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Rationale and objectives Prostate MRI improves detection of clinically significant prostate cancer; however, its diagnostic performance has wide variation. Artificial intelligence (AI) has the potential to assist radiologists in the detection and classification of prostatic lesions. Herein, we aimed to develop and test a cascaded deep learning detection and classification system trained on biparametric prostate MRI using PI-RADS for assisting radiologists during prostate MRI read out. Materials and Methods T2-weighted, diffusion-weighted (ADC maps, high b value DWI) MRI scans obtained at 3 Tesla from two institutions (n = 1043 in-house and n = 347 Prostate-X, respectively) acquired between 2015 to 2019 were used for model training, validation, testing. All scans were retrospectively reevaluated by one radiologist. Suspicious lesions were contoured and assigned a PI-RADS category. A 3D U-Net-based deep neural network was used to train an algorithm for automated detection and segmentation of prostate MRI lesions. Two 3D residual neural network were used for a 4-class classification task to predict PI-RADS categories 2 to 5 and BPH. Training and validation used 89% (n = 1290 scans) of the data using 5 fold cross-validation, the remaining 11% (n = 150 scans) were used for independent testing. Algorithm performance at lesion level was assessed using sensitivities, positive predictive values (PPV), false discovery rates (FDR), classification accuracy, Dice similarity coefficient (DSC). Additional analysis was conducted to compare AI algorithm's lesion detection performance with targeted biopsy results. Results Median age was 66 years (IQR = 60-71), PSA 6.7 ng/ml (IQR = 4.7-9.9) from in-house cohort. In the independent test set, algorithm correctly detected 111 of 198 lesions leading to 56.1% (49.3%-62.6%) sensitivity. PPV was 62.7% (95% CI 54.7%-70.7%) with FDR of 37.3% (95% CI 29.3%-45.3%). Of 79 true positive lesions, 82.3% were tumor positive at targeted biopsy, whereas of 57 false negative lesions, 50.9% were benign at targeted biopsy. Median DSC for lesion segmentation was 0.359. Overall PI-RADS classification accuracy was 30.8% (95% CI 24.6%-37.8%). Conclusion Our cascaded U-Net, residual network architecture can detect, classify cancer suspicious lesions at prostate MRI with good detection, reasonable classification performance metrics.

PURPOSE: Multiple studies demonstrate MRI-targeted biopsy detects more clinically significant cancer than systematic biopsy, however some clinically significant cancers are detected by systematic biopsy only. While these events are rare, we sought to perform a retrospective analysis of these cases to ascertain the reasons that MRI-targeted biopsy missed clinically significant cancer, which was subsequently detected on systematic prostate biopsy. METHODS: Patients were enrolled in a prospective study comparing cancer detection rates by transrectal MRI-targeted fusion biopsy and systematic 12-core biopsy. Patients with an elevated PSA, abnormal digital rectal exam, or imaging findings concerning for prostate cancer underwent prostate MRI and subsequent MRI-targeted and systematic biopsy in the same setting. The subset of patients with grade group (GG) ≥3 cancer found on systematic biopsy and GG≤2 cancer (or no cancer) on MRI-targeted biopsy were classified as MRI-targeted biopsy misses. A retrospective analysis of the MRI and MRI-targeted biopsy real-time screen captures determined the cause of MRI-targeted biopsy miss. Multivariable logistic regression analysis compared baseline characteristics of patients with MRI-targeted biopsy misses to GG-matched patients whose clinically significant cancer was detected by MRI-targeted biopsy. RESULTS: Over the study period of 2007 to 2019, 2103 patients met study inclusion criteria and underwent combined MRI-targeted and systematic prostate biopsies. 41 (1.9%) men were classified as MRI-targeted biopsy misses. Most MRI-targeted biopsy misses were due to errors in lesion targeting (n=21, 51.2%), followed by MRI-invisible lesions (n=17, 40.5%), and MRI lesions missed by the radiologist (n=3, 7.1%). On logistic regression analysis, lower PI-RADS score was associated with having clinically significant cancer missed on MRI-targeted biopsy. CONCLUSION: While uncommon, most MRI-targeted biopsy misses are due to errors in lesions targeting, which highlights the importance of accurate co-registration and targeting when using software-based fusion platforms. Additionally, some patients will harbor MRI-invisible lesions which are un-targetable by MRI-targeted platforms. The presence of a low PI-RADS score despite a high PSA is suggestive of harboring an MRI-invisible lesion.

