Publications by authors named "Maria Merino"

415 Publications

Granulomas in Dermatopathology: Principal Diagnoses - Part 2.

Actas Dermosifiliogr 2021 Apr 20. Epub 2021 Apr 20.

Servicio de Anatomía Patológica, Hospital Universitario El Bierzo, Ponferrada, España; Servicio de Anatomía Patológica, Hospital de La Reina, Ponferrada, España; Unidad de Investigación. Instituto de Investigación Biomédica de A Coruña (INIBIC). Universidad de A Coruña, A Coruña, España. Electronic address:

Part 2 of this series on granulomatous diseases focuses on skin biopsy findings. Whereas the first part treated noninfectious conditions (metabolic disorders and tumors, among other conditions), this part mainly deals with various types of infectious disease along with other conditions seen fairly often by clinical dermatologists.
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http://dx.doi.org/10.1016/j.ad.2021.04.001DOI Listing
April 2021

Granulomas in Dermatopathology: Principal Diagnoses - Part 1.

Actas Dermosifiliogr 2021 Apr 19. Epub 2021 Apr 19.

Servicio de Anatomía Patológica, Hospital Universitario El Bierzo, Ponferrada, España; Servicio de Anatomía Patológica, Hospital de La Reina, Ponferrada, España; Unidad de Investigación. Instituto de Investigación Biomédica de A Coruña (INIBIC). Universidad de A Coruña, A Coruña, España. Electronic address:

This series of 2 articles on dermatopathologic diagnoses reviews conditions in which granulomas form. Part 1 clarifies concepts, discusses the presentation of different types of granulomas and giant cells, and considers a large variety of noninfectious diseases. Some granulomatous diseases have a metabolic origin, as in necrobiosis lipoidica. Others, such as granulomatous mycosis fungoides, are related to lymphomas. Still others, such as rosacea, are so common that dermatologists see them nearly daily in clinical practice.
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http://dx.doi.org/10.1016/j.ad.2021.04.002DOI Listing
April 2021

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

Dual activity of PD-L1 targeted Doxorubicin immunoliposomes promoted an enhanced efficacy of the antitumor immune response in melanoma murine model.

J Nanobiotechnology 2021 Apr 13;19(1):102. Epub 2021 Apr 13.

Department of Pharmaceutical Technology and Chemistry, School of Pharmacy, University of Navarra, 31008, Pamplona, Navarra, Spain.

Background: The immunomodulation of the antitumor response driven by immunocheckpoint inhibitors (ICIs) such as PD-L1 (Programmed Death Ligand-1) monoclonal antibody (α-PD-L1) have shown relevant clinical outcomes in a subset of patients. This fact has led to the search for rational combinations with other therapeutic agents such as Doxorubicin (Dox), which cytotoxicity involves an immune activation that may enhance ICI response. Therefore, this study aims to evaluate the combination of chemotherapy and ICI by developing Dox Immunoliposomes functionalized with monovalent-variable fragments (Fab') of α-PD-L1.

Results: Immunoliposomes were assayed in vitro and in vivo in a B16 OVA melanoma murine cell line over-expressing PD-L1. Here, immune system activation in tumor, spleen and lymph nodes, together with the antitumor efficacy were evaluated. Results showed that immunoliposomes bound specifically to PD-L1 cells, yielding higher cell interaction and Dox internalization, and decreasing up to 30-fold the IC, compared to conventional liposomes. This mechanism supported a higher in vivo response. Indeed, immunoliposomes promoted full tumor regression in 20% of mice and increased in 1 month the survival rate. This formulation was the only treatment able to induce significant (p < 0.01) increase of activated tumor specific cytotoxic T lymphocytes at the tumor site.

Conclusion: PD-L1 targeted liposomes encapsulating Dox have proved to be a rational combination able to enhance the modulation of the immune system by blocking PD-L1 and selectively internalizing Dox, thus successfully providing a dual activity offered by both, chemo and immune therapeutic strategies.
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http://dx.doi.org/10.1186/s12951-021-00846-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042980PMC
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

Using Prostate Imaging-Reporting and Data System (PI-RADS) Scores to Select an Optimal Prostate Biopsy Method: A Secondary Analysis of the Trio Study.

Eur Urol Oncol 2021 Apr 10. Epub 2021 Apr 10.

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

Background: While magnetic resonance imaging (MRI)-targeted biopsy (TBx) results in better prostate cancer (PCa) detection relative to systematic biopsy (SBx), the combination of both methods increases clinically significant PCa detection relative to either Bx method alone. However, combined Bx subjects patients to higher number of Bx cores and greater detection of clinically insignificant PCa.

