Controversies in terminology associated with management of BCG-unresponsive NMIBC in Asia-Pacific.

OBJECTIVES: Examine the understanding of terminologies and management patterns of bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle invasive bladder cancer (NMIBC) in six territories in Asia-Pacific. METHODS: This study involved two phases: (1) a survey with 32 urologists and 7 medical oncologists (MOs) and (2) a factorial experiment and in-depth interviews with 23 urologists and 2 MOs. All clinicians had ≥8 years' experience managing NMIBC patients in Australia, Hong Kong, Japan, South Korea, Singapore, and Taiwan. Data from Phase 1 were summarized using descriptive statistics; content and thematic analyses applied in Phase 2. RESULTS: In phase 1, 35% of clinicians defined BCG-unresponsive as BCG-refractory, -relapse and -resistant, 6% defined it as BCG-refractory and -relapse; 22% classified BCG-failure as BCG-refractory, -relapse, -resistant, and when muscle-invasive bladder cancer is detected. If eligible and willing, 50% (interquartile range [IQR], 50%-80%) of BCG-unresponsive patients would undergo radical cystectomy (RC), and 50% (IQR 20%-50%) of RC-eligible patients would receive bladder-sparing treatment or surveillance. In phase 2, we found that 32%, 88%, and 48% of clinicians, respectively, used "BCG-unresponsive," "BCG-refractory," and "BCG-relapse" in clinical practice but with no consistent interpretation of the terms. Compared with EAU definitions, 8%-60% of clinicians appropriately classified 9 tumor types that are persistent or recurrent after adequate BCG. Fifty percent of clinicians mentioned a lack of bladder-preserving treatment that outperforms RC in quality of life as a reason to retreat BCG-unresponsive patients with BCG. CONCLUSIONS: Our study revealed varied understanding and application of BCG-unresponsive terminologies in practice. There is a need for a uniform and simple definition of BCG-unresponsive disease in Asia-Pacific.

Risk stratification and management of non-muscle-invasive bladder cancer: A physician survey in six Asia-Pacific territories.

OBJECTIVES: Multiple clinical practice guidelines, conflicting evidence, and physician perceptions result in variations in risk stratification among patients with non-muscle-invasive bladder cancer (NMIBC). This study aims to describe the extent of this variation and its impact on management approaches in the Asia-Pacific region. METHODS: We conducted a cross-sectional survey involving 32 urologists and seven medical oncologists with ≥8 years of experience managing early-stage bladder cancer patients across Australia, Hong Kong, Japan, South Korea, Singapore, and Taiwan. The physicians completed an anonymous questionnaire that assessed their risk stratification and respective management approaches, based on 19 NMIBC characteristics. For each NMIBC characteristic, they were required to select one risk group, and their most preferred management approach. RESULTS: Our results demonstrated a higher consensus on risk classification versus management approaches. More than 50% of the respondents agreed on the risk classification of all NMIBC characteristics, but 42% or fewer chose the same treatment option as their preferred choice for all but two characteristics-existence of variant histology (55%) and persistent high-grade T1 disease on repeat resection (52%). Across territories, there was the greatest variation in preferred treatment options (i.e., no treatment, intravesical chemotherapy, or Bacillus Calmette-Guérin [BCG] treatment) for intermediate-risk patients and the highest consensus on the treatment of very high-risk patients, namely radical cystectomy. CONCLUSIONS: Our study revealed considerable variation in risk stratification and management of NMIBC in the region. It is critical to develop practical algorithms to facilitate the recognition of NMIBC and standardize the treatment of NMIBC patients.

Interruption of the long non-coding RNA HOTAIR signaling axis ameliorates chemotherapy-induced cachexia in bladder cancer.