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

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.

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

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.

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.

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.

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.

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.

PURPOSE: We aimed to assess post-interventional and 36-month follow-up results of a single-center, single-arm, in-bore phase I trial of focal laser ablation (FLA) guided by multiparametric magnetic resonance imaging (mpMRI). METHODS: FLA procedures were done in-bore MRI using a transperineal approach. Primary endpoints were feasibility and safety expressed as lack of grade 3 complications. Secondary endpoints were changes in international prostate symptom score (IPSS), sexual health inventory for men (SHIM), quality of life (QoL) scores, and serum prostate specific antigen (PSA) levels. Treatment outcomes were assessed by combined mpMRI-ultrasound fusion-guided and extended sextant systematic biopsy after 12, 24, and optionally after 36 months. RESULTS: Fifteen participants were included. Seven patients (46.67%) had Gleason 3+3 and 8 patients (53.33%) had Gleason 3+4 cancer. All patients tolerated the procedure well, and no grade 3/4 complications occurred. All grade 1 and 2 complications were transient and resolved completely. There was no significant change in mean IPSS from baseline (−1, p = 0.460) and QoL (0, p = 0.441) scores following FLA but there was a significant drop in mean SHIM scores (−2, p = 0.010) compared to pretreatment baselines. Mean PSA significantly decreased after FLA (−2.5, p < 0.001). Seven out of 15 patients (46.67%) had residual cancer in, adjacent, or in close proximity to the treatment area (1 × 4+3=7, 1 × 3+4=7, and 5 × 3+3=6). Four out of 15 patients (26.67%) underwent salvage therapy (2 repeat FLA, 2 radical prostatectomy). CONCLUSION: After 3 years of follow-up we conclude focal laser ablation is safe and feasible without significant complications.

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.

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, ...

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.

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.

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

Background Preoperative chemotherapy is important in the management of women with breast cancer, with the ability to downstage the breast primary tumor and axillary lymph nodes. Long-term studies are needed to identify late toxicities, recurrence patterns, and equivalency with postoperative chemotherapy for recurrence-free survival (RFS) and overall survival (OS). Patients and methods We conducted a single-institution prospective randomized control trial comparing preoperative or postoperative fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamides/granulocyte colony-stimulating factor chemotherapy for women with untreated clinical stage II (T1N1, T2N0, and T2N1) breast cancer. Long-term follow-up was conducted to define toxicities, recurrence patterns and RFS and OS. Results Fifty-three women with clinical stage II breast cancer were randomized, 26 patients to receive preoperative chemotherapy and 27 to receive postoperative chemotherapy. Long-term follow-up, with a median of 25.3 years, was obtained. Local or systemic recurrence occurred in 8 women in the preoperative group and in 10 women in the postoperative group, and recurrences were predominantly within 10 years of treatment. Late toxicities included local upper extremity paresthesia's, upper extremity edema and congestive heart failure in 1 patient each. Analysis revealed no difference in RFS (20-year RFS probabilities; preoperative: 61.3%, postoperative: 54.7%, P=0.42), or in OS between the 2 treatment groups (20-year probabilities, preoperative: 64.6%, postoperative: 62.2%, P=0.44). Twenty-five of 53 patients (47%) were alive and without disease at this follow-up. Conclusion Twenty-five-year follow-up for this prospective randomized trial confirms the equivalency of preoperative versus postoperative chemotherapy with fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamides/granulocyte colony-stimulating factor for stage II breast cancer for both RFS and OS.

Multi-parametric magnetic resonance imaging (mpMRI) permits non-invasive visualization and localization of clinically important cancers in the prostate. However, it cannot fully describe tumor heterogeneity and microstructures that are crucial for cancer management and treatment. Herein, we develop a deep learning framework that could predict epithelium density of the prostate in mpMRI. A deep convolutional neural network is built to estimate epithelium density per voxel-basis. Equipped with an advanced design of the neural network and loss function, the proposed method obtained a SSIM of 0.744 and a MAE of 6.448% in a cross-validation. It also outperformed the competing network. The results are promising as a potential tool to analyze tissue characteristics of the prostate in mpMRI.

