Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic ...alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the
gene (
= 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies (
= 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and
-deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways.
loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.
Abstract Background A growing body of retrospective literature is emerging regarding active surveillance (AS) for patients with small renal masses (SRMs). There are limited prospective data ...evaluating the effectiveness of AS compared to primary intervention (PI). Objective To determine the characteristics and clinical outcomes of patients who chose AS for management of their SRM. Design, setting, and participants From 2009 to 2014, the multi-institutional Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry prospectively enrolled 497 patients with solid renal masses ≤4.0 cm who chose PI or AS. Intervention AS versus PI. Outcome measurements and statistical analysis The registry was designed and powered as a noninferiority study based on historic recurrence rates for PI. Analyses were performed in an intention-to-treat manner. Primary outcomes were overall survival (OS) and cancer-specific survival (CSS). Results and limitations Of the 497 patients enrolled, 274 (55%) chose PI and 223 (45%) chose AS, of whom 21 (9%) crossed over to delayed intervention. AS patients were older, had worse Eastern Cooperative Oncology Group scores, total comorbidities, and cardiovascular comorbidities, had smaller tumors, and more often had multiple and bilateral lesions. OS for PI and AS was 98% and 96% at 2 yr, and 92% and 75% at 5 yr, respectively (log rank, p = 0.06). At 5 yr, CSS was 99% and 100% for PI and AS, respectively ( p = 0.3). AS was not predictive of OS or CSS in regression modeling with relatively short follow-up. Conclusions In a well-selected cohort with up to 5 yr of prospective follow-up, AS was not inferior to PI. Patient summary The current report is among the first prospective analyses of patients electing for active surveillance of a small renal mass. Discussion of active surveillance should become part of the standard discussion for management of small renal masses.
Objective To evaluate the impact of the extent of extraprostatic extension (EPE) on biochemical recurrence-free survival (BCRFS) after radical prostatectomy (RP). Materials and Methods We queried our ...RP database from 2004 to 2013. Extent of EPE on RP was divided into 3 groups: no EPE, focal EPE (F-EPE; a few extraprostatic cancer glands on 1-2 slides), and nonfocal EPE (NF-EPE). Multivariate Cox proportional hazard models determined the influence of EPE on BCRFS. Results A total of 10,750 men underwent RP during the study period. Of these, 7843 men (73.0%) had no EPE, 1258 (11.7%) men had F-EPE, and 1649 men had (15.3%) NF-EPE. Overall BCRFS was worse in men with NF-EPE than those with F-EPE or no EPE. In a multivariate model, F-EPE and NF-EPE were both independently associated with worse BCRFS compared with no EPE (F-EPE: hazard ratio, 2.41; 95% confidence interval, 1.84-3.10; P <.0001; NF-EPE: hazard ratio, 3.57; 95% confidence interval, 2.89-4.40; P <.0001). When stratified by Gleason score in men without seminal vesicle invasion or lymph node metastases, there was no difference in BCRFS for Gleason score <6, 3 + 4 = 7, 4 + 3 = 7, and 8 for F-EPE vs no EPE; however, patients with Gleason score of 9-10 with F-EPE had worse BCRFS. Patients with NF-EPE had significantly worse BCRFS for Gleason score <6, 7, and 8 and a trend for worse BCRFS for Gleason score 9-10 compared with no EPE. Conclusion Although all men with EPE have higher BCRFS after RP, men with NF-EPE have worse BCRFS than those with F-EPE, supporting the need to substratify pT3a prostate cancer in the American Joint Committee on Cancer staging system.
ObjectiveTo compare the perioperative outcomes of robotic partial nephrectomy (RPN) with laparoscopic PN (LPN) performed for small renal masses (SRMs), in a large multi‐institutional series and to ...define a new composite outcome measure, termed ‘optimal outcome’ for the RPN group.
Patients and Methods
Retrospective review of 2392 consecutive cases of RPN and LPN performed in five high‐volume centres from 2004 to mid‐2013. We limited our study to SRMs and cases performed by surgeons with significant expertise with the technique. The Trifecta was defined as negative surgical margin, zero perioperative complications and a warm ischaemia time of ≤25 min. The ‘optimal outcome’ was defined as achievement of Trifecta with addition of 90% estimated glomerular filtration rate preservation and no chronic kidney disease stage upgrading. Univariable and multivariable analysis were used to identify factors predicting Trifecta and ‘optimal outcome’ achievement.
