Prospective study validating a multidimensional treatment decision score predicting the 24-month outcome in untreated patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, the ProVal-MS study.

INTRODUCTION: In Multiple Sclerosis (MS), patients´ characteristics and (bio)markers that reliably predict the individual disease prognosis at disease onset are lacking. Cohort studies allow a close follow-up of MS histories and a thorough phenotyping of patients. Therefore, a multicenter cohort study was initiated to implement a wide spectrum of data and (bio)markers in newly diagnosed patients. METHODS: ProVal-MS (Prospective study to validate a multidimensional decision score that predicts treatment outcome at 24 months in untreated patients with clinically isolated syndrome or early Relapsing-Remitting-MS) is a prospective cohort study in patients with clinically isolated syndrome (CIS) or Relapsing-Remitting (RR)-MS (McDonald 2017 criteria), diagnosed within the last two years, conducted at five academic centers in Southern Germany. The collection of clinical, laboratory, imaging, and paraclinical data as well as biosamples is harmonized across centers. The primary goal is to validate (discrimination and calibration) the previously published DIFUTURE MS-Treatment Decision score (MS-TDS). The score supports clinical decision-making regarding the options of early (within 6 months after study baseline) platform medication (Interferon beta, glatiramer acetate, dimethyl/diroximel fumarate, teriflunomide), or no immediate treatment (> 6 months after baseline) of patients with early RR-MS and CIS by predicting the probability of new or enlarging lesions in cerebral magnetic resonance images (MRIs) between 6 and 24 months. Further objectives are refining the MS-TDS score and providing data to identify new markers reflecting disease course and severity. The project also provides a technical evaluation of the ProVal-MS cohort within the IT-infrastructure of the DIFUTURE consortium (Data Integration for Future Medicine) and assesses the efficacy of the data sharing techniques developed. PERSPECTIVE: Clinical cohorts provide the infrastructure to discover and to validate relevant disease-specific findings. A successful validation of the MS-TDS will add a new clinical decision tool to the armamentarium of practicing MS neurologists from which newly diagnosed MS patients may take advantage. Trial registration ProVal-MS has been registered in the German Clinical Trials Register, `Deutsches Register Klinischer Studien` (DRKS)-ID: DRKS00014034, date of registration: 21 December 2018; https://drks.de/search/en/trial/DRKS00014034.

Effect of Sirolimus vs. Everolimus on CMV-Infections after Kidney Transplantation-A Network Meta-Analysis.

(1) Background: Following renal transplantation, infection with cytomegalovirus (CMV) is a common and feared complication. mTOR-inhibitor (mTOR-I) treatment, either alone or in combination with calcineurininhibitors (CNIs), significantly reduces the CMV incidence after organ transplantation. As of now, there is no information on which mTOR-I, sirolimus (SIR) or everolimus (ERL), has a stronger anti-CMV effect. (2) Methods: The current literature was searched for prospective randomized controlled trials in renal transplantation. There were 1164 trials screened, of which 27 could be included (11,655 pts.). We performed a network meta-analysis to analyze the relative risk of different types of mTOR-I treatment on CMV infection 12 months after transplantation compared to CNI treatment. (3) Results: Four different types of mTOR-I treatment were analyzed in network meta-analyses­SIR mono, ERL mono, SIR with CNI, ERL with CNI. The mTOR-I treatment with the strongest anti-CMV effect compared to a regular CNI treatment was ERL in combination with a CNI (relative risk (RR) 0.27, confidence interval (CI) 0.22−0.32, p < 0.0001). The other mTOR-I therapy groups showed a slightly decreased anti-CMV efficacy (SIR monotherapy (mono): RR 0.35, CI 0.22−0.57, p < 0.001; SIR with CNI: RR 0.43, CI 0.29−0.64, p < 0.0001; ERL mono: RR 0.46, CI 0.22−0.93, p = 0.031). (4) Conclusions: The anti-CMV effect of both mTOR-Is (SRL and ERL) is highly effective, irrespective of the combination with other immunosuppressive drugs. Certain differences with respect to the potency against the CMV could be found between SRL and ERL. Data gained from this analysis seem to support that a combination of ERL and CNI has the most potent anti-CMV efficacy.

