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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

Aim: To compare by micro-costing the costs incurred by quick diagnosis units of tertiary and second-level hospitals. Patients & methods: We included 407 patients from a tertiary and secondary hospital unit. A bottom-up approach was applied. Results: Cost per patient was €577.5 ± 219.6 in the tertiary versus €394.7 ± 92.58 in the secondary unit (p = 0.0559). Mean number of visits and ratio of successive/first visits were significantly higher in the former (3.098 and 2.07 vs 2.123 and 1.12, respectively). Personnel and indirect costs including their percent contribution to overall costs accounted for the main differences. Conclusion: A greater volume of appointments, number of staff and staff time and a greater complexity of patients from the tertiary hospital unit justified the differences in cost outcomes.

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.

Background: Renal cell carcinomas developing in patients with HLRCC syndrome are known to be aggressive single tumors of variable sizes, with a well-established morphology. Other morphological tumor types occurring in association with classic HLRCC tumors as independent neoplasias in this syndrome, have not been clearly recognized and described. We describe four patients with known HLRCC syndrome with confirmed germ line mutation who developed benign oncocytic renal tumors. Since HLRCC can also be oncocytic in many instances, it is important to be aware of the possible benign oncocytic tumors in this patient group. Design: Four patients with known positive germ line FH mutation and known HLRCC syndrome developed associated or new oncocytic tumors. All tumors were morphologically evaluated, IHC staining was done for FH, 2SC, CKIT, CK7, PAX8 and molecular studies were performed with TSO-500 for the evaluation of other genes. Clinicopathological correlation was done in all cases. Results: The tumors had been identified radiologically and were suspicious for malignancy. Age range was 37-73 years, and all the patients were female. Two patients had coexistent HLRCC cancers while two only had the oncocytomas. Localization was left kidney for all the masses, which were brown in color and well circumscribed and varied in size from 0.7 to 4 cm. In one patient, four separate masses were identified with different locations and sizes, but with the same morphology. This specific patient presented with two additional masses in the opposite kidney later. Tumors were composed of large oncocytic cells with prominent granular eosinophilic cytoplasm and dark pyknotic nuclei. No evidence of atypia, mitosis or necrosis was found. FH was positive, 2SC and CK7 were negative on IHC stains, whereas CKIT showed diffuse membranous positivity. Tumors were diagnosed as oncocytomas. All patients were positive for FH germ line mutation and the mutation was also identified in the tissues. Other molecular studies on the patient with multiple tumors showed additional pathogenic ERCC2 inactivating mutation, suggesting germline, which is rarely encountered in kidney tumors. All the patients are alive and free of disease up to 10 years after diagnosis. Conclusion: HLRCC cancers can have a variety of morphologic patterns and frequently have oncocytic features. Clinical information, genetic testing and special techniques are helpful in the diagnosis of these high-grade tumors. Recognizing that other benign indolent tumors with oncocytic features can occur in this syndrome is important to avoid errors in diagnosis and treatment. Citation Format: Dilara Akbulut, Mark Ball, Mark Raffeld, Marston Linehan, Maria J. Merino. Benign oncocytic tumors in the setting of HLRCC syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1518.

390 Background: PCa has inherited risk factors including high genetic risk variants such as BRCA1/2, HOXB13, and DNA mismatch repair genes. mpMRI has been shown to be effective for detection and staging of localized PCa. This study follows participants (prts), born biologically male, without a diagnosis of PCa with known germline pathogenic or likely pathogenic variants (PV) in BRCA1/2, MLH1, MSH2, MSH6, PMS2, EPCAM, HOXB13, ATM, NBN, TP53, CHEK2, PALB2, RAD51C/D, BRIP1, or FANCA-FANCM (NCT03805919). Methods: Up to 500 eligible prts 30-75 years old (yo) with a documented germline PV will enroll. Prts undergo biennial clinical exam and mpMRI, and annual PSA monitoring and are followed at 12-month intervals to determine PSA, prostate cancer diagnosis, and/or disease/survival status until death. Indication for prostate biopsy includes clinical or imaging findings. Biopsy specimens undergo molecular analyses. Results: To date, 175 prts have been enrolled: 169 (97%) White, 3 Hispanic (2%), 1 African American (1%), 1 Asian (1%), and 1 biethnic (1%). Median age is 47 yo. The most common monoallelic PV are: 48.6% BRCA2, 25.1% BRCA1, 6.3% CHEK2 and 5.7% MSH2. PVs in ATM, PALB2, HOXB13, PMS2, MLH1, MSH6, BRIP1, EPCAM and RAD51D are ≤4%. One subject carries three distinct PVs ( BRCA2, CHEK2, BRIP1). Indication for biopsy was found in 26.3% of prts with 22/46 (47.8%) with a PIRADS 4 lesion, 6/46 (13.0%) PIRADS 3 lesion, 12/46 (26.1%) elevated PSA (median=2.8 ng/mL) or 6/46 (13.0%) due to clinical discretion. Adenocarcinoma was diagnosed on 13/39 (33.3%) biopsies with median age at diagnosis=59 yo. 9/13 (69%) prts had a PSA

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.

