Impact of birth season on second-to-fourth digit ratio, prostate volume, and prostate cancer.

PURPOSE: The second-to-fourth digit ratio (digit ratio), which is determined in utero, is associated with exposure to visible sunlight during early pregnancy and the season of birth. The digit ratio is also associated with benign prostatic hyperplasia (BPH) and prostate cancer. This suggests that BPH and prostate cancer may be related to the birth season. Therefore, this study aimed to determine whether prostate volume and prostate cancer were related to the birth season. MATERIALS AND METHODS: A total of 858 male patients with lower urinary tract symptoms were enrolled. The right digit ratio was measured, and the month of birth was surveyed. Serum prostate-specific antigen (PSA) levels were measured, and prostate volumes were measured by transrectal ultrasonography. Patients with suspected prostate cancer underwent prostate biopsy. RESULTS: The mean age, digit ratio, prostate volume, and serum PSA level of 858 patients were 61.6 years, 0.947, 36.2 mL, and 4.24 ng/mL, respectively. Age, serum PSA levels, prostate biopsy rates, and cancer detection rates did not differ significantly according to the birth season. However, compared with the summer birth group, the winter birth group had lower digit ratios (0.951±0.040 vs. 0.941±0.040; p=0.014), larger prostate volumes (33.4±14.9 mL vs. 38.2±20.7 mL; p=0.008), and more prostate cancer (5.3% vs. 11.3%; p=0.031). Multivariate analysis showed that birth season independently predicted prostate cancer. CONCLUSIONS: The relationships of birth season with prostate volume and prostate cancer may be due to differences in the amount of light exposure during early pregnancy.

Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer.

PURPOSE: On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance. PATIENTS AND METHODS: We performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days. RESULTS: A total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 (n = 6); therefore, DL1 was reexplored (n = 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics. CONCLUSIONS: The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit.

Genomic, Transcriptomic, and Proteomic Profiling of Metastatic Breast Cancer.

PURPOSE: Metastatic breast cancer (MBC) is not curable and there is a growing interest in personalized therapy options. Here we report molecular profiling of MBC focusing on molecular evolution in actionable alterations. EXPERIMENTAL DESIGN: Sixty-two patients with MBC were included. An analysis of DNA, RNA, and functional proteomics was done, and matched primary and metastatic tumors were compared when feasible. RESULTS: Targeted exome sequencing of 41 tumors identified common alterations in TP53 (21; 51%) and PIK3CA (20; 49%), as well as alterations in several emerging biomarkers such as NF1 mutations/deletions (6; 15%), PTEN mutations (4; 10%), and ARID1A mutations/deletions (6; 15%). Among 27 hormone receptor-positive patients, we identified MDM2 amplifications (3; 11%), FGFR1 amplifications (5; 19%), ATM mutations (2; 7%), and ESR1 mutations (4; 15%). In 10 patients with matched primary and metastatic tumors that underwent targeted exome sequencing, discordances in actionable alterations were common, including NF1 loss in 3 patients, loss of PIK3CA mutation in 1 patient, and acquired ESR1 mutations in 3 patients. RNA sequencing in matched samples confirmed loss of NF1 expression with genomic NF1 loss. Among 33 patients with matched primary and metastatic samples that underwent RNA profiling, 14 actionable genes were differentially expressed, including antibody-drug conjugate targets LIV-1 and B7-H3. CONCLUSIONS: Molecular profiling in MBC reveals multiple common as well as less frequent but potentially actionable alterations. Genomic and transcriptional profiling demonstrates intertumoral heterogeneity and potential evolution of actionable targets with tumor progression. Further work is needed to optimize testing and integrated analysis for treatment selection.

A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries.

