Assessment of the biodistribution of an [ 18 F]FDG‐loaded perfluorocarbon double emulsion using dynamic micro‐PET in rats

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97497/1/cmmi1532.pd

Accuracy of tumor segmentation from multi-parametric prostate MRI and 18F-choline PET/CT for focal prostate cancer therapy applications

Abstract Background The study aims to assess the accuracy of multi-parametric prostate MRI (mpMRI) and 18F-choline PET/CT in tumor segmentation for clinically significant prostate cancer. 18F-choline PET/CT and 3 T mpMRI were performed in 10 prospective subjects prior to prostatectomy. All subjects had a single biopsy-confirmed focus of Gleason ≥ 3+4 cancer. Two radiologists (readers 1 and 2) determined tumor boundaries based on in vivo mpMRI sequences, with clinical and pathologic data available. 18F-choline PET data were co-registered to T2-weighted 3D sequences and a semi-automatic segmentation routine was used to define tumor volumes. Registration of whole-mount surgical pathology to in vivo imaging was conducted utilizing two ex vivo prostate specimen MRIs, followed by gross sectioning of the specimens within a custom-made 3D-printed plastic mold. Overlap and similarity coefficients of manual segmentations (seg1, seg2) and 18F-choline-based segmented lesions (seg3) were compared to the pathologic reference standard. Results All segmentation methods greatly underestimated the true tumor volumes. Human readers (seg1, seg2) and the PET-based segmentation (seg3) underestimated an average of 79, 80, and 58% of the tumor volumes, respectively. Combining segmentation volumes (union of seg1, seg2, seg3 = seg4) decreased the mean underestimated tumor volume to 42% of the true tumor volume. When using the combined segmentation with 5 mm contour expansion, the mean underestimated tumor volume was significantly reduced to 0.03 ± 0.05 mL (2.04 ± 2.84%). Substantial safety margins up to 11–15 mm were needed to include all tumors when the initial segmentation boundaries were drawn by human readers or the semi-automated 18F-choline segmentation tool. Combining MR-based human segmentations with the metabolic information based on 18F-choline PET reduced the necessary safety margin to a maximum of 9 mm to cover all tumors entirely. Conclusions To improve the outcome of focal therapies for significant prostate cancer, it is imperative to recognize the full extent of the underestimation of tumor volumes by mpMRI. Combining metabolic information from 18F-choline with MRI-based segmentation can improve tumor coverage. However, this approach requires confirmation in further clinical studies.https://deepblue.lib.umich.edu/bitstream/2027.42/142871/1/13550_2018_Article_377.pd

A novel canine model for prostate cancer

BACKGROUND No existing animal model fully recapitulates all features of human prostate cancer. The dog is the only large mammal, besides humans, that commonly develops spontaneous prostate cancer. Canine prostate cancer features many similarities with its human counterpart. We sought to develop a canine model of prostate cancer that would more fully represent the features of human prostate cancer than existing models. METHODS The Ace‐1 canine prostate cancer cell line was injected transabdominally under transrectal ultrasound (TRUS) guidance into the prostates of immunosuppressed, intact, adult male dogs. Tumor progression was monitored by TRUS imaging. Some dogs were subjected to positron emission tomography (PET) for tumor detection. Time of euthanasia was determined based on tumor size, impingement on urethra, and general well‐being. Euthanasia was followed by necropsy and histopathology. RESULTS Ace‐1 tumor cells grew robustly in every dog injected. Tumors grew in subcapsular and parenchymal regions of the prostate. Tumor tissue could be identified using PET. Histological findings were similar to those observed in human prostate cancer. Metastases to lungs and lymph nodes were detected, predominantly in dogs with intraprostatic tumors. CONCLUSIONS We have established a minimally invasive dog model of prostate cancer. This model may be valuable for studying prostate cancer progression and distant metastasis. Prostate 73: 952–959, 2013. © 2013 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98364/1/22642_ftp.pd

PSMA PET Validates Higher Rates of Metastatic Disease for European Association of Urology Biochemical Recurrence Risk Groups: An International Multicenter Study.

The European Association of Urology (EAU) prostate cancer guidelines panel recommends risk groups for biochemical recurrence (BCR) of prostate cancer to identify men at high risk of progression or metastatic disease. The rapidly growing availability of PSMA-directed PET imaging will impact prostate cancer staging. We determined the rates of local and metastatic disease in BCR and biochemical persistence (BCP) of prostate cancer stratified by EAU BCR risk groups and BCP. Methods: Patients with BCR or BCP were enrolled under the same prospective clinical trial protocol conducted at 3 sites (n = 1,777 [91%]: UCLA, n = 662 [NCT02940262]; University of California San Francisco, n = 508 [NCT03353740]; University of Michigan, n = 607 [NCT03396874]); 183 patients with BCP from the Universities of Essen, Bologna, and Munich were included retrospectively. Patients with BCR had to have sufficient data to determine the EAU risk score. Multivariate, binomial logistic regression models were applied to assess independent predictors of M1 disease. Results: In total, 1,960 patients were included. Post-radical prostatectomy EAU BCR low-risk, EAU BCR high-risk, and BCP groups yielded distant metastatic (M1) detection in 43 of 176 (24%), 342 of 931 (37%), and 154 of 386 (40%) patients. For postradiotherapy EAU BCR low-risk and EAU BCR high-risk groups, the M1 detection rate was 113 of 309 (37%) and 110 of 158 (70%), respectively. BCP, high-risk BCR, and higher levels of serum prostate-specific antigen were significantly associated with PSMA PET M1 disease in multivariate regression analysis. PSMA PET revealed no disease in 25% and locoregional-only disease in 33% of patients with post-radical prostatectomy or postradiotherapy EAU BCR high risk. Conclusion: Our findings support the new EAU classification; EAU BCR high-risk groups have higher rates of metastatic disease on PSMA PET than do the low-risk groups. Discordant subgroups, including metastatic disease in low-risk patients and no disease in high-risk patients, warrant inclusion of PSMA PET stage to refine risk assessment