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.

OBJECTIVE. The purpose of this study was to assess the utility of PET with (2S)-2-[[(1S)-1-carboxy-5-[(6-(18F)fluoranylpyridine-3-carbonyl)amino]pentyl]carbamoylamino]pentanedioic acid (18F-DCFPyL)...

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(2)-weighted, diffusion-weighted imaging (DWI; five evenly spaced b values between b = 0–750 s/mm(2)) for apparent diffusion coefficient (ADC) mapping, high b-value DWI (b = 1500 or 2000 s/mm(2)), and dynamic contrast-enhanced T(1)-weighted series were obtained at 3.0T. ASSESSMENT: PI-RADS lesions were segmented by a radiologist. Bounding boxes around the T(2)/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: 2204

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.

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 compar-ing 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.

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). Experimental Design: 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. Results: 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. Conclusion: 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.

PURPOSE: Currently, there is a dearth of data concerning the impact of hypogonadism on prostate cancer detection by imaging. In this study, we evaluated the performance of multiparametric MRI (mpMRI) and mpMRI-TRUS fusion biopsy in hypogonadal patients. MATERIALS AND METHODS: Clinical and pathologic data from a prospectively maintained, single-institution database of patients who underwent 3T mpMRI and fusion biopsy between 2007 and 2016 were analyzed. Hypogonadism was defined by an institutional cutoff of serum testosterone ≤ 180 ng/dL; T2, DWI, and DCE scores were calculated from mpMRI. Cancer detection rates were compared by Chi-square tests. Multivariate logistic regression was undertaken to evaluate the impact of hypogonadism on clinically significant cancer detection by systematic and fusion biopsy. RESULTS: We included 522 patients in our study who had total testosterone levels measured within 90 days of mpMRI. Of these, 49 (9.4%) were hypogonadal. Median total testosterone was 148 ng/dL (IQR 41) in the hypogonadal group, and 304 ng/dL (IQR 132) in the normogonadal group (p < 0.001). Imaging results were comparable between the hypo and normogonadal groups. In the hypogonadal group, systematic biopsy detected clinically significant cancer in 28.6% of patients compared to 40.8% with fusion biopsy. In the normogonadal cohort, systematic and fusion biopsy detected 37.3% and 43.2% CS cancer, respectively. In the hypogonadal cohort, fusion biopsy detected 12.2% more CS cancers compared to systematic biopsy, while it detected only 5.9% more in the normogonadal cohort. On multivariate analysis, hypogonadism was found to be an independent predictor of decreased CS cancer detection on systematic (p = 0.048), but not on fusion biopsy (p = 0.170). CONCLUSIONS: Hypogonadism is an independent predictor of lower CS cancer detection on systematic biopsy. However, it fails to significantly impact CS detection on fusion biopsy with comparable cancer detection rates in both groups. Patients with hypogonadism may benefit more from fusion biopsy than normogonadal patients.

The underlying premise of prostate cancer active surveillance (AS) is that cancers likely to metastasize will be recognized and eliminated before cancer-related disease can ensue. Our study was designed to determine the prostate cancer upgrading rate when biopsy guided by magnetic resonance imaging (MRGBx) is used before entry and during AS.The cohort included 519 men with low- or intermediate-risk prostate cancer who enrolled in prospective studies (NCT00949819 and NCT00102544) between February 2008 and February 2020. Subjects were preliminarily diagnosed with Gleason Grade Group (GG) 1 cancer; AS began when subsequent MRGBx confirmed GG1 or GG2. Participants underwent confirmatory MRGBx (targeted and systematic) followed by surveillance MRGBx approximately every 12 to 24 months. The primary outcome was tumor upgrading to ≥GG3.Upgrading to ≥GG3 was found in 92 men after a median followup of 4.8 years (IQR 3.1-6.5) after confirmatory MRGBx. Upgrade-free probability after 5 years was 0.85 (95% CI 0.81-0.88). Cancer detected in a magnetic resonance imaging lesion at confirmatory MRGBx increased risk of subsequent upgrading during AS (HR 2.8; 95% CI 1.3-6.0), as did presence of GG2 (HR 2.9; 95% CI 1.1-8.2) In men who upgraded ≥GG3 during AS, upgrading was detected by targeted cores only in 27%, systematic cores only in 25% and both in 47%. In 63 men undergoing prostatectomy, upgrading from MRGBx was found in only 5 (8%).When AS begins and follows with MRGBx (targeted and systematic), upgrading rate (≥GG3) is greater when tumor is initially present within a magnetic resonance imaging lesion or when pathology is GG2 than when these features are absent.

