Development of Amorphous Solid Dispersion Sustained-Release Formulations with Polymer Composite Matrix-Regulated Stable Release Plateaus.

PURPOSE: This study was designed to develop ibuprofen (IBU) sustained-release amorphous solid dispersion (ASD) using polymer composites matrix with drug release plateaus for stable release and to further reveal intrinsic links between polymer' matrix ratios and drug release behaviors. METHODS: Hydrophilic polymers and hydrophobic polymers were combined to form different composite matrices in developing IBU ASD formulations by hot melt extrusion technique. The intrinsic links between the mixed polymer matrix ratio and drug dissolution behaviors was deeply clarified from the dissolution curves of hydrophilic polymers and swelling curves of composite matrices, and intermolecular forces among the components in ASDs. RESULTS: IBU + ammonio methacrylate copolymer type B (RSPO) + poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP VA64) physical mixtures presented unstable release behaviors with large error bars due to inhomogeneities at the micrometer level. However, IBU-RSPO-PVP VA64 ASDs showed a "dissolution plateau phenomenon", i.e., release behaviors of IBU in ASDs were unaffected by polymer ratios when PVP VA64 content was 35% ~ 50%, which could reduce risks of variations in release behaviors due to fluctuations in prescriptions/processes. The release of IBU in ASDs was simultaneously regulated by the PVP VA64-mediated "dissolution" and RSPO-PVP VA64 assembly-mediated "swelling". Radial distribution function suggested that similar intermolecular forces between RSPO and PVP VA64 were key mechanisms for the "dissolution plateau phenomenon" in ASDs at 35% ~ 50% of PVP VA64. CONCLUSIONS: This study provided ideas for developing ASD sustained-release formulations with stable release plateau modulated by polymer combinations, taking full advantages of simple process/prescription, ease of scale-up and favorable release behavior of ASD formulations.

Ultrasound-based radiomics score for pre-biopsy prediction of prostate cancer to reduce unnecessary biopsies.

BACKGROUND: Patients undergoing prostate biopsies (PBs) suffer from low positive rates and potential risk for complications. This study aimed to develop and validate an ultrasound (US)-based radiomics score for pre-biopsy prediction of prostate cancer (PCa) and subsequently reduce unnecessary PBs. METHODS: Between December 2015 and March 2018, 196 patients undergoing initial transrectal ultrasound (TRUS)-guided PBs were retrospectively enrolled and randomly assigned to the training or validation cohort at a ratio of 7:3. A total of 1044 radiomics features were extracted from grayscale US images of each prostate nodule. After feature selection through the least absolute shrinkage and selection operator (LASSO) regression model, the radiomics score was developed from the training cohort. The prediction nomograms were developed using multivariate logistic regression analysis based on the radiomics score and clinical risk factors. The performance of the nomograms was assessed and compared in terms of discrimination, calibration, and clinical usefulness. RESULTS: The radiomics score consisted of five selected features. Multivariate logistic regression analysis demonstrated that the radiomics score, age, total prostate-specific antigen (tPSA), and prostate volume were independent factors for prediction of PCa (all p < 0.05). The integrated nomogram incorporating the radiomics score and three clinical risk factors reached an area under the curve (AUC) of 0.835 (95% confidence interval [CI], 0.729-0.941), thereby outperforming the clinical nomogram which based on only clinical factors and yielded an AUC of 0.752 (95% CI, 0.618-0.886) (p = 0.04). Both nomograms showed good calibration. Decision curve analysis indicated that using the integrated nomogram would add more benefit than using the clinical nomogram. CONCLUSION: The radiomics score was an independent factor for pre-biopsy prediction of PCa. Addition of the radiomics score to the clinical nomogram shows incremental prognostic value and may help clinicians make precise decisions to reduce unnecessary PBs.

ATM-AMPKα mediated LAG-3 expression suppresses T cell function in prostate cancer.

