90Y-Daclizumab (Anti-CD25), High-Dose Carmustine, Etoposide, Cytarabine, and Melphalan Chemotherapy and Autologous Hematopoietic Stem Cell Transplant Yielded Sustained Complete Remissions in 4 Patients with Recurrent Hodgkin's Lymphoma.

Background: Despite advances in therapy of Hodgkin's lymphoma (HL), a proportion of patients will not respond or relapse. The authors had previously identified CD25, IL-2Rα, as a target for systemic radioimmunotherapy of HL since most normal cells do not express CD25, but it is expressed by a minority of Hodgkin/Reed-Sternberg (HRS) cells and most Tregs rosetting around HRS cells. Study Design and Treatment: This was a single institution, nonrandomized, open-label phase I/II trial of radiolabeled 90Y-daclizumab, an anti-CD25 monoclonal antibody, BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning treatment followed by autologous hematopoietic stem cell transplant (ASCT). Four patients with refractory and relapsed HL were treated in this trial with 3 patients receiving a single dose of 564.6-574.6 MBq 90Y-daclizumab and the fourth patient receiving two doses of 580.9-566.1 MBq 90Y-daclizumab followed by high-dose chemotherapy and ASCT. Results: All 4 evaluable patients treated with 90Y-daclizumab obtained complete responses (CRs) that are ongoing 4.5-7 years following their stem cell transplant. The spectrum and severity of adverse events were mild and more importantly none of the patients, including several with multiple therapies before this treatment, developed the myelodysplastic syndrome. Discussion: Targeting by daclizumab was not directed primarily at tumor cells, but rather the nonmalignant CD25-expressing T cells adjacent to the HRS cells and 90Y-daclizumab provided strong enough ß emissions to kill CD25-negative tumor cells at a distance by a crossfire effect. Furthermore, the strong ß irradiation killed normal cells in the tumor microenvironment. Conclusions: 90Y-daclizumab (anti-CD25), high-dose BEAM chemotherapy and ASCT was well tolerated and yielded sustained complete remissions in all 4 patients with recurrent HL patients who completed their treatment. Significance: Despite advances, a proportion of patients with HL will not have a CR to their initial treatment, and some with CRs will relapse. They demonstrated that the addition of 90Y-daclizumab into the preconditioning regimen for refractory and relapsed HL patients with high-dose BEAM chemotherapy and ASCT provided sustained CRs in the 4 patients studied. Two of these patients were highly refractory to multiple prior treatments with bulky disease at entry into this study, including 1 patient who never entered a remission and had failed 6 different therapeutic regimens. Despite the small number of patients treated in this study, the sustained clinical benefit in these patients indicates a highly effective treatment. The daclizumab was directed primarily not at HRS cells themselves but toward nonmalignant T cells rosetting around malignant cells. 90Y provided strong ß emissions that killed antigen nonexpressing tumor cells at a distance by a crossfire effect. Furthermore, the strong ß radiation killed normal cells in the tumor microenvironment that nurtured the malignant cells in the lymphomatous mass. The present study supports expanded analysis of 90Y-daclizumab as part of the regimen of ASCT in patients with refractory and relapsed HL.

Impact of Anatomic Location of Bone Metastases on Prognosis in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Whole-body assessments of 18F-NaF positron emission tomography (PET)/computed tomography (CT) provide promising quantitative imaging biomarkers of metastatic castration-resistant prostate cancer (mCRPC). This study investigated whether the distribution of metastases across anatomic regions is prognostic of progression-free survival. PATIENTS AND METHODS: Fifty-four mCRPC patients with osseous metastases received baseline NaF PET/CT. Patients received chemotherapy (n = 16) or androgen receptor pathway inhibitors (n = 38). Semiautomated analysis using Quantitative Total Bone Imaging software extracted imaging metrics for the whole, axial, and appendicular skeleton as well as 11 skeletal regions. Five PET metrics were extracted for each region: number of lesions (NL), standardized maximum uptake value (SUVmax), average uptake (SUVmean), sum of uptake (SUVtotal), and diseased fraction of the skeleton (volume fraction). Progression included that discovered by clinical, biochemical, or radiographic means. Univariate and multivariate Cox proportional hazard regression analyses were performed between imaging metrics and progression-free survival, and were assessed according to their hazard ratios (HR) and concordance (C)-indices. RESULTS: The strongest univariate models of progression-free survival were pelvic NL and SUVmax with HR = 1.80 (NL: false discovery rate adjusted P = .001, SUVmax: adjusted P = .001). Three other region-specific metrics (axial NL: HR = 1.59, adjusted P = .02, axial SUVmax: HR = 1.61, adjusted P = .02, and skull SUVmax: HR = 1.58, adjusted P = .04) were found to be stronger prognosticators relative to their whole-body counterparts. Multivariate model including region-specific metrics (C-index = 0.727) outperformed that of whole-body metrics (C-index = 0.705). The best performance was obtained when region-specific and whole-body metrics were included (C-index = 0.742). CONCLUSION: Quantitative characterization of metastatic spread by anatomic location on NaF PET/CT enhances potential prognostication. Further study is warranted to optimize the prognostic and predictive value of NaF PET/CT in mCRPC patients.

