Targeted next-generation sequencing using a multigene panel in myeloid neoplasms: Implementation in clinical diagnostics.

INTRODUCTION: Detection of mutations in patients with myeloid neoplasms (MNs) has shown great potential for diagnostic and prognostic purposes. Next-generation sequencing (NGS) is currently implemented for the diagnostic profiling of the four major MN subgroups. METHODS: First, we validated the targeted NGS approach using the TruSight Myeloid panel. Next, we screened 287 patients with a clinical suspicion of MN and 61 follow-up patients with documented MN. RESULTS: Validation of the NGS workflow resulted in maximal precision, accuracy, sensitivity, and specificity for gene variants with an allele frequency of at least 5% and a minimal read depth of 300. In our diagnostic screen, we identified at least one somatic mutation in 89% of patients with proven MN. Of the 155 newly diagnosed MN cases, 126 (81%) showed at least one mutation, confirming clonality. Moreover, the co-occurrence of mutated genes in the different MN subentities facilitates their classification and justifies the diagnostic use of a pan-myeloid panel. Furthermore, several of these mutations provide additional prognostic information independently of traditional prognostic scoring systems. CONCLUSION: Pan-myeloid targeted NGS fits elegantly in the routine diagnostic approach of MNs allowing for an improved diagnosis, subclassification, and prognosis.

The uptake of recombinant Factor VIII in the Netherlands.

In comparison with other biotechnology substitutions, the adoption of recombinant Factor VIII (rFVIII) has been relatively slow. We sent a postal questionnaire to all Dutch haemophilia patients and haemophilia-treating physicians, to determine which factors predict whether a patient uses plasma-derived FVIII (pdFVIII) or rFVIII and to investigate patients' and doctors' opinions on both products. Fifty-six per cent of patients received rFVIII. This percentage varied widely between centres. Only one doctor would choose to use pdFVIII if he suffered from haemophilia A himself, and 74% would choose to use rFVIII. Younger patients, those not infected with the human immunodeficiency virus or hepatitis C, and those who did not have family members who used pdFVIII switched more often from pdFVIII to rFVIII. Patients who rated themselves as innovative, who had family members who used rFVIII, and those who were treated in a large haemophilia treatment centre were also more likely to have switched. For physicians and patients alike, the respondents generally did not see large differences between rFVIII and pdFVIII, except for the risk of infections and the knowledge of long-term effects (both larger for pdFVIII). Although haemophilia patients represent one of the most empowered patient groups, physicians appear to have been influential in choosing between pdFVIII and rFVIII.

Variability in abciximab (ReoPro) prescribing: evidence based or budget driven?

PURPOSE: Abciximab improves outcomes in patients undergoing percutaneous transluminal coronary intervention (PTCA). Clinicians, however, have expressed concerns that they do not have enough budget to administer abciximab to all eligible patients. We studied the patterns of prescribing of abciximab and identified factors that correlate with the level of usage. METHODS: In each of all 13 Dutch PTCA centres one opinion-leading cardiologist was approached to provide data on the abciximab prescribing in their centre and to co-operate in an interview on this topic. We performed linear regression analysis in which the level of abciximab prescribing was the dependent variable. Potential determinants investigated were the number of PTCAs performed, the criteria for abciximab prescribing, funding and possible financial restrictions, participation in clinical trials in the past, percentage stenting, and desired level of abciximab prescribing. RESULTS: All 13 PTCA centres in the Netherlands participated in our study. The level of abciximab prescribing varied from 2 to 36% of all PTCAs. The criteria for patient selection significantly differed between centres. Together budget, investigatorship, size, and type of the institution were highly predictive for the level of abciximab prescribing (R2 = 0.93, p < 0.001). The more patients doctors had included in clinical trials in the past, the higher was the likelihood that they had prescribed abciximab. CONCLUSIONS: Shortly after its introduction, patterns of abciximab prescribing varied widely between PTCA centres. There was no agreement on which patients to select for this preventive treatment. Budget and involvement in clinical trials in the past were important predictors of the level of prescribing in each centre.

Suicide risk in placebo-controlled studies of major depression.