Immunotherapy for prostate cancer (PCa) faces serious challenges. Therefore, the co-inhibitory receptors that regulate T cell function of PCa must be elucidated. Here we identified that the inhibitory receptor LAG3 was significantly induced in T cells from PCa patients. Gene array analysis revealed that insufficient ataxia telangiectasia mutated (ATM) gene expression in PCa T cells was responsible for the elevated LAG3 expression. Mechanistically, insufficient ATM expression impaired its ability to activate AMPKα signaling and CD4+ T cell functions, which further enhances the binding of the transcription factors XBP1 and EGR2 to LAG3 promoter. Reconstitution of ATM and inhibition of XBP1 or EGR2 in PCa T cells suppressed LAG3 expression and restored the effector function of CD4+ T cells from PCa. Our study revealed the mechanism of LAG3 upregulation in CD4+ T lymphocytes of PCa patients and may provide insights for the development of immunotherapeutic strategies for PCa treatment.

Prospective observational study on Pazopanib in patients treated for advanced or metastatic renal cell carcinoma in countries in Asia Pacific, North Africa, and Middle East regions: PARACHUTE study.

BACKGROUND: Clinical effectiveness and safety data of pazopanib in patients with advanced or mRCC in real-world setting from Asia Pacific, North Africa, and Middle East countries are lacking. METHODS: PARACHUTE is a phase IV, prospective, non-interventional, observational study. Primary endpoint was the proportion of patients remaining progression free at 12 months. Secondary endpoints were ORR, PFS, safety and tolerability, and relative dose intensity (RDI). RESULTS: Overall, 190 patients with a median age of 61 years (range: 22.0-96.0) were included. Most patients were Asian (70%), clear-cell type RCC was the most common (81%), with a favourable (9%), intermediate (47%), poor (10%), and unknown (34%) MSKCC risk score. At the end of the observational period, 78 patients completed the observational period and 112 discontinued the study; 60% of patients had the starting dose at 800 mg. Median RDI was 82%, with 52% of patients receiving < 85%. Of the 145 evaluable patients, 56 (39%) remained progression free at 12 months, and the median PFS was 10 months (95% CI: 8.48-11.83). 19% of patients (21/109) were long-term responders (on pazopanib for ≥18 months). The best response per RECIST 1.1 was CR/PR in 24%, stable disease in 44%, and PD in 31%. Most frequent (> 10%) TEAEs related to pazopanib included diarrhoea (30%), palmar-plantar erythrodysesthesia syndrome (15%), and hypertension (14%). CONCLUSIONS: Results of the PARACHUTE study support the use of pazopanib in patients with advanced or mRCC who are naive to VEGF-TKI therapy. The safety profile is consistent with that previously reported by pivotal and real-world evidence studies.

Application of nanotechnology in the diagnosis and treatment of bladder cancer.

Bladder cancer (BC) is a common malignancy in the genitourinary system and the current theranostic approaches are unsatisfactory. Sensitivity and specificity of current diagnosis methods are not ideal and high recurrence and progression rates after initial treatment indicate the urgent need for management improvements in clinic. Nanotechnology has been proposed as an effective method to improve theranosis efficiency for both non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). For example, gold nanoparticles (AuNPs) have been developed for simple, fast and sensitive urinary sample test for bladder cancer diagnosis. Nanoparticles targeting bladder cancers can facilitate to distinguish the normal and abnormal bladder tissues during cystoscopy and thus help with the complete removal of malignant lesions. Both intravenous and intravesical agents can be modified by nanotechnology for targeted delivery, high anti-tumor efficiency and excellent tolerability, exhibiting encouraging potential in bladder cancer treatment. Photosensitizers and biological agents can also be delivered by nanotechnology, intermediating phototherapy and targeted therapy. The management of bladder cancer remained almost unchanged for decades with unsatisfactory effect. However, it is likely to change with the fast-developed nanotechnology. Herein we summarized the current utility of nanotechnology in bladder cancer diagnosis and treatment, providing insights for the future designing and discovering novel nanoparticles for bladder cancer management.

