A patient-centred web-based adverse drug reaction reporting system identifies not yet labelled potential safety issues.

PURPOSE: Reporting of adverse drug reactions (ADRs) by patients is essential for a comprehensive risk-benefit evaluation of drugs after marketing, but only few data are available regarding patient-centred web-based ADR reporting systems. Hence, we aimed to analyze ADRs reported by patients with a particular emphasis on novel drugs and serious ADRs not yet labelled in the respective summary of product characteristics (SPC). METHODS: All ADR reports received by a web-based, patient-centred platform ( www.nebenwirkungen.de ) between April 1, 2019, and September 1, 2020, were descriptively analyzed. ADRs and drugs were coded automatically according to MedDRA and ATC classification system. SPC labelling of reported ADRs for novel drugs marketed since 2015 was checked manually. RESULTS: In total, 13,515 patient reports including 29,529 ADRs were received during the study period (serious ADRs [SADRs] n = 1,318; 4.5%). Women were affected in more than two-thirds of ADR reports. The most common patient-reported ADRs were nausea, dizziness and headache, whereas arrhythmia, intestinal obstruction and erectile dysfunction were the most frequent SADRs. Ciprofloxacin, levothyroxine and venlafaxine were the compounds most frequently suspected for causing both ADRs and SADRs. Regarding novel compounds, 289 reports including 739 ADRs were received (mainly fatigue, headache and myalgia). Three hundred thirty-one (44.8%) out of those ADRs were not yet labelled in the respective SPC, whereof twelve were SADRs. CONCLUSION: The majority of patient-reported ADRs were non-serious. However, a relevant number of non-labelled even serious ADRs was reported for novel compounds by patients. Despite well-known limitations of patient-reported ADRs, this web-based ADR reporting system contributes to the identification of new ADRs and thus can help to improve patients' safety complementing other pharmacovigilance instruments.

A methodological comparison of two European primary care databases and replication in a US claims database: inhaled long-acting beta-2-agonists and the risk of acute myocardial infarction.

PURPOSE: Results from observational studies on inhaled long-acting beta-2-agonists (LABA) and acute myocardial infarction (AMI) risk are conflicting, presumably due to variation in methodology. We aimed to evaluate the impact of applying a common study protocol on consistency of results in three databases. METHODS: In the primary analysis, we included patients from two GP databases (Dutch-Mondriaan, UK-CPRD GOLD) with a diagnosis of asthma and/or COPD and at least one inhaled LABA or a "non-LABA inhaled bronchodilator medication" (short-acting beta-2-agonist or short-/long-acting muscarinic antagonist) prescription between 2002 and 2009. A claims database (USA-Clinformatics) was used for replication. LABA use was divided into current, recent (first 91 days following the end of a treatment episode), and past use (after more than 91 days following the end of a treatment episode). Adjusted hazard ratios (AMI-aHR) and 95 % confidence intervals (95 % CI) were estimated using time-dependent multivariable Cox regression models stratified by recorded diagnoses (asthma, COPD, or both asthma and COPD). RESULTS: For asthma or COPD patients, no statistically significant AMI-aHRs (age- and sex-adjusted) were found in the primary analysis. For patients with both diagnoses, a decreased AMI-aHR was found for current vs. recent LABA use in the CPRD GOLD (0.78; 95 % CI 0.68-0.90) and in Mondriaan (0.55; 95 % CI 0.28-1.08), too. The replication study yielded similar results. Adjusting for concomitant medication use and comorbidities, in addition to age and sex, had little impact on the results. CONCLUSIONS: By using a common protocol, we observed similar results in the primary analysis performed in two GP databases and in the replication study in a claims database. Regarding differences between databases, a common protocol facilitates interpreting results due to minimized methodological variations. However, results of multinational comparative observational studies might be affected by bias not fully addressed by a common protocol.

Erythropoietin-induced treatment costs in patients suffering from renal anemia - a comparison between biosimilar and originator drugs.

