Yolanda McKinney

Prostate cancer: value of multiparametric MR imaging at 3 T for detection--histopathologic correlation.

PURPOSE To determine utility of multiparametric imaging performed at 3 T for detection of prostate cancer by using T2-weighted magnetic resonance (MR) imaging, MR spectroscopy, and dynamic contrast material-enhanced MR imaging, with whole-mount pathologic findings as reference standard. MATERIALS AND METHODS This prospectively designed, HIPAA-compliant, single-institution study was approved by the local institutional review board. Seventy consecutive patients (mean age, 60.4 years; mean prostate-specific antigen level, 5.47 ng/mL [5.47 microg/L]; range, 1-19.9 ng/mL [1-19.9 microg/L]) were included; informed consent was obtained from each patient. All patients had biopsy-proved prostate cancer, with a median Gleason score of 7 (range, 6-9). Images were obtained by using a combination of six-channel cardiac and endorectal coils. MR imaging and pathologic findings were evaluated independently and blinded and then correlated with histopathologic findings by using side-by-side comparison. Analyses were conducted with a raw stringent approach and an alternative neighboring method, which accounted for surgical deformation, shrinkage, and nonuniform slicing factors in pathologic specimens. Generalized estimating equations (GEEs) were used to estimate the predictive value of region-specific, pathologically determined cancer for all three modalities. This approach accounts for the correlation among multiple regions in the same individual. RESULTS For T2-weighted MR imaging, sensitivity and specificity values obtained with stringent approach were 0.42 (95% confidence interval [CI]: 0.36, 0.47) and 0.83 (95% CI: 0.81, 0.86), and for the alternative neighboring approach, sensitivity and specificity values were 0.73 (95% CI: 0.67, 0.78) and 0.89 (95% CI: 0.85, 0.93), respectively. The combined diagnostic accuracy of T2-weighted MR imaging, dynamic contrast-enhanced MR imaging, and MR spectroscopy for peripheral zone tumors was examined by calculating their predictive value with different combinations of techniques; T2-weighted MR imaging, dynamic contrast-enhanced MR imaging, and MR spectroscopy provided significant independent and additive predictive value when GEEs were used (P < .001, P = .02, P = .002, respectively). CONCLUSION Multiparametric MR imaging (T2-weighted MR imaging, MR spectroscopy, dynamic contrast-enhanced MR imaging) of the prostate at 3 T enables tumor detection, with reasonable sensitivity and specificity values.

Multiparametric 3T prostate magnetic resonance imaging to detect cancer: histopathological correlation using prostatectomy specimens processed in customized magnetic resonance imaging based molds.

PURPOSE We determined the prostate cancer detection rate of multiparametric magnetic resonance imaging at 3T. Precise one-to-one histopathological correlation with magnetic resonance imaging was possible using prostate magnetic resonance imaging based custom printed specimen molds after radical prostatectomy. MATERIALS AND METHODS This institutional review board approved prospective study included 45 patients (mean age 60.2 years, range 49 to 75) with a mean prostate specific antigen of 6.37 ng/ml (range 2.3 to 23.7) who had biopsy proven prostate cancer (mean Gleason score of 6.7, range 6 to 9). Before prostatectomy all patients underwent prostate magnetic resonance imaging using endorectal and surface coils on a 3T scanner, which included triplane T2-weighted magnetic resonance imaging, apparent diffusion coefficient maps of diffusion weighted magnetic resonance imaging, dynamic contrast enhanced magnetic resonance imaging and spectroscopy. The prostate specimen was whole mount sectioned in a customized mold, allowing geometric alignment to magnetic resonance imaging. Tumors were mapped on magnetic resonance imaging and histopathology. Sensitivity, specificity, positive predictive value and negative predictive value of magnetic resonance imaging for cancer detection were calculated. In addition, the effects of tumor size and Gleason score on the sensitivity of multiparametric magnetic resonance imaging were evaluated. RESULTS The positive predictive value of multiparametric magnetic resonance imaging to detect prostate cancer was 98%, 98% and 100% in the overall prostate, peripheral zone and central gland, respectively. The sensitivity of magnetic resonance imaging sequences was higher for tumors larger than 5 mm in diameter as well as for those with higher Gleason scores (greater than 7, p <0.05). CONCLUSIONS Prostate magnetic resonance imaging at 3T allows for the detection of prostate cancer. A multiparametric approach increases the predictive power of magnetic resonance imaging for diagnosis. In this study accurate correlation between multiparametric magnetic resonance imaging and histopathology was obtained by the patient specific, magnetic resonance imaging based mold technique.

