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1.  Geographic miss of lung tumours due to respiratory motion: a comparison of 3D vs 4D PET/CT defined target volumes 
Background
PET/CT scans acquired in the radiotherapy treatment position are typically performed without compensating for respiratory motion. The purpose of this study was to investigate geographic miss of lung tumours due to respiratory motion for target volumes defined on a standard 3D-PET/CT.
Methods
29 patients staged for pulmonary malignancy who completed both a 3D-PET/CT and 4D-PET/CT were included. A 3D-Gross Tumour Volume (GTV) was defined on the standard whole body PET/CT scan. Subsequently a 4D-GTV was defined on a 4D-PET/CT MIP. A 5 mm, 10 mm, 15 mm symmetrical and 15×10 mm asymmetrical Planning Target Volume (PTV) was created by expanding the 3D-GTV and 4D-GTV’s. A 3D conformal plan was generated and calculated to cover the 3D-PTV. The 3D plan was transferred to the 4D-PTV and analysed for geographic miss. Three types of miss were measured. Type 1: any part of the 4D-GTV outside the 3D-PTV. Type 2: any part of the 4D-PTV outside the 3D-PTV. Type 3: any part of the 4D-PTV receiving less than 95% of the prescribed dose. The lesion motion was measured to look at the association between lesion motion and geographic miss.
Results
When a standard 15 mm or asymmetrical PTV margin was used there were 1/29 (3%) Type 1 misses. This increased 7/29 (24%) for the 10 mm margin and 23/29 (79%) for a 5 mm margin. All patients for all margins had a Type 2 geographic miss. There was a Type 3 miss in 25 out of 29 cases in the 5, 10, and 15 mm PTV margin groups. The asymmetrical margin had one additional Type 3 miss. Pearson analysis showed a correlation (p < 0.01) between lesion motion and the severity of the different types of geographic miss.
Conclusion
Without any form of motion suppression, the current standard of a 3D- PET/CT and 15 mm PTV margin employed for lung lesions has an increasing risk of significant geographic miss when tumour motion increases. Use of smaller asymmetric margins in the cranio-caudal direction does not comprise tumour coverage. Reducing PTV margins for volumes defined on 3D-PET/CT will greatly increase the chance and severity of a geometric miss due to respiratory motion. 4D-imaging reduces the risk of geographic miss across the population of tumour sizes and magnitude of motion investigated in the study.
doi:10.1186/s13014-014-0291-6
PMCID: PMC4278238  PMID: 25511904
4D-PET/CT; Geographic miss; Lung cancer; Margins; Radiotherapy
2.  Association between radiation pneumonitis and tumor response in patients with NSCLC treated with chemoradiation 
Dang and colleagues recently reported in the journal that tumor response to definitive chemoradiation, as assessed using the RECIST criteria, and the risk of radiation pneumonitis were positively correlated in patients with non-small cell lung cancer (NSCLC). We had previously reported similar findings in a study that used positron tomography both to measure tumor response and to assess normal tissue toxicity in patients treated with chemoradiation for NSCLC. Taken together these reports suggest that radiosensitivity of normal tissues and tumors may be strongly linked in a proportion of patients with lung cancer.
doi:10.1186/1748-717X-9-217
PMCID: PMC4283112  PMID: 25318863
Radiation therapy; Lung cancer; Radiosensititivity; Tumour response; Positron emission tomograpy
3.  A prospective observational study of Gallium-68 ventilation and perfusion PET/CT during and after radiotherapy in patients with non-small cell lung cancer 
BMC Cancer  2014;14(1):740.
Background
Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers, and is the leading cause of cancer deaths. Radiation therapy (RT), alone or in combination with chemotherapy, is the standard of care for curative intent treatment of patients with locally advanced or inoperable NSCLC. The ability to intensify treatment to achieve a better chance for cure is limited by the risk of injury to the surrounding lung.
Methods/Design
This is a prospective observational study of 60 patients with NSCLC receiving curative intent RT. Independent human ethics board approval was received from the Peter MacCallum Cancer Centre ethics committee. In this research, Galligas and Gallium-68 macroaggregated albumin (MAA) positron emission tomography (PET) imaging will be used to measure ventilation (V) and perfusion (Q) in the lungs. This is combined with computed tomography (CT) and both performed with a four dimensional (4D) technique that tracks respiratory motion. This state-of-the-art scan has superior resolution, accuracy and quantitative ability than previous techniques. The primary objective of this research is to observe changes in ventilation and perfusion secondary to RT as measured by 4D V/Q PET/CT. Additionally, we plan to model personalised RT plans based on an individual’s lung capacity. Increasing radiation delivery through areas of poorly functioning lung may enable delivery of larger, more effective doses to tumours without increasing toxicity. By performing a second 4D V/Q PET/CT scan during treatment, we plan to simulate biologically adapted RT depending on the individual’s accumulated radiation injury. Tertiary aims of the study are assess the prognostic significance of a novel combination of clinical, imaging and serum biomarkers in predicting for the risk of lung toxicity. These biomarkers include spirometry, 18 F-Fluorodeoxyglucose PET/CT, gamma-H2AX signals in hair and lymphocytes, as well as assessment of blood cytokines.
