Cumulative Impact of Serial Partial Nephrectomy for the Treatment of Recurrent Renal Masses.

PURPOSE: Reoperative partial nephrectomy (RePN) offers several advantages for the treatment of recurrent, multifocal renal masses. RePN has been previously demonstrated to be technical feasibility and delay the need for renal replacement therapy. However, there is still inherent complexity and known risks to reoperative nephrectomy. We studied the largest population of reoperative partial nephrectomies to characterize renal functional outcomes and the likelihood of intra- and post-operative complications. MATERIALS AND METHODS: Query of an institutional surgical registry was conducted. Demographic data, serum creatinine (SCr) for eGFR and protein dipstick results were assessed within 1 week prior to surgery, and postoperative function assessments were studied within a year of surgery. RePN was defined as serial surgical resection of the ipsilateral renal unit. RESULTS: A total of 1131 PNs performed on 663 patients at a single center were retrospectively evaluated. In reoperative cases, median number of operations per renal unit was 2 (range: 2-6). There was a stepwise decline in eGFR with an average decline of 6.1 with each RePN. With each subsequent nephrectomy, surgical duration, estimated blood loss, and incidence of preoperative anemia increased. Postoperative eGFR showed a significant positive association with preoperative eGFR, while negative associations were found with age, number of previous ipsilateral partial nephrectomies, number of tumors, and largest tumor size. High-grade complications were associated with the number of ipsilateral partial nephrectomies, tumors count, and tumor size. Robotic or laparoscopic procedures exhibited a likelihood of Grade 3 or greater complications compared to open surgery. CONCLUSION: RePN contributes to renal dysfunction and an increased risk of surgical complications. Intraoperative blood loss and surgical duration increase with subsequent nephrectomy. Such risks are dependent on the number of prior operative interventions on the kidney, suggesting a stepwise progression of surgical morbidity.

Renal Medullary Carcinoma: A Surveillance, Epidemiology, and End Results (SEER) Analysis.

INTRODUCTION: Renal medullary carcinoma (RMC) is an aggressive and rare renal malignancy that predominantly affects Black patients but is also found in individuals of other ethnicities. To date, only a few hundred cases have been reported in the urologic literature. Due to this extreme rarity, the exact pathophysiology and optimal treatment have yet to be well described. This study aims to determine the predictors of mortality and overall survival outcomes in patients with RMC. METHODS: We utilized the Surveillance, Epidemiology, and End Results Program (SEER) database 18 registries to retrieve demographic and clinical information on patients with RMC between 1996 and 2018. A multivariate analysis was performed to determine predictors of mortality in the study population. Kaplan-Meier survival curves were then created to display the differences in overall survival of Black versus non-Black patients diagnosed with renal medullary carcinoma during the study period. RESULTS: We identified 100 patients diagnosed with renal medullary carcinoma using the SEER Database in the study period. The mean age was 28.0 ± 12.0 (95% confidence interval [CI] 25.7-30.4). Among the patients, 76% were male and 24% were female. Most RMC patients were Black (83%) with only 17% identifying as White. The mean survival in months was 13.8 ± 3.0 (95% CI 7.9-19.7). The majority (70%) of patients in this study presented with distant, metastatic disease at the time of diagnosis. Black patients with RMC were less likely to receive surgery and five times more likely to die in comparison to their White counterparts OR = 5.4 (95% CI 1.09-26.9, P = 0.04). Not only did Black patients have a lower survival rate at 12 mo compared to White patients, but they also continued to experience a sharp decline in survival to 10.2% at 24 mo (P < 0.05) and 7.6% at 48 mo (P < 0.05) following diagnosis of renal medullary carcinoma. CONCLUSIONS: These data confirm that RMC is a rare disease that disproportionately affects Black patients. The prognosis appears to be substantially worse for Black subjects diagnosed with this cancer than non-Black patients. The worse outcomes seen in Black subjects are of an unclear etiology and are yet to be investigated.

Differential VHL Mutation Patterns in Bilateral Clear Cell RCC Distinguishes Between Independent Primary Tumors and Contralateral Metastatic Disease.

