Joanna Shih

Use of serial multiparametric magnetic resonance imaging in the management of patients with prostate cancer on active surveillance

INTRODUCTIONnWe evaluated the performance of multiparametric prostate magnetic resonance imaging (mp-MRI) and MRI/transrectal ultrasound (TRUS) fusion-guided biopsy (FB) for monitoring patients with prostate cancer on active surveillance (AS).nnnMATERIALS AND METHODSnPatients undergoing mp-MRI and FB of target lesions identified on mp-MRI between August 2007 and August 2014 were reviewed. Patients meeting AS criteria (Clinical stage T1c, Gleason grade ≤ 6, prostate-specific antigen density ≤ 0.15, tumor involving ≤ 2 cores, and ≤ 50% involvement of any single core) based on extended sextant 12-core TRUS biopsy (systematic biopsy [SB]) were included. They were followed with subsequent 12-core biopsy as well as mp-MRI and MRI/TRUS fusion biopsy at follow-up visits until Gleason score progression (Gleason ≥ 7 in either 12-core or MRI/TRUS fusion biopsy). We evaluated whether progression seen on mp-MRI (defined as an increase in suspicion level, largest lesion diameter, or number of lesions) was predictive of Gleason score progression.nnnRESULTSnOf 152 patients meeting AS criteria on initial SB (mean age of 61.4 years and mean prostate-specific antigen level of 5.26 ng/ml), 34 (22.4%) had Gleason score ≥ 7 on confirmatory SB/FB. Of the 118 remaining patients, 58 chose AS and had at least 1 subsequent mp-MRI with SB/FB (median follow-up = 16.1 months). Gleason progression was subsequently documented in 17 (29%) of these men, in all cases to Gleason 3+4. The positive predictive value and negative predictive value of mp-MRI for Gleason progression was 53% (95% CI: 28%-77%) and 80% (95% CI: 65%-91%), respectively. The sensitivity and specificity of mp-MRI for increase in Gleason were also 53% and 80%, respectively. The number needed to biopsy to detect 1 Gleason progression was 8.74 for SB vs. 2.9 for FB.nnnCONCLUSIONSnStable findings on mp-MRI are associated with Gleason score stability. mp-MRI appears promising as a useful aid for reducing the number of biopsies in the management of patients on AS. A prospective evaluation of mp-MRI as a screen to reduce biopsies in the follow-up of men on AS appears warranted.

Localized Prostate Cancer Detection with 18F FACBC PET/CT: Comparison with MR Imaging and Histopathologic Analysis

PURPOSEnTo 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.nnnMATERIALS AND METHODSnInstitutional 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.nnnRESULTSn(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).nnnCONCLUSIONn(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.

Impact of pathological tumour characteristics in patients with sarcomatoid renal cell carcinoma

Study Type – Prognosis (case series)

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

OBJECTIVEnThe 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.nnnSUBJECTS AND METHODSnThis 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.nnnRESULTSnOne 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).nnnCONCLUSIONnA 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.

[18F]Fluciclatide in the in vivo evaluation of human melanoma and renal tumors expressing αvβ3 and αvβ5 integrins

Purpose[18F]Fluciclatide is an integrin-targeted PET radiopharmaceutical. αvβ3 and αvβ5 are upregulated in tumor angiogenesis as well as on some tumor cell surfaces. Our aim was to use [18F]fluciclatide (formerly known as [18F]AH111585) for PET imaging of angiogenesis in melanoma and renal tumors and compare with tumor integrin expression.MethodsEighteen evaluable patients with solid tumors ≥2.0xa0cm underwent [18F]fluciclatide PET/CT. All patients underwent surgery and tumor tissue samples were obtained. Immunohistochemical (IHC) staining with mouse monoclonal antibodies and diaminobenzidine (DAB) was applied to snap-frozen tumor specimens, and additional IHC was done on formalin-fixed paraffin-embedded samples. DAB optical density (OD) data from digitized whole-tissue sections were compared with PET SUV80% max, and Patlak influx rate constant (Ki) data, tumor by tumor.ResultsTumors from all 18 patients demonstrated measurable [18F]fluciclatide uptake. At the final dynamic time-point (55xa0min after injection), renal malignancies (in 11 patients) demonstrated an average SUV80% max of 6.4u2009±u20092.0 (range 3.8xa0–xa010.0), while the average SUV80% max for metastatic melanoma lesions (in 6 patients) was 3.0u2009±u20092.0 (range 0.7xa0–xa06.5). There was a statistically significant difference in [18F]fluciclatide uptake between chromophobe and nonchromophobe renal cell carcinoma (RCCs, with SUV80% max of 8.2u2009±u20091.8 and 5.4u2009±u20091.4 (Pu2009=u20090.020) and tumor-to-normal kidney (T/N) ratios of 1.5u2009±u20090.4 and 0.9u2009±u20090.2, respectively (Pu2009=u20090.029). The highest Pearsons correlation coefficients were obtained when comparing Patlak Ki and αvβ5 OD when segregating the patient population between melanoma and RCC (ru2009=u20090.83 for Ki vs. melanoma and ru2009=u20090.91 for Ki vs. RCC). SUV80% max showed a moderate correlation with αvβ5 and αvβ3 OD.Conclusion[18F]Fluciclatide PET imaging was well tolerated and demonstrated favorable characteristics for imaging αvβ3 and αvβ5 expression in melanoma and RCC. Higher uptake was observed in chromophobe than in nonchromophobe RCC. [18F]Fluciclatide may be a useful radiotracer to improve knowledge of integrin expression.