Correlation of Magnetic Resonance Imaging Tumor Volume with Histopathology

PURPOSE The biology of prostate cancer may be influenced by the index lesion. The definition of index lesion volume is important for appropriate decision making, especially for image guided focal treatment. We determined the accuracy of magnetic resonance imaging for determining index tumor volume compared with volumes derived from histopathology. MATERIALS AND METHODS We evaluated 135 patients (mean age 59.3 years) with a mean prostate specific antigen of 6.74 ng/dl who underwent multiparametric 3T endorectal coil magnetic resonance imaging of the prostate and subsequent radical prostatectomy. Index tumor volume was determined prospectively and independently by magnetic resonance imaging and histopathology. The ellipsoid formula was applied to determine histopathology tumor volume, whereas manual tumor segmentation was used to determine magnetic resonance tumor volume. Histopathology tumor volume was correlated with age and prostate specific antigen whereas magnetic resonance tumor volume involved Pearson correlation and linear regression methods. In addition, the predictive power of magnetic resonance tumor volume, prostate specific antigen and age for estimating histopathology tumor volume (greater than 0.5 cm(3)) was assessed by ROC analysis. The same analysis was also conducted for the 1.15 shrinkage factor corrected histopathology data set. RESULTS There was a positive correlation between histopathology tumor volume and magnetic resonance tumor volume (Pearson coefficient 0.633, p <0.0001), but a weak correlation between prostate specific antigen and histopathology tumor volume (Pearson coefficient 0.237, p = 0.003). On linear regression analysis histopathology tumor volume and magnetic resonance tumor volume were correlated (r(2) = 0.401, p <0.00001). On ROC analysis AUC values for magnetic resonance tumor volume, prostate specific antigen and age in estimating tumors larger than 0.5 cm(3) at histopathology were 0.949 (p <0.0000001), 0.685 (p = 0.001) and 0.627 (p = 0.02), respectively. Similar results were found in the analysis with shrinkage factor corrected tumor volumes at histopathology. CONCLUSIONS Magnetic resonance imaging can accurately estimate index tumor volume as determined by histology. Magnetic resonance imaging has better accuracy in predicting histopathology tumor volume in tumors larger than 0.5 cm(3) than prostate specific antigen and age. Index tumor volume as determined by magnetic resonance imaging may be helpful in planning treatment, specifically in identifying tumor margins for image guided focal therapy and possibly selecting better active surveillance candidates.

11C-Acetate PET/CT in Localized Prostate Cancer: A Study with MRI and Histopathologic Correlation

This work characterizes the uptake of 11C-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 11C-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 11C-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. 11C-acetate PET standardized uptake values were compared with multiparametric MRI and pathology. Results: 11C-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 11C-acetate PET/CT and 82.3% and 95.1%, respectively, for MRI. The 11C-acetate accuracy was comparable to that of MRI when only tumors greater than 0.9 cm were considered. In a small cohort (n = 9), 11C-acetate uptake was independent of fatty acid synthase expression using immunohistochemistry. Conclusion: 11C-acetate PET/CT demonstrates higher uptake in tumor foci than in normal prostate tissue; however, 11C-acetate uptake in tumors is similar to that in benign prostate hyperplasia nodules. Although 11C-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.

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.

A Phase I Dosing Study of Ferumoxytol for MR Lymphography at 3 T in Patients With Prostate Cancer

OBJECTIVE The objective of our study was to determine the optimal dose of ferumoxytol for performing MR lymphography (MRL) at 3 T in patients with prostate cancer. SUBJECTS AND METHODS This phase I trial enrolled patients undergoing radical prostatectomy (RP) with bilateral pelvic lymph node dissection (PLND). Three groups of five patients each (total of 15 patients) received IV ferumoxytol before RP with bilateral PLND at each of the following doses of iron: 4, 6, and 7.5 mg Fe/kg. Patients underwent abdominopelvic MRI at 3 T before and 24 hours after ferumoxytol injection using T2- and T2*-weighted sequences. Normalized signal intensity (SI) and normalized SD changes from baseline to 24 hours after injection within visible lymph nodes were calculated for each dose level. Linear mixed effects models were used to estimate the effects of dose on the percentage SI change and log-transformed SD change within visible lymph nodes to determine the optimal dose of ferumoxytol for achieving uniform low SI in normal nodes. RESULTS One patient who was excluded from the study group had a mild allergic reaction requiring treatment after approximately 2.5 mg Fe/kg ferumoxytol injection whereupon the injection was interrupted. The 15 study group patients tolerated ferumoxytol at all dose levels. The mean percentage SI change in 13 patients with no evidence of lymph metastasis was -36.4%, -45.4%, and -65.1% for 4, 6, and 7.5 mg Fe/kg doses, respectively (p = 0.041). CONCLUSION A dose level of 7.5 mg Fe/kg ferumoxytol was safe and effective in deenhancing benign lymph nodes. This dose therefore can be the starting point for future phase II studies regarding the efficacy of ferumoxytol for MRL.

