Effects of Ulmus macrocarpa Extract and Catechin 7-O-ß-D-apiofuranoside on Muscle Loss and Muscle Atrophy in C2C12 Murine Skeletal Muscle Cells.

Muscle atrophy is known to be one of the symptoms leading to sarcopenia, which significantly impacts the quality of life, mortality, and morbidity. Therefore, the development of therapeutics for muscle atrophy is essential. This study focuses on addressing muscle loss and atrophy using Ulmus macrocarpa extract and its marker compound, catechin 7-O-ß-D-apiofuranoside, by investigating their effects on biomarkers associated with muscle cell apoptosis. Additionally, protein and gene expression in a muscle atrophy model were examined using Western blotting and RT-PCR. Ulmus macrocarpa has been used as food or medicine due to its safety, including its roots, barks, and fruit. Catechin 7-O-ß-D apiofuranoside is an indicator substance of plants of the Ulmus genus and has been reported to have various effects such as antioxidant and anti-inflammatory effects. The experimental results demonstrated that catechin glycoside and Ulmus macrocarpa extract decreased the expression of the muscle-degradation-related proteins Atrogin-1 and Muscle RING-Finger protein-1 (MuRF1) while increasing the expression of the muscle-synthesis-related proteins Myoblast determination (MyoD) and Myogenin. Gene expression confirmation experiments validated a decrease in the expression of Atrogin and MuRF1 mRNA and an increase in the expression of MyoD and Myogenin mRNA. Furthermore, an examination of muscle protein expression associated with the protein kinase B (Akt)/forkhead box O (FoxO) signaling pathway confirmed a decrease in the expression of FoxO, a regulator of muscle protein degradation. These results confirm the potential of Ulmus macrocarpa extract to inhibit muscle apoptosis, prevent muscle decomposition, and promote the development of functional materials for muscle synthesis, health-functional foods, and natural-product-derived medicines.

Establishment of canine mammary gland tumor cell lines harboring PI3K/Akt activation as a therapeutic target.

Canine mammary gland tumors (MGT) have a poor prognosis in intact female canines, posing a clinical challenge. This study aimed to establish novel canine mammary cancer cell lines from primary tumors and characterize their cellular and molecular features to find potential therapeutic drugs. The MGT cell lines demonstrated rapid cell proliferation and colony formation in an anchorage-independent manner. Vimentin and α-SMA levels were significantly elevated in MGT cell lines compared to normal canine kidney (MDCK) cells, while CDH1 expression was either significantly lower or not detected at all, based on quantitative real-time PCR (qRT-PCR) analysis. Functional annotation and enrichment analysis revealed that epithelial-mesenchymal transition (EMT) phenotypes and tumor-associated pathways, particularly the PI3K/Akt signaling pathway, were upregulated in MGT cells. BYL719 (Alpelisib), a PI3K inhibitor, was also examined for cytotoxicity on the MGT cell lines. The results show that BYL719 can significantly inhibit the proliferation of MGT cell lines in vitro. Overall, our findings suggest that the MGT cell lines may be valuable for future studies on the development, progression, metastasis, and management of tumors.

The Impact of Ulmus macrocarpa Extracts on a Model of Sarcopenia-Induced C57BL/6 Mice.

Aging leads to tissue and cellular changes, often driven by oxidative stress and inflammation, which contribute to age-related diseases. Our research focuses on harnessing the potent anti-inflammatory and antioxidant properties of Korean Ulmus macrocarpa Hance, a traditional herbal remedy, to address muscle loss and atrophy. We evaluated the effects of Ulmus extract on various parameters in a muscle atrophy model, including weight, exercise performance, grip strength, body composition, muscle mass, and fiber characteristics. Additionally, we conducted Western blot and RT-PCR analyses to examine muscle protein regulation, apoptosis factors, inflammation, and antioxidants. In a dexamethasone-induced muscle atrophy model, Ulmus extract administration promoted genes related to muscle formation while reducing those associated with muscle atrophy. It also mitigated inflammation and boosted muscle antioxidants, indicating a potential improvement in muscle atrophy. These findings highlight the promise of Ulmus extract for developing pharmaceuticals and supplements to combat muscle loss and atrophy, paving the way for clinical applications.

Multigene model for predicting metastatic prostate cancer using circulating tumor cells by microfluidic magnetophoresis.

