Disparities Associated with Shared Decision-making in Prostate Cancer Screening.

BACKGROUND: Prostate cancer screening guidelines recommend shared decision-making (SDM) regarding prostate-specific antigen (PSA) testing. However, it is unclear who undergoes SDM and whether any disparities exist. OBJECTIVE: To examine sociodemographic differences in participation of SDM and its association with PSA testing in prostate cancer screening. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cross-sectional study was conducted among men aged 45-75 yr undergoing PSA screening, using the 2018 National Health Interview Survey database. The evaluated sociodemographic features included age, race, marital status, sexual orientation, smoking status, working status, financial difficulty, US geographic regions, and cancer history. Questions regarding self-reported PSA testing and whether respondents discussed its advantages and disadvantages with their healthcare provider were analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Our primary outcome was to evaluate the possible associations between various sociodemographic factors and undergoing PSA screening and SDM. We used multivariable logistic regression analyses to detect potential associations. RESULTS AND LIMITATIONS: A total of 59596 men were identified, of whom 5605 answered the question regarding PSA testing, with 2288 (40.6%) undergoing PSA testing. Of these men, 39.5% (n = 2226) discussed the advantages and 25.6% (n = 1434) discussed the disadvantages of PSA testing. On a multivariable analysis, older (odds ratio [OR] 1.092; 95% confidence interval [CI] 1.081-1.103, p < 0.001) and married (OR 1.488; 95% CI 1.287-1.720, p < 0.001) men were more likely to undergo PSA testing. Although Black men were more likely to discuss PSA advantages (OR 1.421; 95% CI 1.150-1.756, p = 0.001) and disadvantages (OR 1.554; 95% CI 1.240-1.947, p < 0.001) than White men, this did not correlate with higher rates of PSA screening (OR 1.086; 95% CI 0.865-1.364, p = 0.477). The lack of important clinical data remains a limitation. CONCLUSIONS: Overall, SDM rates were low. Older and married men had an increased likelihood of SDM and PSA testing. Despite higher rates of SDM, Black men had similar rates of PSA testing to White men. PATIENT SUMMARY: We evaluated sociodemographic differences in shared decision-making (SDM) in prostate cancer screening using a large national database. We found that SDM had varying results in different sociodemographic groups.

The association of sexual orientation with prostate, breast, and cervical cancer screening and diagnosis.

PURPOSE: Data on heterogeneity in cancer screening and diagnosis rates among lesbians/gays and bisexuals (LGBs) is lacking. Recent studies showed that LGBs have decreased healthcare utilization compared to heterosexual counterparts. Few studies have examined how sexual orientation impacts cancer screening and prevalence. We, therefore, investigated the association between sexual orientation and prevalent sex-specific cancer including prostate (PCa), breast (BC), and cervical (CC) cancer. METHODS: This was a cross-sectional survey-based US study, including men and women aged 18 + from the Health Information National Trends Survey (HINTS) database between 2017 and 2019. The primary endpoint was individual-reported prostate, breast, and cervical cancer screening and prevalence rates among heterosexual and LGB men and women. Multivariable logistic regression analyses assessed association of various covariates with undergoing screening and diagnosis of these cancers. RESULTS: Overall, 4,441 and 6,333 heterosexual men and women, respectively, were compared to 225 and 213 LGB men and women, respectively. LGBs were younger and less likely to be screened for PCa, BC, and CC than heterosexuals. A higher proportion of heterosexual women than lesbian and bisexual women were screened for CC with pap smears (95.36% vs. 90.48% and 86.11%, p ≤ 0.001) and BC with mammograms (80.74% vs. 63.81% and 45.37%, p ≤ 0.001). Similarly, a higher proportion of heterosexual men than gay and bisexual men were screened for PCa with PSA blood tests (41.27% vs. 30.53% and 27.58%, p ≤ 0.001). CONCLUSION: There were more heterosexuals than LGBs screened for CC, BC, and PCa. However, no association between sexual orientation and cancer diagnosis was found. Healthcare professionals should be encouraged to improve cancer screening among LGBs.

Financial Toxicity and Its Association With Prostate and Colon Cancer Screening.