To present fully automated DL-based prostate cancer detection system for prostate MRI.MRI scans from two institutions, were used for algorithm training, validation, testing. MRI-visible lesions were contoured by an experienced radiologist. All lesions were biopsied using MRI-TRUS-guidance. Lesions masks, histopathological results were used as ground truth labels to train UNet, AH-Net architectures for prostate cancer lesion detection, segmentation. Algorithm was trained to detect any prostate cancer ≥ ISUP1. Detection sensitivity, positive predictive values, mean number of false positive lesions per patient were used as performance metrics.525 patients were included for training, validation, testing of the algorithm. Dataset was split into training (n = 368, 70%), validation (n = 79, 15%), test (n = 78, 15%) cohorts. Dice coefficients in training, validation sets were 0.403, 0.307, respectively, for AHNet model compared to 0.372, 0.287, respectively, for UNet model. In validation set, detection sensitivity was 70.9%, PPV was 35.5%, mean number of false positive lesions/patient was 1.41 (range 0-6) for UNet model compared to 74.4% detection sensitivity, 47.8% PPV, mean number of false positive lesions/patient was 0.87 (range 0-5) for AHNet model. In test set, detection sensitivity for UNet was 72.8% compared to 63.0% for AHNet, mean number of false positive lesions/patient was 1.90 (range 0-7), 1.40 (range 0-6) in UNet, AHNet models, respectively.We developed a DL-based AI approach which predicts prostate cancer lesions at biparametric MRI with reasonable performance metrics. While false positive lesion calls remain as a challenge of AI-assisted detection algorithms, this system can be utilized as an adjunct tool by radiologists.

Familial non-medullary thyroid cancer (FNMTC) is a form of endocrine malignancy exhibiting an autosomal dominant mode of inheritance with largely unknown germline molecular mechanism. Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is another hereditary autosomal dominant cancer syndrome which, if proven to be caused by germline mutations in mismatch repair genes (MMR)—MLHL, MSH2, MSH6, PMS2, and EPCAM—is called Lynch syndrome (LS). LS results in hereditary predisposition to a number of cancers, especially colorectal and endometrial cancers. Tumors in LS are characterized by microsatellite instability (MSI) and/or loss of MMR protein expression in immunohistochemistry (IHC). MSI is a rare event in thyroid cancer (TC), although it is known to occur in up to 2.5% of sporadic follicular TC cases. There are limited data on the role of germline MMR variants FNMTC. The goal of this study was to analyze the potential clinical and molecular association between HNPCC and FNMTC. We performed a cohort study analyzing the demographic, clinical, and pathologic data of 43 kindreds encompassing 383 participants (104 affected, 279 unaffected), aged 43.5 [7-99] years with FNMTC, and performed high-throughput whole-exome sequencing (WES) of peripheral blood DNA samples of selected 168 participants (54 affected by FNMTC and 114 unaffected). Total affected by thyroid cancer members per family ranged between 2 and 9 patients. FNMTC was more prevalent in women (68.3%) and characterized by a median tumor size of 1.0 [0.2-5.0] cm, multifocal growth in 44%, and gross extrathyroidal extension in 11.3%. Central neck lymph node metastases were found in 40.3% of patients at presentation, 12.9% presented with lateral neck lymph node metastases, and none had distant metastases. Family history screening revealed one Caucasian family meeting the clinical criteria for FNMTC and HNPCC, with five members affected by FNMTC and at least eight individuals reportedly unaffected by HNPCC-associated tumors. In addition, two family members were affected by melanoma. Genome Analysis Tool Kit (GATK) pipeline was used in variant analysis. Among 168 sequenced participants, a heterozygous missense variant in the MSH2 gene (rs373226409; c.2120G>A; p.Cys707Tyr) was detected exclusively in FNMTC- HNPCC- kindred. In this family, the sequencing was performed in one member affected by FNMTC, HPNCC-associated tumors and melanoma, one member affected solely by HNPCC-associated tumor, and one member with FNMTC only, as well as seven unaffected family members. The variant was present in all three affected adults, and in two unaffected children of the affected member, under the age of 18 years, and was absent in non-affected adults. This variant is predicted to be damaging/pathogenic in 17/20 in-silico models. However, immunostaining performed on the thyroid tumor tissue of two affected by FNMTC family members revealed intact nuclear expression of MSH2, and microsatellite stable status in both tumors that were tested. Although the MSH2 p.Cys707Tyr variant is rare with a minor allele frequency (MAF) of 0.00006 in Caucasians; it is more common in the South Asian population at 0.003 MAF. Therefore, the MSH2 variant observed in this family is unlikely to be an etiologic factor of thyroid cancer and a common genetic association between FNMTC and HNPCC has not yet been identified. This is the first report known to us on the co-occurrence of FNMTC and HNPCC. The co-occurrence of FNMTC and HNPCC-associated tumors is a rare event and although presented in a single family in our large FNMTC cohort, a common genetic background between the two comorbidities could not be established.