Development and validation of a 25-Gene Panel urine test for prostate cancer diagnosis and potential treatment follow-up.

BACKGROUND: Heterogeneity of prostate cancer (PCa) contributes to inaccurate cancer screening and diagnosis, unnecessary biopsies, and overtreatment. We intended to develop non-invasive urine tests for accurate PCa diagnosis to avoid unnecessary biopsies. METHODS: Using a machine learning program, we identified a 25-Gene Panel classifier for distinguishing PCa and benign prostate. A non-invasive test using pre-biopsy urine samples collected without digital rectal examination (DRE) was used to measure gene expression of the panel using cDNA preamplification followed by real-time qRT-PCR. The 25-Gene Panel urine test was validated in independent multi-center retrospective and prospective studies. The diagnostic performance of the test was assessed against the pathological diagnosis from biopsy by discriminant analysis. Uni- and multivariate logistic regression analysis was performed to assess its diagnostic improvement over PSA and risk factors. In addition, the 25-Gene Panel urine test was used to identify clinically significant PCa. Furthermore, the 25-Gene Panel urine test was assessed in a subset of patients to examine if cancer was detected after prostatectomy. RESULTS: The 25-Gene Panel urine test accurately detected cancer and benign prostate with AUC of 0.946 (95% CI 0.963-0.929) in the retrospective cohort (n = 614), AUC of 0.901 (0.929-0.873) in the prospective cohort (n = 396), and AUC of 0.936 (0.956-0.916) in the large combination cohort (n = 1010). It greatly improved diagnostic accuracy over PSA and risk factors (p < 0.0001). When it was combined with PSA, the AUC increased to 0.961 (0.980-0.942). Importantly, the 25-Gene Panel urine test was able to accurately identify clinically significant and insignificant PCa with AUC of 0.928 (95% CI 0.947-0.909) in the combination cohort (n = 727). In addition, it was able to show the absence of cancer after prostatectomy with high accuracy. CONCLUSIONS: The 25-Gene Panel urine test is the first highly accurate and non-invasive liquid biopsy method without DRE for PCa diagnosis. In clinical practice, it may be used for identifying patients in need of biopsy for cancer diagnosis and patients with clinically significant cancer for immediate treatment, and potentially assisting cancer treatment follow-up.

Strategy for treating vascular emergencies during the COVID-19 pandemic in China.

Coronavirus-caused pneumonia (COVID-19) broke out in December 2019. The virus soon proved to be extremely contagious and caused an international pandemic. Clinicians treating COVID-19 patients face considerable danger of occupational exposure because of the highly infectious nature of the virus, and precautions must be taken to prevent medical staff infections. This article lists important measures that may save the lives of patients and medical staff during the COVID-19 pandemic and help stop the transmission of COVID-19 on hospital grounds. The suggestions include establishing detailed infection control and prevention protocols in the operating room; expediting testing procedures and patient screening for COVID-19; using case-specific treatment planning for vascular patients with COVID-19, favoring minimally invasive methods; and establishing and reinforcing protective awareness of medical personnel.

Use of Vesical Imaging-Reporting and Data System (VI-RADS) for detecting the muscle invasion of bladder cancer: a diagnostic meta-analysis.

