Barbara J. Fueger

Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer

Inhibitors of the kinase mammalian target of rapamycin (mTOR) have shown sporadic activity in cancer trials, leading to confusion about the appropriate clinical setting for their use. Here we show that loss of the Von Hippel-Lindau tumor suppressor gene (VHL) sensitizes kidney cancer cells to the mTOR inhibitor CCI-779 in vitro and in mouse models. Growth arrest caused by CCI-779 correlates with a block in translation of mRNA encoding hypoxia-inducible factor (HIF1A), and is rescued by expression of a VHL-resistant HIF1A cDNA lacking the 5′ untranslated region. VHL-deficient tumors show increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR-dependent manner. Our findings provide preclinical rationale for prospective, biomarker-driven clinical studies of mTOR inhibitors in kidney cancer and suggest that FDG-PET scans may have use as a pharmacodynamic marker in this setting.

Correlation of 6-18F-Fluoro-l-Dopa PET Uptake with Proliferation and Tumor Grade in Newly Diagnosed and Recurrent Gliomas

6-18F-fluoro-l-dopa (18F-FDOPA) measured with PET as a biomarker of amino acid uptake has been investigated in brain tumor imaging. The aims of the current study were to determine whether the degree of 18F-FDOPA uptake in brain tumors predicted tumor grade and was associated with tumor proliferative activity in newly diagnosed and recurrent gliomas. Methods: Fifty-nine patients (40 men, 19 women; mean age ± SD, 44.4 ± 12.3 y) with newly diagnosed (n = 22) or recurrent (n = 37) gliomas underwent 18F-FDOPA PET perioperatively. Tumor tissue was obtained by resection or biopsy in all patients. The tumor grade and Ki-67 proliferation index were obtained by standard pathology assays. Tumor 18F-FDOPA uptake was quantified by determining various standardized uptake value (SUV) parameters (mean SUV, maximum SUV [SUVmax], mean values of voxels with top 20% SUVs, and tumor–to–normal-brain tissue ratios) that were then correlated with histopathologic grade and Ki-67 proliferation index. Results: Fifty-nine lesions in 59 patients were analyzed. 18F-FDOPA uptake was significantly higher in high-grade than in low-grade tumors for newly diagnosed tumors (SUVmax, 4.22 ± 1.30 vs. 2.34 ± 1.35, P = 0.005) but not for recurrent tumors that had gone through treatment previously (SUVmax, 3.36 ± 1.26 vs. 2.67 ± 1.18, P = 0.22). An SUVmax threshold of 2.72 differentiated low-grade from high-grade tumors, with a sensitivity and specificity of 85% and 89%, respectively, using receiver-operating-characteristic curve analysis (area under the curve, 0.86). 18F-FDOPA PET uptake correlated significantly with Ki-67 tumor proliferation index in newly diagnosed tumors (r = 0.66, P = 0.001) but not in recurrent tumors (r = 0.14, P = 0.41). Conclusion: 18F-FDOPA uptake is significantly higher in high-grade than in low-grade tumors in newly diagnosed but not recurrent tumors that had been treated previously. A significant correlation between 18F-FDOPA uptake and tumor proliferation in newly diagnosed tumors was observed, whereas this correlation was not identified for recurrent tumors. Thus, 18F-FDOPA PET might serve as a noninvasive marker of tumor grading and might provide a useful surrogate of tumor proliferative activity in newly diagnosed gliomas.

Performance of 2-Deoxy-2-[F-18]fluoro-d-glucose Positron Emission Tomography and Integrated PET/CT in Restaged Breast Cancer Patients

PurposeThis study was conducted to compare the clinical stage derived from 2-deoxy-2-[F-18]fluoro-d-glucose (FDG) positron emission tomography (PET) to that of integrated PET/computed tomography (CT) in restaged breast cancer patients.ProceduresFifty-eight female patients (age range 29–80 years, mean age ±SD, 53.3 ± 11.7 years) underwent PET/CT restaging for breast cancer. Two experienced nuclear medicine physicians interpreted PET images. A radiologist was added for reading PET/CT studies. A patient-based analysis was performed. Histopathological findings, correlative imaging studies, changes in number, size, and hypermetabolic activity of suspicious lesions and/or patient outcome served as standard of reference for determining the diagnostic accuracy of both modalities.ResultsPET staged 79.3% (46/58) of the patients correctly, overstaged seven (12.1%), and understaged five patients (8.6%). Integrated PET/CT staged 89.7% (52/58) of the patients correctly, overstaged four (6.9%), and understaged two patients (3.4%). The staging accuracy of PET/CT was not significantly better than that of PET alone (p = 0.059). Lesions exhibiting mild hypermetabolic activity, benign inflammatory lesions, and physiological variants largely explained incorrect PET findings.ConclusionIntegrated PET/CT only marginally improves the restaging accuracy over PET alone (p = 0.059) in breast cancer patients.

