Cognitive Dysfunction in Patients Treated with Androgen Deprivation Therapy: A Multimodality Functional Imaging Study to Evaluate Neuroinflammation.

Background: Androgen deprivation therapy (ADT) for prostate cancer is implicated as a possible cause of cognitive impairment (CI). CI in dementia and Alzheimer's disease is associated with neuroinflammation. In this study, we investigated a potential role of neuroinflammation in ADT-related CI. Methods: Patients with prostate cancer on ADT for ≥3 months were categorized as having ADT-emergent CI or normal cognition (NC) based on self-report at interview. Neuroinflammation was evaluated using positron emission tomography (PET) with the translocator protein (TSPO) radioligand [11C]-PBR28. [11C]-PBR28 uptake in various brain regions was quantified as standardized uptake value (SUVR, normalized to cerebellum) and related to blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) choice-reaction time task (CRT) activation maps. Results: Eleven patients underwent PET: four with reported CI (rCI), six with reported NC (rNC), and one status unrecorded. PET did not reveal any between-group differences in SUVR regionally or globally. There was no difference between groups on brain activation to the CRT. Regardless of the reported cognitive status, there was strong correlation between PET-TSPO signal and CRT activation in the hippocampus, amygdala, and medial cortex. Conclusions: We found no difference in neuroinflammation measured by PET-TSPO between patients with rCI and rNC. However, we speculate that the strong correlation between TSPO uptake and BOLD-fMRI activation in brain regions involved in memory and known to have high androgen-receptor expression mediating plasticity (hippocampus and amygdala) might reflect inflammatory effects of ADT with compensatory upregulated/increased synaptic functions. Further studies of this imaging readout are warranted to investigate ADT-related CI.

Total-Body PET Imaging in Infectious Diseases.

Total-body PET enables high-sensitivity imaging with dramatically improved signal-to-noise ratio. These enhanced performance characteristics allow for decreased PET scanning times acquiring data "total-body wide" and can be leveraged to decrease the amount of radiotracer required, thereby permitting more frequent imaging or longer imaging periods during radiotracer decay. Novel approaches to PET imaging of infectious diseases are emerging, including those that directly visualize pathogens in vivo and characterize concomitant immune responses and inflammation. Efforts to develop these imaging approaches are hampered by challenges of traditional imaging platforms, which may be overcome by novel total-body PET strategies.

Total-Body Quantitative Parametric Imaging of Early Kinetics of 18F-FDG.

Parametric imaging has been shown to provide better quantitation physiologically than SUV imaging in PET. With the increased sensitivity from a recently developed total-body PET scanner, whole-body scans with higher temporal resolution become possible for dynamic analysis and parametric imaging. In this paper, we focus on deriving the parameter k1 using compartmental modeling and on developing a method to acquire whole-body 18F-FDG PET parametric images using only the first 90 s of the postinjection scan data with the total-body PET system. Methods: Dynamic projections were acquired with a time interval of 1 s for the first 30 s and a time interval of 2 s for the following minute. Image-derived input functions were acquired from the reconstructed dynamic sequences in the ascending aorta. A 1-tissue-compartment model with 4 parameters (k1, k2, blood fraction, and delay time) was used. A maximum-likelihood-based estimation method was developed with the 1-tissue-compartment model solution. The accuracy of the acquired parameters was compared with the ones estimated using a 2-tissue-compartment irreversible model with 1-h-long data. Results: All 4 parametric images were successfully calculated using data from 2 volunteers. By comparing the time-activity curves acquired from the volumes of interest, we showed that the parameters estimated using our method were able to predict the time-activity curves of the early dynamics of 18F-FDG in different organs. The delay-time effects for different organs were also clearly visible in the reconstructed delay-time image with delay variations of as large as 40 s. The estimated parameters using both 90-s data and 1-h data agreed well for k1 and blood fraction, whereas a large difference in k2 was found between the 90-s and 1-h data, suggesting k2 cannot be reliably estimated from the 90-s scan. Conclusion: We have shown that with total-body PET and the increased sensitivity, it is possible to estimate parametric images based on the very early dynamics after 18F-FDG injection. The estimated k1 might potentially be used clinically as an indicator for identifying abnormalities.

