Clinical and Genomic Landscape of FGFR3-Altered Urothelial Carcinoma and Treatment Outcomes with Erdafitinib: A Real-World Experience.

PURPOSE: Erdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer. We characterized the genetic landscape of FGFR-altered urothelial carcinoma and real-world clinical outcomes with erdafitinib, including on-treatment genomic evolution. EXPERIMENTAL DESIGN: Prospectively collected clinical data were integrated with institutional genomic data to define the landscape of FGFR2/3-altered urothelial carcinoma. To identify mechanisms of erdafitinib resistance, a subset of patients underwent prospective cell-free (cf) DNA assessment. RESULTS: FGFR3 alterations predictive of erdafitinib sensitivity were identified in 39% (199/504) of patients with non-muscle invasive, 14% (75/526) with muscle-invasive, 43% (81/187) with localized upper tract, and 26% (59/228) with metastatic specimens. One patient had a potentially sensitizing FGFR2 fusion. Among 27 FGFR3-altered cases with a primary tumor and metachronous metastasis, 7 paired specimens (26%) displayed discordant FGFR3 status. Erdafitinib achieved a response rate of 40% but median progression-free and overall survival of only 2.8 and 6.6 months, respectively (n = 32). Dose reductions (38%, 12/32) and interruptions (50%, 16/32) were common. Putative resistance mutations detected in cfDNA involved TP53 (n = 5), AKT1 (n = 1), and second-site FGFR3 mutations (n = 2). CONCLUSIONS: FGFR3 mutations are common in urothelial carcinoma, whereas FGFR2 alterations are rare. Discordance of FGFR3 mutational status between primary and metastatic tumors occurs frequently and raises concern over sequencing archival primary tumors to guide patient selection for erdafitinib therapy. Erdafitinib responses were typically brief and dosing was limited by toxicity. FGFR3, AKT1, and TP53 mutations detected in cfDNA represent putative mechanisms of acquired erdafitinib resistance.

Sarcomatoid renal cell carcinoma: MRI features and their association with survival.

OBJECTIVE: To evaluate MRI features of sarcomatoid renal cell carcinoma (RCC) and their association with survival. METHODS: This retrospective single-center study included 59 patients with sarcomatoid RCC who underwent MRI before nephrectomy during July 2003-December 2019. Three radiologists reviewed MRI findings of tumor size, non-enhancing areas, lymphadenopathy, and volume (and percentage) of T2 low signal intensity areas (T2LIA). Clinicopathological factors of age, gender, ethnicity, baseline metastatic status, pathological details (subtype and extent of sarcomatoid differentiation), treatment type, and follow-up were extracted. Survival was estimated using Kaplan-Meier method and Cox proportional-hazards regression model was used to identify factors associated with survival. RESULTS: Forty-one males and eighteen females (median age 62 years; interquartile range 51-68) were included. T2LIAs were present in 43 (72.9%) patients. At univariate analysis, clinicopathological factors associated with shorter survival were: greater tumor size (> 10 cm; HR [hazard ratio] = 2.44, 95% CI 1.15-5.21; p = 0.02), metastatic lymph nodes (present; HR = 2.10, 95% CI 1.01-4.37; p = 0.04), extent of sarcomatoid differentiation (non-focal; HR = 3.30, 95% CI 1.55-7.01; p < 0.01), subtypes other than clear cell, papillary, or chromophobe (HR = 3.25, 95% CI 1.28-8.20; p = 0.01), and metastasis at baseline (HR = 5.04, 95% CI 2.40-10.59; p < 0.01). MRI features associated with shorter survival were: lymphadenopathy (HR = 2.24, 95% CI 1.16-4.71; p = 0.01) and volume of T2LIA (> 3.2 mL, HR = 4.22, 95% CI 1.92-9.29); p < 0.01). At multivariate analysis, metastatic disease (HR = 6.89, 95% CI 2.79-16.97; p < 0.01), other subtypes (HR = 9.50, 95% CI 2.81-32.13; p < 0.01), and greater volume of T2LIA (HR = 2.51, 95% CI 1.04-6.05; p = 0.04) remained independently associated with worse survival. CONCLUSION: T2LIAs were present in approximately two thirds of sarcomatoid RCCs. Volume of T2LIA along with clinicopathological factors were associated with survival.