PURPOSE: We sought to evaluate whether bilateral prostate cancer detected at active surveillance (AS) enrollment is associated with progression to Grade Group (GG) ≥2 and to compare the efficacy of combined targeted biopsy plus systematic biopsy (Cbx) vs systematic biopsy (Sbx) or targeted biopsy alone to detect bilateral disease. MATERIALS AND METHODS: A prospectively maintained database of patients referred to our institution from 2007–2020 was queried. The study cohort included all AS patients with GG1 on confirmatory Cbx and followup of at least 1 year. Cox proportional hazard analysis identified baseline characteristics associated with progression to ≥GG2 at any point throughout followup. RESULTS: Of 579 patients referred, 103 patients had GG1 on Cbx and were included in the study; 49/103 (47.6%) patients progressed to ≥GG2, with 30/72 (41.7%) patients with unilateral disease progressing and 19/31 (61.3%) patients with bilateral disease progressing. Median time to progression was 68 months vs 52 months for unilateral and bilateral disease, respectively (p=0.006). Both prostate specific antigen density (HR 1.72, p=0.005) and presence of bilateral disease (HR 2.21, p=0.012) on confirmatory biopsy were associated with AS progression. At time of progression, GG and risk group were significantly higher in patients with bilateral versus unilateral disease. Cbx detected 16% more patients with bilateral disease than Sbx alone. CONCLUSIONS: Bilateral disease and prostate specific antigen density at confirmatory Cbx conferred greater risk of earlier AS progression. Cbx was superior to Sbx for identifying bilateral disease. AS risk-stratification protocols may benefit from including presence of bilateral disease and should use Cbx to detect bilateral disease.

Objective Increased computational power and improved visualization hardware have generated more opportunities for virtual reality (VR) applications in healthcare. In this study, we test the feasibility of a VR-assisted surgical navigation system for robotic-assisted radical prostatectomy. Material and methods The prostate, all magnetic resonance imaging (MRI) visible tumors, and important anatomic structures like the neurovascular bundles, seminal vesicles, bladder, and rectum were contoured on a multiparametric MRI using an in-house segmentation software. Three-dimensional (3-D) VR models were rendered and evaluated in a side room of the operating room. While interacting with the VR platform, a real-time stereo video capture of the in situ prostate was obtained to render a second 3-D model. The MRI-based model was then overlaid on the real-time model by using an automated alignment algorithm. Results Ten patients were included in this study. All MRI-based VR models were examined by surgeons immediately prior to surgery and at important steps where visualization of the tumors and their proximity to surrounding anatomic structures were critical. This was mainly during the preparation of the prostatic pedicles, neurovascular plexus, the apex, and bladder neck. All participants found the system useful, especially for tumors with locally aggressive growth patterns. For small and centrally located tumors, the system was not considered beneficial due to lack of integration into the robotic console. A fully integrated system with real-time overlays within the robotic stereo viewer was found to be the ideal scenario. Conclusion We deployed a preliminary VR-assisted surgical navigation tool for robotic-assisted radical prostatectomies.

Renal medullary carcinoma (RMC) is one of the most aggressive renal cell carcinomas. It predominantly afflicts young adults and adolescents with sickle cell trait and other sickle hemoglobinopathies, and is refractory to targeted and antiangiogenic therapies used in patients with clear-cell renal cell carcinoma. Platinum-based cytotoxic chemotherapy is the mainstay for RMC treatment. On the basis of recent advances in the diagnosis, management, and clinical trial development for RMC, a panel of experts met in October 2017 and developed updated consensus recommendations to inform clinicians, researchers, and patients. Because RMC often aggressively recurs while patients are still recovering from nephrectomy, upfront chemotherapy should be considered for most patients, including those with localized disease. After safety and dosing information has been established in adults, phase II and III trials enrolling patients with RMC should allow patients aged 12 years and older to be accrued. Patients with the very rare unclassified renal cell carcinoma with medullary phenotype variant should be included in RMC trials. Medical providers should be aware that RMC can afflict subjects of all races, and not only those of African descent, and that the presence of sickle cell trait, or of other sickle hemoglobinopathies, can affect drug responses and toxicity.