Objective: To determine if prebiopsy prostate MRI can identify men who could forgo combined Bx without a substantial risk of missing clinically significant PCa (csPC).

Design, Setting, And Participants: Men with MRI-visible prostate lesions underwent combined TBx plus SBx.

Outcome Measurements And Statistical Analysis: The primary outcomes were detection rates for grade group (GG) ≥2 and GG ≥3 PCa by TBx and SBx, stratified by Prostate Imaging-Reporting and Data System (PI-RADS) score.

Results And Limitations: Among PI-RADS 5 cases, nearly all csPCs were detected by TBx, as adding SBx resulted in detection of only 2.5% more GG ≥2 cancers. Among PI-RADS 3-4 cases, however, SBx addition resulted in detection of substantially more csPCs than TBx alone (7.5% vs 8%). Conversely, TBx added little to detection of csPC among men with PI-RADS 2 lesions (2%) relative to SBx (7.8%).

Conclusions: While combined Bx increases the detection of csPC among men with MRI-visible prostate lesions, this benefit was largely restricted to PI-RADS 3-4 lesions. Using a strategy of TBx only for PI-RADS 5 and combined Bx only for PI-RADS 3-4 would avoid excess biopsies for men with PI-RADS 5 lesions while resulting in a low risk of missing csPC (1%).

Patient Summary: Our study investigated an optimized strategy to diagnose aggressive prostate cancer in men with an abnormal prostate MRI (magnetic resonance imaging) scan while minimizing the risk of excess biopsies. We used a scoring system for MRI scan images called PI-RADS. The results show that MRI-targeted biopsies alone could be used for men with a PI-RADS score of 5, while men with a PI-RADS score of 3 or 4 would benefit from a combination of MRI-targeted biopsy and systematic biopsy. This trial is registered at ClinicalTrials.gov as NCT00102544.
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http://dx.doi.org/10.1016/j.euo.2021.03.004DOI Listing
April 2021

Real world effectiveness of standard of care triple therapy versus two-drug combinations for treatment of people living with HIV.

PLoS One 2021 8;16(4):e0249515. Epub 2021 Apr 8.

Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Background: Since 1996, the standard of care (SOC) therapy for HIV treatment has consisted of a backbone of two nucleoside analogue reverse transcriptase inhibitors (NRTI) paired with a third agent. Use of two-drug combinations (2DC) has been considered for selected patients to avoid toxicities associated with the use of NRTIs. This study aimed to compare the real-world outcomes of integrase strand transfer inhibitor (INSTI)-containing triple therapy (TT) to dolutegravir- (DTG) and/or boosted protease inhibitor (bPI)-based 2DC in a large Spanish cohort of HIV patients.

Methods: A retrospective analysis was performed using data from the VACH cohort, a prospective multicentre Spanish cohort of adult HIV patients. All treatment experienced patients initiating a TT of an INSTI combined with two NRTIs or a 2DC-containing DTG and/or a bPI between 01/01/2012 and 01/06/2017 were included. The unit of analysis was patient-regimens. The overall sample analysis was complemented with two sub-analyses. The first sub-analysis focused on patients treated with a backbone plus DTG compared to those treated with DTG+ one other antiretroviral. The second sub-analysis focused on patients with HIV RNA<50 copies/mL at baseline, irrespective of the regimen used. The following endpoints were assessed: time to discontinuation for any reason, time to switch due to virologic failure, and time to switch due to toxicity (reasons for discontinuation according to clinician report in the database). Time-to-event analyses were conducted using Kaplan-Meier survival curves and Cox regression models.

Results: Overall 7,481 patients were included in the analysis, contributing to 9,243 patient-regimens. Patient characteristics at baseline differed among groups, with the 2DC group being significantly older and having a higher proportion of women, a longer time on ART and a higher number of previous virologic failures. Median (95% Confidence Interval [C.I.]) time to switch was 2.5 years (2.3, 2.7) in 2DC group versus 2.9 years (2.7, 3.0) in TT. Adjusted hazard ratios (95% C.I.) for discontinuation due to any reason, virologic failure and toxicity in the 2DC vs TT group were 1.29 (1.15; 1.44), 2.06 (1.54; 2.77) and 1.18 (0.94; 1.48), respectively. Results were consistent in the two sub-analyses.

