Enhancing the autologous fascial sling procedure: A novel fixation method for treating stress urinary incontinence in female patients.

BACKGROUND: Synthetic mid-urethral sling surgery has long been the standard surgical treatment for stress urinary incontinence (SUI) worldwide. Using an autologous fascial sling is an alternative to reduce adverse events. We evaluated the treatment outcomes of a novel fixation method applied to the autologous transobturator fascial (TOF) sling procedure for female patients with SUI. METHODS: A retrospective study was conducted between 2017 and 2020, including 33 patients with SUI who underwent mid-urethral TOF sling surgery with the novel fixation method. We used a self-locking feature (V-LOC™) that was fixed to each side of skin layer above the obturator foramen, and the tension of the fascia sling was adjusted by manipulating the V-LOC™ suture. We analyzed all data collected through questionnaires, including Urinary Distress Inventory-Short Form (UDI-6), Incontinence Impact Questionnaire-Short Form (IIQ-7), Overactive Bladder Symptom Score (OABSS), and Clinical Global Impressions of Improvement (CGI-I). Adverse events were also recorded. RESULTS: This study included 33 female patients aged 39-79 (mean 59.76 years). Following the procedure, there was a significant reduction in the total scores of UDI-6, IIQ-7, and OABSS (preoperative 9.73±4.35, 10.21±5.79, 6.06±4.03 and postoperative 3.52±3.41, 0.85±3.67, 3.06±2.90, respectively) (p < 0.001). Further analysis of each sub-score of the questionnaires revealed significant improvement in certain symptoms. The mean total score of CGI-I was 2.00 ± 0.80. The maximum flow rate was documented for 18 patients, and no significant reduction was observed after the procedure (p = 0.804). Complications reported included voiding dysfunction in two patients (6.1 %), inguinal pain in one patient (3.0 %), and mild delayed wound healing in one patient (3.0 %). CONCLUSION: This modified TOF sling surgery with a novel fixation method by V-LOC™ suture offers feasibility and adjustability as its main advantages. Our study demonstrated significant improvements in patient outcomes.

Predictors of Contralateral Disease in Men With Unilateral Lesions on Multiparametric Magnetic Resonance Imaging.

OBJECTIVE: To evaluate predictors of contralateral clinically significant prostate cancer (csPCa) in men with biopsy-proven unilateral lesions on magnetic resonance imaging (MRI). METHODS: We retrospectively identified men with no prior diagnosis of PCa with unilateral biopsy-confirmed csPCa within PI-RADS 2-5 lesions within our institutional biopsy database. Multivariate logistic regression was used to identify clinical predictors of contralateral disease. RESULTS: Four hundred ninety men met study inclusion criteria, of which 385 men (78.6%) had no contralateral csPCa and 105 men (21.4%) had contralateral csPCa (Fig. 1). Prior negative biopsy (OR 0.34 [0.14, 0.75], P = .012), prostate-specific antigen density (OR 18.8 [2.77, 249], P = .017), and tumor location in the transverse plane ("Posterior": OR 1.93 [1.02, 3.87], P = .048; "Throughout Transverse Plane": OR 6.56 [2.26, 19.6], P < .001) were significantly associated with contralateral csPCa in multivariate logistic regression models. However, there appear to be no attributes within the MRI-targeted tumor that reliably predict contralateral csPCa (Table 2). CONCLUSION: Approximately 20% of men with unilateral MRI findings and csPCa on targeted biopsy were found to have contralateral csPCa on systematic biopsy (SB). Prior negative biopsy was associated with a decreased odds of contralateral csPCa. Prostate-specific antigen density and tumor in the posterior aspect of or throughout the transverse plane were associated with increased odds of contralateral csPCA. Consideration of these clinical factors may afford an opportunity to only use SB in cases in which the odds of contralateral csPCa are high.

The lncRNA TPT1-AS1 promotes the survival of neuroendocrine prostate cancer cells by facilitating autophagy.