Biodistribution, Tumor Detection, and Radiation Dosimetry of 18F-5-Fluoro-2'-Deoxycytidine with Tetrahydrouridine in Solid Tumors.

In preclinical studies, 5-fluoro-2'-deoxycytidine (FdCyd), an inhibitor of DNA methyltransferase and DNA hypermethylation, has shown treatment efficacy against multiple malignancies by suppressing epigenetic hypermethylation in tumor cells. Several ongoing clinical trials are using FdCyd, and although some patients may respond to this drug, in most patients it is ineffective. Thus, establishing a noninvasive imaging modality to evaluate the distribution of the drug may provide insight into the variable responses. A novel experimental radiopharmaceutical, 18F-labeled FdCyd, was developed as a companion imaging agent to the nonradioactive form of the drug, FdCyd. We present the first-in-humans radiation dosimetry results and biodistribution of 18F-FdCyd, administered along with tetrahydrouridine, an inhibitor of cytidine/deoxycytidine deaminase, in patients with a variety of solid tumors undergoing FdCyd therapy. Methods: This phase 0 imaging trial examined the 18F-FdCyd biodistribution and radiation dosimetry in 5 human subjects enrolled in companion therapy trials. In each subject, 4 sequential PET scans were acquired to estimate whole-body and individual organ effective dose, using OLINDA/EXM, version 1.0. Tumor-to-background ratios were also calculated for the tumor sites visualized on PET/CT imaging. Results: The average whole-body effective dose for the experimental radiopharmaceutical 18F-FdCyd administered in conjunction with tetrahydrouridine was 2.12E-02 ± 4.15E-03 mSv/MBq. This is similar to the radiation dose estimates for 18F-FDG PET. The critical organ, with the highest absorbed radiation dose, was the urinary bladder wall at 7.96E-02 mSv/MBq. Other organ doses of note were the liver (6.02E-02mSv/MBq), kidneys (5.26E-02 mSv/MBq), and gallbladder (4.05E-02 mSv/MBq). Tumor target-to-background ratios ranged from 2.4 to 1.4, which potentially enable tumor visualization in static PET images. Conclusion: This phase 0 imaging clinical trial provides evidence that 18F-FdCyd administered in conjunction with tetrahydrouridine yields acceptable individual organ and whole-body effective doses, as well as modest tumor-to-background ratios that potentially enable tumor visualization. Dose estimates for 18F-FdCyd are comparable to those for other PET radiopharmaceuticals, such as 18F-FDG. Further studies with larger study populations are warranted to assess 18F-FdCyd imaging as a predictor of FdCyd treatment effectiveness.

Quantification of bone flare on 18F-NaF PET/CT in metastatic castration-resistant prostate cancer.

BACKGROUND: Bone flare has been observed on 99mTc-MDP bone scans of patients with metastatic castration-resistant prostate cancer (mCRPC). This exploratory study investigates bone flare in mCRPC patients receiving androgen receptor (AR) inhibitors using 18F-NaF PET/CT. METHODS: Twenty-nine mCRPC patients undergoing AR-inhibiting therapy (abiraterone, orteronel, enzalutamide) received NaF PET/CT scans at baseline, week 6, and week 12 of treatment. SUV metrics were extracted globally for each patient (SUV) and for each individual lesion (iSUV). Bone flare was defined as increasing SUV metrics or lesion number at week 6 followed by subsequent week 12 decrease. Differences in metrics across timepoints were compared using Wilcoxon tests. Cox proportional hazard regression was conducted between global metrics and progression-free survival (PFS). RESULTS: Total SUV was most sensitive for flare detection and was identified in 14/23 (61%) patients receiving CYP17A1-inhibitors (abiraterone, orteronel), and not identified in any of six patients receiving enzalutamide. The appearance of new lesions did not account for initial increases in SUV metrics. iSUV metrics followed patient-level trends: bone flare positive patients showed a median of 72% (range: 0-100%) of lesions with total iSUV flare. Increasing mean SUV at week 6 correlated with extended PFS (HR = 0.58, p = 0.02). CONCLUSION: NaF PET bone flare was present on 61% of mCRPC patients in the first 6 weeks of treatment with CYP17A1-inhibitors. Characterization provided in this study suggests favorable PFS in patients showing bone flare. This characterization of NaF flare is important for guiding treatment assessment schedules to better distinguish between patients showing bone flare and those truly progressing, and should be performed for all emerging mCRPC treatments and imaging agents.

