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•The association of D'Amico intermediate-risk and pathological grade group 1 was studied.•Among intermediate-risk prostate cancer patients, those with pathological grade group 1 have a good biochemical reccurence-free survival.•Downgrading from biopsy grade group ≥2 is rare; thus, radical treatment is recommended for patients with biopsy grade group ≥2.•It provides guidelines to identify patients eligible for active surveillance in D'Amico intermediate-risk group.

The controlling nutritional status (CONUT) score is an objective indicator of general condition from the aspect of nutritional status, calculated from serum albumin, total cholesterol, and total lymphocyte count. The CONUT score is also considered to reflect the degree of tumor-derived chronic inflammation and the host immune status in patients with advanced cancer. To examine the prognostic role of the CONUT score in patients with advanced urothelial carcinoma (aUC) treated with first-line platinum-based chemotherapy. Associations of the CONUT score with clinical parameters and overall survival (OS) were investigated retrospectively in 147 patients with aUC receiving first-line platinum-based chemotherapy at a single cancer center from February 2003 to April 2019. The median (range) CONUT score was 1 (0–7). A higher CONUT score was associated with lower hemoglobin (P < 0.001) and higher C-reactive protein levels (P = 0.023) but not with chemotherapy response (P = 0.432). The median OS for patients with CONUT scores 0–1, 2–3, and ≥4 were 23.3, 14.9, and 9.4 months, respectively (P < 0.001). In the multivariable analysis, a higher CONUT score was independently associated with shorter OS (scores 2–3 vs 0–1, HR 1.58, P = 0.048; scores ≥4 vs 0–1, HR 2.63, P = 0.008) along with poorer performance status (HR 4.79, P < 0.001), primary tumor site of the upper urinary tract (HR 1.70, P = 0.016), higher LDH (HR 3.85, P = 0.036), higher alkaline phosphatase (HR 3.06, P = 0.028), and non-responders to chemotherapy (HR 2.07, P < 0.001). The CONUT score is a prognostic biomarker in patients with aUC receiving first-line platinum-based chemotherapy.

Vesical Imaging-Reporting And Data System (VI-RADS) was proposed to detect muscle-invasive bladder cancer (MIBC). To evaluate the performance of VI-RADS and additional value of apparent diffusion coefficient (ADC) values measured on diffusion-weighted magnetic resonance imaging (MRI) for detecting MIBC. A total of 176 patients undergoing MRI (multiparametric in 97 [55%] and biparametric in 79 [45%]) before transurethral resection of bladder tumor for primary bladder cancer were retrospectively identified. MRI findings were scored according to VI-RADS. The standardized tumor ADC (sT-ADC: tumor ADC/gluteus maximus ADC) was calculated and used to account for the incompatibility among different MRI protocols. The accuracy of VI-RADS, sT-ADC and their combination to detect MIBC was assessed using the AUC of the ROC curve. MIBC was pathologically confirmed in 46 patients (26%). AUC of VI-RADS to detect MIBC was 0.86. When cut-off of VI-RADS was set at≥3 and≥4, sensitivity/specificity were 78% /70% and 63% /96%, respectively. A lower sT-ADC (≤0.894) was significantly associated with muscle invasion (p < 0.01, AUC 0.79) with sensitivity 78% and specificity 79%. Combination of VI-RADS and sT-ADC improved the accuracy (AUC 0.94); sensitivity was 100% when VI-RADS≥3 or sT-ADC≤0.894 was considered positive, and specificity was 99% when VI-RADS≥4 and sT-ADC≤0.894 was considered positive. Incorporation of sT-ADC reduced under-staging of MIBC as VI-RADS < 3 by 100% and over-staging of non-MIBC as VI-RADS≥4 by 80%. Incorporation of ADC values into VI-RADS improves accuracy to detect MIBC in primary bladder cancer patients.

The objective of the study was to identify a subset of men who can avoid systematic multisite biopsy (SyB) among those undergoing magnetic resonance imaging (MRI)-targeted transperineal 4-core biopsy (TgB) without missing clinically significant cancer (SC).