Discussion
By correlating these biomarkers to toxicity outcomes, we aim to identify those patients early who will not tolerate RT intensification during treatment. This research is an essential step leading towards the design of future biologically adapted radiotherapy strategies to mitigate the risk of lung injury during dose escalation for patients with locally advanced lung cancer.
Trials registration
Universal Trial Number (UTN) U1111-1138-4421.
doi:10.1186/1471-2407-14-740
PMCID: PMC4192760  PMID: 25277150
Positron emission tomography; Definitive radiation; Lung cancer; 4D; Adaptive radiotherapy; Biological dose escalation; Biomarkers; Gamma-H2AX; Inflammatory cytokines
4.  Response of BRAF mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis 
Cancer discovery  2014;4(4):423-433.
Deregulated glucose metabolism fulfils the energetic and biosynthetic requirements for tumour growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefit in BRAF mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF mutant melanoma cells. Moreover, we identified a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably, this network of transcription factors, including HIF1α, c-Myc and MondoA, drives glycolysis downstream of BRAFV600, is critical for responses to BRAF inhibition and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor-resistant melanoma cells. Thus, we provide a proof of principle for treatment of melanoma with combinations of BRAF inhibitors and glycolysis inhibitors.
doi:10.1158/2159-8290.CD-13-0440
PMCID: PMC4110245  PMID: 24469106
BRAF; melanoma; metabolism; vemurafenib; glycolysis
5.  Can structural or functional changes following traumatic brain injury in the rat predict the epileptic outcome? 
Epilepsia  2013;54(7):1240-1250.
Summary
Purpose
Post-traumatic epilepsy (PTE) occurs in a proportion of traumatic brain injury (TBI) cases, significantly compounding the disability, risk of injury, and death for sufferers. To date, predictive biomarkers for PTE have not been identified. This study used the lateral fluid percussion injury (LFPI) rat model of TBI to investigate whether structural, functional, and behavioral changes post-TBI relate to the later development of PTE.
Methods
Adult male Wistar rats underwent LFPI or sham-injury. Serial MR and PET imaging, and behavioral analyses were performed over six months post-injury. Rats were then implanted with recording electrodes and monitored for two consecutive weeks using video-EEG to assess for PTE. Of the LFPI rats, 52% (n=12) displayed spontaneous recurring seizures and/or epileptic discharges on the video-EEG recordings.
Key findings
MRI volumetric and signal analysis of changes in cortex, hippocampus, thalamus, and amygdala, 18F-FDG PET analysis of metabolic function, and behavioral analysis of cognitive and emotional changes, at one week, one month, three months, and six months post-LFPI, all failed to identify significant differences on univariate analysis between the epileptic and non-epileptic groups. However, hippocampal surface shape analysis using high dimensional mapping-large deformation identified significant changes in the ipsilateral hippocampus at one week post-injury relative to baseline that differed between rats that would go onto become epileptic versus those who did not. Furthermore, a multivariate logistic regression model that incorporated the one week, one month, and three month 18F-FDG PET parameters from the ipsilateral hippocampus was able to correctly predict the epileptic outcome in all of the LFPI cases. As such, these subtle changes in the ipsilateral hippocampus at acute phases after LFPI may be related to PTE and require further examination.
Significance
These findings suggest PTE may be independent of major structural, functional, and behavioral changes induced by TBI, and suggest more subtle abnormalities are likely involved. However, there are limitations associated with studying acquired epilepsies in animal models that must be considered when interpreting these results, in particular the failure to detect differences between the groups may be related to the limitations of properly identifying/separating the epileptic and non-epileptic animals into the correct group.
doi:10.1111/epi.12223
PMCID: PMC4032369  PMID: 23718645
Post-traumatic epilepsy; Lateral fluid percussion injury; MRI; PET; Epileptogenesis
6.  A prospective investigation into the clinical impact of 4D-PET/CT in the characterisation of solitary pulmonary nodules 
Cancer Imaging  2014;14(1):24.
Background
While the effects of respiratory motion on measuring metabolic signal in PET/CT scanning are well known, it is still standard practice in most centres to scan patients while breathing freely with no correction for the effects of respiratory motion. The aim of this study was to investigate the impact of 4D-PET/CT in classifying lesions in patients with a radiologically-indeterminate solitary pulmonary nodule.
Methods
Twenty consecutive patients with a solitary pulmonary nodule for investigation were prospectively recruited and completed a whole-body (WB)-PET/CT and 4D-PET/CT in the same session. The reporting physician initially classified the nodule using a 5-point scale (Definitely Malignant, Probably Malignant, Indeterminate, Probably benign, Definitely Benign) on the WB-PET/CT. The physician was then shown the 4D-PET/CT and asked if they would re-classify the lesion. Frequency, sensitivity, specificity and accuracy values were calculated for WB-PET/CT alone and then with the addition of the 4D-PET/CT.