BACKGROUND: The term "financial toxicity" or "hardship" is a patient-reported outcome that results from the material costs of cancer care, the psychological impacts of these costs, and the coping strategies that patients use to deal with the strain that includes delaying or forgoing care. However, little is known about the impact of financial toxicity on cancer screening. We examined the effects of financial toxicity on the use of screening tests for prostate and colon cancer. We hypothesized that greater financial hardship would show an association with decreased prevalence of cancer screening. METHODS: This cross-sectional survey-based US study included men and women aged ≥50 years from the National Health Interview Survey database from January through December 2018. A financial hardship score (FHS) between 0 and 10 was formulated by summarizing the responses from 10 financial toxicity dichotomic questions (yes or no), with a higher score associated with greater financial hardship. Primary outcomes were self-reported occurrence of prostate-specific antigen (PSA) blood testing and colonoscopy for prostate and colon cancer screening, respectively. RESULTS: Overall, 13,439 individual responses were collected. A total of 9,277 (69.03%) people had undergone colonoscopies, and 3,455 (70.94%) men had a PSA test. White, married, working men were more likely to undergo PSA testing and colonoscopy. Individuals who had not had a PSA test or colonoscopy had higher mean FHSs than those who underwent these tests (0.70 and 0.79 vs 0.47 and 0.61, respectively; P≤.001 for both). Multivariable logistic regression models demonstrated that a higher FHS was associated with a decreased odds ratio for having a PSA test (0.916; 95% CI, 0.867-0.967; P=.002) and colonoscopy (0.969; 95% CI, 0.941-0.998; P=.039). CONCLUSIONS: Greater financial hardship is suggested to be associated with a decreased probability of having prostate and colon cancer screening. Healthcare professionals should be aware that financial toxicity can impact not only cancer treatment but also cancer screening.

Prostate-specific Antigen Testing in Men with Disabilities: A Cross-sectional Analysis of the Health Information National Trends Survey.

BACKGROUND: Patients with disabilities represent a unique minority population. The incidence of prostate-specific antigen (PSA) testing among this population is unknown. OBJECTIVE: To compare PSA testing rates and associated predictors among men with and without reported disabilities in the USA. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study of the Health Information National Trends Survey (HINTS) for the years 2012, 2013, 2017 and 2019 was conducted in men with reported disabilities. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline demographics of the entire cohort were stratified based on their reported disabilities (none, disabled, deaf, and blind). Each disability was compared separately and in combination with the cohort without disabilities. Multivariable logistic regression models determined clinically significant predictors of PSA testing in men with disabilities compared with those without. RESULTS AND LIMITATIONS: Overall, 782 (15%) men with disabilities were compared with 4569 (85%) men without disabilities. The former cohort was older with a median (interquartile range) age of 65 (56-75) versus 57 (43-67) yr (p < 0.001). On multivariable analysis, men with any disability were less likely to undergo PSA testing (odds ratio 0.77, 95% confidence interval 0.62-0.96, p = 0.018). Variables associated with increased PSA testing included age, having a health care provider, health insurance, and living with a partner. CONCLUSIONS: Inequalities in PSA testing exist among men with disabilities in the USA, especially among the deaf and blind, being less likely to undergo PSA testing. Further research is required to identify and deal with any obstacles in the implementation of equal PSA testing in this unique population. PATIENT SUMMARY: In the USA, men with reported disabilities are less likely to undergo PSA testing than patients without reported disabilities.

Is There a Role for Prone Computed Tomography Before Percutaneous Nephrolithotomy?

