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 technically feasible 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 RePNs to characterize renal functional outcomes and the likelihood of intra- and postoperative complications. MATERIALS AND METHODS: Query of an institutional surgical registry was conducted. Demographic data, serum creatinine for estimated glomerular filtration rate (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 partial nephrectomies 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, tumor 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.

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.

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.

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.

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.

H255Y and K508R missense mutations in tumour suppressor folliculin (FLCN) promote kidney cell proliferation.

Germline H255Y and K508R missense mutations in the folliculin (FLCN) gene have been identified in patients with bilateral multifocal (BMF) kidney tumours and clinical manifestations of Birt-Hogg-Dubé (BHD) syndrome, or with BMF kidney tumours as the only manifestation; however, their impact on FLCN function remains to be determined. In order to determine if FLCN H255Y and K508R missense mutations promote aberrant kidney cell proliferation leading to pathogenicity, we generated mouse models expressing these mutants using BAC recombineering technology and investigated their ability to rescue the multi-cystic phenotype of Flcn-deficient mouse kidneys. Flcn H255Y mutant transgene expression in kidney-targeted Flcn knockout mice did not rescue the multi-cystic kidney phenotype. However, expression of the Flcn K508R mutant transgene partially, but not completely, abrogated the phenotype. Notably, expression of the Flcn K508R mutant transgene in heterozygous Flcn knockout mice resulted in development of multi-cystic kidneys and cardiac hypertrophy in some mice. These results demonstrate that both FLCN H255Y and K508R missense mutations promote aberrant kidney cell proliferation, but to different degrees. Based on the phenotypes of our preclinical models, the FLCN H255Y mutant protein has lost it tumour suppressive function leading to the clinical manifestations of BHD, whereas the FLCN K508R mutant protein may have a dominant negative effect on the function of wild-type FLCN in regulating kidney cell proliferation and, therefore, act as an oncoprotein. These findings may provide mechanistic insight into the role of FLCN in regulating kidney cell proliferation and facilitate the development of novel therapeutics for FLCN-deficient kidney cancer.

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.

Comprehensive genomic and phenotypic characterization of germline FH deletion in hereditary leiomyomatosis and renal cell carcinoma.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a familial cancer syndrome associated with the development of cutaneous and uterine leiomyomas, and an aggressive form of type 2 papillary kidney cancer. HLRCC is characterized by germline mutation of the FH gene. This study evaluated the prevalence and clinical phenotype of FH deletions in HLRCC patients. Patients with phenotypic manifestations consistent with HLRCC who lacked detectable germline FH intragenic mutations were investigated for FH deletion. A series of 28 patients from 13 families were evaluated using a combination of a comparative genomic hybridization (CGH) array and/or CLIA-approved FH deletion/duplication analyses. Thirteen distinct germline deletions were identified in the 13 UOB families, including 11 complete FH gene deletions and 2 partial FH gene deletions. The size of eight evaluated complete FH deletions varied from ∼4.74 Mb to 249 kb, with all deletions resulting in additional gene losses. Two partial FH gene deletions were identified, with one resulting in loss of exon 1 and the upstream region of the FH gene only. Kidney cancer was diagnosed in 9 (32%) of 28 patients and 7 (54%) of 13 families possessing either complete or partial FH deletions. Cutaneous and uterine leiomyomas were observed at similar rates to those in FH point mutation families. Complete or partial FH gene alterations in HLRCC families are associated with all of the canonical HLRCC manifestations, including type 2 papillary kidney cancer and should be screened for in any patient at-risk for this disorder.

Genomic and metabolic characterization of a chromophobe renal cell carcinoma cell line model (UOK276).