The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia.

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.

Induction of Identical IgG HIV-1 Envelope Epitope Recognition Patterns After Initial HIVIS-DNA/MVA-CMDR Immunization and a Late MVA-CMDR Boost.

In the RV144 trial, to date the only HIV-1 vaccine efficacy trial demonstrating a modestly reduced risk of HIV-1 acquisition, antibody responses toward the HIV Envelope protein (Env) variable (V) 2 and V3 regions were shown to be correlated with a reduced risk of infection. These potentially protective antibody responses, in parallel with the vaccine efficacy, however, waned quickly. Dissecting vaccine-induced IgG recognition of antigenic regions and their variants within the HIV-1 Env from different vaccine trials will aid in designing future HIV-1 immunogens and vaccination schedules. We, therefore, analyzed the IgG response toward linear HIV-1 Env epitopes elicited by a multi-clade, multigene HIVIS-DNA priming, and heterologous recombinant modified vaccinia virus Ankara (MVA-CMDR) boosting regimen (HIVIS03) and assessed whether a late MVA-CMDR boost 3 years after completion of the initial vaccination schedule (HIVIS06) restored antibody responses toward these epitopes. Here we report that vaccination schedule in the HIVIS03 trial elicited IgG responses against linear epitopes within the V2 and V3 tip as well as against the gp41 immunodominant region in a high proportion of vaccinees. Antibodies against the V2 and gp41 Env regions were restricted to variants with close homology to the MVA-CMDR immunogen sequence, while V3 responses were more cross-reactive. Boosting with a late third MVA-CMDR after 3 years effectively restored waned IgG responses to linear Env epitopes and induced targeting of identical antigenic regions and variants comparable to the previous combined HIVIS-DNA/MVA-CMDR regimen. Our findings support the notion that anti-HIV-1 Env responses, associated with a reduced risk of infection in RV144, could be maintained by regular boosting with a single dose of MVA-CMDR.

Prognosis of patients with chronic myeloid leukemia presenting in advanced phase is defined mainly by blast count, but also by age, chromosomal aberrations and hemoglobin.

Chronic myeloid leukemia (CML) is usually diagnosed in chronic phase, yet there is a small percentage of patients that is diagnosed in accelerated phase or blast crisis. Due to this rarity, little is known about the prognosis of these patients. Our aim was to identify prognostic factors for this cohort. We identified 283 patients in the EUTOS population-based and out-study registries that were diagnosed in advanced phase. Nearly all patients were treated with tyrosine kinase inhibitors. Median survival in this heterogeneous cohort was 8.2 years. When comparing patients with more than 30% blasts to those with 20-29% blasts, the hazard ratio (HR) was 1.32 (95%-confidence interval (CI): [0.7-2.6]). Patients with 20-29% blasts had a significantly higher risk than patients with less than 20% blasts (HR: 2.24, 95%-CI: [1.2-4.0], P = .008). We found that the blast count was the most important prognostic factor; however, age, hemoglobin, basophils and other chromosomal aberrations should be considered as well. The ELTS score was able to define two groups (high risk vs non-high risk) with an HR of 3.01 (95%-CI: [1.81-5.00], P < .001). Regarding the contrasting definitions of blast crisis, our data clearly supported the 20% cut-off over the 30% cut-off in this cohort. Based on our results, we conclude that a one-phase rather than a two-phase categorization of de novo advanced phase CML patients is appropriate.

Differences in treatment and monitoring of chronic myeloid leukemia with regard to age, but not sex: Results from a population-based study.

There are established guidelines for treatment and monitoring of chronic myeloid leukemia (CML) but little is known about routine care. Data on ICD-10 codes as well as prescribed medications were available for 10.5 million patients in the statutory health insurance system in Bavaria for the years 2010 to 2016. Also, data on the molecular and cytogenetic monitoring were integrated. A total of 1714 adult patients with CML were observed. Only 50.8% received more than 67.5 daily doses per quarter year (target: 91.5) while 18.2% did not receive any tyrosine kinase inhibitor (TKI). The median number of daily doses was at least 80 doses per quarter year for all age groups in men, but decreased to 62 doses in elderly women. With this exception, no differences between men and women were observed. The percentage of patients without any TKI increased with age. The median number of molecular examinations was 3.54 independent of age and sex. Even in a highly developed country, still a considerable number of patients with CML seem to not receive adequate treatment, whereas molecular monitoring can be considered satisfactory.