OBJECTIVES: To comprehensively assess the diagnostic performance of Vesical Imaging-Reporting and Data System (VI-RADS) score for detecting the muscle invasion of bladder cancer. METHODS: PubMed, Web of Science, and Embase were searched up to November 20, 2019. QUADAS-2 tool assessed the quality of included studies. The diagnostic estimates including sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and the area under the curve (AUC) of hierarchical summary receiver operating characteristic (HSROC) were calculated. Further subgroup analysis, meta-regression and sensitivity analysis were conducted. RESULTS: Six studies with 1064 patients were finally included. The pooled sensitivity, specificity, and AUC value were 0.90 (95% CI 0.86-0.94), 0.86 (95% CI 0.71-0.94), and 0.93 (95% CI 0.91-0.95) for VI-RADS 3 as the cutoff value. The corresponding estimates were 0.77 (95% CI 0.65-0.86), 0.97 (95% CI 0.88-0.99), and 0.92 (95% CI 0.89-0.94) for VI-RADS 4 as the cutoff value. Meta-regression analysis revealed that study design (p value 0.01) and surgical pattern of reference standard (p value 0.02) were source of the heterogeneity of pooled sensitivity. No publication bias was observed. CONCLUSIONS: The VI-RADS score can provide a good predictive ability for detecting the muscle invasiveness of primary bladder cancer with VI-RADS 3 or VI-RADS 4 as the cutoff value. KEY POINTS: • VI-RADS score has high sensitivity and specificity for predicting muscle invasion. • The diagnostic efficiencies of VI-RADS 3 and VI-RADS 4 as the cutoff value are similar. • VI-RADS score could be used for detecting muscle invasion of bladder cancer in clinical practice.

Multiparametric MRI for Bladder Cancer: Validation of VI-RADS for the Detection of Detrusor Muscle Invasion.

Background The Vesical Imaging-Reporting and Data System (VI-RADS) scoring system was created in 2018 to standardize imaging and reporting of bladder cancer staging with multiparametric MRI. The system provides a five-point VI-RADS score, which suggests the likelihood of detrusor muscle invasion. Muscle-invasive disease carries a worse prognosis and requires radical surgery. Purpose To determine the performance of the VI-RADS score in detecting muscle-invasive bladder cancer in a cohort of patients undergoing multiparametric MRI before surgery. Materials and Methods In this retrospective study, a total of 340 patients with bladder cancer were identified from a database of consecutive patients undergoing multiparametric MRI from November 2011 to August 2018. The tumor with the largest burden was selected in those patients with multifocal tumors. Bladder tumors were retrospectively categorized according to the VI-RADS five-point scoring system by two readers, independently and in consensus, who were blinded to histologic findings. The VI-RADS score was compared with postoperative pathology for each tumor, and the performance of VI-RADS for determining detrusor muscle invasion was analyzed by using the Cochran-Armitage test. Results Among the 340 patients, there were 296 men and 44 women; the median age was 64.0 years (interquartile range [IQR], 57.0-87.0 years). Of 340 tumors, 255 (75.0%) were verified as non-muscle-invasive and 85 (25.0%) as muscle-invasive bladder cancer. Both the VI-RADS score and its components were associated with muscle-invasive condition (P < .001). The area under the receiver operating characteristic curve for VI-RADS for muscle invasion was 0.94 (95% confidence interval [CI]: 0.90, 0.98). The sensitivity and specificity of a VI-RADS score of 3 or greater were 87.1% (95% CI: 78%, 93%) and 96.5% (95% CI: 93%, 98%), respectively. Conclusion The Vesical Imaging-Reporting and Data System score effectively defines the likelihood of detrusor muscle invasion in bladder cancer and should be considered for evaluation of tumors prior to surgery. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Margolis and Hu in this issue.

Efficacy of intra-arterial chemotherapy combined with intravesical chemotherapy in T1G3 bladder cancer when compared with intravesical chemotherapy alone after bladder-sparing surgery: a retrospective study.