BACKGROUND: Cisplatin-based chemotherapy is the first line of treatment for bladder cancer. However, cisplatin induces muscle wasting associated with NF-κB and cancer cachexia. HOTAIR, an oncogenic long non-coding RNA (lncRNA), promotes cancer progression in different cancers. Crosstalk between HOTAIR and NF-κB is documented. Prothymosin α (ProT) plays important roles in cancer progression and inflammation. However, the potential link between HOTAIR, ProT, and cisplatin-induced cancer cachexia remains unexplored. Here, we investigated the contribution of HOTAIR in cisplatin-induced cancer cachexia and dissected the potential signaling cascade involving the epidermal growth factor receptor (EGFR), ProT, NF-κB, and HOTAIR. MATERIALS AND METHODS: Expression of ProT and HOTAIR transcripts and their correlations in tumor tissues of bladder cancer patients and bladder cancer cell lines were determined by RT-qPCR. Next, levels of phospho-EGFR, EGFR, phospho-NF-κB, and NF-κB were examined by immunoblot analysis in human bladder cancer cells treated with cisplatin. Expression of HOTAIR in cisplatin-treated cells was also assessed by RT-qPCR. Pharmacological inhibitors and overexpression and knockdown approaches were exploited to decipher the signaling pathway. The murine C2C12 myoblasts were used as an in vitro muscle atrophy model. The syngeneic murine MBT-2 bladder tumor was used to investigate the role of mouse Hotair in cisplatin-induced cancer cachexia. RESULTS: Expression of ProT and HOTAIR was higher in bladder tumors than in normal adjacent tissues. There were positive correlations between ProT and HOTAIR expression in clinical bladder tumors and bladder cancer cell lines. Cisplatin treatment increased EGFR and NF-κB activation and upregulated ProT and HOTAIR expression in bladder cancer cells. ProT overexpression increased, whereas ProT knockdown decreased, HOTAIR expression. Notably, cisplatin-induced HOTAIR upregulation was abrogated by EGFR inhibitors or ProT knockdown. ProT-induced HOTAIR overexpression was diminished by NF-κB inhibitors. HOTAIR overexpression enhanced, whereas its knockdown reduced, cell proliferation, cachexia-associated pro-inflammatory cytokine expression, and muscle atrophy. Cachexia-associated symptoms were ameliorated in mice bearing Hotair-knockdown bladder tumors undergoing cisplatin treatment. CONCLUSIONS: We demonstrate for the first time a critical role for HOTAIR and identify the involvement of the EGFR-ProT-NF-κB-HOTAIR signaling axis in cisplatin-induced cachexia in bladder cancer and likely other cancers. Our findings also provide therapeutic targets for this disease.

Low-pressure hydrodistension induces bladder glomerulations in female patients with interstitial cystitis/bladder pain syndrome.

AIMS: The role of hydrodistension in the diagnosis of interstitial cystitis/bladder pain syndrome (IC/BPS) is controversial. This study evaluated the effect of low-pressure hydrodistension on glomerulation formation in female patients diagnosed with the disease. METHODS: Sixty female patients with the clinical diagnosis of IC/BPS and 30 female controls without the disease underwent cystoscopy and hydrodistension. Cold-cup biopsy was taken from bladder posterior wall at sites with normal cystoscopic appearance before hydrodistension in the IC/BPS group. The tissue samples were processed for histology study. Low-pressure (40 cmH2 O) hydrodistension for 2 min was performed and the appearance of glomerulations was compared between the two groups. High-pressure (80 cmH2 O) hydrodistension for 8 min was then performed as a therapeutic measure for the IC/BPS patients. Further changes to the degree of glomerulations were recorded. RESULTS: Histology showed pathological changes in the normal-appearing IC/BPS bladder mucosa including urothelium denudation, inflammatory cell infiltration, stromal edema, fibrosis, and vascular congestion. Low-pressure hydrodistension induced significant glomerulation formation in the patient group (percentage of patients with Grades 0-4: 0%, 8.3%, 40%, 35%, 10%, respectively) while none in the controls. High-pressure hydrodistension further increased the glomerulation grading in the IC/BPS patients. CONCLUSIONS: Structural changes are present in prehydrodistension IC/BPS bladder wall, which may not be macroscopically detectable. Hydrodistension at low pressure is adequate to disrupt the integrity of such diseased mucosa and offers a more discriminative test in the diagnosis of IC/BPS.

Dynamic changes of quality of life in muscle-invasive bladder cancer survivors.