OBJECTIVE: To evaluate whether bilateral, multifocal clear cell renal cell carcinoma (ccRCC) patients can be differentiated by VHL mutation analysis into cases that represent either multiple independently arising primary tumors, or a single primary tumor which has spread ipsilaterally as well as to the contralateral kidney. The nature of kidney cancer multifocality outside of known hereditary syndromes is as yet poorly understood. MATERIALS AND METHODS: DNA from multiple tumors per patient were evaluated for somatic VHL gene mutation and hypermethylation. A subset of tumors with shared VHL mutations were analyzed with targeted, next-generation sequencing assays. RESULTS: This cohort contained 5 patients with multiple tumors that demonstrated a shared somatic VHL mutation consistent with metastatic spread including to the contralateral kidney. In several cases this was substantiated by additional shared somatic mutations in ccRCC-associated genes. In contrast, the remaining 14 patients with multiple tumors demonstrated unique, unshared VHL alterations in every analyzed tumor, consistent with independently arising kidney tumors. None of these latter patients showed any evidence of local spread or distant metastasis. CONCLUSION: The spectrum of VHL alterations within evaluated bilateral, multifocal ccRCC tumors from a single patient can distinguish between multiple independent tumor growth and metastasis. This can be performed using currently available clinical genetic tests and will improve the accuracy of patient diagnosis and prognosis, as well as informing appropriate management.

Priapism and Sickle Cell Disease: Special Considerations in Etiology, Management, and Prevention.

Sickle cell disease (SCD) is an inherited medical condition where sickled red blood cells cause vaso-occlusive crisis. One major complication of SCD is priapism, defined as an erection of the penis lasting over four hours beyond sexual stimulation or orgasm. SCD priapism is caused by sickled erythrocytes obstructing venous outflow and can lead to permanent erectile dysfunction. This article reviews the pathology, physiology, and management of SCD priapism, including potential novel therapeutic agents.

X-Capsular Incision for Tumor Enucleation (X-CITE)-Technique: A Method to Maximize Renal Parenchymal Preservation for Completely Endophytic Renal Tumors.

OBJECTIVE: To describe the X-Capsular Incision for Tumor Enucleation (X-CITE) technique to resect endophytic renal tumors while preserving the overlying renal parenchyma. SUBJECTS AND METHODS: We reviewed 1-year outcomes of 12 consecutive patients with a history of bilateral or multifocal renal tumors who presented to our institution with completely endophytic renal masse(s) between August 2017 and August 2018. Endophytic tumors were resected by making an X-shaped incision in the renal capsule and developing parenchymal flaps overlying the tumor pseudocapsule. Following tumor enucleation, the overlying parenchymal flaps were reapproximated. RESULTS: Median follow up was 19.9 months (range 10.6-14.9). Most patients also had additional exophytic tumors with a median of 5 renal tumors removed per operation with a median largest renal tumor size of 3.2 cm. No intraoperative or postoperative complications occurred. There was no decline in renal function after surgery when comparing median pre- and 12-month postoperative eGFR (94.5 vs 91.5, P= 0.18).). Postoperative nuclear mercaptoacetyltriglycine (MAG-3) renal scans demonstrated equal differential kidney function after surgery. Limitations include short-term follow-up and referral bias at center specializing in multi-focal kidney surgery. CONCLUSION: The X-Capsular Incision for Tumor Enucleation technique is feasible, safe and effective with minimal collateral damage in the treatment of completely endophytic renal masses. Further investigation should identify which patients may benefit from this procedure and explore intermediate and long-term outcomes.

Reoperative Partial Nephrectomy-Does Previous Surgical Footprint Impact Outcomes?

PURPOSE: Historically, open techniques have been favored over minimally invasive approaches for complex surgeries. We aimed to identify differences in perioperative outcomes, surgical footprints, and complication rates in patients undergoing either open or robotic reoperative partial nephrectomy. MATERIALS AND METHODS: A retrospective review of patients undergoing reoperative partial nephrectomy was performed. Patients were assigned to cohorts based on current and prior surgical approaches: open after open, open after minimally invasive surgery, robotic after open, and robotic after minimally invasive surgery cohorts. Perioperative outcomes were compared among cohorts. Factors contributing to complications were assessed. RESULTS: A total of 192 patients underwent reoperative partial nephrectomy, including 103 in the open after open, 10 in the open after minimally invasive surgery, 47 in the robotic after open, and 32 in the robotic after minimally invasive surgery cohorts. The overall and major complication (grade ≥3) rates were 65% and 19%, respectively. The number of blood transfusions, overall complications, and major complications were significantly lower in robotic compared to open surgical cohorts. On multivariate analysis, the robotic approach was protective against major complications (OR 0.3, p=0.02) and estimated blood loss was predictive (OR 1.03, p=0.004). Prior surgical approach was not predictive for major complications. CONCLUSIONS: Reoperative partial nephrectomy is feasible using both open and robotic approaches. While the robotic approach was independently associated with fewer major complications, prior approach was not, implying that prior surgical approaches are less important to perioperative outcomes and in contributing to the overall surgical footprint.