We aimed to isolate circulating tumor cells (CTCs) using a microfluidic technique with a novel lateral magnetophoretic microseparator. Prostate cancer-specific gene expressions were evaluated using mRNA from the isolated CTCs. A CTC-based multigene model was then developed for identifying advanced prostate cancer. Peripheral blood samples were obtained from five healthy donors and patients with localized prostate cancer (26 cases), metastatic hormone-sensitive prostate cancer (mHSPC, 10 cases), and metastatic castration-resistant prostate cancer (mCRPC, 28 cases). CTC recovery rate and purity (enriched CTCs/total cells) were evaluated according to cancer stage. The areas under the curves of the six gene expressions were used to evaluate whether multigene models could identify mHSPC or mCRPC. The number of CTCs and their purity increased at more advanced cancer stages. In mHSPC/mCRPC cases, the specimens had an average of 27.5 CTCs/mL blood, which was 4.2 × higher than the isolation rate for localized disease. The CTC purity increased from 2.1% for localized disease to 3.8% for mHSPC and 6.7% for mCRPC, with increased CTC expression of the genes encoding prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), and cytokeratin 19 (KRT19). All disease stages exhibited expression of the genes encoding androgen receptor (AR) and epithelial cell adhesion molecule (EpCAM), although expression of the AR-V7 variant was relatively rare. Relative to each gene alone, the multigene model had better accuracy for predicting advanced prostate cancer. Our lateral magnetophoretic microseparator can be used for identifying prostate cancer biomarkers. In addition, CTC-based genetic signatures may guide the early diagnosis of advanced prostate cancer.

Expression of VISTA on tumor-infiltrating immune cells correlated with short intravesical recurrence in non-muscle-invasive bladder cancer.

V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint molecule expressed in hematopoietic cells, granulocytes, macrophages, and monocytes. However, few studies to date have investigated VISTA expression, especially its clinical utility, in bladder cancer. The present retrospective study aimed to examine VISTA, programmed death ligand-1 (PD-L1), and CD45 expression by immunohistochemical and immunofluorescence staining of archived pathological tissue samples from 159 patients with primary bladder cancer. The correlation between VISTA expression in immune cells (ICs) and clinicopathologic variables including PD-L1 expression in ICs was examined. Briefly, the rates of VISTA-positive ICs and VISTA-positive tumor cells were 67.9% (108/159) and 30.8% (49/159), respectively. The VISTA expression in ICs of patients with bladder cancer, including those with non-muscle-invasive bladder cancer (NMIBC), was positively correlated with tumor stage, grade, size, and multiplicity. The VISTA expression in ICs was stronger in bladder cancer cases with PD-L1-positive ICs than in those with PD-L1-negative ICs (p < 0.001). The mean intravesical recurrence-free survival was shorter in NMIBC cases with VISTA-positive ICs than in those with VISTA-negative ICs (34.0 vs 39.9 months, p = 0.03, log-rank test). In this first study to investigate VISTA expression in bladder cancer, these results implicate VISTA as a potential immunotherapeutic target and immunologic biomarker in bladder cancer.

Prognostic Impact of Resection Margin Length in Patients Undergoing Resection for Mid-Common Bile Duct Cancer: A Single-Center Experience.

INTRODUCTION: The purpose of this study was to analyze survival outcomes after segmental bile duct resection (BDR) for mid-common bile duct cancer according to the length of the tumor-free BDR margins. METHOD: A total of 133 consecutive patients underwent BDR for mid-bile duct cancers between December 2007 and June 2017. The Cox proportional hazard model was used to verify the cutoff value of the R0 resection margin. The patients were divided into 3 groups according to resection margin status (group 1; R0 resection margin ≥5 mm; group 2, R0 resection margin <5 mm; and group 3, R1 resection margin). RESULTS: The median follow-up period of the study cohort was 24 months. A resection margin of 5 mm in length was verified to be suitable as a reliable cutoff value. The median disease-free and overall survival (OS) periods were 32 and 49 months in group 1, 13 and 20 months in group 2, and 23 and 30 months in group 3, respectively (p = 0.03 and p < 0.001). The length of the tumor-free resection margin (hazard ratio, 2.01; 95% confidence interval, 1.10-3.67; p = 0.022) was independent factor affecting OS. CONCLUSIONS: BDR for mid-bile duct cancer appears to be a feasible surgical option in selected patients with careful preoperative imaging assessment and intraoperative frozen-section diagnosis. Our results suggest achieving a BDR margin ≥5 mm to improve survival outcomes.

Targeted therapy response in early versus late recurrence of renal cell carcinoma after surgical treatment: A propensity score-matched study using the Korean Renal Cancer Study Group database.