BACKGROUND: To explore the dynamic changes and effects of radical cystectomy on quality of life in muscle-invasive bladder cancer survivors. METHODS: Patients with muscle-invasive bladder cancer were randomly recruited in this study. We used the World Health Organization Quality of Life-Brief questionnaire to assess consecutive patients' quality of life. We applied kernel smoothing to illustrate the dynamic changes of the domain and item scores after treatment. Mixed-effects models were constructed to determine the effects of radical cystectomy on the scores of each item and domain of the World Health Organization Quality of Life-Brief questionnaire after controlling demographic and clinical factors. RESULTS: We collected 397 repeated measurements of the World Health Organization Quality of Life-Brief questionnaire from 109 muscle-invasive bladder cancer patients. Forty-two of them received radical cystectomy. Patients with radical cystectomy exhibited higher levels of education, less co-morbidities (i.e., diabetes and heart diseases), but were associated with more malignancies. Construction of mixed-effects models showed patients with radical cystectomy and those with bladder sparing had similar scores in the three main domains and their items, except that of certain items of physical domain. By applying kernel smoothing method, we found that stage III-IV patients consistently showed higher scores on sleep and rest after radical cystectomy for more than 5 years. In contrast, stage II patients receiving radical cystectomy did not show a higher score on the "sleep and rest" item compared with those with bladder sparing operation. CONCLUSIONS: Radical cystectomy may result in sound sleep and rest, especially in those with stage III-IV bladder cancer.

Seminal Vesicle Schwannoma: Transrectal and Intraoperative Sonographic Findings.

Schwannomas, namely neurilemmomas, are benign nerve sheath tumors and comprise the myelin sheaths around the peripheral nerves. Schwannomas commonly occur in the head and neck, or extremities, less found in the mediastinum and retroperitoneum, and rarely in the pelvis. We report a 40-year-old male presenting with an 18-month history of nocturia and urinary frequency. Transrectal ultrasound revealed a well-defined, 2.81 cm × 3.77 cm in size, homogeneous, hypoechoic mass in the tail of the left seminal vesicle, compatible with the finding of a well-demarcated mass at the left seminal vesicle with homogeneous contrast enhancement on computed tomography. He underwent laparoscopic excision of the mass via da Vinci robotic surgical system. Intraoperative sonography showed that the mass exhibited the majority of hypoechoic density with some hyperechoic spots inside. Pathology reveals schwannoma. Both of erectile and ejaculatory functions were claimed postoperatively. Our case report highlights the potential of either intraoperative or preoperative sonography in the assessment of the seminal vesicle schwannoma.

United in Fight against prOstate cancer (UFO) registry: first results from a large, multi-centre, prospective, longitudinal cohort study of advanced prostate cancer in Asia.

OBJECTIVES: To document the management of advanced prostate cancer including diagnosis, prognosis, treatment, and care, in real-world practice in Asia using the United in Fight against prOstate cancer (UFO) registry. PATIENTS AND METHODS: We established a multi-national, longitudinal, observational registry of patients with prostate cancer presenting to participating tertiary care hospitals in eight Asian countries. A total of 3636 eligible patients with existing or newly diagnosed high-risk localised prostate cancer (HRL), non-metastatic biochemically recurrent prostate cancer (M0), or metastatic prostate cancer (M1), were consecutively enrolled and are being followed-up for 5 years. Patient history, demographic and disease characteristics, treatment and treatment decisions, were collected at first prostate cancer diagnosis and at enrolment. Patient-reported quality of life was prospectively assessed using the European Quality of Life-five Dimensions, five Levels (EQ-5D-5L) and Functional Assessment of Cancer Therapy for Prostate Cancer questionnaires. In the present study, we report the first interim analysis of 2063 patients enrolled from study start (15 September 2015) until 18 May 2017. RESULTS: Of the 2063 enrolled patients, 357 (17%), 378 (19%), and 1328 (64%) had HRL, M0 or M1 prostate cancer, respectively. The mean age at first diagnosis was similar in each group, 56% of all patients had extracapsular extension of their tumour, 28% had regional lymph node metastasis, and 53% had distant metastases. At enrolment, 62% of patients had at least one co-morbidity (mainly cardiovascular disease or diabetes), 91.8% of M1 patients had an Eastern Cooperative Oncology Group performance score of <2 and the mean EQ-5D-5L visual analogue score was 74.6-79.6 across cohorts. Treatment of M1 patients was primarily with combined androgen blockade (58%) or androgen-deprivation therapy (either orchidectomy or luteinising hormone-releasing hormone analogues) (32%). Decisions to start therapy were mainly driven by treatment guidelines and disease progression. Decision to discontinue therapy was most often due to disease progression (hormonal drug therapy) or completion of therapy (chemotherapy). CONCLUSION: In the UFO registry of advanced prostate cancer in Asia, regional differences exist in prostate cancer treatment patterns that will be explored more deeply during the follow-up period; prospective follow-up is ongoing. The UFO registry will provide valuable descriptive data on current disease characteristics and treatment landscape amongst patients with prostate cancer in Asia.