Characterization of genetically defined sporadic and hereditary type 1 papillary renal cell carcinoma cell lines.

Renal cell carcinoma (RCC) is not a single disease but is made up of several different histologically defined subtypes that are associated with distinct genetic alterations which require subtype specific management and treatment. Papillary renal cell carcinoma (pRCC) is the second most common subtype after conventional/clear cell RCC (ccRCC), representing ~20% of cases, and is subcategorized into type 1 and type 2 pRCC. It is important for preclinical studies to have cell lines that accurately represent each specific RCC subtype. This study characterizes seven cell lines derived from both primary and metastatic sites of type 1 pRCC, including the first cell line derived from a hereditary papillary renal carcinoma (HPRC)-associated tumor. Complete or partial gain of chromosome 7 was observed in all cell lines and other common gains of chromosomes 16, 17, or 20 were seen in several cell lines. Activating mutations of MET were present in three cell lines that all demonstrated increased MET phosphorylation in response to HGF and abrogation of MET phosphorylation in response to MET inhibitors. CDKN2A loss due to mutation or gene deletion, associated with poor outcomes in type 1 pRCC patients, was observed in all cell line models. Six cell lines formed tumor xenografts in athymic nude mice and thus provide in vivo models of type 1 pRCC. These type 1 pRCC cell lines provide a comprehensive representation of the genetic alterations associated with pRCC that will give insight into the biology of this disease and be ideal preclinical models for therapeutic studies.

Clinical and Molecular Characterization of Microphthalmia-associated Transcription Factor (MITF)-related Renal Cell Carcinoma.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Long term outcomes for patients with von Hippel-Lindau and Pheochromocytoma: defining the role of active surveillance.

INTRODUCTION: Patients with a confirmed germline mutation in the von Hippel-Lindau (VHL) tumor suppressor gene have been followed at the National Cancer Institute since the 1980s. In this study, we identify VHL patients with pheochromocytoma and long-term follow-up to determine the best candidates for active surveillance and surgical resection. METHODS: A prospectively collected database of patients with a confirmed germline VHL mutation was reviewed to identify patients with a history of pheochromocytoma and at least 10 years of follow up. The presence of symptoms was assessed at the time of resection. Imaging data obtained at each clinic visit was reviewed to evaluate mass size and annual growth rate. Catecholamine data were reviewed to evaluate for data above the upper limit of the reference range. Masses that underwent imaging at least 3 months apart were considered in our surveillance cohort. RESULTS: Median follow up was 16.7 years. There was a size-dependent increase in catecholamine production (P<0.05). For 36 masses on active surveillance, growth rate increased exponentially from 0.03 cm/y when masses were <1 cm to 0.32 cm/y when masses were greater than 2 cm. Approximately 1/3 of patients developed another pheochromocytoma after initial resection with a median time of 7.9 years. Partial adrenalectomy was associated with no metastatic events and a steroid-free rate of 97%. CONCLUSION: Active surveillance is a safe strategy for management of VHL associated pheochromocytoma in masses less than 2 cm.

Long-term Functional and Oncologic Outcomes of Partial Adrenalectomy for Pheochromocytoma.