Background: The majority of percutaneous nephrolithotomies (PCNLs) are performed prone, whereas most preoperative CT scans are done supine. The purpose of this pilot study is to determine if there is utility of prone CT scans in preoperative planning for prone PCNL by identifying patient populations at risk for organ injury and tract length-related complications. Materials and Methods: To represent typical preoperative planning using CT, two-dimensional (2D)-axial-prone/supine percutaneous tract measurements were performed by minimizing the distance from the target calix to the posterior-lateral skin in a single axial plane. The minimum distance and organ interception rates for the 2D-axial planning scans were recorded. Results: A total of 60 CT colonography and 13 CT urography patients were included in analysis. There were 42 women and 31 men with unspecified pathology reports ranging in age from 27 to 86 years and in body mass index (BMI) from 17.1 to 49. Multiple logistic regression identified female gender and low BMI as predictors of organ interception on the left. On multiple linear regression comparing the difference in axial prone/supine lengths; BMI, gender, and age were not significant independent predictors of changes in tract length in any pole when prone vs supine. However, shorter supine tracts tended to lengthen when prone, and longer supine tracts tended to shorten. Conclusions: This pilot study has demonstrated that patients with long and short estimates of tract length in the supine position may have shorter and longer tracts, respectively, with repositioning to prone. Thus, prone CT may have benefit when anticipating exceptionally long (>15 cm) tract lengths. Prone scans also revealed more potential organ interceptions, particularly for low BMI and women in the left upper pole. In patients for whom prone CT demonstrates an organ interception, the urologist should consider an alternate target calix or ultrasound-guided percutaneous access to identify the most appropriate needle trajectory.

Association of Race With Cancer-Related Financial Toxicity.

PURPOSE: We investigated the association between race and FT among previous patients with cancer. Studies show that patients with cancer experience financial toxicity (FT) because of their cancer treatment. METHODS: Data on individuals with a cancer history were collected in this cross-sectional study during 2012, 2014, and 2017, from the US Health Information National Trends Survey. This survey is conducted by mail with monetary compensation as an incentive. We specifically assessed responses to two questions: Has cancer hurt you financially? Have you been denied health insurance because of cancer? Multivariable logistic regression analyses were used to assess the associations between these questions and race. RESULTS: Of 10,592 individuals participating, 1,328 men and women (12.5%) with a cancer history were assessed. Compared with Blacks, Whites were found to have a higher rate of insurance (95.4% v 90.0%), were more likely to receive cancer treatment (93.9% v 85%), and had a higher rate of surgical treatment than Blacks (77% v 60%), Hispanics (55%), and others (77%, 60%, 55%, and 74.2%, respectively, P < .001). On multivariable analysis, Blacks were more than five times as likely to be denied insurance (odds ratio, 5.003; 95% CI, 2.451 to 10.213; P < .001) and more than twice as likely to report being hurt financially because of cancer (odds ratio, 2.448; 95% CI, 1.520 to 3.941; P < .001) than Whites. Of all cancer groups analyzed (genitourinary, gynecologic, gastrointestinal, and breast), genitourinary malignancies were the only group in which the rate of reporting being hurt financially varied in a statistically significant manner (Whites 36.7%, Hispanics 62.5%, and Blacks 59.3%, P = .004). CONCLUSION: Our data suggest that race is significantly associated with FT because of cancer. Awareness of racial inequality with regards to FT should be raised among health care workers.

Clinically Advanced Pheochromocytomas and Paragangliomas: A Comprehensive Genomic Profiling Study.

Patients with clinically advanced paragangliomas (CA-Para) and pheochromocytomas (CA-Pheo) have limited surgical or systemic treatments. We used comprehensive genomic profiling (CGP) to compare genomic alterations (GA) in CA-Para and CA-Pheo to identify potential therapeutic targets. Eighty-three CA-Para and 45 CA-Pheo underwent hybrid-capture-based CGP using a targeted panel of 324 genes. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined. The GA/tumor frequencies were low for both tumor types (1.9 GA/tumor for CA-Para, 2.3 GA/tumor for CA-Pheo). The most frequent potentially targetable GA in CA-Para were in FGFR1 (7%, primarily amplifications), NF1, PTEN, NF2, and CDK4 (all 2%) and for CA-Pheo in RET (9%, primarily fusions), NF1 (11%) and FGFR1 (7%). Germline mutations in known cancer predisposition genes were predicted in 13 (30%) of CA-Pheo and 38 (45%) of CA-Para cases, predominantly involving SDHA/B genes. Both CA-Para and CA-Para had low median TMB, low PD-L1 expression levels and none had MSI high status. While similar GA frequency is seen in both CA-Para and CA-Para, germline GA were seen more frequently in CA-Para. Low PD-L1 expression levels and no MSI high status argue against strong potential for novel immune checkpoint inhibitors. However, several important potential therapeutic targets in both CA-Para and CA-Para are identified using CGP.

Comprehensive genomic profiling of histologic subtypes of urethral carcinomas.