Prothymosin-α enhances phosphatase and tensin homolog expression and binds with tripartite motif-containing protein 21 to regulate Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 signaling in human bladder cancer.

Prothymosin-α (PTMA) is a small, acidic protein that is usually transported into the nucleus and involves many cellular and immunological functions. Previous studies demonstrated that aberrant location of PTMA expression exists in human bladder cancer, but the role of PTMA protein expression remains elusive. In this study, we created ectopic nuclear or cytoplasmic PTMA expression in human bladder cancer cells by infecting lentiviruses carrying wild type or deleted nuclear localization signal of the PTMA gene. The in vivo tumorigenesis assay showed PTMA protein with deleted nuclear localization signal promotes J82 xenograft tumor growth in mice and shortens their survival more so than the wild type. Chromatin immunoprecipitation showed that wild-type PTMA protein binds to the PTEN promoter and enhances phosphatase and tensin homolog (PTEN) expression. Through immunoblot proteomics and in vivo ubiquitination studies, PTMA protein can bind with tripartite motif-containing protein 21 (TRIM21) and block its ubiquitination. Also, TRIM21 can downregulate both forms of PTMA protein. In human bladder tumors, loss of nuclear PTMA expression was an unfavorable prognostic indicator for shorter disease-free survival (hazard ratio, 1.54; P = 0.009). Our data support that nuclear PTMA protein serves as a tumor suppressor in bladder cancer through upregulating PTEN and orchestrating TRIM21 for the regulation of Nrf2 signaling.

Incorporating Simplified Fournier's Gangrene Severity Index with early surgical intervention can maximize survival in high-risk Fournier's gangrene patients.

OBJECTIVES: To determine the optimal surgical timing in high-risk patients with Fournier's gangrene by the Simplified Fournier's Gangrene Severity Index. METHODS: From 1989 to 2018, 118 male patients diagnosed with Fournier's gangrene with complete medical records were retrospectively reviewed. Patients' demographics, laboratory parameters at initial diagnosis, Fournier's Gangrene Severity Index and Simplified Fournier's Gangrene Severity Index, and the time interval from emergency room arrival to surgical intervention were collected. The Fournier's gangrene patients were categorized into low-risk (Simplified Fournier's Gangrene Severity Index ≤2) and high-risk groups (Simplified Fournier's Gangrene Severity Index >2). Differences between the variables within the two groups were analyzed. The optimal surgical timing was analyzed with the receiver operating characteristic curve in high-risk Fournier's gangrene patients. RESULTS: The overall mortality of 118 Fournier's gangrene patients was 14.4%. After risk stratification with the Simplified Fournier's Gangrene Severity Index scoring system, the mortality of low-risk and high-risk Fournier's gangrene patients was 1.3% and 41.0%, respectively. In the high-risk group, the time interval from emergency room arrival to surgical intervention was the only variable with a significant difference between survivors and non-survivors (P = 0.039). The optimal surgical timing was determined at 14.35 h, which allowed the highest sensitivity (0.688) and specificity (0.762) to affect mortality. The mortality was significantly lower in high-risk Fournier's gangrene patients with early surgical intervention compared with late intervention (23.8% vs 68.8%, P = 0.007). CONCLUSIONS: The Simplified Fournier's Gangrene Severity Index is a quick and reliable screening tool for first-line physicians to identify high-risk patients with Fournier's gangrene (Simplified Fournier's Gangrene Severity Index >2) who have poor survival outcomes. We recommended early surgical intervention within 14.35 h to maximize the survival of high-risk Fournier's gangrene patients.

Association of Prostate Blood Flow with Male Lower Urinary Tract Symptoms.

