Publications by authors named "Maria J Merino"

252 Publications

Changes in Magnetic Resonance Imaging Using the Prostate Cancer Radiologic Estimation of Change in Sequential Evaluation Criteria to Detect Prostate Cancer Progression for Men on Active Surveillance.

Eur Urol Oncol 2021 Apr 21;4(2):227-234. Epub 2020 Oct 21.

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background: The ability of serial magnetic resonance imaging (MRI) to capture pathologic progression during active surveillance (AS) remains in question.

Objective: To determine whether changes in MRI are associated with pathologic progression for patients on AS.

Design, Setting, And Participants: From July 2007 through January 2020, we identified all patients evaluated for AS at our institution. Following confirmatory biopsy, a total of 391 patients who underwent surveillance MRI and biopsy at least once were identified (median follow-up of 35.6 mo, interquartile range 19.7-60.6).

Outcome Measurements And Statistical Analysis: All MRI intervals were scored using the "Prostate Cancer Radiologic Estimation of Change in Sequential Evaluation" (PRECISE) criteria, with PRECISE scores =4 considered a positive change in MRI. A generalized estimating equation-based logistic regression analysis was conducted for all intervals with a PRECISE score of <4 to determine the predictors of Gleason grade group (GG) progression despite stable MRI.

Results And Limitations: A total of 621 MRI intervals were scored by PRECISE and validated by biopsy. The negative predictive value of stable MRI (PRECISE score <4) was greatest for detecting GG1 to?=?GG3 disease (0.94 [0.91-0.97]). If 2-yr surveillance biopsy were performed exclusively for a positive change in MRI, 3.7% (4/109) of avoided biopsies would have resulted in missed progression from GG1 to?=?GG3 disease. Prostate-specific antigen (PSA) density (odds ratio 1.95 [1.17-3.25], p?=? 0.01) was a risk factor for progression from GG1 to =GG3 disease despite stable MRI.

Conclusions: In patients with GG1 disease and stable MRI (PRECISE score <4) on surveillance, grade progression to?=?GG3 disease is not common. In patients with grade progression detected on biopsy despite stable MRI, elevated PSA density appeared to be a risk factor for progression to?=?GG3 disease.

Patient Summary: For patients with low-risk prostate cancer on active surveillance, the risk of progressing to grade group 3 disease is low with a stable magnetic resonance image (MRI) after 2?yr. Having higher prostate-specific antigen density increases the risk of progression, despite having a stable MRI.
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http://dx.doi.org/10.1016/j.euo.2020.09.004DOI Listing
April 2021

Prognostic Features of Biochemical Recurrence of Prostate Cancer Following Radical Prostatectomy Based on Multiparametric MRI and Immunohistochemistry Analysis of MRI-guided Biopsy Specimens.

Radiology 2021 Apr 13:202425. Epub 2021 Apr 13.

From the Clinical Research Directorate, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute (S.A.H.); Molecular Imaging Branch (S.A.H., S.M., Y.M., T.S., J.S., P.L.C., B.T.), Laboratory of Pathology (M.J.M.), Center for Interventional Oncology (B.J.W.), and Urologic Oncology Branch (S.M., P.A.P.), National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10, Room B3B85, Bethesda, Md 20892; Center for Prostate Disease Research, John P. Murtha Cancer Center, Department of Surgery, Uniformed Services University of the Health Sciences (W.G., D.Y., J.C., I.L.R., S.S., A.D., I.A.S.) and Urology Service (I.L.R.), Walter Reed National Military Medical Center, Bethesda, Md; and Department of Genitourinary Pathology, Joint Pathology Center, Silver Spring, Md (I.A.S.).

Background Although prostate MRI is routinely used for the detection and staging of localized prostate cancer, imaging-based assessment and targeted molecular sampling for risk stratification are an active area of research. Purpose To evaluate features of preoperative MRI and MRI-guided biopsy immunohistochemistry (IHC) findings associated with biochemical recurrence (BCR) of prostate cancer after surgery. Materials and Methods In this retrospective case-control study, patients underwent multiparametric MRI before MRI-guided biopsy followed by radical prostatectomy between 2008 and 2016. Lesions were retrospectively scored with the Prostate Imaging Reporting and Data System (PI-RADS) (version 2) by radiologists who were blinded to the clinical-pathologic results. The IHC staining, including stains for the ETS-related gene, phosphatase and tensin homolog, androgen receptor, prostate specific antigen, and p53, was performed with targeted biopsy specimens of the index lesion (highest suspicion at MRI and pathologic grade) and scored by pathologists who were blinded to clinical-pathologic outcomes. Cox proportional hazards regression analysis was used to evaluate associations with recurrence-free survival (RFS). Results The median RFS was 31.7 months (range, 1-101 months) for 39 patients (median age, 62 years; age range, 47-76 years) without BCR and 14.6 months (range, 1-61 months) for 40 patients (median age, 59 years; age range, 47-73 years) with BCR. MRI features that showed a significant relationship with the RFS interval included an index lesion with a PI-RADS score of 5 (hazard ratio [HR], 2.10; 95% CI: 1.05, 4.21; = .04); index lesion burden, defined as ratio of index lesion volume to prostate volume (HR, 1.55; 95% CI: 1.2, 2.1; = .003); and suspicion of extraprostatic extension (EPE) (HR, 2.18; 95% CI: 1.1, 4.2; = .02). Presurgical multivariable analysis indicated that suspicion of EPE at MRI (adjusted HR, 2.19; 95% CI: 1.1, 4.3; = .02) and p53 stain intensity (adjusted HR, 2.22; 95% CI: 1.0, 4.7; = .04) were significantly associated with RFS. Conclusion MRI features, including Prostate Imaging Reporting and Data System score, index lesion burden, extraprostatic extension, and preoperative guided biopsy p53 immunohistochemistry stain intensity are associated with biochemical relapse of prostate cancer after surgery. © RSNA, 2021 . See also the editorial by Costa in this issue.
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http://dx.doi.org/10.1148/radiol.2021202425DOI Listing
April 2021

Supplementation of the BIOXcell extender with the antioxidants crocin, curcumin and GSH for freezing bull semen.

Res Vet Sci 2021 Mar 29;136:444-452. Epub 2021 Mar 29.