BACKGROUND: To assess the influence of specific histopathologic patterns on MRI diffusion characteristics by performing rigorous whole-mount/imaging registration and correlating histologic architectures observed in prostate cancer with diffusion characteristics in prostate MRIs. METHODS: Fifty-two whole-mount pathology blocks from 15 patients who underwent multiparametric MRI (mpMRI) at a single institution prior to radical prostatectomy were retrospectively analyzed. Regions containing individual morphologic patterns (N=21 patterns, including variations of cribriforming, expansile sheets, single cells, patterns of early intraluminal complexity, and mucin rupture patterns) were digitally annotated by an expert genitourinary pathologist. Distinct tumor foci on each slide were also assigned a Gleason grade and scored as having any high-risk histologic pattern. Digital sections were aligned to MRI using a patient-specific mold and registered using local mean weighted piecewise transformation based on anatomic control points. Density and presence of morphological patterns was correlated to apparent diffusion coefficient (ADC) signal intensity using mixed effects model accounting for nested intra-foci, intra-patient correlation. Influence of intra-tumoral heterogeneity was assessed by affinity propagation clustering (APC) of morphology features and correlated to foci- and cluster-level ADC metrics. RESULTS: One hundred eleven distinct tumor foci were evaluated. Beta diversity, reflecting average morphology representation across inter- and intra-foci areas, demonstrated higher intra-tumor diversity within high-risk foci (P0.05), which was strengthened in cluster-level analysis for intra-foci regions containing high-risk morphologies (P=0.017). In voxel-based analysis, dense regions demonstrate lower ADC, but the presence and density for each morphology influenced ADC independently (ANOVA P

Purpose To retrospectively investigate the radiological presentations of HLRCC-associated renal tumors to facilitate accurate lesion characterization and compare these presentations with simple cysts and characteristics of other subtypes of renal cell carcinoma (RCC) as reported in the literature. Methods The MRI and CT imaging characteristics of 39 pathologically confirmed lesions from 30 patients (20 male, 10 female) with HLRCC syndrome were evaluated by two radiologists. Patients had an average age at diagnosis of 43.8 ± 13.1 years. Lesion characteristics including laterality, homogeneity, diameter (cm), nodularity, septations, T1 and T2 signal intensity, enhancement, and restricted diffusion were recorded. Imaging characteristics of the lesions were further compared to characteristics of benign simple cysts surgically removed at the same time point. Results The examined lesions had a mean diameter of 5.06 ± 3.80 cm, an average growth rate of 2.91 × 10−3 cm/day and an estimated annual growth rate of 1.06 cm/year. 50% of lesions demonstrated nodularity, 65% were mostly T2-hyperintense, 83% demonstrated restricted diffusion in solid portions of the lesions, and 65% had well-defined margins. 76% of patients demonstrated extra-renal manifestations, 53% lymphadenopathy, and 43% distant metastasis. Conclusions Our analysis confirmed that while HLRCC-associated renal lesions demonstrate diversity in imaging presentations, the majority are unilateral and solitary, T2-hyperintense, heterogeneous with well-defined margins, and frequently demonstrate restricted diffusion and nodularity.

Although the amount of medical data keeps increasing, data annotations are scarce and often very difficult to obtain. It is even harder for the case that involves multi-modal imaging or data such as radiology-pathology correlation. In this regard, semi-supervised learning has the potential to leverage unlabeled data for improved medical image analysis. Herein, we propose a semi-supervised learning framework for the dense pixelwise prediction in multi-parametric magnetic resonance imaging (mpMRI). The proposed method predicts the epithelial density in mpMRI per-voxel basis. The ground truth annotations are only obtainable from the corresponding pathology images, which are often unavailable for mpMRI. Introducing unsupervised data augmentation and supervised training signal annealing strategies during training, the proposed method utilizes both labeled and unlabeled mpMRI in an efficient and effective manner. The experimental results demonstrate that the proposed framework is effective in improving the stability and accuracy of the density prediction. The proposed framework achieves the mean absolute error of 6.493, compared to 7.353 by the supervised learning counterpart, outperforming other competing methods. The results suggest that the semi-supervised learning framework could aid in resolving the scarcity of medical data and annotations, in particular for radiology-pathology correlation.