Reproducibility of Multiparametric Magnetic Resonance Imaging and Fusion Guided Prostate Biopsy: Multi-Institutional External Validation by a Propensity Score Matched Cohort

PURPOSEnAs the adoption of magnetic resonance imaging/ultrasound fusion guided biopsy expands, the reproducibility of outcomes at expert centers becomes essential. We sought to validate the comprehensive NCI (National Cancer Institute) experience with multiparametric magnetic resonance imaging and fusion guided biopsy in an external, independent, matched cohort of patients.nnnMATERIALS AND METHODSnWe compared 620 patients enrolled in a prospective trial comparing systematic biopsy to fusion guided biopsy at NCI to 310 who underwent a similar procedure at Long Island Jewish Medical Center. The propensity score, defined as the probability of being treated outside NCI, was calculated using the estimated logistic regression model. Patients from the hospital were matched 1:1 for age, prostate specific antigen, magnetic resonance imaging suspicion score and prior negative biopsies. Clinically significant disease was defined as Gleason 3 + 4 or greater.nnnRESULTSnBefore matching we found differences between the cohorts in age, magnetic resonance imaging suspicion score (each p <0.001), the number of patients with prior negative biopsies (p = 0.01), and the overall cancer detection rate and the cancer detection rate by fusion guided biopsy (each p <0.001). No difference was found in the rates of upgrading by fusion guided biopsy (p = 0.28) or upgrading to clinically significant disease (p = 0.95). A statistically significant difference remained in the overall cancer detection rate and the rate by fusion guided biopsy after matching. On subgroup analysis we found a difference in the overall cancer detection rate and the rate by fusion guided biopsy (p <0.001 and 0.003) in patients with prior negative systematic biopsy but no difference in the 2 rates (p = 0.39 and 0.51, respectively) in biopsy naïve patients.nnnCONCLUSIONSnImproved detection of clinically significant cancer by magnetic resonance imaging and fusion guided biopsy is reproducible by an experienced multidisciplinary team consisting of dedicated radiologists and urologists.

Differentiating Transition Zone Cancers From Benign Prostatic Hyperplasia by Quantitative Multiparametric Magnetic Resonance Imaging.

Objective The aim of this study was to evaluate the value of quantitative diffusion and perfusion parameters to aid in discriminating between transition zone carcinomas and benign prostatic hyperplasia (BPH). Materials and Methods Twenty-four transition zone cancers and BPH nodules were contoured on T2-weighted magnetic resonance imaging (MRI), apparent diffusion coefficient (ADC) maps, and raw dynamic contrast-enhanced (DCE) MRI. Benign prostatic hyperplasia nodules were then stratified into 2 groups based on the presence or absence of a capsule. Apparent diffusion coefficient values, per-voxel Ktrans, kep, vp, and ve were all compared across all groups. Results Average ADCs (×10−6 mm2/s) were 1019.22, 1338.11, and 1272.46 for cancer, encapsulated BPH, and nonencapsulated BPH, respectively. Both subgroups of BPH were found to be significantly different than that of cancer (P < 0.05). No individual DCE-MRI parameter was significantly different between cancer and either BPH group. The area under the curve for ADC alone was 0.83, and no individual DCE imaging parameter improved the area under the curve of ADC. Conclusions Apparent diffusion coefficient may play a role in distinguishing TZ cancers from non-encapsulated BPH nodules that closely resemble 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, 18F-FDG PET/CT can be falsely positive in areas of posttreatment inflammation. 3′-18F-fluoro-3′-deoxy-l-thymidine (18F-FLT) is a structural analog of the DNA constituent thymidine; its uptake correlates with cellular proliferation. This pilot study evaluates the ability of 18F-FLT PET/CT to distinguish viable lymphoma from posttreatment inflammatory changes in 18F-FDG avid residual masses. Methods Twenty-one patients with lymphoma with at least 1 18F-FDG avid residual mass after therapy underwent 18F-FLT PET/CT imaging. 18F-FDG and 18F-FLT uptake values were compared, including quantitative pharmacokinetic parameters extracted from the 18F-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 18F-FDG PET/CT imaging over 1 year); among the remaining 9 patients, 7 lesions resolved or decreased and 2 showed growth indicative of lymphoma. 18F-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 18F-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 18F-FLT SUVest.max of less than 3.0. Conclusions 18F-FLT shows improved specificity over 18F-FDG in distinguishing residual lymphoma from posttreatment inflammation and may be useful in the evaluation of patients with residual 18F-FDG–positive masses after completing therapy.