ABSTRACTIntroduction: The heat shock factor 1 (HSF1) plays a pivotal role in guarding proteome stability or proteostasis by induction of heat shock proteins (HSPs). While HSF1 remains mostly latent in unstressed normal cells, it is constitutively active in malignant cells, rendering them addicted to HSF1 for their growth and survival. HSF1 affects tumorigenesis, cancer progression, and treatment resistance by preserving cancer proteostasis, thus suggesting disruption of HSF1 activity as a potential anticancer strategy.Areas covered: In this review, we focus on the HSF1 activation cycle and its interaction with HSPs, the role of HSF1 in oncogenesis, and development of HSF1-targeted drugs as a potential anticancer therapy for disrupting cancer proteostasis.Expert opinion: HSF1 systematically maintains proteostasis in malignant cancer cells. Although genomic instability is widely accepted as a hallmark of cancer, little is known about the role of proteostasis in cancer. Unveiling the complicated mechanism of HSF1 regulation, particularly in cancer cells, will enable further development of proteostasis-targeted anticancer therapy.Abbreviations:AMPK: AMP-activated protein kinase; DBD: DNA-binding domain; HR-A/B; HR-C: heptad repeats; HSE: heat shock elements; HSF1: heat shock factor; HSPs: heat shock proteins; HSR: heat shock response; MEK: mitogen-activated protein kinase kinase; mTOR: mammalian target of rapamycin; NF1: neurofibromatosis type 1; P-TEFb: positive transcription elongation factor b; RD: regulatory domain; RNAi: RNA interference; TAD: transactivation domain; TRiC: TCP-1 ring complex

Bladder cancer is the most common malignant tumor of the urothelium and is classified into non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Stemness markers such as SOX2 and NANOG are frequently overexpressed in various aggressive cancers, including MIBC; epithelial–mesenchymal transition (EMT) has been proposed as a potential trigger of stemness in cancers. To determine whether cancer stemness is acquired via EMT in bladder cancer, we studied the effect of EMT on the expression of SOX2 and NANOG in bladder cancer cell lines. We also analyzed their expression in clinical tissue samples. Our results revealed that a potent EMT inducer (transforming growth factor β1) reduced the expression of the epithelial marker E-cadherin and increased expression of both SOX2 and NANOG in epithelial-type bladder cancer cells. As for clinical bladder cancer samples, in NMIBC, E-cadherin expression was slightly diminished, and the expression of both SOX2 and NANOG was negligible. In contrast, in MIBC, E-cadherin expression was highly and heterogeneously diminished, while the expression of both SOX2 and NANOG was increased. We also noticed that either E-cadherin or SOX2 (or NANOG) was expressed (ie, in a manner exclusive of each other). In addition, the concentration of E-cadherin showed a significant negative correlation with tumor grade and stage, while expression of SOX2 and NANOG positively correlated with those clinicopathological parameters. These findings suggest that EMT promotes stemness of bladder cancer cells, contributing to tumor aggressiveness. This EMT–cancer stemness axis may also play an important role in the pathogenesis of NMIBC and MIBC.

Bladder cancer is the most common malignant tumor of the urothelium and is classified into non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Stemness markers such as SOX2 and NANOG are frequently overexpressed in various aggressive cancers, including MIBC; epithelial–mesenchymal transition (EMT) has been proposed as a potential trigger of stemness in cancers. To determine whether cancer stemness is acquired via EMT in bladder cancer, we studied the effect of EMT on the expression of SOX2 and NANOG in bladder cancer cell lines. We also analyzed their expression in clinical tissue samples. Our results revealed that a potent EMT inducer (transforming growth factor β1) reduced the expression of the epithelial marker E-cadherin and increased expression of both SOX2 and NANOG in epithelial-type bladder cancer cells. As for clinical bladder cancer samples, in NMIBC, E-cadherin expression was slightly diminished, and the expression of both SOX2 and NANOG was negligible. In contrast, in MIBC, E-cadherin expression was highly and heterogeneously diminished, while the expression of both SOX2 and NANOG was increased. We also noticed that either E-cadherin or SOX2 (or NANOG) was expressed (ie, in a manner exclusive of each other). In addition, the concentration of E-cadherin showed a significant negative correlation with tumor grade and stage, while expression of SOX2 and NANOG positively correlated with those clinicopathological parameters. These findings suggest that EMT promotes stemness of bladder cancer cells, contributing to tumor aggressiveness. This EMT–cancer stemness axis may also play an important role in the pathogenesis of NMIBC and MIBC.

We investigated the prognostic effect of postoperative changes in skeletal muscle mass in 37 patients with metastatic renal cell carcinoma undergoing cytoreductive nephrectomy. Postoperative changes in the skeletal muscle mass, measured on computed tomography images, were significantly associated with overall survival. Thus, postoperative changes in skeletal muscle mass could be a novel biomarker serving as a useful surrogate for prognosis.

This prospective study, consisting of 326 patients with non–muscle-invasive bladder cancer (NMIBC) who underwent 597 tumor resections, demonstrated that a voided urine cytology result that is positive for atypical cells is a predictor of disease progression, independent of histological grade. Time-dependent covariate Cox models appear more sensitive in detecting risk factors for NMIBC progression than conventional time-fixed models. Voided urine cytology may be useful for NMIBC risk stratification.

