Andrew Welch

Positron Emission Tomography Using [18F]-Fluorodeoxy-d-Glucose to Predict the Pathologic Response of Breast Cancer to Primary Chemotherapy

PURPOSE To determine whether [(18)F]-fluorodeoxy-D-glucose ([(18)F]-FDG) positron emission tomography (PET) can predict the pathologic response of primary and metastatic breast cancer to chemotherapy. PATIENTS AND METHODS Thirty patients with noninflammatory, large (> 3 cm), or locally advanced breast cancers received eight doses of primary chemotherapy. Dynamic PET imaging was performed immediately before the first, second, and fifth doses and after the last dose of treatment. Primary tumors and involved axillary lymph nodes were identified, and the [(18)F]-FDG uptake values were calculated (expressed as semiquantitative dose uptake ratio [DUR] and influx constant [K]). Pathologic response was determined after chemotherapy by evaluation of surgical resection specimens. RESULTS Thirty-one primary breast lesions were identified. The mean pretreatment DUR values of the eight lesions that achieved a complete microscopic pathologic response were significantly (P =.037) higher than those from less responsive lesions. The mean reduction in DUR after the first pulse of chemotherapy was significantly greater in lesions that achieved a partial (P =.013), complete macroscopic (P =.003), or complete microscopic (P =.001) pathologic response. PET after a single pulse of chemotherapy was able to predict complete pathologic response with a sensitivity of 90% and a specificity of 74%. Eleven patients had pathologic evidence of lymph node metastases. Mean pretreatment DUR values in the metastatic lesions that responded did not differ significantly from those that failed to respond (P =.076). However, mean pretreatment K values were significantly higher in ultimately responsive cancers (P =.037). The mean change in DUR and K after the first pulse of chemotherapy was significantly greater in responding lesions (DUR, P =.038; K, P =.012). CONCLUSION [(18)F]-FDG PET imaging of primary and metastatic breast cancer after a single pulse of chemotherapy may be of value in the prediction of pathologic treatment response.

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.

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.

Detection of scarred and viable myocardium using a new magnetic resonance imaging technique: blood oxygen level dependent (BOLD) MRI

Background: The identification of viable myocardium in patients with impaired left ventricular contraction secondary to coronary heart disease is important clinically as such myocardium is likely to benefit from revascularisation. Blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) relies on changes in deoxyhaemoglobin concentration under stress for signal generation and could be used for the differentiation between scarred and viable myocardium. Aim: To assess the signal change on BOLD MRI in viable and scarred myocardium as identified by positron emission tomography (PET). Method: 19 patients with impaired left ventricular contraction and at least one akinetic area were enrolled. They underwent rest and dipyridamole stress MRI, using a double breath hold T2* weighted, ECG gated sequence to produce BOLD contrast images, and cine-MRI for wall thickening assessment. Dynamic perfusion and metabolic PET images followed the MRI. Signal change on BOLD MRI and the wall thickening were compared between rest and stress images in hibernating and scarred segments identified by PET on two short axis slices of mid ventricle, with eight segments each. Results: Using PET, 68 segments were identified as hibernating and 42 as scarred. The hibernating segments were found on BOLD MRI to have an average signal change between rest and stress of −9.53%, compared with −2.15% in the scarred segments (p = 0.008). The average wall thickening was 8.7 mm in the hibernating segments compared with 5.9 mm in the scarred segments (p < 0.0001). Conclusions: BOLD MRI with wall thickening may differentiate scarred and viable myocardium and help identify suitable patients for revascularisation. Further larger studies are needed to establish a threshold for detection, sensitivity, and specificity.