The Use of Quantitative Imaging in Radiation Oncology: A Quantitative Imaging Network (QIN) Perspective.

Modern radiation therapy is delivered with great precision, in part by relying on high-resolution multidimensional anatomic imaging to define targets in space and time. The development of quantitative imaging (QI) modalities capable of monitoring biologic parameters could provide deeper insight into tumor biology and facilitate more personalized clinical decision-making. The Quantitative Imaging Network (QIN) was established by the National Cancer Institute to advance and validate these QI modalities in the context of oncology clinical trials. In particular, the QIN has significant interest in the application of QI to widen the therapeutic window of radiation therapy. QI modalities have great promise in radiation oncology and will help address significant clinical needs, including finer prognostication, more specific target delineation, reduction of normal tissue toxicity, identification of radioresistant disease, and clearer interpretation of treatment response. Patient-specific QI is being incorporated into radiation treatment design in ways such as dose escalation and adaptive replanning, with the intent of improving outcomes while lessening treatment morbidities. This review discusses the current vision of the QIN, current areas of investigation, and how the QIN hopes to enhance the integration of QI into the practice of radiation oncology.

PET/CT imaging of renal cell carcinoma with (18)F-VM4-037: a phase II pilot study.

BACKGROUND: Carbonic anhydrase IX (CA-IX) is a potential imaging biomarker of clear cell renal cell carcinoma (ccRCC). Here, we report the results of a phase II clinical trial of a small molecule radiotracer targeting CA-IX ((18)F-VM4-037) in ccRCC. METHODS: Between October 2012 and May 2013, 11 patients with kidney masses underwent (18)F-VM4-037 PET/CT prior to surgery. Dynamic imaging was performed for the first 45 min post injection and whole-body imaging was obtained at 60 min post injection. Tumors were surgically excised or biopsied within 4 weeks of imaging. RESULTS: All patients tolerated the radiotracer well with no adverse events. Ten of the 11 patients had histologically confirmed malignancy. One patient had a Bosniak Type 3 cyst with no tumor found at surgery. Two patients had extrarenal disease and 9 had tumors only in the kidney. Primary ccRCC lesions were difficult to visualize on PET alone due to high uptake of the tracer in the adjacent normal kidney parenchyma, however when viewed in conjunction with CT, the tumors were easily localized. Metastatic lesions were clearly visible on PET. Mean SUV for primary kidney lesions was 2.55 in all patients; in patients with histologically confirmed ccRCC, the mean SUV was 3.16. The time-activity curves (TAC) are consistent with reversible ligand binding with peak activity concentration at 8 min post injection followed by washout. Distribution Volume Ratio (DVR) of the lesions was measured using the Logan graphical analysis method. The mean DVR value across the 9 kidney lesions was 5.2 ± 2.8, (range 0.68-10.34). CONCLUSION: 18F-VM4-037 is a well-tolerated PET agent that allows same day imaging of CA-IX expression. The agent demonstrated moderate signal uptake in primary tumors and excellent visualization of CA-IX positive metastases. While the evaluation of primary ccRCC lesions is challenging due to high background activity in the normal kidney parenchyma, 18F-VM4-037 may be most useful in the evaluation of metastatic ccRCC lesions.

Prospective Study Evaluating Na18F PET/CT in Predicting Clinical Outcomes and Survival in Advanced Prostate Cancer.

