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Supplementary Figure 2 from Loss of ΔNp63α Promotes Invasion of Urothelial Carcinomas via N-Cadherin/Src Homology and Collagen/Extracellular Signal-Regulated Kinase Pathway

p63 plays a critical role in normal development and maintenance of stratified epithelia, including the urothelium. In the normal urothelium, urothelial cells in the basal layers abundantly express the predominant p63 isoform ΔNp63α. We previously showed that (a) ΔNp63α expression at the similar level to the normal urothelium is retained in most low-grade papillary noninvasive (LPN) tumors, whereas frequently lost in high-grade invasive carcinomas, and that (b) loss of ΔNp63α is associated with poor prognosis of invasive bladder urothelial carcinoma patients. However, a functional role of ΔNp63α in progression of urothelial carcinomas remains to be elucidated. Here, we show that loss of ΔNp63α expression promotes invasion of urothelial carcinoma cells. In 5637 cells substantially expressing only ΔNp63α isoform at the protein level, knockdown of endogenous p63 upregulated N-cadherin, which recruited more Src homology and collagen to N-cadherin and activated extracellular signal-regulated kinase (ERK) signaling, and consequently potentiated cell motility, excretion of matrix metalloproteinase-9, and invasion. In T24 cells originally lacking endogenous ΔNp63α expression, exogenous expression of ΔNp63α attenuated invasion by downregulating N-cadherin expression and ERK activity, confirming an invasion-suppressive role of ΔNp63α in urothelial carcinoma cells. We further documented loss of ΔNp63 expression accompanied by N-cadherin upregulation during muscle-invasive recurrence in patients whose bladder cancer had progressed from LPN tumors to muscle-invasive disease. These results suggest that loss of ΔNp63α and subsequent upregulation of N-cadherin is one of the mechanisms underlying progression of bladder cancer. [Cancer Res 2009;69(24):9263–70]

Supplementary Figure 1 from Loss of ΔNp63α Promotes Invasion of Urothelial Carcinomas via N-Cadherin/Src Homology and Collagen/Extracellular Signal-Regulated Kinase Pathway

Objectives To investigate the outcomes and feasibilities of gasless laparoendoscopic single-port clampless sutureless partial nephrectomy. Methods We reviewed 356 consecutive patients with primary unilateral non-metastatic renal masses who underwent gasless laparoendoscopic single-port partial nephrectomy (2011-2018), which was performed retroperitoneally using a three-dimensional flexible endoscope, without vascular clamping or renorrhaphy in principle. Results The median tumor size was 2.5 cm, and 213 (60%), 105 (29%), and 38 (11%) patients had peripheral, central, and hilar tumors, respectively. Clampless and sutureless partial nephrectomy was accomplished in 337 patients (95%), while eight (2%) and 16 (4%) patients required vascular clamping and renorrhaphy, respectively. The median operative time and blood loss were 220 min and 266 mL, respectively; eight patients (2%) received blood transfusion. Clavien-Dindo grade 3a complications occurred in 27 patients (8%); all these patients had urinary leakage treated with ureteral stent placement, one of whom also developed a postoperative pseudoaneurysm. Among 324 patients diagnosed with renal cell carcinoma, six (2%) had positive surgical margins, and one (0.3%) and seven (2%) developed metastatic and local recurrences, respectively. During a median follow-up of 54 months, no patient died from kidney cancer. The median percent decrease in estimated glomerular filtration rate at 3 months after surgery was 5.7%. No patient experienced postoperative acute renal failure, while one patient with preexisting renal impairment started dialysis at 70 months after surgery. Conclusions Clampless and sutureless partial nephrectomy can be safely accomplished in most patients undergoing gasless laparoendoscopic single-port surgery, yielding favorable oncological and functional outcomes.

Objectives To evaluate the oncological and functional outcomes associated with selective tetramodal bladder-sparing therapy, comprising maximal transurethral resection of bladder tumour (TURBT), induction chemoradiotherapy (CRT), and consolidative partial cystectomy (PC) with pelvic lymph node dissection (PLND). Materials and methods In the present study, 154 patients with non-metastatic muscle-invasive bladder cancer (MIBC), prospectively enrolled in the tetramodal bladder-preservation protocol, were analysed. After TURBT and induction CRT, patients showing complete remission were offered consolidative PC with PLND for the achievement of bladder preservation. Pathological response to induction CRT was evaluated using PC specimens. Oncological and functional outcomes after bladder preservation were evaluated using the following endpoints: MIBC-recurrence-free survival (RFS); cancer-specific survival (CSS); overall survival (OS), and cross-sectional assessments of preserved bladder function and quality of life (QoL) including uroflowmetry, bladder diary, International Prostate Symptom Score, Overactive Bladder Symptom Score and the 36-item Short-Form Health Survey (SF-36) score. Results The median follow-up period was 48 months. Complete MIBC remission was achieved in 121 patients (79%) after CRT, and 107 patients (69%) completed the tetramodal bladder-preservation protocol comprising consolidative PC with PLND. Pathological examination in these 107 patients revealed residual invasive cancer (≥pT1) that was surgically removed in 11 patients (10%) and lymph node metastases in two patients (2%). The 5-year MIBC-RFS, CSS and OS rates in the 107 patients who completed the protocol were 97%, 93% and 91%, respectively. As for preserved bladder function, the median maximum voided volume, post-void residual urine volume, and nighttime frequency were 350 mL, 25 mL, and two voids, respectively. In the SF-36, patients had favourable scores, equivalent to the age-matched references in all the QoL scales. Conclusion Selective tetramodal bladder-preservation therapy, incorporating consolidative PC with PLND, yielded favourable oncological and functional outcomes in patients with MIBC. Consolidative PC may have contributed to the low rate of MIBC recurrence in patients treated according to this protocol.