INDEGSAL, Universidad de León, 24071 León, Spain; Molecular Biology (Cell Biology), Universidad de León, 24071 León, Spain. Electronic address:

Semen cryopreservation is routine in cattle, but the results of artificial insemination need improvement. A strategy to these aims is the supplementation of the freezing extender with novel antioxidants. This study aimed at testing the natural antioxidants curcumin and crocin as supplements to the commercial extender BIOXcell for freezing semen from 8 Holstein bulls. We tested curcumin at 0.05 and 0.1 mM (CU0.05, CU0.1) and crocin at 0.5 and 1.5 mM (CR0.5, CR1.5), with 0.5 mM reduced glutathione (GSH0.5) as reference, and a control (CTL, without supplementation). The samples were evaluated post-thawing and after 5 h at 38 °C by CASA for motility and flow cytometry for viability, apoptotic, capacitation, acrosomal status, cytoplasmic and mitochondrial reactive oxygen species (ROS) production, and chromatin status (SCSA). Control and GSH0.5 showed similar results, possibly because of the good protection from BIOXcell. CU0.05 and CU0.1 showed little effects but increased cytoplasmic ROS production and motility ALH. CR0.5 and CR1.5 decreased viability and increased apoptotic features significantly post-thawing and after the incubation, resulting in lower motility (significant after the incubation) but decreasing SCSA %HDS (loose chromatin). Whereas crocin at these concentrations seems incompatible with BIOXcell, maybe because of a prooxidant activity, curcumin use merits further research, considering the elevation of ROS with no significant negative effects.
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http://dx.doi.org/10.1016/j.rvsc.2021.03.025DOI Listing
March 2021

Nascent Prostate Cancer Heterogeneity Drives Evolution and Resistance to Intense Hormonal Therapy.

Eur Urol 2021 Mar 27. Epub 2021 Mar 27.

Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA. Electronic address:

Background: Patients diagnosed with high risk localized prostate cancer have variable outcomes following surgery. Trials of intense neoadjuvant androgen deprivation therapy (NADT) have shown lower rates of recurrence among patients with minimal residual disease after treatment. The molecular features that distinguish exceptional responders from poor responders are not known.

Objective: To identify genomic and histologic features associated with treatment resistance at baseline.

Design, Setting, And Participants: Targeted biopsies were obtained from 37 men with intermediate- to high-risk prostate cancer before receiving 6 mo of ADT plus enzalutamide. Biopsy tissues were used for whole-exome sequencing and immunohistochemistry (IHC).

Outcome Measurements And Statistical Analysis: We assessed the relationship of molecular features with final pathologic response using a cutpoint of 0.05 cm for residual cancer burden to compare exceptional responders to incomplete and nonresponders. We assessed intratumoral heterogeneity at the tissue and genomic level, and compared the volume of residual disease to the Shannon diversity index for each tumor. We generated multivariate models of resistance based on three molecular features and one histologic feature, with and without multiparametric magnetic resonance imaging estimates of baseline tumor volume.

Results And Limitations: Loss of chromosome 10q (containing PTEN) and alterations to TP53 were predictive of poor response, as were the expression of nuclear ERG on IHC and the presence of intraductal carcinoma of the prostate. Patients with incompletely and nonresponding tumors harbored greater tumor diversity as estimated via phylogenetic tree reconstruction from DNA sequencing and analysis of IHC staining. Our four-factor binary model (area under the receiver operating characteristic curve [AUC] 0.89) to predict poor response correlated with greater diversity in our cohort and a validation cohort of 57 Gleason score 8-10 prostate cancers from The Cancer Genome Atlas. When baseline tumor volume was added to the model, it distinguished poor response to NADT with an AUC of 0.98. Prospective use of this model requires further retrospective validation with biopsies from additional trials.

Conclusions: A subset of prostate cancers exhibit greater histologic and genomic diversity at the time of diagnosis, and these localized tumors have greater fitness to resist therapy.

Patient Summary: Some prostate cancer tumors do not respond well to a hormonal treatment called androgen deprivation therapy (ADT). We used tumor volume and four other parameters to develop a model to identify tumors that will not respond well to ADT. Treatments other than ADT should be considered for these patients.
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http://dx.doi.org/10.1016/j.eururo.2021.03.009DOI Listing
March 2021

Succinate Mediates Tumorigenic Effects Succinate Receptor 1: Potential for New Targeted Treatment Strategies in Succinate Dehydrogenase Deficient Paragangliomas.

Front Endocrinol (Lausanne) 2021 12;12:589451. Epub 2021 Mar 12.

Neuroendocrine Oncology and Metabolism, Medical Department I, Center of Brain, Behavior, and Metabolism, University Medical Center Schleswig-Holstein Lübeck, Lübeck, Germany.

Paragangliomas and pheochromocytomas (PPGLs) are chromaffin tumors associated with severe catecholamine-induced morbidities. Surgical removal is often curative. However, complete resection may not be an option for patients with succinate dehydrogenase subunit A-D () mutations. mutations are associated with a high risk for multiple recurrent, and metastatic PPGLs. Treatment options in these cases are limited and prognosis is dismal once metastases are present. Identification of new therapeutic targets and candidate drugs is thus urgently needed. Previously, we showed elevated expression of succinate receptor 1 () in PPGLs and head and neck paragangliomas. Its ligand succinate has been reported to accumulate due to mutations. We thus hypothesize that autocrine stimulation of SUCNR1 plays a role in the pathogenesis of mutation-derived PPGLs. We confirmed elevated SUCNR1 expression in PPGLs and after knockout in progenitor cells derived from a human pheochromocytoma (hPheo1). Succinate significantly increased viability of -transfected PC12 and ERK pathway signaling compared to control cells. Candidate inhibitors successfully reversed proliferative effects of succinate. Our data reveal an unrecognized oncometabolic function of succinate in PPGLs, providing a growth advantage .
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http://dx.doi.org/10.3389/fendo.2021.589451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994772PMC
March 2021

Risk of adverse pathology at prostatectomy in the era of MRI and targeted biopsies; rethinking active surveillance for intermediate risk prostate cancer patients.

Urol Oncol 2021 Mar 15. Epub 2021 Mar 15.

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Urology and Pediatric Urology, University Medical Center Mainz, Mainz, Germany. Electronic address:

Purpose: Men with intermediate risk (IR) prostate cancer (CaP) are often excluded from active surveillance (AS) due to higher rates of adverse pathology (AP). We determined our rate of AP in men who underwent multiparametric MRI (MpMRI) with combined biopsy (CB) consisting of targeted biopsy (TB) and systematic biopsy (SB) prior to radical prostatectomy (RP).

Methods: A retrospective review was conducted of men with Gleason Grade Group (GG) 2 disease who underwent RP after SB alone or after preoperative MRI with CB. AP was defined as either pathologic stage T3a (AP ≥ T3a) or pathologic stage T3b (AP ≥ T3b) and/or GG upgrading. Rates of AP were determined for both groups and those who fit the National Comprehensive Cancer Network (NCCN) definition of favorable IR (FIR) or the low volume IR (LVIR) criteria. Multivariable logistic regression was used to determine predictive factors.