Objective To describe a family in which 3 members presented with mixed epithelial tumor of the kidney (MEST) and were found to possess a germline mutation in CDC73, a gene which is associated with hyperparathyroidism-jaw tumor syndrome (HPT-JT). Materials and Methods Blood and tumor DNA from three family members who presented with a primary diagnosis of MEST was subjected to targeted gene sequencing to identify potential genetic components. Results A germline start codon mutation (p.M1I) in CDC73 was identified in all 3 family members who presented with MEST and 2 tumors from 1 patient demonstrated somatic copy-neutral loss of heterozygosity. Patients presented with no evidence of hyperparathyroidism or jaw tumors, but both female patients had hysterectomies at an early age due to excessive bleeding and numerous fibroids, which is common in HPT-JT. A germline p.M1I mutation has been previously reported in a family with clinical features of HPT-JT. Conclusion Patients with MEST may be at risk for HPT-JT and CDC73 germline mutation testing of MEST patients should be considered.

BACKGROUND: There are conflicting reports on whether familial nonmedullary thyroid cancer is more aggressive than sporadic nonmedullary thyroid cancer. Our aim was to determine if the clinical and pathologic characteristics of familial nonmedullary thyroid cancer are different than nonmedullary thyroid cancer. METHODS: We compared patients with familial nonmedullary thyroid cancer to a cohort of 53,571 nonmedullary thyroid cancer patients from the Surveillance, Epidemiology, and End Results database. RESULTS: A total of 78 patients with familial nonmedullary thyroid cancer from 31 kindreds presented at a younger age (P =.04) and had a greater rate of T1 disease (P =.019), lymph node metastasis (P =.002), and the classic variant of papillary thyroid cancer on histology (P < .001) compared with the Surveillance, Epidemiology, and End Results cohort. Patients with ≥3 affected family members presented at a younger age (P = .04), had a lesser female-to-male ratio (P=.04), and had a greater rate of lymph node metastasis (P =.009). Compared with the Surveillance, Epidemiology, and End Results cohort, we found a higher prevalence of lymph node metastasis in familial nonmedullary thyroid cancer index cases (P =.003) but not in those diagnosed by screening ultrasonography (P =.58). CONCLUSION: Patients with familial nonmedullary thyroid cancer present at a younger age and have a greater rate of lymph node metastasis. The treatment for familial nonmedullary thyroid cancer should be more aggressive in patients who present clinically and in those who have ≥3 first-degree relatives affected.

Introduction: Intravesical Bacillus Calmette-Guerin (BCG) is an effective immunotherapy for non-muscle invasive bladder cancer (NMIBC). However, BCG treatment failure will lead to recurrence and tumor progression. In this study, urinary exosomes content (miRNA profile) was evaluated as a possible marker of BCG treatment response in NMIBC patients. Methods: Urine samples from patients with bladder cancer were collected at the time of surgery and during patient follow up to 1 year. Urine from healthy volunteers were also included. Clinical and pathological information such as tumor grade (High Grade (HG), Low Grade (LG)), depth of invasion (Ta, T1, CIS), and response to BCG treatment was also obtained. Exosome Isolation and total RNA extraction including microRNAs from cell-free urine after centrifugation were obtained. Library preparation for miRNA expression was done (QIAseq® miRNA Library) for Next-Generation Sequencing (NGS) analysis in a NextSeq 2000 single read platform, 75 bp with 15-20 million reads per sample. Reads were then queried against miRDeep2 software for identification. Only miRNAs having at least 20 counts considering all samples were included. After normalization, significantly and deferentially expressed microRNAs (>2-Fold) were selected for analysis. Bioinformatic analysis including sequence alignment was performed under the STAR-based approach. Identified microRNAs were then used to classify/predict the response to treatment and its relationship with other clinicopathologic variables. Results: A total of 56 urine samples from 13 patients were available/used for analysis including 10 High Grade Ta and 3 High Grade T1 patients. Urine from normal healthy donors (N=3) was also included. Clinicopathological features were patients with HGTa=10, HGT1=3 and 3 control samples. Regarding treatment response 9 patients were BCG responders and 4 BCG unresponsive. When compared to BCG unresponsive patients, BCG responders showed 45 differentially expressed miRNAs. Statistically significant differentially expressed miRNAs (Fold-change >2, p value Conclusion: Our study supports the value of urinary exosomal microRNAs as non-invasive biomarkers to predict BCG treatment response in nonmuscle-invasive bladder cancer. Citation Format: Vladimir Valera, Beatriz Walter, Maria J. Merino. Urinary exosome analysis as a marker of treatment response in bladder cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5831.

