Frank Hulstaert

Improved discrimination of AD patients using β-amyloid(1-42) and tau levels in CSF

Objective: To evaluate CSF levels of β-amyloid(1-42) (Aβ42) alone and in combination with CSF tau for distinguishing AD from other conditions. Methods: At 10 centers in Europe and the United States, 150 CSF samples from AD patients were analyzed and compared with 100 CSF samples from healthy volunteers or patients with disorders not associated with pathologic conditions of the brain (CON), 84 patients with other neurologic disorders (ND), and 79 patients with non-Alzheimer types of dementia (NAD). Sandwich ELISA techniques were used on site for measuring Aβ42 and tau. Results: Median levels of Aβ42 in CSF were significantly lower in AD (487 pg/mL) than in CON (849 pg/mL; p = 0.001), ND (643 pg/mL; p = 0.001), and NAD (603 pg/mL; p = 0.001). Discrimination of AD from CON and ND was significantly improved by the combined assessment of Aβ42 and tau. At 85% sensitivity, specificity of the combined test was 86% (95% CI: 81% to 91%) compared with 55% (95% CI: 47% to 62%) for Aβ42 alone and 65% (95% CI: 58% to 72%) for tau. The combined test at 85% sensitivity was 58% (95% CI: 47% to 69%) specific for NAD. The APOE e4 gene load was negatively correlated with Aβ42 levels not only in AD but also in NAD. Conclusions: The combined measure of CSF Aβ42 and tau meets the requirements for clinical use in discriminating AD from normal aging and specific neurologic disorders.

Evidence behind use of intensity-modulated radiotherapy: a systematic review of comparative clinical studies

Since its introduction more than a decade ago, intensity-modulated radiotherapy (IMRT) has spread to most radiotherapy departments worldwide for a wide range of indications. The technique has been rapidly implemented, despite an incomplete understanding of its advantages and weaknesses, the challenges of IMRT planning, delivery, and quality assurance, and the substantially increased cost compared with non-IMRT. Many publications discuss the theoretical advantages of IMRT dose distributions. However, the key question is whether the use of IMRT can be exploited to obtain a clinically relevant advantage over non-modulated external-beam radiation techniques. To investigate which level of evidence supports the routine use of IMRT for various disease sites, we did a review of clinical studies that reported on overall survival, disease-specific survival, quality of life, treatment-induced toxicity, or surrogate endpoints. This review shows evidence of reduced toxicity for various tumour sites by use of IMRT. The findings regarding local control and overall survival are generally inconclusive.

Monitoring Drug Resistance in Chronic Hepatitis B Virus (HBV)-Infected Patients during Lamivudine Therapy: Evaluation of Performance of INNO-LiPA HBV DR Assay

ABSTRACT Sensitive and early detection of emerging hepatitis B virus (HBV) drug resistance may not only help monitor the viral dynamics associated with lamivudine treatment but could also improve therapeutic decision making. This is especially important when new antivirals effective against lamivudine-resistant HBV become available. A total of 159 serum samples from 33 chronic HBV patients receiving lamivudine treatment were analyzed at four centers for the presence of lamivudine-resistant mutations at codons 528 [180] (proposed revised nomenclature according to Stuyver et al. [Hepatology 33:751-757, 2001] shown in brackets), 552 [204], and 555 [207] of the HBV polymerase. Sequencing data were compared with results generated by the INNO-LiPA HBV DR line probe assay (LiPA), an assay based on reverse hybridization of amplified HBV DNA fragments with specific nucleotide probes immobilized on nitrocellulose strips. LiPA provided at least the same information as sequencing for 97.5% of all codons analyzed for codon 528 [180], 95% for codon 552 [204], and 100% for codon 555 [207]. The most common reason for discrepant or indeterminate results (0.4% and 1.5%, respectively) in a small percentage of the population tested could be attributed to polymorphisms not yet covered by LiPA probes. In at least five patients, a mutant could be detected earlier by LiPA than by sequencing. In 15 patients, LiPA detected mixed wild-type and mutant virus populations before viral breakthrough. These results demonstrate that INNO-LiPA HBV DR is a highly sensitive and easily applicable assay for the detection and monitoring of lamivudine-resistant mutations in chronic hepatitis B patients and that the assay is more sensitive than sequencing in detecting mixed mutant and wild-type sequences.