PURPOSE: To assess the efficacy of intra-arterial chemotherapy (IAC) combined with intravesical chemotherapy (IVC) in T1G3 bladder cancer (Bca) after transurethral resection of bladder tumor (TURBT). METHODS: Our study retrospectively reviewed 200 patients with T1G3 BCa who had all undergone TURBT. The patients' medical records were divided into two groups, one group only had IVC with pirarubicin after surgery, and the other group had IAC (cisplatin and epirubicin) combined with IVC after surgery. The patients were monitored regularly by urine cytology and cystoscopy. Survival and recurrence curves were calculated using the Kaplan-Meier method. Tumor recurrence, progression and tumor-specific death rate were compared with Chi-square test. A multivariate analysis was carried out to find out potential confounders. RESULTS: A total of 200 medical record was analyzed, 131 patients received IVC, 69 IAC + IVC treatment, tumor-specific death rate between the combined IAC and IVC compared to IVC alone was 7.25 and 17.6%, respectively (p < 0.05); the tumor recurrence rate between the two groups was 31.8% (22/69) and 44.3%, respectively (58/131) (p < 0.05), and tumor recurred later in the IAC + IVC group (p < 0.05), tumor progression rate was 18.8% (13/69) and 28.2% (37/131), respectively, with p < 0.05. Overall survival was longer in IAC + IVC group (p < 0.05). Using the multivariable regression model, IAC was significantly related to disease recurrence (p < 0.05) and overall survival (p < 0.05). CONCLUSION: T1G3 BCa post-TURBT surgery patients who underwent IAC combined with IVC had a longer overall survival and increased time interval to first recurrence, lower tumor recurrence rate, progression rate and tumor-specific death rate than compared with those who only underwent IVC alone.

MicroRNA-455-3p modulates cartilage development and degeneration through modification of histone H3 acetylation.

Histone acetylation regulated by class I histone deacetylases (HDACs) plays a pivotal role in matrix-specific gene transcription and cartilage development. While we previously demonstrated that microRNA (miR)-455-3p is upregulated during chondrogenesis and can enhance early chondrogenesis, the mechanism underlying this process remains largely unclear. In this study, we characterized the effect of miR-455-3p on histone H3 acetylation and its role during cartilage development and degeneration. We observed that miR-455-3p was highly expressed in proliferating and pre-hypertrophic chondrocytes, while HDAC2 and HDAC8 were primarily expressed in hypertrophic chondrocytes. Meanwhile, miR-455-3p suppressed the activity of reporter constructs containing the 3'-untranslated regions of HDAC2/8, inhibited HDAC2/8 expression and promoted histone H3 acetylation at the collagen 2 (COL2A1) promoter in human SW1353 chondrocyte-like cells. Treatment with the HDAC inhibitor trichostatin A (TSA) resulted in increased expression of cartilage-specific genes and promoted glycosaminoglycan deposition. Moreover, TSA inhibited matrix metalloproteinase 13 (Mmp13) expression and promoted nuclear translocation of SOX9 in interleukin-1-treated primary mouse chondrocytes. Lastly, knockdown of HDAC2/3/8 increased SRY (sex-determining region Y)-box 9 (SOX9) and decreased Runt-related transcription factor 2 (RUNX2) expression. Taken together, these findings suggest that miR-455-3p plays a critical role during chondrogenesis by directly targeting HDAC2/8 and promoting histone H3 acetylation, which raises possibilities of using miR-455-3p to influence chondrogenesis and cartilage degeneration.

Use of two gene panels for prostate cancer diagnosis and patient risk stratification.

Currently, no ideal prostate cancer (PCa) diagnostic or prognostic test is available due to the lack of biomarkers with high sensitivity and specificity. There is an unmet medical need to develop combinations of multiple biomarkers which may have higher accuracy in detection of PCa and stratification of aggressive and indolent cancer patients. The aim of this study was to test two biomarker gene panels in distinguishing PCa from benign prostate and high-risk, aggressive PCa from low-risk, indolent PCa, respectively. We identified a five-gene panel that can be used to distinguish PCa from benign prostate. The messenger RNA (mRNA) expression signature of the five genes was determined in 144 PCa and benign prostate specimens from prostatectomy. We showed that the five-gene panel distinguished PCa from benign prostate with sensitivity of 96.59 %, specificity of 92.86 %, and area under the curve (AUC) of 0.992 (p < 0.0001). The five-gene panel was further validated in a 137 specimen cohort and showed sensitivity of 84.62 %, specificity of 91.84 %, and AUC of 0.942 (p < 0.0001). To define subtypes of PCa for treatment guidance, we examined mRNA expression signature of an eight-gene panel in 87 PCa specimens from prostatectomy. The signature of the eight-gene panel was able to distinguish aggressive PCa (Gleason score >6) from indolent PCa (Gleason score ≤6) with sensitivity of 90.28 %, specificity of 80.00 %, and AUC of 0.967 (p < 0.0001). This panel was further validated in a 158 specimen cohort and showed significant difference between aggressive PCa and indolent PCa with sensitivity of 92.57 %, specificity of 70.00 %, and AUC of 0.962 (p < 0.0001). Our findings in assessing multiple biomarkers in combination may provide new tools to detect PCa and distinguish aggressive and indolent PCa for precision and personalized treatment. The two biomarker panels may be used in clinical settings for accurate PCa diagnosis and patient risk stratification for biomarker-guided treatment.