BACKGROUND: An inherited susceptibility to renal cancers is associated with multiple predisposing genes, but most screening tests are limited to patients with a family history. Next-generation sequencing (NGS)–based multigene panels provide an efficient and adaptable tool for investigating pathogenic germline mutations on a larger scale. This study investigated the frequency of pathogenic germline mutations in renal cancer predisposition genes in patients with sporadic, early-onset disease. METHODS: An NGS-based panel of 23 known and potential renal cancer predisposition genes was used to analyze germline mutations in 190 unrelated Chinese patients under the age of 45 years who presented with renal tumors. The detected variants were filtered for pathogenicity, and then their frequencies were calculated and correlated with clinical features. Germline variants of the fumarate hydratase (FH) and BRCA1-associated protein 1 (BAP1) genes were comprehensively analyzed because of their aggressive potential. RESULTS: In total, 18 patients (9.5%) had germline mutations in 10 genes. Twelve of these 18 patients had alterations in renal cancer predisposition genes (6.3%), and 6 patients had mutations in potential predisposition genes such as BRCA1/2. Notably, pathogenic mutation carriers had a significant family history in second-degree relatives in comparison with those without pathogenic mutations (P < .001). Variants of unknown clinical significance in FH and BAP1 demonstrated evidence of additional somatic loss in tumors CONCLUSIONS: In patients with early-onset disease, a multigene panel identified a high pathogenic germline mutation rate in renal cancer predisposition genes. This study emphasizes the importance of screening patients with early-onset disease for mutations in cancer predisposition genes. Germline screening should be encouraged in early-onset patients to provide personalized medicine and improve patient outcomes.

Background Recurrent adrenocortical carcinoma (ACC) is an aggressive disease with few options offering durable survival benefit. Despite metastasectomy, recurrence is common. Cytoreduction and intraperitoneal chemotherapy have offered improved survival in other advanced cancers. We sought to evaluate the use of cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of recurrent intraperitoneal ACC. Methods A phase II, single institution clinical trial was approved for patients with radiographic evidence of resectable ACC limited to the peritoneum. Patients underwent treatment if optimal cytoreduction was deemed possible at exploratory laparotomy. Primary outcome was intraperitoneal progression-free survival. Secondary outcomes were treatment-related morbidities and overall survival. Results Sixty-three patients were evaluated, of whom 11 met eligibility criteria. Nine patients underwent cytoreduction and HIPEC, including one patient who recurred and was re-treated (n = 10 treatments). One patient could not be optimally cytoreduced for HIPEC and therefore did not receive intraperitoneal chemotherapy. There was no perioperative mortality; perioperative comorbidities were limited to Clavien-Dindo grade 2 or 3 and included hematologic, infectious, and neurologic complications. Seven patients experienced disease recurrence and two patients died of disease during follow-up (median 24 mo). Intraperitoneal progression-free survival was 19 mo, and median overall survival has not yet been reached. Conclusions Cytoreduction and HIPEC can be performed safely in selected patients. Patients with recurrent ACC confined to the peritoneal cavity can be considered for regional therapy in experienced hands. However, disease recurrence is common, and other treatment options should be explored.

Background Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations. Methods Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations. Results Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5–16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7–72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8–18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response. Conclusions Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities. Trial registration ClinicalTrials.gov identifier: NCT02484404. Electronic supplementary material The online version of this article (10.1186/s40425-018-0463-2) contains supplementary material, which is available to authorized users.

Endometrioid endometrial carcinomas (EECs) are the most common histological subtype of uterine cancer. Late-stage disease is an adverse prognosticator for EEC. The purpose of this study was to analyze EEC exome mutation data to identify late-stage-specific statistically significantly mutated genes (SMGs), which represent candidate driver genes potentially associated with disease progression. We exome sequenced 15 late-stage (stage III or IV) non-ultramutated EECs and paired non-tumor DNAs; somatic variants were called using Strelka, Shimmer, Somatic Sniper and MuTect. Additionally, somatic mutation calls were extracted from The Cancer Genome Atlas (TCGA) data for 66 late-stage and 270 early-stage (stage I or II) non-ultramutated EECs. MutSigCV (v1.4) was used to annotate SMGs in the two late-stage cohorts and to derive p-values for all mutated genes in the early-stage cohort. To test whether late-stage SMGs are statistically significantly mutated in early-stage tumors, q-values for late-stage SMGs were re-calculated from the MutSigCV (v1.4) early-stage p-values, adjusting for the number of late-stage SMGs tested. We identified 14 SMGs in the combined late-stage EEC cohorts. When the 14 late-stage SMGs were examined in the TCGA early-stage data, only KLF3 and PAX6 failed to reach significance as early-stage SMGs, despite the inclusion of enough early-stage cases to ensure adequate statistical power. Within TCGA, nonsynonymous mutations in KLF3 and PAX6 were, respectively, exclusive or nearly exclusive to the microsatellite instability (MSI)-hypermutated molecular subgroup and were dominated by insertions-deletions at homopolymer tracts. In conclusion, our findings are hypothesis-generating and suggest that KLF3 and PAX6, which encode transcription factors, are MSI target genes and late-stage-specific SMGs in EEC.