UNLABELLED: This prospective pilot study evaluated the ability of Na(18)F PET/CT to detect and monitor bone metastases over time and its correlation with clinical outcomes and survival in advanced prostate cancer. METHODS: Sixty prostate cancer patients, including 30 with and 30 without known bone metastases by conventional imaging, underwent Na(18)F PET/CT at baseline, 6 mo, and 12 mo. Positive lesions were verified on follow-up scans. Changes in SUVs and lesion number were correlated with prostate-specific antigen change, clinical impression, and overall survival. RESULTS: Significant associations included the following: SUV and prostate-specific antigen percentage change at 6 mo (P = 0.014) and 12 mo (P = 0.0005); SUV maximal percentage change from baseline and clinical impression at 6 mo (P = 0.0147) and 6-12 mo (P = 0.0053); SUV change at 6 mo and overall survival (P = 0.018); number of lesions on Na(18)F PET/CT and clinical impression at baseline (P < 0.0001), 6 mo (P = 0.0078), and 12 mo (P = 0.0029); and number of lesions on Na(18)F PET/CT per patient at baseline and overall survival (P = 0.017). In an exploratory analysis, paired (99m)Tc-methylene diphosphonate bone scans ((99m)Tc-BS) were available for 35 patients at baseline, 19 at 6 mo, and 14 at 12 mo (68 scans). Malignant lesions on Na(18)F PET/CT (n = 57) were classified on (99m)Tc-BS as malignant 65% of the time, indeterminate 25% of the time, and negative 10% of the time. Additionally, 69% of paired scans showed more lesions on Na(18)F PET/CT than on (99m)Tc-BS. CONCLUSION: The baseline number of malignant lesions and changes in SUV on follow-up Na(18)F PET/CT significantly correlate with clinical impression and overall survival. Na(18)F PET/CT detects more bone metastases earlier than (99m)Tc-BS and enhances detection of new bone disease in high-risk patients.

Does focal incidental 18F-FDG PET/CT uptake in the prostate have significance?

PURPOSE: (18)F-FDG PET/CT is used to characterize many malignancies, but is not recommended for localized prostate cancer. This study explores the value of multi-parametric MRI (mpMRI) in characterizing incidental prostate (18)F-FDG uptake. METHODS: Thirty-one patients who underwent (18)F-FDG PET/CT for reasons unrelated to prostate cancer and prostate mpMRI were eligible for this retrospective study. The mpMRI included T2-weighted (T2W), dynamic contrast enhancement (DCE), apparent diffusion coefficient (ADC), and MR spectroscopy (MRS) sequences. Fourteen patients were excluded (n = 8 insufficient histopathology, n = 6 radical prostatectomy before PET), and final analysis included 17 patients. A nuclear medicine physician, blinded to clinicopathologic findings, identified suspicious areas and maximum standardized uptake values (SUV max) on (18)F-FDG PET/CT. Sector-based imaging findings were correlated with annotated histopathology from whole-mount or MRI/transrectal ultrasound fusion biopsy samples. Positive predictive values (PPVs) were estimated using generalized estimating equations with logit link. Results were evaluated with Kruskal-Wallis and Dunn's multiple comparisons tests. RESULTS: The PPV of (18)F-FDG PET alone in detecting prostate cancer was 0.65. Combining (18)F-FDG PET as a base parameter with mpMRI (T2W, DCE, ADC, and MRS) increased the PPV to 0.82, 0.83, 0.83, and 0.94, respectively. All benign lesions had SUV max < 6. Malignant lesions had higher SUV max values that correlated with Gleason scores. There was a significant difference in SUV max per prostate between the Gleason ≥ 4 + 5 and benign categories (p = 0.03). CONCLUSIONS: Focal incidental prostate (18)F-FDG uptake has low clinical utility alone, but regions of uptake may harbor high-grade prostate cancer, especially if SUV max > 6. Using mpMRI to further evaluate incidental (18)F-FDG uptake aids the diagnosis of prostate cancer.

A pilot study of the value of 18F-fluoro-deoxy-thymidine PET/CT in predicting viable lymphoma in residual 18F-FDG avid masses after completion of therapy.

