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BACKGROUND: Distributed statistical analyses provide a promising approach for privacy protection when analyzing data distributed over several databases. Instead of directly operating on data, the analyst receives anonymous summary statistics, which are combined into an aggregated result. Further, in discrimination model (prognosis, diagnosis, etc.) development, it is key to evaluate a trained model w.r.t. to its prognostic or predictive performance on new independent data. For binary classification, quantifying discrimination uses the receiver operating characteristics (ROC) and its area under the curve (AUC) as aggregation measure. We are interested to calculate both as well as basic indicators of calibration-in-the-large for a binary classification task using a distributed and privacy-preserving approach. METHODS: We employ DataSHIELD as the technology to carry out distributed analyses, and we use a newly developed algorithm to validate the prediction score by conducting distributed and privacy-preserving ROC analysis. Calibration curves are constructed from mean values over sites. The determination of ROC and its AUC is based on a generalized linear model (GLM) approximation of the true ROC curve, the ROC-GLM, as well as on ideas of differential privacy (DP). DP adds noise (quantified by the â 2 sensitivity Δ 2 ( f ^ ) ) to the data and enables a global handling of placement numbers. The impact of DP parameters was studied by simulations. RESULTS: In our simulation scenario, the true and distributed AUC measures differ by Δ AUC < 0.01 depending heavily on the choice of the differential privacy parameters. It is recommended to check the accuracy of the distributed AUC estimator in specific simulation scenarios along with a reasonable choice of DP parameters. Here, the accuracy of the distributed AUC estimator may be impaired by too much artificial noise added from DP. CONCLUSIONS: The applicability of our algorithms depends on the â 2 sensitivity Δ 2 ( f ^ ) of the underlying statistical/predictive model. The simulations carried out have shown that the approximation error is acceptable for the majority of simulated cases. For models with high Δ 2 ( f ^ ) , the privacy parameters must be set accordingly higher to ensure sufficient privacy protection, which affects the approximation error. This work shows that complex measures, as the AUC, are applicable for validation in distributed setups while preserving an individual's privacy.
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Algoritmos , Área Sob a Curva , Curva ROC , Humanos , Modelos Lineares , Modelos Estatísticos , Privacidade , Bases de Dados Factuais/estatística & dados numéricosRESUMO
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.
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Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Gerenciamento Clínico , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade , Vigilância da População , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
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.
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Crise Blástica/mortalidade , Leucemia Mieloide de Fase Acelerada/mortalidade , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Crise Blástica/sangue , Crise Blástica/diagnóstico , Crise Blástica/genética , Medula Óssea/patologia , Contagem de Células , Aberrações Cromossômicas , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Hemoglobinas/análise , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide de Fase Acelerada/sangue , Leucemia Mieloide de Fase Acelerada/diagnóstico , Leucemia Mieloide de Fase Acelerada/genética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Células-Tronco Neoplásicas , Prognóstico , Modelos de Riscos Proporcionais , Sistema de Registros , Adulto JovemRESUMO
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.
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Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Guias de Prática Clínica como Assunto , Antineoplásicos/uso terapêutico , Causas de Morte , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Indução de Remissão , Medição de Risco/métodosRESUMO
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).
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Progressão da Doença , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Modelos Teóricos , Adulto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
OBJECTIVE: The objective of this scoping review is to identify and map methods used to incorporate patient preferences into medical algorithms and models as well report on their quantification, balancing, and evaluation in the literature. It will focus on computational methods used for incorporating patient preferences into algorithms and models at an individual level as well as the types of medical algorithms and models where these methods have been applied. INTRODUCTION: Medical algorithms and models are increasingly being used to support clinical and shared decision-making; however, their effectiveness, accuracy, acceptance, and comprehension may be limited if patients' preferences are not considered. To address this issue, it is important to explore methods integrating patient preferences. INCLUSION CRITERIA: This review will investigate patient preferences and their integration into medical algorithms and models for individual-level clinical decision-making. The scoping review will include diverse sources, such as peer-reviewed articles, clinical practice guidelines, gray literature, government reports, guidelines, and expert opinions for a comprehensive investigation of the subject. METHODS: This scoping review will follow JBI methodology. A comprehensive search will be conducted in PubMed, Web of Science, ACM Digital Library, IEEE Xplore, the Cochrane Library, OpenGrey, the National Technical Reports Library, and the first 20 pages of Google Scholar. The search strategy will include keywords related to patient preferences, medical algorithms and models, decision-making, and software tools and frameworks. Data extraction and analysis will be guided by the JBI framework, which includes an explorative and qualitative analysis. REVIEW REGISTRATION: Open Science Framework https://osf.io/qg3b5.