Optimization of the injected activity in dynamic 3D PET: a generalized approach using patient-specific NECs as demonstrated by a series of 15O-H2O scans.

UNLABELLED: The magnitude of the injected activity (A(0)) has a direct impact on the statistical quality of PET images. This study aimed to develop a generalized method for maximizing the statistical quality of dynamic PET images by optimizing A(0). METHODS: Patient-specific noise-equivalent counts (PS-NECs) were used as a metric of the statistical quality of each time frame of a dynamic PET image. Previous methodology developed to extrapolate the NEC as a function of A(0) was extended to dynamic PET, enabling the NEC to be extrapolated as a function of both A(0) and the time after injection. This method allowed A(0) to be optimized after a single scan (at a single A(0)), by maximizing the NEC within the time interval for which the parameter estimation is most sensitive. The extrapolation method was validated by a series of (15)O-H(2)O scans of the body acquired in 3-dimensional mode. Each patient (n = 6) underwent between 3 and 6 scans at 1 bed position. The injected activities were varied over a wide range (140-840 MBq). Noise-equivalent counting rate (NECR) versus A(0) curves and the optimal injected activities were calculated from each injection. RESULTS: PS-NECR versus A(0) curves as extrapolated from different injected activities were consistent (coefficient of variation, typically <5%). The optimal injected activities for an individual, as derived from these curves, were also consistent (maximum coefficient of variation, 4.3%). For abdominal (n = 4) and chest (n = 1) scans, we found optimal injected activities of (15)O-H(2)O in the range of 220-350 MBq for estimating blood perfusion (F) and 660-1,070 MBq for estimating the volume of distribution (V(T)). Higher optimal injected activities were found in the case of a pelvic scan (n = 1; 570 MBq for F and 1,530 MBq for V(T)). CONCLUSION: PS-NECs are a valid and generic method for optimizing the injected activity in PET, allowing scanning protocols to be improved after the collection of an initial, single dynamic dataset. This generic method can be used to estimate the optimal injected activity, which is specific to the patient, tracer, PET scanner, and body region being scanned.

First Human Imaging Studies with the EXPLORER Total-Body PET Scanner.

Within the EXPLORER Consortium, the construction of the world's first total-body PET/CT scanner has recently been completed. The 194-cm axial field of view of the EXPLORER PET/CT scanner is sufficient to cover, for the first time, the entire human adult body in a single acquisition in more than 99% of the population and allows total-body pharmacokinetic studies with frame durations as short as 1 s. The large increase in sensitivity arising from total-body coverage as well as increased solid angle for detection at any point within the body allows whole-body 18F-FDG PET studies to be acquired with unprecedented count density, improving the signal-to-noise ratio of the resulting images. Alternatively, the sensitivity gain can be used to acquire diagnostic PET images with very small amounts of activity in the field of view (25 MBq, 0.7 mCi or less), with very short acquisition times (∼1 min or less) or at later time points after the tracer's administration. We report here on the first human imaging studies on the EXPLORER scanner using a range of different protocols that provide initial evidence in support of these claims. These case studies provide the foundation for future carefully controlled trials to quantitatively evaluate the improvements possible through total-body PET imaging.

Evaluation of CyberKnife® Fiducial Tracking Limitations to Assist Targeting Accuracy: A Phantom Study with Fiducial Displacement.