OBJECTIVES: Renal anemia is a serious concern for morbidity and lower quality-of-life of patients suffering from chronic kidney disease resulting in a high economic burden when administering erythropoiesis-stimulating agents (ESAs). The aim of this study was to estimate erythropoietin-induced treatment costs in patients suffering from renal anemia undergoing dialysis treated with originator or biosimilar drugs. METHODS: A retrospective analysis was undertaken of ESA-related pharmacotherapy between January 1, 2008 and December 31, 2010 based on treatment and pharmacy claims data of 16,895 dialysis patients contained in the database of the Association of Statutory Health Insurance Physicians, Bavaria. All patients received an ESA treatment (ATC code B03XA) and chronic maintenance hemodialysis due to chronic kidney disease stage 5. RESULTS: Total drug expenditures for ESA-originators and biosimilars amounted to € 78.447 million for the 3-year study period. In hemodialysis patients cumulative defined daily doses (DDDs) were 7,727,782.14. Mean costs per DDD were € 10.79 (originators) and € 8.56 (biosimilars). A biosimilar substitution quota of 50% provides a savings potential of € 6.14 million [range € 3.07-9.22 million (25-75% quota)]. CONCLUSION: A more common biosimilar prescription in renal anemia patients suffering from chronic kidney disease provides a noteworthy economic savings potential.

[Hospital admission due to adverse drug events (ADE): an analysis of German routine hospital data of 2006]. / Stationäre Aufnahmen wegen unerwünschter Arzneimittelereignisse (UAE): Analyse der DRG-Statistik 2006.

BACKGROUND: In developed countries 1-5% of all hospital admissions are due to adverse drug events (ADE). An ADE is defined as an injury resulting from medical intervention related to a drug. The established reporting systems and study designs only capture selective data. The objective of the current analysis was to evaluate the rate, distribution and correlations of ADE related admissions by using German routine data. METHODS: ADEs were identified by an array of 502 specified codes of the ICD-10-GM. The evaluation included only verified codes and was carried out by remote queries of the German DRG-Statistics 2006. Hospital admission due to an ADE was identified via the primary diagnosis. RESULTS: Of all hospital admissions 0.92% were revealed to be certainly caused by an adverse drug event. The average age between affected and non-affected was nearly identical for women 53.48 vs. 53.67 years, for men it was reduced by 4 years (48.38 years). The average hospital stay was lower for cases with an ADE, being reduced by 1.3 days for women (6.26 days vs. 7.55 days) and 1.5 days for men (5.91 days vs. 7.42 days). While mortality with an odds ratio (OR) of 0.59 (95% CI 0.57-0.62) was lower in ADE cases, the rate of emergency admissions due to ADE was increased, the OR being 3.10 (95% CI 3.07-3.13). The wards with excess rates of ADE cases were internal medicine, paediatrics, dermatology, intensive care and neurology. CONCLUSIONS: Younger age, reduced hospital stay and lower mortality of ADE cases are contrary to findings in the relevant literature. The DRG-Statistics also comprise populations which often are excluded in established study designs, in particular, children and cases due to medication errors, overdose, poisoning and allergic reactions. As these cases respond easily to prevention and are of significant interest to pharmacovigilance, the use of routine data is valuable for more intense research of ADE.

The LUCAS* consortium: objectives of interdisciplinary research on selected aspects of ageing and health care for older people in an urban community.

BACKGROUND: Decline in functional competence is a major determinant of older persons' needs, the development of dependency, use of care, clinical outcome and mortality. The interactions between rising life expectancy and changes in morbidity and disability warrant interdisciplinary research on functional disability, health promotion and prevention. The LUCAS (Longitudinal Urban Cohort Ageing Study) research consortium was established to study particular aspects of functional competence, its changes with ageing, to detect preclinical signs of functional decline, and to address questions on how to maintain functional competence and to prevent adverse outcome. The questions originate from problems encountered in practical health care provision in different settings, i.e. community, hospital and nursing home. METHODS: The subprojects apply a longitudinal cohort follow-up study, an embedded randomised controlled intervention, cross-sectional comparative, and prospective intervention studies. CONCLUSION: The results will provide instruments to screen for preclinical signs of functional decline and concrete recommendations to sustain independence and prevent adverse outcomes in older age in daily practice.