Wear particles promote reactive oxygen species-mediated inflammation via the nicotinamide adenine dinucleotide phosphate oxidase pathway in macrophages surrounding loosened implants.

BACKGROUND/AIMS: Prosthesis loosening is closely associated with chronic inflammatory cytokine secretion by macrophages, which are activated by wear particles or inflammatory stimulants such as lipopolysaccharide (LPS). Reactive oxygen species (ROS) are critical regulators of inflammation, but their enzymatic sources in response to wear particles and their effects on peri-implant LPS-tolerance remain unclear. METHODS: Three ROS-related enzymes-nicotinamide adenine dinucleotide phosphate oxidase (NOX)-1 and -2 and catalase-were investigated in interface membrane tissues and in titanium (Ti) particle-stimulated macrophages in vitro. The generation of ROS and downstream inflammatory effects were measured with or without pre-incubation with apocynin, an NOX inhibitor. RESULTS: Pre-exposure to Ti particles attenuated NF-κB activation in LPS-stimulated macrophages, indicating that wear particles suppress immune response, which may lead to chronic inflammation. NOX-1 and -2 were highly expressed in aseptically loosened interface membranes and in macrophages stimulated with Ti particles; the particles induced a moderate amount of ROS generation, NF-κB activation, and TNF-α secretion in macrophages, and these effects were suppressed by apocynin. CONCLUSION: Wear particles induce ROS generation through the NOX signaling pathway, resulting in persistent inflammation and delayed loosening. Thus, the suppression of NOX activity may be a useful strategy for preventing prosthesis loosening.

En bloc transurethral resection with 2-micron continuous-wave laser for primary non-muscle-invasive bladder cancer: a randomized controlled trial.

PURPOSE: To evaluate the practicability of en bloc transurethral resection with 2-micron continuous-wave laser as treatment for primary non-muscle-invasive bladder cancer (NMIBC). METHODS: This was a single-center, randomized, controlled trial involving 142 patients with newly diagnosed NMIBC. All patients were randomly assigned in a 1:1 ratio to receive either laser treatment or conventional transurethral resection of bladder tumor (TURBT). All patients received intravesical chemotherapy. Follow-up was performed in 18 months. Primary outcome measure was difference of tumor recurrence rate at the end of study. RESULTS: Baseline characteristics did not differ between patients in two groups. Operation time was longer in laser group than in TURBT group (56.5 ± 37.4 vs. 41.0 ± 29.4 min, P = 0.017). Obturator nerve reflection was noted during TURBT in 18 patients, whereas none was noted during laser resection. Number of T1 tumors was higher in the laser group (25 vs. 15, P = 0.047). According to Kaplan-Meier survival curves, there was no statistical difference in the rate of recurrence in 18 months (P = 0.383). All recurrences were out of the site of first resection, and there was no progression in tumor grade. CONCLUSION: Two-micron continuous-wave laser did not diminish tumor recurrence rate in primary NMIBC for 18-months observation. However, T1 tumors were significantly higher among laser group. Clear and complete tumor bases were easily conserved by laser resection, which may enable pathologists to distinguish the T stages of bladder cancer more easily. Further studies need to be done in future.