To evaluate the significance of the presence or absence of an “inchworm sign” on DWI for the recurrence and progression of T1 bladder cancer. We retrospectively analyzed 91 patients with pT1 urothelial carcinoma who underwent DWI prior to transurethral resection between 2007 and 2016. DWI of the dominant tumors was scrutinized for inchworm signs at b = 1000 s/mm2. The association of the presence of the inchworm sign with progression and recurrence was analyzed; progression was defined as recurrence to stage T2 or higher and/or N+, and/or M1. An inchworm sign was seen in 65 cases (71%), while it was absent in 26 cases. Among the 65, 25 (38%) had confirmed tumor recurrence, while in the remaining 26, 14 (54%) had confirmed recurrence (median time post TURB = 7.9 and 10.1 months for each). At the time of recurrence, the tumor had progressed in one (2%) inchworm-sign-positive and seven (27%) inchworm-sign-negative cases. The progression rate of inchworm-sign-negative cases was significantly higher than that of inchworm-sign-positive cases (hazard ratio = 17.2, p = 0.0017), whereas there was no significant difference in the recurrence rate between two groups. The absence of an inchworm sign and histological grade 3 were independent risk factors for progression (p

OBJECTIVES To evaluate the incidence of perioperative infections without antimicrobial prophylaxis in patients undergoing clean surgeries for adrenal and renal tumors. METHODS We prospectively enrolled 1362 consecutive patients who underwent minimally invasive adrenalectomy (n = 303), radical nephrectomy (n = 499), and partial nephrectomy (n = 560) using the gasless laparoendoscopic single-port surgery technique between 2005 and 2019. In 1059 patients, antimicrobial prophylaxis was not administered. The remaining 303 patients were considered at high risk for infection and received single-dose antimicrobial prophylaxis. The endpoint was the incidence of perioperative infections within 1 month from the surgery date. Perioperative infections were classified into surgical site infections, urinary tract infections, and remote infections. RESULTS Seventy-four patients whose collecting systems were opened during partial nephrectomy were excluded, and the remaining 1013 patients with nonuse of antimicrobial prophylaxis and 275 patients with single-dose antimicrobial prophylaxis were retrospectively analyzed. The incidence of superficial surgical site infections, deep/organ-space surgical site infections, urinary tract infections, and remote infections was 1.6%, 0.7%, 2.8%, and 1.3%, respectively, in patients with nonuse of antimicrobial prophylaxis and 0.4%, 1.8%, 1.5%, and 1.5%, respectively, in patients with single-dose antimicrobial prophylaxis. All patients who developed perioperative infections were successfully treated. No clinical or surgical variables were significantly associated with the incidence of surgical site infections. One limitation of the present study was its nonrandomized and noncontrolled design. CONCLUSIONS In minimally invasive clean surgeries for adrenal and renal tumors, antimicrobial prophylaxis is not necessary when individual risk of infection is considered low.

PURPOSE To examine medium-term outcomes of hemi-gland low-dose-rate brachytherapy as a primary treatment for intermediate-risk prostate cancer. METHODS We recruited intermediate-risk unilateral prostate cancer patients for a prospective trial of hemi-gland brachytherapy. Twenty-four patients underwent hemi-gland iodine-125 seed implantation with a prescribed dose of 160 Gy. Serum prostate-specific antigen (PSA) was measured regularly and follow-up biopsy was scheduled after 2–3 years of treatment. When clinically needed afterward, for-cause biopsy was performed to confirm pathology. Treatment failure (TF)-free survival, which was defined as freedom from radical or systemic therapy, metastases, and cancer-specific mortality, was assessed, as was biochemical failure (BF)-free survival. Urinary and sexual functions were also evaluated. RESULTS Median follow-up duration was 61 months. Twenty-two patients (92%) exhibited a declining trend or decreased value of PSA for 12 months or longer after the treatment. Follow-up biopsy in the initial triennium and for-cause biopsy in the subsequent triennium were performed in 16 and four patients, respectively, and cancer was found from the treated lobe in one patient (4% of the cohort) and significant cancer was found from untreated lobes in four patients (17%) in total. Secondary treatments were performed in six patients successfully. Five-year freedom from BF, TF, and metastasis was 71%, 90%, and 100%, respectively. The International Prostate Symptom Score significantly deteriorated at 3 months and reversed itself afterward. The International Index of Erectile Function 5 had no significant decrease. CONCLUSIONS Hemi-gland low-dose-rate brachytherapy provides favorable medium-term oncological outcomes with genito-urinary functional preservation for men with intermediate-risk unilateral prostate cancer.