BACKGROUND: Carcinoma of the urethra (UrthCa) is an uncommon Genitourinary (GU) malignancy that can progress to advanced metastatic disease. METHODS: One hundred twenty-seven metastatic UrthCa underwent hybrid capture-based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA). Tumor mutational burden was determined on up to 1.1 Mbp of sequenced DNA, and microsatellite instability was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). RESULTS: Forty-nine (39%) urothelial (UrthUC), 31 (24%) squamous (UrthSCC), 24 (19%) adenocarcinomas NOS (UrthAC), and 12 (9%) clear cell (UrthCC) were evaluated. UrthUC and UrthSCC are more common in men; UrthAC and UrthCC are more common in women. Ages were similar in all 4 groups. GA in PIK3CA were the most frequent potentially targetable GA; mTOR pathway GA in PTEN were also identified. GA in other potentially targetable genes were also identified including ERBB2 (6% in UrthUC, 3% in UrthSCC, and 12% in UrthAC), FGFR1-3 (3% in UrthSCC), BRAF (3% in UrthAC), PTCH1 (8% in UrthCC), and MET (8% in UrthCC). Possibly reflecting their higher GA/tumor status, potential for immunotherapy benefit associated with higher tumor mutational burden and PD-L1 staining levels were seen in UrthUC and UrthSCC compared to UrthAC and UrthCC. Microsatellite instability high status was absent throughout. CONCLUSIONS: Comprehensive genomic profiling reveals GA that may be predictive of both targeted and immunotherapy benefit in patients with advanced UrthCa and that could potentially be used in future adjuvant, neoadjuvant, and metastatic disease trials.

Comprehensive genomic profiling of metastatic collecting duct carcinoma, renal medullary carcinoma, and clear cell renal cell carcinoma.

INTRODUCTION AND OBJECTIVE: Unlike clear cell renal cell carcinoma (CCRCC), collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are rare tumors that progress rapidly and appear resistant to current systemic therapies. We queried comprehensive genomic profiling to uncover opportunities for targeted therapy and immunotherapy. MATERIAL AND METHODS: DNA was extracted from 40 microns of formalin-fixed, paraffin-embedded specimen from relapsed, mCDC (n = 46), mRMC (n = 24), and refractory and metastatic (m) mCCRCC (n = 626). Comprehensive genomic profiling was performed, and Tumor mutational burden (TMB) and microsatellite instability (MSI) were calculated. We analyzed all classes of genomic alterations. RESULTS: mCDC had 1.7 versus 2.7 genomic alterations/tumor in mCCRCC ( = 0.04). Mutations in VHL (P < 0.0001) and TSC1 (P = 0.04) were more frequent in mCCRCC. SMARCB1 (P < 0.0001), NF2 (P = 0.0007), RB1 (P = 0.02) and RET (P = 0.0003) alterations were more frequent in mCDC versus mCCRCC. No VHL alterations in mRMC and mCDC were identified. SMARCB1 genomic alterations were significantly more frequent in mRMC than mCDC (P = 0.0002), but were the most common alterations in both subtypes. Mutations to EGFR, RET, NF2, and TSC2 were more frequently identified in mCDC versus mRMC. The median TMB and MSI-High status was low with <1% of mCCRC, mCDC, and mRMC having ≥ 20 mut/Mb. CONCLUSION: Genomic alteration patterns in mCDC and mRMC differ significantly from mCCRCC. Targeted therapies for mCDC and mRMC appear limited with rare opportunities to target alterations in receptor tyrosine kinase and MTOR pathways. Similarly, TMB and absence of MSI-High status in mCDC and mRMC suggest resistance to immunotherapies.

Complications of Ileal Conduits after Radical Cystectomy: Interventional Radiologic Management.