Progression-free Survival After Second Line of Therapy for Metastatic Clear Cell Renal Cell Carcinoma in Patients Treated with First-line Immunotherapy Combinations.

Immunotherapy (IO)-based combinations used to treat metastatic clear cell renal cell carcinoma (ccRCC) include dual immune checkpoint inhibition with ipilimumab and nivolumab (IO/IO) and several combinations of vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors (TKIs) with an immune checkpoint inhibitor (TKI/IO). IO/IO and TKI/IO approaches have not been compared directly, and it is unknown whether patients who do not respond to first-line IO/IO can salvage long-term survival by receiving a second-line TKI. Progression-free survival after second-line therapy (PFS-2) evaluates the ability to be salvaged by second-line therapy. We retrospectively evaluated 173 patients treated with first-line IO/IO or TKI/IO for metastatic ccRCC at Memorial Sloan Kettering Cancer Center and report PFS-2, overall survival, and response to second line of therapy (ORR2nd) for groups defined by first-line category. Although ORR2nd was significantly higher with IO/IO than with TKI/IO (47% vs 13%, p < 0.001), there was no significant difference in median PFS-2 for TKI/IO versus IO/IO (44 vs 23 mo, log-rank p = 0.1) or restricted mean survival time (RMST) for PFS-2 when adjusted for propensity score (33 vs 30 mo; difference 2.6 mo [95% confidence interval {CI}: -2.6, 7.9]; p = 0.3). There was also no significant difference in RMST for overall survival when adjusted for propensity score (38 vs 37 mo; group difference 1.0 mo [95% CI: -3.4, 5.5]; p = 0.7). These findings do not support a change in current utilization practices for IO/IO and TKI/IO treatment strategies for ccRCC. PATIENT SUMMARY: In cases of metastatic clear cell renal cell carcinoma, no significant difference was observed in progression-free survival after second line of therapy between patients receiving ipilimumab plus nivolumab and those receiving a combination of a tyrosine kinase inhibitor and an immune checkpoint inhibitor.

Associations between Pretreatment Body Composition Features and Clinical Outcomes among Patients with Metastatic Clear Cell Renal Cell Carcinoma Treated with Immune Checkpoint Blockade.

PURPOSE: High body mass index (BMI) may lead to improved immune-checkpoint blockade (ICB) outcomes in metastatic clear cell renal cell carcinoma (mccRCC). However, BMI is a crude body size measure. We investigated BMI and radiographically assessed body composition (BC) parameters association with mccRCC ICB outcomes. EXPERIMENTAL DESIGN: Retrospective study of ICB-treated patients with mccRCC. BMI and BC variables [skeletal muscle index (SMI) and multiple adiposity indexes] were determined using pretreatment CT scans. We examined the associations between BMI and BC variables with ICB outcomes. Therapeutic responses per RECIST v1.1 were determined. We compared whole-transcriptomic patterns with BC variables in a separate cohort of 62 primary tumor samples. RESULTS: 205 patients with mccRCC were included in the cohort (74% were male, 71% were overweight/obese, and 53% were classified as low SMI). High-BMI patients experienced longer overall survival (OS) than normal-weight patients [unadjusted HR, 0.66; 95% confidence interval (CI), 0.45-0.97; P = 0.035]. The only BC variable associated with OS was SMI [unadjusted HR comparing low vs. high SMI 1.65 (95% CI: 1.13-2.43); P = 0.009]. However, this OS association became nonsignificant after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium score and line of therapy. No OS association was seen for adiposity and no BC variable was associated with progression-free survival or radiological responses. Tumors from patients with low SMI displayed increased angiogenic, inflammatory, and myeloid signals. CONCLUSIONS: Our findings highlight the relevance of skeletal muscle in the BMI paradox. Future studies should investigate if addressing low skeletal muscle in metastatic patients treated with ICB can improve survival.