Although radical cystectomy with urinary diversion is the standard treatment for muscle-invasive bladder cancer (MIBC), loss of native bladder frequently impairs patient's quality of life (QOL). Bladder-sparing approach incorporating chemoradiotherapy (CRT) improves QOL while not compromising survival outcomes in MIBC patients. In this approach, complete response to induction CRT is a prerequisite for bladder preservation and favorable oncological outcomes. We investigated a strategy to potentiate CRT response of bladder cancer cells by using Hsp90 inhibitors in preclinical models. Hsp90 inhibitors at low concentrations, which did not exert cytocidal effects but inactivated key anti-apoptotic proteins including erbB2, Akt, and NF-κB, efficiently sensitized bladder cancer cells (T24, 5637 and UM-UC-3 cells) to in vitro CRT by enhancing apoptosis. Importantly, the sensitizing effects were not observed in primarily cultured normal human urothelial cells. We also showed that CRT induces accumulation of nuclear phospho-Akt, which antagonizes apoptosis, and that Hsp90 inhibitors block the cellular process. Hsp90 inhibition sensitized bladder cancer cells to in vitro CRT more effectively than sole or combined inhibition of erbB2 and Akt. In mice UM-UC-3 tumor xenografts model, Hsp90 inhibitors successfully potentiated anti-tumor activity of CRT. These results encourage clinical trials of Hsp90 inhibitors to overcome CRT resistance in patients with MIBC.

Hepatocyte growth factor (HGF) receptor Met and hypoxia-inducible factor-1 (HIF-1) signaling pathways are commonly activated in aggressive tumors and promote progression. Since both Met and HIF-1α proteins are heat shock protein (Hsp) 90 clients, Hsp90 inhibitors might be expected to positively impact tumor progression. Here, we systematically evaluated the inhibitory effects of the prototypical Hsp90 inhibitor geldanamycin (GA) on cellular processes involved in invasion and angiogenesis in T24 bladder cancer cells stimulated with HGF and chemical hypoxia. First, we demonstrated the positive feedback loop between Met and HIF-1 pathways, which serves to sustain and amplifies their signaling in T24 cells. GA down-regulated Met by inhibiting new protein maturation, thereby dampening HGF signaling. HGF and chemical hypoxia with CoCl2 cooperatively promoted in vitro invasion and vascular endothelial growth factor (VEGF) secretion, while CoCl2 but not HGF activated urokinase-type plasminogen activator and matrix metalloproteinase 2, both of which promote invasion and angiogenesis. Low dose GA (100 nmol/L) inhibited these processes by suppressing both HGF and HIF-1 pathways. Notably, brief GA pretreatment inhibited in vitro invasion and VEGF secretion induced by HGF as effectively as did continuous treatment. Moreover, we found that GA inhibited activation of focal adhesion kinase, focal adhesion assembly, and actin reorganization induced by HGF and integrin engagement by extracellular matrix. Thus, GA widely suppresses extrinsic stimuli-induced signaling that contribute to tumor invasion and angiogenesis in this bladder carcinoma model, suggesting the utility of Hsp90 inhibitors in preventing tumor progression and metastasis.

Endothelial Per-Arnt-Sim domain protein 1 (EPAS1) is induced under hypoxia and it transactivates a series of genes involved in angiogenesis and energy metabolism. Recent studies showed that EPAS1 is expressed in tumor associated macrophages (TAMs), which have multifaceted roles in tumor progression. We hypothesized that EPAS1 expressed in TAMs may contribute to bladder cancer progression.

The relationship between clinical response to DNA‐damaging drugs and p53 and p21 status in patients with locally advanced transitional cell carcinoma (TCC) of the bladder was assessed. The response to intraarterial chemotherapy (IAC) comprising 100 mg/m2of cisplatin (CDDP) and 40 mg/m2of pirarubicin (THP) and the prognosis were assessed in 23 patients (the mean follow‐up period was 19 months). The p53 gene status of tumors was analyzed at exons 5–8 using polymerase chain reaction‐single strand conformation polymorphism analysis in 19 patients, and paraffinembedded tumor sections were immunostained for p53and p21in 23 patients. The overall objective response rate (incidence of good responders) was 70%. The negative p53 group (n=17) showed a significantly higher objective response rate than the positive p53 group (n=6) (82% vs. 33%; P=0.045). The p53 gene status or p21 staining status was not significantly associated with responsiveness. When the p53 and p21 immunostaining results were combined, good responders were more accurately predicted than by p53 staining status alone; the negative p53/positive p21 group (n=12) showed an objective response rate of 92%, which was significantly higher than that of the positive p53 and/or negative p21 group (45%, n=11) (P=0.027). Cause‐specific survival of the negative p53 group was significantly superior to that of the positive p53 group (P=0.015). Negative p53/positive p21 immunostaining is a possible predictor of favorable chemotherapeutic response in patients with TCC of the bladder.