OBJECTIVES: To investigate the clinicopathological features and outcomes of targeted therapy in patients with recurrence of renal cell carcinoma in <5 years or ≥5 years after the surgical treatment for renal cell carcinoma. METHODS: Patients with metastatic renal cell carcinoma treated with targeted therapy in a multicenter database were retrospectively characterized according to time from surgery to recurrence. Early recurrence was defined as recurrence within 5 years after surgery, and late recurrence was defined as occurring ≥5 years after surgery. The propensity scores for recurrence status were calculated, and patients with late recurrence were matched to patients with early recurrence at a 1:3 ratio. The oncological outcomes of targeted therapy in both groups were compared. RESULTS: Among 716 patients, 512 (71.5%) experienced early recurrence and 204 (28.5%) experienced late recurrence. The patients with late recurrence presented with younger age at surgery, lower tumor stages and Fuhrman grade, and fewer sarcomatoid features and lymphovascular invasion (all P < 0.005). All differences in clinicopathological characteristics before targeted therapy disappeared after matching. Patients with late recurrence had significantly longer median overall survival (56 months vs 36 months; P < 0.0001) and median first-line progression-free survival (12 months vs 8 months; P = 0.031). The early recurrence status was a significantly worse predictor for overall survival and first-line progression-free survival (hazard ratio 1.30, P = 0.007; and hazard ratio 1.76, P < 0.001, respectively). CONCLUSIONS: Late recurrence might have prognostic value in terms of oncological outcomes in metastatic renal cell carcinoma treated with targeted therapy.

Clinical factors that influence the occurrence of symptomatic pseudoaneurysms and arteriovenous fistulas after partial nephrectomy: multi-institutional study of renal function outcomes after one year of selective arterial embolization.

PURPOSE: Renal artery pseudoaneurysms (RAPs) and arteriovenous fistulas (AVFs) are rare but potentially life-threatening complications after partial nephrectomy (PN). Selective arterial embolization (SAE) is an effective method for controlling RAPs/AVFs. We assessed the clinical factors affecting the occurrence of RAPs/AVFs after PN and the effects of SAE on postsurgical renal function. MATERIALS AND METHODS: Four hundred ninety-three patients who underwent PN were retrospectively reviewed. They were placed in either the SAE or the non-SAE group. The effects of clinical factors, including R.E.N.A.L. scores, on the occurrence of RAPs/AVFs were analyzed. The influence of SAE on the estimated glomerular filtration rate (eGFR) during the first postoperative year was evaluated. RESULTS: Thirty-three (6.7%) patients experienced RAPs/AVFs within 8 days of the median interval between PN and SAE. The SAE group had significantly higher R.E.N.A.L. scores, higher N component scores, and higher L component scores (all, p <0.05). In the multivariate analysis, higher N component scores were associated with the occurrence of RAPs/AVFs (Odds ratio: 1.96, p=0.039). In the SAE group, the mean 3-day postembolization eGFR was significantly lower than the mean 3-day postoperative eGFR (p <0.01). This difference in the eGFRs was still present 1 year later. CONCLUSIONS: Renal tumors located near the renal sinus and collecting system were associated with a higher risk for RAPs/AVFs after PN. Although SAE was an effective method for controlling symptomatic RAPs/AVFs after PN, a procedure-related impairment of renal function after SAE could occur and still be present at the end of the first postoperative year.

The cumulative incidence and risk factors of postoperative inguinal hernia in patients undergoing radical prostatectomy.

BACKGROUND: The aim of this study is to investigate the cumulative incidence and risk factors of postoperative inguinal hernia (PIH) in patients undergoing radical prostatectomy, i.e., laparoscopic prostatectomy (LRP) and robot-assisted laparoscopic prostatectomy (RARP). METHODS: This study included 1124 patients who had undergone radical prostatectomy or transurethral resection of bladder tumor from 2011-2016. We compared the cumulative incidence of PIH in the radical prostatectomy groups (460; LRP 341, RARP 119) and the control group (664; transurethral resection of bladder tumor), and we then analyzed the risk factors (age, operative methods, previous abdominal operative history, thickness and width of external oblique muscle and rectus muscle, thickness of abdominal subcutaneous fat layer at Hesselbach's triangle level, body mass index, prostate-specific antigen, operative time, specimen weight, Gleason score, and pathology T-stage) of PIH in the radical prostatectomy groups. RESULTS: The median follow-up period in this study was 39.6 months. In Kaplan-Meier curve analysis, the cumulative incidence of PIH was 5.3, 4.2, and 0.5% for the LRP, RARP, and control groups, respectively (p < 0.001). Multiple logistic regressions showed that thickness of external oblique muscle and width of rectus muscle were significant risk factors (p < 0.001 and p = 0.027). CONCLUSIONS: PIH is considered to be one of the complications of LRP and RARP. Moreover, we suggest that if the thickness of the muscle is <7.3 mm, thoughtful surgical manipulation is needed for radical prostatectomy, and care should be taken to determine whether hernia occurs during follow-up.