A Prospective Comparison of 18F-Sodium Fluoride PET/CT and PSMA-targeted 18F-DCFBC PET/CT in Metastatic Prostate Cancer

The purpose of this study was to compare the diagnostic performance of 18F-DCFBC PET/CT, a first-generation 18F-labeled prostate-specific membrane antigen (PSMA)–targeted agent, and 18F-NaF PET/CT, a sensitive marker of osteoblastic activity, in a prospective cohort of patients with metastatic prostate cancer. Methods: Twenty-eight prostate cancer patients with metastatic disease on conventional imaging prospectively received up to 4 PET/CT scans. All patients completed baseline 18F-DCFBC PET/CT and 18F-NaF PET/CT scans, and 23 patients completed follow-up imaging, with a median follow-up interval of 5.7 mo (range, 4.2–12.6 mo). Lesion detection was compared across the 2 PET/CT agents at each time point. Detection and SUV characteristics of each PET/CT agent were compared with serum prostate-specific antigen (PSA) levels and treatment status at the time of baseline imaging using nonparametric statistical testing (Spearman correlation, Wilcoxon rank). Results: Twenty-six patients had metastatic disease detected on 18F-NaF or 18F-DCFBC at baseline, and 2 patients were negative on both scans. Three patients demonstrated soft tissue–only disease. Of 241 lesions detected at baseline, 56 were soft-tissue lesions identified by 18F-DCFBC only and 185 bone lesions detected on 18F-NaF or 18F-DCFBC. 18F-NaF detected significantly more bone lesions than 18F-DCFBC (P < 0.001). Correlation of PSA with patient-level SUV metrics was strong in 18F-DCFBC (ρ > 0.5, P < 0.01) and poor in 18F-NaF (ρ < 0.3, P > 0.1). When PSA levels were combined with treatment status, patients with below-median levels of PSA (<2 ng/mL) on androgen deprivation therapy (n = 11) demonstrated more lesions on 18F-NaF than 18F-DCFBC (P = 0.02). In PSA greater than 2 ng/mL, patients on androgen deprivation therapy (n = 8) showed equal to or more lesions on 18F-DCFBC than on 18F-NaF. Conclusion: The utility of PSMA-targeting imaging in metastatic prostate cancer appears to depend on patient disease course and treatment status. Compared with 18F-NaF PET/CT, 18F-DCFBC PET/CT detected significantly fewer bone lesions in the setting of early or metastatic castrate-sensitive disease on treatment. However, in advanced metastatic castrate-resistant prostate cancer, 18F-DCFBC PET/CT shows good concordance with NaF PET/CT.

Ferumoxytol enhanced MRI for lymph node staging in prostate cancer.

208 Background: Conventional imaging methods of lymph node staging in prostate cancer are limited. The goal of this study is to determine the utility of ferumoxytol enhanced MRI in lymph node (LN) staging. Methods: This ongoing IRB-approved clinical trial enrolls prostate cancer patients at high risk for LN metastases. Patients first undergo baseline T2 and T2* weighted MRI scans followed by 7.5mg/Kg ferumoxytol injection. Repeat scans are acquired at 24 hr and 48 hr post-injection. The criterion for positive LNs was hyperintense signal indicating failure to take up ferumoxytol. Validation was determined on clinical grounds or by histopathology when available. Results: To date, 11 patients have completed the study. One patient was examined pre-operatively while the other 10 had suspected therapy failure. Median age and PSA were 65 yrs (36-75) and 5.6ng/dL (0.3-201). Of 16 LNs with median size 1.6 x 1.1cm, 10 were true positives, one was false positive and one was false negative with 4 nodes pending valida...