Bone scans, widely used for the detection of bone metastases from prostate carcinoma, can neither quantitate metastatic lesions nor detect osteolytic lesions. Serum concentrations of the carboxyterminal propeptide of Type I procollagen (PICP), the carboxyterminal pyridinoline cross-linked telopeptide of Type I collagen (ICTP), and prostate specific antigen (PSA) were measured by radioimmunoassays in 48 patients with benign prostatic hyperplasia (BPH), 25 patients with prostate carcinoma (PCA) without bone metastases, and 36 patients with PCA and bone metastases. Serum concentrations of PICP were significantly higher in patients with PCA with bone metastases than in patients with BPH or PCA without bone metastases. No significant differences were observed between patients with BPH and those with PCA without bone metastases. Serum ICTP concentrations were significantly higher in patients with PCA than in patients with BPH regardless of the presence or absence of bone metastases. Serum concentrations of PICP, ICTP, and PSA correlated significantly with Soloway's grading system for bone scans. The serum concentrations of PICP and ICTP in patients without bone metastases showed a significant downward trend in response to antiandrogen therapy. These observations suggest that the serum concentrations of PICP and ICTP are quantitative markers of bone metastases from PCA when followed serially in individual patients. Cancer 1997; 80:1760-7. © 1997 American Cancer Society.

A 37-year-old Burmese woman presented with an incidentally found retroperitoneal fat-containing tumor. The tumor was 9 cm in the longest diameter, surrounding the right kidney, and composed of homogenous adipose tissue with thickened septum-like structures and spotty nonadipose structures, which were enhanced on contrast-enhanced computed tomography and magnetic resonance imaging. The tumor did not show either a beak sign or synchronous angiomyolipoma-like lesion in the kidneys. The tumor had irregular septa, thin blood vessels, and spotty small soft-tissue nodules. The tumor did not contain any heterogeneously enhanced solid lesions suspicious for dedifferentiated liposarcomas. Based on these imaging findings, a clinical diagnosis of a well-differentiated liposarcoma was made. Under the consensus of a multidisciplinary cancer board, she was recommended to undergo core-needle biopsy to confirm the clinical diagnosis. However, she declined to undergo biopsy for financial reasons. She underwent kidney-sparing retroperitoneal tumor resection. Histopathologically, the tumor was an angiomyolipoma with positive immunostaining for HMB45 and Melan A. The present case suggests the importance of core-needle biopsy prior to surgical intervention for retroperitoneal fat-containing tumors.

A 78-year-old man who had a horseshoe kidney (HSK) visited us because of gross hematuria and suspicious urine cytology. CT and MRI revealed a right renal pelvic tumor of 28 mm in diameter. He underwent gasless single-port retroperitoneoscopic nephroureterectomy with division of the isthmus via the right pararectal small incision using the RoboSurgeon system. Pathological diagnosis was invasive urothelial carcinoma, grade 3, pT3, pN0, LVI0, RM0. He was discharged from hospital on the 6th postoperative day without any perioperative complication. He has no evidence of disease clinically and radiologically 19 months after the operation. Only a few cases of upper tract urothelial carcinoma complicated by HSK treated with minimally invasive surgery have been reported in English literature. This is the first case successfully managed with RoboSurgeon gasless single-port retroperitoneoscopic nephroureterectomy.

We report a 32-year-old female case of a right adrenal gland mass detected on CT scan at medical checkup. CT and MRI showed a mass of 5.1 cm made of fat and calcification in the right adrenal gland, leading to the clinical diagnosis of adrenal myelolipoma. Because of its relatively large size and the patient’s desire, the patient underwent gasless single-port retroperitoneoscopic adrenalectomy using the RoboSurgeon system. Histopathological examination revealed that the cystic tumor is composed of keratinized epidermis, mature fat, nerve, cartilage, bone, and sebaceous glands compressing the normal adrenal gland, leading to the diagnosis of retroperitoneal mature cystic teratoma. The patient remains free of recurrence 29 months after surgery. Retroperitoneal teratoma is relatively rare but clinically important because of high possibility of malignancy. In a case of an adrenal mass difficult to clinically distinguish retroperitoneal teratoma from adrenal myelolipoma, surgical resection via a minimally invasive approach would be the best therapeutic option.