Transcript Levels of Androgen Receptor Variant 7 and Ubiquitin-Conjugating Enzyme 2C in Hormone Sensitive Prostate Cancer and Castration-Resistant Prostate Cancer.

PURPOSE: This study is designed to identify the androgen receptor variant 7 (AR-V7) status, clinical significance of AR-V7 in hormone sensitive prostate cancer (HSPC). Then, we evaluated AR-V7 and changes of its target gene, ubiquitin-conjugating enzyme E2C (UBE2C) which is an anaphase-promoting complex/cyclosome (APC/C)-specific ubiquitin-conjugating enzyme, in castration-resistant prostate cancer (CRPC) in serial tumor biopsies from patients receiving androgen deprivation therapy. METHODS: We used RT-PCR and Q-PCR assay to evaluate AR-V7, androgen receptor full length (AR-FL), and UBE2C in tumor biopsies from patients with HSPC and CRPC. We examined associations between mRNA expression of AR-V7 and clinicopathologic factors. Furthermore, to identify other potential genes involved in the development of CRPC, RNA sequencing was conducted, using paired prostate cancer (PCa) tissues obtained immediately prior to treatment and at the time of therapeutic resistance. RESULTS: A total of 13 HSPC patients and three CRPC patients were enrolled. Neither a high Gleason score (score of 8 and 9) nor a high risk of PCa (a high risk of locally advanced PCa according to NCCN guidelines) was correlated with mRNA expression of AR-V7 in HSPC (P = 0.153 and P = 0.215). The mRNA expression of AR-FL, but not AR-V7, was significantly associated with the mRNA expression of UBE2C level in HSPC (P = 0.007). However, increased expression of AR-V7, not AR-FL, paralleled increased expression of UBE2C in the CRPC specimens (P = 0.03). AR-V7 expression status before ADT was likely related to shorter CRPC development in patients treating ADT. The result of the RNA-sequencing analysis using serial samples from the same patient before and after castration demonstrated an increased level of the PI3K regulatory subunit 1 (P = 0.018). CONCLUSION: Our study revealed the role of UBE2C as a marker of the androgen signaling pathway in PCa. Differential gene expression analysis using serial samples from the same patient before and after castration revealed potential genes and pathways involved in development of CRPC. Further studies are needed to determine whether these genes and pathways are potential therapeutic target for CRPC. Prostate 77:60-71, 2017. © 2016 Wiley Periodicals, Inc.

Clinical Applicability and Psychometric Properties of Manual Function Test for Patients with Stroke.

The Manual Function Test (MFT) is a tool to assess upper extremity motor impairment associated with stroke. This study investigated psychometric properties of the Korean version of the MFT and to establish normative data. Eighty-one patients were enrolled to evaluate MFT, Fugl-Meyer Assessment (FMA) and manual muscle test (MMT). MFT was completed by eight raters on two occasions separated by 6 weeks. Absolute and relative reliability and validity were examined. Additionally, MFT was assessed on 75 healthy controls of different ages. Intraclass correlation coefficient (ICC) (2,1) values for total and each dimension of Korean MFT ranged from 0.984 to 0.998 in the affected side of hemiplegic patients, indicating inter-rater reliability. Percentage values of standard error of measurement (SEM) and smallest real difference (SRD) ranged 3.10-10.57% and 8.58-29.29% respectively. Test-retest reliability ICCs for all raters were above 0.98. Effect size (ES) and standardized response mean (SRM) were larger in the acute-subacute group (onset to initial evaluation ≤ 4 months) (ES = 0.12; SRM = 0.41) than those in the chronic group (onset to evaluation > 4 months) (ES = 0.01; SRM = 0.11). MFT score was significantly correlated with FMA score (p < 0.001) and MMT score (p < 0.001). In healthy controls, regression analysis indicated that age significantly predicts manual function scores on both dominant and non-dominant. The Korean MFT showed good reliability and validity. Modest responsiveness was observed in patients evaluated early after stroke onset. The Korean MFT is useful in evaluating upper extremity motor deficits for clinical and research purposes.

