A Conversation With Dr Janet Eary of the NCI Cancer Imaging Program on Federal Priorities in Cancer Imaging.

In this video article, Janet F. Eary, MD, who directs the National Cancer Institute Cancer Imaging Program, discusses the program's initiatives, priorities, and future innovations.

Spatially coherent modeling of 3D FDG-PET data for assessment of intratumoral heterogeneity and uptake gradients.

Purpose: Radiomics have become invaluable for non-invasive cancer patient risk prediction, and the community now turns to exogenous assessment, e.g., from genomics, for interpretability of these agnostic analyses. Yet, some opportunities for clinically interpretable modeling of positron emission tomography (PET) imaging data remain unexplored, that could facilitate insightful characterization at voxel level. Approach: Here, we present a novel deformable tubular representation of the distribution of tracer uptake within a volume of interest, and derive interpretable prognostic summaries from it. This data-adaptive strategy yields a 3D-coherent and smooth model fit, and a profile curve describing tracer uptake as a function of voxel location within the volume. Local trends in uptake rates are assessed at each voxel via the calculation of gradients derived from this curve. Intratumoral heterogeneity can also be assessed directly from it. Results: We illustrate the added value of this approach over previous strategies, in terms of volume rendering and coherence of the structural representation of the data. We further demonstrate consistency of the implementation via simulations, and prognostic potential of heterogeneity and statistical summaries of the uptake gradients derived from the model on a clinical cohort of 158 sarcoma patients imaged with F 18 -fluorodeoxyglucose-PET, in multivariate prognostic models of patient survival. Conclusions: The proposed approach captures uptake characteristics consistently at any location, and yields a description of variations in uptake that holds prognostic value complementarily to structural heterogeneity. This creates opportunities for monitoring of local areas of greater interest within a tumor, e.g., to assess therapeutic response in avid locations.

Predictors of 18F-DCFPyL PET/CT Positivity in Patients with Biochemical Recurrence of Prostate Cancer After Local Therapy.

Our objective was to investigate the factors predicting scan positivity and disease location in patients with biochemical recurrence (BCR) of prostate cancer (PCa) after primary local therapy using prostate-specific membrane antigen-targeted 18F-DCFPyL PET/CT. Methods: This was a 2-institution study including 245 BCR PCa patients after primary local therapy and negative results on conventional imaging. The patients underwent 18F-DCFPyL PET/CT. We tested for correlations of lesion detection rate and disease location with tumor characteristics, time from initial therapy, prostate-specific antigen (PSA) level, and PSA doubling time (PSAdt). Multivariate logistic regression analyses were used to determine predictors of a positive scan. Regression-based coefficients were used to develop nomograms predicting scan positivity and extrapelvic disease. Results: Overall, 79.2% (194/245) of patients had a positive 18F-DCFPyL PET/CT result, with detection rates of 48.2% (27/56), 74.3% (26/35), 84% (37/44), 96.7% (59/61), and 91.8% (45/49) for PSAs of <0.5, 0.5 to <1.0, 1.0 to <2.0, 2.0 to <5.0, and ≥5.0 ng/mL, respectively. Patients with lesions confined to the pelvis had lower PSAs than those with distant sites (1.6 ± 3.5 vs. 3.0 ± 6.3 ng/mL, P < 0.001). In patients treated with prostatectomy (n = 195), 24.1% (47/195) had a negative scan result, 46.1% (90/195) showed intrapelvic disease, and 29.7% (58/195) showed extrapelvic disease. In the postradiation subgroup (n = 50), 18F-DCFPyL PET/CT was always negative at a PSA lower than 1.0 ng/mL and extrapelvic disease was seen only when PSA was greater than 2.0 ng/mL. At multivariate analysis, PSA and PSAdt were independent predictive factors of scan positivity and the presence of extrapelvic disease in postsurgical patients, with area under the curve of 78% and 76%, respectively. PSA and PSAdt were independent predictors of the presence of extrapelvic disease in the postradiation cohort, with area under the curve of 85%. Time from treatment to scan was significantly longer for prostatectomy-bed-only recurrences than for those with bone or visceral disease (6.2 ± 6.4 vs. 2.4 ± 1.3 y, P < 0.001). Conclusion:18F-DCFPyL PET/CT offers high detection rates in BCR PCa patients. PSA and PSAdt are able to predict scan positivity and disease location. Furthermore, the presence of bone or visceral lesions is associated with shorter intervals from treatment than are prostate-bed-only recurrences. These tools might guide clinicians to select the most suitable candidates for 18F-DCFPyL PET/CT imaging.