Results
There were no changes in the classification for nodules initially classed as either benign or malignant with the addition of a 4D-PET/CT. However changes were observed between WB and 4D-PET/CT scans in lesions initially classified as indeterminate. When indeterminate lesions were defined as malignant there was a minor increase in sensitivity (from 73% to 75%), in specificity (56%-63%) and in accuracy (65%-70%) but these results do not reach statistical significance. When the Indeterminate lesions were defined as benign there was an increase in sensitivity (from 55% to 67%) but there was a reduction in the specificity (100%-75%) and accuracy (75%-70%) with the addition of the 4D-PET/CT but again the results did not reach statistical significance.
Conclusion
The addition of 4D-PET/CT is most likely to have an impact on those nodules initially classified as indeterminate on standard WB-PET/CT. In lesions classified as benign or malignant on standard WB-PET/CT the addition of a 4D-PET/CT is less likely to impact lesion classification. While 4D-PET/CT does improve the measurement of the metabolic signal, it does not overcome inherent limitations of FDG in differentiating a malignant lesion from inflammatory processes, correct for partial volume effects or compensate for the low intrinsic FDG-avidity of some malignancies.
doi:10.1186/1470-7330-14-24
PMCID: PMC4331829  PMID: 25608679
7.  Assessment of predictors of response and long-term survival of patients with neuroendocrine tumour treated with peptide receptor chemoradionuclide therapy (PRCRT) 
Purpose
To review the response and outcomes of 177Lu-DOTA-octreotate chemoradionuclide therapy (LuTate PRCRT) in patients with neuroendocrine tumour (NET) expressing high levels of somatostatin receptors with uncontrolled symptoms or disease progression.
Methods
A total of 68 patients (39 men; 17 – 76 years of age) who had completed an induction course of at least three cycles of LuTate PRCRT between January 2006 and June 2010 were reviewed. Ten patients were treated for uncontrolled symptoms and 58 had disease progression despite conventional treatment. The majority had four induction LuTate cycles (median treatment duration 5 months and cumulative activity 31 GBq), and 63 patients had concomitant 5-FU radiosensitizing infusional chemotherapy. Factors predicting overall survival were assessed using the log-rank test and Cox proportional hazards regression.
Results
Of those treated for uncontrolled symptoms, 70 % received benefit maintained for at least 6 months after treatment. Among patients with progressive disease 68 % showed stabilization or regression on CT, 67 % on molecular imaging and 56 % biochemically up to 12 months after treatment; 32 patients died. Overall survival rates at 2 and 5 year were 72.1 % and 52.1 %, respectively. Median overall survival was not estimable at a median follow-up of 60 months (range 5 – 86 months). Nonpancreatic primary sites, dominant liver metastases, lesion size <5 cm and the use of 5-FU chemotherapy were statistically significantly associated with objective response. A disseminated pattern and a high disease burden (whole-body retention index) were associated with an increased risk of death. Objective biochemical, molecular imaging and CT responses were all associated with longer overall survival.
Conclusion
A high proportion of patients with progressive NET or uncontrolled symptoms received therapeutic benefit from LuTate with concomitant 5-FU chemotherapy. The achievement of objective biochemical, molecular or CT responses within 12 months was associated with improved overall survival. Patients with a primary pancreatic site and larger lesions (>5 cm) appeared to have lower objective response rates and may need a more aggressive treatment approach.
Electronic supplementary material
The online version of this article (doi:10.1007/s00259-014-2788-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s00259-014-2788-5
PMCID: PMC4159597  PMID: 24844348
177Lu-Octreotate; Neuroendocrine; 5-FU chemotherapy; Response; Predictive factors; Survival
8.  Routes of Delivery for CpG and Anti-CD137 for the Treatment of Orthotopic Kidney Tumors in Mice 
PLoS ONE  2014;9(5):e95847.
We have found previously that the tumor cell lines, Renca (a renal cancer) and MC38 (a colon tumor) which had been injected subcutaneously in mice, could be successfully treated with a combination therapy of an oligodeoxynucleotide (CpG1826) (injected intratumorally) and anti-CD137 antibody (injected intraperitoneally). Thus the combination treatment was expected to initiate a “danger” signal via TLR9 on immune cells, and the anti-CD137 was expected to further activate T cells. In the present study, we found that several other tumor types injected subcutaneously could also be successfully treated with this combination therapy. In addition, we wished to determine if the treatment could work as effectively in an orthotopic metastatic model, which is more physiologically relevant to cancer in humans. Renca was selected as we were familiar with injecting this orthotopically into the outer cortex of the kidney in mice, and it spontaneously metastasizes to lung and abdominal sites. We tested various routes of delivery of CpG combined with intraperitoneal delivery of anti-CD137. Orthotopic tumors were injected with CpG intratumorally, using ultrasound-guided delivery on multiple occasions, combined with anti-CD137 intraperitoneally. A reduction in primary tumor size was observed following intratumoral injection of CpG compared to other treatments. We found that there was a statistically significant increase in survival of mice with orthotopic Renca tumor following intratumoral injection of CpG. However, we determined that the most effective route of delivery of CpG was intravenous, which led to further significantly enhanced survival of mice when combined with anti-CD137 intraperitoneally, likely due to inhibition of metastatic disease. Our data supports future development of this combination therapy for cancer.
doi:10.1371/journal.pone.0095847
PMCID: PMC4008493  PMID: 24788789
9.  Cancer imaging: Quo vadis? 
Cancer Imaging  2014;14(1):1.
doi:10.1186/1470-7330-14-1
PMCID: PMC4212528  PMID: 25609460
10.  The utility of 18 F-FDG PET/CT for suspected recurrent breast cancer: impact and prognostic stratification 
Cancer Imaging  2014;14(1):13.
