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1.  Study of PET scanner designs using clinical metrics to optimize the scanner axial FOV and crystal thickness 
Physics in medicine and biology  2013;58(12):3995-4012.
The aim of this study is to understand the trade-off between crystal thickness and scanner axial FOV (AFOV) for clinical PET imaging. Clinical scanner design has evolved towards 20–25 mm thick crystals and 16–22 cm long scanner AFOV, as well as time-of-flight (TOF) imaging. While Monte Carlo studies demonstrate that longer AFOV and thicker crystals will lead to higher scanner sensitivity, cost has prohibited the building of commercial scanners with > 22 cm AFOV. In this study, we performed a series of system simulations to optimize the use of a given amount of crystal material by evaluating the impact on system sensitivity and NEC, as well image quality in terms of lesion detectability. We evaluated two crystal types (LSO and LaBr3) and fixed the total crystal volume used for each type (8.2 liters of LSO and 17.1 liters of LaBr3) while varying the crystal thickness and scanner AFOV. In addition, all imaging times were normalized so that the total scan time needed to scan a 100 cm long object with multiple bed positions was kept constant. Our results show that the highest NEC/cm in a 35 cm diameter×70 cm long line source cylinder is achieved for an LSO scanner with 10 mm long crystals and AFOV of 36 cm while for LaBr3 scanners, the highest NEC/cm is obtained with 20 mm long crystals and an AFOV of 38 cm. Lesion phantom simulations show best lesion detection performance is achieved in scanners with long AFOV (≥ 36 cm) and using thin crystals (≤ 10 mm of LSO and ≤ 20 mm of LaBr3). This is due to a combination of improved NEC, as well as improved lesion contrast estimation due to better spatial resolution in thinner crystals. Alternatively, for lesion detection performance similar to that achieved in standard clinical scanner designs, the long AFOV scanners can be used to reduce the total scan time without increasing the amount of crystal used in the scanner. In addition, for LaBr3 based scanners, the reduced lesion contrast relative to LSO based scanners requires improved timing resolution and longer scan times in order to achieve lesion detectability similar to that achieved in an LSO scanner with similar NEC/cm.
PMCID: PMC3712794  PMID: 23685783
2.  TOF PET offset calibration from clinical data 
Physics in medicine and biology  2013;58(12):10.1088/0031-9155/58/12/4031.
In this paper, we present a timing calibration technique for time-of-flight positron emission tomography (TOF PET) that eliminates the need for a specialized data acquisition. By eliminating the acquisition, the process becomes fully automated, and can be performed with any clinical data set and whenever computing resources are available. It also can be applied retroactively to datasets for which a TOF offset calibration is missing or suboptimal. Since the method can use an arbitrary data set to perform a calibration prior to a TOF reconstruction, possibly of the same data set, one also can view this as reconstruction from uncalibrated data. We present a performance comparison with existing calibration techniques.
PMCID: PMC3826954  PMID: 23685837
3.  Combining Surface Treatments with Shallow Slots to Improve the Spatial Resolution Performance of Continuous, Thick LYSO Detectors for PET 
Positron emission tomography (PET) detectors based on continuous scintillation crystals can achieve very good performance and have a number of practical advantages compared to detectors based on a pixelated array of crystals. Our goal is to develop a thick continuous detector with high energy and spatial resolution, along with high γ-photon capture efficiency. We examine the performance of two crystal blocks: a 46 × 46 × 14 mm3 and a 48 × 48 × 25 mm3 block of LYSO (Lutetium Yttrium Orthosilicate). Using Maximum Likelihood (ML) positioning based upon the light response function (LRF) in the 14 mm thick crystal, we measure a spatial resolution of 3 mm in the central region of the crystal with degradation near the edges due to reflections off the crystal sides. We also show that we can match the spatial resolution achieved using a 14 mm thick crystal by using a 25 mm thick crystal with slots cut into the gamma entrance surface to narrow the LRF. We also find that we can improve the spatial resolution performance near the detector edges by reducing the reflectivity of the crystal sides, albeit with some loss in energy resolution.