The lncRNA tumor protein translationally controlled 1-antisense RNA 1 (TPT1-AS1) is known for its oncogenic role in various cancers, but its impact on the pathological progression of prostate cancer remains unclear. Our previous study demonstrated that the RE1-silencing transcription factor (REST) regulates neuroendocrine differentiation (NED) in prostate cancer (PCA) by derepressing specific long non-coding RNAs (lncRNAs), including TPT1-AS1. In this study, we revealed that TPT1-AS1 is overexpressed in LNCaP and C4-2B cells after IL-6 and enzalutamide treatment. By analyzing The Cancer Genome Atlas (TCGA) prostate adenocarcinoma dataset, we detected upregulated TPT1-AS1 expression in neuroendocrine-associated PCA but not in prostate adenocarcinoma. Single-cell RNA sequencing data further confirmed the increased TPT1-AS1 levels in neuroendocrine prostate cancer (NEPC) cells. Surprisingly, functional experiments indicated that TPT1-AS1 overexpression had no stimulatory effect on NED in LNCaP cells and that TPT1-AS1 knockdown did not inhibit IL-6-induced NED. Transcriptomic analysis revealed the essential role of TPT1-AS1 in synaptogenesis and autophagy activation in neuroendocrine differentiated PCA cells induced by IL-6 and enzalutamide treatment. TPT1-AS1 was found to regulate the expression of autophagy-related genes that maintain neuroendocrine cell survival through autophagy activation. In conclusion, our data expand the current knowledge of REST-repressed lncRNAs in NED in PCA and highlight the contribution of TPT1-AS1 to protect neuroendocrine cells from cell death rather than inducing NED. Our study suggested that TPT1-AS1 plays a cytoprotective role in NEPC cells; thus, targeting TPT1-AS1 is a potential therapeutic strategy.

Predicting Clinically Significant Prostate Cancer Using Urine Metabolomics via Liquid Chromatography Mass Spectrometry.

PURPOSE: Biomarkers predicting clinically significant prostate cancer (sPC) before biopsy are currently lacking. This study aimed to develop a non-invasive urine test to predict sPC in at-risk men using urinary metabolomic profiles. MATERIALS AND METHODS: Urine samples from 934 at-risk subjects and 268 treatment-naïve PC patients were subjected to liquid chromatography/mass spectrophotometry (LC-MS)-based metabolomics profiling using both C18 and hydrophilic interaction liquid chromatography (HILIC) column analyses. Four models were constructed (training cohort [n=647]) and validated (validation cohort [n=344]) for different purposes. Model I differentiates PC from benign cases. Models II, III, and a Gleason score model (model GS) predict sPC that is defined as National Comprehensive Cancer Network (NCCN)-categorized favorable-intermediate risk group or higher (Model II), unfavorable-intermediate risk group or higher (Model III), and GS ≥7 PC (model GS), respectively. The metabolomic panels and predicting models were constructed using logistic regression and Akaike information criterion. RESULTS: The best metabolomic panels from the HILIC column include 25, 27, 28 and 26 metabolites in Models I, II, III, and GS, respectively, with area under the curve (AUC) values ranging between 0.82 and 0.91 in the training cohort and between 0.77 and 0.86 in the validation cohort. The combination of the metabolomic panels and five baseline clinical factors that include serum prostate-specific antigen, age, family history of PC, previously negative biopsy, and abnormal digital rectal examination results significantly increased AUCs (range 0.88-0.91). At 90% sensitivity (validation cohort), 33%, 34%, 41%, and 36% of unnecessary biopsies were avoided in Models I, II, III, and GS, respectively. The above results were successfully validated using LC-MS with the C18 column. CONCLUSIONS: Urinary metabolomic profiles with baseline clinical factors may accurately predict sPC in men with elevated risk before biopsy.

Real-world safety and effectiveness of radium-223 in patients with metastatic castration-resistant prostate cancer: Interim analyses of the prospective, observational RAPIT study.