Radionuclide, magnetic resonance and computed tomography imaging in European round back slugs (Arionidae) and leopard slugs (Limacidae).

Other than in animal models of human disease, little functional imaging has been performed in most of the animal world. The aim of this study was to explore the functional anatomy of the European round back slug (Arionidae) and leopard slug (Limacidae) and to establish an imaging protocol for comparative species study. Radionuclide images with single photon emission computed tomography (SPECT) and positron emission tomography (PET) were obtained after injections of standard clinical radiopharmaceuticals 99mtechnetium dicarboxypropane diphosphonate (bone scintigraphy), 99mtechnetium mercaptoacetyltriglycine (kidney function), 99mtechnetium diethylenetriaminepentaacetic acid (kidney function), 99mtechnetium pertechnetate (mediated by the sodium-iodide symporter), 99mtechnetium sestamibi (cardiac scintigraphy) or 18F-fluoro-deoxyglucose (glucose metabolism) in combination with magnetic resonance imaging (MRI) and computed tomography (CT) for uptake anatomic definition. Images were compared with anatomic drawings for the Arionidae species. Additionally, organ uptake data was determined for a description of slug functional anatomy in comparison to human tracer biodistribution patterns identifying the heart, the open circulatory anatomy, calcified shell remnant, renal structure (nephridium), liver (digestive gland) and intestine. The results show the detailed functional anatomy of Arionidae and Limacidae, and describe an in vivo whole-body imaging procedure for invertebrate species.

Proton MR Spectroscopy Measurements of White and Brown Adipose Tissue in Healthy Humans: Relaxation Parameters and Unsaturated Fatty Acids.

Background Activation of brown adipose tissue (BAT) in rodents increases lipolysis in white adipose tissue (WAT) and improves glucose tolerance. Adult humans can have metabolically active BAT. Implications for diabetes and obesity in humans require a better characterization of BAT in humans. Purpose To study fat depots with localized proton MR spectroscopy relaxometry and to identify differences between WAT and fluorine 18 fluorodeoxyglucose (FDG) PET/CT proven cold-activated BAT in humans. Materials and Methods Participants were consecutively enrolled in this prospective study (ClinicalTrials.gov identifiers: NCT01568671 and NCT01399385) from August 2016 to May 2019. Supraclavicular potential BAT regions were localized with MRI. Proton densities, T1, and T2 were measured with localized MR spectroscopy in potential BAT and in subcutaneous WAT. FDG PET/CT after cold stimulation was used to retrospectively identify active supraclavicular BAT or supraclavicular quiescent adipose tissue (QAT) regions. MR spectroscopy results from BAT and WAT were compared with grouped and paired tests. Results Of 21 healthy participants (mean age, 36 years ± 16 [standard deviation]; 13 men) FDG PET/CT showed active BAT in 24 MR spectroscopy-targeted regions in 16 participants (eight men). Four men had QAT. The T2 for methylene protons was shorter in BAT (mean, 69 msec ± 6, 24 regions) than in WAT (mean, 83 msec ± 3, 18 regions, P < .01) and QAT (mean, 78 msec ± 2, five regions, P < .01). A T2 cut-off value of 76 msec enabled the differentiation of BAT from WAT or QAT with a sensitivity of 85% and a specificity of 95%. Densities of protons adjacent and between double bonds were 33% and 24% lower, respectively, in BAT compared with those in WAT (P = .01 and P = .03, respectively), indicating a lower content of unsaturated and polyunsaturated fatty acids, respectively, in BAT compared with WAT. Conclusion Proton MR spectroscopy showed shorter T2 and lower unsaturated fatty acids in brown adipose tissue (BAT) than that in white adipose tissue in healthy humans. It was feasible to identify BAT with MR spectroscopy without the use of PET/CT or cold stimulation. © RSNA, 2021 See also the editorial by Barker in this issue. Online supplemental material is available for this article.