OBJECTIVE: To evaluate the recurrence and functional outcomes in a primarily hereditary cohort of patients undergoing partial adrenalectomy for pheochromocytoma. METHODS: A retrospective review from a prospectively managed database of patients undergoing partial adrenalectomy from 1995 to 2018 at the National Cancer Institute was performed. Local recurrence was defined as imaging evidence of a recurrent or de novo lesion on the operative side. Steroid dependency was defined as requiring daily steroid replacement at time of last follow-up. RESULTS: One hundred and twenty-four partial adrenalectomies, removing 162 tumors, were performed in 107 patients. Most patients had a known hereditary predisposition to develop bilateral, multifocal, and recurrent pheochromocytoma. Median tumor size was 2 cm (interquartile range (IQR) 1.5-2.8). Median follow-up was 60 months (IQR 13-131). Local recurrence occurred in 17 patients (15.8%) and were managed with active surveillance or surgery. A single patient (1/106, 0.9%) developed metastatic spread of pheochromocytoma approximately 14 years after his first of 2 partial adrenalectomies and remains alive under active surveillance. Median time to recurrence was 71 months (IQR 26-127) with 10 patients (9.3%) requiring daily steroid replacement at time of last follow-up. CONCLUSION: Partial adrenalectomy offers excellent oncologic and functional outcomes, sparing most patients from lifelong steroid replacement therapy. Recurrences can be easily managed with repeat surgery or active surveillance via functional work-up and imaging. Partial adrenalectomy remains the recommended surgical management for patients pre-disposed to development of bilateral, multifocal and recurrent pheochromocytoma.

Growth Rates of Genetically Defined Renal Tumors: Implications for Active Surveillance and Intervention.

PURPOSE: 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. PATIENTS AND METHODS: We evaluated patients with an inherited kidney cancer susceptibility syndrome as a result of a pathologic germline alteration of VHL, MET, FLCN, or BAP1 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. RESULTS: A total of 292 patients with 435 genetically defined tumors were identified, including 286 VHL-deficient, 91 FLCN-deficient, 52 MET-activated, and 6 BAP1-deficient tumors. There were significant differences in GRs when stratified by genetic alteration. BAP1-deficient tumors had the fastest median GR (0.6 cm/y; interquartile range [IQR], 0.57-0.68 cm/y), followed by VHL-deficient tumors (GR, 0.37 cm/y; IQR, 0.25-0.57 cm/y), FLCN-deficient tumors (GR, 0.10 cm/y; IQR, 0.04-0.24 cm/y), and tumors with MET activation (GR, 0.15 cm/y; IQR, 0.053-0.32 cm/y; P < .001). Tumors from the same patient had similar GRs. Younger age was independently associated with higher GR (P = .005). CONCLUSION: 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 BAP1-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.

Ferumoxytol-Enhanced MR Lymphography for Detection of Metastatic Lymph Nodes in Genitourinary Malignancies: A Prospective Study.

OBJECTIVE. The objective of our study was to evaluate the utility of ferumoxytol-enhanced MR lymphography (MRL) in detection of metastatic lymph nodes (LNs) in patients with prostate, bladder, and kidney cancer. SUBJECTS AND METHODS. This phase 2 single-institution study enrolled patients with confirmed prostate (arm 1), bladder (arm 2), and kidney (arm 3) cancer and evidence of suspected LN involvement. Participants underwent ferumoxytol-enhanced MRL 24 and 48 hours after IV injection of 7.5 mg Fe/kg of ferumoxytol. A retrospective quantitative analysis was performed to determine the optimal timing for ferumoxytol-enhanced MRL using percentage change in normalized signal intensity (SI) from baseline to 24 and 48 hours after injection, which were estimated using the linear mixed-effects model in which time (24 vs 48 hours), diseases status, and time and disease status interaction were the fixed-effects independent variables. Differences in normalized SI values between subgroups of lesions were estimated by forming fixed-effects contrasts and tested by the Wald test. RESULTS. Thirty-nine patients (n = 30, arm 1; n = 6, arm 2; n = 3, arm 3) (median age, 65 years) with 145 LNs (metastatic, n = 100; benign, n = 45) were included. LN-based sensitivity, specificity, positive predictive value, and negative predictive value of ferumoxytol-enhanced MRL was 98.0%, 64.4%, 86.0%, and 93.5%, respectively. Sensitivity and specificity of ferumoxytol-enhanced MRL did not vary by LN size. Metastatic LNs showed a significantly higher percentage decrease of normalized SI on MRL at 24 hours after ferumoxytol injection than at 48 hours after ferumoxytol injection (p = 0.023), whereas the normalized SI values for nonmetastatic LNs were similar at both imaging time points (p = 0.260). CONCLUSION. Ferumoxytol-enhanced MRL shows high sensitivity in the detection of metastatic LNs in genitourinary cancers independent of LN size. The SI difference between benign and malignant LNs on ferumoxytol-enhanced MRL appears similar 24 and 48 hours after ferumoxytol injection, suggesting that imaging can be performed safely within 1 or 2 days of injection. Although ferumoxytol-enhanced MRL can be useful in settings without an available targeted PET agent, issues of iron overload and repeatability of ferumoxytol-enhanced MRL remain concerns for this method.