BACKGROUND: Despite its success in diagnosing and staging lymphoma, F-FDG PET/CT can be falsely positive in areas of posttreatment inflammation. 3'-F-fluoro-3'-deoxy-l-thymidine (F-FLT) is a structural analog of the DNA constituent thymidine; its uptake correlates with cellular proliferation. This pilot study evaluates the ability of F-FLT PET/CT to distinguish viable lymphoma from posttreatment inflammatory changes in F-FDG avid residual masses. METHODS: Twenty-one patients with lymphoma with at least 1 F-FDG avid residual mass after therapy underwent F-FLT PET/CT imaging. F-FDG and F-FLT uptake values were compared, including quantitative pharmacokinetic parameters extracted from the F-FLT time activity curves generated from dynamic data using graphical and nonlinear compartmental modeling. RESULTS: The true nature of the residual mass was confirmed by biopsy in 12 patients (8 positive and 4 negative for viable lymphoma and by follow-up CT and/or repeat F-FDG PET/CT imaging over 1 year); among the remaining 9 patients, 7 lesions resolved or decreased and 2 showed growth indicative of lymphoma. F-FLT PET SUVest.max was significantly higher in tumors than in benign lesions (5.5 [2.2] vs 1.7 [0.6]; P < 0.0001), whereas the difference in F-FDG SUVs was not significant (malignant, 7.8 [3.8] vs benign, 5.4 [2.4]; P = 0.11). All of the benign lesions had an F-FLT SUVest.max of less than 3.0. CONCLUSIONS: F-FLT shows improved specificity over F-FDG in distinguishing residual lymphoma from posttreatment inflammation and may be useful in the evaluation of patients with residual F-FDG-positive masses after completing therapy.

Localized prostate cancer detection with 18F FACBC PET/CT: comparison with MR imaging and histopathologic analysis.

PURPOSE: To characterize uptake of 1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid ((18)F FACBC) in patients with localized prostate cancer, benign prostatic hyperplasia (BPH), and normal prostate tissue and to evaluate its potential utility in delineation of intraprostatic cancers in histopathologically confirmed localized prostate cancer in comparison with magnetic resonance (MR) imaging. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained for this HIPAA-compliant prospective study. Twenty-one men underwent dynamic and static abdominopelvic (18)F FACBC combined positron emission tomography (PET) and computed tomography (CT) and multiparametric (MP) 3-T endorectal MR imaging before robotic-assisted prostatectomy. PET/CT and MR images were coregistered by using pelvic bones as fiducial markers; this was followed by manual adjustments. Whole-mount histopathologic specimens were sliced with an MR-based patient-specific mold. (18)F FACBC PET standardized uptake values (SUVs) were compared with those at MR imaging and histopathologic analysis for lesion- and sector-based (20 sectors per patient) analysis. Positive and negative predictive values for each modality were estimated by using generalized estimating equations with logit link function and working independence correlation structure. RESULTS: (18)F FACBC tumor uptake was rapid but reversible. It peaked 3.6 minutes after injection and reached a relative plateau at 15-20 minutes (SUVmax[15-20min]). Mean prostate tumor SUVmax(15-20min) was significantly higher than that of the normal prostate (4.5 ± 0.5 vs 2.7 ± 0.5) (P < .001); however, it was not significantly different from that of BPH (4.3 ± 0.6) (P = .27). Sector-based comparison with histopathologic analysis, including all tumors, revealed sensitivity and specificity of 67% and 66%, respectively, for (18)F FACBC PET/CT and 73% and 79%, respectively, for T2-weighted MR imaging. (18)F FACBC PET/CT and MP MR imaging were used to localize dominant tumors (sensitivity of 90% for both). Combined (18)F FACBC and MR imaging yielded positive predictive value of 82% for tumor localization, which was higher than that with either modality alone (P < .001). CONCLUSION: (18)F FACBC PET/CT shows higher uptake in intraprostatic tumor foci than in normal prostate tissue; however, (18)F FACBC uptake in tumors is similar to that in BPH nodules. Thus, it is not specific for prostate cancer. Nevertheless, combined (18)F FACBC PET/CT and T2-weighted MR imaging enable more accurate localization of prostate cancer lesions than either modality alone.

Meeting the challenges of PET-based molecular imaging in cancer.

As personalized medicine becomes a reality, there is a need for specific imaging agents that reflect molecular characteristics of a cancer. Fluorodeoxyglucose is an important advance because of its sensitivity. Newer molecular imaging probes offer higher specificity and are categorized as: radiolabeled biomimetics; antibody-antibody fragments and drug-drug-like compounds. Biomimetics have high sensitivity but tend to be less specific as they often engage natural transporters and metabolic pathways. Antibodies and their fragments are specific but may be limited by slow clearance. Labeled drugs and drug-like compounds offer good specificity but may be limited in sensitivity. There are numerous challenges facing molecular imaging related to their complexity. Additionally, fear of ionizing radiation and regulatory constraints have somewhat inhibited clinical translation. However, there is reason for optimism due to economies of scale and a changing health care system, which places a premium on diagnostic accuracy. Although molecular imaging is not likely to become mainstream in the near future, its long-term prospects for doing so are excellent.