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BACKGROUND: Juvenile strokes (< 55 years) account for about 15% of all ischemic strokes. Structured data on clinical outcome in those patients are sparse. Here, we aimed to fill this gap by systematically collecting relevant data and modeling a juvenile stroke prediction score for the 3-month functional outcome. METHODS: We retrospectively integrated and analyzed clinical and outcome data of juvenile stroke and TIA patients treated at the LMU University Hospital, LMU Munich, Munich. Good outcome was defined as a modified Rankin Scale of 0-2 or return to baseline of function. We analyzed candidate predictors and developed a predictive model. Predictive abilities were inspected using Area Under the ROC curve (AUROC) and visual representation of the calibration. The model was validated internally. RESULTS: 346 patients were included in the analysis. We observed a good outcome in n = 293 patients (84.7%). The prediction model for an unfavourable outcome had an AUROC of 89.1% (95% CI 83.3-93.1%). The model includes age NIHSS, ASPECTS, blood glucose and type of vessel occlusion as predictors for the individual patient outcome. CONCLUSIONS: Here, we introduce the highly accurate PREDICT-score for the 3-month outcome after juvenile stroke derived from clinical routine data. The PREDICT-score might be helpful in guiding individual patient decisions and designing future studies but needs further prospective validation which is already planned. Trial registration The study has been registered at https://drks.de (DRKS00024407) on March 31, 2022.
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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.
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(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.
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PURPOSE: To determine the feasibility of computed tomography (CT)-based dynamic myocardial perfusion imaging for the detection of hemodynamically significant coronary artery stenosis, as defined with fractional flow reserve (FFR). MATERIALS AND METHODS: Institutional review board approval and informed patient consent were obtained before patient enrollment in the study. The study was HIPAA compliant. Subjects who were suspected of having or were known to have coronary artery disease underwent electrocardiographically triggered dynamic stress myocardial perfusion imaging. FFR measurement was performed within all main coronary arteries with a luminal narrowing of 50%-85%. Estimated myocardial blood flow (MBF) was derived from CT images by using a model-based parametric deconvolution method for 16 myocardial segments and was related to hemodynamically significant coronary artery stenosis with an FFR of 0.75 or less in a blinded fashion. Conventional measures of diagnostic accuracy were derived, and discriminatory power analysis was performed by using logistic regression analysis. RESULTS: Of 36 enrolled subjects, 33 (mean age, 68.1 years ± 10 [standard deviation]; 25 [76%] men, eight [24%] women) completed the study protocol. An MBF cut point of 75 mL/100 mL/min provided the highest discriminatory power (C statistic, 0.707; P <.001). While the diagnostic accuracy of CT for the detection of anatomically significant coronary artery stenosis (>50%) was high, it was low for the detection of hemodynamically significant stenosis (positive predictive value [PPV] per coronary segment, 49%; 95% confidence interval [CI]: 36%, 60%). With use of estimated MBF to reclassify lesions depicted with CT angiography, 30 of 70 (43%) coronary lesions were graded as not hemodynamically significant, which significantly increased PPV to 78% (95% CI: 61%, 89%; P = .02). The presence of a coronary artery stenosis with a corresponding MBF less than 75 mL/100 mL/min had a high risk for hemodynamic significance (odds ratio, 86.9; 95% CI:17.6, 430.4). CONCLUSION: Dynamic CT-based stress myocardial perfusion imaging may allow detection of hemodynamically significant coronary artery stenosis.
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Angiografia Coronária/métodos , Estenose Coronária/diagnóstico por imagem , Imagem de Perfusão do Miocárdio/métodos , Tomografia Computadorizada por Raios X/métodos , Idoso , Estudos de Viabilidade , Feminino , Reserva Fracionada de Fluxo Miocárdico , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
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.
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Vacinas contra a AIDS/uso terapêutico , Epitopos/imunologia , Proteína gp41 do Envelope de HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Imunização Secundária/métodos , Imunoglobulina G/imunologia , Vacinas de DNA/imunologia , Vacinas Virais/imunologia , Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/imunologia , Reações Cruzadas , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/genética , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/virologia , Voluntários Saudáveis , Humanos , Esquemas de Imunização , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , FilogeniaRESUMO
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.
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Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Probabilidade , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Sistema de Registros , Adulto JovemRESUMO
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.
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Vacinas contra a AIDS/imunologia , Antígenos Virais/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , HIV/imunologia , Imunoglobulina G/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Adolescente , Adulto , Motivos de Aminoácidos , Sequência de Aminoácidos , Especificidade de Anticorpos/imunologia , Antígenos Virais/química , Mapeamento de Epitopos , Epitopos/química , Epitopos/imunologia , Feminino , HIV/classificação , HIV/genética , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Humanos , Esquemas de Imunização , Imunização Secundária , Masculino , Modelos Moleculares , Filogenia , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , Vacinação , Adulto Jovem , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/genéticaRESUMO
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.
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Antineoplásicos/uso terapêutico , Transplante de Rim/mortalidade , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Serina-Treonina Quinases TOR/antagonistas & inibidores , Inibidores de Calcineurina/uso terapêutico , Seguimentos , Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/uso terapêutico , Incidência , Transplante de Rim/efeitos adversos , Transplante de Rim/estatística & dados numéricos , Neoplasias/epidemiologia , Neoplasias/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de TempoRESUMO
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 (pâ¯=â¯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.
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Angiografia por Tomografia Computadorizada , Angiografia Coronária/métodos , Doença da Artéria Coronariana/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Diabetes Mellitus/epidemiologia , Idoso , Doenças Assintomáticas , Doença da Artéria Coronariana/epidemiologia , Estenose Coronária/epidemiologia , Diabetes Mellitus/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Prognóstico , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
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.
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Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Feminino , Humanos , MasculinoRESUMO
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.
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Antineoplásicos/administração & dosagem , Mesilato de Imatinib/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Proteínas Tirosina Quinases/antagonistas & inibidoresRESUMO
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.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
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.