Results: The overall rate of AP ≥ T3b was 21.2% in the SB group vs. 8.6% in the MRI with CB group, P = 0.006. This rate was lowered to 6.8% and 5.6% when men met the definition of NCCN FIR or LVIR, respectively. Suspicion for extraprostatic extension (EPE) (OR 7.65, 95% CI 1.77-33.09, P = 0.006) and positive cores of GG 2 on SB (OR 1.43, 95% CI 1.05-1.96, P = 0.023) were significant for predicting AP ≥ T3b.

Conclusions: Rates of AP at RP after MRI with CB are lower than studies prior to the adoption of this technology, suggesting that more men with IR disease may be considered for AS. However, increasing cores positive on SB and MRI findings suggestive of EPE remain unsafe.
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http://dx.doi.org/10.1016/j.urolonc.2021.02.018DOI Listing
March 2021

Reply by Authors.

J Urol 2021 May 11;205(5):1359-1360. Epub 2021 Mar 11.

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1097/JU.0000000000001547.03DOI Listing
May 2021

Fluorodeoxyglucose-positron emission tomography/computed tomography for differentiation of renal tumors in hereditary kidney cancer syndromes.

Abdom Radiol (NY) 2021 Mar 10. Epub 2021 Mar 10.

Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA.

Purpose: To assess differences in FDG-PET/CT uptake among four subtypes of renal tumors: clear cell RCC (ccRCC), papillary type I and II RCC (pRCC), and oncocytoma.

Methods: This retrospective study investigated 33 patients with 98 hereditary renal tumors. Lesions greater than 1 cm and patients with a timeframe of less than 18 months between preoperative imaging and surgery were considered. FDG-PET/CT images were independently reviewed by two nuclear medicine physicians, blinded to clinical information. Volumetric lesion SUV was measured and used to calculate a target-to-background ratio respective to liver (TBR). The Shrout-Fleiss intra-class correlation coefficient was used to assess reliability between readers. A linear mixed effects model, accounting for within-patient correlations, was used to compare TBR values of primary renal lesions with and without distant metastasis.

Results: The time interval between imaging and surgery for all tumors had a median of 77 (Mean: 139; Range: 1-512) days. Intra-class reliability of mean TBR resulted in a mean κ score of 0.93, indicating strong agreement between the readers. The mixed model showed a significant difference in mean TBR among the subtypes (p < 0.0001). Pairwise comparison showed significant differences between pRCC type II and ccRCC (p < 0.0001), pRCC type II and pRCC type I (p = 0.0001), and pRCC type II and oncocytoma (p = 0.0016). Furthermore, a significant difference in FDG uptake was present between primary pRCC type II renal lesions with and without distant metastasis (p = 0.023).

Conclusion: pRCC type II lesions demonstrated significantly higher FDG activity than ccRCC, pRCC type I, or oncocytoma. These findings indicate that FDG may prove useful in studying the metabolic activity of renal neoplasms, identifying lesions of highest clinical concern, and ultimately optimizing active surveillance, and personalizing management plans.
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http://dx.doi.org/10.1007/s00261-021-02999-9DOI Listing
March 2021

Macronodular adrenal hyperplasia masquerading as an upper pole renal mass.

Urol Case Rep 2021 Jul 12;37:101603. Epub 2021 Feb 12.

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Macronodular hyperplasia (MAH) of the adrenal gland is a rare disease usually presenting with Cushing Syndrome. Although usually readily apparent on imaging, an adrenal tumor in an asymptomatic patient may be mistaken for a renal tumor. We present a patient with combined macro- and micro-nodular adrenal hyperplasia masquerading as an upper pole renal mass. The patient underwent a robotic partial nephrectomy and partial adrenalectomy without complication.
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http://dx.doi.org/10.1016/j.eucr.2021.101603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900682PMC
July 2021

'Case of the Month' from the National Cancer Institute, Bethesda, MD, USA: investigating genetic aberrations in a patient with high-risk prostate cancer.

BJU Int 2021 02;127(2):171-174

Center for Cancer Research, Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1111/bju.15273DOI Listing
February 2021

Characterization of genetically defined sporadic and hereditary type 1 papillary renal cell carcinoma cell lines.

Genes Chromosomes Cancer 2021 Jun 10;60(6):434-446. Epub 2021 Mar 10.

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Renal cell carcinoma (RCC) is not a single disease but is made up of several different histologically defined subtypes that are associated with distinct genetic alterations which require subtype specific management and treatment. Papillary renal cell carcinoma (pRCC) is the second most common subtype after conventional/clear cell RCC (ccRCC), representing ~20% of cases, and is subcategorized into type 1 and type 2 pRCC. It is important for preclinical studies to have cell lines that accurately represent each specific RCC subtype. This study characterizes seven cell lines derived from both primary and metastatic sites of type 1 pRCC, including the first cell line derived from a hereditary papillary renal carcinoma (HPRC)-associated tumor. Complete or partial gain of chromosome 7 was observed in all cell lines and other common gains of chromosomes 16, 17, or 20 were seen in several cell lines. Activating mutations of MET were present in three cell lines that all demonstrated increased MET phosphorylation in response to HGF and abrogation of MET phosphorylation in response to MET inhibitors. CDKN2A loss due to mutation or gene deletion, associated with poor outcomes in type 1 pRCC patients, was observed in all cell line models. Six cell lines formed tumor xenografts in athymic nude mice and thus provide in vivo models of type 1 pRCC. These type 1 pRCC cell lines provide a comprehensive representation of the genetic alterations associated with pRCC that will give insight into the biology of this disease and be ideal preclinical models for therapeutic studies.
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http://dx.doi.org/10.1002/gcc.22940DOI Listing
June 2021

Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase-deficient renal cancer.

Sci Signal 2021 Jan 5;14(664). Epub 2021 Jan 5.

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.
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http://dx.doi.org/10.1126/scisignal.abc4436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039187PMC
January 2021

Magnetic Resonance Imaging-Targeted and Systematic Biopsy for Detection of Grade Progression in Patients on Active Surveillance for Prostate Cancer.

J Urol 2021 May 24;205(5):1352-1360. Epub 2020 Dec 24.

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Purpose: Active surveillance for patients with low and intermediate risk prostate cancers is becoming a more utilized option in recent years. However, the use of magnetic resonance imaging and imaging-targeted biopsy for monitoring grade progression has been poorly studied in this population. We aim to define the utility of magnetic resonance imaging-targeted biopsy and systematic biopsy in an active surveillance population.

Materials And Methods: Between July 2007 and January 2020, patients with diagnosed prostate cancer who elected active surveillance were monitored with prostate magnetic resonance imaging, imaging-targeted biopsy and standard systematic biopsy. Patients were eligible for surveillance if diagnosed with any volume Gleason grade 1 disease and select Gleason grade 2 disease. Grade progression (Gleason grade 1 to ≥2 disease and Gleason grade 2 to ≥3 disease) for each biopsy modality was measured at 2 years, 4 years and 6+ years.