Lymph node assessment in prostate cancer is most commonly performed at the time of radical prostatectomy. We present the case of pre-operative pelvic lymph node sampling with the use of MRI/TRUS fusion-guided biopsy at the time of prostate biopsy. Lymph node pathology revealed metastatic, poorly differentiated prostate cancer, concurrent with Gleason 4 + 5 disease showing perineural invasion. The use of MRI fusion guided biopsy for nodal sampling may be an effective method pre-operative staging and treatment planning for prostate adenocarcinoma. Keywords: MRI/TRUS fusion-guided biopsy, Lymph node biopsy, Prostate cancer, Pre-operative staging

Purpose In the era of multiparametric magnetic resonance imaging (mpMRI) of the prostate gland, incidental findings are occasionally discovered on imaging. We aimed to report our experience of detecting incidental bladder cancers on mpMRI of the prostate in asymptomatic patients without irritative voiding symptoms or microscopic or gross hematuria. Methods A retrospective review was performed on a prospectively maintained database of all men who underwent prostate mpMRI at our institution from 2012 to 2018. Patients who were found to have incidental bladder lesions were identified and baseline demographics, imaging and histopathologic data were recorded. All patients with incidental bladder lesion detection on mpMRI, not attributable to extension of prostate cancer, underwent cystoscopy in addition to a biopsy and/or transurethral resection of bladder tumor (TURBT) if warranted on cystoscopy. Results There were 3147 prostate mpMRIs performed during this period and 25 cases (0.8%) of incidental bladder lesions were detected. These patients did not have any presenting symptoms such as gross or microscopic hematuria to prompt bladder lesion workup. The largest diameter of incidentally discovered bladder lesions ranged from 0.4 cm to 1.7 cm. Of the 25 cases of incidental bladder lesions, five were suspected to be due to prostate cancer invasion into the bladder. Only two of these five patients underwent biopsy, which confirmed prostate adenocarcinoma in both cases. Of the 20 patients without suspected prostate cancer invasion of the bladder, four had no suspicious lesions on cystoscopy to warrant a biopsy. The remaining 16 patients had bladder lesions seen on cystoscopy and underwent a biopsy and/or TURBT. Three of these patients had benign features on pathology (urachal remnant, amyloidosis and inflammation) and the remaining 13 had stage Ta urothelial carcinoma. Seven of these patients had low-grade Ta tumors and six had high-grade Ta tumors. All patients were treated with standard management of TURBT with or without intravesical BCG. There have been no reported cases of recurrence or progression in any of the patients in our cohort at the median follow-up of 26 months (interquartile range,19-40 months). Conclusion mpMRI of the prostate may yield incidental findings, such as small bladder tumors. Awareness of the possibility of incidental bladder lesions is important as 65% of lesions reported in the bladder, not attributable to extension of prostate cancer, proved to be bladder cancer. This may allow for early intervention for asymptomatic patients with undetected bladder cancer prior to disease progression.

BACKGROUND: A perennial challenge in systemic cytotoxic cancer therapy is to eradicate primary tumors and metastatic disease while sparing normal tissue from off-target effects of chemotherapy. Anthracyclines such as doxorubicin are effective chemotherapeutic agents for which dosing is limited by development of cardiotoxicity. Our published evidence shows that targeting CD47 enhances radiation-induced growth delay of tumors while remarkably protecting soft tissues. The protection of cell viability observed with CD47 is mediated autonomously by activation of protective autophagy. However, whether CD47 protects cancer cells from cytotoxic chemotherapy is unknown. METHODS: We tested the effect of CD47 blockade on cancer cell survival using a 2-dimensional high-throughput cell proliferation assay in 4T1 breast cancer cell lines. To evaluate blockade of CD47 in combination with chemotherapy in vivo we employed the 4T1 breast cancer model and examined tumor and cardiac tissue viability as well as autophagic flux. RESULTS: Our high-throughput screen revealed that blockade of CD47 does not interfere with the cytotoxic activity of anthracyclines against 4T1 breast cancer cells. Targeting CD47 enhanced the effect of doxorubicin chemotherapy in vivo by reducing tumor growth and metastatic spread by activation of an anti-tumor innate immune response. Moreover, systemic suppression of CD47 protected cardiac tissue viability and function in mice treated with doxorubicin. CONCLUSIONS: Our experiments indicate that the protective effects observed with CD47 blockade are mediated through upregulation of autophagic flux. However, absence of CD47 in did not elicit a protective effect but it enhanced macrophage-mediated cancer cell cytolysis. Therefore, the differential responses observed with CD47 blockade are due to autonomous activation of protective autophagy in normal tissue and enhancement immune cytotoxicity against cancer cells.