Clinical application of calculated split renal volume using computed tomography-based renal volumetry after partial nephrectomy: Correlation with technetium-99m dimercaptosuccinic acid renal scan data.

OBJECTIVE: To evaluate the clinical application of computed tomography-based measurement of renal cortical volume and split renal volume as a single tool to assess the anatomy and renal function in patients with renal tumors before and after partial nephrectomy, and to compare the findings with technetium-99m dimercaptosuccinic acid renal scan. METHODS: The data of 51 patients with a unilateral renal tumor managed by partial nephrectomy were retrospectively analyzed. The renal cortical volume of tumor-bearing and contralateral kidneys was measured using ImageJ software. Split estimated glomerular filtration rate and split renal volume calculated using this renal cortical volume were compared with the split renal function measured with technetium-99m dimercaptosuccinic acid renal scan. RESULTS: A strong correlation between split renal function and split renal volume of the tumor-bearing kidney was observed before and after surgery (r = 0.89, P < 0.001 and r = 0.94, P < 0.001). The preoperative and postoperative split estimated glomerular filtration rate of the operated kidney showed a moderate correlation with split renal function (r = 0.39, P = 0.004 and r = 0.49, P < 0.001). The correlation between reductions in split renal function and split renal volume of the operated kidney (r = 0.87, P < 0.001) was stronger than that between split renal function and percent reduction in split estimated glomerular filtration rate (r = 0.64, P < 0.001). CONCLUSIONS: The split renal volume calculated using computed tomography-based renal volumetry had a strong correlation with the split renal function measured using technetium-99m dimercaptosuccinic acid renal scan. Computed tomography-based split renal volume measurement before and after partial nephrectomy can be used as a single modality for anatomical and functional assessment of the tumor-bearing kidney.

Commercial Dairy Cow Milk microRNAs Resist Digestion under Simulated Gastrointestinal Tract Conditions.

BACKGROUND: MicroRNAs are small, gene-regulatory noncoding RNA species present in large amounts in milk, where they seem to be protected against degradative conditions, presumably because of their association with exosomes. OBJECTIVE: We monitored the relative stability of commercial dairy cow milk microRNAs during digestion and examined their associations with extracellular vesicles (EVs). METHODS: We used a computer-controlled, in vitro, gastrointestinal model TNO intestinal model-1 (TIM-1) and analyzed, by quantitative polymerase chain reaction, the concentration of 2 microRNAs within gastrointestinal tract compartments at different points in time. EVs within TIM-1 digested and nondigested samples were studied by immunoblotting, dynamic light scattering, quantitative polymerase chain reaction, and density measurements. RESULTS: A large quantity of dairy milk Bos taurus microRNA-223 (bta-miR-223) and bta-miR-125b (∼109-1010 copies/300 mL milk) withstood digestion under simulated gastrointestinal tract conditions, with the stomach causing the most important decrease in microRNA amounts. A large quantity of these 2 microRNAs (∼108-109 copies/300 mL milk) was detected in the upper small intestine compartments, which supports their potential bioaccessibility. A protocol optimized for the enrichment of dairy milk exosomes yielded a 100,000 × g pellet fraction that was positive for the exosomal markers tumor susceptibility gene-101 (TSG101), apoptosis-linked gene 2-interacting protein X (ALIX), and heat shock protein 70 (HSP70) and containing bta-miR-223 and bta-miR-125b. This approach, based on successive ultracentrifugation steps, also revealed the existence of ALIX-, HSP70-/low, and TSG101-/low EVs larger than exosomes and 2-6 times more enriched in bta-miR-223 and bta-miR-125b (P < 0.05). CONCLUSIONS: Our findings indicate that commercial dairy cow milk contains numerous microRNAs that can resist digestion and are associated mostly with ALIX-, HSP70-/low, and TSG101-/low EVs. Our results support the existence of interspecies transfer of microRNAs mediated by milk consumption and challenge our current view of exosomes as the sole carriers of milk-derived microRNAs.

Intravesical prostatic protrusion as a predictor of early urinary continence recovery after laparoscopic radical prostatectomy.