Results: In total, 369 patients had both magnetic resonance imaging-targeted and systematic biopsy and were surveilled for at least 1 year. At 2 years, systematic biopsy, magnetic resonance imaging-targeted biopsy and combined biopsy (systematic+imaging-targeted) detected grade progression in 44 patients (15.9%), 73 patients (26.4%) and 90 patients (32.5%), respectively. Magnetic resonance imaging-targeted biopsy detected more cancer grade progression compared to systematic biopsy in both the low and intermediate risk populations (p <0.001). Of all 90 grade progressions at the 2-year time point 46 (51.1%) were found by magnetic resonance imaging-targeted biopsy alone and missed by systematic biopsy.

Conclusions: Magnetic resonance imaging-targeted biopsy detected significantly more grade progressions in our active surveillance cohort compared to systematic biopsy at 2 years. Our results provide compelling evidence that prostate magnetic resonance imaging and imaging-targeted biopsy should be included in contemporary active surveillance protocols.
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http://dx.doi.org/10.1097/JU.0000000000001547DOI Listing
May 2021

Multifocal Renal Cell Carcinomas With Somatic IDH2 Mutation: Report of a Previously Undescribed Neoplasm.

Am J Surg Pathol 2021 01;45(1):137-142

Urologic Oncology Branch.

Renal cell carcinoma (RCC) is a heterogenous disease composed of several different cancer types characterized by distinct histologies and genetic alterations, including mutation of the Krebs cycle enzyme genes for fumarate hydratase and succinate dehydrogenase (SDH). This report describes a patient with multifocal renal tumors that presented with a novel, biphasic histologic morphology with one component consisting of small cells growing in a diffuse pattern occasionally forming glandular and cystic structures, reminiscent of type 1 papillary RCC, and the other component having larger cells with abundant eosinophilic and clear cytoplasm and appearing in a solid pattern of growth. Genetic analysis of multiple tumors showed that all had a somatic mutation of the IDH2 gene that created the known pathogenic, gain-of-function p.R172M alteration that results in abnormal accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Analysis of multiple tumors demonstrated highly elevated levels of 2-HG and a CpG island methylator phenotype that is characteristic of 2-HG-related inhibition of the Ten-eleven translocation (TET) family of DNA demethylases. In combination with fumarate hydratase-deficient and succinate dehydrogenase-deficient RCCs that have increased levels of the fumarate and succinate oncometabolites, respectively, the mutation of isocitrate dehydrogenase 2 represents the third Krebs cycle enzyme alteration to be associated with oncometabolite-induced RCC tumorigenesis. This study associates the discovery of a new histologic presentation of RCC with the first report of an IDH2 gain-of-function mutation in RCC.
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http://dx.doi.org/10.1097/PAS.0000000000001611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736215PMC
January 2021

Sequential Prostate Magnetic Resonance Imaging in Newly Diagnosed High-risk Prostate Cancer Treated with Neoadjuvant Enzalutamide is Predictive of Therapeutic Response.

Clin Cancer Res 2021 Jan 6;27(2):429-437. Epub 2020 Oct 6.

Genitourinary Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

Purpose: For high-risk prostate cancer, standard treatment options include radical prostatectomy (RP) or radiotherapy plus androgen deprivation therapy (ADT). Despite definitive therapy, many patients will have disease recurrence. Imaging has the potential to better define characteristics of response and resistance. In this study, we evaluated prostate multiparametric MRI (mpMRI) before and after neoadjuvant enzalutamide plus ADT.

Patients And Methods: Men with localized intermediate- or high-risk prostate cancer underwent a baseline mpMRI and mpMRI-targeted biopsy followed by a second mpMRI after 6 months of enzalutamide and ADT prior to RP. Specimens were sectioned in the same plane as mpMRI using patient-specific 3D-printed molds to permit mpMRI-targeted biopsies to be compared with the same lesion from the RP. Specimens were analyzed for imaging and histologic correlates of response.

Results: Of 39 patients enrolled, 36 completed imaging and RP. Most patients (92%) had high-risk disease. Fifty-eight lesions were detected on baseline mpMRI, of which 40 (69%) remained measurable at 6-month follow-up imaging. Fifty-five of 59 lesions (93%) demonstrated >50% volume reduction on posttreatment mpMRI. Three of 59 lesions (5%) demonstrated growth in size at follow-up imaging, with two lesions increasing more than 3-fold in volume. On whole-mount pathology, 15 patients demonstrated minimal residual disease (MRD) of <0.05 cc or pathologic complete response. Low initial mpMRI relative tumor burden was most predictive of MRD on final pathology.

Conclusions: Low relative lesion volume at baseline mpMRI was predictive of pathologic response. A subset of patients had limited response. Selection of patients based on these metrics may improve outcomes in high-risk disease.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855232PMC
January 2021

Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors.

J Clin Oncol 2020 11 11;38(31):3672-3684. Epub 2020 Sep 11.

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Purpose: We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances.

Patients And Methods: Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS).

Results: Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC.

Conclusion: CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.
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http://dx.doi.org/10.1200/JCO.20.01652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605393PMC
November 2020

Prospective Evaluation of PI-RADS Version 2.1 for Prostate Cancer Detection.

AJR Am J Roentgenol 2020 Sep 2:1-6. Epub 2020 Sep 2.

Molecular Imaging Program, National Cancer Institute, National Institutes of Health, 10 Center Dr, Rm B3B85, Bethesda, MD 20892.

The purpose of this study was to prospectively evaluate Prostate Imaging Reporting and Data and System version 2.1 (PI-RADSv2.1), which was released in March 2019 to update version 2.0, for prostate cancer detection with transrectal ultrasound-MRI fusion biopsy and 12-core systematic biopsy. This prospective study included 110 consecutively registered patients who underwent multiparametric MRI evaluated with PI-RADSv2.1 criteria followed by fusion biopsy and systematic biopsy between April and September 2019. Lesion-based cancer detection rates (CDRs) were calculated for prostate cancer (Gleason grade group, > 0) and clinically significant prostate cancer (Gleason grade group, > 1). A total of 171 lesions (median size, 1.1 cm) in 110 patients were detected and evaluated with PI-RADSv2.1. In 16 patients no lesion was detected, and only systematic biopsy was performed. Lesions were categorized as follows: PI-RADS category 1, 1 lesion; PI-RADS category 2, 34 lesions; PI-RADS category 3, 54 lesions; PI-RADS category 4, 52 lesions; and PI-RADS category 5, 30 lesions. Histopathologic analysis revealed prostate cancer in 74 of 171 (43.3%) lesions and clinically significant prostate cancer in 57 of 171 (33.3%) lesions. The CDRs of prostate cancer for PI-RADS 2, 3, 4, and 5 lesions were 20.0%, 24.1%, 51.9%, and 90.0%. The CDRs of clinically significant prostate cancer for PI-RADS 1, 2, 3, 4, and 5 lesions were 0%, 5.7%, 14.8%, 44.2%, and 80.0%. In 16 patients with normal multiparametric MRI findings (PI-RADS 1), the CDRs were 50.0% for PCa and 18.8% for clinically significant prostate cancer. This investigation yielded CDRs assessed with prospectively assigned PI-RADSv2.1 scores. CDRs increased with higher PI-RADSv2.1 scores. These results can be compared with previously published outcomes derived with PI-RADS version 2.0.
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http://dx.doi.org/10.2214/AJR.19.22679DOI Listing
September 2020

A Case Report of Sequential Use of a Yeast-CEA Therapeutic Cancer Vaccine and Anti-PD-L1 Inhibitor in Metastatic Medullary Thyroid Cancer.