Functional and molecular imaging of localized and recurrent prostate cancer.

Prostate cancer is the most common malignancy among American men. Imaging of localized and recurrent prostate cancer is challenging since conventional imaging techniques are limited. New imaging techniques such as multiparametric MRI and PET with targeted tracers have been investigated extensively in the last decade. As a result, the role of novel imaging techniques for the detection of localized and recurrent prostate cancer has recently expanded. In this review, novel functional and molecular imaging techniques used in the management of localized and recurrent prostate cancer are discussed.

The kinetics and reproducibility of 18F-sodium fluoride for oncology using current PET camera technology.

UNLABELLED: We evaluated the kinetics of (18)F-sodium fluoride (NaF) and reassessed the recommended dose, optimal uptake period, and reproducibility using a current-generation PET/CT scanner. METHODS: In this prospective study, 73 patients (31 patients with multiple myeloma or myeloma precursor disease and 42 with prostate cancer) were injected with a mean administered dose of 141 MBq of (18)F-NaF. Sixty patients underwent 3 sequential sessions of 3-dimensional PET/CT of the torso beginning approximately 15 min after (18)F-NaF injection, followed by whole-body 3-dimensional PET/CT at 2 h. The remaining 13 prostate cancer patients were imaged only at 2 and 3 h after injection. Twenty-one prostate cancer patients underwent repeated baseline studies (mean interval, 5.9 d) to evaluate reproducibility. RESULTS: The measured effective dose was 0.017 mSv/MBq, with the urinary bladder, osteogenic cells, and red marrow receiving the highest doses at 0.080, 0.077, and 0.028 mGy/MBq, respectively. Visual analysis showed that uptake in both normal and abnormal bone increased with time; however, the rate of increase decreased with time. A semiautomated workflow provided objective uptake parameters, including the mean standardized uptake value of all pixels within bone with SUVs greater than 10 and the average of the mean SUV of all malignant lesions identified by the algorithm. The values of these parameters for the images beginning at approximately 15 min and approximately 35 min were significantly different (0.3% change per minute). Differences between the later imaging time points were not significant (P < 0.01). Repeated baseline studies showed high intraclass correlations (>0.9) and relatively low critical percentage change (the value above which a change can be considered real) for these parameters. The tumor-to-normal bone ratio, based on the maximum SUV of identified malignant lesions, decreased with time; however, this difference was small, estimated at approximately 0.16%/min in the first hour. CONCLUSION: (18)F-NaF PET/CT images obtained with modest radiation exposures can result in highly reproducible imaging parameters. Although the tumor-to-normal bone ratio decreases slightly with time, the high temporal dependence during uptake periods less than 30 min may limit accurate quantitation. An uptake period of 60 ± 30 min has limited temporal dependence while maintaining a high tumor-to-normal bone ratio.

11C-Acetate PET/CT in localized prostate cancer: a study with MRI and histopathologic correlation.

UNLABELLED: This work characterizes the uptake of (11)C-acetate in prostate cancer (PCa), benign prostate hyperplasia, and normal prostate tissue in comparison with multiparametric MRI, whole-mount histopathology, and clinical markers to evaluate the potential utility of (11)C-acetate for delineating intraprostatic tumors in a population of patients with localized PCa. METHODS: Thirty-nine men with presumed localized PCa underwent dynamic-static abdominal-pelvic (11)C-acetate PET/CT for 30 min and 3-T multiparametric MRI before prostatectomy. PET/CT images were registered to MR images using pelvic bones for initial rotation-translation, followed by manual adjustments to account for prostate motion and deformation from the MRI endorectal coil. Whole-mount pathology specimens were sectioned using an MRI-based patient-specific mold resulting in improved registration between the MRI, PET, and pathology. (11)C-acetate PET standardized uptake values were compared with multiparametric MRI and pathology. RESULTS: (11)C-acetate uptake was rapid but reversible, peaking at 3-5 min after injection and reaching a relative plateau at approximately 10 min. The average maximum standardized uptake value (10-12 min) of tumors was significantly higher than that of normal prostate tissue (4.4 ± 2.05 [range, 1.8-9.2] vs. 2.1 ± 0.94 [range, 0.7-3.4], respectively; P < 0.001); however, it was not significantly different from that of benign prostatic hyperplasia (4.8 ± 2.01 [range, 1.8-8.8]). A sector-based comparison with histopathology, including all tumors greater than 0.5 cm, revealed a sensitivity and specificity of 61.6% and 80.0%, respectively, for (11)C-acetate PET/CT and 82.3% and 95.1%, respectively, for MRI. The (11)C-acetate accuracy was comparable to that of MRI when only tumors greater than 0.9 cm were considered. In a small cohort (n = 9), (11)C-acetate uptake was independent of fatty acid synthase expression using immunohistochemistry. CONCLUSION: (11)C-acetate PET/CT demonstrates higher uptake in tumor foci than in normal prostate tissue; however, (11)C-acetate uptake in tumors is similar to that in benign prostate hyperplasia nodules. Although (11)C-acetate PET/CT is not likely to have utility as an independent modality for evaluation of localized PCa, the high uptake in tumors may make it useful for monitoring focal therapy when tissue damage after therapy may limit anatomic imaging methods.