Abstract CT222: Ferumoxytol enhanced MRI for lymph node staging in genitourinary cancers

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Conventional imaging has limited accuracy in genitourinary (GU) cancer staging. This study examines the utility of ferumoxytol enhanced MRI in lymph node (LN) staging of GU cancers. Methods: This ongoing IRB-approved phase II clinical trial enrolls patients with prostate cancer, renal cell carcinoma, or bladder cancer at high risk for LN metastases. Patients undergo baseline T2 and T2* weighted MRI scans followed by injection of 7.5mg/Kg ferumoxytol. Repeat scans are acquired at 24hr and 48hr post-injection. The criterion for positive LNs was preservation of hyper-intense signal indicating failure to take up ferumoxytol. Validation was by histopathology when available or on clinical grounds, for which LNs that changed size on routine imaging were considered true positives. Results: To date, 13 patients have completed the study. Of 11 prostate cancer patients, one was studied pre-operatively while 10 had suspected therapy failure. Median age and PSA were 65yrs (36-75) and 5.6ng/mL (0.3-201). The other 2 patients had renal cell carcinoma and bladder cancer. Overall, 20 LNs were identified with mean size 1.9cm (0.7-3.8) long axis by 1.3cm (0.6-2.6) short axis. There were 14 true positive LNs, 1 false positive, 1 false negative, and 4 nodes pending validation. Validation was by histopathology for 7 LNs, with 2 nodes pending biopsy, and clinical grounds for 13 LNs, with 2 inconclusive nodes awaiting further validation. Ferumoxytol correctly identified LN status in 9 of 10 patients with validated nodes (Table 1). Conclusions: Ferumoxytol enhanced MRI shows promise in detecting malignant LNs >6mm in GU cancer patients. Since the method involves a conventional MRI unit with off-label use of an FDA-approved agent, it could be widely available. However, further validation is necessary before routine use. Table 1: Preliminary results for LN staging in GU cancer patients using ferumoxytol enhanced MRI | Subject | Study Arm | Gender | Age (yr) | PSA at study initiation (ng/mL) | LN number | LN location | size/long axis (cm) | size/short axis (cm) | Ferumoxytol positive? 1 = yes, 0 = no | Result | |:------- | -------------------- | ------ | -------- | ------------------------------- | --------- | -------------- | ------------------- | -------------------- | ------------------------------------- | ------------ | | 1 | prostate cancer | M | 63 | 25.06 | 1 | R ext iliac | 3.0 | 2.6 | 1 | TP | | | | | | | 2 | L ext iliac | 1.3 | 0.8 | 1 | TP | | 2 | prostate cancer | M | 65 | 73.96 | 1 | L RP | 1.6 | 1.4 | 1 | TP | | | | | | | 2 | L int iliac | 3.8 | 1.9 | 1 | TP | | 3 | prostate cancer | M | 64 | 10.49 | 1 | R ext iliac | 3.0 | 0.9 | 1 | pending | | | | | | | 2 | L ext iliac | 1.9 | 1.1 | | pending | | 4 | prostate cancer | M | 74 | 2.06 | 1 | L RP | 1.7 | 1.5 | 1 | TP | | 5 | prostate cancer | M | 64 | 2.89 | 1 | R ext iliac | 1.6 | 1.1 | 1 | TP | | 6 | prostate cancer | M | 65 | 0.28 | 1 | L int iliac | 1.5 | 0.8 | 1 | TP | | 7 | prostate cancer | M | 75 | 2.87 | 1 | R int iliac | 0.7 | 0.7 | 1 | TP | | 8 | prostate cancer | M | 64 | 27.91 | 1 | R common iliac | 1.7 | 1.7 | 1 | inconclusive | | 9 | prostate cancer | M | 72 | 201.2 | 1 | L RP | 2.3 | 1.7 | | FN | | 10 | prostate cancer | M | 73 | 6.77 | 1 | L int iliac | 1.5 | 1.0 | 1 | TP | | 11 | prostate cancer | M | 36 | 1.35 | 1 | R femoral | 0.8 | 0.8 | 1 | FP | | | | | | | 2 | L ext iliac | 1.5 | 1.0 | 1 | inconclusive | | | | | | | 3 | R perirectal | 0.8 | 0.6 | 1 | TP | | 12 | renal cell carcinoma | F | 41 | N/A | 1 | aortocaval | 2.8 | 2.2 | 1 | TP | | | | | | | 2 | R RP | 3.6 | 2.3 | 1 | TP | | | | | | | 3 | R int iliac | 2.0 | 1.5 | 1 | TP | | 13 | bladder cancer | M | 59 | N/A | 1 | aortocaval | 1.5 | 1.0 | 1 | TP | RP = retroperitoneal, TP = true positive, FN = false negative, FP = false positive, ext = external, int = internal Citation Format: Anna M. Brown, Sandeep Sankineni, Marcelino Bernardo, Dagane Daar, Juanita Weaver, Yolanda McKinney, Anna Couvillon, James L. Gulley, Bradford J. Wood, Peter A. Pinto, William L. Dahut, Ravi Amrit Madan, Peter L. Choyke, Baris Turkbey. Ferumoxytol enhanced MRI for lymph node staging in genitourinary cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT222. doi:10.1158/1538-7445.AM2015-CT222