Mouse models of gastroesophageal junction (GEJ) cancer strive to recapitulate the intratumoral heterogeneity and cellular crosstalk within patient tumors to improve clinical translation. GEJ cancers remain a therapeutic challenge due to the lack of a reliable mouse model for preclinical drug testing. In this study, a novel patient-derived orthotopic xenograft (PDOX) was established from GEJ cancer via transabdominal surgical implantation. Patient tumor was compared to subcutaneously implanted patient-derived tumor xenograft (PDX) and PDOX by Hematoxylin and Eosin staining, immunohistochemistry and next-generation sequencing. Treatment efficacy studies of radiotherapy were performed. We observed that mechanical abrasion of mouse GEJ prior to surgical implantation of a patient-derived tumor in situ promotes tumor engraftment (100%, n=6). Complete PDOX engraftment was observed with rapid intra- and extraluminal tumor growth, as evidenced by magnetic resonance imaging. PDOXs contain fibroblasts, tumor-associated macrophages, immune and inflammatory cells, vascular and lymphatic vessels. Stromal hallmarks of aggressive GEJ cancers are recapitulated in a GEJ PDOX mouse model. PDOXs demonstrate tumor invasion into vasculature and perineural space. Next-generation sequencing revealed loss of heterozygosity with very high allelic frequency in NOTCH3, TGFB1, EZH2 and KMT2C in the patient tumor, the subcutaneous PDX and the PDOX. Immunohistochemical analysis of Her2/neu (also known as ERBB2), p53 (also known as TP53) and p16 (also known as CDKN2A) in PDX and PDOX revealed maintenance of expression of proteins found in patient tumors, but membranous EGFR overexpression in patient tumor cells was absent in both xenografts. Targeted radiotherapy in this model suggested a decrease in size by 61% according to Response Evaluation Criteria in Solid Tumors (RECIST), indicating a partial response to radiation therapy. Our GEJ PDOX model exhibits remarkable fidelity to human disease and captures the precise tissue microenvironment present within the local GEJ architecture, providing a novel tool for translating findings from studies on human GEJ cancer. This model can be applied to study metastatic progression and to develop novel therapeutic approaches for the treatment of GEJ cancer.This article has an associated First Person interview with the first author of the paper.

Sonographic findings of mass-forming extramammary Paget's disease in the scrotum.

Extramammary Paget's disease (EMPD) is a rare cutaneous malignancy involving the scrotum and may be confused with other scrotal malignancy. We describe the sonographic findings of an extremely rare case of mass-forming EMPD of the scrotal wall. Ultrasonography, which shows mild heterogeneous hyperechoic masses with a stalk connected to the dermis, can help predict the depth of vertical invasion of the lesion. The lesion extent should be precisely evaluated because the presence of dermal invasion of EMPD is the risk factor in distant metastasis and is known to result in a worse prognosis. Ultrasonography is a primary imaging modality to evaluate the extent and vertical invasion of EMPD. Surgical local wide excision is the treatment of choice for EMPD and histopathology confirmed the diagnosis.

Adaptive responses in a PARP inhibitor window of opportunity trial illustrate limited functional interlesional heterogeneity and potential combination therapy options.

Poly (ADP-ribose) polymerase inhibitor (PARPi)-based combination therapies are demonstrating efficacy in patients, however, identifying the right combination for the right patient remains a critical challenge. Thus, it is urgent to develop approaches able to identify patients likely to benefit from specific combination therapies. Several groups, including ours, have demonstrated that targeting adaptive responses induced by PARPi increases depth and duration of response. In this study, we instituted a talazoparib (PARPi) monotherapy window of opportunity trial to identify informative adaptive responses in high grade serous ovarian cancer patients (HGSOC). Patients were treated for 7 to 14 days with PARPi monotherapy prior to surgery with tissue samples from multiple sites being collected pre- and post-treatment in each patient. Analysis of these samples demonstrated that individual patients displayed different adaptive responses with limited interlesional heterogeneity. Ability of combination therapies designed to interdict adaptive responses to decrease viability was validated using model systems. Thus, assessment of adaptive responses to PARPi provides an opportunity for patient-specific selection of combination therapies designed to interdict patient-specific adaptive responses to maximize patient benefit.

Hybrid oncocytic/chromophobe renal tumors are molecularly distinct from oncocytoma and chromophobe renal cell carcinoma.

Hybrid oncocytic/chromophobe tumor (HOCT) of the kidney represents a poorly understood clinicopathologic entity with pathologic features that overlap between benign renal oncocytoma (RO) and malignant chromophobe renal cell carcinoma (ChRCC). Consequently, characterization of HOCT and its separation from the foregoing entities are clinically important. The aim of this study was to describe the pathologic and molecular features of HOCT and to compare them with those of RO and ChRCC. We retrospectively identified a cohort of 73 cases with renal oncocytic tumors (19 RO, 27 HOCT, and 27 ChRCC) for whom clinical follow-up data were available by 2 tertiary care hospitals. All cases were sporadic except for 2 HOCTs that were associated with Birt-Hogg-Dubé syndrome. Lesional tissues were retrieved for molecular analysis. We performed targeted gene sequencing of all exons of 261 cancer related genes on a subset of HOCT samples (n = 16). Gene expression profiling of a customized codeset was conducted on 19 RO, 24 HOCT, and 27 ChRCC samples. Clinicopathologic characteristics as well as DNA copy number alterations, mutational and transcriptional features of HOCT derived from sequencing and expression profiling data are described and compared to those in RO and ChRCC. HOCTs were more frequently multifocal and did not exhibit mutations in genes that are recurrently mutated in RO or ChRCC but showed copy number alterations primarily involving losses in chromosomes 1 and X/Y. The mRNA transcript data show that HOCT can be separated from RO and ChRCC. Hence, HOCT appears to represent a distinct renal tumor entity with genomic features that are intermediate between those of RO and ChRCC.

Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy.

We demonstrate that concurrent administration of poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors is effective in inhibiting tumor growth but poorly tolerated. Concurrent treatment with PARP and WEE1 inhibitors induces replication stress, DNA damage, and abrogates the G2 DNA damage checkpoint in both normal and malignant cells. Following cessation of monotherapy with PARP or WEE1 inhibitors, effects of these inhibitors persist suggesting that sequential administration of PARP and WEE1 inhibitors could maintain efficacy while ameliorating toxicity. Strikingly, while sequential administration mirrored concurrent therapy in cancer cells that have high basal replication stress, low basal replication stress in normal cells protected them from DNA damage and toxicity, thus improving tolerability while preserving efficacy in ovarian cancer xenograft and patient-derived xenograft models.

Integrated transcriptomic-genomic tool Texomer profiles cancer tissues.

Profiling of both the genome and the transcriptome promises a comprehensive, functional readout of a tissue sample, yet analytical approaches are required to translate the increased data dimensionality, heterogeneity and complexity into patient benefits. We developed a statistical approach called Texomer ( https://github.com/KChen-lab/Texomer ) that performs allele-specific, tumor-deconvoluted transcriptome-exome integration of autologous bulk whole-exome and transcriptome sequencing data. Texomer results in substantially improved accuracy in sample categorization and functional variant prioritization.

Use of Targeted Next-Generation Sequencing to Identify Activating Hot Spot Mutations in Cherry Angiomas.

Importance: Shared gene variants in benign-malignant process pairs, such as BRAF mutations common to benign nevi and melanoma, are associated with differing phenotypic manifestations. Study of gene mechanisms underlying cherry angioma may uncover previously unknown disease relationships. Objective: To identify somatic mutations present in cherry angioma specimens by using targeted next-generation sequencing. Design, Setting, and Participants: In a single-center case series, 10 formalin-fixed, paraffin-embedded cherry angioma specimens from biopsies performed at Massachusetts General Hospital in Boston from July 10, 2016, to January 23, 2018, were obtained and underwent sequencing across a panel of 323 genes most relevant to cancer. Somatic mutations were curated by excluding variants that were presumed to be germline or of low mapping quality. Main Outcomes and Measures: Identification of somatic mutations associated with cherry angiomas. Results: In 10 cherry angioma tissue samples originating from 6 female and 4 male patients with a median (range) age of 54 (26-79) years, 5 samples (50%) revealed somatic missense mutations in GNAQ (Q209H, Q209R, and R183G) and GNA11 (Q209H). Individually, these mutational hot spots are known to be involved in entities that include congenital and anastomosing hemangiomas, hepatic small-vessel neoplasms (Q209), port-wine stains, and Sturge-Weber syndrome (R183). Both hot spots are associated with blue nevi, melanoma associated with blue nevus, and uveal melanoma. Conclusions and Relevance: In this case series study, the high prevalence of 5 known genetic drivers within the benign cherry angioma entity appears to support the context-dependent role of gene alterations in both benign and malignant proliferations from various cellular origins.

The Efficacy of Early Extracorporeal Shockwave Lithotripsy for the Treatment of Ureteral Stones.