OBJECTIVE: The purpose of this study was to determine if fear of an increased risk of attempted suicide in placebo groups participating in placebo-controlled studies is an argument against the performance of placebo-controlled trials in studies of major depression. METHOD: All short-term and long-term, placebo-controlled, double-blind studies that were part of a registration dossier for the indication of major depression that were submitted to the Medicines Evaluation Board, the regulatory authority of the Netherlands, from 1983 to 1997 were reviewed for attempted suicide. In addition, all long-term, placebo-controlled studies from a MEDLINE search that were conducted in the last decade in patients with major depression were assessed for attempted suicide. RESULTS: In 77 short-term studies with 12,246 patients in dossiers from the Medicines Evaluation Board, the incidence of suicide was 0.1% in both placebo groups and active compound groups. The incidence of attempted suicide was 0.4% in both placebo groups and active compound groups. In eight long-term studies with 1,949 patients, the incidence of suicide in the placebo groups was 0.0% and 0.2% in the active compound groups. Attempted suicide occurred in 0.7% of both placebo groups and active compound groups. In seven long-term MEDLINE studies, the incidence of attempted suicide in the placebo groups was not higher than in the groups treated with active compound. CONCLUSIONS: Fear of increased risk of attempted suicide in the placebo groups should not be an argument against performing short-term and long-term, placebo-controlled trials in major depression.

Short-term efficacy of tricyclic antidepressants revisited: a meta-analytic study.

The original data from the placebo-arms and the tricyclic-arms of all parallel randomized controlled three-arm studies, which had been conducted in the period 1979-1991 for a drug under development in order to obtain marketing authorization for the indication major depression, were included in a meta-analysis. Thirty-two placebo-controlled studies including 4314 patients were analyzed. The intention to treat analysis resulted in 46% responders (at least 50% improvement on the Hamilton Depression Rating Scale) in the tricyclic antidepressant group and 31% in the placebo-group (CI(95%-difference) 11.5-17.1%). The number needed to treat for responders was 7 (CI(95%) 5-8). In 10 out of 32 studies, a statistically significant difference in favor of tricyclic antidepressant compared to placebo was found for responders. The responder rate in the placebo-group varied from 6 to 52%. We conclude that tricyclic antidepressants are efficacious in the short-term treatment of major depression. However, the magnitude of the effect is rather modest. Because 69% of the placebo-controlled studies with a tricyclic antidepressant did not show a statistically significant difference in favor of tricyclic antidepressant and the placebo rate varied considerably from study to study, equivalence studies with tricyclic antidepressant as comparator without a placebo-control are not sufficient for demonstrating efficacy. Therefore in major depression, placebo-controlled studies are still necessary to demonstrate efficacy.

Costs and effects of combining stenting and abciximab (ReoPro) in daily practice.

AIM: The combined use of stents and abciximab in percutaneous coronary intervention has been evaluated in the EPISTENT trial. However, the clinical and economic findings in trials are not necessarily generalisable to a general population setting. We conducted a study in daily clinical practice comparing stented and non-stented patients undergoing coronary angioplasty with abciximab administration. Furthermore, we compare our results with the findings of the EPISTENT trial. METHODS: From 1995 to 1999, refractory unstable patients scheduled for angioplasty and receiving abciximab in a Dutch regional hospital were followed prospectively for 6 months. Total costs were considered in addition to 2 composite clinical endpoints: (1) death or myocardial infarction (MI); and (2) death, MI, or any revascularisation procedure (major adverse cardiac events, MACE). RESULTS: Stented patients (N=101) experienced less MACE than non-stented patients (N=83) (6.9% vs. 16.9%, OR=0.37, P=0.04). The total costs were similar for stented and non-stented patients (EUR 7 844 vs. EUR 7 904, P=0.93). Adjustment for baseline characteristics yielded similar results, although significance subsided. The relative risk reduction of 44% that we found, closely resembles the 42% that was found in the EPISTENT trial. CONCLUSIONS: In everyday practice, as in the EPISTENT trial, the addition of a stent to abciximab treatment does seem to reduce the risk of MACE by about 40% at no additional costs.

Differences in attitudes, knowledge and use of economic evaluations in decision-making in The Netherlands. The Dutch results from the EUROMET Project.

OBJECTIVE: To investigate differences in attitudes, knowledge and actual use of economic evaluations in different groups of decision-makers, and to compare the results from the Netherlands with the overall European results of the European Network on Methodology and Application of Economic Evaluation Techniques (EUROMET) project. DESIGN AND SETTING: Members of the EUROMET group conducted interviews and surveys with politicians, regulators, hospital pharmacists and physicians in The Netherlands. Three approaches of investigation could be adopted: (i) a postal questionnaire survey, (ii) semi-structured interviews, and (iii) a focus-group approach. MAIN OUTCOME MEASURES AND RESULTS: In the Netherlands, decision-makers generally have a positive attitude towards economic evaluations. Nevertheless, their actual use and knowledge of economic evaluations are still limited. Hospital pharmacists and regulators are more objective than physicians and politicians, who also base their judgements on other societal values. Hospital pharmacists and regulators have a greater knowledge of economic evaluations, and they use them more often than the other groups. Most decision-makers do not want to base their decisions strictly on a cost-effectiveness ranking alone. Our findings were similar to the findings in other European countries. CONCLUSIONS: Decision-makers prefer to make their own broad comparisons of advantages and disadvantages, and do not base their decisions solely on a single summary measure.