Background
The incremental value of 18FDG PET/CT in patients with breast cancer (BC) compared to conventional imaging (CI) in clinical practice is unclear. The aim of this study was to evaluate the management impact and prognostic value of 18 F-FDG PET/CT in this setting.
Methods
Sixty-three patients who were referred to our institution for suspicion of BC relapse were retrospectively enrolled. All patients had been evaluated with CI and underwent PET/CT. At a median follow-up of 61 months, serial clinical, imaging and pathologic results were obtained to validate diagnostic findings. Overall Survival (OS) was estimated using Kaplan Meier methods and analyzed using the Cox proportional hazards regression models.
Results
Forty-two patients had a confirmed relapse with 37 (88%) positive on CI and 40 (95%) positive on PET/CT. When compared with CI, PET/CT had a higher negative predictive value (86% versus 54%) and positive predictive value (95% versus 70%). The management impact of PET/CT was high (change of treatment modality or intent) in 30 patients (48%) and medium (change in radiation treatment volume or dose fractionation) in 6 patients (9%). Thirty-nine patients (62%) died during follow-up. The PET/CT result was a highly significant predictor of OS (Hazard Ratio [95% Confidence Interval] =4.7 [2.0-10.9] for PET positive versus PET negative for a systemic recurrence; p = 0.0003). In a Cox multivariate analysis including other prognosis factors, PET/CT findings predicted survival (p = 0.005). In contrast, restaging by CI was not significant predictor of survival.
Conclusion
Our study support the value of 18 F-FDG PET/CT in providing incremental information that influence patient management and refine prognostic stratification in the setting of suspected recurrent breast cancer.
doi:10.1186/1470-7330-14-13
PMCID: PMC4331819  PMID: 25608599
Breast cancer; 18 F-FDG PET/CT; Restaging; Prognosis
11.  Pertuzumab and Erlotinib in Patients With Relapsed Non-Small Cell Lung Cancer: A Phase II Study Using 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Imaging 
The Oncologist  2014;19(2):175-176.
Background.
Combination blockade of human epidermal growth factor receptor (HER) family signaling may confer enhanced antitumor activity than single-agent blockade. We performed a single-arm study of pertuzumab, a monoclonal antibody that inhibits HER2 dimerization, and erlotinib in relapsed non-small cell lung cancer (NSCLC).
Methods.
Patients received pertuzumab (840-mg loading dose and 420-mg maintenance intravenously every 3 weeks) and erlotinib (150-mg or 100-mg dose orally, daily). The primary endpoint was response rate (RR) by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) at day 56 in all patients and those with EGFR wild-type tumors.
Results.
Of 41 patients, 28 (68.3%) experienced treatment-related grade ≥3 adverse events, including pneumatosis intestinalis (3 patients), resulting in early cessation of enrollment. Tissue samples from 32 patients showed mutated EGFR status in 9 of 41 (22%) and wild-type EGFR in 23 of 41 (56%). The FDG-PET RR for patients with assessments at day 56 was 19.5% in all patients (n = 41) and 8.7% in patients with wild-type EGFR NSCLC (n = 23). Investigator-assessed computed tomography RR at day 56 was 12.2%.
Conclusion.
FDG-PET suggests that pertuzumab plus erlotinib is an active combination, but combination therapy was poorly tolerated, which limits its clinical applicability. More research is warranted to identify drug combinations that disrupt HER receptor signaling but that exhibit improved tolerability profiles.
doi:10.1634/theoncologist.2013-0026
PMCID: PMC3926793  PMID: 24457379
12.  In Vivo Measurement of Hippocampal GABAA/cBZR Density with [18F]-Flumazenil PET for the Study of Disease Progression in an Animal Model of Temporal Lobe Epilepsy 
PLoS ONE  2014;9(1):e86722.
Purpose
Imbalance of inhibitory GABAergic neurotransmission has been proposed to play a role in the pathogenesis of temporal lobe epilepsy (TLE). This study aimed to investigate whether [18F]-flumazenil ([18F]-FMZ) PET could be used to non-invasively characterise GABAA/central benzodiazepine receptor (GABAA/cBZR) density and affinity in vivo in the post-kainic acid status epilepticus (SE) model of TLE.
Methods
Dynamic [18F]-FMZ -PET scans using a multi-injection protocol were acquired in four male wistar rats for validation of the partial saturation model (PSM). SE was induced in eight male Wistar rats (10 weeks of age) by i.p. injection of kainic acid (7.5–25 mg/kg), while control rats (n = 7) received saline injections. Five weeks post-SE, an anatomic MRI scan was acquired and the following week an [18F]-FMZ PET scan (3.6–4.6 nmol). The PET data was co-registered to the MRI and regions of interest drawn on the MRI for selected structures. A PSM was used to derive receptor density and apparent affinity from the [18F]-FMZ PET data.