OBJECTIVES: To evaluate the significance of intravesical prostatic protrusion as a predictor of early urinary continence recovery after laparoscopic radical prostatectomy. METHODS: A total of 242 patients who underwent laparoscopic radical prostatectomy were included in the study. Data on incontinence status and the number of pads required per day for urinary incontinence were collected. Urinary continence was defined as no pad use or occasional security pad use. Intravesical prostatic protrusion was measured by the vertical distance from the tip of the protruding prostate to the base of the urinary bladder in the sagittal plane of preoperative magnetic resonance imaging. Continence at 1, 3, 6 and 12 months postoperatively was assessed by dividing the patients into two groups based on the degree of intravesical prostatic protrusion. The correlation between preoperative factors and urinary continence after laparoscopic radical prostatectomy was examined. RESULTS: The urinary continence rates at postoperative month 1, 3, 6 and 12 were 19%, 50%, 79.8% and 92.1%, respectively. In the multivariate logistic analysis, intravesical prostatic protrusion was a significant independent predictive factor of early urinary continence at 1, 3, 6, 9 and 12 months. Markedly improved urinary continence was observed in the non-significant intravesical prostatic protrusion group (intravesical prostatic protrusion <5 mm) at all periods compared with the significant intravesical prostatic protrusion group (intravesical prostatic protrusion ≥5 mm; P < 0.05). CONCLUSIONS: These findings suggest that the likelihood of postoperative urinary incontinence in patients undergoing laparoscopic radical prostatectomy is markedly higher in those with larger intravesical prostatic protrusion, and that intravesical prostatic protrusion is correlated with the duration of postoperative urinary incontinence.

2023 Korean sexually transmitted infections guidelines for non-gonococcal bacterial infection (chlamydia, syphilis, etc.) by the Korean Association of Urogenital Tract Infection and Inflammation.

Non-gonococcal sexually transmitted infections (STIs) include chlamydia, syphilis, and chancroids. Chlamydia is the most common STI caused by Chlamydia trachomatis and is mainly transmitted through sexual intercourse or vertical transmission at birth. Although symptoms are mostly absent or mild, untreated chlamydial infections in females can lead to pelvic inflammatory disease, chronic pelvic pain, and infertility due to the narrowing of fallopian tubes. Syphilis is caused by Treponema pallidum and is divided into phase I, phase II, latent syphilis, and phase III. The incidence of syphilis, including congenital syphilis, has significantly increased in the United States in recent years. The chronic status of this disease can significantly increase morbidity and potentially affect almost all body organs, which, in rare cases, can lead to death. Additionally, untreated maternal syphilis can lead to fetal death and fatal congenital infections in newborns. Chancroid is an STI caused by Haemophilus ducreyi, and its prevalence is gradually decreasing in Korea and worldwide. The symptoms include shallow genital ulcers with suppurative granulomatous inflammation and tender inguinal lymphadenopathy. Chancroids can be differentiated from syphilitic chancres based on their appearance. In contrast to painless chancres, chancroids are painful. Ureaplasma urealyticum, Ureaplasma parvum, and Mycoplasma hominis are considered symbiotic bacteria. Infections caused by these bacteria are usually not considered STIs and do not require treatment unless they are suspected of being associated with infertility. This article presents the 2023 Korean STI guidelines for non-gonococcal bacterial infections.

Impact of variant histology in the prognosis of non­muscle invasive bladder cancer with low­tumor burden: A propensity score­matched analysis with conventional urothelial carcinoma.

Bladder cancer (BCa) with variant histology (VH) is associated with an increased risk of recurrence and progression, as well as worse survival. However, the available literature does not provide the prognostic value of VH based on its tumor burden in non-muscle invasive BCa (NMIBC). The purpose of the present study was to investigate the prognosis of VH in NMIBC with low-tumor volume compared with conventional urothelial carcinoma (UC) with a similar tumor burden. The present single-center study analyzed patients diagnosed with NMIBC and retrospectively characterized them based on their VH status. Propensity scores for VH status were calculated to match patients with VH with those with conventional UC (1:3). The VH group was further divided into two subgroups based on pathological aggressiveness: Aggressive and highly aggressive variants. Oncological outcomes were compared among the three groups. Among the 494 patients with NMIBC, 60 (12.1%) had VH. Patients with VH had a higher tumor stage and grade and more multiple tumors (all P<0.05). In the matched cohort, >80% had tumors <3 cm, and >65% had solitary tumors. During a median follow-up of 42.5 months (range, 4.0-122.0 months), 35.1% (85/240) experienced recurrence and 5.4% (13/240) progressed to muscle-invasive disease. Prognosis did not differ between patients with aggressive or highly aggressive variants and those with conventional UC, including 5-year recurrence-free and pathologic progression-free survival (log-rank, P=0.510 and 0.257, respectively). Intravesical Bacillus Galmette-Guerin was the only factor associated with reduced recurrence (P<0.001). In conclusion, NMIBC with low-tumor burden and VH have similar oncologic outcomes to conventional UC with a similar tumor burden, indicating that bladder-sparing methods currently used for high-risk conventional NMIBC may be effective for managing low-tumor burden NMIBC with VH.