18F-Fluoroestradiol PET Imaging in a Phase II Trial of Vorinostat to Restore Endocrine Sensitivity in ER+/HER2- Metastatic Breast Cancer.

Histone deacetylase inhibitors (HDACIs) may overcome endocrine resistance in estrogen receptor-positive (ER+) metastatic breast cancer. We tested whether 18F-fluoroestradiol PET imaging would elucidate the pharmacodynamics of combination HDACIs and endocrine therapy. Methods: Patients with ER+/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer with prior clinical benefit from endocrine therapy but later progression on aromatase inhibitor (AI) therapy were given vorinostat (400 mg daily) sequentially or simultaneously with AI. 18F-fluoroestradiol PET and 18F-FDG PET scans were performed at baseline, week 2, and week 8. Results: Eight patients were treated sequentially, and then 15 simultaneously. Eight patients had stable disease at week 8, and 6 of these 8 patients had more than 6 mo of stable disease. Higher baseline 18F-fluoroestradiol uptake was associated with longer progression-free survival. 18F-fluoroestradiol uptake did not systematically increase with vorinostat exposure, indicating no change in regional ER estradiol binding, and 18F-FDG uptake did not show a significant decrease, as would have been expected with tumor regression. Conclusion: Simultaneous HDACIs and AI dosing in patients with cancer resistant to AI alone showed clinical benefit (6 or more months without progression) in 4 of 10 evaluable patients. Higher 18F-fluoroestradiol PET uptake identified patients likely to benefit from combination therapy, but vorinostat did not change ER expression at the level of detection of 18F-fluoroestradiol PET.

Evaluating Biochemically Recurrent Prostate Cancer: Histologic Validation of 18F-DCFPyL PET/CT with Comparison to Multiparametric MRI.

Background Prostate cancer recurrence is found in up to 40% of men with prior definitive (total prostatectomy or whole-prostate radiation) treatment. Prostate-specific membrane antigen PET agents such as 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) may improve detection of recurrence compared with multiparametric MRI; however, histopathologic validation is lacking. Purpose To determine the sensitivity, specificity, and positive predictive value (PPV) of 18F-DCFPyL PET/CT based on histologic analysis and to compare with pelvic multiparametric MRI in men with biochemically recurrent prostate cancer. Materials and Methods Men were prospectively recruited after prostatectomy and/or radiation therapy with rising prostate-specific antigen level (median, 2.27 ng/mL; range, 0.2-27.45 ng/mL) and a negative result at conventional imaging (bone scan and/or CT). Participants underwent 18F-DCFPyL PET/CT imaging and 3.0-T pelvic multiparametric MRI. Statistical analysis included Wald and modified χ2 tests. Results A total of 323 lesions were visualized in 77 men by using 18F-DCFPyL or multiparametric MRI, with imaging detection concordance of 25% (82 of 323) when including all lesions in the MRI field of view and 53% (52 of 99) when only assessing prostate bed lesions. 18F-DCFPyL depicted more pelvic lymph nodes than did MRI (128 vs 23 nodes). Histologic validation was obtained in 80 locations with sensitivity, specificity, and PPV of 69% (25 of 36; 95% confidence interval [CI]: 51%, 88%), 91% (40 of 44; 95% CI: 74%, 98%), and 86% (25 of 29; 95% CI: 73%, 97%) for 18F-DCFPyL and 69% (24 of 35; 95% CI: 50%, 86%), 74% (31 of 42; 95% CI: 42%, 89%), and 69% (24 of 35; 95% CI: 50%, 88%) for multiparametric MRI (P = .95, P = .14, and P = .07, respectively). In the prostate bed, sensitivity, specificity, and PPV were 57% (13 of 23; 95% CI: 32%, 81%), 86% (18 of 21; 95% CI: 73%, 100%), and 81% (13 of 16; 95% CI: 59%, 100%) for 18F-DCFPyL and 83% (19 of 23; 95% CI: 59%, 100%), 52% (11 of 21; 95% CI: 29%, 74%), and 66% (19 of 29; 95% CI: 44%, 86%) for multiparametric MRI (P = .19, P = .02, and P = .17, respectively). The addition of 18F-DCFPyL to multiparametric MRI improved PPV by 38% overall (P = .02) and by 30% (P = .09) in the prostate bed. Conclusion Findings with 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) were histologically validated and demonstrated high specificity and positive predictive value. In the pelvis, 18F-DCFPyL depicted more lymph nodes and improved positive predictive value and specificity when added to multiparametric MRI. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Zukotynski and Rowe in this issue.