Front Endocrinol (Lausanne) 2020 7;11:490. Epub 2020 Aug 7.

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States.

Medullary thyroid cancer (MTC) accounts for ~4% of all thyroid malignancies. MTC derives from the neural crest and secretes calcitonin (CTN) and carcinoembryonic antigen (CEA). Unlike differentiated thyroid cancer, MTC does not uptake iodine and I-131 RAI (radioactive iodine) treatment is ineffective. Patients with metastatic disease are candidates for FDA-approved agents with either vandetanib or cabozantinib; however, adverse effects limit their use. There are ongoing trials exploring the role of less toxic immunotherapies in patients with MTC. We present a 61-year-old male with the diagnosis of MTC and persistent local recurrence despite multiple surgeries. He was started on sunitinib, but ultimately its use was limited by toxicity. He then presented to the National Cancer Institute (NCI) and was enrolled on a clinical trial with heat-killed yeast-CEA vaccine (NCT01856920) and his calcitonin doubling time improved in 3 months. He then came off vaccine for elective surgery. After surgery, his calcitonin was rising and he enrolled on a phase I trial of avelumab, a programmed death-ligand 1 (PD-L1) inhibitor (NCT01772004). Thereafter, his calcitonin decreased > 40% on 5 consecutive evaluations. His tumor was subsequently found to express PD-L1. CEA-specific T cells were increased following vaccination, and a number of potential immune-enhancing changes were noted in the peripheral immunome over the course of sequential immunotherapy treatment. Although calcitonin declines do not always directly correlate with clinical responses, this response is noteworthy and highlights the potential for immunotherapy or sequential immunotherapy in metastatic or unresectable MTC.
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http://dx.doi.org/10.3389/fendo.2020.00490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427000PMC
August 2020

Multicenter Multireader Evaluation of an Artificial Intelligence-Based Attention Mapping System for the Detection of Prostate Cancer With Multiparametric MRI.

AJR Am J Roentgenol 2020 10 5;215(4):903-912. Epub 2020 Aug 5.

Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD.

The purpose of this study was to evaluate in a multicenter dataset the performance of an artificial intelligence (AI) detection system with attention mapping compared with multiparametric MRI (mpMRI) interpretation in the detection of prostate cancer. MRI examinations from five institutions were included in this study and were evaluated by nine readers. In the first round, readers evaluated mpMRI studies using the Prostate Imaging Reporting and Data System version 2. After 4 weeks, images were again presented to readers along with the AI-based detection system output. Readers accepted or rejected lesions within four AI-generated attention map boxes. Additional lesions outside of boxes were excluded from detection and categorization. The performances of readers using the mpMRI-only and AI-assisted approaches were compared. The study population included 152 case patients and 84 control patients with 274 pathologically proven cancer lesions. The lesion-based AUC was 74.9% for MRI and 77.5% for AI with no significant difference ( = 0.095). The sensitivity for overall detection of cancer lesions was higher for AI than for mpMRI but did not reach statistical significance (57.4% vs 53.6%, = 0.073). However, for transition zone lesions, sensitivity was higher for AI than for MRI (61.8% vs 50.8%, = 0.001). Reading time was longer for AI than for MRI (4.66 vs 4.03 minutes, < 0.001). There was moderate interreader agreement for AI and MRI with no significant difference (58.7% vs 58.5%, = 0.966). Overall sensitivity was only minimally improved by use of the AI system. Significant improvement was achieved, however, in the detection of transition zone lesions with use of the AI system at the cost of a mean of 40 seconds of additional reading time.
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http://dx.doi.org/10.2214/AJR.19.22573DOI Listing
October 2020

Prospective Evaluation of F-DCFPyL PET/CT in Detection of High-Risk Localized Prostate Cancer: Comparison With mpMRI.

AJR Am J Roentgenol 2020 09 8;215(3):652-659. Epub 2020 Jul 8.

Molecular Imaging Program, National Cancer Institute, National Institutes of Health, 10 Center Dr, Rm B3B85, Bethesda, MD 20814.

The purpose of this study was to assess the utility of PET with (2)-2-[[(1)-1-carboxy-5-[(6-(F)fluoranylpyridine-3-carbonyl)amino]pentyl]carbamoylamino]pentanedioic acid (F-DCFPyL), a prostate-specific membrane antigen (PSMA)-targeted radiotracer, in the detection of high-risk localized prostate cancer as compared with multiparametric MRI (mpMRI). This HIPAA-compliant prospective study included 26 consecutive patients with localized high-risk prostate cancer (median age, 69.5 years [range, 53-81 years]; median prostate-specific antigen [PSA] level, 18.88 ng/mL [range, 1.03-20.00 ng/mL]) imaged with F-DCFPyL PET/CT and mpMRI. Images from PET/CT and mpMRI were evaluated separately, and suspicious areas underwent targeted biopsy. Lesion-based sensitivity and tumor detection rate were compared for PSMA PET and mpMRI. Standardized uptake value (SUV) and PSMA PET parameters were correlated with histopathology score, and uptake in tumor was compared with that in nonmalignant tissue. On a patient level, SUV and PSMA tumor volume were correlated with PSA density. Forty-four tumors (one in Gleason grade [GG] group 1, 12 in GG group 2, seven in GG group 3, nine in GG group 4, and 15 in GG group 5) were identified at histopathology. Sensitivity and tumor detection rate of F-DCFPyL PET/CT and mpMRI were similar (PET/CT, 90.9% and 80%; mpMRI, 86.4% and 88.4%; = 0.58/0.17). Total lesion PSMA and PSMA tumor volume showed a relationship with GG (τ = 0.27 and = 0.08, τ = 0.30 and = 0.06, respectively). Maximum SUV in tumor was significantly higher than that in nonmalignant tissue ( < 0.05). Tumor burden density moderately correlated with PSA density ( = 0.47, = 0.01). Five true-positive tumors identified on F-DCFPyL PET/CT were not identified on mpMRI. In patients with high-risk prostate cancer, F-DCFPyL PET/CT is highly sensitive in detecting intraprostatic tumors and can detect tumors missed on mpMRI. Measured uptake is significantly higher in tumor tissue, and PSMA-derived tumor burden is associated with severity of disease.
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http://dx.doi.org/10.2214/AJR.19.22042DOI Listing
September 2020

PI-RADS® Category as a Predictor of Progression to Unfavorable Risk Prostate Cancer in Men on Active Surveillance.