PURPOSE: To determine the efficacy of early extracorporeal shockwave lithotripsy (e-ESWL) in colic patients with ureteral stones and the patient criteria for the most effective e-ESWL. MATERIALS AND METHODS: 335 patients who received ESWL due to ureteral stone, were divide in two groups: e-ESWL and d-ESWL by the critical cut-off point. we performed the sensitivity and specificity cut-off analyses to identified the critical cut off point. To assess the difference in the factors affecting ESWL success, univariate and multivariate logistic analyses were implemented with using variables: ESWL success; age; gender; BMI; comor-bidity; serum creatinine; stone size; stone location; stone laterality; Hounsfield unit (HU); presence of hydrone-phrosis; and presence of tissue rim. The subgroup analysis for the screened variables was conducted. RESULT: Optimal e-ESWL was defined to occur within a 24-hour critical cut-off time. Multivariate regression anal-ysis concluded with screened variables: age, stone size, stone location, and HU, that ESWL success was 1.85-fold higher in the e-ESWL patient group. The subgroup analyses the following conditions: ? 65 years old by 1.784- fold; ?10 mm stone size by 1.866-fold; mid to distal stone location by 2.234-fold; and ? 815 HU by 2.130-fold. When all the conditions were met, the e-ESWL success was 3.22-fold higher. CONCLUSION: In case of colic due to ureteral stones, the patient is recommended to receive a lithotripsy within the first 24 hours. E-ESWL is recommended especially in patients who are ? 65 years, or with a ureteral stone HU ? 815, sized ? 10 mm, or in a mid to distal location.

Urology as rehabilitation medicine: a literature review.

As a urologist, we usually encounter with two representative functional behaviors, namely, voiding and sexual function. These are not only important but also complex and synchronized so if these functions are impaired, patients need active functional rehabilitation to recover. These functional impairments should be recognized and corrected early because they could not only cause direct damage to the affected functions but also have harmful consecutive consequences such as kidney damage due to voiding abnormality and self-esteem damage due to decreased sexual function. Numerous rehabilitative methods are currently available, which help minimize the negative effects of these functional impairments. In terms of voiding function, pelvic floor muscle exercise, biofeedback, functional magnetic stimulation, neuromodulation, and clean intermittent self-catheterization are representative rehabilitation modalities. In case of children, extra-attention should be paid because this might affect their entire life. In impairment of sexual function, early intervention to maintain male erection is the main target of rehabilitation to prevent corporal fibrosis and penile deformity and increase recovery chance in patients who underwent radical prostatectomy or major surgery. In this review, we will elucidate various rehabilitation methods in urology to further increase our understanding of the rehabilitative characteristics of urology and widen our view of rehabilitation medicine.

Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer.

PURPOSE: We sought to determine the significant genomic alterations in patients with metastatic breast cancer (MBC), and survival outcomes in common genotypes. PATIENTS AND METHODS: High-depth next generation sequencing was performed for 202 genes in tumor and normal DNA from 257 patients with MBC, including 165 patients with ER/PR+ HER2- (hormone receptor positive, HR+ positive), 32 patients with HER2+ and 60 patients with triple negative (ER/PR/HER2-) cancer. Kaplan Meier survival analysis was performed in our discovery set, in breast cancer patients analyzed in The Cancer Genome Atlas, and in a separate cohort of 98 patients with MBC who underwent clinical genomic testing. RESULTS: Significantly mutated genes (SMGs) varied by histology and tumor subtype, but TP53 was a SMG in all three subtypes. The most SMGs in HR+ patients included PIK3CA (32%), TP53 (29%), GATA3 (15%), CDH1 (8%), MAP3K1 (8%), PTEN (5%), TGFBR2 (4%), AKT1 (4%), and MAP2K4 (4%). TP53 mutations were associated with shorter recurrence-free survival (P=0.004), progression-free survival (P=0.00057) and overall survival (P=0.003). Further, TP53 status was prognostic among HR+ patients with PIK3CA mutations. TP53 mutations were also associated with poorer overall survival in the 442 HR+ breast cancer patients in the TCGA (P=0.042) and in an independent set of 96 HR+ MBC who underwent clinical sequencing (P=0.0004). CONCLUSIONS: SMGs differ by tumor subtype but TP53 is significantly mutated in all three breast cancer subtypes. TP53 mutations are associated with poor prognosis in HR+ breast cancer. TP53 mutations should be considered in the design and interpretation of precision oncology trials.

Cancer driver mutation prediction through Bayesian integration of multi-omic data.

Identification of cancer driver mutations is critical for advancing cancer research and personalized medicine. Due to inter-tumor genetic heterogeneity, many driver mutations occur at low frequencies, which make it challenging to distinguish them from passenger mutations. Here, we show that a novel Bayesian hierarchical modeling approach, named rDriver can achieve enhanced prediction accuracy by identifying mutations that not only have high functional impact scores but also are associated with systemic variation in gene expression levels. In examining 3,080 tumor samples from 8 cancer types in The Cancer Genome Atlas, rDriver predicted 1,389 driver mutations. Compared with existing tools, rDriver identified more low frequency mutations associated with lineage specific functional properties, timing of occurrence and patient survival. Evaluation of rDriver predictions using engineered cell-line models resulted in a positive predictive value of 0.94 in PIK3CA genes. Our study highlights the importance of integrating multi-omic data in predicting cancer driver mutations and provides a statistically rigorous solution for cancer target discovery and development.