To report experience with focal brachytherapy (FB) and compare its clinical outcomes with those of radical prostatectomy (RP) in localized prostate cancer.Fifty-one patients with low- to intermediate-risk prostate cancer underwent low-dose-rate FB. Survival rates free from biochemical failure (BF), additional treatment (AT) including re-FB, and whole-gland or systemic salvage therapy (ST) were calculated and oncological risk factors were investigated. Patient-reported outcomes on genitourinary function were also assessed. Using propensity scoring, 51 pair-matched RP patients were selected. Oncological control, urinary continence, and ejaculation status after FB and RP were compared.During a median 5.7-year follow-up, BF, AT, and ST occurred in 12 (24%), 10 (20%), and 4 FB patients (8%), respectively. 6 of 10 AT patients were managed with re-FB alone. In the RP cohort, 3 patients (6%) underwent ST. 5-year BF-free survival rate after FB was 79%. Compared to 5-year ST-free survival rate of 94% after RP, ST-free and AT-free survival rates after FB were 93% (P = 0.813) and 87% (P = 0.049), respectively. Multivariate analyses of FB-treated patients showed that time to PSA nadir was negatively associated with BF and AT (hazard ratio 0.84 and 0.83, respectively, P0.001 for each). The difference in oncological outcomes between low- and intermediate-risk categories was not significant. At 2 years after FB and RP, pad-free continence rates were 100% and 81%, respectively (P = 0.001). Ejaculation was preserved in 67% and 0% of patients who had been capable of ejaculation at baseline, respectively (P0.001).In low- to intermediate-risk prostate cancer, FB-treated patients achieved superior genitourinary function compared to pair-matched RP patients. The need for ST was not substantially different between the 2 treatment cohorts. Over half of patients requiring AT could be managed by re-focal treatment rather than whole-gland ST. Early PSA nadir may predict poor oncological control after FB.

Objective To estimate postoperative residual renal function after radical nephroureterectomy for upper tract urothelial carcinoma using the preoperative dynamic computed tomography renal cortex enhancement ratio in comparison with the split kidney glomerular filtration rate measured by 99m Tc-diethylenetriaminopentacetic acid renography. Methods A total of 47 patients who received radical nephroureterectomy and underwent both preoperative dynamic computed tomography and renography were the model-development cohort; and 109 patients who underwent dynamic computed tomography alone were the validation cohort. Postoperative renal function of the unremoved kidney was estimated using the following formulas: preoperative estimated glomerular filtration rate × the percentage of total renal cortex radiodensity for the intact kidney in Hounsfield units obtained from corticomedullary phase images in the computed tomography-based model, or the percentage of the total glomerular filtration rate measured by renography in the nuclear model. The correlation between observed and estimated postoperative renal function was determined. The computed tomography-based prediction model derived from linear regression analysis was validated externally. Results The correlation of computed tomography-based split renal function with the observed postoperative estimated glomerular filtration rate (r = 0.80) was equivalent to that of nuclear split renal function (r = 0.78). In the validation cohort, the computed tomography-based prediction model showed an equivalently strong correlation (r = 0.78). Conclusions The present study showed that the percentage of total renal cortex radiodensity for the intact kidney is a useful tool for predicting unremoved kidney function in upper tract urothelial carcinoma patients, thereby allowing appropriate patient selection for perioperative cisplatin-based combination chemotherapy.

Objectives To evaluate the incidence and predictors of acute kidney injury after clampless partial nephrectomy, and its impact on intermediate-term renal function. Methods The incidence and severity of acute kidney injury were assessed for 262 patients undergoing clampless partial nephrectomy between 2010 and 2015. The association between perioperative covariates and acute kidney injury was evaluated using multivariate logistic regression analysis. An annual change in estimated glomerular filtration rate from 1 year after surgery was calculated according to the presence or absence of acute kidney injury. An impact of acute kidney injury on postoperative renal impairment, defined as a ≥25% estimated glomerular filtration rate decrease, was evaluated. Results Overall, 21 (8.0%) patients experienced grade 1 acute kidney injury after clampless partial nephrectomy, and grade ≥2 acute kidney injury was not observed. High tumor complexity was the only independent predictor of acute kidney injury. Estimated glomerular filtration rate in patients with acute kidney injury improved within 1 year, and annual estimated glomerular filtration rate changes were similar among patients with or without acute kidney injury. Ultimately, 13 (5.0%) patients showed postoperative renal impairment during the median follow-up period of 37 months. Advanced age and diabetes mellitus were independent risk factors for renal impairment, but acute kidney injury was not. Conclusions The incidence and severity of acute kidney injury after clampless partial nephrectomy are low. Low-grade acute kidney injury after clampless partial nephrectomy does not seem to affect intermediate-term renal function.