Introduction  The underlying assumptions of the CyberKnife® (Accuray, Sunnyvale, CA, US) fiducial tracking system are: i) fiducial positions are accurately detected; ii) inter-fiducial geometry remains consistent (rigid); iii) inter-fiducial geometric array changes are detected and either accommodated with corrections or treatment is interrupted. However: i) soft-tissue targets are deformable & fiducial migration is possible; ii) the accuracy of the tracking system has not previously been examined with fiducial displacement; iii) treatment interruptions may occur due to inter-fiducial geometric changes, but there is little information available to assist subsequent troubleshooting. The purpose of this study was to emulate a clinical target defined with a two, three, or four-fiducial array where one fiducial is displaced to mimic a target deformation or fiducial migration scenario. The objectives: evaluate the fiducial positioning accuracy, array interpretation, & corresponding corrections of the CyberKnife system, with the aim of assisting troubleshooting following fiducial displacement. Methods A novel solid-water phantom was constructed with three fixed fiducials (F1,F2,F3) & one moveable fiducial (F4), arranged as if placed to track an imaginary clinical target. Using either two fiducials (F1,F4), different combinations of three fiducials (F1,F2,F4; F1,F3,F4; F2,F3,F4) or four fiducials (F1,F2,F3,F4), repeat experiments were conducted where F4 was displaced inferiorly at 2-mm intervals from 0-16 mm. Data were acquired at each position of F4, including rigid body errors (RBE), fiducial x, y, & z coordinate displacements, six degrees of freedom (DOF) corrections, & robot center-of-mass (COM) translation corrections. Results Maximum positioning difference (mean±SD) between the reference and live x, y, & z coordinates for the three fixed fiducials was 0.08±0.30 mm, confirming good accuracy for fixed fiducial registration. For two fiducials (F1,F4), F4 registration was accurate to 14-mm displacement and the F4 x-axis coordinate change was 2.0±0.12 mm with each 2 mm inferior displacement validating the phantom for tracking evaluation. RBE was >5 mm (system threshold) at 6-14 mm F4 displacement: however, F1 was misidentified as the RBE main contributor. Further, F1/F4 false-lock occurred at 16 mm F4 displacement with corresponding RBE <3 mm & COM corrections >13 mm. For combinations of three fiducials, F4 registration was accurate to 10-mm displacement. RBE was >5 mm at 6-16 mm F4 displacement: however, F4 false-lock occurred at 12-16 mm with RBE 5-6 mm. For four fiducials, F4 registration was accurate to 4 mm displacement: however, F4 false-lock occurred at 6-16 mm displacement with concerning RBE <2 & <5 at 6 & 8-mm F4 displacement, respectively. False-locks were easily identified in the phantom but frequently uncorrectable. Conclusions Results indicate fiducial positioning accuracy and system output following fiducial displacement depends on the number of fiducials correlated, displacement distance, and clinical thresholds applied. Displacements ≤4 mm were accurately located, but some displacements 6-16 mm were misrepresented, either by erroneous main contributor (two-fiducial array only) or by false-locks and misleading RBE, which underestimated displacement. Operator vigilance and implementation of our practical guidelines based on the study findings may help reduce targeting error and assist troubleshooting in clinical situations.

Stereotactic ablative radiotherapy (SABR) as primary, adjuvant, consolidation and re-treatment option in pancreatic cancer: scope for dose escalation and lessons for toxicity.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) offers an alternative treatment for pancreatic cancer, with the potential for improved tumour control and reduced toxicity compared with conventional therapies. However, optimal dose planning and delivery strategies are unelucidated and gastro-intestinal (GI) toxicity remains a key concern. METHODS: Patients with inoperable non-metastatic pancreatic cancer who received CyberKnife® SABR (18-36 Gy) in three fractions as primary, adjuvant, consolidation or re-treatment options were studied. Patient individualised planning and delivery variables were collected and their impact on patient outcome examined. Linear-quadratic (LQ) radiobiology modelling methods were applied to assess SABR parameters against a conventional fractionated radiotherapy schedule. RESULTS: In total 42 patients were included, 37 (88%) of whom had stage T4 disease. SABR was used > 6 months post-primary therapy to re-treat residual disease in 11 (26.2%) patients and relapsed disease in nine (21.4%) patients. SABR was an adjuvant to other primary therapy for 14 (33.3%) patients and was the sole primary therapy for eight (19.0%) patients. The mean (95% CI) planning target volume (PTV), prescription isodose, percentage cover, minimum dose to PTV and biological effective dose (BED) were 76.3(63.8-88.7) cc, 67.3(65.2-69.5)%, 96.6(95.5-97.7)%, 22.3(21.0-23.6) Gy and 50.3(47.7-53.0) Gy, respectively. Only 3/37 (8.1%) patients experienced Grade 3 acute toxicities. Two (4.8%) patients converted to resectable status and median freedom-from-local-progression (FFLP) and overall survival (OS) were 9.8 and 8.4 months, respectively. No late toxicity was experienced in 27/32 (84.4%) patients; however, four (12.5%) patients - of whom two had particularly large PTV, two had sub-optimal number of fiducials and three breached organ-at-risk (OAR) constraints-showed Grade 4 duodenal toxicities. Longer delivery time, extended treatment course and reduced percentage coverage additionally associated with late toxicity, likely reflecting parameters typically applied to riskier patients. Larger PTV size and longer treatment course associated with OS. Comparator regimen LQ modelling analysis indicated 50% of patients received minimum PTV doses less potent than a conventional radiotherapy regimen, indicating scope for dose escalation. CONCLUSION: The results demonstrate the value of SABR for a range of indications in pancreatic cancer. Dose escalation to increase BED may improve FFLP and OS in inoperable, non-metastatic disease: however concomitant enhanced stringency for duodenal protection is critical, particularly for patients where SABR is more challenging.