18F-DCFPyL PET/CT Imaging in Patients with Biochemically Recurrent Prostate Cancer After Primary Local Therapy.

Our objective was to investigate the lesion detection rate of 18F-DCFPyL PET/CT, a prostate-specific membrane antigen (PSMA)-targeted PET agent, in patients with biochemically relapsed prostate cancer after primary local therapy. Methods: This was a prospective institutional review board-approved study of 90 patients with documented biochemical recurrence (median prostate-specific antigen [PSA], 2.5 ng/mL; range, 0.21-35.5 ng/mL) and negative results on conventional imaging after primary local therapies, including radical prostatectomy (n = 38), radiation (n = 27), or a combination of the two (n = 25). Patients on androgen deprivation therapy were excluded. Patients underwent whole-body 18F-DCFPyL PET/CT (299.9 ± 15.5 MBq) at 2 h after injection. The PSMA PET lesion detection rate was correlated with PSA, PSA kinetics, and original primary tumor grade. Results: Seventy patients (77.8%) showed positive PSMA PET results, with a total of 287 lesions identified: 37 prostate bed foci, 208 lesions in lymph nodes, and 42 in distant sites in bones or organs, Eleven patients had negative results, and 9 patients showed indeterminate lesions, which were considered negative in this study. The detection rates were 47.6% (n = 10/21), 50% (n = 5/10), 88.9% (n = 8/9), and 94% (n = 47/50) for PSA levels of >0.2 to <0.5, 0.5 to <1.0, 1 to <2.0, and ≥2.0 ng/mL, respectively. In postsurgical patients, PSA, PSA doubling time, and PSA velocity correlated with PET results, but the same was not true for postradiation patients. These parameters also correlated with the extent of disease on PET (intrapelvic vs. extrapelvic). There was no significant difference in the rate of positive scans between patients with higher-grade and lower-grade primary tumors (Gleason score of ≥4 + 3 vs. <3 + 4). Tumor recurrence was histology-confirmed in 40% (28/70) of patients. On a per-patient basis, positive predictive value was 93.3% (95% confidence interval, 77.6%-99.2%) by histopathologic validation and 96.2% (95% confidence interval, 86.3%-99.7%) by the combination of histology and imaging/clinical follow-up. Conclusion:18F-DCFPyL PET/CT imaging offers high detection rates in biochemically recurrent prostate cancer patients and is positive in about 50% of patients with a PSA level of less than 0.5 ng/mL, which could substantially impact clinical management. In postsurgical patients, 18F-DCFPyL PET/CT correlates with PSA, PSA doubling time, and PSA velocity, suggesting it may have prognostic value. 18F-DCFPyL PET/CT is highly promising for localizing sites of recurrent prostate cancer.