Intra-arterial chemotherapy plus BCG, a promising combination adjuvant treatment for high-risk NMIBC.

PURPOSE: To develop a novel combination therapy for high-risk nonmuscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT), namely, intra-arterial chemotherapy (IAC) plus BCG immunotherapy, and to compare the feasibility and safety of the 2 therapies. MATERIALS AND METHODS: A retrospective study was conducted on the data of 119 patients who were diagnosed with high-risk NMIBC and underwent TURBT in the past 5 years. Those who did not complete the treatment were excluded, and the remaining 98 patients were divided into 2 groups: both groups received intravesical BCG immunotherapy, while the BCG+IAC group received 4 courses of extra intra-arterial chemotherapy. Clinical and follow-up data were processed using statistical software. RESULTS: The recurrence rate was 22.2% in the BCG+IAC group and 35.8% in the BCG group, whereas the progression rates were 8.9% and 24.5%, respectively. In the Kaplan-Meier plot, a statistically significant difference was observed with respect to recurrence-free survival (p = 0.025), as well as the progression-free survival of the two groups was similar (p = 0.019). A total of 22.2% of the patients with adverse effects of IAC and 79.6% of patients suffered from adverse reactions to BCG immunotherapy, and most of the adverse effects were mild and tolerable. Univariate and multivariate analysis indicated that multifocal and treatment were independent risk factors for recurrence, while the history of recurrence and treatment were independent risk factors for progression. CONCLUSION: IAC could be a promising auxiliary treatment for BCG immunotherapy in decreasing the recurrence and progression rate of high-risk NMIBC with little additional toxicity.

FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation.

Renal cell carcinoma (RCC) is one of the three major malignant tumors of the urinary system and originates from proximal tubular epithelial cells. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of RCC cases and is recognized as a metabolic disease driven by genetic mutations and epigenetic alterations. Through bioinformatic analysis, we found that FK506 binding protein 10 (FKBP10) may play an essential role in hypoxia and glycolysis pathways in ccRCC progression. Functionally, FKBP10 promotes the proliferation and metastasis of ccRCC in vivo and in vitro depending on its peptidyl-prolyl cis-trans isomerase (PPIase) domains. Mechanistically, FKBP10 binds directly to lactate dehydrogenase A (LDHA) through its C-terminal region, the key regulator of glycolysis, and enhances the LDHA-Y10 phosphorylation, which results in a hyperactive Warburg effect and the accumulation of histone lactylation. Moreover, HIFα negatively regulates the expression of FKBP10, and inhibition of FKBP10 enhances the antitumor effect of the HIF2α inhibitor PT2385. Therefore, our study demonstrates that FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to HIF2α blockade by facilitating LDHA phosphorylation, which may be exploited for anticancer therapy.

A non-invasive 25-Gene PLNM-Score urine test for detection of prostate cancer pelvic lymph node metastasis.

BACKGROUND: Prostate cancer patients with pelvic lymph node metastasis (PLNM) have poor prognosis. Based on EAU guidelines, patients with >5% risk of PLNM by nomograms often receive pelvic lymph node dissection (PLND) during prostatectomy. However, nomograms have limited accuracy, so large numbers of false positive patients receive unnecessary surgery with potentially serious side effects. It is important to accurately identify PLNM, yet current tests, including imaging tools are inaccurate. Therefore, we intended to develop a gene expression-based algorithm for detecting PLNM. METHODS: An advanced random forest machine learning algorithm screening was conducted to develop a classifier for identifying PLNM using urine samples collected from a multi-center retrospective cohort (n = 413) as training set and validated in an independent multi-center prospective cohort (n = 243). Univariate and multivariate discriminant analyses were performed to measure the ability of the algorithm classifier to detect PLNM and compare it with the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram score. RESULTS: An algorithm named 25 G PLNM-Score was developed and found to accurately distinguish PLNM and non-PLNM with AUC of 0.93 (95% CI: 0.85-1.01) and 0.93 (95% CI: 0.87-0.99) in the retrospective and prospective urine cohorts respectively. Kaplan-Meier plots showed large and significant difference in biochemical recurrence-free survival and distant metastasis-free survival in the patients stratified by the 25 G PLNM-Score (log rank P < 0.001 and P < 0.0001, respectively). It spared 96% and 80% of unnecessary PLND with only 0.51% and 1% of PLNM missing in the retrospective and prospective cohorts respectively. In contrast, the MSKCC score only spared 15% of PLND with 0% of PLNM missing. CONCLUSIONS: The novel 25 G PLNM-Score is the first highly accurate and non-invasive machine learning algorithm-based urine test to identify PLNM before PLND, with potential clinical benefits of avoiding unnecessary PLND and improving treatment decision-making.