Impact of 3,4-Dihydroxy-6-18F-Fluoro-l-Phenylalanine PET/CT on Managing Patients with Brain Tumors: The Referring Physician's Perspective

We investigated the impact of 18F-DOPA brain PET/CT on the clinical management of patients with known or suspected brain tumors. Methods: A prospective survey of referring physicians was conducted. A pre-PET questionnaire inquired about indication, tumor histology or grade, level of suspicion for tumor recurrence, and planned management. Early post-PET questionnaires asked referring physicians to categorize PET findings as negative, equivocal, or positive; assessed the level of suspicion for primary or recurrent brain tumor; and recorded intended management changes prompted by PET findings. A late follow-up questionnaire 6 mo after the scan aimed at determining patient outcome (recurrence, survival). In addition, all referring physicians were contacted to determine whether management changes intended after 18F-DOPA PET/CT were implemented. Results: Fifty-eight consecutive patients were included. The clinical suspicion for recurrence increased in 33%, remained unchanged in 50%, and decreased in 17% of patients after adding the PET/CT result to the available diagnostic data. The late post-PET questionnaire confirmed recurrence in 26 patients whereas 32 had stable disease or remained disease-free. 18F-DOPA PET/CT resulted in intended management changes in 41% of patients. Changes in intended management from wait and watch to chemotherapy (6 patients [25%]) and from chemotherapy to wait and watch (4 patients [17%]) occurred most frequently. Clinical follow-up revealed that 75% of intended treatment changes were implemented. Conclusion: 18F-DOPA PET/CT changed the intended management of 41% of patients with brain tumors, and intended management changes were implemented in 75% of these. These changes suggest a potentially important clinical role of imaging amino acid transport in the management of brain tumor patients.

Comparison of CT, PET, and PET/CT for staging of patients with indolent non-Hodgkin's lymphoma.

PurposeThe aim was to investigate the potential impact of positron emission tomography (PET)/computed tomography (CT) as compared to PET and CT on the staging of patients with indolent lymphoma.ProceduresPET/CTs from 45 patients with indolent lymphoma undergoing staging or restaging were studied. Clinical follow-up, additional imaging, and histology served as the gold standard.ResultsPET/CT correctly diagnosed 92 nodal regions as positive for lymphomatous involvement and 458 as disease free vs 68 and 449 for PET and 64 and 459 for CT, respectively. The respective sensitivities, specificities, and accuracies were 99%, 100%, and 99.8% for PET/CT, 68%, 97.5%, and 92.2% for PET, and 70%, 100%, and 94.7% for CT. PET/CT performed significantly better than PET (p < 0.001 for sensitivity, specificity, and accuracy) and CT (p < 0.001 for sensitivity and accuracy). PET/CT also correctly identified significantly more extra-nodal lesions (22) than CT (14) and PET (nine).ConclusionsPET/CT provides significantly more accurate information compared to PET and CT for the staging and re-staging of patients with indolent lymphoma.

Bone lesion detection with carrier-added 99mTc-EDTMP in comparison with 99mTc-DPD.

An increased uptake of bone-seeking radiopharmaceuticals into malignant bone lesions could further improve the diagnostic accuracy of routine bone scanning. The tracers used in clinical routine for bone scanning are methylene-diphosphonate (MDP), dicarboxypropane-diphosphonate (DPD) and ethylenediaminetetramethylene-phosphonate (EDTMP). MDP and DPD are usually labelled with 99mTc for diagnostic use, whereas EDTMP is labelled with 153Sm for therapeutic purposes. This study aimed to compare, for the first time, bone scanning with an improved preparation of 99mTc-EDTMP (by the addition of rhenium) (carrier-added) with 99mTc-DPD. Twenty malignant bone lesions were investigated in 10 patients. The ratios of bone lesion to soft tissue (BL/ST) and of bone lesion to normal bone (BL/NB) were compared 3 h after the injection of either compound. Quantitative analysis demonstrated a significant (P<0.05) difference in BL/ST ratio in favour of 99mTc-DPD. The BL/NB ratio was not significantly different. Visual image analysis resulted in a clinically comparable interpretation of imaging studies with the use of 99mTc-DPD and carrier-added 99mTc-EDTMP. These preliminary data support the concept of carrier addition to increase bone uptake by the modification of the complex structure of 99mTc-EDTMP. However, any advantage over conventional 99mTc-based tracers for bone scintigraphy in clinical use needs to be demonstrated in controlled trials.

From In Situ to In Vivo: An In Situ Click-Chemistry-Derived Carbonic Anhydrase II Imaging Agent for Positron Emission Tomography

CA II makes a good PET: Discovering positron emission tomography (PET) probes with high target affinities is challenging. PET probe discovery using in situ click chemistry uses (19) F-bearing fragments as (18) F surrogates. This ensures that the lead hits and PET probes have equivalent chemical or biological characteristics, making PET probe discovery predictable and reliable.

Response to Larry R. White's Letter to the Editor Titled “Comparison of CT, PET, and PET/CT for Staging of Patients with Indolent Non-Hodgkin's Lymphoma: Statistical Errors in Fueger et al. (2009)”

Response to Larry R. Whites Letter to the Editor Titled “Comparison of CT, PET, and PET/CT for Stagingof Patientswith IndolentNon-Hodgkins Lymphoma: Statistical Errors in Fueger et al. (2009)” Barbara J. Fueger, Kristen Yeom, Johannes Czernin, James W. Sayre, Michael E. Phelps, Martin S. Allen-Auerbach Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095( USA Department of Radiology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095( USA Klinik für Nuklearmedizin, AKH Wien, A-1090 Wien, Austria Department of Radiology, Stanford University, Stanford, 94305 CA( USA