CSF phosphorylated tau is a possible marker for discriminating Alzheimer's disease from dementia with Lewy bodies. Phospho-Tau International Study Group.

Abstract Tau and β-amyloid (1–42) (Aβ42) are two independent markers for the early diagnosis of Alzheimers disease (AD). In the present study, biochemical markers were validated as tools for differential diagnosis between AD and dementia with Lewy bodies (DLB). Tau, Aβ42 and phosphotau (181P) were measured in cerebrospinal fluid (CSF) from controls (n=40) and from patients with AD (n=80) or DLB (n=43) using the HT7-AT270 assay (prototype version). In comparison with AD, in DLB no differences were found for Aβ42 and lower phospho-tau. ROC analysis was used to compare the discriminatory power of total tau with that of phospho-tau. The area under the curve (AUC) amounted to 0.782±0.048 (mean ±SE) for tau and to 0.839±0.042 for phospho-tau (p<0.039) for differentiation of AD from DLB. The present results indicate that CSF phospho-tau may be a good marker for differentiation between AD and DLB.

Analytical performance and clinical utility of the INNOTEST (R) PHOSPHO-TAU((181P)) assay for discrimination between Alzheimer's disease and dementia with Lewy bodies

Abstract Background: Total tau (T-tau) and β-amyloid(1-42) (Aβ1-42) levels in cerebrospinal fluid (CSF) can differentiate Alzheimers disease (AD) from normal aging or depressive pseudo-dementia. Differential diagnosis from dementia with Lewy bodies (DLB) in clinical settings is difficult. Methods: The analytical performance of the INNOTEST® PHOSPHO-TAU(181P) assay was validated in terms of selectivity, sensitivity, specificity, precision, robustness, and stability. Clinical utility of the assay alone, or combined with T-tau and Aβ1-42, for discrimination of AD (n=94) from patients suffering from DLB (n=60) or from age-matched control subjects (CS) (n=60) was assessed in a multicenter study. Results: CSF concentrations of tau phosphorylated at threonine 181 (P-tau181P) in AD was significantly higher than in DLB and CS. Discriminant analysis, a classification tree, and logistic regression showed that P-tau181P was the most statistically significant single variable of the three biomarkers for discrimination between AD and DLB. Conclusions: P-tau181P quantification is a robust and reliable assay that may be useful in discriminating AD from DLB. Clin Chem Lab Med 2006;44:1472–80.

Transcatheter aortic valve implantation (TAVI): risky and costly

Many of the 40 000 transcatheter procedures so far carried out cannot be justified on medical or cost effectiveness grounds. Hans Van Brabandt, Mattias Neyt, and Frank Hulstaert examine why practice has gone beyond the evidence