Since their introduction into clinical practice in the 1950s, ileal conduits have been the most common type of urinary diversion used after radical cystectomy worldwide. Although ileal conduits are technically simpler to construct than other forms of urinary diversion, a variety of complications can occur in the early and late postoperative periods. Early complications include urine leakage, urinary obstruction, postoperative fluid collection (eg, urinoma, hematoma, lymphocele, or abscess), and fistula formation. Late complications include ureteroileal anastomotic stricture, stomal stenosis, conduit stenosis, and urolithiasis. Although not directly related to ileal conduits, ureteroarterial fistula can occur in patients with an ileal conduit. Interventional radiologists can play a pivotal role in diagnosis and management of these complications by performing image-guided minimally invasive procedures. In this article, the authors review the surgical anatomy of an ileal conduit and the underlying pathophysiology of and diagnostic workup for complications related to ileal conduits. The authors also discuss and illustrate current approaches to interventional radiologic management of these complications, with emphasis on a collaborative approach with urologists or endourologists to best preserve patients' renal function and maintain their quality of life. ©RSNA, 2020.

Comprehensive Assessment of Immuno-oncology Biomarkers in Adenocarcinoma, Urothelial Carcinoma, and Squamous-cell Carcinoma of the Bladder.

BACKGROUND: In patients with rare histologies of bladder cancer, including adenocarcinoma of the bladder (ACB) and squamous-cell carcinoma (SCC), there are limited standard therapy options, defining an unmet medical need. OBJECTIVE: In this comparative comprehensive genomic profiling (CGP) study, genomic alterations (GAs), and immuno-oncology (IO) biomarkers have been analyzed. DESIGN, SETTING, AND PARTICIPANTS: Within the Foundation Medicine database, 143 cases with centrally reviewed pure ACB, 2142 with pure urothelial carcinoma (UC), and 83 with pure SCC were subjected to CGP. All patients developed advanced disease following a primary diagnosis of bladder cancer. INTERVENTION: CGP using a hybrid capture-based assay and immunohistochemistry (IHC). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) was determined on 114 loci. Programmed cell-death ligand-1 (PD-L1) expression was determined by IHC (Ventana SP-142 assay), with >1% tumor cells (TCs) or tumor-infiltrating lymphocytes (TILs) scoring positive. RESULTS AND LIMITATIONS: Pure ACB patients were younger and more often female than pure UC and pure SCC patients. UC and SCC had a significantly higher median TMB than ACB (p < 0.001). Rare CD274 (PD-L1) amplification cases were more frequently seen in SCC than in UC (5% vs 1%), and were not seen in ACB. MSI high status was very uncommon in all tumor types (0-1%). The frequencies of PD-L1 expression in both TCs and TILs was higher in UC and SCC (both 30%) than in ACB (18%). The results are limited by their retrospective nature and lack of clinical data annotation. CONCLUSIONS: Deep sequencing revealed significant differences in IO biomarkers among the three major subtypes of bladder carcinomas. UC and SCC revealed higher frequencies of PD-L1 expression and higher TMB than ACB, and SCC has the highest frequency of CD274 amplification. The presence of pure SCC features should not disqualify patients for inclusion in IO trials. PATIENT SUMMARY: Tumor samples from patients diagnosed with advanced pure adenocarcinoma of the bladder (ACB) or pure squamous-cell carcinoma (SCC) have been analyzed in terms of frequency of putative immunotherapy biomarkers. The results indicated that pure SCC of the bladder was characterized by genomic features that portend similar response possibilities to immunotherapy compared with the classical pure urothelial carcinoma. Conversely, for pure ACB there might be different therapeutic opportunities, such as targeted therapies against peculiar genomic alterations in selected patients.

Mutation of the co-chaperone Tsc1 in bladder cancer diminishes Hsp90 acetylation and reduces drug sensitivity and selectivity.

The molecular chaperone Heat shock protein 90 (Hsp90) is essential for the folding, stability, and activity of several drivers of oncogenesis. Hsp90 inhibitors are currently under clinical evaluation for cancer treatment, however their efficacy is limited by lack of biomarkers to optimize patient selection. We have recently identified the tumor suppressor tuberous sclerosis complex 1 (Tsc1) as a new co-chaperone of Hsp90 that affects Hsp90 binding to its inhibitors. Highly variable mutations of TSC1 have been previously identified in bladder cancer and correlate with sensitivity to the Hsp90 inhibitors. Here we showed loss of TSC1 leads to hypoacetylation of Hsp90-K407/K419 and subsequent decreased binding to the Hsp90 inhibitor ganetespib. Pharmacologic inhibition of histone deacetylases (HDACs) restores acetylation of Hsp90 and sensitizes Tsc1-mutant bladder cancer cells to ganetespib, resulting in apoptosis. Our findings suggest that TSC1 status may predict response to Hsp90 inhibitors in patients with bladder cancer, and co-targeting HDACs can sensitize tumors with Tsc1 mutations to Hsp90 inhibitors.