Impact of Circulating Tumor Cell-Expressed Prostate-Specific Membrane Antigen and Prostate-Specific Antigen Transcripts in Different Stages of Prostate Cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA)-based images, which visually quantify PSMA expression, are used to determine prostate cancer micrometastases. This study evaluated whether a circulating tumor cell (CTC)-based transcript platform, including PSMA mRNA, could help identify potential prognostic markers in prostate cancer. EXPERIMENTAL DESIGN: We prospectively enrolled 21 healthy individuals and 247 patients with prostate cancer [localized prostate cancer (LPCa), n = 94; metastatic hormone-sensitive prostate cancer (mHSPC), n = 44; and metastatic castration-resistant prostate cancer (mCRPC), n = 109]. The mRNA expression of six transcripts [PSMA, prostate-specific antigen (PSA), AR, AR-V7, EpCAM, and KRT 19] from CTCs was measured, and their relationship with biochemical recurrence (BCR) in LPCa and mCRPC progression-free survival (PFS) rate in mHSPC was assessed. PSA-PFS and radiological-PFS were also calculated to identify potential biomarkers for predicting androgen receptor signaling inhibitor (ARSI) and taxane-based chemotherapy resistance in mCRPC. RESULTS: CTC detection rates were 75.5%, 95.3%, and 98.0% for LPCa, mHSPC, and mCRPC, respectively. In LPCa, PSMA [hazard ratio (HR), 3.35; P = 0.028) and PSA mRNA (HR, 1.42; P = 0.047] expressions were associated with BCR. Patients with mHSPC with high PSMA (HR, 4.26; P = 0.020) and PSA mRNA (HR, 3.52; P = 0.042) expressions showed significantly worse mCRPC-PFS rates than those with low expression. Increased PSA and PSMA mRNA expressions were significantly associated with shorter PSA-PFS and radiological PFS in mCPRC, indicating an association with drug resistance. CONCLUSIONS: PSMA and PSA mRNA expressions are associated with BCR in LPCa. In advanced prostate cancer, PSMA and PSA mRNA can also predict rapid progression from mHSPC to mCRPC and ARSI or taxane-based chemotherapy resistance.

Impact of diabetes mellitus and hypertension on renal function during first-line targeted therapy for metastatic renal cell carcinoma: a retrospective multicenter study.

Background: Renal function deterioration during systemic therapy in patients with metastatic renal cell carcinoma (mRCC) is a long-term concern in treatment planning. Although hypertension (HTN) and diabetes mellitus (DM) are the most common factors that affect chronic kidney disease (CKD) development and progression, their impact on renal function during targeted therapy is unclear. This study investigated whether DM and HTN were associated with a decline in renal function during first-line targeted therapy for mRCC. Methods: This retrospective multicenter study analyzed patients receiving first-line targeted therapy for mRCC. They were classified as follows: group 1: HTN-, DM-; group 2: HTN+, DM-; group 3: HTN-, DM+; and group 4: HTN+, DM+. Changes in renal function and factors affecting progression to stage 4 CKD after targeted therapy were analyzed. Results: Among the 424 enrolled patients, 303 (71.5%) and 121 (28.5%) were treated with sunitinib and pazopanib, respectively [median duration: 10.3 months, interquartile range (IQR), 3.1-37.0 months]. Although all groups showed a decreased mean estimated glomerular filtration rate (eGFR) after treatment (P<0.001 for group 1, group 2, and group 4, P=0.02 for group 3, respectively), there were no significant differences in changes in eGFR (∆eGFR) between groups (P=0.10). However, actual renal function change calculated using percent ∆eGFR (%∆eGFR) showed differences between groups (P=0.02); the %∆eGFR of group 4 was significantly lower compared with group 1 (P=0.008). The mean progression time to stage 4 CKD in group 4 (38.6 months) was significantly shorter compared to the other groups (P<0.001). Multivariate analysis identified increased age (P=0.008), increased number of metastatic sites (P=0.047), and DM and HTN coexistence (P<0.001) as predictors of progression to stage 4 CKD. Conclusions: Patients with DM and HTN experienced further decline in renal function and had a higher risk of progression to stage 4 CKD after targeted therapy compared to patients without these risk factors. Recognition and proactive management of DM and HTN are necessary to facilitate the proper administration of life-prolonging oncological treatments.