Key Findings
The PSM was found to adequately model [18F]-FMZ binding in vivo. There was a significant decrease in hippocampal receptor density in the SE group (p<0.01), accompanied by an increase in apparent affinity (p<0.05) compared to controls. No change in cortical receptor binding was observed. Hippocampal volume reduction and cell loss was only seen in a subset of animals. Histological assessment of hippocampal cell loss was significantly correlated with hippocampal volume measured by MRI (p<0.05), but did not correlate with [18F]-FMZ binding.
Significance
Alterations to hippocampal GABAA/cBZR density and affinity in the post-kainic acid SE model of TLE are detectable in vivo with [18F]-FMZ PET and a PSM. These changes are independent from hippocampal cell and volume loss. [18F]-FMZ PET is useful for investigating the role that changes GABAA/cBZR density and binding affinity play in the pathogenesis of TLE.
doi:10.1371/journal.pone.0086722
PMCID: PMC3897736  PMID: 24466212
13.  The clinical significance and management of lesion motion due to respiration during PET/CT scanning 
Cancer Imaging  2011;11(1):224-236.
Abstract
Lesion movement during positron emission tomography (PET) scan acquisition due to normal respiration is a common source of artefact. A PET scan is acquired in multiple couch positions of between 2 and 5 min duration with the patient breathing freely. A PET-avid lesion will become blurred if affected by respiratory motion, an effect similar to that created when a person moves in a photograph. This motion also frequently causes misregistration between the PET and computed tomography (CT) scan acquired for attenuation correction and anatomical correlation on hybrid scanners. The compounding effects of blurring and misregistration in whole-body PET/CT imaging make accurate characterization of PET-avid disease in areas of high respiratory motion challenging. There is also increasing interest in using PET quantitatively to assess disease response in both clinical reporting and trials. However, at this stage, no response criteria take the effect of respiratory motion into account when calculating the standardized uptake value on a PET scan. A number of different approaches have been described in the literature to address the issue of respiratory motion in PET/CT scanning. This review details the clinical significance of lesion movement due to respiration and discusses various imaging techniques that have been investigated to manage the effects of respiratory motion in PET/CT scanning.
doi:10.1102/1470-7330.2011.0031
PMCID: PMC3266588  PMID: 22201582
Respiratory-gated PET; 4D PET/CT; lesion motion; clinical significance
14.  Prognostic and Predictive Significance of Plasma HGF and IL8 in a Phase III trial of Chemoradiation with or without tirapazamine in locoregionally advanced head and neck cancer 
Clinical Cancer Research  2012;18(6):1798-1807.
Purpose
HGF is a hypoxia-induced secreted protein that binds to cMET and regulates IL8 expression. We evaluated the role of circulating HGF and IL8 as prognostic and predictive factors for efficacy of tirapazamine (TPZ), a hypoxic cell cytotoxin.
Experimental Design
Patients with Stage III–IV head and neck cancer were randomized to receive radiotherapy with cisplatin (CIS) or cisplatin plus TPZ (TPZ/CIS). Eligibility for the substudy included plasma sample availability for HGF and IL8 assay by ELISA and no major radiation deviations (N=498). Analyses included adjustment for major prognostic factors. p16INK4A staining (HPV surrogate) was performed on available tumors. 39 patients had hypoxia imaging with 18FAZA-PET.
Results
Elevated IL8 level was associated with worse overall survival (OS) irrespective of treatment. There was an interaction between HGF and treatment arm (p=0.053): elevated HGF was associated with worse OS in the control but not in the TPZ/CIS arm. Similar trends were observed in analyses restricted to p16INK4A negative patients. Four subgroups defined by high and low HGF/IL8 levels were examined for TPZ effect; the test for interaction with arm was p=0.099. TPZ/CIS appeared to be beneficial for patients with high HGF and IL8, but adverse for low HGF and high IL8. Only HGF correlated with 18FAZA tumor SUV.
Conclusions
IL8 is an independent prognostic factor irrespective of treatment. There is an interaction between HGF and treatment arm. Certain subgroups based on IL8/HGF levels appeared to do better with TPZ/CIS while others do worse; highlighting the complexity of hypoxia targeting in unselected patients.
doi:10.1158/1078-0432.CCR-11-2094
PMCID: PMC3306471  PMID: 22383739
Hypoxia; head and neck cancer; Hepatocyte Growth Factor; Interleukin-8; Plasma
15.  Should positron emission tomography/computed tomography be the first rather than the last test performed in the assessment of cancer? 
Cancer Imaging  2012;12(2):315-323.