Chromophobe renal cell carcinoma (ChRCC) represents 5% of all RCC cases and frequently demonstrates multiple chromosomal losses and an indolent pattern of local growth, but can demonstrate aggressive features and resistance to treatment in a metastatic setting. Cell line models are an important tool for the investigation of tumor biology and therapeutic drug efficacy. Currently, there are few ChRCC-derived cell lines and none is well characterized. This study characterizes a novel ChRCC-derived cell line model, UOK276. A large ChRCC tumor with regions of sarcomatoid differentiation was used to establish a spontaneously immortal cell line, UOK276. UOK276 was evaluated for chromosomal, mutational, and metabolic aberrations. The UOK276 cell line is hyperdiploid with a modal number of 49 chromosomes per cell, and evidence of copy-neutral loss of heterozygosity, as opposed to the classic pattern of ChRCC chromosomal losses. UOK276 demonstrated a TP53 missense mutation, expressed mutant TP53 protein, and responded to treatment with a small-molecule therapeutic agent, NSC319726, designed to reactivate mutated TP53. Xenograft tumors grew in nude mice and provide an in vivo animal model for the investigation of potential therapeutic regimes. The xenograft pathology and genetic analysis suggested that UOK276 was derived from the sarcomatoid region of the original tumor. In summary, UOK276 represents a novel in vitro and in vivo cell line model for aggressive, sarcomatoid-differentiated, TP53 mutant ChRCC. This preclinical model system could be used to investigate the novel biology of aggressive, sarcomatoid ChRCC and evaluate the new therapeutic regimes.

Clinical significance of ureteric 'skip lesions' at the time of radical cystectomy: the M.D. Anderson experience and literature review.

OBJECTIVE: To assess the incidence and clinical significance of 'skip lesions' that are present in proximal but not in distal ureteric sections, which are occasionally found during the pathological examination of ureteric margins during radical cystectomy (RC). PATIENTS AND METHODS: We identified 660 patients who underwent a RC and had at least two permanent margins for a given ureter. In all, 1173 ureters were analysed and classified as follows: 'normal' (no tumour, reactive atypia, mild or moderate dysplasia) or 'abnormal' (severe dysplasia, carcinoma in situ (CIS), or tumour). Transitions from 'normal' distal pathology to 'abnormal' on proximal section(s) determined frequency of skip lesions. Fisher's exact test and the log-rank test were used to study correlations. RESULTS: Ureteric skip lesions were found in 4.8% patients (2.9% ureters). Pathology of skip lesions was CIS in 55.9%, transitional cell carcinoma in 23.5% and severe dysplasia in 20.6%. Skip lesions were associated with lymphovascular invasion (34.4% vs 13.7%, P = 0.004) and advanced pT stage (P = 0.007). On multivariate analysis, skip lesions correlated with lower median overall survival (OS) (inestimable vs 8.2 years, P = 0.014) in patients with pT0 or pTa disease and a trend towards lower OS (2.7 vs 8.8 years, P = 0.066) in pTis disease. Concordance between frozen distal margin and permanent proximal margin varied; sensitivity was 80% in those without and 20% in those with skip lesions. CONCLUSIONS: The presence of a ureteric skip lesion may be associated with lower survival in patients with pT0, pTa or pTis urothelial carcinoma. Thus, while uncommon, ureteric skip lesions should be reported in pathological findings.

Nephron-sparing surgery for multifocal and hereditary renal tumors.

PURPOSE OF REVIEW: Despite the controversy surrounding the benefits of nephron-sparing surgery, multiple absolute indications for nephron-sparing surgery still exist, including the classic indications of hereditary and bilateral kidney tumors. RECENT FINDINGS: Multiple genetic mutations have been identified which lead to hereditary kidney cancer conditions. These are briefly reviewed because the surgical management of hereditary kidney tumors depends on the genetic and histologic subtypes involved. Clear understanding of these hereditary conditions is crucial for proper surgical management of these tumors. SUMMARY: Complex partial nephrectomy for multiple renal tumors, or multiplex partial nephrectomy, requires not only exceptional surgical skills but expertise of numerous nonsurgical methodologies, such as hands-on intraoperative ultrasonography and interpretation of multiple imaging modalities. In addition, multidisciplinary management is crucial for optimal outcomes in patient care. This review evaluates the most advanced surgical techniques and perioperative management required to successfully care for these challenging cases.

Germline PTEN mutation Cowden syndrome: an underappreciated form of hereditary kidney cancer.

PURPOSE: Cowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma. MATERIALS AND METHODS: Patients with Cowden syndrome were evaluated as part of a clinical protocol. Those with a history of renal cell carcinoma underwent review of clinical features, tumor characteristics and family history. Renal tumors were evaluated for loss of heterozygosity. RESULTS: Among 24 patients with Cowden syndrome 4 were identified with renal cell carcinoma (16.7%). Three patients had solitary tumors, 2 with papillary type I histology and 1 with clear cell histology. The fourth patient had bilateral, synchronous chromophobe tumors. No patients had a prior family history of renal cell carcinoma. All patients with renal cell carcinoma had dermatologic manifestations of Cowden syndrome and had macrocephaly. Loss of heterozygosity at the PTEN mutation was identified in 4 tumors (80%). No genotype-phenotype association was found, as the same mutation was identified in different renal cell carcinoma histologies. CONCLUSIONS: Renal cell carcinoma is an underappreciated feature of Cowden syndrome. As most patients lack a prior family history or a distinctive renal cell carcinoma histology, recognition of the associated nonrenal features should target referral for genetic counseling. PTEN loss of heterozygosity is common in Cowden syndrome renal tumors. Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.