CyberKnife Radiosurgery of Skull-base Tumors: A UK Center Experience.

The study aim was to evaluate patient individualized Cyberknife® treatment for heterogeneous skull-base tumors. Patients treated between 2009 and 2013 at The Harley Street Clinic were studied. In total, 66 patients received 15-30 Gy in 1-5 fractions to a median planning target volume (PTV) of 6.4 cc, including patients with secondary, multiple, residual and recurrent tumors, and those with tumors of uncertain pathological type. Outcome analysis was pragmatically restricted to 35 patients who had single, primary tumors treated with curative intent, and sufficient diagnostic and outcome information. Sixteen vestibular schwannoma patients with median PTV 3.8 cc (range 0.81-19.6) received 18-25 Gy in 3-5 fractions: 81% showed no acute toxicity, 50% reported no late toxicity, 71% of symptoms were stable/improved and local control was 100% at 11.4 months median follow-up. Twelve meningioma patients with median PTV of 5.5 cc (range 0.68-22.3) received 17-30 Gy in 1-5 fractions: 83% experienced no acute toxicity, 33% reported no late toxicity, 88% of symptoms were stable/improved and local control was 100% at 22.1 months median follow-up. Seven patients with other tumor types with median PTV of 24.3 cc (range 7.6-100.5) received 15-28.5 Gy in 1-5 fractions: 57% experienced no acute toxicity, 57% reported no late toxicities, 66% of symptoms were stable and local control was 43% at 14.9 months median follow-up. When tumor types were considered together, smaller tumors (PTV < 6.4 cc) showed reduced acute toxicity (p = 0.01). Overall, smaller benign tumors showed low acute toxicity, excellent local control, and good symptom management: a focus on enhanced neurological preservation may refine outcomes. For other tumor types outcome was encouraging: a focus on optimal dose and fractionation scheduling may reduce toxicity and improve local control. Individual patient experiences are detailed where valuable lessons were gained for optimizing local control and minimizing toxicity.

Carbogen and nicotinamide increase blood flow and 5-fluorouracil delivery but not 5-fluorouracil retention in colorectal cancer metastases in patients.

PURPOSE: To examine whether carbogen and nicotinamide increases 5-fluorouracil (5-FU) delivery to colorectal cancer metastases. EXPERIMENTAL DESIGN: Six patients were scanned using positron emission tomography. Two scans were done to coincide with the start of separate chemotherapy cycles. At the second positron emission tomography session, 60 mg/kg nicotinamide was given orally 2 to 3 hours before 10-minute carbogen inhalation. In the middle of carbogen treatment, [15O]H2O (to measure regional tissue perfusion) and then [18F]5-FU (to measure 5-FU tissue pharmacokinetics) were administered. RESULTS: Regions of interest were drawn in 12 liver metastases, 6 spleens, 6 livers, and 12 kidneys. Nicotinamide and carbogen administration increased mean blood pO2 from 93 mm Hg (95% confidence interval, 79-198) to 278 mm Hg (95% confidence interval, 241-316; P = 0.031). Regional perfusion (mL(blood)/min/mL(tissue)) increased in metastases (mean change = 52%, range -32% to +261%, P = 0.024), but decreased in kidney (mean change = -42%, range -82% to -11%, P = 0.0005) and liver (mean change = -34%, range -43% to -26%, P = 0.031). 5-FU uptake at 3.75 minutes (m(2)/mL) increased in tumor (mean change = 40%, range -39% to +196%, P = 0.06) and decreased in kidney (mean change = -25%, range -71% to 12%, P = 0.043). 5-FU delivery measured as K1 increased in tumor (mean change = 74%, range -23% to +293%, P = 0.0039). No differences were seen in [18F]5-FU tumor exposure (net area under curve) and retention. CONCLUSION: Nicotinamide and carbogen administration can increase 5-FU delivery to colorectal cancer liver metastases. Despite an increase in perfusion and 5-FU delivery, the effects were not directly related and did not increase 5-FU retention or tissue exposure.