Virtual contrast enhancement for CT scans of abdomen and pelvis.

Contrast agents are commonly used to highlight blood vessels, organs, and other structures in magnetic resonance imaging (MRI) and computed tomography (CT) scans. However, these agents may cause allergic reactions or nephrotoxicity, limiting their use in patients with kidney dysfunctions. In this paper, we propose a generative adversarial network (GAN) based framework to automatically synthesize contrast-enhanced CTs directly from the non-contrast CTs in the abdomen and pelvis region. The respiratory and peristaltic motion can affect the pixel-level mapping of contrast-enhanced learning, which makes this task more challenging than other body parts. A perceptual loss is introduced to compare high-level semantic differences of the enhancement areas between the virtual contrast-enhanced and actual contrast-enhanced CT images. Furthermore, to accurately synthesize the intensity details as well as remain texture structures of CT images, a dual-path training schema is proposed to learn the texture and structure features simultaneously. Experiment results on three contrast phases (i.e. arterial, portal, and delayed phase) show the potential to synthesize virtual contrast-enhanced CTs directly from non-contrast CTs of the abdomen and pelvis for clinical evaluation.

Somatic mutations as preoperative predictors of metastases in patients with localized clear cell renal cell carcinoma - An exploratory analysis.

OBJECTIVE: Recurrent genomic alterations in clear cell renal cell carcinoma (ccRCC) have been associated with treatment outcomes; however, current preoperative predictive models do not include known genetic predictors. We aimed to explore the value of common somatic mutations in the preoperative prediction of metastatic disease among patients treated for localized ccRCC. MATERIALS AND METHODS: After obtaining institutional review board approval, data of 254 patients with localized ccRCC treated between 2005 and 2015 who underwent genetic sequencing was collected. The mutation status of VHL, PBRM1, SETD2, BAP1 and KDM5C were evaluated in the nephrectomy tumor specimen, which served as a proxy for biopsy mutation status. The Raj et al. preoperative nomogram was used to predict the 12-year metastatic free probability (MFP). The study outcome was MFP; the relationship between MFP and mutation status was evaluated with Cox-regression models adjusting for the preoperative nomogram variables (age, gender, incidental presentation, lymphadenopathy, necrosis, and size). RESULTS: The study cohort included 188 males (74%) and 66 females (26%) with a median age of 58 years. VHL mutations were present in 152/254 patients (60%), PBRM1 in 91/254 (36%), SETD2 in 32/254 (13%), BAP1 in 19/254 (8%), and KDM5C in 19/254 (8%). Median follow-up for survivors was 8.1 years. Estimated 12-year MFP was 70% (95% CI: 63%-75%). On univariable analysis SETD2 (HR: 3.30), BAP1 (HR: 2.44) and PBRM1 (HR: 1.78) were significantly associated with a higher risk of metastases. After adjusting for known preoperative predictors in the existing nomogram, SETD2 mutations remained associated with a higher rate of metastases after nephrectomy (HR: 2.09, 95% CI: 1.19-3.67, P = 0.011). CONCLUSION: In the current exploratory analysis, SETD2 mutations were significant predictors of MFP among patients treated for localized ccRCC. Our findings support future studies evaluating genetic alterations in preoperative renal biopsy samples as potential predictors of treatment outcome.

The spinal distribution of metastatic renal cell carcinoma: Support for locoregional rather than arterial hematogenous mode of early bony dissemination.