[The Longitudinal Urban Cohort Ageing Study (LUCAS)]. / Die Longitudinal-Urban-Cohort-Ageing-Studie (LUCAS).

BACKGROUND: The interactions between rising life expectancy, morbidity and development of disability warrant interdisciplinary research on functional disability, health promotion and prevention as well as healthcare provision for older people. Therefore, the interdisciplinary LUCAS (Longitudinal Urban Cohort Ageing Study) research consortium of university and non-university institutions was established and is coordinated by the research department of the Albertinen-Haus at the University of Hamburg. The aim is to study particular aspects of functional competence, the changes with ageing, to detect pre-clinical signs of functional decline and to address questions on how to maintain functional competence and to prevent adverse outcomes. The research questions have their origin in problems of practical healthcare provision in the different settings of communities, hospitals and nursing homes. The articles of LUCAS subprojects report selected results from the first project phase (2007-2010) which was funded by the German Federal Ministry of Education and Research (BMBF) (Research program"Health in the elderly").). METHODS: The LUCAS subprojects 1-7 applied a true cohort study design with embedded randomized controlled intervention studies and cross-sectional studies for comparative purposes and to prepare intervention studies to be performed in the second project phase. CONCLUSIONS: Results from the first project phase provided new instruments to screen and to assess functional competence in older people (population-based screening). In the second project phase these will be evaluated according to practicability and usefulness. Furthermore, parts of the results will be used by the health reporting system in Hamburg and for intervention studies performed by LUCAS subprojects during the second project phase (LUCAS II).

Persistence with asthma treatment is low in Germany especially for controller medication - a population based study of 483,051 patients.

BACKGROUND: The objective of the present analysis was to evaluate treatment patterns and persistence with treatment of an unselected patient population with a diagnosis of asthma. METHODS: The database of the Bavarian statutory health insurance physician's association (Kassenärztliche Vereinigung) covering 83% of the population was analyzed for an index period from April 2005 to March 2006. Defined daily doses (DDDs) were used to quantify treatment persistence. Results were compared with recent guidelines. RESULTS: The prevalence of physician diagnosed asthma in Bavaria was 4.8% in females and 4.5% in males; only 61.4% of these patients (of a total of n = 483,051) received any anti-asthmatic pharmacotherapy; 68.3% received medical care from their general practitioner, and 8.3% from a pulmonologist alone. Most patients (65.1%) received no more than 90 DDDs of controller medication in the index period of 365 days, only about 1% received medication for the complete index period. Long- (40.1%) and short-acting beta(2)-agonists (65.6%) were used more frequently than inhaled corticosteroids (ICS). 52.8% of asthma patients were treated in accordance with guidelines. CONCLUSIONS: Persistence of asthma patients with medical treatment is low, especially for controller medication. The discrepancy between current knowledge, guidelines and clinical practice is substantial and may question the value of current guidelines for the treatment of patients with asthma in ambulatory care. In addition, the results of this study cast doubt on the impact of contemporary treatment on the decline of asthma mortality seen in recent years in Germany.