The Changing Therapeutic Landscape of Metastatic Renal Cancer.

The practising clinician treating a patient with metastatic clear cell renal cell carcinoma (CCRCC) faces a difficult task of choosing the most appropriate therapeutic regimen in a rapidly developing field with recommendations derived from clinical trials. NCCN guidelines for kidney cancer initiated a major shift in risk categorization and now include emerging treatments in the neoadjuvant setting. Updates of European Association of Urology clinical guidelines also include immune checkpoint inhibition as the first-line treatment. Randomized trials have demonstrated a survival benefit for ipilimumab and nivolumab combination in the intermediate and poor-risk group, while pembrolizumab plus axitinib combination is recommended not only for unfavorable disease but also for patients who fit the favorable risk category. Currently vascular endothelial growth factor (VEGF) targeted therapy based on tyrosine kinase inhibitors (TKI), sunitinib and pazopanib is the alternative regimen for patients who cannot tolerate immune checkpoint inhibitors (ICI). Cabozantinib remains a valid alternative option for the intermediate and high-risk group. For previously treated patients with TKI with progression, nivolumab, cabozantinib, axitinib, or the combination of ipilimumab and nivolumab appear the most plausible alternatives. For patients previously treated with ICI, any VEGF-targeted therapy, not previously used in combination with ICI therapy, seems to be a valid option, although the strength of this recommendation is weak. The indication for cytoreductive nephrectomy (CN) is also changing. Neoadjuvant systemic therapy does not add perioperative morbidity and can help identify non-responders, avoiding unnecessary surgery. However, the role of CN should be investigated under the light of new immunotherapeutic interventions. Also, markers of response to ICI need to be identified before the optimal selection of therapy could be determined for a particular patient.

Genomic Features of Metastatic Testicular Sex Cord Stromal Tumors.

BACKGROUND: Metastatic testicular sex cord stromal tumors of the testis (MSCSTs) comprise an extremely uncommon form of genitourinary malignancy. OBJECTIVE: To perform comprehensive genomic profiling (CGP) to enable the search for potential therapy targets. DESIGN, SETTING, AND PARTICIPANTS: Ten patients with testicular Leydig cell tumors (LCTs), six with Sertoli cell tumors (SCTs), and three with undifferentiated sex cord stromal tumors (USCSTs) and a comparison group of 366 patients with ovarian sex cord stromal tumors (SCSTs) underwent hybrid-capture-based CGP to evaluate all classes of genomic alterations (GAs). The tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) was determined on 114 loci. INTERVENTION: CGP on tumor samples. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Descriptive analyses and differences between histological subgroups were reported. RESULTS AND LIMITATIONS: In these patients, all of whom had metastatic disease at the time of sequencing, the primary testis tumor was sequenced in six (32%) patients and a metastatic site in 13 (68%) patients. The overall frequencies of GAs were similar in LCTs, SCTs, and USCSTs, ranging from 3.0 to 3.5 GAs/tumor. The most frequent untargetable GAs included CTNNB1 and CDKN2A/B, both ranging from 20% to 33% of cases. Targetable GAs were uncommon in all MSCST subgroups, but several tumors showed potential for cell-cycle inhibitors (CDK4 in LCTs), mTOR inhibitors (RICTOR, NF2, and PTEN in all three tumor types), hedgehog inhibitors (PTCH1 in LCTs), and poly(ADP-ribose) polymerase inhibitors (BAP1 in SCTs). No MSI-high status was identified. The TMB was also low in all MSCST groups, and tumors featuring a TMB of ≥10 mutations/Mb were not identified. GA findings from ovarian SCSTs largely recapitulated those from MSCSTs. A lack of clinical outcome correlation is a limitation of the present analyses. CONCLUSIONS: Rare cases of testicular MSCSTs have GAs linked to potential targeted therapy benefits on CGP. In contrast, the lack of MSI-high status and an overall low TMB indicate a likely lack of benefit for immunotherapies. PATIENT SUMMARY: Genomic profiling can guide clinical research and disclose therapeutic opportunities for patients with rare testicular cancers for which standard therapies are lacking.