Several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC) are available, including radium-223 dichloride (223Ra), which was approved based on phase 3 data demonstrating improved overall survival (OS) and a favorable safety profile. To date, real-world evidence for 223Ra use in Taiwan is from three studies of <50 patients. This observational study (NCT04232761) enrolled male patients with histologically/cytologically confirmed mCRPC with bone metastases from centers across Taiwan. 223Ra was prescribed as part of routine practice by investigators. Patients with prior 223Ra treatment were excluded. The primary objective was to assess 223Ra safety; secondary objectives evaluated efficacy parameters, including OS. Overall, 224 patients were enrolled. Most patients had an Eastern Cooperative Oncology Group performance status of 0/1 (79.0%) and ≤20 bone metastases (69.2%); no patients had visceral metastases. 223Ra was first- or second-line therapy in 23.2% and 47.7% of patients, respectively. The total proportion of patients who received 5-6 223Ra cycles was 68.8%; this proportion was greater with first-line use (84.3%) than second- (65.7%) or third-/fourth-line use (64.1%). More chemotherapy-naïve patients (61.9%) completed the 6-cycle 223Ra treatment than chemotherapy-exposed patients (56.7%). Any-grade treatment-emergent adverse events (TEAEs) and serious TEAEs occurred in 54.0% and 28.6% of patients, respectively, while 12% experienced 223Ra-related adverse events. Median OS was 15.7 months (95% confidence interval 12.13-19.51); patients receiving 5-6 223Ra injections and earlier 223Ra use had longer OS than those receiving fewer injections and later 223Ra use. 223Ra provides a well-tolerated and effective treatment for Taiwanese patients with mCRPC and bone metastases.

Survival outcomes of radium-223 therapy for metastatic castration-resistant prostate cancer following national health insurance reimbursement in Taiwan.

BACKGROUND: Radium-223 dichloride (Ra-223) prolongs overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) with symptomatic bone metastases. However, there is considerable variation in outcomes among individuals. We aimed to evaluate the prognostic determinants associated with patient survival following National Health Insurance (NHI) reimbursement for Ra-223 therapy in Taiwan. METHODS: Patients with mCRPC who underwent Ra-223 treatment at Taipei Veterans General Hospital were retrospectively enrolled. Each intravenous Ra-223 dose was administered at 55 kBq/kg at 4-week intervals. Clinical outcomes were obtained from medical records; potential prognostic factors for survival were assessed. Kaplan-Meier analysis was used to generate cumulative survival curves; between-group differences were evaluated using the Chi-squared test. Statistical significance was set at p < 0.05. RESULTS: Seventy-six patients underwent Ra-223 therapy; 62 patients received NHI reimbursement and the remainder self-paid. Fifty patients (65.8%) completed six cycles of treatment; 26 (34.2%) received 1 to 5 cycles. Mortality occurred in 47 patients. Factors significantly associated with survival included ≤five bone metastases ( p = 0.0018), baseline prostate-specific antigen (PSA) ≤36 ng/mL ( p = 0.0004), baseline alkaline phosphate (ALP) <115 U/L ( p = 0.0007), and baseline hemoglobin (Hb) >12 g/dL ( p = 0.0029). Patients who completed six cycles of treatment achieved significantly higher OS compared to those who did not ( p < 0.0001). There has been a 4.4-fold increase in the number of patients since reimbursement began; there was no significant difference in OS between patients who received NHI reimbursement and those who self-paid. CONCLUSION: Administration of Ra-223 demonstrates considerable potential to extend the survival of patients with mCRPC. Survival outcomes may be influenced by various prognostic factors. However, no significant difference in OS was observed subsequent to reimbursement of Ra-223 therapy for mCRPC through the NHI system in Taiwan.

Organ preservation in muscle-invasive urothelial bladder cancer.

PURPOSE OF REVIEW: The most common definitive treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy. However, removing the bladder and surrounding organs poses risks of morbidity that can reduce quality of life, and raises the risk of death. Treatment strategies that preserve the organs can manage the local tumor and mitigate the risk of distant metastasis. Recent data have demonstrated promising outcomes in several bladder-preservation strategies. RECENT FINDINGS: Bladder preservation with trimodality therapy (TMT), combining maximal transurethral resection of the bladder tumor, chemotherapy, and radiotherapy (RT), was often reserved for nonsurgical candidates for radical cystectomy. Recent meta-analyses show that outcomes of TMT and radical cystectomy are similar. More recent bladder-preservation approaches include combining targeted RT (MRI) and immune checkpoint inhibitors (ICIs), ICIs and chemotherapy, and selecting patients based on genomic biomarkers and clinical response to systemic therapies. These are all promising strategies that may circumvent the need for radical cystectomy. SUMMARY: MIBC is an aggressive disease with a high rate of systemic progression. Current management includes neoadjuvant cisplatin-based chemotherapy and radical cystectomy with lymph node dissection. Novel alternative strategies, including TMT approaches, combinations with RT, chemotherapy, and/or ICIs, and genomic biomarkers, are in development to further advance bladder-preservation options for patients with MIBC.