[Epidemiological methods for health services research]. / Epidemiologische Methoden für die Versorgungsforschung

On July 1, 2009, the German Network for Health Services Research [Deutsches Netzwerk Versorgungsforschung e. V. (DNVF e. V.)] approved the Memorandum III "Methods for Health Services Research", supported by the member societies mentioned as authors and published in this Journal (Gesundheitswesen 2009; 71: 505-510). This is an in-depth publication on the "epidemiological methods for health services research". Legal, political and economic steps of intervention in the medical care system modify the health services structures and processes but the impact of such interventions on the medical care users has, so far and in general, not been examined scientifically. Due to this lack of evaluation, there is, also with regard to the economic situation within the health system, no transparency of potentially severe effects on healthy and, particularly, on ill people. For this very reason, the main questions and focuses of medical care research deal with prevalence, causes and effects of over, under and inappropriate supply of health services, the interaction between diagnostics and therapy, the processes across different sectors and the complex interdependences of health services. This part of the Memorandum of Deutsches Netzwerk für Versorgungsforschung e. V. (DNVF e. V., German Network for Health Services Research) will enumerate the methods and instruments that will be used for planned studies and that have been applied for finished studies of health services research and for the evaluation of its quality and value. Health services research takes advantage of the theories and the methods of the disciplines that are involved in its studies. It does not need a specific research methodology; its methods are adapted to the specific research question. It is rather to be expected that certain issues of this research branch and its access to data will lead to the development of new methods.

Preventable ADRs leading to hospitalization - results of a long-term prospective safety study with 6,427 ADR cases focusing on elderly patients.

BACKGROUND: Studies evaluating the impact of age and potentially inappropriate medication (PIM) on avoidable adverse drug reactions (ADRs) are scarce. METHODS: In this prospective, multi-center, long-term (8.5 years) observational study, we analysed ADRs leading to hospitalization in departments of internal medicine. ADRs causality and preventability were assessed using standardised algorithms. PIM was defined based on the PRISCUS-list. Multivariate analyses and estimation of ADR incidence rates were conducted. RESULTS: Of all 6,427 ADR patients, a preventable ADR was present in 1,253 (19.5%) patients (elderly patients ≥70 years: 828). Risk factors for preventable ADRs in elderly patients were multimorbidity, two to four ADR-causative drugs, and intake of particular compounds (e.g. spironolactone) but not sex, PIM usage, or the total number of drugs. Regarding particular compounds associated with preventable ADRs, highest incidence rates for preventable ADRs were found for patients aged ≥70 years for spironolactone (3.3 per 1,000 exposed persons (95% CI: 1.4-6.6)) and intermediate-acting insulin (3.3 per 1,000 exposed persons (95% CI: 1.6-6.1)). CONCLUSION: Avoiding PIM usage seems to be of limited value in increasing safety in elderly patients whereas our results underline the importance of an individualized medication review of the most commonly implicated drugs in preventable ADRs (supported by BfArM FoNr: V-11337/68605/2008-2010).

Cytogenetic response to prior treatment with interferon-alpha is predictive for survival after allogeneic hematopoietic stem cell transplantation in chronic myeloid leukemia.

We investigated the impact of a cytogenetic response (CyR) to IFN prior to and at the time of allogeneic hematopoietic stem cell transplantation (HSCT) on transplant-related mortality (TRM), relapse rate and survival probability after HSCT in 162 transplanted patients with chronic myeloid leukemia. One-hundred-one patients (62.3%) achieved a CyR prior to HSCT. Survival probabilities were higher in patients, who achieved any CyR prior to HSCT than in patients without CyR (63.6 vs 49.2%: P = 0.019). Survival probabilities in patients, who achieved a major CyR were better than in patients with minimal and minor CyR or in patients with no CyR (69.4 vs 58.8% vs 49.2%: P = 0.040). TRM and survival of chronic phase patients without CyR at the time of HSCT were similar to that of patients transplanted in advanced phase. Both groups combined had an outcome inferior to patients with at least minimal CyR (TRM, Gray test: P = 0.016, survival, log-rank test: P = 0.002). Univariate and multivariate analyses identified CyR prior to or at HSCT as a strong and independently favorable prognostic factor. We therefore conclude that allogeneic HSCT in CyR should be investigated prospectively as an alternative treatment option in defined patient groups.

