the analysis. After a median follow-up of 5.9 years, 77 events concerning event-free survival have been observed. Since a strong interactive effect between radiotherapy and tamoxifen has been established, the results are presented in terms of the treatment effects for all four treatment groups separately. Mainly due to the presence of local recurrences, the event rate was about three times higher in the group with BCS only than in the other three groups. No difference could be established between the four treatment groups for distant disease-free survival rates. It is concluded that even in patients with a favourable prognosis, the avoidance of radiotherapy and tamoxifen after BCS increases the rate of local recurrences substantially.

Therapy of small breast cancer: a prospective study on 1036 patients with special emphasis on prognostic factors.

In 1983, The German Breast Cancer Study Group, sponsored by the Federal Ministry of Research and Technology, started a prospective multicenter trial on the treatment of early breast cancer pT1 pN0 M0. Treatment consisted of initial tumorectomy with microscopically free margins and lower axillary dissection. After conformation of a pT1 pN0-stage, additional treatment was either mastectomy or adjuvant radiotherapy (50 Gy in 25 fractions to the entire breast plus 12 Gy electron boost). In medially located tumors, the parasternal and supraclavicular area was also irradiated with 50 Gy. A randomization between both treatment modalities was initially planned but was not feasible and abandoned. Nearly all patients were treated according to their own choice. From November 1983 through December 1989, 1119 patients were recruited. Eighty-three were excluded from the protocol. Out of the remaining 1036 patients, 733 (71%) underwent breast preservation and 303 (29%) mastectomy. A detailed pathohistological examination of all tumorectomy specimens was performed in a pathologic reference center. Oncogen overexpression was evaluated by immunohistological detection of the transmembrane protein p-185 (corresponding to c-erb-B2) in 425 cases. After a median follow-up of 48 months, the frequency of local recurrences (4.7%), regional recurrences (1%), and distant metastases (5.4%) was the same in the breast preservation group and the mastectomy group. The 3-year disease-free survival was 90% after breast preservation and 88% after mastectomy (p = 0.21). In the breast preserving group, 24 patients with microscopically involved margins had a poorer disease-free survival than the study group (75% vs 90% after 3 years). The width of the margins had no impact on prognosis. Other prognostic factors in an univariate and multivariate analysis were tumor size and tumor grade. Age, menopausal status, hormone receptor status, histological tumor type, and treatment (mastectomy vs breast preservation) were not significant. P-185-expression was dependent on tumor grade and was the strongest prognostic factor in an univariate and multivariate analysis (p less than 0.001). The results emphasize the central role of tumor grade for prognosis and suggest the independent prognostic significance of the c-erb-B2 oncogen (corresponding to p-185) in pN0-patients.