J Urol 2020 12 27;204(6):1229-1235. Epub 2020 Jul 27.

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Purpose: We identified baseline imaging and clinical characteristics of patients that may improve risk stratification among patients being evaluated for active surveillance.

Materials And Methods: From July 2007 to January 2020 patients referred to our institution for prostate cancer were evaluated and those who remained on active surveillance were identified. Men underwent multiparametric magnetic resonance imaging upon entry into our active surveillance protocol during which baseline demographic and imaging data were documented. Patients were then followed and outcomes, specifically progression to Gleason Grade Group (GG)3 or greater disease, were recorded.

Results: Of the men placed on active surveillance 344 had at least 1 PI-RADS score documented. For those with an index lesion PI-RADS category of 5, 33% (17/51) had progression to GG3 or greater on active surveillance with a median time to progression of 31 months. When comparing the progression-free survival times and progression rates in each category, PI-RADS category was found to be associated with progression to GG3 or greater on active surveillance (p <0.01). On univariable analysis factors associated with progression included an index lesion PI-RADS category of 5, prostate specific antigen density and the size of the largest lesion. On multivariable analysis only PI-RADS category of 5 and prostate specific antigen density were associated with progression on active surveillance.

Conclusions: PI-RADS lesion categories at baseline multiparametric magnetic resonance imaging during active surveillance enrollment can be used to predict cancer progression to GG3 or greater on active surveillance. This information, along with other clinical data, can better assist urologists in identifying and managing patients appropriate for active surveillance.
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http://dx.doi.org/10.1097/JU.0000000000001307DOI Listing
December 2020

Combined MRI-targeted Plus Systematic Confirmatory Biopsy Improves Risk Stratification for Patients Enrolling on Active Surveillance for Prostate Cancer.

Urology 2020 Oct 15;144:164-170. Epub 2020 Jul 15.

Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Objective: To evaluate the efficacy of combined MRI-targeted plus systematic 12-core biopsy (Cbx) to aid in the selection of patients for active surveillance (AS).

Methods: From July 2007 to January 2020, patients with Gleason Grade Group (GG) 1 or GG 2 prostate cancer were referred to our center for AS consideration. All patients underwent an MRI and confirmatory combined MRI-targeted plus systematic biopsy (Cbx), and AS outcomes based on Cbx results were compared. Cox regression was used to identify predictors of AS failure, defined as progression to ≥ GG3 disease on follow-up biopsies.

Results: Of 579 patients referred for AS, 79.3% (459/579) and 20.7% (120/579) had an initial diagnosis of GG1 and GG2 disease, respectively. Overall, 43.2% of patients (250/579) were upgraded on confirmatory Cbx, with 19.2% (111/579) upgraded to ≥ GG3. For the 226 patients followed on AS, 32.7% (74/226) had benign, 45.6% (103/226) had GG1, and 21.7% (49/226) had GG2 results on confirmatory Cbx. In total, 28.8% (65/226) of patients eventually progressed to ≥ GG3, with a median time to AS failure of 89 months. The median time from confirmatory Cbx to AS failure for the negative, GG1, and GG2 groups were 97, 97, and 32 months, respectively (p < .001). On multivariable regression, only age (hazard ratio 1.06 [1.02-1.11], p < .005) and GG on confirmatory Cbx (hazard ratio 2.75 [1.78-4.26], p < .005) remained as positive predictors of AS failure.

Conclusion: The confirmatory combined MRI-targeted plus systematic biopsy provides useful information for the risk stratification of patients at the time of AS enrollment.
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http://dx.doi.org/10.1016/j.urology.2020.06.061DOI Listing
October 2020

Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial.

Lancet Oncol 2020 08 6;21(8):1099-1109. Epub 2020 Jul 6.

Developmental Therapeutics Branch, Magnuson Clinical Center, Bethesda, MD, USA.

Background: Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL, and RET, which also has an effect on the tumour immune microenvironment by decreasing regulatory T cells and myeloid-derived suppressor cells. In this study, we examined the activity of cabozantinib in patients with metastatic platinum-refractory urothelial carcinoma.

Methods: This study was an open-label, single-arm, three-cohort phase 2 trial done at the National Cancer Institute (Bethesda, MD, USA). Eligible patients were 18 years or older, had histologically confirmed urothelial carcinoma or rare genitourinary tract histologies, Karnofsky performance scale index of 60% or higher, and documented disease progression after at least one previous line of platinum-based chemotherapy (platinum-refractory). Cohort one included patients with metastatic urothelial carcinoma with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Two additional cohorts that enrolled in parallel (patients with bone-only urothelial carcinoma metastases and patients with rare histologies of the genitourinary tract) were exploratory. Patients received cabozantinib 60 mg orally once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate by RECIST in cohort one. Response was assessed in all patients who met the eligibility criteria and who received at least 8 weeks of therapy. All patients who received at least one dose of cabozantinib were included in the safety analysis. This completed study is registered with ClinicalTrials.gov, NCT01688999.

Findings: Between Sept 28, 2012, and Oct, 20, 2015, 68 patients were enrolled on the study (49 in cohort one, six in cohort two, and 13 in cohort three). All patients received at least one dose of cabozantinib. The median follow-up was 61·2 months (IQR 53·8-70·0) for the 57 patients evaluable for response. In the 42 evaluable patients in cohort one, there was one complete response and seven partial responses (objective response rate 19%, 95% CI 9-34). The most common grade 3-4 adverse events were fatigue (six [9%] patients), hypertension (five [7%]), proteinuria (four [6%]), and hypophosphataemia (four [6%]). There were no treatment-related deaths.

Interpretation: Cabozantinib has single-agent clinical activity in patients with heavily pretreated, platinum-refractory metastatic urothelial carcinoma with measurable disease and bone metastases and is generally well tolerated. Cabozantinib has innate and adaptive immunomodulatory properties providing a rationale for combining cabozantinib with immunotherapeutic strategies.

Funding: National Cancer Institute Intramural Program and the Cancer Therapy Evaluation Program.
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http://dx.doi.org/10.1016/S1470-2045(20)30202-3DOI Listing
August 2020

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome: Spectrum of imaging findings.

Clin Imaging 2020 Dec 9;68:14-19. Epub 2020 Jun 9.