Treatment and outcome of 2904 CML patients from the EUTOS population-based registry.

The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.

Gender aspects in chronic myeloid leukemia: long-term results from randomized studies.

Gender-related aspects in chronic myeloid leukemia (CML) have not been studied well. We therefore analyzed 856 patients with Ph/BCR-ABL-positive CML from the German randomized CML-studies I (interferon alpha (IFN) vs hydroxyurea (HU) vs busulfan) and II (IFN+HU vs HU alone). The median observation time was 8.6 years. A total of 503 patients (59%) were male. Female patients were older (51 vs 46 years; P<0.0001), presented with lower hemoglobin (11.7 vs 12.5 g/dl; P<0.0001), higher platelet counts (459 vs 355 x 10(9)/l; P<0.0001), smaller spleen size (3 vs 4 cm below costal margin; P=0.0097), a lower rate of additional cytogenetic aberrations (9 vs 15%; P=0.018) and a less favorable risk profile (P=0.036). The transplantation rate was 14% for female (n=48) and 22% for male patients (n=113). Median survival was longer in female patients (58 vs 49 months; P=0.035) mainly attributable to better survival in the low- and intermediate-risk groups and, independent from risk groups, in the HU group. These results were confirmed by matched-pair analyses based on German population data (n=496, 59 vs 45 months; P=0.0006). This is the first analysis of gender aspects in CML using randomized trials. It demonstrates the relevance of analyses of gender differences in CML and in malignant disease at large.

A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group.

BACKGROUND: Interferon alfa is a conservative and widely used alternative to bone marrow transplantation in treatment of patients with early chronic myeloid leukemia (CML). A meta-analysis was conducted to develop a reliable prognostic scoring system for estimation of survival of patients with CML treated with interferon alfa. METHODS: Patients treated in prospective studies, including major randomized trials, were separated into learning and validation samples. Cox regression analysis and the minimum P-value approach were used to identify prognostic factors for patient survival and to discover groups in the learning sample with the greatest differences in survival. These findings were then validated by applying the new scoring system to patients in the validation sample. RESULTS: We collected data on 1573 patients who were participants in 14 studies involving 12 institutions; 1303 patients (learning sample, n = 981; validation sample, n = 322) were eligible for inclusion in this analysis, and their median survival time was 69 months (range, 1-117 months). Because two previously described prognostic scoring systems failed to discriminate risk groups satisfactorily, we developed a new scoring system that utilizes the following covariates: age, spleen size, blast count, platelet count, eosinophil count, and basophil count. Among 908 patients with complete data in the learning sample, three distinct risk groups were identified (median survival times of 98 months [n = 369; 40.6%], 65 months [n = 406; 44.7%], or 42 months [n = 133;14.6%]; two-sided logrank test, P< or =.0001). The ability of the new scoring system to discriminate these risk groups was confirmed by analysis of 285 patients with complete data in the validation sample (two-sided logrank test, P = .0002). CONCLUSIONS: A new prognostic scoring system for estimating survival of patients with CML treated with interferon alfa has been developed and validated through use of a large dataset.

Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia.

In patients with chronic myeloid leukemia (CML), first-line imatinib treatment leads to 8-year overall survival (OS) probabilities above 80%. Many patients die of reasons unrelated to CML. This work tackled the reassessment of prognosis under particular consideration of the probabilities of dying of CML. Analyses were based on 2290 patients with chronic phase CML treated with imatinib in six clinical trials. 'Death due to CML' was defined by death after disease progression. At 8 years, OS was 89%. Of 208 deceased patients, 44% died of CML. Higher age, more peripheral blasts, bigger spleen and low platelet counts were significantly associated with increased probabilities of dying of CML and determined a new long-term survival score with three prognostic groups. Compared with the low-risk group, the patients of the intermediate- and the high-risk group had significantly higher probabilities of dying of CML. The score was successfully validated in an independent sample of 1120 patients. In both samples, the new score differentiated probabilities of dying of CML better than the Sokal, Euro and the European Treatment and Outcome Study (EUTOS) score. The new score identified 61% low-risk patients with excellent long-term outcome and 12% high-risk patients. The new score supports the prospective assessment of long-term antileukemic efficacy and risk-adapted treatment.