An effective deep-inspiration breath-hold radiotherapy technique for left-breast cancer: impact of post-mastectomy treatment, nodal coverage, and dose schedule on organs at risk.

BACKGROUND: We developed, applied, and prospectively evaluated a novel deep-inspiration breath-hold (DIBH) screening and delivery technique to optimize cardiac sparing in left-breast radiotherapy (RT) at our clinic. The impact of set-up and dose variables upon organs at risk (OAR) dose in DIBH RT was investigated. METHODS AND MATERIALS: All patients with left-breast cancer referred between 2011 and 2014 - of all disease stages, set-up variations, and dose prescriptions - were included. Radiographers used simple screening criteria at CT simulation, to systematically assess patients for obvious DIBH benefit and capability. Selected patients received forward-planned intensity-modulated RT (IMRT) based on a DIBH CT scan. A 3D-surface monitoring system with visual feedback assured reproducible DIBH positioning during gated radiation delivery. Patient, target set-up, and OAR dose information were collected at treatment. RESULTS: Of 272 patients who were screened, 4 withdrew, 56 showed no obvious advantage, and 56 showed benefit but had suitability issues; 156 patients were selected and successfully completed DIBH treatment. The technique was compatible with complex set-up and optimal target coverage was maintained. Comparison of free-breathing (FB) and DIBH treatment plans in the first five patients enrolled confirmed DIBH reduced heart radiation by ~80% (p = 0.032). Low OAR doses were achieved overall: the mean (95% confidence interval [CI]) heart dose was 1.17 (1.12-1.22) Gy, and the mean ipsilateral lung dose was 5.26 (5.01-5.52) Gy. Patients who underwent a standard radiation schedule (40 Gy/15#) after breast-conserving surgery had the lowest OAR doses: post-mastectomy treatment, simultaneous supraclavicular (SCV) node coverage, and alternative dose schedule (50 Gy/25#) were interrelated variables associated with increased OAR risk and compromised ipsilateral lung dose constraints. CONCLUSION: The DIBH technique was successfully implemented and resulted in optimally low heart radiation. All patients who demonstrate sufficient DIBH technique at planning CT are now offered DIBH RT at our clinic. Patients with more advanced disease, particularly those with additional pulmonary risk factors, warrant additional focus to improve lung sparing.

Imaging vascular physiology to monitor cancer treatment.

The primary physiological function of the vasculature is to support perfusion, the nutritive flow of blood through the tissues. Vascular physiology can be studied non-invasively in human subjects using imaging methods such as positron emission tomography (PET), magnetic resonance imaging (MRI), X-ray computed tomography (CT), and Doppler ultrasound (DU). We describe the physiological rationale for imaging vascular physiology with these methods. We review the published data on repeatability. We review the literature on 'before-and-after' studies using these methods to monitor response to treatment in human subjects, in five broad clinical settings: (1) antiangiogenic agents, (2) vascular disruptive agents, (3) conventional cytotoxic drugs, (4) radiation treatment, and (5) agents affecting drug delivery. We argue that imaging of vascular physiology offers an attractive 'functional endpoint' for clinical trials of anticancer treatment. More conventional measures of tumour response, such as size criteria and the uptake of fluorodeoxyglucose, may be insensitive to therapeutically important changes in vascular function.

Assessment of pharmacodynamic vascular response in a phase I trial of combretastatin A4 phosphate.