Review of functional/anatomical imaging in oncology.

Patient management in oncology increasingly relies on imaging for diagnosis, response assessment, and follow-up. The clinical availability of combined functional/anatomical imaging modalities, which integrate the benefits of visualizing tumor biology with those of high-resolution structural imaging, revolutionized clinical management of oncologic patients. Conventional high-resolution anatomical imaging modalities such as computed tomography (CT) and MRI excel at providing details on lesion location, size, morphology, and structural changes to adjacent tissues; however, these modalities provide little insight into tumor physiology. With the increasing focus on molecularly targeted therapies, imaging radiolabeled compounds with PET and single-photon emission tomography (SPECT) is often carried out to provide insight into a tumor's biological functions and its surrounding microenvironment. Despite their high sensitivity and specificity, PET and SPECT alone are substantially limited by low spatial resolution and inability to provide anatomical detail. Integrating SPECT or PET with a modality capable of providing these (i.e. CT or MR) maximizes their separate strengths and provides anatomical localization of physiological processes with detailed visualization of a tumor's structure. The availability of multimodality (hybrid) imaging with PET/CT, SPECT/CT, and PET/MR improves our ability to characterize lesions and affect treatment decisions and patient management. We have just begun to exploit the truly synergistic capabilities of multimodality imaging. Continued advances in the development of instrumentation and imaging agents will improve our ability to noninvasively characterize disease processes. This review will discuss the evolution of hybrid imaging technology and provide examples of its current and potential future clinical uses.

Oncologic Angiogenesis Imaging in the clinic---how and why.

The ability to control the growth of new blood vessels would be an extraordinary therapeutic tool for many disease processes. Too often, the promises of discoveries in the basic science arena fail to translate to clinical success. While several anti angiogenic therapeutics are now FDA approved, the envisioned clinical benefits have yet to be seen. The ability to clinically non-invasively image angiogenesis would potentially be used to identify patients who may benefit from anti-angiogenic treatments, prognostication/risk stratification and therapy monitoring. This article reviews the current and future prospects of implementing angiogenesis imaging in the clinic.

Human dosimetry and preliminary tumor distribution of 18F-fluoropaclitaxel in healthy volunteers and newly diagnosed breast cancer patients using PET/CT.

UNLABELLED: (18)F-fluoropaclitaxel is a radiolabeled form of paclitaxel, a widely used chemotherapy agent. Preclinical data suggest that (18)F-fluoropaclitaxel may be a reasonable surrogate for measuring the uptake of paclitaxel. As a substrate of P-glycoprotein, a drug efflux pump associated with multidrug resistance, (18)F-fluoropaclitaxel may also be useful in identifying multidrug resistance and predicting tumor response for drugs other than paclitaxel. METHODS: After informed consent was obtained, 3 healthy volunteers and 3 patients with untreated breast cancer (neoadjuvant chemotherapy candidates, tumor size > 2 cm) received an intravenous infusion of (18)F-fluoropaclitaxel and then underwent PET/CT. Healthy volunteers underwent serial whole-body imaging over an approximately 3-h interval, and organ (18)F residence times were determined from the time-activity curves uncorrected for decay to determine dosimetry. Radiation dose estimates were calculated using OLINDA/EXM software. For breast cancer patients, dynamic imaging of the primary tumor was performed for 60 min, followed by static whole-body scans at 1 and 2 h after injection. RESULTS: Dosimetry calculations showed that the gallbladder received the highest dose (229.50 µGy/MBq [0.849 rad/mCi]), followed by the small and large intestines (161.26 µGy/MBq [0.597 rad/mCi] and 184.59 µGy/MBq [0.683 rad/mCi]). The resultant effective dose was 28.79 µGy/MBq (0.107 rem/mCi). At approximately 1 h after injection, an average of 42% of the decay-corrected activity was in the gastrointestinal system, with a mean of 0.01% in the tumor. All 3 breast cancer patients showed retention of (18)F-fluoropaclitaxel and ultimately demonstrated a complete pathologic response (no invasive cancer in the breast or axillary nodes) to chemotherapy that included a taxane (either paclitaxel or docetaxel) at surgical resection. The tumor-to-background ratio increased with time to a maximum of 7.7 at 20 min. CONCLUSION: This study demonstrates the feasibility of using (18)F-fluoropaclitaxel PET/CT tumor imaging and provides radiation dosimetry measurements in humans. Although further study is needed, it is hoped that the measured intratumoral (18)F-fluoropaclitaxel distribution can serve as a surrogate for paclitaxel, and potentially other chemotherapeutic agent retention, in solid tumors.