Secondary malignancies in chronic myeloid leukemia patients after imatinib-based treatment: long-term observation in CML Study IV.

Treatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 8-year survival rate of ∼88%. Long-term toxicity of TKI treatment, especially carcinogenicity, has become a concern. We analyzed data of the CML study IV for the development of secondary malignancies. In total, 67 secondary malignancies were found in 64 of 1525 CML patients in chronic phase treated with TKI (n=61) and interferon-α only (n=3). The most common malignancies (n⩾4) were prostate, colorectal and lung cancer, non-Hodgkin's lymphoma (NHL), malignant melanoma, non-melanoma skin tumors and breast cancer. The standardized incidence ratio (SIR) for all malignancies excluding non-melanoma skin tumors was 0.88 (95% confidence interval (0.63-1.20)) for men and 1.06 (95% CI 0.69-1.55) for women. SIRs were between 0.49 (95% CI 0.13-1.34) for colorectal cancer in men and 4.29 (95% CI 1.09-11.66) for NHL in women. The SIR for NHL was significantly increased for men and women. An increase in the incidence of secondary malignancies could not be ascertained. The increased SIR for NHL has to be considered and long-term follow-up of CML patients is warranted, as the rate of secondary malignancies may increase over time.

Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment.

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.

The Munich Polypectomy Study (MUPS): prospective analysis of complications and risk factors in 4000 colonic snare polypectomies.

BACKGROUND AND STUDY AIMS: Screening colonoscopy with polypectomy has been shown to reduce the morbidity and mortality associated with colorectal cancer. However, there is a lack of large and systematic prospective studies of the complications of polypectomy. PATIENTS AND METHODS: Data on all snare polypectomies performed in 13 institutions (six hospitals and seven gastroenterology offices) were recorded prospectively during a 20-month period, including data on a 30-day follow-up period. The primary end points of the study were polypectomy complications, which were classed as "major" or "minor". Risk factors for complications were analyzed for both patient characteristics and polyp parameters. RESULTS: A total of 3976 snare polypectomies in 2257 patients (mean age 64.5 years) were included in the study. The mean polyp size was 1.1 cm, and 72% were sessile. Complications occurred in 9.7% of patients (6.1% of polyps); 75% of these complications were minor; and the mortality rate was zero. Multivariate regression analysis revealed polyp size as the main risk factor, both for complications overall (odds ratio 6.56, 95%CI 4.45-9.67) and for major complications (odds ratio 31.01, 95%CI 7.53-128.1). Right-sided polyp location was a significant risk factor for major complications (odds ratio 2.40, 95%CI 1.34-4.28). Setting a cut-off value of 3% as an acceptable rate for major complications, polyps larger than 1 cm in the right colon or 2 cm in the left colon, and multiple polyps carried an increased risk. CONCLUSIONS: Colonoscopic polypectomy is associated with a 10% rate of complications, but three-quarters of these are of minor clinical significance. More than 90% of the complications can be managed conservatively if adequate endoscopic expertise is available. Guidelines for intensified follow-up after polypectomy should be based on the size, location, and number of a patient's polyps.

Randomized studies with interferon in chronic myelogenous leukemia (CML) and comparative molecular aspects. German CML Study Group.