Normal Values for Parotid Gland and Submandibular-Sublingual Salivary Gland Complex Uptake of 99mTechnetium Pertechnetate using SPECT in Mice with Respect to Age, Sex, and Circadian Rhythm.

AIM: The aim of this study was to establish normal values for parotid gland (PG) and submandibular-sublingual salivary gland complex (SSC) uptake of 99mtechnetium pertechnetate (99mTcO4) as a function of age, sex and circadian rhythm in mice. METHODS: In 12 female (F) and 12 male (M) C57BL/6N mice, nine consecutive SPECT images of 10 min each were acquired as dynamic acquisitions beginning 5 min after intravenous injection of 80 MBq 99mTcO4. Each mouse was imaged in follow-up studies at 1, 3, 6, 12 and 24 months of age. In order to assess for physiologic changes related to circadian rhythm, animals were imaged during light (sleeping phase) as well as during night conditions (awake phase). The percentage tracer uptake of the injected activity is expressed as median %ID. RESULTS: Maximum 99mTcO4 uptake occurred earlier in PG at 11 min compared to SSC at 79 min (p < 0.001). No significant effect of circadian rhythm was observed in PG (p = 0.64) and SSC uptake (p = 0.27). With aging, 99mTcO4 uptake significantly decreased for PG (p < 0.001) while it increased for SSC (p < 0.001). F (0.5) had a significantly higher PG uptake than M (0.3; p < 0.001) up to an age of 24 months. However, SSC uptake of F (4.6) was higher than that of M (3.8; p = 0.014) only at the age of 1 month. Thereafter, F (5.6) had lower SSC uptake than M (9.2; p < 0.001) from 3 months onwards. Normalizing %ID to gland volume showed that F had a significantly higher uptake (%ID/mm3) in both PG (F 0.013; M 0.007; p < 0.001) and in SSC (F 0.110; M 0.075; p < 0.001). CONCLUSION: Uptake patterns differed among PG and SSC with a significant impact of age and sex while circadian rhythm had no significant influence. Therefore, design of salivary gland studies in mice using 99mTcO4 should consider age and sex as relevant factors.

Correction to: a Phase 2 Study of 16α-[18F]-Fluoro-17ß-Estradiol Positron Emission Tomography (FES-PET) as a Marker of Hormone Sensitivity in Metastatic Breast Cancer (MBC).

Two data points from Table 1. (continued) were published in error. The corrected data in Table 1. (continued) are shown, in italic, below.

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.

Normal Values of Thyroid Uptake of 99mTechnetium Pertechnetate SPECT in Mice with Respect to Age, Sex, and Circadian Rhythm.