PET imaging of multidrug resistance in tumors using 18F-fluoropaclitaxel.

The failure of solid tumors to respond to chemotherapy is a complicated and clinically frustrating issue. The ability to predict which tumors will respond to treatment could reduce the human and monetary costs of cancer therapy by allowing pro-active selection of a chemotherapeutic to which the tumor does not express resistance. PET/CT imaging with a radiolabeled form of paclitaxel, F-18 fluoropaclitaxel (FPAC), may be able to predict the uptake of paclitaxel in solid tumors, and as a substrate of P-glycoprotein, it may also predict which tumors exhibit multidrug resistance (MDR), a phenotype in which tumors fail to respond to a wide variety of chemically unrelated chemotherapeutic agents. This article reviews the synthetic, preclinical and early human data obtained during the development phase of this promising new radiopharmaceutical.

Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography.

Docosahexaenoic acid (DHA; 22:6n-3) is a critical constituent of the brain, but its metabolism has not been measured in the human brain in vivo. In monkeys, using positron emission tomography (PET), we first showed that intravenously injected [1-(11)C]DHA mostly entered nonbrain organs, with approximately 0.5% entering the brain. Then, using PET and intravenous [1-(11)C]DHA in 14 healthy adult humans, we quantitatively imaged regional rates of incorporation (K*) of DHA. We also imaged regional cerebral blood flow (rCBF) using PET and intravenous [(15)O]water. Values of K* for DHA were higher in gray than white matter regions and correlated significantly with values of rCBF in 12 of 14 subjects despite evidence that rCBF does not directly influence K*. For the entire human brain, the net DHA incorporation rate J(in), the product of K*, and the unesterified plasma DHA concentration equaled 3.8 +/- 1.7 mg/day. This net rate is equivalent to the net rate of DHA consumption by brain and, considering the reported amount of DHA in brain, indicates that the half-life of DHA in the human brain approximates 2.5 years. Thus, PET with [1-(11)C]DHA can be used to quantify regional and global human brain DHA metabolism in relation to health and disease.

Imaging multidrug resistance with 4-[18F]fluoropaclitaxel.

Multidrug resistance (MDR) is a cause of treatment failure in many cancer patients. MDR refers to a phenotype whereby a tumor is resistant to a large number of natural chemotherapeutic drugs. Having prior knowledge of the presence of such resistance would decrease morbidity from unsuccessful therapy and allow for the selection of individuals who may benefit from the coadministration of MDR-inhibiting drugs. The Tc-99m-labeled single-photon-emitting radiotracers sestamibi and tetrofosmin have shown some predictive value. However, positron-emitting radiotracers, which allow for dynamic quantitative imaging, hold promise for a more accurate and specific identification of MDRtumors.MDR-expressing tumors are resistant to paclitaxel, which is commonly used as a chemotherapeutic agent. 4-[18F]Fluoropaclitaxel (FPAC) is a PET-radiolabeled analogue of paclitaxel. Preclinical studies have shown the uptake of FPAC to be inversely proportional to tumor MDR expression. FPAC PET imaging in normal volunteers shows biodistribution to be similar to that in nonhuman primates. Imaging in a breast cancer patient showed FPAC localization in a primary tumor that responded to chemotherapy, while failure to localize in mediastinal disease corresponded with only partial response.FPAC PET imaging shows promise for the noninvasive pretreatment identification of MDR-expressing tumors. While much additional work is needed, this work represents a step toward image-guided personalized medicine.