Objective Eplerenone (EPL) is a mineralo-corticoid receptor antagonist that is highly selective and has few side effects. This study was conducted to examine whether or not EPL treatment was able to reverse glomerular hyperfiltration, as an indicator of aldosterone renal action, in primary aldosteronism (PA) patients. Methods Changes in the estimated glomerular filtration rate (ΔGFR) were examined in 102 PA patients with EPL treatment. Furthermore, the sequential ΔGFR in 40 patients initially treated with EPL followed by adrenalectomy was examined in order to evaluate the extent of the remaining glomerular hyperfiltration in the patients treated with EPL. Results EPL decreased the GFR at 1 month after treatment. The GFR at baseline was the sole significant predictor for the ΔGFR. Patients initially treated by EPL followed by adrenalectomy showed three different ΔGFR patterns during the treatment, despite having comparable doses of EPL and comparable control of blood pressure and serum potassium levels. The urinary aldosterone excretion was significantly different among these three groups, and the group with no decrease in the GFR after EPL treatment showed greater urinary aldosterone excretion. Glomerular hyperfiltration was completely restored only in 17.5% of our unilateral PA patients after EPL treatment. Conclusion The present study revealed that blockade of aldosterone action by EPL could, at least partially, reverse glomerular hyperfiltration in PA. Whether or not these differential effects on the GFR affect the long-term outcome needs to be investigated, especially in patients with unilateral PA who do not want adrenalectomy and choose the EPL treatment option.

OBJECTIVE To develop a computer-aided diagnosis (CAD) algorithm with a deep learning architecture for detecting prostate cancer on magnetic resonance imaging (MRI) to promote global standardisation and diminish variation in the interpretation of prostate MRI. PATIENTS AND METHODS We retrospectively reviewed data from 335 patients with a prostate-specific antigen level of

The purpose of this study is to validate the Prostate Imaging Reporting and Data System, version 2 (PI-RADSv2), in assessing extracapsular extension (ECE), compared with PI-RADS, version 1 (PI-RADSv1).A total of 210 patients with clinically localized prostate cancer underwent MRI and radical prostatectomy. Two readers independently interpreted the MR images. In PI-RADSv1, 5-point ECE risk scoring was used. In PI-RADSv2, ECE criteria included morphologic features and a tumor-capsule contact length (CL) greater than 10 mm. The diagnostic performance of each PI-RADS version and the cutoff CL were evaluated.ECE was found in 56 patients (26.7%). In PI-RADSv1, maximal accuracy was achieved with a risk score of 3 or greater. At this threshold, positive findings on PI-RADSv1 and PI-RADSv2 were identified in 21.0-34.3% and 49.0-51.4% of patients, respectively. Compared with PI-RADSv1, PI-RADSv2 had higher negative predictive values (84.9-89.1% vs 96.3-97.1%, respectively; p = 0.003 and 0.021, for each reader). PI-RADSv1 and PI-RADSv2 had positive predictive values of 56.9-70.5% and 49.1-50.5%, respectively (p = 0.025 and 0.300, respectively). Interobserver kappa values for PI-RADSv1 and PI-RADSv2 were 0.511 and 0.781, respectively. The best cutoff CL was greater than 10 mm among patients without morphologic features of ECE. For patients positive for ECE on the basis of PI-RADSv2 but not PI-RADSv1, 73.3-74.1% of prostate cancer cases with a biopsy Gleason score of 7 or less and 35.7-44.4% of cases with a biopsy Gleason score of 8 or higher were overstaged.PI-RADSv2 reduces understaging and improves interobserver agreement in ECE assessment. However, overstaging is a concern, and the biopsy Gleason score may have a complementary role in reducing overstaging.

Purpose We investigated whether the standardized apparent diffusion coefficient (ADC) value reflects bladder cancer characteristics across different centers. Methods Ninety-eight bladder cancer patients underwent MRI at two institutions. Standardized tumor ADC (sT-ADC) was calculated by dividing absolute tumor ADC (aT-ADC) by that of gluteus maximus. We compared ADCs between MRI protocols according to grade and T-stage. Results The differences in aT-ADC between MRI protocols were negated by sT-ADC. The best sT-ADC cut-offs to predict cancer aggressiveness in the development cohort worked in the validation cohort compared to the development cohort. Conclusion Standardized ADC overcomes the incompatibility between different MRI protocols.