Cyclotron-based production of 68Ga, [68Ga]GaCl3, and [68Ga]Ga-PSMA-11 from a liquid target

Abstract Purpose To optimize the direct production of 68Ga on a cyclotron, via the 68Zn(p,n)68Ga reaction using a liquid cyclotron target. We Investigated the yield of cyclotron-produced 68Ga, extraction of [68Ga]GaCl3 and subsequent [68Ga]Ga-PSMA-11 labeling using an automated synthesis module. Methods Irradiations of a 1.0 M solution of [68Zn]Zn(NO3)2 in dilute (0.2–0.3 M) HNO3 were conducted using GE PETtrace cyclotrons and GE 68Ga liquid targets. The proton beam energy was degraded to a nominal 14.3 MeV to minimize the co-production of 67Ga through the 68Zn(p,2n)67Ga reaction without unduly compromising 68Ga yields. We also evaluated the effects of varying beam times (50–75 min) and beam currents (27–40 μA). Crude 68Ga production was measured. The extraction of [68Ga]GaCl3 was performed using a 2 column solid phase method on the GE FASTlab Developer platform. Extracted [68Ga]GaCl3 was used to label [68Ga]Ga-PSMA-11 that was intended for clinical use. Results The decay corrected yield of 68Ga at EOB was typically > 3.7 GBq (100 mCi) for a 60 min beam, with irradiations of [68Zn]Zn(NO3)2 at 0.3 M HNO3. Target/chemistry performance was more consistent when compared with 0.2 M HNO3. Radionuclidic purity of 68Ga was typically > 99.8% at EOB and met the requirements specified in the European Pharmacopoeia ( 50% (~ 1.85 GBq, 50 mCi); yields improved as processes were optimized. Labeling yields for [68Ga]Ga-PSMA-11 were near quantitative (~ 1.67 GBq, 45 mCi) at EOS. Cyclotron produced [68Ga]Ga-PSMA-11 underwent full quality control, stability and sterility testing, and was implemented for human use at the University of Michigan as an Investigational New Drug through the US FDA and also at the Royal Prince Alfred Hospital (RPA). Conclusion Direct cyclotron irradiation of a liquid target provides clinically relevant quantities of [68Ga]Ga-PSMA-11 and is a viable alternative to traditional 68Ge/68Ga generators.http://deepblue.lib.umich.edu/bitstream/2027.42/174048/1/41181_2020_Article_106.pd

A Comprehensive Assessment of 68Ga-PSMA-11 PET in Biochemically Recurrent Prostate Cancer: Results from a Prospective Multicenter Study on 2,005 Patients.

We prospectively investigated the performance of the prostate-specific membrane antigen (PSMA) ligand 68Ga-PSMA-11 for detecting prostate adenocarcinoma in patients with elevated levels of prostate-specific antigen (PSA) after initial therapy. Methods: 68Ga-PSMA-11 hybrid PET was performed on 2,005 patients at the time of biochemically recurrent prostate cancer after radical prostatectomy (RP) (50.8%), definitive radiation therapy (RT) (19.7%), or RP with postoperative RT (PORT) (29.6%). The presence of prostate cancer was assessed qualitatively (detection rate = positivity rate) and quantitatively on a per-patient and per-region basis, creating a disease burden estimate from the presence or absence of local (prostate/prostate bed), nodal (N1: pelvis), and distant metastatic (M1: distant soft tissue and bone) disease. The primary study endpoint was the positive predictive value (PPV) of 68Ga-PSMA-11 PET/CT confirmed by histopathology. Results: After RP, the scan detection rate increased significantly with rising PSA level (44.8% at PSA < 0.25%-96.2% at PSA > 10 ng/mL; P < 0.001). The detection rate significantly increased with rising PSA level in each individual region, overall disease burden, prior androgen deprivation, clinical T-stage, and Gleason grading from the RP specimen (P < 0.001). After RT, the detection rate for in-gland prostate recurrence was 64.0%, compared with 20.6% prostate bed recurrence after RP and 13.3% after PORT. PSMA-positive pelvic nodal disease was detected in 42.7% after RP, 40.8% after PORT, and 38.8% after RT. In patients with histopathologic validation, the PPV per patient was 0.82 (146/179). The SUVmax of histologically proven true-positive lesions was significantly higher than that of false-positive lesions (median, 11.0 [interquartile range, 6.3-22.2] vs. 5.1 [interquartile range, 2.2-7.4]; P < 0.001). Conclusion: We confirmed a high PPV for 68Ga-PSMA-11 PET in biochemical recurrence and the PSA level as the main predictor of scan positivity