PURPOSE: To determine whether the type of VHL gene pathogenic variant influences the growth rate or CT enhancement values of renal lesions in VHL patients. MATERIALS AND METHODS: Thirty-two VHL patients (19 male) were selected from a prospectively maintained imaging database for patients that underwent surgical tumor resection between 2014 and 2016. One hundred and eleven VHL lesions were marked for resection and pathology analysis. Whole lesion volumetric segmentation was performed on nephrographic phase of the two most recent contrast-enhanced CT scans before surgery. Intensity distribution curves were obtained from segmentations. A linear mixed model, accounting for within-patient correlations, was used to compare the growth and enhancement differences between different germline pathogenic variant types. RESULTS: There was no significant difference for the lesions’ total growth between different germline pathogenic variants (P value = 0.78). The median growth rate for all lesions was 1.7 cc/year (IQR 0.5, 3.9) with a baseline median size of 4.1 cm(3) (IQR 1.7, 11.7). In complex lesions, the solid portion of the tumor demonstrated a higher growth rate (1.6 cc/year) than cystic portions (0.02 cc/year) which stayed relatively unchanged. Only one pathogenic variant (Splice donor) showed some levels of difference in its relative enhancement from other subtypes. CONCLUSION: The type of germline pathogenic variant on the VHL gene does not affect the growth rate or CT enhancement values of renal lesions in patients with VHL. The absolute growth rate of these tumors may be used in the scheduling of follow-up studies.

Summary Background High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle checkpoint kinase 1 and 2 inhibitor, would be active in BRCA wild-type disease. Methods In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma. All patients had a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type status, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status score 0–2, and adequate haematological, renal, hepatic, and bone-marrow function. Patients received intravenous prexasertib 105 mg/m 2 administered over 1 h every 14 days in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint of investigator-assessed tumour response, based on RECIST version 1.1, was assessed per protocol (assessable patients who had undergone CT imaging at baseline and attended at least one protocol-specified follow-up) and by intention to treat. The final analysis of this cohort of patients with BRCA wild-type high-grade serous ovarian carcinoma is reported here. This ongoing trial is registered with ClinicalTrials.gov, number NCT02203513, and continues to enrol patients for the BRCA -mutated ovarian cancer cohort. Findings Between Jan 20, 2015, and Nov 2, 2016, we enrolled 28 women with a median age of 64 years (IQR 58·0–69·5) who had previously received a median of 5·0 (IQR 2·5–5·0) systemic therapies. Most patients (22 [79%]) had platinum-resistant or platinum-refractory disease. All women received at least one dose of prexasertib, but four (14%) of 28 patients were not assessable for RECIST response. Eight (33%, 95% CI 16–55) of 24 patients assessable per protocol had partial responses. In the intention-to-treat population, eight (29%, 95% CI 13–49) of 28 had a partial responses. The most common (in >10% patients) grade 3 or 4 treatment-emergent adverse events were neutropenia in 26 (93%) of 28 patients, reduced white blood cell count in 23 (82%), thrombocytopenia in seven (25%), and anaemia in three (11%). Grade 4 neutropenia was reported in 22 (79%) patients after the first dose of prexasertib and was transient (median duration 6 days [IQR 4–8]) and recovered without growth-factor support in all cases. The treatment-related serious adverse event of grade 3 febrile neutropenia was reported in two (7%) patients. One patient died during the study due to tumour progression. Interpretation Prexasertib showed clinical activity and was tolerable in patients with BRCA wild-type high-grade serous ovarian carcinoma. This drug warrants further development in this setting, especially for patients with platinum-resistant or platinum-refractory disease. Funding Intramural Research Program of the National Institutes of Health and National Cancer Institute.