BACKGROUND: Quantifying the degree to which spinal involvement of metastatic renal cell carcinoma (mRCC) is a locoregional phenomenon vs. a hematogenous, bone-specific affinity has implications for prognosis and antimetastatic therapy. OBJECTIVE: To investigate the distribution of spinal metastasis in mRCC and to explore relationships between clinical factors and patterns of spinal spread. METHODS: Patients with mRCC and spinal involvement from June 2005 to November 2018 were identified. Clinical and biologic features including primary tumor size and degree of spinal and nonbony metastatic involvement were collected. Spinal distributions were evaluated by the permutation test, with the null hypothesis that metastases are distributed uniformly across levels. RESULTS: One hundred patients with 685 spinal levels involved by mRCC were evaluated. A nonuniform spatial distribution was observed across the cohort (P < 0.001); a preponderance of thoracolumbar involvement was noted with the mode at L3. No significant deviation in metastatic distribution from uniform was observed in right- or left-sided tumors, subgroups of distant or local metastases, or histology. Patients with smaller tumors (<4 cm) and local spread had distribution of spinal metastases not significantly different from uniform (P = 0.292 and P = 0.126, respectively). CONCLUSIONS: These data support a dominant locoregional as opposed to arterial hematogenous mechanism for early spinal dissemination of mRCC. Characterizations of the biologic molecular features contributing to osseous tropism and aggressive tumor biology (as seen in the subset of outlier patients with small tumors who appear to have more uniform spread), have implications for surveillance and are an area of active investigation.

Accelerating Prostate Diffusion-weighted MRI Using a Guided Denoising Convolutional Neural Network: Retrospective Feasibility Study.

PURPOSE: To investigate the feasibility of accelerating prostate diffusion-weighted imaging (DWI) by reducing the number of acquired averages and denoising the resulting image using a proposed guided denoising convolutional neural network (DnCNN). MATERIALS AND METHODS: Raw data from the prostate DWI scans were retrospectively gathered between July 2018 and July 2019 from six single-vendor MRI scanners. There were 103 datasets used for training (median age, 64 years; interquartile range [IQR], 11), 15 for validation (median age, 68 years; IQR, 12), and 37 for testing (median age, 64 years; IQR, 12). High b-value diffusion-weighted (hb DW) data were reconstructed into noisy images using two averages and reference images using all 16 averages. A conventional DnCNN was modified into a guided DnCNN, which uses the low b-value DW image as a guidance input. Quantitative and qualitative reader evaluations were performed on the denoised hb DW images. A cumulative link mixed regression model was used to compare the readers' scores. The agreement between the apparent diffusion coefficient (ADC) maps (denoised vs reference) was analyzed using Bland-Altman analysis. RESULTS: Compared with the original DnCNN, the guided DnCNN produced denoised hb DW images with higher peak signal-to-noise ratio (32.79 ± 3.64 [standard deviation] vs 33.74 ± 3.64), higher structural similarity index (0.92 ± 0.05 vs 0.93 ± 0.04), and lower normalized mean square error (3.9% ± 10 vs 1.6% ± 1.5) (P < .001 for all). Compared with the reference images, the denoised images received higher image quality scores from the readers (P < .0001). The ADC values based on the denoised hb DW images were in good agreement with the reference ADC values (mean ADC difference ranged from -0.04 to 0.02 × 10-3 mm2/sec). CONCLUSION: Accelerating prostate DWI by reducing the number of acquired averages and denoising the resulting image using the proposed guided DnCNN is technically feasible. Supplemental material is available for this article. © RSNA, 2020.

Preoperative nomogram predicting 12-year probability of metastatic renal cancer - evaluation in a contemporary cohort.