Diagnostic Performance of 18F-DCFPyL-PET/CT in Men with Biochemically Recurrent Prostate Cancer: Results from the CONDOR Phase III, Multicenter StudyCONDOR Trial

PurposeCurrent FDA-approved imaging modalities are inadequate for localizing prostate cancer biochemical recurrence (BCR). 18F-DCFPyL is a highly selective, small-molecule prostate-specific membrane antigen-targeted PET radiotracer. CONDOR was a prospective study designed to determine the performance of 18F-DCFPyL-PET/CT in patients with BCR and uninformative standard imaging.Experimental designMen with rising PSA ≥0.2 ng/mL after prostatectomy or ≥2 ng/mL above nadir after radiotherapy were eligible. The primary endpoint was correct localization rate (CLR), defined as positive predictive value with an additional requirement of anatomic lesion colocalization between 18F-DCFPyL-PET/CT and a composite standard of truth (SOT). The SOT consisted of, in descending priority (i) histopathology, (ii) subsequent correlative imaging findings, or (iii) post-radiation PSA response. The trial was considered a success if the lower bound of the 95% confidence interval (CI) for CLR exceeded 20% for two of three 18F-DCFPyL-PET/CT readers. Secondary endpoints included change in intended management and safety.ResultsA total of 208 men with a median baseline PSA of 0.8 ng/mL (range: 0.2-98.4 ng/mL) underwent 18F-DCFPyL-PET/CT. The CLR was 84.8%-87.0% (lower bound of 95% CI: 77.8-80.4). A total of 63.9% of evaluable patients had a change in intended management after 18F-DCFPyL-PET/CT. The disease detection rate was 59% to 66% (at least one lesion detected per patient by 18F-DCFPyL-PET/CT by central readers).ConclusionsPerformance of 18F-DCFPyL-PET/CT achieved the study's primary endpoint, demonstrating disease localization in the setting of negative standard imaging and providing clinically meaningful and actionable information. These data further support the utility of 18F-DCFPyL-PET/CT to localize disease in men with recurrent prostate cancer.See related commentary by True and Chen, p. 3512

A Phase 2 Study of Dose-intensified Chemoradiation Using Biologically Based Target Volume Definition in Patients With Newly Diagnosed Glioblastoma

PURPOSE: We hypothesized that dose-intensified chemoradiation therapy targeting adversely prognostic hypercellular (TV) and hyperperfused (TV) tumor volumes would improve outcomes in patients with glioblastoma. METHODS AND MATERIALS: This single-arm, phase 2 trial enrolled adult patients with newly diagnosed glioblastoma. Patients with a TV/TV \u3e1 cm, identified using high b-value diffusion-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced perfusion MRI, were treated over 30 fractions to 75 Gy to the TV/TV with temozolomide. The primary objective was to estimate improvement in 12-month overall survival (OS) versus historical control. Secondary objectives included evaluating the effect of 3-month TV/TV reduction on OS using Cox proportional-hazard regression and characterizing coverage (95% isodose line) of metabolic tumor volumes identified using correlative C-methionine positron emission tomography. Clinically meaningful change was assessed for quality of life by the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30, for symptom burden by the MD Anderson Symptom Inventory for brain tumor, and for neurocognitive function (NCF) by the Controlled Oral Word Association Test, the Trail Making Test, parts A and B, and the Hopkins Verbal Learning Test-Revised. RESULTS: Between 2016 and 2018, 26 patients were enrolled. Initial patients were boosted to TV alone, and 13 patients were boosted to both TV/TV. Gross or subtotal resection was performed in 87% of patients; 22% were O-methylguanine-DNA methyltransferase (MGMT) methylated. With 26-month follow-up (95% CI, 19-not reached), the 12-month OS rate among patients boosted to the combined TV/TV was 92% (95% CI, 78%-100%; P = .03) and the median OS was 20 months (95% CI, 18-not reached); the median OS for the whole study cohort was 20 months (95% CI, 14-29 months). Patients whose 3-month TV/TV decreased to less than the median volume (3 cm) had superior OS (29 vs 12 months; P = .02). Only 5 patients had central or in-field failures, and 93% (interquartile range, 59%-100%) of the C-methionine metabolic tumor volumes received high-dose coverage. Late grade 3 neurologic toxicity occurred in 2 patients. Among non-progressing patients, 1-month and 7-month deterioration in quality of life, symptoms, and NCF were similar in incidence to standard therapy. CONCLUSIONS: Dose intensification against hypercellular/hyperperfused tumor regions in glioblastoma yields promising OS with favorable outcomes for NCF, symptom burden, and quality of life, particularly among patients with greater tumor reduction 3 months after radiation therapy