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 (8% vs 7.5%). 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.

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(mean) 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.

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 (SDHx) mutations. SDHx 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 (SUCNR1) in SDHB PPGLs and SDHD head and neck paragangliomas. Its ligand succinate has been reported to accumulate due to SDHx mutations. We thus hypothesize that autocrine stimulation of SUCNR1 plays a role in the pathogenesis of SDHx mutation-derived PPGLs. We confirmed elevated SUCNR1 expression in SDHx PPGLs and after SDHB knockout in progenitor cells derived from a human pheochromocytoma (hPheo1). Succinate significantly increased viability of SUCNR1-transfected PC12 and ERK pathway signaling compared to control cells. Candidate SUCNR1 inhibitors successfully reversed proliferative effects of succinate. Our data reveal an unrecognized oncometabolic function of succinate in SDHx PPGLs, providing a growth advantage via SUCNR1.

Extracellular vesicles (EVs) of various types are released or shed from all cells. EVs carry proteins and contain additional protein and nucleic acid cargo that relates to their biogenesis and cell of origin. EV cargo in liquid biopsies is of widespread interest owing to its ability to provide a retrospective snapshot of cell state at the time of EV release. For the purposes of EV cargo analysis and repertoire profiling, multiplex assays are an essential tool in multiparametric analyte studies but are still being developed for high-parameter EV protein detection. Although bead-based EV multiplex analyses offer EV profiling capabilities with conventional flow cytometers, the utilization of EV multiplex assays has been limited by the lack of software analysis tools for such assays. To facilitate robust EV repertoire studies, we developed multiplex analysis post-acquisition analysis (MPA

Extracellular vesicles (EVs) of various types are released or shed from all cells. EVs carry proteins and contain additional protein and nucleic acid cargo that relates to their biogenesis and cell of origin. EV cargo in liquid biopsies of widespread interest due to its ability to provide a retrospective snapshot of cell state at the time of EV release. For the purposes of EV cargo analysis and repertoire profiling, multiplex assays are an essential tool in multiparametric analyte studies but are still being developed for high-parameter EV protein detection. Although bead-based EV multiplex analyses offer EV profiling capabilities with conventional flow cytometers, the utilization of EV multiplex assays has been limited by the lack of software analysis tools for such assays. Therefore, to facilitate robust EV repertoire studies, we have developed a free, open-source software (MPAPASS) for stitched multiplex analysis, EV database-compatible reporting, and visualization of EV repertoires.

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 cm3 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.

Rationale, Aims, and Objectives Quick diagnosis units, a paradigmatic innovative model of hospital ambulatory medicine in Spain, are suggested to be cost-effective. While former studies have been conducted as cost analyses of single units or comparative analyses between these patients and inpatients hospitalized for the same condition, how cost outcomes compare between units of different hospitals and different levels of complexity is unknown. Using micro-costing, the costs of patients managed at quick diagnosis units from a tertiary and a secondary hospital were compared. Methods The study population included 407 patients from each unit who were evaluated over 8 years. Through a bottom-up approach, we analyzed all single cost components that contributed to the mean total cost per patient in both units. Results Patients from the tertiary hospital unit were more likely than those from the secondary hospital to be referred for cancer suggestive symptoms, to have a diagnosis of cancer, and to be referred from the emergency department. Although the ratio of successive/first visits was 3.098 ± 0.6584 in the tertiary vs. 2.123 ± 0.2171 in the secondary hospital unit (P=0.0064), the time to diagnosis was significantly longer in the latter. With a similar mean cost per visit, the cost per patient was \euro577.5 ± \euro219.6 in the tertiary vs. \euro394.7 ± \euro92.58 in the secondary hospital unit (P=0.0559). Personnel and indirect costs including both the monetary estimate and their percent contribution to the mean cost per patient accounted for the main differences between units. Conclusion The ratio of successive/first visits was the main driver of cost differences. A greater complexity of patients from the unit of the tertiary hospital and the inherent characteristics of this type of hospital including volume of patients and staff and staff time justified the differences in the ratio of visits and the cost outcomes.