A comparison of outcomes for standard and multiplex partial nephrectomy in a solitary kidney: The National Cancer Institute experience.

OBJECTIVES: To study the short and intermediate surgical, renal functional, and oncologic outcomes of multiplex partial nephrectomy (mPN) and standard partial nephrectomy (sPN) in the setting of a solitary kidney. PATIENTS AND METHODS: Review of a prospectively maintained database of patients undergoing solitary kidney partial nephrectomy at our institution was performed. Patients were stratified into 2 cohorts: mPN-where 3 or more renal tumors were resected and sPN-where 1 or 2 tumors were resected. Perioperative, renal functional, and oncological outcomes were compared. RESULTS: Ninety-three patients with a solitary kidney underwent a total of 121 surgical procedures; 43 (35.5%) were sPN and 78 (64.4%) were mPN. The total and major (Clavien Grade III and IV) complication rates between sPN and mPN were similar (57.1% vs. 70.1%, P = 0.2; 31.0% vs. 35.1%, P = 0.3). At 12 months post-op, the percentage of patients with eGFR > 45 was similar in each group (sPN 87.0%, mPN 73.7%; P = 0.2), and long-term hemodialysis rates were 4.7% and 6.4%, respectively. Completion nephrectomy was performed in 2.3% of sPN and 2.6% of mPN. At a median follow-up of 40.1 months, the metastasis rate was 8.6% in the sPN group and 4.1% in the mPN group (P = 0.4). CONCLUSIONS: Partial nephrectomy in the setting of a solitary kidney can effectively preserve renal function. The renal functional and oncologic outcomes were similar in sPN and mPN, with low hemodialysis rates and complication rates within the expected range of these operations. Three or more tumors in a solitary kidney should not be a contraindication for nephron sparing surgery.

CDC73 Germline Mutation in a Family With Mixed Epithelial and Stromal Tumors.

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.

Low-dose, short course alteplase treatment of submassive pulmonary embolism: a case series from the National Institutes of Health Clinical Center.

: Guidelines-recommend thrombolytic therapy for pulmonary embolism in patients with severe hemodynamic compromise and low risk of bleeding. Thrombolytics in submassive pulmonary embolism have an unfavorable risk/benefit ratio and remain controversial. Based on our experience with extensive, lower extremity thrombi, nine patients with symptomatic, submassive pulmonary embolisms (five medical, four surgical) were treated with low-dose alteplase (<10 mg/day, infused over 6 h per treatment). Alteplase was delivered by pulse spray and/or directed or undirected central venous catheters depending on clot size and location. All patients improved symptomatically and as determined objectively by pulmonary artery pressures and/or imaging, though acute benefits ranged from substantial to modest. One surgical patient required re-exploration for bleeding at the site of a recent retroperitoneal lymph node dissection. This experience may help guide the design of a randomized controlled trial to determine the safety and efficacy of low-dose alteplase for submassive pulmonary embolism.

Alkaline Phosphatase Kinetics Predict Metastasis among Prostate Cancer Patients Who Experience Relapse following Radical Prostatectomy.