PURPOSE: Clinical evaluation of novel agents that target tumor blood vessels requires pharmacodynamic end points that measure vascular damage. Positron emission tomography (PET) was used to measure the effects of the vascular targeting agent combretastatin A4 phosphate (CA4P) on tumor and normal tissue perfusion and blood volume. PATIENTS AND METHODS: Patients with advanced solid tumors were enrolled onto part of a phase I, accelerated-titration, dose-escalation study. The effects of 5 to 114 mg/m2 CA4P on tumor, spleen, and kidney were investigated. Tissue perfusion was measured using oxygen-15 (15O)-labeled water and blood volume was measured using 15O-labeled carbon monoxide (C15O). Scans were performed immediately before, and 30 minutes and 24 hours after the first infusion of each dose level of CA4P. All statistical tests were two sided. RESULTS: PET data were obtained for 13 patients with intrapatient dose escalation. Significant dose-dependent reductions were seen in tumor perfusion 30 minutes after CA4P administration (mean change, -49% at >or= 52 mg/m2; P =.0010). Significant reductions were also seen in tumor blood volume (mean change, -15% at >or= 52 mg/m2; P =.0070). Although by 24 hours there was tumor vascular recovery, for doses >or= 52 mg/m2 the reduction in perfusion remained significant (P =.013). Thirty minutes after CA4P administration borderline significant changes were seen in spleen perfusion (mean change, -35%; P =.018), spleen blood volume (mean change, -18%; P =.022), kidney perfusion (mean change, -6%; P =.026), and kidney blood volume (mean change, -6%; P =.014). No significant changes were seen at 24 hours in spleen or kidney. CONCLUSION: CA4P produces rapid changes in the vasculature of human tumors that can be assessed using PET measurements of tumor perfusion.

Phase I clinical trial of weekly combretastatin A4 phosphate: clinical and pharmacokinetic results.

PURPOSE: A phase I trial was performed with combretastatin A4 phosphate (CA4P), a novel tubulin-binding agent that has been shown to rapidly reduce blood flow in animal tumors. PATIENTS AND METHODS: The drug was delivered by a 10-minute weekly infusion for 3 weeks followed by a week gap, with intrapatient dose escalation. Dose escalation was accomplished by doubling until grade 2 toxicity was seen. The starting dose was 5 mg/m2. RESULTS: Thirty-four patients received 167 infusions. CA4P was rapidly converted to the active combretastatin A4 (CA4), which was further metabolized to the glucuronide. CA4 area under the curve (AUC) increased from 0.169 at 5 mg/m2 to 3.29 micromol * h/L at 114 mg/m2. The mean CA4 AUC in eight patients at 68 mg/m2 was 2.33 micromol * h/L compared with 5.8 micromol * h/L at 25 mg/kg (the lowest effective dose) in the mouse. The only toxicity that possibly was related to the drug dose up to 40 mg/m2 was tumor pain. Dose-limiting toxicity was reversible ataxia at 114 mg/m2, vasovagal syncope and motor neuropathy at 88 mg/m2, and fatal ischemia in previously irradiated bowel at 52 mg/m2. Other drug-related grade 2 or higher toxicities seen in more than one patient were pain, lymphopenia, fatigue, anemia, diarrhea, hypertension, hypotension, vomiting, visual disturbance, and dyspnea. One patient at 68 mg/m2 had improvement in liver metastases of adrenocortical carcinoma. CONCLUSION: CA4P was well tolerated in 14 of 16 patients at 52 or 68 mg/m2; these are doses at which tumor blood flow reduction has been recorded.

Hypoxia-inducible factor 1alpha expression as an intrinsic marker of hypoxia: correlation with tumor oxygen, pimonidazole measurements, and outcome in locally advanced carcinoma of the cervix.

PURPOSE: Hypoxia-inducible factor (HIF)-1alpha expression was studied retrospectively in locally advanced carcinoma of the cervix in relation to other methods for measuring/assessing tumor hypoxia and outcome after radiotherapy. EXPERIMENTAL DESIGN: HIF-1alpha expression was examined in formalin-fixed tumor biopsies using a semiquantitative scoring system and correlated with measurements of hypoxia obtained using oxygen electrodes, pimonidazole staining, and carbonic anhydrase 9. RESULTS: High HIF-1alpha expression showed a weak correlation with low pO2 (r = -0.26; P = 0.030; n = 72). Weak significant correlations were found between HIF-1alpha and pimonidazole staining (r = 0.34; P = 0.040; n = 36) and carbonic anhydrase IX (r = 0.27; P = 0.001; n = 160). There was no relationship with surviving fraction at 2 Gy. The relationship between HIF-1alpha expression and radiotherapy outcome was examined in 99 patients. HIF-1alpha expression did not correlate with disease stage, grade, tumor size, and patient age. HIF-1alpha alone was not a significant prognostic factor for disease-free survival, metastasis-free survival, or local recurrence-free survival. High HIF-1alpha expression tended to be associated with poor outcome in small tumors but good outcome in large tumors, with statistically significant interactions between HIF-1alpha and tumor size for survival (P = 0.046) and local control (P = 0.009). CONCLUSIONS: In this study, HIF-1alpha had no prognostic significance in locally advanced carcinoma of the cervix. The possible switch in large tumors for an association between high HIF-1alpha expression and good outcome might relate to tumor size-related changes in the balance of genes up-regulated by HIF-1alpha. Whereas angiogenesis-promoting genes might be preferentially up-regulated in small tumors, proapoptotic genes might be induced in large tumors. This hypothesis needs testing in future work.