Envelope-Specific Recognition Patterns of HIV Vaccine-Induced IgG Antibodies Are Linked to Immunogen Structure and Sequence.

Background: A better understanding of the parameters influencing vaccine-induced IgG recognition of individual antigenic regions and their variants within the HIV Envelope protein (Env) can help to improve design of preventive HIV vaccines. Methods: Env-specific IgG responses were mapped in samples of the UKHVC003 Standard Group (UK003SG, n = 11 from UK) and TaMoVac01 (TMV01, n = 17 from Tanzania) HIV vaccine trials. Both trials consisted of three immunizations with DNA, followed by two boosts with recombinant Modified Vaccinia Virus Ankara (MVA), either mediating secretion of gp120 (UK003SG) or the presentation of cell membrane bound gp150 envelopes (TMV01) from infected cells, and an additional two boosts with 5 µg of CN54gp140 protein adjuvanted with glucopyranosyl lipid adjuvant (GLA). Env immunogen sequences in UK003SG were solely based on the clade C isolate CN54, whereas in TMV01 these were based on clades A, C, B, and CRF01AE. The peptide microarray included 8 globally representative Env sequences, CN54gp140 and the MVA-encoded Env immunogens from both trials, as well as additional peptide variants for hot spots of immune recognition. Results: After the second MVA boost, UK003SG vaccinees almost exclusively targeted linear, non-glycosylated antigenic regions located in the inter-gp120 interface. In contrast, TMV01 recipients most strongly targeted the V2 region and an immunodominant region in gp41. The V3 region was frequently targeted in both trials, with a higher recognition magnitude for diverse antigenic variants observed in the UK003SG (p < 0.0001). After boosting with CN54gp140/GLA, the overall response magnitude increased with a more comparable recognition pattern of antigenic regions and variants between the two trials. Recognition of most immunodominant regions within gp120 remained significantly stronger in UK003SG, whereas V2-region recognition was not boosted in either group. Conclusions: IgG recognition of linear antigenic Env regions differed between the two trials particularly after the second MVA boost. Structural features of the MVA-encoded immunogens, such as secreted, monomeric gp120 vs. membrane-anchored, functional gp150, and differences in prime-boost immunogen sequence variability most probably contributed to these differences. Prime-boosting with multivalent Env immunogens during TMV01 did not improve variant cross-recognition of immunodominant peptide variants in the V3 region.

Recruiting young pre-symptomatic children for a clinical trial in type 1 diabetes: Insights from the Fr1da insulin intervention study.

BACKGROUND: Although detection of children at high risk of developing type 1 diabetes and diagnosis of early stages is possible, up to now there exists no approved therapy to delay or prevent type 1 diabetes. Thus it is vital to develop evidence-based interventions. For this a sufficient number of trial participants is crucial but difficult to obtain especially in asymptomatic children. AIM: Identifying family characteristics that lead to or impede trial participation and analyze reasons stated by families for non-participation. METHODS: Participants for the Fr1da Insulin Intervention study are recruited from the Fr1da study, a population based screening for early stage type 1 diabetes in Bavaria. Families with eligible children were invited to enroll. We analyzed sex and age of the child, distance of the family to the study center in Munich and the existence of a first degree family member with type 1 as possible influential factors for study participation. We also analyzed reasons stated by families who declined study participation in a phone interview. RESULTS: Of 146 eligible children 77 (53%) were enrolled into the trial. None of the tested family characteristics differed significantly between the enrolling and the families not participating, but in general enrolling families lived closer to the study site than families not participating. This is also reflected in the reasons given by non-participating families. The most frequent reason stated were time restrictions. The second most frequent reason was the venous blood draw. CONCLUSION: The factors for non-participation identified in this project need be taken into account for the design of future trials in young children to ensure proper recruitment and thus to generate valid results for medical treatment of children. More research on the reason of participation and non-participation in clinical trials is needed.

