Roger T. Staff

Monitoring primary breast cancer throughout chemotherapy using FDG-PET.

We have compared 2-deoxy-2-[18F]-fluoro-d-glucose positron emission tomography (FDG-PET) images of large or locally advanced breast cancers (LABC) acquired during Anthracycline-based chemotherapy. The purpose was to determine whether there is an optimal method for defining tumour volume and an optimal imaging time for predicting pathologic chemotherapy response. Method: PET data were acquired before the first and second cycles, at the midpoint and at the endpoint of neoadjuvant chemotherapy. FDG uptake was quantified using the mean and maximum standardized uptake values (SUV) and the coefficient of variation within a region of interest. Receiver-operator characteristic (ROC) analysis was used to determine the discrimination between tumours demonstrating a high pathological response (i.e. those with greater than 90% reduction in viable tumour cells) and low pathological response. Results: Only tumours with an initial tumour to background ratio (TBR) of greater than five showed a difference between response categories. In terms of response discrimination, there was no statistically significant advantage of any of the methods used for image quantification or any of the time points. The best discrimination was measured for mean SUV at the midpoint of therapy, which identified 77% of low responding tumours whilst correctly identifying 100% of high responding tumours and had an ROC area of 0.93. Conclusion: FDG-PET is efficacious for predicting the pathologic response of most primary breast tumours throughout the duration of a neoadjuvant chemotherapy regimen. However, this technique is ineffective for tumours with low image contrast on pre-therapy PET scans.

Accuracy of T1 measurement in dynamic contrast-enhanced breast MRI using two- and three-dimensional variable flip angle fast low-angle shot

In vivo T1 measurements, used to monitor the uptake of contrast agent by tissues, are typically performed as a first step in implementing compartmental analysis of contrast‐enhanced breast magnetic resonance imaging (MRI) data. We have extended previously described methodology for in vivo T1 measurement (using a variable flip‐angle gradient‐recalled echo technique) to two‐dimensional (2D), fast low‐angle shot (FLASH). This approach requires computational modeling of slice‐selective radiofrequency (RF) excitation to correct for nonrectangular slice profiles. The accuracy with which breast tissue T1 values can be measured by this approach is examined: T1 measurements from phantom and in vivo image data acquired with 2D and 3D FLASH imaging sequences are presented. Significant sources of error due to imaging pulse sequence quality and RF transmit field nonuniformity in the breast coil device that will have detrimental consequences for compartmental analysis are identified. Rigorous quality assurance programs with calibrated phantoms are thus recommended, to verify the accuracy with which T1 measurements are obtained. J. Magn. Reson. Imaging 1999;9:163–171.

Cerebral blood flow and cognitive responses to rivastigmine treatment in Alzheimer's disease.

Twenty seven patients with mild AD were enrolled in a prospective open label controlled study of rivastigmine. Assessments included a range of neuropsychiatric and behavioural measures and rCBF using HMPAO SPECT at baseline, three and six months. Significant enhancement of frontal, parietal and temporal brain blood flow with related psychometric improvement was observed in twelve of the treated patients. A pattern of reduced rCBF and cognitive performance was observed in four unresponsive and eleven untreated patients. The results suggest that alterations in the clinical and cognitive status of patients receiving a cholinesterase inhibitor are paralleled by changes in rCBF. Longitudinal assessment with repeated imaging offers a method of better understanding the effects of cholinesterase inhibition on the AD brain.

Cerebral White Matter Abnormalities and Lifetime Cognitive Change: A 67-Year Follow-Up of the Scottish Mental Survey of 1932

Cerebral white matter abnormalities relate to cognitive functioning in elders. We examine whether this association is (a) independent of mental ability in youth and (b) related to general and/or specific mental abilities. We retested 83 participants of the Scottish Mental Survey of 1932 on a battery of mental tests. Their brains were scanned by magnetic resonance imaging. Three independent ratings (Fazekas) were made of periventricular, and subcortical and deep white matter abnormalities. Structural equation models showed that, irrespective of brain location, white matter abnormalities contributed about 14% of cognitive function variance in old age. Some of this effect might be due to hypertension. This contribution is independent of mental function in early life and is associated with general cognitive ability.