Interaction of patient age and high-grade prostate cancer on targeted biopsies of MRI suspicious lesions.

OBJECTIVES: To evaluate the interaction of patient age and Prostate Imaging-Reporting and Data System (PI-RADS) score in determining the grade of prostate cancer (PCa) identified on magnetic resonance imaging (MRI)-targeted biopsy in older men. PATIENTS AND METHODS: From a prospectively accrued Institutional Review Board-approved comparative study of MRI-targeted and systematic biopsy between June 2012 and December 2022, men with at least one PI-RADS ≥3 lesion on pre-biopsy MRI and no prior history of PCa were selected. Ordinal and binomial logistic regression analyses were performed. RESULTS: A total of 2677 men met study criteria. The highest PI-RADS score was 3 in 1220 men (46%), 4 in 950 men (36%), and 5 in 507 men (19%). The median (interquartile range [IQR]) patient age was 66.7 (60.8-71.8) years, median (IQR) prostate-specific antigen (PSA) level was 6.1 (4.6-9.0) ng/mL, median (IQR) prostate volume was 48 (34-68) mL, and median (IQR) PSA density was 0.13 (0.08-0.20) ng/mL/mL. Clinically significant (cs)PCa and high-risk PCa were identified on targeted biopsy in 1264 (47%) and 321 (12%) men, respectively. Prevalence of csPCa and high-risk PCa were significantly higher in the older age groups. On multivariable analyses, patient age was significantly associated with csPCa but not high-risk PCa; PI-RADS score and the interaction of age and PI-RADS score were significantly associated with high-risk PCa but not csPCa. CONCLUSION: In our cohort, the substantial rate of high-risk PCa on MRI-ultrasound fusion targeted biopsies in older men, and its significant association with MRI findings, supports the value of pre-biopsy MRI to localise disease that could cause cancer mortality even in older men.

High-volume prostate biopsy core involvement is not associated with an increased risk of cancer recurrence following 5-fraction stereotactic body radiation therapy monotherapy.

PURPOSE: Percentage of positive cores involved on a systemic prostate biopsy has been established as a risk factor for adverse oncologic outcomes and is a National Comprehensive Cancer Network (NCCN) independent parameter for unfavorable intermediate-risk disease. Most data from a radiation standpoint was published in an era of conventional fractionation. We explore whether the higher biological dose delivered with SBRT can mitigate this risk factor. METHODS: A large single institutional database was interrogated to identify all patients diagnosed with localized prostate cancer (PCa) treated with 5-fraction SBRT without ADT. Pathology results were reviewed to determine detailed core involvement as well as Gleason score (GS). High-volume biopsy core involvement was defined as ≥ 50%. Weighted Gleason core involvement was reviewed, giving higher weight to higher-grade cancer. The PSA kinetics and oncologic outcomes were analyzed for association with core involvement. RESULTS: From 2009 to 2018, 1590 patients were identified who underwent SBRT for localized PCa. High-volume core involvement was a relatively rare event observed in 19% of our cohort, which was observed more in patients with small prostates (p < 0.0001) and/or intermediate-risk disease (p = 0.005). Higher PSA nadir was observed in those patients with low-volume core involvement within the intermediate-risk cohort (p = 0.004), which was confirmed when core involvement was analyzed as a continuous variable weighted by Gleason score (p = 0.049). High-volume core involvement was not associated with biochemical progression (p = 0.234). CONCLUSIONS: With a median follow-up of over 4 years, biochemical progression was not associated with pretreatment high-volume core involvement for patients treated with 5-fraction SBRT alone. In the era of prostate SBRT and MRI-directed prostate biopsies, the use of high-volume core involvement as an independent predictor of unfavorable intermediate risk disease should be revisited.

Association of the minimal cyclophosphamide equivalent dose and outcome of microdissection testicular sperm extraction in patients with persistent azoospermia after chemotherapy.