Results
In all, 1185 RPN and 646 LPN met our inclusion criteria. Patients in the RPN group were older and had a higher median Charlson comorbidity index and higher R.E.N.A.L. nephrometry score. The RPN group had lower warm ischaemia time (18 vs 26 min), overall complication rate (16.2% vs 25.9%), and positive surgical margin rate (3.2% vs. 9.7%). There was a significantly higher Trifecta rate for RPN (70% vs 33%) and the rate of achievement of ‘optimal outcome’ for the RPN group was 38.5%.
Conclusions
In this large multi‐institutional series RPN was superior to LPN for perioperative surgical outcomes measured by Trifecta. Patients in the RPN group had better outcomes for all three components of Trifecta compared with their LPN counterparts. Our more strict definition for ‘optimal outcome’ might be a better tool for assessing perioperative and functional outcomes after minimally invasive PN. This tool needs to be externally validated.
Published series of growth rates of renal tumors on active surveillance largely consist of tumors without pathologic or genetic data. Growth kinetics of genetically defined renal tumors are not well ...known. Here, we evaluate the growth of genetically defined renal tumors and their association with patient clinical and genetic characteristics.
We evaluated patients with an inherited kidney cancer susceptibility syndrome as a result of a pathologic germline alteration of
or
with at least 1 solid renal mass managed with active surveillance at our institution. Tumor growth rates (GR) were calculated and patients were stratified by genetic alteration and other clinical and genetic factors to analyze differences in growth rates using linear regression and comparative statistics.
A total of 292 patients with 435 genetically defined tumors were identified, including 286
-deficient, 91
-deficient, 52
-activated, and 6
-deficient tumors. There were significant differences in GRs when stratified by genetic alteration.
-deficient tumors had the fastest median GR (0.6 cm/y; interquartile range IQR, 0.57-0.68 cm/y), followed by
-deficient tumors (GR, 0.37 cm/y; IQR, 0.25-0.57 cm/y),
-deficient tumors (GR, 0.10 cm/y; IQR, 0.04-0.24 cm/y), and tumors with
activation (GR, 0.15 cm/y; IQR, 0.053-0.32 cm/y;
< .001). Tumors from the same patient had similar GRs. Younger age was independently associated with higher GR (
= .005).
In a cohort of genetically defined tumors, tumor growth rates varied in a clinically and statistically different manner according to genetic subtype. Rapid growth of
-deficient tumors indicates that these patients should be managed with caution. The faster growth of tumors in younger patients may support more frequent imaging, whereas the slower growth of other tumors may support extended surveillance beyond annual imaging in some instances.
Compatibility of mechatronic devices with the MR environment has been a very challenging engineering task. After over a decade of developments, we report the successful translation to clinical trials ...of our MR safe robot technology. MrBot is a six degree of freedom, pneumatically actuated robot for transperineal prostate percutaneous access, built exclusively of electrically nonconductive and nonmagnetic materials. Its extensive preclinical tests have been previously reported. Here, we present the latest technology developments, an overview of the regulatory protocols, and technically related results of the clinical trial. The Food and Drug Administration (FDA) has approved the MrBot for the biopsy trial, which was successfully performed in five patients. With no trajectory corrections and no unsuccessful attempts to target a site, the robot achieved an MRI-based needle targeting accuracy of 2.55 mm. To the best of our knowledge, this is the first robot approved by the FDA for the MR environment. The results confirm that it is possible to perform safe and accurate robotic manipulation in the MRI scanner, and the development of MR safe robots is no longer a daunting technical challenge.
Objectives. We evaluated the effect of cognitive training among 1,534 participants in the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) randomized controlled trial (RCT) on ...5-year improvements in 3 cognitive-specific measures of locus of control—internal, chance, and powerful others. Methods. ACTIVE was a multisite RCT (age ≥ 65), with 4 groups (memory, reasoning, speed of processing, and no-contact control). Complete 5-year follow-up data were available for 1,534 (55%) of the 2,802 participants. A propensity score model was used to adjust for potential attrition bias. Clinically important improvements (and decrements) in the cognitive-specific locus of control scale scores were defined as greater than or equal to 0.5 SD (medium) and greater than or equal to 1.0 SD (large). Multinomial logistic regression was used to simultaneously contrast those who improved and those who declined with those whose locus of control scale score was unchanged. Results. Statistically significant effects reflecting medium-sized (≥0.5 SD) improvements in internal locus of control between baseline and the 5-year follow-up were found for the reasoning and speed of processing intervention groups who were 76% (p < .01) and 68% (p < .05) more likely, respectively, to improve than the no-contact control group. No improvement effects were found on the chance or powerful others locus of control measures or for the memory intervention group. Conclusion. Cognitive training that targets reasoning and speed of processing can improve the cognitive-specific sense of personal control over one’s life in older adults.