Predictive value of coronary computed tomography angiography in asymptomatic individuals with diabetes mellitus: Systematic review and meta-analysis.

BACKGROUND: Coronary CT angiography (CTA) is generally not established as a screening tool for asymptomatic individuals. However, it is controversial whether this test may have a role for screening asymptomatic individuals with diabetes mellitus (DM) due to the high prevalence of asymptomatic coronary artery disease (CAD) in this subgroup. METHODS: We searched PubMed and EMBASE through May 2017 for studies that reported on the association between findings at coronary CTA and future cardiac events in asymptomatic individuals with DM. Summary hazard ratios for the presence of obstructive CAD (≥50% stenosis), presence of non-obstructive plaque (<50% stenosis), segment involvement score, and segment stenosis score were derived using a random effects regression model. I2 was calculated to quantify between-study heterogeneity and causing factors were identified using meta-regression. RESULTS: A total of 10 studies reporting on 5012 individuals with DM (median age: 62.3 years, median proportion of women: 40.5%) were included in the analysis. The presence of obstructive CAD on coronary CTA (vs. non-obstructive or no CAD) was associated with a significantly elevated risk for adverse events (summary HR: 4.07, 95% CI: 2.30 to 7.21). The estimated summary HR for non-obstructive plaque (vs. no CAD) was 2.17 (95% CI: 1.11 to 4.25). The pooled HRs per unit for segment stenosis score and segment involvement score were 1.44 (95% CI: 0.98 to 2.12), and 1.73 (95% CI: 1.07 to 2.80) respectively. On meta-regression analysis, we observed a trend towards a higher risk estimate in studies with a higher proportion of females (p = 0.1063). CONCLUSION: The presence and extent of CAD on coronary CTA are strong, independent predictors of cardiovascular events in asymptomatic individuals with DM despite heterogeneity between studies in endpoints, study population and length of follow-up.

Effects of mTOR-Is on malignancy and survival following renal transplantation: A systematic review and meta-analysis of randomized trials with a minimum follow-up of 24 months.

BACKGROUND: mTOR-Is positively influence the occurrence and course of certain tumors after solid organ transplantation. The effect of mTOR-Is on the overall incidence of tumors irrespective of their origin is not entirely clear. Furthermore, conflicting data have been shown on mortality under mTOR-Is. METHODS: The current literature was searched for prospective randomized controlled renal transplantation trials. There were 1415 trials screened of which 13 could be included (pts. = 5924). A minimum follow-up of 24 months was mandatory for inclusion. Incidence of malignancies and patient survival was assessed in meta-analyses. RESULTS: The average follow-up of all trials was 40.6 months. Malignancy was significantly reduced under mTOR-Is compared to CNIs (RR 0.70, CI 0.49-0.99, p = 0.046). This effect remained stable when combined with CNIs (RR 0.58, CI 0.34-1.00, p = 0.05). When NMSCs were excluded the risk for malignancy remained significantly reduced under mTOR-I therapy (mono and combi) (RR 0.43, CI 0.24-0.77, p = 0.0046). Graft survival was minimally decreased under mTOR-Is (RR 0.99, CI 0.98-1.00, p = 0.054). This effect was abrogated when mTOR-Is were combined with CNIs (RR 0.99, CI 0.97-1.02, p = 0.50). Patient survival was not different (RR 1.00, CI 0.99-1.01, p = 0.54). CONCLUSIONS: Posttransplant patients have a lower incidence of malignancy when treated with an mTOR-I no matter if it is used in combination with CNIs or not. This beneficial effect remains significant even when NMSCs are excluded. With currently used mTOR-I-based regimen patient and graft survival is not different compared to CNI therapies.

Systematic review and meta-analysis of standard-dose imatinib vs. high-dose imatinib and second generation tyrosine kinase inhibitors for chronic myeloid leukemia.