INTRODUCTION: Metastasis prostate cancer (CaP) occurs in a small fraction of patients. Improved prognostication of disease progression is a critical challenge. This study examined alkaline phosphatase velocity (APV) in predicting distant metastasis-free survival (DMFS). MATERIALS AND METHODS: This retrospective cohort study examined CaP patients enrolled in the Center for Prostate Disease Research (CPDR) multicenter national database who underwent RP and experienced BCR (n=1783). BCR was defined as a PSA ≥ 0.2 ng/mL at ≥ 8 weeks post-RP, followed by at least one confirmatory PSA ≥ 0.2 ng/mL or initiation of salvage therapy. APV was computed as the slope of the linear regression line of all alkaline phosphatase (AP) values after BCR and prior to distant metastasis. APV values in the uppermost quartile were defined as "rapid" and compared to the lower three quartiles combined ("slower"). Unadjusted Kaplan Meier (KM) estimation curves and multivariable Cox proportional hazards analysis were used to examine predictors of DMFS. RESULTS: Of the 1783 eligible patients who experienced post-RP BCR, 701 (39.3%) had necessary AP data for APV calculation. PSA doubling time (PSADT) and APV were strongly associated (p=0.008). No differences in APV were observed across race. In KM analysis, significantly poorer DMFS was observed among the rapid versus slower APV group (Log-rank p=0.003). In multivariable analysis, a rapid APV was predictive of a twofold increased probability of DMFS (HR = 2.2; 95% CI = 1.2, 3.9; p = 0.008), controlling for key study covariates. CONCLUSIONS: Building on previous work, this study found that rapid APV was a strong predictor of DMFS for a broader group of CaP patients, those who undergo post-RP BCR who were enrolled in a longitudinal cohort with long-term follow-up and equal health care access. APV is worth considering as a complementary clinical factor for predicting DMFS.

BHD-associated kidney cancer exhibits unique molecular characteristics and a wide variety of variants in chromatin remodeling genes.

Birt-Hogg-Dubé (BHD) syndrome is a hereditary kidney cancer syndrome, which predisposes patients to develop kidney cancer, cutaneous fibrofolliculomas and pulmonary cysts. The responsible gene FLCN is a tumor suppressor for kidney cancer, which plays an important role in energy homeostasis through the regulation of mitochondrial oxidative metabolism. However, the process by which FLCN-deficiency leads to renal tumorigenesis is unclear. In order to clarify molecular pathogenesis of BHD-associated kidney cancer, we conducted whole-exome sequencing analysis using next-generation sequencing technology as well as metabolite analysis using liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. Whole-exome sequencing analysis of BHD-associated kidney cancer revealed that copy number variations of BHD-associated kidney cancer are considerably different from those already reported in sporadic cases. In somatic variant analysis, very few variants were commonly observed in BHD-associated kidney cancer; however, variants in chromatin remodeling genes were frequently observed in BHD-associated kidney cancer (17/29 tumors, 59%). Metabolite analysis of BHD-associated kidney cancer revealed metabolic reprogramming toward upregulated redox regulation which may neutralize reactive oxygen species potentially produced from mitochondria with increased respiratory capacity under FLCN-deficiency. BHD-associated kidney cancer displays unique molecular characteristics that are completely different from sporadic kidney cancer, providing mechanistic insight into tumorigenesis under FLCN-deficiency as well as a foundation for development of novel therapeutics for kidney cancer.

Differentiating papillary type I RCC from clear cell RCC and oncocytoma: application of whole-lesion volumetric ADC measurement.

PURPOSE: To determine whether objective volumetric whole-lesion apparent diffusion coefficient (ADC) distribution analysis improves upon the capabilities of conventional subjective small region-of-interest (ROI) ADC measurements for prediction of renal cell carcinoma (RCC) subtype. METHODS: This IRB-approved study retrospectively enrolled 55 patients (152 tumors). Diffusion-weighted imaging DWI was acquired at b values of 0, 250, and 800 s/mm2 on a 1.5T system (Aera, Siemens Healthcare). Whole-lesion measurements were performed by a research fellow and reviewed by a fellowship-trained radiologist. Mean, median, skewness, kurtosis, and every 5th percentile ADCs were determined from the whole-lesion histogram. Linear mixed models that accounted for within-subject correlation of lesions were used to compare ADCs among RCC subtypes. Receiver-operating characteristic (ROC) curve analysis with optimal cutoff points from the Youden index was used to test the ability of ADCs to differentiate clear cell RCC (ccRCC), papillary RCC (pRCC), and oncocytoma subtypes. RESULTS: Whole-lesion ADC values were significantly different between pRCC and ccRCC, and between pRCC and oncocytoma, demonstrating strong ability to differentiate subtypes across the quantiles (both P < 0.001). Best percentile ROC analysis demonstrated AUC values of 95.2 for ccRCC vs. pRCC; 67.6 for oncocytoma vs. ccRCC; and 95.8 for oncocytoma vs. pRCC. Best percentile ROC analysis further indicated model sensitivities/specificities of 84.5%/93.1% for ccRCC vs. pRCC; 100.0%/10.3% for oncocytoma vs. ccRCC; and 88.5%/93.1% for oncocytoma vs. pRCC. CONCLUSION: The objective methodology of whole-lesion volumetric ADC measurements maintains the sensitivity/specificity of conventional expert-based ROI analysis, provides information on lesion heterogeneity, and reduces observer bias.