To characterize the clinical presentation, genomic alterations, pathologic phenotype and clinical management of microphthalmia-associated transcription factor (MITF) familial renal cell carcinoma ...(RCC), caused by a member of the TFE3, TFEB, and MITF family of transcription factor genes.
The clinical presentation, family history, tumor histopathology, and surgical management were evaluated and reported herein. DNA sequencing was performed on blood DNA, tumor DNA and DNA extracted from adjacent normal kidney tissue. Copy number and gene expression analyses on tumor and normal tissues were performed by Real-Time Polymerase chain reaction. TCGA gene expression data were used for comparative analysis. Protein expression and subcellular localization were evaluated by immunohistochemistry.
Germline genomic analysis identified the MITF p.E318K variant in a patient with bilateral, multifocal type 1 papillary RCC and a family history of RCC. All tumors displayed the MITF variant and were characterized by amplification of chromosomes 7 and 17, hallmarks of type 1 papillary RCC. We demonstrated that MITF p.E318K variant results in altered transcriptional activity and that downstream targets of MiT family members, such as GPNMB, are dysregulated in the tumors.
Association of the pathogenic MITF variant with bilateral and multifocal type 1 papillary RCC in this family supports its role as a risk allele for the development of RCC and emphasizes the importance of screening for MITF variants irrelevant of the RCC histologic subtype. This study identifies potential biomarkers for the disease, such as GPNMB expression, that may facilitate the development of targeted therapies for patients affected with MITF-associated RCC.
This report describes a case study of a patient with bilateral, multifocal type 1 papillary renal cell carcinoma (RCC) and a family history of RCC that has the germline MITF p.E318K variant, known to predispose to kidney cancer. All tumors demonstrated a papillary type 1 histology and analyses of available tumors identified increased nuclear staining for the MITF transcription factor, somatic amplification of chromosomes 7 and 17, and altered expression of genes associated with tumorigenesis, including potential biomarkers, such as GPNMB. Display omitted
Background
von Hippel–Lindau syndrome (VHL) is an autosomal dominant hereditary syndrome with an increased predisposition of developing numerous cysts and tumors, almost exclusively clear cell renal ...cell carcinoma (ccRCC). Considering the lifelong surveillance in such patients to monitor the disease, patients with VHL are preferentially imaged using MRI to eliminate radiation exposure.
Purpose
Segmentation of kidney and tumor structures on MRI in VHL patients is useful in lesion characterization (e.g., cyst vs. tumor), volumetric lesion analysis, and tumor growth prediction. However, automated tasks such as ccRCC segmentation on MRI is sparsely studied. We develop segmentation methodology for ccRCC on T1 weighted precontrast, corticomedullary, nephrogenic, and excretory contrast phase MRI.
Methods
We applied a new neural network approache using a novel differentiable decision forest, called hinge forest (HF), to segment kidney parenchyma, cyst, and ccRCC tumors in 117 images from 115 patients. This data set represented an unprecedented 504 ccRCCs with 1171 cystic lesions obtained at five different MRI scanners. The HF architecture was compared with U‐Net on 10 randomized splits with 75% used for training and 25% used for testing. Both methods were trained with Adam using default parameters (α=0.001,β1=0.9,β2=0.999$\alpha = 0.001,\ \beta _1 = 0.9,\ \beta _2 = 0.999$) over 1000 epochs. We further demonstrated some interpretability of our HF method by exploiting decision tree structure.
Results
The HF achieved an average kidney, cyst, and tumor Dice similarity coefficient (DSC) of 0.75 ± 0.03, 0.44 ± 0.05, 0.53 ± 0.04, respectively, while U‐Net achieved an average kidney, cyst, and tumor DSC of 0.78 ± 0.02, 0.41 ± 0.04, 0.46 ± 0.05, respectively. The HF significantly outperformed U‐Net on tumors while U‐Net significantly outperformed HF when segmenting kidney parenchymas (α<0.01$\alpha < 0.01$).
Conclusions
For the task of ccRCC segmentation, the HF can offer better segmentation performance compared to the traditional U‐Net architecture. The leaf maps can glean hints about deep learning features that might prove to be useful in other automated tasks such as tumor characterization.
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