PMCID: PMC3783277  PMID: 24077642
4.  DOI Determination by Rise Time Discrimination in Single-Ended Readout for TOF PET Imaging 
IEEE transactions on nuclear science  2013;60(3):
Clinical TOF PET systems achieve detection efficiency using thick crystals, typically of thickness 2–3cm. The resulting dispersion in interaction depths degrades spatial resolution for increasing radial positions due to parallax error. Furthermore, interaction depth dispersion results in time pickoff dispersion and thus in degraded timing resolution, and is therefore of added concern in TOF scanners. Using fast signal digitization, we characterize the timing performance, pulse shape and light output of LaBr3:Ce, CeBr3 and LYSO. Coincidence timing resolution is shown to degrade by ~50ps/cm for scintillator pixels of constant cross section and increasing length. By controlling irradiation depth in a scintillator pixel, we show that DOI-dependence of time pickoff is a significant factor in the loss of timing performance in thick detectors. Using the correlated DOI-dependence of time pickoff and charge collection, we apply a charge-based correction to the time pickoff, obtaining improved coincidence timing resolution of <200ps for a uniform 4×4×30mm3 LaBr3 pixel. In order to obtain both DOI identification and improved timing resolution, we design a two layer LaBr3[5%Ce]/LaBr3[30%Ce] detector of total size 4×4×30mm3, exploiting the dependence of scintillator rise time on [Ce] in LaBr3:Ce. Using signal rise time to determine interaction layer, excellent interaction layer discrimination is achieved, while maintaining coincidence timing resolution of <250ps and energy resolution <7% using a R4998 PMT. Excellent layer separation and timing performance is measured with several other commercially-available TOF photodetectors, demonstrating the practicality of this design. These results indicate the feasibility of rise time discrimination as a technique for measuring event DOI while maintaining sensitivity, timing and energy performance, in a well-known detector architecture.
PMCID: PMC3881366  PMID: 24403611
depth-of-interaction; time-of-flight; PET; lanthanum bromide; PET
5.  Risk-based classification of leukemia by cytogenetic and multiplex molecular methods: results from a multicenter validation study 
Blood Cancer Journal  2012;2(7):e78-.
Modern management of leukemia and selection of optimal treatment approaches entails the analysis of multiple recurrent cytogenetic abnormalities with independent diagnostic or prognostic value. We report the first multicenter validation of a multiplex molecular assay for 12 relevant fusion transcripts relative to cytogenetic methods. Performance was evaluated using a set of 280 adult and pediatric acute or chronic leukemias representative of the variety of presentations and pre-analytical parameters encountered in the clinical setting. The positive, negative and overall agreements were >98.5% with high concordance at each of the four sites. Positive detection of cases with low blast count or at relapse was consistent with a method sensitivity of 1%. There was 98.7% qualitative agreement with independent reference molecular tests. Apparent false negatives corresponded to rare alternative splicing isoforms not included in the panel. We further demonstrate that clinical sensitivity can be increased by adding those rare variants and other relevant transcripts or submicroscopic abnormalities. We conclude that multiplex RT-PCR followed by liquid bead array detection is a rapid and flexible method attuned to the clinical laboratory workflow, complementing standard cytogenetic methods and generating additional information valuable for the accurate diagnosis, prognosis and subsequent molecular monitoring of leukemia.
PMCID: PMC3408638  PMID: 22852047
leukemia; diagnosis; prognosis; molecular classification; RT-PCR; multiplex
6.  Design Study of an In-Situ PET Scanner for Use in Proton Beam Therapy 
Physics in medicine and biology  2011;56(9):2667-2685.
Proton beam therapy can deliver high radiation dose to a tumor without significant damage to surrounding healthy tissue or organs. One way of verifying the delivered dose distribution is to image the short-lived positron emitters produced by the proton beam as it travels through the patient. A potential solution to the limitations of PET imaging in proton beam therapy is the development of a high sensitivity, in-situ PET scanner that starts PET imaging almost immediately after patient irradiation while the patient is still lying on the treatment bed. A partial ring PET design is needed for this application in order to avoid interference between the PET detectors and the proton beam, as well restrictions on patient positioning on the couch. A partial ring also allows us to optimize the detector separation (and hence the sensitivity) for different patient sizes. Our goal in this investigation is to evaluate an in-situ PET scanner design for use in proton therapy that provides tomographic imaging in a partial ring scanner design using time-of-flight (TOF) information and an iterative reconstruction algorithm. A GEANT4 simulation of an incident proton beam was used to produce a positron emitter distribution, which was parameterized and then used as the source distribution inside a water-filled cylinder for EGS4 simulations of a PET system. Design optimization studies were performed as a function of crystal type and size, system timing resolution, scanner angular coverage, and number of positron emitter decays. Data analysis was performed to measure the accuracy of the reconstructed positron emitter distribution as well as the range of the positron emitter distribution.