A four-layer attenuation compensated PET detector based on APD arrays without discrete crystal elements

Scintillation detectors developed for PET traditionally use relatively thick crystals coupled to photomultiplier tubes. To ensure good efficiency the crystals typically measure between 10 and 30 mm thick. Detectors also require good spatial resolution so the scintillator is normally made up of a densely packed array of long thin crystals. In this paper, we present a novel design in which the detection crystal is divided into a number of layers along its length with an avalanche photo diode (APD) inserted between each layer. With thin layers of crystal, it is possible to use a continuous rather than a pixelated crystal. The potential advantages of this design over a conventional PMT-based detector are: (i) improved light collection efficiency, (ii) reduced dependency on dense crystal to achieve good stopping power, (iii) ease of crystal manufacture, (iv) reduced detector dead-time and increased count rate, and (v) inherent depth of interaction. We have built a four-layer detector to test this design concept using Hamamatsu S8550 APD arrays and LYSO crystals. We used the centre 16 pixels of each of the arrays to give an active area of 9.5 mm x 9.5 mm. Four crystals 9.5 mm x 9.5 mm were used with thickness increasing from 2 mm at the front to 2.5 mm, 3.1 mm and 4.3 mm at the back, to ensure a similar count rate in each layer. Calculations for the thickness of the four layers were initially made using the linear attenuation coefficient for photons at 511 keV of LYSO. Experimental results and further simulation demonstrated that a correction to the thickness of each layer should be considered to take into account the scattered events. The energy resolution for each of the layers at 511 keV was around 15%, coincidence-timing resolution was 2.2 ns and the special resolution was less than 2 mm using a statistical-based positioning algorithm.

A three-dimensional ray-driven attenuation, scatter and geometric response correction technique for SPECT in inhomogeneous media.

The qualitative and quantitative accuracy of SPECT images is degraded by physical factors of attenuation, Compton scatter and spatially varying collimator geometric response. This paper presents a 3D ray-tracing technique for modelling attenuation, scatter and geometric response for SPECT imaging in an inhomogeneous attenuating medium. The model is incorporated into a three-dimensional projector-backprojector and used with the maximum-likelihood expectation-maximization algorithm for reconstruction of parallel-beam data. A transmission map is used to define the inhomogeneous attenuating and scattering object being imaged. The attenuation map defines the probability of photon attenuation between the source and the scattering site, the scattering angle at the scattering site and the probability of attenuation of the scattered photon between the scattering site and the detector. The probability of a photon being scattered through a given angle and being detected in the emission energy window is approximated using a Gaussian function. The parameters of this Gaussian function are determined using physical measurements of parallel-beam scatter line spread functions from a non-uniformly attenuating phantom. The 3D ray-tracing scatter projector-backprojector produces the scatter and primary components. Then, a 3D ray-tracing projector-backprojector is used to model the geometric response of the collimator. From Monte Carlo and physical phantom experiments, it is shown that the best results are obtained by simultaneously correcting attenuation, scatter and geometric response, compared with results obtained with only one or two of the three corrections. It is also shown that a 3D scatter model is more accurate than a 2D model. A transmission map is useful for obtaining measurements of attenuation and scatter in SPECT data, which can be used together with a model of the geometric response of the collimator to obtain corrected images with quantitative and diagnostically accurate information.

FDG-PET imaging, EEG and sleep phenotypes as translational biomarkers for research in Alzheimer's disease

The lack of reliable translational procedures applicable to both patients and experimental models are a major obstacle for the advancement of basic research as well as for the development of therapeutics. This is particularly relevant to neurodegenerative disorders such as AD (Alzheimers disease), where the predictive validity of animal models and procedures applied preclinically have met with little success. Two approaches available for human diagnostics are currently experiencing major advancements in preclinical research: in vivo imaging using MRI (magnetic resonance imaging) or PET (positron-emission tomography) and recordings of brain electrical activity via surface EEG (electroencephalogram). The present paper reviews the results obtained so far in rodent AD models, and summarizes advantages and disadvantages of such procedures.