Antitumor imidazotetrazines. 40. Radiosyntheses of [4-11C-carbonyl]- and [3-N-11C-methyl]-8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide) for positron emission tomography (PET) studies.

8-Carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide, 1) is an anticancer prodrug. As part of investigations to probe its postulated mode of action using PET we have developed two rapid radiosynthetic routes for the preparation of temozolomide labeled with the short-lived positron emitter, carbon-11 (t(1/2) = 20.4 min). Reaction of 5-diazoimidazole-4-carboxamide (7) with the novel labeling agent [(11)C-methyl]methyl isocyanate (8) gave [3-N-(11)C-methyl]temozolomide (9) in 14-20% radiochemical yield from [(11)C-methyl]methyl isocyanate (8) (decay corrected). The position of radiolabeling in the 3-N-methyl group was confirmed by [(11/13)C]colabeling and subsequent carbon-13 NMR spectroscopy. Similarly, the reaction of 5-diazoimidazole-4-carboxamide (7) with [(11)C-carbonyl]methyl isocyanate (10) gave [4-(11)C-carbonyl]temozolomide (11) in 10-15% radiochemical yield from [(11)C-carbonyl]methyl isocyanate (10) (decay corrected). Apyrogenic samples of [3-N-(11)C-methyl]temozolomide (9) and [4-(11)C-carbonyl]temozolomide (11), with good chemical and radiochemical purities, have been prepared and used in human PET studies.

Phase II Trial of Cetuximab and Conformal Radiotherapy Only in Locally Advanced Pancreatic Cancer with Concurrent Tissue Sampling Feasibility Study.

BACKGROUND: Preclinical data have indicated the anti-epidermal growth factor receptor (EGFR) agent cetuximab (Erbitux) as a radiosensitizer in pancreatic cancer, but this has not been specifically addressed in a clinical study. We report the results of an original study initiated in 2007, where cetuximab was tested with radiotherapy (RT) alone in locally advanced pancreatic cancer in a phase II trial (PACER). METHODS: Patients (n = 21) received cetuximab loading dose (400 mg/m(2)) and weekly dose (250 mg/m(2)) during RT (50.4 Gy in 28 fractions). Toxicity and disease response end point data were prospectively assessed. A feasibility study of on-trial patient blood and skin sampling was incorporated. RESULTS: Treatment was well tolerated, and toxicity was low; most patients (71%) experienced acute toxicities of grade 2 or less. Six months posttreatment, stable local disease was achieved in 90% of evaluable patients, but only 33% were free from metastatic progression. Median overall survival was 7.5 months, and actuarial survival was 33% at 1 year and 11% at 3 years, reflecting swift metastatic progression in some patients but good long-term control of localized disease in others. High-grade acneiform rash (P = .0027), posttreatment stable disease (P = .0059), and pretreatment cancer antigen 19.9 (CA19.9) level (P = .0042) associated with extended survival. Patient skin and blood samples yielded sufficient RNA and good quality protein, respectively. CONCLUSIONS: The results indicate that cetuximab inhibits EGFR-mediated radioresistance to achieve excellent local control with minimal toxicity but does not sufficiently control metastatic progression in all patients. Translational studies of patient tissue samples may yield molecular information that may enable individual treatment response prediction.

How Kaiser Permanente uses video ethnography of patients for quality improvement, such as in shaping better care transitions.