Purpose To investigate the value of computed (c) diffusion-weighted imaging (DWI) in assessing prostate cancer aggressiveness. Materials and methods Fifty-five patients with peripheral zone prostate cancer who underwent prebiopsy 1.5T magnetic resonance imaging (including native DWI at b-values of 0 and 1000 s/mm2 ) were included. cDWI signal intensities of peripheral zone prostate cancer and nonmalignant prostate tissue were measured. Association between changes in monoexponentially calculated cDWI signals according to different b-values and primary Gleason grades were assessed. Results The cDWI signal intensity of prostate cancer was lower at b = 0 s/mm2 and higher at b = 1000 s/mm2 compared to nonmalignant prostate tissue. The b-value at which the signal intensities of prostate cancer and nonmalignant prostate tissue were equal was defined as the "iso-b-value." On multivariate analysis, only the iso-b-value was a significant predictor of primary Gleason grade 4/5 cancer (P = 0.001). The area under the curve (AUC) of the iso-b-value for diagnosing primary Gleason grade 4/5 cancer was 0.94, and significantly higher than that of the tumor apparent diffusion coefficient (ADC) value with an AUC of 0.68 (P Conclusion cDWI with iso-b-value-based semiquantitative analysis was found to be useful for predicting the aggressiveness of prostate cancer and may potentially outperform tumor ADC measurements in this setting. Level of evidence 3 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:490-496.

INTRODUCTION AND OBJECTIVES:Trimodality bladdersparing therapy has become an accepted treatment for selected patients with muscle-invasive bladder cancer (MIBC). As the presence of hydronephrosis m...

OBJECTIVES To evaluate the impact of fluorodeoxyglucose uptake on positron emission tomography/computed tomography on chemosensitivity and survival in patients with metastatic urothelial carcinoma. METHODS The present study assessed 51 metastatic urothelial carcinoma patients undergoing fluorodeoxyglucose positron emission tomography/computed tomography before first-line systemic chemotherapy. Fluorodeoxyglucose uptake in metastases was evaluated using the maximum standardized uptake value, which was measured for all eligible lesions, and the highest value among the maximum standardized uptake value measurements in each case was defined as the highest maximum standardized uptake value. The associations between the highest maximum standardized uptake value and objective response rate to chemotherapy, progression-free survival or cancer-specific survival were analyzed. For cancer-specific survival, the C-index was compared between multivariate models that incorporated predictors in the Bajorin model including the Karnofsky performance status and the presence of visceral metastasis, and the Apolo model additionally including hemoglobin and albumin levels, with/without the highest maximum standardized uptake value. RESULTS The median age was 69 years. The Karnofsky performance status was ≥80% for all patients. Visceral metastasis was observed in 12 patients (24%). The objective response rate, median progression-free survival and median cancer-specific survival were 61%, 9 and 26 months in the entire cohort, respectively. The higher highest maximum standardized uptake value was significantly associated with a lower objective response rate, shorter progression-free survival and shorter cancer-specific survival (P = 0.01

Background The prognostic significance of tumor location for patients with upper urinary tract urothelial carcinoma (UUT-UC) has been disputed. Several papers have reported that ureteral cancer is associated with worse prognosis. Objective To investigate the prognostic significance of the presence of ureteral tumors in UUT-UC patients who underwent radical nephroureterectomy (RNU). Design, setting, and participants In this multicenter retrospective study, 1068 eligible patients (median follow-up: 40 mo [interquartile range: 17–77 mo]) were divided into three groups based on tumor location: renal pelvic, ureteral, and both–regional (having both renal pelvic and ureteral tumors). The ureteral and both–regional groups were subsequently integrated into the ureteral involvement group to evaluate its prognostic impact. Intervention All patients underwent RNU. Outcome measurements and statistical analysis The prognostic impact of tumor location on survival was analyzed. Results and limitations The renal pelvic, ureteral, and both–regional groups consisted of 507 (47.5%), 430 (40.3%), and 131 (12.3%) patients, respectively. The ureteral and both–regional groups had a higher rate of lymphovascular invasion and lymph node metastasis compared with the renal pelvic group. The renal pelvic and both–regional tumors presented more frequently with locally advanced stages (pT3/T4) compared with the ureteral tumors. The 5-yr cancer-specific survival (CSS) and progression-free survival (PFS) rates of patients in the ureteral (70.5% and 66.7%, respectively) and both–regional groups (64.8% and 57.8%, respectively) were significantly worse than those in the renal pelvic group (81.9% and 78.1%, respectively). In a multivariate analysis, the presence of ureteral involvement was a significant prognostic factor for CSS (hazard ratio [HR]: 1.50; p =0.006) and PFS (HR: 1.35; p =0.023). This study is inherently limited by the biases associated with its retrospective and multicenter design. Conclusions The presence of ureteral involvement had a significant impact on the survival of surgically treated UUT-UC patients associated with a poor prognosis. Patient summary We demonstrated that the ureteral involvement was associated with poor survival compared with patients with renal pelvic tumor only in upper urinary tract urothelial patients treated by nephroureterectomy.