Objective: To investigate whether the minimal cyclophosphamide equivalent dose (mCED), a novel approach for estimating alkylating agent exposure, is associated with the sperm retrieval rates by microdissection testicular sperm extraction (mTESE) in azoospermic postchemotherapy cancer survivors. Design: A retrospective cohort study conducted between 2002 and 2017. Setting: An academic medical center. Patients: A total of 28 azoospermic postchemotherapy cancer survivors who underwent mTESE. Interventions: Chemotherapy exposure and mCED calculation. Main Outcome Measures: The primary outcome was the association between the mCED and sperm retrieval rate using mTESE. The mCED value for each patient's regimen received was estimated using the lowest recommended dosing regimen from the range of recommended doses at the time of administration. Results: Spermatozoa were successfully retrieved in 11 (39.3%) of the patients. Age at the time of receiving chemotherapy and mCED were significant factors associated with sperm retrieval. An mCED of <4,000 mg/m2 had a higher sperm retrieval rate (10/14, 71.4%) than an mCED of >4,000 mg/m2 (0/8, 0). The hormone levels were not significantly different when comparing patients with and without successful sperm retrieval. Seminoma, nonseminomatous germ cell tumor, and acute lymphoblastic leukemia had favorable sperm retrieval rates-100% (2/2), 66.7% (2/3), and 66.7% (2/3), respectively-although the numbers of patients in each group were small. Conclusion: Among this cohort of patients with cancer who required chemotherapy regimens, successful sperm retrieval by mTESE was only noted among cancer survivors receiving an mCED of <4,000 mg/m2.

Sweet Syndrome and Neutrophilic Dermatosis of the Dorsal Hands.

Sweet syndrome is a rare cutaneous condition with a broad clinical differential diagnosis. It can be classified into 3 subtypes: classic, malignancy-associated, and drug-induced. There are numerous associated disorders and provoking medications. Uncommonly, it can present as a multiorgan disease and cause significant morbidity. Systemic corticosteroids are the gold standard of treatment and yield rapid improvements in both lesions and symptoms. Nonsteroidal therapies may be effective alternatives, although high-quality comparative data are lacking. Some treatments for Sweet syndrome have paradoxically been implicated in the induction of disease.

Eligibility Criteria for Active Ulcerative Pyoderma Gangrenosum in Clinical Trials: A Delphi Consensus on Behalf of the UPGRADE (Understanding Pyoderma Gangrenosum: Review and Assessment of Disease Effects) Group.

At present, there are no standardized guidelines for determining patient eligibility for pyoderma gangrenosum (PG) clinical trials. Thus, we aim to determine which clinical features, histopathological features, or laboratory features should be included in active ulcerative PG clinical trial eligibility criteria for treatment-naïve patients and patients already treated with immunomodulating medications (treatment-exposed patients). This study employed 4 rounds of the Delphi technique. Electronic surveys were administered to 21 international board-certified dermatologists and plastic surgeon PG experts (June 2022-December 2022). Our results demonstrated that for a patient to be eligible for a PG trial, they must meet the following criteria: (i) presence of ulcer(s) with erythematous/violaceous undermining wound borders, (ii) presence of a painful or tender ulcer, (iii) history/presence of rapidly progressing disease, (iv) exclusion of infection and other causes of cutaneous ulceration, (v) biopsy for H&E staining, and (vi) a presence/history of pathergy. These criteria vary in importance for treatment-naïve versus treatment-exposed patients. Given the international cohort, we were unable to facilitate live discussions between rounds. This Delphi consensus study provides a set of specific, standardized eligibility criteria for PG clinical trials, thus addressing one of the main issues hampering progress toward Food and Drug Administration approval of medications for PG.