Bladder metastasis from type 2 papillary renal cell carcinoma: A case report.

Renal cell carcinoma (RCC) is a common urinary tumor that may be pathologically divided into different subtypes: clear cell RCC, papillary RCC (PRCC) and chromophobe RCC. The most common organs of RCC metastasis are the lung, liver and bones, while bladder metastasis is rare. The treatment for PRCC metastasis is also a problem due to limited clinical data. Therefore, every single case of PRCC metastasis may significantly contribute to establishing a standard treatment protocol. The present study reported on a patient who suffered from repetitive bladder PRCC metastasis with 1.5 years of follow-up. A 54-year-old male patient was diagnosed with left renal pelvic carcinoma in March 2020 and underwent a laparoscopic radical nephroureterectomy of the left kidney. The postoperative histological examination revealed that the tumor was consistent with a type 2 PRCC. Bladder metastasis was discovered three months after the surgery and transurethral resection of the bladder tumor (TURBT) was performed to eliminate the tumor in the bladder. Only three months after the initial TURBT, bladder metastasis was detected again, combined with lung metastasis. The patient refused to undergo radical cystectomy. Therefore, a second TURBT was arranged and targeted drugs were administered. However, both bladder and lung metastases were insensitive to the treatment strategy applied, although immunotherapy was subsequently added. The patient died in October 2021 due to respiratory failure and cachexia. The report aims to provide the whole treatment progress and lessons learned from this case, which is relatively rare.

Bladder preservation in complicated invasive urothelial carcinoma following treatment with cisplatin/gemcitabine plus tislelizumab: A case report.

BACKGROUND: Invasive urothelial carcinoma (UC) with squamous and glandular differentiation is a highly malignant and complicated pathological subtype, and the standard care is radical cystectomy (RC). However, urinary diversion after RC significantly reduces patient quality of life, thus bladder-sparing therapy has become a research hotspot in this field. Recently, five immune checkpoint inhibitors have been approved for systemic therapy of locally advanced or metastatic bladder cancer by the Food and Drug Administration, but the efficacy of immunotherapy combined with chemotherapy for invasive UC is still unknown, especially for pathological subtypes with squamous and glandular differentiation. CASE SUMMARY: We report the case of a 60-year-old male who complained of repetitive painless gross hematuria and was diagnosed with muscle-invasive bladder cancer with squamous and glandular differentiation, defined as cT3N1M0 according to the American Joint Committee on Cancer, who had a strong desire to preserve the bladder. Immunohistochemical staining revealed that programmed cell death-ligand 1 (PD-L1) expression in the tumor was positive. Thus, a transurethral resection to maximize removal of the bladder tumor was performed under cystoscopy, and the patient subsequently received a combination of chemotherapy (cisplatin/gemcitabine) and immunotherapy (tislelizumab) treatment. No tumor recurrence in the bladder was observed following pathological and imaging examination after 2 cycles and 4 cycles of treatment, respectively. The patient achieved bladder preservation and has been tumor-free for more than two years. CONCLUSION: This case shows that the combination of chemotherapy and immunotherapy might be an effective and safe treatment strategy for PD-L1 expression positive UC with divergent histologic differentiation.