AIM: The aim of this study was to establish normal values for thyroid uptake of 99mtechnetium pertechnetate (99mTcO4) as a function of age, sex and circadian rhythm in mice. METHODS: In 12 female (F) and 12 male (M) C57BL/6N mice, nine consecutive SPECT images of 10 min duration each were acquired as dynamic acquisitions beginning 5 min after intravenous injection of 80 MBq 99mTcO4. Each mouse was imaged in follow-up studies up to 24 months (A: 1 month; B: 3 months; C: 6 months; D: 12 months; E: 24 months). In order to assess for physiologic changes related to circadian rhythm, animals were imaged during light (sleeping phase, SP) as well as during night conditions (awake phase, AP). The percentage tracer uptake of the injected activity is expressed as median %ID. RESULTS: Female mice showed significantly higher uptake than males (F 1.6, M 1.1; p < 0.001). This effect was observed up to the age of 12 months: A (F 1.6, M 1.1; p < 0.001), B (F 1.7, M 1.1; p < 0.001), C (F 1.8, M 1.2; p < 0.001), D (F 1.6, M 1.2; p < 0.001), E (F 1.1, M 1.1; p = 0.79). Impact of age on uptake could be observed in females (p = 0.056) and was not present in males (p = 0.27). A significant effect of circadian rhythm could not be observed in females (SP 1.6, AP 1.7; p = 0.65) but in males (SP 1.2, AP 1.1; p = 0.02). CONCLUSION: This study showed a significant influence of sex on thyroid 99mTcO4 uptake in mice. Sex was also a significant factor affecting age-related changes in uptake in female mice but not in males. In contrast, circadian rhythm had no relevant impact on 99mTcO4 uptake. Therefore, design of thyroid uptake studies in mice using 99mTcO4 should consider animal sex, and in females, age as significant factors affecting uptake. ZIEL:: Ziel dieser Studie war die Erhebung von Normwerten für den Schilddrüsen Uptake von 99mTechnetium-Pertechnetat (99mTcO4) in Abhängigkeit von Alter, Geschlecht und circadianem Rhythmus bei Mäusen. METHODEN: Bei 12 weiblichen (F) und 12 männlichen (M) C57BL/6N Mäusen wurden neun konsekutive SPECT Akquisitionen von jeweils 10 min Dauer 5 min nach intravenöser Injektion von 80 MBq 99mTcO4 durchgeführt. Jede Maus wurde mehrmals bis zu 24 Monaten untersucht (A: 1 Mo; B: 3 Mo; C: 6 Mo; D: 12 Mo; E: 24 Mo). Um Veränderungen auf Grund des circadianen Rhythmus zu erfassen wurden die Tiere während der Hellphase (Schlafphase, SP) sowie während der Dunkelphase (Wachphase, AP) untersucht. Der prozentuale Tracer Uptake ist als Median %ID der injizierten Aktivität aufgeführt. ERGEBNISSE: Weibchen zeigten einen signifikant höheren Uptake als Männchen (F 1,6, M 1,1; p < 0,001). Dieser Effekt wurde bis zu einem Alter von 12 Mo beobachtet: A (F 1,16, M 1,1; p < 0,001), B (F 1,7, M 1,1; p < 0,001), C (F 1,8, M 1,2; p < 0,001), D (F 1,6, M 1,2; p < 0,001), E (F 1,1, M 1,1; p = 0,79). Ein altersabhängiger Einfluss zeigte sich bei Weibchen (p = 0,056), jedoch nicht bei Männchen (p = 0,27). Ein signifikanter Effekt des circadianen Rhythmus konnte bei Männchen (SP 1,2, AP 1,1; p = 0,02) nicht aber bei Weibchen (SP 1,6, AP 1,7; p = 0,65) beobachtet werden. SCHLUSSFOLGERUNG: Diese Studie zeigt einen signifikant geschlechtsabhängigen Einfluss auf den Schilddrüsen Uptake von 99mTcO4 bei Mäusen. Im Gegensatz zu Männchen treten bei Weibchen altersabhängige Veränderungen im Uptake auf. Dagegen hat der circadiane Rhythmus keinen relevanten Einfluss. Folglich sollte bei dem Design von Schilddrüsenuntersuchungen mit 99mTcO4 bei der Maus Geschlecht und bei weiblichen Tieren auch Alter als signifikante Faktoren berücksichtigt werden.

Positron emission tomography-based assessment of metabolic gradient and other prognostic features in sarcoma.

Intratumoral heterogeneity biomarkers derived from positron emission tomography (PET) imaging with fluorodeoxyglucose (FDG) are of interest for a number of cancers, including sarcoma. A range of radiomic texture variables, adapted from general methodologies for image analysis, has shown promise in the setting. In the context of sarcoma, our group introduced an alternative model-based approach to the measurement of heterogeneity. In this approach, the heterogeneity of a tumor is characterized by the extent to which the 3-D FDG uptake pattern deviates from a simple elliptically contoured structure. By using a nonparametric analysis of the uptake profile obtained from this spatial model, a variable assessing the metabolic gradient of the tumor is developed. The work explores the prognostic potential of this new variable in the context of FDG-PET imaging of sarcoma. A mature clinical series involving 197 patients, 88 of whom have complete time-to-death information, is used. Texture variables based on the imaging data are also evaluated in this series and a range of appropriate machine learning methodologies are then used to explore the complementary prognostic roles for structure and texture variables. We conclude that both texture-based and model-based variables can be combined to achieve enhanced prognostic assessments of outcome for patients with sarcoma based on FDG-PET imaging information.

