IntroductionThe aim of the study was to assess the clinical efficacy, safety, and disease-modification effects of tramiprosate (homotaurine, ALZHEMEDTM) in mild-to-moderate Alzheimer’s disease (AD).Material and methodsDouble-blind, placebo-controlled, randomized trial in 67 clinical centres across North America. Patients aged ≥ 50 years, with mild-to-moderate AD (Mini-Mental State Examination score between 16 and 26) and on stable doses of cholinesterase inhibitors, alone or with memantine. Intervention: 78-week treatment with placebo, tramiprosate 100 mg or tramiprosate 150 mg BID. Measurements: Alzheimer Disease Assessment Scale – cognitive subscale (ADAS-cog) and Clinical Dementia Rating – Sum of Boxes (CDR-SB) assessments were performed at baseline and every 13 weeks. Baseline and 78-week magnetic resonance imaging (MRI) hippocampus volume (HV) measurements were conducted in a subgroup of patients.
ResultsA total of 1,052 patients were enrolled and 790 (75.1%) completed the 78-week trial. Patient discontinuation and reasons for withdrawal were similar across groups. Planned analyses did not reveal statistically significant between-group differences. Lack of adequate statistical validity of the planned analysis models led to the development of revised predictive models. These adjusted models showed a trend toward a treatment effect for ADAS-cog (P = 0.098) and indicated significantly less HV loss for tramiprosate 100 mg (P = 0.035) and 150 mg (P = 0.009) compared to placebo. The incidence of adverse events was similar across treatment groups.
ConclusionsThe primary planned analyses did not show a significant treatment effect, but were confounded by unexplained variance. Post-hoc analyses showed a significant treatment-related reduction in HV loss. However, there was only a trend towards slowing of decline on the ADAS-cog and no slowing of decline on the CDR-SB. These results must be interpreted in consideration of the limitations of clinical and disease-modification outcome measures and their relationship, the heterogeneity of the disease and the impact of confounding demographic and clinical variables.
Purpose:To investigate the potential value and relationship of in vivo quantification of apparent diffusion coefficients (ADCs) and T2 relaxation times for characterizing brain tumor cellularity and tumor-related edema.
Materials and Methods:A total of 26 patients with newly diagnosed gliomas, meningiomas, or metastases underwent diffusion-weighted and six-echo multisection T2-preparation imaging. Regions of interest (ROIs) were drawn on conventional MR images to include tumor (as defined by contrast agent enhancement) and immediate and peripheral edema. Areas of necrosis were excluded. Median values of ADCs and T2 in the ROIs were calculated.Results: ADCs for gliomas were similar to those for meningiomas or metastases in all regions. Tumor T2 values for gliomas (159.5 Ϯ 30.6 msec) were significantly higher than those for meningiomas or metastases (125.0 Ϯ 31.1 msec; P ϭ 0.005). Immediate-edema T2 values for meningiomas or metastases (226.0 Ϯ 44.1 msec) were significantly higher than those for gliomas (203.5 Ϯ 32.8 msec; P ϭ 0.033). Peripheral-edema T2 values for gliomas (219.5 Ϯ 41.9 msec) were similar to those for meningiomas or metastases (202.5 Ϯ 26.5 msec; P ϭ 0.377). Both immediate-and peritumoral-edema ADCs and T2 values were significantly higher than those in tumor for both tumor types. ADCs and T2 values from all regions correlated significantly for gliomas (r ϭ 0.95; P Ͻ 0.0001) and for meningiomas or metastases (r ϭ 0.81; P Ͻ 0.0001).
Conclusion:The higher immediate-edema T2 values for nonglial tumors than for gliomas suggest tumor-related edema (vasogenic vs. infiltrated) can be further characterized by using T2 values. There were significant correlations between ADC and T2 values.
Purpose:To investigate the potential value of pre-externalbeam radiation therapy (XRT) choline-to-NAA (N-acetylaspartate) index (CNI), apparent diffusion coefficient (ADC), and relative cerebral blood volume (rCBV) for predicting survival in newly diagnosed patients with glioblastoma multiforme (GBM).
Materials and Methods:Twenty-eight patients with GBM were studied using in vivo proton magnetic resonance spectroscopic imaging ( 1 H MRSI) and diffusion-and perfusionweighted imaging after surgery but prior to XRT. Patients were categorized on the basis of their volumes of morphologic and metabolic abnormalities (volume of CNI Ն 2 and CNI values), normalized ADC (nADC), or rCBV values within the T1 contrast-enhancing and T2 regions. The median survival time was compared.Results: A significantly shorter median survival time was observed for patients with a large volume of metabolic abnormality than for those with a small abnormality (12.0 and 17.1 months, respectively, P ϭ 0.002). A similar pattern was observed for patients with a low mean nADC value compared to those with high mean nADC value within the T2 region (11.2 and 21.7 months, respectively, P ϭ 0.004).A shorter median survival time was also observed for patients with contrast-enhancing residual disease than for those without the presence of contrast enhancement with marginal significance.
Conclusion:The pre-XRT volume of the metabolic abnormality and the nADC value within the T2 region may be valuable in predicting outcome for patients with GBM.
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