OBJECTIVES: Preoperative models, based on patient and tumor characteristics, predict risk for adverse outcomes after nephrectomy. Changes in renal tumor characteristics over the last decades, warrant further evaluation using contemporary cohorts. We aimed to validate a previously published preoperative nomogram predicting 12-year metastasis-free probability after nephrectomy for localized renal tumors in a contemporary cohort. PATIENTS AND METHODS: After obtaining institutional review board approval, data of 1,760 patients who underwent nephrectomy for a localized renal mass between 2005 and 2011 were reviewed. Preoperative images were evaluated for the presence of tumor necrosis, lymphadenopathy, and tumor size. The study outcome was metastatic-free probability. Model discrimination was assessed with Gönen and Heller's concordance probability estimate, and calibration was evaluated. RESULTS: The cohort included 1,102 male and 658 female patients with a median age of 60 years. Most patients presented incidentally (84%). On imaging, 3% had evidence of lymphadenopathy, 55% had necrosis and median tumor diameter was 3.7 cm (interquartile range [IQR]: 2.5, 5.5). Median follow-up in non-metastatic patients was 7.7 years (IQR: 5.3, 9.7). Estimated 12-year metastatic-free probability was 88% (86%-90%). The model showed strong discrimination (concordance probability estimate [CPE]: 0.77), and fair calibration. The time-dependent receiver operating characteristic (ROC) curves showed strong discrimination at all-time points and the area under the curve (AUC) for year 12 was 0.83 (95% Confidence Interval: 0.78-0.89). CONCLUSIONS: We validated the preoperative nomogram of 12-year metastasis-free probability in a contemporary cohort despite different tumor characteristics. Future studies should evaluate the role of preoperative risk stratification in patient selection for neoadjuvant treatment.

Systemic therapy for advanced clear cell renal cell carcinoma after discontinuation of immune-oncology and VEGF targeted therapy combinations.

BACKGROUND: Several phase 3 studies reported positive results for combinations of Immune-Oncology (IO) and Vascular Endothelial Growth Factor (VEGF) targeted therapies in patients with metastatic clear cell Renal Cell Carcinoma (ccRCC). However, there are limited data on outcomes to systemic therapy after IO-VEGF combinations. METHODS: A retrospective analysis was performed on patients with metastatic ccRCC treated at the Memorial Sloan Kettering Cancer Center and Cleveland Clinic who initiated systemic therapy post IO-VEGF including combinations with VEGF receptor (VEGFR) tyrosine kinase inhibitors (IO-TKI) and combinations with the anti-VEGF monoclonal antibody bevacizumab (IO-Bev). The study objectives were to evaluate the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) on systemic therapy post IO-VEGF. RECIST v1.1 criteria were used to determine radiological responses and progression. Survival estimates were evaluated with the Kaplan-Meier methods and the log-rank test from the start of systemic therapy post IO-VEGF to the event of interest. RESULTS: A total of fifty-nine patients were treated post discontinuation of IO-VEGF regimens which included IO-Bev (n = 35; 59%) and IO-TKI (n = 24; 41%). Fifty-eight patients (98%) received IO-VEGF regimens as part of a clinical trial. Subsequent therapies included cabozantinib (n = 22; 37%), axitinib (n = 18; 31%), pazopanib (n = 4; 7%), lenvatinib and everolimus (n = 4; 7%), mTOR inhibitor monotherapy (n = 3; 5%), axitinib and dalantercept (n = 2; 3%), sunitinib (n = 1; 2%), sorafenib (n = 1; 2%), and treatment with agents on unreported clinical trials (n = 4; 7%). Patients treated on unreported clinical trials were excluded from the efficacy analysis. Post IO-VEGF, the ORR was 25% and median PFS was 12.0 months (95% CI, 8.2-24.5). Median OS was 24.5 months (95% CI, 12-NE) and 12 months OS rate was 63.3% (95% CI, 48.6-74.9). We observed no differences post IO-VEGF OS when comparing IO- TKI vs IO-Bev (Log-rank p = 0.73). CONCLUSIONS: Post IO-VEGF, most patients received VEGFR-TKIs. In this setting, VEGFR-TKIs demonstrated clinical activity and remain a viable option for salvage therapy after progression on IO-VEGF.

An evaluation of the role of tumor load in cytoreductive nephrectomy.