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.

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.

Background: Understanding the relationship between tumor genomics and the immune response in cancer has gotten more attention with the advance of immunotherapy. Microsatellite instability (MSI) is a molecular marker that provides prognostic and predictive information in many types of tumors including prostate cancer (PC). In PC, MSI-H and dMMR have been reported anywhere from 1% in primary tumors to up to 12% in metastasis. Reliable testing strategies for MSI/MMR status are critical for clinical management of patients with PC. MSI detection methods include PCR based molecular tests, NGS-based MSI detection or immunohistochemical staining (IHC). We observe technical difficulties in our daily practice with current molecular diagnostic tests. Design: We examined MMR protein expression (MSH2, MSH6, MLH1, PMS2) and PD-L1 by IHC in 30 PC. Results: Among 30 PC tested, 1 tumor (3%) was completely negative for MLH1 and PMS2 and 1 tumor (3%) revealed loss of PMS2 by IHC even though gene panel did not reveal any mutation in PMS2. The PD-L1 IHC was 44% positive, but the single MMR negative biopsy was PD-L1 negative. PD-L1 expression in PC samples did not show correlation with defective MMR expression. Conclusion: In our study, controversial results were obtained. Based on our experience; even though many exons of MMR genes are covered with these panels, there are some exons do not get enough coverage to be analyzed. This low coverage problem creates false negative results. There are also pseudogene pairs of these genes, especially PMS2. For some specific regions, even though there is enough coverage it is impossible to know if the pathogenic variant is on the PMS2 or the pseudogene without additional test. This result suffers from false positive results without a confirmatory test. It is also known that 5% to 11% of MSI-H cases demonstrate intact MMR staining and localization (proficient MMR, pMMR) due to retained antigenicity and nonfunctional protein. So far, in regular practice we use MMR analyzing strategies which set up for colon cancer where the tumor is uniform. PC is more complex; most of the time more than one clone is involving.We believe MSI detection for PC requires improvement the technics of detection, robust set up of testing strategy with high sensitivity and specificity, analyzing strategy and training of pathologists. Due to technical difficulties of the detection, we believe that the prevalence of MSI-high/dMMR PC might be higher than reported in the literature so far. Citation Format: Esra Dikoglu, Xu Naizhen, Luke P. O'Connor, Peter Pinto, Maria J. Merino. The dilemma of the current diagnostic tests for MSI in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 360.

Introduction: The understanding of molecular genetics in PCa provides insight into disease progression and treatment. Less is known about PCa development in men with known high-risk germline pathogenic/likely pathogenic variants in PCa related genes, particularly DNA damage repair (DDR). mpMRI can localize and detect PCa lesions in this population. We are conducting a multicenter natural history study of male participants (prts) with documented germline variant(s) in BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, HOXB13, ATM, NBN, TP53, CHEK2, PALB2, RAD51D, BRIP1, or FANCA who do not have a PCa diagnosis using mpMRI (NCT03805919). Methods: Up to 500 men, 30-75 years old (y/o) will undergo mpMRI evaluation at baseline and every 2 years (yrs). Prts are followed at 12-mo intervals to determine PSA, PCa diagnosis, and/or disease/survival status until death. Indication for prostate biopsy includes PSA >2.0 for 30 - 49 y/o; >2.5 ng/mL for 50 - 75 y/o and/or PIRADS 3+ MRI lesion or clinical discretion. Tissue obtained will undergo full transcriptome analysis. Results: 100 prts have enrolled. Median age is 47 y/o. Median on-study PSA is 0.87 (0.16-10.05 ng/mL). Median PSA density is 0.029. Gene mutations are BRCA2 (40%), BRCA1 (33%), MSH2 (9%), and CHEK2 (4%). Mutations in ATM, HOXB13, MLH1, MSH6, PMS2, and EPCAM are ≤3%. No significant AEs have been observed. Of 96 prts, 25 (26%), had indication for biopsy [PIRADS 4 lesion: 16 (64%), PIRADS 3 lesion: 4 (16%), elevated PSA: 6 (24%), or clinical indication 1: (4%)]. 22 prostate biopsies were performed and 6 prts were diagnosed with PCa. One prt was upstaged on radical prostatectomy (RP). Conclusions: We found mpMRI-based PCa screening in men with high-risk gene mutations, especially DDR genes, is feasible and can be used to identify clinically significant PCa and monitor for disease progression. Future guidelines should consider age, mutation specificity and mpMRI. Accrual and correlative studies (biomarkers, PBMCs) are on-going. AgeMutationPSA (ng/mL)Biopsy Gleason ScoreTreatment65BRCA22.253+3RP52BRCA10.693+3Active Surveillance (AS)62CHEK22.493+3AS59PMS21.033+3AS59CHEK22.243+4Radiation55BRCA21.683+3RP: 4+4=8 Citation Format: Fatima Karzai, Anna Couvillon, Yolanda McKinney, Katherine Lee-Wisdom, Peter L. Choyke, Veda N. Giri, Todd M. Morgan, Heather H. Cheng, Maria J. Merino, Peter A. Pinto, Baris Turkbey, William L. Dahut. A natural history study of men with high-risk genetics for prostate cancer (PCa) using multiparametric MRI (mpMRI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2605.