Abstract
Cancer is a major cause of illness and death in Western society and is associated with a heavy concomitant economic burden. Although use of imaging comprises only a small proportion of the fiscal impact of cancer, its use has been increasing over recent decades, causing concern amongst funders of health care and efforts to constrain the use of new imaging tests with a relatively high unit cost. In clinical practice, positron emission tomography/computed tomography (PET/CT) is generally performed when less expensive tests have left some uncertainty regarding appropriate management. In this setting, its utility relates to provision of incremental diagnostic information. However, given that superior diagnostic information can positively affect patient management, wherein the majority of costs reside, it may be both more efficient and cost effective to go directly to the most accurate investigation in certain situations. For PET/CT, the ability to provide more accurate assessment of metastatic status than is available from conventional diagnostic paradigms provides a rationale for its independent rather than incremental use in patients presenting with either a high likelihood of malignancy or proven malignancy of a locally advanced nature and an accordingly high risk of metastatic disease. A randomized trial design is described that could be used to test this hypothesis.
doi:10.1102/1470-7330.2012.9005
PMCID: PMC3460557  PMID: 23022990
Randomized trial; positron emission tomography/computed tomography; oncology; cost-effectiveness
16.  The motivations and methodology for high-throughput PET imaging of small animals in cancer research 
Over the last decade, small-animal PET imaging has become a vital platform technology in cancer research. With the development of molecularly targeted therapies and drug combinations requiring evaluation of different schedules, the number of animals to be imaged within a PET experiment has increased. This paper describes experimental design requirements to reach statistical significance, based on the expected change in tracer uptake in treated animals as compared to the control group, the number of groups that will be imaged, and the expected intra-animal variability for a given tracer. We also review how high-throughput studies can be performed in dedicated small-animal PET, high-resolution clinical PET systems and planar positron imaging systems by imaging more than one animal simultaneously. Customized beds designed to image more than one animal in large-bore small-animal PET scanners are described. Physics issues related to the presence of several rodents within the field of view (i.e. deterioration of spatial resolution and sensitivity as the radial and the axial offsets increase, respectively, as well as a larger effect of attenuation and the number of scatter events), which can be assessed by using the NEMA NU 4 image quality phantom, are detailed.
doi:10.1007/s00259-012-2177-x
PMCID: PMC3411308  PMID: 22790877
High throughput; Sample size; Clinical PET/CT; Small-animal PET; Planar positron imaging systems; NEMA NU 4; Animal models
17.  Pharmacodynamic analysis of tumour perfusion assessed by 15O-water-PET imaging during treatment with sunitinib malate in patients with advanced malignancies 
EJNMMI Research  2012;2:31.
Background
We evaluated pharmacodynamic changes in tumour perfusion using positron emission tomography (PET) imaging with 15O-water to assess biological response to sunitinib, a multitargeted tyrosine kinase inhibitor.
Methods
Patients with advanced malignancies received sunitinib 50 mg/day orally, once daily for 4 weeks on treatment, followed by 2 weeks off treatment, in repeated 6-week cycles. Quantitative measurement of tumour perfusion was assessed using 15O-water-PET at baseline and after 2 weeks of treatment. At least one reference tumour lesion was included in the fields of view and assessed at both time points. Patients also underwent 18 F-fluorodeoxyglucose (FDG)-PET imaging at baseline and after 2 and 4 weeks of treatment. Radiological response of the reference tumour lesion and overall radiological response were assessed at week 12. Serum pharmacokinetic and biomarker analyses were also performed.
Results
Data were available for seven patients. Compared with baseline, all patients experienced a decrease in reference tumour blood flow ranging from 20 % to 85 % and also a reduction in the FDG standard uptake value ranging from 29 % to 67 %. Six patients experienced a partial metabolic response based on FDG-PET criteria. Four patients had stable disease defined by radiological response (Response Evaluation Criteria in Solid Tumors) lasting between 4 and 12 cycles. An association between perfusion change and clinical benefit, and biomarker levels including vascular endothelial growth factor was observed.
Conclusion
Administering sunitinib to patients with advanced malignancies is associated with early biological responses, including decreased blood flow in secondary tumour deposits.
doi:10.1186/2191-219X-2-31
PMCID: PMC3468361  PMID: 22682364
sunitinib; tumour perfusion; FDG-PET.
18.  An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice  
Mutations in the gene encoding the p110α subunit of PI3K (PIK3CA) that result in enhanced PI3K activity are frequently observed in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis, we generated mice in which a PIK3CA mutation commonly detected in human cancers (the H1047R mutation) could be conditionally knocked into the endogenous Pik3ca locus. Activation of this mutation in the mouse ovary revealed that alone, Pik3caH1047R induced premalignant hyperplasia of the ovarian surface epithelium but no tumors. Concomitantly, we analyzed several human ovarian cancers and found PIK3CA mutations coexistent with KRAS and/or PTEN mutations, raising the possibility that a secondary defect in a co-regulator of PI3K activity may be required for mutant PIK3CA to promote transformation. Consistent with this notion, we found that Pik3caH1047R mutation plus Pten deletion in the mouse ovary led to the development of ovarian serous adenocarcinomas and granulosa cell tumors. Both mutational events were required for early, robust Akt activation. Pharmacological inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. These results demonstrate that the Pik3caH1047R mutation with loss of Pten is enough to promote ovarian cell transformation and that we have developed a model system for studying possible therapies.
doi:10.1172/JCI59309
PMCID: PMC3266789  PMID: 22214849
19.  Quantitative 177Lu SPECT (QSPECT) imaging using a commercially available SPECT/CT system 
Cancer Imaging  2011;11(1):56-66.