Conclusion: In this analysis, time to discontinuation and probability of remaining free of virologic failure were significantly higher in patients on INSTI-based TT compared to DTG- and/or bPI-containing 2DC, with no differences in toxicity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249515PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031389PMC
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

Metabolic Health Together with a Lipid Genetic Risk Score Predicts Survival of Small Cell Lung Cancer Patients.

Cancers (Basel) 2021 Mar 5;13(5). Epub 2021 Mar 5.

Molecular Oncology Group, IMDEA Food Institute, CEI UAM + CSIC, E-28049 Madrid, Spain.

Small cell lung cancer (SCLC) prognosis is the poorest of all types of lung cancer. Its clinical management remains heterogeneous and therefore, the capability to predict survival would be of great clinical value. Metabolic health (MH) status and lipid metabolism are two relevant factors in cancer prevention and prognosis. Nevertheless, their contributions in SCLC outcome have not yet been analyzed. We analyzed MH status and a transcriptomic panel of lipid metabolism genes in SCLC patients, and we developed a predictive genetic risk score (GRS). MH and two lipid metabolism genes, racemase and perilipin 1, are biomarkers of SCLC survival (HR = 1.99 (CI95%: 1.11-3.61) = 0.02, HR = 0.36 (CI95%: 0.19-0.67), = 0.03 and HR = 0.21 (CI95%: 0.09-0.47), respectively). Importantly, a lipid GRS of these genes predict better survival (c-index = 0.691). Finally, in a Cox multivariate regression model, MH, lipid GRS and smoking history are the main predictors of SCLC survival (c-index = 0.702). Our results indicate that the control of MH, lipid gene expression and environmental factors associated with lifestyle is crucial for increased SCLC survival. Here, we propose for the first time, a metabolic precision approach for SCLC patients.
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http://dx.doi.org/10.3390/cancers13051112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961979PMC
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

Pilot study of gadoxetate disodium-enhanced mri for localized and metastatic prostate cancers.

Sci Rep 2021 Mar 11;11(1):5662. Epub 2021 Mar 11.

Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

OATP1B3 is expressed de novo in primary prostate cancer tissue and to a greater degree in prostate cancer metastases. Gadoxetate disodium is a substrate of OATP1B3, and its uptake has been shown to correlate with OATP1B3 expression in other cancers. We aimed to evaluate use of gadoxetate disodium to image prostate cancer and to track its utility as a biomarker. A single center open-label non-randomized pilot study recruited men with (1) localized, and (2) metastatic castration resistant prostate cancer (mCRPC). Gadoxetate disodium-enhanced MRI was performed at four timepoints post-injection. The Wilcoxon signed rank test was used to compare MRI contrast enhancement ratio (CER) pre-injection and post-injection. OATP1B3 expression was evaluated via immunohistochemistry (IHC) and a pharmacogenomic analysis of OATP1B3, NCTP and OATP1B1 was conducted. The mCRPC subgroup (n = 9) demonstrated significant enhancement compared to pre-contrast images at 20-, 40- and 60-min timepoints (p < 0.0078). The localized cancer subgroup (n = 11) demonstrated earlier enhancement compared to the mCRPC group, but no retention over time (p > 0.05). OATP1B3 expression on IHC trended higher contrast enhancement between 20-40 min (p ≤ 0.064) and was associated with contrast enhancement at 60 min (p = 0.0422). OATP1B1 haplotype, with N130D and V174A substitutions, impacted enhancement at 40-60 min (p ≤ 0.038). mCRPC lesions demonstrate enhancement after injection of gadoxetate disodium on MRI and retention over 60 min. As inter-individual variability in OATP1B3 expression and function has both predictive and prognostic significance, gadoxetate disodium has potential as a biomarker in prostate cancer.
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http://dx.doi.org/10.1038/s41598-021-84960-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952731PMC
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

Improving rheumatoid arthritis management within the Spanish National Health System: a social return on investment study.

Clin Exp Rheumatol 2021 Feb 15. Epub 2021 Feb 15.

University of Castilla-La Mancha. Economic Analysis and Finance Department, Toledo, Spain.

Objectives: To define a set of proposals that would improve the current management of patients with rheumatoid arthritis (RA) within the Spanish National Health System (SNHS), and to estimate the impact of their implementation from a social perspective.

Methods: A one-year forecast-type Social Return on Investment (SROI) analysis was performed on the basis of information collected from a scientific literature review, official data, and multiple stakeholders regarding RA. A sub-analysis was performed within the areas of diagnosis, early RA (<2 years from diagnosis), and established RA (≥2 years from diagnosis).