PurposeTo assess the ability of (N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-L-cysteine) (18F-DCFBC), a prostate-specific membrane antigen–targeted PET agent, to detect localized prostate cancer lesions in correlation with multiparametric MRI (mpMRI) and histopathology.MethodsThis He

The PI-RADS™ (Prostate Imaging Reporting and Data System), version 2 scoring system, introduced in 2015, is based on expert consensus. In the same time frame ISUP (International Society of Urological Pathology) introduced a new pathological scoring system for prostate cancer. Our goal was to prospectively evaluate the cancer detection rates for each PI-RADS, version 2 category and compare them to ISUP group scores in patients undergoing systematic biopsy and magnetic resonance imaging-transrectal ultrasound fusion guided biopsy.A total of 339 treatment naïve patients prospectively underwent multiparametric magnetic resonance imaging evaluated with PI-RADS, version 2 with subsequent systematic and fusion guided biopsy from May 2015 to May 2016. ISUP scores were applied to pathological specimens. An ISUP score of 2 or greater (ie Gleason 3 + 4 or greater) was defined as clinically significant prostate cancer. Cancer detection rates were determined for each PI-RADS, version 2 category as well as for the T2 weighted PI-RADS, version 2 categories in the peripheral zone.The cancer detection rate for PI-RADS, version 2 categories 1, 2, 3, 4 and 5 was 25%, 20.2%, 24.8%, 39.1% and 86.9% for all prostate cancer, and 0%, 9.6%, 12%, 22.1% and 72.4% for clinically significant prostate cancer, respectively. On T2-weighted magnetic resonance imaging the cancer detection rate in the peripheral zone was significantly higher for PI-RADS, version 2 category 4 than for overall PI-RADS, version 2 category 4 in the peripheral zone (all prostate cancer 36.6% vs 48.1%, p = 0.001, and clinically significant prostate cancer 22.9% vs 32.6%, p = 0.002).The cancer detection rate increases with higher PI-RADS, version 2 categories.