Abstract
Purpose: The combination of single photon emission computed tomography (SPECT) and computer tomography (CT) that incorporates iterative reconstruction algorithms with attenuation and scatter correction should facilitate accurate non-invasive quantitative imaging. Quantitative SPECT (QSPECT) may improve diagnostic ability and could be useful for many applications including dosimetry assessment. Using 177Lu, we developed a QSPECT method using a commercially available SPECT/CT system. Methods: Serial SPECT of 177Lu sources (89–12,400 MBq) were acquired with multiple contiguous energy windows along with a co-registered CT, and were reconstructed using an iterative algorithm with attenuation and scatter correction. Camera sensitivity (based on reconstructed SPECT count rate) and dead-time (based on wide-energy spectrum count rate) were resolved by non-linear curve fit. Utilizing these parameters, a SPECT dataset can be converted to a QSPECT dataset allowing quantitation in Becquerels per cubic centimetre or standardized uptake value (SUV). Validation QSPECT/CT studies were performed on a 177Lu cylindrical phantom (7 studies) and on 5 patients (6 studies) who were administered a therapeutic dose of [177Lu]octreotate. Results: The QSPECT sensitivity was 1.08 × 10−5 ± 0.02 × 10−5 s−1 Bq−1. The paralyzing dead-time constant was 0.78 ± 0.03 µs. The measured total activity with QSPECT deviated from the calibrated activity by 5.6 ± 1.9% and 2.6 ± 1.8%, respectively, in phantom and patients. Dead-time count loss up to 11.7% was observed in patient studies. Conclusion: QSPECT has high accuracy both in our phantom model and in clinical practice following [177Lu]octreotate therapy. This has the potential to yield more accurate dosimetry estimates than planar imaging and facilitate therapeutic response assessment. Validating this method with other radionuclides could open the way for many other research and clinical applications.
doi:10.1102/1470-7330.2011.0012
PMCID: PMC3205754  PMID: 21684829
Quantitation; SPECT/CT; dead-time; dosimetry; lutetium-177
20.  White fat, factitious hyperglycemia, and the role of FDG PET to enhance understanding of adipocyte metabolism 
EJNMMI Research  2011;1:2.
The development of a hybrid PET/CT led to the recognition of the enhanced glycolysis in brown fat. We report a previously unrecognized mechanism for altered fluorodeoxyglucose (FDG) biodistribution with diffuse white adipose tissue uptake. This occurred during a restaging scan for cervical cancer following administration of insulin in the setting of measured hyperglycemia. The patient's blood sugar normalized, but she experienced symptoms and signs of hypoglycemia. A subsequent history indicated that the patient received intravenous high-dose vitamin C just prior to arrival. Ascorbic acid is a strong reducing agent and can cause erroneous false positive portable glucometer readings. Accordingly, it is likely the patient was euglycemic on arrival and was administered FDG during a period of insulin-induced hypoglycemia. Prominent diffuse white adipose tissue, gastric mucosal, myocardial, and very low hepatic and muscle activity were observed. The case provides insight into the metabolic changes that occur during hypoglycemia and the potential danger of relying on portable glucometer readings. We discuss the potential biological basis of this finding and provide recommendations on the avoidance of this complication.
doi:10.1186/2191-219X-1-2
PMCID: PMC3192468  PMID: 22214514
21.  Orally disintegrating vardenafil tablets for the treatment of erectile dysfunction: efficacy, safety, and patient acceptability 
Background:
Erectile dysfunction (ED) is a well-documented medical condition that is expected to increase significantly over the next several decades, especially as men live longer and the prevalence of diabetes and cardiovascular diseases increase. Pharmacology agents are often the first line treatment approach. Newer solid dosage forms, known as orally disintegrating tablets (ODT), are now available as one treatment option.
Objectives:
To review the drug delivery mechanisms of ODTs in general and to review safety and efficacy of vardenafil ODT (a PDE-5 inhibitor) as a treatment option for management of ED.
Method:
Literature reviews were performed of pharmaceutical dosage forms and the POTENT I (n = 358 subjects) and POTENT II (n = 337 subjects) studies that investigated vardenafil ODT.
Results:
Vardenafil ODT has been successfully used in multiple age groups and in multiple settings with men from various ethnic backgrounds. Efficacy of vardenafil ODT, as measured using the International Index of Erectile Function (IIEF-EF) and from the Sexual Encounter Profile (SEP) was significantly greater than placebo (P < 0.0001) at 12 weeks. Safety profiles were similar to film-coated dosage forms with no patient deaths reported.
Conclusion:
Vardenafil ODT offers a convenient, ready-to-use approach for combating ED. Safety concerns are similar to other PDE-5 inhibitors and practitioners should counsel patients accordingly.
doi:10.2147/PPA.S14030
PMCID: PMC3090379  PMID: 21573049
orally disintegrating tablets; vardenafil; erectile dysfunction
23.  Overview of early response assessment in lymphoma with FDG-PET 
Cancer Imaging  2007;7(1):10-18.