Childhood Socioeconomic Status and Adult Brain Size: Childhood Socioeconomic Status Influences Adult Hippocampal Size

To investigate in older adults without dementia the relationships between socioeconomic status (SES) in childhood and magnetic resonance imaging (MRI)‐derived brain volume measures typical of brain aging and Alzheimers disease (AD).

Delusions in Alzheimer's disease: spet evidence of right hemispheric dysfunction.

Delusional thinking and related behaviours are common symptoms in Alzheimers disease (AD). The aim of the study was to determine if any consistent cerebral image pattern can be identified using Tc99m-hexamethylpropyleneamine (HMPAO) SPET in AD patients with and without delusions. 18 AD patients with delusion and 15 AD patients without delusion underwent neuropsychological testing and regional cerebral blood flow imaging using Tc99m-HMPAO SPET. The reconstructed data was compared using regions of interest drawn over each cerebral lobe and a statistical parametric mapping (SPM) approach. The neuropsychological testing showed that there was no difference in the profiles of the deluded and non deluded AD patients. The imaging results showed a significant degree of image asymmetry. This took the form of a right hemisphere hypoperfusion mainly in the right frontal and limbic regions. The results do not indicate a specific focal site of hypoperfusion in the patients with delusion. They do, however, indicate that delusions in AD may be associated with areas of hypoperfusion in the right anterior hemisphere.

Changes in the rCBF images of patients with Alzheimer's disease receiving Donepezil therapy

Alzheimers disease is associated with a loss in presynaptic cholinergic function. It has been suggested that cholinergic inhibitors such as donepezil hydrochloride (Donepezil) could restore this function and improve some of the symptoms of Alzheimers disease. Previous work has shown that Donepezil improves cognitive and global function in patients with mild to moderate Alzheimers disease. This study reviewed retrospectively 12 patients who had previously had a 99Tcm-hexamethylpropylene amine oxime (99Tcm-HMPAO) single photon emission tomography (SPET) regional cerebral blood flow (rCBF) examination and had gone on to receive Donepezil therapy. These patients were recalled for a further 99Tcm-HMPAO SPET rCBF examination and the image data sets were compared. The results showed an overall increase in global cerebral blood flow (P = 0.04) averaged over the group with a percentage change in blood flow ranging from −1.8% to 6.4%. However, some patients showed a slight decrease in blood flow. When the data were analysed in terms of regional cerebral blood flow, we found that the most significant increase in blood flow occurred in the frontal lobes (P = 0.02).

The use of FDG-PET in assessing axillary lymph node status in breast cancer: a systematic review and meta-analysis of the literature.

Axillary lymph node status is the most powerful prognostic indicator in patients with breast cancer. FDG-PET has been suggested as a non-invasive method of staging the axilla. The aim of this study was to review and aggregate all studies that measured the performance of FDG-PET in patients with breast cancer, using surgically obtained axillary histology as a reference, in a meta-analysis. A systematic review of the literature was performed and data extracted from all eligible studies. These were then analysed using meta-analysis software and summary receiver operating characteristic (SROC) curves were plotted for the aggregate data. The data was then tested to determine which parameters impacted on the sensitivity and specificity of the studies. Sensitivities ranging from 20 to 100% and specificities ranging from 65 to 100% have been reported. An aggregated ROC analysis found an area under the curve of 0.95 (95% CI 0.91–0.97) and a Q* value of 0.89 (95% CI 0.85–0.92) in a total of 25 studies involving 2,460 patients. The AUC and Q* values indicated little difference between the compared study characteristics. The performance of the technique currently remains below, which is required to replace assessment of axillary node status by surgical biopsy and histological assessment. However, sensitivity and specificity are high and FDG-PET may have a role to play under particular circumstances. Moreover, the additional benefit of an assessment of distal metastatic spread provided by FDG-PET requires further investigation.