Pathogenic Germline Variants in 10,389 Adult Cancers.

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

Intralymphatic Immunotherapy With Autologous Semen in a Korean Man With Post-Orgasmic Illness Syndrome.

Post-orgasmic illness syndrome (POIS) is a very rare disease characterized by local allergic symptoms and transient flu-like illness that nearly always occur after masturbation, coitus, or spontaneous ejaculation and last for 2 to 7 days. In a previous case report, 2 patients with POIS received hyposensitization therapy composed of multiple subcutaneous injections of autologous semen that resulted in a gradual decrease of symptoms. However, this procedure requires patients to endure pain and discomfort during frequent subcutaneous injections and preceding masturbations to obtain the autologous semen used for therapy. Recent studies have suggested that intralymphatic immunotherapy is a promising new method of allergen-specific immunotherapy against allergic diseases, showing a faster onset and longer duration of therapeutic effects after only several intralymphatic injections. We report on a case of a Korean man with POIS who received intralymphatic immunotherapy that alleviated POIS-related symptoms and in whom the existence of semen-specific immunoglobulin E was confirmed using immunoglobulin E immunoblotting and enzyme-linked immunosorbent assay. Kim TB, Shim YS, Lee, SM, et al. Intralymphatic Immunotherapy With Autologous Semen in a Korean Man With Post-Orgasmic Illness Syndrome. Sex Med 2018;6:174-179.

The Association of A Number of Risk Factors With Depression in Patients With Prostate Cancer Undergoing Androgen Deprivation Therapy.

PURPOSE: To identify factors affecting depressive symptoms in patients undergoing androgen-deprivation therapy (ADT) to treat prostate cancer. MATERIALS AND METHODS: The patients with prostate cancer visiting the psychiatry department without referral because of depressive symptoms while undergoing ADT participated. To assess depressive symptoms, the Beck Depression Inventory (BDI) was used. To identify the risk factors affecting depressive symptoms, univariate regression and multiple linear regression analyses were implemented. RESULTS: The mean (± SD) age, age when initiating ADT, duration of ADT, serum testosterone level and BDI scores of participants (n = 45) were 73.9 ± 7.9 years, 72 ± 8.5 years, 33 ± 31.6 months, 214.9 ± 219.5 ng/dL and 18 ± 13.5 points. The androgen dependent and independent were 26 and 9 patients. Eight of these androgen-independent patients underwent concurrent chemotherapy. Twenty-one patients were treated with bicalutamide and 24 with leuprolide. Of the clinical variables affecting BDI scores, the type of ADT drug (P < 0.001), serum testosterone level (P = 0.003), and age at diagnosis (P < 0.001) were significant. CONCLUSION: Efforts to diagnose and treat depression appropriately, especially if depressive symptoms change in patients undergoing ADT to treat prostate cancer who are using an LHRH agonist (leuprolide), have low testosteronelevel, or are older at the age when initiating ADT.

Enucleated Weight/Enucleation Time, Is It Appropriate for Estimating Enucleation Skills for Holmium Laser Enucleation of the Prostate? A Consideration of Energy Consumption.

PURPOSE: To date, the parameters for evaluating enucleation efficiency have only considered enucleation time, although operators simultaneously consume both time and energy during holmium laser enucleation of the prostate. This study was undertaken to find a better way of assessing enucleation skills, considering both enucleation time and consumed energy. MATERIALS AND METHODS: One hundred (n=100) consecutive patients who underwent holmium laser enucleation of the prostate from April 2012 to April 2014 by a single surgeon were enrolled. Ten groups of 10 consecutive cases were used to analyze the parameters of enucleation efficiency. RESULTS: The mean enucleation time, consumed energy, and enucleated weight were 41.3±19.2 minutes, 66.2±36.0 kJ, and 26.6±21.8 g, respectively. Concerning learning curves, like enucleation time-efficacy (=enucleated weight/enucleation time), enucleation energy-efficacy (=enucleated weight/consumed energy) also had an increasing tendency. Enucleation ratio efficacy (=enucleated weight/transitional zone volume/enucleation time) plateaued after 30 cases. However, enucleation time-energy-efficacy (=enucleated weight/enucleation time/consumed energy) continued to increase after 30 cases and plateaued at 61 to 70 cases. Furthermore, one-way analysis of variance showed that group means for enucleation time-energy-efficacy (F=3.560, p=0.001) were significantly different, but that those of enucleation ratio efficacy (F=1.931, p=0.057) were not. CONCLUSIONS: When both time and energy were considered, enucleation skills continued to improve even after 30 cases and plateaued at 61 to 70 cases. Therefore, we propose that enucleation time-energy-efficacy should be used as a more appropriate parameter than enucleation ratio efficacy for evaluating enucleation skills.