National Institutes of Health Clinical Center, Radiology and Imaging Sciences, 10 Center Drive, Bethesda, MD 20814, United States of America. Electronic address:

Purpose: To retrospectively investigate the radiological presentations of HLRCC-associated renal tumors to facilitate accurate lesion characterization and compare these presentations with simple cysts and characteristics of other subtypes of renal cell carcinoma (RCC) as reported in the literature.

Methods: The MRI and CT imaging characteristics of 39 pathologically confirmed lesions from 30 patients (20 male, 10 female) with HLRCC syndrome were evaluated by two radiologists. Patients had an average age at diagnosis of 43.8 ± 13.1 years. Lesion characteristics including laterality, homogeneity, diameter (cm), nodularity, septations, T1 and T2 signal intensity, enhancement, and restricted diffusion were recorded. Imaging characteristics of the lesions were further compared to characteristics of benign simple cysts surgically removed at the same time point.

Results: The examined lesions had a mean diameter of 5.06 ± 3.80 cm, an average growth rate of 2.91 × 10 cm/day and an estimated annual growth rate of 1.06 cm/year. 50% of lesions demonstrated nodularity, 65% were mostly T2-hyperintense, 83% demonstrated restricted diffusion in solid portions of the lesions, and 65% had well-defined margins. 76% of patients demonstrated extra-renal manifestations, 53% lymphadenopathy, and 43% distant metastasis.

Conclusions: Our analysis confirmed that while HLRCC-associated renal lesions demonstrate diversity in imaging presentations, the majority are unilateral and solitary, T2-hyperintense, heterogeneous with well-defined margins, and frequently demonstrate restricted diffusion and nodularity.
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http://dx.doi.org/10.1016/j.clinimag.2020.06.010DOI Listing
December 2020

Deep-Learning-Based Artificial Intelligence for PI-RADS Classification to Assist Multiparametric Prostate MRI Interpretation: A Development Study.

J Magn Reson Imaging 2020 11 1;52(5):1499-1507. Epub 2020 Jun 1.

Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Background: The Prostate Imaging Reporting and Data System (PI-RADS) provides guidelines for risk stratification of lesions detected on multiparametric MRI (mpMRI) of the prostate but suffers from high intra/interreader variability.

Purpose: To develop an artificial intelligence (AI) solution for PI-RADS classification and compare its performance with an expert radiologist using targeted biopsy results.

Study Type: Retrospective study including data from our institution and the publicly available ProstateX dataset.

Population: In all, 687 patients who underwent mpMRI of the prostate and had one or more detectable lesions (PI-RADS score >1) according to PI-RADSv2.

Field Strength/sequence: T -weighted, diffusion-weighted imaging (DWI; five evenly spaced b values between b = 0-750 s/mm ) for apparent diffusion coefficient (ADC) mapping, high b-value DWI (b = 1500 or 2000 s/mm ), and dynamic contrast-enhanced T -weighted series were obtained at 3.0T.

Assessment: PI-RADS lesions were segmented by a radiologist. Bounding boxes around the T /ADC/high-b value segmentations were stacked and saved as JPEGs. These images were used to train a convolutional neural network (CNN). The PI-RADS scores obtained by the CNN were compared with radiologist scores. The cancer detection rate was measured from a subset of patients who underwent biopsy.

Statistical Tests: Agreement between the AI and the radiologist-driven PI-RADS scores was assessed using a kappa score, and differences between categorical variables were assessed with a Wald test.

Results: For the 1034 detection lesions, the kappa score for the AI system vs. the expert radiologist was moderate, at 0.40. However, there was no significant difference in the rates of detection of clinically significant cancer for any PI-RADS score in 86 patients undergoing targeted biopsy (P = 0.4-0.6).

Data Conclusion: We developed an AI system for assignment of a PI-RADS score on segmented lesions on mpMRI with moderate agreement with an expert radiologist and a similar ability to detect clinically significant cancer.

Level Of Evidence: 4 TECHNICAL EFFICACY STAGE: 2.
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http://dx.doi.org/10.1002/jmri.27204DOI Listing
November 2020

microRNA Expression Profiling in Young Prostate Cancer Patients.

J Cancer 2020 7;11(14):4106-4114. Epub 2020 Apr 7.

Translational Surgical Pathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda MD.

MicroRNAs (miRNAs) are small, non-coding RNA molecules with multiple roles in many biological processes. Few studies have shown the molecular characteristics in younger prostate cancer (PCa) patients. In this study, we performed miRNA profiling in young PCa (EO-PCa) cases compared with PCa arising in older men (LO-PCa). : Formalin-fixed, paraffin embedded tissue was used. miRNA was extracted for PCR array and NanoString methods. Relative miRNAs expression levels were obtained by comparing young vs older men, and young PCa tumor samples vs normal epithelium. : miRNA profiling showed a different expression pattern in PCa arising in younger men, and young PCa tumoral and its normal counterpart. Nine miRNAs (hsa-miR-140-5p, hsa-miR-146a, hsa-miR-29b, hsa-miR-9, hsa-miR-124-3p, hsa-let-7f-5p, hsa-miR-184, hsa-miR-373, hsa-miR-146b-5p) showed differences in the expression compared to LO-PCa. Fourteen miRNAs were significantly up-regulated (miR-1973, miR-663a, miR-575, miR-93-5p, miR-630, miR-600, miR-494, miR-150-5p, miR-137, miR-25-3p, miR-375, miR-489, miR-888-5p, miR-142-3p), while 9 were found down-regulated (miR-21-5p, miR-363-3p, miR-205-5p, miR-548ai, miR-3195, 145-5p, miR-143-3p, miR-222-3p, miR-221-3p) comparing young PCa tumoral tissue compared to normal counterpart. The higher expression of miR-600 and miR-137 were associated with high Gleason score, extraprostatic extension and lymphatic invasion. : These results suggest that PCa in younger patients has a different expression profile compared to normal tissue and PCa arising in older man. Differentially expressed miRNAs provide insights of molecular mechanisms involve in this PCa subtype.
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http://dx.doi.org/10.7150/jca.37842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196262PMC
April 2020

Determination of the Expression of PD-L1 in the Morphologic Spectrum of Renal Cell Carcinoma.

J Cancer 2020 26;11(12):3596-3603. Epub 2020 Mar 26.

Translational Surgical Pathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.