A 58-year-old woman was referred to our hospital for Cushingoid features and diagnosed as adrenal Cushing's syndrome due to a right adrenocortical mass (60 × 55 mm). The mass was composed of three different tumors; the first one was homogeneously lipid-poor neoplasm measuring 20 × 13 mm located at the most dorsal region, the second one was heterogeneous and lipid-rich tumor containing multiple foci of calcification measuring 50 × 32 mm located at the central region, and the last one was heterogeneous harboring dilated and tortuous vessels and lipid-poor one measuring 35 × 18 mm at the most ventral region of the adrenal gland. A right adrenalectomy was subsequently performed by open surgery. Macroscopic and microscopic analyses revealed that all three tumors were adrenocortical adenomas; the first one represents a pigmented adrenocortical adenoma, the second one adrenocortical adenoma associated with degeneration, and the third one adrenocortical adenoma harboring extensive degeneration. Immunohistochemical analysis of the steroidogenic enzymes also revealed that all of the tumors had the capacity of synthesizing cortisol. This is a very rare case of Cushing's syndrome caused by multiple adrenocortical adenomas including a pigmented adenoma. Immunohistochemical analysis of steroidogenic enzymes contributed to understanding of steroidogenesis in each of these three different adrenocortical adenomas in this case.

Background Tetramodal bladder-preservation therapy includes maximal transurethral resection (TUR), induction chemoradiotherapy (CRT), and consolidative partial cystectomy with pelvic lymph node dissection. Tetramodal bladder-preservation therapy theoretically provides surgical consolidation of chemotherapy- and radioresistant cells. However, its efficacy in providing optimal cancer control for patients with histologic variants of urothelial carcinoma (VUCs) is currently unknown. We compared the oncologic outcomes between patients with muscle-invasive bladder cancer (MIBC) and pure urothelial carcinoma (PUC) and those with MIBC and VUCs after selective tetramodal bladder-preservation therapy. Patients and Methods We prospectively enrolled 154 patients. After maximal TUR and induction CRT, patients with a clinical complete response were offered consolidative partial cystectomy to achieve bladder preservation, with radical cystectomy recommended for the others. The VUCs identified in the maximal TUR samples were categorized according to the 2004 World Health Organization classification. The primary endpoint was cancer-specific survival. The secondary endpoints included the clinical and pathologic response rates to induction CRT and MIBC recurrence-free survival. Results A VUC was identified in 37 patients (24%). The most frequent variants involved glandular differentiation (n = 13), squamous differentiation (n = 11), and micropapillary (n = 8). No difference was found in the clinical complete response rate to CRT between PUC and VUCs (P = .81). On an intention-to-treat basis, the 5-year cancer-specific survival rates for those with PUC (n = 116) and VUC (n = 37) were 82% and 81% (P = .86), respectively. Conclusion Tetramodal bladder-preservation therapy incorporating partial cystectomy could provide favorable locoregional control and survival for patients with VUC. Thus, patients with MIBC need not be excluded from the bladder-preservation approach because of the presence of a variant histologic type.

OBJECTIVES To determine the incidence and preoperative risk factors of post-excisional hypoglycemia in patients undergoing pheochromocytoma resection. METHODS Patients who underwent surgical resection of pheochromocytoma at a single institution were retrospectively enrolled in the present study. The primary end-point was the development of post-excisional hypoglycemia; that is, a serum glucose level

C-reactive protein (CRP), a representative inflammatory marker, could serve as a biomarker in renal cell carcinoma because CRP is an important prognostic factor. However, its detailed mechanism remains unknown. This study showed that higher CRP levels correlated with the tumor immune microenvironment, which leads to a worse prognosis. These findings can help to clarify the underlying mechanisms between the presence of systemic inflammatory reaction and prognosis. The aim of this study is to investigate the association between tumor immune microenvironment and CRP in patients with renal cell carcinoma (RCC) to explore the underlying mechanisms between CRP level and prognosis.Immunohistochemical measurement of CD4, CD8, CD163 (M2 macrophages), and Foxp3 (Regulatory T [Treg] cells) was performed in patients with clear-cell RCC (n = 111) treated with radical or partial nephrectomy at our institution. The association between immunohistochemical status and preoperative serum CRP level and cancer-specific survival (CSS) was analyzed.Thirty-three patients (30%) had a high CRP level (≥ 5.0 mg/L), and the CSS rate was significantly worse among these patients than among the remaining patients (P .001). In patients with strong infiltration of CD8+, Foxp3+, or CD163+ cells, CRP levels were significantly higher (P = .041, P = .001, and P = .035, respectively), and CSS was significantly worse compared with patients with weak infiltration (P = .040, P = .026, and P .001, respectively). In multivariate analysis, strong CD163+ cells infiltration (P = .001) as well as pathologic T3 (P = .036), lymph-node involvement (P = .007), distant metastasis (P .001), and Fuhrman nuclear grade 4 (P = .003) were independent prognostic factors for CSS.Infiltration of the immunosuppressive cells known as Tregs and M2 macrophages in the tumor microenvironment is associated with higher CRP and poor prognosis in patients with clear-cell RCC. CRP could reflect an immunosuppressive microenvironment.