Larger Testicular Volume Is Independently Associated with Favorable Indices of Lung Function.

BACKGROUND: Men with chronic obstructive pulmonary disease, have reduced endogenous testosterone levels, but the relationship between pulmonary function and endogenous testosterone levels, is inconsistent. Testicular volume is a known indicator of endogenous testosterone levels, male fertility, and male potency. In the present study, the authors investigated the relationship, between testicular volume and lung function. METHODS: One hundred and eighty-one South Korean men age 40-70, hospitalized for urological surgery, were retrospectively enrolled, irrespective of the presence of respiratory disease. Study subjects underwent pulmonary function testing, prior to procedures, and testicular volumes were measured by orchidometry. Testosterone levels of patients in blood samples collected between 7 AM and 11 AM, were measured by a direct chemiluminescent immunoassay. RESULTS: The 181 study subjects were divided into two groups, by testicular volume (≥35 mL vs. <35 mL), the larger testes group, had better lung functions (forced vital capacity [FVC]: 3.87±0.65 L vs. 3.66±0.65 L, p=0.037; forced expiratory volume in 1 second [FEV1]: 2.92±0.57 L vs. 2.65±0.61 L, p=0.002; FVC % predicted: 98.2±15.2% vs. 93.8±13.1%, p=0.040; FEV1 % predicted: 105.4±19.5% vs. 95.9±21.2%, p=0.002). In addition, the proportion of patients with a FEV1/FVC of <70%, was lower in the larger testes group. Univariate analysis conducted using linear regression models, revealed that testicular volume was correlated with FVC (r=0.162, p=0.029), FEV1 (r=0.218, p=0.003), FEV1/FVC (r=0.149, p=0.046), and FEV1 % predicted (r=0.178, p=0.017), and multivariate analysis using linear regression models, revealed that testicular volume was a significant predictive factor for FEV1 % predicted (ß=0.159, p=0.041). CONCLUSION: Larger testicular volume was independently associated, with favorable indices of lung function. These results suggest that androgens, may contribute to better lung function.

Sarcomatoid Renal Cell Carcinoma Has a Distinct Molecular Pathogenesis, Driver Mutation Profile, and Transcriptional Landscape.

Purpose: Sarcomatoid renal cell carcinoma (SRCC) ranks among the most aggressive clinicopathologic phenotypes of RCC. However, the paucity of high-quality, genome-wide molecular examinations of SRCC has hindered our understanding of this entity.Experimental Design: We interrogated the mutational, copy number, and transcriptional characteristics of SRCC and compared these data with those of nonsarcomatoid RCC (RCC). We evaluated whole-exome sequencing, single-nucleotide polymorphism, and RNA sequencing data from patients with SRCC (n = 65) and RCC (n = 598) across different parent RCC subtypes, including clear-cell RCC, papillary RCC, and chromophobe RCC subtypes.Results: SRCC was molecularly discrete from RCC and clustered according to its parent RCC subtype, though with upregulation of TGFß signaling across all subtypes. The epithelioid (E-) and spindled (S-) histologic components of SRCC did not show differences in mutational load among cancer-related genes despite a higher mutational burden in S-. Notably, sarcomatoid clear-cell RCC (SccRCC) showed significantly fewer deletions at 3p21-25, a lower rate of two-hit loss for VHL and PBRM1, and more mutations in PTEN, TP53, and RELN compared with ccRCC. A two-hit loss involving VHL predicted for ccRCC and a better prognosis, whereas mutations in PTEN, TP53, or RELN predicted for SccRCC and worse prognosis.Conclusions: SRCC segregates by parent subtype, and SccRCC has a fundamentally different early molecular pathogenesis, usually lacking the classic 3p21-25 deletion and showing distinctive mutational and transcriptional profiles. These features prompt a more precise molecular classification of RCC, with diagnostic, prognostic, and therapeutic implications. Clin Cancer Res; 23(21); 6686-96. ©2017 AACRSee related commentary by Bergerot et al., p. 6381.