Immunotherapy is reportedly an effective form of therapy for some advanced cancers such as lung adenocarcinoma, malignant melanoma and colorectal adenocarcinoma. In renal cell carcinoma (RCC), the role of immunotherapy is under investigation. Programmed Death-Ligand 1 (PD-L1) is a molecule expressed on the surface of certain tumor cells and binds to the Programmed cell death protein 1 (PD-1) on cytotoxic T-cells, an interaction that inhibits the antitumor immune response. The aim of this study is to evaluate PD-L1 expression in the morphologic spectrum of RCC. A total of 172 cases of RCC comprising all types were studied and the PD-L1 was correlated with immune response for CD4 and CD8. Positive membranous staining for PD-L1 was seen in 59 (34%) of the 172 samples. The positive cases were HLRCC (31/53), Type 1 Papillary RCC (10/31), Chromophobe (7/20), Hybrid (3/9), TFE-3 related cancer (3/8), Undifferentiated (3/5), and TFEB tumors (2/2). Clear cell carcinomas, Oncocytomas and SDHB deficient-RCC didn't show any expression of PD-L1; (0/34;0/7;0/3). Our results demonstrated that aggressive forms of RCC such as HLRCC have high expression of PD-L1, in contrast to clear cell renal carcinomas. Our findings support a possible role of anti-PD-L1/PD-1 immunotherapies in the treatment of PD-L1-positive RCC.
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http://dx.doi.org/10.7150/jca.35738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150459PMC
March 2020

Novel renal medullary carcinoma cell lines, UOK353 and UOK360, provide preclinical tools to identify new therapeutic treatments.

Genes Chromosomes Cancer 2020 08 17;59(8):472-483. Epub 2020 Apr 17.

Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States.

Renal medullary carcinoma (RMC) is a rare, aggressive disease that predominantly afflicts individuals of African or Mediterranean descent with sickle cell trait. RMC comprises 1% of all renal cell carcinoma diagnoses with a median overall survival of 13 months. Patients are typically young (median age-22) and male (male:female ratio of 2:1) and tumors are characterized by complete loss of expression of the SMARCB1 tumor suppressor protein. Due to the low incidence of RMC and the disease's aggressiveness, treatment decisions are often based on case reports. Thus, it is critical to develop preclinical models of RMC to better understand the pathogenesis of this disease and to identify effective forms of therapy. Two novel cell line models, UOK353 and UOK360, were derived from primary RMCs that both demonstrated the characteristic SMARCB1 loss. Both cell lines overexpressed EZH2 and other members of the polycomb repressive complex and EZH2 inhibition in RMC tumor spheroids resulted in decreased viability. High throughput drug screening of both cell lines revealed several additional candidate compounds, including bortezomib that had both in vitro and in vivo antitumor activity. The activity of bortezomib was shown to be partially dependent on increased oxidative stress as addition of the N-acetyl cysteine antioxidant reduced the effect on cell proliferation. Combining bortezomib and cisplatin further decreased cell viability both in vitro and in vivo that single agent bortezomib treatment. The UOK353 and UOK360 cell lines represent novel preclinical models for the development of effective forms of therapy for RMC patients.
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http://dx.doi.org/10.1002/gcc.22847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383978PMC
August 2020

Impact of bowel preparation with Fleet's™ enema on prostate MRI quality.

Abdom Radiol (NY) 2020 12;45(12):4252-4259

Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Aim: To investigate the effects of cleansing Fleet's™ enema (FE) on rectal distention and image quality of diffusion-weighted imaging (DWI) in prostate magnetic resonance imaging (MRI).

Methods: This study included 117 prospectively accrued active surveillance patients who underwent prostate MRI both without (prep-) and with bowel preparation consisting of FE (prep+) obtained within 12 months of each other. The anterior-posterior (AP) diameter of the rectum, degree of perceived distention in the rectum and image quality scores were assessed by two independent readers for both (prep- and prep+) scans. DWI distortion was assessed quantitatively using the degree of anatomic mismatches between images obtained at different b values and the T2-weighted MRI. DWI artifact was qualitatively scored based on the presence of blurring, poor signal-to-noise, and artifact lines. The difference in rectal AP diameters between the two methods was tested by the paired Wilcoxon rank test. Stuart Maxell test was used in comparing rectal distention, DWI distortion, and artifact. Reader agreement was estimated by kappa statistics. p values < 0.05 were considered statistically significant.

Results: Mean rectal AP diameter was significantly larger in prep- compared with prep+ scans (p = 0.002). Subjective scores demonstrated inter-reader variability. For instance, the rectal distention score was significantly lower in prep+ for reader 2 (p < 0.001) whereas it was not significant for reader 1 (p = 0.09). Reader 2 also found significant improvement in DWI distortion (p = 0.02) in prep+ scans. There was no significant difference between prep- and prep+ in DWI distortion and artifacts for reader 1 (p = 0.17 and p = 0.49, respectively), or DWI artifacts for reader 2 (p = 0.55). Kappa scores were moderate for rectal distension, but weak for DWI distortion, and artifacts.

Conclusion: Bowel preparation with enema prior to prostate MRI may diminish rectal gas but has modest effects on DWI distortion and overall image quality. The value of bowel prep is not conclusively validated in this study.
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http://dx.doi.org/10.1007/s00261-020-02487-6DOI Listing
December 2020

Spatial density and diversity of architectural histology in prostate cancer: influence on diffusion weighted magnetic resonance imaging.

Quant Imaging Med Surg 2020 Feb;10(2):326-339

Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background: To assess the influence of specific histopathologic patterns on MRI diffusion characteristics by performing rigorous whole-mount/imaging registration and correlating histologic architectures observed in prostate cancer with diffusion characteristics in prostate MRIs.

Methods: Fifty-two whole-mount pathology blocks from 15 patients who underwent multiparametric MRI (mpMRI) at a single institution prior to radical prostatectomy were retrospectively analyzed. Regions containing individual morphologic patterns (N=21 patterns, including variations of cribriforming, expansile sheets, single cells, patterns of early intraluminal complexity, and mucin rupture patterns) were digitally annotated by an expert genitourinary pathologist. Distinct tumor foci on each slide were also assigned a Gleason grade and scored as having any high-risk histologic pattern. Digital sections were aligned to MRI using a patient-specific mold and registered using local mean weighted piecewise transformation based on anatomic control points. Density and presence of morphological patterns was correlated to apparent diffusion coefficient (ADC) signal intensity using mixed effects model accounting for nested intra-foci, intra-patient correlation. Influence of intra-tumoral heterogeneity was assessed by affinity propagation clustering (APC) of morphology features and correlated to foci- and cluster-level ADC metrics.

Results: One hundred eleven distinct tumor foci were evaluated. Beta diversity, reflecting average morphology representation across inter- and intra-foci areas, demonstrated higher intra-tumor diversity within high-risk foci (P<0.05). ADC signal demonstrated an inverse correlation with foci-level Gleason grade (P>0.05), which was strengthened in cluster-level analysis for intra-foci regions containing high-risk morphologies (P=0.017). In voxel-based analysis, dense regions demonstrate lower ADC, but the presence and density for each morphology influenced ADC independently (ANOVA P<0.001).

Conclusions: Architectural features influence ADC characteristics of MRI, with more complex tumors having lower ADC values regulated by presence and density of specific morphologies.
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http://dx.doi.org/10.21037/qims.2020.01.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063286PMC
February 2020