To estimate postoperative residual renal function after radical nephroureterectomy for upper tract urothelial carcinoma using the preoperative dynamic computed tomography renal cortex enhancement ratio in comparison with the split kidney glomerular filtration rate measured byA total of 47 patients who received radical nephroureterectomy and underwent both preoperative dynamic computed tomography and renography were the model-development cohort; and 109 patients who underwent dynamic computed tomography alone were the validation cohort. Postoperative renal function of the unremoved kidney was estimated using the following formulas: preoperative estimated glomerular filtration rate × the percentage of total renal cortex radiodensity for the intact kidney in Hounsfield units obtained from corticomedullary phase images in the computed tomography-based model, or the percentage of the total glomerular filtration rate measured by renography in the nuclear model. The correlation between observed and estimated postoperative renal function was determined. The computed tomography-based prediction model derived from linear regression analysis was validated externally.The correlation of computed tomography-based split renal function with the observed postoperative estimated glomerular filtration rate (r = 0.80) was equivalent to that of nuclear split renal function (r = 0.78). In the validation cohort, the computed tomography-based prediction model showed an equivalently strong correlation (r = 0.78).The present study showed that the percentage of total renal cortex radiodensity for the intact kidney is a useful tool for predicting unremoved kidney function in upper tract urothelial carcinoma patients, thereby allowing appropriate patient selection for perioperative cisplatin-based combination chemotherapy.

Purpose A bladder-sparing strategy is a useful option for patients with muscle-invasive bladder cancer (MIBC), in which the response to chemoradiation therapy (CRT) is primarily important in achieving favorable oncologic outcomes. Our objective is to evaluate the impact of immunohistochemistry (IHC)-based subtyping in MIBC on prediction of CRT response. Methods and Materials Treatment protocol consisted of induction CRT followed by partial or radical cystectomy as consolidative surgery; 118 eligible patients with nonmetastatic MIBC were retrospectively analyzed. Of these patients, 92 eventually underwent partial or radical cystectomy after CRT. We applied the IHC-based subtyping model developed by Lund University, which classifies patients into urobasal (Uro), genomically unstable (GU), and squamous cell cancer-like (SCCL) subtypes. GU and SCCL cancers are supposed to be highly aggressive and to have worse prognoses than Uro. Correlations of subtypes with CRT response were analyzed clinically in all patients and pathologically in 92 cystectomized patients. The impact of each subtype on cancer-specific mortality (CSM) was also analyzed. Results Of all patients, 26 (22%), 61 (52%), and 31 (26%) were classified into Uro, GU, and SCCL subtypes, respectively. Clinical complete response (CR) was achieved in 42% of patients overall after CRT, with a significantly higher proportion in GU patients (52%) and SCCL patients (45%) than in Uro patients (15%; P P = .01, respectively). On multivariate analysis, the GU/SCCL subtype was a significant predictor of clinical CR, as was absence of hydronephrosis or concomitant carcinoma in situ. Analyses for pathologic CR in the cystectomized patients revealed analogous findings. Five-year CSM of Uro, GU, and SCCL patients was 16%, 23%, and 28% overall, respectively, and 19%, 22%, and 23% in cystectomized patients, respectively, with no significant difference among the subtypes. CR status after CRT was significantly and independently correlated with low CSM in both clinical and pathologic evaluations. Conclusions GU and SCCL cancers showed significantly more favorable CRT response than did Uro cancers. IHC-based subtyping may improve clinical decisions about the indication of CRT for MIBC patients.

Aldosterone-producing adenoma (APA) is a form of primary aldosteronism (PA). Recent studies suggested that somatic mutations in the KCNJ5, ATP1A1, ATP2B3, and CACNA1D genes are involved in the pathogenesis of APA. We report a case of a 62-year-old man diagnosed as PA with left adrenal mass. He underwent adrenalectomy for treatment. We identified a novel somatic deletion mutation in ATP2B3 in the adrenal tumor: c.1269_1274delTGTGCT which spans three codons (423-425) resulting in p.Val424_Leu425del. Immunohistochemical analysis revealed strong expression of aldosterone synthase (CYP11B2) in the tumor tissue, which is consistent with APA. Here, we identified a novel somatic deletion mutation in ATP2B3, which results in the amino acid sequences increasing intracellular calcium concentrations as reported previously, leading to increased aldosterone synthase (CYP11B2) expression and following excess aldosterone production in the APA cells. The novel ATP2B3 mutation detected in our case supports the pathogenic significance of the locus spanning the codon 424-426 of ATP2B3.