PURPOSE: To investigate the association of prostate blood flow (PBF) with lower urinary tract symptoms (LUTS) in aged males using Doppler spectral waveform (DSW) analysis. PATIENTS AND METHODS: We performed a prospective analysis involving 133 aged males with clinical diagnosis of LUTS. DSW parameters (peak-systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI)) were measured at bilateral neurovascular bundles (NVB), periurethral, and capsular branches by Doppler transrectal ultrasound with the patient in the right lateral decubitus position. The associations of PBF parameters and the International Prostate Symptom Score (IPSS) were analyzed. RESULTS: Overall, total IPSS scores were significantly correlated with the RI of bilateral NVB vessels (r2 = 0.03, 0.04; p = 0.04, 0.02, respectively), and PSV of left NVB vessels. PSV of bilateral NVB vessels were associated with the storage score (p = 0.022 and p = 0.016), but not with the voiding score. The sum of the frequency and urgency score was also associated with EDV of both capsular and urethral branches (p = 0.043 and p = 0.009, respectively), and PSV of NVB vessels on both sides (p = 0.045 and p = 0.019, respectively). CONCLUSIONS: There is an association between PBF and LUTS, especially with storage symptoms. The findings may provide some insights in understanding the underlying pathophysiology of lower urinary tract dysfunction.

Risk of secondary primary malignancies in survivors of upper tract urothelial carcinoma: A nationwide population-based analysis.

BACKGROUND: To investigate the cancer types and risk factors of secondary primary malignancy (SPM) in patients with upper tract urothelial carcinoma (UTUC) in Taiwan. METHODS: Using National Health Insurance Research Dataset and catastrophic illness registry, we enrolled newly diagnosed UTUC patients from 2000 to 2013. Those without catastrophic illness registration were excluded from the study. The cancer types and hazard ratios (HRs) of subsequent SPMs were calculated according to the antecedent malignancy. We analyzed the risk factors for developing SPMs using multivariate Cox proportional hazard models. RESULTS: A total of 9050 UTUC patients were registered and 2187 (24.2%) patients developed SPMs during the study period. As compared with primary UTUC, the relative risk ratios of SPM was 2.5 folds and 18% higher in those with antecedent non-UC malignancy and with bladder cancer history, respectively. Totally, 387 (37.8%) of 1022 UTUC patients with antecedent non-UC malignancy developed subsequent SPM after UTUC diagnosis. The antecedent and subsequent cancer types are similar and kidney cancer is most common, followed by hepatoma. Multivariate analysis showed that a history of antecedent non-UC malignancy is the most unfavorable factor for SPM development (HR, 2.50; 95% CI, 2.23-2.81), followed by liver disease, male gender, antecedent bladder cancer history, age ≥ 75 years, and chronic kidney disease. CONCLUSIONS: Our study, conducted in Taiwan and involving 9050 UTUC patients, meticulously examined the types of SPM and the associated risk factors. Our research unearthed several pivotal discoveries: a preceding history of non-UC malignancies emerged as the single most influential factor contributing to the occurrence of subsequent cancers, followed by liver disease, male gender, antecedent bladder cancer history, age ≥75 years, and chronic kidney disease. Futhermore, kidney cancer emerged as the predominant subsequent malignancy, closely trailed by hepatoma..

TGF-ß1 conjugated to gold nanoparticles results in protein conformational changes and attenuates the biological function.

Gold nanoparticles (AuNPs) are widely used as carriers or therapeutic agents due to their great biocompatibility and unique physical properties. Transforming growth factor-beta 1 (TGF-ß1), a member of the cysteine-knot structural superfamily, plays a pivotal role in many diseases and is known as an immunosuppressive agent that attenuates immune response resulting in tumor growth. The results reported herein reflect strong interactions between TGF-ß1 and the surface of AuNPs when incubated with serum-containing medium, and demonstrate a time- and dose-dependent pattern. Compared with other serum proteins that can also bind to the AuNP surface, AuNP-TGFß1 conjugate is a thermodynamically favored compound. Epithelial cells undergo epithelial-mesenchymal transition (EMT) upon treatment with TGF-ß1; however, treatment with AuNPs reverses this effect, as detected by cell morphology and expression levels of EMT markers. TGF-ß1 is found to bind to AuNPs through S-Au bonds by X-ray photoelectron spectroscopy. Fourier transform infrared spectroscopy is employed to analyze the conformational changes of TGF-ß1 on the surface of AuNPs. The results indicate that TGF-ß1 undergoes significant conformational changes at both secondary and tertiary structural levels after conjugation to the AuNP surface, which results in the deactivation of TGF-ß1 protein. An in vivo experiment also shows that addition of AuNPs attenuates the growth of TGF-ß1-secreting murine bladder tumor 2 cells in syngeneic C3H/HeN mice, but not in immunocompromised NOD-SCID mice, and this is associated with an increase in the number of tumor-infiltrating CD4⁺ and CD8⁺ T lymphocytes and a decrease in the number of intrasplenic Foxp3(+) lymphocytes. The findings demonstrate that AuNPs may be a promising agent for modulating tumor immunity through inhibiting immunosuppressive TGF-ß1 signaling.