The relationship between vascular and metabolic characteristics of primary breast tumours

The objective of this study was to investigate the relationship between vascular and metabolic characteristics of breast tumours in vivo, using contrast-enhanced dynamic MRI and 2-[18F] fluoro-2-deoxy-d-glucose (FDG) PET imaging. Twenty patients with large or locally advanced primary breast cancers were imaged prior to therapy. MRI data were acquired using a dynamic gradient echo sequence and analysed using two pharmacokinetic models. Static PET data were acquired in 2D mode. A significant association (P<0.05) was observed between the calculated exchange rate constants of both pharmacokinetic models and calculated PET FDG dose uptake ratios (DUR). Statistical analysis showed that the exchange rate constants can explain between 27 and 44% of the variance observed in the PET FDG uptake ratios. A relationship was demonstrated between the vascular and metabolic characteristics of primary breast tumours showing that any assessment of tumour metabolic activity using PET may be controlled at least in part by delivery of uptake agent due to the vascular characteristics of the tumour. MRI and PET provide methods of assessing breast tumour vascularity and metabolism in vivo using the exchange rate constants of dynamic MRI, and DUR of PET, respectively, these measures being related but not equivalent.

Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial

BACKGROUND Leuco-methylthioninium bis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioninium moiety, acts as a selective inhibitor of tau protein aggregation both in vitro and in transgenic mouse models. Methylthioninium chloride has previously shown potential efficacy as monotherapy in patients with Alzheimers disease. We aimed to determine whether LMTM was safe and effective in modifying disease progression in patients with mild to moderate Alzheimers disease. METHODS We did a 15-month, randomised, controlled double-blind, parallel-group trial at 115 academic centres and private research clinics in 16 countries in Europe, North America, Asia, and Russia with patients younger than 90 years with mild to moderate Alzheimers disease. Patients concomitantly using other medicines for Alzheimers disease were permitted to be included because we considered it infeasible not to allow their inclusion; however, patients using medicines carrying warnings of methaemoglobinaemia were excluded because the oxidised form of methylthioninium in high doses has been shown to induce this condition. We randomly assigned participants (3:3:4) to 75 mg LMTM twice a day, 125 mg LMTM twice a day, or control (4 mg LMTM twice a day to maintain blinding with respect to urine or faecal discolouration) administered as oral tablets. We did the randomisation with an interactive web response system using 600 blocks of length ten, and stratified patients by severity of disease, global region, whether they were concomitantly using Alzheimers disease-labelled medications, and site PET capability. Participants, their study partners (generally carers), and all assessors were masked to treatment assignment throughout the study. The coprimary outcomes were progression on the Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Alzheimers Disease Co-operative Study-Activities of Daily Living Inventory (ADCS-ADL) scales from baseline assessed at week 65 in the modified intention-to-treat population. This trial is registered with Clinicaltrials.gov (NCT01689246) and the European Union Clinical Trials Registry (2012-002866-11). FINDINGS Between Jan 29, 2013, and June 26, 2014, we recruited and randomly assigned 891 participants to treatment (357 to control, 268 to 75 mg LMTM twice a day, and 266 to 125 mg LMTM twice a day). The prespecified primary analyses did not show any treatment benefit at either of the doses tested for the coprimary outcomes (change in ADAS-Cog score compared with control [n=354, 6·32, 95% CI 5·31-7·34]: 75 mg LMTM twice a day [n=257] -0·02, -1·60 to 1·56, p=0·9834, 125 mg LMTM twice a day [n=250] -0·43, -2·06 to 1·20, p=0·9323; change in ADCS-ADL score compared with control [-8·22, 95% CI -9·63 to -6·82]: 75 mg LMTM twice a day -0·93, -3·12 to 1·26, p=0·8659; 125 mg LMTM twice a day -0·34, -2·61 to 1·93, p=0·9479). Gastrointestinal and urinary effects were the most common adverse events with both high doses of LMTM, and the most common causes for discontinuation. Non-clinically significant dose-dependent reductions in haemoglobin concentrations were the most common laboratory abnormality. Amyloid-related imaging abnormalities were noted in less than 1% (8/885) of participants. INTERPRETATION The primary analysis for this study was negative, and the results do not suggest benefit of LMTM as an add-on treatment for patients with mild to moderate Alzheimers disease. Findings from a recently completed 18-month trial of patients with mild Alzheimers disease will be reported soon. FUNDING TauRx Therapeutics.