Purpose To evaluate associations of Ki-67 expression with oncologic outcomes in muscle-invasive bladder cancer (MIBC) patients treated with chemoradiotherapy (CRT)-based bladder-sparing protocol. Materials and Methods Between 1998 and 2011, 190 consecutive MIBC patients were treated with CRT-based bladder-sparing protocol. After transurethral resection of the bladder tumor, the patients underwent induction CRT (40 Gy with concurrent cisplatin) followed by partial cystectomy for bladder preservation or radical cystectomy (RC). Included in this study were 94 patients who were histologically diagnosed with urothelial carcinoma and whose tumor tissues before CRT were available for immunohistochemical evaluation of Ki-67 expression status. Results After induction CRT, 16 (17%) and 53 (56%) patients underwent partial cystectomy and RC, respectively, while the remaining 25 (27%) did not undergo cystectomy. Successful bladder preservation was achieved in 34 patients (36%). Higher Ki-67 labeling index (LI) independently predicted CRT response clinically and pathologically. Among the clinicopathologic variables available before CRT and cystectomy, high Ki-67 LI (≥ 20%) was independently associated with better cancer-specific survival (CSS) (5-year CSS rate, 78% vs. 46% for low Ki-67 LI; P = .019). The difference in CSS according to Ki-67 expression status was more remarkable in patients with cT3 disease (5-year CSS rate, 72% vs. 29%; P = .0098). Conclusion High Ki-67 expression predicts favorable CSS in MIBC patients treated with CRT-based bladder-sparing protocol. MIBC patients with high Ki-67 expression status might benefit from CRT-based multimodal approaches in terms of prognosis and quality of life as a result of bladder preservation.

Objective: To determine the diagnostic accuracy of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for detecting metastasis and its impact on patient management with upper tract urothelial carcinoma (UTUC). Patients and Methods: Consecutive patients with UTUC underwent 18F-FDG PET/CT after CT for initial staging (n = 47) and for restaging at recurrence (n = 9). Diagnostic accuracy for detecting metastases with PET/CT and CT was compared statistically. The impact of PET/CT on patient management was assessed by comparing questionnaires that were completed by the attending physicians before and after PET/CT. Results: In the lesion-based analysis, 142 lesions were diagnosed as metastases. The sensitivity of PET/CT was significantly better than that of CT (85 vs. 50%, p = 0.0001). In the patient-based analysis, 22 patients were diagnosed as having metastases. The sensitivity/specificity/accuracy of PET/CT tended to be superior to those of CT, but these values were not significantly different (95, 91, and 93% vs. 82, 85, and 84%; p = 0.25, 0.50, and 0.063, respectively). The clinicians changed their assessments of disease extent and management plans in 18 (32%) and 11 (20%) patients, respectively, based on the PET/CT results. Conclusions: The diagnostic accuracy of PET/CT for detecting metastasis was superior to that of CT. PET/CT provided additional information to the CT-based staging, which had an impact on patient management.

Objectives To identify prostatic quadrants that could be preserved without intervention, using diffusion-weighted magnetic resonance imaging (DWI) and extended core biopsy, as a step toward implementation of quadrant-based focal ablation with potential preservation of erectile and ejaculatory functions, based on comparisons with unilateral hemi-gland ablation. Patients and Methods We conducted a prebiopsy DWI study including 648 quadrants in 162 men who underwent 14-core biopsy including anterior sampling and radical prostatectomy (RP) for localised cancer. Imaging and pathology were analysed on a quadrant basis. Each quadrant was assessed through four-core sampling. Predictive performance of DWI and biopsy for quadrant status was analysed. Results On RP specimens, 170 anterior (52.5%) and 172 posterior quadrants (53.1%) harboured significant cancer. Negative predictive values of DWI, biopsy, and their combination for significant cancer were 79.7%, 70.6%, and 91.1%, respectively, in anterior quadrants, and 78.5%, 81.3%, and 91.7%, respectively, in posterior quadrants. DWI incrementally improved the negative predictive values of biopsy in anterior (P < 0.001) and posterior quadrants (P = 0.025), without untoward impacts on positive predictive values. Negative findings on both DWI and biopsy were identified in posterior quadrants of 109 sides (33.6%), but in entire hemi-glands of 54 sides (16.7%). Conclusions The combination of DWI and 14-core biopsy including anterior sampling efficiently identifies quadrants without significant cancer in men with localised prostate cancer; the remaining quadrants, therefore, could be potential candidate areas for focal ablation. Focal therapy designed based on quadrant-based assessment could be superior to unilateral hemi-gland ablation for preservation of posterior quadrants and retaining of sexual function in more sides.