Keeping patients and caregivers at the center of quality improvement is critical. Kaiser Permanente's Care Management Institute adapted video ethnography to achieve this aim, using video to capture interviews with-and observations of-patients and caregivers, identify patient-centered improvement opportunities, and communicate them effectively to clinical and administrative leaders and front-line staff. This method is particularly effective for helping understand the needs of frail elders, patients nearing the end of life, those with multiple chronic conditions, and other vulnerable people who are not well represented in focus groups and patient advisory councils. As part of an initiative to improve care transitions for elders with heart failure, video ethnography contributed to greatly reduced thirty-day hospital readmission rates, helping reduce readmissions at one medical center from 13.6 percent to 9 percent in six months. It also helped improve the reliability of the readmissions reduction program. When embedded within an established quality improvement framework, video ethnography can be an effective tool for innovating new solutions, improving existing processes, and spreading knowledge about how best to meet patient needs.

Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors.

PURPOSE: Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents. EXPERIMENTAL DESIGN: Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors. RESULTS: Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m(2), then expanded cohorts to 15.4 mg/m(2) in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drug-related dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m(2) or higher. CONCLUSIONS: The maximum tolerated dose was 8.5 mg/m(2) but escalation to 14 mg/m(2) was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m(2) and maximum tumor perfusion reductions were seen at doses of 11 mg/m(2) or higher, the recommended phase II dose is from 11 to 14 mg/m(2).

Molecular Imaging and Pharmacokinetic Analysis of Carbon-11 Labeled Antisense Oligonucleotide LY2181308 in Cancer Patients.

Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating genes involved in tumorigenesis. However, little is known about ASO biodistribution and tissue pharmacokinetics (PKs) in humans, including whether sufficient delivery to target tumor tissue may be achieved. In this preliminary study in human subjects, we used combined positron emission and computed tomography (PET-CT) imaging and subsequent modeling analysis of acquired dynamic data, to examine the in vivo biodistribution and PK properties of LY2181308 - a second generation ASO which targets the apoptosis inhibitor protein survivin. Following radiolabeling of LY2181308 with methylated carbon-11 ([(11)C]methylated-LY2181308), micro-doses (<1mg) were administered to three patients with solid tumors enrolled in a phase I trial. Moderate uptake of [(11)C]methylated-LY2181308 was observed in tumors (mean=32.5ng*h /mL, per mg administered intravenously). Highest uptake was seen in kidney and liver and lowest uptake was seen in lung and muscle. One patient underwent repeat analysis on day 15 of multiple dose therapy, during administration of LY2181308 (750mg), when altered tissue PKs and a favorable change in biodistribution was seen. [(11)C]methylated-LY2181308 exposure increased in tumor, lung and muscle, whereas renal and hepatic exposure decreased. This suggests that biological barriers to ASO tumor uptake seen at micro-doses were overcome by therapeutic dosing. In addition, (18)F-labeled fluorodeoxyglucose (FDG) scans carried out in the same patient before and after treatment showed up to 40% decreased tumor metabolism. For the development of anti-cancer ASOs, the results provide evidence of LY2181308 tumor tissue delivery and add valuable in vivo pharmacological information. For the development of novel therapeutic agents in general, the study exemplifies the merits of applying PET imaging methodology early in clinical investigations.

VEGF-PET imaging is a noninvasive biomarker showing differential changes in the tumor during sunitinib treatment.

Non-invasive imaging of angiogenesis could ease the optimization of antiangiogenesis treatments for cancer. In this study, we evaluated the role of VEGF-PET as a biomarker of dynamic angiogenic changes in tumors following treatment with the kinase inhibitor sunitinib. The effects of sunitinib treatment and withdrawal on the tumor was investigated using the new VEGF-PET tracer (89)Zr-ranibizumab as well as (18)F-FDG PET, and (15)O-water PET in mouse xenograft models of human cancer. The obtained imaging results were compared with tumor growth, VEGF plasma levels and immunohistologic analyzes. In contrast to (18)F-FDG and (15)O-water PET, VEGF-PET demonstrated dynamic changes during sunitinib treatment within the tumor with a strong decline in signal in the tumor center and only minimal reduction in tumor rim, with a pronounced rebound after sunitinib discontinuation. VEGF-PET results corresponded with tumor growth and immunohistochemical vascular- and tumor- markers. Our findings highlight the strengths of VEGF-PET imaging to allow serial analysis of angiogenic changes in different areas within a tumor.