Objective To determine whether supplemental biopsy of hypoechoic ultrasound lesions (HUL) incidentally found during magnetic resonance imaging (MRI)-transrectal ultrasound (TRUS) fusion-targeted prostate biopsy results in improved prostate cancer (PCa) detection. Methods Patients underwent MRI-TRUS-targeted biopsy as part of an ongoing prospective trial from August 2007 to February 2015. For men with HUL, the biopsy pathology of HUL and MRI lesions was classified according to the updated 2014 International Society of Urological Pathology (ISUP) grading system. The detection of PCa by MRI-targeted biopsy with and without HUL biopsy was compared. Results Of 1260 men in the trial, 106 underwent biopsy of 119 HULs. PCa was diagnosed in 52 out of 106 men (49%) by biopsy of either MRI lesions or HUL. Biopsy of HUL in addition to MRI lesions resulted in 4 additional diagnoses of high-grade (ISUP grades 3-5) PCa versus biopsy of MRI lesions alone (20 vs 16 men, P = .046). Three of these cases were upgraded from lower grade (ISUP grades 1-2) PCa on MRI-guided biopsy alone, and only 1 case (1% of cohort) was diagnosed that would have been missed by MRI-guided biopsy alone. Supplemental biopsy of HUL did not change the PCa risk category in 96% (102 out of 106) of men with HUL. Conclusion Supplemental biopsy of HUL yields a small increase in the detection of higher grade PCa as compared with biopsy of MRI lesions alone. As upgrading is rare, routinely screening for HUL during MRI-targeted biopsy remains controversial.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant condition characterized by parathyroid, anterior pituitary and enteropancreatic endocrine cell tumors. Neuroendocrine tumors occur in approximately in 5–15% of MEN1 patients. Very few cases of ovarian NETs have been reported in association with clinical MEN1 and without genetic testing confirmation. Thirty-three-year-old woman with MEN1 was found to have right adnexal mass on computed tomography (CT). Attempt at laparoscopic removal was unsuccessful, and mass was removed via a minilaparotomy in piecemeal fashion. Pathology showed ovarian NET arising from a teratoma. Four years later, patient presented with recurrence involving the pelvis and anterior abdominal wall. She was treated with debulking surgery and somatostatin analogs (SSAs). Targeted DNA sequencing analysis on the primary adnexal mass as well as the recurrent abdominal wall tumor confirmed loss of heterozygosity (LOH) at the MEN1 gene locus. This case represents to our knowledge, the first genetically confirmed case of ovarian NET arising by a MEN1 mechanism in a patient with MEN1. Extreme caution should be exercised during surgery as failure to remove an ovarian NET en masse can result in peritoneal seeding and recurrence. For patients with advanced ovarian NETs, systemic therapy options include SSAs, peptide receptor radioligand therapy (PRRT) and novel agents targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF). Learning points: Ovarian NET can arise from a MEN1 mechanism, and any adnexal mass in a MEN1 patient can be considered as a possible malignant NET. Given the rarity of this disease, limited data are available on prognostication and treatment. Management strategies are extrapolated from evidence available in NETs from primaries of other origins. Care should be exercised to remove ovarian NETs en bloc as failure to do so may result in peritoneal seeding and recurrence. Treatment options for advanced disease include debulking surgery, SSAs, TKIs, mTOR inhibitors, PRRT and chemotherapy. Background Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant condition, caused by a germline mutation in the MEN1 gene, leading to the development of tumors of the parathyroid glands, anterior pituitary and enteropancreatic endocrine cells. NETs are well-differentiated neuroendocrine neoplasms originating from enterochromaffin cells typically disseminated throughout the gastrointestinal and bronchopulmonary system and can also occur in patients with MEN1 (1). NETs are traditionally classified based upon the embryologic site of origin (foregut, midgut or hindgut), morphologic pattern and silver stain affinity differences (insular, trabecular, mucinous, strumal or mixed). Newer classification systems have been developed to emphasize the considerable clinical and histopathologic variability of NETs found within each embryologic site of origin. The most recent WHO 2017 classification differentiates pancreatic NETs into three grades (low, intermediate and high), and other gastrointestinal NETs into two grades (low and intermediate) on the basis of mitotic count per high power field and proliferative index (Ki-67) (2). The majority of MEN1 syndrome-associated NETs are of foregut origin (thymus 24%, bronchus 27%, stomach 3% and duodenum 14%). Ovarian NETs are rare, comprising 0.1% of all ovarian neoplasms, and very few cases of primary ovarian NET in patients with MEN1 syndrome have been reported in the literature (1, 3). However, none of the cases reported confirmed the origin of tumor by a MEN1 mechanism (loss of heterozygosity at MEN1 locus) (1, 4). Given their rarity, data regarding treatment of ovarian NETs are limited. Here, we present a case of primary ovarian NET arising from a teratoma in a patient with MEN1 with targeted DNA sequencing of the tumor. A brief discussion about challenges and recent advances in the management of primary ovarian NETs follows.