OBJECTIVE. 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, ...

Intratumoral heterogeneity (IH) has been recently described as an important contributor to tumor growth through a branched rather than a linear pattern of tumor evolution for renal cell carcinoma. As to whether the miRNA profiling of the different and heterogeneous areas is the same or not, it is not known. This study analyzed the differences and similarities of the miRNA profiles in histologically distinct regions within several RCC tumors. The observed differences may have great implications for the development of predictive biomarkers and the identification of druggable targets with improvement of combinatorial therapeutic approaches for the effective treatment of kidney cancer, as well as for the identification of circulating malignant cells that can be useful to detect tumor recurrences.

OBJECTIVE. The purpose of this study was to assess the utility of PET with (2S)-2-[[(1S)-1-carboxy-5-[(6-((18)F)fluoranylpyridine-3-carbonyl)amino]pentyl]carbamoylamino]pentanedioic acid ((18)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). SUBJECTS AND METHODS. 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 (18)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. RESULTS. 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 (18)F-DCFPyL PET/CT and mpMRI were similar (PET/CT, 90.9% and 80%; mpMRI, 86.4% and 88.4%; p = 0.58/0.17). Total lesion PSMA and PSMA tumor volume showed a relationship with GG (τ = 0.27 and p = 0.08, τ = 0.30 and p = 0.06, respectively). Maximum SUV in tumor was significantly higher than that in nonmalignant tissue (p < 0.05). Tumor burden density moderately correlated with PSA density (r = 0.47, p = 0.01). Five true-positive tumors identified on (18)F-DCFPyL PET/CT were not identified on mpMRI. CONCLUSION. In patients with high-risk prostate cancer, (18)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.

OBJECTIVE. 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. MATERIALS AND METHODS. 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. RESULTS. 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 (p = 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%, p = 0.073). However, for transition zone lesions, sensitivity was higher for AI than for MRI (61.8% vs 50.8%, p = 0.001). Reading time was longer for AI than for MRI (4.66 vs 4.03 minutes, p < 0.001). There was moderate interreader agreement for AI and MRI with no significant difference (58.7% vs 58.5%, p = 0.966). CONCLUSION. 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.

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 (SDHx) mutations. SDHx 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 (SUCNR1) in SDHB PPGLs and SDHD head and neck paragangliomas. Its ligand succinate has been reported to accumulate due to SDHx mutations. We thus hypothesize that autocrine stimulation of SUCNR1 plays a role in the pathogenesis of SDHx mutation-derived PPGLs. We confirmed elevated SUCNR1 expression in SDHx PPGLs and after SDHB knockout in progenitor cells derived from a human pheochromocytoma (hPheo1). Succinate significantly increased viability of SUCNR1-transfected PC12 and ERK pathway signaling compared to control cells. Candidate SUCNR1 inhibitors successfully reversed proliferative effects of succinate. Our data reveal an unrecognized oncometabolic function of succinate in SDHx PPGLs, providing a growth advantage via SUCNR1.

We identified baseline imaging and clinical characteristics of patients that may improve risk stratification among patients being evaluated for active surveillance.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.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 (p0.01). 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.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.

Our objective was to investigate the lesion detection rate of (18)F-DCFPyL PET/CT, a prostate-specific membrane antigen (PSMA)–targeted PET agent, in patients with biochemically relapsed prostate cancer after primary local therapy. Methods: This was a prospective institutional review board–approved study of 90 patients with documented biochemical recurrence (median prostate-specific antigen [PSA], 2.5 ng/mL; range, 0.21–35.5 ng/mL) and negative results on conventional imaging after primary local therapies, including radical prostatectomy (n = 38), radiation (n = 27), or a combination of the two (n = 25). Patients on androgen deprivation therapy were excluded. Patients underwent whole-body (18)F-DCFPyL PET/CT (299.9 ± 15.5 MBq) at 2 h after injection. The PSMA PET lesion detection rate was correlated with PSA, PSA kinetics, and original primary tumor grade. Results: Seventy patients (77.8%) showed positive PSMA PET results, with a total of 287 lesions identified: 37 prostate bed foci, 208 lesions in lymph nodes, and 42 in distant sites in bones or organs, Eleven patients had negative results, and 9 patients showed indeterminate lesions, which were considered negative in this study. The detection rates were 47.6% (n = 10/21), 50% (n = 5/10), 88.9% (n = 8/9), and 94% (n = 47/50) for PSA levels of >0.2 to