Chronic kidney disease and risk of kidney or urothelial malignancy: systematic review and meta-analysis.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent, affecting approximately 11% of U.S. adults. Multiple studies have evaluated a potential association between CKD and urinary tract malignancies. Summary estimates of urinary tract malignancy risk in CKD patients with and without common co-existing conditions may guide clinical practice recommendations. METHODS: Four electronic databases were searched for original cohort studies evaluating the association between CKD and urinary tract cancers (kidney cancer and urothelial carcinoma) through May 25, 2023, in persons with at least moderate CKD and no dialysis or kidney transplantation. Quality assessment was performed for studies meeting inclusion criteria using the Newcastle-Ottawa Scale. Meta-analysis with a random-effects model was performed for unadjusted incidence rate ratios (IRR) as well as adjusted hazard ratios (aHR) for confounding conditions (diabetes, hypertension, and/or tobacco use), shown to have association with kidney cancer and urothelial carcinoma. Sub-analysis was conducted for estimates associated with CKD stages separately. RESULTS: Six cohort studies with 8 617 563 persons were included. Overall, methodological quality of the studies was good. CKD was associated with both higher unadjusted incidence and adjusted hazard of kidney cancer (IRR, 3.36; 95% confidence interval [CI], 2.32-4.88; aHR, 2.04; 95% CI, 1.77-2.36) and urothelial cancer (IRR, 3.96; 95% CI, 2.44-6.40; aHR, 1.40; 95% CI, 1.22-1.68) compared with persons without CKD. Examining incident urinary tract cancers by CKD severity, risks were elevated in stage 3 CKD (kidney aHR, 1.89; 95% CI, 1.56-2.30; urothelial carcinoma aHR, 1.40; 95% CI, 1.18-1.65) as well as in stages 4/5 CKD (kidney cancer aHR, 2.30; 95% CI, 2.00-2.66, UC aHR, 1.24; 95% CI, 1.04-1.49). CONCLUSIONS: Even moderate CKD is associated with elevated risk of kidney cancer and UC. Providers should consider these elevated risks when managing individuals with CKD, particularly when considering evaluation for the presence and etiology of hematuria.

Influence of preoperative body mass index on prognosis for patients with upper urinary tract urothelial carcinoma treated with radical nephroureterectomy.

PURPOSE: The impact of body mass index (BMI) on patients with upper urinary tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU) is controversial. Increasing evidence suggests an age-dependent relationship between obesity and outcomes for some solid organ tumors. Herein, we aimed to assess the prognostic value of preoperative BMI in UTUC patients treated with RNU in Taiwan. METHODS: This was a retrospective single-center study of 468 UTUC patients undergoing RNU during January 2010-December 2017, with preoperative BMI classification and subgroup analysis based on ages of < or ≥ 70 years. All UTUC patients underwent RNU and bladder cuff excision. Overall survival (OS), cancer-specific survival, and disease-free survival (DFS) were analyzed. Fisher's exact test, Mann-Whitney U test, Kaplan-Meier method, and Cox regression model were used for data analysis. RESULTS: The median follow-up duration was 36 months. Patients with higher versus lower BMI (cutoff: 25 kg/m2) showed no differences in OS; older patients had poor OS (hazard ratio [HR] 1.74; 95% confidence interval [CI] 1.24-2.40; p < 0.001). Older age was an independent predictor of poor OS in multivariate Cox regression analysis (p = 0.001). Younger patients with higher BMI (p = 0.02) had better DFS than older patients with no BMI-related survival differences. Higher BMI was an independent predictor of favorable DFS in younger patients in multivariate Cox regression analysis (HR, 0.53; 95% CI 0.28-0.99; p = 0.043). CONCLUSION: Younger UTUC patients with higher BMI were independently associated with a favorable DFS.

Single-cell analysis of castration-resistant prostate cancers to identify potential biomarkers for diagnosis and prognosis of neuroendocrine prostate cancer.

The high heterogeneity and low percentage of neuroendocrine cells in prostate cancer limit the utility of traditional bulk RNA sequencing and even single-cell RNA sequencing to find better biomarkers for early diagnosis and stratification. Re-clustering of specific cell-type holds great promise for identification of intra-cell-type heterogeneity. However, this has not yet been used in studying neuroendocrine prostate cancer heterogeneity. Neuroendocrine cluster(s) were individually identified in each castration-resistant prostate cancer specimen and combined for trajectory analysis. Three neuroendocrine states were identified. Neuroendocrine state 2 with the highest AR score was considered the initial starting state of neuroendocrine transdifferentiation. State 1 and state 3 with distinct high neuroendocrine scores and marker genes enriched in N-Myc and REST target genes, respectively, were considered as two different types of neuroendocrine differentiated cancer cells. These two states contained distinct groups of prostate cancer biomarkers and a strong distinguishing ability of normal versus cancerous prostate across different pathological grading was found in the N-Myc-associated state. Our data highlight the central role of N-Myc and REST in mediating lineage plasticity and classifying neuroendocrine phenotypes.