Clinicopathologic Analysis of Micropapillary Urothelial Carcinoma of the Upper Urinary Tract: Implications for HER2-Targeted Therapy.

Introduction/Background To determine the clinical significance of micropapillary urothelial carcinoma (MPUC) of the upper urinary tract (UTUC) and a potential therapeutic strategy. Patients and Methods A retrospective cohort study was conducted to examine the incidence of micropapillary UTUC from 2010 to 2018 and its clinicopathological characteristics. Clinical outcomes and cancer-specific survival (CSS) were compared between MPUC and conventional UTUC matched by stage within a 6-month variation of receiving surgery. Results A total of 24 MPUC cases were identified out of 901 cases (2.7%) of urothelial carcinoma (UC) of the renal pelvis and ureter. MPUC was significantly smaller (<3 cm) and associated with nodal metastasis compared with conventional UTUC (P = .017 & 0.021, respectively); however, no significant difference was observed for lymphovascular invasion, distant metastasis, or CSS (P > 0.50, respectively) compared with match controls. Six MPUC patients (25%) developed metastasis to the liver, lymph nodes, and lung during follow-up. Patients with HER2-positive MPUC (3 of 4) had a significantly higher risk of metastasis compared with HER2-negative MPUC (3 of 20; P = 0.035). Conclusions MPUC is an aggressive variant of UTUC and usually presents as a small locally advanced disease. HER2 immunohistochemistry may identify the subset of patients with micropapillary UTUC that are candidates for targeted therapy.

Oct4 and Hypoxia Dual-Regulated Oncolytic Adenovirus Armed with shRNA-Targeting Dendritic Cell Immunoreceptor Exerts Potent Antitumor Activity against Bladder Cancer.

Immunotherapy has emerged as a promising modality for cancer treatment. Dendritic cell immunoreceptor (DCIR), a C-type lectin receptor, is expressed mainly by dendritic cells (DCs) and mediates inhibitory intracellular signaling. Inhibition of DCIR activation may enhance antitumor activity. DCIR is encoded by CLEC4A in humans and by Clec4a2 in mice. Gene gun-mediated delivery of short hairpin RNA (shRNA) targeting Clec4a2 into mice bearing bladder tumors reduces DCIR expression in DCs, inhibiting tumor growth and inducing CD8+ T cell immune responses. Various oncolytic adenoviruses have been developed in clinical trials. Previously, we have developed Ad.LCY, an oncolytic adenovirus regulated by Oct4 and hypoxia, and demonstrated its antitumor efficacy. Here, we generated a Clec4a2 shRNA-expressing oncolytic adenovirus derived from Ad.LCY, designated Ad.shDCIR, aimed at inducing more robust antitumor immune responses. Our results show that treatment with Ad.shDCIR reduced Clec4a expression in DCs in cell culture. Furthermore, Ad.shDCIR exerted cytolytic effects solely on MBT-2 bladder cancer cells but not on normal NIH 3T3 mouse fibroblasts, confirming the tumor selectivity of Ad.shDCIR. Compared to Ad.LCY, Ad.shDCIR induced higher cytotoxic T lymphocyte (CTL) activity in MBT-2 tumor-bearing immunocompetent mice. In addition, Ad.shDCIR and Ad.LCY exhibited similar antitumor effects on inhibiting tumor growth. Notably, Ad.shDCIR was superior to Ad.LCY in prolonging the survival of tumor-bearing mice. In conclusion, Ad.shDCIR may be further explored as a combination therapy of virotherapy and immunotherapy for bladder cancer and likely other types of cancer.

Outcome of Non-Muscle Invasive Upper Tract Urothelial Carcinoma Receiving Endoscopic Ablation: An Inverse Probability of Treatment Weighting Analysis.