PURPOSE: Most randomized clinical trials evaluating second generation tyrosine kinase inhibitors (TKI) for the first-line treatment of Chronic Myeloid Leukemia used as comparator the 'standard' dose of 400 mg imatinib daily. Several studies showed higher rates of major molecular remission (MMR) at 12 months with 800 mg compared to 400 mg, suggesting that high-dose imatinib may be the appropriate comparator rather than 400 mg. METHODS: We systematically reviewed randomized trials comparing the two dosages, calculated a common estimator and compared the result to a common estimator of trials evaluating a second generation TKI in comparison with 400 mg imatinib daily. RESULTS: We identified three trials comparing 400-800 mg imatinib resulting in a common relative risk of 1.30 (1.13-1.49) and indicating a significantly higher rate of MMR in patients treated with 800 mg imatinib (p = 0.0003). We identified five trials comparing 400 mg imatinib daily to a second generation TKI. The common relative risk for MMR at 12 months was 1.69 (1.50-1.90, p < 0.0001). Differences in the prognostic profiles precluded a direct comparison of the common efficacy estimates. CONCLUSIONS: We conclude that imatinib was probably not licensed at the optimal dose initially. We suggest that in the future, new TKIs are compared with a higher dose of imatinib. In addition, high-dose imatinib should be considered more often for routine clinical decisions based on the characteristics of the individual patient.

No influence of BCR-ABL1 transcript types e13a2 and e14a2 on long-term survival: results in 1494 patients with chronic myeloid leukemia treated with imatinib.

PURPOSE: The genomic break on the major breakpoint cluster region of chromosome 22 results in two BCR-ABL1 transcripts of different sizes, e14a2 and e13a2. Favorable survival probabilities of patients with chronic myeloid leukemia (CML) in combination with too small patient samples may yet have obstructed the observation of differences in overall survival of patients according to transcript type. To overcome potential power problems, overall survival (OS) probabilities and probabilities of CML-related death were analyzed in 1494 patients randomized to first-line imatinib treatment. METHODS: OS probabilities and probabilities of dying of CML were compared using the log-rank or Gray test whichever was appropriate. Both tests were stratified for the EUTOS long-term survival score. RESULTS: Between the groups with a single transcript, neither OS probabilities (stratified log-rank test: p = 0.106) nor probabilities of CML-related death were significantly different (stratified Gray test: p = 0.256). Regarding OS, the Cox hazard ratio (HR) of transcript type e13a2 (n = 565) to type e14a2 (n = 738) was 1.332 (95% CI 0.940-1.887). Considering probabilities of leukemia-related death, the corresponding subdistribution HR resulted in 1.284 (95% CI 0.758-2.176). Outcome did not change if patients with both transcripts (n = 191) were added to the 738 with type e14a2 only. CONCLUSIONS: The prognostic association of transcript type and long-term survival outcome was weak and without clinical relevance. However, earlier reported differences in the rate and the depth of molecular response could be relevant for the chance of successfully discontinuing TKI treatment. The effect of transcript type on molecular relapse after discontinuation is unknown, yet.

X-ray phase-contrast computed tomography of human coronary arteries.

OBJECTIVE: The objective of this study was to assess the potential of grating-based phase-contrast computed tomography (gb-PCCT) for the detection and characterization of human coronary artery disease in an experimental ex vivo validation study. MATERIALS AND METHODS: The study was approved by the institutional review board, and informed consent was obtained from all patients. Specimens were examined using a conventional low-coherence x-ray tube (40 kV) and a Talbot-Lau grating interferometer. Histopathologic assessment was used as the standard of reference. Signal characteristics of calcified, fibrous (FIB), and lipid-rich (LIP) tissue were visually and quantitatively assessed by phase-contrast Hounsfield units (HU). Conventional absorption-based HU values were also measured. Conservative measurements of diagnostic accuracy for the detection and differentiation of plaque components as well as quantitative measurements of vessel dimensions were obtained, and receiver operating characteristic curve analysis for plaque differentiation was performed. RESULTS: A total of 15 coronary arteries from 5 subjects were available for analysis (386 sections). Calcified, FIB, and LIP displayed distinct gb-PCCT signal criteria. The diagnostic accuracy of gb-PCCT was high with sensitivity, specificity, and negative and positive predictive values of 0.89 or greater for all plaque components with good interrater agreement (к ≥ 0.88). In addition, quantitative measurements of vessel dimensions in gb-PCCT were strongly correlated with measurements obtained from histopathology (Pearson R ≥ 0.86). Finally, phase-contrast Hounsfield units were superior to conventional HU in differentiating FIB and LIP (receiver operating characteristic analysis, 0.86 vs. 0.77, respectively; P < 0.05). CONCLUSIONS: In an ex vivo setting, gb-PCCT provides improved differentiation and quantification of coronary atherosclerotic plaque and may thus serve as a tool for nondestructive histopathology.