REST-repressed lncRNA LINC01801 induces neuroendocrine differentiation in prostate cancer via transcriptional activation of autophagy.

The association between REST reduction and the development of neuroendocrine prostate cancer (NEPC), a novel drug-resistant and lethal variant of castration-resistant prostate cancer (CRPC), is well established. To better understand the mechanisms underlying this process, we aimed to identify REST-repressed long noncoding RNAs (lncRNAs) that promote neuroendocrine differentiation (NED), thus facilitating targeted therapy-induced resistance. In this study, we used data from REST knockdown RNA sequencing combined with siRNA screening to determine that LINC01801 was upregulated and played a crucial role in NED in prostate cancer (PCa). Using The Cancer Genome Atlas (TCGA) prostate adenocarcinoma database and CRPC samples collected in our laboratory, we demonstrated that LINC01801 expression is upregulated in NEPC. Functional experiments revealed that overexpression of LINC01801 had a slight stimulatory effect on the NED of LNCaP cells, while downregulation of LINC01801 significantly inhibited the induction of NED. Mechanistically, LINC01801 is transcriptionally repressed by REST, and transcriptomic analysis revealed that LINC01801 preferentially affects the autophagy pathway. LINC01801 was found to function as a competing endogenous RNA (ceRNA) to regulate the expression of autophagy-related genes by sponging hsa-miR-6889-3p in prostate cancer cells. In conclusion, our data expand the current knowledge of REST-induced NED and highlight the contribution of the REST-LINC01801-hsa-miR-6889-3p axis to autophagic induction, which may provide promising avenues for therapeutic opportunities.

Prediction of clinically significant prostate cancer through urine metabolomic signatures: A large-scale validated study.

PURPOSE: Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically significant PC (sPC) in men at risk. METHODS: Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC). RESULTS: In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS. CONCLUSION: This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.

Treatment of Low-grade Intermediate-risk Nonmuscle-invasive Bladder Cancer With UGN-102 ± Transurethral Resection of Bladder Tumor Compared to Transurethral Resection of Bladder Tumor Monotherapy: A Randomized, Controlled, Phase 3 Trial (ATLAS).

PURPOSE: Low-grade intermediate-risk nonmuscle-invasive bladder cancer is a chronic illness commonly treated by repetitive transurethral resection of bladder tumor. We compared the efficacy and safety of intravesical chemoablation with UGN-102 (a reverse thermal gel containing mitomycin), with or without subsequent transurethral resection of bladder tumor, to transurethral resection of bladder tumor alone in patients with low-grade intermediate-risk nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: This prospective, randomized, phase 3 trial recruited patients with new or recurrent low-grade intermediate-risk nonmuscle-invasive bladder cancer to receive initial treatment with either UGN-102 once weekly for 6 weeks or transurethral resection of bladder tumor. Patients were followed quarterly by endoscopy, cytology, and for-cause biopsy. The primary end point was disease-free survival. All patients were followed for adverse events. RESULTS: Trial enrollment was halted by the sponsor to pursue an alternative development strategy after 282 of a planned 632 patients were randomized to UGN-102 ± subsequent transurethral resection of bladder tumor (n=142) or transurethral resection of bladder tumor monotherapy (n=140), rendering the trial underpowered to perform hypothesis testing. Patients were predominantly male and ≥65 years of age. Tumor-free complete response 3 months after initial treatment was achieved by 92 patients (65%) who received UGN-102 and 89 patients (64%) treated by transurethral resection of bladder tumor. The estimated probability of disease-free survival 15 months after randomization was 72% for UGN-102 ± transurethral resection of bladder tumor and 50% for transurethral resection of bladder tumor (hazard ratio 0.45). The most common adverse events (incidence ≥10%) in the UGN-102 group were dysuria, micturition urgency, nocturia, and pollakiuria. CONCLUSIONS: Primary, nonsurgical chemoablation with UGN-102 for the management of low-grade intermediate-risk nonmuscle-invasive bladder cancer offers a potential therapeutic alternative to immediate transurethral resection of bladder tumor monotherapy and warrants further investigation.