Renal functional outcomes after robotic multiplex partial nephrectomy: the National Cancer Institute experience with robotic partial nephrectomy for 3 or more tumors in a single kidney.

ObjectiveTo identify renal function outcomes after robotic multiplex partial nephrectomy (RMxPNx), we reviewed our institutional database at the National Institutes of Health, National Cancer Institute. To our knowledge, we present the largest series of RMxPNx renal function outcomes to date. Robotic partial nephrectomy has been employed for oncologic control and to prevent dialysis dependence in hereditary multifocal renal cell carcinoma conditions. We have termed robotic surgery on a single kidney with three or more lesions a RMxPNx.Materials and methods We evaluated patients from a prospectively maintained database at a single institution (NIH/NCI) that underwent RMxPNx from 2007 to 2013. Demographic and operative data were compiled with statistical analysis with T test performed to determine renal function outcomes.ResultsA total of 54 patients underwent RMxPNx. Mean number of tumors removed was 8.63 (range 3–52). Mean preoperative creatinine and eGFR were 1.02xa0±xa00.26xa0mg/dL and 85.4xa0±xa021.5xa0mL/min, respectively. Postoperatively, creatinine increased from baseline by 0.45xa0mg/dL (pxa0<xa00.001). Similarly, a mean decrease in eGFR by 24.6xa0mL/min was observed (pxa0<xa00.001). At 3-month follow-up, the creatinine increase from baseline was 0.05xa0mg/dL (pxa0=xa00.10) and mean decrease in eGFR was 3.01xa0mL/min (pxa0=xa00.21). When stratifying based on preoperative CKD stages I–III, similar results were observed.ConclusionRobotic multiplex partial nephrectomy is a safe and feasible approach to patients with multifocal renal masses. These complex surgeries have a demonstrated learning curve, but this minimally invasive approach for nephron-sparing surgery allows patients to preserve renal function where they would otherwise require open surgery or a radical nephrectomy.

Preliminary evaluation of urinary soluble Met as a Biomarker for urothelial carcinoma of the bladder

BackgroundAmong genitourinary malignancies, bladder cancer (BCa) ranks second in both prevalence and cause of death. Biomarkers of BCa for diagnosis, prognosis and disease surveillance could potentially help prevent progression, improve survival rates and reduce health care costs. Among several oncogenic signaling pathways implicated in BCa progression is that of hepatocyte growth factor (HGF) and its cell surface receptor, Met, now targeted by 25 experimental anti-cancer agents in human clinical trials. The involvement of this pathway in several cancers is likely to preclude the use of urinary soluble Met (sMet), which has been correlated with malignancy, for initial BCa screening. However, its potential utility as an aid to disease surveillance and to identify patients likely to benefit from HGF/Met-targeted therapies provide the rationale for this preliminary retrospective study comparing sMet levels between benign conditions and primary BCa, and in BCa cases, between different disease stages.MethodsNormally voided urine samples were collected from patients with BCa (Total: 183; pTa: 55, pTis: 62, pT1: 24, pT2: 42) and without BCa (Total: 83) on tissue-procurement protocols at three institutions and sMet was measured and normalized to urinary creatinine. Normalized sMet values grouped by pathologic stage were compared using non-parametric tests for correlation and significant difference. ROC analyses were used to derive classification models for patients with or without BCa and patients with or without muscle-invasive BCa (MIBCa or NMIBCa).ResultsUrinary sMet levels accurately distinguished patients with BCa from those without (pu2009<u20090.0001, area under the curve (AUC): 0.7008) with limited sensitivity (61%) and moderate specificity (76%), and patients with MIBCa (nu2009=u200942) from those with NMIBCa (nu2009=u2009141; pu2009<u20090.0001, AUC: 0.8002) with moderate sensitivity and specificity (76% and 77%, respectively) and low false negative rate (8%).ConclusionsUrinary sMet levels distinguish patients with BCa from those without, and patients with or without MIBCa, suggesting the potential utility of urinary sMet as a BCa biomarker for surveillance following initial treatment. Further studies are warranted to determine its potential value for prognosis in advanced disease, predicting treatment response, or identifying patients likely to benefit from Met-targeted therapies.