Early assessment of response to chemotherapy with fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) is becoming a routine part of management in patients with Hodgkin lymphoma (HL) and histologically aggressive non-Hodgkin lymphoma (NHL). Changes in FDG uptake can occur soon after the initiation of therapy and they precede changes in tumour volume. Recent studies in uniform populations of aggressive lymphomas (predominantly diffuse large B cell lymphomas) and HL have clarified the value of early response assessment with PET. These trials show that PET imaging after 2–3 chemotherapy cycles is far superior to CT-based imaging in predicting progression-free survival and can be at least as reliable as definitive response assessment at the end of therapy. This information is of great potential value to patients, but oncologists should be cautious in the use of early PET response in determining choice of therapy until some critical questions are answered. These include: When is the best time to use PET for response assessment? What is the best methodology, visual or quantitative? (For HL at least, visual reading appears superior to an SUV-based assessment). Can early responders be cured with less intensive therapy? Will survival be better for patients treated more intensively because they have a poor interim metabolic response? In the future, early PET will be crucial in developing response-adapted therapy but without further carefully designed clinical trials, oncologists will remain uncertain how best to use this new information.
doi:10.1102/1470-7330.2007.0004
PMCID: PMC1974859  PMID: 17766210
Positron emission tomography; Hodgkin lymphoma; non-Hodgkin lymphoma; prognosis, chemotherapy, radiotherapy
24.  PET/CT: will it change the way that we use CT in cancer imaging? 
Cancer Imaging  2006;6(Spec No A):S52-S62.
Accurate staging of cancer is of fundamental importance to treatment selection and planning. Current staging paradigms focus, first, on a detailed delineation of the primary tumour in order to determine its suitability for resection, and, thereafter, on assessment of the presence of metastatic spread that would alter the surgical approach, or mandate non-surgical therapies. This approach has, at its core, the assumption that the best, and sometimes the only, way to cure a patient of cancer is by surgical resection. Unfortunately, all non-invasive techniques in current use have imperfect ability to identify those primary tumours that are able to be completely excised, and even worse ability to define the extent of metastatic spread. Nevertheless, because of relatively low cost and widespread availability, computed tomography (CT) scanning is the preferred methodology for tumour, nodal and systemic metastasis (TNM) staging. This is often supplemented by other tests that have improved performance in particular staging domains. For example, magnetic resonance imaging (MRI), mammography, or endoscopic ultrasound may be used as complementary tests for T-staging; surgical nodal sampling for N-staging; and bone scanning, MRI or ultrasound for M-staging. Accordingly, many patients undergo a battery of investigations but, even then, are found to have been incorrectly staged based on subsequent outcomes. Even for those staged surgically, pathology can only identify metastases within the resection specimens and has no capability for detecting remote disease. As a result of this, many patients undergo futile operations for disease that could never have been cured by surgery. In the case of restaging, the situation is even worse. The sequelae of prior treatment can be difficult to differentiate from residual cancer and the likelihood of successful salvage therapy is even less than at presentation. More deleteriously, patients may be subjected to additional morbid treatments when cure has already been achieved. Thus, in post-treatment follow-up, the presence and extent of disease is equally critical to treatment selection and patient outcome as it is in primary staging. One of the major strengths of positron emission tomography (PET)/CT as a cancer staging modality is its ability to identify systemic metastases. At any phase of cancer evaluation, demonstration of systemic metastasis has profound therapeutic and prognostic implications. Only in the absence of systemic metastasis does nodal status become important, and only when unresectable nodal metastasis has been excluded does T-stage become important. There are now accumulating data that PET/CT could be used as the first, rather than the last test to assess M- and N-stage for evaluating cancers with an intermediate to high pre-test likelihood of metastatic disease based on poor long-term survival. In this scenario, there is great opportunity for subsequently selecting and tailoring the performance of anatomically based imaging modalities to define the structural relations of abnormalities identified by PET, when this information would be of relevance to management planning. Primary staging of oesophageal cancer and restaging of colorectal cancer are illustrative examples of a new paradigm for cancer imaging.
doi:10.1102/1470-7330.2006.9012
PMCID: PMC1805068  PMID: 17114079
Correlative imaging; hybrid imaging; staging; fluorodeoxyglucose (FDG); restaging
25.  PET tracer development—a tale of mice and men 
Cancer Imaging  2006;6(Spec No A):S102-S106.
PET scanning is an emerging technology for the clinical evaluation of many disease processes in man. The vast majority of clinical positron emission tomography (PET) studies are performed using a single tracer, fluorodeoxyglucose. Despite the excellent diagnostic performance of this tracer, it has recognised limitations. New tracers offer the potential to both address these limitations, and to establish new applications for PET. Small animal PET is a logical technique for validating new tracers relevant to human diseases. However, interspecies differences in the handling of chemicals may significantly influence the handling of novel tracers. This requires caution in extrapolating findings in animals to expectations of performance in man. Already there are several examples where biodistribution studies in mice would not have predicted the clinical utility of existing PET tracers. Nevertheless, application of a systematic approach to tracer development is likely to speed transition of new tracers from animals into man.
doi:10.1102/1470-7330.2006.9098
PMCID: PMC1805077  PMID: 17114061
PET; tracer development; fluorine-18; choline; proliferation; fluoro-ethyl-tyrosine; fluorocholine; 3 ′-deoxy-3 ′-fluorothymidine

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