Evaluation of INNO-LIA Syphilis Assay as a Confirmatory Test for Syphilis

ABSTRACT We evaluated the sensitivity and specificity of a new confirmatory test for treponemal antibodies, INNO-LIA Syphilis (Innogenetics NV, Ghent, Belgium), on a large number of sera from a clinical laboratory. This multiparameter line immunoassay (LIA) uses recombinant and synthetic polypeptide antigens derived from Treponema pallidum proteins. In a single-blinded cross-sectional retrospective study, 289 seronegative sera, 219 seropositive sera, and 23 sera with an indeterminate serological status for syphilis were analyzed. All sera were tested by the T. pallidum hemagglutination assay (TPHA), the immunoglobulin (IgG)-fluorescent T. pallidum absorption assay (IgG-FTA-ABS), and the Venereal Disease Research Laboratory (VDRL) test. In addition, some seropositive samples were analyzed by the 19S-IgM-FTA-ABS test, an enzyme immunoassay (IgM-EIA), and the MarDx immunoblotting assay. Based on a consensus diagnosis derived from conventional serology, all of the sera were classified as positive, negative, or indeterminate, and the results were compared with the findings of the INNO-LIA Syphilis assay. The sensitivity and specificity of the LIA were 100% (219 of 219) and 99.3% (286 of 288), respectively. Compared to TPHA and IgG-FTA-ABS, the new test gave a significantly higher number (P = 0.021 and P < 0.0001, respectively) of correct results than either of the other two tests. The multiparameter INNO-LIA Syphilis assay is a useful confirmatory test for syphilis because it increases the reliability of syphilis diagnosis with respect to current conventional techniques.

Cerebrospinal fluid tau and beta-amyloid(1-42) in dementia disorders

The reliability of cerebrospinal fluid (CSF)-tau and CSF-beta-amyloid assays for diagnosis of Alzheimers disease and other dementing disorders such as frontotemporal dementia (FTD), dementia with Lewy bodies (DLB) and Creutzfeldt-Jakob disease (CJD) is reviewed. CSF assessment of the two proteins is useful in early diagnosis of AD and to differentiate it from FTD and DLB. Extremely high CSF-tau levels can discriminate CJD from AD.

Immunogenicity and Tolerability of Intradermal Administration of an HCV E1-Based Vaccine Candidate in Healthy Volunteers and Patients with Resolved or Ongoing Chronic HCV Infection

The tolerability and immunogenicity of intradermal injections of a candidate HCV vaccine, based on the E1 protein of the hepatitis C virus (HCV), was examined in an exploratory study in healthy volunteers, in subjects with a history of resolved HCV infection, and in patients suffering from therapy-resistant chronic HCV. Sub-epidermal injection of three doses of 4 µg of non-adjuvanted E1 vaccine induced much weaker humoral and cellular immune responses in healthy subjects and chronic HCV patients than the intramuscular administration of 20 µg E1 formulated on alum. However, in three subjects who cleared HCV infection, intradermal administration of this low dose of E1 induced rapid and clear anamnestic responses. These data demonstrate that E1-specific immune responses can be induced in resolving HCV infections and that memory (B and T) cells can be restimulated with suboptimal doses of E1 antigen.

PRE-MARKET CLINICAL EVALUATIONS OF INNOVATIVE HIGH-RISK MEDICAL DEVICES IN EUROPE

OBJECTIVES High-quality clinical evidence is most often lacking when novel high-risk devices enter the European market. At the same time, a randomized controlled trial (RCT) is often initiated as a requirement for obtaining market access in the US. Should coverage in Europe be postponed until RCT data are available? We studied the premarket clinical evaluation of innovative high-risk medical devices in Europe compared with the US, and with medicines, where appropriate. METHODS The literature and regulatory documents were checked. Representatives from industry, Competent Authorities, Notified Bodies, Ethics Committees, and HTA agencies were consulted. We also discuss patient safety and the transparency of information. RESULTS In contrast to the US, there is no requirement in Europe to demonstrate the clinical efficacy of high-risk devices in the premarket phase. Patients in Europe can thus have earlier access to a potentially lifesaving device, but at the risk of insufficiently documented efficacy and safety. Variations in the stringency of clinical reviews, both at the level of Notified Bodies and Competent Authorities, do not guarantee patient safety. We tried to document the design of premarket trials in Europe and number of patients exposed, but failed as this information is not made public. Furthermore, the Helsinki Declaration is not followed with respect to the registration and publication of premarket trials. CONCLUSIONS For innovative high-risk devices, new EU legislation should require the premarket demonstration of clinical efficacy and safety, using an RCT if possible, and a transparent clinical review, preferably centralized.