We compared the outcomes in early-stage upper tract urothelial carcinoma (UTUC) patients receiving endoscopic ablation (EA) with radical nephroureterectomy (RNU). From 2004 to 2018, cTa/T1N0M0 UTUC patients undergoing EA and RNU were enrolled. For reducing observational bias, propensity scores based on inverse probability of treatment weighting (IPTW) were utilized for comparing the oncologic outcomes and renal function changes. In total, 65 of 184 cTa/T1 UTUC patients were analyzed after exclusion of 119 patients with end-stage renal disease, and lack of previous ureteroscopic biopsy. The studied patients included 23 who received EA and 42 RNU, and both groups were well balanced after adjusting with IPTW. The median follow-up period was 43.6 months. There was no statistical difference between the two groups in terms of oncological outcome. The EA group exhibited less estimated glomerular filtration rate (eGFR) decline one year later (0.0% vs. 20.2%, p < 0.001) and less worsening of chronic kidney status (13.2% vs. 46.5%, p = 0.026). Among patients receiving EA, high-grade tumors exhibited higher subsequent recurrence in the residual urinary tract than did the low-grade ones. (p = 0.037). In summary, endoscopic ablation preserves renal function without compromising oncological outcome in selected UTUC patients. High-grade tumors should be strictly followed up following endoscopic ablation.

Safety and efficacy of tubeless percutaneous nephrolithotomy in patients on anti-platelet therapy and cirrhotic patients.

Without the temponade effect over nephrostomy tube, postoperative hemorrhage is a major concern to the safety of tubeless percutaneous nephrolithotomy (PCNL) in patients with bleeding tendency. In this study, we would like to report our experience of performing tubeless PCNLs in these patients. At the end of PCNL, we cauterized the bleeding points in access tract for hemostasis to facilitate the achievement of tubeless PCNL. We identified and reviewed 16 patients under antiplatelet agent therapy and 6 patients with liver cirrhosis from 598 tubeless PCNLs performed in a single institute. Among the 16 patients undergoing anti-platelet therapy, the average stone size was 2.8 cm. The average operation time was 84.7 min. The stone-free rate was 87.5%. The average postoperative hospital stay was 3.8 days. Two patients (12.5%) experienced urinary tract infections after operation. There was no uncontrolled hemorrhage during and after operation and only one patient needed postoperative blood transfusion. No patient experienced any thromboembolic complication. Of the six patients with liver cirrhosis, the average stone size was 3.3 cm. The average operation time was 77.5 min. The stone-free rate is 83.4%. The average postoperative hospital stay was 4.0 days. No patient received blood transfusion after operation. There was no patient experiencing urinary tract infection after operation. Our results suggest that with careful hemostasis, tubeless PCNL is a safety modality in the treatment of urinary stone disease in patients on chronic anti-platelet therapy and cirrhotic patients.

Study on the pathophysiological mechanism responsible for lower urinary tract symptoms associated with prostate cancer using an animal model.

OBJECTIVES: To investigate the pathophysiological mechanism leading to lower urinary tract symptoms in prostate cancer (PCa) by using an animal model. METHODS: An orthotopic PCa model in mice was established by injection of human DU145 cells into the prostate gland lateral lobe of NOD.CB17-Prkdcscid /NcrCrlBltw (NOD-SCID) mice. Cancer growth was quantified by a luciferase-based in vivo imaging system (IVIS) serially every 7 days. Comparisons were made for urodynamic parameters, bladder histology, and biological markers until the sixth week. Bladder wall structural changes were assessed by the bladder wall thickness and degree of fibrosis. Biomarker expressions in bladder tissue including muscarinic acetylcholine receptor 2 (M2 ), transient receptor potential cation channel subfamily V member 4 (TRPV4), BCL2-associated X protein (Bax), and caspase3 were evaluated by immunohistochemical staining and immunofluorescence confocal laser scanning microscopy. RESULTS: DU145 cell growth in the prostate was successfully monitored by a luciferase-based IVIS. after orthotopic injection. Using our injection technique, no anatomical obstruction of the bladder outlet and urethra was noted up to 6 weeks after injection. The presence of PCa induced changes in urinary bladder histology, biomarkers, and urodynamic parameters. Cystometry showed features of detrusor overactivity with increased voiding frequency and high-amplitude voiding contractions from the fourth week onward. Histological analyses 4 weeks after DU145 injection demonstrated detrusor thickening and bladder wall fibrosis. Immunohistochemistry showed increased expressions of bladder M2 , TRPV4, Bax, and caspase3 in the PCa mice as early as in the first or second week. CONCLUSIONS: PCa can induce bladder microenvironment changes involving neural receptors and biological mediators leading to histological and functional alterations even in the absence of overt anatomical obstruction.