Four randomized prospective studies on interferon alpha (IFN) in CML report varying degrees of prolongation of the chronic phase of CML and of survival as compared to conventional therapies. There is agreement that IFN prolongs survival as compared to standard busulfan. There is disagreement, however, as to which degree IFN is superior to hydroxyurea. Whereas the randomized studies of the Italian cooperative group and of the British MRC find a statistically significant survival advantage of IFN over hydroxyurea of about 20 months, this difference is only 10 months in the German randomized study and not significant. One reason for this difference might be the more intensive treatment schedule for the hydroxyurea control group in the German study. Other reasons might be differences in risk profiles between the patient groups studied and in strategies of IFN therapy. About 1% of the human genome consists of retroviral or retroviral-like sequences. By analogy to animal models, endogenous retroviruses might also have pathogenic potential in human disease. The transposon-like structure of retroviruses that enables them to integrate at almost any position in the host genome and the capability of retroviruses to serve as efficient vehicles of cellular genes are in support of a pathogenic potential. Furthermore, particles resembling retroviruses have been observed long ago in human embryonic and malignant tissues and cell lines. Sequence information and the transcriptional activity of the endogenous sequences argue against the possibility that these sequences are only fossil relics of early evolutionary periods. Most of the sequences appear to be inactivated by stop codons or frameshifts, making the genomic localization of open reading frames with biological activity difficult. Up to now, mutagenesis by insertion of retroviral-like sequences in sporadic cases of human disease appears to be the only example of pathogenic relevance of retroviruses in man.

Marrow fibrosis, indicator of therapy failure in chronic myeloid leukemia - prospective long-term results from a randomized-controlled trial.

Marrow fibrosis (MF) has rarely been considered in therapy studies on chronic myeloid leukemia (CML), and there is a lack of long-term observations on the basis of sequential bone marrow biopsies (BMBs) taken prospectively during the course of disease. A total of 848 BMBs from 400 patients with Ph(+) CML recruited in the German randomized CML study I were examined for MF before and during therapy. In total, 110 patients had been randomized to receive interferon (IFN)-alpha, and 290 to receive chemotherapy (hydroxyurea (HU): 154, busulfan: 136). During IFN-alpha and HU medication, MF was reduced or did not increase for about 2 years. Evolving or progressive MF was an independent and early predictor of therapy failure about 2 years earlier than indicated by changes in the peripheral blood, spleen size, marrow blast count and cytogenetics (P<0.00005), resulting in a significant shortening of the survival times of patients independent of the type of therapy applied including allografting (multivariate analyses; P<0.00005). The analyzed long-term observations strongly indicate that MF is an independent poor prognostic complication of CML, allowing an early prediction of therapy failure. Consideration of the fiber content in marrow may therefore significantly improve the prediction of therapy efficacy and outcome of disease.

Treatment intensity significantly influencing fibrosis in bone marrow independently of the cytogenetic response: meta-analysis of the long-term results from two prospective controlled trials on chronic myeloid leukemia.

Bone marrow fibrosis (MF) has been shown to indicate therapy failure in Ph(+) chronic myeloid leukemia (CML). However, the results on the development of MF during interferon-alpha therapy of CML are controversial. The significance of the interferon dose has not been considered as yet. In total, 627 bone marrow biopsies taken prospectively from 200 patients with CML recruited in two studies using different doses of interferon-alpha +/- low-dose cytosine arabinoside were examined for MF before and during therapy. The results showed that the risk of MF depended significantly on the interferon-alpha dose applied (P<0.000005). MF progressed during low-dose therapy (3 x 5 x 10(6) IU/week), but was prevented from progression when applying high dose (5 x 10(6) IU/m(2)/per day). MF disappeared when high-dose interferon-alpha was combined with low-dose cytosine arabinoside (P<0.000005). The risk of death markedly increased when MF occurred or progressed (P<0.0009), independent of all other prognostic factors evaluated including the cytogenetic response. In conclusion, the effectiveness of interferon-alpha on MF depends on the treatment intensity. MF reverses when combining high-dose interferon-alpha with low-dose cytosine arabinoside, but progresses when applying low-dose interferon-alpha. MF appears to be a significant early indicator of ineffective therapy in CML.