Prognostic scores for patients with chronic myeloid leukemia under particular consideration of competing causes of death.

Nowadays in many fields of medicine, prognostic scores are used to predict the outcome for individual patients. In chronic myeloid leukemia (CML), the Sokal, the Euro, and the EUTOS score are established prognostic scores which were addressed by the CML management recommendations of the European LeukemiaNet. This review provides a general definition of prognostic scores and explains their meaning. Main differences between the Sokal, the Euro, and the EUTOS score are highlighted. Due to the therapeutic success of tyrosine kinase inhibitors, the proportion of patients with causes of death unrelated to CML is growing. To assess the potential of a drug to prevent dying of CML, causes of death unrelated to CML need to be considered as competing risks. Supported by data of patients randomized to imatinib-based treatments within the German CML study IV, this review also explores the prognostic performance of the established scores if the primary event is death due to CML only and explains the implicit statistical particularities when treating other causes of death as competing risks. In the presence of competing risks, the application of both the cause-specific hazard model and the subdistribution hazard model is recommended when investigating the influence of prognostic factors on the event of interest. Another purpose of this work is to foster the ability of hematologists to interpret the outcome of a cause-specific hazard and a subdistribution hazard model and to understand the differences between them.

Predictive Value of Computed Tomography in Acute Pulmonary Embolism: Systematic Review and Meta-analysis.

BACKGROUND: Many computed tomography (CT) parameters have been proposed as potential predictors of outcome in acute pulmonary embolism. We sought to summarize available evidence on the predictive value of CT severity parameters for short-term clinical outcome in pulmonary embolism. METHODS: We searched PubMed and EMBASE through February 2014 for studies that reported on the association between CT parameters of acute pulmonary embolism severity and short-term (≤6 months) clinical outcome. Risk estimates for quantitative parameters of right ventricular (RV) dysfunction (abnormally increased RV/left ventricular [LV] diameter ratio on transverse sections and 4-chamber views), qualitative parameters of RV dysfunction (abnormal septal morphology and contrast reflux), thrombus load, and central thrombus location were derived using random effect regression analysis. Meta-regression analysis was performed to quantify and explain study heterogeneity. RESULTS: A total of 49 studies with 13,162 patients with acute pulmonary embolism (median age of 61 years, 55.1% were women) who underwent diagnostic CT imaging were included in the analysis. An abnormally increased RV/LV diameter ratio measured on transverse sections was associated with an approximately 2.5-fold risk for all-cause mortality (pooled odds ratio [OR], 2.5; 95% confidence interval [CI], 1.8-3.5) and adverse outcome (OR, 2.3; 95% CI, 1.6-3.4) and a 5-fold risk for pulmonary embolism-related mortality (OR, 5.0; 95% CI, 2.7-9.2). Thrombus load (OR, 1.6, 95% CI, 0.7-3.9; P = .2896) and central location (OR, 1.7; 95% CI, 0.7-4.2; P = .2609) were not predictive for all-cause mortality, although both were associated with adverse clinical outcome. CONCLUSIONS: Across all end points, the RV/LV diameter ratio on transverse CT sections has the strongest predictive value and most robust evidence base for adverse clinical outcomes in patients with acute pulmonary embolism.

A multi-state model approach for prediction in chronic myeloid leukaemia.