Renal cell carcinoma and brain metastasis: Questioning the dogma of role for cytoreductive nephrectomy.

INTRODUCTION: Renal cell carcinoma (RCC) brain metastasis is generally viewed as poor prognostic features and often excludes patients from cytoreductive nephrectomy or participation in clinical trials. We aim to evaluate patients presenting with brain metastasis and their outcomes. METHODS: Surveillance Epidemiology and End Results-18 registries database was queried for all patients with metastatic RCC from 2010 to 2014. Patients with renal cancer as their only malignancy were included. Information was available for metastatic disease to bone, liver, lung, and brain. Patients were then further stratified into those with isolated brain metastases and those with additional metastasis to other sites as well. Overall survival was compared between groups using logrank analysis. RESULTS: A total of 6,667 patients were identified with metastatic RCC. Among them, 775 (12.1%) had brain metastasis at time of diagnosis. Of these patients with brain metastasis, 152 (20.4%) had isolated brain metastasis. Only 23.8% of all patients with brain metastasis underwent cytoreductive nephrectomy, compared to 40.8% of patients with isolated brain metastasis. Patients with brain and other metastasis and brain metastasis only treated by cytoreductive nephrectomy exhibited a median survival of 11 and 33 months, respectively. Those patients who did not undergo cytoreductive nephrectomy experienced a median survival of 4 and 5 months, respectively. CONCLUSION: It appears that selected patients with brain metastasis may experience durable long-term survival. This information may be beneficial for patient counseling, surgical planning, and consideration for inclusion in clinical trials.

Is pelvic lymph node dissection necessary in patients with biopsy proven Gleason 6 prostate cancer? - analysis of the SEER database.

INTRODUCTION: Since the advent of prostate-specific antigen (PSA) screening there has been a decreased incidence of lymph node positive disease (LND). Nevertheless, because of possible upgrading, LND is frequently performed with preoperative Gleason 6 prostate cancer. We utilized the Surveillance Epidemiology and End Results (SEER) database to evaluate the frequency of LND and preoperative variables for node positivity in contemporary patients with preoperative Gleason 6 disease. MATERIALS AND METHODS: SEER-18 registries database was queried for all patients diagnosed with prostate cancer between the years 2010 and 2014. Patients were excluded that had unknown histology or unknown preoperative or postoperative Gleason score. We evaluated the rate of LND, Gleason upgrading, and node positive events. RESULTS: There were 16,544 patients with preoperative Gleason 6 disease that met our inclusion criteria. Of these, 35.4% (5,856 patients) had LND and 64.6% (10,688 patients) did not. Gleason upgrade on final pathology was found in 51.9% and 45.0% of the LND and no LND cohorts, respectively. There were only 62 (1.1%) patients with node positive disease following LND. These patients had higher preoperative PSA and clinical stage disease. CONCLUSION: In a contemporary cohort of patients with preoperative Gleason 6 prostate cancer LND continues to be performed in about 35% of cases. Despite significant rate of Gleason upgrading on final pathology, only 1% will have node positive disease. With available data on morbidity of LND, the LND for preoperative Gleason 6 prostate in contemporary PSA screened cancer cohorts is likely not warranted.

Sporadic renal angiomyolipoma in a patient with Birt-Hogg-Dubé: chaperones in pathogenesis.

Birt-Hogg-Dubé (BHD) is an autosomal dominant genetic syndrome caused by germline mutations in the FLCN gene that predisposes patients to develop renal tumors. Renal angiomyolipoma (AML) is not a renal tumor sub-type associated with BHD. AML is, however, a common phenotypic manifestation of Tuberous Sclerosis Complex (TSC) syndrome caused by mutations in either the TSC1 or TSC2 tumor suppressor genes. Previous case reports of renal AML in patients with BHD have speculated on the molecular and clinical overlap of these two syndromes as a result of described involvement of the gene products in the mTOR pathway. Our recent work provided a new molecular link between these two syndromes by identifying FLCN and Tsc2 as clients of the molecular chaperone Hsp90. Folliculin interacting proteins FNIP1/2 and Tsc1 are important for FLCN and Tsc2 stability as new Hsp90 co-chaperones. Here we present a case of sporadic AML as a result of somatic Tsc1/2 loss in a patient with BHD. We further demonstrate that FNIP1 and Tsc1 are capable of compensating for each other in the chaperoning of mutated FLCN tumor suppressor. Our findings demonstrate interconnectivity and compensatory mechanisms between the BHD and TSC pathways.

Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients.

The tumor suppressors Tsc1 and Tsc2 form the tuberous sclerosis complex (TSC), a regulator of mTOR activity. Tsc1 stabilizes Tsc2; however, the precise mechanism involved remains elusive. The molecular chaperone heat-shock protein 90 (Hsp90) is an essential component of the cellular homeostatic machinery in eukaryotes. Here, we show that Tsc1 is a new co-chaperone for Hsp90 that inhibits its ATPase activity. The C-terminal domain of Tsc1 (998-1,164 aa) forms a homodimer and binds to both protomers of the Hsp90 middle domain. This ensures inhibition of both subunits of the Hsp90 dimer and prevents the activating co-chaperone Aha1 from binding the middle domain of Hsp90. Conversely, phosphorylation of Aha1-Y223 increases its affinity for Hsp90 and displaces Tsc1, thereby providing a mechanism for equilibrium between binding of these two co-chaperones to Hsp90. Our findings establish an active role for Tsc1 as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients-including Tsc2-thereby preventing their ubiquitination and proteasomal degradation.

The metastatic potential of renal tumors: Influence of histologic subtypes on definition of small renal masses, risk stratification, and future active surveillance protocols.

OBJECTIVE: The influence of histology in metastatic potential is often overlooked when discussing the management options of small renal masses (SRM), with size or growth rate often serving as the triggers for the intervention. We aim to re-examine the definition of a SRM by evaluating the metastatic potential of renal masses incorporating tumor size and histology to create metastatic risk tables. MATERIALS AND METHODS: Surveillance Epidemiology and End Results (SEER)-18 registries database was queried for all cases of clear cell, papillary, and chromophobe renal cell carcinoma (RCC) diagnosed between 2004 and 2012. There were 55,478 cases identified that included 43,783, 8,587, and 3,208 cases of clear cell, papillary, and chromophobe, respectively. Tumors were stratified using 1-cm increments to determine the metastatic potential by calculating the metastatic rate at presentation for different size intervals in histologic categories. RESULTS: For all 3 histologies, tumors measuring 5cm or less had a rate of metastatic RCC at presentation of less than 4%. The metastatic potential was highest for clear cell, followed by papillary and then chromophobe tumors. Setting a cutoff of no more than 3% for metastatic potential to be called a SRM, makes clear cell carcinoma and papillary carcinoma a SRM up to 4cm, whereas the chromophobe RCC would be considered a SRM up to 7cm. CONCLUSION: Although clinical staging and tumor size have been the key determinants in decision-making of patients with solid renal tumors, the histology-specific risks of metastatic potential are different for each mass. The definition of a SRM should be based on the metastatic potential and not on tumor size alone. This information could be helpful for counseling and managing patients with SRMs as well as for modifying active surveillance protocols.

Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors.

The molecular chaperone Hsp90 protects deregulated signaling proteins that are vital for tumor growth and survival. Tumors generally display sensitivity and selectivity toward Hsp90 inhibitors; however, the molecular mechanism underlying this phenotype remains undefined. We report that the mitotic checkpoint kinase Mps1 phosphorylates a conserved threonine residue in the amino-domain of Hsp90. This, in turn, regulates chaperone function by reducing Hsp90 ATPase activity while fostering Hsp90 association with kinase clients, including Mps1. Phosphorylation of Hsp90 is also essential for the mitotic checkpoint because it confers Mps1 stability and activity. We identified Cdc14 as the phosphatase that dephosphorylates Hsp90 and disrupts its interaction with Mps1. This causes Mps1 degradation, thus providing a mechanism for its inactivation. Finally, Hsp90 phosphorylation sensitizes cells to its inhibitors, and elevated Mps1 levels confer renal cell carcinoma selectivity to Hsp90 drugs. Mps1 expression level can potentially serve as a predictive indicator of tumor response to Hsp90 inhibitors.