Concurrent SPECT/PET-CT imaging as a method for tracking adoptively transferred T-cells in vivo.

BACKGROUND: The ability of T-cells to traffic to and penetrate tumors impacts the clinical efficacy of T-cell therapy therefore methods to track transferred T-cells in vivo are needed. In this preliminary report, we evaluated the use of concurrent SPECT/PET-CT imaging to monitor the egress of HER-2/neu specific T-cells in a breast cancer patient with extensive bone-only metastatic disease. FINDINGS: Indium (In-111) labeled T-cells demonstrated similar or greater viability than unlabeled T-cells at either a low or high dose of In-111 over a 24-h incubation period in vitro. The function of labeled or unlabeled T-cells was not significantly different (p > 0.05) at either dose. T-cells trafficked to all sites of metastatic disease and infiltrated the tumor as assessed by SPECT imaging. In-111 uptake at 24 h after infusion varied from 3.8 (right proximal humerus) to 6.3 (right sacrum) background corrected counts per pixel and remained elevated at 48 h. Concurrent PET-CT imaging demonstrated a fluorodeoxyglucose flare, measured by increase in tumor site uptake as high as 32 % and at most sites of disease at 48 h. This flare was associated with focal pain after T-cell infusion at metastatic sites. The patient had stable disease for 18 months after completion of T-cell therapy. CONCLUSION: Concurrent SPECT/PET-CT imaging, over a 48-h period after T-cell infusion, provided evidence of T-cell homing to all disease sites as well as a tumor metabolism flare response. This technique may be useful for monitoring T-cell trafficking after autologous as well as chimeric antigen receptor T-cell infusion. TRIAL REGISTRAION: Trial registered at ClinicalTrials.gov registration number NCT00791037, registered 13 November 2008.

S0502: A SWOG Phase III Randomized Study of Imatinib, With or Without Bevacizumab, in Patients With Untreated Metastatic or Unresectable Gastrointestinal Stromal Tumors.

LESSONS LEARNED: Despite having significant rationale, S0502 failed to accrue for a number of reasons.Vetting a trial first, with scientific experts and funding agencies, does not guarantee success, especially when dealing with a rare tumor and/or one with an existing highly effective therapy.In the present case, adding an intravenous drug to an oral medication as part of a regimen expected to be continued for many years likely decreased patient (and physician) convenience and, thus, interest in the study. BACKGROUND: Imatinib mesylate, a potent inhibitor of the KIT and PDGFR tyrosine kinases, is highly effective in the treatment of advanced gastrointestinal stromal tumors (GISTs). However, most imatinib-treated tumors eventually become resistant, accounting for a median progression-free survival of 19-23 months. Expression of vascular endothelial growth factor (VEGF) correlates with poor prognosis in GIST; bevacizumab, a monoclonal antibody against VEGF, is effective in a variety of solid tumors. We postulated combination therapy with imatinib plus bevacizumab would benefit patients with advanced GIST, particularly those reliant on VEGFA-dependent angiogenesis. METHODS: Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial, S0502. At registration, patients were randomly assigned to either imatinib 400 mg (standard) or 800 mg (patients with exon 9 KIT mutations), or imatinib plus bevacizumab, 7.5 mg/kg i.v. every 3 weeks. Patients were treated to progression, symptomatic deterioration, unacceptable toxicity, treatment delay greater than 4 weeks, or patient choice to withdraw from the study. The primary objective was to determine whether the addition of bevacizumab to imatinib would improve progression-free survival (PFS) in first-line treatment of incurable GIST. RESULTS: S0502 opened on April 15, 2008. As of fall 2009, only 12 patients from at least 178 eligible SWOG centers plus those participating through Cancer Trials Support Unit had been entered in the study. Despite an aggressive promotion scheme involving the other cooperative groups and a major GIST patient advocacy group, accrual remained slow. The trial was closed on October 1, 2009, having accrued only 2% of the 572 patients planned. No scientific conclusions were forthcoming because of the small number of patients entered in the study. Two patients of the 6 in the combination arm reported grade 3 toxicities, 1 with proteinuria and 1 with fatigue, upper gastrointestinal hemorrhage, and anemia. CONCLUSION: No conclusions may be drawn from this trial and, thus, the combination of imatinib plus bevacizumab cannot be recommended for use.