Optimal sequential therapy using tyrosine kinase inhibitors as the first-line treatment in patients with metastatic renal cell carcinoma: A nationwide multicenter study.

Objective: The purpose of the study was to identify the best sequence of therapy beginning with a tyrosine kinase inhibitor (TKI) as the first-line therapy for patients with metastatic renal cell carcinoma (mRCC) in terms of overall survival (OS), progression-free survival (PFS), and rates of discontinuation and adverse effects during the treatment period. Methods: This is a retrospective, nationwide multicenter study of patients with mRCC after diagnosis at 10 different tertiary medical centers in Korea from January 1992 to December 2017. We focused on patients at either "favorable" or "intermediate" risk according to the International mRCC Database Consortium criteria, and they were followed up (median 335 days). Finally, a total of 1409 patients were selected as the study population. We generated a Cox proportional hazard model adjusted for covariates, and the different therapy schemes were statistically tested in terms of OS as well as PFS. In addition, frequencies of discontinuation and adverse events were compared among the therapy schemes. Results: Of the primary patterns of treatment sequences (24 sequences), "sunitinib-pazopanib" and "sunitinib-everolimus-immunotherapy" showed the most beneficial results in both OS and PFS with significantly lower hazards than "sunitinib", which is the most commonly treated agent in Korea. Considering that the "TKI-TKI" structure showed relatively higher discontinuation rates with higher adverse effects, the overall beneficial sequence would be "sunitinib-everolimus-immunotherapy". Conclusion: Among several sequential therapy starting with TKIs, "sunitinib-everolimus- immunotherapy" was found to be the best scheme for mRCC patients with "favorable" or "intermediate" risks.

Survival pattern of metastatic renal cell carcinoma patients according to WHO/ISUP grade: a long-term multi-institutional study.

The World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading of renal cell carcinoma (RCC) is classified from grade 1-4, regardless of subtype. The National Comprehensive Cancer Network (NCCN) guidelines (2022) state that if there is an adverse pathological feature, such as grade 3 or higher RCC in stage 1 patients, more rigorous follow-up imaging is recommended. However, the RCC guidelines do not provide specific treatment or follow-up policies by tumor grade. Therefore, this study attempted to find out whether tumor grade affects survival rates in patients with metastatic RCC. The Korean Renal Cancer Study Group (KRoCS) database includes 3108 patients diagnosed with metastatic RCC between September 1992 and February 2017, with treatment methods, progression, and survival data collected from 11 tertiary hospitals. To obtain information on survival rates or causes of death, we utilized the Korea National Statistical Office database and institutional medical records. Data were accessed for research purpose on June, 2023. We then reviewed these sources to gather comprehensive and reliable data on the outcomes of our study cohort. This database was retrospectively analyzed, and out of 3108 metastatic RCC patients, 911 had been identified as WHO/ISUP grade. Grades were classified into either a low-grade (WHO/ISUP grade 1-2) or a high-grade group (WHO/ISUP grade 3-4). The patients were then analyzed related to progression and overall survival (OS). In metastatic clear cell RCC patients, the 1-year OS rate was 69.4% and the median OS was 17.0 months (15.5-18.5) followed up to 203.6 months. When comparing the patient groups, 119 low-grade and 873 high-grade cases were identified. No baseline difference was observed between the two groups, except that the high-grade group had a higher ECOG 1 ratio of 50.4% compared with 34.5% for the low-grade group (p = 0.009). There was a significant difference in OS between high-grade and low-grade groups. OS was 16.0 months (14.6-17.4) in the high-grade group and 28.0 months (21.1-34.9) in the low-grade group (p < 0.001). However, there was no difference in progression-free survival (PFS) rates with 9.0 months (8.0-10.0) for the high-grade group and 10.0 months (6.8-13.2) for the low-grade group (p = 0.377) in first-line treatment. In multivariable analysis, WHO/ISUP grade was a risk factor (HR = 1.511[1.135-2.013], p = 0.005) that influenced the OS. In conclusion, WHO/ISUP grade is a major data source that can be used as a ubiquitous marker of metastatic RCC in pre-IO era. Depending on whether the RCC is high or low grade, the follow-up schedule will need to be tailored according to grade, with higher-grade patients needing more active treatment as it can not only affect the OS in the previously known localized/locoregional recurrence but also the metastatic RCC patient.