We simulated scanners with varying crystal size (2 to 4 mm) and type (LYSO and LaBr3) and our results indicate that 4-mm wide LYSO or LaBr3 crystals (resulting in 4-5-mm spatial resolution) are adequate; for a full-ring, non-TOF scanner we predict a low bias (< 0.6-mm) and a good precision (< 1-mm) in the estimated range relative to the simulated positron distribution. We then varied the angular acceptance of the scanner ranging from 1/2 to 2/3 of 2π; with a partial ring TOF imaging with good timing resolution (≤ 600ps) is necessary to produce accurate tomographic images. A two-third ring scanner with 300ps timing resolution leads to a bias of 1.0-mm and a precision of 1.4-mm in the range estimate. With a timing resolution of 600ps, the bias increases to 2.0-mm while the precision in the range estimate is similar. For a half ring scanner design, more distortions are present in the image, which is characterized by the increased error in the profile difference estimate. We varied the number of positron decays imaged by the PET scanner by an order of magnitude and we observe some decrease in the precision of the range estimate for lower number of decays, but all partial ring scanner designs studied have a precision ≤ 1.5-mm. The largest number tested, 150M total positron decays, is considered realistic for a clinical fraction of delivered dose, while the range of positron decays investigated in this work covers a variable number of situations corresponding to delays in scan start time and the total scan time. Thus, we conclude that for partial ring systems, an angular acceptance of at least 1/2 (of 2π) together with timing resolution of 300ps is needed to achieve accurate and precise range estimates. With 600ps timing resolution an angular acceptance of 2/3 (of 2π) is required to achieve satisfactory range estimates. These results indicate that it would be feasible to develop a partial-ring dedicated PET scanner based on either LaBr3 or LYSO to accurately characterize the proton dose for therapy planning.
PMCID: PMC3144472  PMID: 21464528
7.  Imaging performance of a LaBr3-based PET scanner 
A prototype time-of-flight (TOF) PET scanner based on cerium-doped lanthanum bromide [LaBr3 (5% Ce)] has been developed. LaBr3 has high light output, excellent energy resolution, and fast timing properties that have been predicted to lead to good image quality. Intrinsic performance measurements of spatial resolution, sensitivity, and scatter fraction demonstrate good conventional PET performance; the results agree with previous simulation studies. Phantom measurements show the excellent image quality achievable with the prototype system. Phantom measurements and corresponding simulations show a faster and more uniform convergence rate, as well as more uniform quantification, for TOF reconstruction of the data, which have 375-ps intrinsic timing resolution, compared to non-TOF images. Measurements and simulations of a hot and cold sphere phantom show that the 7% energy resolution helps to mitigate residual errors in the scatter estimate because a high energy threshold (>480 keV) can be used to restrict the amount of scatter accepted without a loss of true events. Preliminary results with incorporation of a model of detector blurring in the iterative reconstruction algorithm show improved contrast recovery but also point out the importance of an accurate resolution model of the tails of LaBr3’s point spread function. The LaBr3 TOF-PET scanner has demonstrated the impact of superior timing and energy resolutions on image quality.
PMCID: PMC2911357  PMID: 19949259
Time-of-flight PET; lanthanum bromide
8.  Advances in understanding the mechanisms and management of persistent pain in older adults† 
British journal of anaesthesia  2008;101(1):111-120.
Older adults with persistent pain are not simply a chronologically older version of younger pain patients. Pain-related disability in older adults may be driven by pain ‘homeostenosis’, that is, diminished ability to effectively respond to the stress of persistent pain. Some of the comorbidities of ageing that can contribute to pain homeostenosis include cognitive and physical impairments, increased sensitivity to suprathreshold pain stimuli, medical and psychological comorbidities, altered pharmacokinetics and pharmacodynamics, and social isolation. A key distinction between older and younger individuals with persistent pain is the normal and pathological ageing-associated brain changes. These may alter the expression and experience of pain with impaired descending inhibition and dysfunction of pain gating mechanisms. Cognizance of these brain changes is needed to guide appropriate evaluation and treatment approaches. This paper reviews data that support these ageing-associated phenomena. Specifically, we discuss age-related changes in the brain (both normal and pathological) and in pain physiology; changes in experience and expression of pain that occur with dementia and contribute to pain homeostenosis; and unique aspects of age and pain-associated psychological function and their contribution to disability. We also present data demonstrating changes in brain morphology and neuropsychological performance that accompany persistent non-malignant pain in older adults and the treatment implications of these brain changes. Finally, preliminary data are presented on the efficacy of mindfulness meditation, a treatment that has been examined explicitly in older adults and targets optimizing brain function and descending inhibition.
PMCID: PMC2841779  PMID: 18487247
age factors; pain; chronic; stress
9.  Experimental evaluation of a simple lesion detection task with Time-of-Flight PET 
Physics in medicine and biology  2008;54(2):373-384.