Modulation of P-glycoprotein at the Human Blood-Brain Barrier by Quinidine or Rifampin Treatment: A Positron Emission Tomography Imaging Study.

Permeability-glycoprotein (P-glycoprotein, P-gp), an efflux transporter at the human blood-brain barrier (BBB), is a significant obstacle to central nervous system (CNS) delivery of P-gp substrate drugs. Using positron emission tomography imaging, we investigated P-gp modulation at the human BBB by an approved P-gp inhibitor, quinidine, or the P-gp inducer, rifampin. Cerebral blood flow (CBF) and BBB P-gp activity were respectively measured by administration of (15)O-water followed by (11)C-verapamil. In a crossover design, healthy volunteers received quinidine and 11-29 days of rifampin treatment during different study periods. CBF and P-gp activity was measured in the absence (control; prior to quinidine treatment) and presence of P-gp modulation. At clinically relevant quinidine plasma concentrations, P-gp inhibition resulted in a 60% increase in (11)C-radioactivity distribution across the human BBB as measured by the brain extraction ratio (ER) of (11)C-radioactivity. Furthermore, the magnitude of BBB P-gp inhibition by quinidine was successfully predicted by a combination of in vitro and macaque data, but not by rat data. Although our findings demonstrated that quinidine did not completely inhibit P-gp at the human BBB, it has the potential to produce clinically significant CNS drug interactions with P-gp substrate drugs that exhibit a narrow therapeutic window and are significantly excluded from the brain by P-gp. Rifampin treatment induced systemic CYP3A metabolism of (11)C-verapamil; however, it reduced the ER by 6%. Therefore, we conclude that rifampin, at its usual clinical dose, cannot be used to induce P-gp at the human BBB to a clinically meaningful extent and is unlikely to cause inadvertent BBB-inductive drug interactions.

Noninvasive imaging of experimental lung fibrosis.

Small animal models of lung fibrosis are essential for unraveling the molecular mechanisms underlying human fibrotic lung diseases; additionally, they are useful for preclinical testing of candidate antifibrotic agents. The current end-point measures of experimental lung fibrosis involve labor-intensive histological and biochemical analyses. These measures fail to account for dynamic changes in the disease process in individual animals and are limited by the need for large numbers of animals for longitudinal studies. The emergence of noninvasive imaging technologies provides exciting opportunities to image lung fibrosis in live animals as often as needed and to longitudinally track the efficacy of novel antifibrotic compounds. Data obtained by noninvasive imaging provide complementary information to histological and biochemical measurements. In addition, the use of noninvasive imaging in animal studies reduces animal usage, thus satisfying animal welfare concerns. In this article, we review these new imaging modalities with the potential for evaluation of lung fibrosis in small animal models. Such techniques include micro-computed tomography (micro-CT), magnetic resonance imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), and multimodal imaging systems including PET/CT and SPECT/CT. It is anticipated that noninvasive imaging will be increasingly used in animal models of fibrosis to gain insights into disease pathogenesis and as preclinical tools to assess drug efficacy.