Commentary on: "Focal cryosurgical ablation of the prostate: a single institute's perspective".

The morbidity of whole gland treatment for prostate cancer is significant. Given the low risk of prostate cancer specific mortality for most men diagnosed with prostate cancer, alternative therapies such as sub-total or hemi-ablation of the prostate and focal ablation of prostate tumors are being investigated. The developing role of imaging for prostate tumors will dramatically change and likely improve the treatment morbidity for low risk prostate tumors. Commentary on: http://www.biomedcentral.com/1471-2490/13/2.

Economic burden of repeat renal surgery on solitary kidney--do the ends justify the means? A cost analysis.

PURPOSE: Despite the high morbidity of repeat renal surgery in patients with multifocal recurrent renal carcinoma, in most patients adequate renal function is preserved to obviate the need for dialysis. To our knowledge the economic burden of repeat renal surgery has not been evaluated. We provide a cost analysis for patients requiring repeat renal surgery on a solitary kidney. MATERIALS AND METHODS: We reviewed the charts of patients treated at the National Cancer Institute who required repeat renal surgery from 1989 to 2010. Functional, oncological and surgical outcomes were evaluated and the costs of repeat renal surgery were calculated. We then compared costs in a cohort of 33 patients who underwent repeat renal surgery on a solitary kidney and in a hypothetical patient cohort treated with uncomplicated nephrectomy, fistula placement and dialysis. All costs were calculated based on Medicare reimbursement rates derived from CPT codes. Cost analysis was performed. RESULTS: Despite a high 45% complication rate, 87% of patients maintained renal function that was adequate to avoid dialysis and 96% remained metastasis free at an average followup of 3.12 years (range 0.3 to 16.4). Compared to the hypothetical dialysis cohort, the financial benefit of repeat renal surgery was reached at 0.68 years. CONCLUSIONS: Repeat renal surgery is a viable alternative for patients with multifocal renal cell carcinoma requiring multiple surgical interventions, especially when left with a solitary kidney. Despite the high complication rate, renal function is preserved in most patients and they have an excellent oncological outcome. The financial benefit of repeat renal surgery is reached at less than 1 year.

Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer.

PURPOSE: Recently, a new renal cell cancer syndrome has been linked to germline mutation of multiple subunits (SDHB/C/D) of the Krebs cycle enzyme, succinate dehydrogenase. We report our experience with the diagnosis, evaluation and treatment of this novel form of hereditary kidney cancer. MATERIALS AND METHODS: Patients with suspected hereditary kidney cancer were enrolled on a National Cancer Institute institutional review board approved protocol to study inherited forms of kidney cancer. Individuals from families with germline SDHB, SDHC and SDHD mutations, and kidney cancer underwent comprehensive clinical and genetic evaluation. RESULTS: A total of 14 patients from 12 SDHB mutation families were evaluated. Patients presented with renal cell cancer at an early age (33 years, range 15 to 62), metastatic kidney cancer developed in 4 and some families had no manifestation other than kidney tumors. An additional family with 6 individuals found to have clear cell renal cell cancer that presented at a young average age (47 years, range 40 to 53) was identified with a germline SDHC mutation (R133X) Metastatic disease developed in 2 of these family members. A patient with a history of carotid body paragangliomas and an aggressive form of kidney cancer was evaluated from a family with a germline SDHD mutation. CONCLUSIONS: SDH mutation associated renal cell carcinoma can be an aggressive type of kidney cancer, especially in younger individuals. Although detection and management of early tumors is most often associated with a good outcome, based on our initial experience with these patients and our long-term experience with hereditary leiomyomatosis and renal cell carcinoma, we recommend careful surveillance of patients at risk for SDH mutation associated renal cell carcinoma and wide surgical excision of renal tumors.

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.

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.

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.