Can the surface electrocardiogram be used to predict myocardial viability

OBJECTIVE To investigate whether QRS morphology on the surface ECG can be used to predict myocardial viability. DESIGN ECGs of 58 patients with left ventricular impairment undergoing positron emission tomography (PET) were studied. 13N-Ammonia (NH3) and 18F-fluorodeoxyglucose (FDG) were the perfusion and the metabolic markers, respectively. The myocardium is scarred when the uptake of both markers is reduced (matched defect). Reduced NH3 uptake with persistent FDG uptake (mismatched defect) represents hibernating myocardium. First, the relation between pathological Q waves and myocardial scarring was investigated. Second, the significance of QR and QS complexes in predicting hibernating myocardium was determined. RESULTS As a marker of matched PET defects, Q waves were specific (79%) but not sensitive (41%), with a 77% positive predictive accuracy and a poor (43%) negative predictive accuracy. The mean size of the matched PET defect associated with Q waves was 20% of the left ventricle. This was not significantly different from the size of the matched PET defects associated with no Q waves (18%). Among the regions associated with Q waves on the ECG, there were 16 regions with QR pattern (group A) and 23 regions with QS pattern (group B). The incidence of mismatched PET defects was 19% of group A and 30% of group B (NS). CONCLUSIONS Q waves are specific but not sensitive markers of matched defects representing scarred myocardium. Q waves followed by R waves are not more likely to be associated with hibernating myocardium than QS complexes.

Positron emission tomography for monitoring response to neoadjuvant therapy in patients with oesophageal and gastro-oesophageal junction carcinoma

AIMS The aim of this review is to consolidate our knowledge on an important and rapidly expanding area of expertise. Numerous methods for predicting response (in terms of pathological response and survival) to neoadjuvant therapy (chemotherapy/chemo-radiotherapy) in oesophageal and junctional cancers have been proposed. This review concerns itself only with the use of positron emission tomography for such a purpose. At present there are no standardised criteria amongst PET trials as to what determines a response according to PET, what is the optimal time to perform PET in relation to the timing of neoadjuvant therapy, and what is the ideal method of quantifying PET tracer uptake. METHODS An electronic search was performed of PubMed, Ovid and Embase websites to identify studies, in the English language, using the search terms: PET; oesophageal; oesophago-gastric; survival; cancer; response; chemotherapy and chemo-radiotherapy. The reference lists were searched manually to identify further relevant studies. RESULTS Twenty-two studies were identified, all using (18)FDG as the tracer, using PET to predict response in terms of pathological response and survival following neoadjuvant therapy (chemotherapy/chemo-radiotherapy). PET had a varying degree of success in predicting both pathological response and survival outcomes, with only one study using PET to influence management decisions. CONCLUSIONS PET seems a promising technique, but large-scale conclusions are hindered by small study numbers, lack of criteria as to what constitutes a response and markedly differing PET imaging times. A large randomised trial concerning a homogeneous group of patients and tumours is required before PET might be used to influence management.

Gamma emission imaging in the management of breast disorders

Breast cancer is the commonest malignancy to affect women. The malignant process may present clinicians with problems in establishing the diagnosis expeditiously, accurately staging the disease and assessing tumour response to primary systemic chemotherapy. Considerable recent interest has focused on the application of imaging techniques that utilize tumour-specific gamma-ray-emitting radiopharmaceuticals to resolve these problems. The wide availability of gamma camera systems makes single photon-imaging techniques, using radiopharmaceuticals incorporating conventional isotopes, attractive options. However, results concerning the detection of the primary breast cancer and the staging of axillary lymph nodes suggest that these techniques would appear to offer no significant advantages, when compared with those obtained using standard diagnostic methods. Dual gamma-ray-emission imaging by positron emission tomography (PET) may offer an alternative solution. Studies performed show that PET can accurately detect primary breast cancers, stage locoregional lymph nodes and visualize distant tumour metastases. Furthermore, PET may be able to monitor early tumour response to chemotherapy agents. It would appear, therefore, that dual gamma emission might have an important role to play in the management of patients with breast cancer.