INTRODUCTION: New radiological tools can accurately provide preoperative three-dimensional spatial assessment of metastatic renal cell carcinoma (RCC). We aimed to determine whether the distribution, volume, shape, and fraction of RCC resected in a cytoreductive nephrectomy associates with survival. METHODS: We retrospectively reviewed 560 patients undergoing cytoreductive nephrectomy, performing a comprehensive volumetric analysis in eligible patients of all detectable primary and metastatic RCC prior to surgery. We used Cox regression analysis to determine the association between the volume, shape, fraction resected, and distribution of RCC and overall survival (OS). RESULTS: There were 62 patients eligible for volumetric analysis, with similar baseline characteristics to the entire cohort, and median survivor followup was 34 months. Larger primary tumors were less spherical, but not associated with different metastatic patterns. Increased primary tumor volume and tumor size, but not the fraction of tumor resected, were associated with inferior survival. The rank of tumors based on unidimensional size did not completely correspond to the rank by primary tumor volume, however, both measurements yielded similar concordance for predicted OS. Larger tumor volume was not associated with a longer postoperative time off treatment. CONCLUSIONS: Primary tumor volume was significant for predicting OS, while the fraction of disease resected did not appear to impact patient outcomes. Although rich in detail, our study is potentially limited by selection bias. Future temporal studies may help elucidate whether the primary tumor shape is associated with tumor growth kinetics.

Cystic Renal Cell Carcinoma: A Report on Outcomes of Surgery and Active Surveillance in Patients Retrospectively Identified on Pretreatment Imaging.

PURPOSE: We evaluated the outcomes of surgical intervention and active surveillance in patients diagnosed with cystic renal cell carcinoma at our hypothesized radiological cutoff of greater than 50% cystic. MATERIALS AND METHODS: We identified all 430 patients with a pathologically confirmed cystic renal mass that fit our criteria from 2000 to 2015. The 292 patients with a lack of computerized tomography, tumors less than 50% cystic on imaging, multifocal tumors and prior renal cell carcinoma were excluded from study. Patients were stratified into benign or malignant subgroups, and radiological, clinicopathological and oncologic features were determined. Univariate and multivariate associations between clinicoradiological parameters in each group were analyzed. We similarly reviewed the records of a separate cohort of patients treated with active surveillance for cystic renal cell carcinoma. RESULTS: Of the 138 identified cases of cystic renal cell carcinoma 102 (73.9%) were renal cell carcinoma and 36 (26.1%) were benign masses. Of the tumors 77.5% were Fuhrman grade 1-2, 83.4% were stage pT2 or less and 65.9% showed clear cell histology. On univariate analysis male gender, a solid component and increasing Bosniak classification were significant for malignancy. In a separate cohort we identified 38 patients on active surveillance. The growth rate was 1.0 mm per year overall and 2.3 mm per year for the solid component. At a median followup of more than 4 years in all cohorts there was no evidence of recurrence or metastasis of cystic renal cell carcinoma. CONCLUSIONS: Patients with unifocal cystic renal cell carcinoma evaluated using a standardized radiological threshold of greater than 50% cystic had an excellent prognosis on active surveillance and after surgical resection.

Bilateral sudden sensorineural hearing loss caused by leptomeningeal carcinomatosis: case report and review.

Leptomeningeal carcinomatosis is a rare condition characterized by diffuse infiltration of the meninges after the metastasis of the solid tumors. Bilateral sudden hearing loss is a rare initial symptom. In this article, we report a 44-year-old male patient with bilateral sudden hearing loss and dizziness. Magnetic resonance imaging showed involvement of the bilateral vestibulocochlear nerves. Malignant cells were detected in cerebrospinal fluid cytology. To the best of our knowledge, leptomeningeal carcinomatosis due to duodenum adenocarcinoma has not been reported before in the English literature. Leptomeningeal carcinomatosis should be kept in mind in patients who have bilateral sudden sensorineural hearing loss.