Multi-state models support prediction in medicine. With different states of disease, chronic myeloid leukaemia (CML) is particularly suited for the application of multi-state models. In this article, we tried to find a model for CML that allows predicting the prevalence of three different states (initial state of disease, remission and progression) in dependence on treatment, adjusted for age, sex and risk score. Based on the German CML Study IV, one of the largest randomised studies in CML, the model was able to represent the known effects of age and risk score on the probabilities of remission and progression. Patients achieving a major molecular remission had a better chance of surviving without progression, but this effect was not significant. Comparing treatments, patient of the high-dose arm had the greatest chance to be in the state "remission" at 5 years but did not seem to have an advantage considering "progression". The proposed illness-death model can be useful for predicting the course of CML based on the patient's individual covariates (trial registration: this is an explorative analysis of ClinicalTrials.gov Identifier: NCT00055874).

Is cytomegalovirus prophylaxis dispensable in patients receiving an mTOR inhibitor-based immunosuppression? a systematic review and meta-analysis.

BACKGROUND: Cytomegalovirus (CMV) is a common opportunistic infection after solid organ transplantation. Cytomegalovirus causes increased morbidity, mortality, and reduced allograft survival. Prophylaxis may help control the virus but is associated with substantial side effects and does not completely prevent virus reactivation; relapses after cessation of the prophylaxis are frequent. Experimental and clinical data suggest that mTOR inhibitors may have an anti-CMV effect. Here, we present a meta-analysis of clinical trials after solid organ transplantation and describe potential mechanisms involved in the anti-CMV effect of mTOR-inhibitors. METHODS: The current literature was reviewed for randomized controlled trials in solid organ transplantation comparing an mTOR-I with a non-mTOR-I (CNI based) treatment. The scientific quality of the trials was assessed by the Jadad score, the use of an effective allocation concealment (AC) and the existence of an intention-to-treat (ITT) analysis. Cytomegalovirus incidence was assessed in studies comparing 1) an mTOR-I-based with a CNI-based immunosuppression (10 trials, n=3,100 patients) and 2) an mTOR-I/CNI combination therapy with a CNI-based immunosuppression (15 trials, n=7,100 patients). RESULTS: In the first meta-analysis, CMV events after solid organ transplantation occurred significantly more often under CNIs (RR=2.27). The second meta-analysis comparing the mTOR-I + CNI combination with a CNI treatment in 15 trials of kidney, heart, and liver transplantation showed again a higher CMV incidence when patients received an mTOR-I free immunosuppression (RR=2.45). CONCLUSIONS: mTOR-inhibitor treatment either alone or in combination with CNIs reduces significantly the CMV incidence after organ transplantation. With the use of an mTOR-inhibitor, CMV prophylaxis may be dispensible.

Acute Myeloid Leukemia (AML): different treatment strategies versus a common standard arm--combined prospective analysis by the German AML Intergroup.

PURPOSE: Identifying true therapeutic progress in patients with acute myeloid leukemia (AML) requires a comparison of treatment strategies and results on the basis of uniform patient selection. To foster comparability across five clinical studies, we introduced a common standard arm combined with a general upfront randomization and performed prospective analyses with adjustment for differences in prognostic baseline characteristics. PATIENTS AND METHODS: Whereas the studies' own regimens differed in chemotherapies, risk adaption, and guidelines for allogeneic stem-cell transplantation, the standard arm contained uniform cytarabine- and anthracycline-based standard-dose remission induction and high-dose consolidation courses. RESULTS: Of 2,995 evaluable patients aged 16 to 60 years, 290 patients were randomly assigned to the common standard arm. Seventy percent of the 290 achieved complete remissions (62% with complete recovery, 8% with incomplete recovery; 95% CI, 65% to 76%). Five-year survival probabilities were 44.3% (95% CI, 37.7% to 50.7%) for overall survival, 44.8% (95% CI, 37.0% to 52.2%) for relapse-free survival, and 31.5% (95% CI, 25.7% to 37.4%) for event-free survival. Neither the unadjusted survival probabilities of the Kaplan-Meier method nor their adjustment for prognostic variables in multiple Cox regression models led to statistically significant different results in the three survival end points when the outcomes of each study were compared with the standard arm. CONCLUSION: A strictly prospective comparison of different treatment strategies in patients with AML did not show clinically relevant outcome differences when compared through a common standard treatment arm. The results provide a representative basis for further therapeutic approaches.