[Clinical evaluation of efficacy and adverse effects in the (European) registration of drugs: what does it mean for the doctor and patient?]. / De klinische beoordeling van werkzaamheid en schadelijkheid bij de (Europese) registratie van geneesmiddelen: wat betekent dit voor de dokter en de patiënt?

The clinical criteria for admission of new drugs to the European common market have become more stringent in recent years. Increasingly often, the manufacturer is required to demonstrate that the new drug offers a clinically visible and relevant benefit to the patient. Efficacy and adverse effects should not only be studied by comparative trials with placebo, the registration authorities also expect the drug to be compared with the standard treatment already available. Such trials should prove that the balance between efficacy and adverse effects of the drug is better than that of placebo and at least as good as the standard treatment, as regards not only statistical significance but also clinical relevance. Therefore, Dutch and European assessment reports and product information may be increasingly useful to prescribers, patients and insurers in determining the role and therapeutic value of new drugs within the existing therapeutic possibilities concerning certain diseases.

Assessment of biotechnology drugs: what are the issues?

Biotechnology is increasingly regarded as an important reservoir for the development of new and innovative, but generally expensive, pharmaceuticals. At the same time, concerns about cost containment have triggered a keen interest in evaluating and comparing the values of diverse health care interventions. In this paper we studied the process of assessment and diffusion of biotechnology drugs by studying three cases, i.e. nebacumab, colony stimulating factors and recombinant human growth hormone. These cases are evaluated in a standardised format, concerning safety, efficacy, cost-effectiveness and ethical, legal and social issues. Many factors that determine the fate of a biotechnology drug seemed to be similar to those of 'classical' drugs. The definition and measurement of clinically relevant outcomes has been identified as a key factor in the assessment process. Another important issue is the relatively small population for the primary indications of biotechnology drugs and the subsequent process of broadening of indications. Paradoxically, the current trend towards evidence-based medicine means that we will increasingly have to make decisions based on 'incomplete' knowledge'.

Interaction of the combined medication with the new low-molecular-weight heparinoid Lomoparan (Org 10172) and acenocoumarol.

A high intravenous dose of the low-molecular-weight heparinoid Lomoparan (Org 10172) was administered to 6 healthy males in a steady state of anticoagulation (Thrombotest) by acenocoumarol. Prothrombin time, activated partial thromboplastin time and Stypven time were prolonged to a degree which was greater than that expected on the base of the summation of the effects by each drug alone. This effect was observed for a period of up to 1 h. The Thrombotest was affected for up to 5 h after the intravenous administration of Org 10172, therefore it is deemed unsuitable for monitoring the combined effects of these two anticoagulants during this period. Acenocoumarol did not affect the pharmacokinetic parameters of Org 10172 with the exception of a slight reduction of the clearance of plasma anti-Xa activity.

Diagnosis and treatment of homozygous protein C deficiency. Report of the Working Party on Homozygous Protein C Deficiency of the Subcommittee on Protein C and Protein S, International Committee on Thrombosis and Haemostasis.

This report summarizes the documented cases of homozygous protein C deficiency in the United States and Europe. Procedures for diagnosing and treating this disorder (both initially and over the long term) have been compiled by a working party on homozygous protein C deficiency of the Subcommittee on Protein C of the International Committee on Thrombosis and Haemostasis. Homozygous protein C deficiency is an autosomal recessive disorder that usually manifests itself by purpura fulminans and, less commonly, by massive large vein thrombosis; severe diffuse intravascular coagulation also develops in these infants, and there is evidence of intrauterine thrombosis. For confirmation of homozygous protein C deficiency in a neonate with purpura fulminans or massive venous thrombosis, the infant should have undetectable protein C activity and both parents should be heterozygous for protein C deficiency. At the onset of symptoms, the initial treatment should be plasma (8 to 12 ml/kg every 12 hours) until all lesions have healed. Two modalities for long-term treatment are accepted as useful in these children: oral anticoagulant therapy or protein C replacement (fresh frozen plasma or prothrombin complex concentrate). Liver transplantation has been performed in only one child, with success. Oral anticoagulation (vitamin K antagonists, maintaining the prothrombin time from one and one-half to two times control values or at the International Normalized Ratio of 2.5 to 4.4) is our recommendation of choice for long-term treatment. With appropriate care, these children are able to be free of coagulopathy and live relatively normal lives.