A new generation of high performance, time-of-flight (TOF) PET scanners have recently been developed. In earlier works the gain with TOF information was derived as a reduction of noise in the reconstructed image, or essentially a gain in scanner sensitivity. These derivations were applicable to analytical reconstruction techniques and 2D PET imaging. In this work we evaluate the gain measured in the clinically relevant task of lesion detection with TOF information in fully-3D PET scanners using iterative reconstruction algorithms. We performed measurements in a fully-3D TOF PET scanner using spherical lesions in uniform, cylindrical phantom. Lesion detectability was estimated for 10-mm diameter lesions using a non-prewhitening matched filter signal-to-noise-ratio (NPW SNR) as the metric. Our results show that the use of TOF information leads to increased lesion detectability, which is achieved with less number of iterations of the reconstruction algorithm. These phantom results indicate that clinically, TOF PET will allow reduced scan times and improved lesion detectability, especially in large patients.
PMCID: PMC2662381  PMID: 19098351
10.  Clinical oncology information network. 
BMJ : British Medical Journal  1994;308(6943):1571.
PMCID: PMC2540470  PMID: 8019331
11.  Clinical oncology information network. 
BMJ : British Medical Journal  1994;308(6922):147-148.
PMCID: PMC2542513  PMID: 8312763
12.  Association of Torulopsis glabrata infections with fluconazole prophylaxis in neutropenic bone marrow transplant patients. 
Because the use of fluconazole prophylaxis had been associated with an increased rate of Candida krusei infections at The John Hopkins Oncology Center, early empiric amphotericin B plus flucytosine were given to febrile neutropenic patients colonized by C. krusei. By this practice, the proportion of fungemias attributable to C. krusei was low (12.5%) in patients receiving fluconazole over a 6-month interval. However, Torulopsis (Candida) glabrata assumed a much higher proportion of fungemias (75%) among patients receiving fluconazole. In vitro susceptibility testing combined with this clinical experience suggests that some T. glabrata isolates are not susceptible to fluconazole and can cause breakthrough infections in patients receiving fluconazole.
PMCID: PMC188080  PMID: 8239594
13.  Gait ataxia as a presenting symptom of malignant epidural spinal cord compression. 
Postgraduate Medical Journal  1986;62(730):745-747.
A 68 year old man with prostatic carcinoma developed spinal cord compression. The sole presenting feature was painless gait ataxia indistinguishable from cerebellar ataxia. He was investigated for cerebellar disease but the correct diagnosis was made when he subsequently presented with paraplegia and classical signs of spinal cord compression. Surgical decompression failed to produce neurological recovery. We discuss the importance of recognizing this unusual presentation of spinal cord compression, its possible mechanism and evidence that it may be under-reported.
PMCID: PMC2418824  PMID: 3774706
14.  Immune complex-mediated cutaneous vasculitis in a scar--the importance of local anatomical factors. 
Postgraduate Medical Journal  1985;61(713):265-266.
A vasculitic rash developed on the legs and arms of a 47 year old woman. Similar vasculitic lesions also erupted in a scar sustained ten years previously. Circulating immune complexes consisting of IgG were detected by Clq binding. We discuss the factors involved in the localization of vasculitic lesions, and in particular stress the role of microvascular injury.
PMCID: PMC2418211  PMID: 3983065
16.  Increased incidence of fungemia caused by Candida krusei. 
Journal of Clinical Microbiology  1986;24(4):581-584.
Candida krusei colonized 12.4% of 868 patients undergoing episodes of therapy-induced granulocytopenia over a 9-year period. The gastrointestinal tract was most frequently colonized, followed by the respiratory tract and urinary tract. Ten patients developed systemic infections with C. krusei; all 10 had two or more positive blood cultures. Nine of the 10 patients were colonized with C. krusei, and 6 were receiving systemic antifungal agents at the time of development of the infection. Seven patients died within 1 month of C. krusei sepsis; systemic candidiasis was seen in the autopsies of the four patients on whom autopsies were performed. Therefore, C. krusei should be recognized as an emerging pathogen in select patient populations.
PMCID: PMC268975  PMID: 3771746
17.  Combination chemotherapy of squamous cell carcinoma of the bronchus with cisplatinum and bleomycin followed by radiotherapy: results of a pilot study. 
Thirteen patients were entered into an uncontrolled pilot study to investigate the response to, and toxicity of, a combination of cisplatinum (20 mg/m2) and bleomycin (6 mg/m2) infused daily for 5 days and repeated every 21 days up to a maximum of 4 cycles, in the treatment of squamous cell carcinoma of the bronchus. This regimen was subsequently followed by a split course of local irradiation. All patients have been followed to death. Six patients showed a partial response to chemotherapy while 7 showed no response or progressive disease. The median survival was 5 months. The median survival of the responders was 15 months and that of the nonresponders 3 months. Two patients developed the syndrome of inappropriate antidiuretic hormone secretion from which one died. The longest survivor, who died 26 months after the commencement of chemotherapy, had severe mediastinal and pulmonary fibrosis.
PMCID: PMC1290498  PMID: 2431141

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