Determinants and Dynamic Changes of Generic Quality of Life in Human Bladder Cancer Patients.

We measured and determined the factors associated with long-term generic quality-of-life (QOL) changes in human bladder cancer patients. We utilized the World Health Organization QOL-Brief questionnaire to assess consecutive patients' QOL at outpatient clinics of our hospital. A mixed-effects model was constructed to investigate the determinants of QOL changes according to each domain and individual item after controlling for demographic and clinical factors, as well as the effect of radical cystectomy. We also applied a kernel smoothing method to describe the long-term dynamic changes after the first definite treatment. In total, 1185 repeated measurements were collected from 343 bladder cancer patients. The mixed-effects models demonstrated that marital status, monthly income, and comorbidity with heart disease and diabetes were significant determinants among all the study participants. Regardless of the urinary diversion type, radical cystectomy contributed to lower scores for all four domains, mainly from 4-5 years after cystectomy, which declined significantly in patients who were older than 60 years. As for non-muscle-invasive bladder cancer (NMIBC) patients with preserved bladders, tumor recurrence was a major predictor for lower scores for sexual activity in the social domain. In summary, generic QOL can be independently influenced by many factors, not only cystectomy and tumor recurrence, which should be discussed with patients before treatment.

Dynamic Changes of Generic Quality of Life after Different Treatments for Localized Prostate Cancer.

Generic quality of life (QoL) is an important issue in decision making related to the primary treatment of localized prostate cancer (PC). This study assessed the dynamic changes of QoL in patients with localized PC under different treatment modalities. From 2013 to 2018, we prospectively assessed QoL scores in patients with localized PC under unitary treatment using the World Health Organization Quality of Life (WHOQOL) BREF version. The trajectories of the QoL scores after different treatments were estimated using a kernel-smoothing method. Dynamic changes in the major determinants were analyzed using a mixed effects model. The clinical features of the participants in our institute were compared with PC patients in Taiwan's cancer registry. A total of 196 patients were enrolled with 491 repeated assessments. The participants shared similar clinical characteristics with the PC patients in Taiwan as a whole. Patients with lower household incomes showed statistically significant lower scores on all four domains and related facets, while PC survivors with comorbidities of anxiety and/or diabetes appeared to be affected on the physical domain and related facets. After controlling for these determinants, patients under active surveillance or observation demonstrated significantly higher QoL scores in the physical and social domains, as well as several facets belonging to these domains, in mixed models compared with patients undergoing radical prostatectomy or radiotherapy within the first year. The generic QoL scores were higher within the first year in patients receiving active surveillance or observation after controlling other significant factors. The difference diminished after one year of post management. More studies are needed to corroborate our findings.

The significance of SMARCB1 in the pathogenesis of renal cell carcinoma with rhabdoid features.

BACKGROUND: Renal cell carcinoma with rhabdoid features (RCC-RF) is an aggressive histologic variant in the adults and is usually unresponsive to standard chemotherapy. METHODS: Expression of SMARCB1/INI1 was examined in primary RCC-RF (n = 5). Stable INI1 with/without prostaglandin E2 receptor 1 (EP1) knockdown cell lines were created in the ACHN and 786-O RCC cell lines and measured for epidermal growth factor receptor (EGFR)-related signaling pathways. Chemosensitivity to targeted drugs in vitro was tested after knocking down of INI1 in both cell lines. The outcome of co-targeting of INI1 and EP1 in RCC was examined using a tumorigenicity assay. RESULTS: Expression of INI1 was markedly reduced at both transcriptional and translational levels in primary RCC-RF. Immunohistochemical expression of INI1 protein was lost in the nuclei of rhabdoid cells compared with conventional RCC (n = 8). Using two cell lines with different genetic background, we showed that knocking down of INI1 activates the EGFR signaling with up-regulated AKT and ERK pathways and sensitizes cancer cells to Erlotinib treatment in vitro. However, cell-line dependent effects were also demonstrated with reference to impact of INI1 or EP1 on cell growth, migration and response to Gefitinib or Everolimus treatment in vitro. CONCLUSION: Inactivation of INI1 may play a role in the pathogenesis of RCC-RF. Erlotinib is recommended in the management of patients with INI1-related RCC.