Results: Stakeholders agreed on a set of 22 proposals, which included incorporating specialised nursing, addressing adherence issues, providing psychological support, or promoting the role of patient associations, among others. Their implementation would require an investment of 289 million euros and yield a social return of 913 million euros, i.e. a social return of 3.16 euros per euro invested (2.92 euros in the worst-case scenario and 3.40 euros in the best-case scenario). The greatest social return relative to investment and the greatest attributed to intangible aspects were observed within the area of early RA.

Conclusions: Evidence-based recommendations for the management of RA are aspirational. Nevertheless, the present study estimated that the implementation of the set of proposals would result in a positive impact relative to the investment needed to implement them. The results may guide management decisions to reduce the burden associated with RA, and help bridge the gap between evidence-based recommendations and routine clinical practice.
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February 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

Metastatic and recurrent adrenocortical cancer is not defined by its genomic landscape.

BMC Med Genomics 2020 11 4;13(1):165. Epub 2020 Nov 4.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.

Background: Adrenocortical carcinoma (ACC) is a rare, often-aggressive neoplasm of the adrenal cortex, with a 14-17 month median overall survival. We asked whether tumors from patients with advanced or metastatic ACC would offer clues as to putative genes that might have critical roles in disease progression or in more aggressive disease biology.

Methods: We conducted comprehensive genomic and expression analyses of ACCs from 43 patients, 30 female, and 42 from metastatic sites, including deep sequencing, copy number analysis, mRNA expression and microRNA arrays.

Results: Copy number gains and losses were similar to that previously reported for ACC. We identified a median mutation rate of 3.38 per megabase (Mb). The mutational signature was characterized by a predominance of C > T, C > A and T > C transitions. Only cancer genes TP53 (26%) and beta-catenin (CTNNB1, 14%) were mutated in more than 10% of samples. The TCGA-identified putative cancer genes MEN1 and PRKAR1A were found in low frequency-4.7 and 2.3%, respectively. The majority of the mutations were in genes not implicated in the etiology or maintenance of cancer. Specifically, amongst the 38 genes that were mutated in more than 9% of samples, only four were represented in Tier 1 of the 576 COSMIC Cancer Gene Census (CCGC). Thus, 82% of genes found to have mutations likely have no role in the etiology or biology of ACC; while the role of the other 18%, if any, remains to be proven. Finally, the transcript length for the 38 most frequently mutated genes in ACC is statistically longer than the average of all coding genes, raising the question of whether transcript length in part determined mutation probability.

Conclusions: We conclude that the mutational and expression profiles of advanced and metastatic tumors are very similar to those from newly diagnosed patients-with very little in the way of genomic aberration to explain differences in biology. With relatively low mutation rates, few major oncogenic drivers, and loss of function mutations in several epigenetic regulators, an epigenetic basis for ACC may be postulated and serve as the basis for future studies.
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http://dx.doi.org/10.1186/s12920-020-00809-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640690PMC
November 2020

Metabolic enzyme ACSL3 is a prognostic biomarker and correlates with anticancer effectiveness of statins in non-small cell lung cancer.

Mol Oncol 2020 12 30;14(12):3135-3152. Epub 2020 Oct 30.

Molecular Oncology Group, IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain.

Lung cancer is one of the most common cancers, still characterized by high mortality rates. As lipid metabolism contributes to cancer metabolic reprogramming, several lipid metabolism genes are considered prognostic biomarkers of cancer. Statins are a class of lipid-lowering compounds used in treatment of cardiovascular disease that are currently studied for their antitumor effects. However, their exact mechanism of action and specific conditions in which they should be administered remains unclear. Here, we found that simvastatin treatment effectively promoted antiproliferative effects and modulated lipid metabolism-related pathways in non-small cell lung cancer (NSCLC) cells and that the antiproliferative effects of statins were potentiated by overexpression of acyl-CoA synthetase long-chain family member 3 (ACSL3). Moreover, ACSL3 overexpression was associated with worse clinical outcome in patients with high-grade NSCLC. Finally, we found that patients with high expression levels of ACSL3 displayed a clinical benefit of statins treatment. Therefore, our study highlights ACSL3 as a prognostic biomarker for NSCLC, useful to select patients who would obtain a clinical benefit from statin administration.
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http://dx.doi.org/10.1002/1878-0261.12816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718959PMC
December 2020

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