Superiority of 68Ga-DOTATATE over 18F-FDG and anatomic imaging in the detection of succinate dehydrogenase mutation (SDHx )-related pheochromocytoma and paraganglioma in the pediatric population.

PURPOSE: To evaluate and compare diagnostic performance of 68Ga-DOTA(0)-Tyr(3)-octreotate (68Ga-DOTATATE) with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) and anatomic imaging using computed tomography and/or magnetic resonance (CT/MR) imaging in detection of SDHx-related pheochromocytomas and paragangliomas (PPGLs) in pediatric patients. METHODS: Nine pediatric patients (5:4, girls:boys; 14.6 ± 2.0 years) with an SDHx-related mutation (SDHB:SDHA:SDHD, n = 7:1:1) were included in this retrospective study. At the time of initial diagnosis, 7/9 patients had metastatic disease. They underwent CT/MR imaging along with PET/CT using 68Ga-DOTATATE (n = 9), 18F-FDG (n = 8), and positron emission tomography-magnetic resonance imaging (PET/MR) using 18F-FDG (n = 1). In this manuscript, 18F-FDG PET/CT refers to both 18F-FDG PET/CT and 18F-FDG PET/MR. The per-lesion, per-region, and per-patient detection rates were compared and calculated for each of the imaging modalities. A composite of all functional and anatomic imaging studies served as the imaging comparator. RESULTS: Eight out of nine patients were positive for PPGLs on the imaging studies that demonstrated 107 lesions in 22 anatomic regions on the imaging comparator. The per-lesion detection rates for 68Ga-DOTATATE PET/CT, 18F-FDG PET/CT, and CT/MR imaging were 93.5% (95%CI, 87.0% to 97.3%); 79.4% (95%CI, 70.5% to 86.6%); and 73.8% (95%CI, 64.5% to 81.9%), respectively. The per-lesion detection rate for 68Ga-DOTATATE PET/CT was significantly higher than that of 18F-FDG PET/CT (p = 0.001) or CT/MR imaging (p < 0.001). In all of the anatomic regions except abdomen, the per-lesion detection rates for 68Ga-DOTATATE PET/CT was found to be equal or superior to 18F-FDG PET/CT, and CT/MR imaging. The per-region detection rate was 100% (95%CI, 84.6% to 100%) for 68Ga-DOTATATE PET/CT and 90.9% (95%CI, 70.8% to 98.9%) for both 18F-FDG PET/CT and CT/MR imaging. The per-patient detection rates for 68Ga-DOTATATE PET/CT, 18FDG PET/CT, and CT/MR imaging were all 100% (95%CI, 63.1% to 100%). CONCLUSION: Our preliminary study demonstrates the superiority of 68Ga-DOTATATE PET/CT in localization of SDHx-related PPGLs in pediatric population compared to 18F-FDG PET/CT and CT/MR imaging with the exception of abdominal (excluding adrenal and liver) lesions, and suggests that it might be considered as a first-line imaging modality in pediatric patients with SDHx-related PPGLs.

Multiplex Partial Nephrectomy, Repeat Partial Nephrectomy, and Salvage Partial Nephrectomy Remain the Primary Treatment in Multifocal and Hereditary Kidney Cancer.

The standard of care treatment for solitary renal cell carcinoma (RCC) tumors 4 cm or less is partial nephrectomy (PNx). However, multifocal kidney cancer presents unique challenges for treating physicians. Historically, total nephrectomy and hemodialysis with possible renal transplant later was the primary therapeutic strategy for these patients. Later, as nephron sparing surgical approaches improved, PNx became the standard of care for patients presenting with multifocal and hereditary RCC. Surgeries to remove multiple renal tumors simultaneously produce different perioperative outcomes and increased risk of complications. Due to these differences in technique and outcomes, the term multiplex partial nephrectomy (MxPNx) has been coined to designate these differences. Here, we discuss the role that MxPNx continues to play in multifocal RCC.